Praveen Guturu

Antiviral Therapy Reduces Risk of Hepatocellular Carcinoma in Patients With Hepatitis C Virus–Related Cirrhosis

BACKGROUND & AIMS The effects of antiviral therapy on prevention of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related cirrhosis are unclear. We performed a systematic review and meta-analysis to assess HCC risk reduction in patients with HCV-related cirrhosis who have received antiviral therapy. METHODS Twenty studies (4700 patients) were analyzed that compared untreated patients with those given interferon (IFN) alone or ribavirin. Risk ratios (RRs) determined effect size using a random effects model. RESULTS Pooled data showed reduced HCC risk in the treatment group (RR, 0.43; 95% confidence interval [CI], 0.33-0.56), although the data were heterogenous (chi(2) = 59.10). Meta-regression analysis showed that studies with follow-up durations of more than 5 years contributed to heterogeneity. Analysis of 14 studies (n = 3310) reporting sustained virologic response (SVR) rates with antiviral treatment showed reduced HCC risk in patients with an SVR, compared with nonresponders (RR, 0.35; 95% CI, 0.26-0.46); the maximum benefits were observed in patients treated with ribavirin-based regimens (RR, 0.25; 95% CI, 0.14-0.46). Meta-analysis of 4 studies assessing the role of maintenance IFN in nonresponders did not show HCC risk reduction (RR, 0.58; 95% CI, 0.33-1.03). No publication bias was detected by the Egger test analysis (P > 0.1). CONCLUSIONS The risk of HCC is reduced among patients with HCV who achieve an SVR with antiviral therapy. Maintenance therapy with IFN does not reduce HCC risk among patients who do not respond to initial therapy. View this articles video abstract atwww.cghjournal.org.

Evolving frequency and outcomes of liver transplantation based on etiology of liver disease.

Background In the background of availability of better treatments for specific liver diseases and listing of nonalcoholic steatohepatitis (NASH) as an etiology for liver transplantation (LT), data are unclear on the impact of disease etiology on the frequency of LT and liver posttransplantation outcomes. Methods The United Network for Organ Sharing database (1994–2009) was queried for adults receiving first LT for primary biliary cirrhosis (PBC; n=3052), primary sclerosing cholangitis (PSC; n=3854), hepatitis C virus (HCV; n=15,147), alcoholic cirrhosis (AC; n=8940), HCV+alcohol (n=6066), NASH (n=1368), cryptogenic cirrhosis (CC; n=5856), hepatitis B virus (HBV; n=1816), and hepatocellular carcinoma (HCC; n=8588). Graft and patient survival were compared and Cox models were built to determine independent prediction of outcomes by disease etiology. Results The frequency of LT increased for NASH, HCC, and HCV+alcohol, remained stable for AC, and decreased for PBC, PSC, HCV, CC, and HBV. The proportion of simultaneous liver-kidney transplants increased from approximately 3% in 2001 to 10% in 2009. Compared with PBC, 5-year graft and patient survival were (a) similar for PSC, NASH, and HBV (80–85%), (b) poorer for AC and CC (hazard ratio, 1–1.5), and (c) worst for HCV, HCV+alcohol, and HCC (hazard ratio, 1.5–2.4). Five-year outcomes for HCV-associated HCC were poorer compared with HCC due to other etiologies. Conclusions LT performed for NASH and HCC are increasing. Potent treatment options resulted in a decrease in number of transplants for HBV, HCV, and PBC. Better treatment modalities for HCV are expected to further reduce the number of LT for HCV. Excellent posttransplantation outcomes for NASH and AC are encouraging, resulting in wider acceptance of transplants for these etiologies.

