Chun-Nung Huang

The Prognostic Predictors of Primary Ureteral Transitional Cell Carcinoma After Radical Nephroureterectomy

PURPOSE We studied the long-term prognosis, and evaluated the predictors of disease specific and recurrence-free survival in a large cohort of patients who had undergone radical nephroureterectomy for primary transitional cell carcinoma of the ureter. MATERIALS AND METHODS From January 1990 to December 2006, 145 patients with primary ureteral transitional cell carcinoma treated with nephroureterectomy and bladder cuff removal at our institution were included in the study. The medical records of these patients were reviewed retrospectively. The clinical and histopathological data were analyzed to evaluate the prognostic predictive factors. Univariate and multivariate statistical analyses were performed. RESULTS The 5-year disease specific survival rates of stage pTa/Tis/T1, pT2, pT3 and pT4 were 94.6%, 81.8%, 47.4% and 0%, respectively. The 5-year recurrence-free survival rates according to tumor grade were 68.4% for low grade and 35.7% for high grade disease. Of the 145 patients subsequent bladder tumors developed in 38 (26.2%), local recurrence developed in 11 (7.6%) and metachronous contralateral upper urinary tract tumor developed in 3 (2.1%). Most patients had subsequent tumor recurrence within the first year after radical surgery. On univariate and multivariate analyses tumor stage, tumor grade, severity of chronic renal disease, synchronous bladder tumor and hematuria were the significant prognostic variables predicting disease specific and recurrence-free survival. CONCLUSIONS Advanced tumor and chronic renal disease stages were significantly associated with a worse prognosis in patients with primary ureteral transitional cell carcinoma who had undergone radical nephroureterectomy. With regard to tumor recurrence, advanced tumor stage, high tumor grade and synchronous bladder tumor were independent risk factors.

Polymorphisms inside MicroRNAs and MicroRNA Target Sites Predict Clinical Outcomes in Prostate Cancer Patients Receiving Androgen-Deprivation Therapy

Purpose: Recent evidence indicates that small noncoding RNA molecules, known as microRNAs (miRNAs), are involved in cancer initiation and progression. We hypothesized that genetic variations in miRNAs and miRNA target sites could be associated with the efficacy of androgen-deprivation therapy (ADT) in men with prostate cancer. Experimental Design: We systematically evaluated 61 common single nucleotide polymorphisms (SNPs) inside miRNAs and miRNA target sites in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan–Meier analysis and Cox regression model. Results: Four, seven, and four SNPs were significantly associated with disease progression, PCSM, and ACM, respectively, after ADT in univariate analysis. KIF3C rs6728684, CDON rs3737336, and IFI30 rs1045747 genotypes remained as significant predictors for disease progression; KIF3C rs6728684, PALLD rs1071738, GABRA1 rs998754, and SYT9 rs4351800 remained as significant predictors for PCSM; and SYT9 rs4351800 remained as a significant predictor for ACM in multivariate models that included clinicopathologic predictors. Moreover, strong combined genotype effects on disease progression and PCSM were also observed. Patients with a greater number of unfavorable genotypes had a shorter time to progression and worse prostate cancer-specific survival during ADT (P for trend < 0.001). Conclusion: SNPs inside miRNAs and miRNA target sites have a potential value to improve outcome prediction in prostate cancer patients receiving ADT. Clin Cancer Res; 17(4); 1–9. ©2010 AACR.

