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ApcMin/+ mouse was a model mouse for human familial adenomatous polyposis, and irradiation at an early age increases tumors in the small and large intestine. To study the effects of antioxidant administration on tumor incidence after continuous whole-body exposure to gamma rays, ApcMin/+ mice were exposed to a medium-dose-rate, 200 mGy/d, from postnatal Day 0 to 21 of age or a high-dose-rate of 0.65 Gy/min (total dose 4.2 Gy) on postnatal Day 7. The dams and pups were supplied with the N-acetylcysteine (NAC) in drinking water (7 g/L), from gestation Day 15 until weaning (21 days-old). A significant increase in the number of intestinal tumors were observed in ApcMin/+ mice irradiated with high dose-rate gamma rays as compared with the non-irradiated controls, but there was no significant difference in tumor counts between the non-irradiated controls and the medium-dose rate irradiation groups. NAC administration did not have any significant effect at least at this dose. These results suggest that the supplementation of anti-oxidant at the early stage of tumorigenesis does not suppress the formation of irradiation-induced small intestinal tumors., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Obesity and type 2 diabetes (T2D) promote inflammation, increasing the risk of colorectal cancer (CRC). High-fat diet (HFD)-induced obesity is key to these diseases through biological mechanisms. This study examined the impact of genetic background on the multimorbidity of intestinal cancer, T2D, and inflammation due to HFD-induced obesity., Methods: A cohort of 357 Collaborative Cross (CC) mice from 15 lines was fed either a control chow diet (CHD) or HFD for 12 weeks. Body weight was tracked biweekly, and blood glucose was assessed at weeks 6 and 12 via intraperitoneal glucose tolerance tests (IPGTT). At the study's endpoint, intestinal polyps were counted, and cytokine profiles were analyzed to evaluate the inflammatory response., Results: HFD significantly increased blood glucose levels and body weight, with males showing higher susceptibility to T2D and obesity. Genetic variation across CC lines influenced glucose metabolism, body weight, and polyp development. Mice on HFD developed more intestinal polyps, with males showing higher counts than females. Cytokine analysis revealed diet-induced variations in pro-inflammatory markers like IL-6, IL-17A, and TNF-α, differing by genetic background and sex., Conclusions: Host genetics plays a crucial role in susceptibility to HFD-induced obesity, T2D, CRC, and inflammation. Genetic differences across CC lines contributed to variability in disease outcomes, providing insight into the genetic underpinnings of multimorbidity. This study supports gene-mapping efforts to develop personalized prevention and treatment strategies for these diseases.

Explorations of the Moon and Mars are planned as future manned space missions, during which humans will be exposed to both radiation and microgravity. We do not, however, know the health effects for such combined exposures. In a ground-based experiment, we evaluated the combined effects of radiation and simulated microgravity on tumorigenesis by performing X-irradiation and tail suspension in C3B6F1 Apc Min /+ mice, a well-established model for intestinal tumorigenesis. Mice were irradiated at 2 weeks of age and underwent tail suspension for 3 or 11 weeks using a special device that avoids damage to the tail. The tail suspension treatment significantly reduced the thymus weight after 3 weeks but not 11 weeks, suggesting a transient stress response. The combination of irradiation and tail suspension significantly increased the number of small intestinal tumors less than 2 mm in diameter as compared with either treatment alone. The combined treatment also increased the fraction of malignant tumors among all small intestinal tumors as compared with the radiation-only treatment. Thus, the C3B6F1 Apc Min /+ mouse is a useful model for assessing cancer risk in a simulated space environment, in which simulated microgravity accelerates tumor progression when combined with radiation exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: The incidence of small intestinal cancer (SIC) is increasing, however, its aetiology remains unclear due to a lack of data from large-scale prospective cohorts. We examined modifiable risk factors in relation to SIC overall and by histological subtype., Methods: We analysed 450,107 participants enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. Cox proportional hazards models were used to estimate univariable and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: During an average of 14.1 years of follow-up, 160 incident SICs (62 carcinoids, 51 adenocarcinomas) were identified. Whilst univariable models revealed a positive association for current versus never smokers and SIC (HR, 95% CI: 1.77, 1.21-2.60), this association attenuated in multivariable models. In energy-adjusted models, there was an inverse association across vegetable intake tertiles for SIC overall (HR T3vsT1 , 95% CI: 0.48, 0.32-0.71, p-trend: < 0.001) and for carcinoids (HR T3vsT1 , 95% CI: 0.44, 0.24-0.82, p-trend: 0.01); however, these attenuated in multivariable models. Total fat was also inversely associated with total SIC and both subtypes but only in the second tertile (SIC univariable HR T2vsT1 , 95% CI: 0.57, 0.38-0.84; SIC multivariable HR T2vsT1 , 95% CI: 0.55, 0.37-0.81). Physical activity, intake of alcohol, red or processed meat, dairy products, or fibre were not associated with SIC., Conclusion: These exploratory analyses found limited evidence for a role of modifiable risk factors in SIC aetiology. However, sample size was limited, particularly for histologic subtypes; therefore, larger studies are needed to delineate these associations and robustly identify risk factors for SIC., (© 2023. The Author(s).)

