BACKGROUND: Peripheral sympathetic nerve injury, resulting from surgery around the abdominal aorta, including retroperitoneal lymph node dissection for testicular cancer, often causes ejaculatory dysfunction (EjD). EjD reduces sexual activity and male fertility. Imipramine (IMI) has been empirically used for EjD. However, research using animal models and clinical studies on EjD is limited. AIM: We investigated the effects of IMI in a rat model of EjD following hypogastric nerve (HGN) injury using apomorphine (APO)-induced ejaculations and lumbar splanchnic nerve (LSN) electrostimulation. METHODS: Thirty-six male Sprague-Dawley rats were divided into six groups: Sham, Sham-IMI, Crush-Vehicle, Crush-IMI, Cut-Vehicle, and Cut-IMI. In the Crush group, the bilateral HGNs were crushed, and in the Cut group, the bilateral HGNs were excised. IMI (1 mg/kg) or Vehicle was administered intraperitoneally 7-30 days after HGN injury. OUTCOMES: Ejaculatory function was assessed weekly using the weight of solid semen ejaculated from the urethral meatus after subcutaneous administration of 0.5 mg/kg APO. Changes in seminal vesicle pressure (SVP) were assessed using APO-induced ejaculation (ΔSVPA) and LSN electrostimulation (ΔSVPE) 30 days after HGN injury. Dunnett's test was used to determine significant differences between groups. RESULTS: In the Crush-IMI group, the mean solid semen weights significantly increased 21 and 28 days after HGN injury compared with those in the Crush-Vehicle group (P = .011 and P = .036, respectively). However, in the Cut-IMI group, no increase in solid semen weight was observed. The ΔSVPA in the Crush-IMI group was higher than that in the Crush-Vehicle group; however, the difference was not statistically significant. Furthermore, ΔSVPE in the Crush-IMI group was significantly higher than that in the Crush-Vehicle group (P = .024). Additionally, the mean seminal vesicle weights in the Crush-IMI group were lower than those in the Crush-Vehicle group at 30 days after HGN injury (P = .014). CLINICAL IMPLICATIONS: IMI improves SV function, suggested that IMI might be useful in patients with EjD. STRENGTHS AND LIMITATIONS: This study shows that IMI has an effect on EjD by improving SV function in a rat model. Limitations include a lack of the mechanisms or the effect of IMI at different doses on EjD. CONCLUSION: This model allowed for the comprehensive assessment of EjD in rats, and IMI attenuated EjD after HGN injury. It aids in the clarification of the mechanism and development of treatments for nerve injury-related EjD.

Introduction: Although immune checkpoint inhibitor-associated myocarditis is relatively rare, it has the highest mortality rate among all immune-related adverse events, at 30–50%. Case Presentation: We encountered a case of advanced renal cancer in which immune checkpoint inhibitor-associated myocarditis was confirmed on autopsy. A 78-year-old man was diagnosed with a left renal tumor secondary to hematuria. A tumor biopsy was performed, and the tumor was diagnosed as cT4N0M1 clear cell renal carcinoma, which was classified as poor risk by the International mRCC Database Consortium. Combination therapy with pembrolizumab and axitinib was initiated. One month later, the patient developed anorexia, dizziness, and fatigue, which were judged to be adverse events due to systemic therapy, and the patient was admitted to the hospital urgently. After admission, the patient experienced a sudden drop in blood pressure and loss of consciousness and was referred to a cardiologist for treatment. Blood tests showed elevated brain‐type natriuretic peptide levels, but echocardiography showed good cardiac function. However, soon thereafter, the patient developed tachycardia, and echocardiography revealed a significant decline in systolic function, leading to the diagnosis of immune checkpoint inhibitor-associated myocarditis. Despite intensive care in the cardiac high-care unit and steroid administration, the patient died. An autopsy revealed necrotic changes in the myocardium, loss of myocardial cells, and severe lymphocyte infiltration, leading to a diagnosis of inhibitor-associated myocarditis. Conclusion: Delay in the initiation of treatment is considered a risk factor for poor prognosis, and the administration of high-dose steroids within 24 h of onset contributes to a better outcome. Herein, we discuss the pathology, diagnosis, and treatment of immune checkpoint inhibitor-associated myocarditis.

OBJECTIVES: To investigate the functional role of latrophilin-1 (LPHN1; encoded by the ADGRL1 gene) and latrophilin-2 (LPHN2; encoded by the ADGRL2 gene), members of the G protein-coupled receptor family, in relation to androgen receptor (AR) signaling, in the outgrowth of bladder cancer. METHODS: Human bladder urothelial carcinoma cell lines were subjected to real-time PCR, western blotting, chromatin immunoprecipitation, MTT assay, and wound-healing assay. Immunostaining was also performed on a set of bladder cancer tissue microarrays consisting of transurethral resection specimens. RESULTS: In bladder cancer cells with endogenous or exogenous AR expression, dihydrotestosterone markedly up-regulated ADGRL1/LPHN1 and ADGRL2/LPHN2 expression. Chromatin immunoprecipitation confirmed AR binding to the promoter regions of ADGRL1 and ADGRL2. Additionally, LPHN ligands (e.g. α-latrotoxin, FLRT3) induced their expression. Knockdown of LPHN1 or LPHN2 via shRNA virus infection significantly reduced cell viability and migration, while the stimulatory effects of LPHN ligands on cell viability were more significant in AR-negative or AR-knockdown lines than in corresponding AR-positive lines. Immunohistochemical analysis in surgical specimens further showed that LPHN1 overexpression (i.e. moderate/strong) in muscle-invasive tumors (n = 62) independently predicted poorer disease-specific survival following radical cystectomy (hazard ratio 2.662, P = 0.031). Analysis of The Cancer Genome Atlas (TCGA) dataset (n = 305, stage II-IV bladder cancer) also revealed that high ADGRL2 expression was associated with significantly worse overall survival. CONCLUSION: These findings suggest that LPHN1 and LPHN2 function as downstream effectors of AR and contribute to the progression of bladder cancer.

Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer and its outgrowth. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptors to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in the progression of bladder cancer. In AR-positive bladder cancer lines, dihydrotestosterone considerably increased the expression levels of ADGRL3 and LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. Treatment with LPHN3 ligands (e.g. α-LTX, FLRT3) resulted in the induction of ADGRL3 expression, as well as cell viability, in bladder cancer lines. By contrast, LPHN3 knockdown via shRNA virus infection significantly reduced the viability and migration of these cells. Immunohistochemistry in transurethral resection specimens further showed a strong correlation between LPHN3 and AR expression. Moreover, LPHN3 positivity in muscle-invasive bladder tumors, as an independent prognosticator, was associated with a significantly higher risk of disease progression and disease-specific mortality following radical cystectomy. These findings suggest that LPHN3 functions as a downstream effector of AR and promotes the growth of bladder cancer.

<jats:title>Abstract</jats:title><jats:p>Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male‐dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G‐protein‐coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the <jats:italic>ADGRL3</jats:italic> gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of <jats:italic>ADGRL3</jats:italic>/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of <jats:italic>ADGRL3</jats:italic>. In SVHUC or SVHUC‐AR cells with exposure to a chemical carcinogen 3‐methylcholanthrene, LPHN3 activation via ligand (e.g., α‐latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In <jats:italic>N</jats:italic>‐butyl‐<jats:italic>N</jats:italic>‐(4‐hydroxybutyl)nitrosamine‐treated female mice, α‐latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non‐muscle‐invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (<jats:italic>p</jats:italic> = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.</jats:p>

OBJECTIVE: To evaluate the effect of intravenous administration of human multilineage-differentiating stress-enduring (Muse) cells on rat postoperative erectile dysfunction (ED) with cavernous nerve (CN) injury without an immunosuppressant. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomised into three groups after CN crush injury. Either human-Muse cells, non-Muse mesenchymal stem cells (MSCs) (both 1.0 × 105 cells), or vehicle was infused intravenously at 3 h after CN injury without immunosuppressant. Erectile function was assessed by measuring intracavernous pressure (ICP) and arterial pressure (AP) during pelvic nerve electrostimulation 28 days after surgery. At 48 h and 28 days after intravenous infusion of Muse cells, the homing of Muse cells and non-Muse MSCs was evaluated in the major pelvic ganglion (MPG) after CN injury. In addition, expressions of C-X-C motif chemokine ligand (Cxcl12) and glial cell line-derived neurotrophic factor (Gdnf) in the MPG were examined by real-time polymerase chain reaction. Statistical analyses and comparisons among groups were performed using one-way analysis of variance followed by the Tukey test for parametric data and Kruskal-Wallis test followed by the Dunn-Bonferroni test for non-parametric data. RESULTS: The mean (SEM) ICP/AP values at 28 days were 0.51 (0.02) in the Muse cell group, 0.37 (0.03) in the non-Muse MSC group, and 0.36 (0.04) in the vehicle group, showing a significant positive response in the Muse cell group compared with the non-Muse and vehicle groups (P = 0.013 and P = 0.010, respectively). In the MPG, Muse cells were observed to be engrafted at 48 h and expressed Schwann cell markers S100 (~46%) and glial fibrillary acidic protein (~24%) at 28 days, while non-Muse MSCs were basically not engrafted at 48 h. Higher gene expression of Cxcl12 (P = 0.048) and Gdnf (P = 0.040) was found in the MPG of the Muse group than in the vehicle group 48 h after infusion. CONCLUSION: Intravenously engrafted human Muse cells recovered rat erectile function after CN injury in a rat model possibly by upregulating Cxcl12 and Gdnf.

The biological or clinical significance of mineralocorticoid receptor (MR) in urothelial cancer remains largely unknown. The present study aimed to determine the functional role of MR in bladder cancer progression. In two of the human bladder cancer lines expressing MR, treatment with a natural MR ligand, aldosterone, significantly reduced cell proliferation and migration, which was restored by three MR antagonists clinically used, spironolactone (except colony formation of androgen receptor-positive cells cultured in the presence of androgens), eplerenone, and esaxerenone. Similarly, MR knockdown via shRNA virus infection resulted in significant increases in cell viability/migration, as well as colony formation, compared with control sublines. In addition, MR knockdown augmented the expression of β-catenin, c-fos, and N-cadherin, and lowered that of E-cadherin and p53, indicating the induction of the cadherin switching. Immunohistochemistry in surgical specimens detected MR signals in 58 (92.1%; 36.5% weakly-positive/1+, 44.4% moderately-positive/2+, and 11.1% strongly-positive/3+) of 63 muscle-invasive bladder cancers, which was significantly lower than in adjacent non-neoplastic urothelial tissues (100%; 15.7% 1+, 37.3% 2+, and 47.1% 3+). Moreover, patients with MR-high (3+) tumor had a significantly lower risk of cancer-specific mortality (P=0.039). Multivariable analysis further showed that strong MR expression was an independent predictor of cancer-specific survival in patients with muscle-invasive bladder cancer (hazard ratio 0.117, P=0.039). These findings suggest that MR signaling functions as a tumor suppressor in urothelial carcinoma and prevents tumor growth. Accordingly, there is a possibility that the concurrent use of anti-mineralocorticoids, particularly eplerenone and esaxerenone, in patients with bladder cancer rather contributes to the promotion of disease progression.

