Coexisting Th1 and Th2 cytokines in patients with collagenous gastritis and implications for its pathogenesis.

OBJECTIVES: Collagenous gastritis (CG) is a rare cause of refractory dyspepsia and anemia that frequently affects children and young adults and whose histological hallmark is chronic mucosal inflammation with a subepithelial collagen band. The etiology remains obscure, and no established treatments exist. We investigated the pathogenesis of CG by determining the expression profiles of genes related to immunity and inflammation in index biopsies. METHODS: Gastric biopsies from 10 newly diagnosed patients with CG were evaluated using the NanoString nCounter assay. Gastric biopsies from 14 normal individuals served as controls. The gene expression ratios for CG versus controls were determined in pooled samples and confirmed in individual samples by quantitative reverse transcription polymerase chain reaction. The results were compared with previously reported expression data from a cohort of patients with collagenous colitis, a colonic disorder with similar morphology, including subepithelial collagen band. RESULTS: CG biopsies featured enhanced expression of key genes encoding both Th1 (IFNγ, TNF-α, IL-2, IL-10, IL-12A, IL-12B, and IL-18) and Th2 cytokines (IL-3, IL-4, IL-5, IL-6, and IL-13). In contrast, biopsies from patients with CC exhibited upregulated Th1 cytokines only. CONCLUSIONS: We show in this first published gene expression profiling study that CG involves simultaneous upregulation of Th1 and Th2 cytokines. This finding is unique, contrasting with other types of chronic gastritis as well as with collagenous colitis, which shares the presence of a collagen band. Involvement of Th2 immunity in CG would support further investigation of potential dietary, environmental, or allergic factors to guide future therapeutic trials.

Pathology and Clinical Significance of Inflammatory Bowel Disease-Associated Colorectal Dysplastic Lesions.

Timely diagnosis and effective management of colorectal dysplasia play a vital role in preventing mortality from colorectal cancer in patients with chronic inflammatory bowel disease. This review provides a contemporary overview of the pathologic and endoscopic classification of dysplasia in inflammatory bowel disease, their roles in determining surveillance and management algorithms, and emerging diagnostic and therapeutic approaches that might further enhance patient management.

Effects of Mirikizumab on Histologic Resolution of Crohn's Disease in a Randomized Controlled Phase 2 Trial.

BACKGROUND & AIMS: Histologic evaluation of mucosal healing in Crohn's disease is an evolving treatment target. We evaluated histologic outcomes for mirikizumab efficacy and associations with endoscopic and 1-year outcomes. METHODS: Biopsy specimens from 1 ileal and 4 colonic segments were evaluated at weeks 0, 12, and 52 from each of the 170 SERENITY participants. Criteria for the weeks 12 and 52 histologic response were no epithelial neutrophils or epithelial damage, or >50% decrease in either the Robarts Histopathology Index or the active Global Histologic Disease Activity Score, and remission (no mucosal neutrophils and no epithelial damage) had to be met in all biopsy specimens. Agreement was evaluated between histologic and endoscopic end points. Associations between 1-year outcomes and week 12 histologic and endoscopic response were evaluated. RESULTS: At week 12, 1000 mg mirikizumab resulted in greater rates of histologic response (66% vs 27%; P < .001) and remission (26% vs 6%; P < .01) than placebo. Rates were numerically similar at 1 year (mirikizumab pooled response, 46%-69%; remission, 13%-31%). Agreement between week 12 histologic and endoscopic response was 69% (Cohen's kappa coefficient [κ] = 0.40) and remission was 83% (κ = 0.38) in all pooled arms, including placebo. At 1 year, the percentage of participants who received any dose of mirikizumab and achieved endoscopic remission differed by their week 12 response: histologic (20%), endoscopic (25%), combined histology-endoscopy (45%), or neither (4%) (P = .003). CONCLUSIONS: In a post hoc analysis of phase 2 data, mirikizumab induced and sustained histologic response and remission in Crohn's disease over 52 weeks. Early combined histologic-endoscopic response was associated with endoscopic remission after 1 year of treatment with mirikizumab (ClinicalTrials.gov NCT02891226).

