kongres - Slovensko združenje za gastroenterologijo in hepatologijo
Revija Slovenskega zdru`enja za gastroenterologijo in hepatologijo Journal of Slovenian Association of Gastroenterology and Hepatology Gastroenterolog Letnik 17, suplement 2, junij 2013 / Volume 17, Supplement 2, June 2013 SLOVENSKO ZDRUŽENJE ZA GASTROENTEROLOGIJO IN HEPATOLOGIJO 3 SLOVENSKEGA ZDRUŽENJA ZA GASTROENTEROLOGIJO IN HEPATOLOGIJO KONGRES Z MEDNARODNO UDELEŽBO Ljubljana, 5.-8. junij 2013 Uvodnik / Introduction Slovensko združenje za gastroenterologijo in hepatologijo je v sodelovanju Univerzitetnih kliničnih centrov v Ljubljani in v Mariboru, skupaj s tujimi strokovnjaki pripravilo sodoben pregled gastroenterološke vede s poudarkom na zgodnjem odkrivanju, zdravljenju in celostni obravnavi starostnika z boleznijo prebavil in bolnikov z rakom prebavil. Gastroenterologija je multidisciplinarna veda, v kateri sodelujejo gastroenterologi in abdominalni kirurgi, skupaj z internisti, kirurgi, radiologi, patologi in pediatri, usmerjenimi v gastroenterologijo. Veda obsega širok spekter benignih in malignih bolezni prebavil, od tistih najbolj pogostih, ki prizadenejo skoraj vsakega človeka vsaj enkrat v življenju, do tistih, ki zahtevajo obravnavo bolnika v univerzitetnih ustanovah. Število bolnikov z boleznimi prebavil narašča zaradi staranja prebivalstva, čezmernega jemanja zdravil, kroničnih vnetij, škodljivih razvad, nepravilne in neuravnotežene prehrane, premajhne telesne dejavnosti in zaradi vse večje incidence raka prebavil, obenem pa tudi zaradi večanja našega znanja, novih tehničnih zmožnosti in daljšega preživetja bolnikov. Združenje za gastroenterologijo in hepatologijo je bilo ustanovljeno leta 1967. leta v Rogaški Slatini. Od samega začetka je delovalo multidisciplinarno, kar dokazuje tudi stroka njenih predsednikov ves čas obstoja. Prvi predsednik s petletnim mandatom je bil internist gastroenterolog, prof. dr. Jože Satler, drugi, kirurg, prof. dr. Mitja Kovič. The Slovenian Association for Gastroenterology and Hepatology - in cooperation with the University Medical Centre Ljubljana and University Medical Centre Maribor and in collaboration with foreign experts - prepared an update of gastroenterology with the emphasis on early detection, treatment and comprehensive approach to elderly patients suffering from digestive diseases and patients with digestive cancer. Gastroenterology is a multidisciplinary science associating gastroenterologists and abdominal surgeons as well as internists, surgeons, radiologists, pathologists and paediatricians dealing with gastroenterology. It covers a wide range of benign and malignant diseases of digestive system, from the most common ones that affect almost every person at least once in their lives to those that need to be treated in university centres. The number of patients with digestive diseases is increasing due to population aging, excessive use of medications, chronic inflammatory conditions, unhealthy habits, unhealthy and unbalanced diet, insufficient physical activity and due to increasingly high incidence of digestive cancer. The number of patients with digestive diseases has also increased due to improved knowledge and new technical capabilities for disease detection and longer survival times of patients. The Slovenian Association for Gastroenterology and Hepatology was established in 1967 in Rogaška Slatina. From the very beginning on, its activities GASTROENTEROLOG V 45 letih svojega delovanja je SZGH pripravilo 86 domačih strokovnih srečanj in 11 mednarodnih srečanj. Najpomembnejše naloge združenja so stalno strokovno izobraževanje, priprava smernic za diagnostiko in zdravljenje, urejanje specializacije iz gastroenterologije, širjenje mreže specialistov gastroenterologov, postavljanje normativov za diagnostične posege in zdravljenje ter skrb za vrednotenje gastroenterološkega dela. V zadnjih letih se je vsakodnevno delo gastroenterologov, predvsem tistih na sekundarnem in terciarnem zdravstvenem nivoju, spremenilo. Vse večji je poudarek na hepatologiji, transplantaciji, zdravljenju z biološkimi zdravili pri bolnikih s kronično vnetno črevesno bolezenijo, zdravljenje s kemoterapevtiki in tarčnimi zdravili pri bolnikih z raki prebavil, še posebej raki hepatobiliarniga in pankreatičnega sistema. Ob tem se uporablja vse več zelo zahtevnih, specifičnih diagnostičnih in terapevtskih endoskopskih posegov. V prvem dnevu 3. gastroenterološkega kongresu z mednarodno udeležbo smo želeli predstaviti novosti v diagnostiki, zdravljenju in paliativni oskrbi bolnikov z boleznimi prebavil. Na tem mestu se moramo zahvaliti naši farmacevtski družbi KRKA, da je omogočila udeležbo na kongresu 70 gastroenterologom iz srednje in južne Evrope. Drugi dan kongresa smo po plenarnih predavanjih, s pomočjo farmacevtske družbe ABBVIE pripravili internacionalni IBD simpozij, na katerem sodelujejo poznani evropski profesorji za področje IBD in slušatelji iz 17 držav iz Evrope in S Afrike. Predavanja, razširjene abstrakte in abstrakte smo objavili v supplementu revije Gastroenterolog, ki je revija Slovenskega združenja za gastroenterologijo in hepatologijo in redno izhaja od leta 1997. Objavljeni prispevki v zborniku so nelektorirani vendar so bili strokovno recenzirani s strani uredništva. Zahvaljujem se vsem predavateljem, gostom, sodelavcem in sponzorjem, ki so omogočili pripravo GASTROENTEROLOG were multidisciplinary what was reflected in specialities of its presidents throughout its existence. The first president with a five-year term was an internist gastroenterologist, prof. dr. Jože Satler, and the second a surgeon, prof. dr. Mitja Kovič. In 45 years of its existence the Slovenian Association of Gastroenterology and Hepatology organized 86 national expert meetings and 11 international meetings. Its most important tasks are expert education, development of guidelines for diagnostics and treatment, directing gastroeneterology specialisation, broadening the network of gastroenterology specialists, setting standards for diagnostic procedures and treatment as well as evaluation of gastroenterological work. In the recent years everyday clinical practice of gastroenterologists, particularly those at the secondary and tertiary levels, has changed. There is an increased emphasis on hepatology, transplantation, biological therapy in IBD, chemotherapy and targeted anti-cancer treatment, especially for hepatobiliary and pancreatic cancer. The number of highly demanding diagnostic and therapeutic endoscopic procedures has increased as well. On the first day of the 3rd International Gastroenterology Congress new methods of diagnostics, treatment and palliative care of patients with digestive diseases are presented. We would like to take this opportunity to thank our pharmaceutical company KRKA, which allowed 70 gastroenterologists from Central and South Europe to attend the congress. On the second day of the congress we prepared – with the help of the pharmaceutical company ABBVIE – an international IBD symposium, in which well-known European IBD professors and attendants from 17 countries of Europe and North Africa will participate. The lectures, extended abstracts and abstracts are published in the supplement of the Gastroeneterolog journal, which is the journal of the Slovenian Associ- 3. kongresa. Zaradi številnih uglednih mednarodnih strokovnjakov in tujih udeležencev, bosta prva dva dni kongresa v angleškem jeziku. Prepričani smo, da so strokovni prispevki na visokem strokovnem nivoju in da bodo tudi v pomoč pri vsakdanjem delu ter vzpodbuda za dobro klinično, znanstveno in raziskovalno delo na področju gastroenterologije in hepatologije. Prof. dr. Borut Štabuc, dr. med. Predsednik slovenskega združenja za gastroenterologijo in hepatologijo ation for Gastroenterology and Hepatology that has regularly been published since 1997. The contributions published in the congress book were scientifically reviewed by the editorial board but not edited. I would like to thank all the lecturers, guests, colleagues and sponsors that contributed to the organization of the 3rd congress. Since several renowned international experts and foreign attendants will participate in the congress, the first two days of the congress will be held in English. We believe that the contributions are at a high expert level and that they will facilitate our everyday work as well as give impetus to good clinical practice and scientific and research work in the field of gastroenterology and hepatology. Professor Borut Štabuc, MD, PhD President of the Slovenian Association for Gastroenterology and Hepatology GASTROENTEROLOG Gastroenterolog ISSN 1408-2756 Gastroenterolog je uradno glasilo Slovenskega združenja za gastroenterologijo in hepatologijo. Objavlja prispevke v slovenskem in angleškem jeziku. Gastroenterolog is the official journal of the Slovene Association for Gastroenterology and Hepatology. It publishes contributions in the Slovene and English language. Naslov uredništva / Editorial office Klinični center Ljubljana Klinični oddelek za gastroenterologijo Japljeva 2, 1525 Ljubljana Glavni urednik / Editor-in-Chief Borut Štabuc Uredniki / Editors Verica Ferlan-Marolt, Eldar Gadžijev, Saša Markovič, Alojz Pleskovič, Milan Stefanovič, Bojan Tepeš Uredniški odbor / Editorial Board David Drobne, Franc Jelenc, Dimitrij Kuhelj, Živa Mrevlje, Rok Orel, Samo Plut, Peter Popovič, Stojan Potrč, Pavel Skok, Valentin Sojar, Lojze M. Šmid Uredniški svet / Editorial Council Anton Cerar, Borut Kocijančič, Pavel Košorok, Miran Koželj, Mirko Omejc, Tatjana Puc Kous, Miran Rems, Marjeta Sedmak, Marjan Skalicky, Bor Urbančič, Mihael Zajec, Dragan Stanisavljevič Priprava za tisk in tisk / Desk-top publishing and printing Studio N, Tina Noč, s. p. Izdajatelj / Publisher Slovensko združenje za gastroenterologijo in hepatologijo Zavod GastroOnko Gastroenterolog izhaja dvakrat letno. Letna naročnina za člane Slovenskega združenja za gastroenterologijo in hepatologijo je vključena v članarino. Naklada 600 izvodov. The journal appears regularly twice yearly. Yearly subscription for members of the Slovene Society for gastroenterology and hepatology is included in the membership fee. Printed in 600 copies. GASTROENTEROLOG Kazalo / Contents Uvodnik / Editorial Borut Štabuc Gastroenterologija v Sloveniji Gastroenterology in Slovenia ..................................................................................................... 1 Jernej Brecelj Cistična fibroza in trebušna slinavka Cystic fibrosis and pancreas ...................................................................................................... 5 Grosek J., Tomazic A., Omejc M., Jelenc F., Djokic M. Vloga laparoskopije pri obravnavi akutnega divertikulitisa sigme (ADS) The role of laparoscopy in management of acute sigmoid diverticulitis (ADS) .............................. 11 Andrej Gruden Endoultrazvočno vodene tankoigelne biopsije cističnih lezij trebušne slinavke Endoscopic ultrasound guided fine needle aspiration of cystic lesions of the pancreas .................. 16 Matjaž Homan Eozinofilni ezofagitis pri otrocih - novosti Eosinophilic esophagitis in children: recent updates .................................................................... 18 Yves Horsman Portal hypertension: its management in 2013.............................................................................. 22 Arpad Ivanecz, Tomaž Jagrič, Matjaž Horvat, Stojan Potrč Kako napovedati izid zdravljenja jetrnih zasevkov raka debelega črevesa in danke? How to predict the treatment outcome of colorectal liver metastases? ........................................... 23 Rado Janša »Zdravljenje napredovalega HCC – slovenske izkušnje« Management of advanced HCC - Slovenian experience................................................................ 25 Franc Jelenc, Robert Juvan Laparoskopske resekcije raka debelega črevesa in danke Laparoscopic surgery for colorectal cancer.................................................................................. 30 Jera Jeruc Benigni in maligni tumorji pri 700 zaporednih apendektomijah Benign and malignant tumors in 700 consecutive appendectomies ............................................... 35 Matjaž Horvat, A. Ivanecz, T. Jagrič, S. Potrč Kako operirati rak želodca pri starostniku? How to operate gastric cancer in elderly patients ........................................................................ 39 Pavle Košorok, Matic Bunič, Kristina Fujs Komloš, Boštjan J. Kocjan, Marija Gačić Štotl, Mario Poljak Vloga HPV okužbe pri raku zadnjika The role of HPV infection in anal cancer .................................................................................... 44 Bojan Krebs, Miran Koželj, Stojan Potrč Protektivne stome po operacijah nizkega raka danke Protective stoma after low anterior resection for rectal cancer...................................................... 48 GASTROENTEROLOG Gregor Norčič Laparaskopska ventralna rektopeksija Laparosopic ventral rectopexy.................................................................................................... 51 Mirko Omejc Zdravljenje lokalno napredovalega raka danke Treatment of locally advanced rectal cancer ............................................................................... 54 Rok Orel Probiotiki pri vnetni črevesni bolezni Probiotics in Inflammatory Bowel Disease.................................................................................. 56 Cvetka Pernat Drobež, Andreja Ocepek Zdravljenje bolnikov z ulceroznim kolitisom: naše izkušnje z adalimumabom Treatment of ulcerative colitis: our experience with adalimumab ................................................. 64 Popovič Peter, Rok Dežman, Miha Štabuc, Manca Garbajs Vloga MR-enterografije pri obravnavi bolnikov s Crohnovo boleznijo MR-Enterography in the management of patients with Crohn‘s disease ........................................ 68 Stojan Potrc, Matjaz Horvat, Arpad Ivanecz, Tomaz Jagric, Marko Hazabent, Bojan Iljevec Zapleti pri kirurškem zdravljenju raka trebušne slinavke Complications in surgical treatment of pancreatic cancer............................................................. 73 Stojan Potrc, Matjaz Horvat, Arpad Ivanecz, Tomaz Jagric, Bojan Iljevec, Irena Oblak, Vaneja Velenik, Janja Ocvirk Napredovali rak želodca – kirurška taktika Advanced gastric cancer – surgical tactic.................................................................................... 76 Primož Sever Gastrointestinalni stromalni tumorji (GIST)-indikacije in principi kirurškega zdravljenja Gastrointestinal stromal tumors (GISTs)-indications and princples of surgical treatment................ 87 Milan Stefanovič, Bojan Tepeš, Borut Štabuc, Dominika Novak Mlakar, Jožica Maučec Zakotnik, Matej Bračko, Snežana Frkovič Grazio Zagotavljanje kakovosti v presejanju - nadzor in resni neželeni učinki Assuring quality in screening- control and severe adverse events .................................................. 91 Borut Štabuc, Lojze M. Šmid Obsevanje in sistemsko zdravljenje raka trebušne slinavke Radiotherapy and systemic treatment of pancreatic cancer..........................................................101 Milan Stefanovič Varna terapevtska kolonoskopija Safe therapeutic colonoscopy......................................................................................................107 Bojan Tepeš Helicobacter pylori - diagnostika, zdravljenje in rezistenca na antibiotike v Sloveniji Helicobacter pylori - diagnostics, treatment and antimicrobial resistance in Slovenia ....................114 Blaž Trotovšek Kirurško zdravljenje tumorjev sotočja jetrnih vodov Surgical treatment for hilar cholangiocarcinoma.........................................................................120 Manfred Mervic, Samo Plut Varikozne krvavitve iz zgornjih prebavil Upper gastrointestinal variceal hemorrhage ................................................................................130 GASTROENTEROLOG Metka Volavšek, Nina Zidar Kaj storiti pri nevidnem karcinomu v reseciranem želodcu? How to deal with invisible carcinoma in the resected stomach?....................................................135 Nina Zidar, Katja Tepeš Zakaj je diagnoza okužbe s citomegalovirusom v prebavilih težavna? Why is it difficult to diagnose cytomegalovirus infection in gastrointestinal tract? .........................138 Borut Štabuc, B. Tepeš, P. Skok, M. Vujasinovič, A. Blinc, M. Čerček, M. Tomšič Slovenske smernice za preprečevanje neželenih učinkov nesteroidnih protivnetnih zdravil, antiagregacijskih in antikoagulantnih učinkovin na prebavila in srčno žilni sistem Slovenian guidelines for prevention of non-steroidal anti-inflammatory, anti-aggregation and anticoagulant agents related adverse effects on gastrointestinal and cardiovascular system ............................................................................142 Povzetki posterjev / Poster abstracts Andreja Ocepek, Cvetka Pernat Drobež Vnetne in rakaste bolezni kože zaradi anti-tnf zdravil pri bolnikih s kroničnimi vnetnimi črevesnimi boleznimi Inflammatory and cancerous skin lesions in inflammatory bowel disease patients treated with anti-tnf therapy..........................................................................................146 Miroslav Vujasinović, Slobodan Vujasinović, Nebojša Djurišić, Tajda Keber The sign of Leser-Trélat - a case report ........................................................................................149 Miroslav Vujasinović, Apolon Marolt, Bojan Tepeš, Jana Makuc, Zdenko Kikec, Nace Robač Vpliv klinične poti na izid zdravljenja bolnikov z akutnim pankreatitisom Impact of clinical pathway on treatment outcome in patients with acute pancreatitis....................150 Milica Miljković, Miroslav Vujasinović, Martin Tretjak, Apolon Marolt, Bojan Tepeš, Karmen Klančnik Ali so bolniki na antikoagulantni terapiji ustrezno zaščiteni pred krvavitvijo iz zgornjih prebavil? Are patients on anticoagulants adequately protected against upper gastrointestinal bleeding? .........153 Nace Robač, Miroslav Vujasinović, Apolon Marolt, Martin Tretjak Rezultati obravnave bolnikov z akutno krvavitvijo iz zgornjih prebavil v splošni bolnišnici: analiza dveletnega obdobja Audit of the menagement of acute upper gastrointestinal bleeding in general hospital: two-year retrospective analysis ...................................................................................................155 Miroslav Vujasinović, Karmen Klančnik, Gregor Kunst, Simona Lavre Biliarni ileus – prikaz dveh primerov Biliary ileus – report of two cases ..............................................................................................159 Betka Popič, Miroslav Vujasinović, Jelka Zaletel, Jana Makuc, Metka Epšek Lenart, Marjana Predikaka, Bojan Tepeš Seroprevalenca celiakije pri bolnikih s sladkorno boleznijo tipa 1 Seroprevalence of celiac disease among patients with type 1 diabetes mellitus ..............................161 Miroslav Vujasinović, Jelka Zaletel, Bojan Tepeš, Betka Popič, Jana Makuc, Metka Epšek Lenart, Marjana Predikaka, Saša Rudolf Eksokrina insuficienca pankreasa pri bolnikih s sladkorno boleznijo Exocrine pancreatic insufficiency in patients with diabetes mellitus .............................................163 GASTROENTEROLOG Miroslav Vujasinović, Bojan Tepeš, Saša Rudolf Eksokrina insuficienca pankreasa pri bolnikih s celiakijo Exocrine pancreatic insufficiency in patients with celiac disease ..................................................165 Miroslav Vujasinović, Bojan Tepeš, Jana Makuc, Jelka Zaletel, Tjaša Vidmar, Saša Rudolf Eksokrina in endokrina insuficienca pankreasa po akutnem pankreatitisu Exocrine and endocrine pancreatic insufficiency after acute pancreatitis......................................167 Miroslav Vujasinović, Nace Robač, Samo Jeverica, Urša Dolinar, Bojan Tepeš Helicobacter pylori eradication rate in carinthian region of Slovenia, 2011-2012..........................170 Miroslav Vujasinović Is adherence to guidelines in treatment of patients with celiac disease satisfactory? ......................171 Katja Novak, Katja Zaletel, Vita Dolžan, Aleksandra Markovič In Slovenian patients with primary biliary cirrhosis genetic polymorphism of glutation s-transferase (GSTP1) contribute to higher prevalence of concomitant autoimmune thyroid disease................................................................................173 R. Janša, J. Tišler-Štuflek, G. Novak, J. Osredkar Permeabilnostni indeks pri bolnikih s celiakijo Permeability index in celiac disease patients ...............................................................................175 Betka Popič, Karmen Klančnik, Miroslav Vujasinović Z liraglutidom povzročen akutni pankreatitis: prikaz primera Liraglutide-induced acute pancreatitis: case report ......................................................................177 Miroslav Vujasinović, Petra Kaplan Hematemeza zaradi erozivnega duodenitisa pri maratoncih – prikaz dveh primerov Hematemesis due to erosive duodenitis in marathon runners – a report of two cases.....................179 Rok Orel, Jakob Zapušek, Gregor Nosan, Marjeta Sedmak, Tanja Kersnik Levart ARC sindrom – klinični primer...................................................................................................180 Miroslav Vujasinović, Martin Tretjak, Bojan Tepeš, Apolon Marolt, Milica Miljković, Karmen Klančnik Ustreznost predpisovanja zaviralcev protonske črpalke Appropriateness of proton pump inhibitors prescribing.................................................................183 Miroslav Vujasinović, Zdenko Kikec, Cirila Slemenik Pušnik S kapecitabinom povzročen transmuralni miokardni infarkt – prikaz primera Capecitabine-induced transmural myocardial infarction – case report ..........................................185 Vanesa Anderle, Nejc Sever, Nataša Smrekar Serious adverse events associated with ferric carboxymaltose administration in patients with inflammatory bowel disease treated with anti-TNF drugs ....................................187 GASTROENTEROLOG Gastroenterologija v Sloveniji Gastroenterology in Slovenia Borut Štabuc* KO za gastroenterologijo, UKC Ljubljana Gastroenterolog 2013; suplement 2: 1–4 Gastroenterologija je multidisciplinarna veda, v kateri sodelujejo gastroenterologi in abdominalni kirurgi, skupaj z internisti, kirurgi, radiologi, patologi in pediatri, usmerjenimi v gastroenterologijo. Benigne in maligne bolezni prebavil predstavljajo eno tretjino vseh bolezni v Sloveniji. Najpogostejše benigne bolezni so gastroezofagealna refluksna bolezen, dispepsija, holecistolitiaza in sindrom razdražljivega črevesa. Najpogostejše maligne bolezni prebavil so rak debelega črevesa in danke, gastroenteropankreatični nevroendokrini tumorji, rak želodca in rak trebušne slinavke. Zaradi vse večjega števila bolnikov in novih diagnostičnih ter terapevtskih metod se je delo gastroenterologov na sekundarnem in terciarnem nivoju spremenilo. Ob spremenjeni zahtevnejši patologiji so diagnostične obdelave vse hitrejše, hospitalizacije vse krajše, zato je nujno potrebno dobro sodelovanje z drugimi specialisti še posebej s specialisti družinske medicine. Leta 2012 je bilo v Sloveniji, ki ima 2 miljona prebivalcev v 10 regionalnih bolnišnicah in v dveh univerzitetnih klinikah zaposlenih 59 specialistov gastroenterologov in 23 specializantov iz gastroenterologije. Obenem je je bilo v teh ustanovah zaposlenih 61 abdominalnih kirurgov oz splošnih kirurgov, ki so usmerjeni v abdominalno kirurgijo ter 21 specializantov za področje abdominalne kirurgije. V Sloveniji v 10 ambu- Gastroenterology is a multidisciplinary science, which involves collaboration between gastroenterologists and abdominal surgeons as well as general internal medicine specialists, surgeons, radiologists, pathologists and pediatricians focused on gastroenterology. Benign and malignant gastrointestinal diseases represent one third of all diseases in Slovenia. The most common benign diseases are gastroesophageal reflux disease, dyspepsia, cholecystolithiasis and irritable bowel syndrome. The most common malignant gastrointestinal diseases are colorecal cancer, gastroenteropancreatic neuroendocrine tumors, gastric cancer and pancreatic cancer. Due to the increasing number of patients and new diagnostic and therapeutic methods, the work of gastroenterologists on the secondary and tertiary level has changed. Newer diagnostic modalities have enabled advanced and faster diagnostics and therefore shorter hospitalisation stay. In light of this good cooperation with other specialists as well as general practicioners is essential. The population in Slovenia in 2012 was 2 million. Its public health system included ten regional and two university hospitals. Alltogether these hospitals employed 59 gastroenterology specialists (or general internal medicine specialists focused on gastroenterology) and 61 abdominal surgeons (or * Prof. dr. Borut Štabuc, dr. med. KO za gastroenterologijo, UKC Ljubljana Japljeva 2, 1000 Ljubljana GASTROENTEROLOG 1 lantah oz. diagnostičnih centrih deluje 17 specialistov gastroenterologov zasebnikov v 3 ambulantah pa 4 abdominalni kirurgi zasebniki. V UKC ljubljana, ki pokriva 2/3 Slovenije je zaposlenih 20 specialistov gastroenterologov in 23 specialistov, abdominalnih kirurgov. V UKC Maribor je zaposlenih 8 specialistov gastroenterologov in 12 specialistov abdominalnih kirurugov. Med tem ko so v obeh terciarnih ustanovah specialisti usmerjeni večinoma v gastroednterologijo, v regionalnih bolnišnicah gastroenterologi vsaj tretjino svojega časa namenijo splošni interni medicini. Vse bolnišnice imajo organizirano 24 urno urgentno gastroenterološko službo. V letu 2012 je bilo zaradi bolezni prebavil hospitaliziranih 12.000 bolnikov na okoli 300 bolniških posteljah Povprečna hospitalizacija je bila 7.5 dni. V ambulantah je bilo zabeleženih 25.000 obravnav od tega je bilo 18000 bolnikov prvič pregledanih. V zasebnih ambulantah je bilo pregledanih še okoli 5000 bolnikov Narejenih je bilo okoli 30.000 gastroskopij od tega 5.500 v zasebnih ambulantah, 16.500 rednih kolonoskopij (5500 zasebniki) in okoli 10.000 kolonoskopij v državnem programu presejanja SVIT. Skupno je bilo narejenih okoli 2000 ERCP od tega 1000 v UKC Ljubljana 300 v Diagnostičnem centru Bled, ostalo v 8 regijskih bolnišnicah. V 7 ustanovah je bilo skupno narejenih okoli 2000 EUZ in 80 EUZ vodenih citoloških punkcij. V 8 ustanovah so gastroenterologi opravili 17.000 ambulantnih UZ preiskav. V 4 bolnišnicah opravljajo abdominalni UZ radiologi. Žal za leto 2012 nimamo podatkov o opravljenem številu operacij oziroma obravnav zaradi benignih in malignih bolezni prebavil. Zdravljenje zahtevnih kirurških in gastroenteroloških bolnikov je v zadnjih letih centralizirano. Tako so radikalne operacije za rake prebavil večinoma v specializiranih ustanovah oziroma v ustanovah, kjer operirajo izkušeni operaterji z velikim številom operacij. Transplantacija jeter in trebušne slinavke se izvaja le v UKC Ljubljana. 2 GASTROENTEROLOG general surgeons focused on abdominal surgery). There were 23 gastroenterology and 21 abdominal surgery residents in training. 17 gastroenterology specialists were employed in private out-patient clinics or diagnostic centers. 4 abdominal surgery specialists were employed in 3 out-patient clinics. UKC Ljubljana provides medical care to about 2/3 of Slovenian population. It employs 20 gastroenterologists and 23 abdominal surgeons. UKC Maribor employs 8 gastroenteologists and 12 abdominal surgeons. Tertiary clinical center employed physicians focus mainly on clinical gastroenterology, while internal medicine specialists (focused on gastroenterology) in regional hospitals deal with general internal medicine cases in about a third of time. In all hospitals a 24-hour emergency gastroenterology service is organized. In 2012, 12,000 patients were admitted due to gastrointestinal pathology. About 300 hospital beds were available on gastroenterology departments, average in-patient hospitalization stay was 7.5 days. 25,000 out-patient visits (18,000 of which for the first time) were recorded, another 5,000 patients were seen at private out-patient clinics or diagnostic centers. 30,000 gastroscopies (5,500 of which were in private clinics) and 16,500 colonoscopies (5,500 of which were in private cinics) were performed. Additional 10,000 colonoscopies were performed in the national screening program SVIT. The total of about 2000 ERCPs were performed, about 1000 at the University Medical Centre Ljubljana, 300 at the Diagnostic Centre Bled, the remainder in 8 regional hospitals. Seven institutions made a combined total of about 2000 EUS and 80 EUS-guided FNA. In eight institutions, gastroenterologists performed 17,000 ultrasound examinations, in four hospitals abdominal ultrasound is performed by radiologists. Unfortunately no data is available on number of surgical procedures for benign and malignant gastrointestinal diseases. Treatment of complex surgical and gastroenterological patients in recent years was centralized. Thus, radical surgery for gastrointestinal cancers Na Gastroenterološki kliniki v Ljubljani je bil ustanovljen oddelek za hepatologijo in transplantacijo jeter, oddelek za KVČB in biološko zdravljenje bolnikov s KVČB, enota za specifično onkološko zdravljenje tumorjev prebavil, gastroenteropankreatičnih nevroendokrinih tumorjev in GISTov, ob endoskopskem oddelku pa še enota za EUZ in EUZ vodene citološke punkcije in enota za funkcionalno diagnostiko. V okvirih Združenja za gastroenterologijo in hepatologijo smo po priporočilih UEMS a izdelali natančen program šest letne specializacije iz gastroenterologije in si pridobili akreditacijo učnih centrov. Specializacija ima skupno deblo splošne interne medicine, ki traja 2 leti, 3 leta obveznega izobraževanja v klinični in endoskopski gastroenterologiji, zadnje, šesto leto je namenjeno induvidualnemu programu dodatnega učenja iz hepatologije, kronične vnetne črevesne bolezni, endoskopije ali internistične onkologije. Odločitev o izbiri je prepuščena izboru specializanta, njegovega mentorja in državnega koordinatorja za področje gastroenterologije. Glede na čakalne dobe za prvi pregled in endoskopske preiskave menimo da je mreža gastroenterologov zasedaj zadovoljivo pokrita in jo bomo v bodoče le počasi poviševali. Glede na povprečno starost slovenskih gastroenterologov, 51 let zadnji dve leti in v bodoče večamo število specializacij iz gastroenterologije. Združenje za gastroenterologijo in hepatologijo je bilo ustanovljeno leta 1967. leta v Rogaški Slatini. V 45 letih svojega delovanja je SZGH pripravilo 86 domačih strokovnih srečanj in 11 mednarodnih srečanj. Najpomembnejša naloga združenja so stalno strokovno izobraževanje, priprava smernic za diagnostiko in zdravljenje, urejanje specializacije iz gastroenterologije, širjenje mreže specialistov gastroenterologov, postavljanje normativov za diagnostične posege in zdravljenje ter skrb za vrednotenje gastroenterološkega dela. V bodoče si želimo glede na potrebe in ekonomske zmožnosti dokončno izdelati mrežo specialistov gastroenterologov, abdominalnih kirurgov, inter- is performed mostly in specialized institutions or in institutions providing experienced surgeons with a large number of operations. Liver and pancreas transplantation is performed only at the UKC Ljubljana. Several subspecialized departments were established at Gastroenterology clinic in Ljubljana: Department of Hepatology and Liver Transplantation, Department of IBD and biological treatment, the unit for specific oncological treatment of tumors of gastrointestinal tract, neuroendocrine tumors and gastroenteropancreatic GIST, the endoscopic department consists of a separate EUS and EUS-FNA unit and a functional diagnostics unit. Slovenian Association of Gastroenterology and Hepatology accepted a rigorous program of six-year specialization in gastroenterology according to the recommendations in the Blue book of UEMS. Local learning centers were accredited. Specialization includes a 2 years common trunk of general internal medicine, 3 years of compulsory education in clinical and endoscopic gastroenterology and elective year (individual additional training in hepatology, inflammatory bowel disease, endoscopy or medical oncology). As the curent waiting time for first examination and endoscopy is acceptable, we believe that the network of gastroenterologists is at the moment sufficient and will only slowly expand in the future. Due to the average age of Slovenian gastroenterologists being 51 years, the number of residents in training in the last two years was increased with another increase being planned in the near future. Association of Gastroenterology and Hepatology was established in 1967 in Rogaška Slatina. In 45 years of its operation SZGH organized 86 national professional meetings and 11 international meetings. The most important tasks of the association are continuous professional education, development of national guidelines for the diagnosis and treatment, management of gastroenterology trainGASTROENTEROLOG 3 nistov, kirurgov, radiologov, patologov in pediatrov usmerjenih v gastroenterologijo. Glede na znane normative specialista za zagotavljanje kakovostnega dela z bolniki, še posebej pri bolnikih, kjer so potrebni zahtevni posegi si bomo prizadevali smotrno delitev dela in centralizacijo posameznih obravnav v tri do štiri specializirane centre. Obenem si bomo prizadevali za tesno sodelovanje z vsemi drugimi strokami, še posebej s specialisti družinske medicine, saj na tem temelji napredek, smotrno načrtovanje diagnostike in zdravljenja ter racionalizacija oskrbe bolnika z boleznijo prebavil. 4 GASTROENTEROLOG ing, expanding the network of gastroenterology specialists, setting the standards and evaluation of diagnostic interventions and treatment as well as assuring adequate financial compensation. In the future, we plan to finalize the network of specialists gastroenterologists, abdominal surgeons, internists, surgeons, radiologists, pathologists and pediatricians focused on gastroenterology according to patient needs and economic capacity. Complex procedures should be refferred to 3 or 4 specialized centers. We will strive to work closely with all other disciplines, especially with family medicine specialists, since only good cooperation enables optimal diagnosis and treatment planning as well as rational streamline patient care with gastrointestinal disease. Cistična fibroza in trebušna slinavka Cystic fibrosis and pancreas Jernej Brecelj* Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko, Pediatrična klinika, Univerzitetni klinični center Ljubljana in Medicinska fakulteta, Univerza v Ljubljani Gastroenterolog 2013; suplement 2: 5–10 Ključne besede: eksokrina insuficienca trebušne slinavke, klinična slika, diagnostika, zdravljenje. Keywords: exocrine pancreatic insufficiency, the clinical picture, diagnosis and treatment. POVZETEK ABSTRACT Cistična fibroza je najpogostejša monogenska genetska bolezen kavkaške rase, ki skrajša življenje. Deduje se avtosomno recesivno. Povzročajo jo številne mutacije gena za klorov kanalček CFTR. Prizadene različne organe, najpogosteje pljuča, trebušno slinavko, jetra in črevo. Bolezen trebušne slinavke v okviru cistične fibroze se pri dojenčkih in otrocih najpogosteje kaže z insuficienco eksokrinega delovanja. Posledica je mekonijski ileus ali sindrom malabsorpcije, ki se kaže kot steatoreja, nepridobivanje telesne teže in pomanjkanje vitaminov, topih v maščobah. S trajanjem bolezni se pri najstnikih in mladih odraslih v 30 % razvije še sladkorna bolezen. Bolniki s cistično fibrozo z ohranjenim delovanjem trebušne slinavke in zdravi prenašalci ene od mutacij gena za cistično fibrozo imajo večje tveganje za vnetje trebušne slinavke. Poleg klasičnega nadomestnega zdravljenja z encimi trebušne slinavke in inzulina pri sladkorni bolezni, razvijajo nove načine zdravljenja z modulatorji klorovih kanalčkov, genskim zdravljenjem in presaditvijo trebušne slinavke. Cistična fibroza je zelo raziskovana bolezen in služi tudi kot model za preizkušanje novih načinov zdravljenja, ki so navedeni v tem prispevku. Cystic fibrosis is the most common monogenic genetic disorder in Caucasians that affects patients’ lifespan. The inheritance pattern is autosomal recessive. It is caused by a number of mutations in the gene for the chloride transmembrane ion channel CFTR. It affects various organs, most commonly the lungs, pancreas, liver and intestine. The involvement of the pancreatic gland is most often reflected by exocrine pancreatic insufficiency in infants and children. It results in meconium ileus or malabsorption syndrome, with steatorrhoea, failure to thrive and deficiencies of lipid soluble vitamins. During the course of the disease one third of teenagers and young adults develop diabetes. Patients with cystic fibrosis with preserved pancreatic function and healthy carriers of a mutation of the gene for cystic fibrosis have an increased risk of pancreatitis. In addition to conventional replacement therapy with pancreatic enzymes and insulin for diabetes, new treatment approaches with chlorine channel modulators, gene therapy and transplantation of the pancreas are currently in experimental phases. Cystic fibrosis is a widely studied disease and serves as a model for testing new treatment approaches, which are also listed in this review. *asist. mag. Jernej Brecelj, dr. med. Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko, Pediatrična klinika Univerzitetni klinični center Ljubljana in Medicinska fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija. GASTROENTEROLOG 5 UVOD Cistična fibroza je najpogostejša monogenska bolezen kavkaške rase, ki skrajša življenjsko dobo. Od leta 1989 je znano, da jo povzroča mutacija gena za transmembranski kanalček (beljakovina CFTR; angl. cystic fibrosis transmembrane regulator protein), ki izloča klor in bikarbonat. Okvara kanalčka povzroča slabšo topnost mucinov in s tem gostejše izločke pljuč, črevesa, žolčnih izvodil in trebušne slinavke. Deduje se avtosomno recesivno (1). Cistična fibroza se pojavlja pri 1 na 3.000 prebivalcev severne Evrope in njihovih potomcev (npr. američani evropskega porekla), med južnoameričani pri 1 na 4.000–10.000, med afroameričani pri 1 na 15.000–20.000, najredkeje pa se pojavlja na Japonskem pri 1 na 350.000 (1). Znanih je že več kot 1.500 različnih mutacij gena CFTR, ki jih, glede na stopnjo okvare kanalčka CFTR, razdelimo v 5 razredov. Klinična slika in teža bolezni sta odvisni od obeh mutacij na genih za CFTR in modificirajočih genov. Najpogostejša mutacija je odsotnost fenilalanina na mestu 508 (mutacija Phe508del ali po starem imenovanju deltaF508), ki je prisotna pri približno dveh tretjinah bolnikov kavkaške rase (1). V Centru za cistično fibrozo na Pediatrični kliniki v Ljubljani, ki vodi 70 bolnikov s cistično fibrozo, jih ima 52 % mutacijo Phe508del na obeh in 33 % na enem alelu (2). Klinična slika cistične fibroze je raznovrstna. Pri 15 % otrok se takoj po rojstvu pokaže z zaporo črevesa z mekonijem (mekonijski ileus). V prvem letu so pri bolnikih, ki imajo eksokrino insuficienco trebušne slinavke, najpogostejši znaki malabsorpcije maščobe s posledicami kot so steatoreja, nepridobivanje telesne teže, podhranjenost, dehidracija, hipoalbuminemija in znaki pomanjkanja vitaminov topnih v maščobah in cinka. Po prvem letu pa je praviloma v ospredju bolezen pljuč, ki se kaže predvsem z okužbami pljuč z bakterijo Pseudomonas aeruginosa in drugimi povzročitelji. Pri 5 % bolnikov je vodilna jetrna bolezen - fokalna biliarna 6 GASTROENTEROLOG ciroza. Kadar se znaki cistične fibroze pojavijo šele v najstniškem ali odraslem obdobju, so to predvsem: vnetje obnosnih votlin in nosni polipi, bronhiektazije, hemoptiza, recidivantni pankreatitisi, portalna hipertenzija in moška nepolodnost zaradi neprehodnosti semenovodov (1,3). Pri osebah z značilnimi simptomi in znaki diagnosticiramo cistično fibrozo, če je koncentracija kloridnih ionov v znoju (iontoforeza) večja kot 60 mmol/l znoja. Diagnozo dodatno potrdimo z genetsko analizo. Z usmerjeno analizo najpogostejših mutacij (običajno 30–40) potrdimo diagnozo pri 90 % bolnikov. Če s to preiskavo ne najdemo 2 mutacij, ki povzročata bolezen, pa je potrebno še sekvencioniranje celega gena CFTR (1). Edini laboratorij, ki opravlja vso diagnostiko cistične fibroze v Sloveniji, od iontoforeze do sekvencioniranja gena CFTR, je na Pediatrični kliniki v Ljubljani. Nekatere navedene preiskave pa so na voljo tudi v drugih bolnišnicah. Zdravljenje je celovito in obsega pogosto in dolgotrajno dajanje parenteralnih in inhalacijskih antibiotikov v visokih odmerkih in s tem preprečitev trajne kolonizacije pljuč z bakterijo Pseudomonas aeruginosa in nekaterimi drugimi bakterijami, fizioterapijo dihal, telesno dejavnost in skrb za dobro prehranjenost bolnikov s cistično fibrozo (1, 3). Zdravljenje bolezni trebušne slinavke je navedeno v nadaljevanju. Zaradi potrebe po celostni obravnavi, ki obsega različna medicinska področja, pa tudi psihološko in socialno obravnavo, je skrb za bolnike s cistično fibrozo najboljša v centrih, ki združujejo vse potrebne strokovnjake (3). Pričakovana življenjska doba se povečuje. V Veliki Britaniji se je v prvem desetletju tega stoletja mediano preživetje podaljšalo z 31 na 37 let (1). Pri otrocih rojenih v sedanjem času pa je predvideno mediano preživetje 41,4 leta (4). To je pomembno zaradi načrtovanja obravnave bolnikov s cistično fibrozo v odrasli dobi in seznanjanje zdravnikov ustreznih specializacij o cistični fibrozi. Namen prispevka je predstaviti bolezen trebušne slinavke pri cistični fibrozi: patogenezo, diagnostiko, zaplete, uveljavljene in novejše načine zdravljenja. s cistično fibrozo koncentracije vitaminov A, E, D, cinka, selena ter protrombinski čas za oceno preskrbljenosti z omenjenimi vitamini in minerali (3). MEHANIZEM NASTANKA BOLEZNI Tabela 1: Posledice pomanjkanja nekaterih vitaminov in mineralov zaradi malabsorpcije pri cistični fibrozi (3, 7). Beljakovina CFTR je transmembranski celični kanalček, ki se tvori v endoplazmatskem retikulumu in se v normalnih razmerah vgradi celično membrano. Za to sta odgovorna 2 dela, ki večkrat prehajata skozi membrano. V notranjosti celice sta dve področji za vezavo nukleotidov, ki preko fosforilacije uravnavata odpiranje kanalčka in s tem izločanje kloridnih in bikarbonatnih ionov. Kadar kanalček CFTR ne deluje, se klor in bikarbonat ne izločata. Sluz se zgosti in v trebušni slinavki zapira izvodila, kar vodi v kronično fibrozo in nadomeščanje funkcionalnega tkiva z maščevjem (5, 6). KLINIČNA SLIKA Pri 85–90 % bolnikov s cistično fibrozo je prizadet eksokrini del trebušne slinavke, kar se pri propadu večine funkcionalnega tkiva trebušne slinavke pokaže s steatorejo. Ta je predvsem posledica pomanjkanja lipaze. Maščobe se ne razgradijo v maščobne kisline, da bi se vsrkale. Blata je veliko, je mastno in izrazito smrdeče, saj nerazgrajene maščobe razgrajujejo črevesne bakterije v svetlini črevesa. Zaradi izgube energije lahko otrok hujša, nekateri pa izgube z blatom nadomestijo z izrazito povečanim vnosom živil in ohranjajo telesno težo (1, 3). Pomanjkljivo vsrkavanja maščob povzroči energetsko pomanjkanje, kar se kaže kot podhranjenost; kasneje se lahko pojavijo tudi hipoalbuminemija in otekline. Malabsorpcija maščob povzroči pomanjkanje vitaminov, topnih v maščobah, cinka in selena. Sprva so odstopanja lahko le laboratorijska, sčasoma pa se klinično izrazijo. Zaradi pomanjkanja cinka niso redke kožne spremembe (1,3). Najpogostejša pomanjkanja vitaminov in mineralov pri cistični fibrozi in njihove posledice so navedene v Tabeli 1. V okviru razširjenih laboratorijskih preiskav določamo enkrat letno pri bolnikih Snov Posledice pomanjkanja Vitamin A nočna slepota, keratomalacija, hiperkeraotza, nagnjenost k okužbam Vitamin D rahitis, osteomalacija, osteoporoza, bolečine v kosteh, zmanjšana mišična moč Vitamin E hemolitična anemija, retinopatija, nevropatija Vitamin K nagnjenost h krvavitvam, osteoporoza Cink zaostanek v rasti in spolnem razvoju, izpadanje las, dermatitis, moteno delovanje imunskega sistema, driska, vnetje jezika Selen kardiomiopatija, zmanjšana mišična moč, bolečine v mišicah DIAGNOSTIKA Delovanje eksokrinega dela trebušne slinavke preverjamo z direktnimi in indirektnimi testi. Direktni temeljijo na analizi aktivnosti pankreatičnih encimov v pankreatičnem soku, ki ga dobimo po stimulaciji s sekretinom in holecitsokininom neposredno iz pankreatičnega izvodila. Preiskava je izvazivna zato se le redko izvaja v omejenem številu centrov (8). Indirektni testi so lažje dostopni, a so manj senzitivni in specifični, posebno pri bolnikih z blažjo insuficienco trebušne slinavke. Razdelimo jih v 3 kategorije (8): 1. Določanje snovi (v krvi ali urinu), ki so jih hidrolizirali pankreatični encimi (npr. test s pankreolaurilom, ki se določa po zaužitju v zbranem urinu). 2. Merjenje neprebavljenih in nevsrkanih hranil v blatu (npr. analiza izločenih maščob z blatom v 72h) ali njihovih oksidacijskih produktov v izdihanem zraku z dihalnimi testi. 3. Merjenje aktivnosti pankreatičnih encimov v blatu (npr. himotripsin, elastaza). GASTROENTEROLOG 7 Najuporabnejši neinvazivni test za oceno eksokrine insuficience pankreasa je določanje elastaze v blatu. Test je specifičen za človeško elastazo, zato nanj jemanje encimov trebušne slinavke ne vpliva, kot to velja npr. za določanje himotripsina, ki ga uporabljamo predvsem za ugotavljanje sodelovanja bolnika pri zdravljenju (kompliance) (8, 9). Trebušna slinavka ima veliko funkcionalno rezervo, zato eksokrina insuficienca blage in zmerne stopnje ne povzročita nujno tudi steatoreje. Hkrati pa je vsrkavanje maščob odvisno tudi od drugih dejavnikov, kot so žolčne kisline, črevesna vsebina in črevesna sluznica. Standardni test za ugotavljanje steatoreje je analiza izločenih maščob z blatom v 72h. Bolnik beleži zaužito prehrano in z enodnevnim zamikom zbira izločeno blato v posodo, ki ga do analize hrani v zamrzovalniku. Iz razlike zaužite in izločene maščobe izračunamo količnik absorpcije maščob. Pri dojenčkih je normalna vrednost nad 85 %, pri otrocih in odraslih pa nad 93 %. Preiskava je zamudna, zahtevna in neprijetna ter se zato uporablja le v izbranih primerih (8). Pri sodelujočih otrocih in odraslih lahko ugotavljamo stopnjo hidrolize maščob z dihalnim testom z označenim ogljikom (C13). Po standardiziranem označenem obroku merimo vsake pol ure označen ogljik v izdihanem zraku. V raziskavi D. C. Herzog in sod. so potrdili, da preiskava loči med zdravimi otroci in otroci s cistično fibrozo in eksokrino insuficienco pankreasa, so pa ugotavljali precejšnje razlike med različnimi meritvami pri istih preiskovancih (10). Preiskava je zamudna, saj traja 6h. Med meritvami morajo biti preiskovanci pri miru, kar je pri otrocih pogosto težko. Potencialna uporabnost je predvsem ugotavljanje ustreznosti nadomeščanja pankreatičnih encimov (8). ZDRAVLJENJE Zdravljenje eksokrine insuficience trebušne slinavke je ustrezno odmerjanje pankreatičnih encimov glede na zaužite maščobe. Odmerek lipaze se največkrat giblje med 500–4.000 enotami na 1 gram zaužitih maščob (3). Poleg uveljavljenega pripravka encimov 8 GASTROENTEROLOG trebušne slinavke živalskega izvora v obliki mikrosfer zaščitenih z ovojem, ki je odporen na želodčno kislino, in je dokazano učinkovit in varen tudi pri mlajših otrocih (11), je v tretji fazi kliničnih preskusov tudi pripravek, ki je pridobljen z genskim inženiringom (12). Njegova učinkovitost in varnost je že dokazana pri otrocih, starejših od 7 let, primerjalnih raziskav med obema vrstama zdravila pa še ni. Ker nadomeščanje pankreatičnih encimov ni idealno, mora bolnik s cistično fibrozo uživati s prehrano večje količine vitaminov, topnih v maščobah, cinka in selena, ter vsaj priporočene odmerke ostalih vitaminov in mikroelementov (13). To dosežemo s posebej prilagojenimi pripravki za bolnike s cistično fibrozo z vitamini in minerali, ki pa so primerni tudi za bolnike z drugimi vzroki za eksokrino insuficienco trebušne slinavke in s holestatskimi boleznimi jeter. ZAPLETI BOLEZNI TREBUŠNE SLINAVKE PRI CISTIČNI FIBROZI Cistični fibrozi pridružena sladkorna bolezen Propadanje tkiva trebušne slinavke lahko povzroči tudi pomanjkljivo izločanje inzulina, ki se kaže najprej kot motena toleranca za glukozo, kasneje pa kot sladkorna bolezen. S starostjo se prevalenca veča. Med najstniki so ugotavljali moteno toleranco za glukozo pri 40 % bolnikov s cistično fibrozo. Pogostejša je pri dekletih. V skupini bolnikov starih 25 let jih je imelo sladkorno bolezen 30 % (1). Zgodnje ugotavljanje razvoja sladkorne bolezni in zdravljenje z inzulinom vpliva tudi na izboljšano delovanje pljuč, zato opravijo bolniki po 10. letu vsako leto oralni glukozotolerančni test. V zadnjem času pa vse več tudi občutljivejšo nekajdnevno kontinuirano merjenje glukoze v medceličnini (3). Podhranjenost Podhranjenost je neodvisen dejavnik za slabši potek bolezni. Pomen dobre prehranjenosti so potrdili v skupini 584 bolnikov s cistično fibrozo z mediano starostjo 21 let, ki so jih spremljali 45 mesecev. Petletno preživetje je bilo boljše (84 %) v skupini bolnikov, ki so imeli težo večjo od 85 % idealne, kot pri tistih z manjšo težo (53 %) (14). Za ustrezno prehranjenost je ključno pravilno nadomeščanje pankreatičnih encimov. Pomembna je tudi zdrava kalorično obogatena prehrana in tudi zdravljenje ostalih organov, ki jih prizadene cistična fibroza (15). Novotvorbe trebušne slinavke Z raziskavami so potrdili nekoliko večje tveganje za nastanek karcinoma trebušne slinavke in tudi drugih delov prebavil pri bolnikih s cistično fibrozo. Patogenetski mehanizem ni znan. Z daljšim preživetjem pa se bo incidenca večala. Preprečevanje temelji na odsvetovanju kajenja (kar je še pomembnejše za pljučno bolezen) in zdravi prehrani bogati z antioksidanti, kot sta vitamin E in selen. V sklopu sekundarne preventive, ki obsega presejanje, pa veljajo zaenkrat enaka priporočila kot za splošno populacijo (16, 17). NOVA ZDRAVLJENJA Modulacija mutiranih CFTR V letu 2011 je odmevala novica o izboljšanju delovanja mutiranih kanalčkov CFTR s potenciatorjem ivakaftorjem, ki povzroči izboljšano delovanje kanalčka CFTR pri določeni mutaciji (G551D). Jemlje se dvakrat dnevno peroralno. Z dvojno-slepo raziskavo pri bolnikih s cistično fibrozo starejših od 12 let, so z 48-tedenskim zdravljenjem potrdili izboljšanje forsiranega ekspiratornega volumna v prvi sekundi (FEV1) za dobrih 10 %, povišanje telesne teže za 2,7 kg, zmanjšanje koncentracije klora v znoju in izboljšanje kakovosti življenja (19). Neposredno izboljšanje delovanja trebušne slinavke z ivakaftorjem še ni bilo dokazano (20). Razvijajo tudi korektorje kanalčkov CFTR in zaviralce prezgodnje prekinitve prepisovanja gena za CFTR, ki pa še niso v klinični uporabi (20). Presaditev trebušne slinavke Pankreatitis Pankreatitis se pojavlja pogosteje pri najstnikih in mladih odraslih s cistično fibrozo, ki imajo ohranjeno delovanje trebušne slinavke. V raziskavi, ki je zajela več kot 10.000 bolnikov s cistično fibrozo iz 29 držav je imelo pankreatitis kadarkoli v življenju 1,24 %. Pogostejši je bil v skupini bolnikov z ohranjenim delovanjem trebušne slinavke (10,3 %), kot pri tistih z eksokrino insuficienco (0,5 %). Povezave z določeno mutacijo niso ugotovili (18). Kar pri 43 % bolnikov z rekurentnim akutnim pankreatitisom ali kroničnim pankreatitisom so dokazali mutacijo vsaj enega gena za CFTR, 11 % pa jih je imelo mutacije na obeh alelih. Po dodatnih preiskavah jih je 21 % izpolnjevalo kriterije za postavitev diagnoze cistična fibroza (17). Presaditve trebušne slinavke pri bolnikih s cistično fibrozo so dveh vrst. Možna je presaditev celotne trebušne slinavke in vspostavitve anastomoze s tankim črevesom, kar izboljša ali normalizira delovanje eksokrinega in endokrinega dela pankreasa. Opisujejo tudi samo presaditev pankreatičnih otočkov. Obe vrsti presaditev sta redki, saj obstaja učinkovito nadomestno zdravljenje s pankreatičnimi encimi in inzulinom. Običajno jih združijo s presaditvijo drugih organov, ki so prizadeti zaradi cistične fibroze, kot so npr. pljuča ali jetra (1,22). Gensko zdravljenje Učinkovitega in varnega genskega zdravljenja cistične fibroze kljub številnim poskusom še niso razvili (20). Z največjo raziskavo genskega zdravljenja cistične fibroze pri 130 bolnikih so začeli letos v Veliki Britaniji. Gen za CFTR v liposomih bodo z inhalacijami prenašali v pljuča mesečno v obdobju enega leta in spremljali učinek na pljuča (23). GASTROENTEROLOG 9 ZAKLJUČKI Cistična fibroza okvari trebušno slinavko na različne načine. Najpogosteje okvari njeno eksokrino delovanje, ki z nadomeščanjem funkcionalnega tkiva s fibrotičnim vodi pogosto tudi v endokrino motnjo delovanja, ki se kaže kot sladkorna bolezen. Pri bolnikih z blažjimi mutacijami ali prenašalci mutacije za cistično fibrozo pa se kaže z nagnjenostjo za nastanek pankreatitisa. Novi načini zdravljenja cistične fibroze obetajo nove pristope tudi za zdravljenje bolezni trebušne slinavke. Do njihove uveljavitve ostaja zelo učinkovito nadomestno zdravljenje eksokrine motnje delovanja z dodajanjem pankreatičnih encimov in endokrine z zdravljenjem z inzulinom. Presaditev trebušne slinavke v celoti ali samo otočkov se izvaja le redko v sklopu presaditve drugih organov. LITERATURA 1. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009; 373(9678): 1891–904. 2. Zolin A, Viviani L, Olesen H, van Rens J. ECFSPR Centre Report (centre 2700, country: SI) Data 2008–2009. Karup: European Cystic Fibrosis Society, 2013. 3. Borinc-Beden A, Brecelj J, Bratanič N, Homan M, Homšak M, et al. Smernice za obravnavo otrok s cistično fibrozo. Zdrav Vestn 2008; 77: 679–92. 4. Urquhart DS, Thia LP, Francis J, Prasad SA, Dawson C, Wallis C, et al. Deaths in childhood from cystic fibrosis: 10-year analysis from two London specialist centres. Arch Dis Child 2013; 98(2): 123–7. 5. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005; 352(19): 1992–2001. 6. Quinton PM. Role of epithelial HCO3 transport in mucin secretion: lessons from cystic fibrosis. Am J Physiol Cell Physiol 2010; 299(6): C1222–33. 7. Mason JB. nutritional assessment and management of the malnourished patient. In: Feldman M, Friedman LS, Brandt LJ, eds. 9th ed. Philadelphia: Saunders, 2010: 52–8. 8. Walkowiak J, Nousia-Arvanitakis S, Henker J, Stern M, Sinaasappel M, Dodge JA. Indirect pancreatic function tests in children. J Pediatr Gastroenterol Nutr 2005; 40(2): 107–14. 10 GASTROENTEROLOG 9. Daftary A, Acton J, Heubi J, Amin R. Fecal elastase-1: utility in pancreatic function in cystic fibrosis. J Cyst Fibros 2006; 5(2): 71–6. 10. Herzog DC, Delvin EE, Albert C, Marcotte JE, Pelletier VA, Seidman EG. 13C-labeled mixed triglyceride breath test (13C MTG-BT) in healthy children and children with cystic fibrosis (CF) under pancreatic enzyme replacement therapy (PERT): a pilot study. Clin Biochem 2008; 41(18): 1489–92. 11. Graff GR, McNamara J, Royall J, Caras S, Forssmann K. Safety and tolerability of a new formulation of pancrelipase delayed-release capsules (CREON) in children under seven years of age with exocrine pancreatic insufficiency due to cystic fibrosis: an openlabel, multicentre, single-treatment-arm study. Clin Drug Investig 2010; 30(6): 351–64. 12. Borowitz D, Stevens C, Brettman LR, Campion M, Wilschanski M, Thompson H; Liprotamase 767 Study Group. Liprotamase long-term safety and support of nutritional status in pancreaticinsufficient cystic fibrosis. J Pediatr Gastroenterol Nutr 2012; 54(2): 248–57. 13. Maqbool A, Stallings VA. Update on fat-soluble vitamins in cystic fibrosis. Curr Opin Pulm Med 2008; 14(6): 574–81. 14. Sharma R, Florea VG, Bolger AP, Doehner W, Florea ND, Coats AJ, et al. Wasting as an independent predictor of mortality in patients with cystic fibrosis. Thorax 2001; 56(10): 746–50. 15. Sinaasappel M, Stern M, Littlewood J, Wolfe S, Steinkamp G, Heijerman HG, et al. Nutrition in patients with cystic fibrosis: a European Consensus. J Cyst Fibros 2002; 1(2): 51–75. 16. Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care: consensus conference report. Chest 2004;125 Suppl 1: 1S–39S. 17. Ooi CY, Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros 2012; 11(5): 355–62. 18. De Boeck K, Weren M, Proesmans M, Kerem E. Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype. Pediatrics 2005; 115(4): e463–9. 19. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365(18): 1663–72. 20. Derichs N. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur Respir Rev 2013; 22(127): 58–65. 21. Fridell JA, Wozniak TC, Reynolds JM, Powelson JA, Hollinger EF, Duncan MW, et al. Bilateral sequential lung and simultaneous pancreas transplant: a new approach for the recipient with cystic fibrosis. J Cyst Fibros 2008; 7(4): 280–4. 22. Lu BR, Esquivel CO. A review of abdominal organ transplantation in cystic fibrosis. Pediatr Transplant 2010; 14(8): 954–60. 23. Kmietowicz Z. Trial is started to see whether gene therapy can improve lung function in cystic fibrosis. BMJ 2012; 344: e2141. Vloga laparoskopije pri obravnavi akutnega divertikulitisa sigme (ADS) The role of laparoscopy in management of acute sigmoid diverticulitis (ADS) Grosek J.*, Tomazic A., Omejc M., Jelenc F., Djokic M. Univerzitetni klinični center Ljubljana, Klinični oddelek za abdominalno kirurgijo Gastroenterolog 2013; suplement 2: 11–15 Ključne besede: divertikulitis, divertikuloza, laparoskopija, Hinchey, Kohler, resekcija debelega črevesa, Hartmannova resekcija Keywords: diverticulitis, diverticulosis, laparoscopy, Hinchey, Kohler, colonic resection, Hartmann`s procedure POVZETEK ABSTRACT Približno 1 % vseh bolnikov z divertikulozo sigme potrebuje operativno zdravljenje. Diskontinuitetna resekcija sigme (t.i. Hartmannova resekcija) je še vedno temelj urgentne kirurške oskrbe pri bolnikih s Hinchey III ali IV divertikulitisom sigme. Tovrstne operacije imajo relativno visoko morbiditeto in mortaliteto, tudi delež ponovnih vzpostavitev kontinuitete črevesa je majhen. Izkušeni kolorektalni kirurgi se zaradi tega pogosto odločajo za kontinuitetno resekcijo, kot alternativa resekciji pri Hinchey III ADS pa pridobiva na veljavi laparoskopska lavaža. V prispevku predstavljamo naše izkušnje in rezultate z zdravljenjem ADS v 5-letnem obdobju od 2008–2012. Laparoskopska lavaža pri Hinchey III ADS bo svoje pravo mesto dobila le z dobro pripravljenimi, randomiziranimi prospektivnimi raziskavami z dovolj dolgim spremljanjem operiranih bolnikov. Trenutno v Evropi potekajo štiri tovrstne raziskave. About 1% of people with colonic diverticulosis need some sort of operation. Hartmann`s procedure still represents the basis for urgent surgical treatment of patients with generalized peritonitis (Hinchey III or IV). These procedures, while simple and efficient, bring along quite high levels of perioperative morbidity and mortality. This is why there has recently been a trend toward a more conservative approach to avoid the risk of high postoperative morbidity and definitive stoma, i.e. laparascopic lavage without colonic resection. Well prepared, prospective, randomized studies with proper follow up are needed. There are 4 such studies conducted in different European centers at this moment. *Grosek J. Univerzitetni klinični center Ljubljana, Klinični oddelek za abdominalno kirurgijo GASTROENTEROLOG 11 UVOD Divertikuloza debelega črevesa je bila včasih izredno redka, sedaj pa se ocenjuje, da je prisotna že pri več kot polovici ljudi v razvitem svetu. Prevalenca narašča s starostjo, oba spola pa sta približno enakomerno prizadeta. V vsaj 75 % je prizadet le sigmoidni del debelega črevesa, v 5–10 % pa so divertikli prisotni po celotnem debelem črevesu3. Divertikli so večinoma klinično nemi in jih naključno odkrijemo pri različnih preiskavah (kolonoskopija, irigografija) zaradi drugih težav. Pri bolnikih, ki jim divertikli povzročajo težave, prevladuje blaga, nespecifična klinična slika, za katero so značilne občasne krčevite bolečine v spodnjem delu trebuha in napihnjenost. Do divertikulitisa, ki nastane zaradi predrtja posameznega divertikla in okolne vnetne reakcije, pride pri 20–30 % bolnikov. Spekter klinične slike zaključuje krvavitev iz divertiklov, do katere lahko pride pri do 15 % bolnikov. Tovrstna krvavitev običajno nastane nenadoma, je precej obilna, svetlo rdeča in se večinoma ustavi sama3,7. – – Generalizirani gnojni peritonitis (nastane kot posledica predrtja poprej omejenega abscesa) Generalizirani sterkoralni peritonitis Kljub temu, da so različni avtorji predlagali oziroma še predlagajo številne druge klasifikacije akutnega divertikulitisa sigme, pa je Hincheyeva klasifikacija kljub starosti še vedno aktualna in omogoča v kombinaciji s Kohlerjevo klasifikacijo izvrstno in racionalno podlago za izbiro najustreznejšega načina zdravljenja. RAZDELITEV Obstajajo številne razdelitve akutnega divertikulitisa sigme. Zelo uporabna je klasifikacija Kohlerja in sodelavcev iz leta 1999, ki bolezen deli v 3 skupine2: – Simptomatski nekomplicirani divertikulitis – Ponavljajoči nekomplicirani divertikulitis – Komplicirani divertikulitis Krvavitev Absces/Flegmona Fistula Perforacija Striktura Gnojni/ Sterkoralni peritonitis Temelj današnjemu razumevanju bolezni pa je že leta 1978 postavil Hinchey s sodelavci, ki je divertikulitis z abscesom razdelil v 4 skupine1: – Perikolični absces ali flegmona – Medenični, intraabdominalni, retroperitonealni absces 12 GASTROENTEROLOG Slika 1. Hincheyeva razdelitev (Iz: Hinchey EJ, Schaal PGH, Richards GK. Treatment of perforated diverticular disease of the colon. Adv Surg 1978) KLINIČNA SLIKA, DIAGNOSTIKA Bolečina v levem spodnjem kvadrantu, lahko slabost z ali brez bruhanja, zmerno povišana telesna temperatura, spremenjeno odvajanje blata in porast laboratorijskih kazalcev vnetja so temeljni klinično in laboratorijski parametri, ki opredeljujejo blago sliko nekompliciranega divertikulitisa, ne glede na časovno komponento (akutni oz. ponavljajoči) 3,7. Povsem na drugem koncu spektra so bolniki z generaliziranim sterkoralnim peritonitisom (Hinchey IV), ki ga povzroči večja perforacija divertikla, okolni organi/strukture predrtja ne zamejijo, končna posledica pa je izlitje črevesne vsebine po vsej trebušni votlini. Bolniki so hudo prizadeti, difuzno peritonitični in septični. Takšno stanje, v odsotnosti ustreznega zdravljenja ali pa če je le to prepozno, vodi v šokovno stanje in smrt. Med obema opisanima skrajnostima pa je raznolika klinična slika. Praktično vedno imajo bolniki povišano telesno temperaturo in porast vnetnih kazalcev v laboratoriju. Če je absces pod trebušno steno, je prisotna tudi močna lokalna občutljivost z mišičnim defansom. Tega ni, če je absces retroperitonealno ali globoko v mali medenici (Hinchey 2). Pride lahko do spontanega predrtja abscesov. V tem primeru se gnojna vsebina razlije po trebušni votlini in pride do difuznega peritonitisa s sepso. Stanje bolnikov se dramatično poslabša in potrebno je takojšnje ukrepanje (Hinchey 3) 1,2,3,7. Če imamo opraviti s kompliciranim divertikulitisom (klasifikacija po Kohlerju), so prisotni dodatni klinični znaki in simptomi. V primeru, da vnetni tumor zapre svetlino črevesa, pride do klasične slike obstruktivnega ileusa debelega črevesa. Pnevmaturija, fekalurija in pogoste okužbe sečil so značilnost fistulacije vnetnega tumorja v sečni mehur. Fistulacija v vagino pa privede do umazanega in smrdečega vaginalnega izcedka2,7. Za diagnozo divertikulitisa so polega anamnestičnih podatkov in zgoraj opisane klinične slike pomembne tudi laboratorijske preiskave (levkocitoza s pomikom v levo, C reaktivni protein, prokalcitonin, pregled urina) in pa slikovna diagnostika. Najpogosteje naredimo UZ trebuha, ki pokaže zadebeljeno steno sigme, prosto tekočino z ali brez omejenih abscesov. Vedno pogosteje se odločimo za CT trebuha, ki odkrije tudi abscese, ki jih včasih zaradi zaplinjenosti trebuha ali same lokacije abscesov na UZ preiskavi spregledamo (retroperitonealno, globoko v mali medenici). CT preiskava pa je zlati standard pri diagnostiki kompliciranih divertikulitisov, pri katerih je prišlo do fistulacij v druge organe. RTG abdomna je pogosto prva slikovna preiskava pri neznačilnih kliničnih manifestacijah (zaprtje,...) ali pri bolnikih, pri katerih se divertikulitis pokaže bodisi kot ileus debelega črevesa ali kjer sumimo na prosti zrak intraperitonealno7. Diferencialno diagnostično moramo pomisliti na različna bolezenska stanja: apendicitis, vnetje sečil, sindrom iritabilnega kolona, nefrolitiazo, ginekološka obolenja, infekcijski/ishemični kolitis, kronično vnetno črevesno bolezen in malignom sigme7. ZDRAVLJENJE Večina divertikulitisov poteka v blagi, nekomplicirani obliki. Sem sodi tudi Hinchey I, kjer je absces manjši in lociran perikolično. Tovrstne oblike zdravimo konzervativno, ambulantno ali hospitalno. Potrebna je bodisi popolna karenca, bodisi zgolj tekoča dieta s počitkom. Uvedemo empirično antibiotično dvotirno terapijo (gentamicin, metronidazol), pogosto boleč predel tudi lokalno hladimo. Dva do tri mesece po sanaciji vnetja je pri bolnikih potrebno opraviti kolonoskopijo za izključitev malignoma7. Pri divertikulitisih z omejenimi večjimi abscesi je poleg opisanega konzervativnega zdravljenja potrebna tudi drenaža abscesov. Ob ustrezni lokaciji le teh je najbolje abscese drenirati perkutano, večinoma pod kontrola ultrazvoka. Če takšna drenaža ni možna ali pa ni uspešna, je potrebna kirurška drenaža, bodisi laparoskopska bodisi klasična7. Komplicirani divertikulitisi s fistulami v sečni mehur ali vagino zahtevajo kirurško zdravljenje. Pri takšnih operacijah poleg abdominalnih kirurgov sodelujejo tudi urologi ali ginekologi. Prizadeti del črevesa je potrebno resecirati, fistulo ekscidirati in defekt na drugem organu prešiti. Resecirani del črevesa pošljemo na histološki pregled8. Divertikulitisi, pri katerih je prišlo do difuznega peritonitisa (Hinchey III in IV), zahtevajo urgentno kirurško zdravljenje. Že vrsto let je zlati standard t.i. Hartmannova resekcija sigme, kjer oboleli del debeGASTROENTEROLOG 13 lega črevesa reseciramo, krn zgornje danke s pomočjo linearnega spenjalnika slepo zapremo ter prosti konec descendensa izpeljemo navzven skozi trepanacijo v trebušni steni v levem mezogastriju kot končno kolostomo. Preteklo je že skoraj 100 let, odkar je Henri A. Hartmann prvič opisal ta poseg, kljub temu pa ima ta operacija zaradi svoje enostavnosti in velike učinkovitosti še vedno pomembno mesto v urgentni abdominalni kirurgiji. Po drugi strani pa imajo tovrstne operacije relativno visoko morbiditeto in mortaliteto, tudi delež ponovnih vzpostavitev kontinuitete črevesa je majhen. Izkušeni kolorektalni kirurgi se zaradi tega pogosto odločajo za kontinuitetno resekcijo, kot alternativa resekciji pri Hinchey III ADS pa pridobiva na veljavi laparoskopska lavaža. Pri Hinchey IV divertikulitisu pa je pravilna oskrba še vedno Hartmannova resekcija sigme8,9. Zdravljenje divertikuloze zaradi ponavljajočih divertikulitisov je kirurško, večinoma laparoskopsko. Prizadeti del črevesa reseciramo in napravimo primarno anastomozo. Odločitev o načinu operacije ni težka, ključna dilema je, kdaj oziroma ali sploh operirati. Hinchey III ali IV divertikulitis je praktično vedno posledica prvega napada bolezni, tako da tega hudega stanja s preventivno resekcijo črevesa praktično ni možno preprečiti. Večinoma se avtorji zatorej strinjajo, da je potrebna individualna obravnava vsakega bolnika posebej7,10. V zadnjem času se je v strokovni literaturi pojavilo več prispevkov (10 člankov, 267 vključenih bolnikov), v katerih avtorji opisujejo laparoskopsko lavažo pri Hinchey III divertikulitisu kot enakovredno alternativo klasični Hartmannovi resekciji sigme. Princip te metode je laparoskopski pristop, pri katerem zgolj speremo trebušno votlino, vstavimo abdominalne drene in nadaljujemo z antibiotično terapijo. Čez nekaj mesecev se potem praviloma odločimo za (laparoskopsko) resekcijo črevesa s primarno anastomozo. Zagovorniki te metode menijo, da na ta način spremenimo purulentno okužbo v flegmonozni divertikulitis, ki ga nato lahko pozdravimo konzervativno. Vprašanje 14 GASTROENTEROLOG pa je seveda, ali ni obolelo črevo, ki pri tej metodi ostane »in situ«, stalen vir okužbe. Avtorji tak pristop ocenjujejo kot odličen z zanemarljivim deležem konverzij in drugih zapletov. Vendar pa nekoliko bolj kritična analiza pokaže na številne pomankljivosti teh prispevkov. Večina teh študij je retrospektivnih, nerandomiziranih, vključenih je relativno majhno število bolnikov v dolgih časovnih intervalih. Skupine bolnikov so zelo heterogene, terapevtski algoritmi niso ustrezno razloženi3-8. DELO IN METODE Ker tudi na našem kliničnem oddelku (enota Zaloška/ Vodnikova- BPD) zdravimo bolnike z akutnim divertikulitisom sigme, smo želeli retrospektivno zbrati podatke za krajše obdobje (2008–2012), z namenom kritično ovrednotiti obseg pa tudi kakovost našega dela. Klinični oddelek za abdominalno kirurgijo v Bolnišnici Petra Držaja je dislocirana enota našega kirurškega oddelka, ki poleg svoje redne dejavnosti opravlja tudi dejavnost urgentne abdominalne kirurgije za odrasle bolnike. Zaradi tega je večina bolnikov z ADS napotenih v to ustanovo. Na Kliničnem oddelku za abdominalno kirurgijo v UKC pa smo zdravili oziroma zdravimo predvsem dve skupini bolnikov z ADS, in sicer bolnike s kompliciranimi oblikami bolezni ter bolnike, ki zaradi drugih pridruženih bolezni potrebujejo oskrbo v terciarni ustanovi. V petletnem obdobju (2008–2012) smo retrospektivno zbrali naslednje podatke: 1. Povprečno število zdravljenih bolnikov 2. Povprečna starost bolnikov 3. Delež žensk/ moških 4. Povprečen čas hospitalizacije 5. Razdelitev bolezni po Hincheyevi klasifikaciji 6. Delež operiranih bolnikov 7. Vrsta resekcije (Hartmann/ anastomoza) 8. Način operacije (Klasično/ laparoskopsko) 9. Stopnja morbiditete/ mortalitete pri operiranih bolnikih REZULTATI ZAKLJUČEK Klinični oddelek za abdominalno kirurgijo, enota UKC Večina bolnikov z divertikli debelega črevesa nima težav oziroma so te blage. Večji del divertikulitisov poteka v blagi, nekomplicirani oblikami in jih pozdravimo konzervativno. Približno 1/4 bolnikov (nekateri menijo, da celo manj- tako govorijo tudi naši rezultati) potrebuje urgentno kirurško zdravljenje. Temelj tega zdravljenja je že davnega leta 1921 prvič opisana Hartmann-ova resekcija sigme, ki je relativno enostavna in ima dobre rezultate. Kljub navdušenju nekaterih kirurgov nad tehniko laparoskopske lavaže brez resekcije črevesa bi bilo mnogo preuranjeno trditi, da je takšen pristop enakovreden uveljavljeni, to je Hartmannovi operaciji. Laparoskopska lavaža pri Hinchey III ADS bo svoje pravo mesto dobila le z dobro pripravljenimi, randomiziranimi prospektivnimi raziskavami z dovolj dolgim spremljanjem operiranih bolnikov. Trenutno v Evropi potekajo štiri tovrstne raziskave. Povprečno smo zdravili 12 bolnikov letno. To so bili večinoma bolniki s kompliciranimi oblikami bolezni oziroma polimorbidni bolniki, ki so potrebovali zdravljenje v terciarnem centru. Povprečna starost je bila 62 let, povprečen čas hospitalizacije pa 13 dni. Hinchey I je bil prisoten pri 30 % bolnikov, Hinchey II pri 46 %, Hinchey III pri 12 % in Hinchey IV prav tako pri 12 % bolnikov. 2/3 bolnikov je bilo operiranih. V 15 % je bila narejena laparoskopska lavaža brez resekcije. V 85 % je bila narejena klasična resekcija obolelega dela debelega črevesa, in sicer v polovici primerov s primarno anastomozo, v polovici primerov pa je bila narejena Hartmannova resekcija. Pooperativna morbiditeta je bila 18 %, pooperativna smrtnost pa 11 %. Klinični oddelek za abdominalno kirurgijo, enota Bolnica Petra Držaja Povprečno smo zdravili 70 bolnikov letno. Povprečna starost je bila 64 let, povprečen čas hospitalizacije pa 6 dni. Bilo je približno enako število žensk in moških. Hinchey I je bil prisoten pri večini, to je 82 % bolnikov, Hinchey II pri 4 %, Hinchey III pri 7 % in Hinchey IV prav tako pri 7 % bolnikov. 