市川 智彦

OBJECTIVES: To examine the effect of alpha 1D/A adrenoceptor inhibitor naftopidil on health-related quality of life (QOL) in men with benign prostatic hyperplasia (BPH). METHODS: A total of 56 newly diagnosed patients with symptomatic BPH were prospectively enrolled and treated with 50 mg naftopidil daily for more than 12 weeks. All underwent pre-treatment documentation of lower urinary tract symptoms, QOL assessment using the international prostate symptom score (IPSS) and King's Health Questionnaire (KHQ), and uroflowmetry. A post-treatment assessment was performed at 12 weeks. RESULTS: IPSS scores as well as QOL index showed a significant improvement after naftopidil administration. Similarly, all seven domains except general health perceptions and social limitations in the KHQ questionnaire were significantly improved. When dividing the patients into overactive bladder (OAB) and non-OAB groups, only the OAB group showed significant improvement in almost all the domains of KHQ. Change ratios of the IPSS were not associated with those of KHQ domain scores in the OAB group. On the other hand, in the non-OAB group more domains presented improvements, which were associated with those of IPSS scores. CONCLUSIONS: Twelve-week treatment with naftopidil for symptomatic BPH patients is associated with significant improvement in the IPSS, QOL index, maximum urinary flow rate, post-void residual urine volume (PVR) and almost all domains in KHQ. KHQ is useful for the evaluation of clinical response in BPH patients, particularly in those with associated OAB.

OBJECTIVES: Although several nomograms for prostate cancer detection have been developed for Western populations, the models constructed on Japanese data would be more useful for the Japanese population because of various differences between Western and Asian populations. We previously developed a model for predicting the probability of a positive initial prostate biopsy using clinical and laboratory data from Japanese males. In the present study, a predictive model for Japanese males with a prostate-specific antigen (PSA) < 10 ng/mL was developed to guide decision-making for prostate biopsies. METHODS: The age, total PSA level, free to total PSA ratio, prostate volume, and the digital rectal examination findings of 1037 Japanese males with a PSA < 10 ng/mL undergoing initial prostate biopsy as part of individual screening were analyzed. For study validation, 20% of these data was randomly reserved. Logistic regression analysis estimated relative risk, 95% confidence intervals, and P-values. RESULTS: Age and the independent predictors of a positive biopsy result (elevated PSA, decreased free to total PSA ratio, small prostate volume, and abnormal digital rectal examination findings) were used to develop a predictive nomogram. The area under the receiver operating characteristic curve was significantly higher for the model (73.0%) than for PSA alone (55.0%). If externally validated, the use of this nomogram could reduce unnecessary biopsies by 26% and overall prostate biopsies by 7.8%. CONCLUSIONS: This predictive nomogram could provide more precise risk-analysis information for individual Japanese patients with PSA levels less than 10 ng/mL and may help to identify patients who need a prostate biopsy.

OBJECTIVE: We evaluated the efficacy of low dose tamsulosin after extracorporeal shock wave lithotripsy (ESWL) in Japanese male patients with ureteral stone. METHODS: One hundred and two Japanese male patients with ureteral stones who underwent ESWL were randomly divided into three groups. Group A (38 patients) was given tamsulosin (0.2 mg/day); group B (30 patients) was given c horeito, a herbal medicine (7.5 g/day); and group C (34 patients) received no medication. Stone clearance was assessed at 1, 7, 14, and 28 days after ESWL using plain abdominal radiography and abdominal ultrasonography. After 28 days, stone delivery was checked every 2 weeks. RESULTS: The stone-free rate was 84.21%, 90%, and 88.24% for groups A, B, and C, respectively (P = 0.3425). The mean expulsion time was 15.66 +/- 6.14 days in group A, 27.74 +/- 25.36 days in group B, and 35.47 +/- 53.70 days in group C. The expulsion time of group A was significantly shorter than that of groups B (P = 0.0116) and C (P = 0.0424). CONCLUSIONS: The addition of tamsulosin to conservative treatment appeared to be effective in shortening the stone expulsion time.