Opinion Statement: Small intestine cancer is rare, accounting for approximately 3% of all gastrointestinal malignancies. The most common histological subtypes include adenocarcinoma, neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). In localised disease, surgery remains the mainstay of treatment and the best approach to improve survival. Current treatment for small intestine adenocarcinoma (SIA) is extrapolated from small studies and data from colorectal cancer (CRC). There is limited evidence to guide therapy in the adjuvant setting. However, there are small phase II studies in the advanced setting providing evidence for the role of chemotherapy and immunotherapy. There is also limited evidence assessing the efficacy of targeted therapies. Small intestine NETs are rare, with evidence for somatostatin analogue therapy, particularly in the low to intermediate-grade well-differentiated tumours. Poorly differentiated NETs are generally managed with chemotherapy but have worse outcomes compared with well-differentiated NETs. The management of small intestine GISTs is largely targeting KIT mutations with imatinib. Recent trials have provided evidence for effective therapies in imatinib-resistant tumours and the potential role of immunotherapy. The aim of this article was to review the evidence for the current management and recent advances in the management of small intestine adenocarcinoma, NETs and GISTs., (© 2023. Crown.)

Background: Gastroenteropancreatic neuroendocrine neoplasms [GEP-NENs] have rarely been reported in association with inflammatory bowel diseases [IBDs]., Methods: An ECCO COllaborative Network For Exceptionally Rare case reports project [ECCO-CONFER] collects cases of GEP-NENs diagnosed in patients with IBD., Results: GEP-NEN was diagnosed in 100 IBD patients; 61% female, 55% Crohn's disease, median age 48 years (interquartile range [IQR] 38-59]). The most common location was the appendix [39%] followed by the colon [22%]. Comprehensive IBD-related data were available for 50 individuals with a median follow-up of 30 months [IQR 11-70] following NEN diagnosis. Median duration of IBD at NEN diagnosis was 84 months [IQR 10-151], and in 18% of cases NEN and IBD were diagnosed concomitantly. At diagnosis, 20/50 were stage-I [T1N0M0], and 28/50 were graded G1 [ki67 ≤2%]. Incidental diagnosis of NEN and concomitantly IBD diagnosis were associated with an earlier NEN stage [p = 0.01 and p = 0.02, respectively]. Exposure to immunomodulatory or biologic therapy was not associated with advanced NEN stage or grade. Primary GEP-NEN were more frequently found in the segment affected by IBD [62% vs 38%]. At the last follow-up data, 47/50 patients were alive, and only two deaths were related to NEN., Conclusions: In the largest case series to date, prognosis of patients with GEP-NEN and IBD seems favourable. Incidental NEN diagnosis correlates with an earlier NEN stage, and IBD-related therapies are probably independent of NEN stage and grade. The association of GEP-NEN location and the segment affected by IBD may suggest a possible role of inflammation in NEN tumorigenesis., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Crohn's disease is associated with an increased risk of adenocarcinoma of the involved portions of the small bowel and colorectum and has similar risk factors to those described in ulcerative colitis, most significantly, extent of bowel involvement, PSC, and duration of unresected disease. Prevention strategies include risk stratification and secondary prevention with colonoscopic screening and surveillance to identify dysplasia or early-stage cancers, with surgery when needed. There is emerging information to suggest that control of inflammation may provide primary prevention of neoplasia, but further studies are required to test this strategy., Competing Interests: Disclosure S. Friedberg has no relevant disclosures. D.T. Rubin has received grant support from Takeda; and has served as a consultant for Abbvie, Altrubio, Arena Pharmaceuticals, Bristol-Myers Squibb, Genentech/Roche, Gilead Sciences, Iterative Scopes, Janssen Pharmaceuticals, Lilly, Pfizer, Prometheus Biosciences, Takeda, and Techlab Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The glucocorticoid receptor NR3C1 is expressed in multiple cell types in the gut and elsewhere. Intestinal epithelial cells both produce and respond to glucocorticoids in different physiological and pathological contexts. In experimental colitis, glucocorticoids have been shown to exert a dual role, dampening inflammation while producing a deterioration in animal status, including death. Mice with tamoxifen-inducible, intestinal epithelial-specific deletion of NR3C1 (NR3C1 ΔIEC mice) are protected against experimental colitis, suggesting glucocorticoid epithelial actions are deleterious. Since glucocorticoids modulate epithelial proliferation, it follows that they may affect the development of colon cancer. In this study, we set out to test this hypothesis using the dextran sulfate sodium-azoxymethane model of colitis-associated cancer. Knockout (KO) mice were found to exhibit a twofold higher tumor load but similar incidence and tumor size. Tumors had a higher trend to extend close to the submucosal layer (36% vs. 0%) in NR3C1 ΔIEC mice, and overexpressed Lgr5 , Egfr , and Myc , consistent with distinct expression of proliferative/stemness markers . Snai1 and Snai2 were upregulated specifically in tumors of NR3C1 ΔIEC mice, suggesting enhanced epithelial to mesenchymal transition in the absence of the intestinal epithelial glucocorticoid (GC) receptor. We conclude that endogenous GC epithelial signaling is involved in colitis-associated cancer. NEW & NOTEWORTHY Mice carrying a tamoxifen-inducible deletion of the glucocorticoid receptor in intestinal epithelial cells (NR3C1 ΔIEC mice) and their corresponding controls were subjected to the azoxymethane-dextran sulfate sodium model of colitis-associated cancer. KO mice exhibit a twofold higher tumor load, with a higher trend to extend close to the submucosal layer (36% vs. 0%), but with similar incidence and tumor size. Colonic tumors in NR3C1 ΔIEC mice showed signs of increased neoplastic transformation and tumor-associated inflammation.

