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Supplemental table 1. Peptide candidates for personalized peptide vaccination

Purpose: The prognosis of platinum-based chemotherapy–resistant metastatic urothelial cancer of the bladder remains poor. Personalized selection of the right peptides for each patient could be a novel approach for a cancer vaccine to boost anticancer immunity.Experimental Design: In this randomized, open-label, phase II study, patients ages ≥18 years with progressive bladder cancer after first-line platinum-based chemotherapy were randomly assigned (1:1) to receive personalized peptide vaccination (PPV) plus best supportive care (BSC) or BSC. PPV treatment used a maximum of four peptides chosen from 31 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for 12 s.c. injections (8 injections, weekly; 4 injections, bi-weekly). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), immune response, and toxicity.Results: Eighty patients were randomly assigned to receive either PPV plus BSC (n = 39) or BSC (n = 41). No significant improvement in PFS was noted [HR, 0.7; 95% confidence interval (CI), 0.4–1.2, P = 0.17]. For the secondary endpoints, PPV plus BSC significantly prolonged OS compared with BSC (HR, 0.58; 95% CI, 0.34–0.99, P = 0.049), with median OS of 7.9 months (95% CI, 3.5–12.0) in the PPV plus BSC and 4.1 months (95% CI, 2.8–6.9) in the BSC. PPV treatment was well tolerated, without serious adverse drug reactions.Conclusions: PPV could not prolong PFS, but OS appeared to be improved with low toxicity and immune responses. Further large-scale, randomized trials are needed to confirm these results. Clin Cancer Res; 22(1); 54–60. ©2015 AACR.

The TITAN study is a randomized, double-blind, placebo-controlled, multinational trial that evaluated apalutamide with androgen deprivation therapy in patients with metastatic castration-sensitive prostate cancer. At the first interim analysis in the Japanese subpopulation (median follow-up 25.7 months), there was an improvement in overall survival and radiological progression-free survival with apalutamide versus placebo. Here, we report the final analysis results for the Japanese subpopulation.Patients were randomized 1:1 to receive apalutamide 240 mg or placebo. After the first interim analysis, protocol treatment was unblinded, and crossover was allowed. Efficacy and safety were evaluated in the preplanned, event-driven final analysis.Fifty-one patients were Japanese (apalutamide n = 28; placebo n = 23). After a median follow-up of 46.0 months, the median overall survival was not reached neither in the apalutamide nor the placebo group; the hazard ratio was 0.45, favoring apalutamide, which was consistent with the overall population. Hazard ratios for time to cytotoxic chemotherapy (0.39), time to pain progression (0.87), and time to chronic opioid use (0.82) also favored apalutamide and were comparable with those of the overall population. Time to prostate-specific antigen progression and progression-free survival 2, respectively, was favored in the apalutamide group (0.21 and 0.44). Apalutamide was associated with higher incidences of rash and fracture in the Japanese subpopulation compared with the overall population.The efficacy of apalutamide with androgen deprivation therapy in Japanese patients was consistent with efficacy demonstrated in the overall population. No new safety concerns emerged with long-term follow-up.

This study aimed to analyze the incidence of subclinical rejection (SCR) in kidney transplantation patients and risk factors associated with SCR.We assessed 80 protocol biopsies taken within 2 years postoperatively in 41 adult patients who underwent living donor kidney transplantation between 2017 and 2020. All patients were on immunosuppressant therapy that included tacrolimus, mycophenolate mofetil, and steroids.The prevalence of Banff Borderline classification at 3, 6, and 12 months after transplantation was 4%, 5%, and 8 %, respectively, whereas none of the biopsies met the Banff criteria for acute T cell-mediated rejection throughout the study period. Active antibody-mediated rejection (ABMR) was only present in 8% of patients at 3 months after transplantation and chronic active ABMR at 6, 12, and 24 months after transplantation was detected in 10%, 13%, and 11% of the patients, respectively. Subgroup analysis revealed that 50% of the 6 patients with preformed anti-donor specific antibodies (DSAs) developed clinical or subclinical active ABMR within 3 months after transplantation, followed by chronic active ABMR according to serial histologic assessment. Conversely, only a small proportion of patients (3%) without preformed DSAs exhibited clinically active ABMR.SCR occurs too infrequently in patients with low immunologic risk and strong contemporary immunosuppression therapy to justify the diagnostic effort of serial protocol biopsies. However, protocol biopsies remain an indispensable tool in renal transplant monitoring and may be especially important in immunologically high-risk patients with pre-existing DSAs.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Background/aim Curcumin is a natural compound of turmeric, which inhibits prostate cancer cell proliferation. This study examined whether treatment of LNCaP prostate cancer cells with the combination of curcumin and dutasteride, a 5-alpha reductase inhibitor, affect proliferation and the amount of testosterone and dihydrotestosterone. Materials and methods LNCaP Cells were incubated with curcumin or the combination of curcumin and dutasteride and cell proliferation was measured at 72 h. LC-MS/MS was used to determine testosterone and dihydrotestosterone concentrations in prostate cancer cells. Results Curcumin combined with dutasteride suppressed proliferation and affected apoptosis of LNCaP cells. The combination of curcumin and dutasteride also reduced the amount of testosterone and dihydrotestosterone in LNCaP cells. The secretion of prostate-specific antigen was inhibited by the combination treatment in a dose-dependent manner. Conclusion Treatment with the combination of curcumin and dutasteride may interfere with the intra-tumoral androgen activity.

