Publications by authors named "Amitabh Srivastava"

128 Publications

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Nutrients 2022 Jun 15;14(12). Epub 2022 Jun 15.

Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN 55907, USA.

Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. The median VH in NCGS was significantly shorter (600, IQR: 400-705) than controls (900, IQR: 667-1112) ( < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390-620) vs. 427 µm (IQR: 348-569, = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls ( < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. : NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.
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http://dx.doi.org/10.3390/nu14122487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230100PMC
June 2022

Evaluation of the efficacy of concentrated growth factor along with bovine-derived xenograft and collagen membrane in the treatment of Degree II mandibular molar furcation defect - A clinicoradiographic study.

J Indian Soc Periodontol 2022 Mar-Apr;26(2):130-136. Epub 2022 Mar 1.

Department of Periodontology, Sardar Patel Postgraduate Institute of Dental and Medical Sciences, Lucknow, Uttar Pradesh, India.

Background: The ultimate goal of furcation defect therapy is furcation closure periodontal regeneration. However, the process of periodontal regeneration is affected by the regenerative environment of signaling molecules and growth factors due to which consistent findings of complete furcation closure could not be attained. In this study, we have evaluated the use of concentrated growth factor (CGF) which provides sustained release growth factors in conjunction with bovine-derived xenograft anorganic bovine bone (ABB) in guided tissue regeneration (GTR) of Degree II mandibular molar furcation defect.

Materials And Methods: Twenty patients with Degree II mandibular molar furcation defects were selected for the study. Each group consisted of 10 patients and a total of 10 sites were treated in each group. The control sites were treated with GTR and ABB, while the experimental sites received CGF mixed with ABB along with GTR. Clinical parameters recorded were Plaque Index, Gingival Index, vertical probing depth, and horizontal probing depth measured at baseline and 6 months. Radiographic parameters such as the vertical height of defect, horizontal depth of defect, and percentage of vertical and horizontal bone fill were recorded at baseline and 6 months.

Results: All the parameters recorded showed a significant reduction from baseline to 6 months in both the groups. Significantly higher vertical and horizontal bone fill was observed in the experimental group as compared to the control group.

Conclusion: The use of CGF showed a positive additive efficacy in enhancing the events of periodontal regeneration in the treatment of Degree II mandibular molar furcation defect.
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http://dx.doi.org/10.4103/jisp.jisp_44_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936011PMC
March 2022

Recommendations for standardizing biopsy acquisition and histological assessment of immune checkpoint inhibitor-associated colitis.

J Immunother Cancer 2022 03;10(3)

Alimentiv Inc, London, Ontario, Canada.

Immune checkpoint inhibitor-associated colitis (ICIC) affects approximately 15% of cancer patients treated with immunotherapy. Although histological evaluation is potentially valuable for both the diagnosis of ICIC and evaluation of disease activity, use in clinical practice is heterogeneous. We aimed to develop expert recommendations to standardize histological assessment of disease activity in patients with ICIC. Using the modified Research and Development/University of California Los Angeles (RAND/UCLA) appropriateness methodology, an international panel of 11 pathologists rated the appropriateness of 99 statements on a 9-point Likert scale during two rounds of anonymous voting. Results were discussed between rounds using moderated videoconferences. There are currently no disease-specific instruments for assessing histological features of ICIC. The panel considered that colonoscopy with at least three biopsies per segment from a total of at least five segments, including both endoscopically normal and inflamed areas, was appropriate for tissue acquisition. They agreed that biopsies should be oriented such that the long axis of the colonic crypts is visualized and should be stained with hematoxylin and eosin. Histological items that the panel voted were appropriate to evaluate in ICIC included the degree of structural/architectural change, chronic inflammatory infiltrate, lamina propria and intraepithelial neutrophils, crypt abscesses and destruction, erosions/ulcerations, apoptosis, surface intraepithelial lymphocytosis, and subepithelial collagen thickness. The appropriateness of routine immunohistochemistry was uncertain. These expert recommendations will help standardize assessment of histological activity in patients with ICIC. The panel also identified the development and validation of an ICIC-specific histological index as a research priority.
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http://dx.doi.org/10.1136/jitc-2022-004560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8928359PMC
March 2022

Clinically significant serrated polyp detection rates and risk for postcolonoscopy colorectal cancer: data from the New Hampshire Colonoscopy Registry.

Gastrointest Endosc 2022 Aug 8;96(2):310-317. Epub 2022 Mar 8.

Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA; Department of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA; New Hampshire Colonoscopy Registry, Lebanon, New Hampshire, USA.

