Acetic acid versus radiofrequency ablation for the treatment of hepatocellular carcinoma: A randomized controlled trial.

PURPOSE: The purpose of this prospective study was to compare the efficacy of percutaneous acetic acid (PAAI) to that of radiofrequency ablation (RFA) in the treatment of small (≤5cm) hepatocellular carcinoma (HCC) using a randomized trial. MATERIAL AND METHODS: Consecutive patients with small HCC underwent clinical, biochemical, and imaging evaluation. Those fulfilling the inclusion criteria (Child's A/B cirrhosis, less than 5 HCC nodules, HCC nodules≤5cm diameter, no extrahepatic disease, patent portal vein, normal coagulation profile with informed consent) were randomly assigned to receive RFA or PAAI. Tumor response and survival rate were estimated. Non-inferiority margin of 10% difference was taken for effectivity of PAAI compared to RFA. RESULTS: Of the 86 patients screened, 55 patients with 67 HCC nodules were included. There were 40 men and 15 women with a mean age of 54.3±10.5 (SD) years (range: 28-71years). Of these, 26 patients had PAAI and 29 had RFA. The clinical, demographic and imaging profiles of the two groups were similar. Complete response was non-inferior to RFA [PAAI 75% and RFA 83.3%, difference 8.3% CI (-12.5% to 29.2%)]. Lower limit of this 95% CI (-12.5%) was lower than the 10% non-inferiority margin difference (8.3%). Survival rates were similar at 12months (PAAI, 81.6% vs. RFA, 71.9%; P=0.68) and at 30months (PAAI, 54.4% vs. RFA, 52%; P=0.50). CONCLUSION: PAAI and RFA have similar efficacy in treating small HCC. PAAI could thus be a cost-effective alternative in situations where RFA is either unavailable or unaffordable.

Avalanches and criticality in self-organized nanoscale networks.

Current efforts to achieve neuromorphic computation are focused on highly organized architectures, such as integrated circuits and regular arrays of memristors, which lack the complex interconnectivity of the brain and so are unable to exhibit brain-like dynamics. New architectures are required, both to emulate the complexity of the brain and to achieve critical dynamics and consequent maximal computational performance. We show here that electrical signals from self-organized networks of nanoparticles exhibit brain-like spatiotemporal correlations and criticality when fabricated at a percolating phase transition. Specifically, the sizes and durations of avalanches of switching events are power law distributed, and the power law exponents satisfy rigorous criteria for criticality. These signals are therefore qualitatively and quantitatively similar to those measured in the cortex. Our self-organized networks provide a low-cost platform for computational approaches that rely on spatiotemporal correlations, such as reservoir computing, and are an important step toward creating neuromorphic device architectures.

CD4+ CD25+ FOXP3+ T cell frequency in the peripheral blood is a biomarker that distinguishes intestinal tuberculosis from Crohn's disease.

BACKGROUND: Distinguishing between Crohn's Disease (CD) and Intestinal Tuberculosis (ITB) has been a challenging task for clinicians due to their similar presentation. CD4+FOXP3+ T regulatory cells (Tregs) have been reported to be increased in patients with pulmonary tuberculosis. However, there is no such data available in ITB. The aim of this study was to investigate the differential expression of FOXP3+ T cells in patients with ITB and CD and its utility as a biomarker. METHODS: The study prospectively recruited 124 patients with CD, ITB and controls: ulcerative colitis (UC) and patients with only haemorrhoidal bleed. Frequency of CD4+CD25+FOXP3+ Tregs in peripheral blood (flow cytometry), FOXP3 mRNA expression in blood and colonic mucosa (qPCR) and FOXP3+ T cells in colonic mucosa (immunohistochemistry) were compared between controls, CD and ITB patients. RESULTS: Frequency of CD4+CD25+FOXP3+ Treg cells in peripheral blood was significantly increased in ITB as compared to CD. Similarly, significant increase in FOXP3+ T cells and FOXP3 mRNA expression was observed in colonic mucosa of ITB as compared to CD. ROC curve showed that a value of >32.5% for FOXP3+ cells in peripheral blood could differentiate between CD and ITB with a sensitivity of 75% and a specificity of 90.6%. CONCLUSION: Phenotypic enumeration of peripheral CD4+CD25+FOXP3+ Treg cells can be used as a non-invasive biomarker in clinics with a high diagnostic accuracy to differentiate between ITB and CD in regions where TB is endemic.

