Chronic Hepatitis Virus Infection Research Articles

2295 Shunt Hunting: A Case of Long-Standing Encephalopathy Secondary to Anatomic Porto-Systemic Shunt

INTRODUCTION: Abernethy malformation is a very rare congenital vascular malformation defined by diversion of portal blood away from liver [1]. Morgen and Superina classified extrahepatic portosystemic shunt into 2 types, as seen in Table 1 [3]. We describe in this case a type II extrahepatic portosystemic shunt. CASE DESCRIPTION/METHODS: A 67-year-old female with history of untreated hepatitis C, major depression disorder, hypertension, peripheral vascular disease, GERD, rheumatoid arthritis and HFrEF was admitted for altered mental status and elevated ammonia level on outpatient labs. This patient has a longstanding history of unexplained encephalopathy and elevated ammonia, treated with lactulose. She has no known history of cirrhosis and denied fevers, chills, nausea, vomiting or GI bleed. Patient was hypertensive on admission at 173/89, tachycardic to 109 and afebrile. She was saturating 98% on 2L O2. Exam was significant for bilateral coarse crackles, RUQ and epigastric tenderness and JVD. Ammonia was 106 on admission. Alkaline phosphatase 112, ALT 39, AST 84. Abdominal ultrasound revealed mildly heterogenous echogenicity of the liver with no evidence of cirrhosis. CT Abdomen was significant for congenital abnormalities including intestinal malrotation, hypoplastic IVC and abnormal pelvic variceal communication with the internal iliac vein, splenic vein and portal venous system (image). Patient underwent transjugular biopsy of liver with hepatic wedge pressures measured at 29 mmHg (gradient 14 mmHg). Pathology showed bridging fibrosis consistent with chronic viral hepatitis infection. Her encephalopathy improved to baseline after treatment with lactulose. DISCUSSION: We present a case of long-standing encephalopathy without cirrhosis, treated with lactulose. The patient also had markedly elevated hepatic portal pressures in the setting of HFrEF, without findings of cirrhosis on pathology. On this admission, CT abdomen/pelvis revealed an anatomic porto-systemic shunt, revealing the etiology of the patient’s unexplained “hepatic” encephalopathy. Multiple intra-abdominal congenital abnormalities were found on CT abdomen/pelvis, including a hypoplastic IVC, intestinal malrotation, and most significantly abnormal variceal communication with the internal iliac vein, splenic vein and portal venous system. The patient's collateral portosystemic shunts describes a type II extrahepatic portosystemic shunt.

Fatigue in chronic hepatitis B patients is significant and associates with autonomic dysfunction

BackgroundFatigue is an important clinical finding in patients with chronic hepatitis virus infection. However, studies assessing fatigue in patients with chronic hepatitis B (CHB) are very limited. This study aimed to quantify the severity of fatigue in patients with CHB, to determine whether perceived fatigue reflects impairment of functional ability, and to explore potential causes.MethodsA total of 133 patients with histologically proven CHB and 59 community controls were assessed using the fatigue impact scale (FIS).ResultsThe degree of fatigue was significantly higher in patients with CHB than in controls (mean (range) FIS 24.9 (0–91) vs. 15.7 (0–31), p < 0.001). Fatigue experienced by patients with CHB was similar to that in primary biliary cirrhosis (PBC) (n = 20) (FIS 22.2 vs. 20.9, p = 0.28). No association was found between FIS and biochemistry and histological parameters of liver disease severity. Significant associations were found between fatigue severity and cognitive impairment (r = 0.39, p < 0.001), daytime somnolence (r = 0.32, p < 0.001), scores of the Chronic Liver Disease Questionnaire (r = − 0.31, p < 0.001), and autonomic symptoms (r = 0.43, p < 0.001). The level of autonomic symptom was the only factor independently associated with the degree of fatigue.ConclusionFatigue is a significant problem of functional ability impairment in CHB and similar in degree to that in PBC patients. Fatigue in patients with CHB appears to be unrelated to the severity of liver disease but is associated with significant autonomic symptoms.

Causes and Clinical Profiles of Ascites at University of Gondar Hospital, Northwest Ethiopia: Institution-Based Cross-Sectional Study.

