Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial.

BACKGROUND: Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. RESULTS: In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11-0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. CONCLUSIONS: Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

[Bilateral Testicular Tumor after Bilateral Orchiopexy : A Case Report].

We report a case of bilateral testicular tumor after bilateral orchiopexy. A 42-year-old man who underwent bilateral orchiopexy in early childhood consulted our hospital due to right testicular enlargement in February 2012. Blood tests revealed elevation of human chorionic gonadotropin ß, and a right testicular tumor was suspected. No metastasis was found on contrast-enhanced computed tomography. Although there was no swelling in the left testis, a heterogeneous hypoechoic mass was detected on left scrotal ultrasonography, and bilateral testicular tumors were supected. Left testis biopsy was performed and an intraoperative rapid diagnosis of a testicular tumor was made. Bilateral high orchiectomy was performed. No recurrence has been found over follow-up for 36 months after surgery.

[Two cases of lower abdominal tumors difficult to differentiate from urachal tumors].

CASE 1: A 28-year-old woman visited a local medical doctor, complaining of abdominal pain, urinary frequency and a sense of residual urine. Magnetic resonance imaging revealed a lower abdominal extraperitoneal tumor, approximately 5 cm in diameter, adjacent to the bladder dome. It was thought to be a urachal tumor, and she was referred to our hospital. A hard hen's egg-sized mass was palpable in the lower abdomen. Urinary analysis was normal. Cytological examination was also negative. Cystoscopy revealed redness in the bladder dome mucosa. Although the preoperative diagnosis was a urachal cancer, the pathological diagnosis on surgery was desmoids, and tumor excision was performed. No recurrence has been seen for 7 years postoperatively. CASE 2: A 71-year-old man complaining of swelling of the lower abdomen was referred to our department because he was suspected to have a urachal tumor, of about 15 cm in diameter, on computed tomography. A hard infant head-sized mass was palpable in the lower abdomen. Urinary analysis was normal. Cystoscopical examination showed a markedly compressed bladder dome, however, no abnormal findings were seen in the mucosa. Although the preoperative diagnosis was a urachal tumor, the intraoperative pathological diagnosis revealed no malignancy. The mass was connected to the bladder dome, and partial cystectomy was conducted. The final pathological diagnosis was a solitary fibrous tumor. No recurrence has been seen for 5 years postoperatively. Because a urachal tumor is highly malignant, radical cystectomy and urinary diversion might be planned preoperatively. However, care should be taken not to be too invasive, considering the possibility of a benign tumor.

Urinary tract infection associated with bacteremia caused by vancomycin-resistant enterococcus following continent urinary diversion.

Key Clinical Message: Even in a country where vancomycin-resistant enterococcus is rare, multidrug-resistant organism precautions are necessary when admitting patients with a history of medical exposure in other countries. On admission, screening is necessary and if infection is confirmed, a multidisciplinary approach involving different specialists is required. Abstract: The patient was a 49-year-old Japanese female living in the United States. Total pelvic exenteration for cervical carcinoma, Miami pouch formation, and ileostomy had been performed in the United States. She returned to Japan to undergo postoperative adjuvant chemotherapy. Fever and abdominal pain occurred 42 days after surgery. She consulted the fever outpatient clinic, and a diagnosis of urinary retention-associated acute renal failure and pyelonephritis was made. We detected vancomycin-resistant enterococcus on urine/blood culture 5 days after admission. Infection control measures were implemented, and the ward was closed for 3 days. We administered linezolid, which was effective for pyelonephritis and bacteremia.

Risk factors for catheter-related bloodstream infections in adult hospitalized patients - multicenter cohort study.