Efficacy of generic oral directly acting agents in patients with hepatitis C virus infection.

Novel direct-acting antivirals (DAAs) are now the standard of care for the management of hepatitis C virus (HCV) infection. Branded DAAs are associated with high sustained virological response at 12 weeks post-completion of therapy (SVR12), but are costly. We aimed to assess the efficacy of generic oral DAAs in a real-life clinical scenario. Consecutive patients with known HCV infection who were treated with generic-oral DAA regimens (May 2015 to January 2017) were included. Demographic details, prior therapy and SVR12 were documented. Four hundred and ninety patients (mean age: 38.9 ± 12.7 years) were treated with generic DAAs in the study time period. Their clinical presentations included chronic hepatitis (CHC) in 339 (69.2%) of cases, compensated cirrhosis in 120 (24.48%) cases and decompensated cirrhosis in 31 (6.32%) cases. Genotype 3 was most common (n = 372, 75.9%) followed by genotype 1 (n = 97, 19.8%). Treatment naïve and treatment-experienced (defined as having previous treatment with peginterferon and ribavirin) were 432 (88.2%) and 58 (11.8%), respectively. Generic DAA treatment regimens included sofosbuvir in combination with ribavirin (n = 175), daclatasvir alone (n = 149), ribavirin and peginterferon (n = 80), ledipasvir alone (n = 43), daclatasvir and ribavirin (n = 37), and ledipasvir and ribavirin (n = 6). Overall SVR12 was 95.9% (470/490) for all treatment regimens. SVR12 for treatment naïve and experienced patients was 97.0% (419/432) and 87.9% (51/58), respectively, P = .005. High SVR12 was observed with various regimens, irrespective of genotype and underlying liver disease status. There were no differences in SVR12 with 12 or 24 weeks therapy. No major adverse event occurred requiring treatment stoppage. Generic oral DAAs are associated with high SVR rates in patients with HCV infection in a real-life clinical scenario.

Sofosbuvir plus ribavirin in treatment-naïve patients with chronic hepatitis C virus genotype 1 or 3 infection in India.

Until 2014, pegylated interferon plus ribavirin was the recommended standard of care for the treatment of chronic hepatitis C virus (HCV) infection in India. This open-label phase 3b study, conducted across 14 sites in India between 31 March 2014 and 30 November 2015, evaluated the efficacy and safety of sofosbuvir plus ribavirin therapy among treatment-naïve patients with chronic genotype 1 or 3 HCV infection. A total of 117 patients with genotype 1 or 3 HCV infection were randomized 1:1 to receive sofosbuvir 400 mg and weight-based ribavirin (1000 or 1200 mg) daily for 16 or 24 weeks. Among those with genotype 1 infection, the primary efficacy endpoint of sustained virologic response at 12 weeks post-treatment (SVR12) was reported in 90% (95% confidence intervals [CI], 73-98) and 96% (95% CI, 82-100) of patients following 16 and 24 weeks of treatment, respectively. For patients with genotype 3 infection, SVR12 rates were 100% (95% CI, 88-100) and 93% (95% CI, 78-99) after 16 and 24 weeks of therapy, respectively. Adverse events, most of which were mild or moderate in severity, occurred in 69% and 57% of patients receiving 16 and 24 weeks of treatment, respectively. The most common treatment-emergent adverse events were asthenia, headache and cough. Only one patient in the 24-week group discontinued treatment with sofosbuvir during this study. Overall, sofosbuvir plus ribavirin therapy achieved SVR12 rates ≥90% and was well tolerated among treatment-naïve patients with chronic genotype 1 or 3 HCV infection in India.

Evaluation of tumor response to intra-arterial chemoembolization of hepatocellular carcinoma: Comparison of contrast-enhanced ultrasound with multiphase computed tomography.