The Potential Impact of Metabolic Syndrome on Erectile Dysfunction in Aging Taiwanese Males

INTRODUCTION Recently, metabolic syndrome (MtS) has received increasing attention. However, investigations regarding the potential impact of MtS and its components on erectile dysfunction (ED) have not been completely clarified. AIM To determine the potential impact of MtS on ED in aging Taiwanese males. MAIN OUTCOME MEASURE The definition of MtS was according to the modified criteria developed by the Bureau of Health Promotion in Taiwan. The presence and severity of ED were evaluated by International Index of Erectile Function 5 (IIEF-5) scores. METHODS A total of 639 subjects with a mean age of 60.2 years (range 40-83) were enrolled during a free health screening. All the men had complete clinical data and questionnaires taken. Clinical variables were compared according to MtS and ED prevalence. Multiple logistic regression analysis was used to determine the independent predictors of ED and MtS. RESULTS Using age-adjusted multivariate logistic regression analysis, our results showed that subjects with ED had significantly higher prevalence of MtS (P<0.01, OR=2.30, 95% CI: 1.44-3.69). The presence of MtS had significant correlation with lower IIEF-5 scores (P<0.01), which were associated with the increment of MtS components number (P<0.01). Among the MtS components, abnormal fasting blood glucose (FBG) was the most significantly independent factor of MtS for ED (P=0.01, OR=1.60, 95% CI: 1.09-2.35). Testosterone levels were significantly lower in subjects with MtS (P=0.05), while inversely correlated with number of MtS components (P<0.01). CONCLUSIONS In aging Taiwanese males, the presence of MtS is strongly associated with ED and abnormal FBG is the most independent predictor for ED. Low testosterone level might be viewed as another possible common denominator for various pathologies linking MtS to ED.

Individual and cumulative association of prostate cancer susceptibility variants with clinicopathologic characteristics of the disease.

BACKGROUND Recent genome-wide association studies have identified several independent single nucleotide polymorphisms (SNPs) strongly associated with prostate cancer (PCa) risk. However, their individual and cumulative associations with clinicopathologic characteristics of the disease remain inconclusive. METHODS We systematically evaluated 20 PCa risk SNPs in a cohort of 320 localized PCa patients receiving radical prostatectomy, and the associations of these variants with age at diagnosis, preoperative prostate-specific antigen concentration, Gleason score, pathologic stage, surgical margin, and lymph node metastasis were evaluated. RESULTS Eight SNPs, rs10486567 at 7p15, rs6465657 at 7q21, rs6983267, rs1447295, and rs4242382 at 8q24, 10993994 at 10q11, rs4430796 at 17q12, and rs266849 at 19q13, were significantly (P< or =0.048) associated with some specific clinicopathologic features. In combination of these 8 SNPs, men who carried 4 or 5, or more than 5 unfavorable alleles had an increasing likelihood of adverse clinicopathologic features, as compared with men who carried fewer than 4 unfavorable alleles (P for trend, 0.031, <0.001, 0.006, and 0.003, for Gleason scores 8-10, advanced pathologic stage, positive surgical margin, and lymph node metastasis, respectively). CONCLUSIONS Our results suggested that loci associated with PCa risk might also have a cumulative and significant association with disease aggressiveness.

The association of eNOS G894T polymorphism with metabolic syndrome and erectile dysfunction.

INTRODUCTION Accumulated evidences have outlined the potential relation between insulin resistance and endothelial dysfunction. The impaired ability of endothelium to synthesize or release nitric oxide may provide a common pathophysiological mechanism in the development of metabolic syndrome (MtS) and erectile dysfunction (ED). AIM The aim of this article was to investigate the genetic susceptibility of endothelial nitric oxide synthase (eNOS) G894T polymorphism underlying the development of both disorders. METHODS A total of 590 subjects with a mean (standard deviation) age of 55.3 years (4.1) were enrolled during a free health screening. Complete clinical data and questionnaires were taken for all subjects. Multivariate logistic regression analysis was used to determine the independent predictors of MtS and ED. The eNOS G894T polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism method. MAIN OUTCOME MEASURES The definition of MtS was according to the modified criteria developed by the Bureau of Health Promotion in Taiwan. Patients with ED were defined as those having a five-item International Index of Erectile Function (IIEF-5) <21. RESULTS Our results showed that the eNOS 894T allele carriers had significantly higher prevalence of MtS and ED (odds ratio [OR]=1.64, 95% confidence interval [CI]=1.05∼2.56, P=0.02 and OR=1.76, 95% CI=1.11∼2.80, P=0.01, respectively) after adjustment for each other and age. Also the T allele carriers had significantly lower IIEF-5 score and more MtS components than G allele carriers (P<0.01 and P<0.01, respectively), which were significantly associated with an increment of the T allele number (P<0.05). CONCLUSIONS The eNOS 894T allele carriers are at greater risk for both MtS and ED, suggesting that eNOS G894T gene polymorphism might play an implication as a common genetic susceptibility factor to develop both disorders.

