Trimodality Therapy With Iodine-125 Brachytherapy, External Beam Radiation Therapy, and Short- or Long-Term Androgen Deprivation Therapy for High-Risk Localized Prostate Cancer: Results of a Multicenter, Randomized Phase 3 Trial (TRIP/TRIGU0907).

PURPOSE: This phase 3 randomized investigation was designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiation therapy (EBRT) for localized high-risk prostate cancer. METHODS AND MATERIALS: This study was conducted at 37 hospitals on men aged 40 to 79 years, with stage T2c-3a, prostate-specific antigen >20 ng/mL, or Gleason score >7, who received 6 months of ADT combined with iodine-125 brachytherapy followed by EBRT. After stratification, patients were randomly assigned to either no further treatment (short arm) or 24 months of adjuvant ADT (long arm). According to the Phoenix definition of failure, the primary endpoint was the cumulative incidence of biochemical progression. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific mortality, overall survival, and grade 3+ adverse events. An intention-to-treat analysis was conducted using survival estimates determined using competing risk analyses. RESULTS: Of 332 patients, 165 and 167 were randomly assigned to the short and long arms, respectively. The median follow-up period was 9.2 years. The cumulative incidence of biochemical progression at 7 years was 9.0% (95% CI, 5.5-14.5) and 8.0% (4.7-13.5) in the short and long arms, respectively (P = .65). The outcomes of secondary endpoints did not differ significantly between the arms. Incidence rates of endocrine- and radiation-related grade 3+ adverse events for the short versus long arms were 0.6 versus 1.8% (P = .62) and 1.2 versus 0.6% (P = .62), respectively. CONCLUSIONS: Both treatment arms showed similar efficacy among selected populations with high-risk features. The toxicity of the trimodal therapy was acceptable. The present investigation, designed as a superiority trial, failed to demonstrate that 30-month ADT yielded better biochemical control than 6-month ADT when combined with brachytherapy and EBRT. Therefore, a noninferiority study is warranted to obtain further evidence supporting these preliminary results.

Efficacy and Safety of First-Line Cytokines versus Sunitinib and Second-Line Axitinib for Patients with Metastatic Renal Cell Carcinoma (ESCAPE Study): A Phase III, Randomized, Sequential Open-Label Study.

BACKGROUND: The sequence of first-line cytokine and second-line molecular targeted therapies may be suitable for some patients with metastatic renal cell carcinoma (mRCC) because of the expectation of complete remission and durable response achieved with cytokine therapy. METHODS: This was a phase III randomized controlled trial investigating the outcomes of low-dose interleukin-2 (IL-2) plus interferon alfa (IFNα) versus sunitinib as the first line and axitinib as the second line in patients with low- and intermediate-risk mRCC. RESULTS: Thirty-five patients were randomly assigned. The total progression-free survival (PFS) to the end of the second line was 29.0 months (95% CI, 11.7-46.3) in the IL-2 + IFNα group and 16.3 months (95% CI, 6.3-26.4) in the sunitinib group. The PFS hazard ratio for the IL-2 + IFNα group relative to the sunitinib group was 0.401 (95% CI, 0.121-1.328; p = 0.135). The hazard ratio for overall survival (OS) was 1.675 (95% CI, 0.418-6.705; p = 0.466), which was better in the sunitinib group than in the IL-2 + IFNα group but not statistically significant. The types of adverse events (AEs) differed significantly, although there was no significant difference in the incidence of AEs. CONCLUSIONS: There was a trend toward better total PFS for IL-2 + IFNα, but it was not significant. There was also no advantage of IL-2 + IFNα in terms of OS. The study was underpowered to draw any definitive conclusions. The results showed no clear advantage of IL-2 + IFNα over sunitinib in the first-line setting; however, it may be an option in some relatively low-risk mRCC cases due to the difference in the AE profile. This trial was registered with the University Hospital Medical Information Network (UMIN), center identifier UMIN 000012522.

The correlation between erectile function and adiponectin levels in men with late-onset hypogonadism.

Aim: This study investigated the relationship between erectile dysfunction (ED) and adiponectin levels in hypogonadal men.Methods: In this study, 218 patients with hypogonadism (mean age: 65.1 ± 8.3 years) were enrolled. All patients underwent physical examinations, with measurement of body mass index, body fat ratio, and waist circumference. The erectile function was assessed using the sexual health inventory for men (SHIM) scoring system. Blood biochemical profiles such as free testosterone, fasting blood glucose, and lipid profile including adiponectin levels were measured. All patients were divided into two groups based on their SHIM score: normal to moderate ED (SHIM score ≥ 12) and severe ED (SHIM score < 12), and the factors associated with severe ED were determined. Patients with severe ED were divided into two groups based on adiponectin levels (cutoff value of 7.0 µg/mL), and their basic characteristics were compared between these two groups.Results: The severe ED group was older and had higher adiponectin levels. In patients with severe ED, various metabolic parameters were significantly worse in the low adiponectin groups than in the non-low adiponectin group.Conclusions: The risk of developing cardiovascular diseases is extremely high in hypogonadal men with severe ED who had lower serum adiponectin levels.

