Hung-Lung Ke

Significant predictive factors for prognosis of primary upper urinary tract cancer after radical nephroureterectomy in Taiwanese patients.

OBJECTIVES To follow up the long-term prognosis of patients who underwent nephroureterectomy for primary upper urinary tract (UUT) cancer and to evaluate the predictive factors of tumour recurrence and survival. METHODS Between January 1990 and June 2005, 260 patients with primary UUT transitional cell carcinoma (TCC) underwent radical nephroureterectomy at our institution. The medical records of these patients were retrospectively reviewed. The clinical and histopathological data were analyzed to evaluate predictive factors. RESULTS The median follow-up time was 52 mo. In total, 89 patients (34.1%) developed subsequent bladder tumours. Predictive factors of bladder tumour recurrence were being male and having renal insufficiency. Local recurrence developed in 16 patients (6.2%); only the tumour stage was significantly associated with local recurrence. Metachronous contralateral UUT tumour was diagnosed in 12 patients (4.6%), with gender being the only predictive factor. Of the 260 patients, 167 (63.9%) were disease-free and alive at a median follow-up of 56.5 mo, and 45 (17.2%) died of urothelial cancer at a median period of 20 mo. Only the tumour stage was a prognostic factor to predict cancer-specific survival. CONCLUSIONS In patients with UUT-TCC after radical nephroureterectomy, tumour stage is the only prognostic factor for both local recurrence and cancer-specific survival. Male patients with renal insufficiency should be alerted to the possibility of bladder tumour recurrence. Because female patients were more likely to develop contralateral recurrences, renal ultrasonography, intravenous pyelography, or retrograde pyelography should be performed more frequently for female patients who live in the high-prevalence area.

The Prevalence of and Risk Factors for Androgen Deficiency in Aging Taiwanese Men

INTRODUCTION Androgen deficiency in aging men has attracted much medical interest. Most studies on androgen deficiency have been conducted in Caucasian populations, and data from other ethnicities are lacking. AIM To evaluate the prevalence of and risk factors for androgen deficiency and symptomatic androgen deficiency in Taiwanese men over 40 years old. METHODS From August 2007 to April 2008, a free health screening was conducted by a medical center in Kaohsiung, Taiwan, and 819 men participated in this health screening. All participants completed a health questionnaire, received a detailed physical examination, and blood samples were drawn between 8:00 and 12:00 am. MAIN OUTCOME MEASURES Serum total testosterone (TT), albumin, and sex hormone-binding globulin levels were measured. The level of free testosterone (FT) was calculated. Clinical symptoms of androgen deficiency were assessed using the Androgen Deficiency in the Aging Male (ADAM) questionnaire. RESULTS Seven hundred thirty-four men who met the inclusion criteria (mean age 57.4 +/- 6.7 years; range: 43-87 years) were included in this study. The prevalence of androgen deficiency was 24.1% based on the criterion of TT level < 300 ng/dL, and 16.6% based on the criterion of both TT < 300 ng/dL and FT < 5 ng/dL. The prevalence of symptomatic androgen deficiency was 12.0%. Both prevalence of androgen deficiency and symptomatic androgen deficiency increased with age. Older age, obesity, and diabetes mellitus were independent risk factors for androgen deficiency and symptomatic androgen deficiency. CONCLUSIONS In a sample of aging Taiwanese men, a substantial proportion had androgen deficiency and symptomatic androgen deficiency, and the prevalence increased with age. Older age, obesity, and diabetes mellitus were independent risk factors for androgen deficiency and symptomatic androgen deficiency. Those potentially modifiable risk factors like obesity and diabetes mellitus should be prevented to maintain normal testosterone levels during aging in men.

Increase sensitivity in detecting superficial, low grade bladder cancer by combination analysis of hypermethylation of E-cadherin, p16, p14, RASSF1A genes in urine.