The Impact of Androgen Receptor CAG Repeat Polymorphism on Andropausal Symptoms in Different Serum Testosterone Levels

INTRODUCTION In addition to a depletion of androgen, attenuated action of androgen receptor (AR) might also contribute to andropausal symptoms. AIM To evaluate the interaction of AR cytosine adenine guanine (CAG) repeat polymorphism and serum testosterone levels and their effect on andropausal symptoms in aging Taiwanese men. METHODS From August 2007 to April 2008, a free health screening for men older than 40 years was conducted by a medical center in Kaohsiung City, Taiwan. All participants received physical examination, answered questionnaires to collect their demographic information and medical histories, completed the Androgen Deficiency in the Aging Male (ADAM) questionnaire, and provided 20-cm(3) whole blood samples for biochemical and genetic evaluation. MAIN OUTCOME MEASURES The ADAM questionnaire was used to evaluate andropausal symptoms. Serum albumin, total testosterone (TT), and sex hormone-binding globulin levels were measured. Free testosterone level was calculated. AR gene CAG repeat polymorphism was determined by direct sequencing. RESULTS Seven hundred two men with the mean age of 57.2 ± 6.5 years were included. There was no significant association between TT levels and the distribution of AR CAG repeat polymorphism. When TT levels were above 340 ng/dL, subjects with AR CAG repeat lengths ~25 showed significantly higher risk of developing andropausal symptoms, as compared with those with AR CAG repeat lengths ~22 (P = 0.006), but this was not observed when TT levels were 340 ng/dL or below. Age and number of comorbidities were also independent risk factors for andropausal symptoms. CONCLUSION In subjects with normal TT concentration, those with longer AR CAG repeat lengths have a higher risk of developing andropausal symptoms. Age and number of comorbidities can also influence the appearance of andropausal symptoms. In clinical practice, a multifactorial approach to evaluate andropausal symptoms and the interactions between those risk factors is suggested.

Associations of the lower urinary tract symptoms with the lifestyle, prostate volume, and metabolic syndrome in the elderly males

This study aimed to evaluate the influence of the lifestyle, prostate volume (PV), and metabolic syndrome (MS) on lower urinary tract symptoms (LUTS) in the elderly males. A total of 764 men aged greater than 40 years were enrolled. Their severities of LUTS were assessed by the International Prostate Symptom Score questionnaire, while their MS was diagnosed according to the criteria developed by the National Cholesterol Education Program Adult Treatment Panel III. Lifestyle factors, PV, and components of MS were compared between no/mild and moderate/severe LUTS groups. In univariate analysis, age, cigarette smoking, alcohol consumption, physical activity, and PV significantly correlated with the severity of LUTS, but the presence or any components of MS did not. Results of multivariate analysis showed that aging, cigarette smoking, lack of regular exercise, and larger PV were independent predictors for moderate/severe LUTS. Notably, the risk factors for LUTS was influenced by the presence of MS. PV may play a role in determining the severity of LUTS for men without MS, while physical activity was the critical factor for men with MS. It was suggested that healthy lifestyle would be beneficial to lessen the severity of LUTS in the elderly males.

