Telomere dysfunction instigates inflammation in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.

Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.

Kras mutation rate precisely orchestrates ductal derived pancreatic intraepithelial neoplasia and pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence of Kras mutations in pancreatic cancer patients, murine models expressing the oncogenic mutant Kras (Krasmut) in mature pancreatic cells develop PDAC at a low frequency. Independent of cell of origin, a second genetic hit (loss of tumor suppressor TP53 or PTEN) is important for development of PDAC in mice. We hypothesized ectopic expression and elevated levels of oncogenic mutant Kras would promote PanIN arising in pancreatic ducts. To test our hypothesis, the significance of elevating levels of K-Ras and Ras activity has been explored by expression of a CAG driven LGSL-KrasG12V allele (cKras) in pancreatic ducts, which promotes ectopic Kras expression. We predicted expression of cKras in pancreatic ducts would generate neoplasia and PDAC. To test our hypothesis, we employed tamoxifen dependent CreERT2 mediated recombination. Hnf1b:CreERT2;KrasG12V (cKrasHnf1b/+) mice received 1 (Low), 5 (Mod) or 10 (High) mg per 20 g body weight to recombine cKras in low (cKrasLow), moderate (cKrasMod), and high (cKrasHigh) percentages of pancreatic ducts. Our histologic analysis revealed poorly differentiated aggressive tumors in cKrasHigh mice. cKrasMod mice had grades of Pancreatic Intraepithelial Neoplasia (PanIN), recapitulating early and advanced PanIN observed in human PDAC. Proteomics analysis revealed significant differences in PTEN/AKT and MAPK pathways between wild type, cKrasLow, cKrasMod, and cKrasHigh mice. In conclusion, in this study, we provide evidence that ectopic expression of oncogenic mutant K-Ras in pancreatic ducts generates early and late PanIN as well as PDAC. This Ras rheostat model provides evidence that AKT signaling is an important early driver of invasive ductal derived PDAC.

Distinct Murine Pancreatic Transcriptomic Signatures during Chronic Pancreatitis Recovery.

We have previously demonstrated that the pancreas can recover from chronic pancreatitis (CP) lesions in the cerulein-induced mouse model. To explore how pancreatic recovery is achieved at the molecular level, we used RNA-sequencing (seq) and profiled transcriptomes during CP transition to recovery. CP was induced by intraperitoneally injecting cerulein in C57BL/6 mice. Time-matched controls (CON) were given normal saline. Pancreata were harvested from mice 4 days after the final injections (designated as CP and CON) or 4 weeks after the final injections (designated as CP recovery (CPR) and control recovery (CONR)). Pancreatic RNAs were extracted for RNA-seq and quantitative (q) PCR validation. Using RNA-seq, we identified a total of 3,600 differentially expressed genes (DEGs) in CP versus CON and 166 DEGs in CPR versus CONR. There are 132 DEGs overlapped between CP and CPR and 34 DEGs unique to CPR. A number of selected pancreatic fibrosis-relevant DEGs were validated by qPCR. The top 20 gene sets enriched from DEGs shared between CP and CPR are relevant to extracellular matrix and cancer biology, whereas the top 10 gene sets enriched from DEGs specific to CPR are pertinent to DNA methylation and specific signaling pathways. In conclusion, we identified a distinct set of DEGs in association with extracellular matrix and cancer cell activities to contrast CP and CPR. Once during ongoing CP recovery, DEGs relevant to DNA methylation and specific signaling pathways were induced to express. The DEGs shared between CP and CPR and the DEGs specific to CPR may serve as the unique transcriptomic signatures and biomarkers for determining CP recovery and monitoring potential therapeutic responses at the molecular level to reflect pancreatic histological resolution.

Comparable Responses in Male and Female Mice to Cerulein-Induced Chronic Pancreatic Injury and Recovery.

