Background and Aims Several different types of non-conventional dysplasia have been recently described in inflammatory bowel disease (IBD). Hypermucinous, goblet cell deficient, and crypt cell dysplasias have received more attention, but there is limited information regarding their clinicopathologic features and clinical outcomes. Methods A total of 126 cases of hypermucinous (n = 55), goblet cell deficient (n = 26), and crypt cell (n = 45) dysplasias from 97 IBD patients were collected from 7 different institutions and analyzed. Results The cohort included 62 (64%) men and 35 (36%) women with a mean age of 49 years (range: 20-78). The majority of affected patients had longstanding IBD (mean duration: 18 years). Nineteen (20%) patients had a concurrent history of primary sclerosing cholangitis. As a group, non-conventional dysplasia was predominantly found in patients with ulcerative colitis (UC) (n = 68; 70%) and occurred in the left colon (n = 80; 63%); however, hypermucinous dysplasia (57%) was the least frequently associated with UC compared with goblet cell deficient (74%) and crypt cell (89%) dysplasias (p = 0.016). Fifty (52%) patients had a history of conventional dysplasia, detected in the same colonic segment as non-conventional dysplasia at a rate of 33%. Goblet cell deficient dysplasia (74%) was more frequently associated with conventional dysplasia than hypermucinous (43%) and crypt cell (48%) dysplasias (p = 0.044). While hypermucinous dysplasia often had a polypoid appearance (58%), crypt cell (96%) and goblet cell deficient (65%) dysplasias were more likely to present as flat/invisible lesions (p < 0.001). Most lesions were low-grade (87%) at diagnosis, but goblet cell deficient dysplasia (31%) more often showed high-grade dysplasia (HGD) than hypermucinous (15%) and crypt cell (0%) dysplasias (p = 0.003). Hypermucinous dysplasia usually demonstrated a tubulovillous/villous architecture (76%), whereas goblet cell deficient dysplasia was predominantly tubular (92%). A flat architecture was exclusively associated with crypt cell dysplasia (100%) (p < 0.001). Immunohistochemical stain results for p53 were available for 33 lesions; 14 (42%) showed strong (3+) and patchy (10-50%) to diffuse (> 50%) nuclear overexpression or null staining pattern, including 4 (33%) of 12 hypermucinous, 2 (29%) of 7 goblet cell deficient, and 8 (57%) of 14 crypt cell dysplastic lesions (p = 0.726). Follow-up biopsies or resections were available for 92 low-grade lesions from 71 patients; 55 (60%) lesions, including 19 (49%) of 39 hypermucinous, 10 (59%) of 17 goblet cell deficient, and 26 (72%) of 36 crypt cell dysplastic lesions (p = 0.116), were associated with subsequent detection of HGD (n = 34; 37%) or adenocarcinoma (n = 21; 23%) at the site of previous biopsy or in the same colonic segment within a mean follow-up time of 12 months (range: < 1-73). Conclusions Hypermucinous, goblet cell deficient, and crypt cell dysplasias have distinct clinicopathologic features but appear to have a similar high risk of association with advanced neoplasia (HGD or adenocarcinoma). Greater than half of the lesions (66%) presented as flat/invisible dysplasia, suggesting that IBD patients may benefit from random biopsy sampling in addition to targeted biopsies. Although not uncommonly associated with conventional dysplasia, non-conventional dysplasia may be the only dysplastic subtype identified in IBD patients. Therefore, it is important to recognize these non-conventional subtypes and recommend complete removal and/or careful examination and follow-up.

Neonatal necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of preterm infants. Increased intestinal epithelium permeability is an early event in NEC pathogenesis. Autophagy and apoptosis are induced by multiple stress pathways which may impact the intestinal barrier, and they have been associated with pathogenesis of diverse gastrointestinal diseases including inflammatory bowel disease. Using both in vitro and in vivo models, this study investigates autophagy and apoptosis under experimental NEC stresses. Furthermore this study evaluates the effect of erythropoietin (Epo), a component of breast milk previously shown to decrease the incidence of NEC and to preserve intestinal barrier function, on intestinal autophagy and apoptosis. It was found that autophagy and apoptosis are both rapidly up regulated in NEC in vivo as indicated by increased expression of the autophagy markers Beclin 1 and LC3II, and by evidence of apoptosis by TUNEL and cleaved caspase-3 staining. In the rat NEC experimental model, autophagy preceded the onset of apoptosis in intestine. In vitro studies suggested that Epo supplementation significantly decreased both autophagy and apoptosis via the Akt/mTOR signaling pathway and the MAPK/ERK pathway respectively. These results suggest that Epo protects intestinal epithelium from excessive autophagy and apoptosis in experimental NEC.

