Real-world use of temsirolimus in Japanese patients with unresectable or metastatic renal cell carcinoma: recent consideration based on the results of a post-marketing, all-case surveillance study.

OBJECTIVE: A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan. METHODS: Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30-60 minutes) in routine clinical settings (observation period: 96 weeks). RESULTS: Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4-8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P < 0.001). Among 654 patients in the effectiveness analysis data set, the response and clinical benefit rates were 6.7% (95% confidence interval 4.9-8.9) and 53.2% (95% confidence interval 49.3-57.1), respectively. The median progression-free survival was 18.3 weeks (95% confidence interval 16.9-21.1). CONCLUSIONS: The safety and effectiveness profile of temsirolimus observed in this study was similar to that observed in the multinational phase 3 study. The results are generalizable to the real-world scenario at the time of this research, and safety and effectiveness of temsirolimus as a subsequent anticancer therapy for renal cell carcinoma warrants further investigation. (ClinicalTrials.gov identifier NCT01210482, NCT01420601).

[Prostate cancer prevention].

Environmental factors, mainly diet, play an important role in the development of prostate cancer. A previous study identified fat and calcium as risk factors, and lycopene, selenium, soy isoflavone, and vitamin E as preventive factors for the development of prostate cancer. However, many previous studies were observational or in vitro/in vivo based, and enough evidence in a large-scale randomized study has not been provided. In the study of food, not only the intake but also the metabolism is important. For soy isoflavone, analysis of enterobacterial flora concerned with its metabolism to equol is in progress.

Non-papillary serous cystadenoma of the epididymis associated with infected hydrocele of the testis: A case report.

A 50-year-old Japanese man with enlargement of the right scrotum was presented to our hospital. Preoperative examination confirmed a multilocular cyst with septa attached to the testis. Radical orchiectomy was performed. Pathological examination revealed closely-located two cysts; larger one was infected hydrocele testis, and smaller one was epithelial cyst, which were immunohistochemically positive widely for estrogen receptor (ER) and partly for progesterone receptor (PR). We concluded that the smaller cyst was serous cystadenoma of the epididymis.

Prostate cancer chemoprevention study: an investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen.

Our previous case-control study suggested that equol, a metabolite of isoflavone, has a preventive effect on prostate cancer. To examine the prostate cancer risk based on isoflavone intake and equol production, we carried out a phase II, randomized, double-blind, placebo-controlled trial of oral isoflavone (60 mg/day) for 12 months. The inclusion criteria were Japanese men between 50 and 75 years of age, a serum prostate-specific antigen level of 2.5-10.0 ng/mL, and a single, negative prostate biopsy within 12 months prior to enrollment. The study included 158 men in eight Japanese centers. Their median age was 66.0 years, and the numbers of equol producers and non-producers were 76 (48%) and 82 (52%), respectively. The majority of adverse events were mild or moderate in severity, and the scheduled intake of tablets was completed by 153 patients (96.8%). The prostate-specific antigen value showed no significant difference before and after treatment. Of the 89 patients evaluated by central pathological review, the incidence of biopsy-detectable prostate cancer in the isoflavone and placebo groups showed no significant difference (21.4%vs 34.0%, P = 0.140). However, for the 53 patients aged 65 years or more, the incidence of cancer in the isoflavone group was significantly lower than that in the placebo group (28.0%vs 57.1%, P = 0.031). These results support the value of isoflavone for prostate cancer risk reduction. A large-scale phase III randomized study of isoflavone tablets in men with different hereditary factors and living environments is warranted. Registered with the UMIN Clinical Trials Registry (UMIN-CTR) for clinical trials in Japan (C000000446).

Analysis of Intravesical Recurrence After Bladder-preserving Therapy for Muscle-invasive Bladder Cancer.

