[Experience of Pembrolizumab Administration in A Patient with Castration-Resistant Microsatellite Instability-High Prostate Cancer].

Castration-resistant prostate cancer and multiple lymph node and ventral bladder metastases in an 87 year-old man progressed despite various systemic therapies, including chemotherapy. Because his prostate surgical specimen displayed a microsatellite instability (MSI) -high status, pembrolizumab 200 mg/body treatment was started. After six courses of treatment, his prostate-specific antigen (PSA) level decreased by 83% versus that at treatment initiation (from 408.78 ng/ml to 69.54 ng/ml), and the para-aortic lymph node metastasis was reduced in size on imaging. After 13 courses, his PSA level (462.59 ng/ml) exceeded that at the start of treatment, and progressive disease was detected on imaging. Although case reports of pembrolizumab for MSI-high prostate cancer remain few because of its rarity, it is an important therapeutic option and further clinical research is required.

Summary of the clinical practice manual for late-onset hypogonadism.

Testosterone plays an important role in maintaining both physical and mental function. Age-related testosterone depletion contributes to the development of angina, arteriosclerosis, obesity, metabolic syndrome, dementia, frailty, and a range of other conditions. A condition involving age-related testosterone depletion and the associated clinical symptoms is defined as late-onset hypogonadism (LOH). LOH is treated by testosterone replacement therapy. Indications for testosterone replacement therapy are determined by evaluating symptoms and signs.

[A Case of Castration-Resistant Prostate Cancer, for which Washed Platelet Concentrate Transfusions were Effective in Treating Disseminated Intravascular Coagulation].

A 62-year-old man was treated for castration-resistant prostate cancer (CRPC) ; however, his condition progressed. The patient planned to visit our department for treatment, including palliative care. However, he visited the emergency room with a complaint of a persistent nose bleed just before visiting our department. He had an active nose bleed, disseminated intravascular coagulation (DIC), and leukoerythroblastosis upon admission. After hospitalization, we performed a bone marrow puncture and biopsy to investigate the cause of the DIC, which revealed a dry tap and hypoplastic bone marrow. This was believed to be due to the progression of CRPC. He developed wheals upon receiving repeated platelet transfusions for the DIC. Although we administered antihistamine and steroids to control these side effects, he additionally developed chills and fever. Because of the difficulty in controlling side effects, we decided to use washed platelets. Thereafter, blood transfusions of washed platelets were performed without the occurrence of side effects. However, the patient died because of the worsening of his condition.

Testicular sperm extraction in a patient with ejaculatory dysfunction after combined androgen blockade therapy for prostate cancer.

INTRODUCTION: Prostate cancer is the most prevalent urological cancer for older men. However, there is still a possibility that a few prostate cancer patients may still wish to have children. CASE PRESENTATION: A 49-year-old male was diagnosed with low-risk prostate cancer. Combined anti-androgen blockade therapy was performed for 8 months prior to radiation therapy. However, he suffered from ejaculatory dysfunction and wished to conceive with his partner. Hormonal therapy was discontinued and he was referred to our clinic for sperm preservation. His ejaculatory function did not recover after 4 months discontinuation of hormonal therapy, subsequently micro-testicular sperm extraction for sperm preservation was successfully performed. CONCLUSION: Sperm preservation in patients with prostate cancer is unusual but it should be considered if the patient's fertility is an issue.

[Ischemic Priapism Associated with Essential Thrombocythemia : A Case Report].

A 71-year-old man visited a local urologist with the complaint of continuous painful erection for three days. Penile cavernosal blood data showed acidosis and hypoxia. Thus he was diagnosed with ischemic priapism. After penile aspiration and injection of phenylephrine, erection was temporary improved. The blood platelet count was 94.5×104/µl and myeloproliferative disease was suspected. He was referred to our hospital and visited us the following day. Since priapism relapsed, we aspirated corpus cavernosum of the penis and injected phenylephrine which was successful. A bone marrow biopsy and genetic test were performed at the department of hematology and the diagnosis of essential thrombocythemia with JAK2 gene mutation was confirmed. By treatment with hydroxyurea, the blood platelet count decreased without priapism recurrence.