Background And Aims: Higher adenoma detection rates reduce the risk of postcolonoscopy colorectal cancer (PCCRC). Clinically significant serrated polyps (CSSPs; defined as any sessile serrated polyp, traditional serrated adenoma, large [≥1 cm] or proximal hyperplastic polyp >5 mm) also lead to PCCRC, but there are no data on associated CSSP detection rates (CSSDRs). We used data from the New Hampshire Colonoscopy Registry (NHCR) to investigate the association between PCCRC risk and endoscopist CSSDR.

Methods: We included NHCR patients with 1 or more follow-up events: either a colonoscopy or a colorectal cancer (CRC) diagnosis identified through linkage with the New Hampshire State Cancer Registry. We defined our outcome, PCCRC, in 3 time periods: CRC diagnosed 6 to 36 months, 6 to 60 months, or all examinations (6 months or longer) after an index examination. We excluded patients with CRC diagnosed at or within 6 months of the index examination, with incomplete examinations, or with inflammatory bowel disease. The exposure variable was endoscopist CSSDR at the index colonoscopy. Cox regression was used to model the hazard of PCCRC on CSSDR controlling for age, sex, index findings, year of examination, personal history of colorectal neoplasia, and having more than 1 surveillance examination.

Results: One hundred twenty-eight patients with CRC diagnosed at least 6 months after their index examination were included. Our cohort included 142 endoscopists (92 gastroenterologists). We observed that the risk for PCCRC 6 months or longer after the index examination was significantly lower for examinations performed by endoscopists with CSSDRs of 3% to <9% (hazard ratio [HR], .57; 95% confidence interval [CI], .39-.83) or 9% or higher (HR, .39; 95% CI, .20-.78) relative to those with CSSDRs under 3%.

Conclusions: Our study is the first to demonstrate a lower PCCRC risk after examinations performed by endoscopists with higher CSSDRs. Both CSSDRs of 9% and 3% to <9% had statistically lower risk of PCCRC than CSSDRs of <3%. These data validate CSSDR as a clinically relevant quality measure for endoscopists.
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http://dx.doi.org/10.1016/j.gie.2022.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296608PMC
August 2022

Subtyping intestinal metaplasia in patients with chronic atrophic gastritis: an interobserver variability study.

Pathology 2022 Apr 25;54(3):262-268. Epub 2022 Feb 25.

Diagnostic and Research Institute of Pathology, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria. Electronic address:

Incomplete gastric intestinal metaplasia (GIM) is associated with an increased risk of gastric cancer. We aimed to examine the interobserver variability of GIM subtyping (incomplete vs complete) in histological diagnosis of patients with chronic atrophic gastritis and to identify factors with potential impact on agreement. Nine international gastrointestinal expert pathologists assessed 46 cases with complete, incomplete or mixed-type GIM on scanned haematoxylin and eosin (H&E)-stained slides. Results were compared with the consensus diagnosis driven by two experts. Interobserver variability was evaluated by kappa statistics. Focusing on the predominant pattern, the agreement between each observer and the consensus diagnosis ranged from 78% to 98%. The level of agreement was moderate to almost perfect (weighted kappa=0.464-0.984). The participating pathologists reached substantial overall agreement (Fleiss' kappa=0.716, 95% confidence interval 0.677-0.755). Misclassification with potential impact on clinical decision making occurred in 5.7% of case ratings. The pattern of GIM (pure GIM versus mixed-type GIM) differed significantly between cases with high and low agreement (p=0.010), while the number of biopsy pieces per sample and the portion of mucosal surface involved by GIM did not. Pathologists who apply subtyping in daily routine performed better than those who do not (p=0.040). In conclusion, subtyping GIM on H&E-stained slides can be achieved satisfactorily with high interobserver agreement. The implementation of GIM subtyping as a risk stratifying tool in current practice guidelines by the European Society of Gastrointestinal Endoscopy (ESGE) and the American Gastroenterological Association (AGA) carries a low rate of misclassification, at least among gastrointestinal expert pathologists.
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http://dx.doi.org/10.1016/j.pathol.2021.12.288DOI Listing
April 2022

Presence of Tim3 and PD-1 CD8 T cells identifies microsatellite stable colorectal carcinomas with immune exhaustion and distinct clinicopathological features.

J Pathol 2022 06 9;257(2):186-197. Epub 2022 Apr 9.

Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

Colorectal carcinoma (CRC) is the second leading cause of cancer mortality worldwide. CRC is stratified into two major groups: microsatellite stable (MSS) and microsatellite instability-high (MSI-H). MSS CRC constitutes the majority of cases, has worse overall prognosis, and thus far has failed to respond to immunotherapies targeting the immune checkpoint receptors PD-1, PD-L1, and CTLA-4. Here we examined the alternate immunotherapy targets Tim-3 and Lag-3, as well as PD-1, on immune cells in a cohort of MSS CRC using immunohistochemistry and flow cytometry together with mutational analysis and clinical data. We found that PD-1 was variably expressed across CD4 tumor-infiltrating lymphocyte (TIL) subtypes, and Tim-3 was mostly restricted to CD4 regulatory T cells. Lag-3, when detected by flow cytometry, was largely coexpressed with Tim-3 and PD-1 in CD4 TILs. Furthermore, Tim-3 PD-1 CD8 TILs accumulated in the tumor and exhibited a dysfunctional or 'exhausted' phenotype. Notably, we observed a subset of patients with a high proportion of Tim-3 PD-1 CD8 TILs and, conversely, a low proportion of Tim-3 PD-1 CD8 TILs, thus stratifying MSS CRC patients based on a feature of immune exhaustion (MSS-ImmEx). MSS-ImmEx patients had abundant Tim-3 PD-1 CD8 TILs, PD-1 CD4 effector, and regulatory T cells, and were enriched for left-sided colon tumors and mutations in the APC tumor-suppressor gene. We further investigated the spatial organization of Tim-3, Lag-3, PD-1, and PD-L1 by immunohistochemistry and found higher levels in the tumor margin; however, MSS-ImmEx tumors exhibited a higher density of Tim-3 cells in the tumor center over MSS-ImmEx tumors. Immunofluorescence revealed a higher density of PD-1 /CD8 cells in the tumor center in this group. Our findings identify a subset of MSS CRC that exhibits evidence of higher prior immune activation (MSS-ImmEx ) in which therapies targeting Tim-3 in conjunction with anti-PD-1 or other immunotherapies may provide clinical benefit. © 2022 The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5877DOI Listing
June 2022

Interobserver agreement of estimating the extent of intestinal metaplasia in patients with chronic atrophic gastritis.

Virchows Arch 2022 Jun 13;480(6):1277-1281. Epub 2021 Dec 13.

Diagnostic and Research Institute of Pathology, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria.

The extent of gastric intestinal metaplasia (GIM) can be used to determine the risk of gastric cancer. Eleven international gastrointestinal expert pathologists estimated the extent of GIM on haematoxylin and eosin (H&E)- and Alcian blue-Periodic acid Schiff (AB-PAS)-stained slides of 46 antrum biopsies in 5% increments. Interobserver agreement was tested with the intraclass correlation coefficient (ICC). Correlation between standard deviation and extent of GIM was evaluated with the Spearman correlation. The interobserver agreement was very good (ICC = 0.983, 95% confidence interval (CI) 0.975-0.990). The use of AB-PAS did not increase the agreement (ICC = 0.975, 95% CI 0.961-0.985). Cases with a higher amount of metaplastic epithelium demonstrated a higher standard deviation (rs = 0.644; p < 0.01), suggesting lower diagnostic accuracy in cases with extensive GIM. In conclusion, estimating the extent of GIM on H&E-stained slides in patients with chronic atrophic gastritis can be achieved satisfactorily with high interobserver agreement, at least among international expert gastrointestinal pathologists.
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http://dx.doi.org/10.1007/s00428-021-03245-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9184363PMC
June 2022

The Frontiers of Serrated Polyps.

Am J Surg Pathol 2022 01;46(1):e64-e70

Department of Pathology, Brigham and Women's Hospital, Boston, MA.

The serrated pathway of carcinogenesis has been the subject of intense investigation over the past 2 decades, but many gaps in our understanding still need to be resolved. Serrated polyp precursors include hyperplastic polyps, sessile serrated polyps, and traditional serrated adenomas. These are considered discrete entities, but there is emerging molecular data to suggest that they may be more closely related to each other than currently believed. The recent US Multi-Society Task Force surveillance guidelines for patients with serrated polyps are admittedly based on low quality evidence. In this brief review, we discuss the limitations in endoscopic detection and pathologic interpretation of serrated polyps and the implications of these diagnostic difficulties on risk prediction and postpolypectomy surveillance recommendations.
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http://dx.doi.org/10.1097/PAS.0000000000001806DOI Listing
January 2022

Spatially organized multicellular immune hubs in human colorectal cancer.

Cell 2021 09 26;184(18):4734-4752.e20. Epub 2021 Aug 26.

Department of Immunology, HMS, Boston, MA, USA.

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
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http://dx.doi.org/10.1016/j.cell.2021.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8772395PMC
September 2021

Inhibin-positive hepatic carcinoma: proposal for a solid-tubulocystic variant of intrahepatic cholangiocarcinoma.

