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In Japanese clinical practice, more patients with high-risk metastatic hormone-naïve prostate cancer receive androgen deprivation therapy (ADT) plus androgen receptor signalling inhibitors or docetaxel than those receiving ADT alone or combined androgen blockade, the former of which was associated with a more favourable prostate-specific antigen response rate and better progression-free survival, time to castrate-resistant prostate cancer, and overall survival.

Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study evaluating pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC). Results from cohorts 4 (C4) and 5 (C5) are presented. Methods: Eligible patients had not received chemotherapy for mCRPC and had responded to enzalutamide prior to developing resistance as defined by Prostate Cancer Clinical Trials Working Group 3 guidelines. Patients with RECIST-measurable disease were enrolled in C4, and patients with bone-only or bone-predominant disease were enrolled in C5. All patients received pembrolizumab 200 mg every 3 weeks for ≤35 cycles with ongoing enzalutamide until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review in C4. Secondary end points included disease control rate (DCR), overall survival, and safety in each cohort and both cohorts combined. Results: A total of 126 patients were treated (C4, n= 81; C5, n= 45). Median age was 72 years (range 43–92), and 87.3% had received ≥6 months of enzalutamide prior to study entry. Confirmed ORR was 12.3% (95% CI 6.1–21.5%) for C4. Median duration of response in C4 was 8.1 months (range, 2.5+ to 15.2), and 5 of these patients experienced an objective response lasting ≥6 months. DCR was 53.1% (95% CI 41.7–64.3%) in C4 and 51.1% (95% CI 35.8–66.3%) in C5. Median overall survival was 17.6 months (95% CI 14.0–22.6) in C4 and 20.8 months (95% CI 14.1–28.9) in C5. Grade ≥3 treatment-related adverse events occurred in 35 patients (27.8%); 2 patients in C4 died from immune-related adverse events (myasthenic syndrome and Guillain-Barré syndrome). Conclusions: The addition of pembrolizumab to ongoing enzalutamide treatment in patients with mCRPC that progressed on enzalutamide after initial response demonstrated modest antitumor activity with a manageable safety profile. Clinical trial registry and ID: ClinicalTrials.gov, NCT02787005.

Background: The phase III SPARTAN study demonstrated that apalutamide significantly improves metastasis-free survival and overall survival vs. placebo in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). However, patients receiving apalutamide experienced falls more frequently vs. those receiving placebo (15.6% vs. 9.0%). Methods: 806 patients with nmCRPC randomized to apalutamide in SPARTAN and treated with apalutamide in addition to ongoing androgen deprivation therapy (ADT) were included in this post-hoc analysis investigating clinical variables associated with a subsequent fall. Time to a fall was assessed with Cox proportional-hazards models adjusted for baseline characteristics and time-varying factors. Statistical inference was based on final multivariable models. Results: Falls were reported for 125/803 (15.6%) patients treated with apalutamide and ADT. Most falls were grade 1 or 2 and did not require hospitalization. Median time from randomization to first fall was 9.2 months (range 0.1–25.3 months). In the final multivariable model of both baseline and after-baseline covariates, baseline patient characteristics (older age, poor Eastern Cooperative Oncology Group performance status, history of neuropathy, and α-blocker use before study treatment) remained significantly associated with fall; after-baseline clinical characteristics significantly associated with time to fall were development of neuropathy, arthralgia, and weight loss before fall. Conclusions: This analysis identified risk factors for fall among nmCRPC patients treated with apalutamide. Clinical management can minimize these identified risks while enhancing patient outcomes. Preventive interventions should be considered when the identified baseline conditions and post-treatment neuropathy, arthralgia, or weight decrease are present, to reduce risk of fall. Trial registration: ClinicalTrials.gov: NCT01946204

Olaparib plus abiraterone has a manageable and predictable safety profile, allowingthe majority of patients to remain on treatment while continuing to receive clinical benefit. Anaemia was the most common adverse event, managed primarily by supportive measures and olaparib dose modification.

In the global Phase-3 Selective Prostate Androgen Receptor Targeting with ARN-509 study, apalutamide plus ongoing androgen deprivation therapy (ADT) significantly increased metastasis-free survival (MFS) and improved other clinical outcomes in men with nonmetastatic castration-resistant prostate cancer (nm-CRPC) who were at high risk of developing metastases. In this subpopulation analysis of Selective Prostate Androgen Receptor Targeting with ARN-509 study, the efficacy and safety of apalutamide plus ADT were evaluated in Japanese patients with nm-CRPC.

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. 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. 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. 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. Bayer Yakuhin Ltd.