14 % bolnikov je bilo operiranih. V 1/3 primerov je bila narejena laparoskopska lavaža brez resekcije. V 2/3 primerov je bila narejena klasična resekcija obolelega dela debelega črevesa, in sicer v 2/3 primerov s primarno anastomozo, v 1/3 primerov pa je bila narejena Hartmannova resekcija. Pooperativna morbiditeta je bila 20 %, pooperativna smrtnost pa 10 %. LITERATURA 1. Hinchey EJ, Schaal PG, Richards GK: Treatment of perforated diverticular disease of the colon. Adv Surg 12:85–109, 1978 2. Kohler L, Suaerland S, Neugebauer E: Diagnosis and treatment of diverticular disease: results of a consensus development conference. Surg Endosc 13: 430–6, 1999 3. Parra-Blanco A: Colonic diverticular disease: patophysiology and clinical picture. Digestion 73 (suppl 1): 47–57, 2006 4. Alamili M, Gogenur I, Rosenberg J: Acute complicated diverticulitis managed by laparoscopic lavage. Dis Colon Rectum 52: 1345–1349, 2009 5. Myers E, Hurley M, et al: Laparoscopic peritoneal lavage for generalized peritonitis due to perforated diverticulitis. Br J Surg 95: 97–101, 2008 6. Bretagnol F, Pautrat K, et al: Emergency laparoscopic management of perforated sigmoid diverticulitis: A promising alternative to more radical procedures. J Am Coll Surg 206:654:657, 2008 7. Rafferty J, et al: Practice parameters for sigmoid diverticulitis. Dis Colon Rectum 49(7): 939–44, 2006 8. Abbas S: Resection and primary anastomosis in acute complicated diverticulitis, a systematic review of the literature. Int J Colorectal Dis 22(4):351–7, 2007 9. Seah DW, Ibrahim S, Tay KH: Hartmann procedure: is it still relevant today? ANZ J Surg 75(6):436–40, 2005 10. Janes S, Meagher A, Frizelle FA: Elective surgery after acute diverticulitis. Br J Surg 92:133–42, 2005 GASTROENTEROLOG 15 Endoultrazvočno vodene tankoigelne biopsije cističnih lezij trebušne slinavke Endoscopic ultrasound guided fine needle aspiration of cystic lesions of the pancreas Andrej Gruden* Klinični oddelek za gastroenterologijo, Interna klinika, Univerzitetni klinični Center, Ljubljana Gastroenterolog 2013; suplement 2: 16–17 Ključne besede: ciste pankreasa, endoskopski ultrazvok, tankoigelna aspiracijska biopsija Keywords: endoscopic ultrasound, pancreatic cyst, fine needle aspiration POVZETEK ABSTRACT Z vse pogostejšo uporabo diagnostičnih tehnik (UZ, CT, MRI) ugotavljamo tudi čedalje več pankreatičnih cist. Pankreatične ciste so lahko ciste, pseudociste ali cistične neoplazme, ki jih nadalje delimo v serozne cistadenome, mucinozne cistične neoplazme (MCN), intraduktalne papilarne mucinozne neoplazme (IPMN) in solidne pseudopapilarne neoplazme. Nekatere pankreatične ciste so benigne, nekatere imajo maligni potencial. Endoskopski ultrazvok s tankoigelno aspiracijsko biopsijo omogoča boljšo detekcijo in karakterizacijo pankreatičnih cist. An increased number of pancreatic cysts are being diagnosed due to the increased use of cross-sectional imaging. Pancreatic cysts can be either true cysts, pseudocysts or cystic neoplasms, while these are further subdivided into serous cystadenomas, mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN) and solid psedopapillary neoplasm. Some pancreatic cyst are benign, others have malignant potential. Endoscopic ultrasound with FNA (fine needle aspiration) cytology and analysis of cystic fluid have led to a better detection and characterization of the cysts. INTRODUCTION into serous cystadenomas, mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN) and solid pseudoapillary neoplasms. As a result of incresased use of cross-sectional imaging (US, CT, MRI), increased number of pancreatic cysts are being diagnosed. Most studies report the prevalence of pancreatic cysts around 2,5% (1, 2). In some studies (3), the prevalence of pancreatic cyst was higher, up to 13,5%. Pancreatic cysts can be true cysts, pseudocysts or cystic neoplasms, while these are further subdivided *Andrej Gruden, dr. med. Klinični oddelek za gastroenterologijo, Interna klinika, Univerzitetni klinični Center, Ljubljana 16 GASTROENTEROLOG Some of pancretic cysts are benign, like pancreatic pseudocyst or serous cystadenoma and do not require resection when asymptomatic. Others like mucinous cysts or intraductal papillary mucinous neoplasms have malignant potential and in these cases surgical resection is often indicated (4). IMAGING Diagnostic methods that are usually used in detection and evaluation of pancreatic cysts include radiologic imaging techniques such as ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI). The primary problem with imaging alone in the evaluation of pancreatic cysts is that there are no clearly differentiating features that allow a high degree of diagnostic accuracy and that imaging alone is inaccurate in differentiating each of the types of pancreatic cysts (5). EUS-FNA FOR PANCREATIC CYSTIC FLUID ASPIRATION Difficulties in establishing an accurate diagnosis with imaging alone have promoted EUS as an useful diagnostic technique in the evaluation of pancreatic cysts. EUS can provide fine detail on the characterisation of the cyst because of the very high spatial resolution. An advantage of the EUS is the possibility to perform FNA for analysis of the cyst fluid (4, 5, 6). The technique of cyst aspiration is relatively straightforward. Cyst is localised under EUS control, needle is inserted via instrument and cyst is targeted. Ussualy single pass with a needle is performed and cyst fluid is aspirated and sent to laboratory for cytology examination and biochemical analysis. If there is any solid component of the cyst, or intracystic mural nodules, it is punctured as well. Cytological evaluation of pancreatic cyst fluid is widely used. Several studies report a sensitivity to be around 50% for the differentiation between mucinous and nonmucinous neoplasms (4, 5, 6). Biochemical analysis of the fluid have been evaluated for seveal years with the underlying thought that markers secreted into the cyst fluid identify the epithelial lining. Amylase is usualy elevated in psedocyst and IPMN and low in MCN and serous cystadenoma. Of the tumor markers, CEA is considered to be the best discriminant marker between a mucinous and nonmucionous cyst. A low CEA level (<5 ng/ml) has been shown to have a sensitivity between 50 and 100% and specificity 77–95% to differentiate between mucinous and nonmucinous cysts. Pseudocysts and serous cystadenomas generally have a low CEA value. The most widely used cutoff for an elevated CEA is 192 ng/ml. This cutoff has sensitivity of 75% and specificity 84% to discriminate between mucinous and nonmucinous cysts (4). Howewer, 25% of mucinous cysts will have CEA level lower than 192 ng/ml (7). It may be possible to improve the analysis of the cyst fluid by combining CEA level and molecular analysis (DNA quantity, K-ras mutation, and allelic imbalance mutations) (7). In most hospital laboratories, 1 to 2 ml of liquid is needed to perform CEA analysis. With some fluid nedeed for citological examination, cyst should be at least 1 to 2 cm in size to obtain sufficient fluid (5). EUS FNA is considered as safe technique to obtain pancreatic cyst fluid with rare, mostly mild complication, but infection, pancretitis and intracystic hemorrhage have been reported in about 2.4% (5). REFERENCES 1. de Jong K, Nio CY, Hermnas JJ, et al. High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations. Clinical gastroenterology and Hepatology. 2010;8(9):806–811 2. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected pancreatic cysts on MDCT. American Journal of Roentgenology. 2008;191 (3):802–807 3. Lee KS, Sekhar A, Rofsky NM, Pedrosa I. Prevalence of incidental pancreatic cysts in the adult population on MR imaging. American Journal of Gastroenterology.2010;105(9):2079–2084 4. de Jong K, Bruno Mj, Fockens P. Epidemiology, Diagnosis, and management of Cystic lesions of the Pancreas. Gastroenterol Res Pract 2012;2012:147465 5. Hawes RH, Clancy J, Hasan M. Endoscopic Ultrasound-Guided Fine Needle Aspiration in Cystic Pancreatic Lesions. Clin Endosc. 2012 June; 45(2):128–31 6. Khalid A, Brugge W. ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. Am J Gastroenterol 2007; 102:2339–49. 7. Bhutani MS, Gupta V, Guha S, Gheonea DI, Saftoiu A. Pancreatic Cyst Fluid Analysisi- A Reviev. Gastrointestin Liver Dis. 2011 Jun;20(2):175–80 Image 1 Needle in the cyst lumen GASTROENTEROLOG 17 Eozinofilni ezofagitis pri otrocih - novosti Eosinophilic esophagitis in children: recent updates Matjaž Homan* Pediatrična klinika Ljubljana Gastroenterolog 2013; suplement 2: 18–21 Ključne besede: eozinofilni granulociti, eozinofilni ezofagitis, sluznica prebavil, biološka zdravila. POVZETEK Eozinofilni ezofagitis je kronična imunsko/antigensko pogojena vnetna bolezen požiralnika, ki se lahko pojavi kadarkoli v življenju. Za dokončno potrditev bolezni je potrebno dokazati prekomerno kopičenje eozinofilnih granulocitov v vsaj enem histološkem preparatu sluznice požiralnika tudi po zdravljenju z visokimi odmerki zaviralcev protonske črpalke. Bolezen odkrivamo vse pogosteje, tako se incidenca eozinofilnega ezofagitisa približuje incidenci kronične vnetne črevesne bolezni. Zdravljenje s hipoalergično dieto je še vedno najpogostejši način terapije. Topični kortikosteroid budezonid z razliko od flutikazona popolnoma obnovi sluznico požiralnika pri bolnikih z eozinofilnim vnetjem. Zdravljenje je dolgotrajno, v primerih, ko ni učinkovito, lahko pride do zoženja požiralnika. V tem primeru je potrebna balonska dilatacija požiralnika, pri čemer število zapletov ni večje kot v primeru zoženja požiralnika druge etiologije. UVOD Eozinofilni ezofagitis (EoE) je kronična bolezen požiralnika, ki je bila prvič opisana pred komaj 30 leti (1). Bolezen sploh ni redka, saj jo diagnosticiramo pri 6 % endoskopiranih bolnikov zaradi kakršne koli simptomatike in pri 15 % bolnikov, ki so imeli opravljeno *Doc. dr. Matjaž Homan, dr. med. Pediatrična klinika Ljubljana, Bohoričeva 20, 1000 Ljubljana 18 GASTROENTEROLOG gastroskopijo zaradi težkega požiranja (2). Kot drugod v razvitem delu sveta tudi v Sloveniji prepoznamo vsako leto več bolnikov z EoE. Večino otrok z EoE v Sloveniji vodimo na Pediatrični kliniki v Ljubljani in po pregledu podatkov zdravimo trenutno 26 otrok z EoE. Ob pogostejšem prepoznavanju bolnikov raste z logaritmično krivuljo tudi število objavljenih raziskav o EoE. Kljub številnim objavam še vedno ostaja veliko nejasnosti glede etiologije bolezni, prognoze in zapletov nezdravljene bolezni, vrste vzdrževalnega zdravljenja itd. V prispevku bom predstavil najnovejša priporočila in pregled trenutnega znanja o EoE pri otrocih. ZNAČILNOSTI EOZINOFILNEGA EZOFAGITISA EoE je kronična imunsko/antigensko pogojena vnetna bolezen požiralnika, za katero je značilna refluksna simptomatika in prisotnost eozinofilne infiltracije v steni požiralnika (3). Ob tem je potrebno izključiti bolezni, kot so gastroezofagealna refluksna bolezen požiralnika in eozinofilna infiltracija požiralnika, odzivna na zdravljenje z inhibitorji protonske črpalke. Diagnoza še vedno temelji na histološkem dokazu > 15 eozinofilnih granulocitov na polje velike povečave v epiteliju požiralnika v vsaj enem izmed histoloških odvzemov, s to razliko, da mora biti prekomerna prisotnost eozinofilnih granulocitov prisotna tudi po dvomesečnem zdravljenju z visokimi odmerki zaviralcev protonske črpalke. Glede na posodobljena priporočila v posameznih primerih lahko govorimo o EoE, tudi če je so v histopatološkem izvidu opisani eozinofilni mikroabsces ali ekstracelularne eozinofilne granule, bazalno celično hiperplazija in široki medcelični prostori. Ob tem je potrebno poudariti, da je nujno potrebno med gastroskopijo odvzeti vsaj dva vzorca sluznice spodnjega dela požiralnika in dva vzorca sluznice zgornjega dela požiralnika. Če odvzamemo pet vzorcev požiralnika, postane občutljivost preiskave skoraj 100 % (4). Pogostost EoE narašča. Če je bilo do leta 2007 opisanih 212 primerov bolnikov z EoE, v zadnjih letih opisujejo prevalenco 0,02 % v Švici (5), 0,44 % v ZDA (6) in 1 % na Švedskem (7). Bolezen se pojavlja pogosteje pri moških. Gen TSLP, ki nosi zapis za citokin, ki vpliva na odgovor Th2, se nahaja na kromosomu X, s čimer lahko deloma razložimo nagnjenost moških k razvoju EoE (8). Poleg mutacije gena TSLP najdemo pri bolnikih z EoE pogosto še mutacijo gena filagrin in gena, ki se nahaja na 5q22 mestu genoma (9, 10). Etiologija EoE še ni popolnoma jasna. Večinoma sprožijo eozinofilno vnetje v steni požiralnika alergeni iz hrane ali zraka. Z alergološkimi testi najpogosteje dokažemo preobčutljivost na beljakovine kravjega mleka, pšenice, soje in rži (11). EoE se najverjetneje lahko razvije tudi po virusni okužbi, po kemični poškodbi sluznice požiralnika in po dolgotrajni terapiji z zaviralci protonske črpalke (23, 13). Klinična slika je nespecifična in je odvisna od starosti. Majhni otroci so neješči, njihova telesna teža počasneje napreduje, pri šolskih otrocih pa prevladujeta bolečina v zgornjem delu trebuha in za prsnico ter bruhanje. Bolečine pri požiranju, zatikanje hrane in zagozdenje kosa hrane v zgornji prebavni cevi se značilno pojavljajo pri adolescentih in odraslih bolnikih. Pri pogovoru z bolnikom in s starši moramo biti natančni, saj otroci lahko z določenimi prehrambnimi navadami zakrijejo težave pri požiranju; izogibajo se npr. čvrste hrane, režejo kose hrane na zelo majhne koščke, zalivajo hrano s tekočino. Med pregledom je potrebno oceniti rast in razvoj otroka, ki se zaradi same bolezni ali dietnega zdravljenja lahko upočasnita (3). Endoskopija zgornjih prebavil z odvzemom bioptov ostaja ‘zlati standard‘ pri diagnostiki EoE. Značilen endoskopski izvid brez histološke potrditve ne zadošča diagnostičnim kriterijem. Bolniki z EoE imajo pogosto tipičen endoskopski izgled sluznice požiralnika, ki je granulirana, razbrazdana ali obročaste strukture. V primeru intenzivnega vnetja so prisotne bele obloge. Izgled sluznice požiralnika je lahko ob endoskopski preiskavi tudi popolnoma normalen. Hirano s sod. je predlagal endoskopsko klasifikacijo EoE z namenom enotne ocene stopnje vnetja in ocene odziva na zdravljenje (14). Otroci z EoE obolevajo pogosto še za drugimi atopičnimi boleznimi, kot so astma, atopični dermatitis, seneni nahod in alergični konjunktivitis in so pogosto preobčutljivi na alergene iz zraka. Pri obravnavi otroka z EoE je zato nujna alergološka obravnava, vključno s krvnimi, kožnimi in krpičnimi alergološkimi testi. EoE in poslabšanja bolezni se pogosteje pojavljajo v določenih mesecih v letu, kar je najverjetneje posledica pridružene alergije na alergene iz zraka. Ob primerno zdravljenih pridruženih boleznih alergične etiologije je tudi možnost za poslabšanje EoE manjša (15). Z izjemo invazivne endoskopske diagnostike s histopatološko obravnavo bioptov ni druge metode, s katero bi opredelili stopnjo alergičnega ezofagitisa. Vrednosti celokupnih IgE, koncentracije eozinofilnih granulocitov v krvi, citokinov IL-5 in IL-13 ne korelirajo zanesljivo s stopnjo eozinofilnega vnetja, zato je potrebno pri otrocih endoskopske preiskave pogosto ponavljati. Furuta s sod. je pred letom dni predstavil Enterotest, ki s pomočjo vrvice, ki jo napeljemo v požiralnik, na različnih dolžinah izmeri z ELISA metodo koncentracijo beljakovin, ki se sprostijo pri degranulaciji eozinofilnih granulocitov v steni požiralnika (major basic protein-1, eosinophil-derived neurotoxin, eosinophil cationic protein, eosinophil peroxidase) (16). Enterotest bo mogoče v prihodnosti nadomestil kontrolne endoskopije zgornjih prebavil, saj koncentracije beljakovin dobro korelirajo s stopnjo eozinofilnega vnetja pri bolnikih z EoE. ZDRAVLJENJE EOZINOFILNEGA EZOFAGITISA Uspešnost zdravljenja EoE je potrebno preveriti z endoskopijo in biopsijo zgornjih prebavil. Tudi če bolnik z EoE nima več težav, to še ne zagotavlja remisije alergiGASTROENTEROLOG 19 čnega vnetja sluznice požiralnika. O uspešni terapiji lahko govorimo, če število eozinofilnih granulocitov po zdravljenju ne preseže 15 celic na polje velike povečave. Zdravljenje s hipoalergično dieto je še vedno najpogostejši način terapije, ki jo uporabljamo pri otrocih z EoE. V primeru da z alergološkimi krvnimi, kožnimi ali krpičnimi testi dokažemo preobčutljivost na določene prehranske alergene, uvedemo ciljano hipoalergično dieto. Uspešnost terapije preverimo z endoskopijo zgornjih prebavil 8 do 12 tednov po uvedbi diete. Če je stena požiralnika še prekomerno infiltrirana z eozinofilnimi granulociti, bolnika zdravimo z ’dieto šest‘, ki ne vsebuje beljakovin mleka, jajc, soje, pšenice, morske hrane in oreščkov. Če se dieta brez šestih skupin živil izkaže kot neučinkovita, predlagamo elementarno prehrano. Elementarna prehrana je najprimernejša terapija za dojenčke in majhne otroke s številnimi alergijami in EoE (3). Če ima otrok težave in se ne strinja oziroma se ne zmore prehranjevati z izključno elementarno prehrano, ga zdravimo z zdravili. Če ga zdravimo z izključno elementarno prehrano, lahko opravimo kontrolno endoskopijo že po 4 do 6 tednih in nato postopno uvajamo manj alergogene vrste hrane. Pri prehranskem zdravljenju je nujno potrebno v obravnavo vključiti dietetika. Če za določeno vrsto hrane s provokacijo dokažemo, da sproži zagon EoE, bo najverjetneje potrebna ciljana dieta do konca življenja (15). Med zdravili so najučinkovitejši sistemski kortikosteroidi. Pri 90 % bolnikov z EoE pride leto dni po prenehanju zdravljenja do ponovitve vnetja. Tako je pri otrocih z EoE potrebno vzdrževalno zdravljenje z nizkimi odmerki kortikosteroidov, ki pogosto povzročijo stranske učinke. Zaradi tega zdravimo bolnike z EoE s sistemsko obliko kortikosteroidov v odmerku 1 mg na kg TT le v primerih izrazito oteženega požiranja, dehidracije, pomembne izgube TT in zoženja požiralnika (3). Topični ali lokalno delujoči kortikosteroidi v obliki pršila ali tekočine viskozne gostote so najpogosteje predpisana zdravila pri zdravljenju EoE. Razen glivičnega vnetja ustne sluznice to zdravljenje nima stranskih učinkov in je dokaj uspešno. Ob prekinitvi terapije z lokalnimi kortikosteroidi pride pogosto do ponovitve bolezni. Do leta 2007 se je pri opisanem 20 GASTROENTEROLOG zdravljenju uporabljal izključno flutikazon v obliki pršila, v zadnjih letih pa ga je nadomestil budezonid v obliki viskozne tekočine. Raziskave so pokazale, da je budezonid enako učinkovit kot flutikazon, poleg tega pa povzroči popolno regeneracijo sluznice požiralnika (17). Odmerek flutikazona je od 88–440 μg 2–4-krat dnevno za otroke in 440–880 μg dvakrat dnevno za adolescente in odrasle bolnike (3). Budezonid je potrebno prejemati v odmerku 1 mg na dan za otroke do desetega leta starosti in 2 mg dnevno za ostale bolnike. V primeru, da učinka ne dosežemo, lahko zvišamo odmerek do 2.8 mg dnevno pri otrocih do desetega leta starosti in do 4 mg dnevno pri starejših od 10 let (18). Topični kortikosteroidi so učinkovitejši pri mlajših otrocih in pri bolnikih, ki nimajo dokazanih alergij (19). Kot pri zdravljenju s sistemskimi kortikosteroidi tudi po ukinitvi topičnih kortikosteroidov pride do zagona EoE. Straumann s sod. je v raziskavi ugotovil, da je bilo 50-tedensko vzdrževalno zdravljenje z nizkimi odmerki topičnega budezonida pri 28 odraslih bolnikih z EoE učinkovito le pri nekaj več kot tretjini bolnikov (20). Med novejše načine zdravljenja bolnikov z EoE sodijo zdravljenje z antagonisti leukotrienskih receptorjev, azatioprinom, 6-merkaptopurinom in z biološkimi zdravili. Izmed naštetih zdravil so najbolj obetavna biološka zdravila. Med najpomembnejše citokine, ki sodelujejo v nastanku in vzdrževanju vnetja, spada IL-5. Protitelesa proti citokinu IL-5 (mepolizumab) so že uporabili v posameznih kliničnih raziskavah pri bolnikih s hudimi oblikami EoE (21). Reslizumab je humanizirano protitelo, ki neutralizira citokinske učinke IL-5. V raziskavo so vključili 226 otrok z EoE, prejeli so 4 odmerke biološkega zdravila. Do kliničnega izboljšanja v večini primerov ni prišlo, zmanjšalo pa se je število eozinofilnih granulocitov v steni požiralnika (22). Bolj ali manj neuspešno so poskušali uporabiti v zdravljenju še omalizumab in infliksimab (23, 24). Če se kljub zdravljenju kot posledica kroničnega vnetja razvije zoženje požiralnika, je potrebna balonska dilatacija. Dolgo časa je veljalo, da je pogostnost zapletov po balonski dilataciji večja pri bolnikih z EoE. Rezultati zadnje metaanalize pa so pokazali, da je šte- vilo teh zapletov podobno kot v primeru drugih indikacij za širjenje požiralnika s pomočjo endoskopa (25). Res pa je, da je pogostnost predrtja požiralnika po dilataciji večje pri bolnikih z EoE, ki imajo zoženje v zgornji tretjini požiralnika in kjer se razvije skoraj popolna zapora lumna prebavne cevi (26). 9. 10. 11. ZAKLJUČEK 12. EoE je kronična bolezen, ki se pojavlja v vseh starostnih skupinah, najpogosteje pa obolimo do štiridesetega leta starosti. Glavni diagnostični kriterij je prekomerna infiltracija stene požiralnika z eozinofilnimi granulociti. EoE in učinek zdravljenja EoE lahko potrdimo samo z endoskopijo zgornjih prebavil, pri kateri odvzamemo biopte požiralnika. Pogostnost bolezni v razvitem svetu hitro narašča. Najpogosteje bolezen zdravimo s hipoalergičnimi dietami, v primeru neuspeha pa uporabimo topično kortikosteroidno terapijo. Tudi če otrok z EoE nima posebnih težav, je potek EoE potrebno endoskopsko spremljati, če že ne zdraviti, saj lahko sčasoma povzroči razvoj strikture požiralnika in motnje peristaltike (27). 13. 14. 15. 16. 17. 18. 19. Če zdravljenje z dietami in kortikosteroidi pri težje potekajočem EoE ne bo imelo učinka, bomo v prihodnosti najverjetneje uporabljali biološka zdravila. LITERATURA 1. Attwood SE, Smyrk TC, Demeester TR, Jones JB. Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome. Dig Dis Sci. 1993; 38(1): 109–16. 2. Kidambi T, Toto E, Ho N, Taft T, Hirano I. Temporal trends in the relative prevalence of dysphagia etiologies from 1999–2009. World J Gastroenterol. 2012; 18(32): 4335–41. 3. Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011; 128(1): 3–20. 4. Gonsalves N, Policarpio-Nicolas M, Zhang Q, Rao MS, Hirano I. Histopathologic variability and endoscopic correlates in adults with eosinophilic esophagitis. Gastrointest Endosc. 2006; 64(3): 313–9. 5. Straumann A, Simon HU. Eosinophilic esophagitis: escalating epidemiology? 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Yves Horsmans* Head of Internal Medicine Department, Cliniques Universitaires Saint-Luc (U.C.L.), Brussels, Belgium Gastroenterolog 2013; suplement 2: 22 Portal hypertension remains one of the major complications of liver cirrhosis and is defined as an hepatic venous pressure gradient (HVPG) of more than 5 mmHg. Clinically significant portal hypertension is defined as HVPG of 10 mmHg or more. Development of gastroesophageal varices and variceal hemorrhage are the most direct consequence of portal hypertension. Over the last decades, significant advancement in the field has led to standard treatment options. In this presentation, Baveno V consensus will be presented by outlining the most important steps which have to be taken into account in the management of the different stages of portal hypertension. In the context of primary prophylaxis, the place of endoscopy, portal pressure gradient measurement, drugs such as non-selective beta-blockers and treatment of primary cause of liver disease will be discussed. At the stage of acute variceal bleeding, the implementation of adequate fluid ressuscitation and transfusion, antibiotics, vasoactive drugs, therapeutic endoscopy and transjugular intrahepatic portosystemic shunt (TIPS) as well as liver transplantation will be put in perspective. A focus on the differences between vasoactive drugs will be presented. Finally, the role of secondary prophylaxis will also be outlined. *Yves Horsmans, M.D., PhD Head of Internal Medicine Department, Cliniques Universitaires Saint-Luc (U.C.L.) Brussels, Belgium 22 GASTROENTEROLOG Kako napovedati izid zdravljenja jetrnih zasevkov raka debelega črevesa in danke? How to predict the treatment outcome of colorectal liver metastases? Arpad Ivanecz*, Tomaž Jagrič, Matjaž Horvat, Stojan Potrč Oddelek za abdominalno in splošno kirurgijo, Univerzitetni klinični center - Maribor Gastroenterolog 2013; suplement 2: 23–24 UVOD BACKGROUND/AIMS Namen prispevka je ugotoviti, ali lahko z biološkimi označevalci ob znanih kliničnih dejavnikih tveganja (CRS) pripomoremo k napovedovanju izida zdravljenja jetrnih zasevkov raka debelega črevesa in danke (RDČD). The aim of this study was to assess whether biological markers can provide additional prognostic information to that supplied by clinical risk score (CRS) for colorectal liver metastases (CRLM). METHODS METODE Opravljen je bil pregled jetrne datoteke našega oddelka. Bolniki izbrani za analizo so bili zdravljeni zaradi zasevkov RDČD s potencialno kurativno resekcijo jeter v obdobju od 1996 do 2011. Izražanje p53, Ki-67 in timidilat sintaze smo določali s tehniko imunohistokemije na izdelanih tkivnih mrežah. A retrospective review of a prospectively maintained database was conducted. Patients selected for this study were treated between 1996 and 2011 with potentially curative liver surgery. p53, Ki-67, and thymidylate synthase were assayed using immunohistochemical techniques on tissue microarrays. RESULTS REZULTATI Izmed 406 bolnikov jih je 98 (24 %) izpolnjevalo kriterije vključitve. Mediani čas sledenja je bil 103 mesece. Statistična analiza je razkrila korelacijo med prekomerno izraženim p53 in visokim CRS (P = 0.058). Po multivariatni analizi je samo visoki CRS ostal negativni napovedni dejavnik preživetja (P = 0.018) in hkrati tudi pokazatelj zgodnje ponovitve obolenja (P = 0.010). Med biološkimi označevalci je po multivariatni analizi samo prekomerno izraženi Ki-67 ostal pozitivni napovedni dejavnik preživetja (P = 0.038). A total of 98 (24%) of 406 patients met the inclusion criteria. The median follow-up was 103 months. Analysis revealed a correlation between p53 protein overexpression and high CRS (P = 0.058). Following multivariate analysis, only high CRS remained an independent negative prognostic predictor for survival (P = 0.018) as well as an indicator of early recurrence of disease (P = 0.010). Of the biological markers investigated, only Ki-67 overexpression was identified as a positive predictor of survival on multivariate analysis (P = 0.038). Arpad Ivanecz* Oddelek za abdominalno in splošno kirurgijo, Univerzitetni klinični center - Maribor, Ljubljanska 5, 2000 Maribor, Slovenija GASTROENTEROLOG 23 ZAKLJUČKI CONCLUSIONS Prekomerno izraženi Ki-67 se je pokazal kot pozitivni napovedni dejavnik preživetja. Samo visoki CRS je ostal neodvisni negativni napovedni dejavnik. Ki-67 overexpression was a positive predictor of survival. Only high CRS remained an independent negative prognostic predictor. 24 GASTROENTEROLOG »Zdravljenje napredovalega HCC – slovenske izkušnje« Management of advanced HCC - Slovenian experience Rado Janša* Clinical Department of Gastroenterology, University Medical Centre, Ljubljana Gastroenterolog 2013; suplement 2: 25–29 Ključne besede: jetrnocelični rak, diagnostika, zamejitev bolezni, napredovala bolezen, naše izkušnje Key words: hepatocellular carcinoma, diagnosis, staging, advanced stage of HCC, our experience with systemic treatment POVZETEK ABSTRACT Jetrnocelični karcinom je bolezen dveh stopenj – ciroze in raka. Pomembno je zdravljenje obeh. Odločitev za optimalno diagnostiko, zamejitev in zdravljenje naj sprejme multidisciplinarni konzilij, ki obravnava vsakega bolnika posebej. Za zamejitev se priporoča sistem Barcelona Clinic Liver Cancer (BCLC). Zdravilo izbora za napredovali HCC je sorafenib. V klinični praksi je ključnega pomena preudarna izbira bolnikov in načina zdravljenja. Analiza zdravljenja naših bolnikov z napredovalim HCC je prikazala, da je zdravljenje s sorafenibom učinkovito in varno. HCC is a two stage disease - cirrhosis and tumor. It is very important to treat both of them. Multidisciplinary groups should decide on the optimal diagnosis, staging and treatment of the individual patient. It is important to use single staging system. BCLC staging system is recommended. Sorafenib is standard of care for advanced HCC. The key point in clinical practise is careful selection of patients and treatment of liver diseases and the tumor. In conclusion, our analysis of group of patients with advanced HCC demonstrates that the therapy with sorafenib is safe and effective. INTRODUCTION cancer in the world and third most common cause of cancer-related death worldwide (2). Hepatocellular carcinoma (HCC) is an epithelial liver tumor of which the cells are mostly similar with hepatocytes (1). The incidence of HCC has risen over the past 2 decades and is expected to increase over the next decade. HCC presents almost all primary cancer of the liver (over 90%) and is a highly lethal malignancy. HCC is the fifth most common World map of the prevalence of HCC is identical to the distribution of hepatitis B (HBV) and hepatitis C (HCV) viral infection. Even today, these two etiologic factors for HCC are very important, although other causes of cirrhosis are important too. *Rado Janša Clinical Department of Gastroenterology, University Medical Centre, Ljubljana GASTROENTEROLOG 25 The liver with advanced fibrosis and cirrhosis undoubtly represents an ideal soil for the development of a HCC. The annual risk of HCC in patients with cirrhosis ranges from 1%–6% (3). It is very important to emphasize that HCC is a two state disease – a HCC TUMOR and an underlying LIVER DISEASE, most commonly cirrhosis (4, 5). HCC represents heterogeneous disease in which dysplastic lesion can evolve into a malignant tumor (6). In less than 10% of cases, HCC occurs in a normal, non-cirrhotic liver. Molecular classification system was described and some HCC contain biliary type cytokeratins (CK7 and/or CK 19) positive cells. This cases have poor prognosis. On the contrary, fibrolamellar type of HCC occuring in younger patients without risk factors is a rare TAB 1: Risk of HCC (Bruix 2010) variant with a slow growing nature and resistence to systemic therapy but significantly better prognosis (7 ,8). Risk factors for development of HCC are different and individual. They may represent accumulation of diferent diseases and form the basis for surveillance program for HCC. Some risk factors represent the cause(s) of liver disease (HBV, HCV, alcohol, iron overload, fatty liver), the severity of the liver disease (advanced fibrosis) and epidemiological factors (male gender, obesity, diabetes) (2) (TAB 1). DIAGNOSIS The diagnosis of HCC is based on the combination of clinical, laboratory and imaging (sometimes even pathology) examination. Imaging has a great value especially in cirrhotic liver. Several studies showed that MRI has a sensitivity and specificity of 75% and 76% for a diagnosis of HCC, which is better than the sensitivity and specificity of 61% and 66% for triple-phase spiral CT (9, 10). The presence of washout in arterially enhancing lesion increases the probability of HCC 65 fold (10). So the main characteristics are arterial hypervascularity and venous or delayed phase washout (9). Sometimes two contrast enhanced studies should be done. If the scan doesn‘t show typical features of HCC, than a second contrast-enhanced study is required. This reduces the frequency of biopsies. Threshold incidence per year Incidence Asian male HBV carriers > age 40 0.2% 0.4%-0.6% per year Asian females HBV carriers >age 50 0.2% 0.3%-0:6% per year HBV carrier with family history of HCC 0.2% Incidence than without family history African/North American Blacks with HBV 0.2% HCC occurs at a younger age 0.2%–1.5% 3%-8% per year STAGING Hepatitis C cirrhosis 1.5% 3%-8% per year Stage IV PBC with cirrhosis 1.5% 3%-8% per year Treatment of HCC depends on the tumor staging, liver function tests and performance status of the patient. Genetic hemochromatosis and cirrhosis 1.5% Unkown but probably >1.5%per year Alpha 1-antitrypsin deficiency and cirrhosis 1.5% Unkown bur probably >1.5% per year Other cirrhosis 1.5% Unkown Population group Cirrhotic HBV carriers 26 GASTROENTEROLOG Staging is very important, because ever more treatments of HCC depend on the tumor staging. Staging systems for HCC have to define our treatment decision and outcome prediction. The BCLC (Barcelona Clinic Liver Cancer) is recommended (evidence 2A, recommendation 1B) (4) (TAB2). TAB 2: BCLC STAGING SYSTEM (BY Liovet 2011) Until 2007, there wasn’t any systemic drug recommended for patients with advanced stage of HCC. Treatment with multi-tyrosine kinase inhibitor – sorafenib is now the standard of care for such patients since 2007 (in Slovenia since 2008). - objective response rate was less than 10% (17). The results of double blind phase III study with the multikinase inhibitor sorafenib were reported. Sorafenib in Child Pugh A patients with advanced HCC was well tolerated and showed significant relative improvement (44%) in overall survival (10,7 months vs 7,9 months) (16,18). A similar benefit of sorafenib was concluded in Asian-Pacific study which included patients in Child Pugh A and B (median OS 6,5 months vs 4,2 months) (17). The most frequently reported drug related side effects were hand-foot-skin reaction, diarrhea, alopecia, fatigue, hypertension and anorexia. Adverse events are mostly Grade 1 or 2 (17). In Gideon-Interim analysis 2010 (511 patients) was reported about 8,6 months of median OS in Child Pugh A and 4,0 months in Child Pough B group of patients (19). The difference between patients with advanced stage and the intermediate stage of HCC is the presence of portal vein involvment and/or extrahepatic spread (4). Sorafenib improves overall survival when compared to placebo (16). Systemic therapy with classic cytotoxic drugs did not improve overall survival rate, even more At University Medical Centre Ljubljana we analysed 71 patients with advanced stage of HCC who were treated with sorafenib in the period between 2008 - 2012. Out of 71 patients we statistically analysed 59 patients. Our decisions for treatment were based on BCLC classification of HCC and were TREATMENT OF ADVANCED HCC OUR EXPERIENCE The base for treatment of HCC is multidisciplinary team decision. Treatment depends on the tumor staging (TAB 3) (11–15). The majority of patients present with advanced stages and are therefore not candidates for curative treatment and/or transarterial chemoembolization (TACE). GASTROENTEROLOG 27 HCC in cirrhosis Child-Pugh, PS 0 Very early stage Single <2cm Early stage 1 nodule<5cm or 3<3cm Curave treatments (resecon, radiofrequency ablaon, liver transplantaon) Child-Pugh A-B, PS 0-2 Intermediate stage Mulnodular, PS 0 Transarterial chemoembolizaon Child-Pugh C*, PS>2 Advanced stage Terminal stage Portal invasion. nodal involvement metastases, PS 1-2 Sorafenib* Symptomac treatment TAB 3: Strategy for staging and treatment assignment in patients diagnosed with HCC (adapted from Bruix e et al., 2005) (10). Abbrevations: PS, performance status, *Poor liver synthetic function due to tumour involvement of the liver.* Only Child-Pugh A. made in multidisciplinary team. In TAB 4,5 and 6 we can see data for gender, etiology and liver function. CONCLUSIONS On the base of our data Kaplan-Meier analysis predicted survival rate and death time rate - TAB 7, TAB 8. HCC is a two stage disease - cirrhosis and tumor. It is very important to treat both of them! Multidisciplinary groups should decide on the optimal diagnosis, staging and treatment of the individual patient. It is important to use single staging system. BCLC staging system is recommended. Sorafenib is standard of care for advanced HCC. The key point in clinical practise is careful selection of patients and treatment of liver diseases and the tumor. In conclusions, our analysis of group of patients with advanced HCC demonstrates that the therapy with sorafenib is safe and effective. TAB 4 TAB 5 Mean interval from diagnosis until treatment with sorafenib was 6,75 months and the duration of treatment was 10,5 months. Average interval of drug usage was 9,29 months. Median survival time from the diagnosis of HCC and those treated with sorafenib (advanced stage HCC, Child Pugh A and B 8) was 16, 8 months (maximal 47 months, minimal 2 months) (12,357 months). 28 GASTROENTEROLOG REFERENCES TAB 6 TAB 7 TAB 8 1. Goodman ZF, Teracciano LM, Tumors and tumor like lesions of the liver. In Burt AD, Portmann BC, Ferrell LD (eds): MacSween s pathology of the liver, 5th edition. London: Churchill Livingston 2007; 761–814. 2. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in diferent geographic regions of he world. J Clin Oncol 2006; 24: 2137–2150. 3. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis. 1999;19:271–285. 4. 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N Engl J Med 2008; 359: 378–390 GASTROENTEROLOG 29 Laparoskopske resekcije raka debelega črevesa in danke Laparoscopic surgery for colorectal cancer Franc Jelenc*, Robert Juvan Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana Gastroenterolog 2013; suplement 2: 30–34 Ključne besede: laparoskopske resekcije, rak debelega črevesa, rak danke Keywords: laparoscopic resections, colorectal cancer POVZETEK ABSTRACT Laparoskopske resekcije raka debelega črevesa in danke so se uveljavile v zadnjih dveh desetletjih. V randomiziranih študijah so potrdili prednost laparoskopskih operacij debelega črevesa zaradi raka pred odprtimi operacijami. Tudi rezultati preživetja po laparoskopskih resekcijah so primerljivi z odprtimi operacijami. Zgodnji rezultati po laparoskopskih resekcijah raka danke so enakovredni rezultatom po odprtih resekcijah, za oceno dolgoročnega preživetja pa bo potrebno več študij. V zadnjih letih se z napredkom tehnologije uveljavljajo nove laparoskopske tehnike operacij skozi en rez (single incision laparoscopy) in operiranja s pomočjo robota. Laparoscopic resections of colorectal cancer have advantages over open surgical procedures, proven in randomized trials, and their frequency is increasing in the last two decades. Early patient survival is comparable to open surgery; long-term survival data is still scarce and more studies are needed. New laparoscopic techniques are evolving in recent years, such as single incision laparoscopy and robotically assisted surgery. UVOD sprejete zadržano zaradi zgodnjih poročil o večjem odstotku metastaz na mestu troakarjev. Postavljala so se vprašanja prednosti laparoskopske operacije pred odprto glede na stroške, daljši čas operacije in tehnično zahtevnost. Še bolj pomembno je bilo vprašanje ali je laparoskopska kirurgija onkološko enakovredna klasičnim pristopom. Kasnejše študije so pokazale, da je pogostost ponovitev bolezni in metastaz na mestu troakarjev enaka kot pri klasičnih operacijah (3). Pred- Rak debelega črevesa in danke je v Sloveniji po pogostnosti pri ženskah na tretjem mestu in pri moških na drugem mestu (1). Kirurgija je še vedno temeljni način zdravljenja raka debelega črevesa in danke. V začetku devetdesetih let so bile narejene prve laparoskopske resekcije debelega črevesa zaradi raka (2). Laparoskopske resekcije črevesa zaradi raka so bile *Doc. dr. Franc Jelenc, dr. med. Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana 30 GASTROENTEROLOG nost laparoskopske metode pred klasično operacijo je v krajši hospitalizaciji, manjši bolečini po operaciji ter hitrejšem okrevanju. Pri rakavem bolniku je potencialna prednost laparoskopskega pristopa v manjši kirurški travmi in manjšem vplivu na imunski sistem, kar naj bi zmanjšalo število ponovitev bolezni in vplivalo na kakovost življenja operiranih bolnikov (4, 5). RAK DEBELEGA ČREVESA V velikih randomiziranih multicentričnih študijah kot so Clinical Outcomes of Surgical Therapy (COST) iz Severne Amerike, Conventional versus LaparoscopicAssisted Surgery in Colorectal Cacer (CLASICC) iz Velike Britanije, European Colon Cancer Laparoscopic or Open Resection (COLOR), Australian Laparoscopic Colon Cancer Surgical trial (ALCCaS), in v študijah posameznih centrov v Hong Kongu, Barceloni in Italiji, so dokazali prednost zgodnjih rezultatov laparoskopskih resekcij pred odprtimi operacijami (6, 7, 8, 9, 10, 11, 12). Velika prednost laparoskopskega pristopa je krajša incizija in posledično manjša bolečina in uporaba analgetikov. Bolniki so po laparoskopskih operacijah potrebovali tudi do 30 % manj analgetikov kot pri klasičnih operacijah (13). Ohtani je s sodelavci ugotovil, da se pljučna funkcija pri bolnikih, ki so bili operirani na laparoskopski način hitreje normalizira (14). Manjša operativna travma vodi do hitrejše vzpostavitve motititete črevesa po laparoskopskih resekcijah (9, 11). Čas hospitalizacije in povratek v normalno aktivnost je daljši po klasičnih operacijah (13). Čas operacije je statistično značilno daljši pri laparoskopskih resekcijah zaradi tehnično bolj zahtevnih postopkov (8, 9, 10, 11). Zaradi boljše preglednosti pa je izguba krvi med operacijo manjša (14). Preklop iz laparoskopske operacije v odprto je potreben, če ni posega mogoče poseg končati varno za bolnika, oziroma zadostiti onkološkim principom. Največkrat so razlogi za preklop preraščajoč tumor, obsežne prirastline in nejasne anatomske prilike, da bi lahko prikazali pomembne anatomske strukture (13). Pomemben dejavnik je tudi izkušenost kirurga, saj odstotek preklopov pada s številom opravljenih posegov. V CLASICC študiji so dokazali pomen učne krivulje, saj se je odstotek preklopov, ki je bil v prvem letu 38 % zmanjšal na 16 % v šestem letu (7). Da bi kirurg uspešno operiral na laparoskopski način, naj bi naredil najmanj 20 laparoskopskih resekcij debelega črevesa, zadosti izkušenj pa naj bi pridobil po opravljenih 20 do 50 laparoskopskih posegih (14). Preklop negativno vpliva na zgodnje in pozne rezultate po laparoskopskih resekcijah. Več je zapletov med operacijo, po operaciji, podaljša se čas hospitalizacije v primerjavi s posegi, ki so dokončani na laparoskopski način. Preživetje bolnikov je krajše zaradi pogostejših lokalnih ponovitev bolezni. V COST in CLASICC študijah je bilo 5-letno preživetje statistično značilno slabše. Razlog je lahko tudi višji stadiji bolezni v katerih so bili operirani ti bolniki (6, 7). Zgodnji rezultati Cochrane analiza 25 randomiziranih kontroliranih študij, v katerih so primerjali laparoskopske in odprte posege zaradi benignih in malignih bolezni debelega črevesa in danke je pokazala, da je bilo statistično značilno manj zapletov po laparoskopskih operacijah v primerjavi z odprtimi (18,2 proti 23 %). Značilno manj je bilo vnetij rane, medtem ko je bil odstotek dehiscenc anastomoz med obema skupinama bolnikov enak. Prav tako je bilo značilno manj ileusov po laparoskopskih posegih (14, 15). V študijah niso ugotovili razlike v pooperativni smrtnosti med laparoskopskimi in odprtimi posegi zaradi raka debelega črevesa (14, 16). Radikalnost kirurške resekcije ocenjujemo z številom odstranjenih bezgavk in velikostjo odstranjenega dela črevesa. Pomenbni so proksimalni, distalni in cirkumferencialni resekcijski robovi, na podlagi katerih patolog oceni radikalnost operacije. V študijah ni razlike med številom odstranjenih bezgavk med laparoskopsko in odprto operacijo (10, 12). V študiji ALCCaS je bil distalni resekcijski rob značilno daljši kot pri odprti operaciji (9). GASTROENTEROLOG 31 Pozni rezultati Kvaliteta življenja V COST študiji so ugotovili, da po laparoskopskih resekcijah debelega črevesa ni več lokalnih ponovitev bolezni kot po odprtih operacijah. Prav tako ni razlike v 5-letnem preživetju. Ti podatki kažejo, da je laparoskopski poseg enakovreden odprtemu in je onkološko varen (17). Te rezultate so potrdili tudi tudi v študijah COLOR in CLASICC. Braga je s sodelavci primerjal laparoskopske in odprte resekcije zaradi raka leve strani debelega črevesa. V analizi je zajel skupino 268 bolnikov. Povprečen čas opazovanja je bil 73 mesecev. 5-letno preživetje in prosti interval sta bila podobna v obeh skupinah. Ni bilo razlike v pojavljanju oddaljenih metastaz in metastaz na mestu troakarjev. V tej študiji niso našli razlike med pojavom incizijskih kil, zaporo črevesa in stenozo anastomoz med obema skupinama (12). Nekatere študije kažejo boljšo kvaliteto življenja po laparoskopskih resekcijah raka debelega črevesa do enega leta, kasneje se ti učinki izenačijo z odprtimi operacijami (22, 23). V drugi randomizirani študiji Lacyja in sodelavcev, v kateri je bil mediani čas opazovanja 95 mesecev, je bilo preživetje bolnikov po laparoskopskih operacijah statistično značilno daljše kot po odprtih operacijah. To se je pokazalo predvsem pri bolnikih z rakom debelega črevesa v stadiju III (18). Dosedanje študije so obravnavale bolnike z lokalno omejenim rakom debelega črevesa. Z napredkom tehnologije, izkušnjami pa raziskujejo tudi vlogo laparoskopskih resekcij pri napredovalih rakih debelega črevesa (19). Vpliv na imunski odgovor organizma Zaradi manjše poškodbe tkiv pri laparoskopskih operacijah naj bi se sproščalo manj citokinov. Posledično naj bi bil zmanjšan imunski odgovor organizma. Vrednosti interlevkina-6 in endotelijskega rastnega faktorja so po laparoskopskih posegih nižje kot po odprtih operacijah. V randomizirani študiji v Singapurju niso opazili razlike v imunskem odgovoru med laparoskopskimi in odprtimi operacijami (20). Verjetno so še drugi mehanizmi, ki vplivajo na imunološki odgovor in posledično boljše preživetje po laparoskopskih posegih (21). 32 GASTROENTEROLOG RAK DANKE Kirurško zdravljenje raka danke se razlikuje od zdravljenja raka debelega črevesa. Če hočemo doseči malo ponovitev bolezni in dober onkološki rezultat moramo narediti totalno mezorektalno ekscizijo (TME) z negativnim radiarnim robom. Pri operaciji moramo tudi paziti na avtonomne živce za ohranitev funkcije sečnega mehurja in seksualne funkcije. Prospektivni podatki iz randomiziranih študij ekspertnih centrov potrjujejo, da so laparoskopske resekcije zaradi raka danke izvedljive. Na voljo so predvsem zgodnji rezultati teh posegov (24,25). Laparoskopija s povečavo slike omogoča boljši pregled struktur male medenice kot ga imamo pri odprti operaciji (24, 26,27). Zgodnji rezultati Po podatkih iz literature ima laparoskopski pristop prednost pred odprtimi operacijami raka danke. Aziz in sodelavci so v meta-analizi ugotovili, da bolniki po laparoskopski operaciji hitreje okrevajo, preidejo na normalno dieto in so manj časa hospitalizirani kot bolniki po odprti operaciji. Manjša je izguba krvi med operacijo, operacijski čas pa je daljši kot pri odprtih operacijah (28). Po laparoskopskih posegih je manj vnetij v rani in manj pljučnih zapletov (29). Objavljene so tudi študije, v katerih avtorji niso ugotovilli prednosti laparoskopske pred odprto operacijo v obolevnosti in zgodnji smrtnosti (30, 31). Po laparoskopskih resekcijah je več dehiscenc anastomoz, kot po odprti operacijah. Prekinitev rektuma z endoskopskim spenjalnikom je pri nizkih tumorjih v ozki medenici težavna. Tudi uporaba več polnil za prekinitev danke poveča tveganje za nastanek dehiscence anastomoze. Neodvisni dejavniki za nastanek dehiscence anastomoze so nizko ležeč tumor v danki, TME in moški spol (24). Merila za onkološko kvaliteto laparoskopske resekcije raka danke so: kvaliteta kirurške resekcije, lokalna ponovitev bolezni in dolgoročno preživetje bolnikov. Najpomembnejša parametra sta distalni in cirkumferencialni resekcijski rob in število odstranjenih bezgav. Večina študij ne poroča o značilni razliki med številom odstranjenih bezgavk in distalnem resekcijskem robu med laparoskopskim in odprtim posegom (29, 30). Podatki CLASICC študije pa poročajo o večjem odstotku pozitivnih cirkumferencialnih robov pri laparoskopskih posegih (12 proti 6 % pri odprtih) (7). Pozni rezultati Lokalna ponovitev bolezni odraža adekvatnost TME in nizke resekcije danke. V študijah Laurenta, Lawa in Morina je bilo 5-letno preživetje po laparoskopskih resekcijah daljše kot po odprtih operacijah in majhen odstotek lokalnih ponovitev bolezni (25, 26, 27). Funkcionalni rezultati Motnje seksualne funkcije in delovanja mehurja so pogoste po operacijah raka danke. Kljub upoštevanju načel TME in ohranitvi živcev zaradi boljše vidljivosti pri laparoskopiji so mnenja nasprotujoča. Quah in sodelavci poročajo o oslabljeni seksualni funkciji po laparoskopskih resekciajh v primerjavi z odprto operacijo (32). V korejski študiji so opazovali težave z mikcijo, ki so po treh mesecih izzvenele (33). Ovire pri uvajanju laparoskopske kolorektalne kirurgije Laparoskopska kirurgija v začetnem obdobju ni bila primerna za starejše bolnike s pridruženimi boleznimi zaradi daljšega operacijskega časa in pnevmoperitoneja. Kasneje so se pokazale prednosti laparoskopije zaradi hitrejšega okrevanja, manj zapletov s strani srca in pljuč in nižjo smrtnostjo (34). Ovira za uvajanje laparoskopije je tudi daljša učna krivulja. Število 30 operacij, ki naj bi jih kirurg izvedel ob asistenci izkušenega kirurga je manjših ustanovah težko dosegljivo. Druge ovire so še daljši operacijski čas, višja cena laparoskopske operacije zaradi opreme in inštrumentov, ki pa se kompenzirajo s krajšo hospitalizacijo in manj zapleti po operaciji. V Veliki Britaniji so leta 2007 pričeli z Nacionalnim trening programom laparoskopske kirurgije. Odstotek laparoskopskih posegov je porastel s 5 % v letu 2005 na 23 % v letu 2009. V ZDA je ta odstotek narastel v letu 2009 na 45 % (35, 36) Nove tehnologije V zadnjih petih letih so se uveljavile resekcije raka debelega črevesa in danke skozi eno incizijo (singleincision laparoscopic surgery, SILS). Pri tej metodi se uvede troakar skozi popek. V troakarju so tri do štiri vstopna mesta za inštrumente. Huscher in sodelavci niso opazovali razlike med standardno laparoskopijo in SILS tehniko po resekcijah raka debelega črevesa in danke (37). Kirurgija s pomočjo robota (da Vinci surgical system, Intuitive Surgical, Sunnivale, CA, USA) se je uveljavila pri radikalni prostatektomiji. Robot se je uveljavil v kirurgiji raka danke. Prednosti robota pred standardnim laparoskopskim pristopom so v tridimenzionalnem vidu, bolj gibljivih inštrumentih in odsotnosti tremorja. V manjših serijah so potrdili prednost uporabe robota pred standardno laparoskopijo (38). ZAKLJUČEK Laparoskopska kirurgija raka debelega črevesa in danke je naredila v zadnjih dveh desetletjih velik napredek. Izboljšani zgodnji rezultati in dobri pozni rezultati so pokazali, da je laparoskopska resekcija dobra metoda zdravljenja raka debelega črevesa. Laparoskopska resekcija raka danke je metoda, ki daje v specializiranih centrih dobre rezultate. 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Laurent C, Leblanc F, Wu¨ trich P et al. Laparoscopic versus open surgery for rectal cancer: long-term oncologic results. Ann Surg 2009;250:54–61. 28. Aziz O, Constantinides V, Tekkis PP et al. Laparoscopic versus open surgery for rectal cancer: a meta-analysis. Ann Surg Oncol 2006;13:413–24. 29. Kang SB, Park JW, Jeong SY et al. Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an open-label randomised controlled trial. Lancet Oncol 2010;11:637–45. 30. Baik SH, Gincherman M, Mutch MG et al. Laparoscopic vs open resection for patients with rectal cancer: comparison of perioperative outcomes and long-term survival. Dis Colon Rectum 2011;54:6–14. 31. Lujan J, Valero G, Hernandez Q et al. Randomized clinical trial comparing laparoscopic and open surgery in patients with rectal cancer. Br J Surg 2009;96:982–9. 32. Quah HM, Jayne DG, Eu KW, et al. Bladder and sexual dysfunction following laparoscopically assisted and conventional open mesorectal resection for cancer. Br J Surg 2002;89:1551–6. 33. Kang SB, Park JW, Jeong SY, et al Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): short-term outcomes of an open-label randomised controlled trial.Lancet Oncol 2010;11:637–45. 34. Tan WS, Chew MH, Lim IAL et al. Evaluation of laparoscopic versus open colorectal surgery in elderly patients more than 70 years old: an evaluation of 727 patients. Int J Colorectal Dis 2012;27:773–80. 35. Lapco Newsletter Summer, 2010. http://www.lapco.nhs.uk/userfiles/file/Lapco%20Newsletter %202010.pdf. Published 2010. 36. Rea JD, Cone MM, Diggs BS et al. Utilization of laparoscopic colectomy in the United States before and after the Clinical Outcomes of Surgical Therapy study group trial. Ann Surg 2011;254:281–8. 37. Huscher CG, Mingoli A, Sgarzini G et al. Standard laparoscopic versus single-incision laparoscopic colectomy for cancer: early results of a randomized prospective study. Am J Surg 2012;204:115–20. 38. Lin S, Jiang HG, Chen ZH et al. Meta-analysis of robotic and laparoscopic surgery for treatment of rectal cancer. World J Gastroenterol 2011;17:5214–20 Benigni in maligni tumorji pri 700 zaporednih apendektomijah Benign and malignant tumors in 700 consecutive appendectomies Jera Jeruc* Inštitut za patologijo, Medicinska fakulteta, Univerza v Ljubljani Gastroenterolog 2013; suplement 2: 35–38 Ključne besede: slepič, appendicitis, tumor slepiča, nevroendookrini tumor, mucinozna neoplazma, GIST Key words: appendix, appendicitis, appendiceal neoplasm, neuroendocrine tumour, mucinous tumour, GIST POVZETEK ABSTRACT Vnetje slepiča (apendicitis) je najpogostejše akutno trebušno vnetje, ki potrebuje kirurško zdravljenje. Histološki pregled odstranjenega slepiča običajno potrdi klinični sum na akutno vnetno dogajanje, včasih pa pokaže tudi druge pomembne diagnoze. Namen raziskave je bil ugotoviti pojavnost in histološke značilnosti tumorjev slepiča v naši populaciji. V raziskavo smo vključili 728 slepičev, ki smo jih v obdobju sedmih let pregledali v naši ustanovi. Appendicitis is one of the most common abdominal inflammatory conditions requiring surgical intervention. Histology usually confirms the clinical suspicion of acute inflammation, but sometimes other clinically relevant diagnoses are made. The aim of our study was to analyse the appendectomies at our institution and to determine incidence and histological spectrum of appendiceal tumours in our population. We reviewed the histopathology results of 728 consecutive appendectomies received in a 7-year period. Primarni tumor smo ugotovili v 30 (4,1 %) primerih, kar je nekoliko večja pojavnost kot je opisano v literaturi. Med njimi je bilo osem nevroendokrinih tumorjev, pet klasičnih adenomov, 11 primerov mucinozne neoplazme nizke stopnje malignosti (v enem primeru v povezavi z psevdomiksomom peritoneja) in trije primeri karcinoma (po en mucinozni, intestinalni in nediferencirani). V enem primeru smo postavili tudi diagnozo multicističnega mezotelioma ter v slepiču redkega gastrointestinlnega stromalnega tumorja. Pri večini primerov je bila napotna diagnoza akutni apendicitis, le pri sedmih, pretežno velikih tumorjih je sum na tumorsko rast postavil že kirurg. Appendiceal tumours were found in 30 cases (4.1%), which is a higher rate than reported in the literature. There were eight endocrine tumours, all G1, five cases of classical adenomas, 11 cases of low-grade appendiceal mucinous neoplasms (one associated with pseudomyxoma peritonei) and three cases of carcinoma (one mucinous adenocarcinoma, one intestinal type, one undifferentiated carcinoma). We also diagnosed one case of multicystic mesothelioma and one gastrointestinal stromal tumour. Most patients presented with acute appendicitis, only in seven patients, mainly large tumours, the diagnosis was suspected already by surgeon. *Doc. dr. Jera Jeruc, dr. med. Inštitut za patologijo, Medicinska fakulteta, Univerza v Ljubljani, Korytkova 2, 1000 Ljubljana, Slovenija GASTROENTEROLOG 35 Histološki pregled odstranjenega slepiča je potrebno opraviti vedno, saj tudi v klinično nesumljivih primerih lahko odkrije številne klinično pomembne bolezni ter celo tumorje. Histopathological examination of appendectomy specimens may reveal many different conditions not previously suspected; therefore, it should be performed in all cases. Introduction Results Appendicitis is one of the most common abdominal conditions demanding surgical intervention. It affects about 10% of population and is thought to be initiated by progressive increases in intraluminal pressure that compromises venous outflow. In 50% to 80% of cases, acute appendicitis is associated with overt luminal obstruction, usually by lymphoid hyperplasia or fecalith (1). Less commonly, symptoms and signs result from other causes such as inflammation in the setting of Crohn’s disease, endometriosis or even tumour. Primary appendiceal tumours are rare neoplasms accounting for 0.2–0.5 of all gastrointestinal tumours and < 2% of all appendectomies (1–7). Neoplastic processes in the appendix are histologically similar to their colonic counterparts. However, especially regarding epithelial neoplasm, the terminology is not standardised among pathologist and reading pathology reports can be a challenging task for the clinical doctors. During the study period, 728 patients had an appendectomy for appendiceal pathology. Appendiceal neoplasm was diagnosed in 31 patients (4.3%). The largest single group of tumours were low grade appendiceal mucinous neoplasms (LAMN) comprising 35.5% of all tumours (Fig. 1A and 1B), followed by neuroendocrine tumours (25.8%) (Fig. 2). The incidence of different histological entities is presented in Table 1. The aim of our study was to determine the incidence and histological spectrum of appendiceal tumours in our population. Most of the patients presented with acute appendicitis with or without abscess formation, some with chronic appendicitis. Only occasionally tumour was Tabela 1. Histološke diagnoze tumorjev slepiča pri 728 zaporednih apendektomijah Table 1. Histological diagnoses of the appendiceal tumours in 728 consecutive appendectomies Type of tumour No. of cases (%) Adenoma 5 (0.7%) Low-grade appendiceal mucinous neoplasm (LAMN) 11 (1.5%) 1 associated with pseudomyxoma peritonei Adenocarcinoma 3 (0.4%) 1 intestinal type 1 mucinous 1 undifferentiated Neuroendocrine tumour 8 (1.1%) all G1 according to WHO 2 with lymph node metastasis GIST 1 (0.1%) Multicystic mesothelioma 1 (0.1%) Folicular lymphoma 1 (0.1%) Metastasis (urothelial carcinoma) 1 (0.1%) Total 31 (4.2%) Materials and methods The study included all appendices received for histological evaluation at the Institute of Pathology of the Medical Faculty at the University of Ljubljana in a seven year period. Appendectomies performed as an incidental procedure during some other operation were excluded. The histology of the appendiceal tumours was evaluated again by experienced pathologists. Demographical data were collected from the patients’ charts. 36 GASTROENTEROLOG Figure 2. Neuroendocrine tumour of the appendix with a characteristic yellow colour. 0.35 to 3.5 cm (mean 1.42 cm), in five patients tumour was less than 1 cm in greatest diameter. In two cases, metastases in lymph nodes were detected. Figure1. Low-grade appendiceal mucinous neoplasm (LAMN). Abundant mucin causing appendiceal distention (A). The mean age of patients with colonic-type adenoma was 59.2 years. There were three tubular adenomas and, one villous and tubulo-villous adenoma each. None of them was associated with mucocele and none of the patients had familial adenomatous polyposis. Among 11 patients with LAMN there were six women and five men, mean age of 58.4 years. In six cases herniation of mucin with or without neoplastic epithelium into the muscularis propria was present, and one of them was associated with pseudomyxoma peritonei. Figure1. Histology shows filiform villi lined by tall mucinous epithelium displaying low-grade cytologic atypia (B). suspected already by surgeon: in one of eight neuroendocrine tumours (the largest one), two out of 11 LAMNs and in two out of three carcinomas. In this series, the mean age of patients with neuroendocrine tumours was 35.4 years with a male-tofemale ratio 1:7. The size of tumours ranged from GIST measuring 1.0 cm was diagnosed in a 11-year-old girl, multicystic mesothelioma was found in a 20-year-old male with clinical signs of acute appendicitis, but without histological signs of inflammation in the appendix. Discussion Primary appendiceal neoplasms are uncommon, being found in approximately 0.5%–1.0% of appendectomy specimens at pathologic evaluation (1–3). In this study the incidence of primary appendiceal tumours was 4.3%. This rate is higher compared to GASTROENTEROLOG 37 most similar studies (2–3, 7–8). Most of previous studies did not include benign and rare types of primary appendiceal tumours such as classical (colonic type) adenomas, lymphomas and tumours of mesothelial origin neither did they include metastatic processes. The number of examined appendices in our study increased from 37 in the first year of the study to 266 in the last year. Since the population covered by out pathology department remained the same during that period we believe that, in the past, not all appendices were sent for the histological evaluation, making the calculated incidence higher. Although the incidence of appendiceal tumours in our study was higher, the distribution of histological entities was similar to previous studies with LAMNs being the most frequent and accounting for more than one third of cases, followed by neuroendocrine tumours representing about one quarter of appendiceal neoplasms (7). On the other hand, according to some authors. neuroendocrine tumours are the most common neoplasms of appendix (9–10). Interestingly, we have not diagnosed a single case of goblet cell carcinoid although we have encountered a few cases in the past. Neuroendocrine tumours tend to be diagnosed at an earlier age than other neoplasms and women predominate (1, 10–11), as was the case in our series. Appendiceal neoplasm is typically associated with acute appendicitis and the diagnosis of tumour is usually difficult to make preoperatively. In our series, a diagnosis was suspected prior to histology report only in a few patients, all of them had large tumours or tumours associated with mucocele. On the other hand, benign processes associated with mucocele can sometimes be misinterpreted as tumours by surgeon. One of three patients with appendiceal carcinoma (undifferentiated carcinoma) also had a moderately differentiated adenocarcinoma of the sigmoid colon. A higher rate of associated cancer in patients with appendiceal neoplasm, especially of synchronous colon carcinoma has previously been reported (6). 38 GASTROENTEROLOG Gastrointestinal stromal tumors (GIST) are rare in the vermiform appendix. Less than 10 cases have been reported so far, all in patients over 50 years of age (12). Interestingly, our patient with appendiceal GIST was an 11-year-old girl. In conclusion, appendiceal neoplasm is a rare gastrointestinal malignancy. Most of them are diagnosed only after histological examination of the resected specimen. Therefore the histological examination of the resected appendix is necessary for establishing the correct diagnosis and can influence further clinical decisions. Especially with appendiceal mucinous neoplasm it is important to remove appendix intact, trying to avoid trauma and possible rupture of the appendix, as this can affect long term outcome. REFERENCES 1. Deans GT, Spence RA. Neoplastic lesions of the appendix. Br J Surg 1995; 82(3): 299–306. 2. Hananel N, Powsner E, Wolloch Y. Adenocarcinoma of the appendix: an unusual disease. Eur J Surg 1998; 164 (11): 859–62. 3. Connor SJ, Hanna GB, Frizelle FA. Appendiceal tumors: retrospective clinicopathologic analysis of appendiceal tumors from 7,970 appendectomies. Dis Colon Rectum 1998; 41(1): 75–80. 4. Lyss AP. Appendiceal malignancies. Semin Oncol 1988; 15(2): 129–37. 5. Machado NO, Chopra P, Pande G. Appendiceal tumour--retrospective clinicopathological analysis. Trop Gastroenterol 2004; 25(1): 36–9. 6. Bucher P, Mathe Z, Demirag A, Morel P. Appendix tumors in the era of laparoscopic appendectomy. Surg Endosc 2004; 18(7): 1063–6. 7. Lee WS, Choi ST, Lee JN, Kim KK, Park YH, Baek JH. A retrospective clinicopathological analysis of appendiceal tumors from 3,744 appendectomies: a single-institution study. Int J Colorectal Dis 2011; 26(5): 617–21. 8. O'Donnell ME, Badger SA, Beattie GC, Carson J, Garstin WI. Malignant neoplasms of the appendix. Int J Colorectal Dis 2007; 22(10): 1239–48. 9. Deschamps L, Couvelard A. Endocrine tumors of the appendix: a pathologic review. Arch Pathol Lab Med 2010; 134(6): 871–5. 10. Lamm-Himmlin D. Montgomery EA. The neoplastic appendix: a practical approach. Diagnostic Histopathology 2011; 17(9): 395–403. 11. Carr NJ, Sobin LH. Neuroendocrine tumors of the appendix. Semin Diagn Pathol 2004; 21(2): 108–19. 12. Agaimy A, Pelz AF, Wieacker P, Roessner A, Wünsch PH, Schneider-Stock R. Gastrointestinal stromal tumors of the vermiform appendix: clinicopathologic, immunohistochemical, and molecular study of 2 cases with literature review. Hum Pathol 2008; 39(8): 1252–7. Kako operirati rak želodca pri starostniku? How to operate gastric cancer in elderly patients Matjaž Horvat*, A. Ivanecz, T. Jagrič, S. Potrč Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika Univerzitetni klinični center Maribor Gastroenterolog 2013; suplement 2: 39–43 Ključne besede: rak želodca, kirurgija, starostniki Keywords: gastric cancer, surgery, elderly POVZETEK ABSTRACT Analizirali smo podatkovno bazo 20 letnega obdobja zdravljenja raka na našem oddelku in primerjali starostnike in mlajše bolnike. Retrospective analysis of gastric cancer surgical treatment data in our clinical department in 20-year period was performed and treatment outcome was compared between younger and older patients. Bolniki in metode. Pri 847 bolnikih smo od 1992 do 2012 napravili R0 resekcijo zaradi raka želodca. Bolnike smo razdelili v skupino mlajših od 70 let in skupino starejših. Primerjali smo predoperativno zdravje in pridruženo obolevnost bolnikov, karakteristike tumorja, vrsto resekcije, rekonstrukcijo, število in vrsto pooperativnih kirurških in splošnih zapletov ter preživetje. Rezultati. Starostniki so imeli slabše zdravje in več pridruženih obolenj (p<0,05). Najpogostejša pridružena obolenja so bila srčno pljučna, ki jim sledijo izolirane srčne bolezni in sladkorna bolezen. Pri podobnih karakteristikah tumorjev in stadijih, smo pri starostnikih opravili manj totalnih gastrektomij, manj ekstenzivnih limfadenekomij in splenektomij (p=0,001, p<0,05, p<0,05). Med skupinama ni bilo razlik v kirurških zapletih (p=0,563), bilo pa je več splošnih pooperativnih zapletov pri starostnikih (p<0,05). Pri skupini starostnikov je bila tudi večja Patients and methods. In the period between 1992 and 2012, 847 R0 gastric cancer resections were performed. Preoperative treatment, comorbidities, tumor characteristics, resection and reconstruction type, surgical complications and survival were compared between patients bellow and above the age of 70 years. Results. Comorbidities (p<0.05) were more frequent in older patients. Tumor characteristics did not differ among groups, however less total gastrectomies, less extensive lymphadenectomies and less splenectomies were performed in older patients (p=0,001, p<0,05, p<0,05). The frequency of surgical complications did not differ among groups (p=0,563), however general complications were more common in older patients (p<0,05), with higher 30 and 60 day mortality (p<0,05) and shorter survival (p<0,05). * Doc. dr. Matjaž Horvat dr. med. Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika, Univerzitetni klinični center Maribor, Ljubljanska 5, 2000 Maribor GASTROENTEROLOG 39 pooperativna 30- in 60-dnevna umrljivost (p<0,05) in krajše preživetje (p<0,05). Zaključki. Operativno zdravljenje starostnikov z < pooperativne obolevnosti in smrtnosti. Onkološki principi, ob manjši operativni invazivnosti, ki je v składu z biološko starostjo, niso ogroženi. UVOD Letna incidenca raka želodca je po podatkih Registra za rak Republike Slovenije iz leta 2006 pri moških 27,18/100.000 in 15,55/100.000 pri ženskah. Bolezen se začne pogosteje pojavljati po 40. letu in doseže vrh med 60. in 80. letom življenja (1). Po nekaterih podatkih naj bi bilo kar 30 % bolnikov z rakom želodca starejših kot 70 let (2). Različne prospektivne in retrospektivne študije so pokazale večjo obolevnost in smrtnost pri starostnikih v primerjavi totalnih in subtotalnih gastrektomij, in limfadenektomijami D2 v primerjavi z limfadenektomijami D1 (3–6). Postavlja se ključno vprašanje, kako s predoperativno oceno tveganja izbrati kandidate za manj ekstenzivno kirurško zdravljenje in s tem znižati pooperativno obolevnost in smrtnost. Pomembno je tudi oceniti, ali manj ekstenzivno kirurško zdravljenje pomeni še spremenljivo krajše preživetje starostnikov z rakom želodca (7). Namen naše študije je bil primerjati lastne rezultate zdravljenja raka želodca pri bolnikih mlajših in starejših od 70 let in vrednotiti njihov izhod zdravljenja. BOLNIKI IN METODE Iz prospektivne 20 letne (1992-2012) podatkovne baze bolnikov, operiranih na Oddelku za abdominalno in splošno kirurgijo UKC Maribor zaradi raka želodca, smo opravili analizo podatkov starostnikov (70 in več let) v primerjavi z ostalimi bolniki pri katerih je bila napravljena R0 resekcija želodca. Zanimala nas je predvsem predoperativna ocena zdravja in število pridruženih obolenj po ASA (klasifikacija po American Society of Anesthesiologists), kot tudi vrsta 40 GASTROENTEROLOG Conclusions. Surgical treatment of gastric cancer is beneficial to older patients and complications and procedure-related morbidity and mortality is within expected limits. Reduced surgical invasiveness due to limits steming form patients biological age is still fully compatible with expected oncological principles and standards. pridruženih obolenj in laboratorijski pokazatelji. Pomemben se nam je zdel tudi obseg resekcije, ki sta jo pogojevala velikost in lokacija tumorja in histološka klasifikacija po Laurenu, ter njegova patološka diferenciacija. Nadalje smo med skupinama primerjali stopnjo limfadenektomije in število splenektomij. Uspeh zdravljenja smo vrednotili s pomočjo pooperativnih zapletov, dolžino ležalne dobe in časom do eventuelne ponovitve bolezni na podlagi rednega sledenja ter TNM klasifikacije. Primerjavo preživetja smo izračunali s pomočjo podatkov iz Registra za rak Republike Slovenije. Podatke smo statistično obdelali s pomočjo programa SPSS 20.0 in pri tem uporabili teste za parametrične in neparametrične spremenljivke. Pri računanju preživetja smo uporabili KaplanMeierjevo metodo. Vrednost P < 0,05 smo smatrali kot statistično pomembno. REZULTATI Na Oddelku za abdominalno kirurgijo UKC Maribor smo v 20 letih (1992 – 2012) operirali 847 bolnikov z rakom želodca, pri katerih je bila po patohistološkem pregledu narejena R0 resekcija. Moških je bilo 533 (62,9 %), žensk pa 314 (37,1 %). Razpon starosti vseh bolnikov je od 19 do 92 let s povprečno starostjo 64,7let. Prikaz porazdelitve bolnikov po starosti prikazuje tabela 1. Bolnikov starejših od 70 let je bilo 300 (35,4 %), 70 ali mlajših pa 547 (64,6 %). Tako v skupini mlajših bolnikov, kot starostnikov je bilo moških več kot žensk. V skupini mlajših bolnikov je odstotek žensk znašal 35,27 in v skupini starostnikov pa 40,12 kar je bilo statistično pomembno (p=0,017). Tabela 1.: bolniki z rakom želodca glede na starost Pri obeh skupinah je imelo največ bolnikov predoperativno oceno ASA 2 (skupina mlajših 53,38 % in skupina starejših 53,66 %). Občutne razlike pa obstajajo pri ASA1, kjer je v skupini mlajših 42,96 % bolnikov in pri starostnikih le 6,66 %, kot tudi pri ASA 3, kjer je stanje obratno. Le majhen delež mlajših bolnikov je imelo preoperativno oceno ASA 3 (3,65 %) in občutno večji delež pri starostnikih (42,96 %). Razlike so statistično pomembne (p<0,05). Razlike obstajajo tudi pri pridruženih obolenjih, oziroma njihovem številu. Pri skupini mlajših bolnikov ni imelo pridruženega obolenja kar 44 % bolnikov, eno ali dve pridruženi obolenji pa 26 % oziroma 27 % bolnikov. Samo 1,4 % bolnikov v mlajši skupini je imelo 3 ali več pridruženih obolenj. Slika je obratna pri starostnikih. Z enim ali dvema pridruženima obolenjema najdemo 79,98 % bolnikov, samo 15,33 % bolnikov ni imelo nobenega pridruženega obolenja in 4,66 % je imelo tri ali več pridruženih obolenj, kar je statistično pomembno (p<0,05). Med pridruženimi obolenji je najpogostejša kombinacija bolezni srca in pljuč, pri mlajših v 40 % in pri starejših v 36 %. Na drugem mestu po pogostnosti pridruženih obolenj so bolezni srca v obeh skupinah (mlajši 24 %, starejši 27 %). Manifesten diabetes je bil pri mlajših prisoten pri 8,1 % in starejših pri 10,6 % bolnikov. Ostale kombinacije pridruženih obolenj, kot so obolenja CŽS in jeter ter druge bolezni so bile redkeje zastopane. Predoperativna primerjava laboratorijskih vrednosti krvi ni pokazala pomembnejših odstopanj med skupinama. Razlika se je pokazala pri predoperativnih vrednostih hemoglobina in celokupnih proteinov. Ti so bili nižji v skupini starostnikov (hemoglobin povprečno 115 g/L, proteini 66,33 g/L), za razliko od mlajših bolnikov (hemoglobin povprečno 124,1 g/L, proteini 69,25 g/L), kar je statistično pomembno (p<0,05, p<0,05). Med skupinami ni bilo pomembnejših razlik v vrednostih tumorskih označevalcev karcino embrionalnega antigena (CEA) in tumorskega označevalca CA 19-9 pred operacijo (p=0,986, p=0,209). Čeprav je največ tumorjev v obeh skupina lokalizirano v distalni in srednji tretjini želodca in je število tumorjev v proksimalni tretjini želodca večje pri mlajši skupini bolnikov (19 % mlajši, 16 % starejši), vendar razlika ni statistično pomembna (p=0,304). Pravtako med skupinama ni statistično pomembne razlike v patohistološki diferenciaciji tumorjev in velikosti tumorja(p=0,052, p=0,781). Obstaja pa statistično pomembna razlika pri histološki diferenciaciji po Laurenu, predvsem na račun večjega števila intestinalnega tipa pri starostnikih (p=0,033). Predoperativni slikovni preiskavi za oceno stadija bolezni (EUZ, CT), ki sta danes obvezen del algoritma preiskav pred operacijo in osnova za potencialno uvedbo neoadjuvantne terapije zaradi širokega časovnega razpona opazovanih bolnikov nista bili izvedeni pri 59 % bolnikov v mlajši skupini in v 63,9 % pri starostnikih. Zadnjih nekaj let pa ta obvezna diagnostika pred operacijo ne pokaže statistično pomembnih razlik v oceni cTNM klasifikacije. Najpogostejši predoperativni stadij v obeh skupinah je cT3cN+ (mlajši bolniki 35 %, starejši bolniki 34,2 %), ostali stadiji med skupinami so primerljivi in se statistično pomembno ne razlikujejo (p=0,886). Obstajajo pomembne razlike med skupinama glede vrste gastrektomije, predvsem na račun večjega deleža subtotalnih gastrektomij pri starostnikih (39,3 %) napram mlajšim bolnikom (28,7 %), manjšega števila totalnih gastrektomij z distalnimi resekcijami požiralnika (starejši bolniki 3,9 %, GASTROENTEROLOG 41 mlajši bolniki 6,3 %) in resekcij krna želodca (starejši bolniki 1,9 %, mlajši bolniki 3,6 %). Klinastih resekcij pri starejših bolnikih je bilo 1 %, pri mlajših bolnikih pa bistveno manj 0,18 %. Pri starejši skupini je bilo opravljenih tudi več proksimalnih resekcij želodca (5 %) kot pri mlajši skupini (1,8 %). Razlike so statistično pomembne (p=0,001). Povprečna hospitalizacija je pri mlajših bolnikih 15,2 dneva in pri starostnikih 15,5 dneva (p=0,693). Vrstam gastrektomije sledijo tudi načini rekonstrucij. Pri starejših je več rekonstrukcij po tipu Bilroth 2 z omega tanko črevesno vijugo in interponatov, pri mlajših pa prednjačijo Roux en Y ezofagojejuno anastomozo, kar je statistično pomembno (p<0,05). Celokupno preživetje je boljše pri skupini mlajših bolnikov in mediana vrednost znaša 1603 dneva, pri starostnikih pa je mediana vrednost 1107 dni (p<0,05). Graf 1. Perioperativna 30- in 60-dnevna smrtnost je večja pri starostnikih (8,9 % in 10,3 %), za razliko od mlajših bolnikov (2,5 % in 3,8 %), kar je statistično pomembno (p<0,05). Intenzivnost limfadenektomije je večja pri mlajši skupini bolnikov večja. Pri 16 % bolnikov v mlajši skupini je bila narejena samo limfadenektomija D1 za razliko od starostnikov, kjer je samo D1 limfadenektomija narejena v 29 %. Ekstenzivnejša limfadenektomija D3 je pri mlajših bolnikih narejena v 24 % in pri starejših v 13,5 %. Gre za statistično pomembne razlike (p<0,05). Splenektomija je bila sestavni del operativnega posega pri mlajših bolnikih v 38 %, pri skupini starejših bolnikov pa v25,1 %, kar je statistično pomembno (p<0,05). Ocena kirurških zapletov pokaže primerljivost obeh skupin (mlajši 13,3 %, starejši 12,3 %, kar je statistično nepomembno (p=0,387). Največji odstotek kirurških zapletov predstavljajo abscesi in krvavitve v obeh skupinah, pri skupini mlajših bolnikov pa še pankreatits in holecistitis. Med vrstami kirurških poopertivnih zapletov med skupinama ni statistično pomembnih razlik (p=0,563). Obstaja pa statistično pomembna razlika splošnih komplikacij med skupinama na račun večjega števila splošnih zapletov pri starostnikih (starostniki 18,6 %, mlajši 10,4 %) (p=0,001). Med skupinama se razlikujejo tudi vrste splošnih zapletov, kjer pri starostnikih prednjačijo febrilna stanja, srčna popuščanja in odpovedi in respiratorni distres, pri mlajših bolnikih pa predvsem respiratorni distres, srčno popuščanje in febrilna stanja (p=0,023). 