Molecular mechanisms in colitis-associated colorectal cancer.

Sustained chronic inflammation of the large intestine leads to tissue damage and repair, which is associated with an increased incidence of colitis-associated colorectal cancer (CAC). The genetic makeup of CAC is somewhat similar to sporadic colorectal carcinoma (sCRC), but there are differences in the sequence and timing of alterations in the carcinogenesis process. Several models have been developed to explain the development of CAC, particularly the "field cancerization" model, which proposes that chronic inflammation accelerates mutagenesis and selects for the clonal expansion of phenotypically normal, pro-tumorigenic cells. In contrast, the "Big Bang" model posits that tumorigenic clones with multiple driver gene mutations emerge spontaneously. The details of CAC tumorigenesis-and how they differ from sCRC-are not yet fully understood. In this Review, we discuss recent genetic, epigenetic, and environmental findings related to CAC pathogenesis in the past five years, with a focus on unbiased, high-resolution genetic profiling of non-dysplastic field cancerization in the context of inflammatory bowel disease (IBD).

Colorectal dysplasia in chronic inflammatory bowel disease: a contemporary consensus classification and interobserver study.

The clinical management of patients with dysplasia in chronic inflammatory bowel disease (IBD) is currently guided by Riddell et al.'s grading system (negative, indefinite, low grade, high grade) from 1983 which was based primarily on nuclear cytoarchitectural characteristics. Although most dysplasia in IBD resembles sporadic adenomas morphologically, other distinctive potential cancer precursors in IBD have been described over time. Recognizing the need for a updated comprehensive classification for IBD-associated dysplasia, an international working group of pathologists with extensive clinical and research experience in IBD devised a new classification system and assessed its reproducibility by having each participant assess test cases selected randomly from a repository of electronic images of potential cancer precursor lesions. The new classification system now encompasses three broad categories and nine sub-categories: 1) intestinal dysplasia (tubular/villous adenoma-like, goblet cell deficient, crypt cell, traditional serrated adenoma-like, sessile serrated lesion-like and serrated NOS), 2) gastric dysplasia (tubular/villous and serrated), and 3) mixed intestinal-gastric dysplasia. In the interobserver analysis, 67% of the diagnoses were considered definitive and achieved substantial inter-rater agreement. The key distinctions between intestinal and gastric lesions and between serrated and non-serrated lesions achieved substantial and moderate inter-rater agreement overall, respectively, however, the distinctions among certain serrated sub-categories achieved only fair agreement. Based on the Riddell grading system, definite dysplasia accounted for 86% of the collective responses (75% low grade, 11% high grade). Based on these results, this new classification of dysplasia in IBD can provide a sound foundation for future clinical and basic IBD research.

Density of Biopsy Sampling Required to Ensure Accurate Histological Assessment of Inflammation in Active Ulcerative Colitis.

BACKGROUND: Histological response to treatment is an important outcome in patients with ulcerative colitis (UC). The accuracy of biopsy-based measurements of inflammation may be limited by error imposed by natural microscopic heterogeneity on the scale of individual biopsies. We determined the magnitude of this error, its histological correlates, and the density of biopsy sampling within mucosal regions of interest required to meet specified benchmarks for accuracy. METHODS: A total of 994 sequential 1-mm digital microscopic images (virtual biopsies) from consecutive colectomies from patients with clinically severe UC were scored by 2 pathologists. Agreement statistics for Geboes subscores and Nancy (NHI) and Robarts Histological Indices (RHI) between random samples from 1 to 10 biopsies and a reference mean score across a 2-cm region of mucosa were calculated using bootstrapping with 2500 iterations. RESULTS: The agreement statistics improved across all indices as the biopsy density increased, with the largest proportional gains occurring with addition of the second and third biopsies. One biopsy achieved moderate to good agreement with 95% confidence for NHI and RHI corresponding to scale-specific errors of 0.40 (0.25-0.66) and 3.02 (2.08-5.36), respectively; and 3 biopsies achieved good agreement with 95% confidence corresponding to scale-specific errors of 0.22 (0.14-0.39) and 1.87 (1.19-3.25), respectively. Of the individual histological features, erosions and ulcers had the greatest impact on the agreement statistics. CONCLUSIONS: In the setting of active colitis, up to 3 biopsy samples per region of interest may be required to overcome microscopic heterogeneity and ensure accurate histological grading.

