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1. Prospective evaluation of antibody response to Streptococcus gallolyticus and risk of colorectal cancer

Author

Butt, J, Jenab, M, Willhauck-Fleckenstein, M, Michel, A, Pawlita, M, Kyro, C, Tjønneland, A, Boutron-Ruault, M-C, Carbonnel, F, Severi, G, Kaaks, R, Kuhn, T, Boeing, H, Trichopoulou, A, La Vecchia, C, Karakatsani, A, Panico, S, Tumino, R, Agnoli, C, Palli, D, Sacerdote, C, Bueno-de-Mesquita, B, Weiderpass, E, Sánchez, M-J, Bonet, C, Murphy, N, Freisling, H, Riboli, E, Tsilidis, K, Aune, D, Waterboer, T, Hughes, D, and Commission of the European Communities

Subjects
BACTEREMIA, Science & Technology, Streptococcus gallolyticus, SEROLOGY, prospective cohort, ASSOCIATION, colorectal neoplasms, DISEASE, Oncology, COLON, ENDOCARDITIS, bacterial serology, antibodies, COHORT, SUBSPECIES GALLOLYTICUS, Oncology & Carcinogenesis, Life Sciences & Biomedicine, 1112 Oncology And Carcinogenesis, BOVIS
Abstract

The gut microbiome is increasingly implicated in colorectal cancer (CRC) development. A subgroup of patients diagnosed with CRC show high antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG). However, it is unclear whether the association is also present pre‐diagnostically. We assessed the association of antibody responses to SGG proteins in pre‐diagnostic serum samples with CRC risk in a case–control study nested within a prospective cohort. Pre‐diagnostic serum samples from 485 first incident CRC cases (mean time between blood draw and diagnosis 3.4 years) and 485 matched controls in the European Prospective Investigation into Nutrition and Cancer (EPIC) study were analyzed for antibody responses to 11 SGG proteins using multiplex serology. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable conditional logistic regression models. Antibody positivity for any of the 11 SGG proteins was significantly associated with CRC risk with 56% positive controls compared to 63% positive cases (OR: 1.36, 95% CI: 1.04–1.77). Positivity for two or more proteins of a previously identified SGG 6‐marker panel with greater CRC‐specificity was also observed among 9% of controls compared to 17% of CRC cases, corresponding to a significantly increased CRC risk (OR: 2.17, 95% CI: 1.44–3.27). In this prospective nested case–control study, we observed a positive association between antibody responses to SGG and CRC development in serum samples taken before evident disease onset. Further work is required to establish the possibly etiological significance of these observations and whether SGG serology may be applicable for CRC risk stratification.

Published
2018

2. Methotrexate for Corticosteroid- Dependent Ulcerative Colitis: Results of a Placebo Randomized Controlled Trial

Author

Carbonnel F, Colombel JF, Filippi J, Katsanos K, Peyrin-Biroulet L, Allez M, Nachury M, Novacek G, Danese S, Abitbol V, Bossa F, Moreau J, Bommelaer G, Bourreille A, Dupas JL, Roblin X, Bouhnik Y, Reinisch W, Farkkila MA, Brixi H, Seksik P, Malamut G, Coulibaly B, Dewit O, Louis E, Deplanque D, Michetti PF, Sarter H, Laharie D, Carbonnel, F, Colombel, Jf, Filippi, J, Katsanos, K, Peyrin-Biroulet, L, Allez, M, Nachury, M, Novacek, G, Danese, S, Abitbol, V, Bossa, F, Moreau, J, Bommelaer, G, Bourreille, A, Dupas, Jl, Roblin, X, Bouhnik, Y, Reinisch, W, Farkkila, Ma, Brixi, H, Seksik, P, Malamut, G, Coulibaly, B, Dewit, O, Louis, E, Deplanque, D, Michetti, Pf, Sarter, H, and Laharie, D

Published
2015

3. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations

Author

Van Assche G, Dignass A, Reinisch W, van der Woude CJ, Sturm A, De Vos M, Guslandi M, Oldenburg B, Dotan I, Marteau P, Ardizzone A, Baumgart DC, D'Haens G, Portela F, Vucelic B, Söderholm J, Escher J, Koletzko S, Kolho KL, Lukas M, Mottet C, Tilg H, Vermeire S, Carbonnel F, Cole A, Novacek G, Reinshagen M, Tsianos E, Herrlinger K, Bouhnik Y, Kiesslich R, Stange E, Travis S, Lindsay J, for the European Crohn's, Colitis Organisation (ECCO, GIONCHETTI, PAOLO, Van Assche G, Dignass A, Reinisch W, van der Woude CJ, Sturm A, De Vos M, Guslandi M, Oldenburg B, Dotan I, Marteau P, Ardizzone A, Baumgart DC, D'Haens G, Gionchetti P, Portela F, Vucelic B, Söderholm J, Escher J, Koletzko S, Kolho KL, Lukas M, Mottet C, Tilg H, Vermeire S, Carbonnel F, Cole A, Novacek G, Reinshagen M, Tsianos E, Herrlinger K, Bouhnik Y, Kiesslich R, Stange E, Travis S, Lindsay J, for the European Crohn's and Colitis Organisation (ECCO, and Gastroenterology and Hepatology