The five-year effects of testosterone replacement therapy on lipid profile and glucose tolerance among hypogonadal men in Japan: a case control study.

Objective: This study investigated the efficacy of 5-year testosterone replacement therapy (TRT) on lipid profile and glucose tolerance in Japanese hypogonadal men.Methods: Fourteen patients, who received continuous TRT for 5 years, and 22 controls with 5-year observations were enrolled. The patients in the TRT group had received intramuscular injections of testosterone enanthate (250 mg) every month for 5 years. We collected the following data: blood pressure, fasting blood sugar (FBS), hemoglobin A1c (HbA1c), total cholesterol, triglyceride (TG), high density lipoprotein-Chol values, and prostate specific antigen (PSA) level at baseline, 1-, 3-, and 5-years from initial intervention. These data were compared between the two groups.Results: There were no statistically significant differences in any other baseline characteristic, excluding SBP, between the two groups. FBS was significantly improved at 3- and 5-year visits in the TRT group compared to the control group. Furthermore, the HbA1c level and TG value demonstrated a significant decrease at 1-, 3-, and 5-years in the TRT group. However, no significant difference in changes to PSA levels from baseline in both groups was observed.Conclusions: Five-year TRT could improve FBS, HbA1c, and TG levels among Japanese hypogonadal men with no significant increase in PSA.

Efficacy and safety of cytokines versus first-line sunitinib and second-line axitinib for patients with metastatic renal cell carcinoma (ESCAPE study): A study protocol for phase III randomized sequential open-label study.

Appropriate protocol for the sequential treatment of metastatic renal cell carcinoma (mRCC) has not been established yet. Some mRCC cases with favorable risk were reported to achieve complete remission and durable response using interferon alfa (IFNα) + low dose interleukin-2 (IL-2). Cytokine therapies may be suitable for some patients with mRCC as first-line therapy. The present study is a phase III, investigator-initiated, multicenter, prospective randomized controlled trial investigating patients with low and intermediate risk mRCC classified by Memorial Sloan-Kettering Cancer Center risk criteria to evaluate the efficacy and safety of sequential treatment with cytokine (IFNα + IL-2) as first-line and axitinib as second-line therapy versus sequential treatment with sunitinib as first-line and axitinib as second-line therapy, which is the current standard treatment for patients with favorable risk. The target sample size was set at 72 patients per group (total 144 cases). The study duration is 7 years, and the duration for recruitment is 4 years. Our expectation of this trial is to clarify first- and second-line sequential treatment for mRCC better, especially in patients with favorable risk and some with intermediate risk. The results of this trial will certainly contribute to new information for the strategy of first- and second-line sequential treatment for mRCC. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) Center identifier UMIN 000012522.

Effect of testosterone replacement therapy on sexual function and glycemic control among hypogonadal men with type 2 diabetes mellitus.

We investigated the effect of testosterone replacement therapy (TRT) on glycemic control and sexual function among hypogonadal men with type 2 diabetes mellitus (T2DM). From the EARTH study, 86 patients (47 in the TRT and 39 in the non-TRT groups) with a diagnosis of T2DM were extracted. We collected data on waist circumference, body mass index, body fat volume, free testosterone, hemoglobin (Hb), fasting blood sugar, and hemoglobin A1c (HbA1c) at baseline and after 12 months. Aging Male Symptoms (AMS) score and International Prostate Symptom Score were obtained. Sexual function was assessed by questions 15 (sexual ability), 16 (morning erections), and 17 (sexual desire) of AMS subscores. The TRT group received intramuscular testosterone enanthate (250 mg) injections every 4 weeks for 12 months. Body fat percentage, Hb, and HbA1c were significantly improved in the TRT group. In addition, sexual ability and frequency, and sexual desire showed a significant improvement in the TRT group after 1 year TRT. On the other hand, any parameters including glycemic control and sexual functions were not significantly improved in non-TRT groups. One-year TRT can improve sexual function and glycemic control among hypogonadal men with T2DM.

Sleep disturbance as a clinical sign for severe hypogonadism: efficacy of testosterone replacement therapy on sleep disturbance among hypogonadal men without obstructive sleep apnea.