BACKGROUND: Risk factors for catheter-related bloodstream infections (CRBSIs) may change over time with progress in infection control. This study was undertaken to explore the current risk factors for CRBSIs in hospitalized patients. METHODS: Adult patients with non-tunneled central venous catheters (CVCs) in 12 Japanese referral hospitals were prospectively enrolled between December 2009 and January 2012. Patients were monitored for CRBSIs for up to 8 weeks from CVC insertion; data were collected regarding patient characteristics, the purpose of CVC insertion, insertion methods, mechanical complications during insertion, and post-insertion catheter care. RESULTS: A total of 892 patients were enrolled in this study. The overall incidence of CRBSIs was 0.40 infections per 1000 catheter-days. Univariate analysis using the Fisher's exact test identified one of the participating hospitals (hospital A; p < 0.001), internal jugular vein catheterization (IJVC) (p = 0.0013), not using maximal sterile barrier precautions (p = 0.030), and the Seldinger technique for catheter insertion (p = 0.025) as significant risk factors for CRBSI. After excluding data from hospital A, only IJVC remained a significant risk factor for CRBSI (p = 0.025). The cumulative probability of remaining without CRBSI was significantly lower in patients with IJVCs than in patients with other catheter routes (p < 0.001; log-rank test). Similarly, the cumulative probability of remaining without catheter removal due to a suspected infection was significantly lower in patients with IJVCs (p = 0.034; log-rank test). CONCLUSIONS: The current study suggests that IJVC might be a risk factor for CRBSI under current infection control conditions.

Comparison of efficacy and safety of 1- and 3-month luteinizing hormone-releasing hormone agonist depots as initial therapies for prostate cancer.

BACKGROUND: We compared the efficacy and safety of 1- and 3-month depots of the luteinizing hormone-releasing hormone (LH-RH) agonist goserelin acetate in prostate cancer patients. METHODS: Patients were randomly assigned to the Direct Group that received the goserelin 3-month depot or the Switch Group that began with the 1-month depot for the first 3 months and then switched to the 3-month depot. All patients were co-administered the antiandrogen agent bicalutamide. Serum testosterone and prostate-specific antigen (PSA) levels and adverse events were recorded at weeks 4, 8, 12, and 24. RESULTS: Baseline testosterone levels in the Direct and Switch Groups were 4.98 and 5.07 ng/mL, respectively (P = 0.798). At each week, the levels in both groups were ≤0.50 ng/mL (castration level) with no significant differences between them. All of the patients in the Switch Group and 98.1 % in the Direct Group had achieved castration levels at week 12, and 100 % had achieved such levels at week 24. Baseline PSA levels in the Direct and Switch Groups were 52.37 and 46.72 ng/mL, respectively (P = 0.793). Levels in both groups dropped continuously, to about 1.0 ng/mL at week 24, with no significant differences between the groups at any time. Three patients in the Direct Group experienced adverse events that were attributed to the co-administered bicalutamide. CONCLUSIONS: There was no difference in the efficacy or safety between the 1- and 3-month depots of goserelin when given as initial prostate cancer treatment in combination with bicalutamide. Patients must be monitored for adverse events associated with bicalutamide.

[A case of adenocarcinoma arising in an ileal conduit].

We report a rare case of adenocarcinoma developing in an ileal conduit. A 78-year-old woman was referred complaining of abdominal pain. She had undergone radical cystectomy and ileal conduit formation for invasive bladder cancer 8 years previously. The pathological diagnosis was urothelial carcinoma, and distant metastasis was not found. She was lost to follow-up over 2 years postoperatively. Computed tomography at this time showed bilateral hydronephrosis. Metastasis was not revealed. Because renal failure progressed and gross hematuria developed, endoscopic examination through the stoma was performed. A mass adjacent to the ureteroileal anastomosis site was found. Biopsy led to a diagnosis of moderately differentiated adenocarcinoma. She died of renal failure 1.5 months after admission. To our knowledge, 9 cases of adenocarcinoma arising in an ileal conduit have previously been reported.

[A case of alpha-fetoprotein-producing female urethral adenocarcinoma].

We report a rare case of alpha-fetoprotein (AFP)-producing female urethral adenocarcinoma. A 52- year-old woman had urinary frequency. Ultrasonography showed a mass near the bladder. Therefore, she was referred to our hospital. Magnetic resonance imaging showed an approximately 4 cm mass at the urethra. Computed tomography did not show any lymphnode metastasis or distant metastasis. High serum levels of AFP were revealed. Carcinoembryonic antigen (CEA) and prostate specific antigen (PSA) were within the normal range. A transvaginal needle biopsy suggested adenocarcinoma. Radical cystourethrectomy and ileal conduit formation were performed. Histopathological diagnosis was adenocarcinoma. Immunohistochemical staining was positive for AFP and CEA, and negative for PSA. Serum AFP normalized immediately postoperatively. Adjuvant chemotherapy or radiotherapy was not performed. Eleven years postoperatively, the patient showed no evidence of tumor recurrence. To our knowledge, this is the first reported case of AFP producing female urethral adenocarcinoma.

