Falk Gastrojournal Review / Contents
Editorial 2 Esophagus Stomach Duodenum 3 – Intestine – 2
Congress News in Brief Symposium 24 “IBD: From Pathophysiology to Personalized Medicine” Oxford (Great Britain), March 2–3, 2 2 – 23 Pancreas 2 – 2
Liver Bile 2 – 3 International Gastroenterological Congresses 2 4 Editorial
Dear colleagues,
Both predisposing genetic factors and environmental factors versus minimally invasive surgery. A single-center randomized may increase the risk of developing celiac disease. For example, study has now demonstrated that an endoscopic transluminal infections in early childhood have repeatedly been linked with approach to treat infected walled-off pancreatic necrosis is asso- an increased risk of celiac disease. A new longitudinal birth co- ciated with significantly fewer complications, lower costs, and hort study in Norway has reported that enterovirus infection better quality of life than is minimally invasive surgery (Bang et al., during early childhood is indeed associated with a higher risk of page 25). celiac disease (Kahrs et al., page 3). In addition to infections, dietary habits and medications may also represent early childhood risk Cardiovascular complications represent a significant extrahe- factors for the development of chronic diseases. As one example, patic manifestation of chronic hepatitis C. A recent study shows early childhood treatment with antibiotics and acid suppressants that successful direct-acting antiviral therapy of the hepatitis C has been linked to the development of obesity (Stark et al., virus infection may be particularly effective at lowering this page 7). The impacts of these medications on the intestinal cardiovascular risk (Butt et al., page 29). There are still no pharma- microbiota may represent a potential pathological mechanism ceutical options available for the treatment of non-alcoholic of this phenomenon. However, it has also been observed that steatohepatitis (NASH), which explains why studies on new some dietary components previously considered to be beneficial therapeutic strategies are of particular importance. In a recent may not actually confer a protective function. A new random- phase 2a study, subcutaneously administered pegbelfermin, a ized study has shown that omega-3 fatty acid intake has no ef- pegylated human fibroblast growth factor 21 analogue, was fect on the development of cardiovascular diseases or cancer shown to significantly reduce the hepatic fat fraction in NASH (Manson et al., page 7). patients while being well tolerated (Sanyal et al., page 32). A multi- center study in Europe recently demonstrated that multidrug- Inflammatory bowel disease (IBD) may greatly impair patients’ resistant bacteria represent a growing problem for patients with health and is a frequent cause of occupational disability. None- decompensated cirrhosis and with acute-on-chronic liver fail- theless, adequate research had previously not been conducted ure that can negatively impact their prognosis (Fernández et al., into whether the diagnosis of IBD is also associated with increased page 35). These findings clearly demonstrate the need for inter- mortality. Now, a population-based study in Sweden by Olén national strategies to stem the spread of multidrug-resistant and colleagues (page 13) has shown that IBD is indeed associated pathogens. with a statistically significant, 3-fold higher risk of mortality when diagnosed before the age of 18. This mortality rate is well above We hope that this selection of current literature will provide you that of the healthy population, and it has not decreased signifi- some new and exciting insights into developments in recent cantly since 1964 despite the introduction of numerous new research that will hopefully be relevant to your daily practice. treatment options. More research is thus needed in order to We wish you an enjoyable and relaxing summer! improve the prognosis for this patient population. Happy reading, Thanks to improved endoscopic resection techniques, it is now possible to successfully remove even large and polypoid lesions such as lateral spreading tumors (LST) by endoscopic surgery. However, these techniques are often associated with a significant risk of relapse. A randomized study has now shown that thermal ablation of the defect margins of LST lesions can reduce the risk of relapse from 21% to 5% (Klein et al., page 18), suggesting that coagulation of this type should be considered as a component of resection. In light of the widespread incidence of vitamin D deficiency both in the general population and among patients with chronic diseases such as IBD, calcium and vitamin D sup- plementation plays an important role in routine clinical practice. It is therefore very surprising that supplementation with calcium or with calcium and vitamin D has now been observed to in- crease the long-term risk of developing sessile serrated adeno- mas or polyps (Crocket et al., page 20). In light of this new finding, Christoph Neumann-Haefelin and Peter Hasselblatt the risk-benefit ratio of vitamin D supplementation must be Department of Internal Medicine II, Medical University Clinic weighed carefully. of Freiburg (Germany)
In recent years, surgical management of infected pancreatic necrosis has shifted away from open necrosectomy to minimally invasive treatment options. However, to date very few studies have compared the use of endoscopic treatment approaches
2 Esophagus ease, including methods to ensure adequate documentation of family medical history. Stomach Duodenum B. Lebwohl, M.D., Division of Gastroenterology and Hepatology, Columbia University Medical Center/New York-Presbyterian Hospital, 180 Fort Washington Avenue, Suite 936, New York, NY 10032, USA, E-Mail: [email protected] ■
BMJ. ;:l
Kahrs CR, Chuda K, Tapia G, Stene LC, Mårild K, Rasmussen T, Rønningen KS, Lundin KEA, Kramna L, Cinek O, Størdal K
Enterovirus as trigger of celiac disease: Nested case-control study within prospective Celiac Disease and birth cohort
Gluten Sensitivity Objective: To determine whether infection with human entero- virus or adenovirus, both common intestinal viruses, predicts development of celiac disease. Clin Gastroenterol Hepatol. ;():– Design: Case-control study nested within Norwegian birth cohort recruited between 2001 and 2007 and followed to September 2016. Faye AS, Polubriaginof F, Green PHR, Vawdrey DK, Tatonetti N, Setting: Norwegian population. Lebwohl B Participants: Children carrying the HLA genotype DR4-DQ8/ DR3-DQ2 conferring increased risk of celiac disease. Low rates of screening for celiac disease Exposures: Enterovirus and adenovirus detected using real- among family members time polymerase chain reaction in monthly stool samples from age 3–36 months. Background and aims: Given the increased morbidity and po- Main outcome measure: Celiac disease diagnosed according to tential mortality of celiac disease, guidelines recommend screen- standard criteria. Celiac disease antibodies were tested in blood ing high-risk individuals, including first-degree relatives of pa- samples taken at age 3, 6, 9, and 12 months and then annually. tients. The authors assessed how commonly celiac disease testing Adjusted odds ratios (aORs) from mixed effects logistic regres- occurs in these individuals and identified factors that influence sion model were used to assess the relation between viral infec- testing. tions before development of celiac disease antibodies and celiac Methods: Relatives of 2081 patients with biopsy-diagnosed disease. celiac disease and followed up at Columbia University Medical Results: Among 220 children, and after a mean of 9.9 (SD 1.6) Center were identified using relationship inference from the years, 25 children were diagnosed as having celiac disease after electronic health record – a validated method that uses emer- screening and were matched to 2 controls each. Enterovirus gency contact information to identify familial relationships. The was found in 370 of 2135 samples (17%) and was significantly authors manually abstracted data from each record and per- more frequent in samples collected before development of ce- formed univariate and multivariate analyses to identify factors liac disease antibodies in cases than in controls (aOR = 1.49, 95% associated with testing relatives for celiac disease. confidence interval [CI]: 1.07–2.06; p = 0.02). The association was Results: Of 539 relatives identified, 212 (39.3%) were tested for restricted to infections after introduction of gluten. High quan- celiac disease, including 50.4% (193/383) of first-degree relatives tity samples (> 100,000 copies/μl) (aOR = 2.11, 95% CI: 1.24–3.60; and 71.5% (118/165) of symptomatic first-degree relatives. Of the p = 0.01) and long lasting infections (> 2 months) (aOR = 2.16, 383 first-degree relatives, only 116 (30.3%) had a documented 95% CI: 1.16–4.04; p = 0.02) gave higher risk estimates. Both the family history of celiac disease. On multivariate analysis, testing was commonly detected enterovirus species Enterovirus A and En- more likely in adults (odds ratio [OR] for 18–39 years vs. younger terovirus B were significantly associated with celiac disease. The than 18 years = 2.27, 95% confidence interval [CI]: 1.12–4.58), rela- association was not found for infections during or after devel- tives being seen by a gastroenterologist (OR = 15.16, 95% CI: opment of celiac disease antibodies. Adenovirus was not associ- 7.72–29.80), relatives with symptoms (OR = 3.69, 95% CI: 2.11–6.47), ated with celiac disease. first-degree relatives of a patient with celiac disease (OR = 4.90, 95% CI: 2.34–10.25), and relatives with a documented family his- Conclusions: In this longitudinal study, a higher frequency of tory of celiac disease (OR = 11.9, 95% CI: 5.56–25.48). enterovirus, but not adenovirus, during early childhood was associated with later celiac disease. The finding adds new Conclusions: By using an algorithm to identify relatives of information on the role of viral infections in the etiology of patients with celiac disease, it was found that nearly 3% of celiac disease. symptomatic first-degree relatives of patients with celiac dis- ease have not received the tests recommended by guide- Dr. K. Størdal, Department of Pediatrics, Østfold Hospital Trust, lines. Health care providers should implement strategies to Postboks 300, 1714 Grålum, Norway, E-Mail: [email protected] identify and screen patients at increased risk for celiac dis- ■
3 EoE Clin Gastroenterol Hepatol. ;():–.e
Dellon ES, Katzka DA, Collins MH, Gupta SK, Lan L, Williams J, Gastroenterology. ;():–.e Hirano I Safety and efficacy of budesonide oral Hirano I, Collins MH, Assouline-Dayan Y, Evans L, Gupta S, Schoepfer AM, Straumann A, Safroneeva E, Grimm M, Smith H, suspension maintenance therapy in patients Tompkins CA, Woo A, Peach R, Frohna P, Gujrathi S, Penenberg DN, with eosinophilic esophagitis Li C, Opiteck GJ, Olson A, Aranda R, Rothenberg ME, Dellon ES; Background and aims: The authors aimed to determine the HEROES Study Group safety and efficacy of budesonide oral suspension (BOS) main- tenance therapy in patients with eosinophilic esophagitis (EoE). RPC, a monoclonal antibody against IL-, Methods: They performed an open-label extension study of a reduces histologic and endoscopic activity 12-week, multicenter, randomized, double-blind, placebo-con- in patients with eosinophilic esophagitis trolled trial. Patients with EoE (11–40 years old) who completed double-blind BOS (n = 45) or placebo therapy (n = 37) received Background and aims: Eosinophilic esophagitis (EoE) is a chronic, 24 weeks’ open-label BOS (2.0 mg once daily for 12 weeks, with esophageal, type 2 inflammatory response associated with in- optional dose increase [1.5–2.0 mg twice daily] for 12 weeks creased serum levels of interleukin 13 (IL-13), which might con- thereafter). Predefined efficacy outcomes included: proportion tribute to its pathogenesis. RPC4046, a recombinant humanized of patients with a histologic response (≤ 6 eosinophils/high- monoclonal antibody against IL-13, prevents its binding to the power field [eos/hpf]) and change in mean peak eosinophil receptor subunits IL-13RA1 and IL-13RA2. The authors performed counts after 24 weeks. Analyses were stratified by patients who a phase 2 trial to evaluate the efficacy and safety of RPC4046 in received placebo (placebo/BOS) or BOS (BOS/BOS) during the patients with EoE. double-blind trial. Methods: They performed a multicenter, double-blind trial of Results: BOS was well tolerated and drug-related adverse events 99 adults with active EoE randomly assigned (1:1:1) to groups given were uncommon (placebo/BOS, 19% [7/37]; BOS/BOS, 4% [2/45]). RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, Incidence of oral candidiasis (1 per group) and esophageal can- from September 2014 through December 2015. Patients were didiasis (placebo/BOS group, n = 4) remained low. Changes in seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They under- morning serum cortisol levels were not clinically relevant. A his- went esophagogastroduodenoscopy and biopsies were collect- tologic response was observed in 49% (16/33) of patients receiv- ed at baseline and week 16. Patients completed a daily dysphagia ing placebo/BOS and 23% (9/39) receiving BOS/BOS. Mean peak symptom diary through week 16 and patient-reported outcome eosinophil counts (baseline vs. week 24 or early termination) data were collected. The primary outcome was change in mean were: placebo/BOS, 118.8 versus 29.1; p < 0.001 and BOS/BOS, 38.1 esophageal eosinophil count in the 5 high-power fields (hpfs) versus 72.4; p = 0.01. Of the patients who responded to double- with the highest level of inflammation. blind therapy, 42% maintained a histologic response during the Results: At week 16, mean changes in esophageal eosinophil open-label extension; 4% of non-responders gained response. count per hpf were a reduction of 94.8 ± 67.3 in patients who Conclusions: In an open-label extension study of patients with received 180 mg RPC4046 (p < 0.0001) and a reduction of 99.9 ± eosinophilic esophagitis, budesonide oral suspension (BOS) 79.5 in patients who received 360 mg RPC4046 (p < 0.0001) com- was well tolerated and drug-related adverse events were un- pared with a reduction of 4.4 ± 59.9 in patients who received common. BOS maintained a histologic response in some initial placebo. The 360-mg RPC4046 group, compared with the pla- responders, but few initial non-responders had a response. cebo group, showed significant reductions in validated endo- scopic severity score at all esophageal locations (p < 0.0001), E.S. Dellon, M.D., Center for Esophageal Diseases and Swallowing, validated histologic grade and stage scores (both p < 0.0001), Division of Gastroenterology and Hepatology, Department of and clinician’s global assessment of disease severity (p = 0.0352); Medicine, University of North Carolina at Chapel Hill, CB #7080, they had a numerical reduction in scores from the dysphagia Bioinformatics Building, 130 Mason Farm Road, Chapel Hill, symptom diary (p = 0.0733). Significant reductions in esophageal NC 227599-7080, USA, E-Mail: [email protected] eosinophil counts and histologic and endoscopic features were ■ observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. Clin Gastroenterol Hepatol. ;():–.e
Conclusions: In a phase 2 trial of patients with eosinophilic Greuter T, Safroneeva E, Bussmann C, Biedermann L, esophagitis, RPC44 (a monoclonal antibody against inter- Vavricka SR, Katzka DA, Schoepfer AM, Straumann A leukin 3) was found to reduce histologic and endoscopic fea- tures compared with placebo. RPC44 was well tolerated. Maintenance treatment of eosinophilic esophagitis with swallowed topical steroids E.S. Dellon, M.D., Center for Esophageal Diseases and Swallowing, alters disease course over a -year follow-up Division of Gastroenterology and Hepatology, Department of period in adult patients Medicine, University of North Carolina at Chapel Hill, CB #7080, Bioinformatics Building, 130 Mason Farm Road, Chapel Hill, Background and aims: Although swallowed topical corticoste- NC 227599-7080, USA, E-Mail: [email protected] roids (STCs) are effective in inducing remission of active eosino- ■ philic esophagitis (EoE), there are few data on maintenance of
4 long-term remission. The authors evaluated the long-term ef- cobacter pylori infection. Patients were followed for 55 months fectiveness of STC therapy for adults with EoE. (median); patients with stages II, III and IV underwent a second Methods: They performed a retrospective study using the Swiss endoscopy/restaging (T-1), and those with stages 0 and I were EoE database and analyzed data on 229 patients with EoE treat- followed clinically and through in-depth clinical and record ed with STCs (175 male; mean age at diagnosis, 39 ± 15 years; checking. End points were OLGA stage at T-1 and development median time until diagnosis, 6 years) from 2000 through 2014. of gastric epithelial neoplasia. Patients were followed for a median of 5 years (interquartile Results: At T-0, 77.6% of patients had stage 0, 14.4% stage I, 5.1% range [IQR], 3–7 years). The authors collected data from 819 fol- stage II, 2.1% stage III and 0.85% stage IV. H. pylori infection was low-up visits on clinical, endoscopic and histological disease detected in 603 patients at T-0 and successfully eradicated in characteristics. The primary end point was proportions of clini- 602 of them; 220 had a documented history of H. pylori eradica- cal, endoscopic, and histological remission in all patients and tion; and 932 were H. pylori naive-negative. Incident neoplastic groups, based on the status and duration of STC treatment. lesions (prevalence = 0.4%; low-grade intraepithelial neoplasia Results: Patients were taking STCs at 336 of the follow-up visits (IEN) = 4; high-grade IEN = 1; GC = 2) developed exclusively in (41.0% of visits). The median duration of STC use before a follow-up patients with stages III–IV. The risk for epithelial neoplasia was visit was 347 days (IQR, 90–750 days) corresponding to 677 doses null in patients at stages 0, I and II (95% CI: 0–0.4), 36.5 per 1000 (IQR, 280–1413 doses) of 0.25 mg each. At the visits, higher pro- person-years in patients at stage III (95% CI: 13.7–97.4) and 63.1 portions of patients who were still taking STCs were in clinical per 1000 person-years in patients at stage IV (95% CI: 20.3–195.6). remission (31.0%) compared to patients not taking STCs (4.5%) (p < 0.001), as well as endoscopic remission (48.8% vs. 17.8%; Conclusions: This prospective study confirms that OLGA (oper- p < 0.001), histologic remission (44.8% vs. 10.1%; p < 0.001), and ative link on gastritis assessment) staging reliably predicts the complete remission (16.1% vs. 1.3%; p < 0.001). Higher cumulative risk for development of gastric epithelial neoplasia. Although doses of STCs and longer durations of treatment were associat- no neoplastic lesions arose in Helicobacter pylori-naive pa- ed with higher proportions of clinical and complete remission. tients, the H. pylori eradication in subjects with advanced stag- No dysplasia or mucosal atrophy was detected. Esophageal es (III–IV) did not abolish the risk for neoplastic progression. candidiasis was observed at 2.7% of visits in patients taking STCs. Prof. Dr. M. Rugge, Surgical Pathology & Cytopathology Unit, Conclusion: In an analysis of data from the Swiss EoE data- Department of Medicine (DIMED), University of Padua, Via base, the authors found maintenance therapy with swallowed Giustiniani, 2, 35128 Padua, Italy, E-Mail: [email protected] topical corticosteroids (STCs) to achieve complete remission ■ at .% of follow-up visits, which was higher than in patients receiving no treatment (.3%). Given the good safety profile of low-dose STC, they advocate for a prolonged treatment. Dose-finding trials are needed to achieve higher remission N Engl J Med. ;():– rates. Mariette C, Markar SR, Dabakuyo-Yonli TS, Meunier B, Pezet D, Dr. T. Greuter, Klinik für Gastroenterologie und Hepatologie, Collet D, D‘Journo XB, Brigand C, Perniceni T, Carrère N, Universitätsspital Zürich, Rämistr. 100, 8091 Zürich, Switzerland, Mabrut JY, Msika S, Peschaud F, Prudhomme M, Bonnetain F, E-Mail: [email protected] Piessen G; Federation de Recherche en Chirurgie (FRENCH); ■ French Eso-Gastric Tumors (FREGAT) Working Group Hybrid minimally invasive esophagectomy for esophageal cancer Barrett’s Esophagus, Esophageal and Gastric Cancer Background: Postoperative complications, especially pulmonary complications, affect more than half the patients who undergo open esophagectomy for esophageal cancer. Whether hybrid Gut. ;():– minimally invasive esophagectomy results in lower morbidity than open esophagectomy is unclear. Rugge M, Meggio A, Pravadelli C, Barbareschi M, Fassan M, Methods: The authors performed a multicenter, open-label, Gentilini M, Zorzi M, De Pretis G, Graham DY, Genta RM randomized, controlled trial involving patients 18–75 years of age with resectable cancer of the middle or lower third of the Gastritis staging in the endoscopic follow-up esophagus. Patients were randomly assigned to undergo trans- thoracic open esophagectomy (open procedure) or hybrid min- for the secondary prevention of gastric imally invasive esophagectomy (hybrid procedure). Surgical quality cancer: A -year prospective study of assurance was implemented by the credentialing of surgeons, patients standardization of technique, and monitoring of performance. Hybrid surgery comprised a 2-field abdominal-thoracic opera- Objective: Operative link on gastritis assessment (OLGA) staging tion (also called an Ivor-Lewis procedure) with laparoscopic for gastritis ranks the risk for gastric cancer (GC) in progressive gastric mobilization and open right thoracotomy. The primary stages (0–IV). This prospective study aimed at quantifying the end point was intraoperative or postoperative complication of cancer risk associated with each gastritis stage. grade II or higher according to the Clavien-Dindo classification Design: A cohort of 1755 consecutive patients with dyspepsia (indicating major complication leading to intervention) within underwent initial (T-0) esophagogastroduodenoscopy with 30 days. Analyses were done according to the intention-to-treat mapped gastric biopsies, OLGA staging and assessment of Heli- principle.
