2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Clinical features and natural history of hepatocellular adenomas: the impact of obesity.

BACKGROUND: Hepatocellular adenoma is a benign tumour associated with bleeding and malignant transformation. Obesity has been linked to hepatic tumourigenesis. AIM: To evaluate the presentation of hepatocellular adenoma in obesity, and the impact of obesity on the clinical course. METHODS: Records of 60 consecutive patients (between 2005 and 2010) with a diagnosis of hepatocellular adenoma from a single tertiary centre were analysed. RESULTS: Fifty six of 60 patients were women, median age was 36years, 75% had history of contraceptive use, 18% were overweight and 55% were obese (BMI ≥30kg/m(2) ). Majority (63%) were asymptomatic; seven patients presented with bleeding. Single (28%) and multiple adenomas (72%) were encountered; size ranged from 1 to 19.7cm. Obesity was more often associated with multiple adenomas (85% vs. 48%, P=0.005), bilobar distribution (67% vs. 33%, P=0.01), lower serum albumin (P=0.007) and co-morbidities of fatty liver (P=0.006), diabetes (P=0.003), hypertension (P=0.006) and dyslipidemia (P=0.03). During median follow-up of 2.6years, there were no instances of bleeding, malignant transformation or death. Thirty four patients underwent therapeutic intervention (17 surgical resection, nine transarterial embolization and eight both interventions sequentially). The rate of complete resection of adenoma(s) was significantly lower in obese patients (8% vs. 69%, P=0.004). In the 26 patients without intervention, tumour size progression was more frequently observed in obese patients (33% vs. 0%, P=0.05). Three of 15 obese patients (20%) lost ≥5% body weight and there was no progression in the liver lesions. CONCLUSIONS: Obesity and features of metabolic syndrome were frequently observed in hepatocellular adenoma. Multiple and bilobar adenomas were more frequent in obese patients. Among patients who were conservatively managed, tumour progression was more often associated with obesity.

Hepatic involvement in a liver transplant recipient with disseminated cryptococcosis.

Cryptococcosis occurs primarily in immunocompromised patients such as organ transplant recipients. Central nervous system and pulmonary infections are documented most frequently; hepatic involvement is rarely reported. We report a case of early hepatic cryptococcosis in a 54-year-old male liver transplant recipient. Two weeks after orthotopic liver transplant, he was readmitted with fever, malaise, diarrhea, and progressive pulmonary infiltrates. On admission, liver-associated enzymes were decreased from those at discharge after transplantation. Blood and bronchoalveolar lavage cultures were positive for Cryptococcus neoformans. Despite treatment with amphotericin B and flucytosine, the patient developed both marked cholestasis and transaminase elevation. A liver biopsy performed 22 days after admission revealed numerous yeast-like organisms in hepatic sinusoids consistent with C. neoformans. Despite treatment, the patient died 55 days after admission and 66 days after transplantation. Our case illustrates hepatic involvement of cryptococcal infection within the first month following transplantation.

Gastritis from NSAIDS to Helicobacter pylori.

Gastritis is a histologic diagnosis. To understand gastritis, the radiologist must have some working knowledge of gastric histology and pathology. Therefore, this article first describes normal histologic and radiologic anatomy. The pathology of gastritis is then presented to give the radiologist a basis for understanding the radiologic findings. Finally, gastritis is discussed from a clinical and radiologic perspective.

Accuracy of EUS in the evaluation of Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma.

BACKGROUND: Nonoperative therapy with intent to cure may be considered for patients with Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma. However, a more advanced stage of disease must be precluded before such treatment. The potential of EUS for this purpose was evaluated. METHODS: EUS was performed in patients with Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma based on endoscopy, endoscopic biopsies, and CT before esophagectomy. EUS findings were compared with surgical/pathologic evaluation. RESULTS: EUS suggested submucosal invasion in 6 patients and lymph node involvement in 5 patients. By surgical/pathologic evaluation, 5 of 22 patients (23%) had unsuspected submucosal invasion and 1 had lymph node involvement. EUS detected all 5 instances of submucosal invasion and the single instance of lymph node involvement. EUS was falsely positive for submucosal invasion in 1 patient and for lymph node involvement in 4 patients. Sensitivity, specificity, and negative predictive values of preoperative EUS for submucosal invasion were 100%, 94%, and 100%, and for lymph node involvement were 100%, 81%, and 100%, respectively. A nodule or stricture noted by endoscopy was associated with an increased likelihood of submucosal invasion. CONCLUSIONS: In patients with Barrett's esophagus and high-grade dysplasia or intramucosal carcinoma, EUS detected otherwise unsuspected submucosal invasion and lymph node involvement. Patients should be evaluated with EUS when nonoperative therapy is contemplated.