Aim The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy. Methods Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (, This study investigated efficacy and safety of abiraterone acetate plus prednisolone in chemotherapy-naive early metastatic castration-resistant prostate cancer patients. Abiraterone acetate plus prednisolone proved to be a beneficial treatment option with regards to its higher response rate.

A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase II trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances the antitumor effects in patients with castration-resistant prostate cancer (CRPC). In this double-blind, placebo-controlled, randomized phase II study, we enrolled chemotherapy-naïve patients with CRPC from ten medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to receive either KRM-20 combined with docetaxel and dexamethasone (n = 25) or placebo with docetaxel and dexamethasone (n = 26). The primary endpoint was the difference in prostate-specific antigen (PSA) decline between each treatment. The rates of > 50% PSA decline in the two arms were similar (56.5% versus 53.8%; P = 0.851). Human leukocyte antigen (HLA)-matched peptide-specific immunoglobulin G (P = 0.018) and CTL (P = 0.007) responses in the KRM-20 arm significantly increased after treatment. The addition of KRM-20 did not increase toxicity. There were no between-group differences in progression-free or overall survival (OS). The addition of KRM-20 was safe, and similar PSA decline and HLA-matched peptide-specific CTL and IgG responses increased in combination with docetaxel and dexamethasone in CRPC patients. Subgroup analysis suggested that this treatment is favorable for CRPC patients with ≥ 26% lymphocytes or PSA levels of

ObjectivesWith novel antiandrogen treatments of varying clinical benefits and risks becoming available, this study investigates how patients with castration-resistant prostate cancer (CRPC) value differences in treatment characteristics.DesignCross-sectional observational study.SettingA discrete choice experiment was conducted. Patients chose between two hypothetical non-metastatic CRPC (nmCRPC) treatments defined by six attributes: risk of fatigue, falls or fracture, cognitive impairment, hypertension, rashes as side effects to treatment and extension of time until cancer-related pain occurs.ParticipantsA total of 137 adult male patients with CRPC with no prior experience with chemotherapy and with Eastern Cooperative Oncology Group status 0–1 were recruited. Patients were excluded if they participated in an investigational programme outside of routine clinical practice, had a clinically relevant medical or psychiatric condition, or diagnosis of visceral/other metastases not related to the prostate, or were otherwise deemed ineligible by the referring physician.Primary outcome measuresRelative preference weights and relative importance of the attributes was estimated by hierarchical Bayesian logistic regression.ResultsAmong the treatment attributes, ‘risk of cognitive impairment as a side effect of treatment’ was the most important attribute (relative importance (RI) (95% CI): 27.47% (24.80% to 30.14%)), followed by ‘extension of time until cancer-related pain occurs’ (RI (95% CI): 17.87% (15.49% to 20.25%)) and the ‘risk of falls or fracture’ (RI (95% CI): 15.99% (14.73% to 17.25%)). The ‘risk of hypertension as a side effect of treatment’ (RI (95% CI): 13.77% (12.73% to 14.81%)) had similar RI as ‘risk of rashes as a side effect of treatment’ (RI (95% CI): 13.17% (12.15% to 14.19%)), followed by the ‘risk of fatigue as a side effect of treatment’ (RI (95% CI): 11.74% (10.75% to 12.73%)).ConclusionsPatients consider the risk of cognitive impairment as a side effect of treatment as the most important attribute in nmCRPC, followed by the extension of time until cancer-related pain occurs, and the risk of falls and fracture. These features should be considered in treatment decision making for nmCRPC in Japan.

Ethnicity might be associated with treatment outcomes in advanced prostate cancer. This study aimed to evaluate the efficacy and safety of androgen deprivation therapy (ADT) combined with apalutamide in East Asians with metastatic castration-sensitive prostate cancer (mCSPC). The original phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial was conducted at 260 sites in 23 countries. This subgroup analysis included patients enrolled in 62 participating centers in China, Japan, and Korea. Radiographic progression-free survival (PFS), time to prostate-specific antigen (PSA) progression, and PSA changes from baseline were compared between groups in the East Asian population. The intent-to-treat East Asian population included 111 and 110 participants in the apalutamide and placebo groups, respectively. The 24-month radiographic PFS rates were 76.1% and 52.3% in the apalutamide and placebo groups, respectively (apalutamide vs placebo: hazard ratio [HR] = 0.506; 95% confidence interval [CI], 0.302-0.849; P = 0.009). Median time to PSA progression was more favorable with apalutamide than placebo (HR = 0.210; 95% CI, 0.124-0.357; P < 0.001). Median maximum percentages of PSA decline from baseline were 99.0% and 73.9% in the apalutamide and placebo groups, respectively. The most common adverse event (AE) was rash in the apalutamide group, with a higher rate than that in the placebo group (37.3% vs 9.1%). The most common grade 3 or 4 AEs were rash (12 [10.9%]) and hypertension (12 [10.9%]) for apalutamide. The efficacy and safety of apalutamide in the East Asian subgroup of the TITAN trial are consistent with the global results.

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.Funding: AstraZeneca.

