Integrated transcriptomics and histopathology approach identifies a subset of rejected donor livers with potential suitability for transplantation.

BACKGROUND: Liver transplantation is an effective treatment for liver failure. There is a large unmet demand, even as not all donated livers are transplanted. The clinical selection criteria for donor livers based on histopathological evaluation and liver function tests are variable. We integrated transcriptomics and histopathology to characterize donor liver biopsies obtained at the time of organ recovery. We performed RNA sequencing as well as manual and artificial intelligence-based histopathology (10 accepted and 21 rejected for transplantation). RESULTS: We identified two transcriptomically distinct rejected subsets (termed rejected-1 and rejected-2), where rejected-2 exhibited a near-complete transcriptomic overlap with the accepted livers, suggesting acceptability from a molecular standpoint. Liver metabolic functional genes were similarly upregulated, and extracellular matrix genes were similarly downregulated in the accepted and rejected-2 groups compared to rejected-1. The transcriptomic pattern of the rejected-2 subset was enriched for a gene expression signature of graft success post-transplantation. Serum AST, ALT, and total bilirubin levels showed similar overlapping patterns. Additional histopathological filtering identified cases with borderline scores and extensive molecular overlap with accepted donor livers. CONCLUSIONS: Our integrated approach identified a subset of rejected donor livers that are likely suitable for transplantation, demonstrating the potential to expand the pool of transplantable livers.

Dietary L-Tryptophan consumption determines the number of colonic regulatory T cells and susceptibility to colitis via GPR15.

Environmental factors are the major contributor to the onset of immunological disorders such as ulcerative colitis. However, their identities remain unclear. Here, we discover that the amount of consumed L-Tryptophan (L-Trp), a ubiquitous dietary component, determines the transcription level of the colonic T cell homing receptor, GPR15, hence affecting the number of colonic FOXP3+ regulatory T (Treg) cells and local immune homeostasis. Ingested L-Trp is converted by host IDO1/2 enzymes, but not by gut microbiota, to compounds that induce GPR15 transcription preferentially in Treg cells via the aryl hydrocarbon receptor. Consequently, two weeks of dietary L-Trp supplementation nearly double the colonic GPR15+ Treg cells via GPR15-mediated homing and substantially reduce the future risk of colitis. In addition, humans consume 3-4 times less L-Trp per kilogram of body weight and have fewer colonic GPR15+ Treg cells than mice. Thus, we uncover a microbiota-independent mechanism linking dietary L-Trp and colonic Treg cells, that may have therapeutic potential.

Liver Transplantation in a Woman with Mahvash Disease.

Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.

Colonic Eosinophilia: Clinicopathologic Study of Paired Right and Left Colon Biopsies from 276 Patients.

OBJECTIVE: This study evaluated differences in eosinophil (Eos) count in the right colon (RC) and left colon (LC) relative to known clinical and pathologic features. METHODS: H&E slides from 276 subjects with biopsies taken from both RC and LC were reviewed. Eos/mm2 were counted in the area with highest concentration then correlated with clinical and pathologic findings for RC and LC. RESULTS: There were higher numbers of Eos/mm2 in RC than in LC (mean 177 vs 122, respectively p<0.0001), and there was significant positive correlation between Eos numbers in the two locations (r=0.57, p<0.001). In RC, the mean Eos/mm2 was 242 with active chronic colitis, 195 with inactive chronic colitis, 160 in microscopic colitis, 144 in quiescent IBD, and 142 with normal histology (p<0.001), and was higher in males (204 vs 164, p=0.022). In LC, mean Eos/mm2 was 186 with active chronic colitis, 168 with inactive chronic colitis, 154 in microscopic colitis, 82 in quiescent IBD, and 84 with normal histology (p<0.001), and was higher in males (154 vs 107, p<0.001). In biopsies with normal histology, RC showed higher mean Eos/mm2 in Asian patients (228 vs 139, p=0.019), and patients with history of UC (205 vs 136, p=0.004), but was not significantly different in patients with or without irritable bowel syndrome with diarrhea (IBS-D) or history of Crohn's disease (CD). In LC the mean Eos/mm2 was higher in males (102 vs 77, p=0.036), and history of CD (117 vs 78, p=0.007), but was not significantly different in patients with or without IBS-D or history of UC. The number of Eos/mm2 was greater in biopsies performed in the summer than during other seasons of the year. CONCLUSION: The mean number of Eos/mm2 in colorectal biopsies varies significantly by location, histopathologic changes, clinical diagnosis, season, gender and ethnicity. Of particular interest is the association between high Eos/mm2 in RC biopsies with otherwise normal histology and clinical history of UC, and in LC biopsies with clinical history of CD. Additional larger and prospective studies that include normal healthy volunteers are needed to establish a reliable cutoff for the histopathologic diagnosis of eosinophilic colitis, taking into consideration the biopsy site within the colon and rectum, as well as patient gender and ethnicity.Presented in part at the annual American College of Gastroenterology meeting, San Antonio, TX October 2019.