PPARγ coactivator-1α (PGC1α), as a co-activator, is known to optimize the action of several transcription factors, including androgen receptor (AR). However, the precise functions of PGC1α in prostate cancer, particularly those via the non-AR pathways, remain poorly understood. Meanwhile, our bioinformatics search suggested that PGC1α could be a direct downstream target of lysine-specific demethylase 5B (KDM5B/JARID1B/PLU1). We herein aimed to investigate how PGC1α induced prostate cancer outgrowth. Immunohistochemistry in radical prostatectomy specimens showed that the levels of PGC1α expression were significantly higher in prostatic adenocarcinoma [H-score (mean ± SD): 179.0 ± 111.6] than in adjacent normal-appearing tissue (16.7 ± 29.9, P<0.001) or high-grade prostatic intraepithelial neoplasia (79.0 ± 94.7, P<0.001). Although there were no strong associations of PGC1α expression with tumor grade or stage, outcome analysis revealed that patients with high PGC1α (H-score of ≥200) tumor had a significantly higher risk of postoperative biochemical recurrence even in a multivariable setting (hazard ratio 5.469, P=0.004). In prostate cancer LNCaP and C4-2 cells, PGC1α silencing resulted in considerable reduction in the levels of prostate-specific antigen expression. Interestingly, PGC1α silencing inhibited the cell viability of not only AR-positive LNCaP/C4-2/22Rv1 lines but also AR-negative PC3/DU145 lines. Chromatin immunoprecipitation assay further revealed the binding of KDM5B to the promoter region of PGC1α in these lines. Additionally, treatment with a KDM5 inhibitor KDM5-C70 considerably reduced the expression of PGC1α and prostate-specific antigen, as well as the cell viability of all the AR-positive and AR-negative lines examined. PGC1α silencing or KDM5-C70 treatment also down-regulated the expression of phospho-JAK2 and phospho-STAT3 in both AR-positive and AR-negative cells. These findings suggest the involvement of PGC1α, as a downstream effector of KDM5B, in prostate cancer progression via both AR-dependent and AR-independent pathways. KDM5B-PGC1α is thus a potential therapeutic target for both androgen-sensitive and castration-resistant tumors. Meanwhile, PGC1α overexpression may serve as a useful prognosticator in those undergoing radical prostatectomy.

BACKGROUND/AIM: Precise molecular mechanisms underlying resistance to cisplatin-based chemotherapy remain unclear, while the activity of estrogen receptor-β (ERβ) has been suggested to be associated with chemosensitivity in urothelial cancer. We aimed to determine if GULP1, an adapter protein known to facilitate phagocytosis, could represent a downstream effector of ERβ and thereby modulate cisplatin sensitivity in bladder cancer. MATERIALS AND METHODS: GULP1 expression and cisplatin cytotoxicity were compared in bladder cancer lines. Immunohistochemistry was used to determine the expression of GULP1 and ERβ in two sets of tissue microarray (TMA) consisting of transurethral resection specimens. RESULTS: The levels of GULP1 expression were considerably higher in ERβ-knockdown sublines than in the respective control ERβ-positive sublines. Estradiol treatment reduced GULP1 expression in ERα-negative/ERβ-positive lines, which was restored by the anti-estrogen tamoxifen. Chromatin immunoprecipitation assay revealed the binding of ERβ to the GULP1 promoter in bladder cancer cells. Moreover, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment, but not to other chemotherapeutic agents, including gemcitabine, methotrexate, vinblastine, and doxorubicin. In the first set of TMA (n=129), the expression of ERβ and GULP1 was inversely correlated (p=0.023), and ERβ(-)/GULP1(+) in 51 muscle-invasive tumors was associated with significantly lower risk of disease progression and cancer-specific mortality. Similarly, in the second set (n=43), patients with ERβ(-)/GULP1(+) muscle-invasive disease were significantly (p=0.021) more likely to be responders to cisplatin-based neoadjuvant chemotherapy before radical cystectomy. CONCLUSION: ERβ activation was found to reduce the expression of GULP1 as a direct downstream target in bladder cancer cells, resulting in the induction of cisplatin resistance.

INTRODUCTION: In testicular cancer, late relapse of teratoma with somatic-type malignancy is rare and associated with a poor survival. A case of retroperitoneal lymph node metastasis of teratoma with somatic-type malignancy 18 years after initial treatment for testicular cancer is reported. CASE PRESENTATION: A 46-year-old man had a 15-mm-sized mass in the para-aortic region 18 years after initial treatment for testicular cancer, without elevated serum alfa-fetoprotein or human chorionic gonadotropin levels. Laparoscopic retroperitoneal lymph node dissection was performed. The pathological findings showed teratoma with somatic-type malignancy, and the findings of primary testicular cancer reported a yolk sac tumor, not teratoma. CONCLUSION: Late relapse of teratoma with somatic-type malignancy was resected by laparoscopic retroperitoneal lymph node dissection. Therefore, long-term follow-up should be considered if patients with small retroperitoneal masses did not undergo retroperitoneal lymph node dissection, and early detection and surgical resection for relapse might be effective.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