Aberrant p53 expression is associated with neoplastic progression in Barrett oesophagus diagnosed as indefinite for dysplasia.

The aim of this study was to investigate the role of immunohistochemical (IHC) expression of p53 and other potential clinical parameters as prognostic markers for predicting neoplastic progression in Barrett oesophagus (BE) patients diagnosed as indefinite for dysplasia (IND). The study included patients with established BE of any extent who had a diagnosis of IND accompanied by concurrent p53 immunohistochemistry (IHC) stain at the index endoscopic procedure and at least one follow-up examination between 2000 and 2021. Correlation between disease progression from IND to higher-grade dysplasia [low-grade dysplasia (LGD), high-grade dysplasia (HGD) and oesophageal adenocarcinoma (EAC)] and clinicopathological parameters were analysed. A total of 149 patients (99 males; mean age 63.3 ± 10.0 years, range = 35-89) were included in the final analysis. Median follow-up was 37.1 months [interquartile range (IQR) = 20.5-59.1 months]. Progression rates from IND to LGD and HGD were 12.1% (18 of 149) and 2.7% (four of 149), respectively. On multivariate analysis, the number of IND diagnoses was significantly associated with progression to both LGD and HGD (P = 0.016 and P < 0.001, respectively). Cox regression analysis showed that aberrant p53 expression was significantly associated with progression to LGD [hazard ratio (HR) = 4.87, 95% confidence interval (CI) = 1.91-12.45, P = 0.001] and HGD (HR = 21.81, 95% CI = 1.88-253.70, P = 0.014). Kaplan-Meier survival analysis also demonstrated that aberrant p53 expression was significantly associated with progression to LGD (P < 0.001) and HGD (P = 0.001). Our results suggest that frequency of IND diagnoses and status of p53 expression can help to stratify risk of neoplastic progression in BE patients with IND.

Baseline Histological Findings Do Not Predict the Risk of Subsequent Extension in Patients with Limited Ulcerative Colitis.

BACKGROUND: Among patients with limited ulcerative colitis (UC), 30% ultimately extend to pancolitis and are at increased risk of adverse clinical outcomes. Risk of endoscopic extension has been found to correlate with clinical features such as early age of onset. AIMS: We sought to determine whether histologic features correlate with disease extension. METHODS: The study population consisted of 40 patients with UC from two large academic centers diagnosed between 2006 and 2017. Eligible cases had a diagnosis of endoscopically limited UC (Montreal E1 or E2) at baseline and ≥ 2 subsequent endoscopic examinations with biopsies. Severity of inflammation was scored using both the Mount Sinai Activity Index and Nancy Histological Index. RESULTS: Patients were divided into two cohorts: those who progressed to pancolitis (Montreal E3) were defined as "Extenders" (n = 21), whereas "Non-extenders" (n = 19) were cases without progression in the follow-up period. The median follow-up time was 58.4 months. The histologic scores in the endoscopically involved mucosa of the index biopsies were not associated with subsequent extension of disease, overall. However, among extender cohort, the index histology scores correlated with biopsy scores at extension (r = 0.455, P = 0.044) and index severity was associated with a shorter time to extension (r = - 0.611, P = 0.003). Furthermore, female patients had a shorter time to extension (P = 0.013). CONCLUSIONS: Histological severity of limited UC is not an independent predictor of extension in UC. However, among patients who subsequently extend, severe inflammation at baseline correlates with shorter progression time and severe inflammation when extension occurs. Patients with limited UC but severe histologic inflammation may warrant more frequent endoscopic surveillance.

International consensus to standardise histopathological scoring for small bowel strictures in Crohn's disease.

OBJECTIVE: Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion. DESIGN: Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures. RESULTS: In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials. CONCLUSION: Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

Colorectal Strictures in Patients With Inflammatory Bowel Disease Do Not Independently Predict Colorectal Neoplasia.