Tumor-associated antigen expression and growth requirements predict tumorigenesis in squamous cell carcinoma.

Squamous cell carcinomas (SCCs) are the most common malignancies in man. While clinical specimens are theoretically ideal to study tumor development and progression, practical difficulties such as normal cell contamination, the presence of different cell types. and limited material make preclinical studies of model systems involving a homogeneous population of normal or transformed cells preferable. Tumor-associated antigens (TAAs) found on the cell surface, including integrins, mucins, cadherins, growth factor receptors, membrane bound antigens, and glycoproteins are known to play an important role in squamous carcinogenesis. We hypothesized that (1) alterations in TAA expression in vitro predict in vivo alterations, (2) analysis of a group of TAAs would provide a better indication of SCC tumorigenesis than any single marker, and (3) SCCs with independence from exogenous growth factors in vitro would demonstrate the most aggressive growth in vivo. The cell line which grew best in vitro without serum or other supplements demonstrated the most rapid tumor growth. whereas cell lines which grew only with supplements rarely formed tumors. Normal keratinocytes. eight SCC and two immortal keratinocyte cell lines were evaluated by flow cytometry for the expression of 10 cell surface markers, including alpha and beta integrins, minor blood group-related carbohydrate determinants. carcinoembryonic antigen-related proteins, E-cadherin, and GA733 (epithelial glycoprotein. epithelial cell adhesion molecule). None of the cell lines with abnormal expression of < or = 2 markers formed tumors, whereas all lines with altered expression of > or = 3 markers formed tumors. Using GA733 expression as an example, we found that altered TAA expression in vitro predicted the presence of TAA alterations in clinical specimens. In summary, in vitro independence from supplements for optimal growth and altered expression of > or = 3 cell surface markers were good predictors of SCC tumorigenesis. These findings may be useful in decreasing the need for whole animal tumorigenicity experiments.

Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBalpha.

The physiological performance of an organ depends on an interplay between changes in cellular function and organ size, determined by cell growth, proliferation and death. Nowhere is this more evident than in the endocrine pancreas, where disturbances in function or mass result in severe disease. Recently, the insulin signal-transduction pathway has been implicated in both the regulation of hormone secretion from beta cells in mammals as well as the determination of cell and organ size in Drosophila melanogaster. A prominent mediator of the actions of insulin and insulin-like growth factor 1 (IGF-1) is the 3'-phosphoinositide-dependent protein kinase Akt, also known as protein kinase B (PKB). Here we report that overexpression of active Akt1 in the mouse beta cell substantially affects compartment size and function. There was a significant increase in both beta-cell size and total islet mass, accompanied by improved glucose tolerance and complete resistance to experimental diabetes.

Lymphoid hyperplasia of the stomach: radiographic findings in five adult patients.

OBJECTIVE: The purpose of our study was to report the radiographic findings of biopsy-proven lymphoid hyperplasia of the stomach in five adult patients. CONCLUSION: Lymphoid hyperplasia of the stomach is characterized by distinctive findings on double-contrast upper gastrointestinal tract barium examinations; all five patients had innumerable tiny (1--3 mm in diameter) round frequently umbilicated nodules that carpeted the mucosa of the gastric antrum or antrum and body. Three of these five patients had associated Helicobacter pylori gastritis. The diagnosis of gastric lymphoid hyperplasia, therefore, can be suggested on the basis of the radiographic findings.

Demonstration of varicella-zoster virus infection in the muscularis propria and myenteric plexi of the colon in an HIV-positive patient with herpes zoster and small bowel pseudo-obstruction (Ogilvie's syndrome).