Rationale: Peutz-Jeghers syndrome (PJS), a rare autosomal dominant disorder, is characterized by mucocutaneous pigmentations, hamartomatous polyps in the gastrointestinal tract, and a high risk of developing various malignancies. To the best of our knowledge, only 1 case of appendiceal carcinoid associated with PJS has been previously reported in the pediatric population., Patient Concerns: We report a 7-year-old girl who was admitted for severe, intermittent abdominal pain and cramps, nausea, and vomiting. Multiple brown melanotic macules on the lips, buccal mucosa, and the tongue were noted., Diagnosis: A plain abdominal X-ray in a standing position revealed dilated intestinal loops with multiple air-fluid levels. A computed tomography scan of the abdomen showing a "coffee bean" appearance of the jejunal loop with a transition point to the duodenal loop. Axial-contrast-enhanced computed tomography scan of the abdomen showing dilated jejunum loops, filled with fluid with the swirled appearance of mesentery typical for volvulus. The diagnosis of PJS was based on clinical findings along with the histopathologic confirmation of the hamartomatous polyps., Interventions: An emergency laparotomy was performed, revealing a jejunojejunal intussusception starting 40 cm from the duodenojejunal flexure. Jejunotomy revealed that a lead-point intussusception was a necrotic hamartomatous polyp. After resecting the involved jejunal necrotic segment, including the polyp, end-to-end jejuno-jejunal anastomosis was performed. Further exploration revealed the presence of a jejunal mass 80 cm from the duodenojejunal flexure identified as another hamartomatous pedunculated polyp. The polyp was resected, and the enterotomy was then closed transversely. The grossly normal appendix was also removed., Outcomes: Clinical findings along with the histopathologically confirmed hamartomatous polyps were consistent with PJS. An appendiceal carcinoid (well-differentiated neuroendocrine tumor, European Neuroendocrine Tumor Society stage pT2) was incidentally detected during histological examination of the appendix. The patient and parents were counseled accordingly, focusing on active surveillance and control of symptoms. Two additional hamartomatous polyps (gastric and jejunal) were detected endoscopically and resected in the fourth postoperative week. A regular, 1-year follow-up and surveillance revealed no complications or recurrences., Lessons: Unusual neoplasms can occasionally be encountered in well-defined syndromes such as PJS. Therefore, active follow-up and surveillance are mandatory for all patients with PJS., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Refractory celiac disease type II (RCD II), also referred to as "cryptic" enteropathy-associated T-cell lymphoma (EATL) or "intraepithelial T-cell lymphoma," is a rare clonal lymphoproliferative disorder that arises from innate intraepithelial lymphocytes. RCD II has a poor prognosis and frequently evolves to EATL. The pathogenesis of RCD II is not well understood and data regarding the immunophenotypic spectrum of this disease and underlying genetic alterations are limited. To gain further biological insights, we performed comprehensive immunophenotypic, targeted next-generation sequencing, and chromosome microarray analyses of 11 RCD II cases: CD4-/CD8- (n=6), CD8+ (n=4), and CD4+ (n=1), and 2 of 3 ensuing EATLs. Genetic alterations were identified in 9/11 (82%) of the RCD II cases. All 9 displayed mutations in members of the JAK-STAT signaling pathway, including frequent, recurrent STAT3 (7/9, 78%) and JAK1 (4/9, 44%) mutations, and 9/10 evaluable cases expressed phospho-STAT3. The mutated cases also harbored recurrent alterations in epigenetic regulators (TET2, n=5 and KMT2D, n=5), nuclear factor-κB (TNFAIP3, n=4), DNA damage repair (POT1, n=3), and immune evasion (CD58, n=2) pathway genes. The CD4-/CD8- and other immunophenotypic subtypes of RCD II exhibited similar molecular features. Longitudinal genetic analyses of 4 RCD II cases revealed stable mutation profiles, however, additional mutations were detected in the EATLs, which occurred at extraintestinal sites and were clonally related to antecedent RCD II. Chromosome microarray analysis demonstrated copy number changes in 3/6 RCD II cases, and 1 transformed EATL with sufficient neoplastic burden for informative analysis. Our findings provide novel information about the immunophenotypic and genomic characteristics of RCD II, elucidate early genetic events in EATL pathogenesis, and reveal potential therapeutic targets., Competing Interests: Conflicts of Interest and Source of Funding: S.H. received honoraria from Illumina, Loxo Oncology, and Medscape; research funding from Bristol Myers Squibb. A.A.G. is a co-investigator with Seattle Genetics, Innate Pharma. Investigator and consultant with StemLine. P.H.G. is on the Advisory board of Johnson & Johnson/Janssen, ImmunogenX, ImusanT. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