Subjects
Complementary Therapies, Male, medicine.medical_specialty, Adolescent, Crohn's disease, post-operative recurrence, fistula, paediatric, pregnancy, psychosomatic, extraintestinal manifestation, Placebo-controlled study, Anti-Inflammatory Agents, Inflammatory bowel disease, Management of Crohn's disease, Skin Diseases, Primary sclerosing cholangitis, law.invention, chemistry.chemical_compound, Mesalazine, Randomized controlled trial, Crohn Disease, law, Adrenal Cortex Hormones, Pregnancy, Recurrence, Intestinal Fistula, Medicine, Humans, Child, business.industry, Tumor Necrosis Factor-alpha, General surgery, Arthritis, Gastroenterology, Antibodies, Monoclonal, General Medicine, medicine.disease, digestive system diseases, Infliximab, Surgery, Anti-Bacterial Agents, Pregnancy Complications, Psychotherapy, Aminosalicylic Acids, chemistry, Purines, Female, business, Immunosuppressive Agents, medicine.drug
Abstract

Principal changes with respect to the 2004 ECCO guidelines Ileocolonoscopy is recommended within the first year after surgery where treatment decisions may be affected (Statement 8C). Thiopurines are more effective than mesalazine or imidazole antibiotics alone in post-operative prophylaxis (Statement 8F). ### 8.1 Epidemiology of post-operative Crohn's disease In the natural history of CD, intestinal resection is almost unavoidable since about 80% of patients require surgery at some stage. Surgery is unfortunately not curative as the disease inexorably recurs in many patients. The post-operative recurrence rate varies according to the definition used: clinical, endoscopic, radiological, or surgical. It is lowest when the repeat resection rate is considered, intermediate when clinical indices are used and highest when endoscopy is employed as the diagnostic tool.1–10 Data from endoscopic follow-up of patients after resection of ileo-caecal disease have shown that in the absence of treatment, the post-operative recurrence rate is around 65–90% within 12 months and 80–100% within 3 years of the operation. The clinical recurrence without therapy is about 20–25%/year.1,10 It has been demonstrated that the post-operative clinical course of CD is best predicted by the severity of endoscopic lesions. Symptoms, in fact, appear only when severe lesions are present and it is not uncommon to observe patients with fairly advanced recurrent lesions at endoscopy who remain asymptomatic.1 For these reasons, clinical indices such as the CDAI have low sensitivity at discriminating between patients with or without post-operative recurrence.11 These data mandate strategies aimed at interrupting or delaying the natural course of post-operative recurrence. Several medications have been tried in an attempt to prevent post-operative recurrence, mostly with disappointing results. The aim of this Consensus was therefore critically to evaluate the optimal strategies for the management of post-operative recurrence in CD. Most, if not all, of the evidence available deals with …

Published
2009

4. [Minimally invasive surgery for diverticula of the thoracic esophagus. Results in 11 patients]

Author

Levard H, Carbonnel F, Perniceni T, Mal F, Denet C, Christos CHRISTIDIS, Mj, Boudet, Godeberge P, and Gayet B

Subjects
Aged, 80 and over, Male, Morphine, Thoracoscopy, Pain, Middle Aged, Postoperative Complications, Treatment Outcome, Diverticulum, Esophageal, Humans, Female, Laparoscopy, Analgesia, Acetaminophen, Aged
Abstract

Surgical treatment of diverticula of the esophagus is associated with substantial mortality and morbidity. Few data have been published concerning results of minimally invasive surgery. The aim of the study was to retrospectively assess the results of minimally invasive surgery (either thoracoscopy or laparoscopy) in a first series of patients with diverticula of the thoracic esophagus.Eleven consecutive patients with symptomatic thoracic diverticula of the esophagus were operated on between December 1992 and March 1999. Five were operated on by right thoracoscopy, 4 by laparoscopy and 2 by thoracoscopy and laparoscopy. The procedure performed varied according to the location and the macroscopic aspect of the diverticulum, as well as of the associated disorders (gastroesophageal reflux, hiatal hernia and/or motor disorders).Postoperative mortality was nil. Three patients developed an esophageal fistula; one with an esophago-bronchial fistula required another operation. Postoperative pain was treated with morphine (median duration 4 days) or IV paracetamol (5 days). Long term results were excellent in 1 patient, good in 6, fair in 2 and poor in 2. These 2 latter patients were operated on another time. One of them was operated on 3 years later for aperistalsis of the esophagus and the other one was operated 4.5 years later for paraesophageal hernia; late results of these operations were fair.These results suggest that minimally invasive surgery does not confer significant benefit compared with open surgery in the treatment of diverticula thoracic esophagus.