5 Results: From October 2009 through April 2012, 103 patients were Conclusion: In a low gastric cancer incidence area, a surveil- randomly assigned to the hybrid-procedure group and 104 to lance program can detect gastric cancer at an early curable the open-procedure group. A total of 312 serious adverse events stage with an overall risk of neoplastic progression of .3% were recorded in 110 patients. A total of 37 patients (36%) in the per year. Use of serological markers in endoscopic surveil- hybrid-procedure group had a major intraoperative or postop- lance programs may improve risk stratification. erative complication, as compared with 67 (64%) in the open- procedure group (odds ratio = 0.31, 95% confidence interval [CI]: Dr. W.J. den Hollander, Department of Gastroenterology 0.18–0.55; p < 0.001). A total of 18 of 102 patients (18%) in the hy- and Hepatology, Erasmus University Medical Center, brid-procedure group had a major pulmonary complication, as ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands, compared with 31 of 103 (30%) in the open-procedure group. At E-Mail: [email protected] 3 years, overall survival was 67% (95% CI: 57–75) in the hybrid- ■ procedure group, as compared with 55% (95% CI: 45–64) in the open-procedure group; disease-free survival was 57% (95% CI: 47–66) and 48% (95% CI: 38–57), respectively. Lancet Oncol. ;():– Conclusions: The authors found that hybrid minimally inva- sive esophagectomy resulted in a lower incidence of intra- Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, operative and postoperative major complications, specifically Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, pulmonary complications, than open esophagectomy, with- Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, out compromising overall and disease-free survival over a Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, period of 3 years. Carlesi R, Das M, Shah MA; RAINFALL Study Group
Prof. Dr. G. Piessen, Department of Digestive and Oncologic Ramucirumab with cisplatin and fluoropyri- Surgery, Claude Huriez University Hospital, rue Michel Polonovski, 59000 Lille, France, E-Mail: [email protected] midine as first-line therapy in patients with ■ metastatic gastric or junctional adenocarcinoma (RAINFALL): A double-blind, randomized, placebo-controlled, phase trial Gut. ;():– Background: Vascular endothelial growth factor (VEGF) and VEGF den Hollander WJ, Holster IL, den Hoed CM, Capelle LG, Tang TJ, receptor 2 (VEGFR-2)-mediated signaling and angiogenesis can Anten MP, Prytz-Berset I, Witteman EM, ter Borg F, den Hartog G, contribute to the pathogenesis and progression of gastric can- Bruno MJ, Peppelenbosch MP, Lesterhuis W, Doukas M, Kuipers EJ, cer. The authors aimed to assess whether the addition of ramu- Spaander MCW cirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic Surveillance of premalignant gastric lesions: gastric or gastroesophageal junction adenocarcinoma. A multicenter prospective cohort study from Methods: For this double-blind, randomized, placebo-con- low incidence regions trolled, phase 3 trial done at 126 centers in 20 countries, patients aged 18 years or older with metastatic, HER2-negative gastric or Objective: International guidelines recommend endoscopic gastroesophageal junction adenocarcinoma, an Eastern Coop- surveillance of premalignant gastric lesions. However, the diag- erative Oncology Group (ECOG) performance status of 0 or 1, nostic yield and preventive effect require further study. The au- and adequate organ function were recruited. Eligible patients thors therefore aimed to assess the incidence of neoplastic pro- were randomly assigned (1:1) with an interactive web response gression and to assess the ability of various tests to identify system to receive cisplatin (80 mg/m², on the first day) plus patients most at risk for progression. capecitabine (1000 mg/m², twice daily for 14 days), every 21 days, Design: Patients from the Netherlands and Norway with a pre- and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, vious diagnosis of atrophic gastritis (AG), intestinal metaplasia every 21 days. 5-Fluorouracil (800 mg/m² intravenous infusion on (IM) or dysplasia were offered endoscopic surveillance. All his- days 1–5) was permitted in patients unable to take capecitabine. tological specimens were assessed according to the updated The primary end point was investigator-assessed progression- Sydney classification and the operative link on gastric intestinal free survival (PFS), analyzed by intention to treat in the first 508 metaplasia (OLGIM) system. In addition, serum pepsinogens patients. The authors did a sensitivity analysis of the primary (PG) and gastrin-17 were measured. end point, including a central review of computed tomography Results: 279 (mean age 57.9 years [SD 11.4], male/female 137/142) scans. Overall survival (OS) was a key secondary end point. patients were included and underwent at least 1 surveillance Findings: Between January 28, 2015, and September 16, 2016, 645 endoscopy during follow-up. The mean follow-up time was patients were randomly assigned to receive ramucirumab plus 57 months (SD 36). Four subjects (1.4%) were diagnosed with fluoropyrimidine and cisplatin (n = 326) or placebo plus fluoro- high-grade adenoma/dysplasia or invasive neoplasia (i.e., gas- pyrimidine and cisplatin (n = 319). Investigator-assessed PFS was tric cancer) during follow-up. Two of these patients were suc- significantly longer in the ramucirumab group than the placebo cessfully treated with endoscopic submucosal dissection, while group (hazard ratio [HR] = 0.753, 95% confidence interval [CI]: the other 2 underwent a total gastrectomy. Compared with pa- 0.607–0.935, p = 0.0106; median PFS 5.7 months [5.5–6.5] vs. 5.4 tients with extended AG/IM (PGI/II ≤ 3 and/or OLGIM stage III–IV), months [4.5–5.7]). A sensitivity analysis based on central inde- patients with limited AG/IM (PG I/II > 3 and OLGIM stage 0–II) pendent review of the radiological images did not corroborate did not develop high-grade adenoma/dysplasia or invasive neo- the investigator-assessed difference in PFS (HR = 0.961, 95% CI: plasia during follow-up (p = 0.02). 0.768–1.203, p = 0.74). There was no difference in OS between
6 groups (HR = 0.962, 95% CI: 0.801–1.156, p = 0.6757; median OS 11,089 (3.3%) a PPI. Antibiotic prescriptions were associated with 11.2 months [9.9–11.9] in the ramucirumab group vs. 10.7 months obesity (hazard ratio [HR] = 1.26, 95% confidence interval: 1.23–1.28). [9.5–11.9] in the placebo group). The most common grade 3–4 This association persisted regardless of antibiotic class and adverse events were neutropenia (85 [26%] of 323 patients in strengthened with each additional class of antibiotic prescribed. the ramucirumab group vs. 85 [27%] of 315 in the placebo H2RA and PPI prescriptions were also associated with obesity, group), anemia (39 [12%] vs. 44 [14%]), and hypertension (32 [10%] with a stronger association for each 30-day supply prescribed. vs. 5 [2%]). The incidence of any-grade serious adverse events The HR increased commensurately with exposure to each addi- was 160 (50%) of 323 patients in the ramucirumab group and 149 tional medication group prescribed. (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramu- Conclusions: Antibiotics, acid suppressants and the combina- cirumab group vs. 21 [7%] in the placebo group) and diarrhea tion of multiple medications in the first 2 years of life are as- (11 [3%] vs. 19 [6%]). There were 7 deaths in each group, either sociated with a diagnosis of childhood obesity. Microbiota- during study treatment or within 30 days of discontinuing study altering medications administered in early childhood may treatment, which were the result of treatment-related adverse influence weight gain. events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric hemorrhage, peritoni- C.M. Stark, M.D., Department of Pediatrics, William Beaumont tis, pneumothorax, septic shock, and sudden death (n = 1 of Army Medical Center, 5005 North Piedras Street, El Paso, each). In the placebo group, these adverse events were cere- TX 79920, USA, E-Mail: [email protected] brovascular accident (n = 1), multiple organ dysfunction syn- ■ drome (n = 2), pulmonary embolism (n = 2), sepsis (n = 1), and small intestine perforation (n = 1). N Engl J Med. ; ( ): – Interpretation: Although the primary analysis for progres- sion-free survival (PFS) was statistically significant, this out- Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, come was not confirmed in a sensitivity analysis of PFS by Gibson H, Albert CM, Gordon D, Copeland T, D’Agostino D, central independent review, and did not improve overall sur- Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, vival. Therefore, the addition of ramucirumab to cisplatin plus Buring JE; VITAL Research Group fluoropyrimidine chemotherapy is not recommended as first- line treatment for this patient population. Marine n- fatty acids and prevention of cardiovascular disease and cancer C.S. Fuchs, M.D., Yale Cancer Center, Smilow Cancer Hospital, 35 Park Street, New Haven, CT 06519, USA, E-Mail: [email protected] Background: Higher intake of marine n-3 (also called omega-3) ■ fatty acids has been associated with reduced risks of cardiovas- cular disease and cancer in several observational studies. Whether supplementation with n-3 fatty acids has such effects in general populations at usual risk for these end points is unclear. Nutrition and Obesity Methods: The authors conducted a randomized, placebo-con- trolled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU/day) and marine n-3 fatty acids (at a dose of Gut. ;( ): – 1 g/day) in the primary prevention of cardiovascular disease and cancer among men ≥ 50 years of age and women ≥ 55 years of Stark CM, Susi A, Emerick J, Nylund CM age in the United States. Primary end points were major cardio- vascular events (a composite of myocardial infarction, stroke, or Antibiotic and acid-suppression medications death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of during early childhood are associated with the composite cardiovascular end point, the composite end obesity point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from Objective: Gut microbiota alterations are associated with obe- cancer. Safety was also assessed. This article reports the results sity. Early exposure to medications, including acid suppressants of the comparison of n-3 fatty acids with placebo. and antibiotics, can alter gut biota and may increase the likeli- Results: A total of 25,871 participants, including 5106 black par- hood of developing obesity. The authors investigated the asso- ticipants, underwent randomization. During a median follow- ciation of antibiotic, histamine-2 receptor antagonist (H2RA) and up of 5.3 years, a major cardiovascular event occurred in 386 proton-pump inhibitor (PPI) prescriptions during early childhood participants in the n-3 group and in 419 in the placebo group with a diagnosis of obesity. (hazard ratio [HR] = 0.92, 95% confidence interval [CI]: 0.80–1.06; Design: They performed a cohort study of U.S. Department of p = 0.24). Invasive cancer was diagnosed in 820 participants in Defense TRICARE beneficiaries born from October 2006 to Sep- the n-3 group and in 797 in the placebo group (HR = 1.03, 95% CI: tember 2013. Exposures were defined as having any dispensed 0.93–1.13; p = 0.56). In the analyses of key secondary end points, prescription for antibiotic, H2RA or PPI medications in the first the HRs were as follows: for the expanded composite end point 2 years of life. A single-event analysis of obesity was performed of cardiovascular events, 0.93 (95% CI: 0.82–1.04); for total myo- using Cox proportional hazards regression. cardial infarction, 0.72 (95% CI: 0.59–0.90); for total stroke, 1.04 Results: 333,353 children met inclusion criteria, with 241,502 (72.4%) (95% CI: 0.83–1.31); for death from cardiovascular causes, 0.96 children prescribed an antibiotic, 39,488 (11.8%) an H2RA and (95% CI: 0.76–1.21); and for death from cancer (341 deaths from
7 cancer), 0.97 (95% CI: 0.79–1.20). In the analysis of death from any uation, even without a provider’s recommendation. Notably, cause (978 deaths overall), the HR was 1.02 (95% CI: 0.90–1.15). No individuals at high risk of upper gastrointestinal bleeding, excess risks of bleeding or other serious adverse events were who benefit from PPIs, were equally likely to have tried observed. stopping PPIs as others. Providers should proactively discuss the risks and benefits of PPIs with their patients, who may Conclusions: Supplementation with n-3 fatty acids did not otherwise make unwise decisions about PPI management on result in a lower incidence of major cardiovascular events or their own. cancer than placebo. J.E. Kurlander, M.D., Department of Internal Medicine, J.E. Manson, M.D., Department of Medicine, Brigham and University of Michigan, 15 East Medical Center Drive, Ann Arbor, Women’s Hospital and Harvard Medical School, 900 Common- MI 48109, USA, E-Mail: [email protected] wealth Avenue, 3rd Floor, Boston, MA 02215, USA, ■ E-Mail: [email protected] ■ Gastroenterology. ;():–.e
Proton-Pump Inhibitors Hansen KE, Nieves JW, Nudurupati S, Metz DC, Perez MC
Dexlansoprazole and esomeprazole do Am J Gastroenterol. ;():– not affect bone homeostasis in healthy postmenopausal women Kurlander JE, Kennedy JK, Rubenstein JH, Richardson CR, Krein SL, De Vries R, Saini SD Background and aims: Epidemiological studies have associated proton-pump inhibitor (PPI) therapy with osteoporotic fractures, Patients’ perceptions of proton-pump inhibitor but it is not clear if PPIs directly cause osteoporosis. The authors risks and attempts at discontinuation: evaluated the effect of dexlansoprazole and esomeprazole on A national survey bone turnover, bone mineral density (BMD), true fractional cal- cium absorption (TFCA), serum and urine levels of minerals, and Objectives: Little is known about how reports on the adverse levels of parathyroid hormone (PTH) in healthy postmenopausal effects of proton-pump inhibitors (PPIs) impact patients’ per- women. ceptions of these drugs and medication use. The authors sought Methods: They performed a prospective, multicenter, double- to determine patients’ level of concern about PPI adverse effects blind study of 115 healthy, postmenopausal women (45–75 years and its association with attempts to discontinue these drugs. of age) from November 4, 2010, through August 7, 2014. Women Methods: This study is an online survey of US adults who use were randomly assigned to groups given dexlansoprazole (60 mg), PPIs for gastroesophageal reflux disease. Topics included aware- esomeprazole (40 mg), or placebo daily for 26 weeks. Plasma ness of and concern about PPI adverse effects, prior discussion levels of procollagen type 1 N-terminal propeptide (P1NP) and with providers, and attempts to stop PPI because of concern C-terminal telopeptide of type 1 collagen (CTX) were measured about adverse effects. For the primary analysis, logistic regres- at 0 (baseline), 13, and 26 weeks. Primary outcomes were per- sion was used to identify associations between having attempt- cent change in P1NP and CTX between weeks 0 and 26. Chang- ed to stop PPI and concern about PPI-related adverse effects, es in serum and urine levels of mineral, BMD, PTH (all subjects), a provider’s recommendation to stop, risk of upper gastrointes- and TFCA (n = 30) were also measured. tinal bleeding (UGIB), age, and gender. Results: Between baseline and week 26, there were no signifi- Results: Among 755 patient participants, mean age was 49 years cant within-group differences in markers of bone turnover; (SD 16), 71% were women, an 24% were at high risk of UGIB. 20% there was a non-significant increase in CTX levels in the dexlan- of patients were able to write in ≥ 1 reported adverse effect, and soprazole group (0.12 ng/ml). The esomeprazole and dexlanso- 46% endorsed awareness of ≥ 1 adverse effect when presented prazole groups had significantly increased levels of P1NP (18.2% with a list, most commonly chronic kidney disease (17%). 33% of and 19.2%, respectively) and CTX (22.0% and 27.4%, respectively) patients were slightly concerned, 32% somewhat concerned, at week 26 compared with the placebo group, although these and 14% extremely concerned about adverse effects. 24% of pa- values remained within normal ranges. There were no statisti- tients had discussed PPI risks and benefits with a provider, and cally significant differences between groups in serum or urine 9% had been recommended to stop. 39% had attempted to levels of minerals, BMD, or PTH at week 26. PPI therapy did not stop their PPI, most (83%) without a provider recommendation. reduce TFCA. Factors associated with an attempt at stopping PPI included: (i) provider recommendation to stop (odds ratio [OR] = 3.26, 95% Conclusions: In a prospective study of postmenopausal women, confidence interval [CI]: 1.82–5.83); (ii) concern about adverse significant increases in markers of bone turnover were found effects (OR = 5.13, 95% CI: 2.77–9.51 for slightly; 12.0, 95% CI: in women given proton-pump inhibitor (PPI) therapy com- 6.51–22.2 for somewhat; and 19.4, 95% CI: 9.75–38.7 for extremely pared with women given placebo, but levels remained within concerned); and (iii) female gender (OR = 1.64, 95% CI: 1.12–2.39). the normal reference range. No significant differences were Patients at high risk of UGIB were as likely to have attempted to found among groups in changes in bone mineral density, stop as others (OR = 0.98, 95% CI: 0.66–1.44). parathyroid hormone, serum or urine levels of minerals, or true fractional calcium absorption. These findings indicate Conclusions: Concern about proton-pump inhibitors (PPIs) is that 2 weeks of treatment with a PPI has no clinically mean- common and strongly associated with attempts at discontin- ingful effects on bone homeostasis.
8 K.E. Hansen, M.D., Associate Professor of Medicine, University Endoscopy of the Upper GI Tract of Wisconsin School of Medicine & Public Health, Room 4124 MFCB, 1685 Highland Avenue, Madison, WI 53705, USA, E-Mail: [email protected] Clin Gastroenterol Hepatol. ;():– ■ Mekaroonkamol P, Dacha S, Wang L, Li X, Jiang Y, Li L, Li T, Shahnavaz N, Sakaria S, LeVert FE, Keilin S, Willingham F, Upper Gastrointestinal Bleeding Christie J, Cai Q Gastric peroral endoscopic pyloromyotomy United European Gastroenterology J. ;():– reduces symptoms, increases quality of life, and reduces health-care use for patients Siau K, Hodson J, Ingram R, Baxter A, Widlak MM, Sharratt C, with gastroparesis Baker GM, Troth T, Hicken B, Tahir F, Magrabi M, Yousaf N, Grant C, Poon D, Khalil H, Lee HL, White JR, Tan H, Samani S, Hooper P, Background and aims: Gastric peroral endoscopic pyloromy- Ahmed S, Amin M, Mahgoub S, Asghar K, Leet F, Harborne MJ, otomy (GPOEM) is becoming a promising treatment option Polewiczowska B, Khan S, Anjum MR, McFarlane M, Mozdiak E, for patients with refractory gastroparesis. The authors aimed to O’Flynn LD, Blee IC, Molyneux RM, Kurian A, Abbas SN, Abbasi A, systematically assess the efficacy of GPOEM and its effects on Karim A, Yasin A, Khattak F, White J, Ahmed R, Morgan JA, health-care use. Alleyne L, Alam MA, Palaniyappan N, Rodger VJ, Sawhney P, Methods: They performed a retrospective study on 30 patients Aslam N, Okeke T, Lawson A, Cheung D, Reid JP, Awasthi A, with refractory gastroparesis who underwent GPOEM from June Anderson MR, Timothy JR, Pattni S, Ahmad S, Townson G, 2015 through July 2017 at a tertiary center and compared out- Shearman J, Giljaca V, Brookes MJ, Disney BR, Guha N, Thomas T, comes with those of 7 patients with refractory gastroparesis who Norman A, Wurm P, Shah A, Fisher NC, Ishaq S, Major G did not undergo the procedure (controls). The primary outcomes were patient-reported reductions in symptoms, based on the Time to endoscopy for acute upper gastro- gastroparesis cardinal symptom index (GCSI), and increases in 8 aspects of quality of life, based on Short Form 36 (SF-36) scores. intestinal bleeding: Results from a prospective Data were collected on the day of the procedure (baseline) and multicenter trainee-led audit at 1 month, 6, 12, and 18 months afterward. Secondary outcomes included visits to the emergency department or hospitalization Background: Endoscopy within 24 hours of admission (early en- for gastroparesis-related symptoms. doscopy) is a quality standard in acute upper gastrointestinal Results: GPOEM was technically successful in all patients and bleeding (AUGIB). The authors aimed to audit time to endosco- significantly reduced GCSI scores in repeated-measure analysis py outcomes and identify factors affecting delayed endoscopy of variance (F2.044,38.838 = 22.319; p < 0.0005). The mean score (> 24 hours of admission). at baseline was 3.5 ± 0.6, at 1 month after GPOEM was 1.8 ± 1.0 Methods: This prospective multicenter audit enrolled patients (p < 0.0005), at 6 months after was 1.9 ± 1.2 (p < 0.0005), at admitted with AUGIB who underwent inpatient endoscopy be- 12 months after was 2.6 ± 1.5 (p < 0.026), and at 18 months after tween November and December 2017. Analyses were performed was 2.1 ± 1.3 (p < 0.016). GPOEM was associated with improved to identify factors associated with delayed endoscopy, and to quality of life: 77.8%, 76.5%, and 70% of patients had significant compare patient outcomes, including length of stay and mor- increases in SF-36 scores, compared with baseline, at 1 month, tality rates, between early and delayed endoscopy groups. 6 months, and 12 months after GPOEM, respectively (F1.71,18.83 = 14.16; Results: Across 348 patients from 20 centers, the median time to p < 0.0005). Compared with controls, patients who underwent endoscopy was 21.2 hours (interquartile range [IQR], 12.0–35.7), GPOEM had significant reductions in GCSI, after being controlled comprising median admission to referral and referral to endos- for baseline score and duration of the disease (F1,31 = 9.001; p = copy times of 8.1 hours (IQR, 3.7–18.1) and 6.7 hours (IQR, 3.0–23.1), 0.005). Patients who received GPOEM had significant reductions respectively. Early endoscopy was achieved in 58.9%, although in number of emergency department visits (from 2.2 ± 3.1 times/ this varied by center (range 31.0–87.5%; p = 0.002). On multivari- month at baseline to 0.3 ± 0.8 times/month; p = 0.003) and hos- able analysis, lower Glasgow-Blatchford score, delayed referral, pitalizations (from 1.7 ± 2 times/month at baseline to 0.2 ± 0.4 admissions between 7:00 and 19:00 hours or via the emergency times/month; p = 0.0002). department were independent predictors of delayed endosco- py. Early endoscopy was associated with reduced length of stay Conclusions: In a retrospective study of patients who under- (median difference 1 day; p = 0.004), but not 30-day mortality went gastric peroral endoscopic pyloromyotomy for refrac- (p = 0.344). tory gastroparesis, the procedure significantly improved symp- toms, increased quality of life, and reduced health-care use Conclusions: The majority of centers did not meet national related to gastroparesis. standards for time to endoscopy. Strategic initiatives in- volving acute care services may be necessary to improve this Q. Cai, M.D., Ph.D., Division of Digestive Diseases, Emory outcome. University School of Medicine, 1365 Clifton Road, B1262, Atlanta, GA 30322, USA, E-Mail: [email protected] Dr. K. Siau, Joint Advisory Group on Gastrointestinal Endoscopy, ■ Royal College of Physicians, 11 St. Andrews Place, Regent’s Park, London, NW1 4LE, UK, E-Mail: [email protected] ■
9 Conclusions and relevance: In this preliminary study of adults with mild-to-moderate ulcerative colitis, -week treatment with anaerobically prepared donor fecal microbiota transplantation (FMT) compared with autologous FMT resulted in a higher likelihood of remission at weeks. Further research is needed Intestine to assess longer-term maintenance of remission and safety.