The retrospective analysis was conducted to compare the clinical outcomes between abiraterone (AA) followed by enzalutamide (ENZA) (AA-ENZA) and the converse (ENZA-AA) sequential treatment in chemotherapy-naive patients with metatstatic castration-resistant prostate cancer. With the exception of the second line prostate-specific antigen response, there was no significant difference in clinical outcomes including combined progression-free survival and overall survival between the AA-ENZA and ENZA-AA groups.

The best sequence between androgen receptor targeted agents (ARTAs) and docetaxel (DTX) for metastatic castration-resistant prostate cancer (mCRPC) is still unclear. The retrospective analysis was conducted to compare the outcomes between ARTA-ARTA and ARTA-DTX sequential treatment in chemotherapy-naive mCRPC patients. The favorable outcome in the ARTA-DTX sequence compared with ARTA-ARTA was observed in the second-line and combined progression-free survival, but not in overall survival.

We retrospectively assessed the bone scan index as a predictor of overall survival in patients with metastatic castration-resistant prostate cancer treated with enzalutamide or abiraterone acetate. Improved bone scan index after these treatments independently predicted longer overall survival.

To investigate the relationship between the Sperm Motility Index and the presence of reactive oxygen species in semen.

The present multicenter retrospective analysis was conducted to reveal the incidence and clinical outcomes of prostate-specific antigen (PSA) flare by abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). The data from 83 patients were analyzed. Using the various definitions of PSA flare, the incidence ranged from 6.0% to 10.8%. Thus, PSA flare is not a reliable sign of disease progression, and abiraterone acetate should not be withdrawn prematurely in patients with mCRPC.

The first indwelling ureteral splint was described in 1967. A ureteral stent can cause unpleasant side effects, such as urinary frequency, urgency, incontinence, hematuria, bladder pain and flank pain, which have a negative impact on a patient’s quality of life. It is necessary to minimize the amount of material in the bladder in order to decrease stent-related symptoms. This study investigated the stent-related symptoms after changing from a double pigtail to a loop-type ureteral stent in the same patient group. This study followed 25 patients who underwent ureteral stent exchange from double pigtail to loop-type ureteral stent between September 2009 and February 2010. Ureteral stents were exchanged using topical, conscious sedation and general anesthesia for the various procedures including stent exchange, before/after shock wave lithotripsy and before/after ureteroscopy. The stent length was selected to be the same as whole ureteral length and the caliber based on the previous stent. A self-administered stent-related symptom questionnaire was used to assess stent-related symptoms in comparison to the previous double-pigtail stents. A total of 25 patients with a median age of 56.5 years underwent ureteral stent exchange. All patients had stone disease except two patients who had ureteral stricture. Almost all of stent-related symptoms without nocturia showed a significantly lower score with the loop-type ureteral stent than in double-pigtail stent. None of the patients experienced urinary tract infection either before or after undergoing ureteral stent exchange. Changing to loop-type ureteral stent significantly decreased ureteral stent-related symptoms.The first indwelling ureteral splint was described in 1967. A ureteral stent can cause unpleasant side effects, such as urinary frequency, urgency, incontinence, hematuria, bladder pain and flank pain, which have a negative impact on a patient’s quality of life. It is necessary to minimize the amount of material in the bladder in order to decrease stent-related symptoms. This study investigated the stent-related symptoms after changing from a double pigtail to a loop-type ureteral stent in the same patient group. This study followed 25 patients who underwent ureteral stent exchange from double pigtail to loop-type ureteral stent between September 2009 and February 2010. Ureteral stents were exchanged using topical, conscious sedation and general anesthesia for the various procedures including stent exchange, before/after shock wave lithotripsy and before/after ureteroscopy. The stent length was selected to be the same as whole ureteral length and the caliber based on the previous stent. A self-administered stent-related symptom questionnaire was used to assess stent-related symptoms in comparison to the previous double-pigtail stents. A total of 25 patients with a median age of 56.5 years underwent ureteral stent exchange. All patients had stone disease except two patients who had ureteral stricture. Almost all of stent-related symptoms without nocturia showed a significantly lower score with the loop-type ureteral stent than in double-pigtail stent. None of the patients experienced urinary tract infection either before or after undergoing ureteral stent exchange. Changing to loop-type ureteral stent significantly decreased ureteral stent-related symptoms.