Background Ascites is a common clinical condition encountered by physicians in day-to-day practice. It is caused by various underlying diseases. Knowing the etiologies is vital because further investigations and definitive treatment largely rely on the specific disease entity considered. Objective The aim of this study was to determine the epidemiology of causes of ascites and complications among patients with ascites from the medical department at the University of Gondar Hospital. Methods Data on sociodemography, major symptoms, and signs, risk factors, past medical illnesses, and results of important investigations were collected using pretested questionnaires among all patients with ascites in the University of Gondar Hospital in a sample size of 52. Data were collected by well-trained physicians and analyzed by using SPSS 16. Results were depicted descriptively with measures of central tendency, dispersion, and using tables and graphs. Results A total of 52 patients were included in this study from November 1, 2018 to March 30, 2019. Thirty (57.7%) of them were males and the majority (77%) of the participants were fifty years old or younger. The mean age was 43.8 (± 14). The majority (86.5%) of the participants were from a rural area. Thirty-eight (73%) patients take alcohol occasionally while 11(21.2%) patients take alcohol frequently or massively. Eight (15.4%) patients reported a history of multiple sexual partners. Herbal medicine use was reported by 28 patients (53.8%). Only 5 (9.6%) patients were overweight. Chronic liver disease (CLD) was the major cause of ascites in this study in 24 (46.2%) patients. The other main causes of ascites were heart failure from various causes (19.2%), tuberculosis and hepatosplenic schistosomiasis contributing to 11.5% each and chronic kidney disease (5.8%). Five (20.8%) CLD patients had spontaneous bacterial peritonitis as a complication. Five (20.8%) and 4 (16.7%) CLD patients had hepatocellular carcinoma and hepatic encephalopathy as complications, respectively. Nine (17.3%) patients had variceal bleeding; six of the patients were diagnosed to have CLD while the remaining patients were having hepatosplenic schistosomiasis. Conclusion In conclusion, liver cirrhosis is the major cause of ascites in Gondar, Ethiopia, while chronic viral hepatitis infections (hepatitis B (HBV) and C (HCV) viruses) are the main causes of liver cirrhosis. The other major causes included heart failure, tuberculosis, and hepatosplenic schistosomiasis. It is wise to consider and give priority to these diseases whenever one is evaluating a patient with ascites.

LETHALITY OF TB PATIENTS, COMBINED WITH THE VIRAL HEPATITIS AND HIV INFECTION IN SAINT-PETERSBURG

Сombination of tuberculosis and viral hepatitis have been registered 2525 newly identified patients in Saint-Petersburg for the period 2006–2017. Some of these patients have been infected with HIV. Fatal outcome in 625 (24,7%) was noted. Patients with tuberculosis and chronic viral hepatitis have had a combination of viral hepatitis B and C in 36% of cases. Patients with combination tuberculosis and chronic hepatitis of unknown etiology experienced a more frequent death (60%) than patients with combination tuberculosis and other chronic viral hepatitis. In patients with concurrent tuberculosis, chronic viral hepatitis and HIV infection, patients infected viral hepatitis B and C were 31,6%. In 160 patients with fatal outcomes had a combination of infections (tuberculosis, viral hepatitis and HIV infection), the mortality rate of persons with hepatitis of unknown etiology was the lowest (42%), compared with a group of individuals affected by viral hepatitis B and C simultaneously (83%). Among patients with tuberculosis, chronic hepatitis and HIV infection, the highest incidence of tuberculosis of the intrathoracic lymph nodes and disseminated pulmonary tuberculosis was registered. Lethal outcomes most often occur in individuals with advanced tuberculosis, in whom the secretion of mycobacteria tuberculosis into the external environment has not been established. Given the high level of mortality in patients with simultaneous defeat of tuberculosis, viral hepatitis and HIV infection, it is necessary to establish their centralized registration in order to study the epidemiological patterns and clinical features of co-infections.

Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets

Chronic hepatitis viral infection, alcoholic intoxication, and obesity cause liver fibrosis, which progresses to decompensated liver cirrhosis, a disease for which medical demands cannot be met. Since there are currently no approved anti-fibrotic therapies for established liver fibrosis, the development of novel modalities is required to improve patient prognosis. In this study, we clarified the anti-fibrotic effects of cell sheets produced from human bone marrow-derived mesenchymal stem cells (MSCs) incubated on a temperature-sensitive culture dish with the chemical compound IC-2. Orthotopic transplantation of IC-2-engineered MSC sheets (IC-2 sheets) remarkably reduced liver fibrosis induced by chronic CCl4 administration. Further, the marked production of fibrolytic enzymes such as matrix metalloproteinase (MMP)-1 and MMP-14, as well as thioredoxin, which suppresses hepatic stellate cell activation, was observed in IC-2 sheets. Moreover, the anti-fibrotic effect of IC-2 sheets was much better than that of MSC sheets. Finally, knockdown experiments revealed that MMP-14 was primarily responsible for the reduction of liver fibrosis. Here, we show that IC-2 sheets could be a promising therapeutic option for established liver fibrosis.