Relationships between androgenic hormones and prostatic tissue growth are complex. It is certainly true that the prostate will not develop without androgens and the gland will atrophy if androgen support is withdrawn. The hormonal hypothesis remains one of the most important hypotheses in the etiology of prostate cancer (PCa), and efforts are continuing to improve the understanding of androgen actions in PCa. Although evidence from epidemiological studies of associations between circulating levels of androgens and PCa risk has been inconsistent, the traditional view that higher testosterone (T) levels represent a risk factor for PCa appears to have little evidentiary support. Reinvestigation of the relationship between T and PCa seems important and necessary if a new, clinically and scientifically rewarding concept is to be constructed. The present review considers the metabolism and intraprostatic action of T, epidemiological evidence, and the association between T and PCa risk.

OBJECTIVES: Chromogranin A (CgA) and neuro-specific enolase (NSE) are gaining acceptance as markers of several types of neuroendocrine tumors and the concentration of CgA and NSE have been reported to be elevated in relation to neuroendocrine differentiation of prostate cancer. The aim of the present study was to examine the correlation between the immunohistochemical (IHC) findings and serum value for CgA and NSE in untreated stage D(2) prostate cancer patients. METHODS: Immunohistochemistry was carried out using antibodies against CgA and NSE in 58 patients and, pretreatment serum CgA and NSE levels were measured by monoclonal immunoradiometric assay in 18 patients with stage D(2) prostate cancer treated by androgen ablation. We examined the relationship of the pretreatment serum level to IHC findings for CgA and NSE in prostate cancer patients to clinicopathological parameters, and prognosis. Also, we evaluated the correlation of IHC findings to serum levels for CgA and NSE. RESULTS: There was a statistically significant correlation between CgA positivity and serum CgA level (P = 0.0421). However, there was no statistically significant correlation between NSE positivity and serum NSE level (P > 0.05). We divided stage D(2) patients into three groups according to IHC positivity of CgA and NSE. The cause-specific survival was significantly poorer in patients with strongly positive (++) patients for independent CgA and combined CgA with NSE (P = 0.0379). Multivariate analysis of cause-specific survivals in patients with stage D(2) prostate cancer demonstrated that strong IHC stain was considered as independent variable associated with greater risk of death (P = 0.0142). CONCLUSION: Neuroendocrine differentiation in stage D(2) prostate cancer has attracted considerable attention as a potentially findings prognosis. Thus, CgA had a stronger relationship between serum levels and IHC positivity in contrast to NSE, suggesting clinical usefulness as a tumor marker in predicting the extent of neuroendocrine differentiation in prostate cancer.

Bone metastases of prostate cancer usually have an underlying osteoclastic component. Bone metastasis is incurable and contributes significantly to disease-specific morbidity and mortality. Management of bone metabolism in patients is a clinically significant issue. Several key factors have been found to be important in tumor-induced promotion of osteoclast activity. Receptor activator of nuclear factor-kappa B ligand (RANKL) is produced by bone metastasis of prostate cancer, enabling these metastasis to induce osteolysis through osteoclast activation. Matrix metalloproteinases (MMPs) are secreted by prostate cancer cells and promote osteolysis primarily through degradation of bone matrix. In this way, many factors derived from prostate cancer metastases can promote osteolysis, and these factors may serve as therapeutic targets. The new agents are targeted to osteoclasts (i.e.: zoledronic acid, anti-RANKL monoclonal antibody, cathepsin K inhibitor, and anti-PTHrP monoclonal antibody), are considered to be standard management in the care of bone metastasis patients in combination with chemotherapy and hormone therapy. In this review, we summarized the current understanding and therapy of bone metastasis in prostate cancer.