PURPOSE: To compare the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) with that of multiphase computed tomography (CT) in the evaluation of tumor response to transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Fifty patients (41 men, 9 women; mean age, 53 years±12.5 [SD]) with a total of 70 HCCs (mean size, 5cm±3 [SD]) were evaluated. Post-TACE therapeutic assessment of HCC was done at 4 weeks. Patients with TACE done earlier and reporting with suspicion for recurrence were also included. Patients with hepatic masses seen on ultrasound were enrolled and subjected to CEUS, multiphase CT and magnetic resonance imaging (MRI). Hyperenhancing area at the tumor site on arterial phase of CEUS/multiphase CT/MRI was termed as residual disease (RD), the patterns of which were described on CEUS. Diagnostic accuracies of CEUS and MPCT were compared to that of MRI that was used as the reference standard. RESULTS: CEUS detected RD in 43/70 HCCs (61%). RD had a heterogeneous pattern in 22/43 HCCs (51%). Sensitivities of CEUS and multiphase CT were 94% (34/36; 95% CI: 81-99%) and 50% (18/36; 95% CI: 33-67%) respectively. Significant difference in sensitivity was found between CEUS and multiphase CT (P=0.0001). CEUS and multiphase CT had 100% specificity (95% CI: 83-100%). CONCLUSION: CEUS is a useful technique for detecting RD in HCC after TACE. For long term surveillance, CEUS should be complemented with multiphase CT/MRI for a comprehensive evaluation.

Hepatic venous outflow tract obstruction: treatment outcomes and development of a new prognostic score.

BACKGROUND: Results of endovascular interventions in hepatic venous outflow tract obstruction (HVOTO) have been reported from limited studies. Treatment outcomes and prognostic scores need further validation. AIM: To evaluate treatment outcomes and prognostic scores for hepatic venous outflow tract obstruction in an Indian population. METHODS: Consecutive patients with hepatic venous outflow tract obstruction diagnosed at a tertiary centre were included. Technical success and clinical response after endovascular interventional therapy were documented. Predictors of survival were assessed with Cox-proportional model. A new score was derived from the factors significant on multivariate analysis and compared with Child-Turcotte-Pugh, model for end-stage liver disease (MELD), Rotterdam prognostic index (PI) and Budd-Chiari syndrome-transjugular intrahepatic portosystemic shunt ( BCS-TIPSS) PI. RESULTS: Three hundred and thirty-four patients (56.6% males), median age 24 (3-62) years were included. Hepatic vein was the commonest site of block-isolated hepatic vonous block in 48%, combined hepatic venous-inferior vena cava block in 46%. Endovascular interventional therapy was performed in 233/334 (70%) with 90% technical success. Clinical response was complete in 166 (71.2%), partial in 58 (24.9%) and no response in nine (3.9%). Majority of cases with HV block did not require TIPSS and could be treated with angioplasty (with/without stenting). On Cox-proportional multivariate analysis, Child class C and response to intervention were independent predictors of outcome and used to derive the All India Institute of Medical Sciences (AIIMS) hepatic venous outflow tract obstruction score. The 5-year survival was 92% (95% CI, 81-97%) for score ≤3, 79% (95%CI, 63-88%) for score >3 and ≤4, and 39% (95% CI, 21-57%) for score >4. The performance of AIIMS hepatic venous outflow obstruction score was superior to other prognostic indices. CONCLUSIONS: Advanced Child class and no response to intervention are associated with poor outcomes. The All India Institute of Medical Sciences hepatic venous outflow tract obstruction score predicts survival better than other prognostic scores.

Genome-wide gene expression analysis for target genes to differentiate patients with intestinal tuberculosis and Crohn's disease and discriminative value of FOXP3 mRNA expression.

BACKGROUND AND AIMS: Crohn's disease (CD) and intestinal tuberculosis (ITB) are both chronic granulomatous conditions with similar phenotypic presentations. Hence, there is need for a biomarker to differentiate between both these two diseases. This study aimed at genome-wide gene expression analysis of colonic biopsies from confirmed cases of ITB and CD in comparison with controls. To evaluate the role of T regulatory cells, forkhead box P3 (FOXP3) mRNA expression was quantified in serum as well as in colonic biopsies from patients with ITB and with the controls. METHODS: Paired samples, including serum and colonic biopsies, were taken from 33 study subjects (CD, ITB and controls), and total RNA was extracted. Human whole genome gene expression microarray analysis was performed using the Illumina HumanWG-6 BeadChip Kit with six total RNA samples of the three groups in duplicates. Real-time PCR for FOXP3 mRNA expression was analyzed in serum samples and colonic biopsy samples (4-CD, 5-ITB, 4-controls). RESULTS: In CD and ITB there was 1.5-fold upregulation of 92 and 382 genes and 1.5-fold downregulation of 91 and 256 genes, respectively. Peroxisome proliferators via the PPARγ pathway were most significantly downregulated (P < 0.005) in CD. Additionally, the IL4/5/6 signaling pathways and Toll-like receptor signaling pathway were identified as significantly differentially regulated (P < 0.005) at > 2-fold change. In ITB, the complement activation pathway, specifically the classical pathway, was the most significantly upregulated. FOXP3 mRNA expression was significantly elevated in colonic biopsies obtained from ITB patients as compared with CD cases (4.70 ± 2.21 vs 1.48 ± 0.31, P = 0.016). CONCLUSIONS: FOXP3 mRNA expression in colonic mucosa could be a discriminatory marker between ITB and CD. Upregulation of the complement activation pathway in ITB suggests that pathogenetic mechanisms for ITB are similar to those of pulmonary tuberculosis. In CD, downregulation of PPARγ was seen in colonic tissue, suggesting that restoration of PPARγ-dependent anti-microbial barrier function may be a therapeutic target.