Dr. S.P. Costello, Inflammatory Bowel Disease Service, Department of Gastroenterology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA 5011, Australia, E-Mail: [email protected] ■
Clin Gastroenterol Hepatol. ;():–.e
Kruis W, Neshta V, Pesegova M, Alekseeva O, Andreev P, IBD Datsenko O, Levchenko O, Abdulkhakov S, Lozynskyy Y, Mostovoy Y, Soloviev K, Dorofeyev AE, Vieth M, Stiess M, Greinwald R, Mohrbacher R, Siegmund B JAMA. ;():– Budesonide suppositories are effective and Costello SP, Hughes PA, Waters O, Bryant RV, Vincent AD, Blatchford P, Katsikeros R, Makanyanga J, Campaniello MA, safe for treating acute ulcerative proctitis Mavrangelos C, Rosewarne CP, Bickley C, Peters C, Schoeman MN, Conlon MA, Roberts-Thomson IC, Andrews JM Background and aims: Although proctitis is the most limited form of ulcerative colitis, it causes unpleasant symptoms. Topical mesalamine, the standard treatment, is not always effective. The Effect of fecal microbiota transplantation on authors conducted a randomized phase 2 trial to determine the -week remission in patients with ulcerative efficacy and safety of 2 doses of a budesonide suppository ver- colitis: A randomized clinical trial sus mesalamine suppositories versus combined budesonide and mesalamine suppositories for proctitis. Importance: High-intensity, aerobically prepared fecal microbi- Methods: They performed a prospective, double-blind, double- ota transplantation (FMT) has demonstrated efficacy in treating dummy, multicenter trial in 337 patients with active proctitis to active ulcerative colitis (UC). FMT protocols involving anaerobic compare the efficacies of 4 different suppository treatments. stool processing methods may enhance microbial viability and Patients were randomly assigned to groups given 2 mg bude- allow efficacy with a lower treatment intensity. sonide suppositories (2 mg BUS; n = 89), 4 mg BUS (n = 79), 1 g Objective: To assess the efficacy of a short duration of FMT thera- mesalamine suppositories (1 g MES; n = 81), or the combination py to induce remission in UC using anaerobically prepared stool. of 2 mg BUS and 1 g MES (n = 88). The study was performed Design, setting, and participants: A total of 73 adults with mild- from November 2013 through July 2015 at 36 study sites in Eu- to-moderately active UC were enrolled in a multicenter, ran- rope and Russia. The primary end point was the time to resolu- domized, double-blind clinical trial in 3 Australian tertiary refer- tion of clinical symptoms, defined as the first of 3 consecutive ral centers between June 2013 and June 2016, with 12-month days with a score of 0 for rectal bleeding and stool frequency. follow-up until June 2017. Results: The mean time to resolution of symptoms in the 4 mg Interventions: Patients were randomized to receive either an- BUS (29.8 days) and combination of 2 mg BUS and 1 g MES (29.3 aerobically prepared pooled donor FMT (n = 38) or autologous days) groups resembled that of the standard 1 g MES treatment FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. (29.2 days), but was significantly longer in the 2 mg BUS group Open-label therapy was offered to autologous FMT participants (35.5 days). Furthermore, proportions of patients with deep, clin- at 8 weeks and they were followed up for 12 months. ical, and endoscopic remission, as well as mucosal healing, were Main outcomes and measures: The primary outcome was ste- similar among the 1 g MES, 4 mg BUS, and combination therapy roid-free remission of UC, defined as a total Mayo score of ≤ 2 groups, but significantly lower in the group that received 2 mg with an endoscopic Mayo score of ≤ 1 at week 8. Total Mayo BUS. No safety signals were observed, and the patients’ treat- score ranges from 0 to 12 (0 = no disease and 12 = most severe dis- ment acceptance was high (67–85% of patients). ease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events. Conclusions: In a multicenter randomized trial, it was found Results: Among 73 patients who were randomized (mean age, that the efficacy and safety of 4 mg budesonide supposito- 39 years; women, 33 [45%]), 69 (95%) completed the trial. The ries in treatment of active proctitis did not differ significantly primary outcome was achieved in 12 of the 38 participants (32%) from those of g mesalamine suppositories. Budesonide sup- receiving pooled donor FMT compared with 3 of the 35 (9%) positories offer an alternative therapy to mesalamine for receiving autologous FMT (difference, 23% [95% confidence in- topical treatment of proctitis. terval: 4–42]; odds ratio = 5.0 [95% confidence interval: 1.2–20.1]; p = 0.03). Five of the 12 participants (42%) who achieved the pri- Prof. Dr. W. Kruis, Gastroenterologie und Pulmologie, mary end point at week 8 following donor FMT maintained re- Evangelisches Krankenhaus Kalk, Buchforststr. 2, 51103 Cologne, mission at 12 months. There were 3 serious adverse events in the Germany, E-Mail: [email protected] donor FMT group and 2 in the autologous FMT group. ■
10 Gut. ;():– ment in post-hoc analyses of data from 2 phase 3 trials of induc- tion therapy with tofacitinib in patients with UC (OCTAVE Induc- Danese S, Vermeire S, Hellstern P, Panaccione R, Rogler G, tion 1 and 2). Fraser G, Kohn A, Desreumaux P, Leong RW, Comer GM, Cataldi F, Methods: The studies comprised patients with moderate-to- Banerjee A, Maguire MK, Li C, Rath N, Beebe J, Schreiber S severe active UC who were intolerant to, or failed by previous treatment with, corticosteroids, thiopurines, and/or tumor ne- crosis factor (TNF) antagonists. Patients received tofacitinib (10 mg Randomized trial and open-label extension twice daily, n = 905) or placebo (n = 234) for 8 weeks. Daily Mayo study of an anti-interleukin- antibody stool frequency and rectal bleeding subscores were calculated in Crohn’s disease (ANDANTE I and II) using diary data from the first 15 days of therapy. Data from sub- groups were analyzed including failure of prior anti-TNF therapy, Objective: Neutralizing pro-inflammatory interleukin-6 (IL-6) baseline corticosteroid use, and baseline serum levels of C-reac- may effectively treat Crohn’s disease (CD). Effects of PF-04236921, tive protein. an anti-IL-6 antibody, in adults with CD are reported. Results: Mean changes were significantly greater in patients giv- Design: Parallel-group, dose-ranging, double-blind trial with en tofacitinib versus placebo in reductions from baseline stool 4-week screening and 12-week treatment periods. After induc- frequency subscore (tofacitinib: -0.27 vs. placebo: -0.11; p < 0.01), tion, patients entered 28-week follow-up or 48-week open-label total number of daily bowel movements (-1.06 vs. -0.27; p < 0.0001), extension (OLE) with 28-week follow-up. Adults with confirmed and rectal bleeding subscore (-0.30 vs. -0.14; p < 0.01) by day 3. CD and inadequate response to anti-tumor necrosis factor (TNF) Compared with placebo, more tofacitinib-treated patients had re- therapy were included. Induction study: 249 patients randomized ductions from baseline in stool frequency subscore (by ≥ 1 point 1:1:1:1 to placebo, PF-04236921 10 mg, 50 mg or 200 mg by subcu- for tofacitinib, 241/837, 28.8% vs. placebo, 39/218, 17.9%; p < 0.01) taneous injection on days 1 and 28. OLE study: PF-04236921 50 mg and rectal bleeding subscore (by ≥ 1 point for tofacitinib, every 8 weeks up to 6 doses followed by 28-week follow-up. 266/830, 32.0% vs. placebo, 43/214, 20.1%; p < 0.01) by day 3. A con- Results: 247 patients were randomized and received treatment sistent effect of tofacitinib was observed in all subgroups. in the induction study. The 200 mg dose was discontinued due to safety findings in another study and was not included in the Conclusions: In a post-hoc analysis of data from phase 3 trials primary efficacy analysis. Crohn’s Disease Activity Index (CDAI)- of induction therapy with tofacitinib in patients with ulcer- 70 response rates with PF-04236921 50 mg were significantly ative colitis, significant improvements in symptoms were found greater than placebo at weeks 8 (49.3% vs. 30.6%; p < 0.05) and among patients given tofacitinib compared with placebo 12 (47.4% vs. 28.6%; p < 0.05) and met the primary end point. within 3 days. These findings indicate the rapid onset of ef- Week 12 CDAI remission rates with PF-04236921 50 mg and pla- fect of this drug in patients with ulcerative colitis. cebo were 27.4% and 10.9%, respectively (16.5% difference; p < 0.05). 191 subjects received treatment in the OLE. Common treatment- S.B. Hanauer, M.D., Professor of Medicine, Feinberg School of emergent and serious adverse events in both studies included Medicine, Northwestern University, 676 North St. Claire Street, worsening CD, abdominal pain and nasopharyngitis. Suite 1400, Chicago, IL 60611, USA, E-Mail: [email protected] Conclusions: PF-4232 mg induced clinical response ■ and remission in refractory patients with moderate-to-severe Crohn’s disease following failure of anti-tumor necrosis factor therapy. Gastrointestinal abscess and perforation were ob- served, a specific focus of attention during future clinical J Crohns Colitis. ;():– development. Moens A, van Hoeve K, Humblet E, Rahier JF, Bossuyt P, Dewit S, Prof. Dr. S. Danese, Department of Gastroenterology, Humanitas Franchimont D, Macken E, Nijs J, Posen A, Strubbe B, Clinical and Research Center and Humanitas University, Van Hootegem A, Van Moerkercke W, Vermeire S, Ferrante M; Via Manzoni 56, 20089 Rozzano, Milan, Italy, Belgian IBD Research and Development group (BIRD) E-Mail: [email protected] ■ Outcome of pregnancies in female patients with inflammatory bowel diseases treated with vedolizumab Clin Gastroenterol Hepatol. ;():– Background and aims: Vedolizumab is an immunoglobulin (Ig) Hanauer SB, Panaccione R, Danese S, Cheifetz A, Reinisch W, G1 anti-α β integrin antibody approved for the treatment of Higgins PDR, Woodworth DA, Zhang H, Friedman GS, 4 7 inflammatory bowel diseases (IBD), but without clear safety data Lawendy N, Quirk D, Nduaka CI, Su C during conception, pregnancy and nursing. Animal studies showed that mucosal vascular addressin cell adhesion molecule 1 Tofacitinib induction therapy reduces (MAdCAM-1) is expressed by maternal vessels in the placenta symptoms within days for patients with and recruits α4β7-expressing cells that are considered important ulcerative colitis for maternal/fetal tolerance. Blocking this interaction by vedoli- zumab might affect this process. The authors aimed to evaluate Background and aims: Tofacitinib is an oral, small molecule pregnancy outcomes in vedolizumab-treated female IBD patients. Janus kinase (JAK) inhibitor for the treatment of ulcerative colitis Methods: They conducted a retrospective, multicenter Belgian (UC). The authors evaluated the onset of symptom improve- observational study. Details on disease activity, prenatal compli-
11 cations, delivery and neonatal outcome were collected through patients survived without colectomy (95% confidence interval a case report form. [CI]: 53–84) and 44% survived without vedolizumab discontinu- Results: 24 pregnancies were reported. Five women had active ation (95% CI: 27–61). No deaths occurred and 4 severe adverse disease at conception and 1 patient flared during pregnancy. events were observed. There were 23 live births. Complications were observed in 25% of pregnancies (premature rupture of membranes, pre-eclamp- Conclusions: In a retrospective analysis of 3 patients with an sia, miscarriage, elective termination and stillbirth) and in 35% active steroid-refractory ulcerative colitis (most refractory to of infants (prematurity, intra-uterine growth retardation, small a tumor necrosis factor antagonist) it was found that initial for gestational age and congenital malformations including hip treatment with a calcineurin inhibitor in combination with dysplasia, pulmonary valve stenosis and Hirschprung’s disease). vedolizumab allowed more than two thirds of patients to Vedolizumab was continued throughout pregnancy in 2 females avoid colectomy. Further studies are needed to assess the and stopped in the 1st and 2nd trimester in 5 and 16 patients, safety of this strategy. respectively. For live born children, the median (interquartile range, IQR) gestational age, weight and Apgar score 5 minutes Prof. Dr. D. Laharie, Service d’Hépatogastroentérologie, after birth were 39 (IQR, 37–39.6) weeks, 3270 (IQR, 3080–3585) Universite Bordeaux, Laboratoire de Bactériologie, Hôpital grams and 10 (IQR, 9–10), respectively. Haut-Lévêque, Centre Hospitalo-Universitaire Bordeaux, 1, avenue de Magellan, 33604 Pessac, France, Conclusions: Although several complications were observed, E-Mail: [email protected] both in mothers and in newborns, no firm conclusions can be ■ drawn. Awaiting prospective and controlled registries, vigi- lance and strict follow-up of pregnant patients treated with vedolizumab seems mandatory. Gut. ;():–
Prof. Dr. M. Ferrante, Department of Gastroenterology and Burisch J, Kiudelis G, Kupcinskas L, Kievit HAL, Winther Andersen K, Hepatology, University Hospitals Leuven, KU Leuven, Andersen V, Salupere R, Pedersen N, Kjeldsen J, D‘Incà R, Herestraat 49, 3000 Leuven, Belgium, Valpiani D, Schwartz D, Odes S, Olsen J, Nielsen KR, Vegh Z, E-Mail: [email protected] Lakatos PL, Toca A, Turcan S, Katsanos KH, Christodoulou DK, ■ Fumery M, Gower-Rousseau C, Chetcuti Zammit S, Ellul P, Eriksson C, Halfvarson J, Magro FJ, Duricova D, Bortlik M, Fernandez A, Hernández V, Myers S, Sebastian S, Oksanen P, Clin Gastroenterol Hepatol. ;():– Collin P, Goldis A, Misra R, Arebi N, Kaimakliotis IP, Nikuina I, Belousova E, Brinar M, Čuković-Čavka S, Langholz E, Pellet G, Stefanescu C, Carbonnel F, Peyrin-Biroulet L, Roblin X, Munkholm P; Epi-IBD group Allimant C, Nachury M, Nancey S, Filippi J, Altwegg R, Brixi H, Fotsing G, de Rosamel L, Shili S, Laharie D; Groupe d‘Etude Natural disease course of Crohn’s disease Thérapeutique des Affections Inflammatoires du tube Digestif during the first years after diagnosis in a (GETAID) European population-based inception cohort: Efficacy and safety of induction therapy An Epi-IBD study with calcineurin inhibitors in combination Objective: The Epi-IBD cohort is a prospective population-based with vedolizumab in patients with refractory inception cohort of unselected patients with inflammatory bowel ulcerative colitis disease from 29 European centers covering a background pop- ulation of almost 10 million people. The aim of this study was to Background and aims: Vedolizumab is used to treat patients assess the 5-year outcome and disease course of patients with with ulcerative colitis (UC), although there is a delay before it is Crohn’s disease (CD). effective. Induction therapy with a calcineurin inhibitor (cyclo- Design: Patients were followed up prospectively from the time sporine or tacrolimus) in combination with vedolizumab as of diagnosis, including collection of their clinical data, demo- maintenance therapy could be an option for patients with an graphics, disease activity, medical therapy, surgery, cancers and active steroid-refractory UC. The authors assessed the efficacy deaths. Associations between outcomes and multiple covariates and safety of this combination. were analyzed by Cox regression analysis. Methods: They performed a retrospective observational study, Results: In total, 488 patients were included in the study. During collecting data from 12 referral centers in France that were in- follow-up, 107 patients (22%) received surgery, while 176 patients cluded in the Groupe d’Etude Thérapeutique des Affections In- (36%) were hospitalized because of CD. A total of 49 patients flammatoires du tube Digestif (GETAID). Information on 39 pa- (14%) diagnosed with non-stricturing, non-penetrating disease tients with an active steroid-refractory UC (31 with active severe progressed to either stricturing and/or penetrating disease. These UC, and 36 failed by treatment with a tumor necrosis factor an- rates did not differ between patients from Western and Eastern tagonist) who received a calcineurin inhibitor as induction ther- Europe. However, significant geographic differences were noted apy along with vedolizumab as maintenance therapy were col- regarding treatment: More patients in Western Europe received lected. Inclusion date was the first vedolizumab infusion. The biological therapy (33%) and immunomodulators (66%) than outcomes were survival without colectomy, survival without did those in Eastern Europe (14% and 54%, respectively; p < 0.01), vedolizumab discontinuation, and safety. while more Eastern European patients received 5-aminosalicy- Results: After a median follow-up period of 11 months, 11 pa- lates (90% vs. 56%; p < 0.05). Treatment with immunomodula- tients (28%) underwent colectomy. At 12 months, 68% of the tors reduced the risk of surgery (hazard ratio [HR] = 0.4, 95%
12 confidence interval [CI]: 0.2–0.6) and hospitalization (HR = 0.3, Inflamm Bowel Dis. ;():– 95% CI: 0.2–0.5). Nugent Z, Singh H, Targownik LE, Bernstein CN Conclusion: Despite patients being treated early and fre- quently with immunomodulators and biological therapy in Western Europe, -year outcomes including surgery and phe- Herpes zoster infection and herpes zoster notype progression in this cohort were comparable across vaccination in a population-based sample of Western and Eastern Europe. Differences in treatment strate- persons with IBD: Is there still an unmet need? gies between Western and Eastern European centers did not affect the disease course. Treatment with immunomodula- Background: The authors aimed to report the rates of herpes tors reduced the risk of surgery and hospitalization. zoster infection (HZI) before and after the introduction of her- pes zoster vaccine (HZVac) and to determine the rates of HZVac Dr. Dr. J. Burisch, Department of Gastroenterology, North Zealand after it became available in Manitoba in 2009. University Hospital, Frederikssundsvej 30, 3600 Frederikssund, Methods: They used the population-based University of Mani- Denmark, E-Mail: [email protected] toba IBD Epidemiology Database to identify cases of inflamma- ■ tory bowel disease (IBD) and controls (1984–2016) who were di- agnosed with HZI before and after 2009 and to determine the rate of HZVac in those older than age 50 years. Furthermore, Gastroenterology. ; (): – they explored predictors of receipt of HZVac among persons with IBD. Olén O, Askling J, Sachs MC, Frumento P, Neovius M, Results: Persons with IBD versus matched controls have higher Smedby KE, Ekbom A, Malmborg P, Ludvigsson JF rates of HZI before diagnosis and postdiagnosis. HZI rates be- fore 2009 per 1000 person-years were increased in persons with Increased mortality of patients with child- IBD (9.2) versus controls (7.2; p < 0.0001). Persons with IBD com- hood-onset inflammatory bowel diseases, pared with controls were more likely to get HZVac (15.5 vs. 12 per compared with the general population 1000 person-years). Persons newly diagnosed with IBD after 2009 and of higher socioeconomic status were more likely to get Background and aims: Childhood-onset inflammatory bowel HZVac. Despite the introduction of HZVac, there was a steady disease (IBD) is believed to be a more severe disease than adult- rise in HZI throughout the study period (annual percent change onset IBD, but there is little information on all-cause and cause- in infection rates of +0.54; p < 0.0001). specific mortality in patients with childhood-onset IBD. The au- thors performed a population-based cohort study, with 50 years Conclusions: The increased risk of herpes zoster infection in of follow-up, to estimate absolute and relative risks for overall inflammatory bowel disease may reflect an inherent risk as- and cause-specific mortality in patients with childhood-onset sociated with the disease or, in those already diagnosed, an IBD, during childhood and adulthood. increased risk secondary to the use of immunomodulating Methods: They identified children with a diagnosis of IBD (< 18 drugs. Herpes zoster vaccine rates are very low, which may years) in the Swedish nationwide health registers (1964–2014, reflect physician and patient knowledge of the vaccine’s n = 9442) and individuals from the general population matched availability and utility and the fact that it is not covered by for sex, age, calendar year, and place of residence (reference the provincially provided health-care plan. group, n = 93,180). Hazard ratios (HRs) for death were estimated using Cox regression separately in patients with ulcerative coli- Dr. C.N. Bernstein, Department of Gastroenterology, University tis (n = 4671), Crohn’s disease (n = 3780), and IBD unclassified of Manitoba, 804F, 715 McDermot Avenue, Winnipeg, (n = 991). HRs were compared among calendar periods. MB R3E 3P4, Canada, E-Mail: [email protected] Results: During 138,690 person-years of follow-up, 294 deaths ■ (2.1/1000 person-years) occurred among the patients with IBD compared with 940 deaths in the reference group (0.7/1000 person-years; adjusted HR = 3.2, 95% confidence interval [CI]: J Crohns Colitis. ;():– 2.8–3.7). Mean age at the end of follow-up was 30 years. HRs were increased for patients with ulcerative colitis (HR = 4.0, 95% CI: Sahami S, Wildenberg ME, Koens L, Doherty G, Martin S, 3.4–4.7) Crohn’s disease (HR = 2.3, 95% CI: 1.8–3.0), and IBD un- D‘Haens GRAM, Cullen G, Bemelman WA, Winter D, Buskens CJ classified (HR = 2.0, 95% CI: 1.2–3.4). Among patients younger than 18 years, there were 27 deaths from IBD (HR = 4.9, 95% CI: Appendectomy for therapy-refractory 3.0–7.7). Among young adults with IBD, no evidence was found ulcerative colitis results in pathological that HRs for death decreased from 1964 through 2014 (p = 0.90). improvement of colonic inflammation: Conclusions: Children with inflammatory bowel disease (IBD) Short-term results of the PASSION study have a 3-fold increase in risk of death when followed through adulthood. The relative risk for death has not decreased with Background and aims: The objective of this study was to exam- development of new drugs for treatment of IBD. ine the modulating effect of an appendectomy on the disease course of therapy-refractory ulcerative colitis (UC) patients, and Dr. Dr. O. Olén, Clinical Epidemiology Unit, T2, Karolinska to analyze appendiceal pathological characteristics predictive University Hospital; Department of Medicine Solna, Karolinska of pathological response. Institutet, 171 76 Stockholm, Sweden, E-Mail: [email protected] Methods: Patients with therapy-refractory UC, and referred for ■ proctocolectomy, were invited to undergo laparoscopic appen-
13 dectomy first. The primary end points were clinical response af- comprised 73 patients affected by TIM and 840 thiopurine-toler- ter 3 and 12 months. Secondary end points were endoscopic re- ant unaffected patients. mission, failure, and pathologic response. Appendiceal specimens, Exposures: Genetic variants associated with TIM. and pre- and postoperative biopsies were histologically graded Main outcomes and measures: Thiopurine-induced myelosup- according to the validated Geboes score. pression, defined as a decline in absolute white blood cell count Results: 30 patients (53% male) with a median age of 40 (inter- to 2.5 x 109/l or less or a decline in absolute neutrophil cell count quartile range [IQR], 33–47) underwent appendectomy, with a to 1.0 x 109/l or less leading to a dose reduction or drug with- median preoperative total Mayo score of 9 (IQR, 8–11). After drawal. 12 months, 9 patients (30%) had lasting clinical response, of Results: Among 1077 patients (398 affected and 679 unaffected; whom 5 (17%) were in endoscopic remission. Pathological evalu- median age at IBD diagnosis, 31.0 [interquartile range, 21.2–44.1] ation was possible in 28 patients. After a median of 13.0 weeks years; 540 women [50%]; 602 diagnosed as having Crohn’s dis- (range 7–51), pathological response was seen in 13 patients (46%), ease [56%]), 919 (311 affected and 608 unaffected) were included with a median decrease of 2 points (range 1–3). Appendiceal in the GWAS analysis and 961 (328 affected and 633 unaffected) inflammation was highly predictive of pathological response in the EWAS analysis. The GWAS analysis confirmed association when compared with no inflammation or extensive ulcerations of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] (85% vs. 20%; p = 0.001). affected vs. 16.4% [100/608] unaffected patients; odds ratio [OR] = 2.3, 95% confidence interval [CI]: 1.7–3.1; p = 5.2 x 10-9). The Conclusions: Appendectomy was effective in one-third of ther- EWAS analysis demonstrated an association with an in-frame apy-refractory ulcerative colitis patients, with a substantial deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% proportion of patients demonstrating complete endoscopic [19/328] affected vs. 0.2% [1/633] unaffected patients; OR = 38.2, remission after year. Pathological response was seen in al- 95% CI: 5.1–286.1; p = 1.3 x 10-8), which was replicated in a differ- most % of patients and was related to active inflammation ent cohort (2.7% [2/73] affected vs. 0.2% [2/840] unaffected pa- in the appendix, limited disease, and shorter disease dura- tients; OR = 11.8, 95% CI: 1.6–85.0; p = 0.03). Carriage of any of tion. These early results suggest that there is a ulcerative coli- 3 coding NUDT15 variants was associated with an increased risk tis patient group that may benefit from appendectomy. (OR = 27.3, 95% CI: 9.3–116.7; p = 1.1 x 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Dr. Dr. C.J. Buskens, Department of Surgery, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Conclusions and relevance: Among patients of European an- The Netherlands, E-Mail: [email protected] cestry with inflammatory bowel disease, variants in NUDT ■ were associated with increased risk of thiopurine-induced my- elosuppression. These findings suggest that NUDT geno- typing may be considered prior to initiation of thiopurine JAMA. ;():– therapy; however, further study including additional valida- tion in independent cohorts is required. Walker GJ, Harrison JW, Heap GA, Voskuil MD, Andersen V, Anderson CA, Ananthakrishnan AN, Barrett JC, Beaugerie L, Dr. T. Ahmad, Royal Devon and Exeter Hospital, Exeter IBD Bewshea CM, Cole AT, Cummings FR, Daly MJ, Ellul P, and Pharmacogenetics Research Group, Research, Innovation, Fedorak RN, Festen EAM, Florin TH, Gaya DR, Halfvarson J, Learning and Development Center, Barrack Road, Exeter EX2 Hart AL, Heerasing NM, Hendy P, Irving PM, Jones SE, Koskela J, 5DW, UK, E-Mail: [email protected] Lindsay JO, Mansfield JC, McGovern D, Parkes M, Pollok RCG, ■ Ramakrishnan S, Rampton DS, Rivas MA, Russell RK, Schultz M, Sebastian S, Seksik P, Singh A, So K, Sokol H, Subramaniam K, Todd A, Annese V, Weersma RK, Xavier R, Ward R, Weedon MN, J Crohns Colitis. ;():– Goodhand JR, Kennedy NA, Ahmad T; IBD Pharmacogenetics Study Group Burisch J, Katsanos KH, Christodoulou DK, Barros L, Magro F, Association of genetic variants in NUDT Pedersen N, Kjeldsen J, Vegh Z, Lakatos PL, Eriksson C, Halfvarson J, Fumery M, Gower-Rousseau C, Brinar M, with thiopurine-induced myelosuppression Čuković-Čavka S, Nikulina I, Belousova E, Myers S, Sebastian S, in patients with inflammatory bowel disease Kiudelis G, Kupcinskas L, Schwartz D, Odes S, Kaimakliotis IP, Valpiani D, D‘Incà R, Salupere R, Chetcuti Zammit S, Ellul P, Importance: Use of thiopurines may be limited by myelosup- Duricova D, Bortlik M, Goldis A, Kievit HAL, Toca A, Turcan S, pression. TPMT pharmacogenetic testing identifies only 25% of Midjord J, Nielsen KR, Winther Andersen K, Andersen V, Misra R, at-risk patients of European ancestry. Among patients of East Arebi N, Oksanen P, Collin P, de Castro L, Hernández V, Asian ancestry, NUDT15 variants are associated with thiopurine- Langholz E, Munkholm P; Epi-IBD group induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM Natural disease course of ulcerative colitis among patients of European ancestry with inflammatory bowel disease (IBD). during the first years of follow-up in a Design, setting, and participants: Case-control study of 491 pa- European population-based inception cohort – tients affected by TIM and 679 thiopurine-tolerant unaffected An Epi-IBD study patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies Background and aims: Few population-based cohort studies (GWAS) and exome-wide association studies (EWAS) were con- have assessed the disease course of ulcerative colitis (UC) in the ducted in patients of European ancestry. The replication cohort era of biological therapy and widespread use of immunomodu-