OBJECTIVE: The cerulein-induced mouse pancreatitis model is a well-established, commonly used representation of human chronic pancreatitis pathology. Although studies report sex-dependent differences in human chronic pancreatitis, there are no studies in this model directly comparing sex response to pancreatic injury and recovery. Therefore, we designed a study to investigate whether sex- dependent differences in chronic pancreatitis injury and recovery exist in the cerulein-induced pancreatitis model. METHODS: Adult male and female C57BL/6 mice were administered cerulein (50 µg/kg, 5 hourly intraperitoneal injections/day, 3 days/week) for 4 weeks to induce chronic pancreatitis; control mice received normal saline injections. Pancreata and blood were harvested at 4 days (as injury group) or 4 weeks (as recovery group) after the last injection. Amylase secretion was measured from the serum. Acinar injury was scored on H&E sections. Fibrosis was assessed by Sirius Red and collagen immunofluorescence staining. RESULTS: Compared to time-matched controls, injury group displayed decreased body and pancreas weight, and increased acinar injury and fibrosis, with no significant differences between males and females. Recovery group demonstrated recovery of body weight, partial recovery of pancreas weight, reversal of acinar injury, and partial reversal of fibrosis, with no significant differences between males and females. Amylase secretion/body weight was similar across all groups. CONCLUSIONS: Male and female mice of the cerulein-induced chronic pancreatitis demonstrate similar responses to chronic pancreatitis injury and recovery. Although this model may not sufficiently emulate sex-dependent responses in human chronic pancreatitis, our study supports that both sexes of mice from this model can be used for the study of chronic pancreatitis.

p53 protein accumulation predicts malignant progression in Barrett's metaplasia: a prospective study of 275 patients.

AIMS: The purpose of this study was to determine prospectively whether p53 protein accumulation in biopsies of Barrett's metaplasia (BM) is a predictor of malignant progression, without relying on dysplasia grading. METHODS AND RESULTS: Sections of formalin-fixed paraffin-embedded tissue from the initial biopsies of 275 patients with BM, who had no high-grade dysplasia (HGD) or oesophageal adenocarcinoma (EAC), were stained for p53 by immunohistochemistry. The mean follow-up was 41 months. p53-positive biopsies were divided into four groups: scattered positive cells, multifocal scattered positive cells, aggregates of positive cells, and multifocal aggregates of positive cells. Kaplan-Meier analysis with the log-rank test was used to determine the rate of progression to HGD/EAC. Of the 275 patients, 227 had initial biopsies that were completely negative for p53, and, of these, one (0.4%) progressed to HGD/EAC; none of 24 (0%) patients with scattered positive cells and none of four (0%) of patients with multifocal scattered positive cells progressed. In contrast, five of 16 (31.25%) patients with aggregates of positive cells and three of four (75%) of those with multifocal aggregates of positive cells progressed to HGD/EAC. Kaplan-Meier analysis with log-rank statistics showed the difference in progression rate between the five groups to be highly significant (P < 0.0001). CONCLUSIONS: We conclude that p53 protein accumulation, detected by immunohistochemistry in aggregates of cells, is a significant predictor of malignant progression in patients with BM.

Differences in clinical importance of Bcl-2 in breast cancer according to hormone receptors status or adjuvant endocrine therapy.

BACKGROUND: Bcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2. In breast cancer, however, Bcl-2 expression has been reported to be a favorable prognostic factor. The positive correlation of Bcl-2 with estrogen receptor (ER)/progesterone receptor (PR) status, and endocrine therapy frequently given for hormone receptor-positive tumors, may obscure the independent pathobiological role of Bcl-2. We constructed a large systematic study to determine whether Bcl-2 has an independent role in breast cancer. METHODS: Bcl-2 expression was immunohistochemically evaluated and compared with other clinicopathological factors, including clinical outcome, in 1081 breast cancer cases with long follow-up, separately analyzing 634 cases without any adjuvant therapy and 447 cases with tamoxifen monotherapy. The χ (2)-test for independence using a contingency table, the Kaplan-Meier method with the log-rank test, and a Cox proportional hazards model were used for the comparison of clinicopathological factors, assessment of clinical outcome, and multivariate analyses, respectively. RESULTS: In both patient groups, Bcl-2 expression strongly correlated with positive ER/PR status, low grade, negative human epidermal growth factor receptor 2 (HER2) status, and small tumor size, as previously reported. Bcl-2 expression did not independently predict clinical outcome in patients with ER-positive and/or PR-positive tumors or in those who received tamoxifen treatment; however, it was an independent unfavorable prognostic factor in patients with ER-negative/PR-negative or triple-negative (ER-negative/PR-negative/HER2-negative) tumors who received no adjuvant therapy. The latter was even more evident in postmenopausal women: those with hormone receptor-negative or triple-negative tumors lacking Bcl-2 expression showed a favorable outcome. CONCLUSION: Bcl-2 expression is an independent poor prognostic factor in patients with hormone receptor-negative or triple-negative breast cancers, especially in the absence of adjuvant therapy, suggesting that the anti-apoptotic effect of Bcl-2 is clearly exhibited under such conditions. The prognostic value of Bcl-2 was more evident in postmenopausal women. The present findings also highlight Bcl-2 as a potential therapeutic target in breast cancers lacking conventional therapeutic targets such as triple-negative tumors. The favorable prognosis previously associated with Bcl-2-positive breast cancer probably reflects the indirect effect of frequently coexpressed hormone receptors and adjuvant endocrine therapy.

