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The ultrastructure of the nuclear envelope (NE) and redundant NE (RNE) of the spermatozoon cannot be observed in detail using conventional electron microscopy. Thus, this study aimed to employ transmission electron microscopy (TEM) and focused ion beam/scanning electron microscopy (FIB/SEM) tomography to fill this research gap. Male mice aged 13 weeks were deeply anesthetized, and the testes and vas deferens were extracted and processed for electron microscopy. In round spermatids, the acrosomal vesicle compressed the nucleus, and the acrosomal center was depressed. The nucleoli concentrated on the contralateral side of the acrosome formation site. In mature spermatozoa, the RNE accumulated in the neck with the residual bodies. The NE pores exhibited a hexagonal pattern. The body surface area and volume of the nuclei of spermatids and spermatozoa in each maturation phase were analyzed using FIB/SEM tomography. The body surface area and volume of the nuclei decreased during spermatid maturation into spermatozoa. The RNE converged at the sperm neck and possessed a honeycomb structure. The method used revealed that the nuclei of spermatids gradually condense as they mature into spermatozoa. This method may be used to analyze small tissues, such as RNE, and detect morphological abnormalities in microtissues, such as spermatozoa.

Androgen deprivation therapy (ADT) has been widely used for the treatment of advanced prostate cancer. However, prognosis and adverse events vary among patients. This study aimed to identify genetic markers able to predict the outcome of ADT. Japanese patients treated with primary ADT for advanced prostate cancer in the KYUCOG-1401 trial were enrolled as a development set. A distinct population of advanced prostate cancer cases treated with ADT was included as a validation set. Single-nucleotide polymorphisms (SNPs) associated with radiographic progression-free survival (PFS) at 1 year and adverse events including de novo diabetes mellitus, arthralgia, and de novo dyslipidemia were identified in the development set by a genome-wide association study (GWAS). The SNPs associated with radiographic PFS in the development study were then genotyped in the validation set. GWAS followed by validation identified SNPs (rs76237622 in PRR27 and rs117573572 in MTAP) that were associated with overall survival in ADT. A genetic prognostic model using these SNPs showed excellent predictive efficacy for PFS and overall survival in ADT. In addition, GWAS showed that several SNPs were associated with de novo diabetes mellitus, arthralgia, and de novo dyslipidemia in ADT. This study identified novel multiple SNPs that correlated with outcomes in ADT. Future studies on correlations affecting the therapeutic efficacy of ADT-based combination therapies would make a valuable contribution to the development of personalized medicine.

Nivolumab and ipilimumab (NIVO + IPI) is standard therapy for patients with advanced renal cell carcinoma (RCC). Absolute lymphocyte count (ALC) is a valuable prognostic factor in patients with various cancers treated with immune checkpoint inhibitors. Herein, we determined the prognostic value of pretreatment ALC in advanced RCC patients treated with NIVO + IPI as first-line therapy. Data from 46 advanced RCC patients treated with NIVO + IPI between September 2018 and August 2022 were retrospectively reviewed and analyzed. Median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with low than high ALC (PFS: p = 0.0095; OS: p = 0.0182). Multivariate analysis suggested that prior nephrectomy [hazard ratio (HR) = 3.854, 95% confidence interval (CI) = 1.433–10.359, p = 0.0075] and pretreatment ALC (HR = 2.513, 95% CI = 1.119–5.648, p = 0.0257) were independent factors for PFS. Our new prognostic ALNx model based on ALC and prior nephrectomy suggested that the poor-risk group was a predictor of significantly worse PFS (p < 0.0001) and OS (p = 0.0016). Collectively, the developed ALNx model may be a novel predictor of response in advanced RCC patients treated with NIVO + IPI.

Although the sequential use of abiraterone and enzalutamide is not recommended because of possible cross-resistance, many patients with metastatic castration-resistant prostate cancer (mCRPC) are receiving sequential abiraterone and enzalutamide in the real world, and a subset of patients can benefit from sequential therapy with these drugs. This study aimed to identify patients who could benefit from the sequential use of enzalutamide after abiraterone use.We included 70 patients with mCRPC who received enzalutamide sequentially following abiraterone treatment. Decline in the prostatespecific antigen (PSA) levels at 4 weeks after enzalutamide initiation and the association between decline in PSA levels and survival were analyzed.Sixteen men (22.9%) achieved a decline of50% in PSA levels after 4 weeks of enzalutamide administration. Overall survival (OS) after enzalutamide among men with50% decline at 4 weeks was significantly better than that among men with a PSA decline50% (not reached vs. 34 months, p=0.008). OS after first-line abiraterone treatment for men with PSA decline50% and50% was not reached and 46 months, respectively (p=0.007). A PSA decline of50% at 4 weeks of enzalutamide administration was an independent predictor of longer OS.A PSA decline of50% at 4 weeks after the start of sequential enzalutamide treatment following abiraterone treatment predicted long-term survival in patients with mCRPC. Early PSA decline can identify patients who benefit from second-line enzalutamide after abiraterone treatment and can be useful as a decision-making tool regarding treatment.

