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Gastroenterology
Journal Prestige (SJR): 7.958
Citation Impact (citeScore): 7
Number of Followers: 197  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0016-5085
Published by Elsevier Homepage  [3158 journals]
  • The Role of the Microbiome in Immunologic Development and its Implication
           For Pancreatic Cancer Immunotherapy
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Vrishketan Sethi, Gerardo A. Vitiello, Deepak Saxena, George Miller, Vikas DudejaOur understanding of the microbiome and its role in immunity, cancer initiation, and cancer progression has evolved significantly over the past century. The “germ theory of cancer” was first proposed in the early 20th century, and shortly thereafter the bacterium Helicobacter pylori, and later Fusobacterium nucleatum, were implicated in the development of gastric and colorectal cancers, respectively. However, with the development of reliable mouse models and affordable sequencing technologies, the most fascinating aspect of the microbiome–cancer relationship, where microbes undermine cancer immune surveillance and indirectly promote oncogenesis, has only recently been described. In this review, we highlight the essential role of the microbiome in immune system development and maturation. We review how microbe-induced immune activation promotes oncogenesis, focusing particularly on pancreatic carcinogenesis, and show that modulation of the microbiome augments the anti-cancer immune response and enables successful immunotherapy against pancreatic cancer.
       
  • Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges
           and Opportunities
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Vinod P. Balachandran, Gregory L. Beatty, Stephanie K. DouganPancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer in the United States by 2025, with 5-year survival at less than 10%. In other recalcitrant cancers, immunotherapy has shown unprecedented response rates, including durable remissions after drug discontinuation. However, responses to immunotherapy in PDAC are rare. Accumulating evidence in mice and humans suggests that this remarkable resistance is linked to the complex, dueling role of the immune system in simultaneously promoting and restraining PDAC. In this review, we highlight the rationale that supports pursuing immunotherapy in PDAC, outline the key barriers that limit immunotherapy efficacy, and summarize the primary preclinical and clinical efforts to sensitize PDAC to immunotherapy.
       
  • Genetics of Familial and Sporadic Pancreatic Cancer
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Laura D. Wood, Matthew B. Yurgelun, Michael G. GogginsIn the previous decade, comprehensive genomic analyses have yielded important insights about the genetic alterations that underlie pancreatic tumorigenesis. Whole-exome and whole-genome sequencing of pancreatic ductal adenocarcinomas have confirmed the critical driver genes altered in the majority of pancreatic cancers, as well as identified numerous less frequently altered driver genes, and have delineated cancer subgroups with unique biological and clinical features. It is now appreciated that pancreatic susceptibility gene alterations are often identified in patients with pancreatic cancer without family histories suggestive of a familial cancer syndrome, prompting recent efforts to expand gene testing to all patients with pancreatic cancer. Studies of pancreatic cancer precursor lesions have begun to elucidate the evolutionary history of pancreatic tumorigenesis and to help us understand the utility of biomarkers for early detection and targets to develop new therapeutic strategies. In this review, we discuss the results of comprehensive genomic characterization of pancreatic ductal adenocarcinoma and its precursor lesions, and we highlight translational applications in early detection and therapy.
       
  • Early Detection of Pancreatic Cancer: Opportunities and Challenges
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Aatur D. Singhi, Eugene J. Koay, Suresh T. Chari, Anirban MaitraMost patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.
       
  • Organ Failure Due to Systemic Injury in Acute Pancreatitis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Parmod K. Garg, Vijay P. SinghAcute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure, which is seen in approximately 20% of all cases of acute pancreatitis and defines “severe acute pancreatitis.” Organ failure typically develops early in the course of acute pancreatitis, but also may develop later due to infected pancreatic necrosis–induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome, and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.
       
  • Current Concepts in Severe Acute and Necrotizing Pancreatitis: An
           Evidence-Based Approach
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Guru Trikudanathan, Daniel R.J. Wolbrink, Hjalmar C. van Santvoort, Shawn Mallery, Martin Freeman, Marc G. BesselinkThe incidence of acute pancreatitis continues to rise, inducing substantial medical and social burden, with annual costs exceeding $2 billion in the United States alone. Although most patients develop mild pancreatitis, 20% develop severe and/or necrotizing pancreatitis, requiring advanced medical and interventional care. Morbidity resulting from local and systemic complications as well as invasive interventions result in mortality rates historically as high as 30%. There has been substantial evolution of strategies for interventions in recent years, from open surgery to minimally invasive surgical and endoscopic step-up approaches. In contrast to the advances in invasive procedures for complications, early management still lacks curative options and consists of adequate fluid resuscitation, analgesics, and monitoring. Many challenges remain, including comprehensive management of the entire spectrum of the disease, which requires close involvement of multiple disciplines at specialized centers.
       
  • Early Intra-Acinar Events in Pathogenesis of Pancreatitis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Ashok Saluja, Vikas Dudeja, Rajinder Dawra, Raghuwansh P. SahPremature activation of digestive enzymes in the pancreas has been linked to development of pancreatitis for more than a century. Recent development of novel models to study the role of pathologic enzyme activation has led to advances in our understanding of the mechanisms of pancreatic injury. Colocalization of zymogen and lysosomal fraction occurs early after pancreatitis-causing stimulus. Cathepsin B activates trypsinogen in these colocalized organelles. Active trypsin increases permeability of these organelles resulting in leakage of cathepsin B into the cytosol leading to acinar cell death. Although trypsin-mediated cell death leads to pancreatic injury in early stages of pancreatitis, multiple parallel mechanisms, including activation of inflammatory cascades, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction in the acinar cells are now recognized to be important in driving the profound systemic inflammatory response and extensive pancreatic injury seen in acute pancreatitis. Chymotrypsin, another acinar protease, has recently been shown be play critical role in clearance of pathologically activated trypsin protecting against pancreatic injury. Mutations in trypsin and other genes thought to be associated with pathologic enzyme activation (such as serine protease inhibitor 1) have been found in familial forms of pancreatitis. Sustained intra-acinar activation of nuclear factor κB pathway seems to be key pathogenic mechanism in chronic pancreatitis. Better understanding of these mechanisms will hopefully allow us to improve treatment strategies in acute and chronic pancreatitis.
       
  • Pancreatitis in Children
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Aliye Uc, Sohail Z. HusainAcute, acute recurrent, and chronic forms of pancreatitis have been increasingly diagnosed in children in the past 2 decades. Risk factors in the pediatric group are broad and appear to be strikingly different compared with the adult cohort. However, the disease burden and impact on quality of life are surprisingly similar in children and adults. This review summarizes the definitions, epidemiology, risk factors, diagnosis, and management of pediatric pancreatitis, identifies features that are unique to the childhood-onset disease, identifies gaps, and proposes recommendations for future opportunities.
       
  • Genetics, Cell Biology, and Pathophysiology of Pancreatitis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Julia Mayerle, Matthias Sendler, Eszter Hegyi, Georg Beyer, Markus M. Lerch, Miklós Sahin-TóthSince the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease–antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.
       
  • Acute Pancreatitis: A Multifaceted Set of Organelle and
           Cellular Interactions
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Aida Habtezion, Anna S. Gukovskaya, Stephen J. PandolAcute pancreatitis is an inflammatory disorder of the exocrine pancreas associated with tissue injury and necrosis. The disease can be mild, involving only the pancreas, and resolve spontaneously within days or severe, with systemic inflammatory response syndrome–associated extrapancreatic organ failure and even death. Importantly, there are no therapeutic agents currently in use that can alter the course of the disease. This article emphasizes emerging findings that stressors (environmental and genetic) that cause acute pancreatitis initially cause injury to organelles of the acinar cell (endoplasmic reticulum, mitochondria, and endolysosomal–autophagy system), and that disorders in the functions of the organelles lead to inappropriate intracellular activation of trypsinogen and inflammatory pathways. We also review emerging work on the role of damage-associated molecular patterns in mediating the local and systemic inflammatory response in addition to known cytokines and chemokine pathways. In the review, we provide considerations for correction of organelle functions in acute pancreatitis to create a discussion for clinical trial treatment and design options.
       
  • Pancreatitis and Pancreatic Cancer
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Ashok Saluja, Anirban Maitra
       
  • Information for Authors and Readers
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s):
       
  • Elsewhere in The AGA Journals
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s):
       
  • Cover 1
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s):
       
  • Signaling Networks That Control Cellular Plasticity in Pancreatic
           Tumorigenesis, Progression, and Metastasis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Howard C. Crawford, Marina Pasca di Magliano, Sulagna BanerjeePancreatic ductal adenocarcinoma is one of the deadliest cancers, and its incidence on the rise. The major challenges in overcoming the poor prognosis with this disease include late detection and the aggressive biology of the disease. Intratumoral heterogeneity; presence of a robust, reactive, and desmoplastic stroma; and the crosstalk between the different tumor components require complete understanding of the pancreatic tumor biology to better understand the therapeutic challenges posed by this disease. In this review, we discuss the processes involved during tumorigenesis encompassing the inherent plasticity of the transformed cells, development of tumor stroma crosstalk, and enrichment of cancer stem cell population during tumorigenesis.
       
  • Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and
           Therapeutic Targets
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 7Author(s): Martin C. Whittle, Sunil R. HingoraniThe desmoplastic reaction of pancreas cancer may begin as a wound healing response to the nascent neoplasm, but it soon creates an insidious shelter that can sustain the growing tumor and rebuff therapy. Among the many cell types subverted by transformed epithelial cells, fibroblasts are recruited and activated to lay a foundation of extracellular matrix proteins and glycosaminoglycans that alter tumor biophysics and signaling. Their near-universal presence in pancreas cancer and ostensible support of disease progression make fibroblasts attractive therapeutic targets. More recently, however, it has also become apparent that diverse subpopulations of fibroblasts with distinct phenotypes and secretomes inhabit the stroma, and that targeted depletion of particular fibroblast subsets could either provide substantial therapeutic benefit or accelerate disease progression. An improved characterization of these fibroblast subtypes, along with their potential relationships to tumor subtypes and mutational repertoires, is needed in order to make anti-fibroblast therapies clinically viable.
       
  • Lanreotide Reduces Liver Growth In Patients With Autosomal Dominant
           Polycystic Liver and Kidney Disease
    • Abstract: Publication date: Available online 22 April 2019Source: GastroenterologyAuthor(s): Rene M.M. van Aerts, Wietske Kievit, Hedwig M.A. D'Agnolo, Charles J. Blijdorp, Niek F. Casteleijn, Shosha E.I. Dekker, Johan W. de Fijter, Maatje van Gastel, Tom J. Gevers, Liyanne F.M. van de Laarschot, Marten A. Lantinga, Monique Losekoot, Esther Meijer, A. Lianne Messchendorp, Myrte K. Neijenhuis, Michelle J. Pena, Dorien J.M. Peters, Mahdi Salih, Darius Soonawala, Edwin M. Spithoven Background and aimsPolycystic liver disease is the most common extra-renal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for the volume-reducing effect of somatostatin analogues. We made use of data from an open-label, randomized trial to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLKV) in patients with ADPKD.MethodsWe performed a 120-week study comparing the reno-protective effects of lanreotide vs standard care in 305 patients with ADPKD (the DIPAK-1 study). For this analysis we studied the 175 patients with polycystic liver disease, with hepatic cysts identified by magnetic resonance imaging and liver volume ≥2000 ml. Of these, 93 patients were assigned to a group that received lanreotide (120 mg subcutaneously every 4 weeks) and 82 to a group that received standard care (blood pressure coKN2ntrol, a sodium-restricted diet, and anti-hypertensive agents). The primary endpoint was percentage change in hTLV between baseline and end of treatment (week 120). A secondary endpoint was change in hTLKV.ResultsAt 120 weeks, hTLV decreased by 1.99% in the lanreotide group (95% CI, –4.21 to 0.24) and increased by 3.92% in the control group (95% CI, 1.56–6.28). Compared to controls, lanreotide reduced the growth of hTLV by 5.91% (95% CI, –9.18 to –2.63; P
       
  • Developing Pharmacologic Treatments for Eosinophilic Esophagitis: Draft
           Guidance from the United States Food and Drug Administration
    • Abstract: Publication date: Available online 22 April 2019Source: GastroenterologyAuthor(s): Erica Lyons, Kathleen Donohue, Jessica J. Lee
       
  • Efficacy of Endoscopic Resection and Selective Chemoradiotherapy for Stage
           I Esophageal Squamous Cell Carcinoma
    • Abstract: Publication date: Available online 20 April 2019Source: GastroenterologyAuthor(s): Keiko Minashi, Keiji Nihei, Junki Mizusawa, Kohei Takizawa, Tomonori Yano, Yasumasa Ezoe, Tomohiro Tsuchida, Hiroyuki Ono, Toshiro Iizuka, Noboru Hanaoka, Ichiro Oda, Yoshinori Morita, Masahiro Tajika, Junko Fujiwara, Yoshinobu Yamamoto, Chikatoshi Katada, Shinichiro Hori, Hisashi Doyama, Tsuneo Oyama, Hiroko Nebiki Background & AimsEsophagectomy is the standard treatment for stage I esophageal squamous cell carcinoma (ESCC). We conducted a single-arm prospective study to confirm the efficacy and safety of selective chemoradiotherapy (CRT) based on findings from endoscopic resection (ER).MethodsWe performed a prospective study of patients with T1b (SM1–2) N0M0 thoracic ESCC; from December 2006 through July 2012, 176 patients underwent ER. Based on the findings from ER, patients received: no additional treatment, for patients with pT1a tumors with a negative resection margin and no lymphovascular invasion (Group A); prophylactic CRT with 41.4 Gy delivered to locoregional lymph nodes, for patients with pT1b tumors with a negative resection margin or pT1a tumors with lymphovascular invasion (Group B); or definitive CRT (50.4 Gy) with a 9-Gy boost to the primary site, for patients with a positive vertical resection margin (Group C). Chemotherapy comprised 5-fluorouracil and cisplatin. The primary endpoint was 3-year overall survival (OS) in Group B, and the key secondary endpoint was 3-year OS for all patients. If lower limits of 90% CIs for the primary and key secondary endpoints exceeded the 80% threshold, the efficacy of combined ER and selective CRT was confirmed.ResultsBased on the results from pathology analysis, 74, 87, and 15 patients were categorized into Groups A, B, and C, respectively. The 3-year OS rates were 90.7% for Group B (90% CI, 84.0%–94.7%) and 92.6% in all patients (90% CI, 88.5%–95.2%).ConclusionsIn a prospective study of patients with T1b (SM1-2) N0M0 thoracic ESCC, we confirmed the efficacy of the combination of ER and selective CRT. Efficacy is comparable to that of surgery, and the combination of ER and selective CRT should be considered as a minimally invasive treatment option. Clinical trial registration no: UMIN-CTR (UMIN000000553).
       
  • Environmental Risk Factors for Inflammatory Bowel Diseases: an Umbrella
           Review of Meta-analyses
    • Abstract: Publication date: Available online 20 April 2019Source: GastroenterologyAuthor(s): Daniele Piovani, Silvio Danese, Laurent Peyrin-Biroulet, Georgios K. Nikolopoulos, Theodore Lytras, Stefanos Bonovas. Background & AimsMultiple environmental factors have been associated with development of inflammatory bowel diseases (IBD). We performed an umbrella review of meta-analyses to summarize available epidemiologic evidence and assess its credibility.MethodsWe systematically identified and appraised meta-analyses of observational studies examining environmental factors and risk of IBD (Crohn’s disease [CD] or ulcerative colitis [UC]). For each meta-analysis we considered the random-effects estimate, its 95% CI, the estimates of heterogeneity and small-study effects, and graded the evidence according to prespecified criteria. Methodologic quality was assessed using AMSTAR 2.ResultsWe examined 183 estimates in 53 meta-analyses of 71 environmental factors related to lifestyles and hygiene, surgeries, drug exposures, diet, microorganisms, and vaccinations. We identified 9 factors that increase risk of IBD: smoking (CD), urban living (CD and IBD), appendectomy (CD), tonsillectomy (CD), antibiotic exposure (IBD), oral contraceptive use (IBD), consumption of soft drinks (UC), vitamin D deficiency (IBD), and non-Helicobacter pylori-like enterohepatic Helicobacter species (IBD). We identified 7 factors that reduce risk of IBD: physical activity (CD), breastfeeding (IBD), bed sharing (CD), tea consumption (UC), high levels of folate (IBD), high levels of vitamin D (CD), Helicobacter pylori infection (CD, UC, and IBD). Epidemiologic evidence for all these associations were of high to moderate strength; we identified another 11 factors associated with increased risk and 16 factors associated with reduced risk with weak credibility. Methodologic quality varied considerably among meta-analyses. Several associations were based on findings from retrospective studies, so it is not possible to determine if these are effects of IBD or results of recall bias.ConclusionsIn an umbrella review of meta-analyses, we found varying levels of evidence for associations of different environmental factors with risk of IBD. High-quality prospective studies with analyses of samples from patients with recent diagnoses of IBD are needed to determine whether these factors cause or are results of IBD, and their pathogenic mechanisms.
       
  • Effects of Promotility Agents on Gastric Emptying and Symptoms: A
           Systematic Review and Meta-analysis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Priya Vijayvargiya, Michael Camilleri, Victor Chedid, Aditya Mandawat, Patricia J. Erwin, M. Hassan MuradBackground & AimsStudies have reported a lack of association between improvements in gastric emptying (GE) and upper gastrointestinal (UGI) symptoms with promotility drugs. However, GE test methods were suboptimal in some studies. We assessed improvements in GE and UGI symptoms in patients given promotility agents in studies with optimal or moderate test methods (scintigraphy or breath test, solid meal,>2 hours duration) compared to studies with suboptimal GE test methods.MethodsWith an expert librarian, we completed an extensive search of publications in the Ovid MEDLINE (1946 to present), EMBASE (1988 to January 2018), and EBM Reviews Cochrane Central Register of Controlled Trials, without restrictions on language or year. Two independent reviewers evaluated the following inclusion criteria: randomized, blinded, parallel, or crossover trials of 5HT4 agonists, D2 receptor antagonist, or ghrelin agonists; trials that measured change in GE (T1/2) or composite UGI symptoms; trials of patients with functional dyspepsia and gastroparesis; and trials of GE test methods. Standardized mean differences (units expressed as SD) were used to standardize symptom assessments that were not uniform across studies. Random effects model was used to analyze data and meta-regression was used to evaluate the association between change in GE and UGI symptoms.ResultsOf 899 studies considered, 22 studies assessed change in GE; 23 evaluated UGI symptoms; and 14 evaluated GE and UGI symptoms. Promotility agents significantly accelerated GE (T1/2) in all studies (mean reduction in T1/2, 16.3 minutes; 95% confidence interval, –22.1 to –10.6 minutes) and in studies that used optimal GE test methods (mean reduction in T1/2, 23.6 minutes; 95% confidence interval, –32.3 to –14.9 minutes). Promotility agents also significantly reduced UGI symptoms (mean reduction, 0.25 SD; 95% confidence interval, –0.37 to –0.13 SD). Meta-regression found no significant association between change in GE and UGI symptoms. However, when only studies with optimal GE test methods were evaluated, there was a significant positive association between improvement in GE and UGI symptoms (P = .02).ConclusionsIn a meta-analysis of published trials, we found promotility agents to significantly accelerate GE (when optimal test methods were used) and to produce significant improvements in UGI symptoms.
       