Hum Pathol 2021 10 20;116:82-93. Epub 2021 Jul 20.

Department of Pathology, University of California, San Francisco, San Francisco, CA 91343, United States. Electronic address:

Inhibin-positive hepatic carcinoma is a rare primary liver neoplasm that resembles sex cord-stromal tumor and thyroid follicular tumors. The term "cholangioblastic variant of intrahepatic cholangiocarcinoma" has been proposed. This study describes the clinicopathologic, immunophenotypic, and molecular features of a small series (n = 6) of this rare tumor. Albumin in situ hybridization (ISH) and capture-based next-generation sequencing (NGS) were also performed. All tumors occurred in young women (mean age 32.5 years, range 19-44 years) as a solitary large mass (mean 15.8 cm, range 6.9-23.5 cm). All tumors showed a highly distinctive morphology with sheets and large nests of tumor cells alternating with tubular and cystic areas imparting a sex cord-like or thyroid follicle-like morphology. Cytologic atypia was mild, and mitotic activity was low. All cases were positive for inhibin, as well as pancytokeratin, CK7, CK19, and albumin ISH. Synaptophysin and chromogranin showed focal or patchy staining, whereas INSM1 was negative. Markers for hepatocellular differentiation, thyroid origin, and sex cord-stromal tumor were negative. There were no recurrent genomic changes based on capture-based NGS of ∼500 cancer genes. Recurrence and/or metastasis was seen in three (50%) cases (follow-up time range for all cases: 5 months to 2 years). In conclusion, this series describes the distinctive morphology, immunophenotypic features, and diffuse albumin staining in six cases of a rare inhibin-positive primary liver carcinoma that runs an aggressive course similar to intrahepatic cholangiocarcinoma. Genomic changes typical of cholangiocarcinoma or hepatocellular carcinoma were not identified, and there were no recurrent genetic abnormalities. We propose the term "solid-tubulocystic variant of intrahepatic cholangiocarcinoma" to reflect the spectrum of morphologic patterns observed in this tumor.
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http://dx.doi.org/10.1016/j.humpath.2021.07.004DOI Listing
October 2021

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

Gut 2022 03 5;71(3):479-486. Epub 2021 May 5.

Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA

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.
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http://dx.doi.org/10.1136/gutjnl-2021-324374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903083PMC
March 2022

A Multi-institutional Study of Peritoneal Recurrence Following Resection of Low-grade Appendiceal Mucinous Neoplasms.

Ann Surg Oncol 2021 Aug 7;28(8):4685-4694. Epub 2021 Jan 7.

Department of Surgery, University of California San Diego, La Jolla, CA, USA.

Background: Peritoneal dissemination of low-grade appendiceal mucinous neoplasms (LAMNs), sometimes referred to as pseudomyxoma peritonei, can result in significant morbidity and mortality. Little is known about the natural history of localized (non-disseminated) LAMNs.

Objective: The goal of this study was to evaluate the risk of peritoneal recurrence in patients with localized LAMNs.

Methods: We performed a multi-institutional retrospective review of patients with pathologically confirmed localized LAMNs. Baseline characteristics, pathology, and follow-up data were collected. The primary endpoint was the rate of peritoneal recurrence.

Results: We identified 217 patients with localized LAMNs. Median age was 59 years (11-95) and 131 (60%) patients were female. Surgical management included appendectomy for 124 (57.1%) patients, appendectomy with partial cecectomy for 26 (12.0%) patients, and colectomy for 67 (30.9%) patients. Pathology revealed perforation in 46 patients (37.7% of 122 patients with perforation status mentioned in the report), extra-appendiceal acellular mucin (EAM) in 49 (22.6%) patients, and extra-appendiceal neoplastic cells (EAC) in 13 (6.0%) patients. Median follow-up was 51.1 months (0-271). Seven (3.2%) patients developed a peritoneal recurrence, with a median time to recurrence of 14.4 months (2.5-47.0). Seven (15.2%) patients with histologic evidence of perforation had recurrence, versus no patients (0%) without perforation (p < 0.001); five (10.2%) patients with EAM versus two (1.2%) patients without EAM (p = 0.007), and one (7.7%) patient with EAC versus six (2.9%) patients without EAC (p = 0.355) had recurrence.

Conclusions: This multi-institutional study represents the largest reported series of patients with localized LAMNs. In the absence of perforation or extra-appendiceal mucin or cells, recurrence was extremely rare; however, patients with any of these pathologic findings require careful follow-up.
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http://dx.doi.org/10.1245/s10434-020-09499-yDOI Listing
August 2021

An IL-27-Driven Transcriptional Network Identifies Regulators of IL-10 Expression across T Helper Cell Subsets.