The expression status of mineralocorticoid receptor (MR) and its biological significance in human urothelial carcinoma remain unknown. The present study aimed to determine the functional role of MR in the development of urothelial cancer. In human normal urothelial SVHUC cells with exposure to a chemical carcinogen 3-methylcholanthrene (MCA), we assessed the effects of a natural MR ligand, aldosterone, and 3 MR antagonists, including spironolactone, eplerenone, and esaxerenone, as well as knockdown of MR via shRNA virus infection, on their neoplastic/malignant transformation. The in vitro system with carcinogen challenge showed that aldosterone and anti-mineralocorticoids significantly prevented and promoted, respectively, the neoplastic transformation of SVHUC cells. Similarly, MR knockdown in SVHUC cells considerably induced MCA-mediated neoplastic transformation, compared with a control subline. In addition, MR knockdown or antagonist treatment resulted in increases in the expression of β-catenin, c-Fos, and N-cadherin, and a decrease in that of E-cadherin. Meanwhile, spironolactone, which is known to possess anti-androgenic activity, rather suppressed the neoplastic transformation of a SVHUC subline stably expressing wild-type androgen receptor, indicating its dominant effect via the androgen receptor pathway. Immunohistochemistry in surgical specimens detected MR signals in 77 (98.7%; 23.1% weak/1+, 42.3% moderate/2+, and 33.3% strong/3+) of 78 non-invasive bladder tumors, which was significantly (P<0.001) lower than in adjacent non-neoplastic urothelial tissues (100%; 20.5% 2+ and 79.5% 3+). Moreover, the risks for disease recurrence after transurethral surgery were marginally lower in female patients with MR-high (2+/3+) tumor (P=0.068) and significantly lower in all patients with MR-high/glucocorticoid receptor-high tumor (P=0.025), compared with respective controls. These findings suggest that MR signaling functions as a suppressor for urothelial tumorigenesis.

CONTEXT.—: Intraductal carcinoma of the prostate (IDC-P) is considered a distinct form of aggressive prostate cancer where comedonecrosis, a grade 5 pattern, is occasionally present. Meanwhile, assigning a Gleason grade to IDC-P remains controversial. OBJECTIVE.—: To assess the clinical significance of necrosis associated with IDC-P. DESIGN.—: We compared radical prostatectomy (RP) findings and oncologic outcomes in men with prostate cancer exhibiting IDC-P with (IDC-P+/N+) versus without (IDC-P+/N-) comedonecrosis. RESULTS.—: Of the 558 RPs examined, IDC-P was present in 213 cases (38.2%), including 167 (78.4%) with IDC-P+/N- and 46 (21.6%) with IDC-P+/N+. When comparing IDC-P+/N- versus IDC-P+/N+ cases, the presence of necrosis was significantly associated with higher tumor grade, higher incidence of pT3/pT3b or pN1 disease, and larger estimated tumor volume. Outcome analysis revealed a significantly higher risk of disease progression in IDC-P+/N+ patients than in IDC-P+/N- patients (P < .001). Significant differences in progression-free survival between IDC-P+/N- and IDC-P+/N+ patients were also seen in subgroups, such as those without (P = .01) or with (P = .03) adjuvant therapy immediately after RP, those with pN0 disease (P < .001), and, more interestingly, those exhibiting conventional Gleason pattern 5 component (P = .02). Multivariate analysis showed significance for IDC-P+/N+ when IDC-P (grade 4) and IDC-P+/N+ (grade 5) were (hazard ratio, 1.768; P = .049) or were not (hazard ratio, 2.000; P = .008) incorporated into the Gleason score. CONCLUSIONS.—: IDC-P+/N+ was found to be associated with worse histopathologic features on RP and poorer prognosis as an independent predictor. Pathologists may thus need to report the presence or absence of not only IDC-P but also comedonecrosis within IDC-P.

CONTEXT.—: Seminal vesicle invasion (SVI) by prostate cancer (pT3b disease) has been considered as a key prognostic factor. OBJECTIVE.—: To assess the clinical impact of T3a lesions (ie, extraprostatic extension other than bladder neck invasion [BNI] or SVI [EPE], microscopic bladder neck invasion [mBNI]) in pT3b disease. DESIGN.—: We compared radical prostatectomy findings and long-term oncologic outcomes in 248 patients with pT3b disease, with versus without EPE/mBNI. RESULTS.—: Extraprostatic extension/mBNI was found in 219 (88.3%)/48 (19.4%) cases, respectively. Extraprostatic extension was significantly associated with higher preoperative prostate-specific antigen (PSA) level, higher rates of positive surgical margin (pSM) and lymphovascular invasion (LVI), and larger tumor volume. Similarly, mBNI was significantly associated with higher PSA level, higher rates of Grade Group(s) 4-5 or 5, pSM, LVI, and pN1, and larger tumor volume. Significant differences in all of these clinicopathologic features (except lymph node metastasis) between EPE-/mBNI+ or EPE+/mBNI- and EPE+/mBNI+ cases were also observed. Outcome analysis revealed that patients with EPE (P < .001) or mBNI (P < .001) had a significantly higher risk of disease progression than respective controls. Notably, there were significant differences in progression-free survival between EPE-/mBNI+ or EPE+/mBNI- cases and EPE-/mBNI- (P = .001) or EPE+/mBNI+ (P < .001) cases. In multivariate analysis, EPE (hazard ratio [HR] = 6.53, P = .009) and mBNI (HR = 2.33, P = .003), as well as EPE-/mBNI+ or EPE+/mBNI- (HR = 11.7, P = .01) and EPE+/mBNI+ (HR = 25.9, P = .002) versus EPE-/mBNI-, showed significance for progression. CONCLUSIONS.—: From these significant findings, we propose a novel pT3b subclassification: pT3b1 (SVI alone without EPE or mBNI), pT3b2 (SVI with either EPE or mBNI), and pT3b3 (SVI with both EPE and mBNI).