6. [Colonic involvement in ileal Crohn's disease]

Author

Peschard S, Carbonnel F, Beaugerie L, Almagne Serrano Hh, D., Fabrice Carrat, Jp, Gendre, and Cosnes J

Subjects
Adult, Male, Colonic Diseases, Adolescent, Crohn Disease, Ileal Diseases, Humans, Female, Middle Aged, Child, Prognosis
Abstract

To determine the risk and predictive factors for colonic extension in patients with ileal Crohn's disease.One hundred and fifty patients with ileal Crohn's disease and no specific colonic lesions on initial colonoscopy were studied retrospectively (median follow-up: 51 months).Twelve patients (8%) developed colonic lesions. Ten-year cumulated risks (95% confidence interval) for colonic extension were 17.2% (range: 5.8-28.6) in the whole group, and 22.4% (range: 8.7-36.1) in the group of 86 patients with repeated colonoscopy. Young age at diagnosis was the only factor predicting colonic extension. Seven patients with colonic extension required immunosuppressive therapy but none underwent surgery.Ileal Crohn's disease has a low tendency for colonic extension. Colonic extension has no major prognostic implications.

7. Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study

Author

Silvio Danese, Jean-Frederic Colombel, Milan Lukas, Javier P Gisbert, Geert D'Haens, Bu'hussain Hayee, Remo Panaccione, Hyun-Soo Kim, Walter Reinisch, Helen Tyrrell, Young S Oh, Swati Tole, Akiko Chai, Kirsten Chamberlain-James, Meina Tao Tang, Stefan Schreiber, Nazimuddin Aboo, Tariq Ahmad, Xavier Aldeguer Mante, Matthieu Allez, Sven Almer, Romain Altwegg, Montserrat Andreu Garcia, Ramesh Arasaradnam, Sandro Ardizzone, Alessandro Armuzzi, Ian Arnott, Guy Aumais, Irit Avni-Biron, Peter Barrow, Ian Beales, Fernando Bermejo San Jose, Abraham Bezuidenhout, Livia Biancone, Michael Blaeker, Stuart Bloom, Bernd Bokemeyer, Fabrizio Bossa, Peter Bossuyt, Guillaume Bouguen, Yoram Bouhnik, Gerd Bouma, Raymond Bourdages, Arnaud Bourreille, Christian Boustiere, Tomas Brabec, Stephan Brand, Carsten Buening, Anthony Buisson, Guillaume Cadiot, Xavier Calvet Calvo, Franck Carbonnel, Daniel Carpio, Jae Hee Cheon, Naoki Chiba, Camelia Chioncel, Nicoleta-Claudia Cimpoeru, Martin Clodi, Gino Roberto Corazza, Rocco Cosintino, Jose Cotter, Thomas Creed, Fraser Cummings, Gian Luigi de' Angelis, Marc De Maeyer, Milind Desai, Etienne Desilets, Pierre Desreumaux, Olivier Dewit, Johanna Dinter, Ecaterina Daniela Dobru, Tomas Douda, Dan Lucian Dumitrascu, Matthias Ebert, Ana Echarri Piudo, Magdy Elkhashab, Chang Soo Eun, Brian Feagan, Roland Fejes, Catarina Fidalgo, Sigal Fishman, Bernard Flourié, Sharyle Fowler, Walter Fries, Csaba Fulop, Mathurin Fumery, Gyula G Kiss, Sonja Gassner, Daniel Gaya, Bastianello Germanà, Liliana Simona Gheorghe, Cyrielle Gilletta de Saint Joseph, Paolo Gionchetti, Adrian-Eugen Goldis, Raquel Gonçalves, Jean-Charles Grimaud, Tibor Gyökeres, Herve Hagege, Andrei Haidar, Heinz Hartmann, Peter Hasselblatt, Buhussain Hayee, Xavier Hebuterne, Per Hellström, Pieter Hindryckx, Helena Hlavova, Frank Hoentjen, Stefanie Howaldt, Ludek Hrdlicka, Kyu Chan Huh, Maria Isabel Iborra Colomino, Florentina Ionita-Radu, Peter Irving, Jørgen Jahnsen, ByungIk Jang, Jeroen Jansen, Seong Woo Jeon, Rodrigo Jover Martinez, Pascal Juillerat, Per Karlén, Arthur Kaser, Radan Keil, Deepak Kejariwal, Dan Keret, Reena Khanna, Dongwoo Kim, Duk Hwan Kim, Hyo-Jong Kim, Joo Sung Kim, Kueongok Kim, Kyung-Jo Kim, Sung Kook Kim, Young-Ho Kim, Jochen Klaus, Anna Kohn, Vladimir Kojecky, Ja Seol Koo, Robert Kozak, Milan Kremer, Tunde Kristof, Frederik Kruger, David Laharie, Adi Lahat-zok, Evgeny Landa, Jonghun Lee, Kang-Moon Lee, Kook Lae Lee, YooJin Lee, Frank Lenze, Wee Chian Lim, Jimmy Limdi, James Lindsay, Pilar Lopez Serrano, Edouard Louis, Stefan Lueth, Giovanni Maconi, Fazia Mana, Steven Mann, John Mansfield, Santino Marchi, Marco Marino, John Marshall, Maria Dolores Martin Arranz, Radu-Bogdan Mateescu, John McLaughlin, Simon McLaughlin, Ehud Melzer, Jessica Mertens, Paul Mitrut, Tamas Molnar, Vinciane Muls, Pushpakaran Munuswamy, Charles Murray, Timna Naftali, Visvakuren Naidoo, Yusuf Nanabhay, Lucian Negreanu, Augustin Nguyen, Thomas Ochsenkuehn, Ambrogio