Prevalence of Chronic Hepatitis B and C Infection in Mongolian Immigrants in the Washington, District of Columbia, Metropolitan Area, 2016-2017.

IntroductionMongolia has the highest liver cancer incidence in the world. Hepatocellular carcinoma is the most prevalent primary liver cancer, and the most common risk factors are hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Although viral hepatitis occurs mostly in the developing world, migration of people from high prevalence countries contributes to the health outcomes of the United States. Data on Mongolian Americans is limited. The objective of this study was to estimate HBV and HCV infection prevalence among Mongolia-born immigrants living in the Washington, District of Columbia, metropolitan area.MethodsWe tested Mongolia-born immigrants for chronic hepatitis at community-based screening events from 2016 to 2017. Descriptive statistics were generated to describe the screening results. Bivariate analysis was conducted to examine the relationship between hepatitis prevalence and sociodemographic characteristics.ResultsOf 634 participants, most did not speak English primarily, were uninsured, and did not have a regular primary care provider. Eighty-two participants (12.9%) had chronic HBV or HCV infection after accounting for HBV and HCV co-infection. Thirty-nine (6.2%) were chronically infected with HBV, and 233 (36.8%) were susceptible to HBV. Sixty-three (9.9%) participants were positive for HCV exposure, and 45 (7.1%) had confirmed chronic HCV infection. While no sociodemographic characteristics were associated with HBV infection, age and primary spoken language (Mongolian) were significantly associated with HCV exposure.ConclusionForeign-born immigrants such as Mongolian Americans have a high prevalence of chronic viral hepatitis infection. Targeted screening, vaccination, and treatment programs can help decrease immigrant risk for developing hepatocellular carcinoma.

Pathogenesis of and New Therapies for Hepatitis D

Hepatitis delta virus (HDV) infection of humans was first reported in 1977, and now it is now estimated that 15-20 million people are infected worldwide. Infection with HDV can be an acute or chronic process that occurs only in patients with an hepatitis B virus infection. Chronic HDV infection commonly results in the most rapidly progressive form of viral hepatitis; it is the chronic viral infection that is most likely to lead to cirrhosis, and it is associated with an increased risk of hepatocellular carcinoma. HDV infection is the only chronic human hepatitis virus infection without a therapy approved by the US Food and Drug Administration. Peginterferon alfa is the only recommended therapy, but it produces unsatisfactory results. We review therapeutic agents in development, designed to disrupt the HDV life cycle, that might benefit patients with this devastating disease.

Elast PQ Ultrasound - a Noninvasive, Reproducible, Easily Performed Method and a New Era in Liver Fibrosis Assessment

Liver fibrosis represents the repair mechanism in liver injury and is a feature of most chronic liver diseases. The degree of liver fibrosis in chronic viral hepatitis infection has major clinical implications and presence of advanced fibrosis or cirrhosis determines prognosis. Treatment initiation for viral hepatitis is indicated in most cases of advanced liver fibrosis and diagnosis of cirrhosis entails hepatology evaluation for specialized clinical care. Liver biopsy is an invasive technique and has been the standard of care of fibrosis assessment for years; however, it has several limitations and procedure related complications. Recently, several methods of noninvasive assessment of liver fibrosis have been developed which require either serologic testing or imaging of liver. Imaging based noninvasive techniques are reviewed here and their clinical use is described. Some of the imaging based tests are becoming widely available, and collectively they are shown to be superior to liver biopsy in important aspects. Clinical utilization of these methods requires understanding of performance and quality related parameters which can affect the results and provide wrong assessment of the extent of liver fibrosis. Familiarity with the strengths and weakness of each modality is needed to correctly interpret the results in appropriate clinical content. A new technique called Elast PQ uses ultrasound shear wave elastography to provide a noninvasive, reproducible, easily performed method of assessing liver fibrosis. It can easily combine a routine ultrasound imaging exam of the liver anatomy with targeted tissue stiffness values, assess liver fibrosis in patient with clinically suspected disease even before abnormalities are detected with ultrasound imaging, evaluate and obtain a baseline stiffness value in patients with chronic liver disease, follow up patients under treatment to monitor progression, stabilization or regression of liver disease and help avoid the need for liver biopsies when elastography results are consistent with other clinical findings. Both the prognosis and potential treatment of chronic liver diseases greatly depend on the progression of liver fibrosis, which is the ultimate outcome of chronic liver damage. Historically, liver biopsy has been instrumental in adequately assessing patients allows clinicians both to obtain diagnosis information and initiate adequate therapy. However, the technique is not exempt of deleterious effects. Multiple diagnostic tests have been developed for the staging of fibrosis using noninvasive methods, most of them in the setting of chronic hepatitis C. The goal of this paper is to review available data on the staging and assessment of liver fibrosis with two methods: serum markers &amp; transient elastography (FibroScan).Faridpur Med. Coll. J. Jan 2018;13(1): 44-46