The aim of this study is to clarify the disibution, shape, and immunohistochemical characteristics of serotonin-immunoreactive neuroendocrine cells (SIR-NECs) in mouse prostate and in the surrounding genital organs by histological and immunohistochemical analysis of the light microscopic serial sections of urethra. We collected lower urinary tracts from 13-week-old mice and observed the distribution pattern and shape of the SIR-NECs by serial light microscopy. The organs on the sections were divided into three anatomical zones to clarify the distribution pattern of SIR-NECs: (1) zone A, the ducts near the prostatic urethra; (2) zone B, the ducts outside the urethral sphincter; and (3) zone C, the acinus areas. Sections were double immune-stained with antibodies against serotonin and one of neuroendocrine-related factors (NRFs), including 10 neural cell markers and eight neurotransmitters, and also 4′,6-diamino-2-phenylindole (DAPI). In addition, SIR-NECs were double immune-stained with antibodies against cytokeratin 5 (CK5) and p63, together with DAPI. SIR-NECs were mostly localized in zone A, and no SIR-NECs were observed in zone C. The proportion of flask-shaped SIR-NECs was approximately 15% in zones A and B. No flask-shaped SIR-NECs were observed in urethral epithelia. The NRFs co-localized with SIR-NEC were calcitonin gene-related peptide, CD56, chromogranin A, neuron-specific enolase, neuron cytoplastic protein 9.5, and synaptophysin (72.3%, 73.2%, 88.9%, 92.3%, 91.7%, and 81.9%, respectively). CK5 and p63 were not co-localized with SIR-NECs. In this study, SIR-NEC of the urethra and the surrounding genital organs was ubiquitous in the urethra and the ducts near the urethra and co-expressed specific nerve-related NRFs.

Objective Programmed cell death-1 antibody therapy has demonstrated improved progression-free survival and overall survival in patients with metastatic renal cell carcinoma. However, there are limited studies on biomarkers that can predict the efficacy of immune checkpoint inhibitors. We examined the influence of peripheral inflammatory biomarkers on the clinical outcomes of patients with metastatic renal cell carcinoma treated with nivolumab. Methods Data of 38 patients with metastatic renal cell carcinoma, who were treated with nivolumab monotherapy after receiving at least one molecular targeted therapy from November 2016 to February 2021, were retrospectively reviewed and analyzed. Results Median progression-free survival and overall survival were significantly shorter in patients with low absolute lymphocyte count ( Conclusion Our study indicates that peripheral absolute lymphocyte count, before nivolumab initiation, is a predictor of poor response in metastatic renal cell carcinoma. Additionally, increased absolute lymphocyte count, 1 month post-nivolumab initiation, can be a predictor of the effects of nivolumab.

Background Pheochromocytoma is a rare tumour producing catecholamines and has been more frequently reported than expected in patients with a Fontan physiology. Case summary The patient was a 39-year-old woman born with a univentricular atrioventricular connection and pulmonary valve stenosis. A Fontan operation was performed when she was 22 years old. At the age of 38, she was diagnosed with pheochromocytoma. The most serious problem was the increased occurrence of supraventricular arrhythmias, which easily caused heart failure. We decided to perform a laparoscopic resection. Postoperative recovery was good. There were no findings of malignancy and all postoperative catecholamine levels normalized. She was discharged home on the 14th day after the surgery, walking unaided. Discussion Diagnosis and treatment by tumour resection in the early phase are crucial in patients who undergo the Fontan procedure. However, patients after Fontan surgery have a very low cardiac reserve. Thus, the decision to perform a surgical treatment is a very difficult one to take. In this case, fenestration had been naturally closed. As fenestration provides a consistent source of systemic ventricular preload, we performed transcatheter fenestration dilatation to improve heart failure management before surgical pheochromocytoma removal. Although laparoscopic surgery is generally considered to be less invasive, pneumoperitoneum may interfere with venous return in Fontan physiology patients. There is also a risk of thrombosis via fenestration. Here, we reported the case of a successful laparoscopic pheochromocytoma resection in an adult Fontan patient.