Perineural invasion (PNI) by prostate cancer detected on systematic sextant biopsy (S-Bx) has been considered as a key prognosticator. However, the clinical significance of PNI on magnetic resonance imaging-targeted biopsy (T-Bx) needs to be further investigated. We assessed 169 patients undergoing T-Bx with concurrent S-Bx, followed by radical prostatectomy (RP) from 2015 to 2019. In all cases where cancer was detected on T-Bx only (n = 34) or both S-Bx and T-Bx (B-Bx; n = 135), PNI was found in 33 (19.5%) T-Bxs. Compared with no PNI, PNI on T-Bx was associated with higher Grade Group on biopsy/RP, higher pT stage, and lymph node metastasis. Outcome analysis revealed a significant difference in the risk of biochemical recurrence after RP between cases with and without PNI on T-Bx (P = 0.021). Next, in the 135 B-Bx cases, PNI was found on S-Bx only (n = 31), T-Bx only (n = 15), or B-Bx (n = 16). Compared with PNI on S-Bx, B-Bx PNI was associated with higher preoperative prostate-specific antigen, higher biopsy GG, higher pT stage, and larger tumor volume. There were no significant differences in any of the clinicopathologic features examined between cases with PNI on T-Bx only vs. B-Bx. Moreover, in this subgroup of patients, PNI on B-Bx was associated with significantly higher risks of biochemical recurrence, compared with PNI on S-Bx only (P = 0.024) or T-Bx only (P = 0.033). In multivariate analysis, PNI on B-Bx showed significance for recurrence (hazard ratio = 2.787, P = 0.034). The presence of PNI on T-Bx, particularly B-Bx, associated with worse histopathologic features on RP and poorer outcomes might thus be useful for risk stratification.

Epidemiological data have indicated that there are some sex-related differences in bladder cancer. Indeed, the incidence of bladder cancer in men has been substantially higher than that in women throughout the world, while women tend to have higher stage disease and poorer prognosis. These gender disparities have prompted to investigate sex hormones and their cognitive receptors in bladder cancer. Specifically, estrogen receptors, including estrogen receptor-α and estrogen receptor-β, have been shown to contribute to urothelial carcinogenesis and cancer progression, as well as to modulating chemosensitivity in bladder cancer, although conflicting findings exist. Meanwhile, immunohistochemical studies in surgical specimens have assessed the expression of estrogen receptors and related proteins as well as its associations with clinicopathologic features of bladder cancer and patient outcomes. This review article summarizes and discusses available data indicating that estrogen receptor signaling plays an important role in urothelial cancer.

Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone (p = 0.083) or together with AR negativity (p = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.

OBJECTIVE: To evaluate the impact of cancer therapy on post-treatment ejaculation in patients with testicular cancer. METHODS: A total of 74 testicular cancer survivors provided completed International Index of Erectile Function-15 questionnaires before and after treatment between 2010 and 2017. Sexual function, particularly ejaculatory function, was evaluated before and after treatment. In this study, patients who answered "1 = almost never/never" or "2 = a few times" for questionnaire number 9 (ejaculation frequency) were defined as having "ejaculation disorder." RESULTS: Of 74 testicular cancer survivors, 50 (68%) had no ejaculation disorders before treatment. Four (44%) of nine survivors, who received chemotherapy and retroperitoneal lymph node dissection, developed ejaculation disorders after treatment. On multivariate analysis, retroperitoneal lymph node dissection was a significant predictor of post-treatment ejaculation disorder (P = 0.042). Of 60 survivors with evaluable ejaculation function after treatment, 24 (40%) did not attempt sexual intercourse, and multivariate analysis showed ejaculation disorder had a significant negative impact on having sexual intercourse (P = 0.035). Furthermore, the mean International Index of Erectile Function-15 scores in the groups with and without ejaculation disorders after treatment were 24.0 and 51.9, respectively (P < 0.001). CONCLUSION: Ejaculation disorders occur at high rate after retroperitoneal lymph node dissection. Many testicular cancer survivors reporting no sexual intercourse have ejaculation disorders, suggesting an adverse impact on sexual life. Urologists should provide proper counselling regarding the risk of ejaculation disorder and its possible impact on sexual life.

Testicular cancer occurs in the testes of the male reproductive system and is the most common cancer in adolescent and young adult (AYA) men. However, recently, there have been more cases of testicular cancer in men older than 40 years. Therefore, trends of testicular cancer during the past 40 years were retrospectively examined, focusing on age and histology. Patients who were diagnosed with testicular cancer at our institution between 1980 and 2019 were enrolled in this study. The patients were divided into groups by the year of diagnosis (1980s, 1990s, 2000s, and 2010s), age at diagnosis (14, 15 to 39, and older than 40 years), and histological type (seminoma and non-seminoma). A total of 563 patients were diagnosed with testicular cancer over the 40-year period. The median age at diagnosis increased continuously, from 28 years to 31 years, 34 years, and 38 years in each period, respectively (p < 0.001). Moreover, most testicular cancer patients were of the AYA generation, whereas the ratio of patients older than 40 years increased significantly since 2000 (p < 0.001). The relative proportion of seminoma also increased more than 50% since 2000. In the seminoma group, median age increased from 31 years to 41 years during the 40-year period (p < 0.001). In conclusion, the age at diagnosis is rising for testicular cancer patients. Clinicians should recognize that testicular cancer affects not only the AYA generation, but there has been a shift to older than 40 years, especially in seminoma.

BACKGROUND: Androgen receptor (AR) activation has been implicated in the pathogenesis of urothelial cancer. However, it remains controversial whether 5α-reductase inhibitors (5α-RIs), which are known for blocking the conversion of testosterone to the more potent androgen dihydrotestosterone and often prescribed for the treatment of, for instance, benign prostatic hyperplasia, contribute to preventing the development of bladder cancer. OBJECTIVE: To determine the role of 5α-RI therapy in urothelial tumorigenesis and tumor progression, using cell line models. METHODS: In a human non-neoplastic urothelial SVHUC subline stably expressing a full-length wild-type human AR (SVHUC-AR) with carcinogen/MCA challenge and human bladder cancer lines, we assessed the effects of three 5α-RIs, dutasteride (up to 100 nM), finasteride (up to 500 nM), and epristeride (up to 5 μM), on neoplastic/malignant transformation and cell growth, respectively. RESULTS: In AR-positive bladder cancer UMUC3 and 5637-AR cells, an AR antagonist bicalutamide significantly inhibited their proliferation, whereas three 5α-RIs failed to do. Similarly, these 5α-RIs did not significantly inhibit the migration of bladder cancer cells induced by the treatment of testosterone which could be metabolized into dihydrotestosterone in culture medium. In MCA-SVHUC-AR cells, induction of their neoplastic transformation by testosterone, which was prevented by bicalutamide, was confirmed. However, no significant inhibitory effects of 5α-RIs on the neoplastic transformation of AR-positive urothelial cells treated with or without testosterone were observed. CONCLUSIONS: Using in vitro models for urothelial cancer, 5α-RI treatment even at supra-pharmacological doses was thus found to have no significant impact on the prevention of both tumorigenesis and tumor progression.