Fabrication and characterization of an inorganic gold and silica nanoparticle mediated drug delivery system for nitric oxide

Nitric oxide (NO) plays an important role in inhibiting the development of hepatic fibrosis and its ensuing complication of portal hypertension by inhibiting human hepatic stellate cell (HSC) activation. Here we have developed a gold nanoparticle and silica nanoparticle mediated drug delivery system containing NO donors, which could be used for potential therapeutic application in chronic liver disease. The gold nanoconjugates were characterized using several physico-chemical techniques such as UV-visible spectroscopy and transmission electron microscopy. Silica nanoconjugates were synthesized and characterized as reported previously. NO released from gold and silica nanoconjugates was quantified under physiological conditions (pH = 7.4 at 37 degrees C) for a substantial period of time. HSC proliferation and the vascular tube formation ability, manifestations of their activation, were significantly attenuated by the NO released from these nanoconjugates. This study indicates that gold and silica nanoparticle mediated drug delivery systems for introducing NO could be used as a strategy for the treatment of hepatic fibrosis or chronic liver diseases, by limiting HSC activation.

Etiopathogenesis of nonalcoholic steatohepatitis: role of obesity, insulin resistance and mechanisms of hepatotoxicity.

Incidence of nonalcoholic fatty liver disease is increasing with an estimated prevalence of 20–30% in developed nations. This is leading to increased incidence of chronic liver disease, cirrhosis, and hepatocellular cancer. It is critical to understand the etiology and pathogenesis of any disease to create therapeutic targets and develop new treatments. In this paper we discuss the etiology and pathogenesis of nonalcoholic steatohepatitis with special focus on obesity, role of insulin resistance, and molecular mechanisms of hepatotoxicity.

Outcome After Liver Transplantation for Cirrhosis Due to Alcohol and Hepatitis C: Comparison to Alcoholic Cirrhosis and Hepatitis C Cirrhosis

Background and Aim: Data on outcome of patients after liver transplantation (LT) for cirrhosis due to hepatitis C virus (HCV+) alcohol are limited. Methods and Results: Analysis from United Network for Organ sharing data set (1991 to 2010) for cirrhotics with first LT for HCV (group I, N=17,722), alcohol or alcoholic cirrhosis (AC; group II, N=9617), and alcohol+HCV (group III, N=6822). Five-year graft and patient survival for group III were similar to group I (73% vs. 69%; P=0.33 and 76% vs. 76%; P=0.87) and worse than group II (70% vs. 74%; P<0.0001 and 76% vs. 79%; P<0.0001). Cox regression analysis adjusted for recipient and donor characteristics showed (a) graft survival for group III similar to group I [hazard ratio (HR) 1.03 (95% confidence interval (CI), 0.97-1.09)] and worse than group II [HR 1.27 (95% CI, 1.19-1.35)] and (b) patient survival for group III worse than both groups I [HR 1.09 (95% CI, 1.02-1.15)] and II [HR 1.27 (95% CI, 1.19-1.36)]. In group III, graft failure was common for graft and patient loss and de novo malignancy more common compared with group I. Conclusions: Patients undergoing LT for cirrhosis due to combined alcohol and HCV have (a) graft survival similar to patients with HCV cirrhosis and worse than AC and (b) worse patient survival compared with AC and HCV cirrhosis. Better strategies for anti-HCV treatment and screening for tumors are needed for patients undergoing LT for combined alcohol and HCV.

New insights into the pathobiology of portal hypertension

Portal Hypertension is a frequent complication of cirrhosis and causes significant morbidity and mortality. Increased intrahepatic resistance is the primary factor but portal hypertension is also associated with changes in systemic and porto‐sytemic collateral circulation. Cirrhosis is a state of vasoregulatory imbalance with excess vasoconstrictors and less vasodilators in hepatic circulation and the reverse is true for systemic circulation. Multiple pathophysiologic mechanisms including endothelial dysfunction, sinusoidal remodeling and angiogenesis are involved in increasing resistance in hepatic vascular bed. Current evidence suggests that these changes in vasoreactivity contribute to a significant proportion of intrahepatic vascular resistance and that they are reversible, providing an attractive target for therapeutic intervention.