Cell Rep 2020 11;33(8):108433

Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Interleukin-27 (IL-27) is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms, including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, and Atf3) and 2 negative (Irf9 and Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10. We report two central regulators, Prdm1 and Maf, that cooperatively drive the expression of signature genes induced by IL-27 in type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3 regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying ll10-deficient mice. Our work provides insights into IL-27-driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs across T helper cell subsets.
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http://dx.doi.org/10.1016/j.celrep.2020.108433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771052PMC
November 2020

Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts.

Gut 2021 05 2;70(5):876-883. Epub 2020 Nov 2.

Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK

Objective: We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients.

Design: The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD.

Results: Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively.

Conclusion: Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD.
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http://dx.doi.org/10.1136/gutjnl-2020-320913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040155PMC
May 2021

Non-conventional dysplasias of the tubular gut: a review and illustration of their histomorphological spectrum.

Histopathology 2021 Apr 24;78(5):658-675. Epub 2021 Jan 24.

Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

The increasing use of gastrointestinal endoscopic procedures has led to the recognition by histopathologists of non-conventional (or special-type) dysplasias of the gastrointestinal tract. These lesions can be recognised in association with prevalent underlying gastrointestinal conditions, such as Barrett oesophagus, chronic atrophic gastritis, and inflammatory bowel disease. The diagnosis of these special types can be challenging, and their biological behaviours are not fully characterised. The aim of this review is to provide a global view of non-conventional dysplastic lesions observed in the various segments of the tubular gastrointestinal tract and describe their salient features. Furthermore, as the clinical implications of these various subtypes have not been broadly tested in practice and are not represented in most management guidelines, we offer guidance on the best management practices for these lesions.
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http://dx.doi.org/10.1111/his.14294DOI Listing
April 2021

Medication-specific variations in morphological patterns of injury in immune check-point inhibitor-associated colitis.

Histopathology 2021 Mar 22;78(4):532-541. Epub 2020 Nov 22.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Aims: A varied spectrum of histopathological changes has been associated with immune checkpoint inhibitor (ICI) colitis. This study was performed to evaluate the prevalence of different histopathological patterns of injury in patients with ICI colitis and their association with specific immune check-point inhibitors.

Methods And Results: Biopsies from patients with clinically and histologically confirmed ICI colitis were reviewed blindly to determine the predominant pattern of injury and to quantitate discrete histological parameters using the Geboes score. Paneth cell metaplasia, intraepithelial lymphocytes, abnormal subepithelial collagen and degree of crypt epithelial apoptosis was also recorded. A total of 86 patients with ICI colitis (ipilimumab, n = 14; ipilimumab + nivolumab, n = 29; nivolumab, n = 20 and pembrolizumab, n = 23) were included. The patterns of injury identified included diffuse active colitis (n = 22), chronic active colitis (n = 22), lymphocytic colitis (LC, n = 16), collagenous colitis (CC, n = 14), graft-versus-host disease-like colitis (n = 7) and mixed colitis (n = 5). Patients on ipilimumab were more likely to have a diffuse active colitis pattern without features of chronicity (P < 0.01) and less likely to have LC (P < 0.05) compared to other ICIs. LC and CC were more common in patients on nivolumab and pembrolizumab relative to other groups (P < 0.05). Chronic active colitis was most frequent in nivolumab patients (P < 0.05), and these patients had received more ICI doses and had been on ICI treatment longer compared to other treatment groups.

Conclusions: ICI colitis should be considered in the differential diagnosis of all the common inflammatory patterns of colitis and shows medication specific differences in patterns of injury.
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http://dx.doi.org/10.1111/his.14248DOI Listing
March 2021

Heading in the Right Dissection: Toward an Endoscopic Cancer Cure in a Patient with Long-Standing Ulcerative Colitis.

Dig Dis Sci 2020 10;65(10):2818-2822

Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1007/s10620-020-06465-2DOI Listing
October 2020

Obesity/Type 2 Diabetes-Associated Liver Tumors Are Sensitive to Cyclin D1 Deficiency.

