Prognostic value of pre-treatment risk stratification and post-treatment neutrophil/lymphocyte ratio change for pembrolizumab in patients with advanced urothelial carcinoma.

BACKGROUND: Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following pembrolizumab treatment in patients with advanced UC. METHODS: We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed. RESULTS: Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (P = 0.0077; RR = 2.42, P = 0.0049; RR = 0.36, P = 0.0047; RR = 2.53, and P = 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (P < 0.0001) and ORR (P < 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (P = 0.0002) and ORR (P = 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (P = 0.0069). CONCLUSIONS: This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.

Identification of curable high-risk prostate cancer using radical prostatectomy alone: who are the good candidates for undergoing radical prostatectomy among patients with high-risk prostate cancer?

BACKGROUND: Currently, there is no consensus regarding which patients with high-risk prostate cancer (PCa) would benefit the most by radical prostatectomy (RP). We aimed to identify patients with high-risk PCa who are treatable by RP alone. METHODS: We retrospectively reviewed data on 315 patients with D'Amico high-risk PCa who were treated using RP without neoadjuvant or adjuvant therapy at the institutions of the Yamaguchi Uro-Oncology Group between 2009 and 2013. The primary endpoint was biochemical progression-free survival (bPFS) after RP. Risk factors for biochemical progression were extracted using the Cox proportional hazard model. We stratified the patients with high-risk PCa into 3 subgroups based on bPFS after RP using the risk factors. RESULTS: At a median follow-up of 49.9 months, biochemical progression was observed in 20.5% of the patients. The 2- and 5-year bPFS after RP were 89.4 and 70.0%, respectively. On multivariate analysis, Gleason score (GS) at biopsy (≥ 8, HR 1.92, p < 0.05) and % positive core (≥ 30%, HR 2.85, p < 0.005) were independent predictors of biochemical progression. Patients were stratified into favorable- (0 risk factor; 117 patients), intermediate- (1 risk factor; 127 patients), and poor- (2 risk factors; 57 patients) risk groups, based on the number of predictive factors. On the Cox proportional hazard model, this risk classification model could significantly predict biochemical progression after RP (favorable-risk, HR 1.0; intermediate-risk, HR 2.26; high-risk, HR 5.03; p < 0.0001). CONCLUSION: The risk of biochemical progression of high-risk PCa after RP could be stratified by GS at biopsy (≥ 8) and % positive core (≥ 30%).

Impact of variant histology on disease aggressiveness and outcome after nephroureterectomy in Japanese patients with upper tract urothelial carcinoma.

BACKGROUND: Patients with urinary bladder urothelial carcinoma (UC) with variant histology have features of more advanced disease and a likelihood of poorer survival than those with pure UC. We investigated the impact of variant histology on disease aggressiveness and clinical outcome after radical nephroureterectomy (RNU) in Japanese patients with upper tract UC (UTUC). Information on variant histology might guide appropriate patient selection for adjuvant therapy after RNU. METHODS: We enrolled 502 UTUC patients treated with RNU in this retrospective cohort study, and analyzed associations of variant histology with clinicopathological variables and disease-specific survival. RESULTS: The median follow-up was 41.4 months. A total of 60 (12.0 %) UTUC patients had variant histology. UTUC with variant histology was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and more lymphovascular invasion (P < 0.0001). Variant histology in all patients was significantly associated with worse disease-specific survival after RNU on univariate analysis (P = 0.0004), but this effect did not remain significant on multivariate analysis. However, variant histology was a significantly independent predictor for disease-specific survival in patients with pT ≥ 3 tumors (P = 0.0095). CONCLUSIONS: UTUC with variant histology might be a phenotype of high-grade, locally aggressive advanced tumors rather than of systemic disease. Variant histology may be useful for selection of patients with pT ≥ 3 UTUC for adjuvant therapy. Prospective studies in a larger number of patients with a centralized pathological review are needed to confirm our results.

Combination of hemoglobin, alkaline phosphatase, and age predicts optimal docetaxel regimen for patients with castration-resistant prostate cancer.