Objective To report a multicenter experience with the management of urachal abscess treatment in Japan. Methods This was a retrospective study of 263 cases of urachal abscess managed at 12 university hospitals in the Kyushu-Okinawa region over a 10-year period. Age, sex, abscess size, clinical symptoms, type of urachal remnants, and treatment were collected and analyzed. Results The average age was 29.8 ± 18.1 years, with males accounting for approximately two-thirds of the study population. The average abscess size was 1.7 cm (range 0-11 cm). The most common presenting symptom was umbilical secretion (66%), followed by abdominal pain (46%). A total of 127 patients (48.3%) were treated with antibiotics alone, whereas 136 patients (51.7%) received surgical treatment. The surgical approach was laparotomy in 75 patients (61.0%) and laparoscopic surgery in 48 patients (39.0%). Regarding the type of urachal remnant, the urachus sinus (180 patients) accounted for 68.4% of the total. Conclusions To our knowledge, this study represents the first report on urachal abscess treatment in Japan. Our data show that the clinical symptoms might vary depending on the type of urachus remnant. It should be noted that gross hematuria, a characteristic symptom of urachal cancer, is rare in patients with urachal abscess.

Immuno-oncology (IO) combination therapy has become the standard of treatment for advanced renal cell carcinoma (RCC). In this retrospective study, we compared the efficacy of first-line molecular targeted therapy (MTT), administered as monotherapy, and IO combination therapy using real-world data of Japanese patients.The clinical information of 202 patients with RCC who received MTT (n=144) or IO combination therapy (n=58) at the Kurume University Hospital from May 2008 to May 2022 was collected and retrospectively analyzed. The Cox proportional hazards model was used for univariate and multivariate analyses, with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated.The patients treated with IO combination therapy had a prolonged progression-free survival (PFS) compared with those treated with MTT (p=0.0038). IO combination therapy was significantly associated with a better PFS in patients with intermediate (p=0.0072) and poor risk (p=0.0411) but not in those with favorable risk (p=0.5434). Furthermore, overall survival with IO combination therapy was significantly better in patients at poor risk (p=0.0335). Multivariate analyses suggested that prior nephrectomy (HR=1.501, 95%CI=1.048-2.150, p=0.0268) and first-line therapy (HR=1.962, 95%CI=1.288-2.986, p=0.0017) were independent prognostic factors for PFS.IO combination therapy significantly improved the PFS of patients with advanced RCC, especially those with intermediate- and poor-risk disease. Further investigations focusing on the improvement of survival are warranted.

To evaluate the effects of sarcopenia and excess visceral fat accumulation on early urinary function after I-125 low-dose-rate brachytherapy for prostate cancer.We retrospectively reviewed consecutive patients who underwent brachytherapy for prostate cancer. Pre-treatment computed tomography was used to measure skeletal muscle index at the L3 level to assess sarcopenia and visceral fat area at the umbilical level. The International Prostate Symptom Score and the University of California Los Angeles Prostate Cancer Index were used to assess quality of life during the 24 months after brachytherapy. Logistic regression analysis was used to examine whether sarcopenia and excess visceral fat accumulation had clinically significant effects on post-treatment quality of life.Among 246 patients, 92 (37.4%) were stratified into the sarcopenia group and 141 (57.3%) into the excess visceral fat accumulation group. The sarcopenia group had significantly lower University of California Los Angeles Prostate Cancer Index urinary function than the non-sarcopenia group 24 months post-brachytherapy. The excess visceral fat accumulation group had significantly poorer International Prostate Symptom Score total, storage, and voiding scores than the non-excess accumulation group 12 months post-brachytherapy. In the multivariate analysis, sarcopenia had a clinically significant adverse effect on the University of California Los Angeles Prostate Cancer Index urinary function at 12 months. Excess visceral fat accumulation had a clinically significant adverse effect on the International Prostate Symptom Score voiding and storage scores at 12 months.Sarcopenia and excess visceral fat accumulation negatively affect urinary function early after I-125 low-dose-rate brachytherapy for prostate cancer.

Introduction Paraganglioma of the urinary bladder is a very rare disease accounting for 0.06% of all bladder tumors. Owing to their rarity and symptomatic variability, preoperative diagnosis is often difficult. Case presentation A 70-year-old male was referred to our department for hematuria. Cystoscopy showed a non-papillary broad-based tumor. Computed tomography and magnetic resonance imaging revealed a 32-mm bladder tumor at the top of the bladder, which suggested muscle-invasive bladder tumor. We diagnosed muscle-invasive bladder cancer or urachal carcinoma, and transurethral resection of the bladder tumor was performed. At the initiation of transurethral resection of the bladder tumor, the systolic blood pressure was elevated to over 200 mmHg. The pathological findings revealed paraganglioma of the urinary bladder, and afterward, a partial cystectomy was performed. Conclusion We herein reported the case of paraganglioma in the bladder whose blood pressure became extremely elevated during transurethral resection of the bladder tumor. In addition, we analyzed important factors for preoperative diagnosis using 162 cases reported in Japan.

