Caspase polymorphisms and prognosis of hepatocellular carcinoma

The aim of our study was to determine the impact of genetic polymorphisms in the caspase (CASP) genes on prognosis of hepatocellular carcinoma (HCC). We genotyped 7 potentially functional polymorphisms in CASP3, CASP7, CASP8, CASP9, CASP10 genes in 362 HCC patients of receiving surgical resection of HCC tumor. The associations of genotype and haplotype with overall survival (OS) and disease free survival (DFS) were analyzed by using the Cox proportional hazards model. We found that the CASP9 rs4645981 C allele was significantly associated with positive effect on DFS (P = 0.011 and 0.016 for CT+CC vs. TT in univariate and multivariate analysis, respectively), CT genotype was associated with a better OS of HCC than the TT genotype both in univariate and multivariate analysis (P = 0.048 and 0.041, respectively). Moreover, the CASP3 rs2705897 GT genotype showed marginally significant association with decreased OS and DFS, compared with the GG genotype. One haplotype TT/TG in CASP3 (constructed by rs12108497 T>C and rs2705897 T>G) was significantly associated with decreased OS and DFS, compared to the common haplotype TT/TT both in univariate analysis (P = 0.021 and 0.026, respectively) and multivariate analysis (P = 0.025 and 0.030, respectively). The haplotype GT/GT in CASP9 (constructed by rs4645978 A>G and rs4645981 C>T) was significantly associated with decreased DFS both in univariate and multivariate analysis (P = 0.012 and 0.010, respectively). In conclusion, the CASP9 rs4645981 polymorphism, CASP3 and CASP9 haplotypes may be useful prognosis markers for HCC patients with surgical resection of tumor

Personalized prostate cancer care: from screening to treatment

Unprecedented progress has been made in genomic personalized medicine in the last several years, allowing for more individualized healthcare assessments and recommendations than ever before. However, most of this progress in prostate cancer (PCa) care has focused on developing and selecting therapies for late-stage disease. To address this issue of limited focus, we propose a model for incorporating genomic-based personalized medicine into all levels of PCa care, from prevention and screening to diagnosis, and ultimately to the treatment of both early-stage and late-stage cancers. We have termed this strategy the "Pyramid Model" of personalized cancer care. In this perspective paper, our objective is to demonstrate the potential application of the Pyramid Model to PCa care. This proactive and comprehensive personalized cancer care approach has the potential to achieve three important medical goals: reducing mortality, improving quality of life and decreasing both individual and societal healthcare costs

Clinical validity and utility of genetic risk scores in prostate cancer

Current issues related to prostate cancer (PCa) clinical care (e.g., over-screening, over-diagnosis, and over-treatment of nonaggressive PCa) call for risk assessment tools that can be combined with family history (FH) to stratify disease risk among men in the general population. Since 2007, genome-wide association studies (GWASs) have identified more than 100 SNPs associated with PCa susceptibility. In this review, we discuss (1) the validity of these PCa risk-associated SNPs, individually and collectively; (2) the various methods used for measuring the cumulative effect of multiple SNPs, including genetic risk score (GRS); (3) the adequate number of SNPs needed for risk assessment; (4) reclassification of risk based on evolving numbers of SNPs used to calculate genetic risk, (5) risk assessment for men from various racial groups, and (6) the clinical utility of genetic risk assessment. In conclusion, data available to date support the clinical validity of PCa risk-associated SNPs and GRS in risk assessment among men with or without FH. PCa risk-associated SNPs are not intended for diagnostic use; rather, they should be used the same way as FH. Combining GRS and FH can significantly improve the performance of risk assessment. Improved risk assessment may have important clinical utility in targeted PCa testing. However, clinical trials are urgently needed to evaluate this clinical utility as well as the acceptance of GRS by patients and physicians

A randomized trial of a pain management intervention for adults receiving substance use disorder treatment

Background and AimsChronic pain is difficult to treat in individuals with substance use disorders and, when not resolved, can have a negative impact on substance use disorder treatment outcomes. This study tested the efficacy of a psychosocial pain management intervention, ImPAT (improving pain during addiction treatment), that combines pain management with content related to managing pain without substance use.DesignSingle‐site, parallel‐groups randomized controlled trial comparing ImPAT to a supportive psychoeducational control (SPC) condition; follow‐up assessments occurred at 3, 6 and 12 months.SettingThe Ann Arbor VA Substance Use Disorder treatment program, USA.ParticipantsVeterans Health Administration patients {n = 129; mean [standard deviation (SD)], age = 51.7 (9.5); 115 of 129 (89%) male; ImPAT (n = 65); SPC (n = 64)}.InterventionImPAT combines principles of cognitive–behavioral therapy and acceptance‐based approaches to pain management with content related to avoiding the use of substances as a coping mechanism for pain. The SPC used a psychoeducational attention control treatment for alcoholism modified to cover other substances in addition to alcohol.MeasurementsPrimary: Pain intensity over 12 months; secondary: pain‐related functioning, frequency of alcohol and drug use over 12 months.FindingsPrimary: randomization to the ImPAT intervention versus SPC predicted significantly lower pain intensity {β [standard error (SE)] = −0.71 (0.29); 95% confidence interval (CI) = −1.29, −0.12}; secondary: relative to the SPC condition, those who received ImPAT also reported improved pain‐related functioning [β (SE) = 0.27 (0.11); 95% CI = 0.05, 0.49] and lower frequency of alcohol consumption [β (SE) = −0.77; 95% CI = −1.34, −0.20]. No differences were found between conditions on frequency of drug use over follow‐up.ConclusionsFor adults with pain who are enrolled in addictions treatment, receipt of a psychological pain management intervention (improving pain during addiction treatment) reduced pain and alcohol use and improves pain‐related functioning over 12 months relative to a matched‐attention control condition.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/133564/1/add13349_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133564/2/add13349.pd