Orlando, Julian Panes Diaz, Maya Paritsky, Dong Il Park, Jihye Park, Luca Pastorelli, Markus Peck-Radosavljevic, Farhad Peerani, Javier Perez Gisbert, Laurent Peyrin-Biroulet, Laurence Picon, Marieke Pierik, Terry Ponich, Francisco Portela, Maartens Jeroen Prins, Istvan Racz, Khan Fareed Rahman, Jean-Marie Reimund, Max Reinshagen, Xavier Roblin, Rodolfo Rocca, Francesca Rogai, Gerhard Rogler, Agnes Salamon, Ennaliza Salazar, Zoltan Sallo, Sunil Samuel, Miquel de los Santos Sans Cuffi, Edoardo Vincenzo Savarino, Vincenzo Savarino, Guillaume Savoye, Andrada Seicean, Christian Selinger, David Martins Serra, Hang Hock Shim, SungJae Shin, Britta Siegmund, Jesse Siffledeen, Wayne Simmonds, Jan Smid, Jose Sollano, Geun Am Song, Alexander Speight, Ioan Sporea, Dirk Staessen, George Stancu, Alan Steel, David Stepek, Victor Stoica, Andreas Sturm, Gyorgy Szekely, Teck Kiang Tan, Carlos Taxonera Samso, John Thomson, Michal Tichy, Gabor Tamas Toth, Zsolt Tulassay, Marcello Vangeli, Marta Varga, Ana Vieira, Stephanie Viennot, Erica Villa, Petr Vitek, Harald Vogelsang, Petr Vyhnalek, Peter Wahab, Jens Walldorf, Byong Duk Ye, Christopher Ziady, Danese S., Colombel J.-F., Lukas M., Gisbert J.P., D'Haens G., Hayee B., Panaccione R., Kim H.-S., Reinisch W., Tyrrell H., Oh Y.S., Tole S., Chai A., Chamberlain-James K., Tang M.T., Schreiber S., Aboo N., Ahmad T., Aldeguer Mante X., Allez M., Almer S., Altwegg R., Andreu Garcia M., Arasaradnam R., Ardizzone S., Armuzzi A., Arnott I., Aumais G., Avni-Biron I., Barrow P., Beales I., Bermejo San Jose F., Bezuidenhout A., Biancone L., Blaeker M., Bloom S., Bokemeyer B., Bossa F., Bossuyt P., Bouguen G., Bouhnik Y., Bouma G., Bourdages R., Bourreille A., Boustiere C., Brabec T., Brand S., Buening C., Buisson A., Cadiot G., Calvet Calvo X., Carbonnel F., Carpio D., Cheon J.H., Chiba N., Chioncel C., Cimpoeru N.-C., Clodi M., Corazza G.R., Cosintino R., Cotter J., Creed T., Cummings F., de' Angelis G.L., De Maeyer M., Desai M., Desilets E., Desreumaux P., Dewit O., Dinter J., Dobru E.D., Douda T., Dumitrascu D.L., Ebert M., Echarri Piudo A., Elkhashab M., Eun C.S., Feagan B., Fejes R., Fidalgo C., Fishman S., Flourie B., Fowler S., Fries W., Fulop C., Fumery M., G Kiss G., Gassner S., Gaya D., Germana B., Gheorghe L.S., Gilletta de Saint Joseph C., Gionchetti P., Goldis A.-E., Goncalves R., Grimaud J.-C., Gyokeres T., Hagege H., Haidar A., Hartmann H., Hasselblatt P., Hebuterne X., Hellstrom P., Hindryckx P., Hlavova H., Hoentjen F., Howaldt S., Hrdlicka L., Huh K.C., Iborra Colomino M.I., Ionita-Radu F., Irving P., Jahnsen J., Jang B., Jansen J., Jeon S.W., Jover Martinez R., Juillerat P., Karlen P., Kaser A., Keil R., Kejariwal D., Keret D., Khanna R., Kim D., Kim D.H., Kim H.-J., Kim J.S., Kim K., Kim K.-J., Kim S.K., Kim Y.-H., Klaus J., Kohn A., Kojecky V., Koo J.S., Kozak R., Kremer M., Kristof T., Kruger F., Laharie D., Lahat-zok A., Landa E., Lee J., Lee K.-M., Lee K.L., Lee Y., Lenze F., Lim W.C., Limdi J., Lindsay J., Lopez Serrano P., Louis E., Lueth S., Maconi G., Mana F., Mann S., Mansfield J., Marchi S., Marino M., Marshall J., Martin Arranz M.D., Mateescu R.-B., McLaughlin J., McLaughlin S., Melzer E., Mertens J., Mitrut P., Molnar T., Muls V., Munuswamy P., Murray C., Naftali T., Naidoo V., Nanabhay Y., Negreanu L., Nguyen A., Ochsenkuehn T., Orlando A., Panes Diaz J., Paritsky M., Park D.I., Park J., Pastorelli L., Peck-Radosavljevic M., Peerani F., Perez Gisbert J., Peyrin-Biroulet L., Picon L., Pierik M., Ponich T., Portela F., Prins M.J., Racz I., Rahman K.F., Reimund J.-M., Reinshagen M., Roblin X., Rocca R., Rogai F., Rogler G., Salamon A., Salazar E., Sallo Z., Samuel S., Sans Cuffi M.D.L.S., Savarino E.V., Savarino V., Savoye G., Seicean A., Selinger C., Serra D.M., Shim H.H., Shin S., Siegmund B., Siffledeen J., Simmonds W., Smid J., Sollano J., Song G.A., Speight A., Sporea I., Staessen D., Stancu G., Steel A., Stepek D., Stoica V., Sturm A., Szekely G., Tan T.K., Taxonera Samso C., Thomson J., Tichy M., Toth G.T., Tulassay Z., Vangeli M., Varga M., Vieira A., Viennot S., Villa E., Vitek P., Vogelsang H., Vyhnalek P., Wahab P., Walldorf J., Ye B.D., and Ziady C.