BACKGROUND/AIM The present study examined the impact of systemic inflammatory markers including C-reactive protein (CRP)/Albumin (Alb) and neutrophil lymphocyte ratio (NLR)/Alb on the prognosis of patients treated with first line molecular targeted therapy for advanced RCC. PATIENTS AND METHODS A total of 131 patients with advanced RCC treated with molecular targeted therapy as first line treatment from May 2008 to April 2019 were retrospectively analyzed. RESULTS High CRP, high NLR, low Alb and high CRP/Alb showed significantly worse progression-free survival (PFS) and overall survival (OS) than low CRP, low NLR, high Alb, low CRP/Alb and low NLR/Alb, respectively. In multivariate analyses, prior nephrectomy (p=0.0321) and NLR/Alb ratio (p=0.0327) were independent prognostic factors for PFS. Furthermore, prior nephrectomy (p=0.0013) and CRP/Alb ratio (p=0.0020) were independent prognostic factors for OS. CONCLUSION CRP/Alb and NLR/Alb ratios are useful and independent prognostic biomarkers in patients with advanced RCC treated with molecular targeted therapy.

The smooth muscle contraction of the vas deferens has the important function of transporting sperm. Interstitial cells (ICs) play a critical role in the pacing and modulation of various smooth muscle organs by interactions with nerves and smooth muscle. Elucidating the three-dimensional (3D) architecture of ICs is important for understanding their spatial relationship on the mesoscale between ICs, smooth muscle cells (SMCs), and nerves. In this study, the 3D ultrastructure of ICs in the smooth muscle layer of murine vas deferens and the spatial relationships between ICs, nerves, and smooth muscles were observed using confocal laser scanning microscopy and focused ion beam/scanning electron microscopy. ICs have sheet-like structures as demonstrated by 3D observation using modern analytical techniques. Sheet-like ICs have two types of 3D structures, one flattened and the other curled. Multiple extracellular vesicle (EV)-like structures were frequently observed in ICs. Various spatial relations were observed in areas between ICs, nerves, and SMCs, which formed a complex 3D network with each other. These results suggest that ICs in the smooth muscle layer of murine vas deferens may have two subtypes with different sheet-like structures and may be involved in neuromuscular signal transmission via physical interaction and EVs.

To analyze the risks and survival outcomes of non-definitive therapy (nDT) for muscle-invasive bladder cancer (MIBC), which may provide useful information for future treatment selection, the present study analyzed 124 patients who were diagnosed with MIBC (cT2-4aN1-2M0) and treated at Kurume University Hospital (Kurume, Japan) with definitive therapy (DT; including radical cystectomy and trimodal therapy) or nDT [transurethral resection of bladder tumor (TURBT) monotherapy or TURBT plus chemotherapy]. Differences in survival outcomes between the two groups were estimated using the Kaplan-Meier method and analyzed using the log-rank test. Cox proportional hazards regression models were used for multivariate analysis of each survival outcome. Of the 124 patients, 45% were treated with nDT, and among these, 50% were treated with TURBT monotherapy and 50% were treated with TURBT plus chemotherapy. Of the patients who chose definitive treatment, 69% were treated with radical cystectomy. The median age in the nDT group was 77 years, which was significantly higher than that in the DT group. Additionally, the proportion of patients with poor performance status, high Charlson comorbidity index and high neutrophil-lymphocyte ratio values was significantly higher in the nDT group. nDT was associated with significantly reduced overall survival, cancer-specific survival and progression-free survival rates, and was a poor prognostic factor for all survival outcomes compared with DT. In conclusion, nDT was associated with a high cancer-related mortality risk. The most appropriate treatment method should be discussed with the patients after providing them with sufficient information on the risks and benefits of each treatment method.

Background/aim Therapeutic targeting of receptor protein tyrosine kinases (PTKs) has proven successful in treating cancer. However, reports about PTKs in treating prostate cancer are few. Elevated expression of the erythropoietin-producing hepatocellular receptor A2 (EPHA2) receptor tyrosine kinase, a transmembrane protein, is associated with poor prognosis of certain cancer types when the enzyme is dephosphorylated. This study investigated whether EPHA2 is useful in predicting the biochemical recurrence of prostate cancer. Patients and methods Data from 241 patients who had undergone total prostatectomy between 2007 and 2011 were used. EPHA2 protein expression was categorized as high or low by two pathologists. The relationship was examined between EPHA2 expression level (high vs. low) and clinicopathological factors including biochemical recurrence. Correlations were examined between EPHA2, low-molecular-weight protein tyrosine phosphatase (LMW-PTP), E-cadherin, and Ki-67. Results EPHA2 expression was high in 121 (50.2%) and low in 120 (49.8%) patients. A log-rank test revealed early biochemical recurrence in the high-expression group. Gleason score, Ki-67 labeling index, and biochemical recurrence were more frequent in the high-expression group. Furthermore, multivariate analyses revealed that high EPHA2 expression was an independent prognostic factor for biochemical recurrence (hazard ratio=3.62, 95% confidence interval=2.39-5.61). Correlations between EPHA2 and both LMW-PTP and Ki-67 labeling index were positive, whereas EPHA2 and E-cadherin were negatively correlated. Conclusion EPHA2 overexpression is predictive of aggressive prostate cancer behavior. EPHA2 may be a powerful prognostic biomarker for decision-making in postoperative follow-up after total prostatectomy, and regarding the need for palliative treatment. Additionally, it may be an important therapeutic target.