Esophageal COX-2 expression is increased in Barrett's esophagus, obesity, and smoking.

BACKGROUND: Increased esophageal cyclooxygenase-2 (COX-2) expression has been associated with Barrett's esophagus (BE); however, it is unknown whether COX-2 expression varies among patient groups with different clinical or socio-demographic factors. METHODS: We conducted a case-control study among eligible patients scheduled for elective esophagogastroduodenoscopy and patients eligible for screening colonoscopy recruited from primary clinics. We compared 39 BE tissue samples and 47 squamous tissue samples from BE cases and 240 squamous tissue samples from controls. Clinical and socio-demographic data were prospectively collected. Immunohistochemical staining for esophageal COX-2 was performed and scored. RESULTS: The median COX-2 score was significantly higher in BE tissue than squamous tissue from cases or controls (p < 0.001). Median COX-2 expression levels were higher in tissue samples from participants with a waist-to-hip ratio (WHR) in the 2nd tertile [unadjusted odds ratio (OR) 2.04; 95 % confidence interval (95 % CI) 1.17-3.57] and 3rd tertile (unadjusted OR 2.24; 95 % CI 1.20-4.16) compared with the 1st tertile and from current smokers compared with former or non-smokers (unadjusted OR 1.68; 95 % CI 1.03-2.75). In the multivariate analysis, WHRs in the 2nd tertile (OR 1.92; 95 % CI 1.07-3.45) and the 3rd tertile (OR 2.14; 95 % CI 1.10-4.16) were associated with high COX-2 compared with the 1st tertile, as was current smoking (OR 1.78; 95 % CI 1.06-2.97) compared with former and non-smoking. CONCLUSION: We found a significant association between elevated esophageal mucosa COX-2 levels and the presence of BE tissue, as well as between elevated COX-2 levels and high WHR and current tobacco smoking. This information may assist in identifying patients likely to benefit from chemoprevention with COX-2 inhibitors.

Secular trends in the incidence of cholangiocarcinoma in the USA and the impact of misclassification.

BACKGROUND AND AIMS: It has been reported that the incidence of intrahepatic cholangiocarcinoma (ICC) has increased in the USA, while extrahepatic cholangiocarcinoma (ECC) has decreased or remained stable. However, neither the recent trends nor the effects of the misclassification of Klatskin tumors are known. METHODS: Using the Surveillance, Epidemiology, and End Results program databases, we calculated the average annual age-adjusted incidence rates (AA-IRs) of ICC and ECC in 4-year time periods (1992-1995, 1996-1999, 2000-2003, 2004-2007). These AA-IRs were calculated with misclassified as well as correctly classified Klatskin tumors. AA-IRs were also calculated based on age, sex, and race. Multivariable Poisson regression models were used to evaluate the secular trends of ICC and ECC. RESULTS: The AA-IR of ICC was 0.92 in 1992-1995 and 0.93 in 2004-2007, while the AA-IR of ECC increased from 0.70 in 1992-1995 to 0.95 in 2004-2007. There was no significant trend in AA-IR of ICC (p = 0.07), while there was a significant increase in ECC across the 4-year time periods (p < 0.001). Klatskin tumors comprised 6.7% of CCs with approximately 90 and 45% misclassified as ICC during 1992-2000 and 2001-2007, respectively. Adjusted Poisson models showed no significant differences in the temporal trend of ICC or ECC due to misclassification of Klatskin tumors. CONCLUSIONS: The incidence of ICC has remained stable between 1992 and 2007 with only slight fluctuations, while the incidence of ECC has been increasing. Misclassification of Klatskin tumors does not appear to play a significant role in the trends of CCs.

Intraintestinal Heterogeneity of Drug Target Expression in Inflammatory Bowel Disease.