Hepatitis B Virus Adaptation to the CD8+ T Cell Response: Consequences for Host and Pathogen.

Chronic viral hepatitis infections are a major public health concern, with an estimated 290 million individuals infected with hepatitis B virus (HBV) globally. This virus has been a passenger in human populations for >30,000 years, and remains highly prevalent in some settings. In order for this endemic pathogen to persist, viral adaptation to host immune responses is pre-requisite. Here, we focus on the interplay between HBV infection and the CD8+ T cell response. We present the evidence that CD8+ T cells play an important role in control of chronic HBV infection and that the selective pressure imposed on HBV through evasion of these immune responses can potentially influence viral diversity, chronicity, and the outcome of infection, and highlight where there are gaps in current knowledge. Understanding the nature and mechanisms of HBV evolution and persistence could shed light on differential disease outcomes, including cirrhosis and hepatocellular carcinoma, and help reach the goal of global HBV elimination by guiding the design of new strategies, including vaccines and therapeutics.

Aflatoxin B1 exposure and the risk of hepatocellular carcinoma in Iranian carriers of viral hepatitis B and C

Hepatocellular carcinoma (HCC) is known as one of the common and fatal cancers in the Asian and African countries. Two significant factors could cause this type of cancer including having diets contaminated with aflatoxin and chronic viral hepatitis infections. This study aimed to compare the level of aflatoxin B1 (AFB1) in those who had viral hepatitis B- and C-related HCC as a case group and a group of patients with chronic hepatitis B or C infections as the control group. This case-control study was conducted on 82 patients including 41 patients with viral hepatitis-related HCC and 41 patients with chronic hepatitis B or C infections. Level of AFB1 was measured using ELISA and compared between groups. Most of the patients in both groups were male and infected with HBV. The patients with HCC with mean age 57.5 years were significantly older than those in the control group with mean age 44.8 years (p < .05). Aflatoxin B1 was detected in 32 (78%) samples in HCC group and 28 (68.3%) samples in non-HCC group (p > .05). The median (IQR) for AFB1 levels in HCC group was 3.87 (3.46) pg/mL, while it was 2.63 (3.14) pg/mL in the control group (p = .018). Our results demonstrate for the first time the exposure to high levels of AFB1 in Iranian patients with HCC which indicate the possible involvement of AFB1 as a major risk factor in the etiology of HCC in patients with hepatitis B and C.

53P - Impact of chronic hepatitis virus infection on the feasibility and efficacy for Asian patients with hepatocellular carcinoma in phase I clinical trials