14 lators. The aim of this study was to assess the 5-year outcome the findings from the capsule. Patients in the control group un- and disease course of patients with UC in the Epi-IBD cohort. derwent endoscopic evaluation (i.e., upper endoscopy, capsule Methods: In a prospective, population-based inception cohort endoscopy, and/or colonoscopy) to identify the source of of unselected patients with UC, patients were followed up from bleeding as directed by the attending gastroenterologist’s inter- the time of their diagnosis, which included the collection of pretation of their clinical presentation. The primary end point their clinical data, demographics, disease activity, medical for this study was the rate of localization of bleeding during therapy, and rates of surgery, cancers, and deaths. Associations hospitalization. between outcomes and multiple covariates were analyzed by Results: 87 patients were included in this study: 45 randomized Cox regression analysis. to the standard of care arm and 42 to the early capsule arm. A Results: A total of 717 patients were included in the study. bleeding source was localized in 64.3% of the patients in the During follow-up, 43 patients (6%) underwent a colectomy and early capsule arm and in 31.1% of the patients in the standard 163 patients (23%) were hospitalized. Of patients with limited of care arm (p < 0.01). The likelihood of endoscopic localization colitis (distal to the left flexure), 90 (21%) progressed to extensive of bleeding over time was greater for patients receiving early colitis. In addition, 92 patients (27%) with extensive colitis expe- capsule endoscopy compared with those in the standard of rienced a regression in disease extent, which was associated care arm (adjusted hazard ratio = 2.77, 95% confidence interval: with a reduced risk of hospitalization (hazard ratio [HR] = 0.5, 1.36–5.64). 95% confidence interval [CI]: 0.3–0.8). Overall, patients were treated similarly in both geographical regions; 80 patients (11%) Conclusions: For patients admitted to the hospital for non- needed biological therapy and 210 patients (29%) received im- hematemesis gastrointestinal bleeding, early capsule endo- munomodulators. Treatment with immunomodulators was scopy is a safe and effective alternative for the detection of found to reduce the risk of hospitalization (HR = 0.5, 95% CI: the source of bleeding. 0.3–0.8). N.B. Marya, M.D., University of California Los Angeles, Conclusions: Although patients in this population-based co- 10945 Le Conte Avenue, PVUB 2114 MC694907, Los Angeles, hort were treated more aggressively with immunomodula- CA 90095-6949, USA, E-Mail: [email protected] tors and biological therapy than in cohorts from the previous ■ 2 decades, their disease outcomes, including colectomy rates, were not different. However, treatment with immunomodu- lators was found to reduce the risk of hospitalization. IBS Dr. Dr. J. Burisch, Department of Gastroenterology, North Zealand University Hospital, Frederikssundsvej 30, 3600 Frederikssund, Denmark, E-Mail: [email protected] Aliment Pharmacol Ther. ;():– ■ Saito YA, Almazar AE, Tilkes KE, Choung RS, Van Norstrand MD, Schleck CD, Zinsmeister AR, Talley NJ
Middle and Lower Gastrointestinal Randomized clinical trial: Pregabalin versus Bleeding placebo for irritable bowel syndrome
Background: Pregabalin is a calcium channel α2δ ligand that Gastrointest Endosc. ;():–.e modifies visceral hypersensitivity in irritable bowel syndrome (IBS) patients. Clinical data for pregabalin in IBS are lacking. Marya NB, Jawaid S, Foley A, Han S, Patel K, Maranda L, Aim: To test the efficacy of pregabalin on gastrointestinal symp- Kaufman D, Bhattacharya K, Marshall C, Tennyson J, Cave DR toms in IBS patients. Methods: A double-blind, placebo-controlled trial was per- A randomized controlled trial comparing formed. Adults meeting IBS Rome III criteria with ≥ 3 pain at- efficacy of early video capsule endoscopy tacks per month were randomized to pregabalin 225 mg versus placebo twice daily for 12 weeks. Questionnaires were complet- with standard of care in the approach to ed weekly. The primary end point was average pain Bowel non-hematemesis gastrointestinal bleeding Symptom Scale (BSS) scores weeks 9–12. An intention-to-treat analysis of covariance evaluated treatment effects on quantita- Background and aims: Patients presenting with non-hema- tive end points, adjusting for age and gender. Adequate relief and temesis gastrointestinal bleeding (NHGIB) represent a diagnos- change in pain score were assessed using a chi-squared test. tic challenge for physicians. The authors performed a random- Results: 85 patients were recruited and randomized. Sample ized controlled trial to assess the benefits of deployment of a characteristics include: mean age 39.4 (SD 14.6), 73 (86%) female, video capsule soon after admission in the management of pa- 37 (44%) IBS-D, 29 (35%) IBS-M, 18 (21%) IBS-C. The pregabalin arm tients presenting with melena, hematochezia, or severe anemia had lower average pain-BSS scores weeks 9–12 (25 vs. 42; p = compared with standard of care management. 0.008). Compared with placebo, the overall IBS BSS severity Methods: Patients admitted with NHGIB were randomized and score was lower in the pregabalin arm (26 vs. 42; p = 0.009). placed into 1 of 2 study groups. In the experimental group, pa- Differences were observed for the diarrhea-BSS and bloating- tients ingested a video capsule soon after admission to the hos- BSS scores (p = 0.049 and 0.016, respectively). No differences pital. These patients had further endoscopic work-up based on between groups were seen for constipation-BSS scores. Ade-
15 quate relief was not different between the 2 arms (46% vs. 36%; Colorectal Cancer p = 0.35). 63% pregabalin versus 45% placebo had a change in pain score ≥ 30 at week 12 from baseline (p = 0.10). Posttreat- ment IBS quality of life scores did not differ between groups. Lancet Oncol. ;():–
Conclusion: This trial suggests that pregabalin may be bene- Benitez Majano S, Di Girolamo C, Rachet B, Maringe C, ficial for irritable bowel syndrome abdominal pain, bloating Guren MG, Glimelius B, Iversen LH, Schnell EA, Lundqvist K, and diarrhea. Christensen J, Morris M, Coleman MP, Walters S
Y.A. Saito, M.D., Division of Gastroenterology and Hepatology, Surgical treatment and survival from colo- Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA, rectal cancer in Denmark, England, Norway, E-Mail: [email protected] ■ and Sweden: A population-based study
Background: Survival from colorectal cancer has been shown to be lower in Denmark and England than in comparable high- Am J Gastroenterol. ;():– income countries. Data from national colorectal cancer regis- tries were used to assess whether differences in the proportion Lackner JM, Jaccard J, Radziwon CD, Firth RS, Gudleski GD, of patients receiving resectional surgery could contribute to in- Hamilton F, Katz LA, Keefer L, Krasner SS, Ma CX, Sitrin MD, ternational differences in colorectal cancer survival. Brenner DM Methods: In this population-based study, the authors collected data from all patients aged 18–99 years diagnosed with primary, Durability and decay of treatment benefit invasive, colorectal adenocarcinoma from January 1, 2010, to of cognitive behavioral therapy for irritable December 31, 2012, in Denmark, England, Norway, and Sweden, bowel syndrome: -Month follow-up from national colorectal cancer registries. They estimated age- standardized net survival using multivariable modelling, and compared the proportion of patients receiving resectional sur- Background: There is a need for safe and effective irritable bowel gery by stage and age. Logistic regression was used to predict syndrome (IBS) treatments that provide immediate and sustained the resectional surgery status patients would have had if they improvement of IBS symptoms, particularly among more severe had been treated as in the best performing country, given their patients. The aim was to assess long-term clinical response of cog- individual characteristics. nitive behavioral therapy (CBT) with reference to IBS education. Findings: Registry data for 139,457 adult patients with invasive Methods: A total of 436 Rome III-diagnosed IBS patients (80% colorectal adenocarcinoma were extracted: 12,958 patients in women, mean age 41 years) were randomized to: 4 session home- Denmark, 97,466 in England, 11,450 in Norway, and 17,583 in Swe- based CBT (minimal contact [MC-CBT]), 10 session clinic-based den. Three-year colon cancer survival was lower in England CBT (standard [S-CBT]), or 4 session IBS education (EDU). Follow- (63.9%, 95% confidence interval [CI]: 63.5–64.3) and Denmark up occurred at 2 weeks and 3, 6, 9, and 12 months following (65.7%, 95% CI: 64.7–66.8) than in Norway (69.5%, 95% CI: treatment completion. Treatment response was based a priori on 68.4–70.5) and Sweden (72.1%, 95% CI: 71.2–73.0). Rectal cancer the Clinical Global Improvement (CGI) Scale (global IBS symp- survival was lower in England (69.7%, 95% CI: 69.1–70.3) than in tom improvement) and IBS Symptom Severity Scale (IBS-SSS). the other 3 countries (Denmark 72.5%, 95% CI: 71.1–74.0; Sweden Results: Posttreatment CGI gains were generally maintained by 74.1%, 95% CI: 72.7–75.4; and Norway 75.0%, 95% CI: 73.1–76.8). No MC-CBT patients at quarterly intervals through 12-month follow- significant differences were found in survival for patients with up with negligible decay. For MC-CBT and S-CBT, 39% and 33% stage I disease in any of the 4 countries. Three-year survival after of respondents maintained treatment response at every follow- stage II or III rectal cancer and stage IV colon cancer was consis- up assessment. The corresponding percent for EDU was 19%, tently lower in England (stage II rectal cancer 86.4%, 95% CI: which was significantly lower (p < 0.05) than for the CBT groups. 85.0–87.6; stage III rectal cancer 75.5%, 95% CI: 74.2–76.7; and On the IBS-SSS, therapeutic gains also showed a pattern of stage IV colon cancer 20.5%, 95% CI: 19.9–21.1) than in Norway maintenance with trends towards increased efficacy over time (94.1%, 95% CI: 91.5–96.0; 83.4%, 95% CI: 80.1–86.1; and 33.0%, in all conditions, with the mean unit reductions between base- 95% CI: 31.0–35.1) and Sweden (92.9%, 95% CI: 90.8–94.6; 80.6%, line and follow-up being approximately -76 at immediate and 95% CI: 78.2–82.7; and 23.7%, 95% CI: 22.0–25.3). Three-year sur- approximately -94 at 12 months (-50 = clinically significant). vival after stage II rectal cancer and stage IV colon cancer was also lower in England than in Denmark (stage II rectal cancer Conclusions: For treatment-refractory irritable bowel syndrome 91.2%, 95% CI: 88.8–93.1; and stage IV colon cancer 23.5%,95% CI: (IBS) patients, home- and clinic-based cognitive behavioral 21.9–25.1). The total proportion of patients treated with resec- therapy resulted in substantial and enduring relief of multi- tional surgery ranged from 47,803 (68.4%) of 69,867 patients in ple IBS symptoms that generally extended to 2-month post England to 9582 (81.3%) of 11,786 in Sweden for colon cancer, treatment. and from 16,544 (59.9%) of 27,599 in England to 4106 (70.8%) of 5797 in Sweden for rectal cancer. This range was widest for J.M. Lackner, Psy.D., Professor of Medicine, Department of patients older than 75 years (colon cancer 19,078 [59.7%] of Medicine, Jacobs School of Medicine and Biomedical Sciences, 31,946 patients in England to 4429 [80.9%] of 5474 in Sweden; Divisions of Behavioral Medicine and Gastroenterology, rectal cancer 4663 [45.7%] of 10,195 in England to 1342 [61.9%] of University at Buffalo, SUNY, 462 Grider Street, Buffalo, NY 14215, 2169 in Sweden), and the proportion of patients treated with re- USA, E-Mail: [email protected] sectional surgery was consistently lowest in England. The age ■ gradient of the decline in the proportion of patients treated
16 with resectional surgery was steeper in England than in the Conclusion: Endocuff Vision significantly improved adenoma other 3 countries in all stage categories. In the hypothetical sce- detection rates in bowel cancer screening patients and should nario where all patients were treated as in Sweden, given their be used to improve colonoscopic detection. age, sex, and disease stage, the largest increase in resectional surgery would be for patients with stage III rectal cancer in Eng- Prof. Dr. C.J. Rees, Department of Gastroenterology, South land (increasing from 70.3% to 88.2%). Tyneside NHS Foundation Trust, South Tyneside District Hospital, Harton Lane, South Shields, Tyne and Wear, NE34 0PL, UK, Interpretation: Survival from colon cancer and rectal cancer E-Mail: [email protected] in England and colon cancer in Denmark was lower than in ■ Norway and Sweden. Survival paralleled the relative provi- sion of resectional surgery in these countries. Differences in patient selection for surgery, especially in patients older than Lancet. ;():– years or individuals with advanced disease, might partly explain these differences in international colorectal cancer Hull MA, Sprange K, Hepburn T, Tan W, Shafayat A, Rees CJ, survival. Clifford G, Logan RF, Loadman PM, Williams EA, Whitham D, Montgomery AA; seAFOod Collaborative Group Dr. S. Benitez Majano, Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Eicosapentaenoic acid and aspirin, alone and Medicine, Keppel Street, Bloomsbury, London WC1E 7HT, UK, in combination, for the prevention of colorectal E-Mail: [email protected] adenomas (seAFOod Polyp Prevention trial): ■ A multicenter, randomized, double-blind, placebo-controlled, x factorial trial Background: The omega-3 polyunsaturated fatty acid eicosa- Colorectal Cancer Screening pentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer chemoprevention, aligned with an excel- lent safety profile. Therefore, the authors aimed to test the effi- Gut. ;():– cacy of EPA and aspirin, alone and in combination and com- pared with a placebo, in individuals with sporadic colorectal Ngu WS, Bevan R, Tsiamoulos ZP, Bassett P, Hoare Z, Rutter MD, neoplasia detected at colonoscopy. Clifford G, Totton N, Lee TJ, Ramadas A, Silcock JG, Painter J, Methods: In a multicenter, randomized, double-blind, placebo- Neilson LJ, Saunders BP, Rees CJ controlled, 2 x 2 factorial trial, patients aged 55–73 years who were identified during colonoscopy as being at high risk in the Improved adenoma detection with Endocuff English Bowel Cancer Screening Programme (BCSP; ≥ 3 adeno- Vision: The ADENOMA randomized controlled mas if at least 1 was ≥ 10 mm in diameter or ≥ 5 adenomas if trial these were < 10 mm in diameter) were recruited from 53 BCSP endoscopy units in England, UK. Patients were randomly allo- Objective: Low adenoma detection rates (ADR) are linked to in- cated (1:1:1:1) using a secure web-based server to receive 2 g creased postcolonoscopy colorectal cancer rates and reduced EPA-free fatty acid (FFA) per day (either as the FFA or triglyceride), cancer survival. Devices to enhance mucosal visualization such 300 mg aspirin per day, both treatments in combination, or pla- as Endocuff Vision (EV) may improve ADR. This multicenter ran- cebo for 12 months using random permuted blocks of randomly domized controlled trial compared ADR between EV-assisted varying size, and stratified by BCSP site. Research staff and par- colonoscopy (EV-AC) and standard colonoscopy (SC). ticipants were masked to group assignment. The primary end Design: Patients referred because of symptoms, surveillance or point was the adenoma detection rate (ADR; the proportion of following a positive fecal occult blood test (FOBT) as part of the participants with any adenoma) at 1 year surveillance colonos- Bowel Cancer Screening Program were recruited from 7 hospi- copy analyzed in all participants with observable follow-up data tals. ADR, mean adenomas per procedure, size and location of using a so-called at-the-margins approach, adjusted for BCSP site adenomas, sessile serrated polyps, EV removal rate, cecal intu- and repeat endoscopy at baseline. The safety population included bation rate, procedural time, patient experience, effect of EV on all participants who received at least 1 dose of study drug. workload and adverse events were measured. Findings: Between November 11, 2011, and June 10, 2016, 709 par- Results: 1772 patients (57% male, mean age 62 years) were re- ticipants were randomly assigned to 4 treatment groups (176 to cruited over 16 months with 45% recruited through screening. placebo, 179 to EPA, 177 to aspirin, and 177 to EPA plus aspirin). EV-AC increased ADR globally from 36.2% to 40.9% (p = 0.02). Adenoma outcome data were available for 163 patients (93%) in The increase was driven by a 10.8% increase in FOBT-positive the placebo group, 153 (85%) in the EPA group, 163 (92%) in the screening patients (50.9% SC vs. 61.7% EV-AC; p < 0.001). EV pa- aspirin group, and 161 (91%) in the EPA plus aspirin group. The tients had higher detection of mean adenomas per procedure, ADR was 61% (100/163) in the placebo group, 63% (97/153) in the sessile serrated polyps, left-sided, diminutive, small adenomas EPA group, 61% (100/163) in the aspirin group, and 61% (98/161) in and cancers (cancer 4.1% vs. 2.3%; p = 0.02). EV removal rate the EPA plus aspirin group, with no evidence of any effect for was 4.1%. Median intubation was a minute quicker with EV-AC EPA (risk ratio [RR] = 0.98, 95% CI: 0.87–1.12; risk difference -0.9%, (p = 0.001), with no difference in cecal intubation rate or with- -8.8–6.9; p = 0.81) or aspirin (RR = 0.99 (95% CI: 0.87–1.12; risk dif- drawal time. EV-AC was well tolerated but caused a minor in- ference -0.6%, -8.5–7.2; p = 0.88). EPA and aspirin were well toler- crease in discomfort on anal intubation in patients undergoing ated (78/176 [44%] had ≥ 1 adverse event in the placebo group colonoscopy with no or minimal sedation. There were no sig- compared with 82 [46%] in the EPA group, 68 [39%] in the aspi- nificant EV adverse events. rin group, and 76 [45%] in the EPA plus aspirin group), although
17 the number of gastrointestinal adverse events was increased in tation of this simple and safe technique could increase the the EPA alone group at 146 events (compared with 85 in the pla- utility of endoscopic mucosal resection, decrease surveil- cebo group, 86 in the aspirin group, and 68 in the aspirin plus lance burdens, and reduce morbidity and mortality from placebo group). Six upper-gastrointestinal bleeding events colorectal cancer. were reported across the treatment groups (2 in the EPA group, 3 in the aspirin group, and 1 in the placebo group). Prof. Dr. M.J. Bourke, Department of Gastroenterology and Hepatology, Endoscopy Unit, Westmead Hospital, Cnr Hawkes- Interpretation: Neither eicosapentaenoic acid (EPA) nor aspi- bury and Darcy Roads, Westmead, NSW 2145, Australia, rin treatment were associated with a reduction in the propor- E-Mail: [email protected] tion of patients with at least colorectal adenoma. Further ■ research is needed regarding the effect on colorectal adeno- ma number according to adenoma type and location. Opti- mal use of EPA and aspirin might need a precision medicine Gastroenterology. ;():–.e approach to adenoma recurrence. Vleugels JLA, Hassan C, Senore C, Cassoni P, Baron JA, Rex DK, Prof. Dr. M.A. Hull, Institute of Biomedical and Clinical Sciences, Ponugoti PL, Pellise M, Parejo S, Bessa X, Arnau-Collell C, University of Leeds, St. James’s University Hospital, Wellcome Kaminski MF, Bugajski M, Wieszczy P, Kuipers EJ, Melson J, Trust Brenner Building, Leeds LS9 7TF, UK, Ma KH, Holman R, Dekker E, Pohl H E-Mail: [email protected] ■ Diminutive polyps with advanced histologic features do not increase risk for metachronous advanced colon neoplasia Gastroenterology. ; (): – .e Background and aims: With advances in endoscopic imaging, Klein A, Tate DJ, Jayasekeran V, Hourigan L, Singh R, Brown G, it is possible to differentiate adenomatous from hyperplastic di- Bahin FF, Burgess N, Williams SJ, Lee E, Sidhu M, Byth K, Bourke MJ minutive (1–5 mm) polyps during endoscopy. With the optical Resect-and-Discard strategy, these polyps are then removed Thermal ablation of mucosal defect margins and discarded without histopathology assessment. However, reduces adenoma recurrence after colonic failure to recognize adenomas (vs. hyperplastic polyps), or dis- endoscopic mucosal resection carding a polyp with advanced histologic features, could result in a patient being considered at low risk for metachronous ad- Background and aims: Colorectal cancer (CRC) can be prevent- vanced neoplasia, resulting in an inappropriately long surveil- ed by colonoscopy and polypectomy. Endoscopic mucosal re- lance interval. The authors collected data from international co- section (EMR) is performed to remove large laterally spreading horts of patients undergoing colonoscopy to determine what colonic lesions that have a high risk of progression to CRC. En- proportion of patients are at high risk because of diminutive doscopically invisible micro-adenomas at the margins of the polyps advanced histologic features and their risk for metachro- EMR site might contribute to adenoma recurrence, which oc- nous advanced neoplasia. curs in 15% to 30% of patients who undergo surveillance. The Methods: They collected data from 12 cohorts (in the United authors aimed to determine the efficacy of adjuvant thermal States or Europe) of patients undergoing colonoscopy after a ablation of the EMR mucosal defect margin in reducing polyp positive result from a fecal immunochemical test (FIT cohort, recurrence. n = 34,221) or undergoing colonoscopies for screening, sur- Methods: They performed a prospective study of 390 patients veillance, or evaluation of symptoms (colonoscopy cohort, with large laterally spreading colonic lesions (≥ 20 mm, n = 416) n = 30,123). Patients at high risk for metachronous advanced referred for EMR at 4 tertiary centers in Australia. After complete neoplasia were defined as patients with polyps that had ad- lesion excision by EMR, lesions were randomly assigned to ther- vanced histologic features (cancer, high-grade dysplasia, ≥ 25% mal ablation of the post-EMR mucosal defect margin (n = 210) villous features), ≥ 3 diminutive or small (6–9 mm) non-advanced or no additional treatment (controls, n = 206). They performed adenomas, or an adenoma or sessile serrated lesion ≥ 10 mm. Us- surveillance colonoscopies with standardized photo docu- ing an inverse variance random-effects model, the proportion of mentation and biopsies of the scar after 5 to 6 months. Patient, diminutive polyps with advanced histologic features, the pro- procedure, and lesion characteristics were similar between the portion of patients classified as high risk because their diminu- groups. The primary end point was detection of lesion recur- tive polyps had advanced histologic features, and the risk of rence at first surveillance colonoscopy. these patients for metachronous advanced neoplasia were cal- Results: A significantly lower proportion of patients who re- culated. ceived thermal ablation of the post-EMR mucosal defect margin Results: In 51,510 diminutive polyps, advanced histologic fea- had evidence of recurrence at first surveillance colonoscopy tures were observed in 7.1% of polyps from the FIT cohort and (10/192, 5.2%) than controls (37/176, 21.0%) (p < 0.001). The relative 1.5% polyps from the colonoscopy cohort (p = 0.044); however, risk of recurrence in the thermal ablation group was 0.25 com- this difference in prevalence did not produce a significant differ- pared with the control group (95% confidence interval: 0.13– ence in the proportions of patients assigned to high-risk status 0.48). Rates of adverse events were similar between the groups. (0.8% of patients in the FIT cohort and 0.4% of patients in the colonoscopy cohort; p = 0.25). The proportions of high-risk pa- Conclusions: In a multicenter randomized trial, thermal abla- tients because of diminutive polyps with advanced histologic tion of the post-EMR mucosal defect margin significantly re- features who were found to have metachronous advanced neo- duced polyp recurrence at first surveillance colonoscopy, plasia (17.6%) did not differ significantly from the proportion of compared with no additional treatment. Routine implemen- low-risk patients with metachronous advanced neoplasia
18 (14.6%) (relative risk for high-risk categorization = 1.13; 95% con- JAMA Intern Med. ;():– fidence interval: 0.79–1.61). Lee JK, Jensen CD, Levin TR, Zauber AG, Schottinger JE, Conclusion: In a pooled analysis of data from 2 international Quinn VP, Udaltsova N, Zhao WK, Fireman BH, Quesenberry CP, cohorts of patients undergoing colonoscopy for screening, Doubeni CA, Corley DA surveillance, or evaluation of symptoms, it was found that diminutive polyps with advanced histologic features do not increase risk for metachronous advanced neoplasia. Long-term risk of colorectal cancer and related deaths after a colonoscopy H. Pohl, M.D., Department of Gastroenterology, Veterans Affairs with normal findings Medical Center, 215 North Main Street, White River Junction, VT 05009, USA, E-Mail: [email protected] Importance: Guidelines recommend a 10-year rescreening in- ■ terval after a colonoscopy with normal findings (negative colo- noscopy results), but evidence supporting this recommenda- tion is limited. Gastrointest Endosc. ;():–.e Objective: To examine the long-term risks of colorectal cancer (CRC) and CRC deaths after a negative colonoscopy result, in Walter B, Klare P, Strehle K, Aschenbeck J, Ludwig L, Dikopoulos N, comparison with individuals unscreened, in a large, communi- Mayr M, Neu B, Hann A, Mayer B, Meining A, von Delius S ty-based setting. Design, setting, and participants: A retrospective cohort study Improving the quality and acceptance of was conducted in an integrated health-care delivery organiza- colonoscopy preparation by reinforced patient tion serving more than 4 million members across Northern Cali- education with short message service: fornia. A total of 1,251,318 average-risk screening-eligible patients (age 50–75 years) between January 1, 1998, and December 31, Results from a randomized, multicenter study 2015, were included. The study was concluded on December 31, (PERICLES-II) 2016. Exposures: Screening was examined as a time-varying expo- Background and aims: Sufficient bowel preparation is crucial sure; all participants contributed person-time unscreened until for successful screening and surveillance colonoscopy. However, they were either screened or censored. If the screening received the rates of inadequate preparation are still high. The authors was a negative colonoscopy result, the participants contributed investigated the effects of reinforcing patient education and person-time in the negative colonoscopy results group until guidance by using the short message service (SMS). they were censored. Methods: In this prospective, endoscopist-blinded, multicenter Main outcomes and measures: Using Cox proportional hazards study, standard instructions pertaining to split-dose preparation regression models, the hazard ratios (HRs) for CRC and related were provided in a verbal and written format to all patients dur- deaths were calculated according to time since negative colo- ing the initial appointment. Patients were randomly assigned noscopy result (or since cohort entry for those unscreened). HRs (1:1) to a group that received reinforced education starting 4 days were adjusted for age, sex, race/ethnicity, Charlson comorbidity before the colonoscopy (SMS group) or to the control group score, and body mass index. which did not receive further education. The primary outcome Results: Of the 1,251,318 patients, 613,692 were men (49.0%); mean was the percentage of insufficient preparation results (Boston age was 55.6 (SD 7.0) years. Compared with the unscreened par- Bowel Preparation Scale [BBPS] score < 6). The secondary out- ticipants, those with a negative colonoscopy result had a re- comes included quality of bowel preparation according to the duced risk of CRC and related deaths throughout the more than BBPS, polyp and adenoma detection rates, and patients’ per- 12-year follow-up period, and although reductions in risk were ceived discomfort in the preparation procedure. attenuated with increasing years of follow-up, there was a 46% Results: The percentage of patients with insufficient bowel lower risk of CRC (HR = 0.54; 95% confidence interval [CI]: preparation was significantly lower in the SMS group (9%) than 0.31–0.94) and 88% lower risk of related deaths (HR = 0.12; in the control group (19%) (p = 0.0013). The mean BBPS score 95% CI: 0.02–0.82) at the current guideline-recommended was significantly higher in the SMS group (7.4 ± 0.1) than in the 10-year rescreening interval. control group (6.5 ± 0.1) (p < 0.0001). Each colon segment had significantly higher BBPS scores in the SMS group. The adenoma Conclusions and relevance: A negative colonoscopy result detection rate and number of detected adenomas in the right in average-risk patients was associated with a lower risk of segment of the colon were higher in the SMS group. SMS mes- colorectal cancer and related deaths for more than 2 years sages were accompanied by a lower level of discomfort during after examination, compared with unscreened patients. These preparation (numeric rating scale) (5.2 SMS vs. 5.8 controls; findings may be able to inform guidelines for rescreening af- p = 0.0042). ter a negative colonoscopy result and future studies to evalu- Conclusions: Reinforced patient education by using SMS mes- ate the costs and benefits of earlier versus later rescreening sages during the 4 days before colonoscopy increased bowel intervals. cleanliness, adenoma detection in the right segment of the colon, and reduced discomfort. J.K. Lee, M.D., Kaiser Permanente Division of Research, Northern California, 2000 Broadway, Oakland, CA 94612, USA, Dr. B.M. Walter, Klinik für Innere Medizin I, Universitätsklinik Ulm, E-Mail: [email protected] Albert-Einstein-Allee 23, 89081 Ulm, Germany, ■ E-Mail: [email protected] ■