Toxic epidermal necrolysis after the administration of enfortumab vedotin for urinary bladder urothelial carcinoma.

Introduction: Enfortumab vedotin is a novel drug for locally advanced or metastatic urothelial carcinoma, but it is associated with a high incidence of skin reactions (up to 47.0%). Case presentation: A 71-year-old male was administered enfortumab vedotin for bladder cancer associated with lymph node metastases. Slight erythema of the upper limbs appeared on Day 5. Erythema gradually worsened. On Day 8, second administration was performed. On Day 12, based on the extents of blisters, erosion, and epidermolysis, a diagnosis of toxic epidermal necrolysis was made. The patient died of multiple organ failure on Day 18. Conclusion: As serious cutaneous toxicity may appear early after the start of administration, it is important to consider the timing of the second administration of the initial course carefully. In cases of skin reaction, reduction or discontinuation should be considered.

Development of male breast cancer in a patient with prostate cancer during androgen deprivation therapy.

INTRODUCTION: Male breast cancer accounts for <1% of all breast cancer. We report a patient with prostate cancer during hormone therapy who developed breast cancer. CASE PRESENTATION: An 88-year-old male underwent androgen deprivation therapy for prostate cancer and developed an induration in the left breast 7 years after the start of treatment. After close examination, he was diagnosed with left breast cancer with lymph node metastasis. The prostate cancer was stable in a hormone-sensitive state. Left mastectomy was performed and the pathological diagnosis was invasive ductal carcinoma. DISCUSSION: In addition to our patient, seven patients who developed breast cancer during hormone therapy for prostate cancer were examined. Five of six patients had stage II or above, and four patients had lymph node metastases. Although local breast symptoms are frequently observed as adverse effects of hormone therapy, caution is warranted regarding male breast cancer.

Muscle invasive urinary bladder urothelial carcinoma presenting with secondary nephrotic symptoms.

INTRODUCTION: Nephrotic syndrome secondary to malignant disease accounts for approximately 10% of cases of nephrotic syndrome in adults. However, urothelial carcinoma of the bladder is a rare cancer, with only four cases reported to date. CASE PRESENTATION: A 76-year-old man presented with chief complaints of edema and anorexia. Laboratory examinations revealed hypoalbuminemia and marked proteinuria, and computed tomography demonstrated multiple bladder tumors. Transurethral resection of the bladder tumors was performed. The pathological diagnosis was urothelial carcinoma with muscular invasion. The patient underwent simple cystectomy and ileal conduit formation, and proteinuria disappeared after 4 weeks. However, urethral recurrence was noted, and he died 35 months after cystectomy. CONCLUSION: Five cases including ours were clinically reviewed. Nephrotic symptoms improved relatively rapidly after surgery in all cases. In contrast to the poor preoperative general condition, postoperative improvement can be expected, and surgical treatment should, therefore, be considered.

Severe necrosis of the glans penis associated with calciphylaxis treated by partial penectomy.

INTRODUCTION: Calciphylaxis is characterized by marked vascular calcification and painful skin ulcers, and it has a poor prognosis. CASE PRESENTATION: The patient was a 72-year-old male. He was referred for penile pain. He had a 4-year history of dialysis therapy under a diagnosis of diabetic nephropathy. Black and yellow necrosis was observed involving the entire glans, accompanying severe pain. Computed tomography revealed marked calcification involving the thoracoabdominal aorta to iliac arteries, the dorsal artery of the penis and the corpus cavernosum, leading to a diagnosis of calciphylaxis. Penile pain gradually exacerbated and partial penectomy was performed. After surgery, penile pain promptly subsided. Pathological examination confirmed marked calcification of the microvascular wall and narrowing of the lumen. CONCLUSION: We reviewed 15 Japanese patients with calciphylaxis who had undergone penile surgery. Surgical treatment was considered to be effective at relieving penile pain, but the prognosis remained poor.

Primary male urethral squamous cell carcinoma presenting with a genital abscess.