  • Correction
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s):
       
  • Reply to “Detection and Analysis of Circulating Epithelial Cells in
           Liquid Biopsies from Patients with Liver Disease”: Implications for
           Transplant Chimerism
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Floris J.M. Roos, Jan N.M. IJzermans, Luc J.W. van der Laan
       
  • Circulating Epithelial Cells in Patients With Liver Disease
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Junfeng Wang, Rui Dong, Shan Zheng
       
  • Lights and Shadows on Fibrates as Second-Line Therapy of Primary Biliary
           Cholangitis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Massimo Colombo, Ana Lleo, Ana Lleo
       
  • How Deep Are the Roots of Barrett’s Esophagus'
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Karol Nowicki-Osuch, Massimiliano Di Pietro
       
  • Gut Microbes Drive T-Cell Infiltration into Colorectal Cancers And
           Influence Prognosis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): John P. Thomas, Devina Divekar, Johanne Brooks, Alastair J.M. Watson
       
  • RNA Analysis Identifies Pathogenic Duplications in MSH2 in
           Patients With Lynch Syndrome
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Blair R. Conner, Felicia Hernandez, Beth Souders, Tyler Landrith, C. Richard Boland, Rachid Karam
       
  • Long-term Outcomes of Fecal Microbiota Transplantation in Patients With
           Cirrhosis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Jasmohan S. Bajaj, Andrew Fagan, Edith A. Gavis, Zain Kassam, Masoumeh Sikaroodi, Patrick M. Gillevet
       
  • Prevalence of Pathogenic Variants of FAN1 in More Than 5000 Patients
           Assessed for Genetic Predisposition to Colorectal, Breast, Ovarian, or
           Other Cancers
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Alice Fievet, Emmanuelle Mouret-Fourme, Chrystelle Colas, Antoine de Pauw, Dominique Stoppa-Lyonnet, Bruno Buecher
       
  • Our New President—Hashem El-Serag, MD, MPH, AGAF
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Fasiha Kanwal
       
  • Plasma Cell Polarization to the Immunoglobulin G Phenotype in
           Hepatocellular Carcinomas Involves Epigenetic Alterations and Promotes
           Hepatoma Progression in Mice
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Yuan Wei, Xiang-Ming Lao, Xiao Xiao, Xu-Yan Wang, Zong-Jian Wu, Qiu-Hui Zeng, Cai-Yuan Wu, Rui-Qi Wu, Zhen-Xin Chen, Limin Zheng, Bo Li, Dong-Ming KuangBackground & AimsLittle is known about the composition and generation of plasma cell subsets in patients with hepatocellular carcinoma (HCC) and how these associate with outcomes. We investigated whether, or how, plasma cells differentiate and function in patients with HCC and mice with liver tumors.MethodsWe analyzed subset composition and distribution of plasma cells in HCC samples from 342 patients who underwent curative resection at the Cancer Center of Sun Yat-sen University in China; samples of non-tumor liver tissue were used as controls. We associated plasma cell profiles with patient outcomes. Tissue-derived leukocytes were analyzed by flow cytometry and real-time polymerase chain reaction. The ability of macrophages to regulate plasma cell differentiation was determined in ex vivo cultures of cells from human HCC tissues. C57BL/6 and BALB/c mice were given injections of Hepa1-6 cells, which formed hepatomas, or H22 cells, which formed ascitic hepatomas. Gene expression patterns were analyzed in human HCC, mouse hepatoma, and non-tumor tissues by real-time polymerase chain reaction. Mice with hepatomas were given injections of GSK126 (an inhibitor of histone H3 lysine 27 methyltransferase [EZH2]) and 5-AZA-dC (an inhibitor of DNA methyltransferases); tumor tissues were analyzed by immunofluorescence and immunohistochemistry for the presence of immune cells and cytokines.ResultsB cells isolated from HCCs had somatic hypermutations and class-switch recombinations to the IgG phenotype that were not observed in non-tumor tissues. Increased level of plasma cells correlated with poor outcomes of patients. Activated CD4+ T cells from HCCs stimulated C-X-C motif chemokine 10 (CXCL10) production by macrophages. CXCL10 bound CXC chemokine receptor 3 on B cells and signaled via extracellular signal–regulated kinase to cause them to become IgG-producing plasma cells. IgG activated Fc receptors on macrophages and induced them to produce interleukin 6, interleukin 10, and C-C motif chemokine ligand 20 (CCL20). In mice with hepatomas, depletion of B cells prevented generation of these macrophage, increased the anti-tumor T cell response, and reduced growth of hepatomas. However, these effects were lost after injection of CXC chemokine receptor 3–positive plasma cells. Human HCC and mouse hepatoma tissues had increased expression of DNA methyltransferase 1 and EZH2 compared with non-tumor tissues. Injection of mice with GSK126 and 5-AZA-dC induced expression of CXCL10 by tumor cells and caused plasma cell polarization, suppression of the anti-tumor T cell response, and hepatoma growth.ConclusionsHuman HCC tissues contain B cells with class-switch recombinations to the IgG phenotype. Activated CD4+ T cells from HCCs stimulate CXCL10 production by macrophages; CXCL10 binds CXC chemokine receptor 3 on B cells and causes them to become IgG-producing plasma cells. IgG activates Fc receptor in macrophages to produce cytokines that reduce the anti-tumor immune response. In mice with hepatomas, depletion of B cells prevented generation of these macrophages, increased the anti-tumor T cell response, and reduced growth of hepatomas. This pathway involves increased expression of DNA methyltransferase 1 and EZH2 by HCC and hepatoma cells.Graphical abstractGraphical abstract for this article
       
  • CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T- and
           CD4+ T-Cell–Dependent Control of Senescence
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Jana C. Mossanen, Marlene Kohlhepp, Alexander Wehr, Oliver Krenkel, Anke Liepelt, Anjali A. Roeth, Diana Möckel, Felix Heymann, Twan Lammers, Nikolaus Gassler, Juliane Hermann, Joachim Jankowski, Ulf P. Neumann, Tom Luedde, Christian Trautwein, Frank TackeBackground & AimsInflammation in the liver provokes fibrosis, but inflammation is also important for tumor surveillance. Inhibitors of chemokine pathways, such as CXCL16 and CXCR6 regulation of lymphocyte trafficking, are being tested as antifibrotic agents, but their effects on the development of hepatocellular carcinoma (HCC) are unclear. We assessed the roles of CXCR6-dependent immune mechanisms in hepatocarcinogenesis.MethodsC57BL/6J wild-type (WT) mice and CXCR6-deficient mice (Cxcr6eGfp/eGfp) were given injections of diethylnitrosamine (DEN) to induce liver cancer and α-galactosylceramide to activate natural killer T (NKT) cells. We also performed studies in mice with conditional, hepatocyte-specific deletion of NEMO, which develop inflammation-associated liver tumors (NemoLPC-KO and NemoLPC-KOCxcr6eGfp/eGfp mice). We collected liver tissues from patients with cirrhosis (n = 43), HCC (n = 35), and neither of these diseases (control individuals, n = 25). Human and mouse liver tissues were analyzed by histology, immunohistochemistry, flow cytometry, RNA expression arrays (from sorted hepatic lymphocytes), and matrix-assisted laser desorption/ionization imaging. Bone marrow was transferred from Cxcr6eGfp/eGfp or WT mice to irradiated C57BL/6J mice, and spleen and liver cells were analyzed by flow cytometry. CD4+ T cells or NKT cells were isolated from the spleen and liver of CD45.1+ WT mice and transferred into CXCR6-deficient mice after DEN injection.ResultsAfter DEN injection, CXCR6-deficient mice had a significantly higher tumor burden than WT mice and increased tumor progression, characterized by reduced intrahepatic numbers of invariant NKT and CD4+ T cells that express tumor necrosis factor and interferon gamma. Livers of NemoLPC-KOCxcr6eGfp/eGfp mice had significantly more senescent hepatocytes than livers of NemoLPC-KO mice. In studies of bone-marrow chimeras, adoptive cell transfer experiments, and analyses of NemoLPC-KO mice, we found that NKT and CD4 T cells promote the removal of senescent hepatocytes to prevent hepatocarcinogenesis, and that this process required CXCR6. Injection of WT with α-galactosylceramide increased removal of senescent hepatocytes by NKT cells. We observed peritumoral accumulation of CXCR6-associated lymphocytes in human HCC, which appeared reduced compared with cirrhosis tissues.ConclusionsIn studies of mice with liver tumors, we found that CXCR6 mediated NKT-cell and CD4+ T-cell removal of senescent hepatocytes. Antifibrotic strategies to reduce CXCR6 activity in liver, or to reduce inflammation or modulate the immune response, should be tested for their effects on hepatocarcinogenesis.
       