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Population, Antibodies, Monoclonal, Humanized, Injections, Subcutaneou, Placebo, Severity of Illness Index, Gastroenterology, Young Adult, Double-Blind Method, Internal medicine, Gastrointestinal Agent, Clinical endpoint, medicine, education, Adverse effect, Aged, Aged, 80 and over, education.field_of_study, Hepatology, business.industry, Middle Aged, medicine.disease, Ulcerative colitis, Infliximab, Treatment Outcome, Etrolizumab, Concomitant, Colitis, Ulcerative, Female, business, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Human, medicine.drug
Abstract

Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

Published
2022
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8. Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial

Author

Laurent Peyrin-Biroulet, Ailsa Hart, Peter Bossuyt, Millie Long, Matthieu Allez, Pascal Juillerat, Alessandro Armuzzi, Edward V Loftus, Elham Ostad-Saffari, Astrid Scalori, Young S Oh, Swati Tole, Akiko Chai, Jennifer Pulley, Stuart Lacey, William J Sandborn, Humberto Aguilar, Tariq Ahmad, Evangelos Akriviadis, Xavier Aldeguer Mante, Istvan Altorjay, Ashwin Ananthakrishnan, Vibeke Andersen, Montserrat Andreu Garcia, Guy Aumais, Irit Avni-Biron, Jeffrey Axler, Kamran Ayub, Filip Baert, Mauro Bafutto, George Bamias, Isaac Bassan, Curtis Baum, Laurent Beaugerie, Brian Behm, Pradeep Bekal, Michael Bennett, Fernando Bermejo San Jose, Charles Bernstein, Dominik Bettenworth, Sudhir Bhaskar, Livia Biancone, Bahri Bilir, Michael Blaeker, Stuart Bloom, Verle Bohman, Francisco Javier Bosques Padilla, Yoram Bouhnik, Gerd Bouma, Raymond Bourdages, Stephan Brand, Brian Bressler, Markus Brückner, Carsten Buening, Franck Carbonnel, Thomas Caves, Jonathon Chapman, Jae Hee Cheon, Naoki Chiba, Camelia Chioncel, Dimitrios Christodoulou, Martin Clodi, Albert Cohen, Gino Roberto Corazza, Richard Corlin, Rocco Cosintino, Fraser Cummings, Robin Dalal, Silvio Danese, Marc De Maeyer, Carlos Fernando De Magalhães Francesconi, Aminda De Silva, Henry Debinski, Pierre Desreumaux, Olivier Dewit, Geert D'Haens, Sandra Di Felice Boratto, John Nik Ding, Tyler Dixon, Gerald Dryden, George Aaron Du Vall, Matthias Ebert, Ana Echarri Piudo, Robert Ehehalt, Magdy Elkhashab, Craig Ennis, Jason Etzel, Jan Fallingborg, Brian Feagan, Roland Fejes, Daniel Ferraz de Campos Mazo, Valéria Ferreira de Almeida Borges, Andreas Fischer, Alan Fixelle, Mark Fleisher, Sharyle Fowler, Bradley Freilich, Keith Friedenberg, Walter Fries, Csaba Fulop, Mathurin Fumery, Sergio Fuster, Gyula G Kiss, Santiago Garcia Lopez, Sonja Gassner, Kanwar Gill, Cyrielle Gilletta de Saint Joseph, Philip Ginsburg, Paolo Gionchetti, Eran Goldin, Adrian-Eugen Goldis, Hector Alejandro Gomez Jaramillo, Maciej Gonciarz, Glenn Gordon, Daniel Green, Jean-Charles Grimaud, Rogelio Guajardo Rodriguez, Zoltan Gurzo, Alexandra Gutierrez, Tibor Gyökeres, Ki Baik Hahm, Stephen Hanauer, John Hanson, William Harlan III, Peter Hasselblatt, Buhussain Hayee, Xavier Hebuterne, Peter Hendy, Melvin Heyman, Peter Higgins, Raouf Hilal, Pieter Hindryckx, Frank Hoentjen, Peter Hoffmann, Frank Holtkamp-Endemann, Gerald Holtmann, Gyula Horvat, Stefanie Howaldt, Samuel Huber, Ikechukwu Ibegbu, Maria Isabel Iborra Colomino, Peter Irving, Kim Isaacs, Kiran Jagarlamudi, Rajesh Jain, Sender Jankiel Miszputen, Jeroen Jansen, Jennifer Jones, John Karagiannis, Nicholas Karyotakis, Arthur Kaser, Lior Katz, Seymour Katz, Leo Katz, Nirmal Kaur, Edita Kazenaite, Reena