42 GASTROENTEROLOG Graf 1: prikaz preživetje med skupino starostnikov in mlajših bolnikov z rakom želodca (R0 resekcija) RAZPRAVA V skupini starostnikov najdemo skoraj 80 % bolnikov z enim ali večimi pridruženimi obolenji; več kot 90 % bolnikov smo uvrstili v skupini ASA 2 in ASA 3. Ob tem ugotavljamo, da so tako lokalizacija tumorja glede na tretjine želodca, njegova velikost, patohistološka diferenciacija in predoperativni stadij primerljivi med obema skupinama. Pri skupini starejših bolnikov smo opravili manjše število totalnih gastrektomij na račun večjega števila subtotalnih gatrektomij in bili manj agresivni pri limfadenektomijah in splenektomijah. Podobne številke in rezultate navajajo v študijah tudi drugi avtorji, ob primerljivih karakteristikah tumorjev med skupino starostnikov in mlajših bolnikov z rakom želodca (8–11). Primerjava pooperativne obolevnosti pokaže nekatere značilnosti predvsem pri primerjavi zapletov povezanih s kirurškim posegom. V naši študiji smo imeli primerljivo pooperativno kirurško obolevnost med skupinama in relativno majhno število zapletov puščanj anastomoz. Najpogostejši kirurški zaplet v naši študiji predstavljajo abscesi in krvavitve, ki jim sledijo pankreatitisi in holecistitisi. Vrste zapletov med skupinama so statistično primerljive. Do drugačnih rezultatov pa je prišel Gretschel v svoji študiji ugotavlja, da je bilo pri skupini starejših bolnikov pomembno več kirurških zapletov. Najpogostejši zaplet predstavljajo puščanja anastomoz, v določenem starostnem intervalu tudi do 9 % (15 bolnikov od 167 v starostnem intervalu od 60 do 75 let) kar sicer ni bilo statistično pomembno. Na drugem in tretjem mestu števila kirurških zapletov so pankreatitisi in pankreatične fistule. Vrste kirurških zapletov v posameznih skupinah so med seboj primerljive (12). Razlago razlik med študijami bi lahko razložili z relativno manjšo skupino bolnikov z R0 resekcijami (363 bolnikov) vključenih v študijo iz Berlina, ki so bili razdeljeni v tri starostna obdobja. Relativno redek zaplet puščanja anastomoz v naši študiji si razlagamo z ozkim krogom kirurgov v naši ustanovi, ki se ukvarja s patologijo raka želodca. Glede nekirurške pooperativne obolevnosti pa tako v naši študiji kot v študijah ostalih avtorjev po številu zapletov prednjačijo starostniki (5, 7, 8, 12). Primerjava vzrokov nekirurških pooperativnih zapletov naše študije z berlinsko pokaže podobnosti v smislu najpogostejših vzrokov, kot so febrilna stanja z respiratornimi distresi in srčnimi zapleti. V obeh študijah so bili tako število in vzroki statistično pomembni v primerjavi med skupinami (12). Več nekirurške pooperativne obolevnosti pri starostnikih je lahko tudi razlog večjo 30- in 60-dnevno pooperativno umrljivost. Podobne podatke navajajo tudi drugi avtorji (8, 10, 11, 12). Čeprav je preživetje skupine starostnikov v naši študiji pomembno krajše, pa le to ni povezano samo z rakom želodca. Pričakovana življenska doba starostnikov je krajša in biologija tumorja pri starostniku drugačna, s počasnejšo rastjo, kar ima lahko za posledico manjši delež s tumorjem povezane umrljivosti (13). V naši študiji smo imeli v skupini starostnikov pomembneje več intestinalnega tipa raka želodca po Laurenu. Zaključimo lahko da je operativno zdravljenje starostnika z rakom želodca ob primerni pripravi in izbiri bolnika smiselno. Starejši bolniki s prikrojenimi kirurškim posegom imajo večjo možnost preživetja, kot bolniki brez operacije (14). Dejstvo je, da sta biološka starost in pridružena obolevnost pomembnejši kot kronološka starost in starost sama ne sme biti izključevalni faktor operativnega posega (15, 16). LITERATURA 1. Žakelj PM, Bračko M, Hočevar M, Pompe KV, Strojan P, Zadnik V, Zakotnik B, et al. Incidenca raka v Sloveniji v letu 2006. Onkološki inštitut, Ljubljana, Register raka za Slovenijo, 2008. 2. Levi F, Lucchini F, Negri E, e tal. Changed trends of cancer mortality in the elderly. Ann Oncol 2001; 12(10):1467–1477. 3. Bozzetti F, Marubini E, Bonfanti G, et al. Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor Study Group. Ann Surg 1999; 230(2): 170–178. 4. Bonenkamp JJ, Songun I, Hermans J, et al. Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients [see comments]. Lancet 1995; 345(8952): 745–748. 5. Adachi Y, Ogawa Y, Sasaki Y, et al. A clinicopathologic study of gastric carcinoma with reference to age of patients. J Clin Gastroenterol 1994; 18(4): 287–290. 6. Tsujitani S, Katano K, Oka A, et al. Limited operation for gastric cancer in the elderly. Br J Surg 1996; 83(6): 836–839. 7. Enzinger PC, Mayer RJ. Gastrointestinal cancer in older patients. Semin Oncol 2004; 31(2): 206–219. 8. Oliveira FJ, Furtado E, Ferrao, et al. Total gastrectomy for gastric cancer in elderly patients. Hepatogastroenterology 1999; 46(25): 616–619. 9. Haga Y, Yagi Y, Ogawa M. Less invasive surgery for gastric cancer prolongs survival in patients over 80 years of age. Surg Today 1999; 29(9): 842–848. 10. Wu CW. Lo SS, Shen KH, et al. Surgical mortality, survival, and quality of life after resection for gastric cancer in the elderly. World J Surg 2000; 24(4): 465–472. 11. Kubota H. Kotoh T, Dhar DK, et al. Gastric resection in the aged (>or = 80 years) with gastric carcinoma: a multivariate analysis of prognostic factors. Aust NZ J Surg 2000; 70(4): 254–257. 12. Gretschel S, Estevez-Schwarz L, Huenerbein M, et al. Gastric cancer surgery in elderly patients. World J Surg 2006; 30: 1468–1474. 13. Aral T, Esaki Y, Inoshita N, et al. Pathological charecteristics of gastric cancer in the elderly. A retrospectiv study of 994 surgical patients. Gastric Cancer 2004; 7(3): 154–159. 14. Matsushita I, hanai H, Kajimura M, et al. Should gastric cancer patients more than 80 years of age undergo surgery? Comparison with patients not treated surgically concerning prognosis and quality of life. J Clin Gastroenterol 2002; 35(1): 29–34. 15. Saidi RF, Bell JL, Dudrick PS. Surgical resection for gastric cancer in elderly patients: is there difference in outcome?. J Surg Res 2004;118(1): 15–20. 16. Piso P, Bektas H, Wener U, et al. Comparison between treatment results for gastric cancer in younger and elderly patients. Zentralbl Chir 2002; 127(4): 270–274. GASTROENTEROLOG 43 Vloga HPV okužbe pri raku zadnjika The role of HPV infection in anal cancer Pavle Košorok1*, Matic Bunič1, Kristina Fujs Komloš2, Boštjan J. Kocjan2. Gačić Štotl Marija1, Mario Poljak2 1 IATROS Medical Centre 2 Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana Gastroenterolog 2013; suplement 2: 44–47 Ključne besede:Rak zadnjika, okužba s humanim virusom papiloma, cepljenje, zmanjšana imunska odpornost. Keywords: Anal cancer, HPV infection, vaccination, immunodeficiency POVZETEK ABSTRACT Okužba s humanim virusom papiloma (HPV) je vse pomembnejša. Poleg benigne patologije se vedno pogostejše tudi maligne spremembe anogenitalnega predela, med katerimi je najbolj poznan rak materničnega vratu. Intenzivne raziskave so privedle do uvedbe cepiva, ki v visokem odstotku ščiti pred rakavimi spremembami, ki jih povzročata seva HPV 16 in 18 – rak materničnega vratu, rak anusa, različni raki v genitalnem predelu in grlu. Cepivo, ki ščiti pred rakastimi spremembami vsebuje še genotipa HPV 6 in 11, ki povzročata benigne anogenitalne bradavice. Poznavanje razširjenosti posameznih genotipov v populaciji je ključno za napoved uspešnosti cepiva. Na pojav bolezni ne vpliva samo okužba z virusom ampak tudi spremljajoči dejavniki – število spolnih partnerjev, homoseksualni in heteroseksualni analni spolni odnosi, sočasna okužba s spolno prenosljivimi boleznimi (sifilis, gonoreja, herpes simplex virus, klamidija). Pogosteje se pojavljajo tudi pri bolnikih z zmanjšano imunsko odpornostjo, pri bolnikih po kemoterapiji in tistih, ki prejemajo imunosupresivna zdravila po transplantaciji organov. Recently, infection with the human papillomavirus (HPV) became increasingly important. Beside the benign pathology, malignant changes of ano-genital region are also increasing, the most known among them is cervical cancer. Intensive research led to the introduction of the vaccine which protects the population of cancerous changes caused by HPV strains 16 and 18 - cervical cancer, anal cancer, cancers of the throat and genital area. The vaccine, which protects against cancer contains also strains HPV 6 and 11, that causes anogenital warts. Knowledge of the prevalence of certain genotypes in the population is essential for predicting the performance of the vaccine. The onset of the disease depends not only from infection, but but also on accompanying circumstances - the number of sexual partners, homosexual and heterosexual anal sex, co-infection with sexually transmitted diseases (syphilis, gonorrhea, herpes simplex virus, chlamydia). Increased frequency is also found in immunodeficient patients, with patients undergoing chemotherapy and those receiving immunosuppressive drugs after organ transplants. The virus enters the body through damaged skin epithe- *Doc. dr. Pavle Košorok, dr. med., spec. krg. IATROS Medical Centre Parmova 51 b, 1000 Ljubljana, Slovenia 44 GASTROENTEROLOG Virus vstopi v telo skozi poškodovati kožni epitelij, naseli se v bazalnih celicah in se s tem izogne normalnemu imunskemu nadzoru. Razmnožuje se v spodnjih plasteh ploščatega epitela. Okuženi keratociti proliferirajo na nenormalen način in povzročijo nastanek genitalnih bradavic (najpogosteje tipa HPV 6 in 11). HPV tipa 16, 18, 31, 33 in 35 povezujemo z nastankom analne displazije in neoplazije. Onkogeni tipi se naselijo v celičnem jedru in zlijejo z gostiteljevim dednim materialom. Pogoste so okužbe z več genotipi virusa naenkrat. lium and resides in the basal cells and thus avoid normal immune surveillance. The virus replicates in the lower layers of flat epithelium. Infected cells proliferate in an abnormal way and cause the formation of genital warts (usually caused by the types HPV 6 and 11). HPV types 16, 18, 31, 33 and 35 are associated with the development of anal dysplasia and neoplasia. Oncogenic types of genes settle in the cell nucleus and incorporate in hereditary material. Infections with multiple genotypes of virus are also frequent. V naši ustanovi že več let sledimo bolnike, okužene s HPV. Med benignimi najpogosteje najdemo HPV 6 in 11, med malignimi genotipi pa je najpogostejši HPV 16. Najdeni so tudi drugi benigni in onkogeni tipi HPV. Pogoste pa so okužbe z več genotipi naenkrat. Our institution follows patients infected with HPV for several years. We usualy confirmed the benign causes such as HPV 6 and 11. The most common malignant genotype in our series was HPV 16. We also found other benign and oncogenic types of HPV. Coexisting infection with more genotypes were also recorded. Cepljenje s štirivalentnim cepivom v velikem odstotku ščiti pred pojavom malignih in benignih obolenj, povzročenih s HPV. Vaccination with the quadrivalent vaccine protects a large percentage of patients from malignant and benign diseases caused by HPV. NASTANEK ANALNEGA KARCINOMA malni episom, medtem, ko se HPV tipa 16 in 18 vgradi v gostiteljevo DNA, kar razloži različno sposobnost za začetek razvoja raka (3,5). Študije Palmerja in sodelavcev (6) kažejo na to, da epitelij prehodne cone analnega kanala kaže embriološke in histološke podobnosti s prehodno cono materničnega vratu. Okužba s HPV povzroča analni karcinom na način, ki ga lahko enačimo z vlogo HPV okužbe pri nastanku karcinoma materničnega vratu (1,2). Mnogi bolniki imajo istočasno analne in genitalne virusne spremembe. Običajno spadajo med populacijo s podobnimi navadami, med drugim tudi povečanim številom spolnih partnerjev. Analni in cervikalni karcinomi so praviloma povzročeni z visokorizičnimi HPV genotipi 16 in 18 (3,4). Danes je znanih že preko 100 različnih genotipov HPV, za vsaj 20 od njih vemo, da okužijo anogenitalni predel. Tipa 6 in 11 na splošno povzročata benigne lezije, kondilome in analno intraepitelialno neoplazijo (AIN) – displazijo nizke stopnje, ki redko napreduje do karcinoma. Nasprotno, HPV genotipov 16, 18, 31, 33, 34 in 35 povzročajo intraepitelijsko displazijo visoke stopnje, carcinoma in situ ter karcinom anusa in materničnega vratu. HPV tipa 6 in 11 ostaja kot ekstrakromoso- Imunokomprimirani bolniki, bolniki na imunosupresivni terapiji (transplantacije ledvic, jeter, srca) in bolniki z rakom po kemoterapiji so izpostavljeni večjemu tveganju okužbe s HPV in večji verjetnosti nastanka ploščatoceličnega karcinoma (7, 8). Pri teh se karcinomi pojavljajo v mlajši dobi, so multifokalni, bolj trdoživi, ponavljajoči in hitro napredujejo. Pri približno 50 % HIV pozitivnih bolnikov lahko dokažemo HPV DNA. Analni karcinom se pojavlja tudi v nerizični populaciji moških in žensk. Zato je treba razmisliti tudi o drugih načinih prenosa v analni kanal. Možno je, GASTROENTEROLOG 45 da gre za interakcijo več vzrokov, kot so vplivi okolja, HPV okužba, imunski status in prisotnost supresivnih genov (9). DIAGNOSTIKA V klinični praksi srečujemo bolnike z razvito benigno ali maligno simptomatiko. Pravilno oceno dobimo s skrbnim pregledom, ki mora zajeti tudi pregled analnega kanala. Pri tem je omogočen histološki odvzem na osnovi katerega je nato možno določiti najboljši način zdravljenja. V naši ustanovi vedno odvzamemo reprezentativni vzorec benignih in malignih sprememb, enega od tipičnih vzorcev pa razdelimo na dva dela od katerih je eden namenjen histološki preiskavi, drugega pa vložimo v tekoči dušik za določitev HPV genotipa. ZDRAVLJENJE Benigne spremembe odstranimo z ekscizijo in elektrokoagulacijo. Sumljiva mesta prav tako požgemo. Karcinomske spremembe pa praviloma ekscidiramo z varnostnim robom. Včasih se pokaže, da imajo tudi navidezno benigne spremembe že malignizirana območja. V takih primerih je potrebna dodatna kirurška oskrba. Redko najdemo napredovale maligne spremembe, kjer je potrebno zdravljenje v sodelovanju z onkologi. PREVENTIVA Tako bolnike z benignimi kot malignimi spremembami redno kontroliramo. Iščemo vidne spremembe. Z brisom analnega kanala pa tako kot pri brisu cervikalnega kanala (cervikalna intraepitelijska neoplazija – CIN) iščemo spremembe v smislu analne intraepitelijske neoplazije – AIN. Posebno skrben nadzor je potreben pri imunokomprimiranih bolnikih in bolnikih okuženih z virusom HIV (10, 11, 12). 46 GASTROENTEROLOG REZULTATI NAŠE ŠTUDIJE V študiji, ki poteka v sodelovanju z Inštitutom za mikrobiologijo in imunologijo MF UL in Inštitutom za patologijo MF UL sledimo vse naše paciente in analiziramo genotipe HPV, ki so prisotni v patoloških spremembah, ki jih odkrivamo. Najpogosteje odkriti genotipi so bili HPV 6 in 11 pri bolnikih z benignimi spremembami, z večjo prevalenco tipa HPV 6 v več različicah. V posameznih primerih je bila najdena tudi kombinirana okužba (HPV 6 in 11). Nekateri HPV pozitivni vzorci so pokazali še druge tipe HPV kot HPV 26, 40, 42, 54, 57, 61, 62, 73, 74, 84, 91, CP 6108 in visoko rizični HPV 16 in 52. Pri tkivnih vzorcih bolnikov z analnim karcinomom je bila vedno najdena HPV DNA. Najpogostejši genotip je bil HPV 16. Pri enem od pacientov z malignomom je bil najdem samo genotip HPV 6, pri enem pa visoko rizični HPV 52 in istočasna okužba z nizko rizičnim humanim papiloma virusom HPV 61. (13, 14) ZAKLJUČEK Karcinome analnega predela v zadnjem času vse pogosteje odkrivamo. Dokazan je vpliv okužbe z humanim papiloma virusom, ki povzroči preskok v karcinomsko raščo. Obstaja več genotipov HPV, ki povzročajo spremembe v anogenitalnem predelu. HPV okužba povzroča spremembe, ki vodijo tudi do raka materničnega vratu. Najbolj patogene vrste humanega papiloma virusa sta genotipa 6 in 11, ki praviloma povzročata samo benigne spremembe (anogenitalne bradavice) ter 16 in 18, ki povzročata rakave spremembe tako na materničnem vratu, kot na zadnjiku. Poleg teh štirih najpogostejših genotipov so znani še nekateri, ki jim pripisujejo onkogeno delovanje. Za nastanek raka zadnjika je v veliki meri odgovorno tudi obnašanje posameznika (vrsta spolnih praks, menjavanje partnerjev, okužbe s spolno prenosljivimi boleznimi, HIV). Pomembno lahko vpliva tudi zmanjšana imunska odpornost pri bolnikih s transplantacijo organov ali ob kemoterapiji. Poznane so tudi posamezne oblike malignih sprememb, za katere za enkrat ni dokazano, da bi bile v zvezi s HPV okužbo, potrebno pa jih je poznati in razlikovati od tistih, kjer je povezava s HPV okužbo dokazana. LITERATURA 1. Frisch M. On the etiology of anal squamosum carcinoma. Dan Med Bull 2002; 49:194–209. 2. Chang GJ, Sheldon A, Welton ML. Epidemiology and natural history of anal HPV infection and ASIL and cancer in the general population.Semin Colon Rect Surg 2004; 15:210–214 3. Saclarides TJ, Klem D. Genetic alterations and virology of anal cancer. Semin Colon Rectal Surg 1995; 6:131–134. 4. Shroyer KR, Kim JG, Manos MM, Greer CE, Pearlman NW, Franklin WA, Papilloma virus found in anorectal squamous carcinoma, not in colon adenocarcinoma. Arch Surg 1992; 127:741–744. 5. Bjorget B, Engeland A, Luostarinen T, et al. Human papilloma virus infection as a risk factor for anal and perianal skin cancer in a prospective study. Br J Cancer 2002; 87:61–64. 6. ¸Palmer JG, Schoelefield JH, Coates PJ, et al. Anal cancer and human papilloma viruses. Dis Colon Rectum 1989; 32:1016–1022. 7. Welton ML. Etiology of human papilloma virus infections and the development of anal squamous intraepithelial lesions. Semin Colon rectal Surg 2004; 15:193–195. 8. Mullerat J, Northover J. Human papilloma virus and anal neoplastic lesions in the immunocompromised (Transplant) patient. Semin Colon Rectal Surg 2004; 15:215–217. 9. Deans GT, McAlee JJA, Spence RAJ. Malignant anal tumors. Br J Surg 1994; 81:501–508. 10. Polefsky JM. Anal squamous intraepithelial lesions in human immunodefeciency virus–positive men and women. Semin Oncol 2000; 27:471–479. 11. Goldstone SE, Winkler B, Wifford LJ, Alt E, Polefsky JM. High prevalence of abal squamous intraepithelial lesions and squamous-cell carcinoma in men who have sex with men as seen in a surgical practice. Dis Colon Rectum 2001; 44:690–698. 12. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Palefasky JM. Cost-effectiveness of screening for anal squamous intraepithelial lesions and cancer in human immunodeficiency virusnegative homosexual and bisexual men. Am J Med 2000; 108:634–641. 13. Fujs Komloš K. Molekularna opredelitev humanih virusov papiloma v papilomih grla in analnih ter genitalnih bradavicah. Doktorska disertacija 2012, Univerza v Ljubljani, Biotehniška fakulteta. 14. Bunič M, Fujs Komloš K, Kocjan B, Gačić M, Košorok P, Poljak M. Distribution of HPV genotypes in Slovenian patients with anogenital warts and anal carcinomas. V: POTOČNIK, Marko (ur.). 18th Alp-Danube-Adria Congress on Sexually Transmitted Diseases and Genital Dermatology, Bled, 5–6 October, 2012. Final program & abstract book. [S. l.]: Agencija Promo, 2012, str. 26–27. GASTROENTEROLOG 47 Protektivne stome po operacijah nizkega raka danke Protective stoma after low anterior resection for rectal cancer Bojan Krebs*, Miran Koželj, Stojan Potrč Oddelek za splošno in abdominalno kirurgijo, Kirurška klinika, UKC Maribor Gastroenterolog 2013; suplement 2: 48–50 Ključne besede: nizka sprednja resekcija, protektivna stoma, anastomoza Keywords: low anterior resection, anastomosis, protective stoma POVZETEK ABSTRACT Uvod. Rak danke je drugi najpogostejši rak v Evropi in nizka sprednja resekcija je zlati standard pri zdravljenju. Najhujši zaplet po taki operaciji je puščanje anastomoze. Za zmanjšanje tveganja večina raziskav priporoča izpeljavo protektivne stome. Ta postopek sicer že sam po sebi predstavlja določeno tveganje pri primarni operaciji, predvsem pa je potrebno računati na možne zaplete pri zapiranju. Introduction. Colorectal cancer is the second most common cancer in Europe and low anterior resection is the gold treatment standard. One of the most serious complications after such operation is anastomotic leakage. To reduce the risk many surgeons recommend fecal derivation with protective stoma. This procedure by itself is not without risk in the time of primary operation, and one must also take in account the possible complications of protective stoma closing. Metode. Retrospektivno smo zbrali podatke o bolnikih, pri katerih smo med leti 2003 in 2012 zaprli protektivno stomo. Bolniki so bili najprej operirani zaradi procesa na danki in ob nizki sprednji resekciji je bila izpeljana stoma. Pregledali smo podatke o osnovni operaciji, tipu stome, času in načinu zapiranja stome, hospitalizaciji, zapletih in preživetju. Rezultati. Med leti 2003 in 2012 smo zaprli stomo pri 171 bolnikih, ki so bili operirani zaradi raka danke. Pri 79 bolnikih je bila napravljena transverzostoma, pri 92 pa ileostoma. Povprečen čas do zapiranja je bil 235 dni po prvi operaciji. V večini primerov smo napravili resekcijo črevesa in anastomozo (114), v 56 primerih pa samo zapiranje Methods. We retrospectively collected data on patients who were operated on closing the stoma between 2003 and 2012. Patients were first operated because of low rectal cancer and low anterior resection was performed with derivation stoma. We reviewed the data of the first operation, type of stoma, time and method of stoma closure, hospitalization time, and complications. Results. Between 2003 and 2012, we closed the stoma in 171 patients who underwent surgery for rectal cancer. In the 79 patients transversostomy and in 92 patients an ileostomy was made. Average time until closure was 235 days after the first operation. In most cases, we performed bowel resection and anastomosis *Bojan Krebs, dr. med. Oddelek za splošno in abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Maribor, Ljubljanska 5, 2000 Maribor 48 GASTROENTEROLOG sprednje stene črevesa brez resekcije. Stopnja zapletov je bila 28 %, medtem, ko je bilo zapletov, ki so zahtevali kirurško ukrepanje 6 %. Trije bolniki (1,8 %) so umrli. (114) and in 56 cases, only the closing of the front wall of intestine without resection was performed. Complication rate was 28%, while surgical intervention was needed in 6%. Three patients (1.8%) have died. Zaključek. Menimo, da je protektivna stoma potrebna pri operacijah raka spodnjih dveh tretjin danke, še posebej po preoperativnem obsevanju. Kljub temu je potrebno biti zelo pazljiv pri zapiranju le te, saj lahko na prvi pogled enostavna operacija pripelje do zelo hudih zapletov, vključno s smrtnim izidom. Conclusion. We believe that the protective stoma is required at operations for rectal cancer in the lower thirds, especially after preoperative oncological therapy. Nevertheless, it is necessary to be very careful at stoma closing, because such at first glance simple operation could lead to very serious complications, including death. UVOD torej bolje bolnika intenzivno spremljati in če do dehiscence pride, izpeljati stomo kasneje. Eden od večjih zapletov kirurgije raka danke je vsekakor dehiscenca anastomoze. Z raznimi postopki poskušamo čim bolj zmanjšati verjetnost, da bi do dehiscence prišlo in če do tega že pride, da bi to imelo čim manjši vpliv na bolnika. Izpeljava protektivne stome je eden od postopkov, ki po večini raziskav bistveno zmanjša delež dehiscenc anastomoz (1–3) Prav tako je klinični potek, če do manjše dehiscence pride, za bolnika bolj ugoden in morda sploh ne zahteva kirurškega ukrepanja. Protektivna stoma je bolj priporočljiva pri bolnikh, ki so prejeli preoperativno obsevanje, pri bolnikih z zelo nizko anastomozo in pa morda tudi pri moških. Kar nekaj raziskav je namreč pokazalo, da imajo moški višjo stopnjo dehiscenc anastomoz. Najverjetneje je to povezano z ožjo medenico, težjo preparacijo in tudi zahtevnejšo rekonstrukcijo v takih pogojih. Nasprotniki tega postopka trdijo, da izpeljava protektivne stome nima bistvenega vpliva na pooperativni potek (4–6). Stopnja dehiscence anastomoz po nizkih resekcijah zaradi raka danke je po raznih podatkih od 6–30 %. Če bi izpeljali stome vsem bolnikom po takih operacijah, bi to pomenilo, da bi 70–94 % bolnikov imeli stomo po nepotrebnem. Tudi dejstvo, da stomo imajo, ne bi zagotovo preprečilo hujših zapletov pri tistih, pri katerih bi resnično prišlo do dehiscence anastomoze. Po trditvah nasprotnikov je Potrebno je misliti tudi na to, da je v račun pri izpeljavi protektivne stome vsekakor potrebno vzeti tudi zaplete pri drugi operaciji, ko bomo stomo zaprli. Tudi za ta poseg je potrebna splošna anestezija, sam poseg pa je, kljub temu, da izgleda relativno enostaven, povezan z dokaj visoko stopnjo zapletov. Objavljenih je več raziskav o zapiranju protektivnih stom in zapletih (7–9). METODE Zbrali smo podatke za vse bolnike, pri katerih smo zaprli protektivno stomo med leti 2003 in 2012. Med njimi smo izbrali bolnike, ki so predhodno bili operirani zaradi nizkega raka danke in izločili vse ostale. Zanimal nas je spol bolnika, starost, prvotna operacija, čas do zapiranja protektivne stome, tip operacije s katero smo stomo zaprli, čas hospitalizacije po operaciji ter zapleti in reševanje le teh. Podatke smo vnesli v preglednico in obdelali z računalniškim programom Microsoft Excel. REZULTATI V opazovanem obdobju smo zaprli stomo pri 171 bolnikih. Med njimi je bilo 71 žensk in 100 moških. Pri 79 bolnikih je bila glede na osebno odločitev operaterja napravljena transversostoma, pri 92 pa ileostoma. Pred zapiranjem smo pri vseh bolnikih GASTROENTEROLOG 49 napravili irigografijo s katero smo ocenili prehodnost anastomoze. Pri 114 bolnikih smo pri zapiranju napravili resekcijo črevesa in nato termino terminalno anastomozo in to predvsem pri bolnikih, ki so imeli predhodno izpeljano ileostomo. Pri 56 bolnikih pa smo zadnjo steno pustili intaktno in z direktnimi šivi zašili sprednjo steno črevesa brez resekcije. Povprečen čas hospitalizacije po operaciji je bil 10 dni z razponom od 4 do 68 dni. Povprečen čas od primarne operacije do zapiranja stome je bil 232 dni z razponom od 75 do 753 dni. Stopnja zapletov je bila 28 odstotkov. Na prvem mestu med zapleti je bil pooperativni ileus pri 25 bolnikih oziroma 14 odstotkih. Večino smo zdravili konzervativno, 7 bolnikov pa smo zaradi pooperativnega ileusa ponovno operirali. Pri 11 bolnikih je prišlo do vnetja v rani kar smo zdravili z razprtjem rane. Pri treh bolnikih je prišlo do dehiscence anastomoze, kar smo zdravili kirurško. Skupno je pri 6 odstotkih bolnikov prišlo do zapletov, ki so zahtevali kirurško ukrepanje. Trije bolniki (1,8 %) so umrli. Pri dveh je bil prvotni zaplet ileus, pri enem pa dehiscenca anastomoze. RAZPRAVA IN ZAKLJUČEK V zadnjih letih je vse več raziskav potrdilo, da protektivna stoma zmanjša delež simptomatskih dehiscenc anastomoz. Glede na te izsledke in naše lastne izkušnje, je izpeljava protektivne stome pri operacijah raka danke srednje in spodnje tretjine standard že vrsto let tudi v naši ustanovi. Po drugi strani pa se moramo zavedati, da je tudi samo zapiranje protektivne stome zahtevna operacija s svojo stopnjo zapletov. V letu 2013 je bila objavljena raziskava, kjer Sharma in sodelavci opozarjajo, da zapiranje ileostome ni tako imenovana »manjša operacija« in da je potrebna enaka previdnost kot pri prvi operaciji (10). Obdelali so podatke za več kot 5000 bolnikov, pri katerih zaprli protektivno ileostomo. Stopnja velikih (major) zapletov je bila 9,3 % in stopnja manjših (minor) zapletov 8,4 %. Smrtnost je bila 0,6 %. 50 GASTROENTEROLOG Tudi naši rezultati dokazujejo, da je stopnja zapletov po tej operaciji nadpovprečno visoka. Res je, da je večina zapletov manjših in smo jih uspeli rešiti konzervativno, vendar pa je tudi stopnja zapletov, ki so zahtevali ponovno operacijo dokaj visoka, pa tudi smrtnost ni zanemarljiva. LITERATURA 1. Montedori A, Cirocchi R, Farinella E, Sciannameo F, Abraha I (2010) Covering ileo- or colostomy in anterior resection for rectal carcinoma. Cochrane Database Syst Rev CD006878 2. Tan WS, Tang CL, Shi L, Eu KW (2009) Meta-analysis of defunctioning stomas in low anterior resection for rectal cancer. Br J Surg 96:462–472 3. Chude GG, Rayate NV, Patris V, Koshariya M, Jagad R, Kawamoto J, Lygidakis NJ.Defunctioning loop ileostomy with low anterior resection for distal rectal cancer: should we make an ileostomy as a routine procedure? A prospective randomized study.Hepatogastroenterology. 2008 Sep–Oct;55(86–87):1562–7 4. Wong NY, Eu KW. A defunctioning ileostomy does not prevent clinical anastomotic leak after a low anterior resection: a prospective, comparative study.Dis Colon Rectum. 2005 Nov;48(11):2076–9. 5. Huh JW, Park YA, Sohn SK.A diverting stoma is not necessary when performing a handsewn coloanal anastomosis for lower rectal cancer.Dis Colon Rectum. 2007 Jul;50(7):1040–6. 6. Pappalardo G, Spoletini D, Proposito D, Giorgiano F, Conte AM, Frattaroli FM Protective stoma in anterior resection of the rectum: when, how and why?Surg Oncol. 2007 Dec;16 Suppl 1:S105–8 7. Bada-Yllán O, García-Osogobio S, Zárate X, Velasco L, Hoyos-Tello CM, Takahashi T.Morbi-mortality related to ileostomy and colostomy closure.Rev Invest Clin. 2006 Nov-Dec;58(6):555–60. 8. Mansfield SD, Jensen C, Phair AS, Kelly OT, Kelly SB.Complications of loop ileostomy closure: a retrospective cohort analysis of 123 patients.World J Surg. 2008 Sep;32(9):2101–6. 9. Chen F, Stuart M.The morbidity of defunctioning stomata.Aust N Z J Surg. 1996 Apr;66(4):218–21. 10. Sharma A, Deeb AP, Rickles AS, Iannuzzi JC, Monson JR, Fleming FJ.Closure of defunctioning loop ileostomy is associated with considerable morbidity.Colorectal Dis. 2013 Apr;15(4):458–62.*Bojan Krebs Laparaskopska ventralna rektopeksija Laparosopic ventral rectopexy Gregor Norčič* KO za abdominalno kirurgijo, UKC Ljubljana Gastroenterolog 2013; suplement 2: 51–53 Ključne besede: rektopeksija, laparaskopska ventralna rektopeksija, prolaps rektuma, intususcepcija Keywords: rectopexy, laparoscopic ventral mesh rectopexy, prolapse of the rectum, Intussusception POVZETEK ABSTRACT Laparaskopska ventralna rektopeksija z mrežico je relativno nova kirurška tehnika zdravljenja prolapsa rektuma. Gre za laparaskopsko različico ene izmed klasičnih transabdominalnih tehnik, ki združuje učinkovitost slednje in minimalno invazivnost. Glede na rezultate iz literature je laparaskopska ventralna rektopeksija z mrežico povezana z dobrimi rezultati zdravljenja in nizko incidenco pooperativnih zapletov. Posledično bi lahko šlo za tehniko izbora pri bolnikih s prolapsom rektuma, ki so sposobni operativnega posega v splošni anesteziji. Laparoscopic ventral mesh rectopexy is a relatively new surgical technique for treating rectal prolapse. It is a laparoscopic version of one of the classic transabdominal techniques that combines its efficiency and minimal invasiveness. Laparoscopic ventral mesh rectopexy is associated with good treatment results and a low incidence of postoperative complications, according to the available published data. It could therefore become a technique of choice in patients with rectal prolapse who are capable of surgical procedure under general anesthesia. UVOD Glede na nejasno teorijo in patogenezo prolapsa rektuma ni presenetljivo, da so se skozi zgodovino razvile različne kirurške tehnike, s katerimi so kirurgi poizkušali odpraviti prolaps rektuma in blažiti pridruženo simptomatiko. Tradicionalno se te kirurške tehnike glede na pristop delijo v dve veliki skupini: perinealne in transabdominalne tehnike. Rektopeksija pomeni fiksacijo rektuma na okolišnje strukture. Gre za kirurško tehniko, ki je namenjena zdravljenju prolapsa rektuma. Prolaps rektuma je bolezen zadnjika, ki prizadene predvsem starejše bolnice. Poleg kozmetične motnje in odvajanja krvi ali sluzi na blato je bolezen povezana tudi s funkcionalno okvaro, ki se kaže kot zaprtje (pri okrog 60 % bolnikov) ali inkontinenca (do 70 % bolnikov). Etiologija prolapsa rektuma ni povsem pojasnjena, obstajajo različne patogenetske teorije njegovega nastanka. (1) Pri perinealnih tehnikah je kirurški poseg omejen na zadnjik in odpiranje trebušne votline ni potrebno. Posledično se jih lahko izvaja v regionalni anesteziji. Te tehnike se zato zdijo posebej primerne za starejše bolnike s pridruženimi boleznimi. Danes *As. mag. Gregor Norčič, dr. med Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana Zaloška 2, 1000 Ljubljana GASTROENTEROLOG 51 se v praksi uporabljata le še dve perinealni tehniki: perinealna resekcija rektuma po Altemeierju in operacija po Delormu. Pri transabdominalnih tehnikah se kirurški poseg zaradi prolapsa rektuma izvede v trebušni votlini. Transabdominalne tehnike se med sabo razlikujejo glede na to, ali pri operaciji odstranimo del debelega črevesa in na kakšen način in kam se fiksira rektum. (2) TRANSABDOMINALNE KIRURŠKE TEHNIKE ZARADI PROLAPSA REKTUMA Klasične abdominalne operacije zaradi prolapsa rektuma so: rektopeksija po Ripsteinu, rektopeksija po Wellsu, rektopeksija po Orr-Loygueu, in resekcija sigmoidnega kolona z rektopeksijo po Frykman-Goldbergu. Pri Ripsteinovi operaciji se rektum anteriorno fiksira na presakralno fascijo z neresorbilnimi šivi ali neresorbilno mrežico. Pri Wellsovi operaciji se za posteriorno fiksacijo rektuma uporablja posebna spužva (»Ivalon sponge«) ali mrežica. Pri operaciji po Orr-Loygueu se rektum vzdolžno lateralno fiksira na promontorij sakruma s pomočjo mrežice. Operacija po Frykman-Goldbergu je indicirana v primeru dolgega sigmoidnega kolona. Najprej se napravi resekcija sigme, nato pa še fiksacija rektuma s šivi. Z razvojem laparaskopske kolorektalne kirurgije so kirurgi opisane transabdominalne tehnike pričeli izvajati na minimalno invaziven - laparaskopski način. Posebej popularna tehnika je postala ventralna laparaskopska rektopeskija z mrežico. Pri tej tehniki gre pravzaprav za Orr- Loyguevo tehniko na laparaskopski način. LAPARASKOPSKA VENTRALNA REKTOPEKSIJA Z MREŽICO Tehniko laparaskopske ventralne rektopeksije z mrežico je opisal D’Hoore s sodelavci leta 2004. Bistvo operacije je laparaskopska mobilizacija rektuma ante52 GASTROENTEROLOG riorno in lateralno do medeničnega dna, posteriorno pa se mezorektuma naj ne bi ločevalo od presakralne fascije. Na ta način naj bi se kirurgi izognili poškodbam avtonomnega živčevja in s tem povezanim funkcionalnim težavam. Na tako razgaljeno sprednjo steno ekstraperitonealnega dela rektuma se nato s posameznimi šivi prišije mrežica. Mrežica je oblikovana v obliko traku, ožji del naj bi bil širok nekoliko manj od rektuma, po dolžini pa naj bi segala od medeničnega dna pa do promontorija sakruma. Na rektum mora biti prišita tako, da poteka od sprednje stene ekstraperitonealnega rektuma preko desne lateralne stene do presakralne fascije desno pararektalno v predelu promontorija sakruma. Na tem mestu se mrežica nato fiksira na presakralno fascijo s ustreznimi sponkami tako, da se doseže ustrezna poprava prolapsa rektuma. Čez mrežico se nato s tekočim šivom rekonstruira peritonej. (3) REZULTATI ZDRAVLJENJA Z LAPARASKOPSKO VENTRALNO REKTOPEKSIJO Z MREŽICO Številni avtorji poročajo o pozitivnih izidih zdravljenja prolapsa rektuma z laparaskopsko ventralno rektopeksijo z mrežico. Tehnika naj bi bila povezana z nizko stopnjo pooperativnih zapletov, visokim deležem izboljšanja funkcionalnih težav in nizko stopnjo recidivov prolapsa rektuma. D’Hoore in sodelavci so prvi poročali o rezultatih zdravljenja z lapatraskopsko ventralno rektopeksijo z mrežico. Od 109 operiranih bolnikov je bila potrebna konverzija iz laparaskopske v klasično tehniko pri 4 bolnikih. Do manjših zapletov je prišlo pri 7 % bolnikov. Do recidiva prolapsa je prišlo pri 3,66 % bolnikov. (4) V preglednem članku, ki zajema 12 nerandomiziranih analiz pri skupaj 728 bolnikih zdravljenih z laparaskopsko ventralno rektopeksijo so avtorji ugotavljali recidiv prolapsa pri 0–15,4 %, zmanjšanje simptomov obstipacije pri 23,9 % in zmanjšanje inkontinence pri 44,9 % bolnikov. Do zapletov je prišlo pri 1,4–47 % bolnikov. (5) Metaanaliza osmih študij pri 467 bolnikih je primerjala laparaskopske tehnike rektopeksije s klasičnimi. Incidenca recidivov prolapsa je bila pri vseh tehnikah podobna in se je gibala do 10 %. Pri bolnikih po laparaskopski rektopesiji z mrežico je prišlo do izboljšanja inkontinence v 27–90 % primerov, do izboljšanja zaprtja pa v 0–84 % primerov. V posameznih študijah so sicer opisovali tudi poslabšanje obeh simptomov pri operiranih bolnikih. (6) Dolgoročni rezultati bolnikov, sledenih po laparaskopski ventralni rektopeksiji v okviru prospektivne študije, govorijo za recidiv prolapsa pri 6 % bolnikov, za izboljšanje zaprtja pri 72 % bolnikov in pojav na novo nastalega zaprtja pri 7 % bolnikov. Pri bolnikih so po operativnem posegu opažali pomembno izboljšanje kakovosti življenja. (7) PRIMERJAVA RAZLIČNIH TEHNIK Obstaja le malo verodostojnih študij, ki bi primerjale različne kirurške tehnike zdravljenja prolapsa rektuma in njihove rezultate. (2) Na podlagi omenjene metaanalize študij, ki je primerjala klasične in laparaskopske tehnike med seboj, lahko zaključimo da so transabdominalne laparaskopske tehnike najmanj enakovredne transabdominalnim klasičnim tehnikam. Laparaskopske tehnike niso povezane z višjo stopnjo zapletov, niti z višjo stopnjo zapletov od klasičnih tehnik. (6) Multicentrična študija na 293 bolnikih izvedena v Veliki Britaniji je poizkušala primerjati transabdominalne in perinealne tehnike, nato pa znotraj obeh skupin še po dve izbrani tehniki: Delormovo in Altemeierjevo operacijo med perinealnimi tehnikami oziroma rektopeksijo s šivi in resekcijo sigmoidnega kolona v kombinaciji z rektopeksijo s šivi. Študija ni pokazala pomembnih razlik med posameznimi tehnikami, vendar je povezana z določenimi pomanjkljivostmi. Največja pomanjkljivost je, da je študija dopuščala diskrecijsko pravico kirurga pri odločitvi za določeno kirurško tehniko. Posledično je bilo med perinealnimi in transabdominalnimi tehnikami dejansko randomiziranih le 49 bolnikov. Druga velika pomanjkljivost pa je ta, da od transabdominalnih operacij ni bila izbrana trenutno najbolj popularna tehnika, to je laparaskopska ventralna rektopeksija z mrežico. (8) Od leta 2010 je v teku nemška multicentrična randomizirana študija, ki med seboj primerja Delormovo tehniko in laparaskopsko resekcijo sigmoidnega kolona v kombinaciji z rektopeksijo s šivi. Rezultate študije še čakamo, vendar tudi ta ne bo dala neposredne primerjave med najbolj popularno perinealno in transabdominalno tehniko. (9) ZAKLJUČEK Glede na dokaze iz literature je laparaskopska ventralna rektopeksija z mrežico povezana z nizko incidenco konverzij, nizko incidenco pooperativnih zapletov, nizko incidenco recidiva prolapsa rektuma in ugodnim funkcionalnim rezultatom zdravljenja. Bolnike s prolapsom rektuma, ki so sposobni kirurškega posega v splošni anesteziji je zato potrebno napotiti h kirurgu, ki obvlada tako laparskopsko kolorektalno kirurgijo kot tudi perinealne tehnike zdravljenja. Le tako bodo lahko ti bolniki deležni optimalne kirurške oskrbe. LITERATURA 1. D’Hoore. Rectal Prolapse, Intussusception, Solitary Rectal Ulcer. In: Herold A., Lehur P.A., Matzel K.E., O’Connell P.R.: Coloproctology. Berlin Heidelberg: Springer 2008: 115–119. 2. Melton GB, Kwaan MR. Rectal prolapse. Surg Clin North Am. 2013; 93:187–98. 3. D’Hoore A, Cadoni R, Penninckx F. Long-term outcome of laparoscopic ventral rectopexy for total rectal prolapse. Br J Surg. 2004; 91:1500–5. 4. D’Hoore A, Penninckx F. Laparoscopic ventral recto(colpo)pexy for rectal prolapse: surgical technique and outcome for 109 patients. Surg Endosc. 2006; 20:1919–23. 5. Samaranayake CB, Luo C, Plank AW, Merrie AE, Plank LD, Bissett IP. Systematic review on ventral rectopexy for rectal prolapse and intussusception. Colorectal Dis. 2010; 12:504–12. 6. Cadeddu F, Sileri P, Grande M, De Luca E, Franceschilli L, Milito G. Focus on abdominal rectopexy for full-thickness rectal prolapse: meta-analysis of literature. Tech Coloproctol. 2012; 16:37–53. 7. Maggiori L, Bretagnol F, Ferron M, Panis Y. Laparoscopic ventral rectopexy: a prospective long-term evaluation of functional results and quality of life. Tech Coloproctol. 2013 Jan 23. [Epub ahead of print] 8. Senapati A, Gray RG, Middleton LJ, Harding J, Hills RK, Armitage NC, et al.. The PROSPER Collaborative Group. PROSPER: a randomised comparison of surgical treatments for rectal prolapse. Colorectal Dis. 2013 Mar 5. [Epub ahead of print] 9. Rothenhoefer S, Herrle F, Herold A, Joos A, Bussen D, Kieser M, et al.. DeloRes trial: study protocol for a randomized trial comparing two standardized surgical approaches in rectal prolapse - Delorme’s procedure versus resection rectopexy. Trials. 2012; 13:155. GASTROENTEROLOG 53 Zdravljenje lokalno napredovalega raka danke Treatment of locally advanced rectal cancer Mirko Omejc* KO za abdominalno kirurgijo, UKC Ljubljana Gastroenterolog 2013; suplement 2: 54–55 Ključne besede: rak danke, neoadjuvantno zdravljenje, regresija tumorja Keywords: rectal cancer, neoadjuvant treatment, tumor regression POVZETEK ABSTRACT Predoperativno zdravljenje lokalno napredovalega raka danke v kliničnem stadiju II (cT3-4, N0, M0) in III (cT1-4, N+, M0) z radiokemoterapijo je postalo standarden način zdravljenja. S tem dosežemo »downsizing« in »downstaging« tumorja kar omogoča večjo možnost R0 resekcije in izboljša lokalno kontrolo tumorja. V primeru popolne regresije tumorja po neoadjuvantnem zdravljenju pa to pomeni za bolnika boljšo prognozo kot pri tumorjih z delno regresijo ali brez regresije tumorja. Preoperative treatment of advanced rectal cancer in clinical stage II (cT3-4, N0, M0) and III (cT1-4, N+, M0) using radiochemotherapy has become standard treatment approach. Tumor downstaging and downsizing increase R0 resection rates and improve local control. Complete tumor regression after neoadjuvant treatment carries better prognosis than partial or no regression. Namen kirurškega zdravljenja raka danke je zagotoviti lokalni nadzor nad rakom in tako izboljšati preživetje ter ohranitev analnega sfinktra, mikcijske in spolne funkcije in ohraniti oziroma izboljšati kakovost bolnikovega življenja. Za odločitev o načinu zdravljenja so ključni predoperativni podatki o lokalizaciji in višini tumorja, globini vraščanja tumorja v steno danke, prizadetosti bezgavk in prisotnosti oddaljenih zasevkov. Pri tumorjih v stadijih pT1/pT2 pN0 je zdravljenje samo kirurško. Pri tumorjih, ki rastejo v muskularis proprijo (T3, T4) in/ali so že zasevali v področne bezgavke (N1, N2) ali v oddaljene organe (M1), pride v poštev poleg kirurškega zdravljenja tudi radiokemoterapija. Na osnovi študij objavljenih v zadnjih letih, ki so dokazale prednost predoperativnega zdravljenja z radio in kemoterapijo v primerjavi s pooperativnim zdravljenjem glede lokalne kontrole tumorja in toksičnosti, se v zadnjih letih vedno bolj uveljavlja predoperativni pristop (1,2). Izbiro bolnikov za predoperativno zdravljenje nam omogoča nuklearna magnetna resonanca (MRI), ki omogoča natančen prikaz mehkih struktur v mali medenici. S to preiskavo lahko prikažemo radialni rob tumorja in njegovo oddaljenost od fascije mezorektuma. Pri bolnikih, pri katerih tumor sega v neposredno bližino fascije ali jo celo prerašča, je lokalnih ponovitev več. Pri takih tumorjih je zato indicirano predoperativno oziroma neoadjuvantno zdravljenje (3). * prof. dr. Mirko Omejc, dr. med. Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana Zaloška 2, 1000 Ljubljana 54 GASTROENTEROLOG Uporabljamo dve shemi predoperativne radioterapije. Dolga shema pomeni pet tednov obsevanja in kemoterapije, ki ji sledi 3- do 8-tedenski premor in nato operacija. Uporablja se pri bolj razširjenih karcinomih z namenom zmanjšati velikost tumorja (angl. downsizing) in razširjenost bolezni (angl. downstaging). Kratka shema radioterapije pa pomeni en teden radioterapije brez dodatka kemoterapije in operacija takoj po zaključenem obsevanju. Uporablja se pri manj razširjenih tumorjih, da bi zmanjšali število lokalnih ponovitev. Vraščanje tumorja v steno rektuma in razširitev v regionalne bezgavke sta glavna dejavnika, ki določata prognozo lokalno napredovalega raka danke. Radioin kemoterapija lahko spremenita patološko T in N kategorijo, saj v različnem obsegu zmanjšata invazijo tumorja v steno rektuma in perirektalne bezgavke. Lahko pride celo do popolnega izginotja tumorskih celic v črevesni steni in bezgavkah (complete response), kar je opisano pri 15–30 % bolnikov z lokalno napredovalim rakom danke po takem zdravljenju. S tem učinkom, »downstaging«, znižanja predoperativnega kliničnega stadija (kategoriji T/N), v primerjavi z patološkim, merimo odgovor tumorja na predoperativno zdravljenje (4, 5). Popolna klinična regresija tumorja (complete clinical regression, cCR), ki pomeni odsotnost klinično dokazljivega rezidualnega tumorja, pa ne pomeni tudi patološko popolno regresijo tumorja (pathologic complete regression, pCR), to je popolno odsotnost vitalnih tumorskih celic. Kljub razvoju številnih diagnostičnih metod zaenkrat brez operacije in patološkega pregleda resektata, še ni mogoče zanesljivo potrditi odsotnosti tumorskih celic v steni črevesa, mezorektumu in bezgavkah. Tudi ob popolni regresiji tumorja v črevesni steni, obstaja možnost zasevkov v regionalnih bezgavkah, kar predstavlja pomemben izziv pri izbiri ustreznega in ev. manj agresivnega ali neoperativnega zdravljenja. Patološko potrjena popolna regresija tumorja v steni črevesa in regionalnih bezgavkah po neoadjuvantnem zdravljenju pomeni za bolnika boljšo prognozo kot pri tumorjih z delno regresijo ali brez regresije tumorja, ne glede na klinični stadij bolezni pred začetkom neoadjuvantnega zdravljenja (7, 8). Zmanjšanje in regresija tumorja olajšata kirurško zdravljenje, lahko pa tak odgovor pomeni tudi bolj ugoden biološki potencial tumorja. Ker predoperativna radioin kemoterapija delujeta na tkiva z dobro prekrvavitvijo in oksigenacijo je učinek takšnega zdravljenja boljši kot pri pooperativnem pristopu in zato delež lokalnih ponovitev bolezni manjši. Zaradi zmanjšanja tumorja je v nekaterih primerih možna nizka sprednja resekcija namesto abdominoperinealne ekscizije in s tem ohranitev kontinuitete prebavne poti. Pomemben je tudi funkcionalni vidik, saj s predoperativnim obsevanjem prizadenemo tumor in del debelega črevesa, ki ga pri operaciji odstranimo, ostanejo pa tkiva, ki niso obsevana, kar omogoča rekonstrukcijo z neobsevanim delom črevesa in zato boljši funkcionalni rezultat (9, 10). LITERATURA 1. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009; 373: 811–820. 2. Pucciarelli S, Gagliardi G, Maretto I, Lonardi S, Friso ML, Urso E et al. Long-term oncologic results and complications after preoperative chemoradiotherapy for rectal cancer: a single-institution experience after a median follow-up of 95 months. Ann Surg Oncol 2009; 16: 893–899. 3. de Campos-Lobato LF, Stocchi L, da Luz Moreira A, Geisler D, Dietz DW, Lavery IC et al. Pathologic complete response after neoadjuvant treatment for rectal cancer decreases distant recurrence and could eradicate local recurrence. Ann Surg Oncol 2011; 18: 1590–1598. 4. Garcia-Aguilar J, Smith DD, Avila K, Bergsland EK, Chu P, Krieg RM; Timing of Rectal Cancer Response to Chemoradiation Consortium. Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg 2011; 254: 97–102. 5. Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U Jr, Silva e Sousa AH Jr et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240: 711–717. 6. Capirci C, Valentini V, Cionini L, De Paoli A, Rodel C, Glynne-Jones R et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 2008; 72: 99–107. 7. Shivnani AT, SmallWJr, Stryker SJ, Kiel KD, Lim S, Halverson AL et al. Preoperative chemoradiation for rectal cancer: results of multimodality management and analysis of prognostic factors. Am J Surg 2007; 193: 389–393. 8. Wheeler JM, Dodds E, Warren BF, Cunningham C, George BD, Jones AC et al. Preoperative chemoradiotherapy and total mesorectal excision surgery for locally advanced rectal cancer: correlation with rectal cancer regression grade. Dis Colon Rectum 2004; 47: 2025–2031. 9. Yeo SG, Kim DY, Kim TH, Chang HJ, Oh JH, ParkW et al. Pathologic complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer: long-term outcomes and prognostic significance of pathologic nodal status (KROG 09–01). Ann Surg 2010; 252: 998–1004. 10. Maas M, Nelemans PJ, Valentini V, Das P, R¨ odel C, Kuo LJ et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11: 835–844. GASTROENTEROLOG 55 Probiotiki pri vnetni črevesni bolezni Probiotics in Inflammatory Bowel Disease Rok Orel* Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko Pediatrična klinika, UKC Ljubljana Gastroenterolog 2013; suplement 2: 56–63 Ključne besede: probiotiki, mikrobiota, kronična vnetna črevesna bolezen Keywords: probiotics, microbiota, chronic inflammatory bowel disease POVZETEK ABSTRACT Nepravilen imunski odziv organizma na črevesne bakterije je eden ključnih dejavnikov pri patogenezi kroničninh vnetnih črevesnih bolezni. Zanimivo možnost zdravljenja predstavljalo probiotiki s svojimi številnimi mehanizmi delovanja, ki vključujejo vpliv na črevesno mikrobioto in njeno presnovo, preprečevanje naseljevanja patogenih mikroorganizmov, utrjevanje črevesne pregrade in usmerjanje črevesnega imunskega odziva. Vendar pa se je potrebno zavedati, da sta poti nastanka Crohnove bolezni in ulceroznega kolitisa različni in da so mehanizmi delovanja, s tem pa tudi klinični učinki probiotikov, specifični za vsak sev. Namen prispevka je pregled klinične učinkovitosti probiotikov pri zdravljenju aktivne oblike ulceroznega kolitisa, paučitisa in Crohnove bolezni in njihove vloge pri vzdrževanju remisije. Aberrant immune response to intestinal bacteria is regarded as crucial factor in the pathogenesis of inflammatory bowel disease. Probiotics with their multiple mechanisms of action including influence on gut microbiota and its metabolism, protection against environmental pathogens, augmentation of gut barrier function and regulation of intestinal immune response represent an interesting therapeutic option. However, it should be reminded that pathologic mechanisms underlying ulcerative colitis and Crohn’s disease differ and actions of probiotics are strain-specific. Therefore, specific probiotic strains or their combinations revealed to be effective in different IBD types as well as their stages of activity. The aim of this paper is to review clinical effectiveness of probiotics for the treatment of active ulcerative colitis, pouchitis and Crohn’s disease and maintenance therapy for these diseases while they are in remission. According to results of high-quality clinical trials the evidence of effectiveness is very strong for the multispecies probiotic VSL#3 in prevention of pouchitis and maintenance therapy of ulcerative colitis. For the latter indication non-pathogenic Escherichia coli strain Nissle 1917 can be also used. There is also a substantial evidence that VSL#3 and maybe E. coli Nissle given simultaneously with Prof. dr. Rok Orel, dr. med., Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko, Pediatrična klinika, UKC Ljubljana Bohoričeva 20, 1525 Ljubljana 56 GASTROENTEROLOG standard anti-inflammatory drugs are more effective in treatment of active ulcerative colitis than standard medical therapy alone. However, at this moment there is not enough evidence of any probiotic strain effectiveness in Crohn’s disease to recommend its routine clinical use. INTRODUCTION Listeria monocitogenes or adherent-invasive Escherichia coli (11). For example, mutations in NOD2/CARD15 gene recognized as an important risk factor for CD, result in deficient function of the key cytoplasmic receptor for recognition of intracellular bacterial peptidoglycan and consequent ineffective cytokine response and killing of intracellular pathogens (9–11). Although the exact etiology of inflammatory bowel disease remains unclear, it is believed that these diseases are the result of aberrant immune responses to intestinal microbes in the gastrointestinal tract in genetically susceptible host (1). There are many evidences that support the hypothesis of the involvement of intestinal microorganisms in the pathogenesis of IBD. In experimental animal models of IBD, genetically engineered to develop spontaneous chronic gut inflammation under standard laboratory conditions, this did not happen when they were raised in a germ-free environment (2, 3). The IBD lesions predominantly occur in the parts of GI tract with the highest density of bacterial microbiota such as terminal ileum and colon (4). In patients with CD, division of the fecal stream proximal to the inflamed mucosa results in reduction of inflammation in the excluded parts of the gut while relapse occurs with restoration of fecal stream and reexposure to luminal contents (5, 6). In addition, antibiotic treatment has been proved to be efficient in specific cases of IBD and in pouchitis (7). Moreover, a recent metaanalysis by Khan et al. showed a significant benefit of antibiotics over placebo for induction of remission in both CD and UC (8). Despite many evidences that intestinal microorganisms are required for triggering and perpetuation of inflammation in IBD, it still remains enigmatic whether a single specific microorganism or a group of microbial agents sharing distinctive characteristics could be responsible or an aberrant immune response to the dysbiosis of the commensal intestinal microbiota plays the major role. Genetic defects found in IBD patients might make these individuals particularly susceptible for the infections with intracellular bacteria such as Mycobacterium avium subspecies paratuberculosis, In contrast with vast majority of E. coli strains that inhabit human intestine as a part of a normal commensal microbiota, some strains acquired specific virulent factors that help them to adhere to intestinal mucosa and invade into it and consequently induce inflammatory response (11). Increased numbers of invasive mucosa-associated or even intramucosal E. coli, designated as adherent-invasive E. coli (AIEC), have been reported in patients with both CD and UC (12–17). AIEC are capable to adhere to and to invade intestinal epithelial cells with macropinocytosis-like process and to survive and replicate within macrophages, inducing the release of large amount of pro-inflammatory cytokines such as TNF-by the infected host cell (18). Even though several specific microorganisms may play an important role, no specific microorganism has been generally recognized as a causal factor. More probably subtle alterations in commensal microbiota composition and function (dysbiosis) can be involved in the pathogenesis of IBD. Numerous studies revealed that fecal microbiota has a different composition in IBD patients compared with controls, and even differences between CD and UC were found. The same is true for mucosa-associated microbiota, a bacterial population present on the mucosal surface that is in direct interaction with the intestinal epithelial and immune system cells (19–22). However, it remains unknown whether the intestinal microbiota triggers or maintains the GASTROENTEROLOG 57 chronicity of inflammatory response in IBD, or its composition is altered as a secondary response to the intestinal inflammation (23). microbes from luminal-mucosal interface by a competition for binding sites on epithelial cell surface or mucus (24, 29). The conventional therapy of IBD is focused on suppression of inflammation with aminosalicilates, steroids, immunomodulatory drugs, and anti-tumor necrosis factor antibodies. Therapeutic strategies directed towards change or restoration of the balance between intestinal bacteria represent attractive alternative or adjunct to the conventional therapy. The effective use of antibiotics to treat perianal CD, postoperative CD, pouchitis and maybe even UC are examples of IBD therapy targeting gut bacteria (7, 24, 25). Moreover, efficacy of therapy of active CD with enteral nutrition can be at least partially attributed to its influence on bacterial microbiota (26). Probiotics communicate with epithelial cells and different sets of cells implicated in both innate and acquired immune response via pattern-recognition receptors (30). They can enhance gut barrier function and reduce intestinal permeability for intestinal microorganisms and other antigens (31) by increasing mucus production (32, 33), induction of production and secretion of different anti-microbial peptides such as defensins, lysozyme, lactoferrin or phospholipase by epithelial cells and enhancement of tight junctions and reduction of epithelial cell apoptosis (24, 34, 35). The potential to manipulate intestinal microbiota with probiotics and prebiotics for positive therapeutic purposes in IBD is an attractive approach gaining great interest of both scientific community and end consumers – patients with IBD. MECHANISMS OF PROBIOTIC EFFECTS IN IBD Probiotics may achieve their therapeutic effect in IBD through many different mechanisms. They can influence the composition of intestinal microbiota and alter metabolic properties of the microbiome (23). They can produce short-chain fatty acids and consequently lower the pH the colonic environment what inhibits the growth of several potentially pathogenic microorganisms. In addition, butyrate plays a trophic role as a nutrient for colonicytes, enhances the repair of injured gut epithelium and acts directly as an anti-inflammatory agent by inactivation of intracellular transcriptional factor NFκB pathway and consequently attenuates the synthesis of inflammatory cytokines (27). A great number of probiotic strains produce antibacterial substances such as hydrogen peroxide, hydrogen sulphide, lactic acid and specific bacteriocins which can be active against pathogenic bacteria (28) and displace deleterious 58 GASTROENTEROLOG Probiotics can directly or indirectly modulate intestinal immune response. Each probiotic strain may have distinct immunoregulatory properties. Very simplified, probiotics can be classified in two groups regarding their influence on the immune system, one exhibiting immunostimulating activities and the other anti-inflammatory properties (36). Numerous studies revealed several mechanisms by which probiotics, including those with proven clinical efficacy in the therapy of IBD, down-regulate inflammatory immune response. Several probiotics are acting through maturation of intestinal dendritic cells and strengthening the regulatory T cell (Treg) response. Tregs are antigen specific T cells which prevent autoimmunity and preserve tolerance towards harmless antigens, including intestinal commensal microbiota (30). They can control excessive NFκB pathway activation and decrease production of pro-inflammatory cytokines such as TNFα, INFγ and IL-8, as well as induce a production and secretion of anti-inflammatory cytokines such as IL-10 and TGFβ (30, 36–38). Regarding facts that pathogenesis of each type of IBD differs and that mechanisms of probiotics action are strain specific and can be very different, it is expectable that for each type and phase of disease different probiotics would be effective. CLINICAL EVIDENCE OF EFFICACY OF PROBIOTICS IN IBD Treatment of active ulcerative colitis Clinical studies on the efficacy of probiotics for the induction of remission in ulcerative colitis gave encouraging, although conflicting results. There are two reports in the literature of succesfull use of an enema of the fecal microbiota from a healthy donor for treatment of active UC (39, 40). It is interesting that in spite of extremely encouraging results of these two reports, no other study using bacteriotherapy has been published. Several studies investigated efficacy of multispecies probiotic VSL#3 containing four strains of lactobacilli (L. casei, L. plantarum, L. acidophilus, L. delbrueckii subsp. bulgaricus), three strains of bifidobacteria (B. longum, B. breve, B. infantis) and one strain of Streptoccocus (S. Salivarius subsp. thermophilus). In these randomized, double-blind, placebo controlled trials they mostly compared VSL#3 as an addition to standard therapy with aminosalicilates, steroids and imunomodulators with standard therapy alone. Without exception, they found a supplementation with VSL#3 to be effective as clinical activity indexes (such as UCAI), as well as endoscopic appearance/hystology were significantly better in probiotic treated groups of UC patients (41–46). In addition, several other probiotic strains (E. coli Nissle 1917 (47), Saccharomyces boulardii (48), Lactobacillus reuteri ATCC 55730 (49), their combinations (BIO-THREE, containing Streptococcus faecalis, Clostridium butyricum and Bacillus mesentericus (50), Bifidobacteria-fermented milk (BFM), containing Bifidobacterium breve strain Yakult, B. bifidum and Lactobacillus acidophilus (51, 52)), or even symbiotic mixtures (Bifidobacterium longum and a prebiotic Synergy 1 (53), Bifidobacterium breve strain Yakult and galacto-oligosaccharide (GOS) (54)) were tested for their capacities of induction remission in active UC. The results of these studies, many of them too small to be conclusive, mostly gave positive results. Several reviews and meta-analyses were performed regarding induction of remission in ulcerative colitis by probiotics in recent years (55–58). In earlier reviews, not enough high-quality studies were found and they were regarded to heterogenous according to methodology and probiotic strains used to enable any firm conclusions. In contrast with older reviews, metaanalysis performed by Zigra et al. showed a significant benefit of probiotic use for induction of remission of UC with pooled relative risk 2.27 (95% CI: 1.00–5.14, P = 0.049) (57). In the most recent review by Jonkers and al. only subgroup-specific meta-analyses per probiotic were performed (58). The only probiotic with several published randomized controlled studies for induction of remission in adult patients with UC was VSL#3. The calculated pooled RR for VSL#3 was 1.69 (95% CI: 1.17–2.43), indicating a significant benefit of VSL#3 over control in inducing remission in active UC. Maintenance of remission in ulcerative colitis There were several published studies in which efficacy of probiotics Escherichia coli Nissle 1917 (47, 59, 60) or VSL#3 (46, 61) was compared to either placebo or standard therapy for maintenance therapy in UC. They revealed that these probiotic are as effective as mesalazine and more effective than placebo for maintenance of remission. In contrast with this, several other studies using some other probiotics such as Lactobacillus rhamnosus GG (62), Probio-Tec-AB-25 containing two probiotic strains, Lactobacillus acidophilus La-5 and Bifidobacterium animalis subspecies lactis BB-12 (63), Lactobacillus salivarius subspecies salivarius UCC118 and Bifidobacterium infantis 35624 (64) did not prove probiotics to be significantly more effective compared to placebo. In conclusion, specific probiotics as Escherichia coli Nissle 1917 and multispecies mixture VSL#3 are probably as efficient as standard maintenance therapy with mesalazine and can be therefore used instead of mesalazine in patients intolerant or allergic to 5-aminosalycilates, or as adjunctive therapy to standard GASTROENTEROLOG 59 therapy to potentially increase the duration of remission. In American Recommendations for probiotic use from 2011 we found a very strong “A” recommendation for the use of two specific probiotics, Escherichia coli Nissle 1917 and multispecies mixture VSL#3, for maintenance of remission in UC (65). American Recommendations for probiotic use from 2011 (65). Clinical guidelines for the management of pouchitis from 2009 suggest the use of VSL#3 in patients with recurrence of pouchitis following antibiotic treatment or having several recurrences despite antibiotic therapy (74). Treatment and prevention of pouchitis Treatment of active Crohn’s disease In some patients with UC in whom the disease do not respond to medical therapy or develop dysplasia or cancer, proctocolectomy with a construction of an ileal pouch-anal anastosis (IPAA) is required. An inflammation of this ileal reservoir (pouch), called pouchitis, developed in between 15 and 50% of such patients. Although the exact etiology of pouchitis is not clear, host genetic factors, fecal stasis, mucosal ischemia and bacterial dysbiosis in the pouch seem to be involved (32, 58). Most patients develop pouchitis in the first year after operation. Antibiotic therapy is generally successful, however the discontinuation of antibiotics is often followed by a recurrence of the disease. Therefore, treatment and prevention of pouchitis with probiotics have been studied extensively. There are only few published clinical studies addressing treatment of active Crohn’s disease with probiotics. Although the Cochrane Collaboration review from 2008 concluded that there was insufficient evidence to make any conclusions about the efficacy of probiotics for induction of remission in CD because of a lack of well designed clinical studies (75), two studies using symbiotics that were not included in this review revealed very promising results. Although several probiotics and their combinations were studied for treatment of pouchitis (66, 67), only studies using already mentioned multispecies preparation VSL#3 showed to be consistently effective both for maintaining remission after its induction with antibiotics or for prevention of pauchitis development after IPAA (68–72). 40–100% of patients taking VSL#3 stayed in remission for one year period in compare with 6% to 15% on placebo. Consequently, the effectiveness of VSL#3 was confirmed by two meta-analysis, revealing that VSL#3 was significantly more effective than placebo in the maintenance therapy of chronic pouchitis (97% vs. 3%, P < 0.0001) and the number needed to treat with VSL#3 to prevent one additional relapse was only 2 (58, 73). According to these findings, multispecies probiotic preparation VSL#3 was granted by A level recommendation for the primary prevention and maintenance of remission of pouchitis after IPAA in the 60 GASTROENTEROLOG In the first, which was unfortunately small open-label uncontrolled trial including only 10 CD patients resistant to the therapy with aminosalicylates and prednisolone, a symbiotic preparation consisting of 3 prebiotic strains (Bifidobacterium breve, Bifidobacterium longum and Lactobacillus casei) and prebiotic psyllium (Plantago ovata) was used. In a one-year period complete response was achieved in 6 patients with 2 able to discontinue corticosteroid therapy completely (76). In recently published randomized, doubleblind, placebo-controlled trial involving 35 patients with active CD, they used a symbiotic therapy comprising probiotic Bifidobacterium longum and prebiotic Synergy 1 (oligofructose and inulin) simultaneously with conventional therapy (77). Comparing pre and post-treatment results there was a significant clinical, endoscopical and histological improvement as well as decrease in TNFα in symbiotic but not in the placebo group. Maintenance of remission in Crohn’s disease Only few high-quality studies were performed to assess the efficacy of probiotics for maintenance of remission achieved with standard medical therapy or surgical resection in Crohn’s disease. Unfortunatelly, none of them showed the efficacy of probiotics (78-83) with an exception of a small trial in which a combination of Saccharomyces boulardii and mesalamine revealed to be significantly more efficient than mesalamine alone (84). In conclusion, at this moment the probiotic use for maintenance of remission in Crohn’s disease is not recommended. However, regarding growing awareness and knowledge about the role of microbiota in the pathogenesis of this disease as well as of the mechanisms of probiotics action, continuing efforts of scientific community to find specific probiotic strains with clinical efficacy in this indication can be expected. CONCLUSIONS Despite profound knowledge about potential mechanisms of pre and probiotic in IBD, the usable data from well-designed high-quality clinical are often to scarce to enable making of clear recommendations for their practical use. There is a very strong evidence supporting use of multispecies probiotic VSL#3 in patients with ileal-pouch-anal-anastomosis for prevention of postoperative pouchitis or its recurrence after induction of remission by antibiotics. In addition, this probiotic product may be an effective adjunct to antibiotic treatment for active pouchitis. Two probiotics, VSL#3 and nonpathogenic strain of Escherichi coli Nissle 1917, can be recommended for maintenance therapy in ulcerative colitis in remission, especially in patients intolerant or allergic to standard medical maintenance therapy, as they are regarded to be equally efficient. Results of several studies support the use of probiotics concomitant with standard medical treatment for induction of remission in ulcerative colitis. However, the evidence supporting their use is much weaker than in maintenance therapy. At the moment, the evidence of efficacy is strongest for VSL#3. 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GASTROENTEROLOG 63 Zdravljenje bolnikov z ulceroznim kolitisom: naše izkušnje z adalimumabom Treatment of ulcerative colitis: our experience with adalimumab Cvetka Pernat Drobež*, Andreja Ocepek Klinični oddelek za gastroenterologijo, Univerzitetni klinični center Maribor Gastroenterolog 2013; suplement 2: 64–67 POVZETEK ABSTRACT Izhodišča. Adalimumab je humano monoklonsko protitelo proti dejavniku tumorske nekroze alfa. Od aprila 2012 ga uporabljamo v zdravljenju ulceroznega kolitisa. Namen naše raziskave je ocena učinkovitosti adalimumaba pri zdravljenju bolnikov z zmerno do hudo potekajočim ulceroznim kolitisom. Background. Adalimumab is a human monoclonal antibody to tumor necrosis factor alpha. It has been used in the treatment of ulcerative colitis since April 2012. The aim of our study is to evaluate efficacy of adalimumab in the treatment of patients with moderate to severe ulcerative colitis. Bolniki in metode. Med avgustom 2012 in marcem 2013 smo začeli zdravljenje z adalimumabom pri 10 bolnikih z zmerno do hudo potekajočim ulceroznim kolitisom, kljub sočasnemu ali predhodnemu zdravljenju z imunosupresorji. 7 je bilo žensk in 3 moški, stari od 21 do 56 let. Ulcerozni pankolitis je bil diagnosticiran pri 4 ženskah in 2 moških. Levostranski ulcerozni kolitis je bil diagnosticiran pri 3 ženskah in 1 moškem. Bolniki so pri prvi aplikaciji prejeli 160 mg adalimumaba, po 2 tednih 80 mg in nato 40 mg vsak drugi teden. Osnovni cilj je bila ocena kliničnega odgovora po 12. tednih zdravljenja. Patients and methods. Between August 2012 and March 2013 we begun treatment with adalimumab in 10 patients with moderate to severe active ulcerative colitis despite concurrent or prior treatment with immunosuppressants. There were 7 females and 3 males, aged from 21 to 56 years. Ulcerative pancolitis was diagnosed in 4 females and 2 males and left-sided ulcerative colitis in 3 females and 1 men. Patients received adalimumab 160 mg at week 0, 80 mg at week 2 and then 40 mg every other week. Primary end point was clinical response at week 12. Rezultati. Klinični odgovor v 12. tednu je bil dosežen pri 5 ženskah in 2 moških. Resno okužbo sta razvili 2 ženski. Results. Clinical response at week 12 was achived in 5 females and 2 males. 