The efficacy of cisplatin-based chemotherapy in patients with bladder cancer is often limited due to the development of therapeutic resistance. Our recent findings in bladder cancer suggested that activation of prostaglandin receptors (e.g. EP2, EP4) or cyclooxygenase (COX)-2 induced cisplatin resistance. Meanwhile, emerging evidence indicates the involvement of estrogen receptor-β (ERβ) signals in urothelial cancer progression. In this study, we aimed to investigate whether ERβ activity was associated with cisplatin sensitivity in bladder cancer. Immunohistochemistry in muscle-invasive bladder cancer specimens from 55 patients who had subsequently received at least 3 cycles of cisplatin + gemcitabine neoadjuvant chemotherapy showed that ERβ was positive in 38% of responders vs. 71% of non-responders (P = 0.016), including 42% of male responders vs. 65% of male non-responders (P = 0.142) and 20% of female responders vs. 100% of female non-responders (P = 0.048). Then, cisplatin cytotoxicity was compared in human bladder cancer cell lines. Control sublines endogenously expressing ERβ were significantly more resistant to cisplatin treatment at its pharmacological concentrations, compared with ERβ knockdown sublines via short hairpin RNA virus infection. An ER modulator tamoxifen increased sensitivity to cisplatin in ERα-negative/ERβ-positive cell lines, while, in an estrogen-depleted condition, 17β-estradiol reduced it. Additionally, western blot showed considerable elevation in ERβ expression in cisplatin-resistant bladder cancer sublines, compared with respective controls. Moreover, treatment with tamoxifen or a COX-2 inhibitor celecoxib increased cisplatin sensitivity even in resistant cells, while COX-2/EP2/EP4 inhibitor treatment resulted in reduced expression of ERβ. The expression and activity of β-catenin known to involve cisplatin resistance was also up-regulated in cisplatin-resistant cells, which was further induced by 17β-estradiol treatment. The present results suggest that estrogen-mediated ERβ signaling plays an important role in modulating cisplatin sensitivity in bladder cancer cells. Targeting ERβ during chemotherapy may thus be a useful strategy to overcome cisplatin resistance especially in female patients with ERβ-positive bladder cancer.

We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.

Androgen receptor (AR) and estrogen receptor-β (ERβ) have been implicated in urothelial tumor outgrowth as promoters, while underlying mechanisms remain poorly understood. Our transcription factor profiling previously performed identified FOXO1 as a potential downstream target of AR in bladder cancer cells. We here investigated the functional role of FOXO1 in the development and progression of urothelial cancer in relation to AR and ERβ signals. In non-neoplastic urothelial SVHUC cells or bladder cancer lines, AR/ERβ expression or dihydrotestosterone/estradiol treatment reduced the expression levels of FOXO1 gene and induced those of a phosphorylated inactive form of FOXO1 (p-FOXO1). In chemical carcinogen-induced models, FOXO1 knockdown via shRNA or inhibitor treatment resulted in considerable induction of the neoplastic transformation of urothelial cells or bladder cancer development in mice. Similarly, FOXO1 inhibition considerably induced the viability, migration, and invasion of bladder cancer cells. Importantly, in FOXO1 knockdown sublines, an anti-androgen hydroxyflutamide or an anti-estrogen tamoxifen did not significantly inhibit the neoplastic transformation of urothelial cells, while dihydrotestosterone or estradiol did not significantly promote the proliferation or migration of urothelial cancer cells. In addition, immunohistochemistry in surgical specimens showed that FOXO1 and p-FOXO1 expression was down-regulated and up-regulated, respectively, in bladder tumor tissues, which was further associated with worse patient outcomes. AR or ERβ activation is thus found to correlate with inactivation of FOXO1 which appears to be their key downstream effector. Moreover, FOXO1, as a tumor suppressor, is likely inactivated in bladder cancer, which contributes in turn to inducing urothelial carcinogenesis and cancer growth.