OBJECTIVES To identify a better set of DNA methylation markers to detect superficial, low grade cancer cell in urine sediment for improving cancer treatment, morbidity, and mortality. MATERIALS AND METHODS Methylation-specific PCR (MSP) assay was used to detect promoter hypermethylation in 4 genes (E-cadherin, p16, p14, and RASSF1A) to identify reliable biomarkers for bladder cancer diagnosis in primary tumor DNA and urine sediment DNA from 57 bladder cancer patients. Urine DNA was compared with 20 healthy controls. RESULTS Fifty-one (90%) tumor DNA and 47 urine DNA (83%) samples from bladder cancer patients revealed hypermethylation in at least 1 of the 4 analyzed genes, whereas all urine samples from normal controls were negative. The sensitivity of MSP assay for detecting E-cadherin, p16, p14 and RASSF1A in tumor cells in voided urine was 35%, 35%, 33%, and 65%, respectively. Diagnostic sensitivity was 75% for combining RASSF1A and p14, and 83% for RASSF1A, p14 and E-cadherin. Urine cytology, however, detect only 13 (28%) cases of cancer or suspicious cancer. For detecting superficial and invasive bladder tumor, urine cytology revealed a sensitivity of 23% (6/26) and 35% (7/20), respectively. In contrast, MSP detected hypermethylation in the urine of 80% (37/46) bladder cancer patients. Moreover, hypermethylation analysis of E-cadherin, p14 or RASSF1A genes in urine sediment DNA detected in 85% (22/26) of superficial, 85% (11/13) of low grade, 75% (15/20) of invasive and 79% (26/33) of high grade bladder cancers. Importantly, hypermethylation was detected in the urine DNA of 90% (18/20) superficial tumors with negative or atypia cytology. CONCLUSIONS Hypermethylation of E-cadherin, p14 or RASSF1A in urine sediment DNA is a potential biomarker for detecting superficial, low grade cancer. Besides, hypermethylation of these 3 genes is a valuable adjunct diagnostic marker to urine cytology, which can enhance the diagnostic accuracy and follow-up treatment of bladder cancer patients.

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.

Should Patients With Primary Upper Urinary Tract Cancer Receive Prophylactic Intravesical Chemotherapy After Nephroureterectomy

PURPOSE We assessed the efficacy of prophylactic intravesical chemotherapy for primary upper urinary tract urothelial cancer after nephroureterectomy during long-term followup. MATERIALS AND METHODS From January 1985 to June 2007, 196 patients with primary upper urinary tract urothelial cancer were included in this study. Patients were divided into group 1-31 who received intravesical epirubicin instillation, group 2-27 who received intravesical mitomycin C instillation and group 3-138 who did not receive prophylactic instillation after nephroureterectomy. We compared the bladder tumor recurrence rate, number of recurrence episodes, time to first bladder tumor recurrence, tumor type, percent of patients with cystectomy and percent who died of urothelial cancer, and the recurrence-free survival rate. RESULTS Of the 196 patients 73 had subsequent bladder recurrence at a mean followup of 55.6 months. There were no significant differences in recurrence type, mean number of bladder tumor recurrences, percent of patients with cystectomy and the cancer specific survival rate. The bladder recurrence rate was lower in group 1 and 2 than in group 3. Mean time to first bladder tumor recurrence was longer in groups 1 and 2. Kaplan-Meier curves of recurrence-free survival rates were significantly increased in groups 1 and 2. CONCLUSIONS Intravesical instillation of epirubicin or mitomycin C appears to be well tolerated and effective for preventing bladder recurrence and prolonging time to first bladder recurrence. Patients should receive prophylactic intravesical chemotherapy after nephroureterectomy.

The Associations Among eNOS G894T Gene Polymorphism, Erectile Dysfunction, and Benign Prostate Hyperplasia‐Related Lower Urinary Tract Symptoms

INTRODUCTION A number of literature has now identified the role of impaired nitric oxide synthase/nitric oxide pathway in the endothelium as the central to the development of erectile dysfunction (ED) and benign prostate hyperplasia-related lower urinary tract symptoms (BPH/LUTS). Recently a few studies have reported the associations between endothelial nitric oxide synthase (eNOS) G894T gene polymorphisms and ED. However, there has been no report investigating the eNOS G894T genetic susceptibility factor for both ED and BPH/LUTS. AIM To investigate the possible associations among eNOS G894T polymorphism, ED, and BPH/LUTS in a Taiwanese population. MAIN OUTCOME MEASURES Patients with ED were defined as those having a 5-item International Index of Erectile Function-5 <21. METHODS In all, 372 Taiwanese men underwent a free health screening were enrolled. All the men had complete clinical data and questionnaires taken. The eNOS G894T polymorphisms were determined using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS Three hundred seventy-two men had a mean (standard deviation) age of 60.2 (8.8) years. With multivariate analysis, our data identified that aging, diabetes mellitus (DM), and eNOS G894T gene polymorphism were three independent common risk factors for both ED and BPH/LUTS (P < 0.001, P = 0.036, and P = 0.039 for ED; P = 0.034, P = 0.004, and P = 0.016 for BPH/LUTS, respectively). The eNOS 894T allele carriers had significantly higher prevalence of ED (77.9% vs. 60.4%, P = 0.012) and higher International Prostate Symptom score (IPSS) (13.3 +/- 10.7 vs. 9.3 +/- 7.8, P = 0.001) than G allele carriers. CONCLUSIONS Our results showed that aging, DM, and eNOS 894T allele carrier gene polymorphism were the three independently common risk factors for both ED and BPH/LUTS in the Taiwanese population. The eNOS 894T allele carriers had significantly higher frequencies of ED and higher IPSS, suggesting that eNOS G894T gene polymorphisms may play an implication as a genetic susceptibility factor for both ED and BPH/LUTS.