First‑line chemotherapy for men with metastatic castration‑resistant prostate cancer (mCRPC) has been employed to improve overall survival (OS) and progression‑free survival (PFS). However, several new agents for CRPC after first‑line chemotherapy prolonged survival by only a few months. To develop a new treatment modality, we conducted a phase III randomized trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)‑A24‑positive patients with castration‑resistant prostate cancer (CRPC) for whom docetaxel chemotherapy failed. This randomized, double‑blind, placebo‑controlled, phase III trial was carried out at 68 medical centers in Japan. Patients were randomly assigned at a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on pre‑existing peptide‑specific immunoglobulin G levels or the corresponding placebo were subcutaneously injected in 6 doses weekly and then bi‑weekly following the maximum of 30 doses until disease progression. The primary end‑point was overall survival (OS). Efficacy analyses were performed by the full analysis set. Between August 2013 and April 2016, 310 patients were randomly assigned, and 306 patients were analyzed. Baseline characteristics were balanced between groups. The estimated median OS was 16.1 months [95% confidence interval (CI), 13‑18.2] with PPV and 16.9 months (95% CI, 13.1‑20.4) with placebo [hazard ratio (HR), 1.04, 95% CI, 0.80‑1.37; P=0.77]. Grade ≥3 adverse events were observed in 41% of both groups. The analysis of treatment arm effects among subgroups revealed lower HRs for OS in favor of the PPV arm in patients with

INTRODUCTION AND OBJECTIVE:Testosterone is the major sex hormone in males and plays an important role in the development of the penis and testes, muscle size, bone growth, sex drive, and sperm prod...

Objective To evaluate the efficacy and safety of apalutamide + androgen deprivation therapy versus androgen deprivation therapy alone in Japanese patients with metastatic castration-sensitive prostate cancer from the phase 3, randomized, global TITAN study. Methods Men with metastatic castration-sensitive prostate cancer randomly (1:1) received 240 mg apalutamide + androgen deprivation therapy or matching placebo + androgen deprivation therapy. The primary efficacy endpoints were radiographic progression-free survival and overall survival. Secondary efficacy endpoints were time to cytotoxic chemotherapy, pain progression, chronic opioid use, and skeletal-related events. Safety was also assessed. Results Of the 1052 patients included in the TITAN study, 51 (4.85%) were Japanese (apalutamide group, n = 28; placebo group, n = 23). In all, 81.8% of patients in the apalutamide and 71.8% in the placebo group did not experience radiographic progression or death, and the hazard ratio for radiographic progression-free survival favored treatment with apalutamide (hazard ratio 0.712, 95% confidence interval 0.205-2.466; P = 0.59). At 24 months, 85.7% of patients in the apalutamide group and 81.5% in the placebo group were alive, and the hazard ratio for overall survival favored apalutamide (hazard ratio 0.840, 95% confidence interval 0.210-3.361; P = 0.805). In the interim analysis, the median radiographic progression-free survival and overall survival were not reached in the apalutamide group and time to cytotoxic chemotherapy was delayed following apalutamide treatment. The safety profile of apalutamide in the Japanese subpopulation was comparable with that of the global population, except for skin rash. Conclusions The results of the present analyses suggest that apalutamide + androgen deprivation therapy in Japanese patients had favorable efficacy compared with androgen deprivation therapy alone, and these findings are comparable to those in the overall population. Apalutamide + androgen deprivation therapy can be considered as one of the therapeutic options for a broad spectrum of metastatic castration-sensitive prostate cancer regardless of prior treatment and disease extent in Japanese patients.

Background To develop a new treatment modality, we conducted a phase 3 randomized trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)-A24-positive patients with castration-resistant prostate cancer (CRPC) for whom docetaxel chemotherapy failed. Methods This randomized, double-blind, placebo-controlled, phase 3 trial was done at 68 medical centers in Japan. Eligible patients were aged 20 years or older, positive immunoglobulin G (IgG) responses to at least 2 of 12 warehouse peptides, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 12 weeks, serum testosterone level of ≤ 50 ng/dl, and satisfactory bone marrow function, hepatic function, and renal function. Patients were randomly assigned in a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on pre-existing peptide-specific IgG levels or the corresponding placebo were subcutaneously injected in 6 doses weekly and then bi-weekly following the maximum of 30 doses until disease progression. The primary end point was overall survival (OS). Efficacy analyses were by the full analysis set. Results Between August 2013 and April 2016, 310 patients were randomly assigned, and 306 patients were analyzed. Baseline characteristics were balanced between groups. The estimated median OS was 16.1 months (95% confidence interval [CI], 13–18.2) with PPV and 16.9 months (95% CI, 13.1–20.4) with placebo (hazard ratio [HR], 1.04, 95% CI, 0.80–1.37; p = 0.77). Grade ≥ 3 adverse events were observed in 41% in both groups. The analysis of treatment arm effects among subgroups revealed lower HRs for OS in favor of the PPV arm in patients with < 64% neutrophils (HR, 0.55, 95% CI, 0.33–0.93; p = 0.03) or ≥ 26% lymphocytes (HR, 0.70, 95% CI, 0.52–0.92; p = 0.02) at base line. Conclusions PPV did not prolong OS in HLA-A24-positive patients with CRPC progressing after docetaxel chemotherapy. Subgroup analysis suggested that the patients with a lower proportion of neutrophils or a higher proportion of lymphocytes at base line can receive survival benefits from PPV treatment.