OBJECTIVE: The present subanalysis of the EARTH study investigates the effects of one year testosterone replacement therapy (TRT) on sleep disturbance among hypogonadal men without obstructive sleep apnea. METHODS: Sleep disturbance was defined as three or more points in question 4 of the aging males symptoms (AMS) questionnaire. All participants completed the AMS scale, International Prostatic Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) and Short Form 36 (SF-36) health survey at baseline and after 12 months. Sexual symptoms were also evaluated based on three AMS subscores (Q15, 16 and 17). RESULTS: We identified 100 patients with sleep disturbance, of whom 48 (24 each in the TRT and control groups) were ultimately included for analysis. All SF-36 categories , AMS scale, IPSS and SHIM score subdomains were significantly worse in patients with sleep disturbance than in those without disturbance. Statistically significant differences in sleep disturbance, erectile symptoms, sexual desire and some domains of the SF-36 were observed between the TRT and control groups after 12 months. CONCLUSION: Sleep disturbance may be one of the clinical signs for severe hypogonadism. Moreover, TRT improved sleep conditions, sexual function and quality of life among hypogonadal men with sleep disturbance.

Metanephric adenoma treated with laparoscopic nephrectomy: A case report.

Metanephric adenoma is an uncommon benign renal tumor that occurs predominantly in adult females and rarely in children. Its histomorphology resembles that of epithelial Wilms' tumor and papillary renal cell carcinoma. From a diagnostic and therapeutic perspective, recognition of this entity is important as it has a more favorable clinical outcome compared with Wilms' tumor and renal cell carcinoma. Metanephric adenoma should not be treated with nephrectomy if the tumor size is small. However, preoperative diagnosis of this disease is extremely challenging. The present study describes a case of this rare disease, which was treated with laparoscopic nephrectomy. The tumor was not clearly enhanced in the early phase on contrast-enhanced computed tomography imaging. The immunohistochemical analysis revealed positive immunoreactivity for vimentin and Wilms' tumor 1, and partial positivity for cytokeratin (CK) AE1/AE3, CK56, and CK34, consistent with metanephric adenoma. Although metanephric adenoma is difficult to diagnose preoperatively, this rare disease must be considered in order to avoid unnecessary surgical procedures in these patients.

Therapies for castration-resistant prostate cancer in a new era: The indication of vintage hormonal therapy, chemotherapy and the new medicines.

When advanced prostate cancer recurred during hormonal therapy and became the castration-resistant prostate cancer, "vintage hormonal therapy," such as antiandrogen alternating therapy or estrogen-related hormonal therapy, was widely carried out in Japan until 2013. This vintage hormonal therapy controlled the progression of castration-resistant prostate cancer. When castration-resistant prostate cancer relapses during these therapies, chemotherapy using docetaxel has been carried out subsequently. Since new hormonal therapies using abiraterone acetate and enzalutamide, which improve the prognosis of castration-resistant prostate cancer, became available in Japan from 2014, therapeutic options for castration-resistant prostate cancer have increased. Furthermore, the improvement of the further prognosis is promising by using cabazitaxel for docetaxel-resistant castration-resistant prostate cancer and radium-223 for castration-resistant prostate cancer with bone metastasis. An increase in therapeutic options gives rise to many questions, including best timing to use them and the indication. Furthermore, physicians have to consider the treatment for the recurrence after having carried out chemotherapy. We want to argue the difference in hormonal therapy between Japan and Western countries, and problems when carrying out new treatments, and the importance of imaging in the present review article.

Effects of testosterone replacement therapy on hypogonadal men with osteopenia or osteoporosis: a subanalysis of a prospective randomized controlled study in Japan (EARTH study).

OBJECTIVE: We investigated the effects of testosterone replacement therapy (TRT) on bone mineral density (BMD) among hypogonadal men with osteopenia/osteoporosis. METHODS: From our previous EARTH study population, 74 patients with a clinical diagnosis of osteopenia or osteoporosis and hypogonadism were included in this study, as the TRT (n = 35) and control (n = 34) groups. The TRT group was administered 250 mg of testosterone enanthate injection every 4 weeks for 12 months. The BMD, waist circumference, body mass index, body fat percentage, and muscle volume were measured at baseline and at 12 months. Blood biochemical data, including total cholesterol, triglycerides, HDL-cholesterol, hemoglobin A1c, and adiponectin values were also evaluated. RESULTS: At the 12-month visit, BMD significantly increased in both groups. However, comparisons on changes of parameter values from baseline to the 12-month visit between the TRT and control groups were significantly different in BMD (5.0 ± 5.0 vs. 3.0 ± 3.2; p = .0434) and in adiponectin value (-0.90 ± 3.33 vs. 0.10 ± 2.04; p = .0192). There were no significant changes in other parameters. CONCLUSIONS: TRT for 12 months could improve BMD with a decrease in adiponectin levels among hypogonadal men with osteopenia/osteoporosis.