Background/aim The present study aimed to examine the influence of antibiotics (AB) on the clinical outcomes of Japanese patients treated with immune check point inhibitors (ICIs) for metastatic renal cell carcinoma (RCC) patients. Patients and methods A total of 31 patients with metastatic RCC treated with ICIs from November 2016 to April 2019 were retrospectively reviewed and analyzed. Results Five patients were treated with AB prior to ICIs treatment. Median progression free survival (PFS) of patients treated with AB vs. patients not treated with AB was 2.8 months and 18.4 months, respectively. The difference between PFS was statistically significant (p=0.0004). In multivariate analyses, AB use (p=0.0377) and presence of immune related adverse events (p=0.0042) were independent prognostic factors for PFS in association with ICIs therapy. Conclusion The use of AB before ICIs treatment was a predictor of poor ICIs response in metastatic RCC.

BACKGROUND/AIM For prostate cancer, positive surgical margins are considered an important predictor of biochemical recurrence. However, biochemical recurrence is observed in approximately 20% of cases, even with negative surgical margins, and some cases require salvage therapy. The elevated expression of low-molecular-weight protein tyrosine phosphatase (LMW-PTP, MW 18 kDa) is associated with a poor prognosis of certain cancers. In this study, we investigated whether the LMW-PTP expression levels could be used as a biomarker of recurrence in prostate cancer with negative surgical margins. MATERIALS AND METHODS The subjects of this retrospective study were 119 patients who underwent total prostatectomy with negative resection margins. LMW-PTP expression was categorized either as a high-expression group or as a low-expression group bye two pathologists. Subsequently, we examined the relationship between LMW-PTP expression levels and clinicopathological factors including biochemical recurrence. RESULTS Evaluation of the immunostained samples by two pathologists was highly reliable, with an Intraclass correlation (ICC) score for two distinct measurements of 0.77 and 0.98, respectively. Seventy-three patients (61.3%) were placed in the LMW-PTP high expression group; and 46 patients (38.7%) were placed in the low expression group. The log-rank test revealed early biochemical recurrence in the high LMW-PTP expression group (p=0.0001). In addition, pathological T stage (p=0.004), lymphatic invasion (p=0.0456), Ki-67 labeling index (p=0.0002), and biochemical recurrence (p

Sulfite oxidase (SUOX) is a metalloenzyme that plays a role in ATP synthesis via oxidative phosphorylation in mitochondria and has been reported to also be involved in the invasion and differentiation capacities of tumor cells. Here, we performed a clinicopathological investigation of SUOX expression in prostate cancer and discussed the usefulness of SUOX expression as a predictor of biochemical recurrence following surgical treatment in prostate cancer. This study was conducted using Tissue Micro Array specimens obtained from 97 patients who underwent radical prostatectomy at our hospital between 2007 and 2011. SUOX staining was used to evaluate cytoplasmic SUOX expression. In the high-expression group, the early biochemical recurrence was significantly more frequent than in the low-expression group (p = 0.0008). In multivariate analysis, high SUOX expression was found to serve as an independent prognostic factor of biochemical recurrence (hazard ratio = 2.33, 95% confidence interval = 1.32-4.15, p = 0.0037). In addition, Ki-67-labeling indices were significantly higher in the high-expression group than in the low-expression group (p = 0.0058). Therefore, SUOX expression may be a powerful prognostic biomarker for decision-making in postoperative follow-up after total prostatectomy and with regard to the need for relief treatment.

Objectives: To evaluate the management and outcome of idiopathic retroperitoneal fibrosis (iRPF) in Japan, and identify its clinical biomarker. Methods: We retrospectively analyzed 129 patients with iRPF treated between January 2008 and May 2018 at 12 university and related hospitals. Patients treated with glucocorticoid were analyzed to identify a predictive biomarker. These patients were classified into three groups according to overall effectiveness (no change: NC, complete response: CR and partial response groups: PR), and each parameter was compared statistically.Results: Male-female ratio was 5: 1, and median age at diagnosis was 69 (33-86) years. Smoking history was reported in 59.6% of the patients. As treatment, 95 patients received glucocorticoid therapy with an overall response rate of 84%. As a result, serum concentration of IgG4 was significantly decreased in NC group compared with the other two groups (56.6mg/dL vs 255mg/dL, 206mg/dL, P=0.0059 and 0.0078). ROC analysis was performed between the non-responder (NC) and responder groups (CR+PR) to identify the cut-off value of serum IgG4 as a predictive marker. As a result, AUC was 0.793 and the values of sensitivity and specificity were 0.85 and 0.64, respectively, under the cut-off values of 67.6mg/dL. Conclusions: In the majority of iRPF patients, glucocorticoid therapy resulted in a favorable response. Pre-treatment serum IgG4 concentration may have potential as a predictive biomarker of steroid treatment.

