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This study aimed to determine whether Helicobacter pylori eradication limits the progression of precancerous changes, manifested as intestinal metaplasia (IM), in patients with reflux esophagitis using long-term esomeprazole. Three hundred twenty-five reflux esophagitis patients were enrolled and randomly assigned to (i) the H. pylori-positive eradication group receiving 1-week triple therapy (n=105); (ii) H. pylori-positive non-eradication controls (n=105); and (iii) H. pylori-negative controls (n=115). All the patients received continuous esomeprazole until sustained symptomatic response, and when possible, shifted to on-demand therapy (ODT) thereafter. Serial gastroscopy was scheduled on enrollment and at the end of the first and second years to assess the prevalence and progression or regression of gastric atrophy (AT) and IM. There were 93 patients in the H. pylori-eradication group, 83 in the non-eradication controls, and 100 in the negative controls to complete the study. The negative controls had no progression of AT and IM during follow-up. For the H. pylori-positive eradication group, there was significant regression of AT and IM during follow-up (P<0.05). In the H. pylori-positive non-treated controls, the prevalence rates of AT and IM were significantly greater on the second year than on enrollment (P<0.05). During the second-year follow-up, the patients in the eradication group achieved more regression and less development of AT and IM than did the non-eradication controls (P<0.001). In patients using long-term esomeprazole for reflux esophagitis, screening for and eradicating H. pylori infection are necessary in order to limit the progression or cause the regression of gastric precancerous changes.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium‐177 dotatate (177Lu‐DOTATATE) has been approved for advanced GEP‐NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression‐free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver‐directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.

Background: Numerous studies have reported on the association between coeliac disease and the otherwise uncommon enteropathy-type T cell lymphoma (ETTL). A systematic risk assessment of more prevalent lymphoma entities, such as B cell and non-intestinal lymphomas, in coeliac disease has not been performed. Aims: In light of the increasing number of patients diagnosed with coeliac disease and the unknown aetiology of malignant lymphomas, we aimed to estimate the distribution and risk of lymphoma subtypes in coeliac disease. Methods: We reviewed and reclassified 56 cases of incident malignant lymphomas occurring in a Swedish population based cohort of 11 650 patients hospitalised with coeliac disease. The observed numbers of lymphoma subtypes were compared with those expected in the Swedish population. Results: The majority (n = 32, 57%) of lymphomas in the cohort were not intestinal T cell lymphomas. Significantly increased risks were observed for B cell non-Hodgkin lymphoma (NHL) (standardised incidence ratio (SIR) 2.2 (95% confidence interval (CI) 1.2–3.6); 11 non-intestinal and five intestinal) and for lymphomas of non-intestinal origin (SIR 3.6 (95% CI 2.3–5.2), 11 B and 14 T cell). Furthermore, 44% of patients with B cell NHL had a history of other autoimmune/inflammatory diseases. The relative risks for T cell NHL (SIR 51 (95% CI 35–68); n = 37) and for primary gastrointestinal lymphomas (SIR 24 (95% CI 16–34); five B and 25 T cell) were markedly increased, as anticipated. Conclusion: Most lymphomas complicating coeliac disease are indeed related to the disease and are not of the ETTL-type. There was a remarkable aggregation of autoimmune/inflammatory disorders, female sex, coeliac disease, and B cell lymphoma.

The intestinal epithelium is a multicellular interface in close proximity to a dense microbial milieu that is completely renewed every 3–5 days. Pluripotent stem cells reside at the crypt, giving rise to transient amplifying cells that go through continuous steps of proliferation, differentiation and finally anoikis (a form of programmed cell death) while migrating upwards to the villus tip. During these cellular transitions, intestinal epithelial cells (IECs) possess distinct metabolic identities reflected by changes in mitochondrial activity. Mitochondrial function emerges as a key player in cell fate decisions and in coordinating cellular metabolism, immunity, stress responses and apoptosis. Mediators of mitochondrial signalling include molecules such as ATP and reactive oxygen species and interrelate with pathways such as the mitochondrial unfolded protein response (MT-UPR) and AMP kinase signalling, in turn affecting cell cycle progression and stemness. Alterations in mitochondrial function and MT-UPR activation are integral aspects of pathologies, including IBD and cancer. Mitochondrial signalling and concomitant changes in metabolism contribute to intestinal homeostasis and regulate IEC dedifferentiation–differentiation programmes in the context of diseases, suggesting that mitochondrial function as a cellular checkpoint critically contributes to disease outcome. This Review highlights mitochondrial function and MT-UPR signalling in epithelial cell stemness, differentiation and lineage commitment and illustrates mitochondrial function in intestinal diseases.