  • Use of Expression Profiles of HBV-DNA Integrated Into Genomes of
           Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Anthony Tanoto Tan, Ninghan Yang, Thinesh Lee Krishnamoorthy, Vincent Oei, Alicia Chua, Xinyuan Zhao, Hui Si Tan, Adeline Chia, Nina Le Bert, Diana Low, Hiang Keat Tan, Rajneesh Kumar, Farah Gillan Irani, Zi Zong Ho, Qi Zhang, Ernesto Guccione, Lu-En Wai, Sarene Koh, William Hwang, Wan Cheng ChowBackground & AimsHepatocellular carcinoma (HCC) is often associated with hepatitis B virus (HBV) infection. Cells of most HBV-related HCCs contain HBV-DNA fragments that do not encode entire HBV antigens. We investigated whether these integrated HBV-DNA fragments encode epitopes that are recognized by T cells and whether their presence in HCCs can be used to select HBV-specific T-cell receptors (TCRs) for immunotherapy.MethodsHCC cells negative for HBV antigens, based on immunohistochemistry, were analyzed for the presence of HBV messenger RNAs (mRNAs) by real-time polymerase chain reaction, sequencing, and Nanostring approaches. We tested the ability of HBV mRNA-positive HCC cells to generate epitopes that are recognized by T cells using HBV-specific T cells and TCR-like antibodies. We then analyzed HBV gene expression profiles of primary HCCs and metastases from 2 patients with HCC recurrence after liver transplantation. Using the HBV-transcript profiles, we selected, from a library of TCRs previously characterized from patients with self-limited HBV infection, the TCR specific for the HBV epitope encoded by the detected HBV mRNA. Autologous T cells were engineered to express the selected TCRs, through electroporation of mRNA into cells, and these TCR T cells were adoptively transferred to the patients in increasing numbers (1 × 104–10 × 106 TCR+ T cells/kg) weekly for 112 days or 1 year. We monitored patients’ liver function, serum levels of cytokines, and standard blood parameters. Antitumor efficacy was assessed based on serum levels of alpha fetoprotein and computed tomography of metastases.ResultsHCC cells that did not express whole HBV antigens contained short HBV mRNAs, which encode epitopes that are recognized by and activate HBV-specific T cells. Autologous T cells engineered to express TCRs specific for epitopes expressed from HBV-DNA in patients’ metastases were given to 2 patients without notable adverse events. The cells did not affect liver function over a 1-year period. In 1 patient, 5 of 6 pulmonary metastases decreased in volume during the 1-year period of T-cell administration.ConclusionsHCC cells contain short segments of integrated HBV-DNA that encodes epitopes that are recognized by and activate T cells. HBV transcriptomes of these cells could be used to engineer T cells for personalized immunotherapy. This approach might be used to treat a wider population of patients with HBV-associated HCC.Graphical abstractGraphical abstract for this article
       
  • MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by
           Stabilizing PDL1
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Hui Li, Chia-Wei Li, Xiaoqiang Li, Qingqing Ding, Lei Guo, Shuang Liu, Chunxiao Liu, Chien-Chen Lai, Jung-Mao Hsu, Qiongzhu Dong, Weiya Xia, Jennifer L. Hsu, Hirohito Yamaguchi, Yi Du, Yun-Ju Lai, Xian Sun, Paul B. Koller, Qinghai Ye, Mien-Chie HungBackground & AimsInhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice.MethodsWe tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3β (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry.ResultsExposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B.ConclusionsIn studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice.
       
  • Polycomb Repressive Complex 2 Proteins EZH1 and EZH2 Regulate Timing of
           Postnatal Hepatocyte Maturation and Fibrosis by Repressing Genes With
           Euchromatic Promoters in Mice
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Jessica Mae Grindheim, Dario Nicetto, Greg Donahue, Kenneth S. ZaretBackground & AimsLittle is known about mechanisms that underlie postnatal hepatocyte maturation and fibrosis at the chromatin level. We investigated the transcription of genes involved in maturation and fibrosis in postnatal hepatocytes of mice, focusing on the chromatin compaction the roles of the Polycomb repressive complex 2 histone methyltransferases EZH1 and EZH2.MethodsHepatocytes were isolated from mixed background C57BL/6J-C3H mice, as well as mice with liver-specific disruption of Ezh1 and/or Ezh2, at postnatal day 14 and 2 months after birth. Liver tissues were collected and analyzed by RNA sequencing, H3K27me3 chromatin immunoprecipitation sequencing, and sonication-resistant heterochromatin sequencing (a method to map heterochromatin and euchromatin). Liver damage was characterized by histologic analysis.ResultsWe found more than 3000 genes differentially expressed in hepatocytes during liver maturation from postnatal day 14 to month 2 after birth. Disruption of Ezh1 and Ezh2 in livers caused perinatal hepatocytes to differentiate prematurely and to express genes at postnatal day 14 that would normally be induced by month 2 and differentiate prematurely. Loss of Ezh1 and Ezh2 also resulted in liver fibrosis. Genes with H3K27me3-postive and H3K4me3-positive euchromatic promoters were prematurely induced in hepatocytes with loss of Ezh1 and Ezh2—these genes included those that regulate hepatocyte maturation, fibrosis, and genes not specifically associated with the liver lineage.ConclusionsThe Polycomb repressive complex 2 proteins EZH1 and EZH2 regulate genes that control hepatocyte maturation and fibrogenesis and genes not specifically associated with the liver lineage by acting at euchromatic promoter regions. EZH1 and EZH2 thereby promote liver homeostasis and prevent liver damage. Strategies to manipulate Polycomb proteins might be used to improve hepatocyte derivation protocols or developed for treatment of patients with liver fibrosis.Graphical abstractGraphical abstract for this article
       
  • Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T
           Cells and Evolve at the Population Level
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Hadi Karimzadeh, Muthamia M. Kiraithe, Valerie Oberhardt, Elahe Salimi Alizei, Jan Bockmann, Julian Schulze zur Wiesch, Bettina Budeus, Daniel Hoffmann, Heiner Wedemeyer, Markus Cornberg, Adalbert Krawczyk, Jassin Rashidi-Alavijeh, Francisco Rodríguez-Frías, Rosario Casillas, Maria Buti, Antonina Smedile, Seyed Moayed Alavian, Andreas Heinold, Florian Emmerich, Marcus PanningBackground & AimsHepatitis D virus (HDV) superinfection in patients with hepatitis B virus (HBV) is associated with rapid progression to liver cirrhosis and hepatocellular carcinoma. Treatment options are limited, and no vaccine is available. Although HDV-specific CD8+ T cells are thought to control the virus, little is known about which HDV epitopes are targeted by virus-specific CD8+ T cells or why these cells ultimately fail to control the infection. We aimed to define how HDV escapes the CD8+ T-cell–mediated response.MethodsWe collected plasma and DNA samples from 104 patients with chronic HDV and HBV infection at medical centers in Europe and the Middle East, sequenced HDV, typed human leukocyte antigen (HLA) class I alleles from patients, and searched for polymorphisms in HDV RNA associated with specific HLA class I alleles. We predicted epitopes in HDV that would be recognized by CD8+ T cells and corresponded with the identified virus polymorphisms in patients with resolved (n = 12) or chronic (n = 13) HDV infection.ResultsWe identified 21 polymorphisms in HDV that were significantly associated with specific HLA class I alleles (P < .005). Five of these polymorphisms were found to correspond to epitopes in HDV that are recognized by CD8+ T cells; we confirmed that CD8+ T cells in culture targeted these HDV epitopes. HDV variant peptides were only partially cross-recognized by CD8+ T cells isolated from patients, indicating that the virus had escaped detection by these cells. These newly identified HDV epitopes were restricted by relatively infrequent HLA class I alleles, and they bound most frequently to HLA-B. In contrast, frequent HLA class I alleles were not associated with HDV sequence polymorphisms.ConclusionsWe analyzed sequences of HDV RNA and HLA class I alleles that present epitope peptides to CD8+ T cells in patients with persistent HDV infection. We identified polymorphisms in the HDV proteome that associate with HLA class I alleles. Some variant peptides in epitopes from HDV were only partially recognized by CD8+ T cells isolated from patients; these could be mutations that allow HDV to escape the immune response, resulting in persistent infection. HDV escape from the immune response was associated with uncommon HLA class I alleles, indicating that HDV evolves, at the population level, to evade recognition by common HLA class I alleles.Graphical abstractGraphical abstract for this article
       
  • Hepatitis D Virus-Specific CD8+ T Cells Have a Memory-Like Phenotype
           Associated With Viral Immune Escape in Patients With Chronic Hepatitis D
           Virus Infection
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Helenie Kefalakes, Christopher Koh, John Sidney, Georgios Amanakis, Alessandro Sette, Theo Heller, Barbara RehermannBackground & AimHepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the antiviral immune response and liver disease pathogenesis.MethodsWe isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8+ T-cell epitopes, and characterized HDV-specific CD8+ T cells. We associated these with HDV sequence variations and clinical features of patients.ResultsWe identified 6 CD8+ T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8+ T cells were as frequent as HBV-specific CD8+ T cells but were less frequent than T cells with specificity for cytomegalovirus, Epstein–Barr virus, or influenza virus. The ex vivo frequency of activated HDV-specific CD8+ T cells correlated with transaminase activity. CD8+ T-cell production of interferon gamma after stimulation with HDV peptides correlated inversely with HDV titer. HDV-specific CD8+ T cells did not express the terminal differentiation marker CD57, and fewer HDV-specific than Epstein–Barr virus–specific CD8+ T cells were 2B4+CD160+PD1+, a characteristic of exhausted cells. Approximately half of the HDV-specific CD8+ T cells had a memory-like PD1+CD127+TCF1hiT-betlow phenotype, which associated with HDV sequence variants with reduced HLA binding and reduced T-cell activation.ConclusionsCD8+ T cells isolated from patients with chronic HDV and HBV infection recognize HDV epitopes presented by multiple HLA molecules. The subset of activated HDV-specific CD8+ T cells targets conserved epitopes and likely contributes to disease progression. The subset of memory-like HDV-specific CD8+ T cells is functional but unable to clear HDV because of the presence of escape variants. ClinicalTrials.gov, Numbers: NCT02511431, NCT00023322, NCT01495585, and NCT00001971. GenBank accession, Number: MK333199-333226Graphical abstractGraphical abstract for this article
       