2 females developed serious infection. * prim. Cvetka Pernat Drobež, dr. med. Klinika za interno medicino, Oddelek za gastroenterologijo, Univerzitetni klinični center Maribor Ljubljanska 5, 2000 Maribor 64 GASTROENTEROLOG Zaključek. Adalimumab je učinkovito zdravilo za indukcijo kliničnega odgovora pri bolnikih z zmerno do hudo potekajočim ulceroznim kolitisom, ki se niso odzvali na zdravljenje s kortikosteroidi in/ali imunosupresorji. Conclusion. Adalimumab is effective in inducing clinical response in patients with moderate to severe ulcerative colitis, who did not respond to therapy with corticosteroids and/or immunosuppressants. UVOD Cilji zdravljenja so sprožiti in vzdrževati remisijo bolezni brez rabe kortikosteroidov (KS), doseči celjenje črevesne sluznice, preprečiti zaplete UK, hospitalizacije in operacije ter preprečiti umrljivost povezano z njim; na ta način bomo izboljšali kvaliteto bolnikovega življenja. Zdravimo ga z aminosalicilati, kortikosteroidi, imunosupresorji, kot sta azatioprin (AZA) in 6-merkaptopurin (6-MP) ter s tarčnimi zdravili. Ulcerozni kolitis (UK) je kronična vnetna bolezen debelega črevesa, ki lahko prizadane celotno debelo črevo, praviloma je največkrat prizadeta danka. Bolezen je kronična, običajno doživljenjska, z akutnimi zagoni vnetja ter vmesnimi krajšimi ali daljšimi remisijami. Obolevajo ljudje v vseh starostnih obdobjih, pogosteje v starosti med 20–30 leti in med 60–80 leti. Glede razširjenosti vnetnega dogajanja razdelimo UK po Montrealski klasifikaciji v ulcerozni proktitis, levostranski UK in ulcerozni pankolitis (1). Norveška študija je na osnovi 10-letnega spremljanja kohorte bolnikov z UK potrdila, da lokalizacija vnetnega dogajanja ni konstantna, ampak se pri 20 % bolnikov širi oralno; pri 83 % bolnikov se zagoni bolezni ponavljajo; pankolitis in pospešena sedimentacija povečujeta tveganje za kolektomijo (2). Bolezen je kronična, najpogosteje poteka v zagonih, remisije so lahko dolge tudi po več let. Značilni simptomi so driska, krvavitve iz danke, številna iztrebljanja krvavkastega sluzavega blata, krčevite bolečine v trebuhu, lažni pozivi k iztrebljanju, povišana telesna temperatura, slabokrvnost in hujšanje. Resnost simptomov je sorazmerna z razširjenostjo bolezni. V klinični praksi je pomembno, da pri bolezni opredelimo aktivnost vnetja, saj le tako izberemo pravilno zdravljenje. Ne obstaja idealna razdelitev UK po aktivnosti vnetja. V zadnjem času jo ocenjujemo z Mayo točkovnikom, ki upošteva število iztrebljanj, prisotnost krvavitev iz danke, endoskopsko oceno črevesne sluznice in zdravnikovo oceno bolnikove bolezni glede prisotnosti ali odsotnosti znakov sistemskega vnetja (3). UK na ta način opredelimo, kot blago, zmerno in hudo potekajočo bolezen. Za zdravljenje UK sta odobreni 2 tarčni zdravili, in sicer infliximab (IFX) in adalimumab (Ada). Obe sta protitelesi proti vnetnemu citokinu, pomembnem v patogenezi UK-dejavniku tumorske nekroze alfa. Obe sta indicirani za zdravljenje zmerno do težko potekajočega UK, neodzivnega na standardno zdravljenje; IFX je indiciran tudi za zdravljenje fulminantno potekajočega UK. Izbor zdravil za zdravljenje UK je odvisen od aktivnosti vnetnega dogajanja in lokalizacije bolezni. Blago potekajoči UK: za indukcijo in vzdrževanje remisije so dovolj učinkoviti oralno ali/in topično delujoči aminosalicilati. Zmerno do težko potekajoči UK: za začetno zdravljenje so potrebna močnejša protivnetna zdravila, kot so KS v optimalnem odmerku. Po umirjanju simptomov, kar pričakujemo v 1 do 4 tednih, pričnemo odmerek zmanjševati. Remisijo vzdržuejmo z aminosalicilati in imunosupresorji. KS uporabljamo najkrajše možno časovno obdobje. Bolnike, ki so na KS-neodzivni, je mogoče prepoznati v 2–4 tednih. Čeprav je pogosta praksa, pa ni dokazov, da bi intravensko dani KS izboljšali odgovor bolnikov, neodzivnih na peroralne KS. Pri teh bolnikih v zdravljenje uvedemo tarčno zdravilo infliximab (3) ali adalimumab (4, 5). GASTROENTEROLOG 65 Pri bolnikih, ki tekom zdravljenja postanejo odvisni od KS, v zdravljenje vključimo imunosupresor ali AZA ali 6-MP, ki so učinkovita zdravila za vzdrževanje remisije, potrebujejo pa vsaj 3 mesečno obdobje, da se pokaže njihov optimalni učinek. Učinkovitost imunosupresorja ocenimo po 12 tednih (6). Če tudi imunosupresorji niso učinkoviti, v zdravljenje uvedemo tarčno zdravilo. Fulminantno potekajoči UK: takšne bolnike zdravimo v bolnišnici s parenteralnimi aplikacijami KS. Če v 3 do 7 dneh ni ustreznega izboljšanja, v zdravljenje vključimo tarčno zdravilo infliximab (7); če tudi tarčno zdravilo ni učinkovito, pride v poštev operativno zdravljenje. OCENA UČINKOVITOSTI ADALIMUMABA V ZDRAVLJENJU ZMERNO DO TEŽKO POTEKAJOČEGA UK; NAŠE IZKUŠNJE Adalimumab je odobren v ZDA, Evropi in na Japonskem za zdravljenje Crohnove bolezni, revmatoidnega artritisa, ankilozirajočega spondilitisa, juvenilnega idiopatskega artritisa, psoriatičnega artritisa in psoriaze. Študiji ULTRA 1 in ULTRA 2 sta potrdili njegovo učinkovitost tudi v zdravljenju zmerno do težko potekajočega UK (4,5). Tako je v Evropi Ada od aprila 2012 registriran tudi za zdravljenje UK. V naši ustanovi smo bolnike z UK pričeli zdraviti z adalimumabom jeseni 2012. Tekom zdravljenja smo in bomo tudi v prihodnje ocenjevali učinkovitost adalimumaba s spremljanjem kliničnega odgovora, klinične remisije in endoskopske remisije UK. Bolniki in metode dela Avgusta 2012 smo začeli zdravljenje z adalimumabom pri bolnikih z zmerno do hudo potekajočim UK. Vsi ti bolniki imajo UK, neodziven na standardno zdravljenje z imunosupresorji. Aktivnost bolezni smo ocenili glede na Mayo točkovnik, upoštevali smo število iztrebljanj, prisotnost rektalne krvavitve, endoskopsko oceno črevesne sluznice in splošno stanje bolnika (3). Bolniki morajo za zdra66 GASTROENTEROLOG vljenje z adalimumabom dosegati vsaj 6 od možnih 12 točk po Mayo točkovniku, endoskopski Mayo mora biti vsaj 2 točki. Diagnoza UK je bila postavljena endoskopsko ob programiranih koloskopijah in potrjena histološko. Citomegalovirusni (CMV) kolitis in Clostridium difficile kolitis sta izključena. Bolniki so praviloma naivni glede zdravljenja s tarčnimi zdravili. Ob uvajanju adalimumaba prejemajo svojo standardna zdravila; odmerek KS zmanjšujemo po sprejetih smernicah, AZA prejema še 3 mesece, z uživanjem aminosalicilatov nadaljuje. Za prvi odmerek prejmejo bolniki 160 mg adalimumaba in po 2 tednih 2. odmerek 80 mg - oba v naši ustanovi, nato si ustrezno poučeni sami aplicirajo 40 mg adalimumaba vsaki drugi teden. Uspeh zdravljenja smo opredelili kot klinični odgovor, klinično remisijo in zacelitev sluznice. Klinični odgovor je bil zadovoljiv, če smo zaznali upad Mayo točk 3 in več, krvavitve iz danke pa so se morale ustaviti. Klinična remisija je bila opredeljena kot skupni Mayo 2 in manj, nobena Mayo podtočka ne sme biti večja od 1. Zacelitev sluznice je opredeljena kot endoskopski Mayo 0 ali 1. Bolnike ocenjujemo na začetku zdravljenja po celotnem Mayo točkovniku; 2., 4., 8., in 12. teden jih ocenjujemo po parcialnem Mayo točkovniku brez endoskopske ocene. Če do 12. tedna ni kliničnega odgovora, opravimo ponovno oceno po celotnem Mayo točkovniku. Če je 12. teden klinični odgovor po parcialnem Mayo točkovniku zadovoljiv, opravimo oceno po celotnem Mayo točkovniku 24 teden. Od avgusta 2012 smo ocenili klinični odgovor pri 10 bolnikih z zmerno do hudo potekajočim UK. 7 je bilo žensk in 3 moški, stari od 21 do 56 let. Ulcerozni pankolitis je bil diagnosticiran pri 4 ženskah in 2 moških. Levostranski UK je bil diagnosticiran pri 3 ženskah in 1 moškem. Bolniki so prejeli prvič 160 mg adalimumaba, po 2 tednih 80 mg in nato 40 mg vsak drugi teden. Osnovni cilj je bila ocena kliničnega odgovora 12. teden. Rezultati Začetni Mayo je bil pri ženskah od 7 do 10 točk, pri moških od 9 do 12 točk. Klinični odgovor v 12. tednu je bil dosežen pri 5 ženskah s parcialnim Mayo 1 do 4 točke in 2 moških s parcialnim Mayo 2 do 4 točke, skupno pri 70 % bolnikov. Pri 1 ženski z nezadovoljivim kliničnim odgovorom smo v zdravljenje dodali KS, pri 1 ženski, zdravljeni z adalimumabom in aminosalicilati, smo zdravljenje prekinili zaradi pomembnih stranskih učinkov, in sicer resne okužbe. Pri 1 moškem ni bilo sprememb niti v parcialnem Mayo niti v celotnem Mayo, po dodatku KS nismo dosegli izboljšanja; zdravljenje z Ada smo prekinili, bolnika smo prevedli na IFX v kombinaciji z AZA. Bolniki so zdravljenje z Ada dobro prenašali, stranskih učinkov je bilo malo. Resno okužbo sta razvili 2 ženski: pri 1 ženski je bilo zdravljenje okužbe uspešno, pri 1 smo morali zdravljenje z Ada prekiniti. RAZPRAVA Naši rezultati potrjujejo ugotovitve študije ULTRA 1, ki je potrdila učinkovitost Ada 160 mg 0. teden, 80 mg 2. teden in nato 40 mg vsaka 2 tedna za indukcijo klinične remisije. Mi smo ocenjevali klinični odgovor 2., 4., 8. in12. teden zdravljenja. Spremljali smo število iztrebljanj, prisotnost krvavitve iz danke in upoštevali zdravnikovo globalno oceno prizadetosti bolnika. Menimo, da je ocena aktivnosti vnetja s parcialnim Mayo točkovnikom za potrebe klinične prakse zadostna; v primeru nezadovoljivega kliničnega odgovora je potrebna tudi endoskopska ocena. adalimumabom bolnik z zmerno do težko potekajočim UK, neodziven na KS in/ali imunosupresive, ki je naiven glede zdravljenja s tarčnimi zdravili in si želi udobja zdravljenja na domu. Na osnovi naših izkušenj ocenjujemo, da je Ada učinkovito zdravilo za indukcijo kliničnega odgovora pri bolnikih z zmerno do hudo potekajočim UK, ki se niso odzvali na zdravljenje s kortikosteroidi in/ali imunosupresorji. LITERATURA 1. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005; 19: 5–36. 2. Solberg IC, Lygren I, Jahnsen J, Aadland E, Hřie O et al. Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study). Scand J Gastroenterol. 2009;44(4):431–40. 3. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353(23): 2462–76. 4. Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011 Jun;60(6):780–7. 5. Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D'Haens G et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012; 142(2): 257–65. 6. Leung Y, Panaccione R, Hemmelgarn B, Jones J. Exposing the weaknesses: a systematic review of azathioprine efficacy in ulcerative colitis. Dig Dis Sci 2008; 53(6): 1455–61. 7. Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005; 128(7): 1805–11. Klinično remisijo bomo pri naših bolnikih ocenjevali po 24 tednu zdravljenja. Ugotovitve študije ULTRA 2 napovedujejo učinkovitost Ada v dolgotrajni klinični remisiji tudi pri naših bolnikih. Naši bolniki so bili naivni glede zdravljenja s tarčnimi zdravili. Analiza podskupin študije ULTRA 2 je pokazala najmočnejši učinek Ada pri bolnikih, ki so bili naivni glede zdravljenja s tarčnimi zdravili; ocena je, da je idealen bolnik za zdravljenje z GASTROENTEROLOG 67 Vloga MR-enterografije pri obravnavi bolnikov s Crohnovo boleznijo MR-Enterography in the management of patients with Crohn‘s disease Popovič Peter*, Rok Dežman, Miha Štabuc, Manca Garbajs Klinični inštitut za radiologijo, Univerzitetni klinični center Ljubljana Gastroenterolog 2013; suplement 2: 68–72 Ključne besede: Crohnova bolezen, slikovna diagnostika, magnetno resonančna enterografija, Key words: Crohn’s disease, diagnostic imaging, magnetic resonance enterography. POVZETEK ABSTRACT Crohnova bolezen (CB) je kronična vnetna črevesna bolezen, ki lahko zajame vse plasti črevesne stene v poteku celotnega prebavnega sistema. Najpogosteje je prizadeto ozko črevo. Magnetno resonančna-enterografija je slikovno preiskovalna metoda, ki se je uveljavila kot metoda izbora za oceno ozkega črevesja pri bolnikih s Crohnovo boleznijo. V tej vlogi nadomešča klasično jejunoileografijo in modernejšo računalniško tomografsko enterografijo. Z magnetno resonančno-enterografijo lahko potrdimo prisotnost bolezni, ocenimo njeno aktivnosti in eventualne zunajčrevesne zaplete (fistule, abscesi). Namen prispevka je predstaviti (1) trenutno vlogo magnetno resonančne-enterografije pri obravnavi bolnika s Crohnovo boleznijo, (2) predstaviti protokol in potek preiskave, (3) primerjati metodo z drugimi slikovno preiskovalnimi metodami in (4) opisati magnetno resonančne-značilnosti Crohnove bolezni v akutnem, penetrantnem in fibrostenozantnem stadiju bolezni. Crohn’s disease (CD) is a chronic inflammatory bowel disease. It can involve any part of the gastrointestinal tract but the small bowel is most commonly involved. It is characterized histologically by the presence of trans-mural inflammation of the bowel wall. Magnetic resonance enterography (MRE) is becoming the first-line diagnostic imaging modality in evaluation of the small bowel in patients with CD. It has surpassed the conventional small-bowel follow-through and modern computed tomographic enterography. MRE can confirm the presence of the CD, is able to assess disease activity and to demonstrate both mural and extramural complications. The purpose of this review is to (1) detail the current role of MRE in the management of patients with CD; (2) describe the protocol of the MRE at our institution; (3) compare MRE with other imaging modalities; (4) discuss the MRE findings in patients with CD in inflammatory, penetrating and stricturing phase of the disease. * asist. dr. Peter Popovič, dr. med. Klinični inštitut za radiologijo, Univerzitetni klinični center Ljubljana Zaloška 2, 1525 Ljubljana 68 GASTROENTEROLOG UVOD Crohnova bolezen (CB) je kronična, ponavljajoča se vnetna bolezen neznane etiologije, ki se običajno pojavi v zgodnjem otroštvu. Največkrat prizadeta organa sta ozko (80 %) in široko črevo, lahko pa je prizadet celotni prebavni trakt, od ust do anusa (1). Za bolezen je značilno vnetje vseh plasti črevesne stene in segmentna prizadetost prebavne cevi. Bolezenske spremembe najprej prizadanejo sluznico, histološko se kažejo kot vnetje s prisotnimi nekazeirajočimi granulomi. Pojavijo se erozije ter ulceracije sluznice in pozneje vnetne zožitve. Razjede sluznice lahko napredujejo v čezstenske razjede, te pa v sinuse, fistule in abscese – v tem stadiju govorimo o penetrantni bolezni. V kroničnem stadiju se v steni razrašča vezivo, kar povzroča zožitve črevesja in posledične obstrukcije. Vse naštete spremembe so lahko v posameznem segmentu črevesne vijuge prisotne istočasno (2). Penetrantni in stenozirajoči stadij bolezni pogosto zahtevata kirurško zdravljenje in se tekom življenja razvijeta pri večini bolnikov s CB (3). MR-ENTEROGRAFIJA Natančna ocenarazsežnosti CB je pogosto težavna (4), vendar pomembna za načrtovanje zdravljenja. Ker je ozko črevo skoraj v celoti nedostopno za endoskopijo, se je pri oceni tega dela že v preteklosti uveljavila slikovna diagnostika, vendar je veljalo, da je diagnostična vrednost magnetnoresonančnega slikanja (ang. magnetic resonance imaging - MRI) zaradi nekaterih značilnosti (npr. sorazmerno dolg čas preiskave v primejavi s CT) omejena na »stabilne« organe in ni primerna za oceno sorazmerno mobilnega črevesja. Z razvojem in uporabo novih, hitrejših sekvenc se je v zadnjem desetletju razvila magnetnoresonančna enterografija (MRE) (slika 1, 2). S to preiskavo lahko ocenjujemo lumen in steno ozkega črevesja ter tudi okolne strukture (5). Pri preiskavi uporabljamo specifične sekvence MRI, ki omogočajo morfološko oceno črevesnih vijug in rekonstrukcijo v več ravneh. Z uporabo enteralnega kontrastnega sredstva zagotovimo razpetost tankočrevesnih vijug, kar omogoča boljšo oceno črevesnega lumna in stene. Za oceno prekrvljenosti posameznih delov črevesnih vijug uporabljamo intravensko kontrastno sredstvo (KS). S kombinacijo vsega naštetega lahko z MRE ocenjujemo prisotnost bolezni in tudi ocenimo stadij, v kateri se bolezen nahaja. Evropska organizacija za Crohnovo bolezen in ulcerozni kolitis (ang. European Crohn’s and Colitis Organisation – ECCO) v svojem zadnjem priporočilu o diagnostiki in zdravljenju CB kot metodi izbora za oceno prizadetosti ozkega črevesja priporoča MRE in CT-enterografijo (6). Po priporočilih ECCO je pomemben argument pri izbiri preiskave tudi izpostavljenost bolnika iozinirajočemu sevanju. Zaradi kombinacije dobre morfološke ocene črevesja in odsotnosti ionizirajočega sevanja je MRE metoda izbora za oceno ozkega črevesja pri bolnikih s CB. PRIMERJAVA Z DRUGIMI MODALITETAMI Poleg MRE v Sloveniji za oceno ozkega črevesja uporabljamo še jejunoileografijo (JIG) in CT- enterografijo (CTE) ter kapsulno endoskopijo (KE). MR-enterografija ima v primerjavi z jejunoileografijo (JIG) precej prednosti. V primerjavi z JIG, ki dobro prikaže le lumen in sluznico, MRE omogoča oceno celotne črevesne stene in tudi oceno zunajčrevesnih struktur, npr. perienteričnega maščevja in pripadajočega mezenterija, povečanih bezgavk v mezenteriju in prikaz abscesov. Izometrične sekvence radiologu omogočajo Slika 1. Poslabšanje znane Crohnove bolezni pri 27-letnem bolniku. (a) Na prekontrastni VIBE sekvenci je viden zadebeljen in zožen daljši odsek terminalnega ileuma. (b) Postkontrastna VIBE sekvenca (60 s po i.v. aplikaciji gadolinijevega KS) - zadebeljena stena vijuge ima hiperintenziven signal – znak akutnega vnetja (puščica). Vidna je tudi poudarjena »vasa recta« (zvezdica) in povečane mezenterialne bezgavke (krajša puščica). Bolnik je bil po opravljeni diagnostiki zdravljen z biološkimi zdravili. GASTROENTEROLOG 69 pregled preiskave v več ravneh, zato superpozicija ne predstavlja problema pri interpretaciji (7). CTE in MRE sta enakovredni pri diagnostiki CB (8). CTE je v primerjavi z MRE hitrejša, bolj dostopna preiskava in je primernejša za bolnike s klavstrofobijo. Največja prednost MRE je odsotnost ionizirajočega sevanja (7). Zaradi narave CB so bolniki pogosto izpostavljeni slikovni diagnostiki, zato je pomembno, da jih, če se le da, ne izpostavljamo čezmernemu iozinirajočem sevanju (9). MRE omogoča tudi boljši prikaz mehkih tkiv, tekočine in edema. Pri KE bolnik poje kapsulo z videokamero. Kapsula nato s pomočjo peristaltike potuje vzdolž črevesja in pri tem ob določenih časovnih intervalih zajema slike črevesne sluznice. Metaanaliza je pokazala, da je kapsulna endoskopija bolj občutljiva pri odkrivanju zgodnje CB, ki je omejena le na spremembe sluznice. KE slabše oceni prizadetost stene črevesja, nemogoča pa je ocena zunajčrevesne prizadetosti (10). IZVEDBA PREISKAVE Priprava bolnika Bolnik na preiskavo pride tešč, vnos hrane je treba prekiniti vsaj 6 ur pred začetkom. Pred preiskavo bolniki peroralno zaužijejo 1–2 litra enteralnega kontrastnega sredstva, ki pripomore k zadostni razpetosti tankočrevesnih vijug. Kontrastna sredstva se med sebojj razlikujejo glede na svoje »obnašanje« na T1 in T2 obteženih sekvencah. Slika 2. 31-letna bolnica s Crohnovo boleznijo v penetrantnem stadiju. (a) Koronarna T2 HASTE, vidni sta dve intraperitonealni tekočinski kolekciji (puščica) – ob operaciji dokazani abscesni kolekciji. (b) Postkontrastna VIBE - »Zvezdast vzorec« (puščica), tipičen videz enteroenteralnih fistul. 70 GASTROENTEROLOG Negativna KS so hipointenzivna (znižan signal) na obeh sekvencah, medtem ko so pozitivna hiperintenzivna (zvišan signal). Večina ustanov uporablja bifazična enteralna KS, ki so imajo hiperintenziven signal na T2 obteženih sekvencah in hipointenziven signal na T1 obteženih sekvencah. Ta KS zaradi dobre kontrastnosti med hiperintenzivnim lumnom in hipointenzivno črevesno steno omogočajo oceno debeline črevesne stene na T2 sekvenci in dobro oceno obarvanja po aplikaciji i.v. KS na T1 sekvencah (11). Druga lastnost enteralnih KS je njihova osmolarnost glede na črevesno vsebino. Hiperosmolarna KS v črevesju delujejo kot osmotsko odvajalo in pripomorejo k boljši razpetosti črevesnih vijug v primerjavi z izoosmolarnimi (npr. voda) (11). Protokol, ki ga uporabljamo na KIR UKC LJ, temelji na priporočilih strokovnih člankov in na lastnih izkušnjah. Bolniki so pred preiskavo tešči 6 ur. V uri pred preiskavo zaužijejo 1,5 litra enteralnega kontrastnega sredstva. Uporabljamo 3 % raztopino sorbitola. Tik pred začetkom preiskave prejmejo intramuskularno injekcijo glukagona, ki zavre peristaltiko črevesja in omogoča boljšo tehnično izvedbo preiskave. Protokol preiskave Izvedba preiskave se razlikuje med različnimi ustanovami. Na KIR UKC Ljubljana preiskave opravljamo na 3T MR-napravi. Sama preiskava traja približno 20 minut. Začnemo s koronarno in aksialno sekvenco HASTE (Half Fourier acquisition single shot turbo spin echo) celotnega abdomna (slika 2a). Omenjena sekvenca je uporabna za oceno anatomije abdomna in širine črevesnih vijug, dobro pa je vidna tudi zadebeljena stena vijug. Nadaljujemo z izometrično sekvenco VIBE (Volumetric Interpolated Breath-hold Examination) pred in po intravenski aplikaciji gadolinijevega kontrastnega sredstva (Slika 1a, 1b, 2b). Slikanje v arterijski fazi opravimo 30 sekund po aplikaciji kontrastnega sredstva, nato pa opravimo še slikanji po 60 sekundah in 3 minutah. Tako časovno zaporedje je optimalno za prikaz progresivnega ojačanja čreve- sne stene, ki je značilno za akutno vnetje v sklopu CB (slika 1b) (12). Na sekvencah poleg anatomije in dinamike obarvanja črevesnih vijug ocenjujemo še stanje mezenterija, mezenterialnega žilja, bezgavk in ugotavljamo prisotnost fistul ali tekočinskih kolekcij v abdomnu. Ocena stadija bolezni: Obravnava bolnika s CB je kompleksna in zahteva multidisciplinaren pristop gastroenterologa, abdominalnega kirurga in radiologa. Radiolog lahko z uporabo MRE poda naslednje odgovore: (1) ali je prizadeto tanko črevo in v kolikšni meri, (2) ali je bolezen v aktivnem ali v kroničnem (fibrostenozantnem) stadiju, (3) ali je prisotna penetrantna bolezen z ekstraintestinalnimi zapleti, (4) oceno odgovora na medikametozno terapijo. Glavna značilnost CB pri MRE je zadebelitev črevesne stene, ki je po navadi povezana z zožitvijo lumna (slika 1a). Najpogosteje je prizadet terminalni ileum, prizadeti pa so tudi drugi odseki v poteku črevesja z vmesnimi odseki neprizadetega črevesja (»skip lezije«). Ključno vprašanje pri vodenju bolnika s CB je ocena aktivnosti bolezni. Glede na radiološki videz lahko CB razdelimo v akutni, penetrantni in fibrostenozirajoči stadij bolezni (13). Ponavadi so pri enem bolniku prisotni različni stadiji bolezni. edema. Po aplikaciji kontrastnega sredstva se signal stene prizadetih vijug intenzivno ojača (slika 1b). Zaradi hipointenzivnega submukoznega edema in hiperintenzivne mukoze in seroze ima vijuga videz razslojenosti. Zaradi aktivnega vnetja in posledične hiperemije je pomnoženo mezenterialno žilje, predvsem vasa recta, kar vidimo kot t.i. znak glavnika (ang. comb sign) (slika 1b) (14). V priležnem mezenteriju je vidna reaktivna limfadenopatija (slika 1b). Obravnava akutnega stadija bolezni brez pridruženih penetrantnih ali fibrostenozantnih sprememb je običajno konservativna/medikamentozna. Fibrostenozantni stadij – V kroničnem stadiju bolezni se začne v stenah vijug tvoriti vezivno tkivo, stene postanejo fibrozirane in rigidne. Na mestu fibroze se lahko tvori zožitev (stenoza) in privede do obstrukcije črevesja. Zaradi dalj časa trajajočega čez stenskega vnetja se ob črevesni vijugi začne odlagati maščevje, ki odriva mezenterično žilje in sosednje črevesne vijuge – govorimo o hipertrofiji mezenteričnega maščevja (ang. fat–wrapping; slika 3), ki je pogosto asimetrično izraženo in bolj izrazito na mezenterielni strani vijug. Videz je specifičen za CB. V akutnem stadiju bolezni so prizadete vijuge ozkega črevesja zadebeljene zaradi submukoznega MR-enterografija lahko loči zožitve, ki so posledica fibroze, od zožitev, v katerih je prisotno akutno vnetje. Razločevanje med njimi je pomembno zaradi različne obravnave; fibrozirana zožitev brez akutnega vnetja se ne odziva na terapijo z zdravili in v primeru simptomatske obstrukcije črevesja zahteva operativno zdravljenje. Slika 3. Bolnik s Crohnovo boleznijo v kroničnem stadiju. a) Pomnoženo mezenterično maščevje v področju terminalnega ileuma (puščica). (b) Po aplikaciji KS ni vidnih znakov za akutno fazo bolezni. Penetrantni stadij – Z napredovanjem bolezni lahko razjede v steni napredujejo do perforacije črevesnih vijug in tvorjenja fistul in intraperitonealnih abscesov. Fistule se tvorijo med vijugami ozkega črevesja (enteroenteralne fistule), lahko pa tudi med tankim črevesjem in drugimi deli prebavne cevi (kolon, želodec), sečnim mehurjem ali s kožo (slika 2b). Pri oceni fistul in sinusov ima MRE visoko občutljivost (> 75 %) in specifičnost (> 99 %) (15). Prisotnost in anatomijo fistule ocenjujemo na postkontrastnih T1-VIBE, kjer imajo zaradi dobre prekrvljenosti hiperintenziven signal (16). GASTROENTEROLOG 71 Po naših izkušnjah je za oceno abscesov najbolje primerjati T2-HASTE (slika 2a) in T1-VIBE sekvence. Na T2-HASTE ima vsebina hiperintenziven signal, signal stene abscesa pa je na postkontrastnih T1-VIBE hiperintenziven. Potrditev abscesa spremeni medikamentozno terapijo bolezni in usmeri nadaljnje zdravljenje v perkutano drenažo oz. operacijo. Ocena učinkovitosti medikamentoznega zdravljenja MRE je učinkovita metoda za oceno učinkovitosti medikamentozne terapije. Opravimo jo v akutnem relapsu bolezni in nato v remisiji. Pri učinkovitem odgovoru na zdravljenje je vidno zmanjšanje debeline prizadetih segmentov in tudi manjše obarvanje prizadetih segmentov po aplikaciji KS, medtem ko zoženje lumna lahko ostaja (17). Biološka zdravila, kot so infliximab in adalimumab, se uporabljajo pri zdravljenju bolnikov s CB, ki je odporna na druge terapije. MRE se utegne izkazati kot učinkovita metoda za oceno uspešnosti in načrtovanja zdravljenja z biološkimi zdravili in bi posledično utegnila zmanjšati prekomerno rabo omenjenih zdravil in stroške zdravljenja Vloga difuzijskega slikanja pri oceni Crohnove bolezni V zadnjih petih letih opravljene manjše študije dokazujejo, da je difuzijsko slikanje najverjetneje v pomoč pri oceni aktivnosti CB v prizadetem črevesju (18). Ocena difuzije omogoča razlikovanje med aktivnim vnetjem in fibrostenozantnim stadijem bolezni. Pri aktivnem vnetju imajo prizadete črevesne vijuge bolj izraženo restrikcijo difuzije (19) kot segmenti črevesja brez aktivnega vnetja. S pomočjo difuzijskega slikanja je zanesljivejše tudi odkrivanje intraabdominalnih abscesov (20). Difuzijsko slikanje bi lahko imelo vlogo pri oceni učinkovitosti zdravljenja, vendar študij s tega področja še ni. ZAKLJUČEK MR-enterografija se je v svetu in pri nas uveljavila kot slikovno preiskovalna metoda izbora pri obravnavi bolnikov s CB. Uporabna je pri potrditvi diagnoze, oceni razširjenosti bolezni in za oceno aktivnosti bolezni. Dobro prikaže spremembe tako v steni 72 GASTROENTEROLOG črevesja kot tudi zunaj črevesja ter zaplete CB kot so obstrukcija, penetrantna bolezen in formacija abscesov. Pomembna prednost MR-enterografije je odsotnost ionizirajočega sevanja, zaradi česar je primerna za uporabo pri mlajših bolnikih. LITARATURA 1. Scaldaferri, F. and C. Fiocchi, Inflammatory bowel disease: progress and current concepts of etiopathogenesis. J Dig Dis, 2007. 8 (4): p. 171–8. 2. Gramlich, T. and R.E. Petras, Pathology of inflammatory bowel disease. Semin Pediatr Surg, 2007. 16 (3): p. 154–63. 3. Louis, E., et al., Behaviour of Crohn’s disease according to the Vienna classification: changing pattern over the course of the disease. Gut, 2001. 49 (6): p. 777–82. 4. Horsthuis, K., et al., Inflammatory bowel disease diagnosed with US, MR, scintigraphy, and CT: meta-analysis of prospective studies. Radiology, 2008. 247 (1): p. 64–79. 5. Furukawa, A., et al., Cross-sectional imaging in Crohn disease. Radiographics, 2004. 24 (3): p. 689–702. 6. Van Assche, G., et al., The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Definitions and diagnosis. J Crohns Colitis, 2010. 4 (1): p. 7–27. 7. Lee, S.S., et al., Crohn disease of the small bowel: comparison of CT enterography, MR enterography, and small-bowel follow-through as diagnostic techniques. Radiology, 2009. 251 (3): p. 751–61. 8. Siddiki, H.A., et al., Prospective comparison of state-of-the-art MR enterography and CT enterography in small-bowel Crohn’s disease. AJR Am J Roentgenol, 2009. 193 (1): p. 113–21. 9. Dixon, A.K. and P. Dendy, Spiral CT: how much does radiation dose matter? Lancet, 1998. 352 (9134): p. 1082–3. 10. Triester, S.L., et al., A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with non-stricturing small bowel Crohn’s disease. Am J Gastroenterol, 2006. 101 (5): p. 954–64. 11. Laghi, A., et al., Oral contrast agents for magnetic resonance imaging of the bowel. Top Magn Reson Imaging, 2002. 13 (6): p. 389–96. 12. Pauls, S., et al., Evaluating bowel wall vascularity in Crohn’s disease: a comparison of dynamic MRI and wideband harmonic imaging contrast-enhanced low MI ultrasound. Eur Radiol, 2006. 16 (11): p. 2410–7. 13. Maglinte, D.D., et al., Classification of small bowel Crohn’s subtypes based on multimodality imaging. Radiol Clin North Am, 2003. 41 (2): p. 285–303. 14. Malago, R., et al., Assessment of Crohn’s disease activity in the small bowel with MR-enteroclysis: clinico-radiological correlations. Abdom Imaging, 2008. 33 (6): p. 669–75. 15. Koh, D.M., et al., MR imaging evaluation of the activity of Crohn’s disease. AJR Am J Roentgenol, 2001. 177 (6): p. 1325–32. 16. Schmidt, S., et al., Diagnostic performance of MRI for detection of intestinal fistulas in patients with complicated inflammatory bowel conditions. Eur Radiol, 2007. 17 (11): p. 2957–63. 17. Sempere, G.A., et al., MRI evaluation of inflammatory activity in Crohn’s disease. AJR Am J Roentgenol, 2005. 184 (6): p. 1829–35. 18. Oto, A., et al., Evaluation of diffusion-weighted MR imaging for detection of bowel inflammation in patients with Crohn’s disease. Acad Radiol, 2009. 16 (5): p. 597–603. 19. Oto, A., et al., Active Crohn’s disease in the small bowel: evaluation by diffusion weighted imaging and quantitative dynamic contrast enhanced MR imaging. J Magn Reson Imaging, 2011. 33 (3): p. 615–24. 20. Chou, C.P., et al., Differentiation between pelvic abscesses and pelvic tumors with diffusion-weighted MR imaging: a preliminary study. Clin Imaging, 2012. 36 (5): p. 532–8. Zapleti pri kirurškem zdravljenju raka trebušne slinavke Complications in surgical treatment of pancreatic cancer Stojan Potrč*, Matjaž Horvat, Arpad Ivanecz, Tomaž Jagrič, Marko Hazabent, Bojan Iljevec Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika, UKC Maribor Gastroenterolog 2013; suplement 2: 73–75 Ključne besede: rak trebušne slinavke, resekcija, zapleti Key words: pancreatic cancer, resection, complications POVZETEK ABSTRACT Kljub napredku kirurških tehnik je preživetje po operacijah zaradi raka trebušne slinavke še vedno slabo. V retrospektivni analizi smo pregledali podatke 286 bolnikov, ki so bili v obdobju od januarja 1999 do decembra 2012 operirani zaradi raka trebušne slinavke. Samo pri 169 bolnikih (82 moških, 87 žensk: povprečna starost 64,7 let) je bilo mogoče opraviti resekcijo, Pri ostalih je bilo obolenje neresektabilno. Bolnike smo razdelili v dve zaporedni skupini obdobja 7 let. Analizirali smo pooperativno obolevnost in umrljivost ter ju primerjali med skupinama. Skupna pooperativna pogostost kirurških, splošnih zapletov in umrljivost so bili 21,3 %, 14,2 % in 5,3 %. Primerjava rezultatov dveh obdobij ni pokazala pomembno različne stopnje pooperativnih zapletov, vendar pa je pooperativna umrljivost v zadnjem 7 letnem obdobju pomembno upadla na 2,6 % (p = 0,025). Tudi dolgoročno preživetje je v zadnjem 7 letnem obdobju daljše, vendar razlika ni statistično značilna. Despite the improvements in surgical technique and the abilities of intensive medical treatment, the results regarding the long term survival are somehow disappointing in pancreas cancer patients. In a retrospective study we reviewed the files of 286 patients operated for pancreatic cancer from January 1999 to December 2012. Of these only 169 (82 male, 87 female, mean age 64,7 years) had pancreatic resection for resectable pancreatic cancer. In the rest the disease was unresectable. Patients were grouped in two successive 7 year periods and compared for perioperative morbidity and mortality and long term survival. The overall incidence of surgical complications, general complications and mortality were 21,3%, 14,2% and 5,3%. There was no significant difference concerning the morbidity between the periods however, the perioperative mortality dropped significantly in the last 7 year period on 2,6% (p = 0,025). The long term survival is insignificant longer in the second period. *Prof. dr. Stojan Potrč, dr. med. Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika, UKC Maribor, Ljubljanska 5, 2000 Maribor, Slovenija GASTROENTEROLOG 73 BACKGROUND Resection of the appropriate part of the pancreas is without any doubt the only treatment which can offer the patient long term survival. However, despite the improvements in surgical technique and the abilities of intensive medical treatment, the results concerning the long term survival are somehow disappointing. Perioperative complications accompanied by high perioperative mortality were very important factors which burdened success of pancreatic resections. However the reports from many experienced centers in the last decade are encouraging. PATIENTS AND METHODS In a retrospective study we reviewed the files of 286 patients operated for pancreatic cancer from January 1999 to December 2012. Of these only 169 (82 male, 87 female, mean age 64,7 years) had pancreatic resection for resectable pancreatic cancer. In the rest, because of locally unresectable or disseminated disease exploration with or without a palliative procedure was performed. Resected specimens were examined according to standard patho-histologic procedure and classified according to Lauren, Ming, WHO, TNM and UICC classification as well as according to differentiation of tumor cells (gradus). For the purposes of the study, we divided the patients after resection in two successive 7 year periods and compared their perioperative morbidity and mortality and long term survival (period 1: from 1999 to 2005, n = 55; period 2: from 2006 to 2012, n = 114). Perioperative and clinicopathological parameters were evaluated and further compared between the two groups of patients. The cut-off date of the study was December 31, 2012. The survival data were obtained from the Cancer Registry of Slovenia. Statistical workup was done by statistical program IBM SPSS 20. For analyses of descriptive variables 74 GASTROENTEROLOG Chi-Square tests was used and for analyses in numeric variables a Student’s t test and MannWhitney tests, where appropriate, were performed. Survival analysis was done by Kaplan-Meier method and multivariate analysis by Cox regression (9, 10). RESULTS The types of resection in these patients were: 39,6% pylorus preserving Whipple resection of the pancreatic head, 37,3% Whipple resection of the pancreatic head, 19,5% left pancreatectomy, 3,6% total pancreatectomy. Overall for pancreatojejunoanastomosis external transanastomotic stents were used in 33,7%, “lost” internal drains in 10,1% of resected patients. External drains were not used any more for the last 7 years. In 28,2% of patients some form of adjuvant oncological treatment was added. Concerning TNM classification, 13,7% were T1, 21,4% were T2, 60,7% were T3, 4,3% were T4, 32,2% were N0 and 65,8% were N1. A curable resection (R0) was possible in 69,2%, the rest (30,8%) were not curable (R1) resections. The univariate survival analysis revealed a better median survival in R0 than in R1 resections (20,5 Vs. 12 months, p = 0,008) as well as its dependance on T (p = 0,041) and N (p = 0,035) stage. Preoperative general condition (ASA), gender, type of operation and adjuvant oncological therapy did not impact the long term survival (p = 1,64, p = 0,26, p = 0,21, p = 0,18). The overall incidence of surgical complications, general complications, perioperative mortality and 5 years survival were 21,3%, 14,2%, 5,3% and 19,2% respectively. Long term survival in patient who survived the perioperative morbidity was comparable to those without perioperative morbidity (p = 0,22). According to Patients after resections from the period 1 (n = 55) were statistically comparable to those from the period 2 (n = 114) regarding the age, gender, type of operation, treatment of complications, adjuvant oncological treatment, the stage T and regarding the curability of the procedure (p = 0,059, p = 0,53, p = 0,30, p = 0,88, p = 0,91, p = 0,85, p = 0,53). But patients in the group 2 were in poorer general condition (ASA) and had more often metastases in the lymph nodes (p < 0,001, p = 0,02 The perioperative surgical and general morbidity decreased impressively in the second period from 29% and 18% to 17% and 12% respectively, it didn’t reach the statistical significance though (p = 0,18 and p = 0,33). The type of complications (4,1% leak from bilioenteric anastomosis, 4,1% leak from the pancreatojejuno anastomosis, 3,6% intraabdominal abscesses, 3,6% gastric emptying syndrome, 2,4% perioperative bleeding, 1,8% disrupted laparotomy, 0,6% colonic ischemia, 0,6% necrotizing pancreatitis) revealed some differences (less gastric emptying syndrome and less of leaks from the pancreatojejuno anastomosis) between the periods, but the difference was only borderline (p = 0,051). However, the mortality dropped significantly (2,6%) in the second period of the study (p = 0,025). The median survival in the second period reveals a slight increase (from 17 months to 21 months) but it is not statistically significant (p = 0,19). CONCLUSION The main goal of surgical treatment of resectable pancreatic cancer - to increase the long term survival substantially - is worldwide still not achieved. In our study only about 20 % of the patients were alive after 5 years. The results of the comparison of two periods indicate significant trends toward lower perioperative morbidity and mortality in the last 7 year period. A slight but again insignificant increase in long term survival is very likely the result of the former factors. In respect to reports from other centers regarding the prognostic factors, and our results cover with them, it seems imperative to diagnose and treat the disease in its early stage. Keeping the perioperative complications and especially the perioperative mortality low is of paramount importance not to come in situations where the treatment would be worse than the disease itself. GASTROENTEROLOG 75 Napredovali rak želodca – kirurška taktika Advanced gastric cancer – surgical tactic Stojan Potrc*,1, Matjaz Horvat1, Arpad Ivanecz1, Tomaz Jagric1, Bojan Iljevec1, Irena Oblak2, Vaneja Velenik2, Janja Ocvirk3 1 Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika, UKC Maribor 2 Oddelek za radioterapijo, Onkološki inštitut Ljubljana 3 Oddelek za internistično onkologijo, Onkološki inšitut Ljubljana Gastroenterolog 2013; suplement 2: 76–86 Ključne besede: napredoval rak želodca, kirurgija, multidisciplinarni pristop Key words: advanced gastric cancer, surgery, multimodality treatment POVZETEK ABSTRACT Kirurška resekcija ostaja edino morebitno ozdravitveno zdravljenje napredovalega raka želodca. V zadnjih letih je perioperativna umrljivost vse nižja, kakovost življenja po posegu višja, srednje preživetje pa počasi dosega tistega na vzhodu. Poleg kirurgije sta pri zdravljenju napredovalega raka želodca pomembni tudi kemo in radioterapija. V prispevku je povzet pregled pristopa k zdravljenju napredovalega raka želodca in predstavljene naše izkušnje. Od začetka leta 2012 do konca leta 2013 smo operirali 1108 bolnikov. Primerjava dveh zaporednih obdobij je pokazala pomembne razlike v razširjenosti resekcij, limfadenektomij, perioperativni morbiditeti in mortalitieti in dolgoročnem preživetju; boljše rezultate dosegamo v kasnejšem obdobju (totalne gastrektomije 77 %, limfadenektomije D1 87 %, 5-letno preživetje 53, srednje preživetje 78 mesecev, perioperativna umrljivost 3 %). Potentially curative surgical resection remains the mainstay treatment for patients with advanced gastric cancer (AGC). The results in term of better long term survival, acceptable and low perioperative morbidity and mortality as well as the patient’s quality of life have improved substantially in western world and are gradually reaching those in the east. Multimodality treatment is important in AGC management. The aim of the present article is to review current approach to AGC treatment and present our treatment results. We report on 1108 patients operated for gastric cancer in the period from January 1st 1992 to December 31st 2012. Comparison of two chronologically successive groups of patients revealed some significant differences regarding the extent of resection, extent of lymphadenectomy, perioperative morbidity and mortality as well as long term survival, all in terms of better results in the recent group (total gastrectomies - 77%, D1 lymphadenectomy - 87%, 5-year survival - 53%; median survival - 78 months, perioperative mortality - 3%). *prof. dr. Stojan Potrc, dr. med., Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika, UKC Maribor, Ljubljanska 5, 2000 Maribor, Slovenija 76 GASTROENTEROLOG INTRODUCTION Potentially curative surgical resection remains the mainstay treatment for patients with advanced gastric cancer (AGC). It presents the only unimodal treatment which itself offers long-term survival. The experiences with radical surgical approach developed in Eastern Asia many decades ago, long time rejected by western surgical society, has now become accepted and implemented also in many high volume centers in Europe. The results in term of better long term survival, acceptable and low perioperative morbidity and mortality as well as the patient’s quality of life have improved substantially presently in western world and are gradually edging those in the east. Unlike the early gastric cancer where recently less aggressive modalities were implemented, for now, there is only limited space for “tailoring” of surgical procedure regarding extend of stomach resection and lymphadenectomy. Including some oncological treatment settings, the multimodality becomes an issue in the global treatment of AGC too. Resection for palliation doesn’t follow this aim and results regarding the survival are disappointing. As with other gastroenterological malignancy additional chemo and/or radiotherapy has in recent decade become a standard for selected groups of patients with AGC in many countries. However, some controversies regarding the timing type and combination of these additional settings still exist. PATIENTS AND METHODS 1108 patients were operated for gastric cancer in the period from January 1st 1992 to December 31st 2012. 989 patients had a resection of the stomach and among this group 847 patients had a potentially curative resection (R0), the reminder had gross or microscopically non curable resections (R2 and R1) or a nonresective procedures were performed. Patients with local carcinosis in the bursa omentalis were included if an R0 recection was performed (UICC stage 4). As table 1 shows less than 13% of patients were in favorable early stage, the rest were patients with AGC. In patients after R0 resection two chronologically successive groups of patients were formed (P1 = 1992–2002 and P2 = 2003–2012). P1 comprised 342 and P2 505 patients. The demographic statistics and results of survival analyses and some significant differences between two groups are revealed in table 1 and 2. Survival analyses and comparison between two periods were separately performed for all R0 resections, for patients with distal sited tumours and for patients with tumours in the proximal third of the stomach (table 2). Regarding the type of resection and extent of lymphadenectomy in potentially curable resections we mostly obeyed the principals from the high volume centre’s in west and east as well as domestic experience by professor Repše in the early nineties in Ljubljana. Presently our surgical strategy and tactics nicely match the S3 guidelines in Germany (1–5). Adjuvant chemo or chemo-radio therapy was started in 2001 and was indicated in 39,2% patients after R0 resections (P 2). Perioperative chemotherapy was started in 2011 and was indicated in 8,2% till now (P 2) (table 1). A subgroup of patients of 99 patients operated between January 2001 and December 2010 with chemo-radiotherapy added to surgery was studied for any survival benefit. Clinical and pathological data were prospectively stored in a computerized data base. Data from the follow-up were obtained by our own outpatient follow-up and by the National cancer registry of Slovenia. Complete follow-up was obtained as of 31st of December 2012. The median follow up period was 94 months. Perioperative mortality was defined by survival of 30 days irrelevant if patients may have already been dismissed from the ward. Resected specimens were examined according to standard patho-histologic procedure and classified according to Lauren, Ming, WHO, TNM and UICC classification as well as according to differentiation of tumor cells (gradus) (6, 7, 8). Statistical workup was done by statistical program IBM SPSS 20. For analyses of descriptive variables Chi-Square tests was used and for analyses in numeric variables a Student’s t-test and Mann-Whitney tests GASTROENTEROLOG 77 where appropriate were performed. Survival analysis was done by Kaplan-Meier method and multivariate analysis by Cox regression (9, 10). CURABILITY OF THE PROCEDURE The strategic aim of the of the treatment in AGC must be a potentially curable resection, however according to the epidemiological data sourced from the National Cancer registry of Slovenia only 60% of all patients registered for gastric cancer received a specific treatment. More than 90% of patients receiving a specific treatment were treated surgically, however only 75–85% of those received an R0 resection (3, 11). It is well documented that R0 resection presents the only unimodal treatment which itself offers long-term survival in treatment in patients with resectable advanced gastric cancer (2, 3, 4). Table 1. Demographic data for all (n= 847) R0 resected patients. Overall and grouped in two chronologically periods (P1 = 1992-2002; n = 342 and P2 = 2003-2012; n = 505) Mean age Gender Site of the tumour Differentiation (G) Lauren classification UICC stage Male Female Distal third Middle third Proximal third Entire Gastric stump G1 G2 G3 G4 Intestinal Diffuse Mixed Ia Ib IIa IIb IIIa IIIb IIIc IV Un classified Metastases in lymph nodes Mean diamether of the tumour Neoadj. onco. th. received Adjuv. onc. th. received Type of resection Extent of lymphadenectomy 78 GASTROENTEROLOG Distal subtotal Total Total+dist. esoph. Proximal Gastric stump Wedge D 1,5 and more P1 P2 all p 64,3 y 59,6% 40,4% 49% 33% 12,6% 1,8% 3,2% 15,7% 30,8% 50,9% 2,5% 45,9% 39,3% 14,9% 9,9% 10,5% 12,6% 10,2% 14% 21,6% 2,6% 0,6% 17,8% 62,7% 59 mm 0 2,6% 50,3% 43,2 1,5% 2% 3,2% 0 67,8% 64,9 y 65.1% 34,9% 32,3% 37,2% 22,2% 5,3% 3% 12,9% 27,4% 59% 0,7% 47,2% 31% 21,8% 14,9% 12,3% 10,3% 14,9% 14,9% 16,2% 7,9% 3% 5,7% 63,4% 65 mm 8,3% 39,2% 20,4% 68,6% 8,3% 4% 3% 0,8% 87,2% 64,6 y 62,9% 37,1% 39,1% 35,7% 18,3% 3,9% 3,1% 12,9% 28,3% 56,9% 1,1% 46,7% 31,2% 19,1% 12,9% 11,6% 11,2% 13,0% 14,5% 18,4% 5,8% 2% 10,6% 63,1% 63,6 mm 5% 24,4% 32,5% 55,3% 5,5% 3,2% 3,1% 0,5% 79% ns ns p<0,0001 ns p=0,015 p<0,0001 ns p<0,0001 p<0,0001 p<0,0001 Demographic data, main characteristics of the tumour, results of patohistological workup (Differentiation of the tumor cells, Lauren classification, UICC stage, proportion of affected of lymph nodes, mean number of affected lymph nodes and mean number of harvested lymph nodes) as well as the results regarding the survival, perioperative morbidity and mortality from the present trail are given in tables 1 and 2. Survival analysis revealed a significant longer overall survival in P2 (49.6 Vs. 31.1 months; p=0.049), however the statistical significance vanish after the mortality was excluded from the calculations. Certainly the prognosis is much impacted by the stage of the disease. Our trail revealed that R0 resected patients having intestinal type of the tumor, with well to moderate differentiated tumour cells (G1 and 2 Vs. G3 and 4), in lower UICC stage, with less infiltration on stomach wall (T stage) and without lymph node metastases have significant better long term survival expectation than those with less favorable differentiation, diffuse Lauren type or otherwise more progressed disease (G: p<0,0001; Lauren: p<0,0001; UICC: p<0,0001; T: p<0,0001; metastases in lymph nodes: p>0,0001). But we must respect significant relation between diffuse type and less differentiated tumours with higher UICC, TNM stages or positive lymph nodes (UICC - G: chi square: p<0,0001; T – G: chi square: p<0,0001; positive lymph nodes: chi square: p<0,0001; UICC - Lauren: chi square: p=0,011; T – Lauren: chi square: p=0,005; pos. lymph nodes - Lauren: chi square: p=0,039). Similar tumour site impacts the survival too. Patients with tumours sited in the distal two thirds have significant better long term survival (p=0.012). However, second period of the study (P2), younger age of the patient, low complication score intestinal type of the tumour, lower T stage, unaffected lymph nodes lower number of affected lymph nodes and higher number of harvested lymph nodes at operation present the most important factors by Cox regression analysis that impact the survival favorably. Our trail reveals that of altogether 1108 patients operated for gastric cancer 12.8% were uncurable R1 and R2 resections. The present and our former analyses revealed significant higher perioperative mortality in comparison to other gastrectomised patients (12%; p = 0.003) whereas the life expectancy of these patients is extremely poor (median survival – 6,6 months) and does not differ at all to those having only a non-resection procedure (11). Although some authors advocate palliative resection in selected groups of patients, we agree with the opinion that in a palliative situation complications of the tumor (bleeding, obstuction) should primarily be treated by interventional or conservative procedures (2, 12, 13, 14). Table 2. Results in survival (over all [n=847], for tumours in distal two thirds [n = 600] and proximal third separately[n = 150]) and overall morbidity and mortality in two chronologically successive periods (P1 and P2 [n = 847]); * perioperative 30 day mortality included, ** perioperative 30 day mortality excluded Overall 5YS* Overall median survival* Overall 5YS** Overall median survival** 5YS distal 2/3 of the stomach** Median survival distal 2/3 of the stomach** 5YS proximal third of the stomach** Median survival proximal third** Over all morbidity- surg. Over all morbidity- gen. Over all 30 day mortality P1 P2 p 38,6% 31,1 months 41,8% 35,5 months 43,3% 40,5 months 24,4% 22,6 months 14,9% 13,7% 7,6% 46% 49,6 months 47,3% 54,3 months 52,3% 74,4 months 37,8% 28,5 months 11,7% 13,1% 3% p=0,049 ns p=0,057 ns ns ns p=0,002 GASTROENTEROLOG 79 EXTENT OF STOMACH RESECTION According to the present accepted standards the extent of stomach resection for AGC (total, distal subtotal, proximal, Trans hiatal extended) is defined by the site of the tumor and Lauren classification. It is generally accepted that the distance from the proximal edge of the tumor to the proximal resection border should be 5 cm in intestinal and 8 cm in diffuse type (1, 2). Consequently, for most of the intestinal type tumours sited in the distal two thirds of the stomach and diffuse type tumours sited in the distal third a distal subtotal gastrectomy presents an appropriate extent of the resection (2–5). In most diffuse type tumours located in the proximal two thirds of the stomach total gastrectomy or in case of tumours in the cardiac region (AEG II and III) transabdominal total gastrectomy extended to distal esophagus will be indicated (2, 15, 16, 17). A frozen section of the proximal resection border on the esophagus must always be done in these types of resections for tumours of the esophagogastric junction (2). Within these limits some “tailoring” may be acceptable but only regarding the type of reconstruction (Roux-en-Y, interposition, pouch…) or surgical approach (open or laparoscopic, trans abdominal or with thoracotomy or combined). It is well proven that for tumours of esophagogastric junction (AEG), at least for AEG II and III tumours, the transabdominal approach and a “transhiatal” resection is superior to combined approach with thoracotomy (2, 15, 17, 18). Proximal gastrectomy can be an alternative for total gastrectomy in patients with proximal sited tumours and is favored by some in selected patients (13). The oncological result concerning long term survival showed no significance in these studies, but quality of live was supposed to be superior to those patients after total extended gastrectomy. Our own experience in this issue is limited to a retrospective nonrandomised study in patients with proximal sited tumours where we compared groups of patients after total with a group after proximal gastrectomy for the quality of life and survival and found no difference in long-term survival and no advantage in quality of life in these selected collec80 GASTROENTEROLOG tive of patients. But due to low patient numbers and for methodological reasons the value of conclusions was limited (19). The type of gastric resections in the present trail is given in the table 1. Total gastrostomies and total gastrostomies extended to distal esophagus present were the most often performed type of resection (71.7%) in P 2 group of patients. The difference between the periods in this issue is significant. It partially reflects a higher number of more proximal sited tumours in the recent decade, however partially it is the consequence of more principal holding of the guidelines adopted by our team in P2. The perioperative morbidity and mortality did not show any significant difference between different types of resection (table 2). The list most feared surgical complication is given in table 3. There was no significant difference regarding the perioperative morbidity and mortality between different types of resection although, after total gastrectomies the incidence of surgical complications was a bit higher but the perioperative mortality (was insignificant) the lowest (table 4). The results of our trail regarding the periopaerative morbidity and mortality match frankly with those of other reports (2, 3, 4, 5, 15, 33). EXTENT OF LYMPHADENECTOMY The optimal extent of lymphadenectomy presents one of the most controversial areas in gastric cancer treatment. Different levels of lymphadenectomy were determined many decades ago by Japanese Table 3. Overall incidence of specific surgical complications in P1 and P2 together (n = 847). Intrabdominal abscess Duodenal stump leak Leak from the EEA* Leak from the GEA* Leak from the EJA* Other surg compl. No surg. Compl Number of patients in the group All GEA All EJA 1,5% 1,1% 0,7 1,8% 0 5,4% 89,5% 568 3,2% 0,7% 0,2% 0 1,2 7,8% 85,9% 275 S3 guidelines in Germany. The arguments in favor of extended lymphadeSurgical General 30 day nectomy (more than D1) complications complications mortality are that removing a larger 7,8% 11,7% 3,9% STG number of nodes more 11,9% 12,5% 2,5% TG accurately stages disease 14,6% 19% 2,4% TG + dist. esophagectomy extent and that failure to 25% 30% 10% Proximal resection 0 0 0 Wedge resection remove these nodes may 6,7% 0 0 Gastric stump resection leave behind the disease ns ns ns p in as many as one-third of patients, which would gastric cancer surgeons. The draining lymph nodes adversely affect survival (21, 22, 23). A consequence for the stomach can be divided into 16 stations: staof more accurate staging is minimisation of stage tions 1 to 6 are perigastric, and the remaining 10 migration (23, 24).The resulting improvement in are located adjacent to major vessels, behind the stage-specific survival may explain, in part, the better pancreas, and along the aorta. results seen in Asian patients. Table 4. The incidence od perioperative morbidity and mortality regarding differenttypes of resection (STG = subtotal gastrectomy, TG = total gastrectomy) By Japanese surgeons lymphadenectomy D1 refers to a limited dissection of only the perigastric lymph nodes, whereas the D2 lymph node dissection is an extended dissection, entailing removal of nodes along the hepatic, left gastric, celiac, and splenic arteries as well as those in the splenic hilum (stations 1–11). A superextended D3 lymphadenectomy refers for additional harvesting of lymph nodes in stations 12 to 16 still defined as a remote disease in the west (18, 19, 20). But the extent of lymphadenectomy was long under discussion in the western world because the benefits in long term survival promised by the extended lymphadenectomies would have been reversed by high level of complications rate experienced by some authors in the West. However, after turbulent discussions between supporters and opponents of lymphadenectomy and supported by many randomised and nonrandomised controlled studies as well in Eastern Asia as in the West, a D2 lymphadenectomy (minus station 10) is now getting more and more adopted as a standard for surgical treatment of advanced gastric cancer in most centers all over the continent. Moreover, a “D2–10” presently has been suggested for the European guidelines for surgical treatment of AGC and is actually included in As shown in table 1, most of our patients in P2 had more than D1,5 and higher levels of lymphadenectomy. The categorisation of lymphadenectomy in our collective of patients showed that significant difference between D1 and D1,5 and more extended lymphadenectomy since the number of lymph nodes harvested in D1 was significant higher in the former group (13 Vs. 23, p<0,0001). The incidence of perioperative complications did not reveal any significant difference moreover, the perioperative 30 day mortality was even significantly less (p=0,001). RATIONALE OF SENTINEL NODE AND MICROMETASTASES Sentinel node mapping is another issue of research. The rationale is to improve the nodal stage and by that to provide more exact treatment (19). It is also used by some to navigate the lymphadenectomy in patient with poor general condition or to tailor the lymphadenectomy in resections for early gastric cancer. The accuracy of more than 98% was reported from Far East, in particular in early stages (T1-T2) (25, 26). Moreover, presenting of sentinel node and searching for micro metastases (present in 30–50% of N0) might be important in staging as well as for decision making concerning adjuvant oncological GASTROENTEROLOG 81 treatment. By definition micro metastases mean the presence of tumor cells –single or in small clusters– detected only by cytokeratin specific immunostaining that could not be detected by ordinary H and E staining (27, 28). Some authors were able to prove that the lymph node micrometastasis is an independent prognostic indicator for patients with histologically node-negative T3 and T4 gastric cancer (27). In addition to the presence of LN micrometastasis, the number and level of micrometastases in the lymph nodes were strongly associated with the survival time of patients (29, 30, 31). In our former analysis we studied the reliability of the Rt PCR method to determine the sentinel node as well as the method of detecting the micrometastases in deemed N0 stages. The results revealed that in 28% nodes negative by conventional patohistological workup of nodes as a matter of fact were affected by micrometastases (32). SPLENECTOMY It has been well shown that splenectomy does not add significantly in postoperative mortality and 5-year survival (34, 35). Splenectomy or/and splenopancreatectomy is not a part of the routine radical resection with D2 lymphadenectomy any more unless the tumor invades either organs. It was suggested to perform splenectomy in case of suspected lymph nodes in station 10 or in proximal tumors in stage T3 or more (34, 35). There is no positive impact on long term survival by splenectomy, moreover, it impacts conversely the perioperative morbidity as it was shown in the Dutch DGST and British MRC studies. (33, 35, 36). In approximately one third of our patients the splenectomy was added to gastrectomy. In the P2 of our trail significant less splenectomies were performed (38% Vs. 29%; p=0.006). Presently we avoid performing splenectomy unless for oncological or operation technical reasons. The hospital stay was significant longer in group of patients with splenectomy (16.6 Vs. 14.7; p=0.005) however, the incidence of perio82 GASTROENTEROLOG perative morbidity and mortality wasn’t different in comparison to non splenectomy group. The survival was not impacted in any way by splenectomy. There are new randomized control studies in progress to clear out the impact of splenectomy in surgical treatment of AGC but unfortunately the results are still not available (37). MULTIORGAN RESECTION In patients with tumors invading adjacent organs a multiorgan resection is indicated to achieve R0 resection. By the reports the multiorgan resection is done in 5–10% of resected patients with advanced gastric cancer (38). Nowadays endoultrasound and CT can predict the infiltration of the gastric tumour in the neigbour organs but surgeons still can meet unclear situations at operation (38, 39). In multivariate analysis, peritoneal dissemination, lymph node ratio, and histologic findings were the predictors of survival (39). Patients with T4 gastric carcinoma, even with lymph node metastasis, might have benefited from aggressive surgery with curative intent. In our experience 60 patients had a multiorgan resection for AGC. The list of additional resected organs is given in table 5. In 50 patients a T4a or T4b stage was confirmed by pathologist, 10 patients had N3 stage. Survival analysis revealed a borderline significant lower survival for this group of patients comparing Table 5. Additional organ resected for oncological reasons Adrenalectomie Cholecystectomie Segmental resection of colon Segmental resection of jejunum Liver excision Left pancreatectomy Left pancreatectomy +adrenalect Left pancreatectomy +colon res Whipple resection Total n % 1 8 5 3 10 24 1 5 3 60 1.7 13.3 8.3 5.0 16.7 40.0 1.7 8.3 5.0 100.0 them with all other R0 resected patients (p=0.046), but when looking in the groups of similar stages (excluded patients with early cancers -T1) the significance vanished (p=0.289). Although having had more extended resection these patient didn’t suffer more surgical complications (12%) comparing to those who didn’t have a multiorgan resection and also the perioperative mortality was low (1.7%). If our patients with infiltration to the neighbor organs wouldn’t have combined resection they didn’t have any chance for long term survival. That gilts not only for T4 case but also for some selected patients with N3 stage. ONCOLOGICAL REGIMENS Despite potentially curative resection of stomach cancer, 50% to 90% of patients die of disease relapse. As with other gastroenterological malignancy additional chemo and/or radiotherapy has in recent decade become a standard for selected groups of patients with AGC in many countries. However, some controversies regarding the timing type and combination of these additional settings still exist. Numerous randomised clinical trials (RCTs) have compared surgery alone with neoadjuvant, adjuvant or perioperative regimens comprising chemotherapy (CTX), or chemo-radiotherapy (CRT) but definitive evidence is lacking (40, 41). Different types of adjuvant CTX (mono-, polychemotherapy) were studied for patients after R0 resection in compare to resection alone (42). Recently well designed phase III studies have been able to show a significant survival benefit if adjuvant CTX was switched to radical gastrectomy with D2 lymphadenectomy. But also other agents (capecitabine and oxaliplatin) have been studied for adjuvant CTX (43). In Japan a mono CTX with S1 (an oral fluoropyrimidine) now presents a standard after R0 resection for AGC (44). Another philosophy but the same aim advocated by some is radiotherapy to be added to adjuvant CTX. In 2001 a randomised control study revealed a significant survival benefit (median - 9 months) for patients receiving CRT after radical surgery in comparison to those with surgery alone (45). However, even this well-designed study was criticised to have included high number of patients with insufficient lymphadenectomy (less than D2) and by that treating inadequate surgery (46). This oncological regiment has become popular in the west especially in USA where it presents a standard adjuvant treatment for patients after gastrectomy for AGC. Between 2001 and 2011 adjuvant CRT gradually became a standard adjuvant treatment for un-disseminated patients with AGC in stages Ib and more in Slovenia. Regarding the multimodal treatment we are able to report our own experience with adjuvant CRT. In our collective of patients between January 2001 and December 2010 altogether 141 R0 resected patients received adjuvant CRT (only) (2.3% in P1 and 26.3% in P2). The aim the analysis was to figure it out if there was any survival benefit for patients receiving adjuvant CRT and to identify possible subgroups in which the benefit would be present. The inclusion criteria are given in table 6. In a retrospective trail patients who met the inclusion criteria were analysed. To achieve as high as possible homogeneity between the control and CRT group, we included all potential candidates for CRT from January 1998 to December 2010. By this we recruited 176 patients. 99 of them received CRT after surgery (CRT-S) and 77 had surgery (S) only. All patients received a fluoropyrimidine based chemotherapy (xeloda only - 35 patients, fluoropyrimidine + cisplatin - 16 patients, Table 6. Inclusion criteria for the analysis of CRT • Histologically confirmed adenocarcinoma of the stomach • Age < 76 years • No neoadjuvant therapy • UICC Stage Ib and more • T>1 • No distant metastases • R0 resection • D>1 lymphadenectomie • Survival > 90 days • Completed CRT GASTROENTEROLOG 83 Table 7. Adjuvant chemo-radiotherapy: Comparability between the group surgery only (S) and chemo-radiotherapy (CRT) p (S Vs. CRT-S) Gender Chi square: ns Age Student t-test: ns ASA Chi square: ns Site of the tumour Chi square: ns Diameter of the tumour Student t-test: ns UICC stage Chi square: ns T stage Chi square: ns N stage Chi square: p = 0.042 (more N0 in S) Harvested LN Student t-test: p = 0,032 (S:25LN; CTR-S: 29LN) of the stomach. This matches well with several studies from the east and west (37, 40, 41, 42). The very important limitation of the adjuvant regimens is the possible impared patients general performance after surgery that can humper or even prevent adjuvant CRT. fluoropyrimidine + leukovorine - 48 patients). The comparability between the groups (CRT-S Vs. S) is presented in table 7. Although more patients survived 5 years in the CRT-S group in compare to S group (42 % Vs. 34 %) the difference was not significant (p=0,075), however observing only patients with proximal sited tumours the difference in survival became highly significant (p = 0.017; p = 0.004) (figure 1 and 2). According to this results CRT added to radical surgery revealed survival benefit only for patients with proximal sited tumours and not for those having tumours in the distal two thirds Neoadjuvant and perioperative CTX for patients with potentially resectable AGC is another option. A Cochrane meta-analysis from 2006 showed a 40% respond rate for the combination of capecitabine with epirubicine and cisplatin. The rationale for this type of oncological management is that in presence of tumor vascularisation the CTX could be more efficacy in particular for micrometastases. Down-sizing/staging of the tumour process and by that a higher R0 are supposed to be the consequence (41). There is some concern regarding the possible progress while on neoadjuvant treatment. Based on the superior compliance of neoadjuvant and/or perioperative settings as compared with Figure 1. Adjuvant chemo-radiotherapy for tumours sited in distal two thirds of the stomach: survival of patients with adjuvant CRT (CRT-S - dotted) and S only (s - clear line) (p = 0.521). Figure 2. Adjuvant chemo-radiotherapy for tumours sited in the proximal third of the stomach: Survival for patients with adjuvant CRT (CRT-S - dotted) and S only (s - clear line) (p = 0.017). 84 GASTROENTEROLOG adjuvant regimens, neoadjuvant and/or perioperative was adopted as a standard in some west European countries and became a standard also in Slovenia since 2011. CONCLUSIONS Contemporary aggressive surgical treatment is in experienced centers a save treatment promising solid long term survival. It remains the milestone treatment, however it seems that surgery will no more act as unimodal treatment of advanced gastric cancer. Although with some drawbacks, many randomised controlled studies have been able to show the potential positive impact of radical resection with D2 lymphadenectomie as well as combined resections for most advanced but resectable cases. 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Int J Clin Oncol (2008) 13: 479–482 Gastrointestinalni stromalni tumorji (GIST)-indikacije in principi kirurškega zdravljenja Gastrointestinal stromal tumors (GISTs)-indications and princples of surgical treatment Primož Sever* Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana Gastroenterolog 2013; suplement 2: 87–90 Ključne besede: Gastrointestinalni stromalni tumor, kirurgija, tarčna zdravila Keywords: Gastrointestinal stromal tumor, surgery, targeted therapy POVZETEK ABSTRACT Gastrointestinalni stromalni tumorji (GIST) so redki tumorji prebavnega trakta, ki so v zadnjih desetih letih doživeli revolucijo na področju diagnosticiranja in zdravljenja. Z odkritjem mutacij genov ki so odgovorni za nastanek GIST, so se razvila nova tarčna zdravila, ki so ob kirurškem zdravljenju močno izboljšala preživetje obolelih. Kirurško zdravljenje je trenutno še vedno edino potencialno kurativno zdravljenje GIST. Gastrointestinal stromal tumors (GIST) are rare tumors of alimentary tract. The last decade was a revolution in diagnosing and treatment of GIST. Gene mutations discoveries responsible for GIST occurrence led to development of new targeted therapy. Using them together with surgery prolonged survival in patients with GIST. Surgical resection is, to date, the only potentially curative treatment of GISTs. UVOD Gastrointestinalni stromalni tumorji (GIST) so najpogostejši mezenhimski tumorji prebavnega trakta. GIST med novotvorbami prebavnega trakta predstavljajo 1–2 % vseh novotvorb z incidenco 1,5-2/100.000 pribivalcev. (1) Za nastanek GIST je odgovorna protoonkogenska mutacija genov proteinov iz družine tirozinskih kinaz (KIT, PDGFRA). Raste submukozno v steni prebavnega trakta, agre- sivnost se ocenjuje na podlagi velikosti tumorja in številu mitoz na 50 polj pri visoki povečavi (HPF). Kirurško zdravljenje še vedno predstavlja edini potencialno kurativni način zdravljenja, ki je še bolj uspešno v kombinaciji s tarčnimi zdravili iz družine inhibitorjev tirozinskih kinaz. *Primož Sever, dr. med. Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana Ljubljana GASTROENTEROLOG 87 KLINIČNA SLIKA ZDRAVLJENJE GIST Bolniki z GIST imajo nespecifične simptome. Približno tretjina je odkritih naključno, ob operativnem zdravljenju druge patologije trebuha (20 %) in obdukciji (10 %). 30 % bolnikov ima anemijo ob krvavitvi, 28 % izgubo telesne teže, 13 % bolečine v trebuhu. Lahko povzročajo nelagodje v trebuhu, zgodnjo sitost, ter pri velikih tumorjih tipno rezistenco. (1) Pojavijo se lahko v katerem koli delu prebavil, najpogosteje na želodcu (50–60 %), tankem črevesu (20–30 %), debelem črevesu (10 %), požiralniku (5 %), v 5 % pa se pojavijo drugje v trebušni votlini (omentum, mezenterij) (2). Ob odkritju bolezni ima 15–47 % bolnikov zasevke, najpogosteje v jetrih, omentumu in peritoneju (3). Način zdravljenja je rezultat multidisciplinarne obravnave vsakega bolnika, v kateri sodelujejo gastroenterolog, kirurg, onkolog, patolog in radiolog. Zdravljenje se prilagodi glede na stadij tumorja. Za tumorje manjše od 2cm, ki imajo manj kot 5 mitoz na 50 HPF je dovolj kirurška odstranitev. Vsi bolniki s tumorji večjimi od 5cm, ki imajo več kot 5 mitoz na 5 HPF prejmejo po kirurški odstranitvi še adjuvantno terapijo z inhibitorji tirozinskih kinaz. Pri metastatskih GIST bolniki prejmejo neoadjuvantno terapijo z inhibitorji tirozinskih kinaz in so nato ponovno predstavljeni kirurškemu zdravljenju, predvsem v smislu citoredukcije. ODKRIVANJE GIST Najpogosteje je GIST ugotovljen s pomočjo ultrazvoka ali ezofagogastroduodenoskopije. Za oceno GIST zgornjih prebavil je zelo uporaben endoskopski ultrazvok. Poleg velikosti, lahko izkušen endoskopist predvidi tudi malgni potencial tumorja glede na prisotnost nepravilnih robov in cističnih vključkov (4). Za oceno tumorja je primerna tudi računalniška tomografija (CT), ki pokaže tudi eventuelne zasevke. Magnetno resonančna preiskava (MRI) je uporabna za oceno zasevkov v jetrih, saj so nekateri povsem enake gostote po CT-ju kot parenhim jeter, kar jih naredi nevidne na CT. Pri diagnosticiranju in sledenju se uporablja tudi pozitronska emisijska tomografija (PET) z F-fluorodeoksiglukozo, ki zlasti pokaže majhne posevke po omentumu, ki so nevidni na CT-ju. Vloga biopsije tumorja ni povsem opredeljena. Pogosto so GIST dobro vaskularizirani, kar predstavlja preveliko tveganje za krvavitev. Tanko-igelna aspiracijska biopsija lahko povzroči rupturo tumorja in implantacijo tumorskih celic po poti biopsije. V primeru postavitve suma na GIST po slikovnih kriterijih in da je le-ta kirurško odstranljiv, biopsija ni potrebna. Biopsija je potrebna za potrditev diagnoze pri bolnikih z neresktabilnim GIST in z njo povezanim začetkom zdravljenja s tarčnimi zdravili. 88 GASTROENTEROLOG Število mitoz <5 na 50 HPF <5 na 50 HPF Velikost tumorja v cm Želodec (%) Jejunum/Ileum (%) Dvanajstnik (%) Rektum (%) <2 0 0 0 0 >2-<5 1,9 4,3 8,3 8,5 >5-<10 3,6 24 >10 12 52 34 57 <2 0 50 ni podatka 54 >2-<5 16 73 50 52 >5-<10 55 85 >10 86 90 86 71 -zelo nizko tveganje visoko tveganje -nizko tveganje -srednje tveganje - Slika 1. Verjetnost metastaziranja GIST glede na velikost tumorja, število mitoz ter lokalizacijo po Milettinen in Lasota (2006) (5). Adjuvantno terapijo z inhibitorji tirozinskih kinaz prejmejo vsi bolniki z visokim tveganjem za metastaziranje, tisti z nizkim tveganjem ga ne prejmejo, bolniki s srednjim tveganjem pa se o adjuvantnem zdravljenju dogovorijo z lečečim onkologom. INDIKACIJE ZA KIRURŠKO ZDRAVLJENJE Ključno vlogo pri odločitvi za kirurško zdravljenje GIST predstavljata velikost in maligni potencial samega tumorja. Vse GIST >2cm je potrebno ne glede na maligni potencial odresecirati. Konkretnih smernic za zdravljenje manjših GIST ni. Trenutno se še ne da predvideti hitrosti rasti, kot tudi ne spreminjanja malignega potenciala tumorja. Tumorje velikosti med 1 in 2 cm je možno endoskopsko spremljati in postaviti indikacije za kirurško zdravljenje v primeru rasti tumorja, ali ko postane ta simptomatski. Optimalni časovni intervali spremljanja še niso določeni, zato je odločitev za spremljanje velikokrat negotova. Ob odločitvi za spremljanje GIST je potreben izdaten pogovor z bolnikom glede tveganja in prednosti take obravnave. (6) Slika 2. Predlagan algoritem obravnave lokaliziranega GIST (6). Opisane so uspešne endoskopske resekcije GIST, vendar niso sprejete zaradi negotovosti glede varnostnega roba, raztrganja tumorja pri trakciji in s tem razsoja. Klasična endoskopska tehnika ne zagotavlja varne resekcije submukozno rastočih GIST. (7) KIRURŠKO ZDRAVLJENJE Kirurško zdravljenje je še vedno edini potencialno kurativni način zdravljenja GIST. Operativni poseg je lahko laparoskopski ali po odprti metodi. Pri mejno resektabilnih tumorjih in tumorjih pri katerih je predvidena razširjena resekcija, je smiselna predoperativna kemoterapija s tarčnimi zdravili. Tumor mora biti makroskopsko v celoti odstranjen z varnostnim robom enega centimetra ter negativnimi histološkimi robovi (R0 resekcija). (8) Tumorji so lahko zelo krhki z obilo nekrotičnega tkiva, zato je potrebna previdna manipulacija v izogib raztrganja pseudokapsule tumorja in s tem razsoja po trebušni votlini. Pseudokapsula tumorja mora biti ohranjena (9). Za razliko od žleznega raka GIST ne vrašča v priležne strukture, jih le odriva, zato se ga lahko odmakne od sosednjih struktur. Ob močni vnetni komponenti je možen videz preraščanja, ki zahteva »en bloc« resekcijo. Slednjo zahtevajo tudi preraščajoči tumorji. Glede na prizadet organ in lokacijo se izbere vrsto operativnega posega. Potrebna je natančna eksploracija trebušne votline zaradi izključitve metastatske bolezni, ki po predoperativni diagnostiki ni bila vidna. Tako je potrebno biti pozoren na eventuelne posevke po omentumu in peritoneju. Ob sumu na zasevke v jetrih se opravi intraoperativni UZ. Večino posegov predstavljajo ekscizije in segmentne resekcije, v poštev pa pridejo tudi netipične in obširne resekcije. Tako je potrebno ob prizadetosti dvanajstnika v predelu papile Vateri narediti pankreatoduodenektomijo. Poseben izziv za kirurga predstavljaja GIST rektuma, zaradi prostorske omejitve medeničnega prostora in pogoste čvrste fiksacije na medenično dno. (10) V primeru tumorja v distalnem rektumu je potrebna abdominoperinealna ekscizija. »Klasičnim« resekcijam se je ob dejstvu, da GIST silno redko zaseva v bezgavke, potrebno izogniti. Laparoskopska kirurgija je varna kirurgija GIST-a ob upoštevanju onkoloških načel (11). Pomembno vlogo pri odločitvi za laparoskopsko odstranitev imata lokacija ter velikost tumorja. Veliki tumorji v predelu kardije in pilorusa niso primerni za laparoskopsko obravnavo. Pomembno je nežna manipulacija s tumorjem z ustreznimi inštrumenti v izogib rupturi pseudokapsule tumorja. Po eksciziji tumorja z varnostnim robom je potrebno preparat pred odstranitvijo iz trebušne votline vstaviti v vrečko. Pogosto pseudokapsula tumorja pri izvleku vrečke skozi rano v trebušni steni poči, kar je nujno potrebno zabeležiti v patohistološki protokol. V primeru manjkajočega tega podatka, se lahko bolnika vodi kot diseminiran GIST. Prednosti laparoskopske metode so boljši estetski rezultat, manj je bolečin, krajša je hospitalizacija in hitrejša vrnitev k vsakodnevnim aktivnostim. Kirurško zdravljenje razširjene bolezni je smiselno, če so spremembe solitarne in v primeru dobre regresije po kemoterapiji. (12) GASTROENTEROLOG 89 ZAKLJUČEK V zadnjih petnajstih letih je viden velik napredek v zdravljenju bolnikov z GIST. Odkritje protoonkogenske mutacije genov, izboljšana diagnostika, izboljšana kirurška tehnika z uvedbo minimalno invazivne kirurgije ter odkritje tarčnih zdravil, je močno povečalo preživetje bolnikov z GIST. Kirurško zdravljenje primarnega, ponovitvenega ali metastatskega tumorja v kombinaciji s tarčnimi zdravili je postal standard zdravljenja GIST. Za dober uspeh zdravljenja je potrebna multidisciplinarna obravnava tako pri diagnosticiranju, zdravljenju in nato vodenju bolnikov z GIST. 90 GASTROENTEROLOG LITERATURA 1. Nilsson B, Bumming P, Meis-Kindblom JM, et al. 