BACKGROUND: We aimed to find the prognostic factors predicting overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) who had docetaxel (DTX) chemotherapy, and to construct a model predicting the optimum number of cycles of DTX. METHODS: A total of 279 CRPC patients who received DTX (≥50 mg/m(2)) every 3-4 weeks were studied retrospectively. Prognostic factors predicting treatment cycles as well as OS were analyzed, and a risk table for predicting treatment cycles was constructed. RESULTS: The longer treatment group (>10 cycles) had a significantly longer OS than the standard treatment group (p < 0.0001). Multivariate analysis demonstrated that a decrease of ≥50 % in prostate-specific antigen (PSA), serum markers at the start of DTX therapy [PSA, alkaline phosphatase (ALP), and C-reactive protein (CRP)], and the number of DTX courses were independent predictors of OS. The risk table employing the combination of three factors [ALP (cut-off 189 IU/L), hemoglobin (11.3 g/dL), and age (65 years) at the start of DTX therapy], and scoring based on the hazard ratio of each risk factor (ALP 4, hemoglobin 2, age 3) could effectively predict the probability of the length of DTX therapy, with lower score (0-6) predicting >10 cycles, and higher score (7-9) predicting ≤5 cycles (p < 0.0001). No significant difference was found regarding grade 3/4 adverse events between the two groups. CONCLUSION: A model using three factors prior to chemotherapy may be beneficial for deciding the duration of DTX therapy in patients with CRPC.

Risk group stratification based on preoperative factors to predict survival after nephroureterectomy in patients with upper urinary tract urothelial carcinoma.

BACKGROUND: After radical nephroureterectomy (RNU), substantial numbers of patients with upper urinary tract urothelial carcinoma (UUT-UC) are ineligible for adjuvant chemotherapy owing to diminished renal function. Accurate preoperative prediction of survival is considered important because neoadjuvant chemotherapy may be as effective for high-risk UUT-UC as for muscle-invasive bladder cancer. We performed risk group stratification to predict survival based on specific preoperative factors. METHODS: We enrolled 536 UUT-UC patients treated with RNU in this retrospective cohort study and assessed preoperative clinical and laboratory variables influencing disease-specific survival. RESULTS: The median follow-up was 40.9 months. Using univariate analysis, tumor location; number of tumors; hydronephrosis; clinical T stage; clinical N category; voided urine cytology; neoadjuvant chemotherapy; hemoglobin; white blood cell (WBC) counts; and C-reactive protein had a significant influence on disease-specific survival (P < 0.05). Multivariate analysis revealed that clinical T stage, voided urine cytology, and WBC were independent predictors (P = 0.041, P = 0.020, and P = 0.017, respectively). We divided patients into three risk groups based on the number of the three independent predictors: 0, low risk; 1, intermediate risk; 2 and 3, high risk. Significant differences in disease-specific survival were found among these risk groups (P ≤ 0.0047). CONCLUSIONS: Our results suggest that risk group stratification based on preoperative clinical T stage, voided urine cytology, and WBC counts may be useful for selection of UUT-UC patients for neoadjuvant chemotherapy. Prospective studies with larger numbers of patients and a longer follow-up period are needed to confirm our results.

Can docetaxel therapy improve overall survival from primary therapy compared with androgen-deprivation therapy alone in Japanese patients with castration-resistant prostate cancer? A multi-institutional cooperative study.

