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BackgroundHistologic features of idiopathic non-cirrhotic portal hypertension (INCPH) may overlap with those without INCPH. Recently, these features have been recognized as part of the larger spectrum of porto-sinusoidal vascular disease (PSVD). We assessed interobserver agreement on histologic features that are commonly associated with INCPH and studied whether a provision of relevant clinical history improves interobserver agreement.MethodsThe examined histologic features include lobular (such as anisocytosis, nodular regeneration, sinusoidal dilatation, increased parenchymal draining veins, and incomplete fibrous septa) and portal tract changes (such as paraportal shunting vessel(s), portal tract remnant, increased number of portal vessels, and obliterative portal venopathy). Thirty-four archived liver samples from patients with (group A) and without (group B) INCPH were retrieved. A total of 90 representative images of lobules (L) and portal tracts (P) were distributed among 9 liver pathologists blinded to true clinical history. Each pathologist answered multiple choice questions based on the absence (Q1) or presence (Q2) of clinical history of portal hypertension. Fleiss' kappa coefficient analysis (unweighted) was performed to assess interobserver agreement on normal versus abnormal diagnosis, in L and P, based on Q1 and Q2.ResultsThe kappa values regarding normal versus abnormal diagnosis were 0.24, 0.24, 0.18 and 0.18 for L-Q1, L-Q2, P-Q1, and P-Q2, respectively. With true clinical history provided, the kappa values were L- 0.32, P-0.17 for group A and L-0.12, P-0.14 for group B. Four pathologists changed their assessments based on the provided history. Interobserver agreement on the interpretation of L and P as normal versus abnormal was slight to fair regardless of provision of clinical history.ConclusionsOur findings indicate that the histologic features of INCPH/PSVD are not limited to patients with portal hypertension and are subject to significant interobserver variation.

Fusobacterium nucleatum, a Gram-negative oral anaerobe, is a significant contributor to colorectal cancer. Using an in vitro cancer progression model, we discover that F. nucleatum stimulates the growth of colorectal cancer cells without affecting the pre-cancerous adenoma cells. Annexin A1, a previously unrecognized modulator of Wnt/β-catenin signaling, is a key component through which F. nucleatum exerts its stimulatory effect. Annexin A1 is specifically expressed in proliferating colorectal cancer cells and involved in activation of Cyclin D1. Its expression level in colon cancer is a predictor of poor prognosis independent of cancer stage, grade, age, and sex. The FadA adhesin from F. nucleatum up-regulates Annexin A1 expression through E-cadherin. A positive feedback loop between FadA and Annexin A1 is identified in the cancerous cells, absent in the non-cancerous cells. We therefore propose a "two-hit" model in colorectal carcinogenesis, with somatic mutation(s) serving as the first hit, and F. nucleatum as the second hit exacerbating cancer progression after benign cells become cancerous. This model extends the "adenoma-carcinoma" model and identifies microbes such as F. nucleatum as cancer "facilitators".

The absence of IFN-[gamma] receptor (IFN-[gamma]R) or STAT1 signaling in donor cells has been shown to result in reduced induction of acute graft-versus-host disease (GVHD). In this study, we unexpectedly observed increased activation and expansion of donor lymphocytes in both lymphohematopoietic organs and GVHD target tissues of IFN-[gamma]R/STAT1-deficient recipient mice, leading to rapid mortality following the induction of GVHD. LPS-matured, BM-derived [Ifngr1.sup.-/-] [Stat1.sup.-/-] DCs (BMDCs) were more potent allogeneic stimulators and expressed increased levels of MHC II and costimulatory molecules. Similar effects were observed in human antigen-presenting cells (APCs) with knockdown of Stat1 by CRISPR/Cas9 and treatment with a JAK1/2 inhibitor. Furthermore, we demonstrated that the absence of IFN-[gamma]R/STAT1 signaling in hematopoietic APCs impaired the presentation of exogenous antigens, while promoting the presentation of endogenous antigens. Thus, the indirect presentation of host antigens to donor lymphocytes was defective in IFN-^R/STAT1-deficient, donor-derived APCs in fully donor chimeric mice. The differential effects of IFN-[gamma]R/STAT1 signaling on endogenous and exogenous antigen presentation could provide further insight into the roles of the IFN-[gamma]/STAT1 signaling pathway in the pathogenesis of GVHD, organ rejection, and autoimmune diseases., Introduction IFN-[gamma] is a pleiotropic cytokine with a central role in host defense and immunopathology and is involved in both innate and adaptive immunity (1, 2). IFN-[gamma] is the only [...]

