Citations

Abstract Background Eosinophils have been implicated in the pathogenesis of ulcerative colitis and have been associated with disease course and therapeutic response. However, associations between eosinophil density, histologic activity, and clinical features have not been rigorously studied. Methods A deep learning algorithm was trained to identify eosinophils in colonic biopsies and validated against pathologists’ interpretations. The algorithm was applied to sigmoid colon biopsies from a cross-sectional cohort of 88 ulcerative colitis patients with histologically active disease as measured by the Geboes score and Robarts histopathology index (RHI). Associations between eosinophil density, histologic activity, and clinical features were determined. Results The eosinophil deep learning algorithm demonstrated almost perfect agreement with manual eosinophil counts determined by 4 pathologists (interclass correlation coefficients: 0.805–0.917). Eosinophil density varied widely across patients (median 113.5 cells per mm2, interquartile range 108.9). There was no association between eosinophil density and RHI (P = 0.5). Significant differences in eosinophil density were seen between patients with Montreal E3 vs E2 disease (146.2 cells per mm2 vs 88.2 cells per mm2, P = 0.005). Patients on corticosteroids had significantly lower eosinophil density (62.9 cells per mm2 vs 124.1 cells per mm2, P = 0.006). No association between eosinophil density and biologic use was observed (P = 0.5). Conclusions We developed a deep learning algorithm to quantify eosinophils in colonic biopsies. Eosinophil density did not correlate with histologic activity but did correlate with disease extent and corticosteroid use. Future studies applying this algorithm in larger cohorts with longitudinal follow-up are needed to further elucidate the role of eosinophils in ulcerative colitis.

Abstract Background Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial (NCT02891226) in patients with Crohn’s disease (CD). The histologic results at Week (W)12 induction and W52 maintenance are presented here. Methods Patients were randomized 2:1:1:2 across 4 treatment arms (PBO, 200, 600, 1000mg miri) administered intravenously (IV) every four weeks (Q4W) at Weeks 0, 4, and 8. Patients who received miri and achieved ≥1 point improvement from baseline (BL) at W12 in Simple Endoscopic Score for Crohn’s Disease (SES-CD) were re-randomized 1:1 into double-blind maintenance to continue their IV dose assignment Q4W (IV/IV) or to 300mg miri SC Q4W (IV/SC); maintenance IV arms were pooled for analysis. W12 non-improvers and all induction PBO patients received 1000mg miri Q4W from W12 through W52. Biopsies from terminal ileum and 4 colonic segments (ascending, transverse, descending, rectum) were obtained during endoscopy at W0, 12 and 52 and scored blind to treatment and response status. Ileum and colon scores were reported separately. Colon scores were derived from the sum of the 4 colonic segments, and total intestine scores from the 4 colonic segments plus ileum. Endpoints were defined post-hoc but prior to performing the analyses and only included patients with active histologic disease at BL (see Table). Histologic response was defined as: a) absence of neutrophils in lamina epithelialis, and absence of epithelial damage, erosions and ulceration or b) decrease of either RHI or GHAS ≥50% from BL. Histologic remission was defined as absence of mucosal neutrophils, epithelial damage, erosions, and ulceration. Deep histologic remission was defined as histologic remission combined with absence of chronic inflammatory cell infiltration of the lamina propria. For assessment of total intestine inflammation, the criteria for response, remission or deep remission must have been met in all 5 bowel segments. Results At W12, histologic response and remission were significantly higher in all segments of the 1000mg group versus PBO (response: ileum p<0.01, total intestine p<0.01, colon p<0.05; remission: ileum p<0.05, colon p<0.05, total intestine p<0.01). Among the W12 improvers, both histologic response and histologic remission at W52 were similar in ileum and colon in the IV/IV group, but lower in ileum than colon in the IV/SC group. All but 2 patients with remission at W52 were in deep histologic remission. Conclusion Patients treated with miri achieved and sustained histologic response and remission over 52 weeks of treatment. Among patients with W52 histologic remission, all but 2 patients achieved deep remission.

Abstract Background The histologic assessment of inflammatory bowel disease (IBD) relies on qualitative grading methods. Although widely accepted, these instruments are time consuming, require specialized training, and suffer from inter-rater disagreement. For these reasons there is a need for more consistent and less biased methods to assess IBD histology. Methods The algorithm was initially developed using hematoxylin and eosin (H&E) stained whole slide images of colon biopsies (238 ulcerative colitis [UC], 30 Crohn’s Disease [CD], and 28 endoscopically normal adjacent [ENA]). The first two stages implement convolutional neural networks (CNN) which segment 11 key anatomical features (Figure 1). The third stage extracts the features and models them for prediction. Results The first stage of the algorithm was validated on an independent test dataset by calculating the intersection-over-union (IoU) for the ground truth and prediction masks, resulting in a value of 0.97. A preliminary validation for stage 2 was performed by randomly selecting 30 unique biopsy sections from the test dataset and applying a 150um x 150um counting frame. An expert gastrointestinal pathologist confirmed correct cell identification by the algorithm for three of the primary inflammatory cell types: plasma cells, eosinophils, and neutrophils which resulted in a sensitivity/specificity of 0.76/0.99, 0.78/1.00, and 1.00/0.98 respectively. The final stage predicts RHI grades which could be directly compared to pathologist reads (Figure 2, 3, and 4). Conclusion This is the first study to demonstrate the value of machine learning to assess histologic activity in IBD. These methods lay the foundations for future work, and we believe stages 1 and 2 can be explored independently to statistically characterize the histologic changes of IBD, enabling the improvement of preexisting grading systems.