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NCNN task force report: optimal management of patients with gastrointestinal stromal tumor (GIST). J Natl Comp Cancer Net 2007; 5 Suppl 2: S-1. 8. Kingham TP, DeMatteo RP. Multidisciplinary Treatment of Gastrointestinal Stromal Tumors. Surg Clin North Am 2009; 89 (1): 217–33. 9. Ng EH, Pollock RE, Munsell MF, et al. Prognostic factors influencing survival in gastrointestinal leiomyosarcomas. Implications for surgical management and staging. 1992; 215: 68–77. 10. Gervaz P, Huber O, Morel P. Surgical management of gastrointestinal stromal tumors. Br J Surg 2009;96:567. 11. Langer C. Gastrointestinal stromal tumors from surgical point of view. Laparoscopic therapy. Chirurg 2008; 79 (7):644–9. 12. Raut CP, Posner M, Desai J, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 2006; 24:2325. Zagotavljanje kakovosti v presejanju - nadzor in resni neželeni učinki Rezultati nadzora Državnega programa presejanja in zgodnjega odkrivanja predrakavih sprememb in raka na debelem črevesu in danki SVIT v letih 2010-2012: 23 centrov, 51 endoskopistov in 24 382 kolonoskopij Assuring quality in screening- control and severe adverse events Results of the control of the National Colorectal Cancer Screening Programme SVIT 2010-2012: 23 centres, 51 endoscopists and 24 382 colonoscopies Milan Stefanovič*1, Bojan Tepeš2, Borut Štabuc3, Dominika Novak Mlakar4, Jožica Maučec Zakotnik4, Matej Bračko5, Snežana Frkovič Grazio5 1Diagnostični center Bled, Pod skalo 4, 4260 Bled, Slovenia 2AM DC Rogaskač, Prvomajska 29A, 3250 Rogaška Slatina, Slovenia 3 University Clinical Center, KOGE, Japljeva 2, 1000 Ljubljana, Slovenia 4National Institute of Public Health, Trubarjeva 2, 1000 Ljubljana, Slovenia 5University Clinical Centre, CGO, Zaloška 2, 1000 Ljubljana, Slovenia Gastroenterolog 2013; suplement 2: 91–100 POVZETEK ABSTRACT V nasprotju z nekaterimi drugimi presejalnimi programi lahko presejanje za raka na debelem črevesu in danki (RDČD) preiskovani osebi povzroči neposredno škodo. Lahko pride do zapletov, kot so krvavitev, perforacija, zaplet zaradi sedacije in neustrezne napotitve na kirurški poseg. Še posebej pomembno je, da se presejanje za RDČD pazljivo spremlja v organiziranem programu, kjer lahko zbiramo podatke o ustreznosti presejanja in obenem nadzorujemo varnost, kakovost in učinkovitost kolonoskopije znotraj presejalnega programa. Unlike some other screening programmes, colorectal cancer screening may cause direct damage to the person who undergoes the examination. Complications may occur, such as bleeding, perforation, complications due to sedation and inappropriate referral to surgery. It is particularly important that colorectal cancer screening is monitored carefully in an organised programme where information about the suitability of screening can be collected, and at the same time safety, quality and efficiency of colonoscopy within the screening programme can be monitored. Nadzor kakovosti je načrtovan tako, da zajema strukturni nadzor v endoskopski enoti, nadzor endoskopske opreme in endoskopskega osebja in Quality control is planned to cover structural control in the endoscopic unit, equipment, staff and the procedure of endoscopic intervention, the result as *Milan Stefanovič Diagnostični center Bled Pod skalo 4, 4260 Bled GASTROENTEROLOG 91 nadzor postopka ali endoskopskega posega ter rezultata kot posledice endoskopskega delovanja, ki se kaže v spremembi zdravstvenega stanja posameznika in populacije kot celote. the consequence of endoscopic activity, shown in the change of the health status of an individual and population as a whole. INTRODUCTION DISCUSSION Nowadays, colonoscopy is widely used in diagnosing and treatment of colorectal diseases. In general, it is a safe, precise and efficient examination and most patients can bear it well. Its advantage over other diagnostic methods is also that it allows simultaneous therapeutic intervention, e.g. polypectomy. Consequently, colonoscopy is in the centre of the screening programme. In order to be able to keep that position, quality must be assured at all times and endoscopic quality standards have to be raised. In Slovenia the network of endoscopic units which carry out colonoscopy for the needs of SVIT is organised by regional approach. In this way we have brought examinations closer to people who are involved in the programme. Colonoscopies for the needs of SVIT can be carried out in outpatient clinics and outside hospitals but those clinics should not be too far from hospitals which provide emergency medical treatment and surgical treatment. Endoscopists in SVIT programme, where the primary screening is immunochemical test that detects occult bleeding from lower digestive system, are expected to detect and endoscopically remove more advanced neoplasmas. This requires qualified staff and appropriate equipment, needed for safe and complete removal of such changes. Colonoscopy quality assurance in SVIT programme will ensure our patients and persons who participate in the colorectal cancer screening programme receive the best colonoscopy, and at the same time complications and missing something become much less likely. The quality is assured by following the guidelines. Programme Council of the National Colorectal Cancer Screening Programme, hereinafter referred to as SVIT, monitors key quality indicators and applies them to granting and extending licences to endoscopists and endoscopic centres which participate in the implementation of the programme. The base for control is quality indicators, adopted by the SVIT Programme Council, responsible for the implementation of the programme at the national level. Information is collected centrally and prospectively and analysed periodically in controls, announced in advance. All endoscopists and endoscopic centres which participate in the implementation of screening are informed about the results. In case of deviating from the set level of quality and in case of serious shortcomings and/or mistakes extraordinary supervisions are carried out. 92 GASTROENTEROLOG In screening period between 2010 -2012, colonoscopies for the needs of SVIT programme were carried out in 23 centres. 51 endoscopists carried out colonoscopies. After the first supervision, two centres ceased to perform the activity for the needs of SVIT (8%). Four endoscopists, one of which retired, ceased to work for the needs of SVIT (7.14%). Three new endoscopists started to work for the needs of SVIT (two specialists in internal medicine and one specialist in abdominal surgery). All centres meet the set criteria regarding minimum standards regarding the premises, equipment and staff. In three centres it was necessary to warn about meeting the standards. Two centres complied with them while the third one left the programme. All centres clean the apparatus mechanically and use disposable devices. Disinfection is strictly controlled. Selected key quality indicators which are monitored and considered decisive in order to find out the quality level of colonoscopies, carried out within SVIT programme Indicator 1 Minimum number of colonoscopies that an endoscopist has to carry out per year. Justification: the number of performed colonoscopies is directly proportional to the percentage of total colonoscopies and inversely proportional to the number of immediate and subsequent complications. This is the share of colonoscopists who carried out at least 200 colonoscopies in one year. The number of colonoscopies that a colonoscopist has to carry out per year in order to be eligible to participate in the colorectal cancer screening programme must not be lower than 200. The more colonoscopies a colonoscopist carries out the more experienced he/she is, and consequently the number of total colonoscopies and detected lesions increases while the complications get less likely. Numerator: Number of colonoscopists who carry out at least 200 colonoscopies per year, within or outside the screening programme. Denominator: number of all colonoscopists in the programme Unit of measurement: colonoscopist (share in per cent) Colonoscopist: Acceptable: 85% ≥ 200 Desired: 100% > 200 Results: In three-years screening period 24 382 colonoscopies were carried out, of which 7494 in 2010, 7872 in 2011 and 9016 in 2012. The number of colonoscopies by centres is shown in Graph 1 below. One to nine colonoscopists were carrying out colonoscopies in an individual centre. Graph 1. Number of colonoscopies per endoscopic centre together between 2010- 2012 (from 232 to 2715). Number of colonoscopies per endoscopist ranged from 61 to 1533 (see Graph 2). It should be taken into account that in addition to screening colonoscopies endoscopists were carrying out also regular diagnostic colonoscopies and consequently most of them reach the number of 200 examinations per year and also the desired number 300. For those who had not achieved that indicator, a transitional period was set and heads of endoscopic centres were advised to organise the work so that this criterion will be met. Thus seven colonoscopists are threatened to have their licences for carrying out colonoscopies for the needs of the national screening programme withdrawn. Graph 2. Number of colonoscopies per endoscopist only within SVIT programme Indicator 2 Appropriate visibility after intestinal preparation Share of colonoscopies with good visibility in relation to all colonoscopies. The cleanliness is assessed by the colonoscopist and he/she documents it with either well or badly cleared. The measure for the assessment is the size of the polyp that can still be seen. Colon is well cleaned when it is cleaned and dirty but still visible (visible lesions are larger than 5 mm) while the colon is badly cleaned when it is dirty and visibility is poor (lesions smaller than 5 mm are not seen) and visibility of the colon is poor. The precondition for quality colonoscopy is suitable preparation of the colon. The visibility must be good and it is an important factor in making the decision about referral to follow-up colonoscopy. GASTROENTEROLOG 93 Numerator: number of colonoscopies with good cleanliness or visibility Denominator: number of colonoscopies carried out Unit of measurement: colonoscopy (share in per cent) Colonoscopist: Acceptable: > 90% good visibility, ≤ 10% bad visibility Desired: ≥ > 95% good visibility, ≤ 5% bad visibility Results: within SVIT programme cleanliness of the intestines before the colonoscopy as one of significant programme quality indicators is monitored regularly. In three years (2010–2012) 24 382 colonoscopies were analysed and excellent cleanliness after preparation of patients with Moviprep was identified in 84.04% of cases and good cleanliness (possible to detect a polyp < 5 mm ) was established in 11.45% of patients. Poor cleanliness of patients (colonoscopy had to be repeated) was established only in 1.97% of patients. Indicator 3 Duration of withdrawing the colonoscope after colonoscopy without the intervention (average, median, minimum and maximum duration). Minimum duration of the examination is 8 minutes which does not include colonoscopies with biopsies and/or polypectomies. Caecum or terminal ileum must be reached during the colonoscopy. Duration of withdrawal with the instrument is closely linked to the rate of detecting adenomas in people who undergo colonoscopy. The sensitivity for detecting adenomas will be greater when the examination of the mucous is more careful, proximally from the haustra, in turns, when the remains of mucous and liquid are better cleared from the intestines. There is a lot of substantiated proof that when the duration of withdrawing the instrument is prolonged, a higher number of adenomas are detected (≥ 6 minutes for normal result without taking into account the time for a therapeutic examination, e.g. polypectomy). Numerator: number of colonoscopies, excluding interventions and duration of the examination ≥ 8 minutes Denominator: number of colonoscopies excluding interventions Unit of measurement: colonoscopy (share in per cent) Colonoscopist: ≥ 90% 8 minutes 94 GASTROENTEROLOG Results: SVIT set 8 min as the minimum duration of withdrawal and examination, excluding the time spent on any other intervention. This information is particularly important for the endoscopists whose ADR (the rate of detecting adenomas) is below average and when interval carcinoma develops. During the supervision (since the time is strictly recorded) no deviations from the set norm were identified. Indicator 4 Per cent in total, colonoscopies carried out to the final part of the colon – total colonoscopies. A) Share of total colonoscopies (reached caecum or terminal ileum) in relation to the number colonoscopies carried out. B) Share of persons who underwent total colonoscopies (reached caecum or terminal ileum) in relation to the number of persons who underwent colonoscopies. Completeness of the examination is the basis for each screening programme. The percentage of total colonoscopies (for adequate proof photographic documentation of mouth of the appendix, valvula Bauchini as typical sign of the caecum or final part of the small intestine is required), should be at least 95% or more, which is the standard, set by the SVIT Programme Council while the standard set in European guidelines is set at 90% or more and the achievement of total colonoscopies in more than 95% is only desired or recommended. A) Numerator: number of carried out total colonoscopies where caecum or terminal ileum is reached, Denominator: number of colonoscopies carried out Unit of measurement: colonoscopy (share in per cent) B) Numerator: number of persons who underwent at least one total colonoscopy where caecum or terminal ileum was reached, Denominator: number of persons who underwent at least one colonoscopy Unit of measurement: person (share in per cent) Screening cycle /reporting period, sex, colonoscopist (for the needs of supervising colonoscopy centres) Acceptable: > 90% Desired: ≥ 95% Results: within SVIT programme this quality indicator shows that the set standard is achieved. Between 2010 and the end of the year 2012 of 24 382 examinations that were carried out on average the share of total colonoscopies was 97.95%. Only three colonoscopists (5.8%) did not reach the threshold of 90% of total colonoscopies while 7 endoscopists did not exceed the desired threshold of ≥ 95% of total colonoscopies. Indicator 5 Rate of detecting adenomas during a colonoscopy (ADR) Justification: At the moment, the rate of detecting adenomas (ADR) is the only quality indicator, associated with the occurrence of interval carcinoma. The advantage of ADR is that it can be measured, calculated and monitored in a simple way. It is well tested and described in practice and also easy to understand. The achievement of the minimum number (threshold) for ADR of an individual screening programme where the age of the screened persons, sensitivity and specifics of the primary screening test (iFOBT), applied in the programme, is defined. ADR significantly differs by sex. This cannot be explained only by the fact that more women than men participate in screening. The rate of detecting adenomas during first colonoscopies (ADR) is the share of first colonoscopies which find a histologically proved adenoma(s) in relation to the total number of first colonoscopies. Numerator: number of first colonoscopies where adenoma was detected Denominator: number of first colonoscopies Unit of measurement: first colonoscopy Screening cycle /reporting period, sex, five-year age classes, colonoscopist, colonoscopy centre There is no generally accepted reference standard for colonoscopies, carried out after positive immunochemical test to occult bleeding. Results: ADR- rate of detecting adenomas. It is undoubtedly the most important indicator for assessing endo- scopic work. This indicator shows some considerable deviations among endoscopists. Interesting, the numbers are almost the same through all three years and the situation is only partially improving which is confirmed also by the comparison of the situation in 2010, 2011 and 2012. Graph No. 3 shows the rates (ADR) for individual endoscopists separately for 2010, 2011 and 2012, and total for three-year period, as well as separately ADR men and ADR women in the three-year screening period. ADR in SVIT programme in 2010: 54.16% (63.56% for men and 43.22% for women). In 2011: 52.89% (63.18% for men and 40.45% for women). In 2012: 54.95% (64.34% for men and 42.16% for women). Total for three years: 54.0% (63.69% for men and 41.94% for women). Mean ADR for individual endoscopists: for year 2010: all patients 51.05% (SD ± 0.10), for men 64.52% (SD ± 0.13) and women 41.52% (SD ± 0.12), 2011: mean ADR 51.52% (SD ± 0.11), for men 61.83 (SD ± 0.13) and women 39.42% (SD±0.12), 2012: mean ADR 52.57% (SD ± 0.11), for men 62.36% (SD ± 0.14) and women 40.97% (SD ± 0.11). Graph 3: shows average ADR together and separately for men and women per individual endoscopists in programme SVIT in three years between 2010 and 2012 Indicator 6 The share of detected adenomas in the left part of the colon in comparison with the share of detected adenomas in the right part of the colon. The right hemicolon includes lienal flexure, transverse colon, hepatic flexure, ascending colon, caecum while the left one includes anus, rectum, sigmoid colon and descending colon. According to the definition all changes (carcinoma and polyps ≥ 1 cm), detected in the period of two years after screening colonoscopy, are considered to be interval changes. GASTROENTEROLOG 95 According to study data it can be concluded that polypectomy can prevent subsequent occurrence of carcinoma in more than 90% of cases. Study data show a better protective role of colonoscopy for the occurrence of interval cancer in the left hemicolon (in 80% of cases) than in the right hemicolon (12–33%). The rate of overlooked changes in the right hemicolon is 2 to 3 times higher than in the left hemicolon. The emphasis should be placed on careful examination of the entire colon. Numerator: number of adenomas, detected in the right/left hemicolon Denominator: number of adenomas, detected in the entire hemicolon Unit of measurement: adenoma (share in per cent) Screening cycle/reporting period, sex Acceptable: ratio left: right = 65%:35% Desired: left < 60%, right > 40% Results: when assessing the quality of colonoscopy it is helpful to compare the rate of detecting adenomas in the right and left hemicolon. The desired ratio between the detections in the right and left hemicolon should be 40:60. There are considerable differences between endoscopist and endoscopic centers regarding number of AP in the left, compared with the number of AP in the right colon. In SVIT programme the average ratio for all centres in three year period for mean percentage was 66.61% (SD ± 0.0824) in the left and 30.69% (SD ± 0.0776) in the right part of the colon. Graph No 4. For the endoscopists ratio between the mean percentage was in 2010: 69.27% (SD ± 0.0965%) in the left and 27.80% (SD ± 0.0983) in the right colon, in 2011: 66.65% (SD ± 0.10) left and 31.14% (SD± 0.10) right and in 2012: 64.02% (SD ± 0.10) left and 47.74% (SD ± 0.91%) right colon. Graph No 5. Indicator 7 Number of detected adenomas in relation to the frequency of detection per colonoscopy with people who have one or more adenomas detected Justification: because ADR has some shortcomings. It is not possible to differentiate the detection of one adenoma and detection of several adenomas during a colonoscopy which means that two colonoscopists with a similar ADR can detect a very different number of 96 GASTROENTEROLOG Graph 4: Ratio as a percentage of AP between the left and right half of the colon for SVIT endoscopic centres Graph 5: Ratio as a percentage of AP between the left and right half of the colon for endoscopists participating in Programme SVIT adenomas. ADR can lead to a very misleading sense of "safety" – when the endoscopist detects one adenoma his/her attention lowers and the efficiency decreases. However, this does not affect ADR which is still sufficient for achieving the appropriate level of "quality". The average number of adenomas per first colonoscopy (mean adenomas per procedure – MAP) and the average number of adenoma per first positive colonoscopy (mean adenomas per positive procedure – MAP+) are two newer colonoscopy quality indicators which, unlike ADR, take into account also the number of detected adenoma during colonoscopy. Numerator: number of all adenomas detected during first colonoscopies Denominator: number of all first colonoscopies (for MAP) or the number of all first colonoscopies with at least one adenoma detected (for MAP+) Unit of measurement: first colonoscopy A graphical presentation of the share of first colonoscopies by the number of detected adenomas in relation to the total number of first colonoscopies (adenomas under the curve or AUC) is being prepared to support the two indicators. Results: rate of detecting adenomas per individual colonoscopy (ADR below the curve) is a more precise indicator of the quality of endoscopist work than ADR itself. There are substantial deviations in this indicator. Graph No. 6 shows the number of detected adenoma per individual colonoscopy with one or more neoplastic changes detected. Similarly big differences (shown in Graph No. 5) are seen in the number of neoplastic changes for all endoscopists who participated in the programme, regardless of the number of examinations carried out. The differences are even up to two and a half times. The average number of detections per programme in 2010: 1.9, in 2011: 2.0, in 2012: 2.0 and Graph 6. Per cent of colonoscopies with the detection of one or more neoplasms. Graph 7. The average number of detected adenomas during colonoscopy when one or more adenomas were detected, for each endoscopist. total for all three years: 2.0. For individual endoscopist the average MAP+ for all three years was between 1.2 and 3.1 (1.9 ± 0.49) Graph No.7. Indicator 8 The share of documented completed colonoscopies in accordance with the rules. An appropriate colonoscopy has a completed electronic record. The prime objective is to ensure proper documenting of endoscopic detections and recommendations, arising from that. The desired outcome is to improve coordination during care, mitigate the risk for the patient and save the costs, incurred by inappropriate interventions. Numerator: number of colonoscopies with completed electronic result Denominator: number of colonoscopies carried out Unit of measurement: colonoscopy (share in per cent) Screening cycle/reporting period Desired: > 95% Results: prompt and periodic data processing for the need of the national colorectal cancer screening programme is extremely important and a condition for the success of the programme itself. The results of screening can be evaluated only by centralised approach and clearly defined quality standards, which is almost impossible without computer support. Epidemiologic data are obtained on the basis of these data and the activity in individual parts of the programme is controlled. Certainly, this does not exclude own control of each endoscopic unit on the basis of achieving a certain level of quality by individual quality indicators. They are applied by all endoscopic centres, involved in screening. Data are collected and analysed centrally. Supervisions have revealed most irregularities in this indicator. This is probably partly due to problems, encountered during the set up and implementation of the information system. In spite of several trainings for endoscopists and endoscopic personnel, completing the form is still not appropriate and certain mistakes are repeated. The information system is constantly being updated and additional trainings, especially for endoscopists, are necessary. GASTROENTEROLOG 97 Indicator 9 The share of persons with interval changes in all persons who underwent colonoscopy without any changes detected. All changes (carcinoma and polyps ≥ 1 cm), detected in the period of two years after screening colonoscopy, are considered to be interval changes. According to research it can be concluded that polypectomy can prevent subsequent occurrence of carcinoma in more than 90% of cases. Colonoscopy is supposed to provide better protection from the occurrence of interval cancer in the left hemicolon (in 80% of cases) compared with right hemicolon (12–33%). The rate of overlooked changes in the right hemicolon is 2 to 3 times higher than in the left hemicolon. The reasons for that are not completely clear: they may result from the fact that changes in the right hemicolon are more aggressive and grow faster or because they emerge from nonpolypoid changes which are more likely to be overlooked during colonoscopy, particularly in case of poor visibility when cleanliness is bad. Numerator: number of persons with interval lesions (carcinoma and changes ≥ 10 mm) Denominator: number of persons who underwent colonoscopy Unit of measurement: person (share in per cent) Endoscopic centre, colonoscopist Interval lesions < 10% Interval carcinoma 0% Results: 3 cases of interval cancer have been recorded until now in SVIT programme. In all cases we could attribute it to molecular and clinical factors which contributed to rapid growth of neoplasm. Of course we do not know that. Undoubtedly, bad visibility, lack of attention by the examiner (duration is too short) affect the emergence of interval changes but these are only assumptions. Also due to these three cases it is necessary to take care about the quality of colonoscopy all the time although unfortunately it cannot be regarded as 100% protection. We believe that these three cases are not definitive number. More reliable data will be available after the processing and publication of data in the Slovenian cancer registry between the years 2010-2012. Till now the latest data is from the year 2009. 98 GASTROENTEROLOG Indicator 10 The share of persons referred to additional intervention when a change was detected during colonoscopy. When the colonoscopist doubts whether he/she will or will be able to remove the detected change which poses a high risk for endoscopic complications, such change must be properly documented (including photo documentation) and marked with a tattoo (SPOT) if needed. Then the patient has to be referred to another centre where endoscopic or surgical procedure will take place. The referral of a patient with a big benign change to surgical intervention and not endoscopic removal may be the reason and it is associated with a higher level of complications. Endoscopic unit and/or endoscopists who carry out colonoscopies for the needs of the programme (patients with a positive faecal occult blood test are supposed to have more complex pathology), must have appropriate knowledge and technical abilities to recognise a change and remove it endoscopically, refer the patient to another institution with more expert knowledge (EMR and ESD). All colonoscopists who participate in the programme, have to have expert knowledge level 3 (removal of small nonpolypoid changes ≤ 20 mm and bigger polypoid, sessile and polypoid changes, and in case the access to the change is technically demanding, they may refer it to a tertiary centre). The fourth level of expert knowledge is required for tertiary centres. These regard limit changes, endoscopic/surgical removals which require a special consensus by the patient. Unsuccessful endoscopic removal or inappropriate referral to surgical therapy is regarded as the colonoscopist's mistake or inappropriate action. Photo and video documentation helps assess the indicator. Numerator: number of persons referred to polypectomy in the same or another institution Denominator: number of persons who had a change detected Unit of measurement: person (share in per cent) Screening cycle /reporting period, colonoscopist (for the needs of supervising colonoscopy centres) Desired: < 5% Results: the share of patients where colonoscopy had to be repeated due to polypectomy of a demanding change in a tertiary centre was needed, was for the entire programme SVIT 1.19% or 291 of all colonoscopies. With the exception of two endoscopists 19.5% and 4.2% each, no one exceed 2.5% referral for polypectomy, to another endoscopic center. Regular consilium discussions of all problematic polyps and especially the case when a change, histologically assessed as pT1,N0,M0, was removed endoscopically, are planned regularly within SVIT programme. cinoma) SVIT National programmes acquires the necessary documentation and then carries out extraordinary supervision. Four such supervisions have been carried out and the reports are kept in the SVIT archives. Table 1 shows cases of serious subsequent complications which occurred after the release from the endoscopic unit. According to the standards in force and comparable data from abroad Slovenian programme does not deviate regarding the number and seriousness of complications. We can even say that they are fewer than in comparable series. Indicator 11 The share of colonoscopies with complications. The indicator is prepared for individual types of complications during colonoscopy and after colonoscopy. Serious complications of colonoscopy are unplanned hospitalization, prolongation of hospitalization, unplanned further treatments, emergency intervention or death. The basis for the definition of complications is MST (Minimal Standard Terminology) Version 3.0 and ASGE-classification. The indicator is one of the main parameters for monitoring the quality of colonoscopy. Endoscopist must have knowledge that allows him to timely recognize and immediately relieve immediate complications during screening colonoscopy. For events that occur up to 30 days after the colonoscopy it is necessary to collect medical records from other sources (internists, surgeons, personal physicians selected). Numerator: the number of complications of colonoscopy Denominator: number of colonoscopy Unit of measurement: colonoscopy (Percentage) Desired: Diagnostic colonoscopy: <0.5% Therapeutic colonoscopy <2.5% Perforations requiring surgical therapy: <1/1000 Immediate or delayed bleeding requiring surgery: <1/1000 Results: unfortunately, complications are an integral and unavoidable part of endoscopy but they are monitored and analysed regularly. In case of serious complications with a patient who is included in the programme (death, perforation, bleeding which requires transfusion or/and surgical treatment, or interval car- Table 1. Colonoscopies with serious complications between 2010-2012. Indicator 12 Analysis of the questionnaire for the participants after colonoscopy. Justification: satisfaction of the person who was examined / patient is very important in assessing the quality of colonoscopy. Patients complete the questionnaire after the colonoscopy and on the basis of the answers the satisfaction can be assessed objectively. Results: an important role in assessing the quality of work, following the adopted guidelines and subjective experience of people in the process of colorectal cancer screening is played by the results of continuous surveys of screened people, done with the help of questionnaires that are sent by mail after the procedure has been carried out. Answers for individual centres and endoscopists are representative as in all GASTROENTEROLOG 99 cases more than 50% of questionnaires are filled in and returned. The questions about the attitude of the endoscopist, staff in the endoscopic unit and personal experience during colonoscopy are practically all assessed by 4 or more (1- very bad, 2- bad, 3-good, 4very good and 5- excellent). The explanatory duty before, during and after the procedure has improved a lot and there are no major problems. The problem is the assessment how painful the colonoscopy is and although the number of answers that people suffered a very strong and (almost) unbearable pain during the examination is lower, it is still too high and with some endoscopists it exceeds 10%. In Slovenia endoscopic interventions in sedation are carried out selectively, which has its advantages and disadvantages. Undoubtedly, when deciding for sedation, financial aspect plays an important role because this has not been settled with the payer (Health Insurance Institute of Slovenia). Higher quality level means also that sedation is available to everybody who wants it and not only to people who need it. Conclusion: Data on the differences in carrying out colonoscopies, also in Slovenia, show that the results can be improved, which can be achieved by constant taking care about the quality by training endoscopists, use of optimal coloscopy technique, keeping appropriate documentation, explaining pathological result and planning endoscopic controls. Only appropriate performance of colonoscopies can optimally decrease mortality and prevent the occurrence of colorectal cancer. Prompt control and improved quality have to be a compulsory part of each colorectal cancer screening programme. 100 GASTROENTEROLOG REFERENCES 1. ASGE/ACG: Quality in Endoscopy. Gastrointest Endosc 2006;58:S1-S38. http://www.asge.org/WorkArea/showcontent.aspx?id=3386 2. Stefanovič M. Vloga in zagotavljanje kakovosti kolonoskopije v državnem programu presejanja in zgodnjega odkrivanja raka na debelem črevesu in danki. Gastroenterolog 2007;11:22-31. http://www.program-svit.si. 3. Zorzi, Manuel, Priscilla Sassoli de’ Bianchi, Grazia Grazzini, Carlo Senore, eds. “Indicatori di qualitŕ per la valutazione dei programmi di screening dei tumori colorettali - Manuale operativo”. Epidemiol Prev 2007; 31 (6): 1-56. http://www.asplazio.it/asp_online/prev_for_doc/files/screening /files_screening/colon_retto/Indicatori_Di_Qualita_Per_La_Val utazione_Dei_Programmi_Di_Screening_Dei_Tumori_Colorett ali.pdf 4. Segnan N, Patrick J, von Karsa L (eds). European guidelines for quality assurance in colorectal cancer screeining and diagnosis – first edition. Luxemburg: Publication Office of the European Union, 2010. https://www.google.si/url?sa=t&rct=j&q=&esrc=s&source=web &cd=2&ved=0CDwQFjAB&url=http%3A%2F%2Fbookshop.eu ropa.eu%2Fen%2Feuropean-guidelines-for-quality-assurance-incolorectal-cancer-screening-and-diagnosis-pbND3210390%2F downloads%2FND-32-10-390-ENC%2FND3210390ENC_001.pdf %3Bpgid%3Dy8dIS7GUWMdSR0EAlMEUUsWb0000ut3WHv eu%3Bsid%3D70fblrp85EbbnOo1Co1FMdhZTYSnxvcf8TU% 3D%3FFileName%3DND3210390ENC_001.pdf%26SKU%3D ND3210390ENC_PDF%26CatalogueNumber%3DND-32-10390-EN- C&ei=H1CGUfn_B6in4gTH54HYAw&usg=AFQjCNF5AD0 wv-aiE6xONUP_4P1zwdnn6Q&sig2=ul5xnRdwcF1HIyeCmw3z3g 5. Rembacken B, Hassan C, Riemann J.F, Chilton A, Rutter M, Dumonceau J.-M, Omar M, Ponchon T. Quality in screening colonoscopy: position statement of the European Society of Gastrointestinal Endoscopy (ESGE). Endoscopy 2012; 44: 957–68. https://www.thieme-connect.de/ejournals/pdf/10.1055/s-00321325686.pdf?issue=10.1055/s-003-24431 Obsevanje in sistemsko zdravljenje raka trebušne slinavke Radiotherapy and systemic treatment of pancreatic cancer Borut Štabuc*, Lojze M. Šmid 1 Klinični oddelek za gastroenterologijo, UKC Ljubljana Gastroenterolog 2013; suplement 2: 101–106 Keywords: pancreatic cancer, chemotherapy, radiochemotherapy Ključne besede: rak trebušne slinavke, kemoterapija, radiokemoterapija POVZETEK ABSTRACT V Sloveniji je za rakom trebušne slinavke v letu 2009 zbolelo 357 bolnikov, kar predstavlja nadaljevanje rasti incidence te bolezni v zadnjih letih. Radikalno kirurško zdravljenje je edino zdravljenje z možnostjo ozdravitve, adjuvantno onkološko zdravljenje pa pomembno podaljša čas srednjega preživetja po kirurškem posegu. Zdravljenje metastatske bolezni zadnjih 15 let temelji na gemcitabinu. Nedavne raziskave pa so pokazale pomembno podaljšanje preživetja pri uporabi kombinacije 5-FU, irinotekana in oksaliplatina (FOLFIRINOX) ter kombinacije gemcitabina z nab-paklitakselom. The incidence of pancreatic cancer is rising and 357 new patients were recorded in Slovenia in 2009. Surgery remains the only potentially curative treatment and adjuvant therapy brings survival benefit. Treatment of metastatic disease was based on gemcitabine monotherapy for the past 15 years. Recent studies of 5-FU, irinotecan and oxaliplatin regimen (FOLFIRINOX) and gemcitabine combination with nab-paclitaxel show survival benefit and are new first-line treatment options for these patients. INTRODUCTION stry data for 2009, the incidence of pancreatic cancer was 18.5 per 100.000, which means 357 new cases (1). Pancreatic cancer is the 10th most common cancer diagnosed and the 4th most common cause of death resulting from cancer. Median survival is approximately three to six months, and only 2% of patients will be alive five years after diagnosis. Incidence rates are virtually identical to mortality rates with a range of 2.1 to 18.5 per 100.000 people. According to the Slovenian Cancer Regi- The only curative treatment of pancreatic cancer is radical surgery, however this type of treatment is possible only with stage I (T1 – T2, N0) and sometimes stage II (T3 N0, T1 – T3, N1) disease. It is well known that age is inappropriate criteria for patient selection and that extended lymphade- * Prof. dr. Borut Štabuc, dr. med. KO za gastroenterologijo, UKC Ljubljana Japljeva 2, 1000 Ljubljana GASTROENTEROLOG 101 nectomy brings no survival benefit; among 100 patients with pancreatic cancer, radical resection is possible in 20 patients only. Median survival in this patient group is 15 months and only four patients will be alive at five years. On the other hand, radiation and chemotherapy or best supportive care are the treatment option for 80% of patients with pancreatic cancer. The medium survival in this group of patients is between three and six months and only 2% will be alive at three years. ADJUVANT CHEMOTHERAPY AND CHEMO-RADIATION THERAPY OF PANCREATIC CANCER According to the American Gastroenteorology Association medical position statement from 1999, adjuvant therapy with 5-FU based chemo-radiation regimen should be considered after surgical resection(2). This medical position statement was based on one pivotal study, which supports adjuvant chemoradiotherapy in patients with resected pancreatic cancer. This small study that enrolled 43 patients and showed a median survival benefit of 20 months versus 11 months with significant fiveyear survival difference (18% versus 8%) in patients who received bolus 5-FU with radiation therapy for one year compared to those with who did not (3). Small sample size was the most important weakness of this study. motherapy. The chemotherapy-only arm showed statistically significant benefit over the observation arm in median survival (20.1 months versus 15.5 months; P=0.009), while the chemoradiation therapy arm showed worse median survival (15.9 months versus 17.9 months; p=0.05). The main weakness of this study was possible selection bias as patients and clinicians were allowed to select which arm to enter. Additional concern was suboptimal radiotherapy, allowing the final radiotherapy dose to be left to the judgment of the treating radiotherapists (5). These confusing and inconsistent results of the published randomized trials, which failed to provide clear evidence in support to the use of chemoradiation as adjuvant therapy after pancreatic cancer resection, spawned several new studies. One retrospective study, covering a 30-year period at Mayo clinic, evaluated overall survival of 472 patients after radical (R0) resection of pancreatic cancer. Significantly better survival was observed in patients who received adjuvant chemoradiotherapy (25.2 months) compared to those with no adjuvant treatment (19.2 months, p=0.001). The difference in survival can not be attributed to tumor biology - patients receiving adjuvant therapy had more adverse prognostic factors than those not receiving adjuvant therapy (p=0.001) (6). However, EORTC study in 207 patients with pancreatic and ampullary cancer compared treatment with infusional 5-FU and radiotherapy given in split curses (40 Gy) or observation only and showed only a trend towards benefit of chemoradiation in terms of medium survival (24.5 months versus 19 months; p=0.2008) (4). This study was criticized for its radiotherapy component - suboptimal lower dose and split curses. Analysis of Prospectively Collected Database at the Johns Hopkins Hospital of 616 patients showed similar effect of adjuvant concurrent FU-based chemoradiotherapy. Results confirmed significant improvement in survival after pancreatic cancer resection. Patients receiving chemoradiotherapy experienced longer median (21.2 versus 14.4 months; P < .001), 2-year (43.9% v 31.9%), and 5-year (20.1% v 15.4%) survival in comparison to those who received no adjuvant treatment (7). ESPAC–1 enrolled 541 patients with resected pancreatic cancer comparing, in a complicated trial design, post operative observation, chemoradiation, chemotherapy and chemoradiation followed by che- In a Randomized EORTC-40013-22012/FFCD9203/GERCOR phase II study, 90 patients were randomly assigned to receive either four cycles of gemcitabine or gemcitabine for two cycles followed 102 GASTROENTEROLOG by weekly gemcitabine with concurrent radiation (50.4 Gy). Median disease free survival was 12 months in the chemoradiotherapy arm and 11 months in the control arm. Median overall survival was 24 months in both arms. First local recurrence was less frequent in the CRT arm (11% vs. 24%) (8). In the CONKO-001 study, Oettle et al. randomized 368 patients with resected pancreatic cancer to gemcitabine chemotherapy for six months, or observation only. This trial showed a statistically significant disease-free survival benefit (13.4 months versus 6.9 months; P<0.001) of gemcitabine versus observation. Adjuvant treatment with gemcitabine showed a trend toward overall survival benefit (22.1 months versus 20.2 months; P=0.06), which was later reported statistically significant (9). dard treatment after pancreatic cancer resection, especially in Asian population. These trials clearly show the benefit of adjuvant chemotherapy; data regarding radiotherapy is less clear as direct comparisons are rare and it may not be required for majority of patients. Most importantly - it should be noted that we still lack good criteria for selection of patients for surgical treatment. Despite resectability, we still loose 30% of patients with stage 1 and 2 disease after radical surgery in first six months. NEOADJUVANT TREATMENT OF PANCREATIC CANCER Neoptolemos et al. report on ESPAC-3 study in which 1088 patients with an R0/R1 resection for pancreatic ductal adenocarcinoma were randomized within 8 weeks of surgery to receive either bolus 5-FU/leucovorin or gemcitabine for 6 months versus observation. The median overall survival of patients treated with gemcitabine did not differ from that of patients treated with 5-FU (23.6 months versus 23.0 months; p=0.39) (10). However, safety and dose intensity favored gemcitabine in this study. Neoadjuvant therapy has several potential advantages. Better tumor response is aided by delivery of chemotherapy and /or radiation to an intact and well-vascularized primary tumor, furthermore it provides early treatment of micrometastatic diseases and offers a time interval within which unfavorable tumor biology unmasks and identifies patients in whom surgery would not be of benefit. It can reduce the risk of pancreatic leakage after surgical reconstruction and lower the rate of local recurrences to less than 10%. Despite these advantages, there is no evidence and no clinical trials that would support the administration of chemoterapy and/or chemoradiation in the preoperative period. Randomized phase III adjuvant chemotherapy study comparing gemcitabine versus S1 in patients with resected pancreatic cancer (JASPAC 01) conducted in Japan enrolled 385 patients. This trial showed significantly higher overall two-year survival of S1 treated patients in comparison to the gemcitabine arm (two-year over all survival 70% (95% confidence interval 63%–76%) versus 53% (46%–60%)). There was also significant difference in median disease free survival with 23,2 months (95% confidence interval 17,5–32 months) in the S1 arm and 11,2 months (9.7–13.5 months) in the gemcitabine arm (11). Adjuvant chemotherapy with S1 for resected pancreatic cancer patients was shown to be superior to gemcitabine and S1 may be considered new stan- The University of Texas MD Anderson Cancer Center evaluated neoadjuvant chemoradiation strategies for resectable pancreatic cancer in a series of nonrandomized phase II trials. The 276 patients enrolled in these trials met identical eligibility criteria, which included objective, computed tomography based determination of resectability and histologic confirmation of PC, and the patients underwent resection with a uniform surgical technique. Median overall survival durations as long as 34 months were observed among the 54%–74 % of enrolled patients who completed all therapy, including surgery; in contrast, patients who did not complete treatment had median overall survival times of only 7–11 months (12). GASTROENTEROLOG 103 TREATMENT OF LOCALLY ADVANCED PANCREATIC CANCER The median survival of patients with locally advanced pancreatic cancer is better when compared to metastatic disease. The question of optimal treatment for locally advanced disease remains unresolved. Chemotherapy alone and chemoradiation therapy trials report medium survival of ten months. In the European Union, chemotherapy alone remains standard of care. One recent meta-analysis suggested gemcitabine based chemoradiation therapy may be both, more effective and more toxic than 5-FU based chemoradiation (13). In a recent prospective clinical trial, presented at ASCO GI 2013, 74 patients with locally advanced pancreatic cancer were randomized after 4 cycles of combination chemotherapy to either gemcitabine or capecitabine radiotherapy arm. The split radiation dose in both arms was 15,4 Gy. Medium overall survival was significantly higher in patients with capecitabine radioterapy arm -15,2 months versus 13,4 months in the Gemcitabine radioterapy arm (p=0. 012). Median progression free survival was also longer in this arm (20 versus 10.4 months). Furthermore, following induction chemotherapy the combination of radiotherapy with capecitabine was significantly less toxic than combination with gemcitabine. The benefit was archived with no compromise in local control and improvement in overall survival. TREATMENT OF METASTATIC PANCREATIC CANCER In the last 15 years the gemcitabine in dose 1000 mg per m2 on weekly schedule has been standard treatment for metastatic pancreatic cancer. In prospective clinical trial conducted by Buris at al in 1997, 126 patients were randomized in two treatment arms with either 5-FU or gemcitabine. The difference in progression free survival and medium overall survival was significant across the two arms (medium overall survival – 5.65 months in gemcitabine versus 4.41 104 GASTROENTEROLOG months in 5-FU arm, 1 year survival 18 % in gemcitabine and 2% in 5-FU arm, p=0.002). Furthermore, the survival benefit was accompanied by significant clinical benefit in gemcitabine arm patients (14). Several trials with combination chemotherapy approaches aimed to improve treatment efficacy in following years. In an attempt to assess the combination of gemcitabine with a fluoropyrimidine, phase III trial was performed, comparing combination chemotherapy with gemcitabine plus capecitabine (GemCap) versus single-agent gemcitabine in 319 patients with advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive either GemCap (oral capecitabine 650 mg/m2 twice daily on days 1 to 14 plus Gem 1,000 mg/m2 by 30-minute infusion on days 1 and 8, every 3 weeks) or gemcitabine alone. Median overall survival time was 8.4 and 7.2 months in the GemCap and gemcitabine arms, respectively (p= 0.234). Post-hoc analysis in patients with good Karnofsky performance status (score of 90 to 100) showed a significant prolongation of median overall survival in the GemCap arm compared to the gemcitabine monotherapy arm (10.1 v 7.4 months, respectively; p=0.014) (15). Combination chemotherapy trial with gemcitabine and oxaliplatin in metastatic pancreatic cancer randomized 156 patients into gemcitabine and 157 patients into gemcitabine with oxaliplatin (GemOx) arm. The combination was found to be significantly superior to gemcitabine in terms of response rate (26.8% and 7.1%, respectively; p = 0.044), clinical benefit (42.3% and 8.3%; p = .01), median progression free survival (5.8 and 3.7 months, p = 0.04). One-year survival probability was 27.8% in the gemcitabine arm and 34.7% in the GemOx arm (p =0.22). Median overall survival time did not differ significantly and was 7.1 months for gemcitabine monotherapy and 9.0 months for GemOx combination (p=0.13; HR 1.20; 95 % CI 0.95 to 1.54) (16). As showed by another trial with 360 enrolled patients, irinotecan plus gemcitabine combination does not affect overall survival or time to progression when compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer (median overall survival 6.3 months and 6.6 months, respectively) (17). The first gemcitabine combination regimen, which showed modest improvement in overall survival over gemcitabine monotherapy, was gemcitabine with erlotinib. One-year overall survival of 24% versus 17% was reported for the combination and monotherapy (HR 0.76), respectively. The study also supported the concept of effective EGFR pathway targeting in pancreatic cancer patients(18). Recently, gemcitabine monotherapy was compared to another promising combination in 342 patients with metastatic pancreatic cancer. They were randomized to either 5-FU, irinotecan, oxaliplatine (FOLFORINOX) combination or gemcitabine monotherapy arm and median overall survival was significantly longer in the FOLFIRINOX arm with 11.1 months as compared with 6.8 months in the gemcitabine arm (p<0.001). Median progressionfree survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (p<0.001). Not surprisingly, the FOLFIRINOX regimen was associated with higher rates of grade 3 and 4 toxicities than gemcitabine and 42.5% of patients in the experimental arm received G-CSF and almost 1/4 of the patients had grade 3 or 4 fatigue. 10–15% experienced grade 3 or 4 vomiting, diarrhea, or neuropathy(19). MPACT recently compared the combination of nabpaclitaxel with gemcitabine, in a international phase III study; 842 patients were randomized and significant survival benefit was reported for the combination in comparison to gemcitabine monotherapy (median overall survival 8.5 versus 6.7 months, respectively). One-year survival was 35% in the experimental and 22 % in the control arm, a 5 % relative difference. Hematological toxicity and neuropathy levels were acceptable and manageable and the combination of gemcitabine with nab-paclitaxel may be considered a new standard for the treatment of patients with metastatic pancreatic cancer. CONCLUSION Pancreatic cancer remains a malignancy with grave prognosis. Adjuvant therapy after radical surgery improves patient survival. In metastatic disease, gemcitabine monotherapy remained the main treatment option in the last 15 years. No clear survival benefit was achieved with gemcitabine combination chemotherapy until modest two-week median survival improvement was shown by addition of EGFR-targeting erlotinib. FOLFIRINOX regimen has proven more effective than gemcitabine, however study population selection and unfavorable toxicity profile prohibit its wide use. Nab-paclitaxel combination with gemcitabine has recently emerged as a possible new standard treatment for metastatic pancreatic cancer, which is yet to be implemented into everyday practice. REFERENCES 1. Primic Žakelj M. Rak v Sloveniji 2008. Ljubljana: Onkološki inštitut, Epidemiologija in register raka, Register raka Republike Slovenije; 2011. 2. American gastroenterological association medical position statement: epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. Gastroenterology. 1999 Dec;117(6):1463–84. 3. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch. Surg. Chic. Ill 1960. 1985 Aug;120(8):899–903. 4. Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann. Surg. 1999 Dec;230(6):776–782; discussion 782–784. 5. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med. 2004 Mar 18;350(12):1200–10. 6. Corsini MM, Miller RC, Haddock MG, Donohue JH, Farnell MB, Nagorney DM, et al. Adjuvant radiotherapy and chemotherapy for pancreatic carcinoma: the Mayo Clinic experience (1975–2005). J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2008 Jul 20;26(21):3511–6. 7. Herman JM, Swartz MJ, Hsu CC, Winter J, Pawlik TM, Sugar E, et al. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2008 Jul 20;26(21):3503–10. GASTROENTEROLOG 105 8. Van Laethem J-L, Hammel P, Mornex F, Azria D, Van Tienhoven G, Vergauwe P, et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD9203/GERCOR phase II study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2010 Oct 10;28(29):4450–6. 9. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. Jama J. Am. Med. Assoc. 2007 Jan 17;297(3):267–77. 10. Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. Jama J. Am. Med. Assoc. 2012 Jul 11;308(2):147–56. 11. Maeda A, Boku N, Fukutomi A, Kondo S, Kinoshita T, Nagino M, et al. Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 in patients with resected pancreatic cancer: Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01). Jpn. J. Clin. Oncol. 2008 Mar;38(3):227–9. 12. Katz MHG, Fleming JB, Lee JE, Pisters PWT. Current status of adjuvant therapy for pancreatic cancer. Oncologist. 2010;15(11):1205–13. 13. Zhu C-P, Shi J, Chen Y-X, Xie W-F, Lin Y. Gemcitabine in the chemoradiotherapy for locally advanced pancreatic cancer: a meta-analysis. Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol. 2011 May;99(2):108–13. 14. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 1997 Jun;15(6):2403–13. 106 GASTROENTEROLOG 15. Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2007 Jun 1;25(16):2212–7. 16. André T, Tournigand C, Rosmorduc O, Provent S, MaindraultGoebel F, Avenin D, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. Esmo. 2004 Sep;15(9):1339–43. 17. Rocha Lima CM, Green MR, Rotche R, Miller WH Jr, Jeffrey GM, Cisar LA, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2004 Sep 15;22(18):3776–83. 18. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2007 May 20;25(15):1960–6. 19. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 2011 May 12;364(19):1817–25. Varna terapevtska kolonoskopija Safe therapeutic colonoscopy Milan Stefanovič* Diagnostični center Bled Gastroenterolog 2013; suplement 2: 107–113 Ključne besede: kolonoskopija, varnost, šolanje, polipektomija Key words: colonoscopy, safety, training, polypectomy. POVZETEK ABSTRACT Tveganje pri izvajanju kolonoskopije je večplastno in na to vpliva več dejavnikov. Dejavnik tveganja je lahko endoskopist, endoskopski tim kot celota ali njegov del in oprema v endoskopski enoti, ki je na voljo v danem trenutku. Ne nazadnje je lahko dejavnik tveganja tudi bolnik pri katerem se izvaja poseg. Vloga zdravnika endoskopista je najpomembnejša in odločujoča. Kot vodja tima in nosilec dejavnosti je zdravnik endoskopist odgovoren za strukturo in kakovost procesa. Odgovoren je za eventualne napake v organizaciji in delu endoskopske enote kot celote ali posameznikov s katerimi sodeluje v timu. Zelo pomembno je njegovo znanje, izkušnje in stalna praksa. Za opravljanje kolonoskopije je potreben tretji nivo znanja. Nedvomno je število opravljenih posegov in zahtevnost posegov, ki jih je sposoben opraviti v soodvisnosti z izidom zdravljenja. Ne tako redko je tu prisoten tudi konflikt, ko je potrebno pretehtati kje je meja in kaj lahko naredimo v danih okoliščinah in kje je meja pri doseganju tehnične odličnosti. Poleg preprečevanje zapletov mora endoskopist biti sposoben pravočasno prepoznati in razrešiti zaplet(e) in oskrbeti urgentna stanja. Risks, associated with colonoscopy are multi-layered and affected by several factors. Risk factors may include the endoscopist, endoscopic team as a whole or a part of it, and equipment in the endoscopic unit which is available at a given moment. The patient who undergoes colonoscopy may also be a risk factor. The role of the endoscopist doctor is the most important and decisive. As the head of the team, the doctor is responsible for the structure and quality of the process, including any mistakes in the organisation and work, done by the endoscopic unit as a whole or individuals in the team. Consequently, doctor’s knowledge, experience and constant practical work are of utmost importance. Colonoscopy requires the third level of knowledge. Undoubtedly, the number and complexity of procedures that the doctor is able to carry out are interdependent on the outcome of the treatment. Furthermore, conflicts are often present when it has to be decided where the boundary is and what can be done in given circumstances and where is the limit in the achievement of technical excellence. In addition to preventing complications the endoscopist has to be able to recognise and solve complications and take care of possible emergency conditions in due time. * Prim. Milan Stefanovič, M.D. Diagnostični center Bled, Pod skalo 4 4260 Bled GASTROENTEROLOG 107 INTRODUCTION The prerequisite for reliable and safe colonoscopy is an endoscopic unit and/or endoscopists who have the required knowledge and technical abilities to recognise changes and endoscopically remove them, or refer such patient to a tertiary institution with more expert knowledge /EMR and ESD) or to an abdominal surgeon. All endoscopists should have expert knowledge level 3 (removal of big polypoid, pedunculated and sessile changes, and smaller non-polypoid changes ≤ 20 mm). The fourth level of expert knowledge is required for tertiary centres. These regard limit changes, endoscopic/surgical removals which require a special consensus by the patient (1, 2). DISCUSSION Today we have the mechanisms to separate high quality endoscopic examinations, carried out by an endoscopist with appropriate theoretical and technical skills from an examination, carried out by an examiner who lacks such skills. Patients, doctors and health system require a guarantee that endoscopy is carried out only by properly qualified experts (endoscopists). Fortunately, side effects and complications are rare, and their type, seriousness and frequency cannot be used for efficient assessment of the quality of the endoscopist’s work. Certain quality indicators have been selected which allow for more efficient control and implementation of measures for keeping and raising the quality level of colonoscopies (1, 2). In order to be able to carry out a colonoscopy procedure successfully, the endoscopist must be cognitively reliable which means that he/she is able to recognise abnormalities, interpret them and define the strategy of treatment accordingly. Each type of endoscopy includes also technical requirements that the endoscopist has to meet after the completion of studies. The level of competency for carrying out high quality colonoscopy and removal of high-risk changes depends also on the competency of the endoscopic 108 GASTROENTEROLOG team and the equipment which is available: highly qualified team needs suitable equipment and consumables, which means that any problem that occurs may be solved. The requisites for safe colonoscopy in an endoscopic unit are: – employees have the required knowledge and level of competency; – unit has all the required equipment; and – In case of serious complications the patient can be cared for locally and then safely transferred to another health care institution which has all the conditions for further treatment of such patient. Shortcomings may be detected by appropriate assessing and testing of abilities and competencies and then removed by additional theoretical and practical training, and also by new investments. The most suitable indicator for assessing whether the training in the field of gastrointestinal endoscopy was successful is the level of successful examinations. This rate and the rate of complications can provide an objective picture of the endoscopist‘s performance, compared with the statistics of experienced endoscopists. However, it is more difficult to identify and monitor information about overlooked changes, which means that appropriate documentation in the form of electronic records and photo documentation is very important. When assessing the performance, the level of satisfaction of people who have undergone the procedure is also very important as it affects the patient’s decision about coming to the agreed follow-up endoscopy (4, 5). According to the information, there are substantial differences in previous training, number of treated cases and individual endoscopists among endoscopic units, hospitals and private practices. The definition of proper qualification of an endoscopist for independent work and individual type of endoscopy is still difficult. Most endoscopic associations rely on the assessment regarding the number of procedures carried out, and more or less on the teacher’s subjective assessment. The number of procedures carried out for individual types of endoscopy used to be a criterion for the achievement of appropriate knowledge, but in most cases the numbers were set too low. It was found out that the learning curve is much slower and gradual, and the number of required endoscopic procedures which is the condition for appropriate qualification is much higher than it had been anticipated. Today’s requirements are probably higher also due to the application of new, more and more sophisticated technologies and complex endoscopic procedures. The achieved level of endoscopic knowledge can be maintained only by constant work and keeping the routine. The definition of proper qualification has to be unified, which is the task of the national association. Undoubtedly, the number of examinations carried out is very important for the qualification and performance of an endoscopist, but it is much more important to meet and achieve the required level of individual quality indicators. The American Society for Gastrointestinal Endoscopy (ASGE) has defined 21 general quality indicators which refer to the assessment of quality of the entire Gastrointestinal Endoscopy () before, during and after endoscopic procedure. 14 special quality indicators were defined for the needs of colonoscopy, including the rate of achieving total colonoscopy to caecum, duration of withdrawal, rate of detecting adenomas and removal of detected polyps (6). In Slovenian National Colorectal Cancer Screening Programme (SVIT Programme) among others 12 quality indicators which refer to colonoscopy are monitored. The acceptable and desired quality levels have been set for most of them: 1. Share of colonoscopists with the minimum number of colonoscopies carried out 2. Appropriate visibility after intestinal preparation 3. Share of total colonoscopies 4. Duration of examination during the withdrawal of colonoscope 5. Rate of detecting adenomas in people who undergo colonoscopy 6. Ratio in the rate of detecting adenomas during colonoscopy of the left and right part of the colon 7. Rate of detecting adenomas in people who undergo colonoscopy below the curve where also the number of detected adenomas per colonoscopy and average number of adenomas per colonoscopy with adenoma are taken into account 8. Referral of the patient to polypectomy to another centre 9. Share of complications after colonoscopy 10. Significant interval changes after colonoscopy with a positive test to occult bleeding 11. Appropriate documenting of the colonoscopies carried out, and 12. Appropriate referral to follow-up colonoscopy. In addition to the above, endoscopic units are controlled, which includes assessing the premises, equipment and staff (for extending and issuing accreditation upon the inclusion into the SVIT programme). Answers in the questionnaires, filled in by people who participated in SVIT screening programme, are also used in the assessment. All these measures require prospective collection for each colonoscopy and for all people who carry out colonoscopies. Collection itself is not sufficient. Analysis and taking appropriate measures will contribute to improving the level of quality (7). Achieving appropriate quality levels in the field of gastrointestinal endoscopy will ensure preventing undesired complications and doctors’ errors in the best possible way. Some practical advice for safe polypectomy If we want to remove a polyp we have to find it first! There is a lot of information which proves that during colonoscopy neoplasms, even cancer, is overlooked. The rate of missed and overlooked changes differs among endoscopists which confirms that scrupulous and careful examination, using appropriate colonoscopic equipment is of key importance GASTROENTEROLOG 109 for ensuring quality colonoscopy which will prevent overlooking colorectal cancer (8-11). foration. It has to be checked prior to the resection whether all the required devices are available (clips, noradrenaline, loops, knives, APC catheter). 2. It is important to discuss the matter with the patient before you begin the procedure. Patient’s plans after the intervention (important events, longer travelling…) have to be taken into account. 3. In case of elective removal of complex polyps it is recommended to make an action plan, before the procedure, with the endoscopic staff and make sure that all the required devices are available. Repeated preparation is important as well (MoviPrep in shared dose) even if the change is in the rectosigmoid part of the colon. Be careful with antithrombotic medications (follow the guidelines) (12, 13). Each endoscopist should aim at safe and total removal of all colon polyps (without bleeding and perforation) (without repetition at the place of the removal). Most polyps are small and not difficult to remove (> 90%). However, sometimes they may pose a challenge. What should we pay special attention to? 1. High risk of bleeding (pedunculated polyps on thick stalks, big sessile polyps) because of the high number of veins which feed the change and which have to be cut during polypectomy (+ antithrombotic conditions). 2. High risk of perforation (big sessile polyps, big LSTs and non-polypoid changes in caecum and right hemicolon) due to a big cut, required for the removal of such changes. 3. High risk of residue and/or recidivism (incomplete removal) in certain patients where some parts of the polyp were not removed (12, 13). Some additional useful advice for safe and successful polypectomy: – Electrocauterisation contributes to practically everything – perforations and most bleedings during polypectomy. Small polyps can be efficiently removed by cold techniques: biopsy and loop without electrocauterisation for 1–3 mm polyps, and loop without electrocauterisation for 3–10 mm polyps, depending on its shape. As most small polyps are not threatening for the patient, we have to be careful when deciding for the removal with ELR and we always have to consider the risk benefit factor (14–16). – When using »cold loop« some millimetres of the surrounding healthy mucosa can be grabbed into the loop (14). – Use of »hot« biopsy forceps is not recommended. In addition to higher risk of perforation there is no guarantee (in spite of the general belief) that the entire polyp will be burnt. It has been shown that in 16–28 per cent of cases residual neoplastic tissue remains in the colon after such removal (14). It is not easy to answer the question how to decide when a complex polyp is detected during screening colonoscopy. If you are not ready for therapeutic procedure: 1. Mark the spot with a tattoo (SPOT) one haustrum from the change; avoid injecting into the polyp because fibrosis may occur and prevent later endoscopic removal. 