Gastrointestinal symptomatology as a complication of herpes zoster (HZ) is extremely rare, with the majority of reported cases showing only temporal or radiological evidence of GI tract involvement by varicella zoster virus (VZV) infection. We present the first case of documented direct VZV infection in the muscularis propria of the gut presenting as intestinal pseudo-obstruction (Ogilvie's syndrome). The patient was a 34-yr-old HIV+ man who developed small bowel pseudo-obstruction in association with disseminated cutaneous HZ. A partial ileocolectomy specimen demonstrated a focal ulcer in the terminal ileum. Immunohistochemistry against VZV gpI demonstrated diffuse staining of the muscularis propria and myenteric plexi throughout the length of the specimen. Viral particles consistent with Herpesviridae were shown to be present ultrastructurally. We postulate that the viral infection in the neuronal plexi and muscularis propria caused muscle injury leading to pseudo-obstruction.

Central venulitis in pediatric liver allografts.

Central venulitis (CV), a distinct histologic lesion described in adult liver transplants, can occur with acute portal tract rejection or in isolation (ICV). Possible etiologies include immunosuppressive drug toxicity, acute cellular rejection, viral hepatitis, ischemic injury, and recurrent disease. This study was designed to characterize ICV and to assess its potential etiology in pediatric liver recipients because this population generally does not develop recurrent disease or viral hepatitis. All posttransplantation liver biopsy specimens that were obtained from children who received liver allografts over a 4-year period were reviewed. ICV was identified in 12 of 127 posttransplantation biopsies and in 7 of 45 allograft recipients. Only 4 liver transplantations were performed for potentially recurrent diseases (primary sclerosing cholangitis). ICV first appeared in posttransplantation biopsy specimens significantly later than did portal rejection alone. The finding of CV was not significantly correlated with elevation of Tacrolimus levels, reason for transplantation, donor/recipient cytomegalovirus (CMV) status or blood type, cold ischemic times, or the incidence of outflow obstruction. The responses of CV to therapy were variable and, although the majority of cases resolved, several episodes persisted or recurred. In conclusion, ICV occurs in 16% of pediatric liver allograft recipients and does not appear to be related to recurrent disease, viral hepatitis, drug toxicity, or graft ischemia. CV may be a variant of acute rejection, but longer follow-up is required to determine the most adequate therapy for this entity.

Adenocarcinoma in colonic brushing cytology: High-grade dysplasia as a diagnostic pitfall.

Cytologic evaluation of brushing specimens obtained from the colon may be useful in the diagnosis of neoplastic and inflammatory lesions, as previous studies have reported favorable sensitivity and specificity figures for this procedure. In this study, we report our experience with 80 colonic brushings examined over a 5-yr period. Thirty cases received an atypical or malignant cytologic diagnosis. Nineteen of 20 cases diagnosed cytologically as adenocarcinoma revealed adenocarcinoma on biopsy; one case showed only adenomatous epithelium on biopsy and subsequent resection. Cases diagnosed cytologically as "atypical" or "adenomatous" showed adenocarcinoma, adenoma, and inflammatory conditions upon biopsy. Slides from 30 atypical/malignant cases were retrospectively reviewed for a number of cytomorphologic features and were correlated with the histologic diagnosis. Cases from histologically confirmed adenocarcinoma tended to show greater degrees of altered nuclear polarity, nuclear pleomorphism, membrane irregularities, and chromatin pattern alterations than those from histologically proven adenomatous or inflammatory lesions. The most likely cause of a false-positive diagnosis in this setting is sampling of an adenoma with high-grade dysplasia which fails to meet histologic criteria for adenocarcinoma (invasion of the underlying muscularis mucosae). Thus, in the second part of the study, we examined histologic sections from surgically excised adenomas to determine the frequency with which profound nuclear atypia is at least focally present, potentially resulting in a false-positive cytology diagnosis upon brushing. Slides from 51 cases were reviewed; cytologic atypia beyond that typically observed in adenomas was not observed in 43% of cases. However, profound nuclear atypia was present in 6% of cases; cytologic evaluation of a brushing specimen from these lesions may have resulted in a false-positive diagnosis of adenocarcinoma, despite the histologic diagnosis of adenoma with severe dysplasia. The remaining cases demonstrated intermediate degrees of atypia. These findings serve to quantitate the frequency with which cytohistologic discrepancies might be expected for mass lesions of the colon.

Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats.