To explore the largely unknown etiology of small intestine cancer, we examined metabolic factors and risk of small intestine cancer overall and by subtypes. Among 404 220 women and 403 265 men in six European cohorts, we applied Cox regression with adjustment for smoking and body mass index (BMI), to calculate sex-specific hazard ratios (HRs) of small intestine cancer by levels of BMI, mean arterial pressure (MAP) and plasma total cholesterol, triglycerides and glucose. We also calculated HRs for these factors combined (metabolic score; MetS) and used Wald test statistics to investigate pairwise interactions between metabolic factors on risk. We also performed analyses separately per subtype (neuroendocrine tumors [NETs] and adenocarcinomas). During a median follow-up of 16.9 years, 144 women and 195 men were diagnosed with small intestine cancer, including 184 NETs and 99 adenocarcinomas. Among men, no main associations or interactions between metabolic factors were observed in relation to the risk of small intestine cancer. Among women, triglycerides were positively and linearly associated with risk (HR per standard deviation [SD]: 1.23, 95% confidence interval [CI]: 1.04-1.46), and a positive association was also observed for the MetS (HR per SD: 1.25, 95% CI: 1.02-1.52). Positive interactions were observed among women between triglycerides and cholesterol (P = .0005), and between MAP and glucose (P = .009), on risk. Glucose was positively associated with adenocarcinomas among women. This large, prospective study suggests that elevated triglycerides, and metabolic factors in interaction, confer an increased risk of small intestine cancer among women, but not among men., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Background: Gastric precancerous lesion (GPL) is a necessary stage in the occurrence and development of gastric cancer. At present, the incidence of gastric cancer is increasing year by year. It is important to prevent and control gastric cancer through early detection and intervention. Banxia Xiexin Decoction (BXD) has a good effect in improving symptoms, reducing inflammation, promoting the repair of gastric mucosa, reversing its atrophy and intestinal metaplasia. BXD may be a foreground choice for the treatment of GPL., Methods: Randomized controlled trials of BXD for GPL will be searched in the relevant database, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), and Chinese Scientific Journal Database (VIP database). The studies of electronic searches will be exported to EndNote V.9.1 software. We will run meta-analyses using the Review Manager (RevMan) V.5.3 software. Any disagreement will be solved in consultation with a third reviewer., Results: Our study aims to explore the efficacy of BXD for GPL and to provide up-to-date evidence for clinical of GPL., Conclusion: The conclusion of this study will provide evidence for the efficacy of BXD on GPL., Inplasy Registration Number: INPLASY 202130102., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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.

Background: Multimorbidity of intestinal cancer (IC), type 2 diabetes (T2D) and obesity is a complex set of diseases, affected by environmental and genetic risk factors. High-fat diet (HFD) and oral bacterial infection play important roles in the etiology of these diseases through inflammation and various biological mechanisms., Methods: To study the complexity of this multimorbidity, we used the collaborative cross (CC) mouse genetics reference population. We aimed to study the multimorbidity of IC, T2D, and obesity using CC lines, measuring their responses to HFD and oral bacterial infection. The study used 63 mice of both sexes generated from two CC lines (IL557 and IL711). For 12 weeks, experimental mice were maintained on specific dietary regimes combined with co-infection with oral bacteria Porphyromonas gingivalis and Fusobacterium nucleatum , while control groups were not infected. Body weight (BW) and results of a intraperitoneal glucose tolerance test (IPGTT) were recorded at the end of 12 weeks, after which length and size of the intestines were assessed for polyp counts., Results: Polyp counts ranged between 2 and 10 per CC line. The combination of HFD and infection significantly reduced ( P  < .01) the colon polyp size of IL557 females to 2.5 cm 2 , compared to the other groups. Comparing BW gain, IL557 males on HFD gained 18 g, while the females gained 10 g under the same conditions and showed the highest area under curve (AUC) values of 40 000-45 000 (min mg/dL) in the IPGTT., Conclusion: The results show that mice from different genetic backgrounds respond differently to a high fat diet and oral infection in terms of polyp development and glucose tolerance, and this effect is gender related., Competing Interests: The authors have declared no conflicts of interest., (© 2021 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Objective: Crohn's disease (CD) is associated with increased risk of small bowel cancer (SBC), but previous studies have been small. We aimed to examine the risk of incident SBC and death from SBC in patients with inflammatory bowel disease (IBD)., Design: In a binational, population-based cohort study from Sweden and Denmark of patients with IBD during 1969-2017 and matched reference individuals from the general population, we evaluated the risk of incident SBC and death from SBC. Cox regression was used to estimate adjusted hazard ratios (aHRs)., Results: We identified 161 896 individuals with IBD (CD: 47 370; UC: 97 515; unclassified IBD: 17 011). During follow-up, 237 cases of SBC were diagnosed in patients with IBD (CD: 24.4/100 000 person-years; UC: 5.88/100 000 person-years), compared with 640 cases in reference individuals (2.81/100 000 person-years and 3.32/100 000 person-years, respectively). This corresponded to one extra case of SBC in 385 patients with CD and one extra case in 500 patients with UC, followed up for 10 years. The aHR for incident SBC was 9.09 (95% CI 7.34 to 11.3) in CD and 1.85 (95% CI 1.43 to 2.39) in UC. Excluding the first year after an IBD diagnosis, the aHRs for incident SBC decreased to 4.96 in CD and 1.69 in UC. Among patients with CD, HRs were independently highest for recently diagnosed, childhood-onset, ileal and stricturing CD. The relative hazard of SBC-related death was increased in both patients with CD (aHR 6.59, 95% CI 4.74 to 9.15) and patients with UC (aHR 1.57; 95% CI 1.07 to 2.32)., Conclusion: SBC and death from SBC were more common in patients with IBD, particularly among patients with CD, although absolute risks were low., Competing Interests: Competing interests: JA has served as a consultant for Aetion and BioFire diagnostics. OO has been PI on projects at Karolinska Institutet partly financed by investigator-initiated grants from Janssen and Ferring. He also reports a grant from Pfizer in the context of a national safety monitoring programme. None of those studies has any relation to the present study. The Karolinska Institutet has received fees for Olén’s lectures and participation on advisory boards from Janssen, Ferring, Takeda and Pfizer regarding topics not related to the present study. JA acts or has acted as PI for agreements between Karolinska Institutet and grants from AbbVie, Bristol-Myers Squibb, Eli Lilly, Merck, Pfizer, Roche, Samsung Bioepis, Sanofi and UCB, mainly in the context of a national safety monitoring programme for immunomoduators in rheumatology (ARTIS). JLF coordinates a study unrelated to the present study on behalf of the Swedish IBD Quality Register (SWIBREG). That study has received funding from Janssen. JH has served as speaker and/or advisory board member for AbbVie, Celgene, Celltrion, Ferring, Hospira, Janssen, MEDA, Medivir, MSD, Olink Proteomics, Pfizer, Prometheus Laboratories, Sandoz/Novartis, Shire, Takeda, Tillotts Pharma, Vifor Pharma and UCB. He also has received grant support from Janssen, MSD and Takeda. The Department of Clinical Epidemiology, Aarhus University Hospital, receives funding for other studies from companies in the form of research grants to (and administered by) Aarhus University. None of these studies has any relation to the present study., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in Apc Min/+ mutant mice., Methods: An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into Apc Min/+ mice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry., Results: Intestines from Apc +/+ mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fc-transduced Apc Min/+ mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of Apc Min/+ mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from Apc Min/+ mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from Apc Min/+ mice expressing RSPO1-Fc back to the same level as in the adenomas from mice given the control vector., Conclusions: Expression of RSPO1 in Apc Min/+ mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The impact of alcohol drinking on gastric precancerous lesions remains unclear. We investigated the relationship of alcohol intake with risk of atrophic gastritis (AG) and intestinal metaplasia (IM)., Methods: This study included 202,675 Korean adults free from AG and IM on their initial endoscopy who were followed with repeated endoscopic examinations. A parametric proportional hazards model was used to estimate the adjusted HR (aHR) with 95% confidence interval (CI) for incident AG and IM based on endoscopic diagnosis., Results: During a mean follow-up of 4.7 years, 64,853 incident AG cases and 4,536 IM cases were identified. Alcohol consumption including drinking frequency, quantity, and binge drinking were consistently associated with increased risk of both AG and IM in a dose-response manner. After adjustment for confounders, the multivariable aHRs (95% CIs) for incident IM comparing average alcohol intake of <10, 10-<20, 20-<40, and ≥40 g/day with lifetime abstainers were 1.27 (1.02-1.56), 1.34 (1.07-1.66), 1.50 (1.20-1.86), and 1.54 (1.23-1.93), respectively. Former drinkers were also at a higher risk for AG and IM compared with lifetime abstainers. These associations were consistently observed in never smokers and in time-dependent analyses., Conclusions: In a large cohort of Korean individuals, alcohol intake even at low levels was independently associated with increased risk of developing endoscopic AG and IM, supporting a role of alcohol consumption in the pathogenesis of AG and IM, the precursor lesions of stomach cancer., Impact: Alcohol consumption from low-level drinking may contribute to gastric carcinogenesis., (©2020 American Association for Cancer Research.)