Background In the global Phase-3 Selective Prostate Androgen Receptor Targeting with ARN-509 study, apalutamide plus ongoing androgen deprivation therapy (ADT) significantly increased metastasis-free survival (MFS) and improved other clinical outcomes in men with nonmetastatic castration-resistant prostate cancer (nm-CRPC) who were at high risk of developing metastases. In this subpopulation analysis of Selective Prostate Androgen Receptor Targeting with ARN-509 study, the efficacy and safety of apalutamide plus ADT were evaluated in Japanese patients with nm-CRPC. Methods The primary efficacy end point was MFS. Secondary efficacy end points were time to metastasis, progression-free survival, symptomatic progression, initiation of cytotoxic chemotherapy, and overall survival. Safety and pharmacokinetic parameters were also assessed. Results Fifty-five Japanese patients with ongoing ADT were randomized (apalutamide: n = 34, placebo: n = 21). Median treatment duration was 5.7 months in the apalutamide group and 11.0 months in the placebo group. Median MFS was not reached in the apalutamide group (95% confidence interval: 10.97, not estimable) and was 18.23 months (95% confidence interval: 11.04, 18.50) in the placebo group. Secondary end points were improved in the apalutamide group. The safety profile of apalutamide with ADT was comparable with the global population, and no new safety signals were identified in this Japanese subpopulation. Although, apalutamide exposure tended to be higher in the Japanese subpopulation compared with the non-Japanese population, this was likely to be explained by body weight and considered not clinically meaningful. Conclusion In the Japanese subpopulation, treatment with apalutamide with ADT resulted in favorable efficacy outcomes with comparable benefit-risk profile to the global population with nm-CRPC who are at high-risk of developing metastases.

Background To date, research has not determined the optimal procedure for adjuvant androgen deprivation therapy (ADT) in patients with locally advanced prostate cancer (PCa) treated for 6 months with neoadjuvant ADT and external-beam radiation therapy (EBRT). Methods A multicenter, randomized, phase 3 trial enrolled 303 patients with locally advanced PCa between 2001 and 2006. Participants were treated with neoadjuvant ADT for 6 months. Then, 280 patients whose prostate-specific antigen levels were less than pretreatment levels and less than 10 ng/mL were randomized. All 280 participants were treated with 72 Gy of EBRT in combination with adjuvant ADT for 8 months. Thereafter, participants were assigned to long-term ADT (5 years in all; arm 1) or intermittent ADT (arm 2). The primary endpoint was modified biochemical relapse-free survival (bRFS) with respect to nonmetastatic castration-resistant prostate cancer (nmCRPC) progression, clinical relapse, or any cause of death. Results The median follow-up time after randomization was 8.2 years. Among the 136 and 144 men assigned to trial arms 1 and 2, respectively, 24 and 30 progressed to nmCRPC or clinical relapse, and 5 and 6 died of PCa. The 5-year modified bRFS rates were 84.8% and 82.8% in trial arms 1 and 2, respectively (hazard ratio, 1.132; 95% confidence interval, 0.744-1.722). Conclusions Although modified bRFS data did not demonstrate noninferiority for arm 2, intermittent adjuvant ADT after EBRT with 14 months of neoadjuvant and short-term adjuvant ADT is a promising treatment strategy, especially in a population of responders after 6 months of ADT for locally advanced PCa.

Objectives：To evaluate the efficacy and safety of once-daily oxybutynin patch for overactive bladder (OAB) patients not tolerating oral antimuscarinic drugs. Methods：We prospectively investigated 43 OAB patients treated with once-daily oxybutynin patches for dry mouth and constipation due to oral antimuscarinic drugs. Results：Oxybutynin patch treatment for 8 weeks significantly improved the visual analogue scale scores for dry mouth and constipation；total score and subscore (mean number of urgency episodes and daily micturitions) for OAB symptoms；and King’s Health Questionnaire scores for social limitations, emotions and sleep/energy (P＝0.016 and 0.001；0.008, 0.041 and 0.015；and 0.007, 0.003 and 0.026, respectively). The 3-day frequency volume chart showed significant improvement in hours of undisturbed sleep（P＝0.011）. Eight patients had adverse reactions at the application site and withdrew from the study, while others only developed mild erythema and pruritus. Conclusions：Oxybutynin patch reduces adverse reactions caused by oral antimuscarinic drugs.

Introduction：To evaluate the efficacy and safety of once daily phosphodiesterase type 5 inhibitor(PDE5i) tadalafil as an add-on treatment for men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia（BPH/LUTS）refractory to an alpha 1-blocker（a1-blocker）. Materials and Methods：This study enrolled men aged ＞50 years with BPH/LUTS and erectile dysfunction(ED) that were refractory to ＞3 months of a1-blocker. We defined “refractory” as an international prostate symptoms score (IPSS) of ＞8 and a maximum flow rate (Qmax) ＜15 despite in no space take of an a1-blocker. Patients with contraindications to phosphodiesterase-5 inhibitors；those with symptoms of other diseases that were difficult to differentiate from BPH/LUTS；and those with postvoid residual of ＞100 ml were excluded. Eligible patients received added-on treatment with tadalafil 5 mg/day for 12 weeks. Results：Tadalafil add-on treatment significantly improved the IPSS parameters in terms of total score（P＜0.001）, subscore for storage（P＝0.001）, subscore for voiding（P＜0.001）, and quality of life（P＝0.002）. The 3-day frequency volume chart showed significant improvements in mean number of daily nocturnal micturations（P＝0.002）, nocturnal polyuria index（P＝0.001）, and hours of undisturbed sleep（P＝0.006）. Five patients dropped out because of an adverse event：two with a headache, two with dizziness and one with dyspepsia. There were no serious adverse events. Conclusion：Tadalafil add-on treatment was effective for patients with BPH/LUTS and ED that were resistant to a1-blockers.