  • Estrogen Activation of G-Protein–Coupled Estrogen Receptor 1 Regulates
           Phosphoinositide 3-Kinase and mTOR Signaling to Promote Liver Growth in
           Zebrafish and Proliferation of Human Hepatocytes
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Saireudee Chaturantabut, Arkadi Shwartz, Kimberley J. Evason, Andrew G. Cox, Kyle Labella, Arnout G. Schepers, Song Yang, Mariana Acuña, Yariv Houvras, Liliana Mancio-Silva, Shannon Romano, Daniel A. Gorelick, David E. Cohen, Leonard I. Zon, Sangeeta N. Bhatia, Trista E. North, Wolfram GoesslingBackground & AimsPatients with cirrhosis are at high risk for hepatocellular carcinoma (HCC) and often have increased serum levels of estrogen. It is not clear how estrogen promotes hepatic growth. We investigated the effects of estrogen on hepatocyte proliferation during zebrafish development, liver regeneration, and carcinogenesis. We also studied human hepatocytes and liver tissues.MethodsZebrafish were exposed to selective modifiers of estrogen signaling at larval and adult stages. Liver growth was assessed by gene expression, fluorescent imaging, and histologic analyses. We monitored liver regeneration after hepatocyte ablation and HCC development after administration of chemical carcinogens (dimethylbenzanthrazene). Proliferation of human hepatocytes was measured in a coculture system. We measured levels of G-protein–coupled estrogen receptor (GPER1) in HCC and nontumor liver tissues from 68 patients by immunohistochemistry.ResultsExposure to 17β-estradiol (E2) increased proliferation of hepatocytes and liver volume and mass in larval and adult zebrafish. Chemical genetic and epistasis experiments showed that GPER1 mediates the effects of E2 via the phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin pathway: gper1-knockout and mtor-knockout zebrafish did not increase liver growth in response to E2. HCC samples from patients had increased levels of GPER1 compared with nontumor tissue samples; estrogen promoted proliferation of human primary hepatocytes. Estrogen accelerated hepatocarcinogenesis specifically in male zebrafish. Chemical inhibition or genetic loss of GPER1 significantly reduced tumor development in the zebrafish.ConclusionsIn an analysis of zebrafish and human liver cells and tissues, we found GPER1 to be a hepatic estrogen sensor that regulates liver growth during development, regeneration, and tumorigenesis. Inhibitors of GPER1 might be developed for liver cancer prevention or treatment.Transcript ProfilingThe accession number in the Gene Expression Omnibus is GSE92544.Graphical abstractGraphical abstract for this article
       
  • Correction of Defective T-Regulatory Cells From Patients With Crohn’s
           Disease by Ex Vivo Ligation of Retinoic Acid Receptor-α
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Rimma Goldberg, Cristiano Scotta, Dianne Cooper, Einat Nissim-Eliraz, Eilam Nir, Scott Tasker, Peter M. Irving, Jeremy Sanderson, Paul Lavender, Fowzia Ibrahim, Jonathan Corcoran, Toby Prevost, Nahum Y. Shpigel, Federica Marelli-Berg, Giovanna Lombardi, Graham M. LordBackground & AimsCrohn’s disease (CD) is characterized by an imbalance of effector and regulatory T cells in the intestinal mucosa. The efficacy of anti-adhesion therapies led us to investigate whether impaired trafficking of T-regulatory (Treg) cells contributes to the pathogenesis of CD. We also investigated whether proper function could be restored to Treg cells by ex vivo expansion in the presence of factors that activate their regulatory activities.MethodsWe measured levels of the integrin α4β7 on Treg cells isolated from peripheral blood or lamina propria of patients with CD and healthy individuals (controls). Treg cells were expanded ex vivo and incubated with rapamycin with or without agonists of the retinoic acid receptor-α (RARA), and their gene expression profiles were analyzed. We also studied the cells in cytokine challenge, suppression, and flow chamber assays and in SCID mice with human intestinal xenografts.ResultsWe found that Treg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. The pathway that regulates the expression of integrin subunit α is induced by retinoic acid (RA). Treg cells from patients with CD incubated with rapamycin and an agonist of RARA (RAR568) expressed high levels of integrin α4β7, as well as CD62L and FOXP3, compared with cells incubated with rapamycin or rapamycin and all-trans retinoic acid. These Treg cells had increased suppressive activities in assays and migrated under conditions of shear flow; they did not produce inflammatory cytokines, and RAR568 had no effect on cell stability or lineage commitment. Fluorescently labeled Treg cells incubated with RAR568 were significantly more likely to traffic to intestinal xenografts than Treg cells expanded in control medium.ConclusionsTreg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. Incubation of patients’ ex vivo expanded Treg cells with rapamycin and an RARA agonist induced expression of α4β7 and had suppressive and migratory activities in culture and in intestinal xenografts in mice. These cells might be developed for treatment of CD. ClinicalTrials.gov, Number: NCT03185000.
       
  • Systems Biology Analyses Show Hyperactivation of Transforming Growth
           Factor-β and JNK Signaling Pathways in Esophageal Cancer
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Andrew E. Blum, Srividya Venkitachalam, Durgadevi Ravillah, Aruna K. Chelluboyina, Ann Marie Kieber-Emmons, Lakshmeswari Ravi, Adam Kresak, Apoorva K. Chandar, Sanford D. Markowitz, Marcia I. Canto, Jean S. Wang, Nicholas J. Shaheen, Yan Guo, Yu Shyr, Joseph E. Willis, Amitabh Chak, Vinay Varadan, Kishore GudaBackground & AimsEsophageal adenocarcinoma (EAC) is resistant to standard chemoradiation treatments, and few targeted therapies are available. We used large-scale tissue profiling and pharmacogenetic analyses to identify deregulated signaling pathways in EAC tissues that might be targeted to slow tumor growth or progression.MethodsWe collected 397 biopsy specimens from patients with EAC and nonmalignant Barrett’s esophagus (BE), with or without dysplasia. We performed RNA-sequencing analyses and used systems biology approaches to identify pathways that are differentially activated in EAC vs nonmalignant dysplastic tissues; pathway activities were confirmed with immunohistochemistry and quantitative real-time polymerase chain reaction analyses of signaling components in patient tissue samples. Human EAC (FLO-1 and EsoAd1), dysplastic BE (CP-B, CP-C, CP-D), and nondysplastic BE (CP-A) cells were incubated with pharmacologic inhibitors or transfected with small interfering RNAs. We measured effects on proliferation, colony formation, migration, and/or growth of xenograft tumors in nude mice.ResultsComparisons of EAC vs nondysplastic BE tissues showed hyperactivation of transforming growth factor-β (TGFB) and/or Jun N-terminal kinase (JNK) signaling pathways in more than 80% of EAC samples. Immunohistochemical analyses showed increased nuclear localization of phosphorylated JUN and SMAD proteins in EAC tumor tissues compared with nonmalignant tissues. Genes regulated by the TGFB and JNK pathway were overexpressed specifically in EAC and dysplastic BE. Pharmacologic inhibition or knockdown of TGFB or JNK signaling components in EAC cells (FLO-1 or EsoAd1) significantly reduced cell proliferation, colony formation, cell migration, and/or growth of xenograft tumors in mice in a SMAD4-independent manner. Inhibition of the TGFB pathway in BE cell lines reduced the proliferation of dysplastic, but not nondysplastic, cells.ConclusionsIn a transcriptome analysis of EAC and nondysplastic BE tissues, we found the TGFB and JNK signaling pathways to be hyperactivated in EACs and the genes regulated by these pathways to be overexpressed in EAC and dysplastic BE. Inhibiting these pathways in EAC cells reduces their proliferation, migration, and formation of xenograft tumors. Strategies to block the TGFB and JNK signaling pathways might be developed for treatment of EAC.Graphical abstractGraphical abstract for this article
       
