Segmental Duodenal Resections: Toward Defining Indications, Complexity, and Coding.

BACKGROUND: Segmental resections of the duodenum are uncommonly performed and are technically challenging due to intimate relationships with the biliary tree, pancreas, and superior mesenteric vessels. The objective of this study was to assess indications, operative strategy, and outcomes of duodenal resections and to advocate that this form of resection deserves its own unique Current Procedural Terminology (CPT) and Relative Value Unit (RVU) structure. METHODS: Patients undergoing isolated and partial duodenal resection from 2008-2023 at University of Tennessee Health Science Center affiliated hospitals were retrospectively reviewed. Factors examined included clinical presentation, diagnostic evaluation, operative time, and technique, 90-day morbidity and mortality, and pathologic and survival outcomes. RESULTS: Thirty-one patients were identified with majority female and a median age of 61. Diagnostic studies included computed tomography and upper (including push) endoscopy. Reconstruction most often involved side-to-side duodenojejunostomy following distal duodenal resection. Intraoperative evaluation (IOE) of the biliary tree was utilized to assess and protect pancreaticobiliary structures in eleven patients. Median operative time was 206 min, increasing to 236 min when IOE was necessary. Procedure-related morbidity was 23% with one 90-day mortality. Median postoperative length of stay was 9 days. Pathology included benign adenoma, adenocarcinoma, GIST, neuroendocrine neoplasms, and erosive metastatic deposit. CONCLUSION: Duodenal resections can be effectively employed to safely address diverse pathologies. These procedures are characterized by long operative times, extended hospital stays, and an incidence of postoperative complications that mimics that of pancreatic resection. This work highlights the need for modification to the CPT system to accurately define these distinct procedures for future research endeavors and development of a more accurate valuation unit.

Peri-Ampullary Metastasis From Endometrial Adenocarcinoma: A Rare Etiology of Obstructive Jaundice.

Endometrial cancer is the commonest gynecologic malignancy, of which adenocarcinoma is the most common histologic type. While most women who relapse present with local symptoms within 3 years of the initial diagnosis, metastatic disease usually involves the abdominal cavity and liver. Herein we present a rare case of a patient with a remote history of endometrial adenocarcinoma status-post curative surgical resection and adjuvant therapy who presented with obstructive jaundice proved to be secondary to peri-ampullary metastasis of uterine adenocarcinoma.

Deregulation of Hippo kinase signalling in human hepatic malignancies.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and hepatoblastoma (HB) are the main hepatic malignancies with limited treatment options and high mortality. Recent studies have implicated Hippo kinase pathway in cancer development, but detailed analysis of Hippo kinase signalling in human hepatic malignancies, especially CC and HB, is lacking. METHODS: We investigated Hippo kinase signalling in HCC, CC and HB using cells and patient samples. RESULTS: Increased expression of yes-associated protein (Yap), the downstream effector of the Hippo kinase pathway, was observed in HCC cells, and siRNA-mediated knockdown of Yap resulted in decreased survival of HCC cells. The density-dependent activation of Hippo kinase pathway characteristic of normal cells was not observed in HCC cells and CCLP cells, a cholangiocarcinoma cell line. Immunohistochemistry of Yap in HCC, CC and HB tissues indicated extensive nuclear localization of Yap in majority of tissues. Western blot analysis performed using total cell extracts from patient samples and normal livers showed extensive activation of Yap. Marked induction of Glypican-3, CTGF and Survivin, the three Yap target genes was observed in the tumour samples. Further analysis revealed significant decrease in expression and activity of Lats kinase, the main upstream regulator of Yap. However, no change in activation of Mst-2 kinase, the upstream regulator of Lats kinase was observed. CONCLUSIONS: These data show that Yap induction mediated by inactivation of Lats is observed in hepatic malignancies. These studies highlight Hippo kinase pathway as a novel therapeutic target for hepatic malignancies.

Celiac disease autoantibodies in severe autoimmune liver disease and the effect of liver transplantation.

BACKGROUND/AIMS: Celiac disease (CD) is associated with primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. We investigated the following: (i) the prevalence of tissue transglutaminase antibodies (tTGAs) and endomysial antibodies (EMAs) in end-stage autoimmune liver disease (ESALD), (ii) the correlation among auto-antibodies and the human leucocyte antigen (HLA) haplotype, and (iii) the effect of liver transplantation on antibody kinetics. METHODS: Pretransplantation sera from 488 patients (310 with ESALD, and 178 with non-autoimmune disease) were tested for tTGAs. Positive samples were also tested for EMAs, and retested 6-12 and > or = 24 months post-transplantation. Results were correlated with the HLA type of the recipient. RESULTS: Serological evidence of CD was found in 3% (ESALD) vs. 0.6% (non-autoimmune) of the patients (five-fold increased risk in ESALD). The prevalence of tTGAs (14.2 vs. 5.4%, P=0.0001) and EMAs (4.3 vs. 0.78%, P=0.01) was significantly higher in patients with the HLA-DQ2 or HLA-DQ8 haplotypes. tTGAs and EMAs normalized in 94 and 100%, respectively, without gluten exclusion post-transplantation. Post-transplantation, of the five patients with symptoms of 'classical' CD, three improved. Intestinal lymphoma was diagnosed in another two cases with clinically 'silent' CD. CONCLUSIONS: Patients with ESALD, especially those who are HLA-DQ2 or HLA-DQ8 positive had a high prevalence of CD-associated antibodies. Both tTGAs and EMAs decreased post-transplantation without gluten withdrawal. Immunosuppression may improve symptoms of CD, but might not prevent progression to intestinal lymphoma.