HASPIN has been identified as a nuclear Ser/Thr kinase specifically expressed in haploid germ cells. HASPIN kinase inhibitors were recently isolated, and their antitumor activity reported. Colorectal cancer occurs with high incidence worldwide. In this study, we examined whether HASPIN inhibitor CHR-6494 suppresses cancer progression in Apc mice, a familial colon tumor disease model. Mice were treated by intraperitoneal injection of CHR-6494 for 50 days. Following the treatment period, intestinal polyps were counted and testosterone and spermatogenesis levels were observed. Intraperitoneal administration of CHR-6494 significantly inhibited intestinal polyp development and recovered body weight in Apc mice. Although spermatogenesis was inhibited with increasing age in Apc mice, CHR-6494 significantly improved blood testosterone levels and spermatogenesis. Our results suggest that HASPIN inhibitors may be useful as anti-cancer agents and for the treatment of hypogonadism in colorectal cancer patients.

Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery., Competing Interests: The authors declare no conflict of interest.

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.

Celiac disease (CD) is a risk factor for developing small-bowel carcinoma with a 14-fold higher risk compared with general population. As small-bowel carcinomas associated with CD (CD-SBCs) are extremely rare, very few molecular data are available about their pathogenesis, and information about their transcriptomic profiling is lacking. We generated RNA-seq data on 13 CD-SBCs, taken from the largest well-characterized series published so far, collected by the Small Bowel Cancer Italian Consortium, and compared the tumor transcriptional signatures with the four Consensus Molecular Subtypes (CMS) of colorectal carcinoma by applying the "CMS classifier." CpG Island Methylator Phenotype (CIMP) was evaluated using methylation-sensitive multiple ligation-dependent probe amplification. Up to 12 of 13 cancers fell within the two main subtypes exhibiting high immune and inflammatory signatures, i.e., subtypes 1 and 4. The first and predominant subset was commonly microsatellite unstable, and exhibited CIMP and high CD3+ and CD8+ T cell infiltration. Moreover, it showed increased expression of genes associated with T helper 1 and natural killer cell infiltration, as well as upregulation of apoptosis, cell cycle progression, and proteasome pathways. By contrast, cancers falling in subtype 4 showed prominent transforming growth factor-β activation and were characterized by complement-associated inflammation, matrix remodeling, cancer-associated stroma production, and angiogenesis. Parallel histologic and histochemical analysis confirmed such tumor subtyping. In conclusion, two molecular subtypes have been consistently identified in our series of CD-SBCs, a microsatellite instability-immune and a mesenchymal subtype, the former likely associated with an indolent and the latter with a worse tumor behavior.