Pyoderma gangrenosum (PG) is a skin disease characterized by an unknown neutrophilic infiltration in dermis and a nonbacterial destructive ulcer. Post-operative PG is an extremely rare type that occurs around surgical sites during the immediate post-operative period. It is usually diagnosed as surgical site infection at the time of presentation. The condition rapidly worsens despite antibiotic treatment and debridement. We report on a case of post-operative PG in a 64-year-old man after radical prostatectomy. Following the operation, redness and pus from surgical site rapidly progress although repeated antibiotic therapy and debridement were performed. Although the patient received appropriate debridement and broad-spectrum antibiotic treatment, the ulcerative lesion spread surrounding drain region and the condition of the skin region deteriorated. The diagnosis of PG was made by a skin biopsy that presented only neutrophilic invasion in the dermis without vasculitis, tumor, or malignancy. Finally, the patient died of lesion progression in whole body and multiple organ dysfunction. Considering PG along with ulcers, wounds, and post-operative complications is critical for prompt diagnosis and proper treatment.

The PROPHET (Prostate Cancer: Prostate Health Index Trial) is a prospective study to clarify the diagnostic impact of laboratory based and prostate volume adjusted p2PSA ([-2] proenzyme prostate specific antigen) related indexes on prostate cancer and clinically significant prostate cancer with prostate specific antigen less than 10 ng/ml.Between April 2015 and March 2017, 421 men 50 to 79 years old in the prostate specific antigen range above age specific cutoffs and below 10 ng/ml were registered in the PROPHET. We investigated the diagnostic impacts of various clinical laboratory based free prostate specific antigen related and p2PSA related indexes on any grade and high Gleason grade group prostate cancer.Of the 363 eligible participants 179, 141 and 80 were diagnosed with any grade, and Gleason Grade Group 2-5 and 3-5 prostate cancer, respectively. The AUC-ROCs distinguishing nonprostate cancer vs prostate cancer, nonprostate cancer plus low Gleason Grade Group and low volume vs remaining prostate cancer with a higher Gleason Grade group or a higher volume on the PHI (Prostate Health Index) were significantly superior to the AUC-ROCs of prostate specific antigen and free-to-total prostate specific antigen. At 90% sensitivity in all investigated p2PSA related indexes the false-positive rate was superior to that of prostate specific antigen and free-to-total prostate specific antigen in any group comparison in terms of the Gleason Grade Group and positive biopsy cores. In 35% to 42% of men without prostate cancer and/or those with less aggressive prostate cancer the PHI would avoid unnecessary biopsy.Laboratory based p2PSA related indexes were significantly superior for detecting clinically significant prostate cancer compared to free-to-total prostate specific antigen. The indexes those would avoid up to 42% of prostate biopsies in men without aggressive cancer while maintaining 90% sensitivity.

Background: To develop a new treatment modality, we conducted a phase 3 randomised trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA) -A24-positive patients with castration-resistant prostate cancer (CRPC) for whom docetaxel chemotherapy failed. Methods: This randomized, double-blind, placebo-controlled, phase 3 trial was done at 68 medical centers in Japan. Eligible patents were aged 20 years or older with HLA-A24-positive, CRPC progressing after docetaxel chemotherapy, positive immunoglobulin G (IgG) responses to at least 2 of 12 warehouse peptides, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 12 weeks, serum testosterone level of ≤ 50 ng/dl, and satisfactory bone marrow function, hepatic function, and renal function. Patients were randomly assigned in a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on pre-existing peptide-specific IgG levels or the corresponding placebo were subcutaneously injected in 6 doses weekly and then bi-weekly following the maximum of 30 doses until disease progression. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS) and immune responses. Efficacy analyses were by the full analysis set. Findings: Between August 2013 and April 2016, 310 patients were randomly assigned (207 to PPV and 103 to placebo), and 306 patients were analyzed by the full analysis set (204 to PPV and 102 to placebo). Baseline characteristics were balanced between groups. The estimated median OS was 16.1 months (95% confidence interval [CI], 13–18·2) with PPV and 16·9 months (95% CI, 13·1–20·4) with placebo (hazard ratio [HR], 1·04; 95% CI, 0·80–1·37; p=0·77). The median PFS was not significantly different between groups. Grade < 3 adverse events were observed in 41% in both groups. The most common AEs were < grade 3 injection site reactions in both groups. The analysis of treatment arm effects among subgroups revealed lower HRs for OS in favor of the PPV arm in patients with < 64% neutrophils (HR, 0·55; 95% CI, 0·33–0·93, p=0·03) or ≥ 26% lymphocytes (HR, 0·70; 95% CI, 0·52–0·92, p=0·02) at base line by the significant interaction test (p=0·003 or p=0·007). Interpretation: PPV did not prolong OS or PFS in HLA-A24-positive patients with CRPC progressing after docetaxel chemotherapy. Subgroup analysis suggested that the patients with a lower proportion of neutrophils or a higher proportion of lymphocytes at base line can receive survival benefits from PPV treatment. Trial Regstration: This study is registered with UMIN Clinical Trials Registry (UMIN000011308), and patient enrollment is complete. Funding Statement: This study was supported by grants from the Japan Agency for Medical Research and Development (No. 18im0110802h0008) and Fujifilm Company. Declaration of Interests: MN has served as an advisory board consultant for BrightPath biotherapeutics Co. Ltd. KI received research funding from Taiho Pharmaceutical Company. SN has served as a consultant to BrightPath biotherapeutics Co. Ltd and received an honorarium from Sanofi. All other authors declare no competing interests. Ethics Approval Statement: The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was approved by institutional review boards or ethical committees at all of the institutions. All patients were Japanese and provided written informed consent before participating in this study.