Khanna, Sunil Khurana, Joo Sung Kim, Young-Ho Kim, Sung Kook Kim, Dongwoo Kim, Jochen Klaus, Dariusz Kleczkowski, Pavel Kohout, Bartosz Korczowski, Georgios Kouklakis, Ioannis Koutroubakis, Richard Krause, Tunde Kristof, Ian Kronborg, Annette Krummenerl, Limas Kupcinskas, Jorge Laborda Molteni, David Laharie, Adi Lahat-zok, Jonghun Lee, Kang-Moon Lee, Rupert Leong, Henry Levine, Jimmy Limdi, James Lindsay, Nilesh Lodhia, Edward Loftus, Randy Longman, Pilar Lopez Serrano, Edouard Louis, Maria Helena Louzada Pereira, John Lowe, Stefan Lueth, Milan Lukas, Giovanni Maconi, Finlay Macrae, Laszlo Madi-Szabo, Uma Mahadevan-Velayos, Everson Fernando Malluta, Fazia Mana, Peter Mannon, Gerasimos Mantzaris, Ignacio Marin Jimenez, Maria Dolores Martin Arranz, Radu-Bogdan Mateescu, Felipe Mazzoleni, Agnieszka Meder, Ehud Melzer, Jessica Mertens, Konstantinos Mimidis, Brent Mitchell, Tamas Molnar, Gregory Moore, Luis Alonso Morales Garza, Reme Mountifield, Vinciane Muls, Charles Murray, Bela Nagy, Markus Neurath, Augustin Nguyen, Remo Panaccione, William Pandak, Julian Panes Diaz, Jihye Park, Luca Pastorelli, Bhaktasharan Patel, Markus Peck-Radosavljevic, Gyula Pecsi, Farhad Peerani, Javier Perez Gisbert, Martin Pesta, Robert Petryka, Raymond Phillips, Marieke Pierik, Vijayalakshmi Pratha, Vlastimil Prochazka, Istvan Racz, Graham Radford-Smith, Daniel Ramos Castañeda, Odery Ramos Júnior, Jaroslaw Regula, Jean-Marie Reimund, Bryan Robbins, Xavier Roblin, Francesca Rogai, Gerhard Rogler, Jerzy Rozciecha, David Rubin, Azalia Yuriria Ruiz Flores, Maciej Rupinski, Grazyna Rydzewska, Sumona Saha, Simone Saibeni, Agnes Salamon, Zoltan Sallo, Bruce Salzberg, Douglas Samuel, Sunil Samuel, William Sandborn, Edoardo Vincenzo Savarino, Anja Schirbel, Robert Schnabel, Stefan Schreiber, John Scott, Shahriar Sedghi, Frank Seibold, Jakob Seidelin, Ursula Seidler, Ahmad Shaban, Ira Shafran, Aasim Sheikh, Alex Sherman, Haim Shirin, Patryk Smolinski, Geun Am Song, Konstantinos Soufleris, Alexander Speight, Dirk Staessen, Andreas Stallmach, Michael Staun, Daniel Stein, Hillary Steinhart, Jonathas Stifft, David Stokesberry, Andreas Sturm, Keith Sultan, Gyorgy Szekely, Kuldeep Tagore, Hugo Tanno, Lena Thin, Syed Thiwan, Carlton Thomas, Michal Tichy, Gabor Tamas Toth, Zsolt Tulassay, Jan Ulbrych, John Valentine, Marta Varga, Eduardo Vasconcellos, Byron Vaughn, Brenda Velasco, Francisco Velazquez, Severine Vermeire, Erica Villa, Aron Vincze, Harald Vogelsang, Miroslava Volfova, Lucine Vuitton, Petr Vyhnalek, Peter Wahab, Jens Walldorf, Mattitiahu Waterman, John Weber, L. Michael Weiss, Anna Wiechowska-Kozlowska, Elise Wiesner, Thomas Witthoeft, Robert Wohlman, Barbara Wozniak-Stolarska, Bruce Yacyshyn, Byong-Duk Ye, Ziad Younes, Lígia Yukie Sassaki, Cyrla Zaltman, Stefan Zeuzem, Neurosurgery, ANS - Neurovascular Disorders, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Peyrin-Biroulet L., Hart A., Bossuyt P., Long M., Allez M., Juillerat P., Armuzzi A., Loftus E.V., Ostad-Saffari E., Scalori A., Oh Y.S., Tole S., Chai A., Pulley J., Lacey S., Sandborn W.J., Aguilar H., Ahmad T., Akriviadis E., Aldeguer Mante X., Altorjay I., Ananthakrishnan A., Andersen V., Andreu Garcia M., Aumais G., Avni-Biron I., Axler J., Ayub K., Baert F., Bafutto M., Bamias G., Bassan I., Baum C., Beaugerie L., Behm B., Bekal P., Bennett M., Bermejo San Jose F., Bernstein C., Bettenworth D., Bhaskar S., Biancone L., Bilir B., Blaeker M., Bloom S., Bohman V., Bosques Padilla F.J., Bouhnik Y., Bouma