Metabotropic glutamate receptors as drug targets.

L-glutamate (Glu), the main excitatory amino acid neurotransmitter in the mammalian central nervous system, is involved in many physiological functions, including learning and memory, but also in toxic phenomena occurring in numerous degenerative or neurological diseases. These functions mainly result from its interaction with Glu receptors (GluRs). The broad spectrum of roles played by glutamate derived from the large number of membrane receptors, which are currently classified in two main categories, ionotropic (iGluRs) and metabotropic (mGluRs) receptors. The iGluRs are ion channels, permeant to Na(+) (Ca(2+)) while the mGluRs belongs to the superfamily of G-protein coupled receptors (GPCRs). Despite continuous efforts over more than two decades, the use of iGluR agonists or antagonists to improve or inhibit excitatory transmission in pathological states still remains a major challenge, though the discovery and development of recent molecules may prove it worthwhile. This probably results form the vital role of fast excitatory transmission in many fundamental physiological functions. Since the discovery of mGluRs, hope has emerged. Indeed, mGluRs are mainly involved in the regulation of fast excitatory transmission. Consequently, it was logically thought that modulating mGluRs with agonists or antagonists might lead to more subtle regulation of fast excitatory transmission than by directly blocking iGluRs. As a result of intensive investigation, new drugs permitting to discriminate between these receptors have emerged. Moreover, a new class of molecules acting as negative or positive allosteric modulators or mGluRs is now available and appears to be promising. In the following, we will review the classification of mGluRs and the functions in which mGluRs are involved. We will focus on their potential as therapeutic targets for improving numerous physiological functions and for different neurodegenerative and neuropsychiatric disorders, which are related to malfunction of Glu signaling in human beings.

Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae?

BACKGROUND/AIMS: The etiology and pathogenesis of primary biliary cirrhosis (PBC) remain elusive. Both an infectious etiology and molecular mimicry have been implicated. The aim is to study the prevalence of Chlamydial antigens and RNA in the liver tissue of patients with PBC. METHODS: We compared the prevalence of Chlamydial antigen and RNA in 25 explants with PBC who underwent orthotopic liver transplantation with 105 explanted livers from other chronic liver disease. We also studied 14 liver biopsies from patients with early stages of PBC. Donor livers were also studied. RESULTS: In all 39 patients with PBC, Chlamydia pneumoniae antigens were present but not Chlamydia trachomatis, and only 9/105 (8.5%) of patients in the other categories were positive (P<0.01) for C. pneumoniae. Eight explanted PBC livers were tested for C. pneumoniae 16S RNA by in situ hybridization and were positive. CONCLUSIONS: The presence of C. pneumoniae antigen and RNA in liver tissue of patients with PBC suggests that C. pneumoniae antigen may trigger an immune response based on molecular mimicry.

Successful endoscopic treatment of mediastinal pseudocysts.

Mediastinal pseudocysts can pose a diagnostic and therapeutic challenge to the clinician and surgeon. Recognizing their presence and instituting appropriate therapy can reduce morbidity and mortality. This report describes unusual clinical features in a patient presenting with multiple mediastinal pseudocysts due to pancreatic duct leak secondary to pancreatic duct stenosis and an entrapment of a pancreatic duct stone. Successful endoscopic therapy averted the need for surgery.

Hepatitis B virus enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity by increasing TRAIL-R1/death receptor 4 expression.

BACKGROUND/AIMS: Apoptosis by death receptors, such as Fas and tumor necrosis factor (TNF)-alpha receptor-1, play a significant role in the pathogenesis of hepatitis B virus (HBV)-infections. Although liver also expresses death receptors for TNF-related apoptosis-inducing ligand (TRAIL), information is lacking regarding the effects of HBV on apoptosis by TRAIL. Thus, the aims of this study were to examine the effects of HBV replication on TRAIL cytotoxicity. METHODS: Hep G2 and Hep G2.215 cells, the latter which is stably transfected with HBV, were employed for these studies. RESULTS: TRAIL-mediated cell killing was concentration-dependent and greater in Hep G2.2.15 cells at all doses as compared to the parent cell line, Hep G2 cells. Cell death by apoptosis was confirmed by demonstrating caspase activation and inhibition of cell killing by a caspase inhibitor, zVAD-fmk. TRAIL-R1/DR4 protein expression was enhanced in Hep G2.2.15 cells as compared to Hep G2 cells. Lamivudine treatment reduced TRAIL-mediated apoptosis and TRAIL-R1/DR4 expression in Hep G2.2.15 cells. In Hep G2 cells transfected with the HBV-encoded X antigen (HBxAg), sensitivity to TRAIL-mediated apoptosis and TRAIL-R1/DR4 expression were both increased. CONCLUSIONS: TRAIL-induced apoptosis is enhanced by the level of HBV replication in human hepatocytes, in part, by HBxAg-dependent upregulation of TRAIL-R1/DR4.