Population-standardized genetic risk score: the SNP-based method of choice for inherited risk assessment of prostate cancer

Several different approaches are available to clinicians for determining prostate cancer (PCa) risk. The clinical validity of various PCa risk assessment methods utilizing single nucleotide polymorphisms (SNPs) has been established; however, these SNP-based methods have not been compared. The objective of this study was to compare the three most commonly used SNP-based methods for PCa risk assessment. Participants were men (n = 1654) enrolled in a prospective study of PCa development. Genotypes of 59 PCa risk-associated SNPs were available in this cohort. Three methods of calculating SNP-based genetic risk scores (GRSs) were used for the evaluation of individual disease risk such as risk allele count (GRS-RAC), weighted risk allele count (GRS-wRAC), and population-standardized genetic risk score (GRS-PS). Mean GRSs were calculated, and performances were compared using area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV). All SNP-based methods were found to be independently associated with PCa (all P 0.05 for comparisons between the three methods), and all three SNP-based methods had a significantly higher AUC than family history (all P < 0.05). Results from this study suggest that while the three most commonly used SNP-based methods performed similarly in discriminating PCa from non-PCa at the population level, GRS-PS is the method of choice for risk assessment at the individual level because its value (where 1.0 represents average population risk) can be easily interpreted regardless of the number of risk-associated SNPs used in the calculation

Race-specific genetic risk score is more accurate than nonrace-specific genetic risk score for predicting prostate cancer and high-grade diseases

Genetic risk score (GRS) based on disease risk-associated single nucleotide polymorphisms (SNPs) is an informative tool that can be used to provide inherited information for specific diseases in addition to family history. However, it is still unknown whether only SNPs that are implicated in a specific racial group should be used when calculating GRSs. The objective of this study is to compare the performance of race-specific GRS and nonrace-specific GRS for predicting prostate cancer (PCa) among 1338 patients underwent prostate biopsy in Shanghai, China. A race-specific GRS was calculated with seven PCa risk-associated SNPs implicated in East Asians (GRS7), and a nonrace-specific GRS was calculated based on 76 PCa risk-associated SNPs implicated in at least one racial group (GRS76). The means of GRS7 and GRS76 were 1.19 and 1.85, respectively, in the study population. Higher GRS7 and GRS76 were independent predictors for PCa and high-grade PCa in univariate and multivariate analyses. GRS7 had a better area under the receiver-operating curve (AUC) than GRS76 for discriminating PCa (0.602 vs 0.573) and high-grade PCa (0.603 vs 0.575) but did not reach statistical significance. GRS7 had a better (up to 13% at different cutoffs) positive predictive value (PPV) than GRS76. In conclusion, a race-specific GRS is more robust and has a better performance when predicting PCa in East Asian men than a GRS calculated using SNPs that are not shown to be associated with East Asians

Caspase polymorphisms and prognosis of hepatocellular carcinoma

<div><p>The aim of our study was to determine the impact of genetic polymorphisms in the caspase (CASP) genes on prognosis of hepatocellular carcinoma (HCC). We genotyped 7 potentially functional polymorphisms in <i>CASP3</i>, <i>CASP7</i>, <i>CASP8</i>, <i>CASP9</i>, <i>CASP10</i> genes in 362 HCC patients of receiving surgical resection of HCC tumor. The associations of genotype and haplotype with overall survival (OS) and disease free survival (DFS) were analyzed by using the Cox proportional hazards model. We found that the <i>CASP9</i> rs4645981 C allele was significantly associated with positive effect on DFS (<i>P</i> = 0.011 and 0.016 for CT+CC vs. TT in univariate and multivariate analysis, respectively), CT genotype was associated with a better OS of HCC than the TT genotype both in univariate and multivariate analysis (<i>P</i> = 0.048 and 0.041, respectively). Moreover, the <i>CASP3</i> rs2705897 GT genotype showed marginally significant association with decreased OS and DFS, compared with the GG genotype. One haplotype TT/TG in <i>CASP3</i> (constructed by rs12108497 T>C and rs2705897 T>G) was significantly associated with decreased OS and DFS, compared to the common haplotype TT/TT both in univariate analysis (<i>P</i> = 0.021 and 0.026, respectively) and multivariate analysis (<i>P</i> = 0.025 and 0.030, respectively). The haplotype GT/GT in <i>CASP9</i> (constructed by rs4645978 A>G and rs4645981 C>T) was significantly associated with decreased DFS both in univariate and multivariate analysis (<i>P</i> = 0.012 and 0.010, respectively). In conclusion, the <i>CASP9</i> rs4645981 polymorphism, <i>CASP3</i> and <i>CASP9</i> haplotypes may be useful prognosis markers for HCC patients with surgical resection of tumor.</p></div

Kaplan-Meier survival curves of <i>CASP9</i> rs4645981 with clinical outcomes of 362 HCC patients.

<p>(A) disease free survival (DFS) (B) overall survival (OS).</p