Polymorphisms in MicroRNA Binding Sites Predict Colorectal Cancer Survival.

Background: MicroRNAs (miRNAs) mediate negative regulation of target genes through base pairing, and aberrant miRNA expression has been described in cancers. We hypothesized that single nucleotide polymorphisms (SNPs) within miRNA target sites might influence clinical outcomes in patients with colorectal cancer. Methods: Sixteen common SNPs within miRNA target sites were identified, and the association between these SNPs and overall survival was assessed in colorectal cancer patients using Kaplan-Meier analysis, Cox regression model, and survival tree analysis. Results: Survival tree analysis identified a higher-order genetic interaction profile consisting of the RPS6KB1 rs1051424 and ZNF839 rs11704 that was significantly associated with overall survival. The 5-year survival rates were 74.6%, 62.7%, and 57.1% for the low-, medium-, and high-risk genetic profiles, respectively (P = 0.006). The genetic interaction profile remained significant even after adjusting for potential risk factors. Additional in silico analysis provided evidence that rs1051424 and rs11704 affect RPS6KB1 and ZNF839 expressions, which in turn is significantly correlated with prognosis in colorectal cancer. Conclusion: Our results suggest that the genetic interaction profiles among SNPs within miRNA target sites might be prognostic markers for colorectal cancer survival.

Common variants in IGF1 pathway genes and clinical outcomes after radical prostatectomy.

BACKGROUND: Insulin-like growth factor-1 (IGF1) pathway plays a critical role in malignant transformation, and epidemiology studies have also shown that single nucleotide polymorphisms (SNPs) in IGF1 pathway genes are associated with prostate cancer risk. However, the clinical significance of these SNPs on prostate cancer aggressiveness and prognosis after radical prostatectomy (RP) has not been determined. METHODS: We evaluated the associations of 4 common SNPs in IGF1 and IGF1R with age at diagnosis, preoperative prostate-specific antigen (PSA) level, pathologic Gleason score, pathologic stage, surgical margin, lymph node metastasis, and PSA recurrence in a cohort of 320 localized prostate cancer patients receiving RP. The prognostic significance on time to PSA recurrence was also assessed by Cox proportional hazards model. RESULTS: IGF1 rs2946834 alleles/genotypes and an IGF1 specific haplotype AT, containing the minor allele of rs2946834, were associated (P ≤ 0.028) with a 1.49- to 2.22-fold higher risk of having advanced-stage prostate cancer. In addition, a genetic interaction profile consisting of IGF1 rs2946834 and IGF1R rs2016347 was significantly associated with PSA recurrence (P = 0.033). CONCLUSIONS: Our study is the first to evaluate the impact of SNPs in IGF1 pathway genes on PSA recurrence. A genetic interaction between IGF1 rs2946834 and IGF1R rs2016347 might be a predictor of outcomes following RP.

Vitamin D receptor gene variants and clinical outcomes after androgen-deprivation therapy for prostate cancer.

PURPOSE: Molecular epidemiology studies have shown that vitamin D receptor (VDR) gene polymorphisms are associated with prostate cancer risk. However, the prognostic value of these polymorphisms on clinical outcomes in prostate cancer patients receiving androgen-deprivation therapy (ADT) has not been determined. METHODS: We evaluated the association of five common VDR polymorphisms, ApaI, Tru9I, BsmI, FokI, and Cdx2, with clinicopathologic characteristics and clinical outcomes, including disease progression, prostate cancer-specific mortality, and all-cause mortality, in a cohort of 601 prostate cancer patients treated with ADT. RESULTS: Of the five VDR polymorphisms, FokI rs2228570 and BsmI rs1544410 were associated with Gleason score at diagnosis (P = 0.043) and prostate-specific antigen nadir following ADT (P = 0.023), respectively. The haplotype analysis revealed that the A-A-G (ApaI-Tru9I-BsmI) compared with C-G-G individuals were more likely to have high Gleason score (P = 0.050). However, none of these polymorphisms were significantly associated with disease progression and mortality after ADT. CONCLUSIONS: This is the largest study to date investigating the association of VDR polymorphisms and clinical outcomes in prostate cancer patients receiving ADT. Polymorphisms in the VDR gene might be associated with Gleason score, but these polymorphisms had no main effect on predicting response to ADT.

Genetic polymorphisms of matrix metalloproteinases and clinical outcomes in colorectal cancer patients.

BACKGROUND: Colorectal cancer metastasis is a multistep process involving degradation of extracellular matrix components by proteolytic enzymes. Among them, matrix metalloproteinases (MMPs) are the principal degrading enzymes and their expressions/activities are also correlated with survival. Much research has showed the associations between genetic polymorphisms in MMPs and risk of colorectal cancer; however, their prognostic significance has not been well determined. METHODS: We selected and genotyped 4 cancer-associated single nucleotide polymorphisms (SNPs) in a cohort of 282 colorectal cancer patients. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. RESULTS: The relative risks of developing distant metastasis after curative surgery were higher in individuals with minor homozygote AA genotype than in those with GG/GA genotypes at MMP2 rs243866 (P = 0.012). Survival tree analysis also identified a higher-order genetic interaction profile consisting of MMP2 rs243866 and MMP2 rs2285053 that was significantly associated with distant metastasis-free survival (P trend = 0.016). After adjusting for possible confounders, the genetic interaction profile remained significant (P trend = 0.050). CONCLUSIONS: These results suggest that genetic variations in the MMP2 might be potential predictors of distant metastasis-free survival after curative surgery.