OBJECTIVE: The aim of the present study was to analyze the pattern of recurrences after bladder-preserving therapy for muscle-invasive bladder cancer. METHODS: The subjects were 77 patients with T2-3N0M0 bladder cancer whose bladder was preserved by intra-arterial chemotherapy and radiation. The patterns of the first recurrences were retrospectively analyzed. RESULTS: With a median follow-up of 38.5 months, 17 patients (22.1%) experienced intravesical recurrence without metastasis, 14 (82.4%) of which were cases of non-muscle-invasive bladder cancer recurrence and 3 (17.6%) of which were muscle-invasive bladder cancer recurrences. Muscle-invasive bladder cancer recurred at the same site as the initial tumor site in all three cases, whereas non-muscle-invasive bladder cancer recurred at different sites in 64% of the patients in that group. The peak hazard of the non-muscle-invasive bladder cancer recurrence was observed at around a year after treatment. Recurrent non-muscle-invasive bladder cancer was of a significantly lower histological grade with lower Ki-67-labeling indices than the initial muscle-invasive bladder cancer. Twelve (85.7%) of 14 patients with non-muscle-invasive bladder cancer recurrence achieved disease-free status. The multivariate analysis revealed that multiplicity, grade and tumor size were significantly correlated with the recurrence (P= 0.0001, 0.0442 and 0.0412, respectively). CONCLUSIONS: Most of the recurrences after bladder-preserving therapy were cases of non-muscle-invasive bladder cancer. The recurrence pattern and characteristics of the tumors did not differ from those of primary non-muscle-invasive bladder cancer. Patients with high-risk factors would be candidates for prophylactic intravesical therapy for non-muscle-invasive bladder cancer recurrence.

Efficacy and safety of dutasteride on prostate cancer risk reduction in Asian men: the results from the REDUCE study.

OBJECTIVE: A post hoc analysis of Asian men in the REDUCE study was conducted to investigate whether the outcomes were in line with those of the overall population. METHODS: REDUCE was a 4-year international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Inclusion criteria were men between 50 and 75 years of age, a serum prostate-specific antigen level of 2.5-10.0 ng/ml (50-60 years) or 3.0-10.0 ng/ml (>60 years), and a single, negative prostate biopsy (6-12 cores) within 6 months before enrollment. The primary endpoint was biopsy-detectable prostate cancer. This post hoc analysis included subjects who were recorded as Asian. RESULTS: A total of 134 Asians, including 57 Japanese, were randomized to the study treatment. During the study period, the incidence of prostate cancer in the placebo and dutasteride groups was 19.6% (11/56) and 9.3% (5/54), respectively (relative risk reduction, 54%; 95% confidence intervals, -27 to 83%, P = 0.12), in the Asian subpopulation. Fewer tumors with the Gleason scores of 7-10 and 8-10 were detected among dutasteride-treated men. Although the incidences of drug-related sexual adverse events were higher in the dutasteride group, only in rare occasions did they lead to drug discontinuation. CONCLUSIONS: The incidence of prostate cancer in the dutasteride group was lower than that in the placebo group, although the difference was not significant. These results paralleled those for the overall population and support the value of dutasteride for prostate cancer risk reduction in Asian men with an increased risk of prostate cancer.

Isolation and characterization of the equol-producing bacterium Slackia sp. strain NATTS.

Several kinds of carbohydrates such as sorbose, adonitol, and melezitose were found to enhance equol production from daidzein in an in vitro human fecal culture. Sorbose, one of the most effective carbohydrates, was used as a carbohydrate source for isolating the NATTS strain, which was a Gram-positive, non-spore-forming rod bacterium with high ability to convert daidzein to equol isolated from the 7th maintenance culture. The strain was found to belong to the genus Slackia family Coriobacteriaceae by 16S rRNA sequence-based analysis, and the prevalence of the Slackia sp. in Japanese adults was examined by reverse transcription-quantitative PCR (RT-qPCR), which was found to be 40% at a mean population level of 10(6) cells per gram of feces.

Bladder Cancer Working Group report.