The efficacy and safety of short-acting testosterone ointment (Glowmin) for late-onset hypogonadism in accordance with testosterone circadian rhythm.

INTRODUCTION: It is well known that there is a reduction of circadian rhythm in blood testosterone levels with aging. Our previous report revealed that 3 mg of short-acting testosterone ointment (Glowmin: GL) elevated serum testosterone levels to within the physiological range for 4-6 h. The aim of this study was to clarify the clinical efficacy and safety of GL used topically once every morning, to enhance the circadian rhythm of testosterone, for late-onset hypogonadism (LOH). METHODS: A total of 61 LOH patients received 3 mg of GL topically once a day in the morning on scrotal skin for 24 weeks. The clinical efficacy of GL was evaluated by the aging males symptoms (AMS) scale, and blood sampling tests were measured before and after GL treatment. RESULTS: Mean patients age was 55.3 ± 9.2 years old. Total AMS scores at 4, 12, and 24 weeks after GL treatments significantly decreased. The results of sub-analysis of AMS, including psychological, physical, and sexual factors also significantly improved after GL treatments. No severe adverse reactions or abnormal laboratory data were reported. CONCLUSIONS: This study shows that TRT for LOH with once daily GL treatment supports testosterone circadian rhythm and should be considered to be an effective and safe therapy for LOH.

FGF2 Has Distinct Molecular Functions from GDNF in the Mouse Germline Niche.

Both glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2) are bona fide self-renewal factors for spermatogonial stem cells, whereas retinoic acid (RA) induces spermatogonial differentiation. In this study, we investigated the functional differences between FGF2 and GDNF in the germline niche by providing these factors using a drug delivery system in vivo. Although both factors expanded the GFRA1+ subset of undifferentiated spermatogonia, the FGF2-expanded subset expressed RARG, which is indispensable for proper differentiation, 1.9-fold more frequently than the GDNF-expanded subset, demonstrating that FGF2 expands a differentiation-prone subset in the testis. Moreover, FGF2 acted on the germline niche to suppress RA metabolism and GDNF production, suggesting that FGF2 modifies germline niche functions to be more appropriate for spermatogonial differentiation. These results suggest that FGF2 contributes to induction of differentiation rather than maintenance of undifferentiated spermatogonia, indicating reconsideration of the role of FGF2 in the germline niche.

Administration of daily 5 mg tadalafil improves endothelial function in patients with benign prostatic hyperplasia.

INTRODUCTION: Tadalafil is a promising phosphodiesterase (PDE) 5 inhibitor prescribed for erectile dysfunction (ED). Daily low dose (5 mg) of tadalafil has also been used for the treatment of male lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH). PDE5 inhibitors induce relaxation of smooth muscle cells in the urethra, prostate, bladder neck, and blood vessels. The aim of this study was to investigate the efficacy of tadalafil on vessels endothelial function, in patients with male LUTS symptoms associated with BPH. METHODS: The Institutional Review Board (IRB) approved this clinical study and informed consents had been obtained from 81 BPH patients. The following male LUTS parameters: international prostate symptom score (IPSS), overactive bladder symptom score (OABSS), voiding volume, max and mean voiding flow on voiding flowmetry examination and post-voiding residual urine (RU) were compared at 0, 1, 3, 6, and 12 months after a daily dose of 5 mg tadalafil. In addition, erectile function was evaluated by the sexual health inventory for men (SHIM) score and vessels endothelial function and peripheral neuropathy were assessed by the brachial-ankle pulse wave velocity (baPWV), ankle brachial index (ABI), and vibration perception threshold (VPT) at 0, 3, 6, and 12 months after treatment. RESULTS: The mean age of 81 patients was 66.4 ± 11.4 years old. Their prostate size was 30.2 ± 22.1 ml. Male LUTS parameters including IPSS, OABSS, and RU showed significant improvement from 1 to 12 months after tadalafil administration. Max and mean voiding flow was significantly increased at 6 months after tadalafil treatment. The SHIM score showed significant improvement after 3 months. Whilst, the results of baPWV also showed significant improvement from 3 to 12 months. ABI was also significantly improved at 6 months. However, there was no change in the VPT at any time point. CONCLUSIONS: Tadalafil is effective for both male LUTS and ED. It is also shown that tadalafil improves baPWV, which we can conclude that higher vessels elasticity has been obtained. This major finding of this study shows that tadalafil has the potency to improve vessels endothelial dysfunction in patients with BPH.