Evaluating Comparative Effectiveness With Observational Data Endoscopic Ultrasound and Survival in Pancreatic Cancer

A previous observational study reported that endoscopic ultrasound (EUS) is associated with improved survival in older patients with pancreatic cancer. The objective of this study was to reevaluate this association using different statistical methods to control for confounding and selection bias.

Missed adenomas in patients with inadequate bowel preparation

Ihab I. El Hajj, MD, MPH Leticia Luz, MD Division of Gastroenterology and Hepatology Department of Internal Medicine Indiana University Medical Center Indianapolis, Indiana, USA Rosen Dimitrov, MD Department of Pathology and Laboratory Services Indiana University Medical Center Indianapolis, Indiana, USA Mohammad Al-Haddad, MD Division of Gastroenterology and Hepatology Department of Internal Medicine Indiana University Medical Center Indianapolis, Indiana, USA

Evaluation and management of gastrointestinal bleeding

Non-variceal upper gastrointestinal bleeding continues to be an important cause of morbidity and mortality. The most common causes include peptic ulcer disease, Mallory-Weiss syndrome, erosive gastritis, duodenitis, esophagitis, malignancy, angiodysplasias and Dieulafoys lesion. Initial assessment and early aggressive resuscitation significantly improves outcomes. Upper gastrointestinal endoscopy continues to be the gold standard for diagnosis and treatment. We present a comprehensive review of literature for the evaluation and management of non-variceal upper gastrointestinal bleeding.