We present a rare case of a neonate with PHACES syndrome (posterior fossa malformations, large facial hemangiomas, cerebral arterial anomalies, cardiovascular anomalies, eye anomalies and sternal clefting or supraumbilical raphe) and diffuse hemangiomatosis of the ileum, presenting with multiple intestinal perforations and peritonitis. The infant was successfully treated with propranolol and methylprednisolone as well as octreotide, tranexamic acid, and supportive therapy for massive intestinal bleeding.

Background: Incidence of small-intestine neuroendocrine tumors (SINT) has been increasing in the United States over the past 40 years, with higher incidence in Utah than elsewhere. As information about how these tumors arise is limited, elucidating lifestyle factors associated with SINT in a statewide cohort could potentially identify those at risk to help mitigate their effects., Methods: Cases of SINT with a carcinoid histology (8240 or 8241) diagnosed in Utah from 1996 to 2014 with no prior history of cancer within 5 years ( n = 433) were matched to population controls (1:10 ratio). Tobacco and alcohol exposures before case diagnosis were identified from International Classification of Diseases codes in statewide medical records and from self-reported data captured at patient encounters beginning in 1996. Multivariate logistic regression was used to estimate risk of SINT associated with tobacco and alcohol in cases compared with controls., Results: An increased risk of SINT was observed in tobacco-exposed individuals compared with unexposed [OR, 1.44; 95% confidence interval (CI), 1.11-1.86; P = 0.006]. Those who were exposed to alcohol exhibited an increased risk of SINT (OR, 1.62; 95% CI, 1.05-2.49; P = 0.03)., Conclusions: This study supports tobacco and alcohol use as risk factors for SINT, independent of family history. However, low rates of smoking and alcohol use in Utah coupled with higher rates of SINT suggest other factors may contribute to development of these tumors., Impact: Although tobacco and alcohol modestly contribute to risk, our study suggests in addition to greater detection of tumors, other as-of-yet undefined exposures may drive rising SINT incidence., (©2019 American Association for Cancer Research.)

Innate lymphoid cells (ILCs) comprise a recently identified subset of innate immune cells that are mainly localized to mucosa-associated tissues. Although they have not yet been fully characterized, they can generally be divided into ILC1s, ILC2s, and ILC3s. ILCs and their corresponding cytokines act as important mediators of the early stages of the immune response during inflammation, tissue repair, and the maintenance of epithelial integrity. Consequently, the dysregulation of ILC subsets might promote inflammation and cancer. Numerous studies have demonstrated that these cells play an important role in maintaining the microecological balance of the small intestine; however, their specific roles in mediating inflammation in this tissue and tumorigenesis remain unclear and controversial. In this review, we focus on recent progress that has helped to gain a better understanding of the role of ILCs in intestinal homeostasis, chronic inflammation, and cancer. Further focused research on the regulation and role of ILCs in intestinal homeostasis and pathology will help to reveal valuable diagnostic and therapeutic targets for the treatment of intestinal diseases., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2019 Jing Wu et al.)

Inflammatory bowel disease (IBD) is a multifactorial human intestinal disease that arises from numerous, yet incompletely defined, factors. Two main forms, Crohn's disease (CD) and ulcerative colitis (UC), lead to a chronic pathological form. Heat shock proteins (HSPs) are stress-responsive molecules involved in various pathophysiological processes. Several lines of evidence link the expression of HSPs to the development and prognosis of IBD. HSP90, HSP70 and HSP60 have been reported to contribute to IBD in different aspects. Moreover, induction and/or targeted inhibition of specific HSPs have been suggested to ameliorate the disease consequences. In the present review, we shed the light on the role of HSPs in IBD and their targeting to prevent further disease progression.

We recently described a positive feedback loop connecting c-MYC, NAMPT, DBC1 and SIRT1 that contributes to unrestricted cancer cell proliferation. Here we determine the relevance of the loop for serrated route intestinal tumorigenesis using genetically well-defined Braf V600E and K-ras G12D mouse models. In both models we show that c-MYC and SIRT1 protein expression increased through progression from hyperplasia to invasive carcinomas and metastases. It correlated with high NAMPT expression and was directly associated to activation of the oncogenic drivers. Assessing functional and molecular consequences of pharmacological interference with factors of the loop, we found that inhibition of NAMPT resulted in apoptosis and reduced clonogenic growth in human BRAF-mutant colorectal cancer cell lines and patient-derived tumoroids. Blocking SIRT1 activity was only effective when combined with a PI3K inhibitor, whereas the latter antagonized the effects of NAMPT inhibition. Interfering with the positive feedback loop was associated with down-regulation of c-MYC and temporary de-repression of TP53, explaining the anti-proliferative and pro-apoptotic effects. In conclusion we show that the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop contributes to murine serrated tumor progression. Targeting the feedback loop exerted a unique, dual therapeutic effect of oncoprotein inhibition and tumor suppressor activation. It may therefore represent a promissing target for serrated colorectal cancer, and presumably for other cancer types with deregulated c-MYC., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.