Silodosin versus naftopidil in the treatment of premature ejaculation: A prospective multicenter trial.

OBJECTIVES: To determine the efficacy of two α1-adrenoceptor antagonists with different affinities for α1-adrenoceptor subtypes, silodosin and naftopidil, in the treatment of premature ejaculation. METHODS: This was a prospective, open-label, multicenter trial. A total of 26 patients with untreated acquired premature ejaculation were enrolled. Premature ejaculation was defined based on the International Society for Sexual Medicine recommendation. Patients self-administered on demand silodosin 4 mg or naftopidil 25 mg 1 h before intercourse, alternating drugs at least three times each. Clinical global impression change for premature ejaculation, premature ejaculation profile, and intravaginal ejaculation latency time were evaluated at baseline and during treatment. RESULTS: Due to clinical global impression change, 24 patients (92%) and 12 patients (46%) reported improvement in their own premature ejaculation problems under silodosin and nafitopidil administration, respectively. Silodosin treatment produced a significantly higher improvement rate compared with naftopidil (P = 0.0002). Objectively, silodosin significantly prolonged intravaginal ejaculation latency time compared with baseline and naftopidil (P < 0.01). Mean intravaginal ejaculation latency times were 1.9, 4.1, and 7.6 min at baseline, control and with silodosin, respectively. The rate of reduced semen volume during silodosin treatment was higher than during naftopidil treatment. There were no adverse systemic effects in either group. CONCLUSIONS: Silodosin, a highly selective α1A-adrenoceptor antagonist, produces greater improvements in premature ejaculation profiles and related symptoms along with intravaginal ejaculation latency time in acquired premature ejaculation patients with or without erectile dysfunction. This result supports the clinical use of silodosin as an alternative treatment for premature ejaculation.

Are urge incontinence and aging risk factors of erectile dysfunction in patients with male lower urinary tract symptoms?

INTRODUCTION: Several studies have indicated that erectile dysfunction (ED) patients also suffer from lower urinary tract symptoms (LUTS). We investigated a group of men with LUTS and assessed their sexual function with the aim of being able to predict ED risk factors and introduce ED treatments earlier for this patient group. METHODS: International Prostate Symptom Score (IPSS), Overactive Bladder Symptoms Score (OABSS) and Sexual Health Inventory for Men (SHIM) score were obtained from 236 men with LUTS at their first out-patients visit. Clinical parameters such as body mass index, prostate volume, residual urine volume and prostate specific antigen were also evaluated. The relationship between the SHIM score and other clinical data was analyzed. RESULTS: According to the SHIM score, ED in men with LUTS was severe 15%, moderate 19%, moderate to mild 28%, mild 17%, normal 7% and data was incomplete in 14%. Based on the results of a multivariate analysis, aging (p < 0.001) and OAB severity (p = 0.024) were significantly correlated to severe and moderate ED. Furthermore, among OAB symptoms score items, urge urinary incontinence was a risk factor for severe and moderate ED (p = 0.005). CONCLUSION: Aging and OAB (notably urinary urge incontinence) are risk factors for severe and moderate ED in men with LUTS.

Male infertility and androgen replacement therapy for subjects with bilateral testicular tumors.

PURPOSE: The purpose of this study was to investigate andrological aspects, including male infertility and androgen deficiency, after treatments of bilateral testicular tumors. METHODS: Five subjects with bilateral testicular cancer were clinically analyzed between April 1996 and March 2013. RESULTS: The mean age at initial treatment was 29.4 ± 3.3 years old. In the 4 metachronous cases, a contralateral tumor occurred after 79.0 ± 50.0 months. Histologically, bilateral seminoma occurred in 3 cases and seminoma and nonseminoma was combined in 2 cases. All subjects underwent bilateral orchiectomy, with additional chemotherapy, radiation therapy, and surgery for metastasis. No tumor recurrence was observed in the 5-34 years following initial treatment. Two subjects married following bilateral orchiectomy after receiving informed consent from their wives. One had two children before contralateral testicular treatment. The other was single and had undergone micro-testicular sperm extraction at contralateral orchiectomy, although no sperm was found. The other one was unknown because long-term followup failed. Androgen replacement therapy (ART) was applied for 4 subjects, and relieved physical and psychological symptoms due to testosterone deficiency without adverse reactions. CONCLUSIONS: ART safely and effectively relieves symptoms in subjects with bilateral testicular tumors. However, male infertility treatment is insufficient, and more aggressive management may be required.