BACKGROUND: To verify the actual clinical benefit of docetaxel (DOC) therapy and to explore the prognostic factors that may predict overall survival in Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: Baseline characteristics-matched CRPC patients who received conventional androgen-deprivation therapy (ADT) or ADT plus DOC were compared retrospectively. The primary endpoint was overall survival (OS) from primary therapy. Secondary endpoints were response of tumor(s), prostate-specific antigen (PSA) levels, and toxicity. RESULTS: Median OS was significantly longer in the DOC group (n = 117) than the control group (n = 118) (94.0 vs. 70.0 months, P = 0.0077) and the corresponding hazard ratio (HR) for death in DOC group was 0.566 [95% confidence interval (95%CI) 0.370-0.867; P = 0.0088]. Effective DOC groups [medium dose (50-69 mg/m(2)) and high dose (≥70 mg/m(2))] had significantly longer median OS than control even when survival times were calculated from the start of castration-resistant events (151 vs. 36 months; P = 0.0173) and the corresponding HR for death in the DOC group was 0.515 (95%CI 0.293-0.903; P = 0.0205). In multivariate analysis, statistically significant prognostic indicators were Gleason score, time to CRPC events, and receipt of DOC therapy. Response rate of both measurable lesion and PSA was not significantly different between each DOC dose group. Grade 3 or 4 adverse events associated with low- [30-49 mg/m(2)], medium-, and high-dose DOC were 21.9, 35.7, and 90.7%, respectively. No death due to DOC therapy was reported. CONCLUSION: Treatment with DOC improves OS from primary therapy compared with conventional ADT alone in Japanese patients with CRPC.

Human chorionic gonadotrophin treatment prior to microdissection testicular sperm extraction in non-obstructive azoospermia.

BACKGROUND: Despite the improved success rate of sperm retrieval by microdissection testicular sperm extraction (micro-TESE), methods to stimulate spermatogenesis in men with non-obstructive azoospermia (NOA) remain unexplored. The aim of this study was to evaluate the effects of hCG-based hormonal stimulation in men with NOA on the success of sperm retrieval by micro-TESE. METHODS: Forty-eight men with NOA who had negative sperm retrieval results by the micro-TESE procedure were included. A second micro-TESE was subsequently performed on these men: 20 were not treated by any hormonal therapy, and 28 subjects received daily subcutaneous injections of hCG for 4-5 months prior to the second micro-TESE. Recombinant FSH was added if endogenous gonadotrophin levels decreased during the hCG stimulation. The sperm retrieval rate at the second micro-TESE; the levels of gonadotrophins, testosterone and estradiol; and the effects of hormonal therapy on testicular histology were evaluated. RESULTS: Among the 28 men with hCG stimulation, 15 (54%) showed decreased LH and FSH levels (0.67 ± 0.10 and 0.96 ± 0.14 mIU, mean ± SEM, respectively) due to elevated serum testosterone (9.5 ng/dl). Sperm were obtained at the second micro-TESE from six men who had received hormonal therapy (21%), whereas no sperm were retrieved from untreated men (P < 0.05). Success at the second micro-TESE was more likely if histology at the first micro-TESE showed hypospermatogenesis. CONCLUSIONS: The Leydig cells of the testis can respond positively to exogenous hCG even under hypergonadotropic conditions. HCG-based hormonal therapy prior to a second micro-TESE attempt is effective in men with hypospermatogenesis.

The prevalence of Peyronie's disease in Japan: a study in men undergoing maintenance hemodialysis and routine health checks.

INTRODUCTION: The incidence of Peyronie's disease (PD) in the general population is believed to be as high as 20%. However, most of the data concerning the prevalence of PD have been obtained from Caucasian populations. AIM: The aim of this study was to examine the prevalence of PD in Asia and among men undergoing hemodialysis and discuss the pathophysiology of PD. METHODS: A total of 1,090 men who received a routine health check at our hospital (control group) as well as 130 male patients undergoing maintenance hemodialysis were enrolled. The diagnosis of PD was based on a palpable penile plaque. MAIN OUTCOME MEASURES: Hemodialysis patients were asked about their sexual activity and completed the International Index of Erectile Function-5 questionnaires. The differences between patients' and hemodialysis-associated factors, comorbidities, and medications were statistically assessed for patients with and without PD. RESULTS: The prevalence of PD was significantly increased among hemodialysis patients (12 patients: 9.2%) relative the control group (six men: 0.6%) (P<0.0001, odds ratio: 18.4). In both groups, the plaques were primarily allocated dorsally. In the hemodialysis patients with PD, the frequency of masturbation (P<0.05) and the incidence of moderate or severe erectile dysfunction (P<0.01) were significantly higher than those among hemodialysis patients without PD. In comparison with patients without PD, the number of acetate dialysate users was significantly higher among patients with PD (P<0.05), and none of the PD patients used angiotensin-related antihypertensive drugs (P<0.05). CONCLUSIONS: The prevalence of PD in healthy Japanese men is low (0.6%), which suggests the existence of racial differences in the prevalence of PD. Moreover, these results indicate that hemodialysis increases the incidence of PD. The differences in the characteristics between male hemodialysis patients with and without PD provide new insights into the pathophysiology and therapeutic window of PD.