Introduction The incidence of prostate cancer in Japan continues to increase, necessitating the continued development of effective therapies and strategies. Recent advances in treatments have improved the prognosis of metastatic disease and highlighted the importance of treating bone metastases to reduce the incidence of skeletal complications and improve patients’ quality of life. With the increasing number of treatment options that have become available, including bone-targeted therapy with the alpha emitter radium-223 dichloride (Ra-223), Japanese clinicians are faced with making difficult decisions on the choice of optimal treatment strategy. In such situations, guidance based on expert opinions can be beneficial. Methods A panel meeting of 27 Japanese experts in the management of prostate cancer was held to share opinions and to establish consensus recommendations on key clinical questions. Panelists were asked to vote on more than 40 questions pertinent to prostate cancer, and the answers helped guide a comprehensive discussion. Results The panel reached a consensus on key topics related to the optimal treatment strategy for Ra-223 therapy, namely, that patients with symptomatic, metastatic castration-resistant prostate cancer (CRPC) would benefit most from the use of this agent and that this treatment therapy should be provided before chemotherapy. Other topics that achieved consensus included: monitoring for osteoporosis and providing treatment if necessary during androgen deprivation therapy; performing magnetic resonance imaging in the presence of discrepancies in bone scintigram and computed tomography scans; monitoring alkaline phosphatase during CRPC treatment; using osteoclast-targeting in patients with CRPC with bone metastases; and using osteoclast-targeted agents combined with Ra-223. Conclusion These consensus recommendations and the updated information which became available subsequent to the panel meeting included here provide useful information for clinicians to aid in designing optimal treatment strategies for their patients. Funding Bayer Yakuhin Ltd. Electronic supplementary material The online version of this article (10.1007/s40487-018-0088-0) contains supplementary material, which is available to authorized users.

Smooth muscle contraction of the epididymis plays an important role in sperm transport. Although PDGFRα-positive interstitial cells (PDGFRα (+) ICs) are thought to be involved in controlling smooth muscle movement via intercellular signaling, they have not yet been reported to date in the epididymis. Therefore, we aimed to investigate the morphological characteristics of PDGFRα (+) ICs in the interstitial space of the murine epididymis. Immunohistochemistry showed that PDGFRα (+) ICs co-labeled with CD34 (PDGFRα (+) CD34 (+) ICs were distributed in the interstitial space of the murine epididymis from the initial segment (IS) to the cauda of the epididymis. PDGFRα (+) ICs that were not co-labeled with CD34 (PDGFRα (+) CD34 (-) ICs) were observed just beneath the epithelium from the corpus to the cauda but not in the IS. Both types of PDGFRα (+) ICs were in close proximity to each other as well as the surrounding nerves and macrophages. In addition, PDGFRα (+) CD34 (-) ICs beneath the epithelium were also in close proximity to the basal cells. Using transmission electron microscopy, we identified ICs that possessed elongated and woven cellular processes and were in close proximity to each other, surrounding the cells in the interstitial space. In the murine epididymis, it is suggested that there are two subtypes of ICs that show different distribution patterns depending on the segment, which may reflect segmental differences in mechanisms of sperm transport, forming a cellular network by physical interactions in the murine epididymis.

The aim of this study is to clarify the disibution, shape, and immunohistochemical characteristics of serotonin-immunoreactive neuroendocrine cells (SIR-NECs) in mouse prostate and in the surrounding genital organs by histological and immunohistochemical analysis of the light microscopic serial sections of urethra. We collected lower urinary tracts from 13-week-old mice and observed the distribution pattern and shape of the SIR-NECs by serial light microscopy. The organs on the sections were divided into three anatomical zones to clarify the distribution pattern of SIR-NECs: (1) zone A, the ducts near the prostatic urethra; (2) zone B, the ducts outside the urethral sphincter; and (3) zone C, the acinus areas. Sections were double immune-stained with antibodies against serotonin and one of neuroendocrine-related factors (NRFs), including 10 neural cell markers and eight neurotransmitters, and also 4',6-diamino-2-phenylindole (DAPI). In addition, SIR-NECs were double immune-stained with antibodies against cytokeratin 5 (CK5) and p63, together with DAPI. SIR-NECs were mostly localized in zone A, and no SIR-NECs were observed in zone C. The proportion of flask-shaped SIR-NECs was approximately 15% in zones A and B. No flask-shaped SIR-NECs were observed in urethral epithelia. The NRFs co-localized with SIR-NEC were calcitonin gene-related peptide, CD56, chromogranin A, neuron-specific enolase, neuron cytoplastic protein 9.5, and synaptophysin (72.3%, 73.2%, 88.9%, 92.3%, 91.7%, and 81.9%, respectively). CK5 and p63 were not co-localized with SIR-NECs. In this study, SIR-NEC of the urethra and the surrounding genital organs was ubiquitous in the urethra and the ducts near the urethra and co-expressed specific nerve-related NRFs.