To determine the diagnostic merit or demerit of genetic procedures using fluorescence in situ hybridization (FISH) for detecting both new and recurrent urothelial cancer, we analyzed the specimens from 81 out-patients with asymptomatic haematuria, aged over 40, in comparison with urine cytology. Of 10 with atypical cytology, 6 showed positive for FISH, and of these, 4 manifested urothelial cancer. FISH showed higher sensitivity in low/intermediate grade cases compared with cytology (FISH; 66.7% vs cytology; 11.1%). Of 15 primary bladder cancer, 4 showed recurrence, and all of these cases showed a positive FISH reaction, but only 1 in cytology. The sensitivity, specificity and accuracy of FISH tests were 81.2, 72.3 and 74.1%, respectively, and these of cytology were 37.5, 98.5 and 86.4% respectively. The FISH test was superior to cytology for sensitivity, but specificity and accuracy were inferior. The FISH tests could be a potent procedure for detecting urothelial cancer in cases of low/intermediate grade, atypical cytology and surveillance setting.

Androgens play an important role in human many organs. However, the serum levels of androgens are decreasing with aging. Currently, synthesized androgens are used for several diseases. In this review, we mentioned about the clinical use of these androgens.

We investigated the clinical efficacy of milnacipran (Serotonin-Noradrenalin Reuptake Inhibitor: SNRI) in prostate cancer patients who suffer from hot flushes. Our study included 12 patients who had taken hormone therapy for at least 3 months prior to the trial entry. All patients had severe hot flushes at least 3 times daily. Among 12 patients, 7 subjects received milnacipran 25 mg orally once a day and 5 subjects received 50mg once a day. The questionnaire was used to measure the frequency and severity of hot flushes at baseline, and at 6 and 12 weeks. At 12 weeks, 9 patients were available for the evaluation. Four patients received 50 mg per day and 5 patients received 25 mg per day. The patients with > or =50% decrease in baseline hot flash score were observed in 3 out of 4 who received 50 mg and 2 out of 5 who received 25 mg per day. The frequency of hot flushes had significantly decreased at the 12 weeks period than the baseline in the milnacipran 50 mg per day treatment group (p < 0.05, paired t-test). Adverse events were observed in 3 patients: 2 cases of nausea and 1 case of constipation. However, all of them were mild to moderate. These results indicated that milnacipran 50 mg per day therapy is effective in the treatment of hot flushes, which is the side effect of hormone therapy for prostate cancer.

OBJECTIVE: We evaluated health-related quality of life (HRQOL) in Japanese men receiving androgen deprivation therapy (ADT) for prostate cancer. METHODS: Fifty-six men were enrolled in this study. HRQOL was prospectively measured before ADT, and at 3, 6 and 12 months after treatment began, using a general (36-item Short-Form Health Survey) and disease-specific (the University of California, Los Angeles Prostate Cancer Index) HRQOL questionnaire. RESULTS: In the general HRQOL questionnaire, patients with stage B (n = 22) or C (n = 17) disease showed a decline in vitality at 6 and 12 months (P < 0.05 for both). Stage D patients (n = 17) had improvements in bodily pain at 3 and 12 months (P < 0.05 for both), vitality at 12 months (P < 0.05), role-emotional at 6 months (P < 0.05), and mental health at 3 months (P < 0.05). When clinical stages were not considered, there were no significant changes in the 36-item Short-Form Health Survey. As for the disease-specific HRQOL, urinary function improved after ADT at 6 and 12 months (P < 0.05 for both), and urinary bother decreased at 3 (P < 0.05), 6 (P < 0.005) and 12 months (P < 0.05). Sexual function decreased at 3 (P < 0.05), 6 (P < 0.005) and 12 months (P < 0.005) but sexual bother improved at 6 and 12 months (P < 0.05 for both). If patients were stratified by clinical stages, similar findings were observed. CONCLUSIONS: General HRQOL was mostly unaffected by ADT in Japanese men. Disease-specific questions indicated an increase in urinary function. Although deterioration of sexual function was marked, most patients did not report sexual bother. Our results shed new light on the impact of ADT on HRQOL and could provide useful information about patient-centered outcome evaluations.