OBJECTIVE: There has been no significant improvement in remission rate in inflammatory bowel disease (IBD) despite several new drugs being introduced in the past two decades. Post-treatment biopsies sometimes show histologic healing in some areas of the intestine while other areas within the same intestine continue to show active inflammation. The aim of this short descriptive study was to determine whether heterogeneous treatment response in IBD may be caused by heterogeneous expression of treatment targets within the same intestine. METHODS: Six cases of Crohn's disease and five cases of ulcerative colitis in which moderate to severe active inflammation was present in at least two biopsies from the same intestine obtained during the same endoscopy procedure were entered in the study. Sections were stained for TNFα and phospho-JAK1 (p-JAK1) using immunohistochemistry. Expression of TNFα and p-JAK1 was recorded as high when the staining intensity was moderate or high, or low when there was no or week staining. The number of eosinophils per high power field was counted in the area of peak density. RESULTS: Different sites within the same intestine from IBD patients with moderate to severe active inflammation may express different levels of TNFα and p-JAK1. For example, in one patient with Crohn's disease with histologically moderate to severe activity in biopsies from the ileum (site 1) and cecum (site 2), there was high expression of p-JAK1 and low TNFα in the ileum biopsy with the exact opposite in the cecum biopsy (low p-JAK1 and high TNFα expression). In this example neither small molecule drug targeting JAK1 nor anti-TNFα biologic given as single agent therapy would be expected to induce histologic remission in both actively inflamed sites in this patient. CONCLUSIONS: The heterogeneous expression of treatment targets within the same intestine may explain why some patients with IBD may not have complete remission on single drug. Studies are needed to determine whether assay for target expression in mucosal biopsies from IBD patients can help to optimize treatment selection.

Aging- and alcohol-associated spatial transcriptomic signature in mouse acute pancreatitis reveals heterogeneity of inflammation and potential pathogenic factors.

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via Visium spatial transcriptomics, eight distinct tissue clusters were revealed from aggregated transcriptomes of aging and young AAP mice: five acinar, two stromal, and one islet, which were then merged into three clusters: acinar, stromal, and islet for the comparative analysis. Compared to young AAP mice, > 1300 differentially expressed genes (DEGs) and approximately 3000 differentially regulated pathways were identified in aging AAP mice. The top five DEGs upregulated in aging AAP mice include Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp with heterogeneous distributions among the clusters. Taken together, this study demonstrates spatial heterogeneity of inflammatory processes in aging AAP mice, offering novel insights into the mechanisms and potential drivers for AAP development. KEY MESSAGES: Mechanisms regarding high mortality of AAP in aging remain undefined. An aging AAP mouse model was developed recapturing clinical exhibition in humans. Spatial transcriptomics identified contrasted DEGs in aging vs. young AAP mice. Top five DEGs were Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp in aging vs. young AAP mice. Our findings shed insights for identification of molecular drivers in aging AAP.

Increased Gremlin1 Expression in Pancreatic Ductal Adenocarcinoma Promotes a Fibrogenic Stromal Microenvironment.

OBJECTIVE: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts (CAFs) and immune cells. Gremlin1 (Grem1) is a profibrogenic factor that promotes tumorigenesis in several cancers. However, the role of Grem1 in the PDAC microenvironment is not adequately defined. METHODS: We correlated Grem1 levels with activated stroma and immune cells in human PDAC using The Cancer Genome Atlas (TCGA) RNA-sequencing data and characterized the expression of Grem1 transcripts and isoforms in pancreatic cell lines and PDAC tissues. We assessed the role of Grem1 in the microenvironment by in vitro studies. RESULTS: Grem1 expression is associated with an activated stroma and increased M1 and M2 macrophages. Only full length Grem1 variant 1 and isoform 1 were detectable in human pancreatic cells, and remarkably high levels of Grem1 were observed in pancreatic fibroblasts (P < 0.05). Immunohistochemistry detected Grem1 protein in PDAC tumor cells and stromal cells, which correlated with infiltrating macrophages in PDAC tumors. Grem1 knockdown in CAFs suppressed transforming growth factor (TGF)-ß-induced extracellular matrix proteins (P < 0.05). Grem1 recombinant protein treatment in vitro increased M1 and M2 macrophages (P < 0.05). CONCLUSIONS: Grem1 acts as a profibrogenic factor in the PDAC microenvironment via modulation of fibroblasts and macrophages. Grem1 may have the potential to be developed as a therapeutic target for PDAC.

Overexpression of Gremlin1 in Crohn's Disease-Associated Bowel Strictures.