We present a case of COVID-19 hepatitis in a living donor liver allograft recipient whose donor subsequently tested positive for COVID-19. The patient is a female infant with biliary atresia (failed Kasai procedure). She recovered well, with improving liver function tests for 4 days. On postoperative day 4 the patient developed respiratory distress and fever. COVID-19 testing (polymerase chain reaction) was positive. Liver function test results increased approximately 5-fold. Liver biopsy showed moderate acute hepatitis with prominent clusters of apoptotic hepatocytes and associated cellular debris. Lobular lymphohistiocytic inflammation was noted. Typical portal features of mild to moderate acute cellular rejection were also noted. doi: 10.5858/arpa.2020-0186-SA, A novel coronavirus (2019-nCoV, SARS-CoV2, or COVID-19) with significant morbidity and mortality was detected in Wuhan, China, in December 2019. (1) Though respiratory failure appears to be the primary mechanism [...]

Objective. Evaluate the incidence of nephrogenic systemic fibrosis (NSF) in patients with liver disease in the peritransplant period. Materials and Methods. This IRB approved study retrospectively reviewed patients requiring transplantation for cirrhosis, hepatocellular carcinoma (HCC), or both from 2003 to 2013. Records were reviewed identifying those having gadolinium enhanced MRI within 1 year of posttransplantation to document degree of liver disease, renal disease, and evidence for NSF. Results. Gadolinium-enhanced MRI was performed on 312 of 837 patients, including 23 with severe renal failure (GFR < 30 mL/min/1.73 cm(2)) and 289 with GFR > 30. Two of 23 patients with renal failure developed NSF compared to zero NSF cases in 289 patients with GFR > 30 (0/289; P < 0.003). High dose gadodiamide was used in the two NSF cases. There was no increased incidence of NSF with severe liver disease (1/71) compared to nonsevere liver disease (1/241; P = 0.412). Conclusion. Renal disease is a risk factor for NSF, but in our small sample our evidence suggests liver disease is not an additional risk factor, especially if a low-risk gadolinium agent is used. Noting that not all patients received high-risk gadolinium, a larger study focusing on patients receiving high-risk gadolinium is needed to further evaluate NSF risk in liver disease in the peritransplant period.

Context.--In advanced gastric, esophageal, and gastroesophageal junction adenocarcinomas (GE-GEJ-AC) that overexpress ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2), anti-HER2 monoclonal antibody therapy confers survival benefit. To select patients for treatment, HER2 expression and gene amplification are evaluated by immunohistochemistry (IHC) and in situ hybridization. Objective.--To determine whether GE-GEJ-AC tested for HER2 on biopsy specimens of a primary tumor show different IHC scores and/or HER2 amplification by in situ hybridization in matched resection specimens, potentially changing therapy eligibility. Design.--Immunohistochemistry and silver in situ hybridization were performed in biopsy and/or resection specimens from 100 patients. HER2 testing was performed in matched resection and biopsy specimens of 15 cases to determine whether GE-GEJ-AC with IHC scores of 0, 1+, and 2+ in biopsy and resection specimens had different IHC and silver in situ hybridization results. Results.--The IHC 3+ cases showed HER2 amplification in 4 of 5 cases (80%), and IHC scores of 0, 1+, and 2+ showed 3.5%, 14.3%, and 23.5% HER2 amplification by silver in situ hybridization. Among the 15 paired biopsy and resection specimens, 9 (60%) had at least pT2 stage GE-GEJ-AC with HER2 IHC scores of 0, 1+, or 2+ in the biopsy, and 2 of those 9 cases (22%) had IHC 3+ and HER2 amplification by silver in situ hybridization on the resection specimen. Conclusions.--Our data suggest that HER2 testing should be repeated on resection specimens of GE-GEJ-AC with HER2 IHC scores of negative (0 and 1+) or equivocal (2+) and in situ hybridization amplification negative biopsy specimen results to evaluate for HER2 heterogeneity when patients are being considered for anti-HER2 therapy. doi: 10.5858/arpa.2017-0039-OA, Gastric adenocarcinoma is the most frequent malignancy arising in the stomach, and nearly 1 million new cases were estimated to have occurred in 2012, representing the fifth most common malignancy [...]

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC‐reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection‐stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC‐specific mucosal pentraxin (Mptx2) in activated PCs. A PC‐specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen‐induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression. Synopsis: Changes in Paneth cell (PC) gene expression and function have been linked to various inflammatory intestinal diseases, such as Crohn's disease. Here, a single‐cell transcriptomic analysis of PC heterogeneity in mice identifies a CD74+ PC subset that is expanded upon inflammation or infection to secrete innate immune response molecules. Single‐cell transcriptome analysis reveals that PC heterogeneity can be modified by microbiota colonization in germ‐free mice.A CD74+ PC subset is expanded upon mouse infection with invasive pathogens, in mouse models of ileitis, and in inflammatory bowel disease–patient biopsies.Paneth cell‐specific ablation of MyD88 pathway dampens the expansion and secretory function of CD74+ PCs upon infection.Deletion of Mptx2, a mucosal pentraxin that is enriched in CD74+ PCs, reduces complement activation and inflammation upon infection. [ABSTRACT FROM AUTHOR]

To the Editor.--For the past 2 months, New York City has been the epicenter of the ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus). The disease [...]