Background: Mismatch repair (MMR)-deficiency increases the risk of colorectal tumorigenesis. To determine whether the tumors develop on a normal or disturbed epigenetic background and how radiation affects this, we quantified genome-wide histone H3 methylation profiles in macroscopic normal intestinal tissue of young radiated and untreated MMR-deficient VCMsh2 LoxP/LoxP (Msh2 -/- ) mice months before tumor onset., Results: Histone H3 methylation increases in Msh2 -/- compared to control Msh2 +/+ mice. Activating H3K4me3 and H3K36me3 histone marks frequently accumulate at genes that are H3K27me3 or H3K4me3 modified in Msh2 +/+ mice, respectively. The genes recruiting H3K36me3 enrich in gene sets associated with DNA repair, RNA processing, and ribosome biogenesis that become transcriptionally upregulated in the developing tumors. A similar epigenetic effect is present in Msh2 +/+ mice 4 weeks after a single-radiation hit, whereas radiation of Msh2 -/- mice left their histone methylation profiles almost unchanged., Conclusions: MMR deficiency results in genome-wide changes in histone H3 methylation profiles preceding tumor development. Similar changes constitute a persistent epigenetic signature of radiation-induced DNA damage.

Colorectal cancer (CRC) is a highly prominent cause of cancer-related deaths worldwide. Although the functions of immune cells in the colorectal tumor microenvironment are complex and heterogeneous, dysregulated changes in the composition and activation state of immune cells are believed to represent key events supporting the establishment of pro- or anti-tumorigenic immune states. Recently, innate lymphoid cells (ILCs) emerged as central innate immune mediators during both gastrointestinal homeostasis and inflammatory pathologies. Hence, ILCs might also represent promising targets in the context of cancer therapy and are increasingly recognized as innate immune cells with potent immunomodulatory properties. In this review, we summarize the pleiotropic roles of the different ILC subsets for intestinal homeostasis and discuss the recent evidence on their potential involvement in the development and growth of intestinal cancers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The successful performance of ostomies for the treatment of different diseases has been described since 1706. We report herein the first case of successful ostomy utilizing a synthetic stoma created in a patient with peritoneal carcinomatosis., Clinical Case: A 40-year-old woman presented with abdominal carcinomatosis due to psammomatous papillotubular adenocarcinoma consistent with primary ovarian carcinoma. The patient had negative estrogen and progesterone receptors and Ki-67 proliferative activity was 83%. She was initially treated with cytoreduction therapy, chemotherapy, and hyperthermic intraperitoneal chemotherapy. Because the patient presented with enteric perforations and the extensive tumor invasion and adhesions in all the intestinal segments made it impossible to create autologous decompression stomas, a synthetic stoma was constructed., Conclusions: Synthetic stomas can be a good treatment option when autologous stomas can not be created., (Copyright: © 2019 Permanyer.)

Background: Vulvar Paget disease (VPD) is extremely rare and thought to be associated with other malignancies., Objectives: To evaluate the risk of developing breast, intestinal and urological malignancies in patients with VPD compared with the general population, and in particular to focus on the risk of malignancy in patients with cutaneous noninvasive VPD., Methods: Data on the oncological history of patients with any type of VPD between 2000 and 2015 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. Follow-up data and a control group from the general population were obtained from the Netherlands Cancer Registry. After correction for age and calendar year at time of diagnosis, standardized incidence ratios (SIRs) for the first 3 years after VPD diagnosis were estimated with 95% confidence intervals (CIs)., Results: We identified 199 patients with a first diagnosis of VPD [164 noninvasive, 35 (micro)invasive] between 2000 and 2015. The SIR of developing an associated malignancy in the first 3 years after diagnosis was 4·67 (95% CI 2·66-7·64). This was due mainly to the high incidence of intestinal malignancies among patients with secondary VPD. Subgroup analysis for cutaneous noninvasive VPD did not reveal a significantly increased risk for associated malignancies: SIR 2·08 (95% CI 0·76-4·62)., Conclusions: Of our patients with VPD, 76·9% were diagnosed with cutaneous noninvasive VPD, and this group has no increased risk for developing malignancies of the breast, intestine or urological tract. Our study suggests that routine screening for these malignancies in patients diagnosed with cutaneous noninvasive VPD may not be necessary., (© 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background & Aims: The enzyme stearoyl-coenzyme A desaturase 1 (SCD or SCD1) produces monounsaturated fatty acids by introducing double bonds into saturated bonds between carbons 9 and 10, with oleic acid as the main product. SCD1 is present in the intestinal epithelium, and fatty acids regulate cell proliferation, so we investigated the effects of SCD1-induced production of oleic acid in enterocytes in mice., Methods: We generated mice with disruption of Scd1 selectively in the intestinal epithelium (iScd1 -/- mice) on a C57BL/6 background; iScd1 +/+ mice were used as controls. We also generated iScd1 -/- Apc Min/+ mice and studied cancer susceptibility. Mice were fed a chow, oleic acid-deficient, or oleic acid-rich diet. Intestinal tissues were collected and analyzed by histology, reverse transcription quantitative polymerase chain reaction, immunohistochemistry, and mass spectrometry, and tumors were quantified and measured., Results: Compared with control mice, the ileal mucosa of iScd1 -/- mice had a lower proportion of palmitoleic (C16:1 n-7) and oleic acids (C18:1 n-9), with accumulation of stearic acid (C18:0); this resulted a reduction of the Δ9 desaturation ratio between monounsaturated (C16:1 n-7 and C18:1 n-9) and saturated (C16:0 and C18:0) fatty acids. Ileal tissues from iScd1 -/- mice had increased expression of markers of inflammation activation and crypt proliferative genes compared with control mice. The iScd1 -/- Apc Min/+ mice developed more and larger tumors than iScd1 +/+ Apc Min/+ mice. iScd1 -/- Apc Min/+ mice fed the oleic acid-rich diet had reduced intestinal inflammation and significantly lower tumor burden compared with mice fed a chow diet., Conclusions: In studies of mice, we found intestinal SCD1 to be required for synthesis of oleate in the enterocytes and maintenance of fatty acid homeostasis. Dietary supplementation with oleic acid reduces intestinal inflammation and tumor development in mice., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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 ( 177 Lu-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., (© 2018 American Cancer Society.)