Background: In Asia, chronic hepatitis B and C virus infections (CHVI) are major risk factors for liver fibrosis and hepatocellular carcinoma (HCC). Patients with advanced HCC have limited effective therapeutic options and are potential candidates for early phase clinical trials for new anti-cancer agents. The impact of CHVI on the feasibility and efficacy for patients with HCC in Phase I trials (P-Is) has not been reported or elucidated in Western countries. Methods: We retrospectively analyzed the characteristics and outcomes of HCC patients participating in P-Is, with emphasis on CHVI. Patients testing positive for anti-hepatitis C virus (HCV) antibody or hepatitis B virus surface antigen (HBsAg) were diagnosed with CHVI. Results: Eighty-five patients were enrolled in P-Is at our center. There were no significant differences in the clinical and laboratory variables, including the liver function test results, between the 46 (54%) CHVI-positive and 39 (46%) CHVI-negative patients in this study. The median time to treatment failure (TTF) and overall survivals (OS) from enrollment of the P-I were 60 days (95% confidence interval [CI]: 51–85) and 412 days (95% CI: 267–478), respectively. There is no significant difference between positive and negative for hepatitis virus in the best response based on the RECIST. The frequency of abnormal liver function test (LFT) adverse events (grade ≥ 3) was significantly different among CHVI-positive and -negative patients. No patient discontinued P-I treatment secondary to abnormal LFT results or developed reactivation of hepatitis virus, and no treatment-related mortality was observed. Multivariate analysis revealed that the number of prior systemic treatments significantly contributed to poor TTF (≥2; HR: 2.1, 95% CI: 1.3–3.6, P = 0.004) and that poor Eastern Cooperative Oncology Group Performance Status significantly contributed to poor OS (≥1; HR: 1.9, 95% CI: 1.0–3.4, P = 0.04). Conclusions: CHVI did not independently predict TTF and OS. Abnormal LFT adverse events could be related to CHVI but did not lead to discontinuation of P-I treatment. Thus, patients advanced HCC with CHVI can be enrolled in the P-Is. Legal entity responsible for the study: N/A Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest.

Impact of statin use on the prognosis of patients with hepatocellular carcinoma undergoing liver resection: a subgroup analysis of patients without chronic hepatitis viral infection

BackgroundStatins have been reported to reduce the risk of hepatocellular carcinoma (HCC). The effect of perioperative statin use on the prognosis of HCC patients undergoing liver resection remains unclear. MethodsWe retrospectively analyzed 643 patients who underwent curative liver resection for HCC. Patients negative for hepatitis B surface antigen and hepatitis C antibody were classified as the non-B non-C HCC subgroup (n = 204). Perioperative statin users were defined as patients preoperatively receiving statin medications and maintaining > 28 cumulative defined daily doses after liver resection. The recurrence-free survival (RFS) and overall survival (OS) according to statin use were analyzed in the overall HCC cohort or in the non-B non-C HCC subgroup. ResultsAmong a total of 643 (HCC) patients, 43 patients (6.7%) received perioperative statin medications. In statin users, the proportion of non-B non-C HCC patients was significantly higher than in nonstatin users. Statin users had a high prevalence of obesity and diabetes, as well as dyslipidemia. The liver function of statin users was better than that of nonstatin users. The multivariate survival analysis revealed that use of statins was significantly associated with improvement of RFS (hazard ratio [HR], .42; 95% confidence interval [CI], 0.25–0.71; P = .001), but not with OS (HR, 0.62; 95% CI, 0.30–1.27; P = .19). In the subgroup analysis of the non-B non-C HCC cohort, statin use was significantly associated with improvement of RFS (HR, 0.47; 95% CI, 0.22–0.99; P = .04). ConclusionPerioperative statin use was associated with an improvement of RFS in HCC patients undergoing curative liver resection.

Biological therapy in arthritis patients with hepatitis B or C infection: a multicenter retrospective case series.

Reactivation of viral hepatitis B (HBV) and C (HCV) has been reported in various case reports of patients with arthritis on biological therapy. The objective of this study was to describe the clinical characteristics and outcomes of arthritis patients with HBV or HCV treated with biological therapy. This is a retrospective case series including all patients above 13 years of age with arthritis patients from four centers in Saudi Arabia with concurrent chronic viral hepatitis infection (HBV or HCV) who received biological agents in the rheumatology clinics during their course of their disease from duration of the disease onset until last outpatient visit up to November 2015. Demographic information, full details about the hepatitis status of each patient, rheumatic disease diagnosis and different therapies used were reviewed. We identified 10 cases each with HBV and HCV on biological therapy. The mean age in the HBV group was 51 (34-85) years and 80% were females. Eight patients had rheumatoid arthritis (RA), one patient had RA/systemic lupus erythematosus, and one had human immunodeficiency virus related-arthritis. Seven were chronic inactive HBsAg carriers and three had chronic active HBV. Nine HBV patients received prophylactic antiviral therapy. Two cases with chronic HBV had reactivation with no elevation of the transaminases.The mean age in the HCV group was 54 (23-79) years and all were female RA patients. Three had detectable hepatitis C virus-ribonuecleic acid (HCV-RNA) before the start of biological therapy. Nine HCV patients received antiviral treatment and seven had a sustained virologic response (SVR) before start of biological treatment. Three patients had detectable HCV-RNA during the course of biological therapy. One of the three was a non-responder and two were relapsers. One of the patients with HCV relapse was started on sofosbuvir plus ribavirin and achieved SVR on follow-up. We report the successful use of biological therapy in arthritis patients with hepatitis B infection with antiviral therapy with no detoriation of their viral status. Due to the lack of sufficient prospective studies demonstrating the rate of HCV flare on biological therapy, caution should be exercised and careful monitoring with liver enzymes and viral load is mandated in vulnerable HCV RNA patients. Treatment should be individualized by the rheumatologist in collaboration with the hepatologist to minimize complications.