EPIDEMIOLOGY OF BLADDER CANCER: Bladder cancer is the 7th most common cancer in men and the 17th most common in women in the world. The incidence of bladder cancer varies considerably among countries, with the highest incidence rates seen in Western countries and the lowest rates in Asian countries. In recent years, the mortality rate due to bladder cancer has been stable or decreased gradually. LIFESTYLE AND UROTHELIAL CARCINOMA: Occupational risks, environmental risks, dietary habits and cigarette smoking are lifestyle factors known to influence the development of urothelial carcinoma. Although the relative risk of bladder cancer associated with occupations is small, the public health impact may be significant. The Western pattern of diet is associated with a significant increase in the risk of bladder cancer. It has been found that smoking accounts for more than 50% of bladder cancers in men and 30% in women. Urological patients' awareness of smoking as a risk factor for bladder cancer is lower than their awareness regarding other smoking-related disease entities. Counseling patients regarding the risk of tobacco is a role for urologists. GENETIC SUSCEPTIBILITY TO UROTHELIAL CARCINOMA: Recent single-nucleotide polymorphism genetic studies in relation to bladder carcinogenesis have revealed several associated genetic polymorphisms of detoxification or DNA repair genes, such as NAT2, GST and OGG1. That information is important in relation to environmental risk factors and ethnic differences and will help predict the prognosis of patients with bladder cancer. Further studies are needed to confirm potential gene-gene and gene-environmental interactions leading to bladder carcinogenesis.

A case of metastatic testicular cancer complicated by pulmonary hemorrhage due to choriocarcinoma syndrome.

A 40-year-old man was referred to our hospital for treatment of metastatic testicular cancer. Computerized tomography revealed multiple lung, liver, and retroperitoneal lymph node metastases. In addition, magnetic resonance imaging revealed multiple brain metastases. Induction chemotherapy with bleomycin, etoposide, and cisplatin was started the day after a high orchiectomy. The pathological diagnosis of the surgical specimen was yolk sac carcinoma. The serum human chorionic gonadotropin (hCG) was markedly increased to 630,000 mIU/ml, which suggested the presence of a choriocarcinoma element at metastatic sites. The patient subsequently suffered respiratory failure due to pulmonary hemorrhage. Intensive supportive care prevented a fatal outcome. Physicians who treat advanced testicular tumors should be aware of the potential complication of acute pulmonary hemorrhage, called choriocarcinoma syndrome, in cases with a high hCG level, which indicates a rapidly progressive and high-volume choriocarcinoma.

Pattern of intravesical recurrence after surgical treatment for urothelial cancer of the upper urinary tract: a single institutional retrospective long-term follow-up study.

OBJECTIVES: To estimate the risk of intravesical recurrence in patients with primary urothelial cancer of the upper urinary tract. METHODS: Ninety patients who underwent radical nephroureterectomy for clinically localized urothelial cancer of the upper urinary tract were initially considered. Those with a previous and/or concomitant history of bladder cancer, and those who had previously received systemic chemotherapy were excluded. Overall, data from 60 patients with no evidence of bladder cancer and distant or lymph node metastasis were retrospectively reviewed. The clinical course and the risk pattern of intravesical recurrence were estimated by using a smoothing technique on estimated hazard function plots. Multivariate analysis was carried out using a Cox proportional hazards regression model. RESULTS: Mean patient age was 64.7 years. Median follow up was 51.3 months. Thirty patients (50%) had intravesical recurrence during the follow-up period. The peak of intravesical recurrence was detected in the early period (less than 2.5 years) after surgery. The intravesical recurrence hazard became lower afterwards. Nevertheless, it persisted over a long period of time. On univariate and multivariate analyses, none of the clinical or pathological parameters had a statistically significant impact on intravesical recurrence. CONCLUSIONS: Even if an intravesical recurrence in patients with upper urinary tract urothelial cancer is more likely in the early period, it persists over a long period of time. This might reflect different mechanisms of recurrence, having a significant impact on the definition of the optimal treatment and follow-up schedules.

Real-time elastography for the diagnosis of prostate cancer: evaluation of elastographic moving images.