OBJECTIVES: The aim of the present study was to evaluate the clinical value of the pretreatment serum testosterone (T) level as a potential predictor of prostate cancer risk in screening for prostate cancer. MATERIALS AND METHODS: The subjects were 420 patients suspected of having prostate cancer who underwent prostate biopsy, and whose pretreatment T levels were recorded. We checked for association between the presence of prostate cancer and the following clinical factors: pretreatment serum T level, age, pretreatment prostate-specific antigen (PSA) level, digital rectal examination findings, ratio of free to total PSA, prostate volume, and PSA density (PSAD). RESULTS: Overall, there was no significant difference in mean pretreatment T level between patients diagnosed with cancer (3.9+/-2.4 ng/ml) and patients diagnosed with benign prostate disease (BPD; 3.7+/-1.7 ng/ml); diagnosis was based on prostate biopsy. However, among patients with PSA <10 ng/ml, the pretreatment T level was significantly higher in patients diagnosed with prostate cancer (4.2+/-2.6 ng/ml) than in patients diagnosed with BPD (3.6+/-1.4 ng/ml) (p=0.007); a similar trend was observed among patients with PSAD <0.15 ng/ml/cc. Multivariate analysis indicated that pretreatment T level was an independent significant predictor of positive prostate biopsy (p=0.020). Additionally, the serum T level was significantly lower in patients with a Gleason score >or=7 (3.7+/-2.1 ng/ml) versus a score <7 (4.2+/-1.7 ng/ml) (p=0.030). Also, serum T levels were significantly higher in well-differentiated prostate cancer (4.8+/-2.1 ng/ml) versus moderately differentiated (3.8+/-1.3 ng/ml) or poorly differentiated (3.7+/-1.4 ng/ml) (p<0.01). CONCLUSIONS: Among relatively low-risk patients, serum T level was an independent significant predictor of positive prostate biopsy, suggesting that the efficiency of prostate cancer screening can be improved by including measurement of serum T level.

OBJECTIVES: Laparoscopic surgery for kidney treatment is a common procedure. However, the efficacy of this procedure in patients with several comorbidities has not been well investigated. We conducted a retrospective comparison of results of laparoscopic surgery between patients with several comorbidities and patients with no comorbidity to access the efficacy and safety of this procedure. METHODS: The subjects were 20 patients with three or more comorbidities (group A) and 46 patients with less than three comorbidities (group B). These 66 patients were 48 men and 18 women with a mean age of 62.3 years (age range, 24-83 years). The data from these two groups were compared for American Society of Anesthesiology (ASA) physical status score, previous surgical history, duration of surgery, estimated blood loss, tumor size, complications during and after surgery, conversion rates, time to oral intake, and length of hospital stay. RESULTS: The initial ASA score and age were significantly higher for the patients with comorbidities (P < 0.0001, P = 0.0008, respectively). All other variables before, during, and after surgery were similar for both laparoscopic groups. However, the incidence of atelectasis of laparoscopy was higher than that of open surgery. CONCLUSIONS: Laparoscopic nephrectomy for patients with comorbidities is safe and minimally invasive. Further investigation to prevent atelectasis is necessary.

BACKGROUND: To investigate the optimal treatment of locally advanced prostate cancer, a prospective randomized trial was conducted to compare radical prostatectomy plus endocrine therapy versus external beam radiotherapy plus endocrine therapy. METHODS: One hundred patients with T2b-3N0M0 prostate cancer were enrolled and 95 were evaluated. Of 95 cases, 46 underwent radical prostatectomy with pelvic lymph node dissection and 49 were treated with external beam radiation by linear accelerator with 40-50 Gy to the whole pelvis and 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiotherapy and continued thereafter. The long-term outcome and morbidity were examined. RESULTS: Median follow-up period was 102 months. At 10 years overall survival rates in the surgery group were better than the radiation group (76.2% versus 71.1% for biochemical progression-free rates; P=0.25, 83.5% versus 66.1% for clinical progression-free rates; P=0.14, 85.7% versus 77.1% for cause-specific survival rates; P=0.06, and 67.9% versus 60.9% for overall survival rates; P=0.30), although none of them reached statistical significance. Erectile dysfunction was recognized in almost all patients as a result of continuous endocrine therapy. Incontinence requiring more than one pad per day was observed more frequently in the surgery group than the radiation group (P<0.01). CONCLUSIONS: For the treatment of patients with locally advanced prostate cancer, when combined with endocrine therapy, either radical prostatectomy or external beam radiotherapy demonstrated favorable long-term outcomes. The radiation dose of 60-70 Gy might not be enough for the local treatment of locally advanced prostate cancer.