Chronic viral hepatitis and its association with liver cancer

Chronic infection with hepatitis viruses represents the major causative factor for end-stage liver diseases, including liver cirrhosis and primary liver cancer (hepatocellular carcinoma, HCC). In this review, we highlight the current understanding of the molecular mechanisms that drive the hepatocarcinogenesis associated with chronic hepatitis virus infections. While chronic inflammation (associated with a persistent, but impaired anti-viral immune response) plays a major role in HCC initiation and progression, hepatitis viruses can also directly drive liver cancer. The mechanisms by which hepatitis viruses induce HCC include: hepatitis B virus DNA integration into the host cell genome; metabolic reprogramming by virus infection; induction of the cellular stress response pathway by viral gene products; and interference with tumour suppressors. Finally, we summarise the limitations of hepatitis virus-associated HCC model systems and the development of new techniques to circumvent these shortcomings.

Levels of hepatic Th17 cells and regulatory T cells upregulated by hepatic stellate cells in advanced HBV-related liver fibrosis

BackgroundLiver fibrosis which mainly occurs upon chronic hepatitis virus infection potentially leads to portal hypertension, hepatic failure and hepatocellular carcinoma. However, the immune status of Th17 and Treg cells in liver fibrosis is controversial and the exact mechanisms remain largely elusive.MethodsLiver tissues and peripheral blood were obtained simultaneously from 32 hepatitis B virus infected patients undergoing surgery for hepatocellular carcinoma at the medical center of Sun Yat-sen University. Liver tissues at least 3 cm away from the tumor site were used for the analyses. Levels of Th17 cells and regulatory T cells were detected by flow cytometry analysis and immunohistochemistry. In vitro experiment, we adopted magnetic cell sorting to investigate how hepatic stellate cells regulate the levels of Th17 cells and regulatory T cells.ResultsWe found that hepatic Th17 cells and regulatory T cells were increased in patients with advanced stage HBV-related liver fibrosis. Hepatic stellate cells upregulated the levels of Th17 cells and regulatory T cells via PGE2/EP2 and EP4 pathway.ConclusionsWe found that the increased levels of Th17 cells and regulatory T cells were upregulated by hepatic stellate cells. These results may provide insight into the role of hepatic stellate cells and Th17 cells and regulatory T cells in the persistence of fibrosis and into the occurrence of hepatocellular carcinoma following cirrhosis.

Upregulation of miR-137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common malignancies worldwide. More than 80% of patients with HCC are not good candidates for curative surgical resection due to advanced liver cirrhosis caused by underlying chronic hepatitis virus (B or C) infection. Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced HCC. Although, sorafenib currently sets the new standard for advanced HCC treatment, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical. In the present study, we found that adenine nucleotide translocator2(ANT2) was upregulated in sorafenib‑resistant HCC Huh7 cells (Huh7-R) and its overexpression promoted sorafenib resistance. ANT2 induced the formation of cancer-initiating cell(CIC) phenotypes and promoted metastasis-associated traits in the Huh7 cells. Silencing of miR-137 upregulated ANT2 protein expression in the Huh7 cells. miR-137 was downregulated in the Huh7-R cells, compared with that in the Huh7 cells and its restoration reversed sorafenib resistance in the Huh7-R cells. Restoration of miR-137 inhibited formation of CIC traits and attenuated the abilities of migration and invasion in the Huh7-R cells. Moreover, we demonstrated that high-intensity focused ultrasound(HIFU) in unresectable HCC upregulated serum miR-137. Combining HIFU and sorafenib may be a wise option for advanced and unresectable HCC.