Cancer Res 2020 08 30;80(16):3215-3221. Epub 2020 Jun 30.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Type 2 diabetes, which is mainly linked to obesity, is associated with increased incidence of liver cancer. We have previously found that in various models of obesity/diabetes, hyperinsulinemia maintains heightened hepatic expression of cyclin D1, suggesting a plausible mechanism linking diabetes and liver cancer progression. Here we show that cyclin D1 is greatly elevated in human livers with diabetes and is among the most significantly upregulated genes in obese/diabetic liver tumors. Liver-specific cyclin D1 deficiency protected obese/diabetic mice against hepatic tumorigenesis, whereas lean/nondiabetic mice developed tumors irrespective of cyclin D1 status. Cyclin D1 dependency positively correlated with liver cancer sensitivity to palbociclib, an FDA-approved CDK4 inhibitor, which was effective in treating orthotopic liver tumors under obese/diabetic conditions. The antidiabetic drug metformin suppressed insulin-induced hepatic cyclin D1 expression and protected against obese/diabetic hepatocarcinogenesis. These results indicate that the cyclin D1-CDK4 complex represents a potential selective therapeutic vulnerability for liver tumors in obese/diabetic patients. SIGNIFICANCE: Obesity/diabetes-associated liver tumors are specifically vulnerable to cyclin D1 deficiency and CDK4 inhibition, suggesting that the obese/diabetic environment confers cancer-selective dependencies that can be therapeutically exploited.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442681PMC
August 2020

Non-invasive monitoring of chronic liver disease via near-infrared and shortwave-infrared imaging of endogenous lipofuscin.

Nat Biomed Eng 2020 08 22;4(8):801-813. Epub 2020 Jun 22.

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.

Monitoring the progression of non-alcoholic fatty liver disease is hindered by a lack of suitable non-invasive imaging methods. Here, we show that the endogenous pigment lipofuscin displays strong near-infrared and shortwave-infrared fluorescence when excited at 808 nm, enabling label-free imaging of liver injury in mice and the discrimination of pathological processes from normal liver processes with high specificity and sensitivity. We also show that the near-infrared and shortwave-infrared fluorescence of lipofuscin can be used to monitor the progression and regression of liver necroinflammation and fibrosis in mouse models of non-alcoholic fatty liver disease and advanced fibrosis, as well as to detect non-alcoholic steatohepatitis and cirrhosis in biopsied samples of human liver tissue.
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http://dx.doi.org/10.1038/s41551-020-0569-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310386PMC
August 2020

Colorectal Cancer Screening for the Serrated Pathway.

Gastrointest Endosc Clin N Am 2020 Jul 8;30(3):457-478. Epub 2020 Apr 8.

Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

Serrated polyps are classified into hyperplastic polyps, sessile serrated adenomas/polyps, and traditional serrated adenomas. Although all serrated polyps share characteristic colonic crypts serrations, distinguishing hyperplastic polyps from sessile serrated adenomas/polyps is challenging. Traditional serrated adenomas are cytologically dysplastic lesions; sessile serrated adenomas/polyps develop cytologic dysplasia as they progress to colorectal cancer. A flat and pale appearance of serrated polyps may make detection difficult. Endoscopic mucosal resection has higher rates of complete resection. Close surveillance is recommended for sessile serrated adenomas/polyps, sessile serrated adenomas/polyp with dysplasia, hyperplastic polyps ≥10 mm, and traditional serrated adenomas.
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http://dx.doi.org/10.1016/j.giec.2020.02.007DOI Listing
July 2020

Safety of Immune Checkpoint Inhibitors in Patients With Pre-Existing Inflammatory Bowel Disease and Microscopic Colitis.

JCO Oncol Pract 2020 09 13;16(9):e933-e942. Epub 2020 May 13.

Harvard Medical School, Boston, MA.

Purpose: Enterocolitis is among the leading adverse events associated with immune checkpoint inhibitors (ICIs). There are limited retrospective data regarding the safety of ICIs in patients with inflammatory bowel disease (IBD; ulcerative colitis, Crohn's disease) because they have been generally excluded from clinical trials testing ICIs. Furthermore, there are no outcome data available in patients with microscopic colitis, a leading cause of chronic diarrhea. We aimed to study the safety of ICIs in patients with cancer with pre-existing IBD or microscopic colitis.

Methods: We retrospectively reviewed the records of patients with cancer treated at our institution who received at least 1 dose of either a programmed cell death-1 (PD-1)/ PD-1 ligand inhibitor, cytotoxic T-lymphocyte-associated antigen 4 inhibitor, or both between 2011 and 2018. We identified patients with pre-existing IBD or microscopic colitis.

Results: Of 548 patients with solid tumor treated with an ICI, we identified 25 with pre-existing colitis (21 IBD; 4 microscopic colitis). An enterocolitis flare occurred in 7 patients (28%): 3 of 4 patients (75%) with microscopic colitis and 4 of 21 (19%) with IBD. All were treated with systemic corticosteroids, 2 required an anti-tumor necrosis factor agent, and one required an anti-integrin agent and colectomy for treatment of refractory colitis. ICI therapy was discontinued in all patients who experienced an enterocolitis flare.