Changes in penile length after radical prostatectomy: investigation of the underlying anatomical mechanism.

OBJECTIVE: To measure changes in penile length (PL) over time before and after radical prostatectomy (RP), and to investigate the underlying mechanisms for these changes. PATIENTS AND METHODS: The stretched PL (SPL) of 102 patients was measured before, 10 days after, and at 1, 3, 6, 9, 12, 18 and 24 months after RP. The perpendicular distance from the distal end of the membranous urethra to the midline of the pelvic outlet was measured on mid-sagittal magnetic resonance imaging (MRI) slice at three time points: preoperatively; 10 days after RP; and 12 months after RP. Pre- and postoperative SPLs were compared using paired Student's t-test. Predictors of PL shortening at 10 days and at 12 months after RP were evaluated on univariate and multivariate analyses. RESULTS: The SPL was shortest 10 days after RP (mean PL shortening from preoperative level: 19.9 mm), and gradually recovered thereafter. SPL at 12 months after RP was not significantly different from preoperative SPL. On MRI examination, the distal end of membranous urethra was found to have moved proximally (mean proximal displacement: 3.9 mm) at 10 days after RP, and to have returned to the preoperative position at 12 months after RP. On univariate analysis, only the volume of the removed prostate was a predictor of SPL change at 10 days after surgery; on multivariate analysis, the association was not statistically significant. No predictor of SPL change was found at 12 months after RP. CONCLUSION: The SPL was shortest at 10 days after RP and gradually recovered thereafter in the present study. Anatomically, the glans and corpus spongiosum surrounding the urethra are an integral structure, and the proximal urethra is drawn into the pelvis during urethrovesical anastomosis. This is the first report showing that slight vertical repositioning of the membranous urethra after RP causes changes in SPL over time. These results can help inform patients about changes in penile appearance after RP.

Understanding prostate-specific antigen dynamics in monitoring metastatic castration-resistant prostate cancer: implications for clinical practice.

Availability of novel hormonal therapies as well as docetaxel and cabazitaxel treatment for metastatic castration-resistant prostate cancer (CRPC) has changed the outlook for this group of patients with improvements in progression-free survival and overall survival. Physicians often diagnose the progression of prostate cancer using serum prostate-specific antigen (PSA). However, serum PSA is not always correlated with the clinical status in CRPC. To evaluate the PSA dynamics with greater precision, understanding of the control of PSA and of the mechanisms of development of CRPC is needed. Moreover, it is necessary to use new hormonal therapies with an appropriate timing to optimally improve the prognosis and the QOL of the patients. In the present review, we ascertain the PSA dynamics and the mechanisms of the development of CRPC to assist in optimal utilization of the new treatments for mCRPC.

The correlation between highly sensitive C-reactive protein levels and erectile function among men with late-onset hypogonadism.

We investigated the correlation between highly sensitive C-reactive protein (hs-CRP) levels and erectile function, and assessed the clinical role of hs-CRP levels in men with late-onset hypogonadism (LOH) syndrome. For 77 participants, we assessed Sexual Health Inventory for men (SHIM) score, Aging Male Symptoms (AMS) score and International Prostate Symptom Score (IPSS). We also evaluated free testosterone (FT), hs-CRP, total cholesterol, triglyceride levels, high density lipoprotein cholesterol, hemoglobin A1c, body mass index, waist size and blood pressure. We attempted to identify parameters correlated with SHIM score and to determine the factors affecting cardiovascular risk based on hs-CRP levels. A Spearman rank correlation test revealed that age, AMS score, IPSS and hs-CRP levels were significantly correlated with SHIM score. Age-adjusted analysis revealed that hs-CRP and IPSS were the independent factors affecting SHIM score (r= -0.304 and -0.322, respectively). Seventeen patients belonged to the moderate to high risk group for cardiovascular disease, whereas the remaining 60 belonged to the low risk group. Age, FT value and SHIM score showed significant differences between the two groups. A multivariate regression analysis demonstrated that SHIM score was an independent factor affecting cardiovascular risk (OR: 0.796; 95%CI: 0.637-0.995).