OBJECTIVE: One of the most serious complications of Crohn's disease is intestinal strictures that may lead to bowel obstruction. Understanding the underlying mechanisms of stricture formation is essential in order to develop more effective nonsurgical prevention and treatment modalities. The aim of this pilot study was to determine whether Gremlin1, a protein implicated in fibrogenesis and smooth muscle proliferation, is overexpressed in Crohn's-associated bowel strictures. METHODS: Paired sections from three strictured and non-strictured surgically resected bowel from patients with Crohn's disease were evaluated for Gremlin1 expression by immunohistochemistry. RESULTS: Strictured areas from all three specimens showed strong Gremlin1 staining in the hypertrophic muscularis mucosae area compared to no staining in the mucosa or muscularis propria in the same sections and in contrast to sections from non-strictured areas which were negative. CONCLUSIONS: This short report is the first to describe the overexpression of Gremlin1 in the hypertrophied muscularis mucosae of strictured small intestine from patients with Crohn's disease. Additional studies are needed to elucidate the potential role of Gremlin1 in the etiopathogenesis of Crohn's disease strictures, and to investigate whether targeting Gremlin1 may be an option for preventing or treating strictures in patients with Crohn's disease.

Incomplete Intestinal Metaplasia of the Stomach Is more Related to Bile Reflux than Chronic Gastritis.

OBJECTIVE: Incomplete intestinal metaplasia (IIM) of the stomach is associated with higher risk of progression to dysplasia and gastric cancer than complete intestinal metaplasia (CIM). Whether the causative factors underlying IIM are different from those underlying CIM is currently unknown. In a recent study, bile acids were found to induce gastric intestinal metaplasia (IM) in mice by activating STAT3 signaling and accelerated the development of dysplasia. The aim of this study was to determine whether there are differences in associations between IIM and CIM and clinicopathologic features known to be associated with intestinal metaplasia, bile reflux, and activated STAT3. METHODS: Fifty-two consecutive gastric biopsies with IM were examined for the type of metaplasia, presence of inflammation, and Helicobacter pylori (H. pylori) status. Immunohistochemical staining was performed for phospho-STAT3 (p-STAT3) and evaluated by image analysis. The type of IM was then correlated with relevant clinicopathologic variables and p-STAT3 expression. RESULTS: Seven cases had IIM only, 31 had CIM only, and 14 had both CIM and IIM (CIIM). Significantly fewer cases with IIM had chronic gastritis than either CIM or CIIM (43%, 93%, 79%, respectively, p=0.005). H. pylori was not detected in any of the IIM cases but was positive in 29% of CIM and 29% of CIIM. Fifty-seven percent of patients with IIM had a history of cholecystectomy compared to 25% of those with CIM and 23% of those with CIIM. The mean BMI was 32.3 kg/m2 for patients with IIM compared to 28 kg/m2 for those with CIM and 31.2 kg/m2 for those with CIIM. Median p-STAT3 for biopsies with was IIM was 6.36 compared to 3.54 for CIM and 6.27 for CIIM. Reactive gastropathy was present in 57% of biopsies with IIM, 39% of CIM and 50% of CIIM. CONCLUSION: In contrast to CIM, IIM is significantly less likely to be associated with chronic gastritis. CIIM also tended to be less associated with H. pylori infection and more associated with reactive gastropathy, history of cholecystectomy, higher BMI, and higher median p-STAT3. These results tend to suggest that IIM is probably more likely to be associated with bile reflux than H. pylori-associated gastritis. Larger studies are needed to confirm these findings.Presented in part at Digestive Disease Week 2023, Chicago, IL, May 6, 2023.

Collagenous Gastritis: An Atypical Presentation of a Rare Disease.

Collagenous gastritis is a rare inflammatory condition of unknown etiology defined histologically by subepithelial deposition of collagen bands ≥ 10 µm in the lamina propria. Adults typically present with diarrhea, often attributed to concurrent collagenous sprue or collagenous colitis. Children more commonly present with abdominal pain and anemia, with inflammation typically limited to the stomach. Herein, we present a case of collagenous gastritis in a 38-year-old female with a history of iron deficiency and hypothalamic amenorrhea who presented with a one-year history of microcytic anemia. Celiac disease panel, Helicobacter pylori testing, and anti-parietal cell and intrinsic factor antibodies were negative. Esophagogastroduodenoscopy revealed diffusely erythematous and nodular gastric mucosa in the antrum and pylorus. Biopsy from the gastric body showed complete loss of oxyntic glands and deposition of a thick band of collagen under the surface epithelium infiltrated by a few eosinophils, consistent with collagenous gastritis with severe atrophy. She was treated with omeprazole 40 mg daily for six weeks and iron supplementation. Our patient's symptoms and endoscopic findings are consistent with previously described pediatric, but not adult, cases of collagenous gastritis, yielding insight into the variable clinical presentation of this rare disease.