Synchronous occurrence of triple primary cancers of urinary tract is quite rare and represents a difficult treatment challenge. Here, we report a case of a 78-year-old man with synchronous renal cell carcinoma, urothelial carcinoma of urinary bladder and adenocarcinoma of prostate within a short period. To the best of our knowledge, this is the 20th reported of triple primary cancers of urinary tract and the first synchronous case with bone metastasis in the literature.

Although numerous studies have reported that a positive surgical margin (PSM) is the most important predictive factor for biochemical recurrence (BCR) of prostate cancer (PCa), only a small number of studies have evaluated the predictive value of the Gleason score (GS) of the tumor at the margin in radical prostatectomy (RP). The present study aimed to investigate the preoperative factors that predict PSM and the significant predictive factors for BCR in cases with PSM. In addition, it was examined whether documenting the GS of the tumor at the margin in pathological reports is useful as a predictive factor for BCR. Data of 241 patients with PCa who underwent RP at Kurume University Hospital (Kurume, Japan) between January 2007 and December 2011 were retrospectively reviewed. The median follow-up period was 72 months and 122 patients had at least one PSM. The time to BCR was significantly shorter in patients with PSM than in those with a negative surgical margin. Multivariate analysis demonstrated that10 ng/ml prostate-specific antigen at diagnosis (P=0.024) and25% positive core at biopsy (P=0.041) were independent prognostic preoperative factors for PSM. The GS of the tumor at the margin was equal, lower and higher than those of the main tumor in 74 (60.7%), 16 (13.1%) and 32 (26.2%) RPs, respectively. The BCR rates were 35.7, 55.1 and 82.1% in patients whose GS of the tumor at the margin was 6, 7 and 8-10, respectively (P=0.0017). The GS of the tumor at the PSM (P=0.038) and anatomic location of the PSM (P=0.04) were identified as independent prognostic preoperative factors for BCR, whereas the GS of the main tumor and margin length were not. These results suggest that documenting the GS at the margin in pathological reports is useful as a predictive factor for BCR.

Purpose Prostate cancer with median lobe hyperplasia (MLH) is a relative contraindication for permanent prostate brachytherapy (PPB) because of an increased risk of post-implant dysuria and technical difficulties associated with achieving stability while implanting within the intravesical tissue. We examined treatment outcome, seed migration, and urination disorders after treatment in MLH patients in order to determine to what degree MLH implants could be stabilized. Material and methods Between March 2007 and December 2016, 32 patients had MLH identified radiologically on magnetic resonance imaging, and 193 patients did not have MLH (non-MLH). All patients were treated with loose seeds. In this study, seed migration was defined as a seed distant from the target (≥ 1.5 cm) and/or with no dosimetric contribution to the target. The MLH patients were divided into 2 MLH groups of mild (< 10 mm) and severe (≥ 10 mm) MLH by measuring the distance between the posterior transitional zone and the prostatic tissue protruding into the bladder. We retrospectively analyzed seed migration, dose-volume histograms (DVH), and genitourinary toxicity. Results MLH was classified as mild in 24 patients and severe in 8. Seed migration occurred in 61 (31.6%) of 193 non-MLH patients and 10 (31.5%) of 32 MLH patients. Implant seed migration and low-dose level of median lobe tended to be high in severe MLH cases. International Prostate Symptom Score (IPSS) peaked one month after implantation, but then resolved slowly and returned to around the pre-treatment level after one year. There were no severe complications. Conclusions MLH does not appear to be a strong contraindication for low-dose-rate brachytherapy. However, we found that the seed migration and degree of cold spots tended to be higher in severe MLH cases than in others; therefore, close attention when treating severe MLH cases must be paid.