OBJECTIVE: Elastography is a technique for detecting the stiffness of tissues. We applied elastography for the diagnosis of prostate cancer and evaluated the usefulness of elastography for prostate biopsy. METHODS: The subjects of this study were 311 patients who underwent elastography during prostate needle biopsy at Hitachi General Hospital. Strain images obtained during compression of the prostate tissue were displayed on a monitor and recorded on the computer. The elastographic moving images (EMI) were evaluated retrospectively. The evaluable images and biopsy results were compared in terms of the feasibility and accuracy. RESULTS: The median patient age was 67 years (range 50-85 years), the median serum level of prostate-specific antigen was 8.4 ng/ml (range 0.3-82.5 ng/ml) and the median prostate volume was 42.6 ml (range 12-150 ml). Among the 311 patients, prostate cancer was detected in 95 patients (30%) by biopsy. The diagnostic sensitivity was 37.9% for digital rectal examination (DRE) and 59.0% for transrectal ultrasonography (TRUS), whereas it was 72.6% for elastography and 89.5% for the combination of TRUS and elastography. Elastography-positive EMIs with negative biopsies were eventually determined to be due to benign prostatic hyperplasia. CONCLUSION: Elastography has a significantly higher sensitivity for the detection of prostate cancer than the conventionally used examinations including DRE and TRUS. It is a useful real-time diagnostic method because it is not invasive, and simultaneous evaluation is possible while performing TRUS.

[Urological cancer].

Chemotherapy has a major role in the multidisciplinary treatment of urological cancer. Especially cisplatin-based combination chemotherapy plays a central role in the treatment of bladder cancer and testicular cancer. Intravesical chemotherapy for non-muscle-invasive bladder cancer has a clear impact on tumor recurrence when immediately instilled after TURBT and when used in an adjuvant setting. However, there is no clear evidence of an impact on progression. The consensus is that anticancer drugs should be used preferentially over BCG for low-risk disease. Systemic combination chemotherapy for muscle-invasive bladder cancer yields high response rates but suboptimal longterm outcomes for advanced bladder cancer. GC therapy provides similar efficacy in terms of overall survival and progression-free survival compared with M-VAC but with a superior safety profile. In the treatment of prostate cancer, docetaxel has become the treatment of choice for patients with hormone refractory cancer. A treatment strategy for testicular cancer has been established, and a high response rate is obtained even in advanced cancer. However, further innovations in treatment for patients with poor prognosis are required. Thus, new anticancer drugs such as taxanes and gemcitabine were added to cisplatin-based chemotherapy, and a treatment of urological cancer is progressing.

[Sorafenib(Nexavar)].

Sorafenib(Nexavar)is a multikinase inhibitor, with disruptive activity at intracellular C-RAF, B-RAF and mutant BRAF receptors, and extracellular C-KIT, FLT-3, VEGFR-2, VEGFR-3 and PDGFRb receptors. In the phase III study, as compared with placebo, treatment with sorafenib significantly prolonged progression free survival(PFS)in patients with advanced renal cell carcinoma in whom previous therapy has failed. Diarrhea, rash, fatigue, hand-foot skin reactions, and hypertension were the most common adverse events associated with sorafenib. As sorafenib was associated with similar rates of clinically manageable side effects in elderly patients as compared to younger patients, response rates to sorafenib in elderly patients were comparable to those of younger patients. Sorafenib was approved multinationally for the treatment of advanced and/or metastatic renal cell carcinoma. Sorafenib and sunitinib are reference standards of care for the treatment of advanced renal cell carcinoma and are recommended by current clinical guidelines. For the future, research of biomarker, adverse drug reaction, and combined regimens are needed to maximize the effects of molecular-targeted drugs.

Urinary cytology and nuclear matrix protein 22 in the detection of bladder cancer recurrence other than transitional cell carcinoma.