We describe the first case of a 25-year-old patient with gender identity disorder (GID) who underwent cryopreservation of sperm prior to male-to-female (MTF) sex reassignment surgery in Japan. The patient wanted to freeze sperm to keep open the option of conceiving a child in the future. The ethics committee of our institution discussed the case and officially approved cryopreservation of sperm before sex reassignment surgery. Compared with foreign countries, sperm cryopreservation of GID is not recognized and guidelines have yet been published in Japan. Here, we report sperm cryopreservation for MTF before sex reassignment surgery.

症例は36歳男性.頻尿,排尿時痛,残尿感および食思不振を主訴に近医受診.抗生剤投与されるも症状軽快せず,当院紹介受診となる.初診時検査で,白血球,好酸球,IgEの上昇を認め,経腹膀胱超音波検査,MRIで膀胱壁の著明な肥厚を認めた.また,膀胱鏡検査では膀胱三角部を除く膀胱粘膜の著明な浮腫状所見を認め,上部消化管内視鏡検査では胃粘膜及び十二指腸粘膜も同様の浮腫状所見であった.確定診断のため膀胱全層針生検を施行し,病理所見では膀胱平滑筋内に著明な好酸球浸潤を認めたため好酸球性膀胱炎と診断.点滴ステロイド療法を開始し,症状軽快,画像上も改善を認めステロイド内服に切り替えたのち退院した., A 36-years-old man with pollakisuria and digestive symptom was referred to our hospital. A blood test showed inclease of serum white blood cell,eosinophil and IgE. Imaging study showed thickening of bladder wall, and endoscopy of bladder and stomach showed severe mucosal edema. Because there was a suspicion of the allergic diseases, we carried out transabdominal needle biopsy of bladder. Because of the pathological finding of severe eosinophilic infiltration into smooth muscle of urinary bladder, we diagnosed a case of eosinophilic cystitis. After that we started up steroid therapy immediately, he was recovering from pollakisuria and digestive symptom.

Purpose: The prognosis of platinum-based chemotherapy–resistant metastatic urothelial cancer of the bladder remains poor. Personalized selection of the right peptides for each patient could be a novel approach for a cancer vaccine to boost anticancer immunity. Experimental Design: In this randomized, open-label, phase II study, patients ages ≥18 years with progressive bladder cancer after first-line platinum-based chemotherapy were randomly assigned (1:1) to receive personalized peptide vaccination (PPV) plus best supportive care (BSC) or BSC. PPV treatment used a maximum of four peptides chosen from 31 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for 12 s.c. injections (8 injections, weekly; 4 injections, bi-weekly). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), immune response, and toxicity. Results: Eighty patients were randomly assigned to receive either PPV plus BSC (n = 39) or BSC (n = 41). No significant improvement in PFS was noted [HR, 0.7; 95% confidence interval (CI), 0.4–1.2, P = 0.17]. For the secondary endpoints, PPV plus BSC significantly prolonged OS compared with BSC (HR, 0.58; 95% CI, 0.34–0.99, P = 0.049), with median OS of 7.9 months (95% CI, 3.5–12.0) in the PPV plus BSC and 4.1 months (95% CI, 2.8–6.9) in the BSC. PPV treatment was well tolerated, without serious adverse drug reactions. Conclusions: PPV could not prolong PFS, but OS appeared to be improved with low toxicity and immune responses. Further large-scale, randomized trials are needed to confirm these results. Clin Cancer Res; 22(1); 54–60. ©2015 AACR.

The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce CTLs against 12 different TAA in patients with castration-resistant prostate cancer (CRPC). Patients received each of three different randomly assigned doses of KRM-20 (6, 20, or 60 mg) once a week for 6 weeks. KRM-20 was applicable for patients with positive human leukocyte antigen (HLA) A2, A3, A11, A24, A26, A31 or A33 alleles, which cover the majority of the global population. To evaluate the minimum immunological effective dose (MIED), peptide-specific CTL and immunoglobulin G (IgG) responses, and immune suppressive subsets were evaluated during the vaccination. Total of 17 patients was enrolled. No serious adverse drug reactions were encountered. The MIED of KRM-20 in CTL or IgG response calculated by logistic regression model was set as 16 or 1.6 mg, respectively. The frequency of immune suppressive subsets was fewer in the 20 mg cohort than that in 6 or 60 mg cohort. Clinical responses determined by prostate-specific antigen levels were two partial responses (from the 20 mg cohort), five no changes and ten progressive diseases. Twenty milligrams of KRM-20 could be recommended for further studies because of the safety and ability to augment CTL activity.