19 Gut. ;():– Diverticular Disease
Crockett SD, Barry EL, Mott LA, Ahnen DJ, Robertson DJ, Anderson JC, Wallace K, Burke CA, Bresalier RS, Figueiredo JC, Am J Gastroenterol. ;():– Snover DC, Baron JA Järbrink-Sehgal ME, Rassam L, Jasim A, Walker MM, Talley NJ, Calcium and vitamin D supplementation Agréus L, Andreasson A, Schmidt PT and increased risk of serrated polyps: Diverticulosis, symptoms and colonic Results from a randomized clinical trial inflammation: A population-based colonoscopy study Objective: Serrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, Introduction: Low-grade chronic inflammation has been sug- but etiological factors for these lesions are largely unknown. The gested to play a role in uncomplicated asymptomatic and authors aimed to determine the effects of calcium and vitamin symptomatic diverticular disease. However, population-based D supplementation on the incidence of serrated polyps (SPs) studies are lacking. The authors investigated whether commu- in general and hyperplastic polyps and SSA/Ps specifically. nity participants with diverticulosis, with or without symptoms, Design: Participants with ≥ 1 adenoma at baseline were random- would have colonic inflammation on histology and serology. ized to receive 1200 mg/day of elemental calcium, 1000 IU/day of Methods: In a nested case-control study of 254 participants vitamin D3, both or neither agent. Treatment continued for 3 or from the population-based colonoscopy (PopCol) study, colonic 5 years, when risk of polyps was determined from surveillance histological inflammatory markers and serological C-reactive colonoscopy (treatment phase). Outcomes after treatment protein levels were analyzed in cases with diverticulosis and ceased were also assessed (observational phase). Adjusted risk controls without diverticulosis. Statistical methods included ratios (aRRs) of SPs were determined via multivariable general- logistic and linear regression models. ized linear models. Results: Background variables including age (p = 0.92), sex Results: SPs were diagnosed in 565 of 2058 (27.5%) participants (p = 1.00), body mass index (p = 0.71), smoking (p = 0.34), and during the treatment phase and 329 of 1108 (29.7%) during the recent antibiotic exposure (p = 0.68) were similar between cas- observational phase. In total, 211 SSA/Ps were identified during es and controls. Cases reported more abdominal pain (p = 0.04) follow-up. In the treatment phase, there was no effect of either and diarrhea symptoms (mushy and high-frequency stools) calcium or vitamin D on incidence of SSA/Ps. However, during than controls (p = 0.01 and p = 0.03, respectively) but were oth- the later observational phase, elevated risks of SSA/Ps associat- erwise similar. The median C-reactive protein levels were similar ed with calcium alone and calcium + vitamin D treatment (aRR among cases and controls (1.05 mg/l [0.3–2.7] vs. 0.8 [0.4–2.2]; = 2.65, 95% confidence interval: 1.43–4.91, and aRR = 3.81, 95% CI: p = 0.53). There was a trend of increased numbers of cecal lym- 1.25–11.64, respectively) were observed. phoid aggregates in cases versus controls (p = 0.07), but no other associations between diverticulosis and inflammatory Conclusion: In a large multicenter chemoprevention study, markers on histology were found. Similarly, no serological or evidence was found that calcium and vitamin D supplementa- mucosal inflammation was associated with symptomatic cases tion increased the risk of sessile serrated adenomas or polyps. of diarrhea or abdominal pain versus asymptomatic controls. This appeared to be a late effect: – years after supplementa- tion began. These possible risks must be weighed against the Conclusions: In a general community sample, both asymp- benefits of calcium and vitamin D supplementation. tomatic and symptomatic diverticulosis are not associated with colonic mucosal inflammation. Other explanations for symptomatic colonic diverticulosis need to be identified. S.D. Crockett, M.D., Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Department of Medicine, M.E. Järbrink-Sehgal, M.D., Ph.D., Assistant Professor of University of North Carolina at Chapel Hill, CB #7080, Medicine, Department of Gastroenterology, Baylor College Bioinformatics Building, 130 Mason Farm Road, Chapel Hill, NC, of Medicine, 2002 Holcombe Blvd., Houston, TX 77033, USA, 227599-7080, USA, E-Mail: [email protected] ■ E-Mail: [email protected] ■
20 Congress News in Brief
Symposium 214 “IBD: From Pathophysiology to Personalized Medicine” Oxford (Great Britain), March 29–30, 2019
On the long, winding path to personalized medicine in IBD care by Dr. Beate Fessler
The call for personalized medicine is growing louder in borns, the composition of the microbiome depends on the mode nearly all fields of medicine, and inflammatory bowel dis- of childbirth, and during early childhood it develops into a micro- ease (IBD) is no exception. The path to personalized treat- biota with a high degree of instability and rapidly increasing ment of IBD will be difficult, as it will require rigorous diversity. Meanwhile, adults have unique and differentiated mi- basic research within the fields of pathophysiology, ge- crobiota whose composition changes much more slowly than netics, and immunology, as well as collaborations with in children. The intestinal microbiota can be influenced by envi- clinical practitioners. However, there is no other feasible ronmental factors such as diet and illness, but also by genetics. way forward, as it is quite apparent that a great unmet As P. Rosenstiel explained, the interactions between the host medical need for individualized medicine still exists de- and the microbiome are dependent on “epithelial gene expres- spite the innovations in recent years. Many small steps in sion”. For example, human Paneth cells harboring a variant ver- this direction were presented at the 214th Symposium of sion of an autophagy gene (ATG16L1 T300A) exhibit endoplas- the Falk Foundation in Oxford. mic reticulum (ER) stress. In a mouse model in which wild-type and ATG16L1 ∆IEC mice were given water containing antibiotics, Gastroenterologists share the hope that personalized medicine microbial diversity was not restored in the transgenic mice. As will enable highly-effective treatment of every patient that is P. Rosenstiel noted, “these mice lost their resilience”. H. Sokol also well-tolerated. Several tenuous steps in this direction have also pointed out that the risk of IBD correlates with the number indeed been made in clinical practice. However, maintaining of antibiotic therapies during childhood. The aggressive effects this progress will require input from basic research, as this pro- of environmental factors on the intestinal microbiome are trans- vides the underlying insights that are needed to develop tailored generational, as they can persist for several generations and medicine. Basic researchers have been focusing with particular be passed onto future generations. These changes may be irre- intensity on the genetics and immunology underlying bowel versible and may potentially increase an individual’s baseline inflammation, as well as the precise pathophysiological mecha- risk of IBD. Potential therapeutic options include fecal micro- nisms at the mucosal barrier and the importance of the micro- biota transplantation, next-generation probiotics, and postbiotics. biome. However, finding solutions has not proven easy. If any- thing has become clear to researchers over recent years, it is the complexity of inflammatory processes in IBD – and it is precisely this complexity that makes it so difficult to answer the key ques- Pathogenesis of IBD tion: Which therapy should be administered to which patient? Activation of the gastrointestinal immune system toward gut microbiota in genetically susceptible hosts and under Prof. H. Sokol, Saint-Antoine Hospital, Paris (France), defined the the influence of environment pathogenesis of IBD as the “activation of the gastrointestinal im- mune system against the gut flora in genetically predisposed patients under the influence of environmental factors” (Fig. 1). Environment Genes Microbiota The human microbiome plays a crucial role in determining the pathogenesis and clinical course of chronic inflammatory dis- eases. According to Prof. P. Rosenstiel, University Hospital of Kiel (Germany), the microbiome varies greatly from one individual IBD to the next, as well as from oral to rectal localization within each individual. The microbiome also varies over time, as its compo- sition changes dramatically in different phases of life. In new- Fig. : Pathogenesis of IBD (source: presentation by H. Sokol)
21 Congress News in Brief
Gut immune cells: an exciting new landscape allele could be identified by NUDT15 genotyping before starting therapy. A polymorphism in HLA-DQA1-HLA-DRB1 also increases The impact of intestinal immune processes on Crohn’s disease the risk of pancreatitis. and ulcerative colitis has also generated excitement. The different immune cells within the intestinal milieu engage distinct meta- M.C. Dubinsky also shared a number of practical tips for opti- bolic signatures. While this was once considered to be a second- mizing thiopurine therapy: ary consequence of cell differentiation and activation, metabolic – Measuring TPMT levels before the start of therapy regulation has now emerged as a key driver of multiple facets of – Frequent blood counts during the first 12 weeks and every the immune response. As explained by Dr. M.Z. Cader, Univer- 3 months thereafter sity of Cambridge (Great Britain), an intriguing development in – Monitoring thiopurine levels this space is the discovery of a risk gene for Crohn’s disease on – Wearing a sun hat and sunscreen are recommended chromosome 13 (C13orf31) that is also termed FAMIN (fatty acid – Annual skin checks and annual pap smear metabolism-immunity nexus). This gene plays a major role in – Avoid combination therapy in certain patients (such as older metabolic regulation, as it controls the oxidation and synthesis patients) of endogenous fatty acids as well as the levels of acyl-CoA. At – Check EBV status the same time, FAMIN also supports a novel immunometabolic signaling pathway that is essential for the production of macro- phage ATP and the generation of mitochondrial reactive oxy- Optimizing TNFi therapy gen species (ROS) with antimicrobial activity. As Prof. J.-F. Colombel, Mount Sinai School of Medicine, New York (USA), explained, the effectiveness of biologics is limited: Only Optimizing management of thiopurine therapy about one-quarter of Crohn’s disease patients achieved overall remission after 52 weeks of TNFi therapy in pivotal trials. Patients Personalized medicine is already being utilized by researchers also need to be advised of the risk of side effects, especially who are using genetics, immunology, and pathophysiology to lymphoma, noted J.-F. Colombel. In order to optimize treat- improve the use of currently available medications, for example ment, he recommended early intervention, targeted treatment, thiopurine monotherapy of IBD using drugs such as azathioprine. and monitoring of the outcome of treatment closely (Fig. 3). As Prof. M.C. Dubinsky, Mount Sinai Hospital, New York (USA), However, ultimately the most important decision is choosing emphasized, the beneficial effects of azathioprine in combina- the right drug for each patient. He listed several clinical factors tion with TNF-α inhibitors (TNFi) on clinical symptoms and the that are predictors of non-response to TNFi, including advanced mucosa are well established: Infliximab levels are higher, and ADA age, very early onset IBD (VEO-IBD), and biomarkers such as low (anti-drug antibody) titers are lower. A post-hoc analysis of the albumin, as well as the intestinal expression of certain genes in- SONIC trial confirmed that these benefits do indeed result from cluding TNFAIP6, S100A8, IL-11, G0S2, and S100A9TREM-1. In light higher drug concentrations. M.C. Dubinsky recommended ad- of the ever-increasing number of available TNFi and other bio- ministering the lowest concentration of thiopurines necessary logics, he noted that “we need more comparative data from meta- to achieve the pharmacokinetic benefits of the combination analyses, real-world data, and direct head-to-head studies”. The therapy. The ideal targets are 6-TGN levels of > 235 pmol/8 x 108 current challenge for personalized medicine is to identify which RBC with 6-MMP levels < 5,700 pmol/8 x 108 RBC (Fig. 2). How patients are suitable for TNFi. IBD can also be treated using anti- ever, the risks of thiopurines are also well known, in particular bodies targeting interleukin-12 and interleukin-23. According to myelosuppression and pancreatitis. Genetics may allow targeted Prof. B. Siegmund, Charité Universitätsmedizin Berlin (Germany), therapy of thiopurines in the future. For example, genetic variants these antibodies are particularly effective at treating psoriasis of NUDT15 appear to be associated with a much higher risk of and “psoriasis-like” lesions. The benefit of biologics that only in- thiopurine-induced myelosuppression. Patients with this risk hibit interleukin-23 is currently under investigation.
Thiopurine metabolite profiles: Optimizing effi cacy of anti-TNFs interpretation in non-responding patients
Change the course Absent 6-TGN/ Low 6-TGN/ Low 6-TGN/ Therapeutic/High 6-TGN/ High 6-TGN/ of IBD Absent 6-MMP Low 6-MMP High 6-MMP Therapeutic/High 6-MMP High 6-MMP
Thiopurine- Thiopurine-Unter- Non-Adherence Underdosing Overdosing resistant dosierungrefractory Tight control Tight Treat to target to Treat Early intervention
Education Increase dose Allopurinol Another drug Decrease dose Patient communication
Fig. 2: Profiles of thiopurine metabolites (source: presentation by M.C. Dubinsky/ Fig. 3: The three pillars of treatment optimization (source: presentation by J.-F. adapted from Gearry RB, et al. J Gastroenterol Hepatol. 2005;20:1149–57) Colombel/Colombel JF, et al. Gastroenterology. 2017;152:351–61)
22 Congress News in Brief
Migration of immune cells from the gut to joints vedolizumab that blocks the cellular adhesion molecule α4β7 integrin. He also mentioned etrolizumab, anti-MAdCAM, oral It would be logical to assume that rheumatoid arthritis afflicts peptides, and S1P1 agonists as future prospects. Etrolizumab is a joints, while IBD afflicts the gut. However, the reality is some- humanized antibody that targets the β7 subunit of the α4β7 and what more complicated: Both of these disorders are more closely αEβ7 integrins. Approximately one-fifth of the patients in the intertwined than it would appear at first glance. For example, the EUCALYPTUS study achieved clinical remission. Oral peptides tar- development of targeted cytokine inhibitors – many of which geting α4β7 are also of interest, as these represent an alternative are effective against both chronic disorders – has paved a path to antibodies. Sphingosine-1-phosphate receptor modulators – away from organ-based disease classifications toward mechanism- which have been previously used to treat multiple sclerosis – based classifications. However, a disrupted intestinal barrier also are also promising candidates, as demonstrated by studies on appears to be an important trigger of joint inflammation in ozanimod. However, according to B.G. Feagan, the next genera- genetically predisposed patients. According to Prof. G. Schett, tion of biologic therapy will be combination therapies. None- University Hospital Erlangen (Germany), a disrupted gastrointes- theless, he acknowledged that TNFi remain important agents for tinal barrier may be a trigger for arthritis. In this scenario, acti- inducing remission. According to Prof. G. van Assche, University vated immune cells migrate from the bowel to the joints via the Hospital Leuven (Belgium), the proper role of Janus kinase (JAK) gut-joint axis. Restoring the barrier function in the gut inhibits inhibitors also remains uncertain, as it is difficult to predict the the development of arthritis. Larazotide has been shown in an safety and effectiveness of individual members of this class due animal model to inhibit the migration of immune cells from the to their multifunctional roles. Tofacitinib, a JAK1/3 inhibitor, is gut to the joints. already in clinical use, while the selective JAK1 inhibitor upada citinib is currently in the approval process. However, there is still no data available for IBD from large safety cohorts. The microbiome as a therapeutic target
Fecal microbiota transplantation (FMT) is one of the novel What will the future bring? therapeutic approaches just around the corner. As Prof. A. Hart, St. Mark’s Hospital, London (Great Britain), explained, the micro- Prof. G. D’Haens, Academic Medical Center Amsterdam (The biome plays a crucial role in the clinical course of IBD for a large Netherlands), provided a glimpse into the future of personalized number of patients. It also presents an attractive therapeutic treatment of IBD. To date, there are only a small number of evi- target, as reflected by the positive effects of FMT on several dis- dence-based practice recommendations that take phenotypic orders including ulcerative colitis (Fig. 4). Nonetheless, many diversity into account. G. D’Haens sees patient stratification as questions remain unanswered, including which individuals the way forward, with diagnostic tools that allow the type of represent ideal donors and which methods of administration disease to be predicted becoming equally established in clinical are feasible. Furthermore, as Prof. M.F. Neurath, University Hos- practice as point-of-care diagnostic testing. pital Erlangen (Germany), explained, it remains unclear whether transplanting “normal” bacteria is sufficient, or whether these bacteria first need to be modulated in order for them to colo- Scientific organizers: nize and survive in the gut. Prof. M.F. Neurath, University of Erlangen-Nuremberg (Germany) Prof. A. Kaser, University of Cambridge (Great Britain) Can oral peptides compete against antibodies? Prof. F. Powrie, University of Oxford (Great Britain)
Dr. B.G. Feagan, London (Ontario, Canada), underscored the im- portance of agents that are selective for the gut, for example
Summary of microbiome changes in IBD which promote barrier dysfunction
Ü Depleted species Û Excess of species
Roseburia Proteobacteria Faecalibacterium prausnitzi Fusobacteria
Butyrate producers Mucin degraders
Reduced diversity and richness and temporal instability in IBD
Fig. 4: Changes to the microbiome in IBD (source: presentation by A. Hart/ St. Mark‘s Hospital/Imperial College London)
23 Symposium 216
Building Bridges in IBD
September 13–14, 2019 Brussels, Belgium
Congress Venue Square Brussels Meeting Centre Glass Entrance Mont des Arts/Kunstberg 1000 Brussels Belgium
Scientific Organization I. Dotan, Petah Tikva (Israel) D. Rachmilewitz, Jerusalem (Israel) S. Vermeire, Leuven (Belgium)
FALK FOUNDATION e.V. Congress Department Leinenweberstr. 5 Tel.: +49-761/1514-125 79108 Freiburg Fax: +49-761/1514-359 Germany E-Mail: [email protected] www.falk-foundation-symposia.org
Falk_Anzeigen_E_2019.indd2019 3 31.07.18 10:58 Conclusions: In a randomized trial of patients, an endo- scopic transluminal approach for infected necrotizing pancre- atitis, compared with minimally invasive surgery, significantly Pancreas reduced major complications, lowered costs, and increased Symposium 216 quality of life.
S. Varadarajulu, M.D., Center for Interventional Endoscopy, Florida Hospital, 601 East Rollins Street, Orlando, FL 32803, USA, E-Mail: [email protected] ■
Building Bridges in IBD Pancreas. ;():–
Dong E, Chang JI, Verma D, Butler RK, Villarin CK, Kwok KK, Chen W, Wu BU
Acute/Chronic Pancreatitis Enhanced recovery in mild acute pancreatitis: A randomized controlled trial Gastroenterology. ; (): – .e Objectives: Acute pancreatitis (AP) is a leading cause of hospi- talization for a gastrointestinal illness in the United States. The September 13–14, 2019 Bang JY, Arnoletti JP, Holt BA, Sutton B, Hasan MK, authors hypothesized that enhanced recovery approaches may Navaneethan U, Feranec N, Mel Wilcox C, Tharian B, Hawes RH, lead to earlier time to refeeding in patients with AP. Brussels, Belgium Varadarajulu S Methods: They performed a double-blind, randomized con- trolled trial of patients admitted with mild AP from July 2016 to Congress Venue An endoscopic transluminal approach, April 2017 at a tertiary medical center. Participants were randomly compared with minimally invasive surgery, assigned to receive either enhanced recovery consisting of non- Square Brussels reduces complications and costs for patients opioid analgesia, patient-directed oral intake, and early ambula- with necrotizing pancreatitis tion versus standard treatment with opioid analgesia and phy- Meeting Centre sician-directed diet. Primary study end point was time to oral Glass Entrance Background and aims: Infected necrotizing pancreatitis is a highly refeeding on an intention-to-treat basis. Secondary end points Mont des Arts/Kunstberg morbid disease with poor outcomes. Intervention strategies have included differences in pancreatitis activity scores, morphine equivalents, length of stay, and 30-day readmissions. 1000 Brussels progressed from open necrosectomy to minimally invasive ap- proaches. The authors compared outcomes of minimally inva- Results: 46 participants were enrolled. The median age was 53.1 Belgium sive surgery versus endoscopic approaches for patients with in- years, and 54.3% were female. There was significant reduction fected necrotizing pancreatitis. in time to successful oral refeeding in the enhanced recovery Methods: They performed a single-center, randomized trial of versus standard treatment group (median, 13.8 vs. 124.8 hours; 66 patients with confirmed or suspected infected necrotizing p < 0.001). Pancreatitis activity scores trended lower at 48–96 pancreatitis who required intervention from May 12, 2014, through hours among patients assigned to enhanced recovery (mean, March 24, 2017. Patients were randomly assigned to groups that 43.6 vs. 58.9; p = 0.32). No differences found in length of stay or received minimally invasive surgery (laparoscopic or video-assist- 30-day readmissions. ed retroperitoneal debridement, depending on location of col- lection, n = 32) or an endoscopic step-up approach (translumi- Conclusion: In this randomized controlled trial, enhanced re- nal drainage with or without necrosectomy, n = 34). The primary covery was safe and effective in promoting earlier time to end point was a composite of major complications (new-onset refeeding in patients hospitalized with acute pancreatitis. multiple organ failure, new-onset systemic dysfunction, enteral or pancreatic-cutaneous fistula, bleeding and perforation of a B.U. Wu, M.D., Kaiser Permanente Los Angeles Medical Center, Scientific Organization visceral organ) or death during 6 months of follow-up. Center for Pancreatic Care, 1526 North Edgemont Street, Floor 7, I. Dotan, Petah Tikva (Israel) Results: The primary end point occurred in 11.8% of patients Los Angeles, CA 90027, USA, E-Mail: [email protected] D. Rachmilewitz, Jerusalem (Israel) who received the endoscopic procedure and 40.6% of patients ■ S. Vermeire, Leuven (Belgium) who received the minimally invasive surgery (risk ratio = 0.29, 95% confidence interval: 0.11–0.80; p = 0.007). Although there was no significant difference in mortality (endoscopy 8.8% vs. Clin Gastroenterol Hepatol. ;():– surgery 6.3%; p = 0.999), none of the patients assigned to the endoscopic approach developed enteral or pancreatic-cutane- Corral JE, Mareth KF, Riegert-Johnson DL, Das A, Wallace MB ous fistulae compared with 28.1% of the patients who under- went surgery (p = 0.001). The mean number of major complica- Diagnostic yield from screening asymptomatic tions per patient was significantly higher in the surgery group individuals at high risk for pancreatic cancer: (0.69 ± 1.03) compared with the endoscopy group (0.15 ± 0.44) A meta-analysis of cohort studies (p = 0.007). The physical health scores for quality of life at FALK FOUNDATION e.V. Congress Department 3 months was better with the endoscopic approach (p = 0.039) Background and aims: There have been few studies of abdomi- Leinenweberstr. 5 Tel.: +49-761/1514-125 and mean total cost was lower ($75,830) compared with $117,492 nal imaging screening of individuals at high risk for pancreatic 79108 Freiburg Fax: +49-761/1514-359 for surgery (p = 0.039). cancer (based on family history or genetic variants). The authors Germany E-Mail: [email protected] www.falk-foundation-symposia.org 25
Falk_Anzeigen_E_2019.indd2019 3 31.07.18 10:58 performed a meta-analysis of prospective cohort studies to de- Design: Data from 6 European population-based cancer regis- termine the diagnostic yield and outcomes of abdominal imag- tries and the US Surveillance, Epidemiology, and End Results (SEER) ing screening for asymptomatic individuals at high risk. Program database during 2003–2016 were analyzed. Age-standard- Methods: Through a systematic review of multiple electronic ized resection rates for overall and stage I–II pancreatic cancers databases and conference proceedings through July 2017, they were computed. Associations between resection and demo- identified prospective cohort studies (> 20 patients) of asymp- graphic and clinical parameters were assessed using multivari- tomatic adults determined to be at high risk of pancreatic can- able logistic regression models. cer (lifetime risk > 5%, including specific genetic-associated Results: A total of 153,698 records were analyzed. In population- conditions) who were screened by endoscopic ultrasound (EUS) based registries in 2012–2014, resection rates ranged from 13.2% and/or magnetic resonance imaging (MRI) to detect pancreatic (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to lesions. The primary outcome was identification of high-risk pan- 68.7% (Denmark) for stage I–II tumors, with great international creatic lesions (high-grade pancreatic intraepithelial neoplasia, variations. During 2003–2014, resection rates only increased in high-grade dysplasia, or adenocarcinoma) at initial screening, the United States, the Netherlands and Denmark. Resection was and overall incidence during follow-up. Summary estimates were significantly less frequently performed with more advanced tu- reported as incidence rates per 100 patient-years. mor stage (odds ratios for stage III and IV vs. stage I–II tumors = Results: 19 studies were identified comprising 7085 individuals 0.05–0.18 and 0.01–0.06 across countries) and increasing age at high risk for pancreatic cancer; of these, 1660 patients were (ORs for patients 70–79 and ≥ 80 vs. those < 60 years = 0.37–0.63 evaluated by EUS and/or MRI. 59 high-risk lesions were identi- and 0.03–0.16 across countries). Patients with advanced-stage fied (43 adenocarcinomas: 28 during the initial exam and 15 dur- tumors (stage III–IV: 63.8–81.2%) and at older ages (≥ 70 years: ing follow-up surveillance) and 257 patients underwent pancre- 52.6–59.5%) receiving less frequently resection comprised the atic surgery. Based on the meta-analysis, the overall diagnostic majority of diagnosed cases. Patient performance status, tumor yield screening for high-risk pancreatic lesions was 0.74 (95% confi- location and size were also associated with resection application. dence interval [CI]: 0.33–1.14), with moderate heterogeneity among studies. The number needed to screen to identify 1 patient with Conclusion: Rates of pancreatic cancer resection remain low a high-risk lesion was 135 (95% CI: 88–303). The diagnostic yield in Europe and the United States with great international vari- was similar for patients with different genetic features that in- ations. Further studies are warranted to explore reasons for creased risk, and whether patients were screened by EUS or MRI. these variations.