Biliary complications of arterial chemoembolization of hepatocellular carcinoma.

RATIONALE AND BACKGROUND: Transarterial chemoembolization (TACE) is the most frequently used palliative therapy for unresectable hepatocellular carcinoma (HCC). It is a safe and effective procedure with few major and minor complications. Rarely, biliary complications are also encountered following TACE. The goal of our study was to investigate the incidence and the presentation of biliary complications following TACE in patients with HCC. MATERIAL AND METHODS: In this retrospective study, data of patients with HCC who underwent TACE between June 2002 to December 2014 were obtained from the records. Their detailed information about the procedure of TACE, diagnosis of biliary complications and subsequent management details were reviewed. RESULT: One hundred and sixty-eight patients with HCC underwent 305 procedures of TACE. Of these, biliary complications of various severities developed in 6 (3.6%) patients leading to an incidence of 1.9% (6/305). Minimal intrahepatic biliary dilatation (IHBD) occurred in three, biliary stricture in one and intrahepatic biloma in two patients. Supportive management was undertaken for IHBD patients while percutaneous aspiration and naso-biliary drainage was performed for the infected bilomas. CONCLUSION: Biliary complications following TACE are infrequent. Diagnosis should be suspected clinically and confirmed with imaging. Treatment depends on the severity. Enforcing specific measures can minimize its frequency.

Incidence and risk factors of hepatocellular carcinoma in patients with hepatic venous outflow tract obstruction.

BACKGROUND: Frequency of hepatocellular carcinoma (HCC) in hepatic venous outflow tract obstruction (HVOTO) is unclear and risk factors in HVOTO associated with HCC are unknown. AIM: To assess the incidence of HCC and to identify risk factors for HCC in primary HVOTO. METHODS: In the consecutive primary HVOTO patients evaluated between 1989 to 2013, the incidence of HCC among HVOTO was assessed in a retrospective cohort study and identification of the risk factors for HCC in HVOTO patients done by a case-control study. RESULTS: Of the 421 HVOTO patients, 8 had HCC at presentation (prevalence 1.9%). Another 8 of the remaining 413 developed HCC during 2076.2 person-years follow-up (mean 5.03 + 4.65 years, range 0.08-20 years). The cumulative incidence of HCC was 3.5% (95% CI 1.28-9.2%) at 10 years. The case-control study included 16 HCC as cases and remaining 405 as controls. Controls were predominantly males (M:F - 230:175), mean age 29 ± 10.3 years. Cases were predominantly females with an older age of 36.2 ± 11.4 years (P < 0.01, OR = 1.06, CI 1.0-1.10%). Presence of cirrhosis (P < 0.001), combined inferior vena cava (IVC) and hepatic vein (HV) block (P < 0.03, OR = 5.58, CI 1.43-25.30%) and long-segment IVC block (P < 0.02, OR = 6.50, CI 1.32-32.0%) were significantly higher among cases than controls. CONCLUSIONS: Hepatic venous outflow tract obstruction is a risk factor for HCC. The cumulative incidence of HCC in HVOTO is low and progressively increases over time. Those with liver cirrhosis, combined IVC and HV block and long-segment IVC block are at risk to develop HCC and need active surveillance.

Immunohistochemistry for the diagnosis of hepatitis E virus infection.