Longitudinal ultrasound imaging and network modeling in rats reveal sex-dependent suppression of liver regeneration after resection in alcoholic liver disease.

Liver resection is an important surgical technique in the treatment of cancers and transplantation. We used ultrasound imaging to study the dynamics of liver regeneration following two-thirds partial hepatectomy (PHx) in male and female rats fed via Lieber-deCarli liquid diet protocol of ethanol or isocaloric control or chow for 5-7 weeks. Ethanol-fed male rats did not recover liver volume to the pre-surgery levels over the course of 2 weeks after surgery. By contrast, ethanol-fed female rats as well as controls of both sexes showed normal volume recovery. Contrary to expectations, transient increases in both portal and hepatic artery blood flow rates were seen in most animals, with ethanol-fed males showing higher peak portal flow than any other experimental group. A computational model of liver regeneration was used to evaluate the contribution of physiological stimuli and estimate the animal-specific parameter intervals. The results implicate lower metabolic load, over a wide range of cell death sensitivity, in matching the model simulations to experimental data of ethanol-fed male rats. However, in the ethanol-fed female rats and controls of both sexes, metabolic load was higher and in combination with cell death sensitivity matched the observed volume recovery dynamics. We conclude that adaptation to chronic ethanol intake has a sex-dependent impact on liver volume recovery following liver resection, likely mediated by differences in the physiological stimuli or cell death responses that govern the regeneration process. Immunohistochemical analysis of pre- and post-resection liver tissue validated the results of computational modeling by associating lack of sensitivity to cell death with lower rates of cell death in ethanol-fed male rats. Our results illustrate the potential for non-invasive ultrasound imaging to assess liver volume recovery towards supporting development of clinically relevant computational models of liver regeneration.

Lymphocytic Esophagitis Is Not Similar to Eosinophilic Esophagitis Except for Seasonal Variation.

OBJECTIVE: Unlike eosinophilic esophagitis (EoE), there is no consensus on the minimum number of intraepithelial lymphocytes (IEL) that is diagnostic of lymphocytic esophagitis (LyE). The aim of this study was to determine whether significant correlations exist between the numbers of intraepithelial lymphocytes (IEL) in esophageal biopsies and clinical and endoscopic manifestations usually associated with EoE. METHODS: H&E slides from esophageal biopsies from 330 patients were reviewed. The number of IEL and intraepithelial eosinophils (IEE) per mm2 was counted in the area with the highest concentration in each biopsy. The numbers were then correlated with clinical and endoscopic findings. RESULTS: As expected, a higher number of IEE was significantly associated with food impaction (p=0.001), dysphagia (p=0.021), esophageal stricture (p=0.017), rings (P<0.0001), and furrows (p<0.0001). By contrast, there was no significant association between increased IEL and any of the aforementioned clinical and endoscopic features in the original 330 patients or in a subset of 233 patients with no IEE. Interestingly, the number of both IEE and IEL varied significantly by the season when the biopsy was obtained, being lowest in the fall and highest in the spring (p=0002 for IEE and p<0.0001 for IEL). CONCLUSION: In esophageal biopsies, increased IEL has no significant correlation with food impaction or dysphagia or with esophageal stricture, rings, or furrows. There is significant variation in the number of IEL depending on the season when the biopsy is obtained, which has not been previously reported.

Acute Liver Failure Requiring Liver Transplantation due to Acute Hepatitis A Virus Infection.