  • Biomarkers Associated With Response to Regorafenib in Patients With
           Hepatocellular Carcinoma
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Michael Teufel, Henrik Seidel, Karl Köchert, Gerold Meinhardt, Richard S. Finn, Josep M. Llovet, Jordi BruixBackground & AimsIn a phase 3 trial (RESORCE), regorafenib increased overall survival compared with placebo in patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. In an exploratory study, we analyzed plasma and tumor samples from study participants to identify genetic, microRNA (miRNA), and protein biomarkers associated with response to regorafenib.MethodsWe obtained archived tumor tissues and baseline plasma samples from patients with HCC given regorafenib in the RESORCE trial. Baseline plasma samples from 499 patients were analyzed for expression of 294 proteins (DiscoveryMAP) and plasma samples from 349 patients were analyzed for levels of 750 miRNAs (miRCURY miRNA PCR). Tumor tissues from 7 responders and 10 patients who did not respond (progressors) were analyzed by next-generation sequencing (FoundationOne). Forty-six tumor tissues were analyzed for expression patterns of 770 genes involved in oncogenic and inflammatory pathways (PanCancer Immune Profiling). Associations between plasma levels of proteins and miRNAs and response to treatment (overall survival and time to progression) were evaluated using a Cox proportional hazards model.ResultsDecreased baseline plasma concentrations of 5 of 266 evaluable proteins (angiopoietin 1, cystatin B, the latency-associated peptide of transforming growth factor beta 1, oxidized low-density lipoprotein receptor 1, and C-C motif chemokine ligand 3; adjusted P ≤ .05) were significantly associated with increased overall survival time after regorafenib treatment. Levels of these 5 proteins, which have roles in inflammation and/or HCC pathogenesis, were not associated with survival independently of treatment. Only 20 of 499 patients had high levels and a reduced survival time. Plasma levels of α-fetoprotein and c-MET were associated with poor outcome (overall survival) independently of regorafenib treatment only. We identified 9 plasma miRNAs (MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645) whose levels significantly associated with overall survival time with regorafenib (adjusted P ≤ .05). Functional analyses of these miRNAs indicated that their expression level associated with increased overall survival of patients with tumors of the Hoshida S3 subtype. Next-generation sequencing analyses of tumor tissues revealed 49 variants in 27 oncogenes or tumor suppressor genes. Mutations in CTNNB1 were detected in 3 of 10 progressors and VEGFA amplification in 1 of 7 responders.ConclusionWe identified expression patterns of plasma proteins and miRNAs that associated with increased overall survival times of patients with HCC following treatment with regorafenib in the RESORCE trial. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with HCC most likely to respond to regorafenib. ClinicalTrials.gov number NCT01774344. NCBI GEO accession numbers: mRNA data (NanoString): GSE119220; miRNA data (Exiqon): GSE119221
       
  • A Missense Variant in PTPN22 is a Risk Factor for Drug-induced
           Liver Injury
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Elizabeth T. Cirulli, Paola Nicoletti, Karen Abramson, Raul J. Andrade, Einar S. Bjornsson, Naga Chalasani, Robert J. Fontana, Pär Hallberg, Yi Ju Li, M. Isabel Lucena, Nanye Long, Mariam Molokhia, Matthew R. Nelson, Joseph A. Odin, Munir Pirmohamed, Thorunn Rafnar, Jose Serrano, Kári Stefánsson, Andrew Stolz, Ann K. DalyBackground & AimsWe performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.MethodsWe performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.ResultsWe associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28–1.62; P = 1.2 × 10–9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P = .01). The minor allele frequency showed the same effect size (OR> 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10–6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10–6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01.ConclusionsIn a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
       
  • Frailty Associated With Waitlist Mortality Independent of Ascites and
           Hepatic Encephalopathy in a Multicenter Study
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Jennifer C. Lai, Robert S. Rahimi, Elizabeth C. Verna, Matthew R. Kappus, Michael A. Dunn, Mara McAdams-DeMarco, Christine E. Haugen, Michael L. Volk, Andres Duarte-Rojo, Daniel R. Ganger, Jacqueline G. O’Leary, Jennifer L. Dodge, Daniela Ladner, Dorry L. SegevBackground & AimsFrailty is associated with mortality in patients with cirrhosis. We measured frailty using 3 simple tests and calculated Liver Frailty Index (LFI) scores for patients at multiple ambulatory centers. We investigated associations between LFI scores, ascites, and hepatic encephalopathy (HE) and mortality.MethodsAdults without hepatocellular carcinoma who were on the liver transplantation waitlist at 9 centers in the United States (N = 1044) were evaluated using the LFI; LFI scores of at least 4.5 indicated that patients were frail. We performed logistic regression analyses to assess associations between frailty and ascites or HE and competing risk regression analyses (with liver transplantation as the competing risk) to estimate sub-hazard ratios (sHRs) of waitlist mortality (death or removal from the waitlist).ResultsOf study subjects, 36% had ascites, 41% had HE, and 25% were frail. The odds of frailty were higher for patients with ascites (adjusted odd ratio 1.56, 95% confidence interval [CI] 1.15–2.14) or HE (odd ratio 2.45, 95% CI 1.80–3.33) than for those without these features. Larger proportions of frail patients with ascites (29%) or HE (30%) died while on the waitlist compared with patients who were not frail (17% of patients with ascites and 20% with HE). In univariable analysis, ascites (sHR 1.52, 95% CI 1.14–2.05), HE (sHR 1.84, 95% CI 1.38–2.45), and frailty (sHR 2.38, 95% CI 1.77–3.20) were associated with waitlist mortality. In adjusted models, only frailty remained significantly associated with waitlist mortality (sHR 1.82, 95% CI 1.31–2.52); ascites and HE were not.ConclusionsFrailty is a prevalent complication of cirrhosis that is observed more frequently in patients with ascites or HE and independently associated with waitlist mortality. LFI scores can be used to objectively quantify risk of death related to frailty—in excess of liver disease severity—in patients with cirrhosis.
       
  • Magnitude, Risk Factors, and Factors Associated With Adenoma Miss Rate of
           Tandem Colonoscopy: A Systematic Review and Meta-analysis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Shengbing Zhao, Shuling Wang, Peng Pan, Tian Xia, Xin Chang, Xia Yang, Liliangzi Guo, Qianqian Meng, Fan Yang, Wei Qian, Zhichao Xu, Yuanqiong Wang, Zhijie Wang, Lun Gu, Rundong Wang, Fangzhou Jia, Jun Yao, Zhaoshen Li, Yu BaiBackground & AimsWe performed a systematic review and meta-analysis to comprehensively estimate adenoma miss rate (AMR) and advanced AMR (AAMR) and explore associated factors.MethodsWe searched the PubMed, Web of Science, and Ovid EMBASE databases for studies published through April 2018 on tandem colonoscopies, with AMR and AAMR as the primary outcomes. We performed meta-regression analyses to identify risk factors and factors associated with outcome. Primary outcomes were AMR and AAMR and secondary outcomes were AMR and AAMR for different locations, sizes, pathologies, morphologies, and populations.ResultsIn a meta-analysis of 43 publications and more than 15,000 tandem colonoscopies, we calculated miss rates of 26% for adenomas (95% confidence interval [CI] 23%–30%), 9% for advanced adenomas (95% CI 4%–16%), and 27% for serrated polyps (95% CI 16%–40%). Miss rates were high for proximal advanced adenomas (14%; 95% CI 5%–26%), serrated polyps (27%; 95% CI 16%–40%), flat adenomas (34%; 95% CI 24%–45%), and in patients at high risk for colorectal cancer (33%; 95% CI 26%–41%). Miss rates could be decreased by adequate bowel preparation and auxiliary techniques (P = .06; P = .04, and P = .01, respectively). The adenoma detection rate (ADR), adenomas per index colonoscopy, and adenomas per positive index colonoscopy (APPC) were independently associated with AMR (P = .02, P = .01, and P = .008, respectively), whereas APPC was the only factor independently associated with AAMR (P = .006). An APPC value greater than 1.8 was more effective in monitoring AMR (31% vs 15% for AMR P < .0001) than an ADR value of at least 34% (27% vs 17% for AMR; P = .008). The AAMR of colonoscopies with an APPC value below 1.7 was 35%, vs 2% for colonoscopies with an APPC value of at least 1.7 (P = .0005).ConclusionsIn a systematic review and meta-analysis, we found that adenomas and advanced adenomas are missed (based on AMR and AAMR) more frequently than previously believed. In addition to ADR, APPC deserves consideration as a complementary indicator of colonoscopy quality, if it is validated in additional studies.Graphical abstractGraphical abstract for this article
       
  • Predict, Resect, Identify and Discard Strategy with Full-field Optical
           Coherence Tomography: Two Steps Forward, One Step Back
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Fan Yang, Dan Ma, Zhaoshen Li
       
  • Effects of Oral Anticoagulants and Aspirin on Performance of Fecal
           Immunochemical Tests in Colorectal Cancer Screening
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Kristin Ranheim Randel, Edoardo Botteri, Katrine Maria Kauczynska Romstad, Svein Oskar Frigstad, Michael Bretthauer, Geir Hoff, Thomas de Lange, Øyvind HolmeBackground & AimsThe fecal immunochemical test (FIT) is the tool most frequently used for colorectal cancer (CRC) screening worldwide. It is unclear how the use of aspirin and oral anticoagulants in the screening population affects the diagnostic performance of FIT.MethodsWe performed a cross-sectional study in an ongoing CRC screening trial in Norway. Participants aged 50–74 years with a positive result from an FIT (>15 μg hemoglobin/g feces) and subsequent colonoscopy (reference standard) were included. Those who used regular aspirin, warfarin, or direct-acting oral anticoagulants (DOACs) were defined as users. Non-users were matched according to age, sex, screening center, and screening round. The primary outcomes were the positive predictive value (PPV) for CRC and advanced adenoma.ResultsAmong 4908 eligible participants, 1008 used aspirin, 147 used warfarin, 212 used DOACs, and 3541 were non-users. CRCs were found in 234 individuals and advanced adenomas in 1305 individuals. The PPV for CRC was 3.8% for aspirin users vs 6.4% for matched non-users (P = .006), The PPV for advanced adenoma in aspirin users was 27.2% vs 32.6% for matched non-users (P = .011). For DOAC, the PPV for CRC was 0.9% in users vs 6.8% in matched non-users (P = .001). The PPV for advanced adenoma in DOAC users was 20.5% vs 32.4% in matched non-users (P = .002). There was no significant difference in PPV for CRC or advanced adenoma in warfarin users compared to non-users.ConclusionsIn a large screening cohort in Norway, regular use of aspirin and particularly DOACs, were associated with lower PPV of FIT for detection of CRCs and advanced adenomas. ClinicalTrials.gov ID NCT01538550.Graphical abstractGraphical abstract for this article
       