99 Background: To investigate a clinical response of GnRH antagonist monotherapy against CAB therapy for mHSPC. Methods: Histopathological confirmed mHSPC patients were randomly assigned to GnRH antagonist monotherapy group (Group A) and CAB group (Group B). A deferred CAB therapy by adding bicalutamide to GnRH antagonist was performed in Group A after PSA progression. The primary endpoint was PSA progression free survival (PSA-PFS). The secondary endpoints were time to CAB treatment failure (CAB-TTF), radiographic progression free survival (rPFS), overall survival (OS), change of PSA, effect on hormone dynamics, change of bone metabolic markers, effect on lipid metabolism, adverse events (AE). This trial was registered with UMIN-CTR (UMIN000014243). Results: A total of 200 patients (101 patients in Group A and 99 in Group B) were registered from June 2014 to June 2017. The PSA-PFS was significantly better in Group B (HR (95% CI) =1.40 (1.01-1.95), p=0.041) as shown in the table. Time to CAB treatment failure (TTF) tended to be better in Group A, but there was no statistically significant difference in CAB-TTF between two groups (Table). rPFS and OS were also not statistically significant difference (Table). Time to PSA nadir was significantly shorter in Group B (HR (95% CI) = 0.72 (0.54 - 0.97), p = 0.028). The proportion of patients whose serum testosterone did not reach or maintain the castration level was more frequent in Group A (significant difference at 60 weeks, p = 0.046). There was no significant difference in the effect of bone metabolic markers and lipid metabolism between two groups. In terms of AE, injection-site-reaction was more frequent in Group A. Conclusions: LH-RH agonist CAB therapy (Group B) prolonged PSA-PFS compared to LH-RH antagonist monotherapy (Group A), probably due to the higher frequency of insufficient achievement of castration level in Group A. However, a deferred CAB therapy by adding bicalutamide to GnRH antagonist resulted in no difference in CAB-TTF, rPFS and OS. Clinical trial information: UMIN000014243.[Table: see text]

Aim To investigate prognostic factors for patients with advanced renal cell carcinoma (RCC) treated with axitinib as second-line therapy. Patients and methods This study included 35 patients with RCC who received axitinib as second-line therapy after the failure of first-line tyrosine kinases inhibitor from November 2012 to March 2017. Results In univariate analyses, the following factors were associated with poor prognosis: bone and extrapulmonary metastasis for progression-free survival; and prior nephrectomy, Memorial Sloan Kettering Cancer Center risk classification, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification of poor, extrapulmonary metastasis and early tumor response for overall survival. Multivariate analyses identified the following factors as independent poor prognostic effects: extrapulmonary metastasis for progression-free survival, and no prior nephrectomy, IMDC risk classification of poor and extrapulmonary metastasis for overall survival. Conclusion Axitinib as second-line treatment is effective for patients with pulmonary metastasis alone of RCC, but not for those with extrapulmonary metastasis.

Localisation of platelet-derived growth factor receptor-α (PDGFRα) (+) cells expressing small-conductance Ca 2+ -activated K + (SK3) channels in the urinary bladder was investigated, while putative roles of SK3 (+) PDGFRα (+) cells in suppressing detrusor smooth muscle (DSM) spontaneous activity were explored. In guinea-pig bladder, immunohistochemistry for SK3 channels, PDGFRα or vimentin was examined, as were the effects of purinergic agonists on spontaneous phasic contractions (SPCs). In bladder of PDGFRα-GFP mice, the effects of purinergic agonists on intracellular Ca 2+ signaling in PDGFRα (+) cells or DSM cells in situ and SPCs were investigated. SK3 (+) cells co-expressing PDGFRα or vimentin were distributed in DSM bundles but not inter-bundle spaces or lamina propria. SK3 (+) cells had a stellate- or spindle-shape cell body extending processes. MRS2365 (100 nM or 1 μM), a P2Y 1 agonist, caused a transient contraction without inhibiting SPCs in both DSM and lamina propria. In PDGFRα-GFP mice bladder, MRS2365, (100 nM), ADP (100 μM) or ATP (100 μM) increased the Ca 2+ level of PDGFRα (+) cells without suppressing spontaneous Ca 2+ transients in neighboring DSM cells, and also failed to suppress SPCs. Preferential localisation of SK3 positive PDGFRα (+) cells in DSM bundles appears to indicate their functional interaction with DSM cells. However, increases in Ca 2+ level of PDGFRα (+) cells upon purinergic stimulation are not associated with the inhibition of Ca 2+ or contractile activity in DSM cells. Thus, it is unlikely that the SK3-dependent hyperpolarisation generated in SK3 expressing PDGFRα (+) cells is transmitted to DSMs to suppress their excitability.

Lymphoma of the urinary bladder is uncommon, and upper urinary tract obstruction due to lymphoma is rare. Herein, we report a case of malignant lymphoma of the bladder with bilateral hydronephrosis in a 67-year-old female who presented with oliguria. Ultrasonography and computed tomography demonstrated a thickened posterior bladder wall and bilateral hydronephrosis. Whole-body positron emission tomography–computed tomography revealed abnormal accumulation in the right iliac internal lymph nodes. Trans-urethral bladder biopsy led to a histopathological diagnosis of non-Hodgkin diffuse large B-cell malignant lymphoma of the bladder. After bilateral nephrostomy, the patient was treated with six cycles of combination chemotherapy including rituximab, cyclophosphamide, daunorubicin, vincristine, and prednisolone (R-CHOP) and two cycles of rituximab alone. Complete remission was maintained during the 3 years of follow-up.