We investigated whether obesity and sociodemographic factors at adolescence are associated with incident gastroenteropancreatic neuroendocrine tumors (GEP-NET).Our cohort included 2.3 million Israeli adolescents examined at ages 16 to 19 years between 1967 and 2010. The baseline database included sex, country of birth, residential socioeconomic status (SES), body-mass index (BMI) and height. Participants were followed through linkage with the National Cancer Registry up to 2012. We identified 221 cases of GEP-NET (66 pancreatic, 52 gastric, 39 rectal, 27 appendiceal, 23 small bowel and 14 colonic). Immigration from the Former Soviet Union (FSU) was associated with the risk of small bowel and rectal NET's, [Hazard Ratio (HR) 4.79, 95% Confidence Interval (CI) 1.37-16.76 and 3.43, 95% CI 1.20-9.83, respectively].Height >75th percentile and BMI ≥ 85th percentile were associated with increased risk of gastric NET (HR 2.25 95% CI 1.14-4.42 and HR 2.38, 95% CI 1.19-4.75, respectively). Female sex was associated with appendiceal NET (HR 2.30, 95% CI 1.06-4.96) while male gender was associated with an increased risk for NET of the small bowel [HR 4.72 (95% CI 1.10-20.41)].In conclusion, our findings suggest different risk factor associations with the various GEP-NETS: immigrants from the FSU were at increased risk for small bowel and rectal NET; increased height and weight were associated with the risk of gastric NET and females were at increased risk for appendiceal NET. Further focus on the FSU population is indicated in addition to studies verifying the association of BMI and height with gastric NET., (© 2018 UICC.)

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.

In recent years, there have been important scientific advances in the biologic characterization of neuroendocrine neoplasms and in their treatment. This review will describe these scientific advances, the evolving systemic treatment approaches, and important topics to be addressed in future research.

Purpose: The risk of malignant tumors developing in association with juvenile polyposis syndrome (JPS) was evaluated to explore the optimal treatment for this rare disease., Methods: We reviewed the data on JPS cases reported in Japan between January, 1971 and March, 2016., Results: A total of 171 cases were evaluable. Of these 171 patients, 83 (48.5%) were female and the median age at diagnosis was 28 years (range 1-80 years). The polyps were located in the stomach alone (n = 62; 36.3%), in the stomach and intestine (n = 47; 27.4%), or in the colorectum alone (n = 62; 36.3%). The sites of malignant tumors were the stomach (n = 31), colorectum (n = 29), small intestine (n = 2), breast (n = 1), and thyroid (n = 1). The lifetime risk (at 70 years) of any malignant tumor was 86.2%. The lifetime risk of gastric cancer was 73.0% and that of colorectal cancer was 51.1%. The risk of these cancers developing was dependent on the type of polyp distribution., Conclusions: Long-term surveillance of the stomach and colorectum based on the phenotype of JPS seems a reasonable approach to monitor these patients for the development of malignant tumors.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses. Increasing evidence suggests a role for TREM-1 not only in acute pathogen-induced reactions but also in chronic and non-infectious inflammatory disorders, including various types of cancer. Here, we demonstrate that genetic deficiency in Trem1 protects from colorectal cancer. In particular, Trem1 -/- mice exhibited reduced tumor numbers and load in an experimental model of inflammation-driven tumorigenesis. Gene expression analysis of Trem1 -/- versus Trem1 +/+ tumor tissue demonstrated distinct immune signatures. Whereas Trem1 -/- tumors showed an increased abundance of transcripts linked to adaptive immunity, Trem1 +/+ tumors were characterized by overexpression of innate pro-inflammatory genes associated with tumorigenesis. Compared to adjacent tumor-free colonic mucosa, expression of Trem1 was increased in murine and human colorectal tumors. Unexpectedly, TREM-1 was not detected on tumor-associated Ly6C - MHC class II + macrophages. In contrast, TREM-1 was highly expressed by tumor-infiltrating neutrophils which represented the predominant myeloid population in Trem1 +/+ but not in Trem1 -/- tumors. Collectively, our findings demonstrate a clear role of TREM-1 for intestinal tumorigenesis and indicate TREM-1-expressing neutrophils as critical players in colorectal tumor development.

Immunosuppressive agents and biological agents are widely used for therapy in patients with inflammatory bowel disease (IBD). However, these therapies may be associated with an increased risk of malignancy. There is evidence that exposure of the therapeutic agents such as thiopurine and anti-tumor necrosis factor for IBD is associated with an increased risk of lymphoproliferative disorders, skin cancers, or uterine cervical cancers. This article reviews the malignancies associated with the use of immunosuppressive agents and biological agents in IBD.

Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (β-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear β-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat β-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.