[OVERALL SURVIVAL EVALUATION OF PROSTATE CANCER PATIENTS TREATED WITH ANDROGEN DEPRIVATION THERAPY BY ESTIMATING FLUCTUANT PATTERNS OF METABOLIC FACTOR SERUM LEVELS].

(Background) The effects of fluctuant patterns of serum alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels on overall survival of patients with prostate cancer (PC) treated with androgen deprivation therapy (ADT) remain unclear. (Methods) We enrolled 236 patients with PC and divided into 3 cohorts by fluctuant patterns of serum levels of ALP and LDH between at baseline and at 1 year later, or at diagnosis of castration-resistant prostate cancer (CRPC): intermediate, within interquartile range (IQR) [I]; lower than IQR [L]; higher than IQR [H]. (Results) In the 1 year later ALP cohort, all parameters except age were significantly different. In the L cohort, 75% of patients had bone metastasis and > 50% developed CRPC or died. In the 1 year later LDH cohort, Eastern Cooperative Oncology Group-performance status (ECOG-PS) and clinical metastasis classification were significantly different among the cohorts. In the CRPC/ALP cohorts, baseline prostate-specific antigen values and clinical metastasis classification were significantly different among the cohorts, and all cases had metastasis in the L cohort. In the CRPC/LDH cohort, the L cohort had higher ECOG-PS and shorter time to CRPC. In the 1 year later ALP cohort, the hazard ratio (HR) for death of the L and H cohort to the I cohort was 3.77 and 2.27, respectively and both were significant. In the CRPC/LDH cohort, the HR for death of L cohort to I cohort was 1.99. (Conclusions) Larger fluctuations in serum ALP and LDH levels were a sign of poorer prognosis, especially for patients in the L cohort.

[EFFECT OF NEW ANDROGEN RECEPTOR AXIS-TARGETED AGENTS ON SURVIVAL OF CASTRATION-RESISTANT PROSTATE CANCER].

(Background)The real world's effect of new androgen receptor axis-targeted agents (ARATs) on survival of castration-resistant prostate cancer (CRPC) remains unclear in Japan. (Aims)The primary aim was to determine the clinical benefit of ARATs on survival of CRPC patients. The secondary aim was to evaluate predictive factors affecting the survival of CRPC patients. (Patients and results)Among 236 patients treated with androgen deprivation therapy (ADT), 68 patients developed CRPC; two groups of 34 patients were treated with ARATs (A cases) or conventional ADT (V cases). In a median follow-up of 61.5 months, 20 A and 22 V cases died of cancer. Median survival time (MST) from diagnosis was 99 and 66 months for A and V cases, respectively, and MST from CRPC to death were 50.5 and 44.5 months, respectively. There were no significant differences between both cases. The hazard ratio for death from diagnosis or CRPC progression of the A cases to V cases was 0.711; 95% confidence interval (CI), 0.371 to 1.362; P = 0.3037, or 0.805; 95% CI, 0.434 to 1.491; P=0.4899, respectively. Multivariable analysis revealed that a unique and significant independent prognostic factor from diagnosis was time to CRPC. (Conclusions)In this small retrospective study, we could not determine the clinical benefit of new ARATs compared with conventional ADT on survival of CRPC patients, and a unique and significant independent prognostic factor from diagnosis was time to CRPC. We need to validate these results in a future multi-institutional study.