Significant associations of prostate-specific antigen nadir and time to prostate-specific antigen nadir with survival in prostate cancer patients treated with androgen-deprivation therapy

Objective. The influence of prostate-specific antigen (PSA) kinetics on the outcome of metastatic prostate cancer (PCa) after androgen-deprivation therapy (ADT) remains poorly characterised. We evaluated the prognostic significance of PSA nadir and time to PSA nadir as well as their interactive effect on prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT. Methods. A total of 650 men with advanced or metastatic PCa treated with ADT were studied. The prognostic significance of PSA nadir and time to PSA nadir on PCSM and ACM were analysed using Kaplan–Meier analysis and the Cox regression model. Results. On multivariate analysis, clinical M1 stage, Gleason Score 8–10, PSA nadir ≥ 0.2 ng/ml and time to PSA nadir < 10 months were independent predictors of PCSM and ACM. The combined analysis showed that patient with higher PSA nadir and shorter time to PSA nadir had significantly higher risk of PCSM and ACM compared to those with lower PSA nadir and longer time to PSA nadir (hazard ratios = 6.30 and 4.79, respectively, all P < 0.001). Conclusions. Our results suggest that higher PSA nadir level and faster time to reach PSA nadir after ADT were associated with shorter survival for PCa.

Significant associations of prostate cancer susceptibility variants with survival in patients treated with androgen-deprivation therapy

Androgen‐deprivation therapy (ADT) is the most common therapy for advanced prostate cancer, but the prognosis significantly differs among individuals. In this study, we evaluated recently identified 19 prostate cancer susceptibility variants as prognostic predictors for the survival after ADT. A total of 601 prostate cancer patients treated with ADT were enrolled in this study cohort. The prognostic significance of the prostate cancer risk variants on disease progression, prostate cancer‐specific mortality (PCSM) and all‐cause mortality (ACM) after ADT were assessed by Kaplan–Meier analysis and Cox regression model. Two polymorphisms, rs16901979 and rs7931342, were significantly associated with PCSM (p = 0.005 for rs16901979 and p = 0.038 for rs7931342), and rs16901979 was also associated with ACM (p = 0.003) following ADT. Although the effect of rs7931342 was attenuated after controlling for other known clinical prognostic factors, rs16901979 remained a significant predictor for PCSM and ACM after ADT (p = 0.002). Moreover, the addition of the rs16901979 status in current clinical staging system further enhanced the risk prediction on PCSM and ACM particularly for the high‐risk patients with distant metastasis (p < 0.017). In conclusion, this is the first study showing that prostate cancer risk variants, such as rs16901979, might improve outcome prediction following ADT, thus allowing identification of high‐risk patients who might benefit from appropriate adjuvant therapy.

Genetic Variants in CASP3, BMP5, and IRS2 Genes May Influence Survival in Prostate Cancer Patients Receiving Androgen-Deprivation Therapy

Several genome-wide association studies (GWAS) have been conducted to identify the common single nucleotide polymorphisms (SNPs) that influence the risk of prostate cancer. It was hypothesized that some prostate cancer-associated SNPs might relate to the clinical outcomes in patients treated for prostate cancer using androgen-deprivation therapy (ADT). A cohort of 601 patients who have received ADT for prostate cancer was genotyped for 29 SNPs that have been associated with prostate cancer in Cancer Genetic Markers of Susceptibility GWAS, and within the genes that have been implicated in cancer. Prognostic significance of these SNPs on the disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan-Meier analysis and Cox regression model. Three SNPs, namely CASP3 rs4862396, BMP5 rs3734444 and IRS2 rs7986346, were found to be closely associated with the ACM (P≤0.042), and BMP5 rs3734444 and IRS2 rs7986346 were also noted to be significantly related to the PCSM (P≤0.032) after adjusting for the known clinicopathologic predictors. Moreover, patients carrying a greater number of unfavorable genotypes at the loci of interest had a shorter time to ACM and PCSM during ADT (P for trend <0.001). Our results suggest that CASP3 rs4862396, BMP5 rs3734444 and IRS2 rs7986346 may affect the survival in patients after ADT for prostate cancer, and the analysis of these SNPs can help identify patients at higher risk of poor outcome.