BACKGROUND: Colorectal strictures have been considered independent risk factors for neoplasia in patients with inflammatory bowel disease (IBD). We examined the association between colorectal stricture and subsequent risk of colorectal neoplasia (CRN) in patients with IBD colitis undergoing colonoscopic surveillance. METHODS: We conducted a retrospective cohort analysis of patients with IBD colitis enrolled in colonoscopic surveillance for CRN at an academic medical center between 2005 and 2017. Inclusion criteria were IBD involving the colon for ≥8 years (or any duration with primary sclerosing cholangitis [PSC]) undergoing surveillance. Exclusion criteria were advanced CRN (ACRN; colorectal cancer [CRC] or high-grade dysplasia [HGD]) prior to or at enrollment, prior colectomy, or limited (<30%) disease extent or proctitis. Multivariable logistic and Cox regression analysis estimated the association between colorectal stricture on the index colonoscopy and ACRN, CRN (indefinite dysplasia, low-grade dysplasia, HGD, CRC), or colectomy. RESULTS: Among 789 patients with IBD undergoing CRC surveillance, 72 (9%; 70 with Crohn's colitis) had a colorectal stricture on index colonoscopy. There was no significant difference in the frequency of ACRN or requirement for colectomy between patients with vs without a colorectal stricture (P > .05). Colorectal stricture was not associated with subsequent ACRN (adjusted odds ratio [aOR], 1.41; 95% CI, 0.49-4.07), CRN (aOR, 1.15; 95% CI, 0.51-2.58), or colectomy (aOR, 1.10; 95% CI, 0.65-1.84). CONCLUSIONS: In this analysis of patients with IBD colitis undergoing CRN surveillance, the presence of a colorectal stricture was not independently associated with risk of ACRN or colectomy. Multicenter, prospective studies are needed to confirm these findings, particularly in patients with ulcerative colitis-associated colorectal stricture.

Constrictive and Hypertrophic Strictures in Ileal Crohn's Disease.

BACKGROUND & AIMS: Strictures in Crohn's disease (CD) are classically attributed to fibromuscular hypertrophy of the intestinal wall. We have identified and characterized CD-related ileal strictures that result instead from mural constriction (ie, reduced external circumference). METHODS: Twenty-four strictures and internal controls from 17 adults with obstructive CD were analyzed by cross-sectional morphometry. RESULTS: The stricture-to-control circumference ratios (CRs) ranged from 0.53 to 1.7. Six strictures with CR ≥1.0, designated hypertrophic, had concentrically thickened walls, mean 3-fold increases in cross-sectional area and stainable fibromucular tissue, and high transmural inflammation scores. In contrast, 18 strictures with CR <1.0, designated constrictive, had thin, pliant walls, cross-sectional areas and stainable fibromuscular tissue comparable with control values, and low transmural inflammation scores. Eight mildly constrictive strictures also showed mild fibromuscular mural expansion that fell short of statistical significance. Twelve of 18 constrictive strictures (67%) occurred multiply (2-4 strictures per specimen) in contrast with hypertrophic strictures, all of which occurred singly (P = .01). Constriction correlated quantitatively with circumferential serosal fat wrapping (P = .003) and was associated with myenteric lymphocytic plexitis (P = .02). Disease duration was shortest among subjects with constrictive strictures and correlated with increasing circumference (CR ≤0.8, 6.3 ± 6.2 years; CR >0.8, 8.7 ± 6.4 years; and CR ≥1.00, 13.7 ± 5.0 years, respectively; P = .03). CONCLUSIONS: Constrictive ileal strictures in CD differ pathologically and clinically from hypertrophic strictures, featuring little or no fibromuscular mural expansion, frequent multiplicity, and earlier onset. Mesenteric fat wrapping and myenteric plexitis may contribute to their pathogenesis. Pathologic manifestations of constriction and hypertrophy can coexist, suggesting that stricture heterogeneity may be shaped in part by the dynamics of constrictive and hypertrophic processes.

The association between pre-colectomy thiopurine use and risk of neoplasia after ileal pouch anal anastomosis in patients with ulcerative colitis or indeterminate colitis: a propensity score analysis.