We recently demonstrated that silodosin, a selective α1-blocker often prescribed for the symptomatic treatment of benign prostatic hyperplasia (BPH), could inactivate a c-fos proto-oncogene regulator ELK1 in bladder cancer cells possessing a functional androgen receptor (AR). However, the clinical impact of α1-blockers on the development and progression of bladder cancer remained poorly understood. In the present study, we investigated if α1-blockers clinically used, including silodosin, tamsulosin, and naftopidil, could prevent the neoplastic/malignant transformation and cell growth, using non-neoplastic urothelial SVHUC sublines with carcinogen/MCA challenge and bladder cancer lines, respectively. Bladder cancers in men treated with silodosin, tamsulosin, or naftopidil for their BPH were then compared. Silodosin at 1-10 µM significantly inhibited the neoplastic transformation of MCA-SVHUC-AR cells, but not that of AR-negative MCA-SVHUC-control cells. In MCA-SVHUC-AR, silodosin significantly reduced the expression levels of oncogenes (c-fos/NF-κB1) and induced those of tumor suppressors (p27/PTEN). However, tamsulosin (up to 1 µM) or naftopidil (up to 10 µM) failed to significantly inhibit the neoplastic transformation of AR-positive or AR-negative urothelial cells. Similarly, cell proliferation/migration of AR-positive bladder cancer lines was considerably inhibited only by silodosin. Meanwhile, the incidence of bladder cancer in patients with silodosin [49/540 (9.1%)] was marginally lower, compared to those with tamsulosin [64/523 (12.2%); P=0.094] or tamsulosin or naftopidil [64+28/523+236 (12.1%); P=0.082]. There were no significant differences in tumor grade/stage among the 3 cohorts. Outcome analysis revealed lower risks for disease progression of non-muscle-invasive bladder tumors in the silodosin group than in the naftopidil group (P=0.011) or tamsulosin+naftopidil groups (P=0.035). Similarly, silodosin patients with muscle-invasive tumor had lower risks for disease progression, compared with tamsulosin (P=0.006) or tamsulosin+naftopidil (P=0.028) patients. Multivariate analysis further showed that silodosin treatment in those with non-muscle-invasive tumor was associated with improved progression-free survival, compared with naftopidil (hazard ratio=0.086; 95% confidence interval=0.008-0.905; P=0.041) or tamsulosin/naftopidil (hazard ratio=0.128; 95% confidence interval=0.016-1.036; P=0.054) treatment. Our in vitro studies thus indicate that both urothelial tumorigenesis and tumor growth are inhibited by silodosin, but not by tamsulosin or naftopidil. Clinical data further suggest that even pharmacological doses (e.g. 0.1 µM) of silodosin contribute to preventing bladder cancer progression.

Recent preclinical evidence has indicated that both androgen receptor (AR) inactivation and glucocorticoid receptor (GR) transrepression are associated with suppression of urothelial carcinogenesis. We therefore assessed the effect of a unique compound, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride (Compound A; CpdA), which could function as an AR antagonist as well as a GR ligand, on urothelial tumorigenesis. Using the in vitro system with GR-positive non-neoplastic urothelial SVHUC cells stably expressing AR (SVHUC-AR), neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene (MCA) was inhibited similarly by an anti-androgen hydroxyflutamide and a glucocorticoid prednisone, and more strongly by CpdA. CpdA also prevented the neoplastic transformation of AR-negative MCA-SVHUC cells, which was diminished by a GR antagonist RU486, but failed to prevent that of GR knockdown MCA-SVHUC cells. In MCA-SVHUC-AR cells, CpdA significantly reduced the expression levels of oncogenes (c-Fos/c-Jun/c-Myc) and induced those of tumor suppressors (UGT1A/p21/p27/p53/PTEN). Additionally, a potent carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine induced bladder cancer in all of 8 mock-treated mice versus 4 (50%) of flutamide-treated (P = 0.021), 4 (50%) of prednisone-treated (P = 0.021), or 2 (25%) of CpdA-treated (P = 0.002) animals. Finally, CpdA was found to reduce AR transactivation and selectively induce GR transrepression (i.e. suppression of NF-κB transactivation and expression of its regulated genes), but not GR transactivation (i.e. activation of glucocorticoid-response element-mediated transcription and expression of its targets) in SVHUC cells. These findings suggest that CpdA suppresses urothelial tumorigenesis via both the AR and GR pathways, which may consequently provide an effective option of chemoprevention for bladder cancer, especially in patients with superficial disease following transurethral surgery.

<h4>Background</h4>Perivesical lymph nodes (PVLNs) are occasionally isolated during grossing of cystectomy specimens. However, the prognostic implications of the involvement of PVLNs in bladder cancer patients, especially those with comparisons to pN0 disease, remain poorly understood.<h4>Methods</h4>A retrospective review identified 115 radical cystectomy cases where PVLNs had been histologically assessed. These cases were then divided into 4 groups - Group 1 (n = 76): PVLN-negative/other pelvic lymph node (non-PVLN)-negative; Group 2 (n = 5): PVLN-positive/non-PVLN-negative; Group 3 (n = 17): PVLN-negative/non-PVLN-positive; and Group 4 (n = 17): PVLN-positive/non-PVLN-positive.<h4>Results</h4>pT stage at cystectomy was significantly higher in Group 3 (P = 0.013), Group 4 (P < 0.001), Groups 2 and 4 (P < 0.001), or Groups 2-4 (P < 0.001) than in Group 1. However, the number of positive PVLNs (mean: 1.8 vs. 2.1; P = 0.718) or the rate of extracapsular extension in the PVLNs (40% vs. 65%, P = 0.609) was not significantly different between Group 2 and Group 4. Kaplan-Meier analysis and log-rank test revealed significantly (P < 0.05) higher risks of disease progression (Group 3/Group 4), cancer-specific mortality (Group 2/Group 3/Group 4), and overall mortality (Group 4), compared with Group 1. Multivariate analysis further showed metastasis to both PVLN and non-PVLN (Group 4), PVLN (Groups 2 and 4), or PVLN and/or non-PVLN (Groups 2-4) as an independent prognosticator for cancer-specific mortality and overall survival. There were also insignificant (P = 0.096) and significant (P = 0.036) differences in cancer-specific survival and overall survival, respectively, between Group 3 versus Group 4, and the trend of the latter was confirmed by subset multivariate analysis (hazard ratio = 3.769; P = 0.099).<h4>Conclusions</h4>Worse prognosis was observed in bladder cancer patients with isolated PVLN metastasis (vs. pN0 disease especially for cancer-specific survival), PVLN metastasis with or without non-PVLN metastasis (vs. pN0 disease), and concurrent PVLN and non-PVLN metastases (vs. PVLN-negative/non-PVLN-positive disease especially for overall survival). These findings indicate the importance of thorough histopathological assessment of PVLNs in radical cystectomy specimens.