[ADVERSE EFFECTS OF ANDROGEN DEPRIVATION THERAPY ON PATIENTS WITH PROSTATE CANCER AND ITS EFFECT ON OVERALL SURVIVAL].

(Background) Patients with prostate cancer, which progresses slowly compared with other cancers, are generally older, and not a few are solely treated with androgen-deprivation therapy (ADT). The physical effects of ADT on bone health, body composition, and hematological parameters must be carefully considered. (Methods) We collected the clinical records of 185 men with pathologically diagnosed prostate cancer who were treated with ADT at our hospital. The primary aim of the study was to determine the prevalence and severity of adverse effects caused by ADT. The second aim was to analyze the effect of fluctuation in the rate of these adverse effects on overall survival (OS). (Results) The median age of patients was 75 years. After ADT for 1 or 2 years, evaluation of bone mineral density revealed median losses of 3% and 6%, respectively. After ADT for 1 year, body mass index was significantly increased by a median 2.1%, and total cholesterol and hemoglobin levels were significantly increased and decreased, respectively. The local and systemic symptoms of subcutaneous granuloma and hot flashes were experienced by 39% and 21.6% patients, respectively. Mono- and multivariate analysis revealed that significant fluctuation in the rate of adverse events after 1-year ADT did not affect OS. (Conclusion) Prevalence and severity of adverse effects caused by ADT were acceptable and almost all patients could be treated in the outpatient clinic, and significant fluctuation in the rate of adverse effects had no effect on OS.

[A STUDY OF MULTIPARAMETER ANALYSIS OF SERUM URIC ACID LEVELS -A STUDY IN APPARENTLY HEALTHY JAPANESE MEN AND WOMEN].

(Background) Hyperuricemia is associated with hypertension, vascular disease, cardiovascular events, and renal dysfunction. Several studies have reported the relationship between serum uric acid (UA) level and clinical outcome in the general population. However, most such studies have not quantitatively evaluated the association between UA and age, body mass index (BMI), and estimated glomerular filtration rate (eGFR). (Method) From April 2015 to March 2016, a total 10,133 healthy individuals underwent multiphasic screening at our medical checkup center. Among all participants, eGFR was evaluated in 1,684 men and 1,195 women. The data of this cohort were reviewed and analyzed. (Results) The median age of men and women was 51.0 and 50.0 years, respectively. Median serum UA was 6.1 mg/dL in men and 4.5 mg/dL in women. The prevalence of hyperuricemia was 23.9% in men and 8.5% in women. In all 10-year age groups, men had significantly higher serum UAs than women. In men, no significant differences of serum UA were observed among 10-year age groups. Menopause-associated increases in serum UA among women were observed. Men in their 20s to 50s and women in their 30s to 60s showed significant differences in serum UA between each BMI category in the same age decade. Both men and women in their 40s to 60s showed significant differences in serum UA between each eGFR category in the same age decade. We used the results of multiple regression analysis to derive equations to predict the associations among these variables, as follows: men, UA (mg/dL) = 5.637+0.065 × (BMI) - 0.014 × (eGFR) (R2 = 0.059, P < 0.0001); women < 50 years old, UA (mg/dL) = 4.068+0.065 × (BMI) - 0.014 × (eGFR) (R2 = 0.091, P < 0.0001) and women > 50 years old, UA (mg/dL) = 4.311+0.075 × (BMI) - 0.017 × (eGFR) (R2 = 0.116, P < 0.0001). (Conclusions) We present epidemiological evidence indicating that the levels of serum UA vary with BMI and eGFR in both sexes. In women, it should be recognized that menopause is independently associated with higher levels of UA.

[LOCAL REACTIONS OF LUTEINIZING HORMONE-RELEASING HORMONE AGENTS AND ITS EFFECTS ON CLINICAL OUTCOMES IN PROSTATE CANCER PATIENTS].