Hepatitis E virus (HEV) is an emerging pathogen and the most common cause of acute viral hepatitis all over the world. We describe here an immunohistochemical method for the detection of HEV antigens (pORF2 and pORF3) in formalin-fixed, paraffin-embedded liver tissues using monoclonal antibodies raised against two of the virus proteins (pORF2 and pORF3). We analysed their specificity and sensitivity in comparison with serology and nucleic acid detection in cases of acute liver failure (ALF). We used this test on 30 liver biopsies collected post-mortem from the patients of ALF caused by HEV infection. These cases were selected on the basis of positive results for enzyme immunoassay (IgM anti-HEV). Of the 30 cases taken from the archives of the Department of Pathology, the antibodies successfully stained all. However, only 25 serum samples (83.3%) of these were positive for HEV RNA. Fifteen controls used (Five noninfected liver tissues, five HBV- and five hepatitis C virus-infected liver tissues) were all negative. The immunohistochemical assay described here may prove a valuable tool for the detection of HEV infection in biopsy, autopsy and explant liver tissues and can serve as a link along with other available tests to delineate the extent of HEV-associated problem worldwide.

Radiological interventions in HVOTO--practical tips.

Hepatic venous outflow tract obstruction (HVOTO) comprises of constellation of disorders causing obstruction of hepatic venous outflow or suprahepatic inferior vena cava (IVC) or both and leading to increased hepatic sinusoidal pressure and portal hypertension. Clinical presentation in HVOTO includes both acute onset or chronic insidious onset of the disease and predominant clinical manifestations consist of ascites, hepatomegaly, and portal hypertension. IVC/hepatic vein (HV) web or thrombosed hepatic veins replaced by fibrotic constriction or thrombus in suprahepatic IVC is encountered as the pathogenic process at such obstructions. Due to advances in radiologic techniques there has been a changes in the management protocol of HVOTO with surgery or liver transplantation reserved for patients not suitable for radiological interventions or requiring liver transplantation. The present article reviews the techniques of various radiological interventions in HVOTO and their efficacy.

Transarterial chemoembolization for hepatocellular carcinoma: significance of extrahepatic collateral supply.

PURPOSE: Transarterial chemoemblization (TACE) is the most common treatment modality for treating patients of large unresectable hepatocellular carcinoma (HCC). Extrahepatic collateral arterial supply (ECS) to these large tumors is not uncommon. This study was designed to assess the significance and outcome of TACE in patients of HCC with ECS. MATERIALS AND METHODS: A total of 85 patients of HCC of Barcelona clinic liver cancer (BCLC) stage B/C who fulfilled the following inclusion criteria--Child's A/B cirrhosis, normal main portal vein and tumor bulk involvement less than 50% of the liver-were included. TACE was done using cisplatin 100 mg, doxorubicin 50 mg and 20 ml lipiodol followed by gelfoam embolization. Presence of extrahepatic supply to the tumor was looked for in suspected cases. When the collateral supply to the mass was documented, additional chemoembolization through the extrahepatic feeding collateral was attempted. If this was unsuccessful, then the treatment was completed by percutaneous acetic acid ablation (PAI). RESULTS: Eight patients showed the presence of additional extrahepatic supply to the liver tumor. The sources included inferior phrenic artery, intercostals, internal mammary artery, omental arteries, gastroduodenal artery and branch of the superior mesenteric artery. Successful chemoembolization through these collaterals was achieved in five cases and complete response was noted on follow-up. In the remaining three cases, chemoembolization could not be done and PAI was performed subsequently. CONCLUSIONS: Hepatocellular carcinoma having extrahepatic collateral supply requires additional chemoembolization through the collateral to enhance the efficacy of TACE failing which an alternative locoregional therapy of percutaneous ablation may be resorted to.

Study of cellular immune response against Hepatitis E virus (HEV).

Hepatitis E virus infection (HEV) is a major cause of acute viral hepatitis in the developing world. The immunopathology of HEV infections has not yet been elucidated. The virus is noncytopathic, and therefore, liver injury may be attributed to immune-mediated damage by cytotoxic T cells and natural killer cells. Therefore, we studied the nature of immune cells involved in HEV-induced liver damage using immunohistochemistry in liver biopsies taken from patients with HEV-induced acute liver failure and demonstrated a significant infiltration of activated CD8(+) T cells containing granzymes. These findings suggest the possible involvement of cytotoxic T cells in disease pathogenesis during HEV infection.