Bcl6, a sequence-specific transcriptional repressor, is important for generation and maintenance of memory CD8(+) T cells. Although memory CD8(+) T cells are generated from effector CD8(+) T cells, a role for Bcl6 in effector CD8(+) T cells is largely unknown. We show here that Bcl6 expression was transiently induced in activated CD8(+) T cells and continuously up-regulated in effector CD8(+) T cells. The amount of granzyme B mRNA among effector molecules produced by effector CD8(+) T cells inversely correlated with the amount of Bcl6 mRNA in CD8(+) T cells. Overexpression of Bcl6 in CD8(+) T cells resulted in lower killing activity at their effector phase, supporting the reduction of granzyme B expression in effector CD8(+) T cells by Bcl6. We identified a putative Bcl6-binding DNA sequence in the promoter region of the granzyme B gene. Binding of Bcl6 to the Bcl6-binding sequence was detected in naive CD8(+) T cells but not in activated CD8(+) T cells by chromatin immunoprecipitation assay. Furthermore, the Bcl6-binding sequence was required for Bcl6 to repress the luciferase reporter gene expression controlled by the granzyme B promoter. Thus, the granzyme B gene is a molecular target of Bcl6 in effector CD8(+) T cells.

OBJECTIVES: To identify the prognostic factors in patients with recurrent renal cell carcinoma after nephrectomy, various factors were assessed, with special attention to serum immunosuppressive acidic protein (IAP) and its doubling time. METHODS: Age, sex, stage, grade, histopathologic type, primary tumor size, site and number of metastatic organs, time to recurrence, IAP levels before nephrectomy and at the diagnosis of recurrence, and IAP doubling time just before recurrence were analyzed in 125 patients with recurrent renal cell carcinoma after nephrectomy. RESULTS: Univariate analysis identified stage, grade, histopathologic type, primary tumor size, time to recurrence, IAP level at the diagnosis of recurrence, and IAP doubling time as significant prognostic factors. After exclusion of confounding factors, multivariate analysis showed that IAP doubling time was the most potent independent prognostic factor. Patient survival rates dichotomized according to IAP doubling time were compared at 100-day intervals from 100 to 700 days and 1000 and 2000 days. The maximal difference in survival rate was found when the cutoff level in the IAP doubling time was set at 200 days. CONCLUSIONS: The results of our study have shown that the IAP doubling time is a potent prognostic factor in patients with recurrent renal cell carcinoma. Periodic checkups with serum IAP level monitoring are recommended to predict prognosis after recurrence.

A 60-year-old woman with chromophobe cell renal carcinoma arising from the atophic right kidney during long-term haemodialysis was reported. The right renal tumour was detected incidentally by abdominal ultrasound examination. She received right nephrectomy through flank incision, and the pathological diagnosis was an eosinophilic variant of chromophobe cell renal carcinoma. Chromophobe cell renal carcinoma is a relatively rare subtype of renal cell carcinoma (5%), and the rate of this subtype on a long-term haemodialysis was quite low (0.6-0.7%), and almost all these patients had acquired cystic disease accompanied with haemodialysis. By contrast, our case occurred in the atrophic kidney (non-cystic kidney), and this might be the first case report of chromophobe cell renal carcinoma arising from an atrophic kidney in a patient on long-term haemodialysis.

A 62-year-old man was admitted to our hospital complaining of lower abdominal mass and weight loss. Computed tomography and magnetic resonance imaging studies revealed a large tumor occupying the pelvis and expanding into inferior vena cava, which reached to the renal pedicle. Open biopsy was undergone under general anesthesia. Histopathological diagnosis was inflammatory fibrosarcoma. Five courses of chemotherapy including vincristine, actinomycin-D and cyclophosphamide (VAC) resulted in 35% reduction of the tumor volume in one direction, indicating that VAC could be an alternative effective therapy for inoperable inflammatory fibrosarcoma.