(Background) Currently, luteinizing hormone-releasing hormone (LH-RH) agonists and antagonists are used for androgen-deprivation therapy (ADT). However, they are associated with subcutaneous granuloma, rubor, dolor, calor, and eventual ulcer and/or abscess formation. The prevalence of these adverse effects, causes and mechanisms, and effects on serum testosterone levels and clinical outcomes are poorly understood. (Method) We collected the clinical records of men with pathologically diagnosed prostate cancer who were followed in our hospital. The primary aim of the study was to determine the prevalence of granuloma formation, its causes, and the mechanisms involved. The secondary aim was to analyze the effects of subcutaneous induration on serum testosterone levels and clinical outcomes. (Results) Overall, 185 men using leuprorelin (n=161; median age, 75 years), degarelix (n=21; median age, 76), or goserelin (n=3; median age, 76) were analyzed. In the leuprorelin cohort, 51 patients (33.5%) had subjective and/or objective subcutaneous induration and 2 (1.2%) had a large lesion (diameter > 3.0 cm). In the degarelix cohort, 18 patients (85.7%) developed induration and 8 (38%) had a large lesion. One month after the start of ADT, patients in the leuprorelin and degarelix cohorts had median serum testosterone levels that reached the same level as that after castration. There was no significant difference in the overall survival rate between the leuprorelin and degarelix cohorts. There was no significant difference in the serum testosterone level or overall survival rate between patients with or without induration. (Conclusions) The local adverse effects of LH-RH agents are prevalent, but we can regulate the adverse effects by understanding the mechanism involved. The formation of subcutaneous induration did not affect the serum testosterone level or clinical outcome.

ARHGAP29 expression may be a novel prognostic factor of cell proliferation and invasion in prostate cancer.

Yes­associated protein (YAP) is a transcription­coupling factor that plays a central role in the Hippo pathway, and its activation regulates cell proliferation and carcinogenesis. YAP activation has been reported in various malignancies, conferring tumors with migratory and invasive abilities. Several studies have suggested that YAP expression is closely associated with prostate cancer. Furthermore, YAP has been revealed to regulate destabilization of F­actin associated with the cytoskeleton via Rho GTPase­activating protein 29 (ARHGAP29), suggesting that ARHGAP29 is associated with cancer metastasis. In the present study, the functions of ARHGAP29 were examined in four prostate cancer cell lines (22Rv1, LNCaP, DU145 and PC­3) and it was revealed that upregulation of ARHGAP29 in LNCaP and DU145 cells with the lowest expression of ARHGAP29 promoted cell proliferation and invasion. Conversely, ARHGAP29 knockdown in PC­3 cells with its highest expression level significantly reduced cell proliferation and invasion. In addition, immunohistochemistry of specimens from 133 patients who underwent radical prostatectomy was performed to investigate the clinical association between ARHGAP29 expression and prognosis in prostate cancer patients. Multivariate analysis demonstrated that ARHGAP29 was an independent prognostic factor for biochemical progression­free survival (P=0.0123). These findings indicated that ARHGAP29 in prostate cancer may be a potential prognostic biomarker and therapeutic target.

Effects of hemodialysis on testicular volume and oxidative stress in humans.