OBJECTIVE: To assess the value of nuclear matrix protein-22 (NMP22), compared with urinary cytology, in predicting the recurrence of bladder cancer that is not transitional cell carcinoma (non-TCC). PATIENTS AND METHODS: We tested the sensitivity, specificity and the predictive accuracy of NMP22 in the context of non-TCC bladder cancer recurrence, and compared it to the performance of urinary cytology. The study group comprised 2687 patients with history of non-muscle-invasive bladder cancer from 10 centres across four continents. RESULTS: The mean patient age was 64.8 years and 75.4% were men; of all patients, 513 (19.1%) had positive urinary cytology, 906 (33.7%) had a positive NMP22 test (>or=10 units/mL) and 80 (3.0%) had non-TCC recurrence. Most of these, i.e. 60 (75%), were stage >or=T2. The sensitivity and specificity of urinary cytology were, respectively, 20.0% and 94.8%, vs 77.5% and 81.8% for NMP22 of >or=10 units/mL. The predictive accuracy of urinary cytology was 57.5%, vs 87.1% for NMP22 >or= 10 units/mL. A combined model that included dichotomized NMP22 and urinary cytology was 85.3% accurate. CONCLUSION: The ability of a NMP22 level of >or=10 units/mL to predict non-TCC recurrence was better than that of urinary cytology, suggesting that NMP22 might have a role in the surveillance of patients at risk of non-TCC recurrence.

Negative impact of metabolic syndrome on the responsiveness to sildenafil in Japanese men.

INTRODUCTION: Several recent studies suggested that the prevalence of erectile dysfunction (ED) was higher in men with metabolic syndrome (MS). AIM: We analyzed the impact of MS on the responsiveness to sildenafil. METHODS: A total of 133 ED patients were evaluated for the prevalence of MS and graded on severity of ED. MS was diagnosed according to the International Diabetes Federation (IDF) definition. The severity of ED was evaluated by the International Index of Erectile Function (IIEF) questionnaire. Hormonal parameters were measured for all patients, and the IIEF questionnaire was conducted after administration of eight tablets of 50-mg doses of sildenafil. If the scores to questions 3 and 4 of the IIEF were 4 or higher after administration, the patients were defined as responders to sildenafil. MAIN OUTCOME MEASURES: To clarify the negative impact of MS on the responsiveness to sildenafil. RESULTS: The mean age of the patients was 56.9 years, and 25 patients were diagnosed with MS. The IIEF-erectile function score and the response rate for sildenafil decreased as the number of MS components increased. Logistic regression analysis showed that the presence of MS along with severity of ED and history of pelvic surgery were significant independent risk factors of nonresponse for sildenafil. The hazard ratio for the presence of MS was 3.30 (95% confidence interval [CI]: 1.17-9.73). No meaningful association was observed between total testosterone or free testosterone levels and MS in this population. CONCLUSION: We demonstrated the negative impact of MS on the responsiveness to sildenafil. Erectile function and response rate for sildenafil decreased as the number of MS components increased.

Efficacy and safety of gemcitabine monotherapy in patients with transitional cell carcinoma after Cisplatin-containing therapy: a Japanese experience.

BACKGROUND: In Japan, the standard chemotherapy for advanced transitional cell carcinoma (TCC) of the urothelium is MVAC (methotrexate, vinblastine, adriamycin, cisplatin). However, a second-line therapy is still required for patients with recurrent TCC who discontinued MVAC because of toxicity or have MVAC refractory tumors. METHODS: We evaluated gemcitabine monotherapy in patients with advanced TCC who were previously treated with a platinum-based regimen. Gemcitabine (1000 mg/m2) was given once a week for three consecutive weeks followed by a week of rest. This cycle was repeated at least three times, or until disease progression or intolerable adverse events were observed. RESULTS: Of the 46 patients entered into this study, 44 received gemcitabine. Performance status (PS) at study entry was: PS 0 (30 patients), PS 1 (12 patients) and PS 2 (2 patients). Stages III/IV were observed in 1/9 patients; the other 34 patients had relapsed after surgery. All 44 patients had been previously treated with a platinum-based regimen. The overall response rate was 25%, 1-year survival rate 52.3%, median survival time 12.6 months and median progression free survival 3.1 months. The major grade 3/4 hematological toxicity was neutropenia (47.7%), and the major grade 3/4 non-hematological toxicity was anorexia (9.1%). All adverse drug reactions seen in the study were manageable. CONCLUSION: Gemcitabine monotherapy is a sufficiently active and well-tolerated therapy for patients who have previously undergone chemotherapy with a platinum-based regimen.