  • Postprandial Nutrient Handling and Gastrointestinal Hormone Secretion
           After Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Maria S. Svane, Kirstine N. Bojsen-Møller, Christoffer Martinussen, Carsten Dirksen, Jan L. Madsen, Søren Reitelseder, Lars Holm, Jens F. Rehfeld, Viggo B. Kristiansen, Gerrit van Hall, Jens J. Holst, Sten MadsbadBackground & AimsSleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) induce substantial weight loss and improve glycemic control in patients with type 2 diabetes, but it is not clear whether these occur via the same mechanisms. We compared absorption rates of glucose and protein, as well as profiles of gastro-entero-pancreatic hormones, in patients who had undergone SG or RYGB vs controls.MethodsWe performed a cross-sectional study of 12 patients who had undergone sleeve gastrectomy, 12 patients who had undergone RYGB, and 12 individuals who had undergone neither surgery (controls), all in Denmark. Study participants were matched for body mass index, age, sex, and postoperative weight loss, and all had stable weights. They received continuous infusions of stable isotopes of glucose, glycerol, phenylalanine, tyrosine, and urea before and during a mixed meal containing labeled glucose and intrinsically phenylalanine-labeled caseinate. Blood samples were collected for 6 hours, at 10- to 60-minute intervals, and analyzed.ResultsThe systemic appearance of ingested glucose was faster after RYGB and SG vs controls; the peak glucose appearance rate was 64% higher after RYGB, and 23% higher after SG (both P < .05); the peak phenylalanine appearance rate from ingested casein was 118% higher after RYGB (P < .01), but similar between patients who had undergone SG and controls. Larger, but more transient increases in levels of plasma glucose and amino acids were accompanied by higher secretion of insulin, glucagon-like peptide 1, peptide YY, and cholecystokinin after RYGB, whereas levels of ghrelin were lower after SG, compared with RYGB and controls. Total 6-hour oral recovery of ingested glucose and protein was comparable among groups.ConclusionsPostprandial glucose and protein absorption and gastro-entero-pancreatic hormone secretions differ after SG and RYGB. RYGB was characterized by accelerated absorption of glucose and amino acids, whereas protein metabolism after SG did not differ significantly from controls, suggesting that different mechanisms explain improved glycemic control and weight loss after these surgical procedures. ClinicalTrials.gov ID NCT03046186.Graphical abstractGraphical abstract for this article
       
  • Development and Validation of a Mucosal Impedance Contour Analysis System
           to Distinguish Esophageal Disorders
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Dhyanesh A. Patel, Tina Higginbotham, James C. Slaughter, Muhammad Aslam, Elif Yuksel, David Katzka, C. Prakash Gyawali, Melina Mashi, John Pandolfino, Michael F. VaeziBackground & AimsDiagnostic testing for chronic esophageal disorders relies on histopathology analysis of biopsies or uncomfortable transnasal catheters or wireless pH monitoring, which capture abnormal intraluminal refluxate. We therefore developed a balloon mucosal impedance (MI) catheter system that instantly detects changes in esophageal mucosal integrity during endoscopy over a long segment of the esophagus. We performed a prospective study to evaluate the ability of a balloon-incorporated MI catheter to detect and evaluate esophageal disorders, including gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE).MethodsWe performed a prospective study of 69 patients undergoing esophagogastroduodenoscopy with or without wireless pH monitoring. Patients were classified as having GERD (erosive esophagitis or abnormal pH; n = 24), EoE (confirmed with pathology analysis of tissues from both distal and proximal esophagus; n = 21), or non-GERD (normal results from esophagogastroduodenoscopy and pH tests; n = 24). Receiver operating characteristic curves and area under the operating characteristic curve (AUC) were used to compare the accuracy of balloon MI in diagnosis. Probabilities of assignment to each group (GERD, non-GERD, or EoE) were estimated using multinomial logistic regression. Association between MI patterns and diagnoses were validated using data from patients seen at 3 separate institutions.ResultsMI pattern along the esophageal axis differed significantly (P 
       
  • G-Protein–Coupled Receptors Are Dynamic Regulators of Digestion and
           Targets for Digestive Diseases
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Meritxell Canals, Daniel P. Poole, Nicholas A. Veldhuis, Brian L. Schmidt, Nigel W. BunnettG-protein–coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. In the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication among cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of more than one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have shown that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs and has shown opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract.
       
  • Diagnosis, Development, and Treatment of Portal Vein Thrombosis in
           Patients With and Without Cirrhosis
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Nicolas M. Intagliata, Stephen H. Caldwell, Armando TripodiPortal vein thrombosis unrelated to solid malignancy is common in patients with cirrhosis, but less frequently observed in patients without cirrhosis. Prompt diagnosis and management of acute symptomatic portal vein thrombosis are essential. Failure to detect and treat thromboses can result in mesenteric ischemia, chronic cavernous transformation, and complications of portal hypertension. In patients with cirrhosis, development of portal vein thrombosis is often insidious and remains undetected until its incidental detection. Management of portal vein thrombosis in patients with cirrhosis is more controversial. However, there are data to support treatment of specific patients with anticoagulation agents. We review the common and distinct features of portal vein thromboses in patients without liver tumors, with and without cirrhosis.
       
  • A Shiny Liver!
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Fady G. Haddad, Stephen Mulrooney
       
  • An Extraordinary Rare Cause of Acute Dyspnea in an Adult
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Spyridon Davakis, Ali Kordzadeh, Alexandros Charalabopoulos
       
  • Unwell Adolescent Patient Presenting to the Emergency Department with
           Distended Abdomen
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): David Keohane, Adeel Zafar Syed, Eamon G. Kavanagh
       
  • A Painful Diagnosis to Swallow
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Michiel Bronswijk, Paul Christiaens, August Van Olmen
       
  • A Hypervascular Mass at the Papilla of Vater
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Takeharu Nakamura, Natsumi Oe, Tomoaki Matsumori
       
  • A Fierce Battle in the Liver to Kill the Enemy From Gut
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Pil Soo Sung, Eun Sun Jung, Seung Kew Yoon
       
  • Abdominal Pain and Prolonged Fever of Unknown Cause in a 14-Year-Old Boy
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Megumi Yoshitake, Shuhei Fukunaga, Takuji Torimura
       
  • An Unusual Lesion of the Colon Resembling a Submucosal Tumor
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Yohei Yabuuchi, Kinichi Hotta, Daisuke Aizawa
       
  • A Foreign Cause of Abdominal Pain
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Michiel Bronswijk, Chris Aelvoet, Paul Christiaens
       
  • An Uncommon Cause of Fever and Altered Levels of Liver Enzymes
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Jana G. Hashash, Dima Ibrahim, Nesrine A. Rizk
       
  • Gastric Ulcer in a Patient with Metastatic Lung Cancer
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Meeta Desai, Vikas Chitnavis, Douglas Grider
       
  • Democratizing Endoscopic Submucosal Dissection: Single-Operator Fully
           Robotic Colorectal Endoscopic Submucosal Dissection in a Pig Model
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Pietro Mascagni, Sun Gyo Lim, Claudio Fiorillo, Philippe Zanne, Florent Nageotte, Lucile Zorn, Silvana Perretta, Michel de Mathelin, Jacques Marescaux, Bernard Dallemagne
       
  • Role of CXCR6 in Antitumor Immune Surveillance
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Tae Hyun Kim, Sang Geon Kim
       
  • Has PD-1 MET Its Match in Hepatocellular Carcinoma'
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Joseph W. Franses, Andrew X. Zhu
       
  • Metabolic Alterations as a Signpost to Early Pancreatic Cancer
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Natalia Khalaf, Brian M. Wolpin
       
  • Can We Move on From the Discussion of Direct Antiviral Agents and Risk of
           Hepatocellular Carcinoma Recurrence'
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Jean-Charles Nault, Pierre Nahon
       
  • Effects of Oral Anticoagulant and Aspirin Use on Ability of Fecal
           Immunochemical Tests to Detect Advanced Neoplasia
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Manon C.W. Spaander, Ernst J. Kuipers
       
  • Promoting Leadership by Women in Gastroenterology—Lessons Learned
           and Future Directions
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Monina Pascua, Tatyana Kushner, Zibing Woodward
       
  • Evolving Trends in Machine Perfusion for Liver Transplantation
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Phillipp Dutkowski, James V. Guarrera, Jeroen de Jonge, Paulo N. Martins, Robert J. Porte, Pierre-Alain Clavien
       
  • Facing the Opioid Crisis: Practical, Effective Actions We Can Take
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Sameer Awsare, Carol Havens, Joseph Lippi
       
  • Covering the Cover
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s): Andrew T. Chan, Christopher S. Williams
       
  • Information for Authors and Readers
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s):
       
  • Elsewhere in The AGA Journals
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s):
       
  • Cover 1
    • Abstract: Publication date: May 2019Source: Gastroenterology, Volume 156, Issue 6Author(s):
       
  • Molecular Characterization of sessile serrated adenoma/polyps from a large
           African American cohort
    • Abstract: Publication date: Available online 17 April 2019Source: GastroenterologyAuthor(s): Hassan Ashktorab, Don Delker, Priyanka Kanth, Ajay Goel, John M. Carethers, Hassan Brim
       