G., Bourdages R., Brand S., Bressler B., Bruckner M., Buening C., Carbonnel F., Caves T., Chapman J., Cheon J.H., Chiba N., Chioncel C., Christodoulou D., Clodi M., Cohen A., Corazza G.R., Corlin R., Cosintino R., Cummings F., Dalal R., Danese S., De Maeyer M., De Magalhaes Francesconi C.F., De Silva A., Debinski H., Desreumaux P., Dewit O., D'Haens G., Di Felice Boratto S., Ding J.N., Dixon T., Dryden G., Du Vall G.A., Ebert M., Echarri Piudo A., Ehehalt R., Elkhashab M., Ennis C., Etzel J., Fallingborg J., Feagan B., Fejes R., Ferraz de Campos Mazo D., Ferreira de Almeida Borges V., Fischer A., Fixelle A., Fleisher M., Fowler S., Freilich B., Friedenberg K., Fries W., Fulop C., Fumery M., Fuster S., G Kiss G., Garcia Lopez S., Gassner S., Gill K., Gilletta de Saint Joseph C., Ginsburg P., Gionchetti P., Goldin E., Goldis A.-E., Gomez Jaramillo H.A., Gonciarz M., Gordon G., Green D., Grimaud J.-C., Guajardo Rodriguez R., Gurzo Z., Gutierrez A., Gyokeres T., Hahm K.B., Hanauer S., Hanson J., Harlan III W., Hasselblatt P., Hayee B., Hebuterne X., Hendy P., Heyman M., Higgins P., Hilal R., Hindryckx P., Hoentjen F., Hoffmann P., Holtkamp-Endemann F., Holtmann G., Horvat G., Howaldt S., Huber S., Ibegbu I., Iborra Colomino M.I., Irving P., Isaacs K., Jagarlamudi K., Jain R., Jankiel Miszputen S., Jansen J., Jones J., Karagiannis J., Karyotakis N., Kaser A., Katz L., Katz S., Kaur N., Kazenaite E., Khanna R., Khurana S., Kim J.S., Kim Y.-H., Kim S.K., Kim D., Klaus J., Kleczkowski D., Kohout P., Korczowski B., Kouklakis G., Koutroubakis I., Krause R., Kristof T., Kronborg I., Krummenerl A., Kupcinskas L., Laborda Molteni J., Laharie D., Lahat-zok A., Lee J., Lee K.-M., Leong R., Levine H., Limdi J., Lindsay J., Lodhia N., Loftus E., Longman R., Lopez Serrano P., Louis E., Louzada Pereira M.H., Lowe J., Lueth S., Lukas M., Maconi G., Macrae F., Madi-Szabo L., Mahadevan-Velayos U., Malluta E.F., Mana F., Mannon P., Mantzaris G., Marin Jimenez I., Martin Arranz M.D., Mateescu R.-B., Mazzoleni F., Meder A., Melzer E., Mertens J., Mimidis K., Mitchell B., Molnar T., Moore G., Morales Garza L.A., Mountifield R., Muls V., Murray C., Nagy B., Neurath M., Nguyen A., Panaccione R., Pandak W., Panes Diaz J., Park J., Pastorelli L., Patel B., Peck-Radosavljevic M., Pecsi G., Peerani F., Perez Gisbert J., Pesta M., Petryka R., Phillips R., Pierik M., Pratha V., Prochazka V., Racz I., Radford-Smith G., Ramos Castaneda D., Ramos Junior O., Regula J., Reimund J.-M., Robbins B., Roblin X., Rogai F., Rogler G., Rozciecha J., Rubin D., Ruiz Flores A.Y., Rupinski M., Rydzewska G., Saha S., Saibeni S., Salamon A., Sallo Z., Salzberg B., Samuel D., Samuel S., Sandborn W., Savarino E.V., Schirbel A., Schnabel R., Schreiber S., Scott J., Sedghi S., Seibold F., Seidelin J., Seidler U., Shaban A., Shafran I., Sheikh A., Sherman A., Shirin H., Smolinski P., Song G.A., Soufleris K., Speight A., Staessen D., Stallmach A., Staun M., Stein D., Steinhart H., Stifft J., Stokesberry D., Sturm A., Sultan K., Szekely G., Tagore K., Tanno H., Thin L., Thiwan S., Thomas C., Tichy M., Toth G.T., Tulassay Z., Ulbrych J., Valentine J., Varga M., Vasconcellos E., Vaughn B., Velasco B., Velazquez F., Vermeire S., Villa E., Vincze A., Vogelsang H., Volfova M., Vuitton L., Vyhnalek P., Wahab P., Walldorf J., Waterman M., Weber J., Weiss L.M., Wiechowska-Kozlowska A., Wiesner E., Witthoeft T., Wohlman R., Wozniak-Stolarska B., Yacyshyn B., Ye B.-D., Younes Z., Yukie Sassaki L., Zaltman C., and Zeuzem S.

