Muhammad Shaalan Beg

The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: A meta-analysis

Objectives:The PNPLA3 rs738409 single-nucleotide polymorphism is known to promote nonalcoholic steatohepatitis (NASH), but its association with fibrosis severity and hepatocellular carcinoma (HCC) risk is less well-defined. The objectives of this study were to determine the association between PNPLA3 and liver fibrosis severity, HCC risk, and HCC prognosis among patients with liver disease.Methods:We performed a systematic literature review using the Medline, PubMed, Scopus, and Embase databases through May 2013 and a manual search of national meeting abstracts from 2010 to 2012. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios (ORs), according to PNPLA3 genotype, were calculated using the DerSimonian and Laird method for a random effects model.Results:Among 24 studies, with 9,915 patients, PNPLA3 was associated with fibrosis severity (OR 1.32, 95% confidence interval (CI) 1.20–1.45), with a consistent increased risk across liver disease etiologies. Among nine studies, with 2,937 patients, PNPLA3 was associated with increased risk of HCC in patients with cirrhosis (OR 1.40, 95% CI 1.12–1.75). On subgroup analysis, increased risk of HCC was demonstrated in patients with NASH or alcohol-related cirrhosis (OR 1.67, 95% CI 1.27–2.21) but not in those with other etiologies of cirrhosis (OR 1.33, 95% CI 0.96–1.82). Three studies, with 463 patients, do not support an association between PNPLA3 and HCC prognosis but are limited by heterogeneous outcome measures. For all outcomes, most studies were conducted in homogenous Caucasian populations, and studies among racially diverse cohorts are needed.Conclusions:PNPLA3 is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with nonalcoholic steatohepatitis or alcohol-related cirrhosis.

Meta‐analysis: underutilisation and disparities of treatment among patients with hepatocellular carcinoma in the United States

Despite wide availability of treatment options for hepatocellular carcinoma (HCC), several studies have suggested underutilisation in clinical practice.

Outcome of Diffuse Large B-Cell Lymphoma in the United States Has Improved Over Time but Racial Disparities Remain: Review of SEER Data

BACKGROUND Diffuse large B-cell non-Hodgkin lymphoma (DLBCL) outcome in the United States has not been reported outside the context of clinical trials. PATIENTS AND METHODS We reviewed the Surveillance, Epidemiology, and End Results (SEER) registry and compared survival trends among DLBCL patients from 1973 to 2004. RESULTS We identified 59,728 patients (mean age, 63 years; 54.4% men, 86.7% white) and had staging information for 57%, including 30% early-stage (I/II) and 27% advanced-stage (III/IV). Median overall survival (OS) from 1973 to 1979, 1980 to 1989,1990 to 1999, and 2000 to 2004 was 15, 18, 20, and 47 months, respectively (P < .005). For the period from 2000 to 2004, 4-year OS was 46%. Outcome was better in white patients than in black (47 months versus 29 months) (P = .001). Median OS for patients younger than 60 years old was not reached versus 23 months for patients older than 60 years. CONCLUSION The outcome of DLBCL in the United States has improved significantly in the era of monoclonal antibodies; however, racial disparities remain.

Oxaliplatin-induced immune mediated thrombocytopenia

Oxaliplatin is a third generation platinum compound used in patients with advanced colorectal carcinoma. Recently, the mechanism of a rare drug-induced immune thrombocytopenia in patients receiving oxaliplatin has been described. This complication is caused by oxaliplatin-dependent antibodies directed against platelet surface glycoproteins, and is unrelated to myelosuppression. In this report, we describe two patients who developed thrombocytopenia immediately soon after receiving oxaliplatin. Sensitization presumably had occurred after receiving oxaliplatin during preceding courses of multiagent chemotherapy that included oxaliplatin.

Yttrium-90 radioembolization of hepatic metastases from colorectal cancer

Liver metastases from colorectal cancer (CRC) result in substantial morbidity and mortality. The primary treatment is systemic chemotherapy, and in selected patients, surgical resection; however, for patients who are not surgical candidates and/or fail systemic chemotherapy, liver-directed therapies are increasingly being utilized. Yttrium-90 (Y-90) microsphere therapy, also known as selective internal radiation therapy (SIRT) or radioembolization, has proven to be effective in terms of extending time to progression of disease and also providing survival benefit. This review focuses on the use of Y-90 microsphere therapy in the treatment of liver metastases from CRC, including a comprehensive review of published clinical trials and prospective studies conducted thus far. We review the methodology, outcomes, and side effects of Y-90 microsphere therapy for metastatic CRC.

A Variant in PNPLA3 Associated With Fibrosis Progression but not Hepatocellular Carcinoma in Patients With Hepatitis C Virus Infection.

BACKGROUND & AIMS A single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain containing 3 gene (PNPLA3, rs738409) has been associated with fibrosis and development of hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis, although its association with outcomes in patients with hepatitis C virus (HCV) infection is less clear. We evaluated the association between this SNP in PNPLA3 and fibrosis progression and development of HCC among HCV-infected patients. METHODS We performed a secondary analysis of data from participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial. Patients were randomly assigned to groups given weekly pegylated interferon or no further therapy for 3.5 y and then followed without further treatment until October 2009. Multivariate logistic regression was used to identify factors associated with fibrosis at baseline, fibrosis progression (defined as 2-point increase in Ishak score), and HCC development. RESULTS Among 937 HCV patients with known PNPLA3 genotype, 384 (41.0%) had cirrhosis at baseline. The PNPLA3 CG/GG SNP at rs738409 was significantly associated with the presence of cirrhosis (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.34-2.30), after adjusting for age, sex, diabetes, and race. Among 493 patients without cirrhosis at baseline who had at least 1 follow-up biopsy, 142 had fibrosis progression. In multivariate analyses, fibrosis progression was associated with obesity (OR, 1.67; 95% CI, 1.11-2.51) and the PNPLA3 CG/GG genotype (OR, 1.70; 95% CI, 1.13-2.56). PNPLA3 genotype was not associated with HCC development (P = .85). Using these data to update prior meta-analysis results, the rs738409 SNP in PNPLA3 was not significantly associated with development of HCC in HCV-infected patients (OR 1.29; 95% CI, 0.97-1.99). CONCLUSIONS Based on data from the HALT-C trial, the PNPLA3 CG/GG SNP at rs738409 is associated with fibrosis progression but not development of HCC in patients with HCV infection.

Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.

Cost-Effectiveness Analysis of Intensity Modulated Radiation Therapy Versus 3-Dimensional Conformal Radiation Therapy for Anal Cancer

PURPOSE To compare the cost-effectiveness of intensity modulated radiation therapy (IMRT) and 3-dimensional conformal radiation therapy (3D-CRT) for anal cancer and determine disease, patient, and treatment parameters that influence the result. METHODS AND MATERIALS A Markov decision model was designed with the various disease states for the base case of a 65-year-old patient with anal cancer treated with either IMRT or 3D-CRT and concurrent chemotherapy. Health states accounting for rates of local failure, colostomy failure, treatment breaks, patient prognosis, acute and late toxicities, and the utility of toxicities were informed by existing literature and analyzed with deterministic and probabilistic sensitivity analysis. RESULTS In the base case, mean costs and quality-adjusted life expectancy in years (QALY) for IMRT and 3D-CRT were

Outcome of patients with myelodysplastic syndromes in the Veterans Administration population

32,291 (4.81) and

Quantification of renal steatosis in type II diabetes mellitus using dixon-based MRI.

28,444 (4.78), respectively, resulting in an incremental cost-effectiveness ratio of