Abstract Background: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer–specific survival. Methods: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer–specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components. Results: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer–specific survival (HD, −1.15; 95% CI, −2.76 to 0.47 per 100,000 person-years; P = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location. Conclusions: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer–specific survival. Impact: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.

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.

Abstract Background Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks. Methods Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided. Results The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups. Conclusions Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

Abstract Background Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite. Methods Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite. Results Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P = .04). Conclusion In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.

Aims. Mucinous cystic neoplasms (MCNs) are cystic neoplasms with mucinous epithelium surrounded by ovarian-like stroma. Extraovarian MCN occurring in the liver and pancreas have been well characterized. However, only rare case reports of MCN arising outside of these locations have been reported. MCNs arising in unusual locations should enter the differential diagnosis of mucinous intra-abdominal tumors and must be distinguished from more common mimics. Therefore, we aimed to examine a series of MCNs of the retroperitoneum and mesentery to characterize the clinicopathologic features of this entity. Methods and results. Seven MCNs arising in the abdominal mesentery or retroperitoneum were retrospectively identified. A clinicopathologic, histologic, and immunohistochemical (keratin 7, keratin 19, keratin 20, calretinin, inhibin-α, steroidogenic factor-1 (SF-1), estrogen receptor (ER), progesterone receptor (PR), PAX8, CDX2, and CD10) analysis was performed. All 7 MCNs were from females with a median age of 41 years old and a median size of 8 cm. All cases demonstrated mucinous with or without concomitant non-mucinous epithelium overlying spindle cell ovarian-like stroma. Luteinized cells were noted. The epithelium was positive for keratin 7 and keratin 19 in all 7 cases, while the stroma expressed ER, PR, and SF-1 in all cases stained. Calretinin was focally positive in the stroma of 3 of 7 cases, while inhibin-α was focally expressed in 5 of 6 cases. Conclusions. These results highlight the clinicopathologic, histologic, and immunophenotypic similarities between MCNs of the mesentery, retroperitoneum, pancreas, and liver. Overlapping features suggest a common histogenesis for all MCNs, which could include periductal fetal mesenchyme, aberrant migration of primordial germ cells, or abnormal differentiation or metaplasia of the embryonic coelomic epithelium.

Abstract It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes—people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 MLH1, 314 MSH2, 126 MSH6, 71 PMS2, and 22 EPCAM) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided P > .05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided P = .51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.

Abstract Background and Aims To correlate histologic activity in surveillance colonoscopies with the development of colorectal neoplasia in ulcerative colitis [UC]. Methods Colorectal biopsies during surveillance [N = 764] from 52 UC patients with colorectal neoplasia were compared to 122 patients without neoplasia enrolled in a prospective natural history registry. All biopsies were scored using validated histologic scoring systems (Geboes score, Nancy histopathologic index [NHI], and Robarts histopathologic index [RHI]). Clinical, endoscopic, and histologic data were correlated with the development of colorectal neoplasia. Results In multivariable analysis, mean RHI (hazard ratio [HR] 1.07 for each 1-unit increase in RHI, 95% confidence interval [CI] 1.03–1.12, p = 0.002) and mean NHI [HR 1.89 for each 1-unit increase in NHI, 95% CI 1.34–2.67, p = 0.002] for the entire surveillance period were significantly associated with colorectal neoplasia development. Shorter surveillance interval and increasing age were associated with increased risk of neoplasia development whereas mean Mayo endoscopic score was not significant. To generate a clinically useful measure of neoplasia risk, mean histologic activity in the preceding 5 years before the study endpoint was correlated with neoplasia development. In the preceding 5 years of surveillance, a mean RHI ≥ 8 had a 7.53-fold increased risk [95% CI 2.56–12.16, p < 0.001] and mean NHI ≥ 1.9 had a 5.89-fold increased risk [95% CI 2.18–15.92, p < 0.001] of developing colorectal neoplasia. Conclusions Persistent histologic activity during multiple surveillance episodes is an independent predictor of colorectal neoplasia. Mean RHI and mean NHI during a 5-year colonoscopic surveillance period can be used to assess risk for colorectal neoplasia and optimize UC surveillance.