PURPOSE: Male infertility is a serious problem in patients on hemodialysis. Our understanding is that end stage renal disease or hemodialysis causes poor semen quality but the mechanism leading to impaired spermatogenesis is largely unknown. MATERIALS AND METHODS: Testicular volume in 120 patients on maintenance hemodialysis was compared with that in age matched healthy controls. Volume was correlated with clinical findings. In 10 testicular biopsy specimens from patients on hemodialysis who visited our infertility clinic Western blotting was performed to examine the generation of 4-HNE modified proteins, which are markers of oxidative stress, and the expression of proliferating cell nuclear antigen. Interstitial fibrosis was determined by Masson's trichrome staining. RESULTS: Mean bilateral testicular volume in patients on hemodialysis was significantly smaller than that in healthy controls (31.7 vs 36.4 ml, p <0.01) in a hemodialysis duration dependent manner (r = -0.32, p <0.01). The increase in serum ferritin correlated inversely with testicular volume (r = -0.25, p <0.01). The generation of 4-HNE modified proteins was significantly increased 3.1-fold in patients on hemodialysis, following the 60% decreased expression of proliferating cell nuclear antigen. Quantitative analysis of Masson's trichrome staining revealed increased interstitial fibrosis in patients on hemodialysis compared with that in controls (41.5% vs 14.8%, p <0.01). Serum ferritin, proliferating cell nuclear antigen expression and interstitial fibrosis correlated with the generation of 4-HNE modified proteins (p <0.05). CONCLUSIONS: Testicular volume, which is a parameter of spermatogenesis, is impaired in patients on hemodialysis and oxidative stress is considered to be involved in the process. Serum ferritin is a useful parameter for predicting oxidative stress in the testis.

Tumor-infiltrating lymphocytes derived from human renal cell carcinoma: clonal analysis of its characteristics.

AIM: To assess the characteristics of activated tumor-infiltrating lymphocytes (TIL), we report the isolation, growth response, and functional analysis of a CD4(-) CD8(+) TIL-clone derived from human renal cell carcinoma (RCC). METHODS: Bulk TILs were expanded from a human RCC and the lymphocytes were separated into a CD8(+) enriched population. Subsequently, using the limiting dilution technique, a TIL clone was established and its growth response, phenotype and cytotoxic activity were analyzed. RESULTS: A clone, T16-13, by day 94 numbering 1 x 10(7) cells, was harvested and characterized as a CD4(-) CD8(+) clone. On day 144, the cytotoxic activity of this clone against the autologous tumor was relatively high (2.3 +/- 0.7 LU(30)/10(6) cells). Meanwhile, against allogeneic renal tumors, there was no cytotoxic activity (-0.1 LU(30)/10(6) cells). CONCLUSIONS: A TIL clone possessing modest autologous tumor-specific cytotoxicity can be isolated from human RCC. The characteristics analysis of various TIL clones may provide a better understanding of an RCC tumor microenvironment and may help to establish new modalities for the treatment of patients with metastatic kidney cancer.

Evaluation of lower urinary tract symptoms and how bothersome it was with or without urinary incontinence in apparently healthy persons of both sexes.

We evaluated the effect of urinary incontinence on the degree of being bothersome in apparently healthy males and females by a questionnaire survery. From March to May, 2003 apparently healthy subjects underwent multiphasic health screening after informed of the nature of this study and were asked to fill out the questionnaires of International Prostate Symptom Score (IPSS) with IPSS QOL index (IPSS-QI) and the short form version of the Urogenital Distress Inventory (UDI-6). The data were subjected to analytical studies. Of the 388 participants who responded completely to both questionnaires, 172 (44.3%) had urinary incontinence; 143 were women (36.9%) and 29 men (7.5%). The mean age of the women was 46.0 years (range 18.0 to 76.0) and that of men was 47.5 years (range 22.0 to 76.0). Compared with continent participants, women and men with mixed urinary incontinence had a significantly higher IPSS severity (P = 0.0002 and P = 0.0014, respectively). In terms of contribution on QOL impairment, the women and men with mixed urinary incontinence considered it significantly more bothersome compared with continent participants (P = 0.0004 and P = 0.0003, respectively). These data showed that urinary incontinence was relatively common among apparently healthy women, but not men, and type of incontinence had a different impact on the degree of being bothersome in both sexes.

Evaluation of hematuria and proteinuria positivity in relation to ageing in 6,651 apparently healthy men and women.