Conclusions: Based on meta-analysis, 3 patients at high risk Dr. L. Jansen, Klinische Epidemiologie und Alternsforschung, for pancreatic cancer must be screened to identify patient Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer with a high-risk pancreatic lesion. Further studies are needed Feld 581, 69120 Heidelberg, Germany, to determine whether screening reduces mortality and is cost E-Mail: [email protected] effectiveness for individuals at high-risk of pancreatic cancer. ■
M.B. Wallace, M.D., Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA, E-Mail: [email protected] N Engl J Med. ;():– ■ Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, Choné L, Francois E, Artru P, Biagi JJ, Lecomte T, Assenat E, Faroux R, Ychou M, Volet J, Sauvanet A, Breysacher G, Pancreatic Tumors Di Fiore F, Cripps C, Kavan P, Texereau P, Bouhier-Leporrier K, Khemissa-Akouz F, Legoux JL, Juzyna B, Gourgou S, O‘Callaghan CJ, Jouffroy-Zeller C, Rat P, Malka D, Castan F, Bachet JB; Gut. ;():– Canadian Cancer Trials Group; Unicancer-GI-PRODIGE Group
Huang L, Jansen L, Balavarca Y, Molina-Montes E, Babaei M, FOLFIRINOX or gemcitabine as adjuvant van der Geest L, Lemmens V, Van Eycken L, De Schutter H, therapy for pancreatic cancer Johannesen TB, Fristrup CW, Mortensen MB, Primic-Žakelj M, Zadnik V, Becker N, Hackert T, Mägi M, Cassetti T, Sassatelli R, Background: Among patients with metastatic pancreatic cancer, Grützmann R, Merkel S, Gonçalves AF, Bento MJ, Hegyi P, combination chemotherapy with fluorouracil, leucovorin, irino- Lakatos G, Szentesi A, Moreau M, van de Velde T, Broeks A, tecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival Sant M, Minicozzi P, Mazzaferro V, Real FX, Carrato A, Molero X, than gemcitabine therapy. The authors compared the efficacy and Besselink MG, Malats N, Büchler MW, Schrotz-King P, Brenner H safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer. Resection of pancreatic cancer in Europe Methods: They randomly assigned 493 patients with resected pan- and USA: An international large-scale study creatic ductal adenocarcinoma to receive a modified FOLFIRINOX highlighting large variations regimen (oxaliplatin [85 mg/m² of body-surface area], irinotecan [180 mg/m², reduced to 150 mg/m² after a protocol-specified safety Objective: Resection can potentially cure resectable pancreatic analysis], leucovorin [400 mg/m²], and fluorouracil [2400 mg/m²] cancer and significantly prolong survival in some patients. This every 2 weeks) or gemcitabine (1000 mg/m² on days 1, 8, and 15 large-scale international study aimed to investigate variations in every 4 weeks) for 24 weeks. The primary end point was disease- resection for pancreatic cancer in Europe and the United States free survival. Secondary end points included overall survival and and determinants for its utilization. safety.
26 Results: At a median follow-up of 33.6 months, the median dis- of laparoscopic pancreatoduodenectomy (complications and ease-free survival was 21.6 months in the modified-FOLFIRINOX mortality), and the primary outcome of phase 3 was time to group and 12.8 months in the gemcitabine group (stratified haz- functional recovery in days, defined as all of the following: ade- ard ratio [HR] for cancer-related event, second cancer, or death quate pain control with only oral analgesia, independent mobil- = 0.58, 95% confidence interval [CI]: 0.46–0.73; p < 0.001). The ity, ability to maintain more than 50% of the daily required ca- disease-free survival rate at 3 years was 39.7% in the modified- loric intake, no need for intravenous fluid administration, and no FOLFIRINOX group and 21.4% in the gemcitabine group. The medi- signs of infection (temperature < 38.5 °C). an overall survival was 54.4 months in the modified-FOLFIRINOX Findings: Between May 13 and December 20, 2016, 42 patients group and 35.0 months in the gemcitabine group (stratified HR were randomized in the phase 2 part of the trial. Two patients for death = 0.64, 95% CI: 0.48–0.86; p = 0.003). The overall sur- did not receive surgery and were excluded from analyses in ac- vival rate at 3 years was 63.4% in the modified-FOLFIRINOX cordance with the study protocol. Three of 20 patients (15%) died group and 48.6% in the gemcitabine group. Adverse events of within 90 days after laparoscopic pancreatoduodenectomy, com- grade 3 or 4 occurred in 75.9% of the patients in the modified- pared with none of 20 patients after open pancreatoduode- FOLFIRINOX group and in 52.9% of those in the gemcitabine nectomy. Based on safety data from the phase 2 part of the trial, group. One patient in the gemcitabine group died from toxic the data and safety monitoring board and protocol committee effects (interstitial pneumonitis). agreed to proceed with phase 3. Between January 31 and No- vember 14, 2017, 63 additional patients were randomized in Conclusions: Adjuvant therapy with a modified FOLFIRINOX phase 3 of the trial. Four patients did not receive surgery and regimen led to significantly longer survival than gemcitabine were excluded from analyses in accordance with the study pro- among patients with resected pancreatic cancer, at the ex- tocol. After randomization of 105 patients (combining patients pense of a higher incidence of toxic effects. from both phase 2 and phase 3), of whom 99 underwent sur- gery, the trial was prematurely terminated by the data and safety Dr. T. Conroy, Department of Medical Oncology, Institut de monitoring board because of a difference in 90-day complica- Cancérologie de Lorraine, 6, avenue de Bourgogne, CS 30519, tion-related mortality (5 [10%] of 50 patients in the laparoscopic 54519 Vandoeuvre-lès-Nancy Cedex, France, pancreatoduodenectomy group vs. 1 [2%] of 49 in the open E-Mail: [email protected] pancreatoduodenectomy group; risk ratio [RR] = 4.90, 95% con- ■ fidence interval [CI]: 0.59–40.44; p = 0.20). Median time to func- tional recovery was 10 days (95% CI: 5–15) after laparoscopic pancreatoduodenectomy versus 8 days (95% CI: 7–9) after open Lancet Gastroenterol Hepatol. ;():– pancreatoduodenectomy (log-rank p = 0.80). Clavien-Dindo grade III or higher complications (25 [50%] of 50 patients after van Hilst J, de Rooij T, Bosscha K, Brinkman DJ, van Dieren S, laparoscopic pancreatoduodenectomy vs. 19 [39%] of 49 after Dijkgraaf MG, Gerhards MF, de Hingh IH, Karsten TM, Lips DJ, open pancreatoduodenectomy; RR = 1.29, 95% CI: 0.82–2.02; Luyer MD, Busch OR, Festen S, Besselink MG; Dutch Pancreatic p = 0.26) and grade B/C postoperative pancreatic fistulas (14 [28%] Cancer Group vs. 12 [24%]; RR = 1.14, 95% CI: 0.59–2.22; p = 0.69) were compara- ble between groups. Laparoscopic versus open pancreatoduode- Interpretation: Although not statistically significant, laparo- nectomy for pancreatic or periampullary tumors scopic pancreatoduodenectomy was associated with more (LEOPARD-): A multicenter, patient-blinded, complication-related deaths than was open pancreatoduo- randomized controlled phase / trial denectomy, and there was no difference between groups in time to functional recovery. These safety concerns were un- Background: Laparoscopic pancreatoduodenectomy may im- expected and worrisome, especially in the setting of trained prove postoperative recovery compared with open pancreato- surgeons working in centers performing ≥ 2 pancreatoduo- duodenectomy. However, there are concerns that the extensive denectomies annually. Experience, learning curve, and annual learning curve of this complex procedure could increase the risk volume might have influenced the outcomes; future research of complications. The authors aimed to assess whether laparo- should focus on these issues. scopic pancreatoduodenectomy could reduce time to functional recovery compared with open pancreatoduodenectomy. Prof. Dr. M.G. Besselink, Department of Surgery, Cancer Center Methods: This multicenter, patient-blinded, parallel-group, ran- Amsterdam, University of Amsterdam, Meibergdreef 9, 1105 AZ domized controlled phase 2/3 trial was performed in 4 centers Amsterdam, The Netherlands, E-Mail: [email protected] in the Netherlands that each do ≥ 20 pancreatoduodenecto- ■ mies annually; surgeons had to have completed a dedicated training program for laparoscopic pancreatoduodenectomy and have done ≥ 20 laparoscopic pancreatoduodenectomies before trial participation. Patients with a benign, premalignant, or ma- lignant indication for pancreatoduodenectomy, without signs of vascular involvement, were randomly assigned (1:1) to under- go either laparoscopic or open pancreatoduodenectomy using a central web-based system. Randomization was stratified for annual case volume and preoperative estimated risk of pancreatic fistula. Patients were blinded to treatment allocation. Analysis was done according to the intention-to-treat principle. The main objective of the phase 2 part of the trial was to assess the safety
27 Conclusion: In a systematic review and meta-analysis, a low rate of HBsAg seroclearance in untreated and treated patients was found (pooled annual rate, approximately %). Seroclear- Liver ance occurred mainly in patients with less active disease. Pa- Bile tients with chronic hepatitis B virus infection should therefore be counseled on the need for lifelong treatment, and curative therapies are needed.
M.H. Nguyen, M.D., Professor of Medicine, Division of Gastro- enterology and Hepatology, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304, USA, E-Mail: [email protected] or Dr. Dr. C.-Y. Wu, Division of Translational Research, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, HBV Taipei City, Taiwan, E-Mail: [email protected] ■ Gastroenterology. ;():–.e
Yeo YH, Ho HJ, Yang HI, Tseng TC, Hosaka T, Trinh HN, Kwak MS, J Viral Hepat. ;():– Park YM, Fung JYY, Buti M, Rodríguez M, Treeprasertsuk S, Preda CM, Ungtrakul T, Charatcharoenwitthaya P, Li X, Li J, Song J, Yang F, Wang S, Tikande S, Deng Y, Tang W, Cao G Zhang J, Le MH, Wei B, Zou B, Le A, Jeong D, Chien N, Kam L, Lee CC, Riveiro-Barciela M, Istratescu D, Sriprayoon T, Chong Y, Efficacy and safety of antiviral treatment Tanwandee T, Kobayashi M, Suzuki F, Yuen MF, Lee HS, Kao JH, on blocking the mother-to-child transmission Lok AS, Wu CY, Nguyen MH of hepatitis B virus: A meta-analysis
Factors associated with rates of HBsAg sero- Nucleo(s)tide analogues (NAs) have been administered as ad- clearance in adults with chronic HBV infection: junctive therapy to interrupt the mother-to-child transmission A systematic review and meta-analysis (MTCT) of hepatitis B virus (HBV). The efficacy and safety of this method remain controversial. A meta-analysis was conducted Background and aims: Seroclearance of hepatitis B surface an- to evaluate the efficacy and safety of NAs treatment during tigen (HBsAg) is a marker for clearance of chronic hepatitis B virus pregnancy. The differences among different agents and initia- (HBV) infection, but reported annual incidence rates of HBsAg tion trimesters were analyzed. A total of 9228 mother-infant seroclearance vary. The authors performed a systematic review pairs in 59 studies (32 randomized controlled trials [RCTs] and and meta-analysis to provide more precise estimates of HBsAg 27 non-RCTs) were included in this meta-analysis. NAs signifi- seroclearance rates among subgroups and populations. cantly reduced the risk of MTCT, as indicated by seropositivity of Methods: They searched PubMed, Embase, and the Cochrane hepatitis B surface antigen (HBsAg) (risk ratio [RR] = 0.51, 95% library for cohort studies that reported HBsAg seroclearance in confidence interval [CI]: 0.45–0.57) and HBV DNA in newborns adults with chronic HBV infection with more than 1 year of fol- (RR = 0.22, 95% CI: 0.18–0.26). No differences in the efficacy of in- low-up and at least 1 repeat test for HBsAg. Annual and 5-, 10-, terrupting HBV MTCT were evident among lamivudine, telbivu- and 15-year cumulative incidence rates were pooled using a dine and tenofovir disoproxil fumarate. The NA was more effec- random-effects model. tive when administered from the second than from the third Results: They analyzed 34 published studies (with 42,588 pa- trimester as indicated by HBV DNA (RR: the second vs. the third tients, 303,754 person-years of follow-up, and 3194 HBsAg sero- 0.08 vs. 0.22; p = 0.010), but this effect was not evident as indicat- clearance events), including additional and updated aggregated ed by HBsAg (RR: the second vs. the third 0.46 vs. 0.53; p = 0.596). data from 19 studies. The pooled annual rate of HBsAg seroclear- Antiviral treatment initiated from the second trimester did not ance was 1.02% (95% CI: 0.79–1.27). Cumulative incidence rates confer a higher risk of safety problems in the newborns com- were 4.03% at 5 years (95% CI: 2.49–5.93), 8.16% at 10 years (95% CI: pared with treatment from the third trimester, as indicated by 5.24–11.72), and 17.99% at 15 years (95% CI: 6.18–23.24). There were weight (p = 0.064), length (p = 0.491) and malformation rate no significant differences between the sexes. A higher propor- (p = 0.635) of newborns. tion of patients who tested negative for HBeAg at baseline had seroclearance (1.33%; 95% CI: 0.76–2.05) than those who tested Conclusions: Lamivudine, telbivudine and tenofovir disoproxil positive for HBeAg (0.40%; 95% CI: 0.25–0.59) (p < 0.01). Having fumarate are equally effective in blocking the mother-to- HBsAg seroclearance was also associated with a lower baseline child transmission of hepatitis B virus. Antiviral treatment can
HBV DNA level (6.61 log10 IU/ml; 95% CI: 5.94–7.27) versus not be applied from the second trimester, without obvious safety having HBsAg seroclearance (7.71 log10 IU/ml; 95% CI: 7.41–8.02) concerns.
(p < 0.01) and with a lower level of HBsAg at baseline (2.74 log10 IU/ml; 95% CI: 1.88–3.60) versus not having HBsAg seroclearance Prof. Dr. G. Cao, Department of Epidemiology, Second Military
(3.90 log10 IU/ml, 95% CI: 3.73–4.06) (p < 0.01). HBsAg seroclear- Medical University, 800 Xiangyin Road, Shanghai 200433, China, ance was not associated with HBV genotype or treatment his- E-Mail: [email protected] tory. Heterogeneity was substantial across the studies (I2 = 97.49%). ■
28 Liver Int. ;():– The authors compared the risk of hepatocellular carcinoma (HCC) and hepatic events in nucleos(t)ide analogue (NA)-treated pa- Viganò M, Loglio A, Labanca S, Zaltron S, Castelli F, Andreone P, tients with and without HBsAg seroclearance. Messina V, Ganga R, Coppola N, Marrone A, Russello M, Methods: They performed a territory-wide retrospective cohort Marzano A, Tucci A, Taliani G, Fasano M, Fagiuoli S, Villa E, study on all patients with CHB who had received entecavir and/ Bronte F, Santantonio T, Brancaccio G, Occhipinti V, Facchetti F, or tenofovir disoproxil fumarate (TDF) for at least 6 months be- Grossi G, Rumi M, Lampertico P tween 2005 and 2016 from Hospital Authority, Hong Kong. Pa- tients’ demographics, comorbidities, and laboratory parameters Effectiveness and safety of switching to were analyzed. The primary outcome was HCC. The secondary entecavir hepatitis B patients developing outcomes were hepatic events including cirrhotic complications, liver transplantation, and liver-related mortality. kidney dysfunction during tenofovir Results: A total of 20,263 entecavir/TDF-treated patients with CHB Background and aims: Tenofovir disoproxil fumarate (TDF) is were identified; 17,499 (86.4%) patients had complete viral sup- recommended for chronic hepatitis B (CHB) treatment, but it pression; 376 (2.1%) achieved HBsAg seroclearance. At a median may induce kidney dysfunction whose management is not yet (interquartile range, IQR) follow-up of 4.8 (IQR, 2.8–7.0) years, 603 known. This Italian, multicenter, retrospective study aimed to (3.5%) and 121 (4.4%) patients with and without complete viral assess the efficacy and safety of switching to entecavir (ETV) pa- suppression developed HCC; 2 (0.5%) patients with HBsAg sero- tients who developed TDF-associated glomerular and/or tubular clearance developed HCC. Compared to complete viral suppres- dysfunction. sion, lack of complete viral suppression was associated with a Methods: A total of 103 TDF-treated patients were included as higher risk of HCC (7.8% vs. 5.6% at 8 years, Gray’s test, p < 0.001) follows: age 64 years, 83% male, 49% cirrhotics, 98% with un- (adjusted hazard ratio [aHR] = 1.69, 95% confidence interval [CI]: detectable HBV DNA, 47% with previous lamivudine resistance 1.36–2.09; p < 0.001); patients who achieved functional cure had a (LMV-R) and 71% previously treated with adefovir. 29 (28%) were lower risk of HCC (0.6% vs. 5.6% at 8 years, Gray’s test, p < 0.001) switched to ETV because estimated glomerular filtration rate (aHR = 0.24, 95% CI: 0.06–0.97; p = 0.045) but not hepatic events (aHR = 0.99, 95% CI: 0.30–3.26; p = 0.991). (eGFRMDRD) was < 60 ml/min, 37 (36%) because blood phosphate (P) levels were < 2.5 mg/dl and 37 (36%) for both reasons. Kidney, Conclusions: Patients who achieved hepatitis B surface anti- liver and virological parameters were recorded every 4 months gen seroclearance on top of complete viral suppression with thereafter. entecavir/tenofovir disoproxil fumarate treatment may have a Results: During 46 (4–115) months of ETV treatment, all patients’ lower risk of hepatocellular carcinoma but not hepatic events. renal parameters significantly improved as follows: creatinine from 1.30 to 1.10 mg/dl (p < 0.0001), eGFRMDRD from 54 to 65 ml/min Prof. Dr. V.W.-S. Wong, Department of Medicine and Therapeutics, (p = 0.002), P from 2.2 to 2.6 mg/dl (p < 0.0001) and maximal tubule Faculty of Medicine, 9/F Prince of Wales Hospital, The Chinese phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/l University of Hong Kong (CUHK), 30–32 Ngan Shing Street, (p < 0.0001). 13 patients (52%) improved their eGFRMDRD class, Shatin, Hong Kong SAR, E-Mail: [email protected] P levels were normalized in 13 (35%), and 8 (22%) showed im- ■ provements in both parameters. Viral suppression was main- tained in all but 5 patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV-naive HCV patients, and 11% in LMV-R patients (p = 0.018).
Conclusions: Entecavir is an effective and safe rescue strategy Gastroenterology. ; (): – .e for chronic hepatitis B patients who develop renal dysfunction during long-term tenofovir disoproxil fumarate treatment. Butt AA, Yan P, Shuaib A, Abou-Samra AB, Shaikh OS, Freiberg MS Prof. Dr. P. Lampertico, CRC “A.M. e A. Migliavacca” Center for the Study of Liver Disease, Division of Gastroenterology and Direct-acting antiviral therapy for HCV Hepatology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore infection is associated with a reduced risk Policlinico, University of Milan, Via F. Sforza, 35, 20122 Milan, of cardiovascular disease events Italy, E-Mail: [email protected] ■ Background and aims: Infection with hepatitis virus C (HCV) is associated with an increased risk of cardiovascular disease (CVD) J Hepatol. ;():– events. It is not clear whether treatment with direct-acting anti- viral (DAA) agents affects risk of CVD. Yip TCF, Wong GLH, Chan HLY, Tse YK, Lam KLY, Lui GCY, Methods: The authors searched the Electronically Retrieved Co- Wong VWS hort of HCV-Infected Veterans database for patients with chron- ic HCV infection (n = 242,680) and identified patients who had HBsAg seroclearance further reduces hepato- been treated with a pegylated interferon and ribavirin regimen cellular carcinoma risk after complete viral (n = 4436) or a DAA-containing regimen (n = 12,667). Treated pa- suppression with nucleos(t)ide analogues tients were matched for age, race, sex, and baseline values with patients who had never received treatment for HCV infection Background and aims: In treated patients with chronic hepa- (controls). All subjects were free of any CVD event diagnosis of titis B (CHB) who have achieved complete viral suppression, it is HCV infection at baseline. The primary outcome was incident unclear if functional cure as indicated by hepatitis B surface an- CVD events, identified by International Classification of Diseases, tigen (HBsAg) seroclearance confers additional clinical benefit. Ninth Edition, Clinical Modification or International Classifica-
29 tion of Diseases, Tenth Edition code, in the different groups and HCC treatment and initiation of antiviral therapy as indepen- in patients with versus without a sustained virological response dent risk factors for HCC recurrence. HCC recurrence in stage to therapy. 0, A, B, and C was found in 56 (41%), 60 (44%), 19 (14%), and Results: There were 1239 incident CVD events (7.2%) in the treated 1 (0.7%) patients in the IFN group and 35 (44%), 32 (40%), 11 (14%), groups and 2361 events (13.8%) in the control group. Incidence and 2 (2.5%) patients in the DAA group, respectively (p = 0.70). rates were 30.9 per 1000 patient-years (95% confidence interval [CI]: 29.6–32.1) in the control group and 20.3 per 1000 patient- Conclusions: Hepatocellular carcinoma recurrence rates and years (95% CI: 19.2–21.5) in the treated groups (p < 0.0001). Treat- patterns after initiation of antiviral therapy did not differ be- ment with pegylated interferon and ribavirin (hazard ratio [HR] = tween patients who received interferon-based therapy and 0.78; 95% CI: 0.71–0.85) or a DAA regimen (HR = 0.57; 95% CI: direct-acting antiviral therapy. 0.51–0.65) was associated with a significantly lower risk of a CVD Dr. R. Tateishi, Department of Gastroenterology, Graduate event compared with no treatment (controls). Incidence rates School of Medicine, The University of Tokyo, 7-3-1 Hongo, for CVD events were 23.5 per 1000 patient-years (95% CI: 21.8–25.3) Bunkyo-ku, Tokyo 113-8655, Japan, E-Mail: [email protected] in the group treated with the pegylated interferon and ribavirin ■ regimen, 16.3 per 1000 patient-years (95% CI: 14.7–18.0) in the group treated with a DAA regimen, and 30.4 (95% CI: 29.2–31.7) in the control group. A sustained virological response was asso- J Viral Hepat. ;():– ciated with a lower risk of incident CVD events (HR = 0.87; 95% CI: 0.77–0.98). Dirks M, Haag K, Pflugrad H, Tryc AB, Schuppner R, Wedemeyer H, Conclusions: In an analysis of a cohort of hepatitis C virus (HCV)- Potthoff A, Tillmann HL, Sandorski K, Worthmann H, Ding X, infected veterans, treatment of HCV infection was associated Weissenborn K with a significant decrease in risk of cardiovascular disease (CVD) events. Patients treated with a direct-acting antiviral Neuropsychiatric symptoms in hepatitis C regimen and patients who achieved sustained virological re- patients resemble those of patients with sponses had the lowest risk for CVD events. autoimmune liver disease but are different A.A. Butt, M.D., Professor of Medicine, VA Pittsburgh Healthcare from those in hepatitis B patients System, Building 30, Mailstop 151, University Drive C, Pittsburgh, PA 15240, USA, E-Mail: [email protected] Chronic fatigue, mood alterations and cognitive impairment are ■ frequent accessory symptoms of HCV infection. Fatigue and mood alterations have also been observed in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but not in hepatitis B J Hepatol. ;():– virus (HBV) infection, thus indicating an autoimmune response as possible cause of HCV infection-associated encephalopathy. Nishibatake Kinoshita M, Minami T, Tateishi R, Wake T, Data, however, are sparse. This study aimed to prove that HCV Nakagomi R, Fujiwara N, Sato M, Uchino K, Enooku K, patients feature similar to those with autoimmune liver disease Nakagawa H, Asaoka Y, Shiina S, Koike K but contrary to HBV patients regarding neuropsychiatric symp- toms. A total of 132 non-cirrhotic patients (HCV: 46, HBV: 22, AIH: Impact of direct-acting antivirals on early 27, PBC: 29, AIH/PBC: 8) completed questionnaires addressing recurrence of HCV-related HCC: Comparison the domains mentioned above. 88 underwent a comprehen- with interferon-based therapy sive neuropsychological assessment. Patient groups were com- pared among each other and to 33 healthy controls. Fatigue, Background and aims: It remains controversial whether direct- anxiety and depression scores were significantly increased, and acting antivirals (DAAs) accelerate the recurrence of hepatitis C- the Short-Form-36 (SF-36) mental score significantly decreased related hepatocellular carcinoma (HCC) after curative therapy. in all patient groups compared to controls. Fatigue was signifi- This study aimed to evaluate HCC recurrence after DAA treat- cantly more pronounced in HCV than in HBV patients. HCV pa- ment of chronic hepatitis C. tients scored significantly worse than HBV patients but not AIH Methods: The authors enrolled patients with a history of suc- and PBC patients in the SF-36. HCV, AIH and PBC but not HBV cessful radiofrequency ablation treatment for hepatitis C-related patients did significantly worse than controls in word learning. HCC who received antiviral therapy with DAAs (DAA group: Recognition of words was impaired in HCV, AIH and PBC patients 147 patients) or with interferon (IFN)-based therapy (IFN group: and recognition of figures in HCV patients, exclusively (p ≤ 0.002). 156 patients). They assessed HCC recurrence rates from the initi- HCV patients did also worse than controls and HBV patients ation of antiviral therapy using the Kaplan-Meier method and concerning alertness and working memory (p ≤ 0.001). evaluated risk factors for HCC recurrence by multivariate Cox proportional hazard regression analysis. The recurrence pattern The neuropsychiatric profiles of hepatitis C virus patients are was categorized as follows: intrahepatic recurrence with a single similar to those of autoimmune hepatitis and primary biliary tumor < 2 cm (stage 0), a single tumor or up to 3 tumors ≤ 3 cm cholangitis patients but differ from those of hepatitis B virus (stage A), multinodular (stage B), and extrahepatic metastasis or patients, suggesting an autoimmune response as a possible macrovascular invasion (stage C). cause for these differences. Results: The recurrence rates at 1 and 2 years were 39% and 61% in the IFN group and 39% and 60% in the DAA group, respec- Prof. Dr. K. Weissenborn, Klinik für Neurologie, Medizinische tively (p = 0.43). Multivariate analysis identified higher lens culi- Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, naris agglutinin-reactive fraction of α-fetoprotein level, a history Germany, E-Mail: [email protected] of multiple HCC treatments, and a shorter interval between ■
30 J Viral Hepat. ;():– vere forms of the chronic viral hepatitis. However, there is a scar- city of data on the global burden of HDV infection. Knop V, Hofmann WP, Buggisch P, Klinker H, Mauss S, Günther R, Design: The authors searched PubMed, Embase, Cochrane Library Hinrichsen H, Hüppe D, Pfeiffer-Vornkahl H, Simon KG, Berg T, and China Knowledge Resource Integrated databases from Jan- Manns MP, Friedrich-Rust M; German Hepatitis C Registry uary 1, 1977, through December 31, 2016. They included studies with a minimum sample size of 50 patients. Their study analyzed Estimation of liver fibrosis by non-commercial data from a total of 40 million individuals to estimate the preva- serum markers in comparison with transient lence of HDV by using Der-Simonian Laird random-effects mod- el. The data were further categorized according to risk factors. elastography in patients with chronic hepatitis C Results: From a total of 2717 initially identified studies, only 182 virus infection receiving direct-acting anti viral articles from 61 countries and regions met the final inclusion cri- treatment teria. The overall prevalence of HDV was 0.98% (95% confidence interval [CI]: 0.61–1.42). In hepatitis B surface antigen (HBsAg)- Treatment decisions are based on extent of fibrosis in patients positive population, HDV pooled prevalence was 14.57% (95% CI: with chronic hepatitis C virus (HCV) infection. Non-invasive diag- 12.93–16.27): Seroprevalence was 10.58% (95% CI: 9.14–12.11) in nostic tools may help to avoid liver biopsy. The authors investi- mixed population without risk factors of intravenous drug gated the diagnostic accuracy of non-commercial serum scores use (IVDU) and high-risk sexual behavior (HRSB). It was 37.57% in comparison with transient elastography (TE). Data analysis (95% CI: 29.30–46.20) in the IVDU population and 17.01% (95% CI: was undertaken based on 2458 patients enrolled in the German 10.69–24.34) in HRSB population. Hepatitis C Registry, in a prospective, observational study. As- partate aminotransferase-to-platelet ratio index (APRI), Forns Conclusion: The authors found that approximately .% of index and Fibrosis-4 (FIB-4) score were calculated and the diag- hepatitis B surface antigen carriers (without intravenous drug nostic accuracy was compared to TE. As estimated by TE, 955 use [IVDU] and high-risk sexual behavior [HRSB]) were coin- (38.9%) patients had absence of significant fibrosis (SF), 736 (29.9%) fected with hepatitis D virus (HDV), which is 2-fold of what patients had SF, and 767 (31.2%) patients were shown to have cir- has been estimated before. They also noted a substantially rhosis. Patients with absence of SF had a sustained virological higher HDV prevalence in the IVDU and HRSB population. response (SVR) rate of 97.9%, whereas SVR was attained in 96.2% Their study highlights the need for increased focus on the and 92.2% in those with SF and cirrhosis, respectively (p < 0.0001). routine HDV screening and rigorous implementation of hep- The area under the receiver-operating characteristic curve atitis B virus vaccine program. (AUROC), sensitivity and specificity in discriminating of SF were 0.789, 0.596 and 0.939 by APRI; 0.838, 0.852 and 0.748 by Forns Dr. H.-G. Xu and Dr. S. Pan, Department of Laboratory Medicine, index; and 0.828, 0.658 and 0.946 by FIB-4 score. AUROCs for the The First Affiliated Hospital of Nanjing Medical University, prediction of cirrhosis, sensitivity and specificity were 0.881, 0.851 Nanjing 210029, China, E-Mail: [email protected] and and 0.854 by APRI; 0.846, 0.948 and 0.628 by Forns index; and E-Mail: [email protected] 0.907, 0.907 and 0.848 by FIB-4 score. ■ In conclusion, in the present multicenter real-world cohort, significant fibrosis and cirrhosis were predicted with high ac- curacy with non-commercial serum markers using transient elastography (TE) as reference. Further prospective long-term Metabolic and Inherited follow-up is necessary to compare biomarkers with TE con- Liver Disease cerning liver-related outcome and overall mortality.