2. Avoid biopsy from flat/non-polypoid change and refer the patient to a centre with appropriate experience; biopsies cause submucosal fibrosis and limit rising after injecting into submucosa and prevent EMR. If you decide for resection of a complex lesion: 1. The precondition for endoscopic removal of such change is appropriate knowledge required for controlling bleeding and per110 GASTROENTEROLOG – Use of weak coagulation current is associated with higher risk of belated bleeding while a mixed current for cutting, results in immediate bleeding. At the moment there are several different units on the market and they are all suitable for endoscopic polypectomies. Some »surgical« units (ERBE, Olympus) alternate the current for coagulation with the current for cutting. The unit constantly calculates the tissue resistance and performs coagulation, followed by short pulses of cutting current. When a thick stem is being cut, it is good to start with the use of pure coagulation and only then the alternating current because in this way immediate bleeding is avoided (12). – Ligation loops have proved to be efficient in preventing immediate and belated bleedings after the ELR of pedunculated polyps. Several endoscopists say that they are demanding for use, especially in case of big pedunculated polyps, when they are needed the most. The volume of the polyp can be reduced by injecting adrenaline into the head of the polyp (13). – When saline-adrenaline solution is injected into submucosa, immediate bleeding after polypectomy is prevented (1:100.000/1:200.000). – Clips should prevent bleeding!? (if fitted correctly). Prophylactic placement of clips is recommended. – – Submucosal injection should prevent perforation!? Submucosal injection is very important for successful EMR as it separates mucosa from muscularis propria and reduces the risk of bleeding. This is followed by either en-bloc or resection by parts (piece-meal) (13, 18). In most cases we inject into the centre of the change. Proximal injection is applied when the polyp reaches behind the haustrum – sometimes this is done best in retroflexion. Injecting by parts (dynamic submucosal injecting) is applied in case of very big changes which are removed also by parts (piece-meal). Sometimes even up to 30–50 cc has to be injected but there are no special limitations for the volume (19). – During ELR of a pedunculated polyp they have to be (when feasible) grabbed about 1/3 of the distance of the polyp head from the colon wall. This means that enough stem is left so that it can be grabbed in case of bleeding and at the same time appropriate distance from the polyp ensures safe resection in case the invasion has progressed into the stem (malign polyp). It is recommended to inject diluted adrenaline into the thick stem prior to the ELR (12, 14). – Several big sessile polyps which could have been removed endoscopically are still removed by surgeons. Endoscopic therapy is better for the patient. Long-term results of EMR by parts are excellent. Endoscopic therapy is also cheaper. The rate of complications is low (no dehiscence, no hernia…). The disadvantage is that endoscopic controls are needed (the first after 3 to 4 months) and also the second one in one year is compulsory). Disadvantages for the endoscopist: the complications which occur are endoscopist’s complications; the procedure is not valued correctly (17). – Limitations in endoscopic polypectomy of sessile polyps: – the polyp grows and extends into the mouth of the appendix, – it expands (grows) into the terminal ileum, – a polyp which covers more than 50-60% the colon circumference in the ascending colon and rectum and more than 30% in sigma. – a polyp which grows over two neighbouring haustra can be non-resectable when the area between the haustra is deep and relatively unreachable (12). GASTROENTEROLOG 111 – Big non-polypoid changes should not be biopsied as this way (fibrosis) causes false negative sign of lifting (»non-lifting) during later planned polypectomy. – Adding methylene blue into the solution for submucosal injection during resection by parts results in better visual limitation of neoplastic borders. Alternatively, NBI can be used. The edges can be cut separately with an eccentric loop (Wilson Cook). Alternatively, Argon plasma can be used. The depth of the injury in case of laser depends on the duration of the pulse in intensity. Low power and short pulse are required in caecum and ascending colon (12). – Retroflexion may facilitate access at difficult areas. Retroflexion is applied without any difficulties on the ascending colon and rectum. When gastroscope is used, retroflexion can also be used in left hemicolon. – Indian ink (SPOT = pure carbon particles) is the best for marking. All changes which are ≥ 20 mm should be marked as they are quite likely to be malign polyps (> 10%), as well as the changes that the surgeon would find difficult to find as they are so small. Marks should be some centimetres from the change at least between two spots (mesenteric and antimesenteric). After injection with saline solution we make a bubble into which the ink is injected. Changes in caecum and rectum do not have to be marked prior to the planned surgery or in order to control the spot of ELR during subsequent endoscopic controls (13, 20). – ESD is a technique, developed in Japan. It is time-consuming and associated with higher risk of complications (4.7% of perforations). It is questionable whether it really has such a big advantage over peace-meal EMR by which almost all benign polyps can be removed. ESD in rectosigma is technically more demanding than ESD in the stomach. However, it seems 112 GASTROENTEROLOG that in ideal conditions the method is reasonable and it is definitely better than surgery which can be even more dangerous and expensive. At the moment the indications are not clear and defined enough. In Japan the following are the (possible) indications for ESD: wide base lesions ≥ 2 cm which cannot be removed en bloc, non-granulated/locked type, pit pattern V, Sm1 carcinoma, scarred lesions (submucous fibrosis), sporadic lesions in case of ulcerative colitis and residual early carcinoma after incomplete previous EMR. The conditions to start ESD are primarily clearly defined and acceptable indications, well-qualified and equipped endoscopic team and the rate of complications have to remain low. Secondary requisites, which are time and money, have to be taken into account as well. Japanese results for Ro + en bloc resection 75.7%, perforations 4.7% (21, 22). The criteria for carrying out ESD are appropriate experience with the minimum of 1000 colonoscopies and more than 200 standard EMRs carried out as well as experience in managing complications. Due to the above reasons the procedure is limited to selected or tertiary centres. CONCLUSIONS The endoscopist must have appropriate technical knowledge and ability to judge in detecting and removing abnormalities in colon and rectum. Colonoscopy has to be fast, safe and as little unpleasant as possible, with enough time for examination, safe removal and withdrawal of removed changes for subsequent pathohistological examination. During the examination all abnormalities should be detected and assessed and the decision for further action should be made. The procedure is carried out only when and if needed and all the neoplastic changes are withdrawn. Such high quality and safe colonoscopy requires teamwork and appropriate equipment of the endoscopic unit. Nursing staff have to make sure that the patient is comfortable and under constant supervi- sion during the examination so that the endoscopist can focus on the procedure itself. Endoscopic nurses also provide technical support for proper functioning of the endoscopic equipment and make sure that the required endoscopic devices are available at all times. Last but not least they also provide support in therapeutic procedures, e.g. polypectomy. Endoscopists and endoscopic nurses have to constantly analyse their work in the light of carrying out the procedures, together with pathologists and surgeons if possible so as to optimally improve the outcome for the patients. Quality and safe colonoscopy depends also on proper maintenance and regular servicing of the equipment and prompt purchasing of devices for the scope and type of procedures, carried out in the endoscopic unit. Devices for solving complications after the removal of high-risk changes, such as bleeding and in some cases perforations have to be available. Endoscopic equipment is expensive and when it is used constantly it is exposed to substantial burdening. The equipment has to be maintained by qualified personnel. Maintenance and repair of old instruments is sometimes more expensive than replacement with new instruments. REFERENCES 1. Stefanovič M; Zagotavljanje kakovosti v državnem programu presejanja za raka debelega črevesa in danke in njegovega zgodnjega odkrivanja. Gastroenterolog 2007;11:22–31. 2. Segnan N, Patrick J, von Karsa L (eds). European guidelines for quality assurance in colorectal cancer screeining and diagnosis – first edition. Luxemburg: Publication Office of the European Union, 2010. 3. European Board of Gastroenterology and Hepatology. Speciality Training Programme and Curriculum for Gastroenterology and Hepatology. The EB Gastrohep Training Programme: The blue book 2012. (http://www.eubog.org/docs/Blue_Book.pdf) 4. Bjorkman D, Popp J. Measuring the quality of endoscopy. Gastrointest Endosc 2006 Apr;63(4 Suppl):S1–2. 5. Naylor G, Gatta L, Butler A, Duffet S, Wilcox M, Axon AT, O'Mahony S. Setting up a quality assurance program in endoscopy. Endoscopy 2003 Aug;35(8):701–7. 6. ASGE/ACG: Quality in Endoscopy. Gastrointest Endosc 2006;58:S1S38 (http://www.asge.org/WorkArea/showcontent.aspx?id=3386) 7. Ključni indikatorji kakovosti Programa SVIT (Državni program presejanja in zgodnjega odkrivanja predrakavih sprememb in raka na debelem črevesu in danki). Ljubljana: Inštitut za varovanje zdravja. In press 2013. 8. Kaminski M, Regula J, Kraszewska E, Polkowski M, Wojciechowska U, Didkowska J, et al. Quality Indicators for Colonoscopy and the Risk of Interval Cancer. N Engl J Med 2010; 362: 1795–1803. 9. Wilkins T, LeClair B, Smolkin M, Davies K, Thomas M, Taylor M, Strayer S. Screening Colonoscopies by Primary Care Physicians: A Meta-Analysis. Ann Fam Med 2009; 7: 56–62. 10. Baxter N, Goldwasser M, Paszat L, Saskin R, Urbach R, Rabeneck L. Association of colonoscopy and death from colorectal cancer. Ann Intern Med. 2009; 150 :1–8. 11. Rex D. Colonoscopic withdrawal technique is associated with adenoma miss rates. Gastrointest Endosc 2000; 51: 33–6. 12. Cohen J. Successful Training in Gastrointestinal Endoscopy. 1th ed.: Wiley-Blackwell; 2011. 13. Soetikon R, Raju G. Challanging colon polyps: EMR. In Endoscopy at its best, 2011 ASGE annual postgraduate course. May 8–9, 2011 Chicago, Illinois. 14. Rex D. Difficult Colonic Polyps. In Gastrointestinal Endoscopy Best Practices: Today and Tomorrow, 2007 ASGE annual postgraduate course. May 23–24, 2007 Washington, DC. 15. Repici A, Hassan C, Vitetta E, Ferrara E, Manes G, Gullotti G et al. Safety of cold polypectomy for < 10 mm polyps at colonoscopy: a prospective multicenter study. Endoscopy 2012;44:27–31. 16. Hewett D, Rex D. Colonoscopy and diminutive polyps: hot or cold biopsy or snare? Do I send to pathology? Clin Gastroenterol Hepatol 2011;9:102–5. 17. Rex D. Endoscopic Mangement of Colonic Polyps. In Integrating Endoscopic Advances into Clinical Practice, 2009 ASGE postgaduate course. October 23, 2009 San Diego, California. 18. Kaltenbach T, Soetikno R. Endoscopic mucosal resection of nonpolypoid colorectal neoplasm. Gastrointest Endosc Clin N Am. 2010:503–14. 19. Soetikon R, Kaltenbach T. Dynamic submucosal injection technique. Gastrointest Endosc Clin N Am. 2010:497–502. 20. Sawaki A, Nakamura T, Suzuki T, Hara K, Kato T, Kato T, et al. A two-step method for marking polypectomy sites in the colon and rectum. Gastrointest Endosc 2003;57:735–7. 21. Uraoka T, Parra-Blanco A, Yahagi N. Colorectal Endoscopic Submucosal Dissection. J Gastroenterol Hepatol. 2013;28(3):406–14. 22. Tanaka S, Terasaki M, Hayashi N, Oka S, Chayama K. Warning for unprincipled colorectal endoscopic submucosal dissection: Accurate diagnosis and reasonable treatment strategy. Dig Endosc. 2013 March; 25(2): 107–116. (Published online 2012 December 20. doi: 10.1111/den.12016) GASTROENTEROLOG 113 Helicobacter pylori - diagnostika, zdravljenje in rezistenca na antibiotike v Sloveniji Helicobacter pylori - diagnostics, treatment and antimicrobial resistance in Slovenia Bojan Tepeš* FEBG AMDC Rogaška Gastroenterolog 2013; suplement 2: 114–119 Ključne besede: antimikrobne sheme, Helicobacter pylori, indikacije za zdravljenje, rezistenca na antibiotike. Key words: antimicrobial therapy, drug resistance, Helicobacter pylori, indication for therapy. POVZETEK ABSTRACT Po priporočilih Slovenskega združenja za gastroenterologijo in hepatologijo zdravnik družinske medicine na osnovi neinvazivnih diagnostičnih metod, urea dihalnega testa (UBT) ali določanja monoklonalnih protiteles proti Helicobacter pylori (H. pylori) v blatu, začne zdravljenje H. pylori okužbe pri bolniki z znano razjedo dvanajstnika, pri družinskih članih prvega dednega reda bolnika z rakom želodca in pred uvedbo dolgotrajnega zdravljenja s salicilati in nesteroidnimi protivnetnimi zdravili. Druge indikacije za zdravljenje so v domeni gastroenterologa, ki diagnozo okužbe postavi z invazivnimi testi ob endoskopiji (hitri ureazni test, histologija, kultura). Slovenian Society for Gastroenterology and Hepatology in his recommendations divides indications for Helicobacter pylori (H. pylori) treatment between general practitioners (GP) and gastroenterologist. GP makes a diagnosis of H. pylori infection with urea breath test (UBT) or with monoclonal antibody-based H. pylori stool antigen test and starts treatment in case of known duodenal ulcer patient, first grade relatives of patient with gastric cancer and before starting long term therapy with nonsteroidal anti-inflammatory drugs and salicylates. All other treatment indications are in domain of gastroenterologist who during upper GI endoscopy use rapid urease biopsy test, histology or culture to diagnose the infection. Način zdravljenja je odvisen od podatkov o lokalni rezistenci H. pylori na antibiotike. V Sloveniji je rezistenca po zadnjih podatkih iz leta 2012 na klaritromicin 14,3 %, na metronidazol pa 22,2 %. V primeru, da je rezistenca H. pylori na klaritromicin manjša kot 15 %–20 %, je začetno zdravljenje sedem dni z zaviralcem protonske črpalke (ZPČ), amoksicilinom (A) / metronidazolom (M) in klaritromicinom (K) dvakrat dnevno. Uspeh zdravljenja preverimo mesec dni po končanem zdravljenju z UBT. Kontrolna The treatment algorithm is dependent on H. pylori local resistance data. H. pylori resistance in Slovenia in 2012 was 14,3% to clarithromycin (C) and 22,2% to metronidazole (M). In case of C resistance under 15%–20% triple therapy with proton pump inhibitor (PPI) - C- A (amoxicillin) / M bid seven days is recommended. The eradication success should be controlled with urea breath test or H. pylori stool antigen test one month or more after treatment. Control * Prof. dr. Bojan Tepeš, dr. med., specialist internist gastroenterolog FEBG AMDC Rogaška, Prvomajska 29 A 3250 Rogaška Slatina 114 GASTROENTEROLOG endoskopija s histologijo je potrebna pri bolnikih z razjedo želodca ali MALT limfomom. endoscopy is performed only in gastric ulcer or MALT lymphoma patients. V primeru neuspeha zdravljenja je naslednje priporočeno zdravljenje desetdnevno zdravljenje s koloidnim bizmutom subcitratom - oksitetraciklinom - metronidazolom in ZPČ (štiritirna terapija z bizmutom), ki pa ga v Sloveniji še nimamo. Druga možnost je desetdnevno zdravljenje ZPČ-A-K-M dvakrat dnevno. Kot zdravljenje tretjega reda svetujemo desetdnevno zdravljenje ZPČ -A – levofloksacin (L) ali pa zdravljenje po antibiogramu. Recommended second line treatment is ten day colloidal bismuth subcitrate (CBS) - oxytetracycline (T) – M - PPI therapy.This treatment is not available in Slovenia at the moment. The other second line treatment is ten day quadruple non bismuth therapy (PPI - A - K- M bid). This four drugs can be prescribed also as a sequential therapy (PPI and A bid for 5 days followed by PPI- C - M bid for another five days). Third line treatment is ten day PPI – A – levofloxacin (L) bid or treatment according to the result of culture and antibiotic susceptibility. V kolikor je lokalna rezistenca H. pylori na klaritromicin večja kot 20 %, kot prvo zdravljenje priporočamo štiritirno zdravljenje z bizmutom ali štiritirno zdravljenje brez bizmuta (ZPČ-A-K-M) dvakrat dnevno ali ista zdravila v obliki sekvenčnega zdravljenja (ZPČ – A pet dni in nato ZPČ - K - M naslednjih pet dni dvakrat dnevno). V kolikor je to zdravljenje neuspešno, je zdravljenje drugega izbora z ZPČ - A - L. Zdravljenje tretjega izbora, v kolikor je potrebno, je vedno po antibiogramu. Pri bolnikih, ki so alergični na penicillin, je začetno zdravljenje ZPČ - M - K. V kolikor je rezistenca na klaritromicin večja kot 20 % je prvo zdravljenje štiritirno zdravljenje z bizmutom. Nadaljna zdravljenja so po antibiogramu. DIAGNOSTIKA HELICOBACTER PYLORI INFEKCIJE Specialist družinske medicine V Sloveniji specialist družinske medicine v skladu s priporočili Slovenskega združenja za gastroenterologijo in hepatologijo (SZGH; 1) diagnosticira in zdravi okužbo s Helicobacter pylori v sledečih primerih: 1. Bolnik z razjedo na dvanajstniku 2. Sorodniki prvega reda bolnika z rakom želodca 3. Bolniki pred uvedbo kroničnega zdravljenja s salicilati in nesteroidnimi protivnetnimi zdravili (NSPVZ) In case of clarithromycin resistance higher than 20%, first line is treatment is ten day quadruple bismuth or nonbismuth therapy (quadruple or sequential). In case of failure, ten day therapy PPI – A – L bid is recommended. Third line therapy is prescribed according to culture and antibiotic susceptibility. In patients allergic to penicillin PPI - M - C is recommended. In case of C resistance higher than 20% CBS quadruple therapy should be used. All further therapies should be prescribed according to culture and antibiotic susceptibility. Kot diagnostično metodo za ugotavljanje okužbe je potrebno uporabiti urea dihalni test (UBT) ali pa monoklonalni test ugotavljanja H. pylori v blatu (HPB; 2). Senzitivnost UBT je med 88 % in 95 %, specifičnost pa 95 % (3). Senzitivnost HPB je 94 %, specifičnost pa 92 % (4). HPB je manj natančen tudi pri bolnikih s krvavitvijo iz zgornjih prebavil (5). Pred testom za H. pylori bolnik 1 mesec ne sme jemati antibiotikov, 14 dni pa ne zaviralcev protonske črpalke (ZPČ; 2). Dokazovanje okužbe s H. pylori s serološkimi testi ni natančno in ni nujno odraz prisotne okužbe, saj so lahko protitelesa prisotna še več let po ozdravitvi okužbe. Senzitivnost seroloških testov je 85 %, GASTROENTEROLOG 115 specifičnost pa le 79 % (6). Dokazovanje protiteles proti H. pylori v slini ali urinu ima še slabšo natančnost kot dokazovanje protiteles v serumu (7). Specialist gastroenterolog V vseh ostalih primerih indikacijo za ugotavljanje okužbe s H. pylori in zdravljenje poda gastroenterolog. Indikacije za zdravljenje so: 1. Bolnik z razjedo želodca ali dvanajstnika z ali brez komplikacij. 2. Bolnik z MALT limfomom 3. Bolnik z dispepsijo po končani diagnostični obdelavi 4. Bolnik z zapleti ob jemanju salicilatov ali NSPVZ 5. Bolniki z prekancerozo želodca (atrofija, intestinalna metaplazija) 6. Bolnik po endoskopski odstranitvi zgodnjega raka želodca ali delni resekciji želodca zaradi raka želodca 7. Bolnik pred začetkom dolgotrajnega zdravljenja z ZPČ 8. Bolnik z rezistentno anemijo, idiopatsko trombocitopenično purpuro, kronično urtikarijo. 9. Vsak bolnik okužen s H. pylori. Okužba z bakterijo H. pylori je odgovorna za vsaj 71 % do 95 % vseh rakov želodca (8). Zato smo v novih smernicah SZGH, enako kot so to storile tudi nekatere druge države s srednjo in visoko incidence raka želodca, priporočili uvedbo presejanja prebivalcev v starosti med 20–30 let na prisotnost okužbe s H. pylori in zdravljenje okuženih. Le tako bomo lahko zmanjšali incidenco raka na želodcu (1, 9–11). Da je s takšnim pristopom to mogoče, dokazujejo rezultati iz Tajvana, ki je takšen način obravnave zdravih nosilcev H. pylori okužbe že uvedel. Ob tem pa se je zmanjšala tudi pojavnost dispepsije in razjed želodca in dvanajstnika (12). Gastroenterologi okužbo ugotavljamo z invazivnimi testi ob endoskopiji zgornjih prebavil. Največkrat uporabimo hitri urea bioptični test (HUT). Potrebno 116 GASTROENTEROLOG je odvzeti po dva biopta iz korpusa in antruma. Senzitivnost testa je med 90 % in 95 %, specifičnost pa 95 % do 100 %. Drugi invazivni test je histologija, ki nam poleg potrditve prisotnosti okužbe da podatek o vrsti gastritisa in prisotnosti prekanceroz želodca. Natančnost izvida je odvisna od izkušenosti preiskovalca. Odvzem vzorcev za kulturo in antibiogram nam poleg potrditve okužbe da tudi podatke o občutljivosti H. pylori na antibiotike. To metodo uporabljamo po dveh neuspelih poiskusih zdravljenja (13). ZDRAVLJENJE OKUŽBE S H. PYLORI Uspeh zdravljenja je odvisen od rezistence bakterije H. pylori na antibiotike, sodelovanja bolnika, dolžine trajanja zdravljenja, vrste in odmerka ZPČ, CYP 2C19 in MDR1 polimorfizmov, ki vplivajo na uspešnost zniževanja kisline z ZPČ, debelosti in kajenja, vrste seva H. pylori in endoskopske diagnoze (14, 15). Rezistenca H. pylori na antibiotike v Sloveniji Uspeh ozdravitve okužbe s H. pylori pade iz 91 % pri na metronidazol občutljivih sevih bakterije H. pylori na 76 % pri na metronidazol rezistentnih sevih. Rezistenca je relativna, saj jo je mogoče premagati s podaljšanjem zdravljenja in povečanjem odmerka zdravila (16). Dosti bolj pomembna kot razistenca na metronidazol je rezistenca H. pylori na klaritromicin. Eradikacija H. pylori pade iz 95 % pri na klaritromicin občutljivih sevih na samo 40 % pri rezistentnih sevih (17). Zato je nujno potrebno, da poznamo podatke o nacionalni rezistenci bakterije H. pylori na antibiotike. V Sloveniji se je v zadnjih desetih letih primarna rezistenca na metronizadol in klaritromicin spremenila. Leta 1999 je bila rezistenca na klaritromicin 3,7 %, na metronidazol pa 18, 5 % (18), leta 2009 pa je bila na klaritromicin 17,5 %, na metronidazol pa 18,6 % (Tabela 1; 19). Po še neobjavljenih podatkih za leto 2012 je bila rezistenca na klaritomicin 14,3 %, Tabela 1. Sprememba rezistence H. pylori na antibiotike v Sloveniji Table 1. Change of H. pylori resistance to antibiotics in Slovenia Antibiotik Leto 2000 Leto 2010 Leto 2012 (v %) (v %) (v %) N=27 N=78 N=153 Amoksicilin 0 0 0 Cipro/Levofloksacin 0 2,3 5,6 Klaritromicin 3,7 16,3 14,3 Metronidazol 18,5 17,2 22,2 Rafampicin / / 8,1 na metronidazol 22,2 % in na levofloksacin 5,6 %. Slovenija je v evropskem povprečju glede rezistence na klaritromicin in metronidazol in pod povprečjem glede rezistence na levofloksacin (20). Zdravljenje ob nizki lokalni rezistenci na klaritromicin Po priporočilih Maastricht IV naj se klaritromicin ne uporablja v primeru, ko je lokalna rezistenca na klaritromicin večja kot 15 %–20 %, metronidzol pa ne v primeru lokalne rezistence večje kot 40 % (11). V priporočilih SZGH iz leta 2010 smo glede na naše podatke o rezistenci še vedno predlagali trotirno shemo (ZPČ - klaritromicin – amoksicilin, dvakrat dnevno, 7 dni, ZAK) z izjemo, da bi se pri bolnikih, ki so bili v življenju večkrat zdravljeni z makrolidi, klaritromicin zamenjal z metronidazolom, ZAM (Tabela 2, 1). Rezultati sedemdnevnega zdravljenja s shemo ZAK v Sloveniji so bili po objavljenih podatkih 82 % leta 1997 (21) in 80 % leta 2008 (22). Uspehi zdravljenja s shemo ZAM pa so bili 82,6 % v letu 1997 in 78,6 % v letu 2008. Uspeh zdravljenja s shemo ZAK se je v zadnjih letih v nekateri delih Slovenije zmanjšal. Po še neobjavljenih podatkih iz Koroške je bil uspeh sheme ZAK v letih 20011 in 2012 med 69 % in 72,1 % (23). Nasprotno pa je bila enaka shema po preliminarnih rezultatih raziskave SZGH v letu 2012 v Sloveniji še vedno 80 % (24). Tabela 2. Zdravljenje okužbe s H. pylori prvega izbora po priporočilih SZGH Table 2. First line treatment of H. pylori infection according to SZGH Zdravljenje H pylori okužbe Predhodno zdravljenje z makrolidi - + ZPČ 2 X stand.odmerek Klaritromicin 2 X 500 mg ZPČ 2 X stand. odmerek Metronidazol 2 x 400 mg Amoksicilin 2 X 1000 mg Amoksicilin 2 x 1000 mg 7 dni 7 dni Uspešnost zdravljenja preverimo mesec dni po končnem zdravljenju z UBT ali HPB. Bolnik mesec dni pred kontrolo ne sme jemati antibiotikov, 14 dni pa ne ZPČ (1). Pri približno 20 % bolnikov ne uspemo odstraniti okužbe po prvem zdravljenju. Uspeh klasičnega trotirnega zdravljenja je mogoče izboljšati z : a) Zviševanjem odmerka ZPČ. Rezultati meta analize pokažejo, da se ob dvigu odmerka ZPČ na 2 X 40 mg uspeh zdravljenja izboljša za 6 %–10 % v primerjavi z nižjimi odmerki (25). b) Podaljšanje trajanja zdravljenja. Več meta analiz je ugotovilo, da podaljšanje zdravljenja na 10 dni izboljša uspeh zdravljenja za 4 %, podaljšanje na 14 dni pa za 5–6 % (26–28). Zdravljenje druge izbire mora biti desetdnevno. Pri nas smo glede nadaljnih možnosti zdravljenja relativno omejeni. Trenutno ne razpolagamo s preparati bizmuta in oksitetraciklina. Zato kot možno zdravljenja druge izbire svetujemo sekvenčno terapijo (prvih pet dni ZPČ in amoksicilin dvakrat dnevno, nato pa še pet dni ZPČ - klaritromicin - metronidazol dvakrat dnevno). Druga možnost je štiritirno zdravljenje brez bizmuta (ZPČ - amoksicilin – metronidazol - klaritromicin dvakrat dnevno) ali pa zdravljenje po antibiogramu. Preliminarni rezultati sekvenčnega zdravljenja in štiritirnega zdravljenja v okviru raziskave SZGH (kot prvega zdravljenja) ugotavljajo 94 % in 95 % uspešnost odstranitve bakterije. GASTROENTEROLOG 117 Tabela 3. Možnosti zdravljenja H. pylori okužbe po nespelem zdravljenju prvega izbora Table 3. Treatment options of H. pylori infection after first line treatment failure Zdravljenje H pylori okužbe Zdravljenje prvega izbora je neuspešno Kultura, antibiogram in usmerjeno zdravljenje 10 dni Koloidni bizmut subcitrat 4 X 120 mg Sekvenčno zdravljenje Rešilno zdravljenje ZPČ 2 X st. odm - ZPČ 2 X stand.odm. Metronidazol Amoksicilin 3 X 400 mg 2 x 1000 mg Oksitetraciklin 5 dni 4 X 500 mg ZPČ 2 X st. odm ZPČ 2 X st. odmerek Klaritromicin 10 dni 2 X 500 mg Metronidazol 2 x 400 mg 5 dni Tabela 4. Priporočila za zdravljenje Maastricht IV Table 4. Maastrich IV treatment recomendation V naših razmerah bi bila idealna shema drugega reda zdravljenje s štiritirno shemo z bizmutom (koloidni bizmut subcitrat (KBS) – oksitetraciklin - metronidazol in ZPČ dvakrat dnevno), ki pa je trenutno nimamo na razpolago. V tujini so prva tri zdravila na voljo v obliki ene kapsule, kar izboljša sodelovanje bolnika. Štiritirnno zdravljenje z bizmutovimi preparati po neuspelem zdravljenju prvega reda ima 80 % uspešnost ozdravitve (29, 30). Levofloksacin je antibiotik, ki je bodisi v trotirni shemi z ZPČ in amoksicilinom ali v sekvenčni shemi 118 GASTROENTEROLOG - Amoksicilin 2 x 1000 mg in : 1. Levofloksacin 2 x 500 mg ali 2. Rifabutin 2 x 150 mg ali 3. Furazolidon 2 X 200 mg pokazal dobre rezultate kot terapija drugega izbora. Ker pa H. pylori hitro razvije rezistenco nanj, ga v Sloveniji svetujemo kot reševalno shemo tretjega reda (31, 32). Druga možnost je zdravljenje po antibiogramu. Ob upoštevanju danih priporočil je skupna uspešnost zdravljenja H. pylori okužbe v raziskavi Rokkasa 98,1 % (33), pri nas pa 97,7 % (22). Zdravljenje ob visoki rezistenci na klaritromicin V državah z več kot 15 %–20 % rezistenco H. pylori na klaritromicin trotirne klasične sheme ne smemo uporabljati. V teh državah je najbolje začeti s štiritirnim zdravljenjem z KBS. V primeru neuspeha tega zdravljenja se kot drugo zdravljenje svetuje ZPČ – amoksicilin levofloksacin dvakrat dnevno (34, 35). V kolikor tudi to zdravljenje ni uspešno, je naslednje zdravljenje glede na rezultate antibiograma (Tabela 4). Večja težava je pri bolnikih, ki so alergični na penicilin. V tem primeru se svetuje ZPČ -klaritromicin - metronidazol dvakrat dnevno teden dni v državah z nizko stopnjo rezistence na klaritromicin. V primeru rezistence H. pylori na klaritromicin, ki je večja kot 20 %, pa štiritirno zdravljenje s KBS (11). Naslednja zdravljenja, v kolikor so potrebna, so po antibiogramu. Kot možno obliko reševalnega zdravljenja (tretji poizkus) je navedeno tudi zdravljenje z rifampicinom. V meta analizi je ta shema pokazala 79 % učinkovitost zdravljenja (36). Kljub temu ga zaradi možnosti ustvarjanja rezistence in možnih kasnejših težav zdravljenja mikobakterij ne svetujemo. Ugotavljamo tudi, da je v Sloveniji rezistenca H. pylori na rifampicin (8,1 %) višja kot v drugih državah. LITERATURA 1. Tepeš B, Štabuc B. Priporočila Slovenskega združenja za gastroenterologijo in hepatologijo za zdravljenje okužbe z bakterijo Helicobacter pylori. Zdrav vestn 2011, 80: 647–56. 2. Tepeš B. Diagnostika okužbe z bakterijo Helicobacter pylori. Farm vestn 1998; 49353–61. 3. Howden CW, Hunt RH. Guidelines for the management of Helicobacter pylori infection. Ad Hoc Committee on practice Parameters of the American College of gastroenterology. Am J Gastroenterol 1998; 93:2330–8. 4. Vaira D, Malfertheiner P, Megraud F, Axon ATR, Deltenre M, Hirschl AM, et al. Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. HpSA European study group. Lancet 1999; 354:30–3. 5. van Leerdam ME, van der Ende A, ten Kate FJ, Rauws EA, Tytgat GN. Lack of accuracy of the noninvasive Helicobacter pylori stool antigen test in patients with gastroduodenal ulcer bleeding. Am J Gastroenterol. 2003; 98: 798–801. 6. Loy CT, Irwig LM, Katelaris PH, Talley NJ. Do commercial serological kits for Helicobacter pylori infection differ in accuracy? A meta-analysis. Am J Gastroenterol 1996; 91:1138–44. 7. Luzza F, Maletta M, Imeneo M, Marcheggiano A, Iannoni C, Biancone L, Pallone F. Salivary-specific immunoglobulin G in the diagnosis of Helicobacter pylori infection in dyspeptic patients. Am J Gastroenterol. 1995; 90:1820–3. 8. Ekstrom AM, Held M, Hansson LE, Engstrand L, Nyren O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001; 121:784–91. 9. Asaka M, Kato M, Takahashi S, Fokuda Y, Sugiyama T, Ota H, Uemura N, et al. Guidelines for the management of Helicobacter pylori infection in Japan: 2009 revised edition. Helicobacter 15; 1–20. 10. Talley NJ, Fock KM, Moayyedi P. Gastric cancer consensus conference recommends Helicobacter pylori screening and treatment in asymptomatic persons from high risk populations to prevent gastric cancer. Am J Gastroenterol 2008; 103: 510–14. 11. Malfertheiner P, Megraud F, O’Morain Ca, Atherton J, Axon ATR, Bazzoli F, et al. Management of Helicobacter pylori infection –the Maastricht IV/ Florence Consensus Report Gut 2012;61:646–64. 12. Lee YC, Chen TH, Chiu HC, Shun CT, Chiang H, Liu TY, Wu MS, Lin JT. The benefit of mass eradication of Helicobacter pylori infection: a community-based study of gastric cancer prevention. Gut 2012; 61:1050–7. 13. Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808–25. 14. Tepeš B, Gubina M. Razlogi za neuspeh antimikrobnega zdravljenja okužbe z bakterijo Helicobacter pylori in naše terapevtske možnosti. Zdrav Vestn 2004; 73: 5003–6. 15. Essa AS, Kramer JR, Graham DY, Treiber G. Meta-analysis: fourdrug, three antibiotic,non-bismuth-containing ‘‘concomitant therapy’’ versus triple therapy for Helicobacter pylori eradication. Helicobacter 2009; 14: 109–18. 16. Lind T, Mégraud F, Unge P, Bayerdörffer E, O'Morain C, Spiller R, et al. The MACH2 study: role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies.Gastroenterology. 1999 ;116 :248–53. 17. Bazzoli F, Berretti D, De Luca L, Nicolini G, Pozzato P, Fossi S,et al. What can be learnt from the new data about antibiotic resistance? Are there any practical clinical consequences of Helicobacter pylori antibiotic resistance? Eur J Gastroenterol Hepatol. 1999 ; 11 Suppl 2: 39–42. 18. Gubina M, Tepeš B, Gorenšek M, Križman I, Ihan A, Poljak M. Sensitivity of Helicobacter pylori to eight antibiotics. The 5th International conference of the Macrolides, Azolides, Streptogromines and ketolides. Sevilla 2000. 86. 19. Jeverica S, Tepeš B, Ihan A, Škvarč M. Primarna odpornost bakterije Helicobacter pylori. Zdrav vestn 2010; 79: 25–30. 20. Megraud F, Coenen S, Versporten A, Kist M, Lopez-Brea M,Hirschl, et al. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption Gut 2013;62:34–42. 21. Tepeš B. Primerjava dveh trotirnih antimikrobnih shem zdravljenja okužbe z bakterijo Helicobacter pylori. Zdrav vestn 2000; 69: 505–8. 22. Tepeš B, Ojsteršek Z. Uspešnost zdravljenja okužbe s Helicobacter pylori v Sloveniji v letu 2008. Zdrav Vestn 2010; 79: 19–24. 23. Vujasinovič M, Robač N, Jeverica S, Tepeš B. Helicobacter pylori eradication rates in Corinthian region of Slovenia in the years 2011 and 2012, Gastroenterolog, poslano v objavo. 24. Tepeš B, Vujasinovič M, Šeruga M, Stefanovič M, Jeverica S. 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Meta-analysis: duration of first-line protonpump inhibitor based triple therapy for Helicobacter pylori eradication. Ann Intern Med 2007;147:553–62. 29. Dore MP, Graham DY, Mele R, Marras, L., Nieddu, Katelaris, P et al. Colloidal bismuth subcitrate-based twicea-day quadruple therapy as primary or salvage therapy for Helicobacter pyloriinfection. Am J Gastroenterol 2002; 97:857–60. 30. Lin CK, Hsu PI, Lai KH, Lo GH, Tseng HH, Lo CC, et al. Oneweek quadruple therapy is an effectivesalvage regimen for Helicobacter pylori infection in patients after failure of standard triple therapy. J Clin Gastroenterol 2002; 34:547–51. 31. Ayala G, Galván-Portillo M, Chihu L, Fierros G, Sanchez A, LópezCarrillo L, et al., Study Group Resistance to antibiotics and characterization of Helicobacter pylori strains isolated from antrum and body from adults in Mexico. Microb Drug Resist 2011;17:149–55. 32. Tepeš B, O'Connor A,Gisbert J, O'Morain C. Treatment of Helicobacter pylori infection 2012. Helicobacter 2012, 17 (Suppl1) 36–42. 33. Rokkas T, Sechopoulos P, Robotis I, Margantinis G, Pistiolas D. Cumulative H.pylori eradication rates in clinical practice by adopting first and second line regimens proposed by Maastricht III consensus and a third line empirical regimen. Am J Gastroenterol 2009; 104: 21–5. 34. Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-basedrescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther 2006;23:35–44. 35. Saad RJ, Schoenfeld P, Kim HM, et al. Levofloxacin-based triple therapy versusbismuth-based quadruple therapy for persistent Helicobacter pylori infection:a meta-analysis. Am J Gastroenterol 2006;101:488–96. 36. Gisbert J P, Calvet X, Review article: rifabutin in the treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther 2012; 35: 209–221. GASTROENTEROLOG 119 Kirurško zdravljenje tumorjev sotočja jetrnih vodov Surgical treatment for hilar cholangiocarcinoma Blaž Trotovšek* Univerzitetni klinični center Ljubljana Gastroenterolog 2013; suplement 2: 120–129 Ključne besede: Tumor sotočja jeternih vodov, Klatskinov tumor, kirurško zdravljenje, presaditev jeter, neoadjuvantna radiokemoterapija. Key words: hilar cholangiocarcinoma, surgical treatment, liver transplantation, neoadjuvant radiochemotherapy. POVZETEK ABSTRACT Uvod. Učinkovita diagnostika in zdravljenje bolnikov s tumorji sotočja jetrnih vodov temelji na sodelovanju gastroenterologov, interventnih radiologov, onkologov in kirurgov. Neresektabilni tumorji sotočja jetrnih vodov imajo slabo prognozo, toda napredek v kirurških tehnikah nudi vse večjemu številu bolnikov možnost dolgoročnega preživtja. Članek povzema sodobne smernice kirurškega zdravljenja in rezultate preživetja pri bolnikih z maligno zožitvijo visoko v jetrni lini. Background. Effective diagnosis and treatment of patients with hilar cholangiocarcinoma is based on the synergy of endoscopists, interventional radiologists, oncologists, radiotherapists and surgeons. Unresected hilar cholangiocarcinoma has a dismal prognosis, but advances in staging and surgical techniques have given well-selected patients a chance of long-term survival if curative resection is possible. This review summarizes the state of the art of surgical treatment, and outcome for patients with biliary obstruction at the hilus of the liver. Metode. Popolna odstranitev rakastega tkiva nudi bolniku s tumorjem sotočja jetrnih vodov edino možnost za ozdravitev in dolgo preživetje. Obravnavali smo različne kirurške posege s poudarkom na perioperativni obolevnosti, umrljivosti, radikalnosti posega in pogostosti ponovitve bolezni. Ocenili smo rezultate zdravljenja s pomočjo 5-letnega preživetja. Rezultati. Desna hemihepatektomija in trisekciektomija z resekcijo 1. segmenta zagotavlja najširše varnostne robove in najvišjo stopnjo preživetja, še posebej ob hkratni načrtovani resekciji razcepišča portalne vene. Desna trisekciektomija z resekcijo razcepišča portalne vene nudi 72 % 5-letno preži- * Blaž Trotovšek Univerzitetni klinični center Ljubljana, Zaloška cesta 7 1525 Ljubljana, Slovenija 120 GASTROENTEROLOG Methods. Complete removal of all cancerous tissues offers patients with hilar cholangiocarcinoma the only chance for cure and long-term survival. Different surgical procedures were evaluated with special emphasis on perioperative morbidity, mortality, radicality and recurrence rate. Outcomes of radical surgical treatment including 5-year survival were assessed. Results. Right hemihepatectomy or right trisectionectomy guarantee the highest radicality rate and the best long-term results, especially when resection of vetje ob radikalnem posegu. Brez resekcije portalne vene so rezultati slabši. Ob desni trisekciektomiji brez resekcije portalne vene je 5-letno preživetje 52 % in ob desni hemihepatektomiji le 23 %. Zaključek. Posledici razširjenih kirurških posegov sta večje število radikalnih resekcij in izboljšano preživetje bolnikov s tumorji sotočja jetrnih vodov. Pri bolnikih z nizkim stadijem bolezni, ki zaradi kronične bolezni jeter ali zajetosti lokalnih žilnih struktur niso primerni za resekcijsko zdravljenje, presaditev jeter z neoadjuvantno kemoradioterapijo omogoča izboljšanje preživetja.Radikalni razširjeni posegi predstavljajo temelj kirurškega zdravljenja danes in v bližnji prihodnosti. Vse bolnike s tumorji sotočja jetrnih vodov mora obravnavati multidisciplinarna skupina strokvnjakov. INTRODUCTION Although a relatively rare tumor, hilar cholangiocarcinoma (HC) also known as Klatskin tumor, comprises up to 50–70% of all cases of bile duct carcinomas. Approximately 3–5 new cases per 100,000 are diagnosed annually in Europe, but the incidence and mortality are increasing worldwide. The absence of early symptoms leads to the diagnosis of most HC tumors at an advanced incurable stage. Only painless obstructive jaundice indicates rarely earlier stages, but it is nevertheless often a sign of advanced disease. Negative resection margins enhanced by major hepatic resections are associated with improved outcome, but the close vicinity of these tumors to the portal vein, to the hepatic arteries and the liver parenchyma is one of the main obstacles to accomplish this goal. There has been a growing recognition that HC vs. distal cholangiocarcinoma have a distinct biological behaviour and natural history, as well as a therapeutic treatment strategy. This has led the latest (seventh) edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to divide perihilar and distal cholangiocarcinoma into distinct staging subgroups. Distal cholangiocarcinomas have a close proximity to the pancreatic head; therefore, portal bifurcation is performed on a regular basis. A 5-year survival of 72% was reported in R0 resected patients with portal vein resection. Without portal vein resection 5-year survival was 52% in R0 patients undergoing right trisectionectomy and 23% in right hemihepatectomy. Conclusion. Extended surgical resection resulted in increased rate of R0 resections and significantly improved survival. For patients with early stage hilar cholangiocarcinoma which is unresectable, liver transplantation with neoadjuvant chemoradiotherapy provides survival benefit. Extended resections remain the cornerstone of surgical treatment today and in near future. Candidates for resection should be considered by a specialized, multidisciplinary team. their surgical management involves many of the principles applied for pancreatic head cancer. Intrahepatic cholangiocarcinomas are usually treated with extended hepatic resection, while surgical management of HC has evolved since its original description due to improvements in preoperative diagnosis and a multidisciplinary perioperative management. The improved surgical treatment of HC in the past decades, not only owes to changed surgical strategy, but also to better patient selection and improved preoperative work-up of candidates for resection. The co-work of endoscopists, interventional radiologists, oncologists and surgeons, has equally contributed to these improved results. Although cholangiocarcinoma can arise anywhere within the biliary tree, tumors involving the biliary confluence represent the majority of cases, accounting for 50% to 70% of all patients. Patients with HC commonly present with advanced disease that is not amenable to surgical treatment, and recurrence rates are high even after complete resection. However, complete removal of all cancerous tissues offers HC patients the only chance for cure and long-term survival. Almost every patient undergoing potentially curative resection for HC requires a major partial hepaGASTROENTEROLOG 121 tectomy to ensure disease-free resection margins. However, extensive resections for patients with HC have been associated with significant morbidity and mortality rates, which even at high volume centers are on the order of 10% to 15%. There appears to be controversy regarding the selection of patients for whom extensive hepatic resection is indicated, the type of hepatectomy indicated, i.e. right- or left- sided hepatectomy, and whether routine caudate lobe resection is necessary. The rationale for surgical treatment requires the knowledge provided by T-stage of radial and longitudinal malignancy extension, and of N and M stages. A correct preoperative assessment is often difficult to achieve. Significant data on lymph node involvement and correlated prognosis are still lacking in the literature. Surgical choices are now determined mainly by local extension of disease. Nowadays resectability criteria differ from those of the past: vascular involvement with portal and/or arterial infiltration is not considered any longer as an absolute contraindication to resection. The lack of consensus largely arises from the difficulty of diagnosing precisely the proximal tumour extension before surgical resection or even during laparotomy. The main purpose of surgical therapy of HC is to achieve not only curative resection but also to apply the general rules of oncological surgery which has to succeed in the following: – no-touch technique to avoid seeding of the tumour, – no intra-operative open tumour biopsy – liver preserving technique with residual functioning parenchyma of at least 30–40%, – flank of hepatectomy is indicated by the predominant site of the lesion, – R0 resection of biliary tract with tumour-free margin of at least 1 cm on proximal and distal biliary tract confirmed by frozen section, – prevention of contamination of the operative field with bile to avoid cell spreading – caudate lobe resection, isolated or associated with extended hepatectomy, – removal of the lymph nodes and connective tissues in the hepatoduodenal ligament in superior retropancreatic space and around the common hepatic artery. In the past, hilar cholangiocarcinoma was treated by biliary tract resection and limited hepatic resection. Recent data in the literature have shown that associated hepatic resection significantly increases the rate of R0 resection, with a better long-term outcome. Postoperative morbidity and mortality rates after major resection have decreased because of preoperative improvement of hepatic function in patients with HC (biliary drainage, portal embolisation), a better selection of patients and an evolvement of surgical techniques. Surgical option is determined by tumour stage, and type of procedure selected so, that guarantees a better probability of curative resection and therefore a better prognosis. GENERAL PRINCIPLES HC remains one of the most difficult management problems in terms of staging and radical treatment. It has long been recognised that surgical resection with complete removal of all cancer tissues offers the only chance for cure and long-term survival. Several studies have confirmed the importance of hepatic resection achieving a negative resection margin. 122 GASTROENTEROLOG The close relationship of the neoplasm with portal bifurcation, right hepatic artery and hepatic parenchyma makes it difficult to achieve the aforementioned principles. Radial spread of the lesion to surrounding structures is facilitated by the absence of a muscular layer in the biliary duct. Infiltrative growth of HC is the most frequent pattern and determines periductal and perineural extension along the ducts and Glisson spaces. These are the reasons why wide (>10mm) tumourfree surgical margins must be obtained. RESECTABILITY ASSESSMENT Evaluation of patients with HC involves mainly assessment of resectability, since resection is the only curative therapy. As a general rule, an R0 resection must be carried out preserving sufficient vascularised future remnant liver with adequate biliary drainage. The definition of resectability has changed in recent years. Into consideration has to be taken (1): – physical status of the patient and liver function, – biliary extent of neoplasm, – vascular involvement, – presence of lobe atrophy, – lymph-node involvement and presence of distant metastases margin does not have a statistical significance on survival compared to negative margin cases (4). When a margin is positive on frozen section, the biliary resection should be extend when technically feasible. If HC extends peripherally to the second segmental ramification of the second order intrahepatic biliary radicles on both sides, the patient is considered to be unresectable. Radial diffusion extends to the hepatoduodenal ligament and to the perivascular connective tissue of the hepatic artery and portal vein that are close to the biliary tract. This aspect determines the choice of type of hepatectomy and likely associated vascular resection. VASCULAR INVOLVEMENT Portal Vein PATIENT FACTORS Surgeon has to assess the patient’s general condition for a major surgical procedure that usually includes hepatectomy. Resection is generally precluded if the patient is medically unfit or otherwise unable to tolerate a surgical procedure, or in the presence of significant co-morbidity and chronic liver disease. BILIARY EXTENT OF MALIGNANCY The infiltrative growth of HC includes longitudinal and radial extension. Longitudinal extension is either mucosal or submucosal and is correlated to the macroscopic aspect of the neoplasm (2). The former is more frequent in the papillary or nodular types and can spread 20 mm beyond the macroscopic margin of the lesion in 40% of cases; the latter is typical of invasive types and spreads on average 6 mm. The submucosal invasive type in all cases spreads less than 10 mm, while the noninvasive mucosal type is limited to within 20 mm in 90% of the cases (3). Considering these data, a macroscopic margin of 10 mm can be considered sufficient for eradication of invasive HC. However additional removal of any noninvasive component is still required. The presence of invasive carcinoma on the resected margin worsens the outcome while the presence of carcinoma in situ on the Portal invasion is generally associated with homolateral lobar atrophy but it is not considered a contraindication to resection. Portal resection in advanced cases or in “enbloc” portal resection during extended right hepatectomy present different results in patient survival. Portal infiltration may be classified in three histological grades or levels (5): – Grade 0: no involvement – Grade I: cancer invasion limited to the tunica adventitia or media – Grade II: cancer invasion arriving at the tunica intima. Portal resection is a negative prognostic factor but it improves outcome compared with non-resected patients. Three and 5-year survival were 26 and 10%, respectively, in patients with hepatic and portal combined resection, and 54 and 37% in patients who underwent hepatic resection alone (p<0.0001), respectively. At multivariate analysis, only macroscopic portal invasion is considered an independent prognostic factor (RR 2.18; p<0.02), while microscopic invasion is not (5). Portal resection does not increase complications and mortality rate, which was about 10% (6, 7). More recently similar morbidity rate (48%) GASTROENTEROLOG 123 was reported in patients who underwent combined portal resection vs. hepatic resection alone with no mortality using the “en-bloc resection” technique before hepatic dissection (8). Neuhaus (7) reported 5year survival of 65% in R0 cases after combined liver and portal vein resection using the “en-bloc resection” technique and these results showed that portal resection associated with hepatectomy can improve the chances of long-term survival. Concerning extension of portal invasion, the encasement or occlusion of the main portal vein proximal to its bifurcation, or bilateral portal venous encasement by cancer are by most considered a contraindication to resection. Hepatic Artery Data on arterial vascular resection are few. Recently there have been reported cases of hepatic artery resection, mainly right branch, during extended left hepatectomy for advanced HC. However, the data on the prognostic value of such operations are still lacking. Invasion of proper hepatic artery or of the artery of remnant liver is a contraindication to surgical resection (9). Although recent reports of major hepatectomy with hepatic artery reconstruction show a low mortality (0–8%) and that it can be done safely, this procedure has higher morbidity and mortality rates than is hepatectomy itself. For this reason, at present, hepatic artery reconstruction associated with major hepatectomy is advisable only in the advanced tumour where R0 resection can be accomplished with arterial resection. The Nagoya study recommends that the only absolute contraindication for resection is bilateral arterial encasement by HC (6). Lobar Atrophy Lobar atrophy is associated with occlusion of the portal vein supplying the affected liver segment or section by HC. As s contraindication to surgery is considered when: – atrophy of one hepatic lobe with contralateral portal vein branch encasement or occlusion, – atrophy of one hepatic lobe with contralateral tumour extension to secondary biliary radicles, 124 GASTROENTEROLOG Lymph-Node metastases Lymph-node metastases are common finding and are present in more than 50% of the patients with HC. There was no involvement of lymph nodes in 47% cases, regional and para-aortic involvement was observed in 35% and 17%, respectively. Survival was closely related to nodal involvement: 5-year survival in N0 patients was 31%, 15% in regional N+ and 12% in para-aortic N+ (10). Considering the outcome of patients with para-aortic lymph node metastases, the survival was significantly better in patients with microscopically positive nodes than in patients with macroscopically observed involvement of lymph nodes, with a 5-year survival of 29 vs. 0%, respectively. Kosuge et al. reported a mean and median survival of 79 months and 39 months, respectively, in N0 patients, 52 and 26 months in regional N+, and 15 and 14 months in N+ beyond regional. Five-year survival was 38% in N0, 30% in regional N+ (similar survival, not statistically significant) and 0% at 3-year survival in N+ beyond regional nodes (11). To date, performing surgical resection in patients with wide and macroscopic involvement of nonregional lymph nodes does not appear justified. It has not yet been proved that extended lymphadenectomy guarantees improvement in survival in HC but we believe that a methodical nodal dissection of hepatoduodenal ligament and hilum, proper and common hepatic artery, periduodenal, retroduodenal, peripancreatic, celiac, paraaortaic lymph nodes must always be performed associated with R0 resection, at least until data are more consistent and conclusive. Extrahepatic Disease Adjacent extrahepatic organ invasion is not an absolute contraindication to resection. A concomitant pancreatic resection is indicated when HC longitudinaly spreads in the lower intrapancreatic bile duct and/or massive peripancreatic head and pericholedochal lymph nodes metastases are suspected. In nodal infiltration, pancreatic resection is disputable, as distant nodal involvement represents a negative prognostic factor. First reported results of concomitant pancreatic resection for HC had an operative mortality of 35% and 5-year survival of 6% (12) mainly because of postoperative hepatic insufficiency, biliary leaks and pancreatic fistula. Two stage procedure with delayed pancreatic reconstruction was therefore proposed to decrease the risk of such extensive procedure (13), and mortality rate decreased considerably in small series of patients (14) reported. Metastatic Disease Distant metastases diagnosed preoperatively or intraoperatively presents an absolute contraindication for resection. The only possible exception can be the occurrence of hepatic metastases limited in the lobe to be resected, but the prognosis in these patients is dismal, with no 5-year survival. Indications for surgical resection The indication for surgical procedure is based on careful evaluation of the patient’s physical status, hepatic function and stage of the disease. The strategy of hepatic resection is defined preoperatively based on knowledge of longitudinal and radial extension of the malignancy. Currently, there is no clinical staging system available that stratifies patients preoperatively into subgroups based on potential for resection. The modified BismuthCorlette classification (15) stratifies patients based only on the extent of biliary involvement by tumour, and the AJCC staging system is based largely on pathological criteria and has little applicability for preoperative staging or predicting resectability. Jarnagin proposed the preoperative staging system based on local tumour-related factors that determine resectability: biliary ductal involvement, vascular involvement, and lobar atrophy. Unfortunately it does not aid in establishing the type of resection to perform (16). Surgical decision-making depends on the assessment of longitudinal infiltration of the biliary duct that determines which liver segments must be resected and the type of biliary reconstruction. Vascular invasion is useful for determining the flank of hepatectomy. The extent of hepatic resection needs to be evaluated on the basis of the hepatic function and of the volume of future remnant liver. Isolated extrahepatic bile duct resection Isolated extrahepatic resection of the biliary tract is by some indicated for treatment of Bismuth-Corlette types I and II. The procedure is considered oncologically inefficient because cholangiography does not accurately provide information about longitudinal cancer extension and submucosal tumour extension at proximal margins and skip-type lesions render assessment by imaging modalities difficult. Moreover, in the group of patients who undergo margin-negative resections, hepatic resection is the only independent predictor of improved survival on multivariate analysis, suggesting that a more limited resection is ineffective for complete tumour clearance (16). There were no 5-year survival among patients who had undergone biliary resection alone (17). Similar results were reported by Miyazaki et al with 5-year survival of 0% in patients with biliary tract resection alone vs. 27% in patients with additional hepatic resection (18). In a large series reported by Nimura all patients who had undergone isolated biliary tract resection died within 65 months (6). These data were confirmed by others who reported 5-year survival of 0 vs. 35% in patients who had undergone R0 biliary tract resection alone vs. additional hepatic resection, respectively (19). This type of procedure has a high recurrence rate (75–90%), mainly on the proximal resection margin (20). The indication for this procedure is limited to highrisk patients with tumour in an early stage (T1 and T2) and accompanied by poor hepatic function. It is not recommended even as palliative treatment, since endoscopic and percutaneous drainages are preferred. GASTROENTEROLOG 125 Autonomous segment 1 resection (S1) Resection of S1 is always indicated in association with hepatectomy when the tumour involves biliary confluence. Frequency of involvement of biliary branches of S1 varies from 48% (21) to 96% (22). Involvement is the consequence of infiltrative growth along the epithelium of biliary duct, direct infiltration of parenchyma or periductal spread in interstitial tissue. The importance of S1 is now widely accepted (22). 5-year survival of 46% with hepatectomy and additional S1 resection, and 12% without S1 resection was reported (23). Isolated S1 resection associated with resection of extrahepatic biliary tract is restricted to the cases with malignancy growing into the biliary bifurcation and is confined between the right and left hepatic ducts with the sole involvement of the branches to S1. The results of isolated S1 resection do not reach those of more extended hepatic resections with reported 3-year survival of 30% after isolated S1 resection vs. 75% after right hepatectomy (p=0.013) (24). Central hepatic resections Central hepatectomies consisting of left medial sectionectomy with S1 resection (S1+S4), right anterior sectionectomy with S1 resection (S1+S5, S8) and central hepatic bisectionectomy with S1 resection (S1+S4, S5, S8), are proposed mainly by Japanese authors (6,25). These tissue-sparing hepatectomies should minimise postoperative risk of hepatic failure in highrisk patients, still maintaining a potentially curative R0 resection. Resection is generally difficult and time consuming, while results in two parenchymal section lines and caudate resection, with increased risk for bile leak and increased morbidity. Often it is not possible to obtain an adequate length of free margin on the biliary ducts, because of anatomical realtions. Preserving the portal bifurcation and especially the right and left hepatic arteries, leads to oncological problems of radicality. Right hepatic artery which runs very close to the biliary confluence presents the biggest challange for this type of procedure. Biliary tract reconstruction is complex and requires a greater number of anastomoses. Shimada et al. compared the 126 GASTROENTEROLOG results of major hepatectomies with those of central hepatic resections. Curability rate (R0:R1) was 77% and 54%, respectively. The results for central resection were very similar to that of biliary resection alone (50%). Biliary leaks were more frequent in central resections (27 vs.3%), caused either by resection line leaks or by numerous bilio-digestive anastomoses (4.8±1.8). Mortality rate was 0% in central resections and 13% in major hepatectomy, and 5-year survival rates were 15 and 25%, respectively. The reason for non-curative resection in central resections is almost always inadequate proximal surgical margin (26) or residual tumour on portal bifurcation or hepatic artery (27). Central resections should be limited to high-risk patients in whom the tumour is confined longitudinally to the right or left hepatic duct and does not invade any of segmental hepatic ducts. Extended right resections When the right hepatic duct or both hepatic ducts are invaded equally (Bismuth-Corlette types II, IIIa), right hemihepatectomy or right trisectionectomy are indicated. In cases with hilar infiltration involving right intrahepatic ducts without extension to segment 4, right hemihepatectomy with S1resection is indicated. When infiltration of segment 4 is suspected right trisectionectomy with S1 resection is indicated. These operations are believed by most authors to guarantee the highest radicality rate and the best long-term results, especially when resection of portal bifurcation is performed on a regular basis (19). Right hepatectomy is more likely to be associated with a negative resection margin because the common bile duct is on the right side of the hepatoduodenal ligament with the right hepatic artery close behind its proximal portion. Right hepatic artery is frequently invaded by cancer at this site, whereas the left and middle hepatic artery runs on the left side of the ligament and are not associated with the bile duct until the end of the transverse portion of the left hepatic duct. The extrahepatic part of the left hepatic duct is longer (up to 30 mm), with a more distant segmental ramification, than that of the right hepatic duct. Therefore dissection is performed away from the tumour. The portal bifurcation is resected without dissection close to tumour and an end-to-end anastomosis of the portal trunk to the left portal vein will result in a straight course of the vessel, reducing the possibility for kinking. The resection line after right trisectionectomy is short and surface small. S1 resection can be carried out easily in patients undergoing right hemihepatectomy. After portal vein resection, venous reconstruction with the left than with the right portal vein is technically less demanding, due to the long umbilical part of the left portal vein. Implementing “no-touch technique” with right trisectionectomy and portal resection, Neuhaus et al. reported a 5-year survival of 72% in R0 resected patients with portal vein resection vs. 52% in R0 patients with right trisectionectomy and 23% in patients with right hemihepatectomy without portal resection (19). Extended left resections The most common indication for left liver resections in HC is spread of the tumour to left segmental biliary ducts thus rendering impossible right trisectionectomy with highest survival rates. When tumour involves the bifurcation and spreads towards left intrahepatic ducts left hemihepatectomy with S1 resection is performed. When the involvement is extended to the right anterior segment left trisectionectomy with S1 resection is the recommended procedure. Right portal pedicles are shorter, determining a more demanding portal vein reconstruction. Right hepatic artery which lies close to bile duct and tumour, may hamper the procedure and facilitate tumour seeding during its mobilisation. The right biliary duct is short (5–10 mm) before its segmental bifurcation, thus reducing the chance of obtaining an adequate resection margin. Reported 5-year survival is worse in left-sided procedures than right ones 28 vs. 50% (27) and 34 vs. 44% (22). Most of the studies confirmed those results and results of survival are significantly better in right than left hepatectomies (p>0.0013) (15). Liver transplantation for HC HC was thought to be an ideal indication for liver transplantation in the early days of the transplantation era. HC as localized lesion in the liver hilum with low spreading potential, it was thought to be removed completely by extrahepatic bile duct resection combined with total hepatectomy and replacement of a cadaveric homograft. Actually, in even palliatively or nontreated patients a curative resection could be achieved in most cases by liver transplantation (28,29). Encouraging oncological surgical results, with perioperative outcome similar to that in patients receiving liver transplantation for other indications, malignant as well as benign,were followed by disapointing long-term survival. Tumor recurrence was the most common reason (80%) for death after successful liver transplantation and there were no survivor 2 years postoperatively (28). Other authors reported similar results, with high rates of local tumor recurrence and only a small minority of patients surviving for more than 2 years (28–30), The long-term survival was disappointing, even for early stages of the disease (31). Owing to these disappointing results and the increasing donor organ shortage, organs were not allocated to the patients with HC Based on the biological behavior of hilar cholangiocarcinoma and the rationale of the surgical oncological principle of wide resection margins and “no-touch” technique, the procedure, termed “extended bile duct resection”, was developed. Basically it combined total hepatectomy and liver transplantation with a cephalic pancreatoduodenectomy (32). The surgical radicality of the procedure was excellent, with a curative resection of 93% and perioperative mortality of 14%. But, as in series of cluster transplantation, the majority of the patients in this study had advanced tumor stages. 60% of patients treated with this procedure developed tumor recurrence, mostly local peritoneal carcinomatosis. Compared to the long-term survival rates after liver transplantation alone, the long-term survival rate was clearly better, and reached 45% at 3 years after curative resection (33). However, due to the improving results after conventional combined extrahepatic bile duct resection and partial hepatectomy (34) neither abdominal organ cluster transGASTROENTEROLOG 127 plantation nor extended bile duct resection became commonly used surgical approaches in the treatment of HC. Current indications for liver transplantation in HC Recently reported results have shown increased survival rates after liver transplantation for hilar cholangiocarcinoma. The latest 1-, 3-, 5- and 10-year-survival rates of the 201 patients transplanted for hilar cholangiocarcinoma in Europe were 67%, 41%, 31%, and 22%, respectively (35). Iwatsuki et al. reported a series of 27 patients with hilar cholangiocarcinoma who underwent liver transplantation, either because of the extent of the tumor or because of concomitant advanced cirrhosis, severe sclerosing cholangitis, or both, precluding partial hepatectomy. The 1-, 3- and 5-year survival rates in these patients were 59.3%, 36.2%, and 36.2%,respectively. These long-term results included a perioperative mortality rate of 22.2% (36). Currently, liver transplantation for the treatment of HC should be taken into consideration in patients with underlying liver pathology that precludes liver resection. In particular, patients with PSC, who have a high incidence of this cancer, may be suitable for transplantation. Besides the existence of an underlying liver disease or cirrhosis, the tumor stage may be important for the indication. Recent results have revealed a markedly improved outcome in patients with early tumor stages (38). In particular, the absence of nodal involvement and a locally restricted character of the tumour seems to be correlated with favorable results after liver transplantation (38,39). However, there are currently no generally accepted selection criteria for liver transplantation in patients with HC. Considerations regarding the selection of patients with malignant hepatic tumors for liver transplantation are largely influenced by the question of whether such use of cadaveric grafts would penalize other patients on the waiting list with benign ant other malignant liver diseases. Living-donor liver transplantation might become one of the answers to this dilemma in the future. But first the results in the liver-transplanted patients have to justify the risk for the donors. For further improvement of the results after liver transplantation for HC, interest has been focused on adjuvant and neoadjuvant treatment options over the past few years. Clinical trials of new protocols in highly selected patients have shown encouraging results. In a study patients with lymph node-negative HC received liver transplantation after neoadjuvant radiochemotherapy. The protocol included brachytherapy delivered through percutaneous transhepatic catheters and intravenous infusion of 5-FU until transplantation. Five of the 11 patients (45%) were alive and free of tumor 2.8–14.5 years after transplantation (37). A study from the Mayo Clinic treated 28 patients with unresectable, localized, and lymph node-negative stage I/II hilar cholangiocarcinoma with external-beam irradiation, systemic 5-FU, and brachytherapy with 192-Iridium plus oral capecitabine before liver transplantation. Perioperative mortality was 10.7% and recurrence rate was 14.2%, 22–63 months after transplantation. The 1-, 3- and 5-year survival rates in this cohort were 92%, 82%, and 82%, respectively, a finding which is comparable to overall results for liver transplantation and better than survival rates after surgical resection (38). However, only patients with tumor stages I and II were selected for these studies. In addition, morbidity after neoadjuvant radiochemotherapy and liver transplantation was considerable. 128 GASTROENTEROLOG CONCLUSIONS Surgical resection remains the mainstay of treatment of HC as of today. Over the last decades, the radicality of surgery has increased. Since the patient will benefit from early surgery, the balance of preconditioning and early surgery is of crucial importance in clinical decision making. Despite the advancement in preoperative diagnosis, the decision can often only be made intraoperatively. Right trisectionectomy (segments 4–8 and 1) is a standard procedure for HC Bismuth–Corlette Type III–IV. This is a straightforward procedure with excellent results of resectability and survival. However, the function of liver remnant must often be improved. Portal vein embolisation helps to achieve hypertrophy of left lateral section and biliary drainage should be performed also on remnant liver parenchyma to speed up regeneration of cholestatic liver remnant. Liver transplantation and neoadjuvant radiochemotherapy is another step in radicality of surgical treatment of HC. This type of procedure requires vast resources and influences other patients on a waiting list for liver transplantation. The results are promising, but further studies are necessary. REFERENCES 1. Tsao JI, Nimura Y, Kamiya J. Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience. Ann Surg 2000; 232(2): 166–74. 2. Sakamoto E, Nimura Y, Hayakawa N. The pattern of infiltration at the proximal border of hilar bile duct carcinoma: a histologic analysis of 62 resected cases. 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GASTROENTEROLOG 129 Varikozne krvavitve iz zgornjih prebavil Upper gastrointestinal variceal hemorrhage Manfred Mervic*, Samo Plut Klinični oddelek za gastroenterologijo, Interna klinika, UKCL, Ljubljana Department of gastroenterology, Division of internal medicine, University Medical Centre Ljubljana Gastroenterolog 2013; suplement 2: 130–134 POVZETEK ABSTRACT Varikozna krvavitev iz zgornjih prebavil je najhujši zaplet portalne hipertenzije. Zdravljenje bolnikov s krvavitvijo iz varic je zahtevno. Celotno preživetje bolnikov se je v zadnjih letih izboljšalo, vendar je umrljivost še vedno tesno povezana z nezmožnostjo nadzora začetne krvavitve ali zgodnje ponovne krvavitve. Začetni ukrepi so namenjeni stabiliziranju bolnika: zavarovanje dihalne poti in dovajanje nadomestkov tekočin. Čim hitreje je treba začeti zdravljenje z vazoaktivnimi zdravili (terlipresin, somatostatin in njegovi analogi), saj je zmanjšanje tlaka v portalnem sistemu povezano z učinkovitejšim nadzorom nad krvavitvijo in olajša kasnejše endoskopske posege. Pri približno 20 % bolnikov s krvavitvijo iz varic se med hospitalizacijo razvije okužba. Antibiotična profilaksa izboljša preživetje. Zdravila izbora so kinoloni in intravenozni cefalosporini. Endoskopsko zdravljenje izboljša nadzor nad krvavitvijo in zmanjša tveganje za ponovno krvavitev ter umrljivost. Ligacija varic je učinkovitejša od skleroterapije. V primeru krvavitve iz varic želodca so priporočljivi tkivni adhezivi. Pri bolnikih z jetrno cirozo moramo ob postavitvi diagnoze napraviti gastroskopijo ter ob prisotnosti velikih varic pričeti s primarno profilakso z zdravili ali endoskopsko ligaturo (ki jo ponavljamo do eradi- Variceal bleeding is one of the most severe complications of portal hypertension. Due to high mortality the management ofvariceal bleeding remains a clinical challenge. *Manfred Mervic Klinični oddelek za gastroenterologijo, Interna klinika, UKCL Japljeva 2, Ljubljana 130 GASTROENTEROLOG Although overall survival has improved in recent years, mortality is still closely related to failure to control initial bleeding or early rebleeding. Initial procedures are to secure and protect the airway, and administer volume replacement to stabilize the patient. Treatment with vasoactive drugs should be started as soon as possible, since a reduction in portal pressure is associated with a better control of bleeding and may facilitate later endoscopic procedures. Terlipressin, somatostatin and analogues improve control of bleeding. Approximately 20% of patients with variceal bleeding will suffer from an infection, when they are hospitalized. Antibiotic prophylaxis improves survival. Quinolones or intravenous cephalosporins should be preferred. Endoscopic therapy increases control of bleeding and decreases the risks of rebleeding and mortality. Ligation is more effective than sclerotherapy. In case of gastric variceal bleeding, tissue adhesives should be used. Gastroscopy should be performed in all patient with liver cirrhosis and if large varices are found pri- kacije). Sekundarno profilakso uvedemo takoj po končanem zdravljenju akutne varikozne krvavitve. Zdravili izbora sta propranolol ali karvedilol. Učinkovitost medikamentozne primarne in sekundarne profilakse je priporočljivo preveriti z invazivnim merjenjem portalnega tlaka. V sekundarni profilaksi pride v poštev kombinirano zdravljenja in v primeru neuspešnosti le tega dodatni ukrepi (portosistemski shunt in presaditev jeter). mary prophilaxis (medical or endoscopical) should be initiated. Secondary prophylaxis should start as soon as possible after the discontinuation of the vasoactive drug used for the treatment of the bleeding episode. Drugs of choice are propranolol and carvedilol. Efficacy of prophylaxis should be evaluated by invasive portal pressure measurement. If innitial secondary prophylaxis fails, combination treatment or additional interventions (porto-systemic shunt and liver transplant) should be considered. MERILA IN OPREDELITEV PORTALNE HIPERTENZIJE Endoskopska ocena varic požiralnika in želodca ali merjenje HVPG sta diagnostični metodi za odkrivanje klinično pomembne portalne hipertenzije. Vzrok portalne hipertenzije je v večini primerov ciroza jeter, manj pogosti vzroki pa so necirotična fibroza jeter, tromboza portalne vene, obstrukcija jetrnih ven, policistična bolezen jeter, jetrne metastaze, konstriktivni perikarditis. Najpogostejša vzroka za jetrno cirozo sta prekomerno uživanje alkohola in virusni hepatitis. Krvavitev iz varic požiralnika ali želodca je najpomembnejši zaplet portalne hipertenzije. Prva krvavitev iz varic se v 30 % primerov konča s smrtjo bolnika. Do zgodnje ponovitve krvavitve v obdobju šestih tednov po prvi krvavitvi pride pri 40 % bolnikov. Tveganje ponovitve je največje prvih pet dni, nato se šest tednov postopoma zmanjšuje in se po tem obdobju skoraj izenači s tveganjem za krvavitev pred prvo krvavitvijo. Na tveganje ponovitve močno vpliva stopnja ciroze in velikost varic. Tlak v veni porte določimo z vensko kateterizacijo. Izmerimo prosti tlak v jetrnih venah (Free Hepatic Venous Pressure - FHVP) in zagozditveni tlak v jetrnih venah (Wedged Hepatic Venous Pressure - WHVP). Gradient tlaka jetrnih ven (Hepatic Venous Pressure Gradient – HPVG) je enak tlaku v portalni veni. Pri zdravih ljudeh je HPVG < 5 mm Hg, o portalni hipertenziji pa govorimo, ko se poveča nad to vrednost. DIAGNOSTIKA PORTALNE HIPERTENZIJE Bolnike z jetrno cirozo ob postavitvi diagnoze gastroskopiramo. Varice požiralnika in želodca opredelimo kot majhne (premer < 5 mm) ali velike (premer >5 mm). Bolnikom s kompenzirano jetrno cirozo brez varic ponavljamo gastroskopijo na 2-3 leta. HVPG je trenutno edina učinkovita diagnostična metoda za spremljenje učinkovitosti farmakološkega zdravljenja portalne hipertenzije. PREPREČEVANJE NASTANKA VARIC Dobro zdravljenje osnovne jetrne bolezni lahko zmanjša portalno hipertenzijo in prepreči njene zaplete. Spontana regresija varic je redka. Zdravljenje z neselektivnimi zaviralci receptorjev beta (Non-selecive Beta-blockers – NSBB) nastanka varic pri bolnikih s portalno hipertenzijo ne prepreči, zato pri bolnikih brez varic ni priporočljivo. Klinično pomembna portalna hipertenzija nastane pri HVPG > 10 mm Hg. Napoveduje nastanek varic požiralnika in želodca in dekompenzacijo jetrne ciroze. GASTROENTEROLOG 131 PRIMARNA PROFILAKSA – Invazivno merjenje HVPG je trenutno edina učinkovita diagnostična metoda za spremljenje učinkovitosti farmakološkega zdravljenja portalne hipertenzije. Znižanje HVPG na ≤12 mmHg ali za ≥ 20 % glede na osnovni tlak, je dokazano povezano z zmanjšanjem verjetnosti krvavitve. Povprečni dnevni odmerek s katerimi dosežemo ciljno zmanšanje HVPG je 80 mg propranolola in 12,5 mg karvedilola. – V centrih, kjer je tovrstna diagnostika na voljo, je ocena učinkovitosti zdravljenja s NSBB z invazivnim merjenjem HVPG verjetno smiselna. Vendar pa ker 60 % bolnikov z majhnimi varicami, ki jih zdravimo s NSBB in ciljnega znižanja HVPG ne dosežemo, v 2 letih ne zakrvavi, invazivna kontrola učinkovitosti v primeru primarne profilakse ni priporočena. Pri bolnikih z velikimi varicami je invazivno merjenje zaradi ocene uspešnosti terapije priporočljivo. – Ni konsenza o nadaljevanje zdravljenja s NSBB pri bolnikih, kjer s hemodinamskim invazivnim merjenjem uspešosti NSBB ne potrdimo. Vendar pa je možno, da NSBB koristijo tudi pri bolnikih kjer ciljnega znižanja HVPG ne dosežemo. Varice požiralnika in želodca opredelimo kot majhne (premer < 5 mm) ali velike (premer > 5 mm). Dodatne endoskopske značilnosti (rdeča znamenja) nimajo prognostične vrednosti in naj ne vplivajo na odločitev o zdravljenju. Vse bolnike z velikimi varicami moramo zdraviti z NSBB ali z endoskopsko ligaturo (Endoscopic Variceal Band Ligation - EVBL). Trenutno ni dokazov ki bi podpirali kombinirano zdravljenje (NSBB + EVBL) v smislu primarne profilakse. Primarna profilaksa z NSBB je (kljub pomanjkanju dokazov) priporočena tudi pri bolnikih z izoliranimi varicami želodca. Bolnike s kompenzirano jetrno cirozo in majhnimi varicami, ki niso zdravljeni z beta blokatorji, gastrokopiramo vsako leto in spremljemo napredovanje varic. Vendar se lahko tudi pri njih odločimo za primarno profilakso z NSBB, saj le ta zmanjša verjetnost krvavitve in napredovanje varic. Pri bolnikih, ki jih zdravimo z NSBB, endoskopsko presejanje ni potrebno. Zdravila izbora iz skupine beta zaviralcev sta propranolol ali karvedilol. Podatki kažejo, da je morda karvedilol učinkovitejši v primarni preventivi varikozne krvavitve. V primeru kontraindikacij za zdravljenje z NSBB, če jih bolniki ne prenašajo ali pa le ti niso učinkoviti, je v primeru velikih varic indicirana EVBL. Nadzor uspešnosti zdravljenja z NSBB – Odmerek NSBB postopno zvišujemo do zmanjšanja srčne frekvence v mirovanju za 25 % (vendar ne ≤ 50/min) ali dokler ne postanejo simptomatski do maksimalnega dnevnega odmerka (propranilol 160 mg/dan, karvedilol 25 mg/dan). Nekateri od teh bolnikov (a ne vsi) bodo zaščiteni pred krvavitvijo iz varic. Ocena uspešnosti NSBB z zmanjšanjem srčne frekvence ne korelira z zmanjšanjem portalnega tlaka ali manjšo verjetnostjo krvavitve. 