INTRODUCTION: Hepatitis A infection (HAV) is generally characterized by an acute icteric illness or may have a subclinical self-limited course, although rarely, can result in fulminant hepatitis and death. In 2019, the City of Philadelphia declared a public health emergency due to an HAV outbreak. We are reporting a series of four cases of acute liver failure (ALF) requiring liver transplantation (LT) due to acute HAV. METHODS: Chart review and case descriptions of four patients with acute HAV-related ALF who were expeditiously evaluated, listed as Status 1A, and who underwent LT between August 2019 and October 2019 at Thomas Jefferson University Hospital. RESULTS: All four patients presented with acute hepatocellular jaundice and had a positive HAV IgM, and all other causes of ALF were excluded. All four cases met the American Association for the Study of Liver Diseases (AASLD) criteria for ALF. Three of the four cases met King's College Criteria of poor prognosis for nonacetaminophen-induced ALF. All four patients underwent successful LT and were discharged six to twelve days postoperatively. One patient died of disseminated Aspergillus infection five months after LT, while the others have had excellent clinical outcomes shown by one-year follow-ups. All four explants had remarkably similar histological changes, revealing acute hepatitis with massive necrosis accompanied by a prominent lymphoplasmacytic inflammatory infiltrate and bile ductular proliferation. CONCLUSION: Although rare, patients presenting with acute HAV need close monitoring as they may rapidly progress to ALF. Early referral to a transplant center afforded timely access to LT and yielded overall good one-year survival. Widespread HAV vaccination for high-risk individuals is an essential strategy for preventing disease and curbing such future outbreaks.

The Significance of So-Called Equivocal Immunohistochemical Staining for Cytomegalovirus in Colorectal Biopsies.

CONTEXT.­: Recent studies examining immunohistochemical staining of colorectal biopsies for cytomegalovirus (CMV) reported that some cases showed only occasional small positive nuclei that were called equivocal for CMV. OBJECTIVES.­: To determine the extent and clinical significance of equivocal CMV staining in colorectal biopsies. DESIGN.­: Two-hundred twenty-one consecutive cases of colon and rectal biopsies that were stained for CMV by immunohistochemistry were retrieved from our files and reviewed. Staining results were recorded as negative, unequivocal, or equivocal. Results were correlated with clinicopathologic data, results of polymerase chain reaction studies for CMV, and treatment history. RESULTS.­: Fifty-two cases (24% of all tested, 63% of positive cases) showed equivocal staining for CMV, and of these, 41 had follow-up information. Polymerase chain reaction for CMV was performed largely on blood samples and was not found to be sensitive for the detections of CMV proctocolitis. Of 25 patients who received antiviral treatment, 21 (84%) had complete resolution of symptoms, compared with 8 of 16 (50%) who did not receive antivirals (P = .02). There was no statistically significant difference in response to antiviral drugs in patients with equivocal and unequivocal CMV staining (P = .17). CONCLUSIONS.­: Equivocal CMV staining likely represents true CMV proctocolitis. Prospective studies are needed to confirm these findings.

Mesonephric Adenocarcinoma of the Uterine Corpus: Report of 2 Cases and Review of the Literature.

Mesonephric adenocarcinoma (MNA) is believed to arise from benign mesonephric remnants or hyperplasia located in the lateral walls of the uterine cervix. They are uncommon in other sites of the gynecologic tract, and exceptionally rare in the uterine corpus. So far, only 30 cases of uterine MNA have been reported in the literature, as a result, the etiology, clinical behavior, choice of treatment, and histogenesis of uterine MNA are still unclear. In this study, we report 2 cases of MNA of uterine corpus. One case involved the inner half of myometrium with endometrial involvement; the second case involved the outer half of myometrium without endometrial involvement. We also reviewed the clinical and pathologic presentations of this rare entity, and discussed the histogenesis of uterine corpus MNA based on recent molecular findings.

Primary pulmonary lymphoproliferative neoplasms.

Pulmonary lymphoproliferative neoplasms are rare lung tumors and account for <1% of all lung tumors. Among them, primary pulmonary lymphomas (PPL) constitute the majority, which include Non-Hodgkin's lymphoma (NHL) that comprise of mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphomas and other rare types of NHL and lymphomatoid granulomatosis. HL, which arises secondary to contiguous spread from the mediastinum, is the rarest type of PPL. Other entities described within the umbrella of pulmonary lymphoproliferative neoplasms include pleural lymphomas and posttransplant lymphoproliferative disorders (PTLD) - which occurs in the poststem cell and organ transplant patients. These neoplasms although rare, have a favorable prognosis, which does not depend on disease resectability. Moreover, with its nonspecific presentation, diagnosis is challenging, which often leads to delayed diagnosis or misdiagnosis in many cases. Therefore, knowledge of this entity is important for the practicing pulmonologist. This review article aims to describe the clinical presentation, diagnosis and management of primarily the entities within PPL, as well as pleural lymphomas and PTLD.