ObjectiveFecal microbiota transplantation (FMT) is an investigational treatment for diseases thought to involve alterations in the intestinal microbiota including ulcerative colitis (UC). Case reports have described therapeutic benefit of FMT in patients with UC, possibly due to changes in the microbiota. We measured the degree to which the transplanted microbiota engraft following FMT in patients with UC using a donor similarity index (DSI).MethodsSeven patients with mild to moderate UC (UC disease activity index scores 3–10) received a single colonoscopic administration of FMT. Metagenomic sequence data from stool were analyzed using an alignment-free comparison tool, to measure the DSI, and a phylogenetic analysis tool, to characterize taxonomic changes. Clinical, endoscopic, histologic, and fecal calprotectin outcome measures were also collected.ResultsOne of 5 patients from whom sequencing data were available achieved the primary endpoint of 50% donor similarity at week 4; an additional 2 patients achieved 40% donor similarity. One patient with 40% donor similarity achieved clinical and histologic remission 1 month after FMT. However, these were lost by 2−3 months, and loss correlated with a decrease in DSI. The remaining patients did not demonstrate clinical response or remission. Histology scores improved in all but 1 patient. No patients remained in remission at 3 months after FMT.ConclusionsFollowing a single colonoscopic fecal transplant, a DSI of 40-50% is achieved in about two-thirds of recipients. This level of engraftment correlated with a temporary clinical improvement in only 1/5 patients. Larger sample sizes could further validate this method for measuring engraftment, and changes in transplant frequency or method might improve microbiota engraftment and efficacy.Trial RegistrationClinicalTrials.gov NCT01742754

Background Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer. The standard method of surveillance for neoplasia in UC by colonoscopy is invasive and can miss flat lesions. We sought to identify a gene expression signature in non-dysplastic mucosa without active inflammation that could serve as a marker for remote neoplastic lesions. Methods Gene expression was analyzed by cDNA microarray in 5 normal controls, 4 UC patients without dysplasia, and 11 UC patients harboring remote neoplasia. Common gene ontology pathways of significantly differentially expressed genes were identified. Expression of genes which were progressively and significantly up-regulated from controls, to UC without neoplasia, to UC with remote neoplasia were evaluated by real time PCR. Several gene products were also examined by immunohistochemistry. Results 468 genes were significantly up-regulated and 541 genes were significantly down-regulated in UC patints with neoplasia compared to UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly up-regulated from controls to non-dysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increased expression of S100A9 and REG1α in UC-associated cancer and in non-dysplastic tissue from UC patients harboring remote neoplasia, compared to UC patients without neoplasia and controls. Conclusions Gene expression changes occurring as a field effect in the distal colon of patients with chronic UC identify patients harboring remote neoplastic lesions. These markers may lead to a more accurate and less invasive method of detection of neoplasia in patients with inflammatory bowel disease.

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Many normal tissues undergo age-related drift in DNA methylation, providing a quantitative measure of tissue age. Here, we identify and validate 781 CpG islands (CGI) that undergo significant methylomic drift in 232 normal colorectal tissues and show that these CGI continue to drift in neoplasia while retaining significant correlations across samples. However, compared with normal colon, this drift advanced ($3-4-fold) faster in neoplasia, consistent with increased cell proliferation during neoplastic progression. The observed drift patterns were broadly consistent with modeled adenoma-to-carcinoma sojourn time distributions from colorectal cancer incidence data. These results support the hypothesis that, beginning with the founder premalignant cell, cancer precursors frequently sojourn for decades before turning into cancer, implying that the founder cell typically arises early in life. At least 77% to 89% of the observed drift variance in distal and rectal tumors was explained by stochastic variability associated with neoplas-tic progression, whereas only 55% of the variance was explained for proximal tumors. However, gene-CGI pairs in the proximal colon that underwent drift were significantly and primarily negatively correlated with cancer gene expression, suggesting that methylomic drift participates in the clonal evolution of colorectal cancer. Methylomic drift advanced in colorectal neoplasia, consistent with extended sojourn time distributions, which accounts for a significant fraction of epigenetic heterogeneity in colorectal cancer. Importantly, these estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing colorectal cancer incidence. Significance: These findings present age-related methylomic drift in colorectal neoplasia as evidence that premalignant cells can persist for decades before becoming cancerous. See related commentary by Sapienza, p. 437

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In this series of cases, pan-hypopituitarism was the most common recognizable clinical association with neonatal giant cell hepatitis. However, most cases of neonatal giant cell hepatitis remain idiopathic and histological features do not readily distinguish among the various etiologies.