132 GASTROENTEROLOG Endoskopska skleroterapija, vstavitev transjugularnega intrahepatalnega portosistemskega shunta (TIPSS) ali zdravljenje z isosorbid-5-mononitratom (ISMN) za primarno profilakso niso priporočeni. ZDRAVLJENJE AKUTNE KRVAVITVE IZ VARIC Osnovni cilji zdravljenja krvavitve iz varic požiralnika in želodca so: – korekcija hipovolemije in hemodinamska stabilizacija – čim hitrejša zaustavitev krvavitve – preprečevanje ponovne zgodnje krvavitve (znotraj 72 ur) – preprečevanje zapletov povezanih s krvavitvijo Predpogoji za zdravljenje: – prostori in oprema za stalno hemodinamsko monitorizacijo bolnika (dobro usposobljeni specializirani intenzivni oddelek) – stalno merjenje saturacije krvi s kisikom – nastavitev iv. kanala za hemodinamsko stabilizacijo in zdravljenje šoka – intubacija pred endoskopskim posegom pri masivni in hemodinamsko nekontrolirani krvavitvi iz varic, hepatični komi (III. In IV. stopnje), nezmožnosti vzdrževanja saturacije krvi s kisikom nad 90 %, pri sumu na aspiracijo Nadomeščanje krvi – kri nadomeščamo previdno in vzdržujemo koncentracijo hemoglobina med 70–80 g /l oz. več glede na bolnikovo starost, pridružene bolezni, hemodinamski status, aktivnost krvavitve. – sistolni tlak naj bo 90–100 mm Hg, srčna frekvenca 100/min ali manj – nadomeščanje trombocitov in zdravljenje koagulopatije ni potrebno. Bolnike z močno iztirjeno koagulacijo T<30000/mikroL ali pč <0,3 lahko zdravimo z koncentriranimi trombociti ali svežo zmrznjeno plazmo – zdravljenje z rekombinantnim faktorjem VIIa ni smiselno Antibiotično zdravljenje – je pomemben del zdravljenja varikozne krvavitve – krvavitev iz varic je v 30–40 % povezana z okužbo – preventivno zdravljenje z antibiotiki je priporočljivo takoj ob ugotovitvi krvavitve in pred endoskopskim zdravljenjem. – zdravljenje znižuje število bakterijskih okužb, zmanjšuje možnost ponovne krvavitve in umrljivost – zdravimo z amoksicilinom in klavulansko kislino 1,2 g/8 ur iv ali z norfloksacinom 2 x 400 mg p.o ali ceftriaksonom 1g na dan i.v. Zdravljenje naj traja 7 dni. Zdravljenje hepatične encefalopatije – bolnike s prisotno hepatično encefalopatijo zdravimo z laktulozo ali visoko klizmo – učinek preventivnega zdravljenja hepatične encefalopatije z laktulozo ni dokazan SPECIFIČNI UKREPI Farmakološko zdravljenje – pri sumu na krvavitev iz varic začnemo takoj in pred endoskopskim posegom z zdravljenjem z vazoaktivnimi zdravili – zdravila dajemo v kontinuirani infuziji ali v obliki iv injekcij 1. Somatostatin 250 mcg iv v bolusu, nato 250 mcg/h v infuziji (v primeru hude krvavitve npr. aktivna krvavitev ob endoskopiji, lahko uporabimo dvojni odmerek) 2. Oktreotid 50 mcg iv v bolusu, nato 50 mcg/h v infuziji 3. Terlipresin 2 mg iv/ 4 ur, nato, če bolnik ne krvavi več po 24 urah 1 mg iv /4 ure – zdravljenje nadaljujemo do 5 dni po začetku krvavitve. Endoskopsko zdravljenje – bolnike z varikozno krvavitvijo endoskopiramo čim prej po hemodinamski stabilizacijo oz. najkasneje 12 ur po sprejemu v bolnišnico – bolnikom z blago in hemodinamsko nepomembno krvavitvijo, ki ne potrebujejo transfuzije lahko napravimo elektivno gastroskopijo – ligacija varic je priporočena metoda zdravljenja. Skleroterapija je primerna, če je ligacija varic tehnično prezahtevna zaradi pogojev med posegom – endoskopsko zdravljenje s tkivnim adhezivom je priporočeno pri krvavitvi iz varic želodca. Pri krvavitvi iz varic požiralnika jo uporabimo le v izjemnih primerih nekontrolirane krvavitve. – eritromicin lahko izboljša vidljivost med endoskopijo GASTROENTEROLOG 133 Zgodnja vstavitev TIPS v primeru neuspeha endoskopskega zdravljenja (v prvih 72 urah): – bolniki z jetrno cirozo Child C in varikozno krvavitvijo (vendar Child-Pugh score <14) – bolniki z jetrno cirozo Child B in aktivno varikozno krvavitvijo med endoskopijo kljub zdravljenju z vazoaktivnimi zdravili in antibiotiki – bolniki z HVPG ≥20 mm Hg in akutno varikozno krvavitvijo – pred posegom je potrebno upoštevati standardne izključitvene kriterije (srčno popuščanje, tehnične kontraindikacije) – akutna hepatična encefalopatija ni kontraindikacija za vstavitev TIPS V primeru kontraindikacij za medikamentozno zdravljenje, napravimo bolnikom EVBL. Zdravljenje s ISMN ni alternativa NSBB. V primeru kontraindikacij za EVBL je zdravjenje izbora kombinirana terapija z NSBB in ISMN. Zdravljenje bolnikov, ki so iz varic zakrvaveli kljub sekundarni profilaksi – Pri bolnikih z nizkim tveganjem za ponovno krvavitev (začetna jetrna bolezen) ponovno poskusimo napraviti EVBL. Če kljub kombiniranem zdravljenju (NSBB + EBVL) bolnik vsaj dvakrat ponovno zakrvavi, je indicirana vstavitev TIPSS. V redkih primerih je potrebna operativna vzpostavitev portosistemskega shunta. Kirurška devaskularizacija je rešilna terapija če ostale možnosti niso učinkovite ali možne. – Pri bolnikih z visokim tveganjem za ponovno krvavitev je indicirana vstavitev TIPSS, če kljub kombiniranem (NSBB + EBVL) zdravljenju vsaj 2x ponovno zakrvavijo. Rekurentne krvavitve so indikacija za transplanatacijo jeter. SEKUNDARNA PROFILAKSA S sekundarno profilakso pričnemo čimprej, idealno 6. dan po krvavitvi (ali prenehanju zdravljenja z vazoaktivnimi zdravili). Terapija izbora je kombinirano zdravljenje z NSBB in EVBL. Podatki pridobljeni iz študij na področju primarne profilakse kažejo na to, da je karvedilol verjetno vsaj enako učinkovit kot propranolol. LITERATURA Monoterapija z NSBB je zadostno zdravljenje, če lahko učinek NSBB preverimo z invazivnim merjenjem HVPG. Bolnike, pri katerih s terapijo z NSBB ne dosežemo zadostnega učinka pride v poštev kombinacija NSBB in ISMN, ob kontoli HVPG. Če učinek še vedno ni zadosten je potrebna EVBL. Propranolol titriramo do minimalno 80 mg/dan v 2–3 odmerkih. Karvedilol titriramo do minimalno 12.5 mg/dan v 2 odmerkih. EBVL pričnemo po 2–3 tednih in jih ponavljamo do popolne eradikacije varic. Majhne rezidualne varice po EBVL so še sprejemljiv rezultat. Bolniki z napredovalo jetrno boleznijo, ki so krvaveli iz varic, so potencialni kandidati za presaditev jeter. Z sekundarno profilakso nadaljujemo do presaditve. TIPSS je smiselno napraviti bolnikom uvrščenim na čakalno listo za presaditev jeter. 134 GASTROENTEROLOG 1. Garcia-Tsao G, Bosch J, Groszmann R. Portal hypertension and variceal bleeding, unresolved issues. Summary of an American Association for the study of liver disease and European Association for the study of the liver single-topic conference. Hepatology 2008;47:1764–1772. 2. Grace ND, Groszmann RJ, Garcia-Tsao G, Burroughs AK, Pagliaro L, Makuch RW, et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology 1998;28:868–880. 3. de Franchis R; Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2010 Oct;53(4):762–8. 4. Austrian Consensus on the Definition and Treatment of Portal Hypertension and its Complications M. Peck-Radosavljevic1, M. Trauner2, F. Schreiber2 (for the Austrian Society of Gastroenterology and Hepatology.Endoscopy 2005; 37(7): 667–673 Kaj storiti pri nevidnem karcinomu v reseciranem želodcu? How to deal with invisible carcinoma in the resected stomach? Metka Volavšek*, Nina Zidar Inštitut za patologijo Medicinske fakultete Univerze v Ljubljani Gastroenterolog 2013; suplement 2: 135–137 Ključne besede: želodec, nevidni rak, biopsijski rak, patologija Key words: stomach, invisible cancer, biopsy cancer, pathology POVZETEK ABSTRACT Kadar v biopsiji želodčne sluznice odkrijemo karcinom brez makroskopsko (endoskopsko) vidne lezije, govorimo o »biopsijskem« ali »nevidnem« karcinomu. Takšni primeri so redki in zahtevajo skrbno obdelavo ter dobro sodelovanje med klinikom in patologom. V prispevku predstavljava dva bolnika, pri katerih je bila ob gastroskopiji odvzeta biopsija in ugotovljen adenokarcinom. Pri obeh je bila narejena resekcija želodca, vendar pri rutinskem histopatološkem pregledu v odstranjenem želodcu nismo našli karcinoma. Po dodatnem odvzemu številnih vzorcev in ponovnem pregledu prvotnih biopsij smo pri enem bolniku našli majhen rezidualni intramukozni pečatnocelični adenokarcinom. Pri drugem bolniku kljub pregledu številnih vzorcev nismo našli karcinoma. Ponovni pregled biopsije je potrdil nedvomno prisotnost karcinoma, kar je kazalo z veliko verjetnostjo, da je bil karcinom z endoskopsko biopsijo v celoti odstranjen. Obravnava bolnikov z nevidnim karcinomom je zahtevna in bo uspešna le ob dobrem sodelovanju med klinikom in patologom. When we detect cancer in gastric mucosa biopsy sample without macroscopic (endosopic) visible lesion we talk about »invisible«or»biopsy«cancer. Such cases are rare and require a good cooperation between the clinical physician and pathologist. In this paper we present two patients, who underwent gastroscopy and whose biopsy revealed adenocarcinoma. In both cases, the gastric resection was performed, but the pathohistological examination of the resected stomach did not confirm the carcinoma. After additional sample taking and patohistological examination of a number of samples we found a small residual intramucosal signet cell adenocarcinoma in one of the patients. In the case of the second patient we did not find cancer, despite examination of many additional samples. Review of the biopsy samples confirmed the presence of carcinoma, which suggests that the cancer was completely removed. Treatment of patients with invisible carcinoma is challenging and will only be successful in a good cooperation between the clinician and pathologist. *doc. dr. Metka Volavšek, dr. med. Inštitut za patologijo Medicinske fakultete Univerze v Ljubljani Korytkova 2, 1000 Ljubljana GASTROENTEROLOG 135 UVOD Karcinom želodca je kljub napredku pogosto odkrit v napredovalem stadiju, zato so uspehi zdravljenja in preživetje še vedno slabi. Naš cilj je zato odkriti čim več bolnikov v čim bolj zgodnjem stadiju bolezni (1). Poseben izziv so zato tisti bolniki, pri katerih je karcinom odkrit tako zgodaj, da še ni makroskopsko (endoskopsko) vidne lezije. Tak karcinom imenujemo »biopsijski« ali »nevidni« karcinom (iz angl.: biopsy cancer, invisible cancer) (2). Običajno gre za bolnike z gastritisom, pri katerih je bila odvzeta biopsija naključno oz. predvsem zaradi opredelitve gastritisa in morebitne okužbe s helikobaktrom. O pogostnosti nevidnega (biopsijskega) karcinoma želodca je v literaturi malo podatkov. Kim in sod. (3) so v 8-letnem obdobju med 633 bolniki obravnavali 5 takih primerov (0,8 %), napoved bolezni je bila v tej seriji odlična. Nekateri avtorji menijo, da v takih primerih radikalno kirurško zdravljenje ni vedno nujno potrebno, svetujejo predvsem endoskopsko mukozno ali submukozno resekcijo in fotodinamično terapijo (2). Obravnava takih bolnikov zahteva predvsem dobro sodelovanje med patologom in klinikom, sicer lahko pride do neprijetnih zapletov. Predstavljava dva bolnika, pri katerih v reseciranem želodcu ni bilo makroskopsko vidnega karcinoma. Primer št. 1 Pri 45-letnem bolniku je bila zaradi več mesecev trajajočih dispeptičnih težav narejena gastroskopija, odvzeta sta bila dva biopsijska vzorca antralne sluznice, v katerih je bila blaga fibroza, v epiteliju pa atipije, sumljive za blago displazijo. Helikobaktrov nismo našli. Čez en mesec je bila gastroskopija ponovljena, odvzetih je bilo več biopsij, v katerih smo našli znake blago aktivnega kroničnega, HP pozitivnega pangastritisa z blago intestinalno metaplazijo. V vzorcih iz angularne gube je bil prisoten intramukozni pečatnocelični adenokarcinom. En teden po zadnji gastroskopiji je bila narejena resekcija želodca. Pri pregledu reseciranega želodca 136 GASTROENTEROLOG nismo našli makroskopsko vidnega tumorja ali kakih drugih sprememb. Za histopatološki pregled smo odvzeli tkivne vzorce po protokolu in vse bezgavke, vendar tumorja nismo našli, v 34 pregledanih bezgavkah ni bilo zasevkov. Ponovno smo pregledali prvotno biopsijo in še enkrat potrdili diagnozo intramukoznega pečatnoceličnega adenokarcinoma. Odvzeli smo številne dodatne vzorce in v 106. vzorcu našli droben intramukozni pečatnocelični adenokarcinom, ki je meril v premeru 7 mm. Primer št. 2 83-letni bolnik z avtoimunskim gastritisom je bil sprejet v bolnišnico zaradi hematemeze. Pri gastroskopiji so našli dva hemoragična polipa in jih odstranili. Histološki pregled je pokazal, da gre za erodirana hiperplastična polipa, v enem je bil prisoten tudi intramukozni adenokarcinom intestinalnega tipa. Po odstranitvi polipov se je krvavitev večkrat ponovila, zato je bila narejena gastrektomija. Pri pregledu reseciranega želodca smo našli nekoliko stanjšano, zglajeno sluznico v korpusu in več slabo zamejenih področij zadebeljene sluznice. Makroskopsko vidnega tumorja nismo našli. Mikroskopski pregled je pokazal spremembe, značilne za avtoimunski gastritis. V korpusu je bilo tudi več hiperplastičnih polipov, v antrumu pa nevroendokrini tumor premera do 3 mm (mikrokarcinoid). Kljub pregledu številnih vzorcev nismo našli karcinoma ali displazije, v bezgavkah ni bilo zasevkov. Zaprosili smo za ponovni pregled biopsije, ki je bila opravljena v drugi ustanovi, in še enkrat potrdili prisotnost intramukoznega adenokarcinoma intestinalnega tipa v enem od odstranjenih hiperplastičnih polipov. Področje resekcijskega roba je bilo delno poškodovano, vendar je zelo verjetno potekalo v zdravem tkivu, kar je kazalo na možnost, da je bil karcinom odstranjen endoskopsko. RAZPRAVA IN ZAKLJUČKI Opisana dva primera kažeta na možne probleme pri obravnavi bolnikov z nevidnim rakom želodca, pri katerih je bila na osnovi biopsijsko potrjene diagnoze narejena kirurška resekcija želodca, v reseciranem želodcu pa ni bilo makroskopsko (endoskopsko) vidne lezije. Da se izognemo neprijetnim zapletom, je potrebno dobro sodelovanje med patologom in kliničnim zdravnikom in dosledno upoštevanje strokovne doktrine (3, 4). 1. Pri vsaki endoskopski biopsiji je nujno potreben podatek o mestu odvzema, če je biopsij več, morajo biti za vsako lokalizacijo (npr. korpus, antrum, angularna guba) poslane ločeno in jasno označene. 2. Potrebujemo tudi podatke o predhodni biopsiji: v kateri ustanovi je bila narejena, kje je bila odvzeta in kakšna je bila histopatološka diagnoza. Koristno je, če je mesto predhodne biopsije na resektatu označeno. Možnih vzrokov, da karcinoma v resektatu ne najdemo, je več (3). 1. Pri zelo majhnem karcinomu je vedno mogoče, da je bil karcinom odstranjen endoskopsko in ga zato v reseciranem organu ne najdemo. 2. Čeprav pri vsakodnevnem delu patologi strogo upoštevamo veljavno strokovno doktrino, v literaturi vsi aspekti niso povsem jasno opredeljeni. Tako npr. ni jasnih navodil, koliko dodatnih vzorcev je potrebno, če po pregledu vzorcev v skladu z veljavno doktrino karcinoma ne najdemo. Ta odločitev je prepuščena patologu. 3. Vedno je potrebno upoštevati tudi možnost, da je prišlo do zamenjave vzorcev na kateremkoli nivoju (pri odvzemu biopsije na kliniki ali pri obdelavi biopsijskih vzorcev in izvidov na oddelku za patologijo). Če strogo upoštevamo veljavne protokole, do zamenjave ne sme priti. V izjemnih primerih lahko s pomočjo genetskih testov preverimo, ali tkivni vzorec pripada domnevnemu bolniku ali ne. Zanesljivost sodobnih testov, ki jih pri nas opravljajo na Inštitutu za sodno medicino Medicinske fakultete v Ljubljani pa tudi v drugih ustanovah, je približno 98 % (5). V primeru »biopsijskega« karcinoma, ki je odkrit naključno, brez makroskopsko vidne lezije, priporočajo čimprejšnjo ponovitev gastroskopije (»second look ali rescue endoscopy«) in biopsije (6), po možnosti v treh dneh, saj naj bi bilo mesto predhodne biopsije tri dni po odvzemu še prepoznavno. Pomembno je tudi število odvzetih biopsijskih vzorcev, saj občutljivost biopsijske diagnostike karcinoma narašča s številom vzorcev: pri 4 do 6 vzorcih znaša za želodčni karcinom med 93 % in 97 % (7, 8). K uspešnosti pripomore tudi uporaba sodobne tehnologije (9). Z opisanimi primeri dveh bolnikov sva želeli opozoriti na pomen natančne obravnave na vseh nivojih, s katerimi lahko preprečimo neprijetne zaplete pri obravnavi resekcije večjih organov zaradi zgodnjega karcinoma in se izognemo napakam, pa tudi nepotrebnim dolgotrajnim in dragim postopkom. LITERATURA 1. Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med 1995; 333: 32–41. 2. Rabenstein T, May A, Gossner L, Manner H, Pech O, Günter E, et al. Invisible gastric carcinoma detected by random biopsy: long-term results after photodynamic therapy. Endoscopy 2008; 40: 899–904. 3. Kim ES, Jeon SW, Park SY, Park YD, Chung YJ, Yoon SJ, et al. Where has the tumor gone? The characteristics of cases of negative pathologic diagnosis after endoscopic mucosal resection. Endoscopy 2009; 41: 739–45. 4. Kim, ES, Jeon SW. Unfound gastric signet ring-cell adenocarcinoma after gastric biopsy. Reply. Endoscopy 2009; 42: 430. 5. Solis-Munoz P, Solis-Herruzo J A, Lopez-Alonso G, et al. Unfound gastric signet ring-cell adenocarcinoma after gastric biopsy. Endoscopy 2010; 42: 429–30. 6. Simone A, Casadei A, De Vergori E, et al. Rescue endoscopy to identify site of gastric dysplasia or carcinoma found at random biopsies. Dig Liver Dis 2011; 43: 721–25. 7. Lal N, Bhasin DK, Malik AK, Gupta NM, Singh K, Mehta SK. Optimal number of biopsy specimens in the diagnosis of carcinoma of the oesophagus. Gut 1992; 33: 724–6. 8. Voutilainen ME, Juhola MT. Evaluation of the dignostic accuracy of gastroscopy to detect gastric tumors: clinicopathological features and prognosis of patients with gastric cancer missed in endoscopy. Eur J Gastroenterol Hepatol 2005; 17: 1345–9. 9. Yalamarthi S, Witherspoon P, McCole D, Auld CD. Missed diagnoses in patients with upper gastrointestinal cancers. Endoscopy 2004; 36: 874–9. GASTROENTEROLOG 137 Zakaj je diagnoza okužbe s citomegalovirusom v prebavilih težavna? Why is it difficult to diagnose cytomegalovirus infection in gastrointestinal tract? Nina Zidar*, Katja Tepeš Inštitut za patologijo Medicinske fakultete Univerze v Ljubljani Gastroenterolog 2013; suplement 2: 138–141 Ključne besede: citomegalovirus, prebavila, diagnoza, imunosupresija Keywords: cytomegalovirus, gastrointestinal tract, diagnosis, immunosuppression POVZETEK ABSTRACT Citomegalovirus (CMV) je pomemben povzročitelj bolezni prebavil, zlasti pri imunosuprimiranih bolnikih in pri kritično bolnih, redko tudi pri sicer zdravih osebah. Klinične in endoskopske značilnosti so nespecifične. Diagnozo postavimo iz biopsije na podlagi celic velikank z jedrnimi inkluzijami z videzom sovjega očesa, vendar so le-te v prebavilih, zlasti v debelem črevesu, pogosto maloštevilne in ne povsem značilnega videza. V takih primerih lahko diagnozo postavimo s pomočjo imunohistokemične preiskave. Imunohistokemično preiskavo za dokaz CMV je zato potrebo opraviti pri vseh imunosuprimiranih bolnikih in pri vseh z nepojasnjenimi ulkusi in erozijami v prebavilih. Zaradi opisanih značilnosti je diagnostika CMV bolezni v prebavilih zahtevna in bo uspešna le ob dobrem sodelovanju med kliniki in patologi. Cytomegalovirus (CMV) is an important human pathogen affecting gastrointestinal tract. It occurs mainly in immunocompromised and critically ill patients, only seldom in otherwise healthy subjects. Clinical and endoscopic features are nonspecific. The diagnosis is made by patohistological findings of giant cells with basophilic nuclear inclusions (owl’s eye). However, in gastrointestinal tract, particularly in colon mucosa, those findings are often scarce and lack the characteristic appearance. In such cases, the diagnosis is made by means of immunohistology, which should be performed in all immunocompromised patients as well as in all patients with etiologically unexplained ulcers and erosions. Because of these characteristics the diagnosis of CMV infection in the gastrointestinal tract presents challenge and requires good cooperation between clinicians and pathologists. *prof. dr. Nina Zidar, dr. med. Inštitut za patologijo Medicinske fakultete Univerze v Ljubljani Korytkova 2, 1000 Ljubljana 138 GASTROENTEROLOG UVOD Virus citomegalije (CMV), imenovan tudi humani herpesvirus 5 (HHV-5), spada v poddružino betaherpesvirusov. CMV povzroča okužbe povsod po svetu, pri osebah vseh starosti, brez sezonskega nihanja in epidemij. Primarna okužba povzroči pri osebah z normalnim imunskim odzivom infekcijski mononukleozi podobno bolezen z neznačilnimi znaki in simptomi, kot so slabo počutje, zvišana telesna temperatura, povečane bezgavke, jetra in vranica ter limfocitoza, ki večinoma mine brez zapletov. Pri osebah z zmanjšanim imunskim odzivom ima hujši potek in se lahko konča smrtno. Najslabšo napoved ima intersticijska pljučnica, retinitis, encefalitis, hepatitis in pankreatitis (1, 2). Po primarni okužbi preide CMV v latentno obliko: virusna DNK je prisotna v mnogih celicah, npr. v endotelijskih celicah, makrofagih in mieloidnih progenitorskih celicah. Virus se lahko kasneje kadarkoli reaktivira in povzroči simptomatsko bolezen, zlasti v stanjih zmanjšane imunske odzivnosti. Prekuženost odraslih je visoka, v razvitem svetu med 40 % in 100 %, in narašča s starostjo (3-5). Reaktivacija CMV pri zmanjšani imunski odzivnosti lahko prizadene različne organe in vodi v nastanek pljučnice, hepatitisa, retinitisa, kolitisa, encefalitisa. Prebavila, še posebej debelo črevo, so med najpogosteje prizadetimi organi (3). Kljub mnogim raziskavam je v zvezi s prizadetostjo prebavil pri reaktivaciji CMV še mnogo nejasnosti, npr. kateri so klinični in histopatološki diagnostični kriteriji, katere diagnostične metode so optimalne in katere bolnike je potrebno zdraviti s protivirusnimi zdravili (6, 7). KLINIČNE, MAKROSKOPSKE IN MIKROSKOPSKE ZNAČILNOSTI OKUŽBE S CMV V PREBAVILIH Okužba s CMV prizadene v prebavilih najpogosteje debelo črevo, redkeje požiralnik in želodec, izjemoma ustno votlino in žrelo (8-11). Običajno gre za reaktivacijo virusa. Prizadetost prebavil je lahko izolirana ali del sistemske CMV bolezni. Ogroženi so predvsem imunosuprimirani bolniki, npr. po presaditvi organov ali kostnega mozga, pri zdravljenju s kortikosteroidi, citostatiki, pri okužbi s HIV, pa tudi kritično bolni (npr. bolniki s sepso, cirozo, opeklinami (12–14). Posebej ogroženi so tudi bolniki s kronično vnetno boleznijo, zlasti tisti z ulceroznim kolitisom, ki so zdravljeni s kortikosteroidi (3, 7). V novejšem času opozarjajo, da lahko klinično pomembna CMV bolezen v prebavilih prizadene tudi sicer zdrave osebe (15, 16). Klinična slika je neznačilna. Pri prizadetosti požiralnika je najpogostejši znak bolečina pri požiranju, pri prizadetosti želodca pa nekateri navajajo kot značilni znak posturalno bolečino v epigastriju, ki je najbolj intenzivna v stoječem položaju, blažja v sedečem in najblažja v ležečem položaju, ter upočasnjeno praznjenje želodca (17, 18). Pri kolitisu je najpogostejši klinični znak driska, krvavitev in bolečine v trebuhu. CMV okužbo prebavil pogosto spremljajo tudi slabost, bruhanje, zvišana telesna temperatura in izguba telesne teže, kot zaplet se lahko razvije perforacija (19). Makroskopske (endoskopske) spremembe so nespecifične: pri večini bolnikov so prisotne erozije ali ulkusi, ulkusi so pogosto multipli in veliki (slika 1A in B). Lahko so prisotni tudi eritem (slika 1A), edem sluznice, zadebeljene sluznične gube, vnetni polipi (11, 20, 21). Slika 1. Levo: operacijski preparat sigmoidnega črevesa pri bolnici z ishemično boleznijo srca in CMV kolitisom: eritem sluznice in ulkusi. Desno: operacijski preparat debelega črevesa pri bolnici s Crohnovo boleznijo, pri kateri je prišlo do reaktivacije CMV in perforacije črevesa: multipli obsežni ulkusi. GASTROENTEROLOG 139 Mikroskopsko so za CMV bolezen diagnostične velike celice z bazofilnimi jedrnimi in/ali citoplazmatskimi inkluzijami s halojem (videz sovjega očesa), ki jih z lahkoto prepoznamo, za potrditev je priporočljivo opraviti imunohistokemično reakcijo (slika 2A in B). Značilne celice velikanke z inkluzijami pa so v prebavilih, zlasti v debelem črevesu, pogosto maloštevilne. Kambham in sod. (22) so analizirali gostoto CMV-pozitivnih celic v debelem črevesu pri bolnikih z ulceroznim kolitisom z reaktivacijo CMV in ugotovili nizko gostoto – le 0,01 do 2.65 celic/mm2. Poleg tega po naših izkušnjah v prebavilih, zlasti v debelem črevesu, pogosto ne najdemo značilnih celic velikank z virusnimi inkluzijami. V literaturi na to značilnost CMV kolitisa opozarjajo le redki avtorji. Kambham in sod. (22) so pri 10 bolnikih z imunohistokemično potrjenim CMV kolitisom našli značilne virusne inkluzije pri treh bolnikih, atipične inkluzije pri treh bolnikih, pri ostalih bolnikih pa v biopsijskih vzorcih niso opazili inkluzij. Slika 2. CMV gastritis pri bolniku s plazmocitomom in amiloidozo, zdravljenem s citostatiki. Levo: epitelijska celica z značilno jedrno inkluzijo in granulirano citoplazmo. Desno: pozitivna imunohistokemična reakcija na CMV v epitelijski celici z inkluzijo v jedru in citoplazmi. V biopsijskem vzorcu pogosto vidimo le povsem neznačilne spremembe, predvsem proliferacijo granulacijskega tkiva v dnu erozij ali ulkusov (slika 3A). V teh primerih nam pravilno diagnozo omogoči imunohistokemična preiskava, ki je lahko pozitivna tudi v celicah, ki nimajo jasno vidnih inkluzij ali pa so le-te majhne in komaj opazne (slika 3B). Imunohistokemično preiskavo na CMV je zato potrebno narediti pri vseh imunosuprimiranih bolnikih, pa tudi pri tistih, ki imajo v prebavilih nepojasnjene erozije ali ulkuse. 140 GASTROENTEROLOG Slika 3. CMV kolitis pri bolnici s Crohnovo boleznijo. Levo: proliferacija granulacijskega tkiva v dnu ulkusa, brez značilnih celic z inkluzijami. Desno: pozitivna imunohistokemična reakcija na CMV v endotelijski celici v eni od kapilar v granulacijskem tkivu. DIAGNOSTIKA OKUŽBE S CMV V PREBAVILIH Za ugotavljanje okužbe s CMV je na voljo več metod z različno občutljivostjo in specifičnostjo (23), ki jih lahko izvajamo na vzorcih krvi, seruma, levkocitov, izoliranih iz periferne krvi, telesnih tekočin ali na tkivnih vzorcih. Metode, ki se izvajajo na vzorcih krvi ali levkocitov, imajo v diagnostiki CMV bolezni v prebavilih omejeno vrednost, ker je CMV bolezen v prebavilih običajno posledica reaktivacije pri seropozitivnih osebah in ker običajno ni del sistemske CMV okužbe. Nudijo le podatke o predhodni izpostavljenosti CMV in identificirajo osebe, pri katerih lahko pride do reaktivacije virusa (24, 25). Reaktivacijo CMV v prebavilih lahko zanesljivo ugotovimo le s histopatološkim pregledom tkivnega vzorca. Histopatološka diagnoza temelji na celicah velikankah z virusnimi inkluzijami. Slabost je predvsem v majhni občutljivosti (10–87 %) (3), saj so značilne inkluzije maloštevilne in v biopsiji lahko niso zajete, poleg tega so v prebavilih pogosto neznačilne (atipične) in jih ne prepoznamo (25–27). Če ob histopatološkem pregledu biopsije naredimo tudi imunohistokemijo ali in situ hibridizacijo, naraste občutljivost na pribl. 93 % (3, 25, 26, 28). Pri tem običajno uporabimo komercialna protitelesa proti zgodnjemu jedrnemu antigenu, ki se pojavi 9 do 96 ur po okužbi oz. reaktivaciji virusa. Pozitivna imunohistokemična preiskava torej kaže na zgodnjo aktivno virusno replikacijo (22, 29). Novejša priporočila svetujejo tudi uvedbo kvantitivne tkivne PCR (verižne reakcije s polimerazo) (25), ki je sicer najbolj natančna in občutljiva metoda za dokazovanje virusne okužbe, vendar zaenkrat še ni jasnih priporočil o uporabi te metode pri CMV bolezni, saj pozitivna reakcija pomeni prisotnost virusa (latentna okužba), ne pa tudi aktivne bolezni (3, 30). ZAKLJUČEK Reaktivacija CMV v prebavilih je pomembne vzrok obolevnosti in umrljivosti zlasti pri imunosuprimiranih in kritično bolnih, posebej ogroženi so bolniki s kronično vnetno črevesno boleznijo, zdravljeni s kortikosteroidi. Klinična in endoskopska slika sta običajno neznačilni. Zanesljivi način diagnostike reaktivacije CMV v prebavilih je biopsija. Značilne celice velikanke z virusnimi inkluzijami v prebavilih, zlasti v debelem črevesu, pogosto niso prisotne, zato je potrebno narediti imunohistokemično preiskavo za dokaz CMV pri vseh imunosuprimiranih bolnikih in pri vseh z nepojasnjenimi ulkusi in erozijami v prebavilih. Zaradi opisanih značilnosti je diagnostika CMV bolezni v prebavilih zahtevna in bo uspešna le ob dobrem sodelovanju med kliniki in patologi. LITERATURA 1. Koren S, Meško Meglič K, Jeverica S. Herpesvirusi. In: Poljak M, Petrovec M, eds. Medicinska virologija. Ljubljana: Medicinski razgledi, 2011: 15–30. 2. Crough K, Khanna R. Immunobiology of cytomegalovirus: from bench to bedside. Clin Microbiol Rev 2009; 22: 76–98. 3. Garrido E, Carrera E, Manzano R, Lopez-Sanroman A. Clinical significance of cytomegalovirus infection in patients with inflammatory bowel disease. World J Gastroenterol 2013; 19: 17–25. 4. Emery VC. Cytomegalovirus: recent progress in understanding pathogenesis and control. QJM 2012; 105: 401–5. 5. Britt W. Manifestations of human cytomegalovirus infection: proposed mechanisms of acute and chronic disease. Curr Top Microbiol Immunol 2008; 325: 417–70. 6. Matsuoka K, Iwao Y, Mori T, Sakuraba A, Yajima T, Hisamatsu T, et al. Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients. Am J Gastroenterol 2007; 102: 331–7. 7. Hommes DW, Sterringa G, van Deventer SJ, Tytgat GN, Weel J. The pathogenicity of cytomegalovirus in inflammatory bowel disease: a systematic review and evidence-based recommendations for future research. Inflamm Bowel Dis 2004; 10: 245–50. 8. Lemonovich TL, Watkins RR. Update on cytomegalovirus infections of the gastrointestinal system in solid organ transplant recipients. Curr Infect Dis Rep 2012; 14: 33–40. 9. Baroco AL, Oldfield EC. Gastrointestinal cytomegalovirus disease in the immunocompromised patient. Curr Gastroenterol Rep 2008; 10: 409–16. 10. You DM, Johnson MD. Cytomegalovirus infection and the gastrointestinal tract. Curr Gastroenterol Rep 2012; 14: 334–42. 11. Reggiani Bonetti L, Losi L, Di Gregorio C, Bertani A, Merighi A, Bettelli S, et al. Cytomegalovirus infection of the upper gastrointestinal tract: a clinical and pathological study of 30 cases. Scand J Gastroenterol 2011; 46: 1228–35. 12. Kim CH, Bahng S, Kang KJ, Ku BH, Jo YC, Kim JY, et al. Cytomegalovirus colitis in patients without inflammatory bowel disease: a single center study. Scand J Gastroenterol 2010; 45: 1295–301. 13. Jain M, Duggal S, Chugh TD. Cytomegalovirus infection in nonimmunosuppressed critically ill patients. J Infect Dev Ctries 2011; 5: 571–9. 14. Limaye AP, Boeckh M. CMV in critically ill patients: pathogen or bystander? Rev Med Virol 2010; 20: 372–9. 15. Rafailidis PI, Mourtzoukou EG, Varbobitis IC, Falagas ME. Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review. Virol J 2008; 5: 47. 16. Galiatsatos P, Shrier I, Lamoureux E, Szilagyi A. Meta-analysis of outcome of cytomegalovirus colitis in immunocompetent hosts. Dig Dis Sci 2005; 50: 609–16. 17. Li W, Fan H, Yiping L. Postural gastric pain as a sign of cytomegalovirus gastritis in renal transplant recipient: a casebased review. Transplant Proc 2009; 41: 3956–8. 18. Nowak TV, Goddard M, Batteiger B, Cummings OW. Evolution of acute cytomegalovirus gastritis to chronic gastrointestinal dysmotility in a nonimmunocompromised adult. Gastroenterology 1999; 116: 953–8. 19. Mégarbane B, Résičre D, Ferrand J, Raskine L, Vahedi K, Baud FJ. Difficulties in assessing cytomegalovirus-associated gastric perforation in an HIV-infected patient. BMC Infect Dis 2005; 5: 28. 20. Kakugawa Y, Kami M, Matsuda T, Saito Y, Kim SW, Fukuda T, et al. Endoscopic diagnosis of cytomegalovirus gastritis after allogeneic hematopoietic stem cell transplantation. World J Gastroenterol 2010; 16: 2907–12. 21. Suzuki H, Kato J, Kuriyama M, Hiraoka S, Kuwaki K, Yamamoto K. Specific endoscopic features of ulcerative colitis complicated by cytomegalovirus infection. World J Gastroenterol 2010; 16: 1245–51. 22. Kambham N, Vij R, Cartwright CA, Longacre T. Cytomegalovirus infection in steroid-refractory ulcerative colitis: a case-control study. Am J Surg Pathol 2004; 28: 365–73. 23. Roblin X, Pillet S, Oussalah A, Berthelot P, Del Tedesco E, Phelip JM, et al. Cytomegalovirus load in inflamed intestinal tissue is predictive of resistance to immunosuppressive therapy in ulcerative colitis. Am J Gastroenterol 2011; 106: 2001–8. 24. You DM, Johnson MD. Cytomegalovirus infection and the gastrointestinal tract. Curr Gastroenterol Rep 2012; 14: 334–42. 25. Rahier JF, Ben-Horin S, Chowers Y, Conlon C, De Munter P, D'Haens G, et al; European Crohn's and Colitis Organisation (ECCO). 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GASTROENTEROLOG 141 Slovenske smernice za preprečevanje neželenih učinkov nesteroidnih protivnetnih zdravil, antiagregacijskih in antikoagulantnih učinkovin na prebavila in srčno žilni sistem Slovenian guidelines for prevention of non-steroidal anti-inflammatory, anti-aggregation and anticoagulant agents related adverse effects on gastrointestinal and cardiovascular system Borut Štabuc*, B. Tepeš, P. Skok, M. Vujasinovič, A. Blinc, M. Čerček, M. Tomšič KO za gastroenterologijo, UKC Ljubljana Gastroenterolog 2013; suplement 2: 142–145 POVZETEK ABSTRACT Neželene učinke nesteroidnih protivnetnih (NSAR), antiagregacijskih in antikoagulantnih učinkovin lahko preprečimo s smotrnim predpisovanjem, z eradikacijo okužbe z bakterijo helikobakter pilori in z zaviralci protonske črpalke (ZPČ). NSAR ne prepisujemo bolnikom z visokim tveganjem za gastrointestinalne ali srčno žilne zaplete. Adverse effects of nonsteroidal anti-inflammatory (NSAIDs), anti-aggregation and anticoagulant agents can be prevented by rational prescribing, the eradication of infection with the bacterium Helicobacter pilori and proton pump inhibitors (PPIs). NSAIDs should not be prescribed to patients at high risk for gastrointestinal or cardiovascular complications. Prior to long-term antiplatelet therapy diagnosis and treatment of infection with Helicobacter pilori is recommended. Antiplatelet and anticoagulant therapy is generally not interrupted. In patients at increased risk for adverse effects in the upper gastrointestinal tract, PPI should be prescribed in the standard dose of 20 mg of omepazole, esomeprazole or pantoprazole daily or 15 mg of lansopazole daily. Pred dolgotrajnim antiagregacijskim zdravljenjem se priporoča ugotavljanje in zdravljenje okužbe s helikobakter pilori. Aniagregacijskega in antikoagulantnega zdravljenja praviloma ne prekinjamo. Bolnikom z večjim tveganjem za neželene učinke na zgornjih prebavilih preventivno predpisujemo ZPČ v standardnem odmerku 20 mg/dan omeprazola, esomeprazola in pantoprazola ali 15 mg/dan lansoprazola. * Prof. dr. Borut Štabuc, dr. med. KO za gastroenterologijo, UKC Ljubljana Japljeva 2, 1000 Ljubljana 142 GASTROENTEROLOG S povzetkom priporočil, ki so rezultat skupnega dela gastroenterologov, revmatologov, kardioologov in družinskih zdravnikov želimo osvežiti znanje slovenskih zdravnikov pri preprečevanju in predpisovanju tovrstnih učinkovin in ZPČ. These guidelines are a product of the joint effort of gastroenterologists, rheumatologists, cardiologists and family physicians and are intendet to refreshen the knowledge of Slovenian doctors in the prevention and prescribing of these agents and PPIs. INTRODUCTION Most common side effects include dyspepsia, erosions, duodenal/gastric ulcer and gastrointestinal hemorrhage. Life-threatening complications such as perforation, peptic ulcer bleeding and gastrointestinal obstruction occur in 1.5% of patients. The overall mortality rate due to NSAID adverse effects on the gastrointestinal tract is 1 to 2%. The use of non-steroidal anti-inflammatory (NSAID), anti-aggregation and anticoagulant agents is associated with many side effects that increase morbidity, mortality and hospital admission rate, especially in elderly patients. Based on their mechanism of action, NSAIDs are subclassified into classical (diclofenac, ibuprofen, indomethacin, naproxen and ketoprofen), which inhibit cyclooxygenase 1 and 2 (COX-1 and COX-2), partially selective COX-2 NSAIDs (meloxicam, nimesulide, etodolac), which in therapeutic doses inhibit COX-1 at a lesser degree than classical NSAIDs and COX-2-selective coxibs (celecoxib, etoricoxib), which selectively inhibit COX-2. Oral anti-aggregation agents are subclassified into cyclooxygenase inhibitors (ASA), phosphodiesterase inhibitors (dipyridamole) and ADP receptor P2Y12 blockers (thienopyridines (ticlopidine, clopidogrel, prasugrel) and ticagrelor). PAR1 thrombin receptor blockers are beeing developed (currently at the stage of clinical trials). Glycoprotein receptor IIb/IIIa inhibitors are only available in parenteral form. Oral anticoagulation medicines are subclassified into vitamin K antagonists (warfarin) and direct oral anticoagulants (dabigatran (thrombin inhibitor), rivaroxaban and apiksaban (factor Xa inhibitor)). Adverse effects depend of the type of substance, dosage, combination therapy and duration of treatment. Incidence and severity of adverse effects is significantly affected by concomitant treatment with glucocorticoids, anti-aggregation and anticoagulant agents as well as comorbidity and individual patient characteristics. All NSAIDs are cardiotoxic and may increase the risk of arterial hypertension, congestive heart failure, thrombosis, heart attack and stroke. It is estimated that 20% of hospital admissions of patients with congestive heat failure is related to NSAIDs usage. As some NSAIDs (due to competitive binding to COX-1) prevent acetylsalicylic acid (ASA) to irreversibly bind to COX-1, patients requireing combination therapy should be advised to take ASA at least 2 hours before the traditional NSAIDs. Prevention of NSAID and ASA related adverse effects on gastrointestinal system according to the degree of risk for cardiovascular complications (table 1). Risk factors for adverse events include: age over 65 years, history of gastrointestinal symptoms in the upper gastrointestinal tract, history of peptic ulcer disease (PUD), history of gastrointestinal bleeding, maximum dose of NSAID, concomitant administration of ASA (low dose), anticoagulant therapy, corticosteroids or selective serotonin reuptake inhibitors (SSRI) and infection with bacterium Helicobacter pylori (HP). Patients without risk factors for gastrointestinal adverse events present the low risk group. Those with one or two risk factors are at medium risk while GASTROENTEROLOG 143 those with three or more or those who have had an ulcer complication as well as those receiving concomitant anticoagulation therapy fall into the category of high risk. Half of all PUD of the upper gastrointestinal tract is caused by HP infection. HP infection increases the risk of NSAID and ASA related complications of ulcer disease. Slovenian Association of Gastroenterology and Hepatology therefore recommends HP testing, eradication therapy as well as confirmation of successful eradication prior to long-term treatment with NSAID or ASA. All patients recieving NSAID, anticoagulant and anti-aggregation agents with a history of ulcer disease or complications after an ulcer should be tested aswell. Table 1. Prevention of NSAID and ASA related adverse effects on gastrointestinal system according to the degree of risk for cardiovascular complications. Low risk for cardiovascular disease High risk for cardiovasculat disease (concomitant use of ASA) Low risk for ulcer disease complications classical NSAID (HP-eradication) naproksen <1g + PPI + HPeradication Medium risk for ulcer disease complications classical NSAID+PPI or coxib (HP-eradication) naproksen < 1g + PPI + HPeradication High risk for ulcer disease complications coxib + PPI + HP- no NSAID; PPI + eradication; HP-eradication; continuous continuous monitoring monitoring Prevention of anti-aggregation and anticoagulant therapy related adverse effects on gastrointestinal system Patients on dual antiplatelet therapy are at 2 to 3 fold higher risk of gastrointestinal bleeding (GIB) compared to those recieving ASA only. PPI significantly reduces the risk of GIB due to clopidogrel particularly in patients with more than three risk factors. Recent prospective studies did not confirm 144 GASTROENTEROLOG the increased risk of cardiovascular complications (cardiovascular death, myocardial infarction, stroke) and thrombosis in coronary stents in patients recieving PPI (regardless of the substance) and clopidogrel/prasugrel. CYP2C19 polymorphism does not correlate with an increased risk of cardiovascular complications and thrombosis in coronary stents. Studies have shown that combination therapy of ASA and heparin or low molecular weight heparin (LMWH) increase the risk of GIB for 50%. Triple therapy (ASA, clopidogrel and anticoagulant) presents a 3.2 to 6.6 fold increased risk of GIB (when compared to dual antiplatelet therapy) and should be prescribed only in indications with proven benefits of this type of treatment. In case of tripple therapy including warfarin, international normalised ratio (INR) should be between 2 and 2.5. In patients with high or very high risk of thromboembolic complications and concomitant high risk invasive procedure (risk of bleeding), oral anticoagualtion should be stopped and temporary LMWH should be temporary introduced. Sometimes intravenous platelet receptor IIbIIIa inhibitor eptifibatide is used as well, although there are no evidence-based recommendation. The minimal duration of dual antiplatelet therapy (ASA and one of the P2Y12 receptor inhibitors) after an acute coronary syndrome is 1 month in patients who received a bare metal stent (BMS) and 6 months in patients who received a drug eluting stent (DES). As long-term dual antiplatelet therapy is needed after DES placement, patients with three or more risk factors for GIB should not receive DES. In these patients, concomitant use of NSAID and glucocorticoids should be avoided. Treatment with standard dose PPI significantly reduces the risk of bleeding from the upper gastrointestinal tract (Table 2). In case of GIB, dual antiplatelet therapy is not interrupted. If however it has already been interrupted, it should be re-introduced in three or at latest in seven Table 2. Prevention of anti-aggregation and anticoagulant therapy related adverse effects on gastrointestinal system Dual antiplatelet Dual antiplatelet therapy + therapy anticoaguation* Low risk for ulcer disease complications PPI Medium risk for ulcer disease complications PPI PPI High risk for ulcer disease complications PPI; continuous monitoring PPI; continuous monitoring, consider benefit vs. risk days. A cardiology consult should be sought before ommiting antiplatelet therapy. In case of severe and life threatening GIB, where endoscopical or radiological treatment fails, platelet transfusion could be beneficial (however there is no clear evidence it is effective). Use of recombinant factor VIIa is not recommended due to increased risk of stent thrombosis. In the case of gastrointestinal bleeding in patients on triple therapy, warfarin should be replaced with LMWH, clopidogrel and ASA therapy should not be interrupted. Treatment in such patients should be discussed by a multidisciplinary team of gastroenterologists and cardiologists. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. REFERENCES 1. Lanas A, Garcia –Tell G, Armada B, Oteo-Alvaro A. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal riskand cardiovascular history in patients with diagnoses of osteoarthritis. BMC Medicine 2011;9:38-44 2. Anithrombotic therapy and prevention of thrombosis,9th ed:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2012;141 (2 suppl) 3. Rostom A, Moayyedi P, Hunt R. Canadian consensus guidelines on-long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection. Aliment Pharmacol Ther 2009;29:481-96 4. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) * Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2012;33:1635-1701) 5. Hamm CW, Bassand JP, Agewall S,et all. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the 16. 17. 18. management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 2999-3054. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360-1420 Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of non-steroidal anti-inflammatory drugs. A meta analysis. Ann Intern Med 1991;115:787-96 Lanza FL, Chan FK, Quigley EM for the Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009;104:728-38) European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) * Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2012;33:1635-1701) Bhatt DL,Cryer BL,Contant CF, Cohen M, et al. Clopidogrel with or without Omeprazole in Coronary Artery Disease. NEJM 2010; 363:1909-17 Malfertheiner P, Megraud F, O’Morain CA, Atherton J, Axon ATR, BazzoliF, et al. Management of Helicobacter pylori infection the Maastricht IV/ Florence Consensus Report. Gut 2012;61:646-64) Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ et al. ACCF/ACG/AHA 2010 Expert concensus document on the concomitant use of proton pump inhibitors and thienopyridines: A focus update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. J Am Coll Cardiol 2010;56: 2051-66 Chan FK, Hung LD, Wong VW, Leung VK, Kung NN, e tal. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005 20; 352 :238-44 Biondi-Zoccai GC, Lotrionte M, Agostoni P e tal. A systematic review and meta-analysis on the hazards of dicontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart j 2006;27:2667-74 Chan FK, Abraham NS, Scheiman JM and Laine L Management of patients on nonsteroidal anti-inflammatory drugs: A clinical practice recommendation from the first international working party on gastrointestinal and cardiovascular effects of nonsteroidal anti-inflammatory drugs and anti-platelet agents. Am J Gastroenterol 2008;103:2908-18 Steg PG, James SK, Atar D, Badano LP, ESC Committee for Practice Guidelines (CPG), et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC).Eur Heart J 2012; Aug 24. [Epub ahead of print] Bhatt DL,Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID UseA Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2008;52(18):1502-1517 ESC Press Releases.Omission of aspirin from antiplatelet regimen reduces incidence of bleeding without compromising safety in patients taking oral anticoagulants and having coronary stent placement: the WOEST study. 28. Aug 2012 http://www.escardio.org/about/press/press-releases/esc12munich/Pages/HL3-WOEST.aspx GASTROENTEROLOG 145 Vnetne in rakaste bolezni kože zaradi anti-TNF zdravil pri bolnikih s kroničnimi vnetnimi črevesnimi boleznimi Inflammatory and cancerous skin lesions in inflammatory bowel disease patients treated with anti-tnf therapy Andreja Ocepek*, Cvetka Pernat Drobež Oddelek za gastroenterologijo, Klinika za interno medicino, Univerzitetni klinični center Maribor Department for gastroenterology, Clinic for internal medicine, University medical center Maribor Gastroenterolog 2013; suplement 2: 146–148 UVOD INTRODUCTION Bolezenske spremembe kože sodijo med najpogostejše stranske učinke zdravljenja z anti-TNF zdravili. (1–6) Dosedanje raziskave so pokazale, da se pri bolnikih s kroničnimi vnetnimi črevesnimi boleznimi (KVČB), pojavijo pri približno 20–25 %. (1, 4, 5) Med kožnimi odzivi na anti-TNF zdravila najpogosteje srečamo reakcije na mestu injiciranja, okužbe kože, ne-melanomski rak kože in psoriaza, redko pa pride do pojava sindroma podobnega lupusu, Stevens-Johnsonovega sindroma, eritema multiforme in toksične epidermalne nekroze. (6) Predstavljamo skupino bolnikov s KVČB, ki smo jih v naši ustanovi zdravili z anti-TNF zdravili in pri katerih so se pojavile vnetne in rakaste bolezni kože. Skin lesions are most frequently observed adverse reactions to anti-TNF therapy. (1–6) In inflammatory bowel disease (IBD) patients their incidence is 20–25%. (1, 4, 5) Most common skin side effects of anti-TNF are injection site reactions, cutaneous manifestations of infusion reactions, cutaneous infections, non-melanoma skin cancer, and psoriasis. Rare lesions include lupus-like syndrome, StevensJohnson syndrome, erythema multiforme and toxic epidermal necrolysis. (6) We present our group of IBD patients treated with anti-TNF therapy who developed inflammatory or cancerous skin lesions. METODE Medical charts of all IBD patients treated with anti-TNF therapy from january 2007 to february 2013 were retrospectively reviwed, in search of inflammatory or cancerous skin lesions as side effects of therapy. Opravili smo retrospektivno analizo medicinske dokumentacije vseh bolnikov s KVČB, ki smo jih zdravili z anti-TNF zdravili od januarja 2007 do februarja 2013, s poudarkom na vnetnih in rakastih boleznih kože kot stranski učinek te vrste zdravljenja. METHODS * Andreja Ocepek, dr. med. Oddelek za gastroenterologijo, Klinika za interno medicino, Univerzitetni klinični center Maribor Ljubljanska 5, 2000 Maribor 146 GASTROENTEROLOG REZULTATI RESULTS V raziskavo smo zajeli 125 bolnikov, 65 moških in 60 žensk, povprečne starosti 42,2 let (od 24,3 do 70,6 let). Pri 18 bolnikih (14,4 %), 10 moških (55,6 %) in 8 ženskah (44,4 %), je prišlo do stranskih učinkov na koži. 11 bolnikov (61,1 %) smo zdravili zaradi Chronove bolezni in 7 bolnikov (38,9 %) zaradi ulceroznega kolitisa. Pri 16 bolnikih (12,8 %) so se pojavile vnetne bolezni kože in sicer psoriaziformni izpuščaji pri 7 bolnikih (38,9 %), ekcematoidni izpuščaji pri 3 bolnikih (16,7 %), neopredeljene kožne spremembe pri 3 bolnikih (16,7 %) in druge spremembe (alopecija, hiperkeratoza, bulozni pemfigoid) pri 3 bolnikih (16,7 %). Pri večini bolnikov (9 oz. 50 %) smo kožne spremembe opazovali na koži udov, pri 3 bolnikih (16,7 %) na trupu, 1 bolnik (5,5 %) je imel spremembe na trupu in udih, 1 bolnica (5,5 %) na obrazu, pri 2 bolnikih (11 %) je bilo prizadeto lasišče. Odkrili smo 3 primere bazoceličnega karcinoma (BCC) pri 2 bolnikih (1,6 %), pri bolniku na infliksimabu na koži nosu in pri bolnici na adalimumabu na koži hrbta in ingvinalnega področja. 12 bolnikov (77,8 %) je prejemalo infliksimab, 4 bolniki (22,2 %) adalimumab, 2 bolnika (11,1 %) pa zaporedno obe zdravili. Povprečni čas od uvedbe anti-TNF zdravila do pojava kožnih sprememb je bil 14,9 mesecev (2 do 39 mesecev). Vsi bolniki so bili pregledani pri dermatologu, oba bolnika z BCC pa pri plastičnem kirurgu, ki je vse 3 karcinome odstranil v zdravo. Le pri 1 bolniku (5,5 %) z buloznim pemfigoidom smo morali anti-TNF zdravilo ukiniti, pri vseh ostalih bolnikih smo zdravljenje nadaljevali, kožne spremembe pa so izginile ali se omilile po lokalnem dermatološkem zdravljenju. In study we included 125 IBD patients, 65 male and 60 female, with average age 42,2 years (24,3 to 70,6 years). 18 patients (14,4%), 10 male (55,6%) and 8 female (44,4%), developed skin side effects. 11 patients (61,1%) were treated for Chron's disease and 7 patients (38,9%) for ulcerative colitis. In 16 patients (12,8%) inflammatory skin lesions were found, psoriasiform lesions in 7 patients (38,9%), eczematiform lesions in 3 patients (16,7%), undefined lesions in 3 patients (16,7%) and other lesions (alopecia, hyperkeratosis, bullous pemphigoid) in 3 patients (16,7%). Most frequently skin lesions affected arms and legs (in 9 patients or 50%), only trunk was affected in 3 patients (16,7%), trunk, arms and legs were affected in 1 patient (5,5%), only face in 1 patient (5,5%) and scalp in 2 patients (11%). 3 cases of basocellulare carcinoma (BCC) were discovered in 2 patients (1,6 %), on the nose in a male patient on infliximab and on the back and in the inguinal region in a female patient on adalimumab. 12 patients with skin side effects (77,8%) were treated with infliximab, 4 patients (22,2%) with adalimumab and 2 patients (11,1 %) with both drugs consecutively. Skin lesions developed after a median time of 14,9 months (2 to 39 months) after initiating anti-TNF therapy. All patients were refered to a dermatologist, both patients with BCC were operated by a plastic surgeon, and all 3 lesions were removed with a clean safety margin. In one patient (5,5%) with bullous pemphigoid anti-TNF therapy had to be stopped, in all other patients therapy was continued, and skin lesions disappeared or were alleviated by topical dermatological therapy. ZAKLJUČEK CONCLUSIONS Kožne spremembe so pogost stranski učinek anti-TNF zdravil. V skupini naših bolnikov s KVČB smo tovrstne zaplete zdravljenja ugotovili pri 14,4 % bolnikov. Le v 1 primeru (5,5 %) smo morali anti-TNF zdravilo ukiniti, pri vseh ostalih bolnikih je zadoščalo lokalno dermatološko zdravljenje. Oba bolnika z BCC sta bila uspešno kirurško zdravljenja in pod rednim nadzorom s strani plastičnega kirurga nadaljujeta z anti-TNF zdravljenjem. Skin side effects are frequent in patients treated with anti-TNF agents. In our group of IBD patients inflammatory and cancerous skin lesions developed in 14,4% of patients. Only in one patient (5,5%) anti-TNF therapy wos stopped, in all other patients topical dermatological therapy was sufficient. Both patients with BCC were treated surgicaly and are continuing with anti-TNF therapy under surgical surveillance. GASTROENTEROLOG 147 LITERATURA/REFERENCES 1. Cleynen I, Vermeire S. Paradoxical inflammation induced by anti-TNF agents in patients with IBD. Gastroenterol Hepatol. 2012;9:496–503. 2. Moustou AE, Matekovits A, Dessinioti C, Antoniou C, Sfikakis PP, Stratigos AJ. Cutaneous side effects of antietumor necrosis factor biologic therapy: A clinical review. J Am Acad Dermatol. 2009;61(3):486–504. 3. Miehsler W, Novacek G, Wenzl H, Vogelsang H, Knoflach P, et al. A decade of infliximab: The Austrian evidence based consensus on the safe use of infliximab in inflammatory bowel disease. J Chrons Colitis. 2010;4:221–56. 4. Fidder H, Schnitzler F, Ferrante M, Noman M, Katsanos K, et al. Longterm safety of infliximab in the treatment of inflammatory bowel disease: a single center cohort study. ECCO ABSTRACTs. 2007;3. 5. Guerra I, Algaba A, Pérez-Calle JL, Chaparro M, Marín-Jiménez I, et al. Induction of psoriasis with anti-TNF agents in patients with inflammatory bowel disease: A report of 21 cases. J Chrons Colitis. 2012;6:518–23. 6. Mocci G, Marzo M, Papa A, Armuzzi A, Guidi L. Dermatological adverse reactions during anti-TNF treatments: Focus on inflammatory bowel disease. J Chrons Colitis. 2013; In Press. 148 GASTROENTEROLOG The sign of Leser-Trélat - a case report Miroslav Vujasinović*,1, Slobodan Vujasinović2, Nebojša Djurišić3, Tajda Keber4 1 Slovenj Gradec General Hospital, Department of Internal Medicine 2 Center for Dermatology 3 Izola General Hospital, Department of Dermatology 4 Medical Faculty at the University of Maribor Gastroenterolog 2013; suplement 2: 149 ABSTRACT The Leser-Trélat sign is characterized by the sudden appearance and rapid increase in both the size and number od seborrheic keratoses. Existence of the sign of Leser-Trélat should prompt a search for underlying malignancy. Adenocarcinoma is the most common malignant neoplasm (approximately 67%) associated with this paraneoplastic syndrome (the sign of Leser- Trélat). The most common primary tumor site is gastrointestinal tract (approximately 72%). We present a case of Leser-Trélat sign in patient with colon adenocarcinoma. Sixty-five years old patient with history of benign prostatic hyperplasia was presented in dermatology ambulance due to the skin changes on his back. All changes have been operated and histopathology showed sebborhoic keratosis. Due to the sudden onset of sebborheic keratosis a further gastroenterology work-up was suggested. There were no pathologic findings in internal clinical examination and laboratory tests (including tumor markers). A colonoscopy was performed and a rectosigmoid tumor was found. Histology showed adenocarcinoma. Abdominal ultrasound and plain chest radiography were normal. Patient underwent operative procedure without complication. Pathologic staging of adenocarcinoma was T1N0M0. Five years after operation the patient’s clinical status is normal. * Miroslav Vujasinović, MD MSc Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1 Slovenj Gradec 2380, Slovenia GASTROENTEROLOG 149 Vpliv klinične poti na izid zdravljenja bolnikov z akutnim pankreatitisom Impact of clinical pathway on treatment outcome in patients with acute pancreatitis Miroslav Vujasinović*,1, Apolon Marolt1, Bojan Tepeš2, Jana Makuc1, Zdenko Kikec1, Nace Robač1 1 Department of Internal Medicine, Slovenj Gradec General Hospital 2 Abakus Medico Diagnostic Centre Gastroenterolog 2013; suplement 2: 150–152 UVOD INTRODUCTION Akutni pankreatitis (AP) je eden najpogostejših razlogov za hospitalizacijo med boleznimi prebavil, povezan je z visoko stopnjo umrljivosti in visokimi stroški zdravljenja. Acute pancreatitis (AP) is one of the most common reasons for hospitalization among all gastrointestinal diseases, and is associated with high mortality and costs of treatment. BOLNIKI IN METODE PATIENTS AND METHODS Opredeliti učinek klinične poti (KP) in nadzor nad kazalci kakovosti (KK) zaradi ocene uspešnosti zdravljenja bolnikov z AP. To determine the impact of clinical pathway (CP) and control of indicators of quality (IOQ) on the outcome of treatment in patients with AP. KP je bila sestavljena iz naslednjih KK: odvzem vseh potrebnih laboratorijskih preiskav ob sprejemu (vključno z lipidogramom in transferinom z zmanjšanim deležem ogljikovih hidratov), določitev etiologije AP, ultrazvok trebuha (UZ) narejen znotraj 24 ur po sprejetju v bolnišnico, opravljena računalniška tomografija (CT) trebuha v primerih z sumom na nekrozo, vendar ne prej kot po 48 urah po sprejemu v bolnišnico, uporaba antibiotične terapije, uporaba protibolečinske terapije, ustreznost hidracije, kontrola vitalnih parametrov in morebitna premestitev v intenzivno enoto (IU), opravljena endoskopska retrogradna holangio- CP consisted of the following IOQ: performance of all laboratory tests on admission (including lipids and carbohydrate deficient transferrin), determination of etiology of AP, ultrasound of the abdomen (US) performed in the first 24 hours after admission to hospital, contrast-enhanced computed tomography (CECT) of the abdomen in all cases of suspected necrosis but not in the first 48 hours after admission, appropriate use of antibiotic therapy, pain control, appropriate hydration, control of hemodynamic parameters and transfer to the Intensive Care Unit (ICU) if necessary, performing of endoscopic retro- * Miroslav Vujasinović, MD MSc Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1 Slovenj Gradec 2380, Slovenia 150 GASTROENTEROLOG pankreatikografija (ERCP) pri bolnikih z biliarno etiologijo, morebitno kirurško zdravljenje, nasveti in spremljanje bolnikov po odpustu. Po uvedbi klinične poti za AP je vsa medicinska dokumentacija mesečno analizirana na oddelčnih sestankih s poudarkom na najpogostejših pomanjkljivostih zdravljenja. Primerjali smo rezultate dveh časovnih obdobij v Splošni bolnišnici Slovenj Gradec: pred (2006–2007) in po (2010–2012) sprejetju klinične poti za AP. Primerjali smo dolžino ležalne dobe v naši bolnišnici z ležalno dobo v drugih bolnišnicah. grade cholangiopancreatography (ERCP) in all patients with biliary etiology, surgical treatment if necessary, advice of outpatient follow-up in all patients after discharge. All medical records after the introduction of CP are analyzed monthly and are discussed at the departmental meeting with emphasis on the most common deficiencies of the treatment. We compared results of two periods in our centre: before (2006-2007) and after (2010-2012) implementation of CP. Comparison of length of stay with that in other Slovenian hospitals was performed. REZULTATI V treh letih po sprejemu klinične poti smo zdravili 139 bolnikov: 81 (58,3 %) moških in 58 (41,7 %) žensk, povprečne starosti 59,6 ±17,3 let. Najbolj pogosta etiologija AP je bil alkohol in žolčni kamni (38,8 % oboje), sledi nepojasnjeni AP (11,5 %), z zdravili povzročen AP, hipertrigliceridemija, zaplet po ERCP (2,9 % vsi) in tumorji (2,2 %). Povprečna starost bolnikov z alkoholno etiologijo je bila 50 ±12,6 let in so bili skoraj 17 let mlajši kot bolniki z etiologijo žolčnih kamnov (t-test=12.819, p=0,000). Etiologija bolezni je bila povezana s spolom bolnika (Fisher exact test = 44.329, p = 0.000): žolčni kamni so bili značilno več prisotni pri ženskah (61 %) kot pri moških (39 %); ravno obratno je pri alkoholnem pankreatitisu, ki ga je bistveno več pri moških (89 %) kot pri ženskah (11 %), Chi-square =39.398, df=3, p=0,000. Uporaba antibiotikov je po uvedbi klinične poti pomembno upadla (od 70,3 % na 51,8 %; p=0,003). Ni bilo statistično pomembne razlike v umrljivosti (1,8 % proti 2,9 %). Trajanje hospitalizacije je na našem oddelku v primerjavi s slovenskim povprečjem izrazito krajše (p=0,018). RESULTS There were 139 patients treated in the three-year period after introduction of CP: 81 (58.3%) male and 58 (41.7%) female, mean age 59.6±17.3 years. The most common etiologies were alcoholism and gallstones (38.8% each), followed by unexplained (11.5%), drug-induced, hypertriglyceridemia, post ERCP (2.9% each) and tumors (2.2%). Mean age of patients with alcoholic etiology was 50±12.6 years and were almost 17 years younger than patients with etiology of gallstones (t-test = 12.819, p =0.000). The etiology of the disease was found to be associated with gender of the patient (Fisher exact test = 44.329, p = 0.000): gallstones were found significantly more often in females (61%) than in males (39%) and alcoholic pancreatitis was significantly more frequent with males (89%) than females (11%). Antibiotic therapy was prescribed in 72 (51.8%) of patients. The most frequent morphological condition was interstitial edematous pancreatitis in 60.4% of patients, followed by acute peripancreatic fluid collection (25.9%), necrotizing pancreatitis (12.2 ) and pancreatic pseudocysts (1.4%). GASTROENTEROLOG 151 ZAKLJUČEK Uvedba klinične poti za obravnavo AP in nadzor nad kazalci kakovosti so izboljšali zdravljenje bolnikov z AP v vseh opazovanih parametrih: zmanjšala se je ležalna doba, manj je nepojasnjenega AP, upadla je uporaba antibiotikov (brez sprememb v umrljivosti). Abdominal US was performed in all patients in the first 24 hours. CE CT was performed in 57 (41%) patients. One hundred and five (75.5%) patients had one attack of AP. Thirty-two (23.0 ) patients were treated in ICU. Four patients died (2.9%). We found an increase in the number of alcoholic and gallstone pancreatitis on the account of a decrease in unexplained etiology in 2010–12, compared to 2006–7. The differences in the structure are statistically significant (Chi-square =39.398, df= 3, p=0.000). The use of antibiotics significantly decreased after implementation of CP (from 70.3% to 51.8%; p=0.003). There was no statistically significant difference in mortality between two periods (1.8% vs. 2.9%). Length of stay in Slovenj Gradec General Hospital is significantly shorter compared to Slovenian average (p=0.018). CONCLUSIONS Introduction of CP and control of IOQ has improved the treatment of patients with AP in all observed parameters: reduced length of stay, reduced percentage of unexplained cases, reduced use of antibiotic therapy (without changes in total mortality) 152 GASTROENTEROLOG Ali so bolniki na antikoagulantni terapiji ustrezno zaščiteni pred krvavitvijo iz zgornjih prebavil? Are patients on anticoagulants adequately protected against upper gastrointestinal bleeding? Milica Miljković*,1, Miroslav Vujasinović1, Martin Tretjak1, Apolon Marolt1, Bojan Tepeš2, Karmen Klančnik3 1 Department of Internal Medicine, Slovenj Gradec General Hospital 2 Abakus Medico Diagnostic Centre 3 Medical Faculty at the University of Maribor Gastroenterolog 2013; suplement 2: 153–154 IZHODIŠČA BACKGROUND Zaradi velike pojavnosti srčno žilnih obolenj, ki povzročajo trombembolične zaplete, se bolnikom pogosto predpiše antikoagulacijsko zdravljenje s peroralnimi antikoagulacijskimi zdravili (AZ). AZ so povezana s povečanim tveganjem za krvavitev iz zgornjih prebavil, še posebej pri starejših bolnikih s sočasno predpisanimi acetilsalicilno kislino (ASK), klopidogrelom, kortikosteroidi, nesteroidnimi analgoantirevmatiki (NSAR) in zaviralci privzema serotonina (SRI). Zaviralci protonske črpalke (ZPČ) so zdravila, ki omogočajo učinkovito zaščito pred krvavitvami iz zgornjih prebavil. Due to the high prevalence of cardiovascular diseases anticoagulant medications (AC) are commonly prescribed. Treatment with AC is related to an increased incidence of acute upper gastrointestinal bleeding (AUGIB) especially in older patients and concomitant treatment with acetylsalicylic acid (ASA), clopidogrel, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAID) and serotonin reuptake inhibitors (SRI). Proton pump inhibitors (PPI) are drugs with good protective effect against AUGIB. NAMEN IN METODE A retrospective analysis of medical documentation of 442 consecutive patients with anticoagulant treatment was performed. We analyzed demographic features, indications for treatment with AC, history of AUGIB and the prescription of PPI. Opravili smo retrospektivno analizo medicinske dokumentacije 440 zaporednih bolnikov v ambulanti za trombotične bolezni, ki prejemajo AZ. Analizirali smo demografske podatke, indikacije za AZ, anamnestične podatke o krvavitvah iz zgornjih prebavil in predpis ZPČ. AIMS AND METHODS * Milica Miljković, dr. med. Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1, 2380 Slovenj Gradec, Slovenia GASTROENTEROLOG 153 REZULTATI RESULTS Med 440 bolniki je bilo 242 moških in 196 žensk, povprečna starost je bil 75,8 ± 6,22 let (65-94 let). Indikacija za predpis AZ je bila atrijska fibrilacija pri 282, prisotnost mehanskih zaklopk pri 59, pljučna embolija pri 52 in globoka venska tromboza pri 47 bolnikih. There were 442 patiens (189 male and 243 female), mean age 75,8 ± 6,2 years (range 65-94). Varfarin je bil predpisan pri 389 (88,4 %), acenokumarol pri 49 (11,1 %) in dabigatran pri 2 bolnikih (0,5 %). ASK, NSAR, kortikosteroidi in SRI so bili sočasno predpisani pri 11 (2,5 %), 7 (1,6 %), 3 (0,7 %) in 35 bolnikih (8,0 %). Osem (1,8 %) bolnikov je imelo v anamnezi podatek o predhodni krvavitvi iz zgornjih prebavil. Indications for treatment with AC were: atrial fibrillation (AF) and stroke in 284 patients, valve replacement in 59 patients, pulmonary embolism in 52 patients and deep venous thrombosis in 47 patients. Warfarin was prescribed in 391 (88,4%) patients, acenocoumarol in 49 (11,1%) patients and dabigatran in 2 (0,5%) patients. ASA, NSAID, corticosteroids and SRI were concomitantly prescribed in 11 (2,5%), 7 (1,6%), 3 (0,7%) and 35 (8,0%) cases, respectively. Eight (1,8%) patients had history of AUGIB. ZPČ so bili predpisani 97 bolnikom (22 %) z AZ v mononoterapiji, 26 bolnikom (41,3 %) z AZ in sočasno predpisanimi zdravili (17 bolnikov je prejemalo SRI, 7 NSAR in 2 kortikosteroide) in 2 bolnikoma (25 %) z AZ in anamnezo predhodne krvavitve. 343 bolnikov (78 %) starejših od 65 let ni imelo predpisanega ZPČ. Pri 57 bolnikih (58,5 %) je bil ZPČ predpisan v ustrezni standardni dozi, pri 26 (26,8 %) je bila doza previsoka, pri 14 (14,4 %) pa doza ni bila znana. ZAKLJUČEK Zaščita zgornjih prebavil pri bolnikih, ki prejemajo peroralna anitkoagulacijska zdravila, ni zadostna. Vsi bolniki, ki poleg teh zdravil prejemajo zdravila z dodatnim tveganjem (predvsem ASK in NSAR) bi morali imeti predpisan ZPČ, še posebej starejši od 65 let in tisti s predhodno krvavitvijo iz zgornjih prebavil. Potrebno je pripraviti slovenska priporočila z jasnimi navodili za predpis ZPČ pri bolnikih z AZ in dodatnimi dejavniki tveganja za krvavitev iz zgornjih prebavil. 154 GASTROENTEROLOG PPI were prescribed in 97 (22,0%) patients with AC in monotherapy, in 26 (41,3%) patients with AC and concomitant therapy (17 with SRI, 7 with NSAR and 2 with corticosteroids) and in 2 patients (25%) with AC and history of AUGIB. There were 317 (71,7%) patients (all older than 65 years) without PPI. In 58,8% of patients PPI was prescribed in proper dose (standard), in 26,8% the prescribed dose of PPI was too high and in 14,4% the dose was unknown. CONCLUSIONS Gastric protection in patients on AC therapy is not satisfactory. All patients were older than 65 years which classifies them as a group of patients with higher risk of AUGIB. All patients with AC therapy and concomitant NSAID or/and ASA therapy should be treated with PPI in standard dose, especially those older than 65 years and history of AUGIB. Gastric protection in patients with AC therapy without concomitant therapy (ASA, NSAR) and history of AUGIB should be exactly specified in national guidelines. Rezultati obravnave bolnikov z akutno krvavitvijo iz zgornjih prebavil v splošni bolnišnici: analiza dveletnega obdobja Audit of the menagement of acute upper gastrointestinal bleeding in general hospital: two-year retrospective analysis Nace Robač*, Miroslav Vujasinović, Apolon Marolt, Martin Tretjak Department of internal medicine, Slovenj Gradec General Hospital Gastroenterolog 2013; suplement 2: 155–158 UVOD INTRODUCTION Akutna krvavitev iz zgornjih prebavil (AKZP) je resen in pogost problem v klinični praksi in je povezan z visoko stopnjo umrljivosti. Acute upper gastrointestinal bleeding (AUGIB) is a serious and common problem in clinical practice and is associated with a significant mortality rate. BOLNIKI IN IN METODE PATIENTSS AND METHODS Namen študije je bil opredeliti demografske podatke bolnikov s krvavitvijo iz zgornjih prebavil, indikacije za gastroskopijo, dejavnike tveganja, etiologijo krvavitve, endoskopske najdbe, prognozo, trajanje hospitalizacije in izid zdravljenja. The aim of the study was to determine demographic characteristics of patients with upper gastrointestinal bleeding, indications for gastroscopy, risk factors, etiology of bleeding, endoscopic findings, prognostic factors, duration of hospital stay and outcome. Naredili smo retrospektivni pregled medicinske dokumentacije bolnikov s krvavitvijo iz zgornjih prebavil (novi sprejemi in hospitalizirani bolniki), ki so se zdravili v Splošni bolnišnici Slovenj Gradec od januarja 2010 do decembra 2011. V študijo so bili vključeni bolniki s hematemezo in/ali meleno pri katerih je bila opravljena endoskopska preiskava zgornjih prebavil. We performed a retrospective review of medical documentation of patients with AUGIB (new admissions and in-hospital patients) treated at our hospital from January 2010 to December 2011. We included patients with hematemesis and/or melena in whom endoscopic examination was performed. Analizirani so bili naslednji demografski in klinični podatki: spol, starost, zgodovina jemanja zdravil: * Nace Robač, MD Department of internal medicine, Slovenj Gradec General Hospital Gosposvetska 1, 2380 Slovenj Gradec, Slovenia GASTROENTEROLOG 155 acetilsalicilna kislina (ASA), klopidogrel, varfarin, kortikosteroidi, nesteroidni antirevmatiki (NSAR), nizkomolekularni heparini (NMH), inhibitorji ponovnega prevzema serotonina (SRI), zaviralci protonske črpalke (ZPČ), pridružene internistične bolezni, srčna frekvenca, krvni tlak, sečnina in hemoglobin. Analizirani so bili naslednji endoskopski podatki: endoskopske najdbe in opravljen hemostatski ukrep. Prisotnost Helicobacter pylori smo dokazali s histopatološko analizo biopta ali s hitrim ureaznim testom med endoskopijo. Vsakega bolnika smo ocenili po Blatchford in Rockall lestvici. Izid zdravljenja je bil ocenjen na podlagi števila ponovnih krvavitev in kirurških intervencij. The following demographic and clinical data were analyzed: gender, age, the history of drug intake (acetylsalicylic acid [ASA], clopidogrel, warfarin, corticosteroids, nonsteroidal anti-inflammatory drugs [NSAID], low-weight molecular heparins [LWMH], serotonin reuptake inhibitors [SRI], proton pump inhibitors [PPI]), concomitant internal diseases, heart rate, blood pressure, blood urea nitrogen and hemoglobin concentration. The following endoscopic data were analyzed: endoscopic findings and hemostatic treatment applied. Helicobacter pylori status was determined histologically and/or by rapid urease test during endoscopy. The Rockall and Blatchford scores were calculated for each patient. The outcome was analyzed on the basis of rebleeding rate and surgical rate. REZULTATI Analiziranih je bilo 191 bolnikov, povprečne starosti 65,3±16,6 let. Razmerje med moškimi (67,5 %) in ženskami (32,5 %) je bilo 2:1. Moški so bili povprečno 8 let mlajši kot ženske (statistično pomembno: p = 0,02). Več kot 2/3 bolnikov (67,5 %) je bilo starejših od 61 let. RESULTS There were 191 patients, mean age 65.3±16.6 years. The ratio between men (67.5%) and women (32.5%) was 2:1. Men were 8 years younger than women (statistically significant; p = 0.002). More than two thirds (67.5%) of all patients were older than 61 years. Najbolj pogosti endoskopski najdbi sta bili želodčni in duodenalni ulkus (45 %), sledijo gastritis (16,8 %) in varice požiralnika (12,6 %). Gastric and duodenal ulcers were most common endoscopic findings (45%) followed by gastritis (16.8%) and esophageal varices (12.6 ). Polovica bolnikov (50,3 %) je imela pozitivno anamnezo jemanja enega ali več zdravil, ki bi lahko povišala možnost krvavitev iz zgornjih prebavil : acetilsalicilna kislina (23 %), klopidogrel (3,7 %), NSAR (9,9 %), kortikosteroidi (2,1 %), SRI (5,8 %), antikoagulantna zdravila (17,8 %). A half of patients (50.3%) had a history of intake of one or more drugs that have the potential to increase the risk of AUGIB: ASA (23%), clopidogrel (3.7%), NSAID (9.9 %), corticosteroids (2.1%), SRI (5.8%) and anticoagulants (17.8%). 