Abstract: Angiotensin II (Ang-II) plays a key role as a vasoconstrictor in controlling blood pressure and electrolyte/fluid homeostasis. Recently it has also been shown that this peptide is a cytokine, acting as a growth factor in cardiovascular and stromal cells. In addition, the physiological function of Ang-II seems to be similar in prostate cancer and stromal cells. It is widely assumed that Ang-II facilitates the growth of both cells, and its receptor blockers (ARBs) have the potential to inhibit the growth of various cancer cells and tumors through the Ang-II receptor type 1 (AT1 receptor). The mechanism of cell growth inhibition by ARBs has been considered to be that of suppression of the signal transduction systems activated by growth factors or cytokines in prostate cancer cells, and suppression of angiogenesis. This review highlights the possible use of ARBs as novel agents for prostatic diseases including prostate cancer and benign hypertrophy, and covers related literature.

It is known that the renin-angiotensin system (RAS) plays a fundamental role not only as a vasoconstrictor incontrolling blood pressure and electrolyte/fluid homeostasis, but also as a mitogenic factor through the Ang-II type-1(AT1) receptor in smooth muscle cells and cardiac myocytes. Angiotensin II (Ang-II) is indeed thought to be a growthfactor, and Ang-II receptor blockers (ARBs), a class of antihypertensive agent, suppress signal transduction pathwaysmediated by several growth factors or cytokines, through the AT1 receptor. There is increasing evidence that the RAS isimplicated in the development of various cancers. We previously demonstrated that ARBs have the potential to inhibit thegrowth of prostate cancer cells and tumors through the AT1 receptor. This review highlights the possibility of ARBs asnovel agents for prostate cancer as well as other cancers, and reviews the literature on this area.

An apparent low prevalence of cancer in hypertensive patients receiving angiotensin converting enzyme inhibitors is reported; however, the molecular mechanisms have not been elucidated. Angiotensin-II (Ang-II) is well known to be associated with hypertension, as a main peptide of the renin-angiotensin system, and its detailed molecular mechanisms have recently been elucidated. For instance, Ang-II directly activates the mitogenic signal transduction pathway through the angiotensin-II type-1 (AT1) receptor in smooth muscle cells and cardiac myocytes. Ang-II receptor blockers (ARBs), a class of antihypertensive agent, suppress signal transduction pathways mediated by growth factors such as epidermal growth factor (EGF), through the AT1 receptor. Our studies demonstrated that an ARB had the potential for antiproliferative effects and inhibition of angiogenesis in prostate cancer cells. The AT1 receptor is categorized in the guanosine phosphate binding protein-coupled receptors (GPCRs), which are viewed as critical regulators of the interactions between epithelial and stromal cells. Hence, we consider that in overcoming prostate cancer, it is very important to inhibit GPCR signaling in cancer cells by ARBs. It is unclear how prostate cancer growth changes from being hormone dependent to independent, and no effective therapy has therefore been developed. Our clinical data revealed that ARB administration decreased prostate specific antigen (PSA) and improved performance status in patients with hormone-refractory prostate cancer. This review provides an insight into the key role of Ang-II and the possibility of ARBs for molecular targeting of mitogenesis and angiogenesis in prostate cancer.

Extensive allelotyping studies have implicated several tumor-suppressor loci on chromosomes 3p, 5q, 6q, 8p, 9pq, 10q, 11q, 14q, 17p, 18q and 19p in human kidney tumorigenesis. The PTEN (also called MMAC1 and TEP1) gene, a candidate tumor suppressor located at chromosome 10q23.3, is mutated in a variety of sporadic malignancies as well as in patients with Cowden disease. To investigate the potential role of the PTEN gene in renal tumorigenesis, we searched for abnormalities of the gene in 68 primary renal-cell carcinomas (RCCs) as well as in 17 renal carcinoma–derived cell lines, using DNA-SSCP, sequencing and microsatellite analysis. Five of 68 (7.5%) primary RCCs exhibited intragenic mutations (3 missense, 1 deletion and 1 splice-site), and 1 of 17 (5.9%) cell lines had an insertion mutation. Loss of heterozygosity of the PTEN gene occurred in 25% of primary RCCs, including the 3 cases with intragenic mutation and the 1 PTEN-mutated cell line. Clinical and histopathological examinations revealed that 4 of the 5 primary tumors with PTEN mutation were high-grade, advanced clear-cell RCCs with distant metastases or renal vein tumor invasions, resulting in poor prognostic courses. The other was a low-stage papillary/chromophilic RCC. Our data suggest that PTEN mutation is observed in a subset of RCCs and that, especially in clear-cell RCCs, it occurs as a late-stage event and may contribute to the invasive and/or metastatic tumor phenotype. © 2001 Wiley-Liss, Inc.