BACKGROUND: Many elderly men suffer from benign prostatic hyperplasia (BPH). Recently, chronic ischemia in the prostate has been suggested to be related to BPH. Thus, the impact of chronic ischemia on the development of prostatic hyperplasia and the efficacy of phosphodiesterase type 5 (PDE5) inhibitor for hyperplasia were evaluated in a rat model with chronic ischemia induced by local atherosclerosis. METHODS: Eighteen male Sprague-Dawley rats were divided into three groups: sham operation, regular diet, placebo (SRP); arterial endothelial injury, high cholesterol diet, placebo (AHP); or arterial endothelial injury, high cholesterol diet, and tadalafil as a PDE5 inhibitor (AHT). The endothelial injury in the common iliac arteries was performed using a 2-Fr Fogarty arterial embolectomy catheter through an incision in the femoral artery into the common iliac artery. Diet and oral drugs were administrated for 8 weeks after surgery. At 8 weeks, blood flow to the ventral prostate (VP) was measured using laser speckle blood flow analysis, and the VP was histologically evaluated. RESULTS: In the AHP group, prostatic blood flow was reduced, and mean VP weight and the interstitial area were significantly enlarged compared with the SRP group. In the AHT group, tadalafil administration obviously ameliorated the reduction of prostatic blood flow relative to the AHP group. Importantly, mean VP weight and the morphological changes in the AHT group were significantly smaller than those in the AHP group. CONCLUSIONS: Enlargement of the VP resulted from chronic ischemia induced by local arteriosclerosis. Also, administration of tadalafil attenuated VP enlargement. Chronic ischemia in the prostate might thus contribute to the development of BPH, and PDE5 inhibitors might provide an innovative approach to preventing BPH.

OBJECTIVE: To evaluate renal damage after off-clamp partial nephrectomy (PN) using a novel surgical device, piezo actuator-driven pulsed water jet (ADPJ) system. METHODS: Sprague-Dawley rats were divided into 4 groups and subjected to sham operation, off-clamp PN by the piezo ADPJ system, radio knife, and soft coagulation, which have been used as thermal coagulation devices. Urine and blood samples were collected, and residual kidneys were harvested at 1, 7, 14, 30, and 90 days after PN. Serum blood urea nitrogen, creatinine, and urinary and serum kidney injury molecule-1 KIM-1 levels were measured. Morphological features and the extent of renal ischemia of resection surfaces were evaluated by hematoxylin-eosin staining and immunostaining using antibodies to 1-methyladenosine, respectively. In addition, the expression levels of KIM-1 mRNA extracted from each resection surface were analyzed by quantitative real-time reverse transcription polymerase chain reaction. RESULTS: Serum blood urea nitrogen and creatinine were significantly lower with the piezo ADPJ system than with soft coagulation. Urinary and serum KIM-1 levels were also significantly decreased with the ADPJ. The extent of 1-methyladenosine immunostaining was significantly less with the ADPJ than with thermal coagulation devices. The expression levels of KIM-1 mRNA were also lower in the ADPJ system group. CONCLUSION: The piezo ADPJ system might attenuate renal damage after off-clamp PN.

We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.

Prostate cancer patients with initial PSA 100 ng/ml or greater who received transrectal ultrasoundguided prostate biopsy and were staged as M0 by imaging studies from 2011 to 2014 in seven hospitals, were enrolled in the study. Castration-resistant prostate cancer (CRPC)-free survival was compared between the two treatment groups : androgen deprivation therapy (ADT) alone and ADT plus local therapy. Of 142 prostate cancer patients with initial PSA 100 ng/ml or greater, 49 (34.5%) had no metastases and final analysis was performed on 46 patients. Thirty one M0 patients received ADT alone, and 15 received ADT plus local therapy. During follow-up (median 31 months, range 1-56 months) 13 patients (42%) in the ADT alone group progressed to CRPC. One- and two-year CRPC-free survival rates were 72.5 and 53%, respectively. No patients with ADT plus local therapy developed CRPC, and time to CRPC was prolonged significantly (p=0.002). On multivariate analysis for the group with ADT alone, PSA nadir of more than 0. 2 ng/ml and cN1 were independent predictors for progression to CRPC (p=0.009, 0.031). About one third of prostate cancer patients with initial PSA 100 ng/ml or greater had clinically no metastases. Local therapy to prostate combined with ADT may prolong time to CRPC compared with ADT alone. A subset of men with a PSA nadir of more than 0.2 ng/ml after ADT and cN1 could benefit from local therapy.

A 44-year-old man discovered a swollen right testis more than 4 years earlier. He was brought to our hospital because of abdominal pain and vomiting. Enhanced computed tomography (CT) showed a swollen right testis, lung nodules, and swollen retroperitoneal and mediastinal lymph nodes. The swollen lymph nodes compressed the duodenum, causing ileus. HCG, HCG-β, and AFP levels were normal, but the LDH level was high (2,933 IU/L). A diagnosis of testicular cancer with lung and lymph node metastases was made, and a right orchidectomy was performed. However, the pathological diagnosis was unclear, and it was necessary to consult another pathologist, but this took .6 weeks. While awaiting the pathological diagnosis, the patient was given chemotherapy with two 3-week courses of BEP. On pathological examination, the tumor consisted of small round cells with a rosette-like arrangement. Cartilage and keratinized tissues were also present. Immunohistochemical staining was positive for CD56, synaptophysin, vimentin, GFAP, and CD99 (MIC2), but negative for AE1/AE3, OCT-4, chromogranin, INI-1, and desmin. The patient was then diagnosed as having a primitive neuroectodermal tumor and teratoma. The metastatic lymph nodes decreased in size after chemotherapy; therefore, two further courses of BEP were added. However, CT showed disease progression. The patient refused further therapy and returned home. Eight months later, he was hospitalized because of swollen retroperitoneal and mediastinal lymph nodes and ileus. Despite treatment with radiation therapy, which resulted in decreased lymph nodes, the patient died. This was a very rare case, the first such case in Japan.