29 bolnikov (15,2 %) je jemalo ZPČ pred nastankom krvavitve iz zgornjih prebavil. Twenty-nine patients (15.2%) were using PPI prior to AUGIB (in a half of cases AUGIB has developed despite PPI use). Povezava med Rockall in Blatchford lestvico za opredelitev življenjske nevarnosti je srednje močna (0,573;p=0,000). Pri bolnikih s krvavitvijo iz varic požiralnika sta bili Blatchford in Rockall lestvici neu- Correlation between Rockall and Blatchford scores for the determination of life risk was medium strong (0.573; p = 0.000). In patients with variceal bleeding both Blatchford and Rockall scores were useless 156 GASTROENTEROLOG porabni (statistično nepomembni: r=0,397, p=0,055). Lestvici sta imeli najboljšo povezavo pri bolnikih z normalnimi endoskopskimi izvidi (r=0,709; p=0,010), srednje dobro povezavo pri bolnikih z želodčnimi in duodenalnimi ulkusi (r=0,429, p=0,000). Srednja vrednost Bletchford lestvice pri 5 bolnikih ki so umrli, je bila 12,8±1,3, Rockall lestvice pa 5,8±1,9. Pri 7,3 % bolnikih z vrednostjo Bletchford lestvice 0 ni bilo potrebno nobeno hemostatsko zdravljenje. (statistically non-significant: r= 0.397, p= 0.055). Both scores have best correlation in patients with normal endoscopic findings (r= 0.709, p= 0.010) and medium strong correlation in patients with gastric and duodenal ulcers (r= 0.429, p= 0.000). Mean Blatchford score in 5 patients who died was 12.8±1.3, and mean Rockall score was 5.8±1.9. In 7.3% of patients with Blatchford score 0, no hemostatic treatment was necessary. Melena je bila indikacija za endoskopsko preiskavo pri 114 bolnikih (59,7 %), hematemeza pri 72 bolnikih (37,7 %), oboje pa pri 5 (2,6 %) bolnikih. An indication for endoscopy was melena in 114 patients (59.7%), hematemesis in 72 patients (37.7%) and both in 5 (2.6%) patients. Večina bolnikov je bila hospitaliziranih (87,4 %); 12,6 % pa je bilo ambulantnih obravnav. The majority of patients were hospitalized (87.4%) and 12.6% were treated as outpatients. Prisotnost Helicobacter pylori (HP) smo testirali pri 92 bolnikih (48,2 %): 63 (33 %) je bilo negativnih, 29 (15.2 %) je bilo pozitivnih. Helicobacter pylori (HP) status was known in 92 patients (48.2): 63 (33%) were negative and 29 (15.2) were positive. Pri vseh bolnikih (100 %) je bil ob sprejemu predpisan ZPČ. In all patients (100 %) PPI were prescribed on admission and endoscopy was carried out within 12 hours. Endoskopska preiskava je bila pri vseh bolnikih narejena znotraj 12 ur. Endoscopy finding was normal in 12 patients (6.3%). Normalen endoskopski izvid je imelo 12 bolnikov (6,3 %). Endoscopic hemostatic treatment was performed in 105 (55%) patients. The mean hospital stay was 9.3±9.6 days. Endoskopsko hemostatsko zdravljenje je bilo opravljeno pri 105 bolnikih (55 %). Povprečje ležalne dobe je bilo 9,3 dni. Pet bolnikov (2,9 %) je umrlo zaradi gastrointestinalne krvavitve: 4 bolniki so imeli varice požiralnika, en bolnik je imel želodčni ulkus (povprečna starost 60,6 ± 18,1 let). Five patients (2.9%) died due to the gastrointestinal bleeding: 4 patients with esophageal varices and 1 patient with gastric ulcer (mean age 60.6 ±18.1 years). Mortality due to comorbidity was 7.9%. Two patients (1.04%) had rebleeding and surgical treatment. Umrljivost zaradi komorbidnosti je bila 7,9 %. Dva bolnika (1,04 %) sta imela ponovno krvavitev in sta potrebovala kirurško zdravljenje. GASTROENTEROLOG 157 ZAKLJUČKI CONCLUSIONS Smrtnost zaradi AKZP je zelo nizka, posebej pri krvavitvah, ki nimajo izvora iz varic požiralnika. Mortality of AUGIB is very low, especially in nonvariceal bleeding. Krvavitev iz varic požiralnika je najpogostejši vzrok smrti. Variceal bleeding is the commonest cause of death. Smrt po AKZP je redka brez pridruženih komorbidnih stanj. Najpogostejša endoskopska najdba je bila krvavitev zaradi ulkusa. Death following AUGIB is unusual in the absence of co-morbidity. The commonest endoscopic diagnosis was peptic ulcer bleeding. Rebleeding and surgical rates are very low. Ponovitev kvavitve in kirurški posegi so zelo redki. Benefits of Rockall and Blatchford scores are limited. Koristi Blatchford in Rockall lestvic so omejene. Odstotek opravljenih urgentnih endoskopij znotraj 12 ur je maksimalen (100 %); je izrazito večji v primerjavi z drugimi študijami in je glavni razlog za dobro prognozo bolnikov z AKZP. 158 GASTROENTEROLOG The percentage of urgent endoscopies performed within the first 12 hours is maximal (100%); it is significantly higher in comparison with other studies and is the main reason for a good outcome in patients with AUGIB. Biliarni ileus – prikaz dveh primerov Biliary ileus – report of two cases Miroslav Vujasinović*,1, Karmen Klančnik2, Gregor Kunst3, Simona Lavre4 1 Department of Internal Medicine; Slovenj Gradec General Hospital 2 Medical Faculty at the University of Maribor 3 Department of Surgery; Slovenj Gradec General Hospital 4 Department of Radiology; Slovenj Gradec General Hospital Gastroenterolog 2013; suplement 2: 159–160 POVZETEK ABSTRACT Žolčni kamni lahko ulcerirajo skozi žolčnik v dvanajstnik in prehajajo distalno po tankem črevesju. Za povzročitev mehanske obstrukcije črevesja morajo biti običajno večji od 2,5 cm. Gallbladder stones may ulcerate through the gall bladder into the duodenum and pass down the small bowel. Stones that cause mechanical small bowel obstruction are usually larger than 2.5 cm. Izraz biliarni ileus je prvič uporabil Bartolin leta 1654 v povezavi z mehansko obstrukcijo črevesja, ki je nastala zaradi zagozditve enega ali več žolčnih kamnov v gastrointestinalnem traktu. The term gallstone ileus was first coined by Bartolin in 1654 and referred to the mechanical intestinal obstruction due to impaction of one or more large gallstones within the gastrointestinal tract. Kronično draženje in konzervativno zdravljenje akutnih zagonov holecistitisa privedeta ob dekubitusu stene postopno do razvoja notranje biliarne fistule v prebavni trakt. Chronic irritation and conservative treatment of acute cholecystitis, together with decubitus of the wall, gradually lead to the development of internal biliary fistula in the digestive tract. V primeru zagozditve kamna v duodenumu ali pilorusu govorimo o Bouveretovem sindromu, ki ga je prvi opisal francoski internist Leon Bouveret leta 1896. A gastric outlet obstruction secondary to an impacted gallstone in the duodenum or pylorus is called Bouveret syndrome (it was first described in 1896 by the French internist Leon Bouveret). Postavitev diagnoze biliarnega ileusa je težka, po navadi temelji na rentgenoloških ugotovitvah. Riglerjeva triada, ki jo sestavljajo pnevmobilija, The diagnosis of biliary ileus is difficult, usually depending on the radiographic findings. The Rigler’s triad includes pneumobilia, ectopic radio- * Miroslav Vujasinović, MD MSc Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1 Slovenj Gradec 2380, Slovenia GASTROENTEROLOG 159 ektopičen radiopačen kamen in črevesna napihnjenost, je diagnostična najdba za biliarni ileus v primeru, ko sta prisotna vsaj dva od treh kriterijev. CT abdomna s kontrastom je postal najpomembnejši način diagnostike biliarnega ileusa zaradi njegove dobre ločljivosti. Vidimo lahko črevesne vijuge in prisotnost kamnov v črevesju, brez motenj s strani kosti ali zraka v črevesju. Zaradi nizke pojavnosti tega stanja ni enotnega mnenja kakšen kirurški poseg je najboljši za zdravljenje. Optimalno kirurško zdravljenje je ena operacija v eni fazi, sestavljena iz enterotomije, holecistektomije in poprave oz. zapore fistule. V primerih visoko rizičnih pacientov pa se naredi le enterotomija z odstranitvijo kamna. Prikazana sta dva primera biliarnega ileusa. 160 GASTROENTEROLOG opaque gallstone, and intestinal distention, and is considered diagnostic for biliary ileus when two of the three criteria are present. Abdominal contrast enhance computed tomography becomes the most important modality in diagnosing biliary ileus because the visibility of bowel loops and gallstone within the loops is not obscured with bones and air in the loops. There is no uniform surgical procedure for this disease because of its low incidence. Optimal surgical treatment is one stage procedure: cholecystectomy, fistula repair and enterotomy with removal of impacted stone or just an enterotomy with stone removal in high risk patients. We describe two cases of biliary ileus. Seroprevalenca celiakije pri bolnikih s sladkorno boleznijo tipa 1 Seroprevalence of celiac disease among patients with type 1 diabetes mellitus Betka Popič*,1, Miroslav Vujasinović1, Jelka Zaletel2, Jana Makuc1, Metka Epšek Lenart1, Marjana Predikaka1, Bojan Tepeš3 1 Department of Internal Medicine; Slovenj Gradec General Hospital 2 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana 3 Abakus Medico Diagnostic Centre Gastroenterolog 2013; suplement 2: 161–162 UVOD BACKGROUND Celiakija (CD) je sistemska, imunsko pogojena bolezen, ki jo sproži zaužit gluten pri genetsko dovzetnih osebah. Prizadane 0,6–1,0 % svetovne populacije. Prevalenca pri odraslih je znotraj posameznih evropskih držav zelo različna, kar ni povsem pojasnjeno. Bolezen se najpogosteje kaže s kronično drisko, hujšanjem in meteorizmom Coeliac disease (CD) is a systemic immune-mediated disorder triggered by dietary gluten in genetically susceptible persons. It affects 0.6 to 1.0 % of the population worldwide. Prevalence shows large unexplained differences in adult age across different European countries. Frequent symptoms and signs include chronic diarrhea, weight loss, and abdominal distention. CD is one of the most frequent autoimmune disorders occurring in type 1 diabetes mellitus (T1DM). HLA class II molecules DQ2 and DQ8 have been identified as key genetic risk factors in both diseases. The prevalence of CD in T1DM varies in different studies - from 2.6 % to 13.8 %. It is well accepted that much CD remains undiagnosed in the community. CD je ena najpogostejših avtoimunskih bolezeni, ki se pojavljajo pri sladkorni bolezni tipa 1 (SB1). Obe bolezni sta povezani z nekaterimi HLA (human leukocyte antigen) aleli in sicer HLA DQ2 in HLA DQ8. Prevalenca CD pri bolnikih s SB1 je po podatkih različnih študij od 2,6-13,8 %. Znano je, da velik del CD ostaja neodkrit. * Betka Popič, MD Department of Internal Medicine; Slovenj Gradec General Hospital, Gosposvetska 1 2380 Slovenj Gradec, Slovenia GASTROENTEROLOG 161 CILJI IN METODE AIMS/METHODS Cilj študije je bil določiti seroprevalenco CD pri naših bolnikih s SB1. V raziskavo smo vključili 44 zapovrstnih bolnikov z znano SB1. Določili smo serumska IgA protitelesa proti tkivni transglutaminazi (IgAtTg). Pridobljene podatke prikazujemo številčno (procenti) oziroma s srednjo vrednostjo ± standardna deviacija. The aim of our study was to determine seroprevalence of CD among our patients with T1DM. Fourty four eligible consequtive patients with T1DM were included in the study. Diagnosis of T1DM was established from health records. Diagnosis of CD was established by IgA tissue transglutaminase antibodies (IgAtTg). Data are shown as numerous ( %) and mean ± standard deviation. REZULTATI 44 preiskovancev z znano SB1 smo testirali na IgAtTg, od tega 20 (45,5 %) žensk in 24 (54,5 %) moških. Starost bolnikov je bila 47,3±12,5 let, trajanje SB1 pa 26,2±9.0 let. Seropozitivni so bili trije bolniki (6,8 %), dva moška in ena ženska. Moška sta bila stara 27 in 30, ženska pa 38 let. Vsi trije pacienti so zavrnili nadaljnjo diagnostiko (gastroduodenoskopijo z biopsijo in genetsko testiranje). ZAKLJUČEK Raziskava je potrdila visoko prevalenco CD pri odraslih bolnikih s SB1 (6–7- krat pogosteje, kot pri ostali populaciji). Naši rezultati so primerljivi z izsledki podobnih študij iz drugih držav. V visokorizičnih skupinah, kot so pacienti s SB1, bi bilo smiselno aktivno iskati neprepoznano CD. 162 GASTROENTEROLOG RESULTS Fourty four adults with T1DM have been screened for CD. There were 20 (45,5 %) female and 24 (54,5 %) male, mean age 47,3 ± 12,5 years. Mean time of DM duration was 26,2 ± 9,0 years. Three patients (two male and one female) had positive IgAtTg (6,8 %). Males were 27 and 30 years old and female was 38 years old. All three patients declined additional diagnostic methods (gastroduodenoscopy with biopsies and genetic testing). CONCLUSION Study confirmed a high prevalence of CD in adult patients with T1DM (6-7 times more frequent than in general population). Our data is comparable with results of similar studies around the world. Therefore, a strategy of case finding among highrisk populations, such as patients with T1DM may be an effective way to identify unrecognized CD. Eksokrina insuficienca pankreasa pri bolnikih s sladkorno boleznijo Exocrine pancreatic insufficiency in patients with diabetes mellitus Miroslav Vujasinović*,1, Jelka Zaletel2, Bojan Tepeš3, Betka Popič1, Jana Makuc1, Metka Epšek Lenart1, Marjana Predikaka1, Saša Rudolf4 1 Department of Internal Medicine; Slovenj Gradec General Hospital 2 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana 3 Abakus Medico Diagnostic Centre Rogaska 4 Department of Radiology, University Medical Centre Maribor Gastroenterolog 2013; suplement 2: 163–164 Key words: exocrine, pancreatic, insufficiency, diabetes mellitus, fecal elastase-1 UVOD INTRODUCTION Pri bolnikih s sladkorno boleznijo (SB) se lahko pojavi eksokrina insuficienca pankreasa (EPI). Tako pogostost EPI kot njena klinična pomembnost ostajata sporni. Cilj študije je bil določiti, ali je pri bolnikih s SB prisotna EPI. Exocrine pancreatic insufficiency (EPI) can occur in patients with diabetes mellitus (DM). Incidence of EPI and its clinical significance remain poorly defined. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with DM. BOLNIKI IN METODE V raziskavo smo vključili 150 zapovrstnih bolnikov z več kot 5 let trajajočo SB in sicer 50 bolnikov s SB tipa 1, 50 bolnikov s SB tipa 2, ki se zdravijo z inzulinom ter 50 bolnikov s SB tipa 2 na peroralni antidiabetični terapiji. Starost preiskovancev je bila 59,0±12,0 let, trajanje SB pa 15,0±9,9 let. EPI smo definirali kot koncentracijo elastaze-1 v blatu (E1) pod 200 μg/g (ELISA metoda). PATIENTS AND METHODS One hundred and fifty consecutive patients, mean age 59.0 (±12.0 years), with DM lasting at least 5 years were included in the study. We included 50 patients with type 1 DM (DM1), 50 insulin-treated patients DM type 2 (DM2-ins) and 50 non-insulin treated patients with DM type 2 (DM2-non-ins). Diagnosis of DM was established from health records, lasting 15.0±9.9 years on average. EPI was diagnosed with a fecal elastase-1 concentration (FE1) of less than 200 μg/g (ELISA). * Corresponding author: Miroslav Vujasinović, MD MSc Slovenj Gradec General Hospital, Department of Internal Medicine, Gosposvetska 1, 2380 Slovenj Gradec, Slovenia Phone: +386 2 8823 400, Fax: +386 2 8823 505 GASTROENTEROLOG 163 REZULTATI RESULTS E1 je bila znižana pri 8 bolnikih (5,4 %): pri 4 (2,7 %) blago (100–200 μg/g) in pri 4 (2,7 %) pomembno znižana (<100 μg/g). V skupini bolnikov s SB tipa 1 je bila EPI prisotna pri treh, v skupini s SB tipa 2, ki se zdravijo z insulinom pri petih bolnikih. V skupini bolnikov s SB tipa 2 na peroralni terapiji EPI nismo dokazali pri nobenem preiskovancu. FE1 was reduced in 8 (5.4%) patients: mildly reduced (100–200 μg/g) in 4 patients (2.7%) and markedly reduced (< 100 μg/g) in 4 patients (2.7%). Frequency of EPI was 3 in DM1, 5 in DM2-ins and none in DM2-non-ins groups. ZAKLJUČEK EPI in DM occured less frequently than in previous studies, probably due to our strict exclusion criteria (age, alcohol intake). However, these results may have an impact on the daily work of clinicians from different fields of medicine (gastroenterology, diabetology and general practice). Follow-up of patients with DM should also include the evaluation of exocrine pancreatic function. EPI se pri naših bolnikih s SB pojavlja redkeje, kot je bilo opisovano v prejšnjih študijah, najverjetneje zaradi strogih izključitvenih kriterijev (starost, vnos alkohola). Kljub temu imajo rezultati lahko pomemben klinični vpliv pri vsakdanjem delu različnih specialistov (gastroenterologi, diabetologi, specialisti družinske medicine). Spremljanje pacientov s SB bi moralo vsebovati tudi oceno tveganja za EPI. 164 GASTROENTEROLOG CONCLUSIONS Eksokrina insuficienca pankreasa pri bolnikih s celiakijo Exocrine pancreatic insufficiency in patients with celiac disease Miroslav Vujasinović*,1, Bojan Tepeš2, Saša Rudolf3 1 Department of Internal Medicine; Slovenj Gradec General Hospital 2 Abakus Medico Diagnostic Centre 3 Department of Radiology, University Medical Centre Maribor Gastroenterolog 2013; suplement 2: 165–166 UVOD INTRODUCTION Povezava med celiakijo (CD) in eksokrino insuficienco pakreasa (EPI) je bila prvič opisana leta 1957. Od takrat je bilo z različnimi diagnostičnimi metodami opravljenih mnogo raziskav. Cilj študije je bil ugotoviti, ali je pri naših bolnikih s CD prisotna EPI. Prikazujemo prve podatke. Since 1957 when it was first reported the association between celiac disease (CD) and exocrine pancreatic insufficiency (EPI) was a topic of many researches in which different diagnostic methods were used. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with CD in our population. We are presenting preliminary results. BOLNIKI IN METODE Eksokrino funkcijo pankreasa smo določili s koncentacijo elastaze-1 v blatu (E1). Blago insuficienco smo definirali pri koncentraciji E1 < 200μg/g, pomembno pa pri koncentraciji <100 μg/g. Diagnozo CD smo postavili z določitvijo IgA protiteles proti tkivni transglutaminazi (IgAtTg) v serumu in potrdili z odvzemom biopsije iz dvanajstnika. Preiskovance smo razdelili v tri skupine: A – novoodkrita CD; B – bolniki z znano CD na brezglutenski dieti; C – bolniki z znano CD na normalni prehrani (zavračajo dieto). Pridobljene podatke prikazujemo številčno (procenti) oziroma s srednjo vrednostjo ± standardna deviacija. PATIENTS AND METHODS Pancreatic exocrine function was determined by the fecal elastase-1 concentration (FEC) and insufficiency was classified as moderately (FEC < 200 μg/g) or severely impaired (FEC < 100 μg/g). CD was diagnosed by serologic testing using IgA anti tissue transglutaminase antibody (IgAtTg) and small bowel biopsy using Marsh classification. Patients were divided into three groups: A - newly diagnosed CD; B - known CD patients on a gluten-free diet (GFD) and C - patients with known CD on a normal diet (those who refused medical advice). Data are shown as numerous ( %) and mean±standard deviation. * Miroslav Vujasinović, MD MSc Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1 Slovenj Gradec 2380, Slovenia GASTROENTEROLOG 165 REZULTATI RESULTS Trenutno je v raziskavo vključenih 46 bolnikov, 34 žensk (73,9 %) in 12 moških (26,1 %). Starost preiskovancev je 44,4±17,0 let (od 20 – 76), trajanje CD pa 5,8±7,8 let. 13 bolnikov (28,3 %) je po klasifikaciji po Marshu razvrščenih v tip 3; 9 (19,5 %) v tip 2; 8 bolnikov (17,4 %) v tip 1; 16 pa je po Marshu nerazvrščenih (ni podatka o histologiji v medicinski dokumentaciji). Pri večini vključenih preiskovancev (n=37; 80,4 %) gre za znano CD na brezglutenski dieti, manj je novoodkritih (n=5; 10,9 %), najmanj pa tistih, pri katerih je CD že znana, a zavračajo dieto (n=4; 8,7 %). E1 je bila znižana pri dveh bolnikih (4,35 %): zmerno znižana (E1 131 μg/g) pri 69 – letnemu moškemu z novoodkrito CD Marsh 1 in pomembno znižana (E1 63 μg/g) pri 24 – letni ženski z znano CD Marsh 3 na brezglutenski dieti. There are currently 46 patients included in the study, 34 (73.9 %) female and 12 (26.1 %) male, mean age 44.4±17,0 years (range 20-76). Mean duration of CD was 5.8±7.8 years. There were 13 (28.3 %) patients with Marsh 3 CD; 9 (19.5 %) patients with Marsh 2 CD; 8 (17.4 %) patients with Marsh 1CD and 16 (34.8 %) Marsh non-classified patients (no histology data in medical records). The majority of patients had known CD on GFD (n=37; 80.4 %) followed by newly diagnosed CD (n=5; 10.9 %) and known CD without GFD (n=4; 8.7 %). FEC was reduced in 2 (4.35 %) patients: moderately reduced (FEC 131 μg/g) in 69– year-old male with newly diagnosed CD Marsh 1 and severely reduced (FEC 63 μg/g) in 24–year-old female with known CD Marsh 3 on GFD. CONCLUSIONS ZAKLJUČEK EPI se pri naših bolnikih pojavlja redkeje, kot je bilo opisovano v prejšnjih študijah. Kljub temu imajo rezultati lahko pomemben klinični vpliv. Spremljanje pacientov s CD bi moralo vsebovati tudi oceno eksokrine funkcije pankreasa. 166 GASTROENTEROLOG EPI occurred much less frequently than in previous studies. However, these results may have an impact on the daily work of the clinician. Routine follow-up of patients with CD should include evaluation of pancreatic exocrine function. Eksokrina in endokrina insuficienca pankreasa po akutnem pankreatitisu Exocrine and endocrine pancreatic insufficiency after acute pancreatitis Miroslav Vujasinović*,1, Bojan Tepeš2, Jana Makuc1, Jelka Zaletel3, Tjaša Vidmar1, Saša Rudolf4 1 Department of Internal Medicine; Slovenj Gradec General Hospital 2 Abakus Medico Diagnostic Centre 3 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana 4 Department of Radiology, University Medical Centre Maribor Gastroenterolog 2013; suplement 2: 167–169 UVOD INTRODUCTION Eksokrina insuficienca pankreasa (EIP) in sladkorna bolezen tipa 3c (SBt3c) se lahko pojavita pri bolnikih po prebolelem akutnem pankreatitisu (AP). Incidenca EIP in SBt3c ter njuna klinična pomembnost ostajata sporni. V prispevku predstavljamo preliminarne rezultate opravljene študije. Exocrine pancreatic insufficiency (EPI) and type 3c diabetes mellitus (T3cDM) can occur in patients after acute pancreatitis (AP). Incidence of EPI and T3cDM and clinical significance of both remains controversial. We are presenting preliminary results of our study. PATIENTS AND METHODS BOLNIKI IN METODE Namen raziskave je bil ugotoviti, ali sta eksokrina in endokrina funkcija pri bolnikih po prebolelem AP okvarjeni in oceniti njuno povezavo z etiologijo ter resnostjo AP. Ocena eksokrine funkcije pankreasa je temeljila na koncentraciji fekalne elastaze-1 (KFE) in je bila klasificirana kot zmerno (KFE < 200 μg/g) ali hudo (KFE < 100 μg/g) znižana. Endokrina funkcija pankreasa pa je bila ocenjena po kriterijih Diabetološkega združenja Slovenije, ki so skladni s kriteriji SZO. Stopnja resnosti in morfologija AP sta bili določeni po revidirani Atlanta klasifikaciji in definicijah mednarodnega konsenza 2012. Podatki so prikazani numerično ( %) in kot povprečje±standarna deviacija. The aim of the study was to determine whether exocrine and endocrine pancreatic function are impaired in patients after AP and to evaluate its relationship to etiology and severity of AP. Pancreatic exocrine function was determined by the fecal elastase1 concentration (FEC) and insufficiency was classified as moderately (FEC < 200 μg/g) or severely impaired (FEC < 100 μg/g). Pancreatic endocrine function was determined by Slovenian Society for Diabetes criteria which are in accordance with World Health Organization criteria in patients without prior DM. The severity and morphology of AP were determined by a revised Atlanta classification and definitions by international consensus 2012. Data are shown as numerous (%) and mean±standard deviation. * Miroslav Vujasinović, MD MSc Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1 Slovenj Gradec 2380, Slovenia GASTROENTEROLOG 167 REZULTATI RESULTS Trenutno je vključenih 55 bolnikov; 36 (65,5 %) moških in 19 (34,5 %) žensk, povprečna starost je 56,3±13,4 let. There are currently included 55 patients; 36 (65.5%) men and 19 (34.5 %) women, mean age 56.3±13.4 years. Najpogostejša vzroka AP sta bila alkohol (n=22; 40 %) in žolčni kamni (n=22; 40 %), sledijo nepojasnjeni AP (n=6; 10,9 %), AP zaradi hipertrigliceridemije (n=3; 5,5 %) in z zdravili povzročeni AP (n=2; 3,6 %). Most common etiologies of AP were alcohol (n=22; 40 %) and gallstones (n=22; 40 %), followed by unexplained (n=6; 10.9 %), hypertriglyceridemia (n=3; 5.5 %) and drug-induced (n=2; 3.6 %). Mean followup after attack was 2.8±4.9 years (range 1-20 years). Povprečen čas sledenja po AP je bil 2,8±4,9 let (obdobje 1–20 let). There are 43 (78.2 %) patients after one attack and 12 (21.8 %) after two or more attacks. 43 (78,2 %) bolnikov je prebolelo eno epizodo AP in 12 (21,8 %) dve ali več. In 34 (61.8 %) patients the clinical course of AP was mild; in 13 (23.6 %) moderately severe and in 8 (14.6 %) severe. Pri 34 (61,8 %) bolnikih je bil klinični potek blag ; pri 13 (23,6 %) zmerno hudo ter pri 8 (14.6 %) hudo potekajoč. FEC was reduced in 9 (16.4 %) patients: in 2 patients moderately reduced (100-200 μg/g) and in 7 patients severely reduced (< 100 μg/g). KFE je bila zmanjšana pri 9 (16,4 %) bolnikih: pri 2 bolnikih zmerno (100–200 μg/g) in pri 7 bolnikih močno zmanjšana (< 100 μg/g). T3cDM was present in 7 (12.7 %) patients (2 of them had both EIP and T3cDM). SBt3c je bila prisotna pri 7 (12,7 %) bolnikih (2 od njih sta imela tako EIP kot SBt3c). EIP was present in 9 patients: in 2 after severe AP; in 3 after moderately severe AP and in 4 after mild AP. EIP je bila prisotna pri 9 bolnikih: pri 2 po hudem AP, pri 3 po zmerno hudem AP in pri 4 po blagem AP. T3cDM was present in 7 patients: in 2 after severe AP; in 1 after moderately severe AP and in four after mild AP. SBt3c je bila prisotna pri 7 bolnikih: pri 2 po hudem AP, pri 1 po zmerno hudem AP in pri 4 po blagem AP. EIP je bila najpogostejša pri bolnikih z alkoholno etiologijo AP (7 od 9), sledijo žolčni kamni (2 od 9). SBt3c je bila prisotna pri 3 bolnikih z žolčnimi kamni, 2 bolnikih z alkoholno in 2 bolnikih z hiperlipemično etiologijo. 168 GASTROENTEROLOG EPI was more common in patients with alcoholic etiology (7 out of 9) followed by gallstone etiology (2 out of 9). T3cDM was present in 3 patients with gallstone, 2 patients with alcohol and 2 patients with hyperlipemic etiology. ZAKLJUČKI CONCLUSIONS EIP in SBt3c sta se pojavljala mnogo redkeje kot v prejšnjih študijah. EPI and T3cDM occurred much less frequently than in previous studies. EIP je pogostejša pri bolnikih z alkoholno etiologijo AP. EPI is more common in patients with alcoholic etiology of AP. SBt3c ni povezana s specifično etiologijo AP. T3cDM is not related to specific etiology of AP. Dosedaj nismo odkrili povezave med stopnjo AP, EIP ter SBt3c. Kljub temu bi rezultati študije lahko imeli vpliv na vsakodnevno delo zdravnikov v različnih vejah medicine (gastroenterologija, diabetologija, družinska medicina). So far we have not found an association between severity of AP, EIP and T3cDM. Sledenje bolnikov po AP bi moralo vključevati oceno eksokrine in endokrine funkcije pankreasa. However, these results may have an impact on the daily work of the clinician in different fields of medicine (gastroenterology, diabetology and general practice). Follow-up of patients after AP should include evaluation of pancreatic exocrine and endocrine function. GASTROENTEROLOG 169 Helicobacter pylori eradication rate in carinthian region of Slovenia, 2011–2012 Miroslav Vujasinović*,1, Nace Robač1, Samo Jeverica2, Urša Dolinar2, Bojan Tepeš3 1 Department of Internal Medicine, Slovenj Gradec General Hospital 2 Institute for Microbiology and Immunology, Medical Faculty Ljubljana 3 Abakus Medico Diagnostic Centre Rogaška Gastroenterolog 2013; suplement 2: 170 BACKGROUNDS Antimicrobial resistance is the leading cause for the treatment failure of Helicobacter pylori (HP) infection. In the majority of countries including Slovenia the eradication rate of primary therapy is below 80%. So far, we didn’t have any data about HP eradication rate in Carinthian region on the North-East of Slovenia. METHODS Retrospective analysis of all patients who underwent eradication treatment for HP infection in Slovenj Gradec General Hospital from 2011 to 2012 was performed. Demographic characteristics of patients and eradication rates after different antimicrobial treatment regimens were analysed. Secondary resistance to antimicrobial agents was calculated from all cases where antimicrobial susceptibility testing was performed. RESULTS Total of 324 patients were included in the analysis: 60.2% (n=195) female and 39.8% (n=129) male, mean age 52.1±15.2 years). 7-days triple therapy with proton pump inhibitor (PPI), amoxicillin and clarithromycin (PAC) was prescribed in 87.7% (n=284) of patients as the first-line treatment, 11,7% (n=38) of patients received 7-days triple therapy with PPI, amoxicillin and metronidazole (PAM) and 0,6% (n=2) of patients received 7-days triple therapy with PPI, clarithromycin and metronidazole (PCM). The eradication rate with the first-line therapy was 70,7% intention to treat (ITT) analysis and 70,9% per protocol (PP) analysis. Cumulative eradication rate for up to four lines of therapy was 89,9% ITT analysis and 99,7% PP analysis. Culture and sensitivity was performed in 16,4% (n=53) of patients. Secondary resistance rates for clarithromycin, metronidazole, levofloxacin, amoxicillin and tetracycline among patients after treatment failure were 84,6%, 70,0%, 7,7%, 2,5% and 0,0%, respectively. CONCLUSIONS The eradication rate of the first-line therapy is critically low. However, cumulative eradication rate is still high, but below the eradication rate in Slovenia reported in previous studies. Optimization of the treatment strategies for the HP eradication is needed. Systematic surveillance of antimicrobial resistance of HP is mandatory. * Miroslav Vujasinović, MD MSc Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1 Slovenj Gradec 2380, Slovenia 170 GASTROENTEROLOG Is adherence of guidelines in treatment of patients with celiac disease satisfactory? Miroslav Vujasinović* Department of Internal Medicine, Slovenj Gradec General Hospital Gastroenterolog 2013; suplement 2: 171–172 BACKGROUND Celiac disease (CD) is a common autoimmune disorder with a prevalence of 1% in western population. Patients affected by CD should be treated and followed-up by a multidisciplinary team. betes mellitus, connective tissue diseases, microscopic colitis, changes in bone mineral density, skin disorders, pancreatic exocrine insufficiency, liver diseases, neurologic diseases), access to an advocacy group and screening of family members. RESULTS PATIENTS AND METHODS To determine adherence to treatment of patients with CD according to international recommendations: guidelines on the recognition and assessment of CD in children and adults from the British National Institute for Health and Clinical Excellence in 2009 (1), the American Gastroenterological Association 2006 guidelines for the diagnosis and management of celiac disease (2) and Up To Date recomendations on management of CD in adults (3). Medical documentation of 28 consecutive patients (all Slovene, Caucasians) with confirmed CD was analyzed. The following data were determined: monitoring the response to a gluten-free diet (GFD) with serologic testing, consultation with a skilled dietitian including education about the disease, identification and treatment of nutritional deficiencies (iron, calcium, phosphorus, folate, vitamin B12, vitamin D), screening for concomitant diseases (autoimmune thyroid disease, lactose intolerance, type 1 dia- There were 28 patients: 19 (67,9%) female and 9 (32,1%) male, mean age 39,6 ±16,2 years (range 18–69). Mean time from diagnosis of CD was 6,3 ±3,5 years (range 1–23). All patients were monitoring the response to a gluten-free diet with serologic testing: 4 patients (14,3%) had positive IgA tissue transglutaminase (TTG) due to the non-compliance. All compliant patients on GFD (24 out of 28 = 85,7%) are in remission (without gastrointestinal symptoms). Twenty-three patients (82,1%) had consultation with a skilled dietitian including education about the disease. Nutritional deficiencies were found in following percentages: iron deficiency in 6 (21,4%) patients, vita- * Miroslav Vujasinović, MD MSc Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1 Slovenj Gradec 2380, Slovenia GASTROENTEROLOG 171 min D deficiency in 22 (78,5%) patients, calcium deficiency in 1 (3,5%) patient and folate deficiency in 2 (7,1%) patients. Concomitant diseases were found in following percentages: lactose intolerance in 16 (57,1%), microscopic colitis in 2 (7,1%) patients, Hashimoto thyroiditis in 2 (7,1%) patients, pancreatic exocrine insufficiency in 2 (7,1%) patients, skin disorders in 5 (17,8%) patients and osteopenia/osteoporosis in 3 (37,5%) patients (dual-energy X-ray absorptiometry was performed in only 8 patients). All patients were advised to join the support group (Slovene Celiac Society). Screening of family members were advised in all patients and CD was found in close relatives in 6 families (21,4%). 172 GASTROENTEROLOG CONCLUSIONS Vitamin D defficiency is most common nutritional defficiency in patients with CD. Lactose intolerance is most common concomitant disease in patients with CD. All patients with good compliance (on GFD) are currently without gastrointestinal complaints. Adherence to the international guidelines is satisfactory. REFERENCES 1. National Institutes of Health Consensus Development Conference Statement. Celiac Disease 2004. Available at: http://consensus.nih.gov/ (accessed on April 17, 2013). 2. AGA Institute. AGA Institute Medical Position Statement on the Diagnosis and Management of Celiac Disease. Gastroenterology 2006; 131:1977–80. 3. Ciclitira PJ. Management of celiac disease in adults. In: UpToDate, Basow DS (edit), UpTodate, Waltham, MA, 2013 In Slovenian patients with primary biliary cirrhosis genetic polymorphism of glutation s-transferase (GSTP1) contribute to higher prevalence of concomitant autoimmune thyroid disease Katja Novak*,1, Katja Zaletel2, Vita Dolžan3, Aleksandra Markovič1 1 University Clinical Center Ljubljana, Division of Internal Medicine, Clinical Dep. for Gastroenterology 2 University Clinical Center Ljubljana, Department of Nuclear Medicine, Dep. for Thyroid diseases 3 University of Ljubljana, Faculty of Medicine, Institute of Biochemistry, Pharmacogenetics Laboratory Gastroenterolog 2013; suplement 2: 173–174 AIM OF STUDY METHODS Glutathione S-transferases (GST) are a large family of isoenzymes that catalyse conjugation reactions of reduced glutathione. However GST-mu 1 (GSTM1), GST-theta 1 (GSTT1) and GST-pi l (GSTP1) also play an important role in cellular protection against damage caused by reactive oxygen species. Genetic polymorphisms of genes coding for these enzymes alter enzyme activity by reducing antioxidant defense mechanisms, which are known to contribute to the pathogenesis of many autoimmune diseases. Primary billiary cirrhosis (PBC) is a rare autoimmune liver disease, characterized by progressive destruction of small intra-hepatic bile ducts and gradual development of billiary cirrhosis. PBC is frequently associated with autoimmune thyroid disease (AITD), which reportedly affects 15 to 25 percent of patients with PBC. The aim of our research was to determine the influence of GSTM1, GSTT1 and GSTP1 polymorphisms on concomitant AITD in Slovenian PBC patients. The study population consisted of 92 patients (91 females and 1 male) with PBC. All the patients were examined for the presence of thyroid disease. AITD was diagnosed in patients with positive specific thyroid autoantibodies and with characteristic hypoechoic ultrasound pattern. Polymorphic GSTM1 and GSTT1 genes deletions (null alleles) were identified using multiplex PCR. Both genes were simultaneously amplified in a single-step PCR reaction together with the beta-globin gene as the internal positive control and PCR products were visualized on a 2% agarose gel stained with ethidium bromide. Custom TaqMan SNP genotyping assays were used to determine GSTP1 Ile105Val and Ala114Val polymorphisms. Statistical analysis (Pearson Chi-Square, Fisher’s Exact Test, Odds Ratio, 95% Confidence Interval) were performed using IBM SPSS Statistics version 20.0. * Katja Novak University Clinical Center Ljubljana, Division of Internal Medicine, Clinical Dep. for Gastroenterology, Japljeva 2, 1000 Lubljana, Slovenia GASTROENTEROLOG 173 RESULTS CONCLUSIONS Among 92 PBC patients AITD was confirmed in 30 (32.6%) and excluded in 62 (67.4%). GSTM1 null and GSTT1 null allele and GSTP1 Ala114Val frequency distribution did not differ between PBC patients with and without concomitant AITD. GSTP1 Ile105Val genotype distribution significantly differed between PBC patients with and withouth concomitant AITD (Pearson p=0.007). In particular, PBC patients with homozygous GSTP1 105Val/105Val genotype had significantly higher risk for concomitant AITD (Pearson p=0,005, Fisher p=0.010, OR=8.500, 95% CI=1.571-45.979). (Table 1). Our results suggest that the presence of GSTP1 105Val allele may contribute to higher prevalence of AITD in PBC patients. 174 GASTROENTEROLOG Permeabilnostni indeks pri bolnikih s celiakijo Permeability index in celiac disease patients R. Janša*,1, J. Tišler-Štuflek2, G. Novak1, J. Osredkar2 1 University Medical Centre Ljubljana, Division of Internal Medicine, Department of Gastroenterology Univerzitetni klinični center Ljubljana, Klinični oddelek za gastroenterologijo 2 University Medical Centre Ljubljana, Clinical Institute of Clinical Chemistry and Biochemistry Univerzitetni klinični center Ljubljana, Klinični inštitut za klinično kemijo in biokemijo Gastroenterolog 2013; suplement 2: 175–176 Glavna funkcija tankega črevesja je prebava črevesne vsebine, absorpcija hranil in elektrolitov ter vzdrževanje vodne homeostaze. Tanko črevo ima zelo pomembno vlogo kot pregrada med človeškim organizmom in zunanjim okoljem. Mehanizem pregrade omogoča selektivno prepustnost za makromolekul. Nekatere bolezni imajo pomemben vpliv na celovitost tankega črevesja, tako se ta razlikuje, če primerjamo zdravo populacijo z bolniki s celiakijo. Zaradi izravnave črevesne sluznice in sprememb tesnih stikov med enterociti kot posledice vnetja, imajo ljudje s celiakijo običajno višje vrednosti permeabilnostnega indeksa v urinu. Višje vrednosti so posledica večje absorbcije laktuloze zaradi sprememb tesnih stikov med eritrociti in šibke absorpcije manitola zaradi izravnave sluznice. The primary function of the small intestine is the digestion of the intestinal contents, the absorption of nutrients and electrolytes and water homeostasis maintenance. However, small intestine has a very important role as a barrier between the human organism and the external environment. The mechanism of the barrier enables selective permeability for some macromolecules. Some diseases have an important influence on small intestine's integrity. The small intestine's integrity differs when comparing healthy people and people with Coeliac disease. Due to the intestinal mucosa level off and changes of tight junctions among enterocytes as a result of the inflammation, people with Coeliac disease express typically higher values of the permeability index in the urine. The higher values are the result of the intensively absorbed lactulose through modification in tight junctions among enterocytes and a weak absorption of mannitol due to the level off of intestinal mucosa. * R. Janša University Medical Centre Ljubljana, Division of Internal Medicine, Department of Gastroenterology Zaloška cesta 2, 1000 Ljubljana, Slovenia; GASTROENTEROLOG 175 METODE METHODS Permeabilnostni indeks je predlog za novo metodo, ki temelji na prepustnost tankega črevesa za dve molekuli različnih velikosti: manjše molekule manitola in večje molekule laktuloze. Naša skupina je bila sestavljena iz 10 bolnikov in 10 kontrol. Merili smo koncentracijo sladkorja v peturnem vzorcu urina po popitju raztopine, ki je vsebovala laktulozo in manitol. Permeabilnostni indeks je kvocient med koncentracijo laktuloze in manitola v urinu. Laktulozo in manitol v urinu smo merili z absorpcijsko spektroskopijo. The permeability index is a suggestion for a new method, based on small intestine's permeability for the two molecules of different sizes: the smaller molecule mannitol and the larger molecule lactulose. Our group consisted of 10 patients and 10 controls. We measured the concentration of sugars in fivehour urine samples after drinking a solution containing lactulose and mannitol. The permeability index is the quotient of the lactulose and mannitol concentrations. The principle of the detection of lactulose and mannitol in the urine was absorption spectroscopy. REZULTATI Raziskava je pokazala, da so vrednosti permeabilnostnnega indeksa signifikantno razlikujejo med obema skupinama. Specifičnost metode je 100 % in občutljivost 60 %. Vrednost AUC pri ROC krivulji je 0,990. ZAKLJUČKI Študija dokazuje, da je permeabilnostni indeks primerni marker prepustnosti tankega črevesja pri ljudeh s celiakijo. Spremenjena prepustnost za makromolekule je posledica sprememb v Zonulinski proteinski frakciji tesnih stikov in izravnavi vnete intestinalne sluznice. Kljub malemu vzorcu je možno zaključiti, da je permeabilnostni indeks pomemben potencialni diagnostični test pri bolnikih s celiakijo. 176 GASTROENTEROLOG RESULTS The study shows that the values of the permeability index significantly differ between the two groups of the people. We assessed the diagnostic value (specificity, sensitivity) of the test and compared the results between groups with the ROC curve. The specificity of the method was 100 % and the sensitivity 60 %. The AUC value is 0,990. CONCLUSIONS The study proves that the permeability index is an appropriate marker of the small intestine’s permeability when it comes to people with Coeliac disease. Different permeability is the consequence of changes in Zonulin protein fraction of tight junctions and result is different permeability for macromolecules. Despite the small samples of the study it can be concluded that the permeability index is an important potential diagnostic test when it comes to people with Coeliac disease. Z liraglutidom povzročen akutni pankreatitis Liraglutide-induced acute pancreatitis Betka Popič1, Karmen Klančnik2, Miroslav Vujasinović1 1 Department of Internal Medicine, Slovenj Gradec General Hospital 2 Medical Faculty at the University of Maribor Gastroenterolog 2013; suplement 2: 177–178 UVOD INTRODUCTION Zdravila so redko vzrok akutnega pankreatitisa (AP). Povzročijo ga le v 0,1-2 % primerov. Liraglutid je sintetični analog humanega glukagonu podobnega peptida-1 (GLP-1), katerega uporabljamo za zdravljenje sladkorne bolezni tipa 2. Razvščamo ga v skupino agonistov receptorjev GLP-1. Apliciramo ga podkožno enkrat dnevno. Klinične študije so pokazale možno povezavo med GLP-1 analogi in nastankom AP. Prikazujemo primer z liraglutidom povzročenega AP. Drug-induced acute pancreatitis (AP) is not common. It has been estimated that only 0,1-2 % of all cases are drug-induced. Liraglutide is synthetic analogue of human glucagon-like peptide-1 (GLP-1) for treating type 2 diabetes mellitus. It is classified as a GLP-1 receptor agonist, developed for once-daily subcutaneous administration. A possible association between GLP-1 analogues and AP has been suggested. PRIKAZ PRIMERA CASE SUMMARY 50-letna ženska z znano sladkorno boleznijo tipa 2 je bila sprejeta na Oddelek za interno medicino zaradi tri dni trajajoče bolečine v trebuhu. Teden dni pred sprejemom smo uvedli liraglutid v dnevni dozi 1,2 mg. Ob sprejemu smo ugotovili naslednje laboratorijske izvide: lipaza 3,59 μkat/L, amilaza 1,75 μkat/L, C-reaktivni protein 19,3 mg/L, levkociti 12,7x109/L; testi jetrne funkcije, lipidogram, kalcij in transferin z nizkim deležem ogljikovih hidratov (CDT) so bili v mejah normale. Ultrazvok A 50-year old woman with type 2 diabetes mellitus (DM) was admitted to the Department of Internal Medicine with three days history of abdominal pain. One week prior to admission patient’s treatment of DM was changed and liraglutide was induced at daily dose of 1,2 mg. At admission the following laboratory values were found: serum lipase 3,59 μkat/L; amylase 1,75 μkat/L, C-reactive protein 19,3 mg/L, white blood count 12.7x109/L; normal liver function tests, lipids, calcium and carbohydrate deficient We present a case of liraglutide-induced AP. * Betka Popič, MD Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1, 2380 Slovenj Gradec, Slovenia GASTROENTEROLOG 177 Naknadno je bil narejen endoskopski ultrazvok, ki je pokazal cistično lezijo v telesu pankreasa premera 7 mm. CT s kontrastom je bil normalen. Leto dni po prebolelem AP je bolničino klinično stanje brez posebnosti. transferrin. Abdominal ultrasound revealed inhomogeneous pancreatic parenchyma with normal gallbladder and bile ducts. Liraglutide was discontinued and combination of glibenclamide and metformin was introduced. Abdominal pain was alleviated with spasmolytic and analgetic therapy. On the 9th hospital day the patient was discharged to home care in clinically stable condition. Additionaly, endoscopic ultrasound was performed and cystic lesion in pancreatic body (7 mm in diameter) was found. Contrast-enhanced computed tomography was unremarkable. One year after AP her clinical status is unremarkable. ZAKLJUČEK CONCLUSIONS Liraglutid in drugi analogi GLP-1 so lahko vzrok za nastanek AP. Bolnike moramo pred uporabo tega zdravila opozoriti na možne stranske učinke ter poučiti o simptomih AP. Liraglutide and other analogues of GLP-1 could be associated with AP. Patients should be aware of sideeffects and informed about symptoms of AP. trebuha je pokazal nehomogen parenhim trebušne slinavke, žolčnik in žolčni vodi so bili brez posebnosti. Ukinili smo liraglutid in uvedli kombinacijo glibenklamida in metformina. Ob bolečini je prejemala spazmolitično in analgetično terapijo. Devetega dne zdravljenja je bila bolnica v stabilnem stanju odpuščena v domačo oskrbo. 178 GASTROENTEROLOG Hematemeza zaradi erozivnega duodenitisa pri maratoncih – prikaz dveh primerov Hematemesis due to erosive duodenitis in marathon runners – a report of two cases Miroslav Vujasinović*,1, Petra Kaplan2 1 Department of Internal Medicine, Slovenj Gradec General Hospital 2 Division of Internal Medicine, Medical Emergency Unit, University Medical Centre Ljubljana Gastroenterolog 2013; suplement 2: 179 Key words: hematemesis, duodenitis, runners POVZETEK ABSTRACT Gastrointestinalne težave so pogoste med tekačih na dolge proge. Simptomi se lahko pojavijo med ali takoj po naporni vadbi. Tek na dolge proge postaja vse bolj priljubljen s sodelovanjem večjega števila pripravljenih in manj pripravljenih udeležencev na tekmovanjih. Leta 2006 je v vseh kategorijah Ljubljanskega maratona sodelovalo 8287 tekačev. Leta 2012 je število udeležencev iz 41 držav poraslo na Gastrointestinal complaints are common in long distance runners. The symptoms may occur during or immediately after a strenuous workout. Long distance running is becoming very popular and large numbers of trained and untrained people participate in competitions. In 2006, a total of 8287 competitors participated in Ljubljana marathon in all categories and in 2012 that number increased to 16302 runners from 41 countries. We report two cases of marathon runners who were presented at the Medical Emergency Unit after having vomited black gastric content which was Hemoccult positive. Their previous medical histories were normal; they did not take any medications and denied any recent illnesses, but before and during the race they had no fluid intake. An urgent upper endoscopy showed erosive gastritis and severe erosive bulbitis with no sign of active bleeding. Both patients were discharged without any sequelae. Due to a continuous increase in the number of marathon participants with many of them not properly trained, physicians and first aid teams should be aware of gastrointestinal compliants in longdistance runners. 16 302. Predstavljamo dva primera maratoncev, ki sta bila obravnavana na Internistični prvi pomoči zaradi bruhanja črne želodčne vsebine. Bolnika sta imela normalno osebno anamnezo, nista uživala zdravil, pred in tekom tekmovanja pa nista uživala tekočine. Urgentna endoskopija zgornjih prebavil je pokazala erozivni gastritis in hudi erozivni duodenitis brez znakov aktivne krvavitve. Oba bolnika sta bila odpuščena v domačo oskrbo brez trajnih zdravstvenih posledic. Zaradi stalnega naraščanja števila udeležencev maratona, med katerimi je veliko slabo pripravljenih, se morajo zdravniki in ekipe nujne pomoči zavedati gastrointestinalnih težav pri tekačih na dolge proge. * Corresponding author: Miroslav Vujasinović MD MSc Slovenj Gradec General Hospital, Department of Internal Medicine Gosposvetska 1, 2380 Slovenj Gradec, Phone: +386 2 8823400, Fax: +386 2 8823505, E-mail: mvujas@gmail.com GASTROENTEROLOG 179 ARC sindrom – klinični primer Rok Orel*, Jakob Zapušek, Gregor Nosan, Marjeta Sedmak, Tanja Kersnik Levart Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko Pediatrična klinika, UKC Ljubljana Gastroenterolog 2013; suplement 2: 180–182 POVZETEK ABSTRACT Kratica ARC označuje trojico kliničnih znakov, ki so značilni za sindrom: Artrogripoza, Renalna tubulna acidoza s Fanconijevim sindromom in holestaza (ang. Cholestasis). Gre za autosomno recesivno bolezen, pri kateri se pojavi mutacija VPS33B gena (15q26), ki kodira regulacijo zlivanja membran celic preko SNARE proteinov. V klinični sliki so pogosto pridruženi še huda distrofija, ihtioza, nagnjenost h krvavitvam zaradi motene agregacije trombocitov zaradi odsotnost alfa granul, v 10 % so pridružene tudi malformacije srca. Prisotna so lahko tudi telesna stigmata z nizko položenimi ušesi, prominentnim čelom in velikimi palci. Prognoza bolezni je slaba, praviloma otroci umrejo do drugega leta starosti. Glavna razloga smrti so septična stanja in krvavitve ob diagnostičnih posegih, zato se bioptična diagnostika pri otrocih s sumom na ARC sindrom odsvetuje, nadomestiti jo mora genetska analiza. Predstavljen je klinični primer dečka, ki je bil voden na Pediatrični kliniki Univerzitetnega kliničnega centra Ljubljana z dokazanim ARC sindromom. ARC acronime is used to describe initial letters of clinical signs that are present in patients with this condition. These are Arthrogryposis, Renal tubular acidosis along with Fanconi syndrome and Cholestasis. It is an autosomal recesive disorder due to mutation of VPS33B gene (15q26), that encodes proper membrane fusion by SNARE proteins. This condition is often associated with severe dystrophy, ichthyosis, tendency for bleeding due to disfunctional platelet aggregation on account of absent alpha granules, in 10 % of cases cardiac abnormalities may be present. Corporal stygmata may also be present, often as low seated ears, prominent forehead and large thumbs. Prognosis is lethal, death occures till second year of age. Major causes of death are sepsis and bleedings during invasive diagnostic procedures, this is why genetic analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome. A case report article of a boy with ARC syndrome, who was treated in Children’s hospital of University medical centre Ljubljana, is presented below. Prof. dr. Rok Orel, dr. med., Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko, Pediatrična klinika, UKC Ljubljana Bohoričeva 20, 1525 Ljubljana 180 GASTROENTEROLOG PRIKAZ PRIMERA V porodnišnici Postojna se je novembra 2011 rodil deček, H.A., plod prve nosečnosti, rojen po normalni poti. Porodna teža 3490, porodna dolžina 50 cm, obseg glave 36 cm, Apgar 9/10/10. V družinski anamnezi ni bilo odstopanj, tako oče kot mati sta bila oba zdrava, doma iz Bosne in Hercegovine, brez konsangvinitete. Težave so se pri dečku pričele tretji dan po porodu, kazale so se kot nenapredovanje na telesni teži, potreboval je infuzijo, pojavila se je konjugirana hiperbilirubinemija, policitemija ter metabolna acidoza s pH 7.28 in presežkom baze –12. Presejalni testi so bili normalni, UZ kolkov D-IIa in L-1a. Decembra 2011 je bil deček v starosti 7 dni premeščen na neonatalni oddelek Pediatrične klinike Univerzitetnega kliničnega centra Ljubljana. Ob sprejemu je bil deček hipoton, izražene je imel znake distrofije, prisoten je bil ikterus, obojestransko se je izrazil calcaneovalgus in displazija desnega kolka. V laboratorijskih izvidih je bila v ospredju hiperkloremična metabolna acidoza in proteinurija. V smislu izključevanja metabolopatij so bili vsi izvidi (laktat, piruvat, NH3, galaktoza, alfa 1 antitripsin, aminokisline v serumu, organske kisline v serumu in urinu, iontoforeza) v mejah normale. Morebitne okužbe s hepatotropnimi patogeni so bile izključene. Opravljen je bil UZ glave, kjer je bil ob prvem pregledu postavljen sum na krvavitev v horoidni pletež stranskih ventriklov, kontrolni UZ izvid je bil v mejah normale. Zaradi tubularne okvare ledvic je že na neonatalnem oddelku prejemal redno terapijo z NaHCO3. Poslan je bil vzorec krvi v Birmingham za genetsko analizo – potrjena VP33B mutacija. Deček je bil nato voden multidisciplinarno s strani konziliarnih subspecialistov. Težave so po enem mesecu postale vse izrazitejše. S strani gastroenterološke obravnave je bila v ospredju vse izrazitejša distrofija. Deček je bil sprva hranjen z Aptamil ADC (Allergy digestive care) formulo. Pogosto je hrano zavračal, nemalokrat tudi bruhal. Zato je imel vstavljeno nazogastrično sondo, po kateri je bil dohranjevan z MCT (srednjeverižnimi trigliceridnimi) olji in dodatkom glukoznega polimera in 2 % rižka. Kljub nazogastrični sondi se težave z nenapredovanjem teže še vedno niso izboljšale. Zato je bil dečku uveden CVK za parenteralno hranjenje. Na parente- ralni prehrani ob vzporedni enteralni prehrani preko nazogastrične sonde je deček začel pridobivati na teži. Blato na kri je bilo negativno, analiza blata na prebavljivost pa je pokazala malabsorbcijo maščob in proteinov. UZ trebuha je bil v mejah normale. Opravi tudi scintigrafijo jeter (HIDA), ki pokaže intrahepatalno holestazo. Izključen je bil sindrom Allagile. Hepatalna biopsija je bila glede na genetsko potrjeno diagnozo kontraindicirana. Uvedena je bila terapija z ursodeoksiholno kislino. S strani nefrološke obravnave je bila v ospredju tubularna okvara ledvic s Fanconijevim sindromom, redno je prejemal terapijo z NaHCO3. S strani hematološke obravnave je bilo najti v krvi sive trombocite z odsotnimi alfa granulami. Ob tem je bila koagulacija normalna. S strani ortopedske obravnave je deček sprva nosil mavčne longete, nato opornice po Otto Borlinu. S strani kardiološke obravnave ni bilo posebnosti, UZ srca je bil v mejah normale. Tudi s strani imunološke obravnave ni bilo najti posebnosti. Meseca januarja 2012 je bil za dečka opravljen timski konzilij, kjer so bili glede na dečkovo klinično stanje in potrjeno diagnozo sprejeti naslednji sklepi: 1. Pri dečku so invazivne diagnostične preiskave kontraindicirane. 2. Operacija po Kasaiu ni smiselna, ker so ekstrahepatalni vodi prehodni. 3. Ponovno se dečku uvede popolna enteralna prehrana preko nazogastrične sonde. 4. Sprejet sklep o odstopu od reanimacijskih postopkov v soglasju s starši. Deček je bil nato v bolnišnični obravnavi še do meseca marca 2012, v tem času je prebolel tri sepse, iz hemokultur je dvakrat porasla E. coli in enkrat S. aureus. V mesecu marcu je bil nato na željo staršev odpuščen v domačo oskrbo na terapiji z ursodeoksiholno kislino, NaHCO3 in enteralnim hranjenjem preko nazogastrične sonde z Aptamil ADC (Allergy digestive care) formulo z dodatki. Maja 2012 je bil deček zadnjič hospitaliziran, kjer mu je bila uvedena paliativna terapija s tramadolom in morfijem. Umrl je v starosti 7 mesecev. GASTROENTEROLOG 181 KLINIČNI PRIMER • H.A., deček, 1. nosečnost, PT 3490g, PD 50, OG 36, Apgar 9/10/10 • Družinska anamneza: bp, ni konsangvinitete, starši iz Bosne in Hercegovine • Porodnišnica: slabo napredovanje telesne teže, ihtioza, konjugirana hiperbilirubinemija, policitemija, metabolna acidoza ARC SINDROM Artrogripoza Renalna tubulna acidoza (Fanconijev sindrom) Cholestaza z normalnim gGT • pogosto pridruženo: huda distrofija, ihtioza, nagnjenost h • • • • krvavitvam zaradi motene agregacije trombocitov z odsotnostjo alfa granul, v 10% pridružene malformacije srca lahko so prisotna telesna stigmata z nizko položenimi ušesi, prominentnim čelom in velikimi palci autosomno recesivna bolezen, mutacija VPS33B gena (15q26), ki kodira regulacijo zlivanja membran celic preko SNARE proteinov glavna razloga smrtnosti: septična stanja ter krvavitve ob diagnostičnih posegih prognoza: smrt do drugega leta življenja Neonatalni oddelek Pediatrične klinike Univerzitetnega kliničnega centra Ljubljana: • Klinična slika: distrofija, hipotonija, ikterus, bilateralni calcaneovalgus, displazija D kolka • Izvidi: hiperkloremična metabolna acidoza, proteinurija. Metabolni screening, iontoforeza in alfa 1 antitripsin v mejah normale. Sindrom Allagile izključen. Okužbe s hepatotropnimi patogeni izključene • HIDA: intrahepatalna holestaza • Hepatalna biopsija: kontraindicirana • DGN: ARC sindrom • Gastroenterološka obravnava: Sprva hranjenje z Aptamil ADC (Allergy digestive care) formulo, nato vstavitev nazogastrične sonde in dodatek MCT (srednjeverižnih trigliceridnih) olj, glukoznega polimera in 2% rižka. Zaradi hude distrofije še parenteralna prehrana. TH: ursodeoksiholna kislina • Nefrološka obravnava: tubularna okvara ledvic s Fanconijevim sindromom. TH: NaHCO3 • Hematološka obravnava: Sivi trombociti brez alfa granul, normalna koagulacija • Ortopedska obravnava: Mavčne longete, opornice po Otto Borlinu • Kardiološka obravnava: Ultrazvok srca v mejah normale • Imunološka obravnava: Brez odstopanj od normale • Birmingham: Genetska analiza: Mutiran gen VP33B Potek bolezni: • 3 x sepsa - 2x E.coli in 1x Staph. Aureus Smrt po šestih mesecih od postavitve diagnoze CASE REPORT • H.A., boy, 1. pregnancy, BW 3490g, BL 50, HC 36, Apgar score 9/10/10 • Familial history: normal, no consangvinity, parents from Bosnia and Herzegovina • Nursery: failure to thrive, ichthyosis, hyperbilirubinemia, policythemia, metabolic acidosis ARC SYNDROME Arthrogryposis Renal tubular acidosis (Fanconi syndrome) Cholestasis with normal gGT • often associated with: severe dystrophy, ichthyosis, tendency for bleeding due to disfunctional platelet aggregation on account of absent alpha granules, in 10% of cases cardiac abnormalities are present • corporal stygmata may be present, often as low seated ears, prominent forehead and large thumbs • autosomal recesive disorder, mutation of VPS33B gene (15q26), that encodes proper membrane fusion by SNARE proteins • major causes of death: septic states and bleedings during invasive diagnostic procedures prognosis: death till second year of age Department of neonatology, Children's hospital, University medical centre Ljubljana: • Chlinical manifestations: dystrophy, hypotonia, icterus, bilateral calcaneovalgus, displastic right hip joint • Blood tests: hyperchloremic metabolic acidosis, proteinuria. Metabolnic screening, iontophoresis and alpha 1 antitripsine showed no pathological deviations. Allagile syndrome was excluded. Hepatopatothropic pathogens were excluded • HIDA: intrahepatal cholestasis • Hepatal biopsy: contraindicated • DGN: ARC syndrome • Gastroenterological management: firstly fed with Aptamil ADC (Allergy digestive care) formula, followed by insertion of nasogastric probe and addition of MCT (mid – chain trigliceride) oils, glucose polimere and 2% rice jelly to the diet, followed by parenteral feeding due to severe dystrophy. TH: ursodeoxycholic acid • Nephrological management: tubular kidney disfunction with Fanconi syndrome. TH: NaHCO3 • Hematological management: grey platelets without alpha granules, normal coagulation tests • Orthopedic management: leg plasters, Otto Borlin splints • Cardiological management: cardiac sonography normal • Imunological management: no disorders found • Birmingham: genetic analysis: VP33B gene mutation Disease outcome: 182 GASTROENTEROLOG • 3 x sepsis - 2x E.coli and 1x Staph. Aureus Death after six months from diagnosis date Ustreznost predpisovanja zaviralcev protonske črpalke Appropriateness of proton pump inhibitors prescribing Miroslav Vujasinović*,1, Martin Tretjak1, Bojan Tepeš2, Apolon Marolt1, Milica Miljković1, Karmen Klančnik3 1 Department of Internal Medicine, Slovenj Gradec General Hospital 2 Abakus Medico Diagnostic Centre Rogaška 3 Medical Faculty at the University of Maribor Gastroenterolog 2013; suplement 2: 183–184 IZHODIŠČA BACKGROUND Zaviralci protonske črpalke (ZPČ) so glavno z dokazi podprto zdravilo za zdravljenje obolenj zgornjega prebavnega trakta, kot so gastroezofagealna refluksna bolezen, dispepsija in ulkusna bolezen. ZPČ so ena izmed najpogosteje predpisanih zdravil v Sloveniji, ocenjena vrednost predpisanega esomeprazola, pantoprazola in omeprazola je v letu 2011 znašala 16 milijonov evrov. Objavljenih je bilo več poročil o neustreznem predpisovanju ZPČ. Raziskava iz Velike Britanije je pokazala, da ima ZPČ predpisan 24 % bolnikov napotenih v bolnišnici, od teh le 54 % z ustrezno indikacijo. Proton pump inhibitors (PPI) are the most important evidence based drugs for treatment of different upper gastrointestinal tract diseases. They are among the most often prescribed drugs in Slovenia with estimated cost of 16 million EUR in 2011. There have been numerous reports of inappropriate prescribing. In a British study only 51 % of patients admitted to a general hospital had an appropriate indication. We are presenting preliminary results. Predstavljamo lastne preliminarne rezultate. NAMEN IN METODE Za oceno ustreznosti predpisovanja ZPČ glede na priporočila smo retrospektivno pregledali medicinsko dokumentacijo 500 zaporednih bolnikov, ki so bili napoteni v ambulanto internistične prve pomoči Oddelka za interno medicino SB Slovenj Gradec. Analizirali smo demografske podatke, AIMS AND METHODS To evaluate the indications for use of PPI in accordance with the currently recommendations. A retrospective analysis of medical documentation of 500 consecutive patients sent to Department of Internal Medicine for urgent assessment. We analyzed demographic features, indications and the adequacy of PPI prescription. * Miroslav Vujasinović, MD MSc Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1 Slovenj Gradec 2380, Slovenia GASTROENTEROLOG 183 vzrok napotitve, predpis in indikacijo za predpis ZPČ ter ustreznost te indikacije. REZULTATI Med 500 bolniki je bilo 251 žensk (50,2 %) in 249 (49,8 %) moških. Povprečna starost je bila 63,3 ± 17,4 let (18–95 let). Večina bolnikov je bila napotenih zaradi srčnih bolezni (26 %), preostali zaradi bolezni prebavil (21,4 %), pljuč (16 %), živčnega sistema (7,8 %), žilja (7 %) ter drugih obolenj. ZPČ je imelo predpisanih 121 bolnikov (24,2 %), tretjina v skupini z boleznimi prebavil. Najpogosteje predpisan ZPČ je bil pantoprazol (v 79,3 %). Ustrezna indikacija je bila najdena pri 69 bolnikih (57 %), najpogosteje kot zaščita zgornjih prebavil ob sočasnem jemanju antiagregacijskih zdravil (33 %), peroralnih antikoagulacijskih zdravil (23,6 %), kortikosteroidov (9,7 %) in nesteroidnih analgoantirevmatikov (5,6 %). Pri 52 bolnikih (43 %) ustrezne indikacije za predpis ZPČ nismo našli. ZAKLJUČEK Naši podatki kažejo na visok delež neustrezno predpisanih ZPČ. V tej skupini bo potrebna nadaljnja analiza medicinske dokumentacije in pridobitev podatkov s strani osebnih zdravnikov z namenom boljšega razumevanje razlogov za neustrezno predpisovanje. Neustrezno predpisovanje ZPČ dviguje zdravstvene stroške in bolnike izpostavlja nepotrebnemu tveganju za stranske učinke. Potrebno bo poskrbeti za skrbnejše upoštevanje priporočil in redno spremljanje indikacije za predpis ZPČ pri posameznem bolniku. 184 GASTROENTEROLOG RESULTS There were 500 patiens: 251 female (50.2%) and 249 (49.8%) male; mean age 63.3 ± 17.4 years (range 18–95). The majority of patient were presented due to cardiac disorders (26%), followed by gastrointestinal (21.4%), pulmonary (16%), neurologic (7.8%), vascular (7%) and other disorders. 121 patients (24.2%) had a PPI therapy (one third of them were in the group of patients with gastrointestinal disorders). The most often prescribed PPI was pantoprazole (79.3%). An appropriate indication for PPI therapy was found in 69 patients (57%), most often as gastric protection with concomitant therapy (33.3% were taking antiplatelet agents, 23.6% anticoagulants, 9.7% corticosteroids and 5.6% NSAID). In 52 patients (43%) an appropriate indication could not be found. CONCLUSIONS Our study found high rates of patients in whom appropriate indication for PPI prescribing could not be found. In that group of patients further analysis of medical documentation and telephone survey of general practitioners should be performed. Inappropriate prescribing of PPI raises healthcare cost and exposes patients to potential harmful side effects. Effort has to be made to change the PPI prescribing policy in primary care. Indication for PPI prescription should be assessed periodically. Reasons for inadequate PPI prescriptions need to be explored in more depth to tailor interventions promoting appropriate PPI prescribing. S kapecitabinom povzročen transmuralni miokardni infarkt – prikaz primera Capecitabine-induced transmural myocardial infarction – case report Miroslav Vujasinović*, Zdenko Kikec, Cirila Slemenik Pušnik Department of Internal Medicine, Slovenj Gradec General Hospital Gastroenterolog 2013; suplement 2: 185–186 IZHODIŠČA BACKGROUND Kapecitabin je široko uporabljen kemoterapevtik iz skupine neantraciklinskih pripravkov. Je peroralna oblika in predzdravilo 5-fluorouracila (5-FU), ki se uporablja pri zdravljenju raka črevesja in danke, dojke, želodca in trebušne slinavke v kombinaciji z ostalimi kemoterapevtiki ali samostojno. Miokardni infarkt je zelo redek neželen učinek. Predstavljamo primer bolnice brez predhodno znanih kardiovaskularnih simptomov, pri kateri je prišlo do razvoja transmuralnega miokardnega infarkta tekom terapije s kapecitabinom. Capecitabine is a widely used nonanthracycline cancer chemotherapy agent. It is an orally administrated pro-drug of 5-fluorouracil (5-FU) and is used in the treatment of colorectal, breast, gastric and pancreatic cancers, both as a single agent and as a component of a combination chemotherapy. Myocardial infarction is an uncommon adverse effect. We present a case of a female patient without previous cardiovascular symptoms who developed transmural myocardial infarction during the treatment with capecitabine. PRIKAZ PRIMERA CASE REPORT 59-letna bolnica je bila sprejeta na Oddelek za interno medicino zaradi anamnestičnega podatka o pet dni trajajoči torakalni bolečini, ki se je razvila tekom četrtega ciklusa kemoterapije s kapecitabinom. Oktobra 2011 je bila opravljena resekcija transverzalnega dela debelega črevesa zaradi adenokarcinoma in nato uvedena adjuvantna kemoterapija s kapecitabinom. Ob sprejemu so bile v elektrokardiogramu vidne elevacije ST veznice v spodnjestenskih A 59-year-old female was admitted to the Department of Internal Medicine with a history of chest pain of 5-days’ duration during the fourth cycle of capecitabine treatment. In October 2011 she uderwent a surgical resection due to adenocarcinoma of the transversal colon followed by adjuvant chemotherapy with capecitabine. On admission, the electrocardiogram showed ST-segment elevation in inferior leads. The ishaemic changes were addi- * Miroslav Vujasinović, MD MSc Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1 Slovenj Gradec 2380, Slovenia GASTROENTEROLOG 185 odvodih. Ishemične spremembe so bile dodatno potrjene s povišanimi vrednostmi visoko senzitivnega troponina T in z ehokardiografsko preiskavo srca. Bolnico smo zdravili z nizkomolekularnim heparinom in antiagregacijsko terapijo. tionaly confirmed by very high levels of high sensitive troponin T and echocardiographic examination. The patient was treated with low molecular weight heparin and anti-agregation therapy. CONCLUSION ZAKLJUČEK Miokardni infarkt je redek neželen učinek pri bolnikih zdravljenih s kapecitabinom. Spekter s kapecitabinom povzročenih kardiotoksičnih sprememb je širok in vključuje: angino, aritmije, miokardni infarkt in nenadno srčno smrt. Poročajo o 3–9 % incidenci kardiotoksičnosti. Simptomi se lahko pojavijo drugi ali tretji dan po uvedbi kapecitabina. Predvideva se, da so mehanizemi nastanka stranskih učinkov kapecitabina enaki kot pri intravenski aplikaciji 5FU. Najverjetnejši mehanizmi kardiotoksičnosti so: toksičen učinek na endotelij koronarnega žilja, toksični miokarditis, spazem koronarnih arterij in tromboza. Prvi ukrep pri pojavu kardiotoksičnosti zaradi kapecitabina je takojšnja prekinitev jemanja zdravila. Zaradi vse večje uporabe v onkološkem zdravljenju, moramo biti zdravniki pozorni na pojav kardiotoksičnosti, še posebej pri bolnikih z znano ishemično boleznijo srca v anamnezi. 186 GASTROENTEROLOG Myocardial infarction is a rare condition in patients during treatment with capecitabine. The spectrum of capecitabine-induced cardiotoxicity is wide and icludes angina, arrhythmias, myocardial infarction and sudden death. The reported incidence of cardiotoxicity ranges from 3 to 9 %. Published case reports indicate that symptoms may occur within two to three days after the initiation of capecitabine therapy. It has been postulated that capecitabine has the same mechanism of the side effect as intravenous 5-FU. Possible mechanisms are: direct toxic effects on the coronary endothelial intima, toxic myocarditis, coronary artery vasospasm and thrombosis. The main treatment of capecitabineinduced cardiotoxicity is withdrawal of the drug. Due to its increasing use in oncologic therapy, specialists should be aware of cardiotoxicity especially when used in patients with the history of ishaemic heart disease. Serious adverse events associated with ferric carboxymaltose administration in patients with inflammatory bowel disease treated with anti-TNF drugs Vanesa Anderle*, Nejc Sever, Nataša Smrekar Clinical Department of Gastroenterology, University Clinical Centre Ljubljana, Japljeva 2, Slovenia Gastroenterolog 2013; suplement 2: 187–188 INTRODUCTION METHODS Iron deficiency anemia is very common among the patients with a chronic illness. The prevalence among the inflammatory bowel disease (IBD) patients is up to 75%. About 20–30% patients present with iron deficiency without anemia. Both conditions are an important cause of chronic fatigue syndrome in IBD patients. International guidelines recommend parenteral iron replacement for treating iron deficiency anemia in IBD patients. However there are more adverse events documented with parenteral iron compared to oral supplements especially in patients with an active disease. Ferric carboxymaltose (FCM) is considered a safe drug. The medical records of 62 patients who received parenteral ferric carboxymaltose during the period from 1.1.2011 to 2.2.3013 were analysed. Data included the underlying disease, serum iron levels, CRP, treatment with biologic drugs (anti-tumor necrosis factor alpha (anti-TNF)) and any observed adverse events associated with biologic therapy or FCM application. Serious adverse events were described as: low blood pressure, chest pain, dyspnea, tachycardia, nausea, generalized urticarial (hives), excessive sweating and flushing. * Vanesa Anderle, dr. med. Clinical Department of Gastroenterology, University Clinical Centre Ljubljana Japljeva 2, Slovenia GASTROENTEROLOG 187 RESULTS The underlying disease distribution is displayed in a pie chart 1. 25 patients were male and 37 were female. Of 53 patients with IBD 32 (60,4 %) were treated with anti-TNF drugs, 16 were receiving infliximab and 16 patients adalimumab. Of 62 patients in the study group the adverse events were observed in 4 (6,5 %) patients (3 female and 1 male). All of the affected individuals had an inflammatory bowel disease and were receiving anti-TNF therapy. Three patients had Crohn’s disease and one ulcerative colitis. Two patients were receiving adalimumab and two infliximab. Both individuals on adalimumab were previously treated with infliximab. One individual had a documented allergic reaction to infliximab. The severity of the underlying disease at the time of the adverse event is unfortunately not available. The exact mechanism causing the adverse events is unclear. Possible mechanism is IgG mediated reaction between the FCM and the anti-TNF drug (IgG antibody) or between the FCM and antibodies developed against the biologic drug. Currently there is a lack of evidence to classify this reaction as anaphylaxis. CONCLUSION Serious adverse events associated with ferric carboxymaltose (FCM) were only observed in IBD patients receiving anti-TNF drugs. All events occurred after the first administration of FCM. Possible mechanism is cross reaction between FCM and anti-TNF drug (IgG antibody) or FCM and antibodies developed against the biologic drug. Caution is advised administering FCM to IBD patients treated with anti-TNF drugs. Pie chart 1 - Underlying disease Cirrhosis; 2% Coeliac disease; 6% Diagnostic evaluation; 6% Ulcerative colitis; 23% 188 GASTROENTEROLOG Crohn's disease; 63%
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