Conclusion: In our cohort, exacerbation of enterocolitis occurred in a notable percentage of patients with IBD and a majority of patients with microscopic colitis, leading to discontinuation of ICIs. Although these data suggest that patients with cancer with pre-existing IBD/microscopic colitis may be treated with ICIs, additional studies are needed to validate our results.
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http://dx.doi.org/10.1200/JOP.19.00672DOI Listing
September 2020

Early and accurate detection of bacterial isolates from dental plaque in subjects with primary, mixed, and permanent dentition by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technique.

J Indian Soc Periodontol 2020 Mar-Apr;24(2):104-108. Epub 2020 Jan 27.

Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.

Background: Bacterial colonization of dentition in different age groups can impact prognosis in different dental diseases. Latest diagnostic technique such as matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF) is increasingly being used for accurate identification of bacteria. This study was undertaken to evaluate the MALDI-TOF MS technique to identify bacterial pathogens from dental plaques in subjects with primary, mixed, and permanent dentition.

Materials And Methods: The study included 150 subjects of different age groups and were divided into three groups - Group A: Subjects with primary dentition ( = 50), Group B: Subjects with mixed dentition ( = 50), and Group C: Subjects with permanent dentition ( = 50). Subgingival dental plaque samples were collected from buccal and lingual surfaces of premolar and molar teeth. Clinical parameters such as gingival index were recorded. Samples were cultured in routine aerobic and anaerobic medium. Bacterial growths were assessed by semiquantitative methods. Bacterial isolates were confirmed by MALDI-TOF MS technique.

Results: MALDI-TOF MS detected all the culture-grown bacteria. In primary dentition group, purple and yellow complex bacteria predominated. spp. was the predominant bacteria (51%) followed by (19%) and spp. (19%). In mixed dentition and permanent group also, spp. was predominant (46%) followed by spp. (24%) and (19%). However, in both groups, orange complex bacteria (bridge complex) such as and red complex bacteria (, 3%) were seen. For majority of bacteria, the load increased with age.

Conclusions: The bacterial isolates showed a distinct age-specific colonization. The use of advanced technique such as MALDI-TOF MS is helpful in the detection of periodontal pathogens, and the effective oral health programs can be implemented to minimize the risk of periodontal diseases.
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http://dx.doi.org/10.4103/jisp.jisp_303_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069104PMC
January 2020

BCL9 provides multi-cellular communication properties in colorectal cancer by interacting with paraspeckle proteins.

Nat Commun 2020 01 7;11(1):19. Epub 2020 Jan 7.

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells. The B-cell lymphoma 9 (BCL9) oncogene functions as a transcriptional co-activator of the Wnt/β-catenin pathway, which plays critical roles in CRC pathogenesis. Here we have identified a β-catenin-independent function of BCL9 in a poor-prognosis subtype of CRC tumors characterized by expression of stromal and neural associated genes. In response to spontaneous calcium transients or cellular stress, BCL9 is recruited adjacent to the interchromosomal regions, where it stabilizes the mRNA of calcium signaling and neural associated genes by interacting with paraspeckle proteins. BCL9 subsequently promotes tumor progression and remodeling of the tumor microenvironment (TME) by sustaining the calcium transients and neurotransmitter-dependent communication among CRC cells. These data provide additional insights into the role of BCL9 in tumor pathogenesis and point towards additional avenues for therapeutic intervention.
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http://dx.doi.org/10.1038/s41467-019-13842-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946813PMC
January 2020

Sequestration of simulated carbon dioxide (CO) using churning cementations waste and fly-ash in a thermo-stable batch reactor (TSBR).

Environ Sci Pollut Res Int 2020 Aug 3;27(22):27470-27479. Epub 2020 Jan 3.

Department of Chemical Engineering and Technology, IIT (BHU), Varanasi, Uttar Pradesh, 221005, India.

The degrees of mineral carbonation in (a) construction and demolition waste (C&DW) and (b) a mixture of cement and fly ash were studied through a dynamic experimental method to determine the variation in the rate and extent of CO sequestration achievable under simulated outdoor conditions. A number of experiments were performed in a self-designed rotating batch reactor by churning the two samples together with CO, which was passed through the mixtures by using water vapor as the medium of transfer. At an injection flow rate of 1 L/min for CO, the theoretical extent of carbonation was observed to be 39.1% for the mixture of cement and fly ash and 25% for C&DW. It was further observed that upon increasing the CO flow rate to 10 L/min, the carbonation in the mixture of cement and fly ash increased by 37.2% after 15 h of rotation at 60 rounds per hour (rph) for a temperature of 40 °C. Weighing, scanning electron microscopy (SEM), and energy dispersive spectrometry (EDS) were performed for the samples before and after the batch reaction to study the quantitative, qualitative and morphological aspects of the process.
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http://dx.doi.org/10.1007/s11356-019-07342-wDOI Listing
August 2020

Endoscopic submucosal dissection of esophageal metastatic melanoma.