BACKGROUND: The risk of neoplasia of the pouch or residual rectum in patients with ulcerative colitis (UC) who undergo total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA) is incompletely investigated. Thiopurine use is associated with a reduced risk of colorectal neoplasia in patients with UC. We tested the hypothesis that thiopurine use prior to TPC may be associated with a reduced risk of primary neoplasia after IPAA. METHODS: We conducted a retrospective cohort analysis of patients from a tertiary referral center from January 2008 to December 2017. Eligible patients with UC or IC underwent TPC with IPAA and had at least two pouchoscopies with biopsies ≥ 6 months after surgery. Propensity score analysis was conducted to match thiopurine exposed vs unexposed groups based on clinical covariates. Multivariable Cox regression analysis estimated the risk of neoplasia. RESULTS: A total of 284 patients with UC or IC (57.4% male, median age 35.6 years) were analyzed. Ninety-seven patients (34.2%) were confirmed to have thiopurine exposure ≥ 12 weeks immediately prior to TPC ("exposed") and 187 (65.8%) were confirmed to have no thiopurine exposure for at least 365 days prior to TPC ("non-exposed"). Compared to non-exposed patients, patients with thiopurine exposure less often had dysplasia (7.2% vs 23.0%, p = 0.001) and had lower grades of dysplasia before colectomy. After IPAA, patients with neoplasia were older (44.0 vs 34.8 years, p = 0.03), more likely to have had dysplasia as colectomy indication (44.4% vs 15.4%, p = 0.007), and more likely to require pouch excision (55.6% vs 10.2%, p < 0.0001), compared to patients without neoplasia. On propensity-matched cohort analysis, no factors were significantly associated with risk of primary neoplasia. CONCLUSION: Thiopurine exposure for at least the 12 weeks prior to TPC in patients with UC or IC does not appear to be independently associated with risk of primary neoplasia following IPAA.

Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension.

BACKGROUND AND AIMS: Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension. METHODS: We performed RNA sequence analysis of biopsy specimens from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsy specimens were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments. RESULTS: Differentially expressed genes were identified in the endoscopically inflamed biopsy specimens taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsy specimens transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation, and homeodomain pathways. A subset of these genes in inflamed biopsy specimens was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and poly(ADP-ribose) polymerase 14 (PARP14) was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsy specimens of patients with limited UC that subsequently extended. CONCLUSION: Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.

Impact of pathological response after neoadjuvant chemotherapy on adjuvant therapy decisions and patient outcomes in gastrointestinal cancers.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is frequently used in gastrointestinal cancers (GIC), and pathological, radiological, and tumor marker responses are assessed during and after NAC. AIM: To evaluate the relationship between pathologic, radiologic, tumor marker responses and recurrence-free survival (RFS), overall survival (OS), adjuvant chemotherapy (AC) decisions, and the impact of changing to a different AC regimen after poor response to NAC. METHODS AND RESULTS: Medical records of GIC patients treated with NAC at Mount Sinai between 1/2012 and 12/2018 were reviewed. One hundred fifty-six patients (58.3% male, mean age 63 years) were identified. Primary tumor sites were: 43 (27.7%) pancreas, 62 (39.7%) gastroesophageal, and 51 (32.7%) colorectal. After NAC, 31 (19.9%) patients had favorable pathologic response (FPR; defined as College of American Pathologists [CAP] score 0-1). Of 107 patients with radiological data, 59 (55.1%) had an objective response, and of 113 patients with tumor marker data, 61 (54.0%) had a ≥50% reduction post NAC. FPR, but not radiographic or serological responses, was associated with improved RFS (HR 0.28; 95% CI 0.11-0.72) and OS (HR 0.13; 95% CI 0.2-0.94). Changing to a different AC regimen from initial NAC, among all patients and specifically among those with unfavorable pathological response (UPR; defined as CAP score 2-3) after NAC, was not associated with improved RFS or OS. CONCLUSIONS: GIC patients with FPR after NAC experienced significant improvements in RFS and OS. Patients with UPR did not benefit from changing AC. Prospective studies to better understand the role of pathological response in AC decisions and outcomes in GIC patients are needed.

Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms.

BACKGROUND & AIMS: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance. METHODS: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions. RESULTS: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms. CONCLUSIONS: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.

An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials.

BACKGROUND & AIMS: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. METHODS: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. RESULTS: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. CONCLUSIONS: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.

Interobserver agreement and the impact of mentorship on the diagnosis of inflammatory bowel disease-associated dysplasia among subspecialist gastrointestinal pathologists.

The diagnosis of inflammatory bowel disease (IBD)-associated dysplasia is challenging, and past studies have demonstrated considerable interobserver variability in such diagnoses. This study aimed to assess interobserver agreement in IBD dysplasia diagnoses among subspecialty GI pathologists and to explore the impact of mentorship on diagnostic variability. Twelve GI pathologist mentees and 7 GI pathologist mentors reviewed 163 digitized slides. Participants rendered a diagnosis of negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, or high-grade dysplasia and provided a confidence level for each case. Interobserver agreement and reliability were assessed using Cohen's and Fleiss' kappa (κ) statistics and intraclass correlation coefficient (ICC) analysis. The overall κ coefficient was 0.42 (95% CI: 0.38-0.46). The overall ICC was 0.67 (95% CI: 0.62-0.72). Κ coefficients ranged from 0.31 to 0.49 for mentor/mentee pairs and from 0.34 to 0.55 for pairs of mentees of the same mentor. The combined κ coefficient was 0.44 (95% CI: 0.39-0.48) for all mentees and 0.39 (95% CI: 0.34-0.43) for all mentors. Common features in low agreement cases included mucosal atrophy, areas of stark contrast, serrations, decreased goblet cells, absent surface epithelium, and poor orientation. Participants were confident in most diagnoses, and increased confidence levels generally correlated with higher interobserver agreement. Interobserver agreement among subspecialist GI pathologists in this curated cohort of IBD dysplasia cases was fair to moderate. Mentorship during GI pathology fellowship does not appear to be a significant factor contributing to interobserver variability, but increased experience also does not seem to improve interobserver agreement.

Whole Slide Imaging for Teleconsultation: The Mount Sinai Hospital, Labcorp Dianon, and Philips Collaborative Experience.

BACKGROUND: With the emergence of whole slide imaging (WSI) and widespread access to high-speed Internet, pathology labs are now poised to implement digital pathology as a way to access diagnostic pathology expertise. This paper describes a collaborative partnership between a high-volume reference diagnostic laboratory (Labcorp) and an academic pathology department (Mount Sinai Hospital) in the transition from a traditional glass slide service to a digital platform. Using the standard framework of implementation science, we evaluate the consistency and quality of the Philips IntelliSite Pathology Solution (PIPS) in delivering save and efficient diagnostic services. MATERIALS AND METHODS: Digital and glass slide diagnoses of all consult cases were documented over a 12-month period. The Proctor guideline was used to quantitatively and qualitatively measure (e.g., focus group studies, field notes, and administrative data) implementation success. Lean techniques (e.g., value stream mapping) were applied to measure changes in efficiency with the transition to a digital platform. RESULTS: Our study supports the acceptability, high adoption, appropriateness, feasibility, fidelity, and sustainability of the digital pathology platform. The digital portal also improved the quality of patient care by increasing efficiency, effectiveness, safety, and timeliness. The intraobserver concordance rate was 100%. The digital transition resulted in a reduction in turnaround time from 86 h to an average 35 min and a 20-fold increase in efficiency of the consultation process. CONCLUSION: As the pathology community contemplates digital pathology as a transformational tool in providing broad access to diagnostic expertise across time and space, our study provides an implementation strategy along with evidence that the digital platform is safe, effective, and efficient.

Intestinal Inflammation Modulates the Expression of ACE2 and TMPRSS2 and Potentially Overlaps With the Pathogenesis of SARS-CoV-2-related Disease.

BACKGROUND AND AIMS: The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication within enterocytes. METHODS: Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation, and IBD treatment. RESULTS: A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and nonbiologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. In addition, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. CONCLUSIONS: These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19. Preprint doi: https://doi.org/10.1101/2020.05.21.109124.