INTRODUCTION: Primary urethral cancer is a rare disease accounting for <1% of all urological cancer cases. We encountered a patient with urethral squamous cell carcinoma diagnosed during treatment of a genital abscess. CASE PRESENTATION: A 69-year-old male was referred to our hospital for recurrent urethritis and swelling of the scrotum. The genital skin was atrophic with a purulent discharge. A diagnosis of epididymitis-induced genital abscess was made, and conservative treatment was administered. However, local infection recurred and the infected tissue was resected 4 months after the first examination. The pathological diagnosis was squamous cell carcinoma. Subsequently, radical surgery was performed, but the patient died 17 months postoperatively. CONCLUSION: Four patients with primary urethral squamous cell carcinoma presenting as genital abscess have been reported. Careful examination is necessary while considering a malignant tumor as an underlying disease.

Patient with inguinal hernia containing the urinary bladder complicated by bladder stones.

INTRODUCTION: We encountered a patient in whom bladder inguinal hernia complicated by bladder stones was incidentally diagnosed. Bladder inguinal hernia containing stones in the prolapsed bladder is rare and only two cases have been reported. CASE PRESENTATION: The patient was an 82-year-old male in whom ascending colon cancer and inguinal hernia containing the urinary bladder were diagnosed based on abdominal computed tomography performed to examine anemia. The urinary bladder contained several small stones. Radical surgery for the hernia and lithotripsy of the urinary bladder were concomitantly performed with right colectomy. On stone analysis, the stones were found to be uric acid calculi. CONCLUSION: In the three patients with inguinal hernia containing the urinary bladder complicated by stones, including our patient, two-stage urination, organic lower urinary tract obstruction, and prolapse of the urinary bladder reaching the scrotum were noted in all patients.

Effects of natriuretic peptides on intracavernous pressure and blood pressure in conscious rats.

INTRODUCTION: Natriuretic peptides activate particulate guanylyl cyclases and have been shown to induce penile erection in rats, rabbits, and humans. AIM: We investigated the effects of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) on intracavernous pressure (ICP) and systemic blood pressure (BP) in conscious, free-moving rats. METHODS: ICP and BP were measured in male Sprague-Dawley rats after catheters were inserted into the crus corpus cavernosum and carotid artery, respectively. Natriuretic peptides were given by intravenous bolus (3, 10, and 30 nmol/kg) or continuous (0.1 and 1 nmol/kg/minute) administration. MAIN OUTCOME MEASURES: The number of animals with increases in ICP were determined. Amplitudes and durations of ICP responses and changes in BP were also evaluated. RESULTS: More animals had multiple transient increases of ICP in response to ANP and BNP than to CNP. The increases in ICP were transient and appeared to be an "all or none" response. ANP and BNP decreased BP more than CNP, especially with bolus administration. CONCLUSIONS: These findings show that in rats, erectile responses can be initiated by ANP, BNP, and less effectively, by CNP. ANP and BNP have a high affinity for the natriuretic peptide receptor-A, suggesting that this receptor is involved in the responses.

[Adult Wilms' tumor mimicking adrenal tumor: case report].

A 33-year-old woman was referred to our hospital for further examination of a right adrenal mass 4.5 cm in diameter. Hormonal findings were normal. Computed tomography, magnetic resonance image and angiograpy demonstrated non-functioning adrenal tumor. Right nephrectomy was performed, because the tumor adhered firmly to the upper pole of the right kidney. The pathological diagnosis was nephroblastoma (nephroblastic type, complex subtype). Postoperative chemotherapy was started for stage III Wilms' tumor. However, peripheral neuropathy such as numbness of the fingers developed. Therefore, chemotherapy was discontinued in the fifth week. The patient is currently alive without recurrence 17 months postoperatively. In adult patients, postoperative chemotherapy for nephroblastoma is often interrupted due to side effects. Further studies on the protocol for adults is necessary.

[Full-term delivery following intracytoplasmic sperm injection in a case of male hypogonadotropic hypogonadism after 8-year treatment with HCG and HMG].