Prevalence of chronic viral hepatitis infections in Karaj, Iran.

IntroductionViral hepatitis is challenging for health and blood safety. Studies carried out on blood donors can help find the frequency and trending of hepatitis B and C infections in a community and also safety of donation. The study aim is to determine the prevalence of HBV and HCV in Karaj blood donors over a four year period between 2010 to 2013.MethodsThis study reports the results of a cross sectional seroepidemiological study of hepatitis B and C in blood donors. Data on hepatitis infection and demographic characteristics of donors were gathered from blood donor registries. Frequency of hepatitis infections were described with 95% confidence interval. Chi square and logistic regression were used for analysis.ResultsThe frequency of HBV and HCV infection in Karaj blood donors was 0.40% and 0.18% respectively. In first time donors, HBV and HCV positivity risk was respectively 3.59 and 4.8 fold in people with primary education (OR=3.59; 95% CI between 2.68-4.80) comparing to academic level. Frequency of hepatitis B has decreased significantly (P<0.001) during study period but frequency of Hepatitis C has not changed significantly.ConclusionThe frequencies of HBV and HCV infection in Karaj blood donor population is low. There are equal infection rates within both genders. This must be considered in controlling transmission of infection in this area.

Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

BACKGROUNDVenetoclax(VEN), a once daily oral inhibitor of BCL2, has demonstrated high response rates and acceptable toxicity in patients with relapsed or refractory (R/R) CLL both as a single agent and in combination with the anti-CD20 monoclonal antibodies rituximab and obinutuzumab (formerly GA-101, G), where minimal residual disease (MRD) negative responses have been observed in the majority of patients. Ibrutinib (IBR), a once daily oral inhibitor of the Brutontyrosine kinase, likewise induces remissions in the majority of treated patients, but complete response (CR) is uncommon even after prolonged administration. Early genetic studies have demonstrated that BCL2 over-expression rescues BTK deficient XID murine B-cells from spontaneous apoptosis (J Immunol 1996), so we hypothesized that combination therapy would more efficiently achieve deep response endpoints. We report phase 1b results of a single-institution phase 1b/2 study of G, IBR, and VEN to characterize the safety and preliminary efficacy of the combination.METHODSPatients with CLL relapsed after or refractory to ≥1 prior therapy and who required treatment were eligible. Enrolled patients had ECOG ≤1 and preserved end-organ function, including creatinine clearance ≥50 mL/min/m2. Patients with chronic viral hepatitis infection, uncontrolled autoimmunecytopenia, active Richter transformation, and known cysteine-481 BTK mutation or clinical disease progression during treatment with a cysteine-481-binding BTK inhibitor were excluded. G, IBR, and VEN were started sequentially over the first 3 of fourteen 28-day cycles as detailed in the table. To establish the safety of VEN in combination with OBIN and IBR, VEN dose was escalated in 3 x 3 cohorts (100, 200, 400 mg) to a maximum planned dose of 400 mg daily. Dose limiting toxicity (DLT) was defined during the third cycle. Risk assessment for VEN dose ramp-up was conducted according to US prescribing information. Adverse events were assessed and graded using CTCAE v4.03. Response assessment according to IWCLL 2008 criteria, including bone marrow biopsy with 4-colorimmunophenotyping of marrow and peripheral blood (PB) for MRD, occurs after cycles 8 and 14.RESULTSTwelve R/R patients have been treated in the phase 1b portion of the trial. Median age was 57 years (range: 42-70) and median prior therapies was 1 (range: 1-7). Baseline genetic risk features includedunmutatedIGHV in 11 (92%),del(17p) in 1 (8%), del(11q) in 8 (67%), and complex abnormal karyotype in 5 (42%) patients. Tumor lysis (TLS) risk was low in 1 (8%), medium in 7 (58%), and high in 4 (33%) patients at study entry. In general, observed toxicities for the combination were consistent with those reported for the single agents. DLTs were not observed at any VEN dose level, establishing VEN 400 mg daily as safe in combination with standard doses of G and IBR. The most common grade ≥3 adverse events (regardless of attribution) were neutropenia (50%), lymphopenia (33%),hypertension(25%), and fatigue (17%). Grade 1/2 adverse events occurring in over half the patients included bruising (all grade 1, 83%), infusion related reaction (75%), hypertension (67%), headache (67%), hyperuricemia (all grade 1, 75%), hypocalcemia (75%), and diarrhea (all grade 1, 67%), AST and/or ALT elevation (58%), and rash (50%). No cases of either clinical or laboratory TLS were observed. All patients remain on therapy and 6 have reached response assessment after completing 8 cycles of therapy. All 6 have achieved objective response: 5 PR, including 1 MRD-negative in PB (VEN 100) and 1 MRD-negative in both PB and marrow (VEN 100), and 1 CR with MRD-negative PB and marrow (VEN 200).CONCLUSIONSG, IBR, and VEN can be safely administered in combination at doses standard for the treatment of CLL. DLTs were not observed, establishing VEN 400 mg as the recommended phase 2 dose in combination with G and IBR. Adverse events were manageable and largely consistent with those reported in the single agent phase 2 studies. Objective responses, including MRD-negative responses, have been observed among all R/R patients from the first dose cohorts. Accrual continues to parallel phase 2 cohorts of R/R (n=25) and TN (n=25) patients. Updated phase 1b toxicity and response data will be presented. [Display omitted] DisclosuresJones:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Pharmacyclics: Consultancy; Novartis Oncology: Consultancy; Innate Pharma: Research Funding.