Human TR3 orphan receptor is a member of the steroid/thyroid hormone receptor superfamily and is the human homologue of the proteins encoded by the rat NGFI-B and mouse nur77genes. These genes are induced rapidly by androgens/growth factors and may have functions related to cell proliferation, differentiation, and apoptosis. To investigate the TR3 orphan receptor gene transcriptional regulation, a 2.3-kilobase genomic DNA fragment containing the TR3 orphan receptor gene promoter region was isolated, sequenced, and characterized. Sequence homology search within this promoter region revealed some potential cis-acting elements such as cAMP response element, interleukin-6 response element, estrogen response element, and GC box. Deletion analysis and chloramphenicol acetyltransferase assay also showed a novel cis-acting element of TR3 orphan receptor gene (NCAE-TR3), 200-181 base pairs upstream of the transcriptional start site. Gel retardation assay further demonstrated that some nuclear factors can bind to this NCAE-TR3. Together, our data suggest that NCAE-TR3 could be a new enhancer element associated with the transcription of an early response gene for mitogenesis and apoptosis.

Telomerase activity has been detected in a wide variety of human tumor types. We analyzed the telomerase activity in association with the acquisition of prostate cancer.

A hormone response element, CNTFRα-NBRE (5′-AAAGGTCA-3′) has been identified in the fifth intron of the α component of ciliary neurotrophic factor receptor gene (CNTFR-I5) for the human TR3 orphan receptor (TR3). A specific binding between in vitro expressed TR3 and CNTFRα-NBRE was demonstrated by using electrophoretic mobility shift assay. A reporter gene assay using chloramphenicol acetyltransferase (CAT) showed that CNTFR-I5 has an enhancer activity that could be induced by TR3 in a dose-dependent manner. This induction was significantly reduced in the absence of CNTFRα-NBRE. Together, these results indicate CNTFRα-NBRE is sufficient to mediate TR3 action in inducing the enhancer activity of CNTFR-I5. Our finding may, therefore, suggest CNTFRα is a target gene regulated by TR3 and expand the role of TR3 in the nervous system.

•Castration-resistant prostate cancer often metastasizes to bone.•TAS-115 is an oral multikinase inhibitor with activity against bone metastases.•TAS-115 300 mg achieved a bone scan index of ≤ 66.7% in docetaxel-naïve patients.•TAS-115 300 mg reduced serum bone alkaline phosphatase by > 30% in > 50% of patients.•TAS-115 showed acceptable safety and tolerability, even combined with abiraterone.

Introduction. Horseshoe kidney is one of the most common congenital renal fusion anomalies. Due to its poor mobility and abnormal vasculature form, surgeons should pay close attention to all anatomical variations. Case Presentation. An 83-year-old woman was referred to our hospital because of left renal tumor in a horseshoe kidney incidentally found by her previous hospital. We performed laparoscopic partial nephrectomy. The pathological diagnosis was clear cell renal cell carcinoma. G2 INFα V-pT1a with a negative surgical margin. No evidence of recurrence has been noted, and the renal function is well preserved at 28 months after surgery. Conclusion. When performing laparoscopic partial nephrectomy for renal carcinoma, especially a horseshoe kidney, preoperative imaging is crucial for identifying the location of the renal vessels.

The renin-angiotensin system (RAS) plays a critical role in the regulation of the cardiovascular system, and the RAS is present in various local organ systems. A retrospective cohort study raised the possibility of protection against cancer by the use of angiotensin converting enzyme (ACE) inhibitors. It has been reported that angiotensin II (Ang-II) is implicated in the development or invasion of several kinds of cancer tissue. There has recently been clinical evidence supporting the involvement of Ang-II in carcinogenesis. Continuously, several studies concerning the association between antihypertensive medication and cancer risk have been reported. This special issue of CCDT aims to provide an overview of important aspects on the cutting edge of RAS in cancer. Gallagher et al. focus on studies examining the RAS in pulmonary cancers and whether clinical intervention in this pathway may serve as an effective chemotherapeutic or chemopreventive modality for lung cancer. Ino et al. present the role of the RAS in the progression of gynecologic cancers and the clinical potential of blocking the RAS as a promising strategy for treatment. The review by Leung et al. appraises the current research progress on the role of the RAS in pancreatic cancer, and discusses the potential for developing drugs to target the RAS for treatment of pancreatic cancer. Ruiter et al. summarize the insertion/deletion polymorphism in the ACE gene in association with the risk of cancer and consequently on its potential role as therapeutic drug target in cancer. Yoshiji et al. concentrate upon the possible application of widely available agents, ACE inhibitor and/or angiotensin-II type I receptor blocker (ARB) against hepatocellular carcinoma as alternative agents in clinical practice. Uemura et al. present a potential role of the RAS in various aspects of prostate cancer, and useful treatment or chemoprevention by using ARBs for prostate cancer.