Subjects
Adult, Male, Ulcerative Colitis Flare, medicine.medical_specialty, Asia, Adolescent, Oceania, Population, Antibodies, Monoclonal, Humanized, Injections, Subcutaneou, Placebo, Severity of Illness Index, law.invention, Middle East, Young Adult, Maintenance therapy, Randomized controlled trial, law, Internal medicine, Gastrointestinal Agent, medicine, Adverse effect, education, Aged, Aged, 80 and over, Tumor Necrosis Factor Inhibitor, education.field_of_study, Hepatology, business.industry, Remission Induction, Gastroenterology, Middle Aged, South America, medicine.disease, Ulcerative colitis, Europe, Treatment Outcome, Etrolizumab, North America, Colitis, Ulcerative, Female, business, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Human
Abstract

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

Published
2022

9. Non-colorectal intestinal tract carcinomas in inflammatory bowel disease: Results of the 3rd ECCO Pathogenesis Scientific Workshop (II)

Author

Janneke van der Woude, Bernd Bokemeyer, Laurence J. Egan, John K. Triantafillidis, Francesco Selvaggi, Gianluca Pellino, Paula Borralho Nunes, Franck Carbonnel, Marcus Harbord, Tine Jess, Renata D'Incà, Gastroenterology & Hepatology, Egan, L, D'Inca, R, Jess, T, Pellino, Gianluca, Carbonnel, F, Bokemeyer, B, Harbord, M, Nunes, P, Van der Woude, J, Selvaggi, Francesco, and Triantafillidis, J.

Subjects
Doença de Crohn, Colorectal cancer, pouch-anal anastomosis, Neoplasias Intestinais, Doenças Inflamatórias Intestinais Doenças Inflamatórias Intestinais, Gastroenterology, Inflammatory bowel disease, regional enteritis, Crohn Disease, ileal pouch, Risk Factors, ulcerative-colitis, Anus neoplasms, human-papillomavirus infection, risk-factors, Crohn's disease, General Medicine, Anus Neoplasms, Prognosis, Jejunal neoplasms, Adenocarcinoma, complicating crohns-disease, medicine.medical_specialty, Intestinal Neoplasm, Colonic Pouches, Rectal neoplasms, Inflammatory Bowel disease, SDG 3 - Good Health and Well-being, Internal medicine, Intestinal Neoplasms, medicine, Humans, population-based cohort, Gastrointestinal cancer, Colitis, Ileal neoplasms, Colonic pouches, Jejunal Neoplasms, Rectal Neoplasms, business.industry, Carcinoma, Cancer, restorative proctocolectomy, Congresses as Topic, Inflammatory Bowel Diseases, medicine.disease, digestive system diseases, Ileal Neoplasms, of-the-literature, Risk factor, business
Abstract

Patients with inflammatory bowel diseases (IBD) have an excess risk of certain gastrointestinal cancers. Much work has focused on colon cancer in IBD patients, but comparatively less is known about other more rare cancers. The European Crohn's and Colitis Organization established a pathogenesis workshop to review what is known about these cancers and formulate proposals for future studies to address the most important knowledge gaps. This article reviews the current state of knowledge about small bowel adenocarcinoma, ileo-anal pouch and rectal cuff cancer, and anal/perianal fistula cancers in IBD patients. (C) 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Published
2014
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10. Challenges to the Design, Execution, and Analysis of Randomized Controlled Trials for Inflammatory Bowel Disease

Author

Jean Yves Mary, Silvio Danese, Walter Reinisch, Geert R. D'Haens, Jean-Frederic Colombel, Richard N. Fedorak, S. B. Hanauer, Marc Lémann, F. Carbonnel, Brian G. Feagan, Paul Rutgeerts, William J. Sandborn, D'Haens, G, Feagan, B, Colombel, Jf, Sandborn, Wj, Reinisch, W, Rutgeerts, P, Carbonnel, F, Mary, Jy, Danese, S, Fedorak, Rn, Hanauer, S, Lemann, M, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology

Subjects
medicine.medical_specialty, Endpoint Determination, Statistics as Topic, Disease, Placebo, Inflammatory bowel disease, Gastroenterology, law.invention, Randomized controlled trial, law, Internal medicine, medicine, Humans, Intensive care medicine, Randomized Controlled Trials as Topic, Crohn's disease, Hepatology, biology, business.industry, Tumor Necrosis Factor-alpha, C-reactive protein, Antibodies, Monoclonal, medicine.disease, Inflammatory Bowel Diseases, Ulcerative colitis, Clinical trial, Treatment Outcome, Research Design, biology.protein, business
Abstract

Treatment of inflammatory bowel disease has greatly improved with the development of targeted, monoclonal antibody–based therapies. Tumor necrosis factor antagonists are frequently used to treat patients with Crohn's disease or ulcerative colitis, but they have side effects and their efficacy often decreases with use. New, more effective drugs are therefore needed and in development. However, many agents that appeared to be promising in preclinical studies have failed to show efficacy in clinical trials. We discuss possible reasons for the failures of these reagents in trials, which include the high rate of response to placebo, an inadequate range of doses, inappropriate timing of end point measurements, the changing therapeutic environment, and the competitive trial system. We also review regulatory guidelines for end points and trial design and recommend ways to improve trials.

Published
2012

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