Dr. V. Knop, Medizinische Klinik 1, Universitätsklinikum Frankfurt, Gastroenterology. ;():–.e Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany, Loomba R, Sanyal AJ, Kowdley KV, Terrault N, Chalasani NP, E-Mail: [email protected] Abdelmalek MF, McCullough AJ, Shringarpure R, Ferguson B, ■ Lee L, Chen J, Liberman A, Shapiro D, Neuschwander-Tetri BA
Factors associated with histologic response HDV in adult patients with non-alcoholic steato- hepatitis Gut. ;():– Background and aims: Non-alcoholic steatohepatitis (NASH) is Chen HY, Shen DT, Ji DZ, Han PC, Zhang WM, Ma JF, Chen WS, a leading cause of liver transplantation, and many trials are un- Goyal H, Pan S, Xu HG derway to evaluate potential therapies. The farnesoid X receptor ligand obeticholic acid (OCA) in the NASH treatment trial evalu- Prevalence and burden of hepatitis D virus ated the effects of OCA versus placebo on histologic response infection in the global population: (defined as decrease in non-alcoholic fatty liver disease activity A systematic review and meta-analysis score [NAS] by ≥ 2, with no worsening of fibrosis); 45% of pa- tients had a histologic response to OCA (25 mg), and 21% had a Objective: Hepatitis D virus (HDV) is a defective virus that com- response to placebo (p < 0.01). The authors performed a sec- pletes its life cycle only with hepatitis B virus (HBV). The HBV with ondary analysis of data from this trial to identify clinical param- HDV superinfection has been considered as one of the most se- eters associated with a histologic response.
31 Methods: They used a logistic regression model with a stepwise study team and had no further involvement) were masked to selection procedure to identify baseline and early on-treatment treatment groups. The primary outcomes were safety and the factors associated with a histologic response at 72 weeks. Base- absolute change in hepatic fat fraction after 16 weeks of treat- line demographics, liver histology, medical history, concomitant ment. All patients who were randomly assigned to groups and medications, cardiometabolic parameters, and serum biochem- received the study drug or placebo were included in the primary istry, as well as the changes over the course of the trial (at weeks analyses. 12 and 24), were evaluated as potential predictors of a histologic Findings: Between May 12, 2015, and August 4, 2016, 184 over- response. The model was cross-validated by a jackknife method, weight or obese patients with NASH were screened for study in- and performance was evaluated with the area under the receiv- clusion. Of these, 95 patients (52%) were excluded because they er-operating characteristic curve (AUROC). no longer met study criteria and 80 patients (43%) entered the Results: The logistic regression model found that OCA treat- placebo lead-in phase. After further exclusions, 75 patients (94%) ment, baseline NAS > 5, baseline triglyceride level ≤ 154 mg/dl, were randomly assigned to groups, received at least 1 dose of baseline international normalized ratio ≤ 1, baseline aspartate treatment (25 patients to receive 10 mg pegbelfermin once a day; aminotransferase level ≤ 49 U/l, and a decrease in alanine ami- 24 patients to receive 20 mg pegbelfermin once a week, and notransferase level at week 24 by ≥ 17 U/l, to be significantly as- 26 patients to receive placebo), and were included in the pri- sociated with histologic response (AUROC, 0.83, 95% confidence mary analysis. A prespecified interim analysis at week 8 showed interval: 0.77–0.89; p < 0.0001). a greater than expected change in the primary outcome and supported early closing of patient enrollment, since this analysis Conclusions: In a secondary analysis of data from a clinical indicated that the full planned sample size was not needed. We trial of obeticholic acid in patients with non-alcoholic steato- observed a significant decrease in absolute hepatic fat fraction hepatitis, the authors identified routine clinical and laboratory in the group receiving 10 mg pegbelfermin daily (-6.8% vs. -1.3%; glyceride levels, and a decrease in alanine aminotransferase p = 0.0004) and in the group receiving 20 mg pegbelfermin level) to significantly associate with histologic markers of re- weekly (-5.2% vs. -1.3%; p = 0.008) compared with the placebo sponse. group. Most adverse events were mild; the most common events were diarrhea in 8 of 49 patients (16%) treated with pegbelfer- R. Loomba, M.D., Professor of Medicine, Division of Gastro- min and 2 of 26 patients (8%) treated with placebo and nausea enterology, University of California at San Diego, ACTRI Bldg., in 7 patients (14%) treated with pegbelfermin and 2 patients (8%) 1W202, 9500 Gilman Drive, La Jolla, CA 92093-0887, USA, treated with placebo. There were no deaths, discontinuations due E-Mail: [email protected] to adverse events, or treatment-related serious adverse events. ■ Interpretation: Treatment with subcutaneously administered pegbelfermin for weeks was generally well tolerated and Lancet. ; ( ): – significantly reduced hepatic fat fraction in patients with non- alcoholic steatohepatitis (NASH). Further study of pegbelfer- Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, min is warranted in patients with NASH. Additional studies Harrison SA, Abdelmalek MF, Lawitz EJ, Halegoua-DeMarzio D, that use liver biopsies would allow for the assessment of peg- Kundu S, Noviello S, Luo Y, Christian R belfermin’s effects on liver histology. Moreover, further stud- ies should allow assessments of the safety and effectiveness Pegbelfermin (BMS-), a PEGylated of pegbelfermin in a larger number of patients. fibroblast growth factor analogue, in E.D. Charles, M.D., Bristol-Myers Squibb, Lawrenceville, patients with non-alcoholic steatohepatitis: NJ 08648, USA, E-Mail: [email protected] A randomized, double-blind, placebo- ■ controlled, phase a trial
Background: Pegbelfermin (BMS-986036), a PEGylated human J Hepatol. ;():– fibroblast growth factor 21 (FGF21) analogue, has previously been shown to improve markers of metabolism and liver fibrosis in Ajmera VH, Terrault NA, VanWagner LB, Sarkar M, Lewis CE, obese patients with type 2 diabetes. In this phase 2a study, the Carr JJ, Gunderson EP authors aimed to evaluate the safety and efficacy of pegbelfer- min in patients with non-alcoholic steatohepatitis (NASH). Methods: In this multicenter, randomized, double-blind, place- Longer lactation duration is associated bo-controlled, parallel-group, phase 2a study, they recruited with decreased prevalence of non-alcoholic adults (aged 21–75 years) with a body-mass index of at least fatty liver disease in women 25 kg/m2, biopsy-confirmed NASH (fibrosis stage 1–3), and a he- patic fat fraction of at least 10% when assessed by magnetic Background and aims: Lactation lowers blood glucose and tri- resonance imaging-proton density fat fraction. These patients glycerides, and increases insulin sensitivity. The authors hypoth- were enrolled at 17 medical centers in the USA. Eligible patients esized that a longer duration of lactation would be associated were stratified by type 2 diabetes status and they were random- with lower prevalence of non-alcoholic fatty liver disease (NAFLD), ly assigned (1:1:1) by a computer-based system to receive subcu- which is the leading cause of chronic liver disease in the United taneous injections of placebo once a day, 10 mg pegbelfermin States. once a day, or 20 mg pegbelfermin once a week, all for 16 weeks. Methods: Participants from the Coronary Artery Risk Develop- Participants, the study team administering treatment, and in- ment in Young Adults cohort study who delivered ≥ 1 child vestigators analyzing outcomes (who were independent of the post-baseline (Y0: 1985–1986), and underwent CT quantification of
32 hepatic steatosis 25 years following cohort entry (Y25: 2010–2011) frequency of 1 per 421. The prevalence is lowest in those of East were included (n = 844). The duration of lactation was summed Asian, South Asian, and Finnish ancestry. for all post-baseline births, and NAFLD at Y25 was assessed by central review of CT images and defined by liver attenuation Conclusion: Using 2 disease variants in LIPA, these data can ≤ 40 Hounsfield Units after exclusion of other causes of hepatic reassure clinicians that lysosomal acid lipase deficiency (LAL-D) steatosis. Unadjusted and multivariable logistic regression ana- is an ultra-rare disorder. Given the therapeutic capability of lyses were performed using an a priori set of confounding vari- sebelipase α, investigation for LAL-D might be included in ables; age, race, education, and baseline body mass index. second-line metabolic screening in non-alcoholic fatty liver Results: Of 844 women who delivered after baseline (48% black, disease. 52% white, mean age 49 years at Y25 exam), 32% reported lacta- tion duration of 0–1 month, 25% reported > 1 to 6 months, 43% Dr. J.P. Mann, Department of Paediatrics, University of reported > 6 months, while 54 (6%) had NAFLD. Longer lacta- Cambridge, Box 116, Level 8, Cambridge Biomedical Campus, tion duration was inversely associated with NAFLD in unadjusted Cambridge CB2 0QQ, UK, E-Mail: [email protected] ■ logistic regression. For women who reported > 6 months lacta- tion compared to those reporting 0–1 month, the odds ratio [OR] for NAFLD was 0.48 (95% confidence interval [CI]: 0.25–0.94; p = 0.03) and the association remained after adjustment for Lancet. ;():– confounders (adjusted OR = 0.46; 95% CI: 0.22–0.97; p = 0.04). Ovadia C, Seed PT, Sklavounos A, Geenes V, Di Illio C, Chambers J, Conclusions: A longer duration of lactation, particularly > Kohari K, Bacq Y, Bozkurt N, Brun-Furrer R, Bull L, Estiú MC, months, is associated with lower odds of non-alcoholic fatty Grymowicz M, Gunaydin B, Hague WM, Haslinger C, Hu Y, liver disease (NAFLD) in mid-life and may represent a modi- Kawakita T, Kebapcilar AG, Kebapcilar L, Kondrackienė J, fiable risk factor for NAFLD. Koster MPH, Kowalska-Kańka A, Kupčinskas L, Lee RH, Locatelli A, Macias RIR, Marschall HU, Oudijk MA, Raz Y, Rimon E, Shan D, V.H. Ajmera, M.D., Assistant Professor of Medicine, Division Shao Y, Tribe R, Tripodi V, Yayla Abide C, Yenidede I, Thornton JG, of Gastroenterology, University of California San Diego, Chappell LC, Williamson C 9500 Gilman Drive MC 0887, La Jolla, CA 92093, USA, E-Mail: [email protected] Association of adverse perinatal outcomes ■ of intrahepatic cholestasis of pregnancy with biochemical markers: Results of aggregate and individual patient data meta-analyses J Hepatol. ;():– Background: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the Carter A, Brackley SM, Gao J, Mann JP concentration of specific biochemical markers is unclear. The authors aimed to quantify the adverse perinatal effects of intra- The global prevalence and genetic spectrum hepatic cholestasis of pregnancy in women with increased se- of lysosomal acid lipase deficiency: rum bile acid concentrations and determine whether elevated A rare condition that mimics NAFLD bile acid concentrations were associated with the risk of still- birth and preterm birth. Background and aims: Lysosomal acid lipase deficiency (LAL-D) Methods: They did a systematic review by searching PubMed, is an autosomal recessive condition that may present in a mild Web of Science, and Embase databases for studies published form (cholesteryl ester storage disease [CESD]), which mimics from database inception to June 1, 2018, reporting perinatal out- non-alcoholic fatty liver disease (NAFLD). It has been suggested comes for women with intrahepatic cholestasis of pregnancy that CESD may affect 1 in 40,000 and is underdiagnosed in NAFLD when serum bile acid concentrations were available. Inclusion clinics. Therefore, the authors aimed to estimate the prevalence criteria were studies defining intrahepatic cholestasis of preg- of LAL-D using analysis of genetic variation in LIPA. nancy based upon pruritus and elevated serum bile acid Methods: Medline and Embase were systematically searched for concentrations, with or without raised liver aminotransferase previously reported disease variants and prevalence estimates. concentrations. Eligible studies were case-control, cohort, and Previous prevalence estimates were meta-analyzed. Disease vari- population-based studies, and randomized controlled trials, with ants in LIPA were annotated with allele frequencies from gno- at least 30 participants, and that reported bile acid concentra- mAD and combined with unreported major functional variants tions and perinatal outcomes. Studies at potential higher risk of found in humans. Pooled ethnicity-specific prevalences for LAL-D reporter bias were excluded, including case reports, studies not and CESD were calculated using the Hardy-Weinberg equation. comprising cohorts, or successive cases seen in a unit; they also Results: Meta-analysis of existing genetic studies estimated the excluded studies with high risk of bias from groups selected prevalence of LAL-D as 1 per 160,000 (95% CI: 1 per 65,025–761,652) (e.g., a subgroup of babies with poor outcomes were explicitly using the allele frequency of c.894G>A in LIPA. A total of 98 pre- excluded), conference abstracts, and letters to the editor with- viously reported disease variants in LIPA were identified, of which out clear peer review. The authors also included unpublished 32 of 98 were present in gnomAD, giving a prevalence of 1 per data from 2 UK hospitals. They did a random-effects meta-analy- 307,482 (95% CI: 257,672–366,865). Wolman disease was associated sis to determine risk of adverse perinatal outcomes. Aggregate with more loss-of-function variants than CESD. When this was data for maternal and perinatal outcomes were extracted from combined with 22 previously unreported major functional va- case-control studies, and individual patient data (IPD) were re- riants in LIPA identified in humans, the pooled prevalence of quested from study authors for all types of study (as no control LAL-D was 1 per 177,452 (95% CI: 149,467–210,683) with a carrier group was required for the IPD analysis) to assess associations
33 between biochemical markers and adverse outcomes using transplantation were analyzed to determine whether markers of logistic and stepwise logistic regression. cholestasis could identify patients with recurrence of PBC (based Findings: The authors assessed 109 full-text articles, of which on histologic analysis). Patients were followed for a median 6.9 23 studies were eligible for the aggregate data meta-analysis years (interquartile range, 6.1–7.9 years). (5557 intrahepatic cholestasis of pregnancy cases and 165,136 con- Results: PBC recurred in 22% of patients after 5 years and 36% trols), and 27 provided IPD (5269 intrahepatic cholestasis of preg- after 10 years. Age at diagnosis < 50 years (hazard ratio [HR] = 1.79; nancy cases). Stillbirth occurred in 45 (0.91%) of 4936 intra- 95% confidence interval [CI]: 1.36–2.36; p < 0.001), age at liver hepatic cholestasis of pregnancy cases and 519 (0.32%) of 163,947 transplantation < 60 years (HR = 1.39; 95% CI: 1.02–1.90; p = 0.04), control pregnancies (odds ratio [OR] = 1.46 [95% confidence in- use of tacrolimus (HR = 2.31; 95% CI: 1.72–3.10; p < 0.001), and bio- terval [CI]: 0.73–2.89]; I2 = 59.8%). In singleton pregnancies, still- chemical markers of severe cholestasis (bilirubin ≥ 100 µmol or birth was associated with maximum total bile acid concen- alkaline phosphatase > 3-fold the upper limit of normal) at 6 tration (area under the receiver operating characteristic curve months after liver transplantation (HR = 1.79; 95% CI: 1.16–2.76; [ROC AUC]) = 0.83 [95% CI: 0.74–0.92]), but not alanine amino- p = 0.008) were associated with higher risk of PBC recurrence, transferase (ROC AUC = 0.46 [0.35–0.57]). For singleton pregnan- whereas use of cyclosporine reduced risk of PBC recurrence cies, the prevalence of stillbirth was 3 (0.13%; 95% CI: 0.02–0.38) (HR = 0.62; 95% CI: 0.46–0.82; p = 0.001). In multivariable Cox re- of 2310 intrahepatic cholestasis of pregnancy cases in women gression with time-dependent covariate, recurrence of PBC sig- with serum total bile acids of < 40 µmol/l versus 4 (0.28%; 95% CI: nificantly associated with graft loss (HR = 2.01; 95% CI: 1.16–3.51; 0.08–0.72) of 1412 cases with total bile acids of 40–99 µmol/l p = 0.01) and death (HR = 1.72; 95% CI: 1.11–2.65; p = 0.02). (hazard ratio [HR] = 2.35 [95% CI: 0.52–10.50]; p = 0.26), and versus 18 (3.44%; 95% CI: 2.05–5.37) of 524 cases for bile acids of 100 µmol/l or Conclusions: Younger age at the time of diagnosis with primary more (HR = 30.50 [95% CI: 8.83–105.30]; p < 0.0001). biliary cholangitis (PBC) or at liver transplantation, tacrolimus use, and biochemical markers of cholestasis after liver trans- Interpretation: The risk of stillbirth is increased in women plantation are associated with PBC recurrence. PBC recurrence with intrahepatic cholestasis of pregnancy and singleton preg- reduces odds of graft and patient survival. Strategies are need- nancies when serum bile acids concentrations are of µmol/l ed to prevent PBC recurrence or reduce its negative effects. or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they Prof. Dr. A.J. Montano-Loza, Division of Gastroenterology and can probably be reassured that the risk of stillbirth is similar Liver Unit, Department of Medicine, University of Alberta, to that of pregnant women in the general population, pro- 8540 112 Street NW, Zeidler Ledcor Center, Edmonton, vided repeat bile acid testing is done until delivery. AB T6G 2X8, Canada, E-Mail: [email protected] ■ Prof. Dr. C. Williamson, Department of Women and Children’s Health, King’s College London, Hodgkin Building, Guy’s Campus, London SE1 1UL, UK, E-Mail: [email protected] Cirrhosis ■
Hepatology. ;():–
Autoimmune Liver Disease Forde KA, Fallon MB, Krowka MJ, Sprys M, Goldberg DS, Krok KL, Patel M, Lin G, Oh JK, Mottram CD, Scanlon PD, Kawut SM; Pulmonary Vascular Complications of Liver Disease 2 Study Group Gastroenterology. ;():–.e Pulse oximetry is insensitive for detection Montano-Loza AJ, Hansen BE, Corpechot C, Roccarina D, of hepatopulmonary syndrome in patients Thorburn D, Trivedi P, Hirschfield G, McDowell P, Poupon R, Dumortier J, Bosch A, Giostria E, Conti F, Parés A, Reig A, evaluated for liver transplantation Floreani A, Russo FP, Goet JC, Harms MH, van Buuren H, Screening for hepatopulmonary syndrome (HPS) using pulse Van den Ende N, Nevens F, Verhelst X, Donato MF, Malinverno F, oximetry is recommended in liver transplant (LT) candidates be- Ebadi M, Mason AL; Global PBC Study Group cause mortality is increased, independently of the severity of the oxygenation defect. LT exception points may be afforded to Factors associated with recurrence of primary those with HPS and severe hypoxemia. The authors assessed biliary cholangitis after liver transplantation the screening characteristics of pulse oximetry for HPS. The Pul- and effects on graft and patient survival monary Vascular Complications of Liver Disease 2 study is a mul- ticenter, prospective cohort study of adults undergoing their Background and aims: Primary biliary cholangitis (PBC) fre- first LT evaluation. Patients underwent protocolized assessment quently recurs after liver transplantation. The authors evaluated of oxygen saturation by pulse oximetry (SpO2), arterial blood risk factors associated with recurrence of PBC and its effects on gas, spirometry, and contrast-enhanced echocardiography (CE). patient and graft survival in a multicenter, international cohort HPS was defined as an alveolar-arterial gradient ≥ 15 mmHg (the Global PBC Study Group). (≥ 20 mmHg if age > 64 years), intrapulmonary vascular dilatation Methods: They collected demographic and clinical data from on CE, and absence of lung disease. The study sample included 785 patients (89% female) with PBC who underwent liver trans- 363 patients. Of these, 75 (20.7%; 95% confidence interval [CI]: plantation (mean age, 54 ± 9 years) from February 1983 through 16.6–25.2) met the criteria for HPS. The area under the receiver-
June 2016, among 13 centers in North America and Europe. Re- operating characteristic curve (or c-statistic) for SpO2 in discrimi- sults from biochemical tests performed within 12 months of liver nating HPS was 0.59 (95% CI: 0.51–0.66). An SpO2 < 96%, recom- 34 mended by practice guidelines as a threshold to require further p = 0.02), and recent hospitalization (OR = 1.93; p = 0.04) were testing, had low sensitivity (28%; 95% CI: 18–28). The c-statistic of identified as independent predictors of MDR infection. The preva-
SpO2 in discriminating HPS with a partial pressure of oxygen lence of MDROs in the second series (392 infections/284 patients) (PaO2) < 60 mmHg (eligible for LT exception points) was 0.76 was 23%; 38% in culture-positive infections. A mild increase in the (95% CI: 0.46–1.00). An SpO2 cutoff of < 96% had higher sensitivity rate of carbapenem-resistant Enterobacteriaceae was observed for detecting HPS with PaO2 < 60 mmHg (71%; 95% CI: 38–100) in this series. but was still inadequate. Conclusions: Multidrug-resistant bacterial infections consti- Conclusion: Pulse oximetry is not sufficiently sensitive to screen tute a prevalent, growing and complex healthcare problem in for hepatopulmonary syndrome (HPS) in liver transplant (LT) patients with decompensated cirrhosis and acute-on-chronic candidates. Arterial blood gas and contrast-enhanced echo- liver failure across Europe, negatively impacting on progno- cardiography are required in LT candidates for diagnosis of HPS. sis. Strategies aimed at preventing the spread of antibiotic resistance in cirrhosis should be urgently evaluated. K.A. Forde, M.D., Ph.D., Assistant Professor of Medicine, Center for Clinical Epidemiology and Biostatistics Perelman School Dr. J. Fernández, Liver Unit, Hospital Clínic de Barcelona, of Medicine University of Pennsylvania 423 Guardian Drive, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain, 722 Blockley Hall Philadelphia, PA 19104-6021, USA, E-Mail: [email protected] E-Mail: [email protected] ■ ■