Objectives To investigate factors influencing the degree of difficulty in finding and maintaining an appropriate plane on the surgical capsule of the prostate during holmium laser enucleation of the prostate. Methods A total of 116 men undergoing holmium laser enucleation of the prostate for benign prostate hyperplasia between January 2010 and September 2013 at our hospital were included in this analysis. The degree of difficulty in finding and maintaining the plane of the surgical capsule of the prostate was retrospectively evaluated and graded by using video-based analysis according to newly defined criteria (grade I, least difficult; grade IV, most difficult). Factors influencing the degree of difficulty were investigated. Results Video analysis was possible in 99 of 116 patients. Decapsulation difficulty in decapsulation was deemed as being grade I in 32 patients, grade II in 31 patients, grade III in 20 patients and grade IV in 16 patients. Preoperative dutasteride therapy was the only factor associated with an increasing level of difficulty in decapsulation during holmium laser enucleation of the prostate. Conclusions Although preoperative dutasteride therapy effectively reduces intraoperative blood loss, surgeons with limited experience should be careful with the use of dutasteride, because its administration might increase surgical difficulty during holmium laser enucleation of the prostate.

A 71-year-old man was referred to our department due to inflammation in the right scrotum. A tumor in the right spermatic cord was suspected on palpation, and abdominal computed tomography revealed a 4-cm mass in the tail of the pancreas and a low-density lesion in the liver segment 6. In addition, the patient's serum level of CA19-9 was high, at 135.7 U/mi. We referred the patient to our institution's Department of Gastroenterology, where he was diagnosed as having a liver metastasis from pancreatic cancer. Despite three courses of gemcitabine and erlotinib combination therapy for pancreatic cancer, his serum level of CA19-9 increased to 744.0 U/m, indicating no response to chemotherapy. Because uncontrollable pain developed in the right scrotum and right inguinal area during the course of treatment, inguinal orchiectomy was performed for pain management and pathological diagnosis. Careful examination revealed a hard, whitish tumor occupying the right spermatic cord and extending from the epididymis to the internal inguinal ring. Because a palpable mass in the peritoneum near the internal inguinal ring was detected, part of the peritoneum was resected concurrently. Pathological findings were remarkable with spermatic cord metastasis and peritoneal dissemination from pancreatic cancer. Pain subsided postoperatively and no analgesics were needed. Pancreatic cancer accompanied by spermatic cord metastasis and peritoneal dissemination is extremely rare. Surgical resection in the present case provided effective treatment of the intractable pain due to spermatic cord metastasis. To the best of our knowledge, this is only the 14th case reported in Japan of spermatic cord metastasis from pancreatic cancer as a primary cancer.

症例は49 歳女性.左水腎症と骨盤内リンパ節腫大の精査目的で当院紹介.CT・MRI で左下部尿管に造影効果を認める凹凸不整な腫瘍病変を認め,逆行性尿管造影で左尿管の完全閉塞を認めた.自然尿及び洗浄尿の細胞診は陰性であったが,画像所見から左尿管癌と診断し左尿管全摘除術を施行した.病理組織診で尿管子宮内膜症と診断され,術後は合併症なく退院した., A 49-years-old woman with left hydronephrosis was referred to our hospital. Computed tomography and magnetic resonance imaging showed an irregular contrast enhanced mass of the ureter. A retrograde pyelography showed complete obstruction of the left ureter. Cytology of urine and irrigated ureteral urine were both negative for malignamt cells. Left ureteronephrectomy was performed under clinical diagnosis of the ureteral tumor. Pathological examination of surgical revealed endometriosis of the uteter. She was in good health at 6 months after the surgery with no evidence of recurrence.

【目的】水腎症の原因である腎盂尿管移行部閉塞(Uretero-Pelvic Junction Obstruction;UPJO)の病因を形態的に分類し,患者背景,術後の経過との関連性について検討した.【方法】2009年3月から2013年4月までに獨協医科大学越谷病院で施行した腹腔鏡下腎盂形成術(Laparoscopic Pyeloplasty;LPP)38症例について検討した.術中所見とビデオの見直しから以下のように3つの病因に分類した.Type 1:血管による閉塞を有するもの.Type 2:肥厚した被膜が腎盂尿管を包み込むもの.Type 3:硬い被膜に包まれ尿管の屈曲,狭窄を認めるもの.上記病因と術前後における症状,腹部超音波所見および利尿レノグラムを用いて評価した手術成績について比較検討した.【結果】38症例を手術ビデオで見直した結果,Type 1は14例,Type 2は13例,Type 3は11例であった.小児症例はType 1の症例が少なく,Type 2およびType 3が多かった.各Typeでの術後の症状,腹部超音波所見,利尿レノグラムの改善率に有意差はなかった.【結語】UPJOの形態と年齢には関連を認めたが,術後成績には明らかな違いは認めなかった., Background:To analyze the relationship between the etiology of ureteropelvic junction obstruction (UPJO) and surgical outcomes using laparoscopic clear view during pyeloplasty. Method:Total 38 patients who underwent laparoscopic pyeloplasty by Anderson-Hynes technique from 2009 March to 2013 April at Dokkyo Medical University Koshigaya Hospital, were enrolled into the study. According to the structure of the ureteropelvic junction under the laparoscopic view UPJO was divided to 3 types, type 1 (n= 14):vascular causes of ureteral obstruction, type 2 (n= 14):the presence of adhesion around UPJ, type 3 (n= 11):the presence of angulation due to ureteral kinks or adhesion. The relationships between types of UPJO and surgical outcomes were analyzed.Results:Many of pediatric patient were included in type 2 and 3. Types of UPJO were not related to operation time, symptom, abdominal ultrasonography, and results of diuretic renogram.Conclusion:Most of pediatric patients with hydronephrosis had no vascular cause. There are no significant differences between each types and surgical success rate in patients underwent laparoscopic pyeloplasty.