Hepatitis A Vaccination in healthcare workers

Mark S. Kindy Department of Neurosciences, Medical University of South Carolina, and the Ralph H. Johnson VA Medical Center, USA Recently, interest in semiallogeneic vaccines has been increasing, as shown by the publication of successful preclinical and clinical studies by us and others that validate this immunotherapeutic approach to cancer, viral diseases such as the acquired immunodefi ciency syndrome and neurological diseases. Th ese reports indicate that treatment with semiallogeneic vaccines can induce a specifi c immune response against various tumors and against the human immunodefi ciency virus. Experimental studies using inbred mice and their syngeneic tumors initially established that 1) inoculation of semiallogeneic cell hybrids (derived from the fusion of syngeneic tumor cells with an allogeneic cell line) protects the animal host from subsequent lethal challenges with unmodifi ed syngeneic tumor cells; 2) adoptive transfer of immunity required T lymphocytes; and 3) the enhanced immunity was not the result of an allogeneic eff ect per se, because the tumor-associated antigens and alloantigens needed to be on the same cell (the hybrid). Human studies with semiallogeneic cell hybrids have focused on the use of therapeutic vaccines for cancer. Because of the many technical problems associated with obtaining suffi cient amounts of autologous tumor cells for the preparation of patient-specifi c cancer vaccines, and because of evidence that allogeneic eff ects may enhance the antitumor immune response, it seemed reasonable to combine the best of both approaches (autologous and allogeneic), because semiallogeneic hybrids focus allorecognition and major histocompatibility complex self-restricted recognition on the same cell and, therefore, in the same microenvironment. Our studies demonstrate the feasibility of using semiallogenic vaccines to treat a variety of tumors and neurological disease.Daming Zhu Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Disease, National Institutes of Health, USA Malaria is one of most deadly infectious diseases in the world, with an estimated 350-500 million people suff ering from malaria episodes and nearly 1 million deaths per year. Most of these episodes are caused by Plasmodium falciparum and P. vivax parasites. Th e world is in urgent need of a vaccine to combat against malaria. Th e quality control is one of the most important processes in vaccine research and development because it directly relates to the safety and effi cacy of the vaccines. Th is presentation will focus on the quality control evaluation of malaria sub-unit vaccines. Th e biophysical/biochemical/biological methods involved in evaluating vaccine purity, identity, integrity, stability and potency will be discussed. Th ese methods should have general applications for the quality control evaluation of subunit vaccines.Olga Borges University of Coimbra, Portugal Th e development of oral and nasal formulations for under-utilized vaccines in order to simplify their transport, storage and administration in poor countries is considered a challenge [1]. In fact, for eff ective oral immunization, antigens must be protected from the acidic and proteolytic environment of the gastrointestinal tract, effi ciently taken up by cells of the gut associated lymphoid tissue (GALT) and an appropriate immune response must be induced [2]. With this in mind we have been working on the design of chitosan-based particles as adjuvant for mucosal vaccination and recently a new delivery system was evaluated as adjuvant for oral administration of the recombinant hepatitis B antigen (HBsAg) [3]. In this previous work we obtained some promising results, like high titers of anti-HBsAg IgG in serum and antiHBsAg sIgA in mice intestinal washings. However, a high percentage of non-responder mice were observed. Th erefore, the main objective of the group is to develop more sophisticated chitosan-based delivery systems associating to the particles not only the antigens but also an immunopotentiator. Th ree diff erent chitosan-based formulations were developed associating to them aluminum salts, a mast cell activator (c48/80 compound) and CpGODN. An overview of the work done by group on the development of a mucosal hepatitis B vaccine, as well as in vitro results of these new adjuvants will be present during the congress.Yasuyuki Ishi RIKEN Research Center for Allergy and Immunology, Japan Invariant natural killer T (iNKT) cells having Th e invariant T cell antigen receptor (TCR)  chain are a unique population to regulate the immune response between the innate and acquired immunity. iNKT cells interact with glycolipids presented via CD1d molecule on antigen-presenting cells (APCs), resulting in the activation of killing activity and the production of a variety of cytokines. KRN7000, alpha-galacosyl ceramide (-GalCer), among glycolipids functions as the powerful ligand for not only rodent but also primate iNKT cells. As iNKT cells potentially have two bi-directional functions, one is immune activation and the other is immune suppression, it was expected that KRN7000 would be utilized as an adjuvant for various vaccines of cancer, infectious and immune diseases. However, the pharmaceutical development of KRN7000 is not successful because of the bi-directional functions of iNKT cells. In our recent studies, two functions of immune activation and suppression are dissected by the in vivo delivery system of KRN7000. Dendritic cells (DCs), the professional APCs, could be used as delivery cells of KRN7000 for immune activation. Systemic administration of KRN7000-pulsed DCs preferentially enhanced protective immunity against tumors and infection by microbes. In contrast, liposomal formulation of KRN7000 could be delivered to the marginal zone B220positive cells in a spleen, induce regulatory T cells (Treg) and diminish immune responses in model animals of autoimmunity, allergic diseases and graft versus host diseases (GvHD).Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Egypt Th e success of anti-tumor immunity depends on the generation of functionally eff ective T cells. Adoptive cell therapy (ACT) of autologous tumor-reactive T cells aft er chemotherapy a nd followed by vaccination is a promising approach for generation of functional T cells for cancer immunotherapy. Th is ACT modality consists of in vitro stimulation of T cells from a host own peripheral blood or tumor and then infusing them back to the same host blood followed by vaccination regimen such as peptide or peptide-pulsed dendritic cells (DCs). Th e host is irradiated or treated with chemotherapeutic drug such as cyclophosphamide (CTX) prior ACT to induce lymphopenia. Th e cellular and molecular mechanisms underlying the benefi cial eff ects of lymphodepletion in the context of adoptive T cell therapy and vaccination, however, are not well understood. Defi ning these mechanisms would signifi cantly improve the application of lymphodepletion to ACT. Our recent studies have identifi ed expansion of DCs, the central player of immune response, as a potential mechanism. We have utilized the toll-like receptor 3 (TLR3) agonist poly(I:C), a synthetic viral mimic double-stranded RNA, to induce the full activation of DCs expanded in vivo aft er chemotherapy and during vaccination with defi ned tumor antigens, resulting in effi cacious therapeutic anti-tumor responses. Our results reveal that the combination of T cell therapy and vaccination in the presence of a potent adjuvant such as a TLR agonist at precise timing post chemotherapy opens a new avenue for cancer immunotherapy that can be translated into the clinical setting to cure diff erent cancers.