Kidney Cancer Linked to Chronic Hepatitis in the Asia-Pacific: A Population-Based Analysis

Background: The association of renal cancer with viral hepatitis infection remains unclear. Using an insurance data set, this population-based case-control study evaluated the association of renal cancer with chronic hepatitis virus infection in an endemic area of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Methods: We enrolled 17,747 patients with renal cancer during the period from 2000 to 2011 from the National Health Insurance Research Database of Taiwan. The control group comprised 35,494 randomly selected people without renal cancer matched by age and gender to the patients in the study group. ORs were calculated to assess the association of chronic hepatitis virus infection with renal cancer by using logistic regression analysis. Results: Renal cancer was associated with HBV and HCV infection (OR 1.38, 95% CI 1.24-1.54; OR 1.24, 95% CI 1.07-1.44, respectively). An analysis stratified by gender and age revealed that young male HBV carriers had a higher risk of renal cancer compared with men without viral hepatitis (age <55 years: OR 1.94, 95% CI 1.57-2.39; 55≤ age <64 years: OR 1.40, 95% CI 1.05-1.86). Male HCV-infected patients aged <55 years (OR 1.90, 95% CI 1.11-3.26) and female HCV carriers aged between 55 and 64 years (OR 1.59, 95% CI 1.00-2.53) had a significantly higher risk of renal cancer compared with their counterparts. Conclusions: Renal cancer is significantly associated with chronic hepatitis infection, particularly in younger HBV-infected men.

Association of Sjögrens Syndrome in Patients with Chronic Hepatitis Virus Infection: A Population-Based Analysis.

ObjectiveThe association between Sjögren’s syndrome (SS) and chronic hepatitis virus infection is inconclusive. Hepatitis B (HBV) and hepatitis C virus (HCV) infections are highly prevalent in Taiwan. We used a population-based case-control study to evaluate the associations between SS and HBV and HCV infections.Materials and MethodsWe identified 9,629 SS patients without other concomitant autoimmune diseases and 38,516 sex- and age-matched controls without SS from the Taiwan National Health Insurance claims data between 2000 and 2011. We utilized multivariate logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the associations between SS and HBV and HCV infections. Sex- and age-specific (<55 and ≥55 years) risks of SS were evaluated.ResultsThe risk of SS was higher in patients with HCV than in those without chronic viral hepatitis (OR = 2.49, 95% CI = 2.16–2.86). Conversely, HBV infection was not associated with SS (OR = 1.10, 95% CI = 0.98–1.24). Younger HCV patients were at a higher risk for SS (<55 years: OR = 3.37, 95% CI = 2.62–4.35; ≥55 years: OR = 2.20, 95% CI = 1.84–2.62). Men with HCV were at a greater risk for SS (women: OR = 2.26, 95% CI = 1.94–2.63; men: OR = 4.22, 95% CI = 2.90–6.16). Only men with chronic HBV exhibited a higher risk of SS (OR = 1.61, 95% CI = 1.21–2.14).ConclusionHCV infection was associated with SS; however, HBV only associated with SS in men.