Sepsis is the leading cause of death in surgical intensive care units. Although both mild sepsis secondary to cecal ligation and single puncture (CLP) and fulminant, double puncture CLP (2CLP) may provoke hepatocyte death, we hypothesize that regeneration compensates for cell death after CLP but not 2CLP. In male Sprague-Dawley rats, hepatic necrosis, as determined by serum alpha-glutathione S-transferase (alpha-GST) levels, was significantly but equally elevated over time after both CLP and 2CLP. Apoptosis, evaluated using both terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and morphological examination, was minimal after both CLP and 2CLP. Regeneration, assayed by staining tissue for incorporation of exogenously administered bromodeoxyuridine, was present after CLP but not after 2CLP. To further substantiate impaired regeneration, steady-state levels of mRNAs encoding JunB, LRF-1, and cyclin D1 were determined. After 2CLP, the absence of JunB, LRF-1, and cyclin D1 mRNAs confirmed failed activation of the mitogen-activated protein kinase-linked proliferative pathway and progression through the cell cycle. Therefore, failed hepatocyte regeneration may be a manifestation of hepatic dysfunction in fulminant sepsis.

Short-segment Barrett's esophagus: findings on double-contrast esophagography in 20 patients.

OBJECTIVE: The purpose of this study was to determine the findings of short-segment Barrett's esophagus on double-contrast esophagography. MATERIALS AND METHODS: A review of pathology and endoscopy data revealed 142 patients with short-segment Barrett's esophagus, which was defined as columnar epithelium in the distal esophagus extending 3 cm or less above the gastroesophageal junction at endoscopy with histopathologic confirmation of intestinal metaplasia. Twenty of these patients underwent double-contrast esophagography. These 20 patients comprised our study group. The original radiology reports and images were reviewed to determine the findings on double-contrast esophagography. Medical records were also reviewed to determine the clinical findings and treatment. RESULTS: Double-contrast esophagrams revealed hiatal hernias in 18 patients (90%), gastroesophageal reflux in 16 (80%), reflux esophagitis in seven (35%), peptic scarring or strictures in 11 (55%), and a reticular mucosal pattern in none. A total of 14 patients (70%) had morphologic findings of reflux disease with esophagitis alone (three patients), peptic scarring or strictures alone (seven patients), or both (four patients), but the remaining six (30%) had hiatal hernias or gastroesophageal reflux as the only radiographic finding. CONCLUSION: Double-contrast esophagography revealed morphologic findings of reflux disease with esophagitis, peptic scarring or strictures, or both in 70% of patients with short-segment Barrett's esophagus. Thus, the absence of esophagitis or peptic scarring or strictures on double-contrast esophagography does not exclude the possibility of short-segment Barrett's esophagus.

Cytomegalovirus colitis complicating ulcerative colitis in the steroid-naive patient.

We report a case of cytomegalovirus (CMV) presenting as acute refractory colitis in a patient with a pre-existing 14-month history of ulcerative colitis (UC) who had never previously been treated with corticosteroids or immunosuppressants. A review of existing literature and previous cases of patients with coincident CMV and UC are examined, stratifying these cases based upon absence or presence of corticosteroid use. To date, only five previous case reports of CMV colitis in patients naive to corticosteroids have been described, and only one previous case has had UC diagnosed over 4 wk before the development of CMV colitis. We further discuss the relationship between these two diseases as well as the diagnosis, treatment, patient characteristics, and outcome of CMV infection of the colon in patients with underlying UC. We discuss the need to consider the diagnosis of CMV colitis in patients with refractory UC who are not receiving corticosteroid treatment as well as those who are refractory and are being treated with immunosuppressants and/or corticosteroids.

Activation of interleukin-6/STAT3 and liver regeneration following transplantation.