A 19-year-old male, who had undergone bilateral orchiopexy at 5 years of age in the Department of Pediatric Surgery, was referred to our clinic presenting with bilateral small testes. Bilateral testis volume was 4 ml involving a small penis and scant pubic hair per Tanner Stage 2. Serum luteinizing hormone, follicle stimulating hormone and testosterone levels were low. Results of hormonal loading tests, including luteinizing hormone-releasing hormone (LH-RH) and human chorionic gonadotropin (HCG), were positive. Brain computed tomographic scan revealed no abnormal findings. The diagnosis of male hypogonadotropic hypogonadism was rendered based on these data. Administration of LH-RH for 1 year was ineffective. Subsequently, HCG and human menopausal gonadotropin (HMG) treatments were initiated. The symptoms of male insufficiency improved; moreover, sperm formation was apparent following HCG and HMG treatments. The patient has received HCG and HMG injections for eight years; furthermore, his wife delivered a boy consequent to the first intracytoplasmic sperm injection.

Enhancement of apomorphine-induced penile erection in the rat by a selective alpha(1D)-adrenoceptor antagonist.

1. Effects of A-322312 (alpha(1B)-adrenoceptor (AR) antagonist), A-119637 (alpha(1D)-AR antagonist), prazosin (non-selective alpha(1)-AR antagonist), and yohimbine (alpha(2)-AR antagonist) were studied in rat corpus cavernosum (CC) and cavernous artery (Acc) preparations. Effects of intracavernous (i.c.) or intraperitoneal (i.p.) administration of alpha(1)-AR antagonists on apomorphine-induced erections were investigated. 2. A-119637 attenuated electrically induced contractions in isolated CC (-logIC(50); 8.12+/-0.15), and relaxed noradrenaline (NA)-contracted preparations by more than 90% at 10(-7) M. At the same concentration, the -logEC(50) value for NA in Acc was altered from 6.79+/-0.07 to 4.86+/-0.13. In the CC and Acc, prazosin similarly inhibited contractile responses. 3. Inhibitory effects of A-322312 (10(-7) M) in electrically activated CC were 32.3+/-5.1%, whereas no effect on concentration-response curves for NA was observed in the Acc. Yohimbine (10(-8) M and 10(-7) M), enhanced electrically-induced contractions in isolated CC by 20 to 50%. At 10(-6) M, inhibitory effects of yohimbine were obtained. 4. A-119637 (0.3 micromol kg(-1), i.p.) tripled the number of erections, and produced a 6 fold increase in the duration of apomorphine-induced erectile responses. A-322312, prazosin, or yohimbine did not enhance erections induced by apomorphine. None of the alpha(1)-AR antagonists significantly increased ICP upon i.c. administration. Decreases in blood pressure were seen with A-119637 and prazosin. 5. The present findings show that there is a functional predominance of the alpha(1D)-AR subtype in the rat erectile tissue, and that blockade of this receptor facilitates rat penile erection induced by a suboptimal dose of apomorphine.

Animal models for studying penile hemodynamics.

Animal models for the study of erectile function monitoring the changes in intracavernous pressure (ICP) during penile erection was reviewed. The development of new models using small commercially-available experimental animals, rats and mice, in the last decade facilitated in vivo investigation of erectile physiology. The technique enabled to evaluate even subtle erectile responses by analyzing ICP and systemic blood pressure. Moreover, the method has been well improved and studies using conscious animal models without the influence of any drug or anesthesia are more appropriate in exploring the precise physiological and pharmacological mechanisms in erection. Also, more natural and physiological sexual arousal instead of electrical or pharmacological stimulation is desirable in most of the studies. This article reviewed the development of ICP studies in rats and mice.

[A difficult case of advanced testicular choriocarcinoma effectively treated by chemotherapy and resection of lung metastasis].

A 25-year-old man who suffered from cough, sputum, and swelling of left scrotal contents was admitted to our hospital. We found testicular choriocarcinoma with multiple lung, liver, and brain metastases. The patient received 5 courses of VIP therapy (cisplatin, etoposide, ifosfamide) and 1 course of high-dose chemotherapy (carboplatin, etoposide, cyclophospamide) with peripheral blood stem cell transplantation. One year later, the patient underwent surgery for resection of lung metastasis after 1 course of chemotherapy (cisplatin, etoposide). Pathological diagnosis showed a remnant of choriocarcinoma. Three years and three months after surgery, no recurrence of the choriocarcinoma has been found.