The large GTPase dynamin is required for hepatitis B virus protein secretion from hepatocytes.

BACKGROUND/AIMS: The hepatocellular transport pathways and cellular proteins utilized during the packaging and secretion of hepatitis B virus are poorly understood. In this study, we tested if the large GTPase dynamin, a protein involved in vesicle formation and secretion at the trans-Golgi network in hepatocytes, is also used by hepatitis B virus (HBV) in secreting viral proteins. METHODS: Using HepG2.2.15 cells expressing the full-length HBV genome, we tested the effects of wild-type and mutant dynamin on the localization and secretion of two hepatitis B antigens, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Distribution of these two antigens was analyzed morphologically in cells transiently transfected with wild-type or mutant dynamin constructs, whereas secretion of the antigens was measured by testing for antigen levels in the media of transfected cells. RESULTS: Mutant dynamin was found to induce a striking redistribution of HBsAg and HBeAg to a perinuclear compartment, as well as a decrease in the levels of HBsAg and HBeAg present in cell culture media indicating a reduction in viral protein secretion. At the electron microscopy level, cells expressing the mutant dynamin showed a marked accumulation of viral particles in dilated cisternae of an uncharacterized cellular compartment. CONCLUSIONS: Intact dynamin function is required for secretion of HBV proteins from hepatocytes through an uncharacterized cellular compartment.

Etiology of nonresponsive celiac disease: results of a systematic approach.

OBJECTIVES: Nonresponse or relapse of symptoms is common in patients with celiac disease treated with gluten free diet. Refractory sprue (RS) is defined as initial or subsequent failure of a strict gluten-free diet to restore normal intestinal architecture and function in patients who have celiac-like enteropathy. The aims of this study were: 1) to identify causes of persistent symptoms in patients referred with presumed diagnosis of nonresponsive celiac disease (NCD); and 2) to characterize patients with true RS. METHODS: Patients were identified who had been systematically evaluated for NCD between January 1997, and May 2001. Patient records and small bowel biopsy results were reviewed. RESULTS: A total of 55 patients were referred with a presumed diagnosis of NCD. Six did not have celiac disease and had other diseases responsible for their symptoms. Diarrhea, abdominal pain, and weight loss were the most common reasons for evaluation in cases of NCD, whereas weight loss, steatorrhea, and diarrhea were the most common presenting features of RS (nine patients). Of the 49 patients with celiac disease, 25 were identified as having gluten contamination. Additional diagnoses accounting for persistent symptoms included: pancreatic insufficiency, irritable bowel syndrome, bacterial overgrowth, lymphocytic colitis, collagenous colitis, ulcerative jejunitis, T-cell lymphoma, pancreatic cancer, fructose intolerance, protein losing enteropathy, cavitating lymphadenopathy syndrome, and tropical sprue. CONCLUSIONS: Based on this study, we conclude the following: 1) gluten contamination is the leading reason for NCD; 2) of NCD cases, 18% are due to RS; and 3) alternative diseases or those coexistent with celiac disease and gluten contamination should be ruled out before a diagnosis of RS is made.

Celiac Disease.

Individuals with celiac disease present with a wide array of symptoms and signs. Celiac disease can result in substantial injury to the small intestine, deleterious effects on other organ systems, and an overall doubling of mortality. The role of the gastroenterologist is primarily to make the diagnosis and then to ensure that patients with celiac disease receive up-to-date and accurate instructions on diet. It is our opinion that gastroenterologists should participate in the follow-up of what is in fact a form of inflammatory bowel disease. The failure to identify and treat patients with substantial problems may result in an excess of preventable morbidity and mortality. Intestinal biopsy is the definitive method of making the diagnosis of celiac disease, provided the patient has not excluded gluten from his or her diet, because exclusion of gluten results in negative serologic test results and normal small intestinal biopsy samples. The removal of gluten from the diet can result in a total recovery of gut function and a correction of most other consequences. The response is usually so complete that patients should consider themselves to be basically healthy as long as they stay away from the offending foods. However, the execution and maintenance of the "theoretically simple" exclusion of gluten is difficult. The condition is permanent and mandates adherence to a lifelong gluten-free diet; even small amounts of gluten can result in injury to the intestinal lining. The diet is restrictive and requires the patient to be careful about food choices. Therefore, patient education and motivation are crucial to a successful outcome. The correction of vitamin and mineral deficiencies may be helpful in aiding recovery; vitamin D and calcium supplementation often is recommended. No drug therapy has been proven to suppress the disease.