Colonic Eosinophilia: Clinicopathologic Study of Paired Right and Left Colon Biopsies from 276 Patients.

OBJECTIVE: This study evaluated differences in eosinophil (Eos) count in the right colon (RC) and left colon (LC) relative to known clinical and pathologic features. METHODS: H&E slides from 276 subjects with biopsies taken from both RC and LC were reviewed. Eos/mm2 were counted in the area with highest concentration then correlated with clinical and pathologic findings for RC and LC. RESULTS: There were higher numbers of Eos/mm2 in RC than in LC (mean 177 vs 122, respectively p<0.0001), and there was significant positive correlation between Eos numbers in the two locations (r=0.57, p<0.001). In RC, the mean Eos/mm2 was 242 with active chronic colitis, 195 with inactive chronic colitis, 160 in microscopic colitis, 144 in quiescent IBD, and 142 with normal histology (p<0.001), and was higher in males (204 vs 164, p=0.022). In LC, mean Eos/mm2 was 186 with active chronic colitis, 168 with inactive chronic colitis, 154 in microscopic colitis, 82 in quiescent IBD, and 84 with normal histology (p<0.001), and was higher in males (154 vs 107, p<0.001). In biopsies with normal histology, RC showed higher mean Eos/mm2 in Asian patients (228 vs 139, p=0.019), and patients with history of UC (205 vs 136, p=0.004), but was not significantly different in patients with or without irritable bowel syndrome with diarrhea (IBS-D) or history of Crohn's disease (CD). In LC the mean Eos/mm2 was higher in males (102 vs 77, p=0.036), and history of CD (117 vs 78, p=0.007), but was not significantly different in patients with or without IBS-D or history of UC. The number of Eos/mm2 was greater in biopsies performed in the summer than during other seasons of the year. CONCLUSION: The mean number of Eos/mm2 in colorectal biopsies varies significantly by location, histopathologic changes, clinical diagnosis, season, gender and ethnicity. Of particular interest is the association between high Eos/mm2 in RC biopsies with otherwise normal histology and clinical history of UC, and in LC biopsies with clinical history of CD. Additional larger and prospective studies that include normal healthy volunteers are needed to establish a reliable cutoff for the histopathologic diagnosis of eosinophilic colitis, taking into consideration the biopsy site within the colon and rectum, as well as patient gender and ethnicity.Presented in part at the annual American College of Gastroenterology meeting, San Antonio, TX October 2019.

A Common Infection in a Highly Atypical Patient: Hematochezia From a Cytomegalovirus Colonic Ulcer in a Young and Healthy Immunocompetent Patient.

Gastrointestinal (GI) cytomegalovirus (CMV) infections are far more common in immunocompromised as opposed to immunocompetent patients. Immunocompetent patients who develop GI tract CMV infections are typically older with medical comorbidities. As such, descriptions of GI CMV infections in younger immunocompetent patients are lacking. Here, we present a case of a GI CMV infection in a young and healthy immunocompetent patient. A 41-year-old male with hyperlipidemia and hypothyroidism presented with painless, intermittent hematochezia. He denied changes in bowel habits or appetite, abdominal pain, fevers, chills, fatigue, or weight loss. His history was pertinent for insertive and receptive intercourse with one male partner. Medications were emtricitabine/tenofovir for pre-exposure prophylaxis, levothyroxine, and atorvastatin. A colonoscopy revealed a cecal ulcer surrounded by nodular-appearing mucosa that felt firm and friable when biopsied. The remaining colon and terminal ileum were normal. There was no diverticulosis or hemorrhoids. Pathology was positive for CMV. A subsequent serological evaluation revealed a normal complete blood count and comprehensive metabolic panel. Tests for human immunodeficiency virus, syphilis, viral hepatitis, chlamydia, and gonorrhea were negative. He was treated with valganciclovir 900 mg twice daily for 21 days. A subsequent test for CMV deoxyribonucleic acid polymerase chain was negative. Hematochezia resolved. A repeat colonoscopy revealed normal mucosa in the cecum. GI CMV infections in immunocompetent patients are rare and typically occur in older patients with medical comorbidities. Further, such case reports are needed to inform clinicians about risk factors and the presentation of GI CMV infections in young healthy immunocompetent patients.