Reducing the time needed to administer a sustained attention test in patients with stroke.

Administering a sustained attention test often takes a lengthy time, which can hamper routine assessments in clinical settings. Therefore, we first proposed a method to reduce the time needed for administering a sustained attention test (the Computerized Digit Vigilance Test, C-DVT). The method was to retrieve 5 segments from different trial positions of the original C-DVT testing. Then we compared the concurrent validity, convergent validity, and random measurement error of the examinees' performance on these segments to find the segment with better psychometric properties. The 5 segments were as follows: the first 50% of testing, the 21st~50th percentile of testing, the first 60% of testing, the 31st~60th percentile of testing, and the 36th~65th percentile of testing. Then we compared the validities and random measurement error of the examinees' performance on these segments. Ninety patients with stroke participated in the validity study, and 44 of them participated in the random measurement error study. The patients' scores on the 5 segments were highly correlated with those of the C-DVT (Pearson's r ≥ 0.98), indicating excellent concurrent validity. The patients' scores on the 5 segments were moderately correlated with those of the Tablet-based Symbol Digit Modalities Test (Pearson's r = -0.51~-0.48), indicating sufficient convergent validity. The amounts of random measurement error (percent standard error of measurement) were all limited: 5.1% for the C-DVT, 6.6% for the first 50% of testing, 6.0% for the 21st~50th percentile of testing, 6.1% for the first 60% of testing, 6.0% for the 31st~60th percentile of testing, and 6.1% for the 36th~65th percentile of testing. The patients needed on average 3~4 minutes to complete all the aforementioned testing. The patients' scores on the 5 segments showed excellent concurrent validity, sufficient convergent validity, and limited amounts of random measurement error in patients with stroke. We suggest the 31st~60th percentile of testing segment for users because it had the lowest amount of random measurement error and can reduce the time needed for formal testing by about 40%.

Impact of an antimicrobial stewardship program with multidisciplinary cooperation in a community public teaching hospital in Taiwan.

BACKGROUND: Reports of antimicrobial stewardship programs (ASPs) in community hospitals are limited, with the major focus on specific agents, small settings, or short time periods. Here we present the outcomes of cost control, consumption restraint, and quality of care after a 3-year multidisciplinary ASP in a 415-bed community public teaching hospital. METHODS: Three strategies for improving antimicrobial stewardship were implemented: education, clinical pharmacists-based intervention, and regular outcome announcement. The steering panel of the program was a committee composed of infection specialists, attending physicians, clinical pharmacists, nurses, and medical laboratorists. RESULTS: Semiannual data from July 2009 to June 2012 was analyzed. Antibiotic costs declined from $21,464 to $12,146 per 1,000 patient-days (-43.4%). Approximately $2.5 million was saved in 3 years, and estimated labor cost was $3,935 per month. Defined daily dose per 1,000 patient-days were diminished from 906.7 to 717.5 (-20.9%). Significant reductions were found in the consumption of aminoglycosides, first-generation cephalosporins, and aminopenicillins. However, through comprehensive auditing, increasing consumption of fourth-generation cephalosporins and fluoroquinolones was noticed. No significant difference in the quality of care (ie, length of stay, incidence of health care associated infections, and mortality) was observed. CONCLUSIONS: The multidisciplinary ASP was beneficial to reduce antibiotic cost and consumption. The strategies were practical and worthy to be recommended to community health care settings.

Common genetic variants in Wnt signaling pathway genes as potential prognostic biomarkers for colorectal cancer.

Compelling evidence has implicated the Wnt signaling pathway in the pathogenesis of colorectal cancer. We assessed the use of tag single nucleotide polymorphisms (tSNPs) in adenomatous polyposis coli (APC)/ß-catenin (CTNNB1) genes to predict outcomes in patients with colorectal cancer. We selected and genotyped 10 tSNP to predict common variants across entire APC and CTNNB1 genes in 282 colorectal cancer patients. The associations of these tSNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. The 5-year overall survival rate was 68.3%. Survival tree analysis identified a higher-order genetic interaction profile consisting of the APC rs565453, CTNNB1 2293303, and APC rs1816769 that was significantly associated with overall survival. The 5-year survival overall rates were 89.2%, 66.1%, and 58.8% for the low-, medium-, and high-risk genetic profiles, respectively (log-rank P = 0.001). After adjusting for possible confounders, including age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, perineural invasion, and lymph node involvement, the genetic interaction profile remained significant. None of the studied SNPs were individually associated with distant metastasis-free survival and overall survival. Our results suggest that the genetic interaction profile among Wnt pathway SNPs might potentially increase the prognostic value in outcome prediction for colorectal cancer.