  • Reconciliation of Recent Helicobacter pylori Treatment Guidelines in a
           Time of Increasing Resistance to Antibiotics
    • Abstract: Publication date: Available online 15 April 2019Source: GastroenterologyAuthor(s): Carlo A. Fallone, Steven F. Moss, Peter Malfertheiner Increasing resistance to antibiotics, worldwide, has adverse effects on the effectiveness of standard therapies to eradicate Helicobacter pylori infection. We reviewed guidelines developed by expert groups in Europe, Canada, and the United States for the treatment of Helicobacter pylori infection. We compared the recommendations of these guidelines, reconciled them, and addressed the increasing resistance of H pylori to antibiotic therapy regimens. The guidelines recommend bismuth for first-line treatment, replacing clarithromycin-based triple therapy. There is consensus for concomitant 4-drug therapy as an alternative, especially when bismuth is not available. When therapy is unsuccessful, it is likely due to resistance to clarithromycin, levofloxacin, and/or metronidazole; these drugs, if previously used, should be avoided in subsequent eradication attempts. Second-line therapies should be bismuth quadruple therapy or levofloxacin triple therapy, depending on suspected resistance, reserving rifabutin-based triple and high-dose dual amoxicillin proton pump inhibitor therapy for subsequent treatment attempts The increasing resistance of H pylori to antibiotic therapy necessitates local availability of susceptibility tests for individuals, and establishment of regional and national monitoring programs to develop evidence-based locally relevant eradication strategies. Further studies into the development of more easily accessible methods of resistance testing, such as biomarker analysis of stool samples, are required. Options under investigation include substituting vonoprazan for proton pump inhibitors, adding probiotics, and vaccine development. Narrow-spectrum antibiotics and new therapeutic targets could be identified based on genomic, proteomic, and metabolomic analyses of H pylori.
       
  • Model to Calculate Harms and Benefits of Early vs Delayed Liver
           Transplantation for Patients with Alcohol-Associated Hepatitis
    • Abstract: Publication date: Available online 15 April 2019Source: GastroenterologyAuthor(s): Brian P. Lee, Sumeyye Samur, Ozden O. Dalgic, Emily D. Bethea, Michael R. Lucey, Ethan Weinberg, Christine Hsu, Mary E. Rinella, Gene Y. Im, Oren K. Fix, George Therapondos, Hyosun Han, David W. Victor, Michael D. Voigt, Sheila Eswaran, Norah A. Terrault, Jagpreet Chhatwal Background & AimsEarly liver transplantation (without requiring a minimum period of sobriety) for severe alcohol-associated hepatitis (AH) is controversial—many centers delay eligibility until a specific period of sobriety (such as 6 months) has been achieved. To inform ongoing debate and policy, we modeled long-term outcomes of early vs delayed liver transplantation for patients with AH.MethodsWe developed a mathematical model to simulate early vs delayed liver transplantation for patients with severe AH and different amounts of alcohol use after transplantation: abstinence, slip (alcohol use followed by sobriety), or sustained use. Mortality of patients before transplantation was determined by joint-effect model (based on model for end-stage liver disease [MELD] and Lille scores). We estimated life expectancies of patients receiving early vs delayed transplantation (6-month wait before placement on the waitlist) and life-years lost attributable to alcohol use after receiving the liver transplant.ResultsPatients offered early liver transplantation were estimated to have an average life expectancy of 6.55 life-years, compared to an average life expectancy of 1.46 life-years for patients offered delayed liver transplants (4.49-fold increase). Net survival benefit from early transplantation was highest for patients with Lille scores of 0.50–0.82 and MELD scores of 32 or more. Patients who were offered early transplantation and had no alcohol use afterward were predicted to survive 10.85 years compared to 3.62 years for patients with sustained alcohol use after transplantation (7.23 life-years lost). Compared with delayed transplantation, early liver transplantation increased survival times in all simulated scenarios and combinations of Lille and MELD scores.ConclusionsIn a modeling study of assumed carefully selected patients with AH, early vs delayed liver transplantation (6 months of abstinence from alcohol before transplantation) increased survival times of patients, regardless of estimated risk of sustained alcohol use following transplant. These findings support early liver transplantation for patients with severe AH. The survival benefit was maintained in all simulated extreme scenarios, but should be confirmed in prospective studies. Sustained alcohol use following transplantation significantly reduced but did not eliminate the benefits of early transplantation—strategies are needed to prevent and treat post-transplantation use of alcohol.
       
  • High-fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett’s
           Esophagus via IL8 and Alterations to the Gut Microbiome
    • Abstract: Publication date: Available online 15 April 2019Source: GastroenterologyAuthor(s): Natasha Stephens Münch, Hsin-Yu Fang, Jonas Ingermann, H. Carlo Maurer, Akanksha Anand, Victoria Kellner, Vincenz Sahm, Maria Wiethaler, Theresa Baumeister, Frederik Wein, Henrik Einwächter, Florian Bolze, Martin Klingenspor, Dirk Haller, Maria Kavanagh, Joanne Lysaght, Richard Friedman, Andrew J. Dannenberg, Michael Pollak, Peter R. Holt Background & AimsBarrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to progression of BE to EAC in mice.MethodsTg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD), or crossbred with mice that express human IL8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative PCR, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals, or neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s rRNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions.ResultsL2-IL1B mice fed a HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues, compared to mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 mRNAs (epithelial progenitors) compared to mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice on HFD to L2-IL1B mice on control diet accelerated tumor development.ConclusionsIn a mouse model of BE, we found that a HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
       
  • Methylation Tolerance-based Functional Assay to Assess Variants of Unknown
           Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch
           Syndrome
    • Abstract: Publication date: Available online 15 April 2019Source: GastroenterologyAuthor(s): Delphine Bouvet, Sahra Bodo, Annie Munier, Erell Guillerm, Romane Bertrand, Chrystelle Colas, Alex Duval, Florence Coulet, Martine Muleris Background & AimsApproximately 75% of patients with suspected Lynch syndrome carry variants in MLH1 or MSH2—proteins encoded by these genes are required for DNA mismatch repair (MMR). However, 30% of these are variants of unknown significance (VUS). A assay that measures cell response to the cytotoxic effects of a methylating agent can determine the effects of VUS in MMR genes and identify patients with constitutional mismatch repair-deficiency syndrome. We adapted this method to test the effects of VUS in MLH1 and MSH2 genes found in patients with suspected Lynch syndrome.MethodsWe transiently expressed MLH1 or MSH2 variants in MLH1- or MSH2-null human colorectal cancer cell lines (HCT116 or LoVo), respectively. The MMR process causes death of cells with methylation-damaged DNA bases, so we measured proportions of cells that undergo death following exposure to the methylating agent; cells that escaped its toxicity were considered to have variants that affect function of the gene product. Using this assay, we analyzed 88 variants (mainly missense variants), comprising a validation set of 40 previously classified variants (19 in MLH1 and 21 in MSH2) and a prospective set of 48 VUS (25 in MLH1 and 23 in MSH2). Prediction scores were calculated for all VUS according to the recommendations of the American College of Medical Genetics and Genomics, based on clinical, somatic, in silico, population and functional data.ResultsThe assay correctly classified 39/40 variants in the validation set. The assay identified 12 VUS that did alter function of the gene product and 28 VUS that did not; the remaining 8 VUS had intermediate effects on MMR capacity and could not be classified. Comparison of assays results with prediction scores confirmed the ability of the assay to discriminate VUS that affected the function of the gene products from those that did not.ConclusionsUsing an assay that measures the ability of the cells to undergo death following DNA damage induction by a methylating agent, we were able to assess whether variants in MLH1 and MSH2 cause defects in DNA MMR. This assay might be used to help assessing the pathogenicity of VUS in MLH1 and MSH2 found in patients with suspected Lynch syndrome.
       
  • A rare cause of multiple hepatic masses
    • Abstract: Publication date: Available online 14 April 2019Source: GastroenterologyAuthor(s): Sung Bum Kim, Jae Woon Kim, Joon Hyuk Choi
       
  • Making the Stomach Pump Better: The Answer for Gastroparesis'
    • Abstract: Publication date: Available online 26 March 2019Source: GastroenterologyAuthor(s): Christopher K. Rayner, Karen L. Jones, Michael Horowitz
       
  • CME Exam 2: Development and Validation of a Mucosal Impedance Contour
           Analysis System to Distinguish Esophageal Disorders
    • Abstract: Publication date: Available online 28 March 2019Source: GastroenterologyAuthor(s):
       
  • CME Exam 3: Direct-Acting Antiviral Therapy not Associated with Recurrence
           of Hepatocellular Carcinoma in a Multicenter North American Cohort Study
    • Abstract: Publication date: Available online 28 March 2019Source: GastroenterologyAuthor(s):
       
  • CME Exam 1: Democratizing Endoscopic Submucosal Dissection:
           Single-Operator Fully Robotic Colorectal Endoscopic Submucosal Dissection
           in a Pig Model
    • Abstract: Publication date: Available online 27 March 2019Source: GastroenterologyAuthor(s):
       
  • Reply
    • Abstract: Publication date: Available online 27 March 2019Source: GastroenterologyAuthor(s): Irun Bhan, Martin Aryee, David T. Ting
       
  • Reply
    • Abstract: Publication date: Available online 27 March 2019Source: GastroenterologyAuthor(s): Frederic Prat, Frédéric Beuvon, Marine Camus
       
  • In Memoriam: Wendy Atkin 1947–2018
    • Abstract: Publication date: Available online 26 March 2019Source: GastroenterologyAuthor(s): David Lieberman, Ann Graham Zauber, Julietta Patnick
       
 
 
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