We examined the positivity of hematuria and proteinuria in relation to ageing in 6,651 apparently healthy persons (2,556 women and 4,095 men) who underwent multiphasic health screening in our Medical Checkup Center. Commercially available dipsticks were used. The time from urine collection to dipstick analysis was within 60 minutes. The mean age of women was 48.2 years (range 10 to 82) and that of men was 49.9 years (range 7 to 89). Approximately 30.1, 1.5, and 0.7% of the women had hematuria, proteinuria, and hematoproteinuria, respectively; and 11.4, 4.0, 1.5% of the men had the corresponding urine abnormalities, respectively. Hematuria was 2.6 times more common in women than in men, and proteinuria was 2.7 times more common in men than in women. The positivity of hematuria increased linearly with age in women (Rs = 0.943, P = 0.0350). On the other hand, the positivity of proteinuria or hematoproteinuria was not correlated with age (P = 0.8386 and P = 0.0639, respectively). In men, the positivity of hematuria or hematoproteinuria was not correlated with age (P = 0.0845 and P = 0.0845, respectively). However, the positivity of proteinuria in those more than 30-year age group increased linearly with age (Rs = 1.000, P = 0.0455). The true meaning of such gender- and/or age-related differences in urinary abnormalities remains to be determined.

[Does alpha1-blocker provide additional improvement of quality-of-life in patients with overactive bladder?--a multi-center prospective randomized trial between anti-cholinergic (propiverine chloride) with and without alpha1-blocker (urapidil)].

AIM: Storage/filling symptoms caused by overactive bladder (OAB) are bothersome to patients. The aim of this study is to clarify if alpha1-blocker provides additional benefit in combination with anticholinergic treatment in patients with OAB. METHODS: In total, 100 patients (men/women: 43/57, mean age: 71.3 years) who had frequency (more than eight times a day) and urgency (more than three times a week) were prospectively randomized, and allocated to two groups (monotherapy group [n = 52]: propiverine alone or combination group [n = 48]: propiverine plus urapidil). The primary end point was to compare the improvement of storage symptoms (numbers of frequency, urgency, disappearance of urge incontinence) as well as patients' quality of life (QOL) assessed by King's Health Questionnaires (KHQ) at baseline, 2 weeks, and 6 weeks after the start of treatment in both groups. The second end point was to evaluate the safety of these agents. RESULTS: Statistically significant improvements in terms of urgency and frequency were observed in both groups at two-weeks after the start of treatment as compared with baseline (p < 0.01 and < 0.05, respectively), while no inter-group difference was observed between the two groups. Significant improvement of QOL was observed after six weeks treatment in overall mean score, general health perception, incontinence impact, sleep/energy domains in both groups as compared with baseline. No significant difference was observed in terms of toxic events between the two groups. CONCLUSIONS: Although both groups showed identical improvement of storage symptoms and tolerability, no additional benefit of alpha1-blocker was observed.

Extracellular miR-224 as a prognostic marker for clear cell renal cell carcinoma.

Exosome-miRNAs (exo-miR) have recently been identified as modulators of cancer progression and distant metastasis. We previously found that intracellular miR-224 is up-regulated and significantly related to cancer invasion and metastasis in clear cell renal cell carcinoma (ccRCC). We therefore investigated the role of exosome miR-224 in ccRCC and explored the interaction between intra- and extracellular miR-224 in renal cell carcinoma. To validate the method for isolating exosomes from blood samples or cell culture media, we examined exosome morphology using transmission electron microscope (TEM). We investigated the relationship between exo-miR-224 expression and patient prognosis in 108 ccRCC patients. We isolated exosomes from a metastatic renal cancer cell line and tested their effects on a primary renal cancer cell line with several functional analyses. We found that the high expression level exo-miR-224 group has significantly shorter progression-free survival, cancer-specific survival, and overall survival compared with the low expression group. In multivariate analysis, a high level of exo-miR-224 was a significant risk factor related to all prognoses investigated. After adding exosomes from a metastatic RCC cell line to a primary RCC cell line, cell proliferation and invasion were increased while the percentage of apoptotic cells was significantly decreased. Intracellular levels of miR-224 were significantly up-regulated in the primary renal cancer cell line. Extracellular miR-224 in exosomes impacts on patient prognosis and is a potential prognostic biomarker for ccRCC patients.