Osteopontin overexpression predicts poor prognosis of upper urinary tract urothelial carcinoma

OBJECTIVES Studies indicate overexpression of osteopontin (OPN) promotes carcinogenesis, progression and metastasis of multiple human malignancies. However, the function of OPN in urothelial carcinoma (UC) of the upper urinary tract has not been investigated. This study evaluates the clinical significance of OPN expression in upper urinary tract UC. MATERIALS AND METHODS One hundred and ten cases (median age = 64, range = 24-84 years) of renal pelvic or ureter UC were retrospectively reviewed in this study. OPN expression were evaluated by immunohistochemistry staining on paraffin-embedded section of the tumor and scored by two qualified pathologists. RESULTS High OPN expression was found in 54 (49.1%) of the cancer specimens. OPN expression was not significantly correlated with tumor T stage (P = 0.761), N stage (P = 0.339) or grade (P = 0.349). However, OPN expression was differently expressed by gender (P = 0.012) and cancer location (P = 0.026). OPN expression did not correlate with bladder recurrence-free (P = 0.661) or extra-bladder recurrence-free (P = 0.787) survival, but high OPN expression was a significant predictor for cancer-specific survival (P = 0.014). CONCLUSION Our findings indicated that higher OPN expression is a potential biomarker to predict patient survival. Further study is necessary to investigate the role of OPN in the carcinogenesis of upper urinary tract UC.

Nuclear factor‐κB activation predicts an unfavourable outcome in human upper urinary tract urothelial carcinoma

To examine the hypothesis that nuclear factor‐κB (NF‐κB), a transcription factor involved in anti‐apoptosis, invasion, and angiogenesis, plays a role in the carcinogenesis of upper urinary tract urothelial carcinoma (UUT‐UC) and has prognostic value for survival.

Hypermethylation of E-cadherin, p16, p14, and RASSF1A genes in pathologically normal urothelium predict bladder recurrence of bladder cancer after transurethral resection

OBJECTIVES This study investigated the hypermethylation of E-cadherin, p16, p14, and RASSF1A in pathologically normal urothelium to predict recurrence of bladder cancer after transurethral resection. MATERIALS AND METHODS Samples of bladder tumor and paired pathologically normal urothelium were obtained from 50 bladder cancer patients. The status of promoter hypermethylation in these four genes was investigated by methylation-specific polymerase chain reaction. The clinicopathologic data in these patients were also analyzed in order to evaluate the clinical implication of aberrant methylation in bladder cancer recurrence. RESULTS Hypermethylation of E-cadherin (30%), p16 (16%), p14 (14%), and RASSF1A (36%) was detected in the pathologically normal urothelium samples. Promoter hypermethylation occurred frequently in both pathologically normal urothelium and tumor samples from bladder cancer patients, and increased with progression from normal to bladder cancer at E-cadherin (P = 0.067), p16 (P < 0.001), p14 (P = 0.01), and RASSF1A (P = 0.01). No significant correlation was observed between hypermethylation in any genes and muscle/organ invasion and stage/grade, except p14. However, p14 hypermethylation in pathologically normal urothelium samples was associated with shorter recurrence-free interval (P = 0.019). CONCLUSIONS p14 hypermethylation could be involved in early stage of bladder carcinogenesis, and p14 hypermethylation in pathologically normal urothelium samples should be considered a predictor of bladder cancer recurrence.

Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to rapidly screen for albuminuria.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is used as an alternative method for the rapid diagnosis of albuminuria. This technique requires no further sample pretreatment than simply mixing the urine sample with a MALDI matrix and drying under ambient conditions. The resulting MALDI mass spectra reveal albumin ions having charges ranging from +1 to +5. The detection of albumin is possible using any of the three most common MALDI matrices - sinapinic acid (SA), 2,5-dihydroxybenzoic acid (2,5-DHB), or 4-hydroxy-alpha-cyanocinnamic acid (alpha-CHC). Using this analytical approach, the limit of detection for albumin in urine is 10(-6) M, approximately 5 to 10 times lower than that detectable through conventional chemical testing.