Three-weekly docetaxel with prednisone is feasible for Japanese patients with hormone-refractory prostate cancer: a retrospective comparative study with weekly docetaxel alone.

BACKGROUND: We previously reported that weekly treatment with docetaxel alone is useful for and well tolerated by patients with hormone-refractory prostate cancer (HRPC). Here, we compare it with the regimen of docetaxel once every 3 weeks (q3w) plus daily prednisone (PSL) based on a TAX 327 trial in order to clarify the efficacy and toxicity of docetaxel regimens in Japan. METHODS: Thirty-two patients with HRPC were treated with docetaxel weekly (regimen 1) or docetaxel q3w plus PSL daily (regimen 2) at Tsukuba University Hospital and the changes in serum prostate-specific antigen (PSA), tumor size and survival were evaluated. The dose of docetaxel in regimen 1 was based on our previous report and that of regimen 2 was modified from a TAX 327 trial. RESULTS: A >50% decrease in PSA was observed in 53% of the patients with a median time to progression of 3.5 months and 69% with 8.5 months with regimens 1 and 2, respectively. Patients who received regimen 2 had a significantly better survival rate than those who received regimen 1. Myelosuppression and neuropathy were statistically more frequent in regimen 2 than in regimen 1. CONCLUSION: A regimen of docetaxel q3w with PSL daily was associated with a high rate of PSA reduction and prolongation of patient survival. Although docetaxel has not been approved in Japan yet, this treatment is considered feasible for Japanese patients with HRPC.

Does tumor size or microvascular invasion affect prognosis in patients with renal cell carcinoma?

BACKGROUND: We retrospectively evaluated the effects of tumor size and microvascular tumor invasion on the clinical outcomes of patients who had undergone radical nephrectomy for renal cell carcinoma (RCC). METHODS: One-hundred and sixty-two patients who received radical nephrectomy for localized or locally invasive RCC from 1989 to 2002 were included. We evaluated a new cut-off value for tumor size by dividing patients into groups by tumor diameter from 3.0 to 7.0 cm in 1.0 cm increments and compared the prognosis with that predicted by the 2002 TNM classification. We also re-classified localized microvascular tumor invasion as invasive disease. RESULTS: Univariate analyses showed a 5.0 cm cut-off provided the greatest difference in recurrence (p = 0.004) and survival (p = 0.001). Microvascular invasion made no significant difference in tumor recurrence and tumor-specific survival. However, in the new categories used in this study, survival in the locally invasive group was poor compared with the localized group. CONCLUSION: Our study showed that a tumor diameter of 5.0 cm might be the critical size to determine the prognosis of patients with localized RCC. Microvascular invasion seemed to have the necessity of re-evaluation in the TNM classification for patients with RCC.

Background Variables for the Patients with Invasive Bladder Cancer Suitable for Bladder-preserving Therapy.

OBJECTIVE: The present study was undertaken to identify the patients suitable for bladder preservation by analysis of our data. METHODS: The subjects of this study were all 72 patients with T2-3N0M0 bladder cancer who underwent bladder-preserving therapy in our institute. The therapy involved intra-arterial chemotherapy with MTX and CDDP and concomitant radiotherapy. RESULTS: Of the evaluable 70 cases, complete response (CR) was confirmed in 57 cases (81.4%). Among 56 bladder preserved cases, 47 (83.9%) preserved their functioning bladder, and 9 underwent salvage radical cystectomy at the following period. The median follow-up was 45.3 months. The 5-year cause-specific survival rate was 81% and the 5-year overall survival rate was 66%. On the basis of the results of univariate analysis, variables contributing to CR were selected. In T2, tumor size of 3 cm was scored 1, whereas single tumor was scored 0 and multiple were scored 1. In T3, tumor size of 3 cm was scored 1, whereas G2 was scored 0 and G3 scored 1. The CR rates were 93.8, 92.6, and 62.9% for total scores of 0, 1, and 2, respectively (P = 0.003; score 0 or 1 versus 2). The overall survival rate was significantly higher in the former group (P = 0.003). CONCLUSION: Bladder-preserving therapy can be acceptable for cases of single T2N0M0 tumor with a size of