Low Grade Carcinoma Ex-Pleomorphic Adenoma: Diagnosis and Diagnostic Challenges Caused by Fine Needle Aspiration: Report of Three Cases and Review of Literature.

Low grade carcinoma ex pleomorphic adenoma (LG CXPA) is a rare low grade malignant neoplasm arising from preexisting pleomorphic adenoma (PA). LG CXPA demonstrates no overt cytological atypia, and can be difficult to distinguish from cellular PA. Invasive growth is one of the hallmarks of LG CXPA, e.g., tumor extends beyond the capsule and into adjacent non-neoplastic tissue. However, it is known that capsular and vascular invasion, as well as the presence of stroma-rich PA in soft tissue without a capsule (pseudopodia) can be seen in PA. These histological findings have no prognostic significance and are not diagnostic of malignancy. In addition, recurrent PA typically presents as numerous nodules extending into soft tissue and skeletal muscle, which again are not considered malignant features. Thus, "infiltrative growth" of LG CXPA is difficult to define and diagnosis is challenging to many practicing pathologists. In this study, we report three cases of LG CXPA. We review the diagnostic criteria for LG CXPA, and discuss the diagnostic challenges caused by fine needle aspiration (FNA) changes. FNA is widely used as a cost-effective, quick and accurate method for diagnosing salivary gland lesions. Histological changes post-FNA are usually focal and mild, and are not causes of diagnostic difficulties. According to our knowledge, this is the first report of LG CXPA complicated with FNA changes.

Hemoglobin Wayne Trait with Incidental Polycythemia.

Hemoglobinopathies, caused by mutations in the globin genes, are one of the most common inherited disorders. Many of the hemoglobin variants can be identified by hemoglobin analysis using conventional electrophoresis and high performance liquid chromatography; however hemoglobin DNA analysis may be necessary in other cases for confirmation. Here, we report a case of a rare alpha chain hemoglobin variant, hemoglobin Wayne, in a 47-year-old man who presented with secondary polycythemia. Capillary zone electrophoresis and high performance liquid chromatography revealed a significant amount of a hemoglobin variant, which was further confirmed by hemoglobin DNA sequencing as hemoglobin Wayne. Since the patient was not homozygous for hemoglobin Wayne, which is associated with secondary polycythemia, the laboratory diagnosis in this case was critical in ruling out hemoglobinopathy as the etiology of his polycythemia.

Anaplastic Transformation in Mandibular Metastases of Follicular Variant of Papillary Thyroid Carcinoma: A Case Report and Review of the Literature.

Anaplastic transformation of well-differentiated thyroid carcinomas at distant metastatic sites is a rare condition. Most cases described in the literature have occurred in the thyroid or regional lymph nodes. We report a case of anaplastic transformation of the follicular variant of papillary thyroid carcinoma in mandibular metastases. A 76-year-old female presented with a painful and enlarging mandibular mass. She had been treated in the past for the follicular variant of papillary thyroid carcinoma. A palliative hemi-mandibulectomy was performed. Histology revealed a metastatic papillary thyroid carcinoma, follicular variant, with an unusual finding of solid pleomorphic epithelioid and spindle cell areas, consistent with anaplastic transformation.

Prostate Adenocarcinoma Metastasis to the Bilateral Ureters: a Rare but Potentially Important Finding.

The ureter is an extremely rare location for metastasis from prostate carcinoma. Here we present an autopsy case of an 82-year-old gentleman with history of prostate carcinoma who exhibited bilateral urinary tract obstruction secondary to metastatic prostate carcinoma. Our extensive literature search revealed only 44 cases of prostate carcinoma with ureteral metastasis worldwide that had been reported in the last century. Though it is an unusual pattern, ureteral metastasis should always be considered for a patient with urinary obstruction in the setting of prostate adenocarcinoma.