Purpose The purpose of this meta-analysis was to assess the associations between inflammatory bowel disease (IBD) and risk of the gastric, small bowel and colorectal cancer. Methods We searched the PubMed and Web of Science for observational studies published before June 2020, and the quality of each included study was evaluated according to the Newcastle–Ottawa–Scale. Results Twenty-six studies comprising 531 449 IBD patients and more than 65 million reference individuals were included. Although IBD was significantly associated with 67% increased risk of the total gastric, small bowel and colorectal cancer. After stratifying by cancer location, IBD mainly increased the risk of intestinal cancer instead of gastric cancer. Furthermore, Crohn’s disease (CD) significantly increased the risk of both small bowel cancer and colorectal cancer, while ulcerative colitis (UC) only increased the risk of colorectal cancer. In subgroup analysis, associations between IBD and risk of total gastric, small bowel and colorectal cancer were similar between male and female, except for that male IBD patients but not female had a significantly higher risk of small bowel cancer. Additionally, IBD patients in different geographical areas had different associations with risk of various gastrointestinal tract cancers. Conclusions IBD is mainly associated with increased risk of cancers in the lower gastrointestinal tract, including small bowel cancer and colorectal cancer. Because studies about the association between IBD and risk of gastric cancer and the populations in Asia are limited, more observational studies are required in the future.

Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data. The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates. Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed. The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn’s disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly ( p  = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly ( p  = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1 + immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1 + cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1 + microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous polyposis coli (APC) gene (ApcMin/⁺ mice). There was also a decrease in inflammatory cytokines and proinflammatory mediators, reduced infiltration of lymphocytes including T cells, and preservation of intestinal architecture and the presence of APC protein in intestinal epithelial cells. Interestingly, IL-17A ablation also corrected immunological abnormalities such as splenomegaly and thymic atrophy in ApcMin/⁺ mice. CD4 T cells from ApcMin/⁺ mice showed hyperproliferative potential in vitro and in vivo and increased levels of IL-17A and IL-10. The effector CD4 T cells from ApcMin/⁺ mice were more resistant to regulatory T cell-mediated suppression. Finally, these CD4 T cells induced colitis in immunodeficient mice upon adoptive transfer, whereas the ablation of IL-17A in CD4 T cells in ApcMin/⁺ mice completely abolished this pathogenic potential in vivo. Taken together, our results show that CD4 T cell-derived IL-17A promotes spontaneous intestinal tumorigenesis with altered functions of CD4 T cells in ApcMin/⁺ mice.

ObjectiveThe aim of our study was to estimate the incidence of digestive cancers within a cohort of asbestos-exposed workers.MethodsOur study was based on a cohort of 2024 participants occupationally exposed to asbestos. The incidence of digestive cancers was calculated from 1 January 1978 to 31 December 2009 and compared with levels among the local general population using Standardised Incidence Ratios (SIRs). Asbestos exposure was assessed using the company’s job-exposure matrix.Results119 cases of digestive cancer were observed within our cohort, for an expected number of 77 (SIR=1.54 (1.28 to 1.85)). A significantly elevated incidence was observed for peritoneal mesothelioma, particularly in women. Significantly elevated incidences were also observed among men for: all digestive cancers, even when excluding peritoneal mesothelioma (SIR=1.50 (1.23 to 1.82)), oesophageal cancer (SIR=1.67 (1.08 to 2.47)) and liver cancer (SIR=1.85 (1.09 to 2.92)). Concerning colorectal cancer, a significant excess of risk was observed for men with exposure duration above 25 years (SIR=1.75 (1.05 to 2.73)).ConclusionsOur results are in favour of a link between long-duration asbestos exposure and colorectal cancer in men. They also suggest a relationship between asbestos exposure and cancer of the oesophagus in men. Finally, our results suggest a possible association with small intestine and liver cancers in men.