Hepatology. ;():– J Hepatol. ; (): – Hernández-Gea V, Procopet B, Giráldez Á, Amitrano L, Fernández J, Prado V, Trebicka J, Amoros A, Gustot T, Wiest R, Villanueva C, Thabut D, Ibañez-Samaniego L, Silva-Junior G, Deulofeu C, Garcia E, Acevedo J, Fuhrmann V, Durand F, Martinez J, Genescà J, Bureau C, Trebicka J, Llop E, Laleman W, Sánchez C, Papp M, Caraceni P, Vargas V, Bañares R, Piano S, Palazon JM, Castellote J, Rodrigues S, Gluud LL, Noronha Ferreira C, Janicko M, Albillos A, Alessandria C, Soriano G, Welzel TM, Barcelo R, Cañete N, Rodríguez M, Ferlitsch A, Mundi JL, Laleman W, Gerbes A, De Gottardi A, Merli M, Coenraad M, Gronbaek H, Hernández-Guerra M, Sassatelli R, Dell’Era A, Saliba F, Pavesi M, Jalan R, Ginès P, Angeli P, Arroyo V; European Senzolo M, Abraldes JG, Romero-Gómez M, Zipprich A, Casas M, Foundation for the Study of Chronic Liver Failure (EF-Clif) Masnou H, Primignani M, Krag A, Nevens F, Calleja JL, Jansen C, Robic MA, Conejo I, Catalina MV, Albillos A, Rudler M, Alvarado E, Multidrug-resistant bacterial infections in Guardascione MA, Tantau M, Bosch J, Torres F, Garcia-Pagán JC; patients with decompensated cirrhosis and International Variceal Bleeding Observational Study Group with acute-on-chronic liver failure in Europe and Baveno Cooperation
Background and aims: Antibiotic resistance has been increas- Preemptive TIPS improves outcome in high- ingly reported in patients with decompensated cirrhosis in sin- risk variceal bleeding: An observational study gle-center studies. Prospective investigations reporting broad epidemiological data are scarce. The authors aimed to analyze Patients admitted with acute variceal bleeding (AVB) and Child- epidemiological changes in bacterial infections in patients with Pugh C score (CP-C) or Child-Pugh B plus active bleeding at decompensated cirrhosis. endoscopy (CP-B+AB) are at high risk for treatment failure, re- Methods: This was a prospective evaluation of 2 series of pa- bleeding, and mortality. A preemptive transjugular intrahepatic tients hospitalized with decompensated cirrhosis. The Canonic portosystemic shunt (p-TIPS) has been shown to improve sur- series included 1146 patients from Northern, Southern and West- vival in these patients, but its use in clinical practice has been ern Europe in 2011. Data on epidemiology, clinical characteristics challenged and not routinely incorporated. The present study of bacterial infections, microbiology and empirical antibiotic aimed to further validate the role of p-TIPS in a large number of schedules were assessed. A second series of 883 patients from high-risk patients. This multicenter, international, observational Eastern, Southern and Western Europe was investigated be- study included 671 patients from 34 centers admitted for AVB tween 2017–2018. and high risk of treatment failure. Patients were managed ac- Results: A total of 455 patients developed 520 infections (39.7%) cording to current guidelines, and use of drugs and endoscopic in the first series, with spontaneous bacterial peritonitis, urinary therapy (D+E) or p-TIPS was based on individual center policy. tract infections and pneumonia the most frequent infections. p-TIPS in the setting of AVB is associated with a lower mortality Nosocomial episodes predominated in this series. Nearly half of in CP-C patients compared with D+E (1-year mortality 22% vs. the infections were culture-positive, of which 29.2% were caused 47% in D+E group; p = 0.002). Mortality rate in CP-B+AB patients by multidrug-resistant organisms (MDROs). MDR strains were was low, and p-TIPS did not improve it. In CP-C and CP-B+AB more frequently isolated in Northern and Western Europe. Ex- patients, p-TIPS reduced treatment failure and rebleeding (1-year tended-spectrum β-lactamase-producing Enterobacteriaceae cumulative incidence function probability of remaining free of were the most frequent MDROs isolated in this series, although the composite end point: 92% vs. 74% in the D+E group; p = 0.017) prevalence and type differed markedly among countries and and development of de novo or worsening of previous ascites centers. Antibiotic resistance was associated with poor progno- without increasing rates of hepatic encephalopathy. sis and failure of antibiotic strategies, based on third-generation cephalosporins or quinolones. Nosocomial infection (odds ratio Conclusion: A preemptive transjugular intrahepatic portosys- [OR] = 2.74; p < 0.001), intensive care unit admission (OR = 2.09; temic shunt (p-TIPS) must be the treatment of choice in Child-
35 Pugh C patients with acute variceal bleeding. Because of 8 patients with both); 80 of these patients had favorable Baveno the strong benefit in preventing further bleeding and ascites, VI status and none had VNT. Progression of PH was studied in p-TIPS could be a good treatment strategy for patients with 548 patients; during a follow-up period of 61.2 (interquartile Child-Pugh B plus active bleeding. range, 39.5–80.6) months, 105 of these patients (19.1%) had pro- gression of PH. Lack of a SVR and grade 1 EV were independent- Dr. Dr. V. Hernández-Gea, Barcelona Hepatic Hemodynamic ly associated with progression of PH. At the time of PH progres- Laboratory, Liver Unit, Hospital Clínic, University of Barcelona, sion, all patients had unfavorable Baveno VI status. Achieving Villarroel 170, 08036 Barcelona, Spain, favorable Baveno VI status after a SVR was associated with the E-Mail: [email protected] absence of PH progression. Favorable Baveno VI status and SVR were independently associated with survival. or Prof. Dr. J.C. Garcia-Pagán, Barcelona Hepatic Hemodynamic Conclusions: In an analysis of data from a large cohort of pa- Laboratory, Liver Unit, Hospital Clínic, University of Barcelona, tients with hepatitis B virus- or hepatitis C virus-associated Villarroel 170, 08036 Barcelona, Spain, E-Mail: [email protected] cirrhosis in France, the authors’ validated the Baveno VI guide- ■ lines on screening and surveillance of portal hypertension, even for patients who achieved a sustained response to anti- viral therapy. Gastroenterology. ;():–.e Prof. Dr. D. Thabut, Service d’Hépato-gastroentérologie, Thabut D, Bureau C, Layese R, Bourcier V, Hammouche M, Centre Hospitalier Universitaire Paris-Groupe Hospitalier La Pitié Cagnot C, Marcellin P, Guyader D, Pol S, Larrey D, De Lédinghen V, Salpêtrière-Charles Foix - Hôpital Pitié-Salpêtrière, 47–83, Ouzan D, Zoulim F, Roulot D, Tran A, Bronowicki JP, Zarski JP, boulevard de l’Hôpital, 75013 Paris, France, Goria O, Calès P, Péron JM, Alric L, Bourlière M, Mathurin P, E-Mail: [email protected] ■ Blanc JF, Abergel A, Serfaty L, Mallat A, Grangé JD, Attali P, Bacq Y, Wartelle-Bladou C, Dao T, Pilette C, Silvain C, Christidis C, Capron D, Bernard-Chabert B, Hillaire S, Di Martino V, Sutton A, Audureau E, Roudot-Thoraval F, Nahon P; Hepatology. ;():– ANRS CO12 CirVir group Kim D, Li AA, Perumpail BJ, Gadiparthi C, Kim W, Cholankeril G, Validation of Baveno VI criteria for screening Glenn JS, Harrison SA, Younossi ZM, Ahmed A and surveillance of esophageal varices in patients with compensated cirrhosis and Changing trends in etiology-based and a sustained response to antiviral therapy ethnicity-based annual mortality rates of cirrhosis and hepatocellular carcinoma Background and aims: Management of patients with cirrhosis in the United States includes endoscopic screening and surveillance to detect esopha- geal varices (EV) and prevent bleeding. However, the Baveno VI With recent improvements in the treatment of end-stage liver guidelines recommend avoiding endoscopies for patients with disease (ESLD), a better understanding of the burden of cirrho- liver stiffness measurements below 20 kPa and platelet counts sis and hepatocellular carcinoma (HCC) is needed in the United above 150,000 (favorable Baveno VI status) and endoscopic as- States. A population-based study using the US Census and na- sessment of patients with higher levels of liver stiffness and plate- tional mortality database was performed. The authors identified let counts (unfavorable Baveno VI status). The authors aimed to the age-standardized etiology-specific mortality rates for cirrho- validate the Baveno VI guidelines, evaluating outcomes of pa- sis and HCC among US adults ages ≥ 20 years from 2007 to 2016. tients in the ANRS-CO12 CirVir cohort with compensated cirrhosis They determined temporal mortality rate patterns by joinpoint associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) analysis with estimates of annual percentage change (APC). Age- infection, with or without a sustained response to antiviral ther- standardized cirrhosis-related mortality rates increased from apy (SVR). 19.77/100,000 persons in 2007 to 23.67 in 2016 with an annual in- Methods: They performed an ancillary study using data from crease of 2.3% (95% confidence interval [CI]: 2.0–2.7). The APC in 891 patients in the ANRS CO12 CirVir cohort, treated at 35 centers mortality rates for hepatitis C virus (HCV)-cirrhosis shifted from a in France, with HCV or HBV infection and biopsy-proven cirrhosis, 2.9% increase per year during 2007 to 2014 to a 6.5% decline per Child-Pugh A scores, no previous complications, and no hepa- year during 2014 to 2016. Meanwhile, mortality for cirrhosis from tocellular carcinoma who underwent an endoscopic procedure alcoholic liver disease (ALD, APC 4.5%) and non-alcoholic fatty and had interpretable liver stiffness measurements and platelet liver disease (NAFLD, APC 15.4%) increased over the same period, counts. Progression of portal hypertension (PH) was defined as whereas mortality for hepatitis B virus (HBV)-cirrhosis decreased the onset of varices needing treatment (VNT) or PH-related with an average APC of -1.1%. HCC-related mortality increased from bleeding. SVR was defined as undetectable level of HCV RNA by 3.48/100,000 persons in 2007 to 4.41 in 2016 at an annual rate of polymerase chain reaction assay (< 50 IU/ml) 12 weeks after the 2.0% (95% CI: 1.3–2.6). Etiology-specific mortality rates of HCC end of treatment or an undetectable level of HBV DNA. The pri- were largely consistent with cirrhosis-related mortality. Minority mary aims were to validate the Baveno VI guidelines for screen- populations had a higher burden of HCC-related mortality. ing and surveillance of EV in patients with compensated cirrho- sis and to study the effects of a SVR on the progression of PH. Conclusion: Cirrhosis-related and hepatocellular carcinoma Results: A total of 200 patients achieved a SVR (22.4%; 94 pa- (HCC)-related mortality rates increased between 2 and 2 tients with HCV infection, 98 patients with HBV infection, and in the United States. However, mortality rates in hepatitis C
36 virus-cirrhosis demonstrated a significant decline from 24 HCC to 2, during the direct-acting antiviral era. Mortality rates for alcoholic liver disease/non-alcoholic fatty liver disease- cirrhosis and HCC have continued to increase, whereas hepa- Hepatology. ;():– titis B virus-cirrhosis-related mortality declined during the -year period. Importantly, minorities had a disproportionately Kao WY, Su CW, Tan ECH, Lee PC, Chen PH, Tang JH, Huang YH, higher burden of end-stage liver disease-related mortality. Huo TI, Chang CC, Hou MC, Lin HC, Wu JC
A. Ahmed, M.D., Professor of Medicine, Division of Gastro- Proton-pump inhibitors and risk of hepato- enterology and Hepatology, Stanford University School of cellular carcinoma in patients with chronic Medicine, 750 Welch Road # 210, Palo Alto, CA 94304, USA, E-Mail: [email protected] hepatitis B or C ■ Researchers have hypothesized that the long-term use of pro- ton-pump inhibitors (PPIs) can increase the risk of developing cancer. However, the association between PPI use and hepato- J Hepatol. ;():– cellular carcinoma (HCC) risk is unclear. Using data from the Tai- wan National Health Insurance Research Database for the peri- Kim HY, So YH, Kim W, Ahn DW, Jung YJ, Woo H, Kim D, Kim MY, od between 2003 and 2013, the authors identified 35,356 patients Baik SK with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. Propensity score matching (1:1 ratio) by gender, age, Non-invasive response prediction in prophy- cohort entry year, comorbidity, and medication resulted in the lactic carvedilol therapy for cirrhotic patients inclusion of 7492 pairs of patients (PPI users and non-PPI users) for analyses. Multivariate and stratified analysis using the Kaplan- with esophageal varices Meier method and Cox proportional hazards models were per- formed in order to estimate the association between PPI use Background and aims: Non-selective beta-blockers (NSBBs) are and the risk of developing HCC. In the HBV cohort, 237 patients the mainstay of primary prophylaxis of esophageal variceal bleed- developed HCC during a median follow-up of 53 months. How- ing in patients with liver cirrhosis. The authors investigated ever, PPI use was not associated with an increased risk of devel- whether non-invasive markers of portal hypertension correlate oping HCC (adjusted hazard ratio [aHR] = 1.25, 95% confidence with hemodynamic responses to NSBBs in cirrhotic patients interval [CI]: 0.90–1.73; p = 0.18). In the HCV cohort, 211 patients with esophageal varices. developed HCC; but again, PPI use was not associated with Methods: In this prospective cohort study, 106 cirrhotic patients an increase in the risk of developing HCC (aHR = 1.19, 95% CI: with high-risk esophageal varices in the derivation cohort re- 0.88–1.61; p = 0.25). No relationship was observed between a ceived carvedilol prophylaxis, and completed paired measure- dose-dependent effect of PPI use and HCC risk. Subgroup anal- ments of hepatic venous pressure gradient, liver stiffness (LS), ysis also confirmed that PPI use was not correlated to an in- and spleen stiffness (SS) at the beginning and end of dose titra- creased HCC risk. tion. LS and SS were measured using acoustic radiation force impulse imaging. A prediction model for hemodynamic response Conclusion: Based on a retrospective population-based co- was derived, and subject to an external validation in the valida- hort study throughout Taiwan, where the prescription of pro- tion cohort (63 patients). ton-pump inhibitors (PPIs) is tightly regulated, PPI use is not Results: Hemodynamic response occurred in 59 patients (55.7%) associated with the risk of developing hepatocellular carci- in the derivation cohort, and in 33 patients (52.4%) in the vali- noma among patients with chronic hepatitis B virus or hepa- dation cohort, respectively. Multivariate logistic regression anal- titis C virus infections. ysis identified that ΔSS was the only significant predictor of hemodynamic response (odds ratio = 0.039, 95% confidence in- Prof. Dr. C.-W. Su, Division of Gastroenterology, Department terval: 0.008–0.135; p < 0.0001). The response prediction model of Medicine Taipei Veterans General Hospital, No. 201, (ModelΔSS = 0.0490–2.8345 x ΔSS; score = (exp[ModelΔSS])/ Sec. 2 Shih-Pai Road, Peitou District, Taipei 11217, Taiwan, (1 + exp[ModelΔSS]) showed good predictive performance (area E-Mail: [email protected] under the receiver-operating characteristic curve [AUC], 0.803) using 0.530 as the threshold value. The predictive performance or of the ModelΔSS in the validation set improved using the same Dr. E.C.-H. Tan, National Research Institute of Chinese Medicine threshold value (AUC, 0.848). Ministry of Health and Welfare, No. 155-1, Sec. 2 Linong Street, Beitou District, Taipei 11221, Taiwan, E-Mail: [email protected] Conclusion: A new model based on dynamic changes in spleen ■ stiffness exhibited good performance in predicting hemo- dynamic response to non-selective beta-blocker prophylaxis in patients with high-risk esophageal varices.
Dr. W. Kim, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of Korea, E-Mail: [email protected] ■
37 Hepatology. ;():– Mehta N, Dodge JL, Roberts JP, Hirose R, Yao FY Symposium 217 Alpha-fetoprotein decrease from > to < ng/ml in patients with hepatocellular carcinoma leads to improved posttransplant outcomes
High alpha-fetoprotein (AFP) > 1000 ng/ml is associated with poor outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC). A new national policy has been implemented West Meets East: Functional Meets for AFP > 1000 ng/ml requiring a decrease to < 500 ng/ml be- fore LT, but there is a paucity of data on the optimal AFP thresh- old before LT. The authors aimed to evaluate the effects of a Organic Gastrointestinal reduction in AFP from > 1000 ng/ml to different AFP thresholds before LT on survival and HCC recurrence after LT using the United Network for Organ Sharing database. They identified Diseases 407 patients who underwent transplantation between January 2005 and September 2015 and who had AFP > 1000 ng/ml at least once before LT. The last AFP measurement before LT was November 29–30, 2019 > 1000 ng/ml in 72.0%, decreased from > 1000 to 101–499 ng/ml in 9.6%, and decreased to ≤ 100 ng/ml in 14.3%. Local-regional Singapore therapy was not performed in 45.4% of patients with AFP > 1000 ng/ml at LT versus 12.8% of those with AFP of 101–499 ng/ml and 10.3% of those with AFP ≤ 100 ng/ml at LT (p < 0.001). Kaplan- Congress Venue Meier 5-year post-LT survival for those with AFP > 1000 ng/ml at LT was 48.8% versus 67.0% for those with a decrease in AFP to Parkroyal 101–499 ng/ml (p < 0.001) and 88.4% for those with AFP ≤ 100 ng/ml at LT (p < 0.001). HCC recurrence probability at 5 years was 35.0% on Beach Road for patients with AFP > 1000 ng/ml versus 13.3% for patients with 7500 Beach Road AFP of 101–499 ng/ml and 7.2% for patients with AFP ≤ 100 ng/ml Singapore 199591 at LT (p < 0.001). In multivariable analysis, a decrease in the AFP Singapore to 101–499 ng/ml was associated with a > 2-fold reduction in posttransplant mortality (p = 0.01) and a nearly 3-fold reduction in HCC recurrence (p = 0.02) compared with AFP > 1000 ng/ml at LT.
Conclusion: These results demonstrated significantly improved posttransplant outcomes when restricting liver transplan- tation to patients with a reduction in alpha-fetoprotein from > to < ng/ml, validating the recently implemented national policy.
N. Mehta, M.D. Division of Gastroenterology Department of Medicine, University of California San Francisco, 400 Parnassus Ave., San Francisco, CA 94143, USA, E-Mail: [email protected] ■ Scientific Organization G. Barbara, Bologna (Italy) K.-A. Gwee, Singapore (Singapore) G. Holtmann, Brisbane (Australia) W. Kruis, Cologne (Germany) C.J. Ooi, Singapore (Singapore)
FALK FOUNDATION e.V. Congress Department Leinenweberstr. 5 Tel.: +49-761/1514-125 79108 Freiburg Fax: +49-761/1514-359 Germany E-Mail: [email protected] www.falk-foundation-symposia.org 38
Falk_Anzeigen_E_2019.indd2019 4 31.07.18 10:58 Symposium 217
West Meets East: Functional Meets Organic Gastrointestinal Diseases
November 29–30, 2019 Singapore
Congress Venue Parkroyal on Beach Road 7500 Beach Road Singapore 199591 Singapore
Scientific Organization G. Barbara, Bologna (Italy) K.-A. Gwee, Singapore (Singapore) G. Holtmann, Brisbane (Australia) W. Kruis, Cologne (Germany) C.J. Ooi, Singapore (Singapore)
FALK FOUNDATION e.V. Congress Department Leinenweberstr. 5 Tel.: +49-761/1514-125 79108 Freiburg Fax: +49-761/1514-359 Germany E-Mail: [email protected] www.falk-foundation-symposia.org
Falk_Anzeigen_E_2019.indd2019 4 31.07.18 10:58 September 17–20, 2019, Glasgow, Great Britain International BASL219 Annual Meeting of the British Association Gastroenterological for the Study of the Liver Telephone: +44 1543 442154 Congresses E-Mail: [email protected] Website: https://www.basl.org.uk
July 5–6, 2019, St. Petersburg, Russia September 20–22, 2019, Chicago, IL, USA Symposium 215 ILCA 219 IBD: From Diagnosis to Therapy 13th Annual Conference of the Telephone: +43 1 40400-4741 International Liver Cancer Association Telefax: +43 1 40400-4735 Telephone: +32 2 3202531 E-Mail: [email protected] E-Mail: [email protected] Website: www.falk-foundation-symposia.org Website: https://ilca2019.org
July 15–19, 2019, Snowmass Village, CO, USA September 21–24, 2019, Istanbul, Turkey 41st Annual Aspen Conference World Congress of Gastroenterology (WCOG) on Pediatric Gastrointestinal Disease Telephone: +90 312 4540000 Telephone: +1 513 636-6732 Telefax: +90 312 4540001 Telefax: +1 513 636-7574 E-Mail: [email protected] E-Mail: [email protected] Website: https://wcog2019.org Website: https://cchmc.cloud-cme.com September 25–27, 2019, Vienna, Austria September 4–7, 2019, Seoul, South Korea 14th Scientific and Annual Meeting 7th Biennial Congress of the Asian-Pacific of the European Society of Coloproctology (ESCP) Hepato-Pancreato-Biliary Association (A-PHPBA 219) Telephone: +44 131 6246040 Telephone: +82 2 34527245 Telefax: +44 131 6246045 Telefax: +82 2 5218683 E-Mail: [email protected] E-Mail: [email protected] Website: http://www.escp.eu.com/escp-2019 Website: http://www.aphpba2019.org September 26–28, 2019, Sevilla, Spain September 5–7, 2019, Innsbruck, Austria NAFLD Summit 219 XXXIInd Workshop of the European Helicobacter Telephone: +41 22 8070360 and Microbiota Study Group – EHMSG 219 Telefax: +41 22 3280724 Telephone: +43 1 405138318 E-Mail: [email protected] Telefax: +43 1 4051383918 Website: http://www.easl.eu E-Mail: [email protected] Website: https://helicobacterorg.wixsite.com/ehmsg2019
September 8–10, 2019, Adelaide, SA, Australia GESA Australian Gastroenterology Week (AGW) Telephone: +61 466 574 002 E-Mail: [email protected] Imprint Website: http://agw2019.org.au
September 12–13, 2019, Interlaken, Switzerland Jahreskongress 219 der Schweizerischen Gesellschaft für Gastroenterologie (SGGSSG) der Schweizerischen Gesellschaft für Viszeralchirurgie (SGVC) der Swiss Association for the Study of the Liver (SASL) Telephone: +41 31 3324-110 Telefax: +41 31 3324-112 E-Mail: [email protected] Publisher: Falk Foundation e.V. Website: http://www.sggssg.ch Leinenweberstr. 5 D-79108 Freiburg i. Br. (Germany) September 13–14, 2019, Brussels, Belgium Telephone: +49 761 1514-0, Telefax: +49 761 1514-321 Symposium 216 E-Mail: [email protected] Building Bridges in IBD www. falkfoundation.org Telephone: +32 1634-4225 Telefax: +32 1634-4399 E-Mail: [email protected] Published: quarterly Website: www.falk-foundation-symposia.org Editors: PD Dr. Peter Hasselblatt, Head of the Freiburg Outpatient Clinic for Ileal Diseases, and PD Dr. Christoph Neumann-Haefelin, September 16–17, 2019, Bethesda, MD, USA Head of the Gerok Liver Center, Medical University Clinic of Alcoholic and Nonalcoholic Steatohepatitis: Freiburg, D-79106 Freiburg i. Br. (Germany) Pathogenesis and Mechanisms of Liver Injury Joint NIAAA-NIDDK Research Workshop Telephone: +1 800 8608747 or +1 866 5691162 E-Mail: [email protected] Website: https://www.niddk.nih.gov
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