Objective: Overproduction of reactive oxygen species results in oxidative stress, a deleterious process that damages cell structure as well as lipids, proteins, and DNA. Oxidative stress plays a major role in various human diseases, such as oligoasthenozoospermia syndrome. Materials and methods: We evaluated the effectiveness of antioxidant co-supplementation therapy using vitamin C, vitamin E, and coenzyme Q10 in men with oligoasthenozoospermia. Overall, 169 infertile men with oligoasthenozoospermia received antioxidant therapy with 80 mg/day vitamin C, 40 mg/day vitamin E, and 120 mg/day coenzyme Q10. We evaluated spermiogram parameters at baseline and at 3 and 6 months of follow-up. Results: Significant improvements were evident in sperm concentration and motility following coenzyme Q10 therapy. Treatment resulted in 48 (28.4%) partner pregnancies, of which 16 (9.5%) were spontaneous. Significant improvements in sperm cell concentration and sperm motility were observed after 3 and 6 months of treatment. Conclusions: Vitamin C, vitamin E, and coenzyme Q10 supplementation resulted in a significant improvement in certain semen parameters. However, further studies are needed to empirically determine the effect of supplementation on pregnancy rate.

5033 Background: To develop a new treatment modality, we conducted a phase III randomized trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA) -A24 positive patients with castration-resistant prostate cancer (CRPC) who failed docetaxel chemotherapy. Methods: Patients were randomly assigned in a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebo were subcutaneously injected 6 doses weekly followed the maximum of 30 doses bi-weekly until disease progression. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS) and immune responses. Results: From August 2013 to April 2016, 310 patients were randomly assigned (207 to PPV and 103 to placebo), and 306 patients were analyzed by the full analysis set (204 to PPV and 102 to placebo). Baseline characteristics were balanced between groups. Estimated median OS was 16.1 months (95% CI, 13 to 18.2) with PPV and 16.9 months (95% CI, 13.1 to 20.4) with placebo (HR, 1.04; 95%CI, 0.79 to 1.37; P = 0.77). Median PFS was also not significantly different among them. Median Grade ≥ 3 adverse events were observed in 41% in both groups. The analysis of treatment arm effects among various subgroups revealed a lower HR for OS in favor of the PPV arm in patients with a < 64% neutrophil proportion (HR, 0.55; 95%CI, 0.33 to 0.93), with a significant interaction test ( P = 0.003). Conclusions: PPV did not prolong either OS or PFS in HLA-A24 positive patients with CRPC progressing after docetaxel chemotherapy. Clinical trial information: 0000113088.

When sperm cannot be retrieved from the testes of patients with azoospermia due to spermatogenic dysfunction (ASD), there is no rational way for the patient to become a biological father. We investigated the possibility of inducing spermatogenesis in such patients by hormonal therapy with recombinant human follicle-stimulating hormone (rhFSH) alone. Twenty-six ASD patients who could not obtain spermatozoa by microdissection testicular sperm extraction (micro-TESE) were confirmed to have arrested spermatogenesis at the late stage of maturation arrest. They were subsequently treated with 75-150 IU two times/week rhFSH alone for 12 months. The primary endpoint was the appearance of sperm in ejaculate, and we followed the patients to determine the outcome of inseminating their partners. After rhFSH treatment, mature spermatozoa were found in the ejaculate in five of 26 (19.2%) patients, all of whom showed histology of non-uniform type maturation arrest. Intracytoplasmic sperm injection of the mature spermatozoa resulted in two ongoing clinical pregnancies (insemination success rate, 40.0%). Recombinant human follicle-stimulating hormone treatment can be used as an advanced assisted reproductive technology to improve spermatogenesis in some azoospermic patients with maturation arrest of spermatogenesis and is a potential treatment option after unsuccessful micro-TESE.

Estrogen exposure has been linked to a risk of testicular germ cell cancers, although predominantly in animal studies. In the human testis, estrogen receptor beta (ER-β) mediates the physiological action of estrogen. We describe a case of a 30-year-old transgender woman (male-to-female [MtF]) with gender dysphoria who developed a mature testicular teratoma with positive estrogen receptor beta expression while receiving cross-sex hormonal therapy with estradiol and progesterone. Although the presence of hormone receptors does not always imply that hormones have played a role in the development of the tumor, a contribution of exposure to exogenous estrogen in this case cannot be ruled out.