VideoGIE 2019 Nov 14;4(11):501-504. Epub 2019 Sep 14.

Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1016/j.vgie.2019.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834970PMC
November 2019

Morphological spectrum of immune check-point inhibitor therapy-associated gastritis.

Histopathology 2020 Mar 18;76(4):531-539. Epub 2020 Feb 18.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Aims: Immune check-point inhibitors are frequently used in the treatment of a variety of solid tumours. The mechanism of action of these drugs involves up-regulation of cytotoxic T cells, which can lead to a lack of self-tolerance and immune-related adverse events, including those involving the gastrointestinal tract. This study was performed to characterise the histological features of immune check-point inhibitor therapy-associated gastritis.

Methods And Results: Gastric biopsies from patients on immune check-point inhibitor therapy with clinical suspicion of drug-associated gastrointestinal injury were identified. The predominant histological pattern of injury, distribution of injury, degree of tissue eosinophilia and prominence of apoptosis were recorded. Presenting symptoms, treatment and follow-up data were obtained by medical chart review. The 12 patients included in the study group were treated with ipilimumab, nivolumab or pembrolizumab for a variety of tumours. Symptoms at presentation included nausea, vomiting and diarrhoea. Chronic active gastritis with intra-epithelial lymphocytosis and prominent apoptosis was seen in eight of 12 patients, and was the most useful combination for the diagnosis of drug-induced gastritis in these patients. Four patients showed focal enhancing gastritis with a lymphohistiocytic cuff around inflamed glands reminiscent of Crohn's disease. One of those four patients was homozygous for the ATG16L1 Crohn's disease-associated gene variant, but had no history of inflammatory bowel disease. Ten patients responded to medication withdrawal and steroid therapy, while two required treatment with infliximab.

Conclusions: Awareness of the morphological spectrum of immune check-point inhibitor therapy-associated gastritis is important for the accurate diagnosis and prompt management of these patients.
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http://dx.doi.org/10.1111/his.14029DOI Listing
March 2020

Traditional serrated adenomas: what the endoscopist should know.

Gastrointest Endosc 2019 10;90(4):647-650

Brigham and Women's Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1016/j.gie.2019.06.024DOI Listing
October 2019

Histopathology Scoring Systems of Stenosis Associated With Small Bowel Crohn's Disease: A Systematic Review.

Gastroenterology 2020 01 30;158(1):137-150.e1. Epub 2019 Aug 30.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute; Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address:

Background & Aims: Stenosis is a common complication of Crohn's disease (CD) that has no effective medical therapy. Development of antifibrotic agents will require testing in randomized controlled trials. Computed tomography enterography- and magnetic resonance enterography-based technologies might be used to measure outcomes in these trials. These approaches have been validated in studies of patients with symptomatic strictures who underwent imaging evaluations followed by resection with histopathologic grading of the intestinal tissue for inflammation and/or fibrosis (the reference standard). Imaging findings have correlated with findings from quantitative or semiquantitative histologic evaluation of the degree of fibromuscular stenosis and/or inflammation on the resection specimen. However, it is not clear whether histologic findings are an accurate reference standard. We performed a systematic review of all published histologic scoring systems used to assess stenosing CD.

Methods: We performed a comprehensive search of Embase and MEDLINE of studies through March 13, 2019, that used a histologic scoring system to characterize small bowel CD and assessed inflammatory and fibrotic alterations within the same adult individual. All scores fitting the criteria were included in our analysis, independent of the presence of stricturing disease, as long as inflammation and fibrosis were evaluated separately but in the same scoring system.

Results: We observed substantial heterogeneity among the scoring systems, which were not derived from modern principles for evaluative index development. None had undergone formal validity or reliability testing. None of the existing indices had been constructed according to accepted methods for the development of evaluative indices. Basic knowledge regarding their operating properties were lacking. Specific indices for evaluating the important pathologic component of myofibroblast hypertrophy or hyperplasia have not been proposed.

Conclusions: In a systematic review of publications, we found a lack of validated histopathologic scoring systems for assessment of fibromuscular stenosis. Data that describe the operating properties of existing cross-sectional imaging techniques for stenosing CD should be questioned. Development and validation of a histopathology index is an important research priority.
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http://dx.doi.org/10.1053/j.gastro.2019.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649049PMC
January 2020
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