Treatment Outcome of Low-dose Interleukin-2 Therapy in Patients with Metastatic Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is one of the most fatal urological malignancies. Approximately 30% of patients with RCC have metastasis at initial diagnosis and another 30% have metastasis after radical nephrectomy. Immunotherapy using interferon-α (IFN-α) and interleukin-2 (IL-2) has been the main treatment for metastatic RCC (mRCC) patients, with this therapy being still occasionally recommended. The aims of this study were to evaluate the efficacy of low-dose IL-2 and to investigate the prognosis of the patients. Study subjects included 37 patients who were clinically diagnosed with mRCC and received low-dose IL-2 therapy between December 1999 and October 2014. We investigated the relationship between prognosis and clinical features. The median overall survival (OS), that was calculated from the first use of cytokine therapy, was 19.8 months, while the median progression-free survival (PFS) was 3.82 months. PFS was prolonged in patients who received IL-2 as first-line therapy or second-line therapy following IFN-α therapy. IL-2 therapy should be used as a first- or second-line therapy following IFN-α therapy. IL-2 may have a lower response if it is used after molecular-targeted therapy or other treatments.

Aplastic anemia associated with severe hemorrhagic cystitis following radiotherapy for prostate cancer.

Hemorrhagic cystitis is a rare complication following radiotherapy for intrapelvic cancer types, including cervical cancer, bladder cancer and prostate cancer. The severity of hemorrhagic cystitis is different in each case, although symptoms improve spontaneously in certain cases, and often significant morbidity requiring numerous interventions occurs. Since no treatment strategy exists with high evidences for such severe hemorrhagic cystitis, urologists have difficulty in solving the bleeding and pain, which the patients suffer. Aplastic anemia is a rare blood disorder, with an incidence reported as 2/1 million individuals annually. Patients have a risk of diffuse bleeding for presentation with anemia, thrombocytopenia and neutropenia. The present report presented a case of severe hemorrhagic cystitis remitted successfully by the treatment for underlying aplastic anemia.

Clinical Features and Treatment Outcomes in Patients with Extragonadal Germ Cell Tumors: A Single-center Experience.

BACKGROUND: The prognosis for non-seminomatous extragonadal germ cell tumors (EGCTs), especially mediastinal, has been shown to be worse than for seminomatous EGCTs. PATIENTS AND METHODS: Fourteen patients with EGCT (seven pure seminomas and seven non-seminomas) were treated at the Kanazawa University Hospital between 1992 and 2014; the primary tumor sites were mediastinum in nine patients and retroperitoneum in five patients. All patients were treated with cisplatin-based combination chemotherapeutic regimens followed by a multimodal strategy that included high-dose chemotherapy (HDCT), aggressive surgery, and early salvage chemotherapy. RESULTS: Although all patients with seminomatous EGCT achieved long-term survival, almost all patients with non-seminomatous EGCT had elevated serum tumor markers and high mortality rates. However, we experienced that patients with mediastinal non-seminomatous EGCT achieved long-term cancer-free survival with HDCT. The 5-year overall survival of patients with seminomatous and non-seminomatous EGCT was 100% and 44%, respectively. CONCLUSION: Herein we describe the treatment outcomes of patients with EGCT at our Institute and propose HDCT reconsideration for poor-risk patients.

Validation of TNM classification for metastatic prostatic cancer treated using primary androgen deprivation therapy.

PURPOSE: The current tumor-node-metastasis (TNM) classification system has been used for many years. The prognosis of patients with metastatic prostate cancer (mPC) treated using primary androgen deprivation therapy (PADT) was analyzed according to the TNM classification. METHODS: A total of 5618 cases with lymph node metastases only (N1M0), non-regional lymph node metastasis (M1a), bone metastasis (M1b), and distant metastasis (M1c) were selected from the Japanese Study Group of Prostate Cancer database. Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were calculated using Kaplan-Meier analysis. The influence of clinical variables on patient prognosis was evaluated using the Cox proportional hazard regression model. RESULTS: The 5-year OS, CSS, and PFS were 76.0, 83.2, and 38.8% in N1M0, 57.5, 69.0, and 23.0% in M1a, 54.0, 63.1, and 23.0% in M1b, and 40.0, 51.5, and 16.6% in M1c, respectively. OS, CSS, and PFS worsened as the stages progressed. OS, CSS, and PFS were all significantly worse in N1M1b compared with N0M1b. Multivariate analysis revealed that OS and CSS were worse in patients with a Gleason score ≥8 and that combined androgen blockade (CAB) treatment provided better OS than non-CAB treatments at any tumor stage. However, OS and CSS were worse in individuals with a prostate-specific antigen >100 ng/ml only in M1b. CONCLUSIONS: Patient prognosis worsened with stage progression; therefore, current TNM classification system of mPC for PADT was shown to be trustworthy. Each PC cell that develops bone or lymphoid metastasis may exhibit different characteristics.