BACKGROUND: Every liver that is procured, stored, and transplanted experiences injury from cold ischemia and reperfusion. Most recover quickly, but some grafts sustain enough injury to result in prolonged organ dysfunction or require retransplantation. The molecular mechanisms involved in early graft function and recovery following cold ischemia and reperfusion (I/R) after liver transplantation have not been well defined. Interleukin (IL)-6 is a critical factor in the mitogenic response within the liver, and is important for cell cycle progression and protection from injury. Activation of the latent transcription factor, STAT3, is dependent on IL-6 release. The role of the IL-6/STAT3 pathway and hepatocellular regeneration in graft recovery and cell cycle progression following cold ischemia and reperfusion was studied in a rat liver transplant orthotopic (OLT) model. Methods. Rat OLT was performed in a syngeneic model. The presence, time course, and magnitude of expression of IL-6, STAT3 activation, and upregulation of target immediate early genes were determined in liver grafts with minimal (<1 h) and prolonged (12 h) cold preservation times followed by transplantation. Progression of the cell cycle and replication was confirmed by BrdU uptake. RESULTS: Prolonged cold ischemia resulted in increased IL-6 expression and STAT3 activation. This correlated with upregulation of junB, c-fos, c-myc, and c-jun, immediate early genes associated with hepatic regeneration. Extensive DNA replication was present in livers with 12-h ischemia, demonstrating successful completion of the cell cycle. CONCLUSIONS: The participation of the IL-6/STAT3 pathway leading to cell cycle progression and regeneration is an important component in the recovery of organs immediately following cold preservation and transplantation.

An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis.

OBJECTIVES: Previous research has demonstrated that ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARs) reduce inflammation in two different murine models of colitis. This study was designed to examine the potential efficacy of rosiglitazone, a ligand for the gamma subtype of PPARs, as a therapy for active ulcerative colitis. METHODS: Fifteen patients with mild to moderately active ulcerative colitis despite therapy with 5-aminosalicylic acid compounds were enrolled in an open-label study of rosiglitazone (4 mg b.i.d. p.o.) for 12 wk. Thirteen of 15 patients were receiving concomitant therapy with corticosteroids and/or immunomodulator medications. Disease activity was measured with the Disease Activity Index. RESULTS: After 12 wk of therapy, four patients (27%) had achieved clinical remission, of whom three (20%) also had an endoscopic remission. Four additional patients (27%) had a clinical response without achieving remission. Two patients were hospitalized with worsened disease activity, and one patient was withdrawn for nephrotic syndrome. CONCLUSIONS: These data suggest that ligands for the gamma subtype of PPARs may represent a novel therapy for ulcerative colitis. A double blind, placebo-controlled, randomized trial is warranted.

p16(INK4a) expression begins early in human colon neoplasia and correlates inversely with markers of cell proliferation.

BACKGROUND & AIMS: p16(INK4a) is a cell cycle inhibitor and a major tumor-suppressor protein, but the regulation of p16(INK4a) is poorly understood and the physiologic settings in which it exerts its antiproliferative effects are unknown. A role for p16(INK4a) in intestinal neoplasia is suggested by the observation that the promoter region is methylated in a subset of human colon tumors. We examined the expression of the protein in specimens representing the full spectrum of neoplastic progression in the human colon and determined whether expressing cells showed evidence of cell cycle inhibition. METHODS: We studied p16(INK4a) expression by immunoprecipitation, immunoblotting, reverse-transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and immunofluorescence in matched normal and neoplastic colonic tissue from 70 patients. RESULTS: p16(INK4a) expression was very low in normal mucosa, with staining observed in rare epithelial cells at the base of crypts. A distinctly higher expression was found in 4 of 7 aberrant crypt foci, 32 of 36 adenomas, 18 of 28 primary carcinomas, and 5 of 5 metastatic carcinomas. Within each neoplasm p16(INK4a) staining was heterogeneous, with higher expression commonly seen in areas bordering normal tissue. p16(INK4a) staining correlated inversely with that of Ki67, cyclin A, and the retinoblastoma protein, suggesting that cell cycle progression was inhibited. CONCLUSIONS: These results suggest that p16(INK4a) expression begins in the earliest detectable stages of neoplastic progression in the human colon and exerts a continuous, piecemeal constraint on tumor growth.

Giant hyperplastic polyps in the stomach: radiographic findings in seven patients.

OBJECTIVE: We reassessed the radiographic findings of giant hyperplastic polyps in the stomach on double-contrast upper gastrointestinal examinations in seven patients. CONCLUSION: Giant hyperplastic polyps in the stomach may be manifested by distinctive findings on double-contrast barium studies, appearing as polypoid lesions with multiple lobulated components that form a conglomerate mass. Nevertheless, endoscopy and biopsy are required to rule out a polypoid carcinoma as the cause of these findings.