[Role of androgen in the elderly. Clinical androgen replacement therapy for late-onset hypogonadism].

Late-onset hypogonadism (LOH) is defined as the condition caused by the decline of testosterone by aging, along with various symptoms, including physical, psychological and sexual disturbance. Thus the principle of treatment for LOH is Androgen replacement therapy (ART) , and ART has been applied primarily in order to alleviate the various symptoms in LOH patients. The indication of ART for LOH is determined based on LOH symptoms assessed by aging males' symptoms (AMS) score and serum free testosterone levels. In abroad, several routes are available for the administration of testosterone, such as injection, patch, oral administration, etc. In Japan, intramuscular injection of testosterone enanthate every 2 to 4 weeks is widely indicated for treatment of LOH. It has also reported that ART using testosterone ointment once or twice a day appeared to improve those LOH symptoms. ART is a significant and safe procedure for anti-aging in male.

[Laparoscopic nephrectomy for patients with infected nonfunctioning kidney due to ureteropelvic junction stenosis : report of two cases].

We report two cases of infected nonfunctioning kidney due to ureteropelvic junction (UPJ) stenosis treated by laparoscopic surgery. Patient 1 : A 78-year-old woman was referred to our clinic complaining of left flank pain and high fever up. Asymptomatic UPJ stenosis with mild hydronephrosis was diagnosed 9 years ago at our clinic. Therefore we followed her up with no treatment. Computed tomography (CT) scan revealed left severe hydronephrosis. Antibiotic chemotherapy was performed without percutaneous nephrostomy. Laparoscopic nephrectomy was performed with the resected renal size of 10 cm in greatest diameter and the operative time of 262 min. The pathological diagnosis was atrophic kidney with pyelonephritis. Patient 2 : A 28-year-old man was referred to our clinic complaining of left flank pain and high fever up. CT scan revealed a left severe hydronephrosis due to UPJ stenosis. Following percutaneous nephrostomy,antibiotic chemotherapy was performed. Laparoscopic nephrectomy was performed with the resected renal size of 6 cm in greatest diameter and the operative time of 140 min. The pathological diagnosis was atrophic kidney with pyelonephritis. Laparoscopic nephrectomy for infected nonfunctioning kidney due to UPJ stenosis is feasible and safe. With dense perinephric adhesions and failure to progress,we should consider early open conversion to reduce morbidity.

[Laparoscopic resection of retroperitoneal schwannoma : report of three cases and review of 22 cases in Japanese literature].

Retroperitoneal schwannoma is a rare tumor. Only 19 cases have been reported to be treated by laparoscopic surgery. We performed successful laparoscopic excision of retroperitoneal schwannoma using the four-trocar in three patients who had a left retroperitoneal mass. The patients were two women and one man. They were 62, 60 and 57 years old. The tumor was 70, 45 and 50 mm in greatest diameter and operative time was 204, 243 and 254 min. respectively. The pathological diagnosis of the tumor was schwannoma. There was no morbidity or mortality. Preoperative diagnosis of schwannoma is very difficult. However schwannoma is a benign tumor with a good prognosis. This laparoscopic excision for retroperitoneal schwannoma is effective and rather safe.

[Adrenalectomy for metastatic adrenal tumor from uterine leiomyosarcoma: a case report].

A 63-year-female was referred to our department for close examination and treatment of a left adrenal tumor found by positron emission tomography and computed tomography. She underwent abdominal total hysterectomy and bilateral salpingo-oophorectomy for uterine leiomyosarcoma 19 years ago. After the operation, she received 2 resections for peritoneal recurrence and 7 resections for pulmonary metastases. Magnetic resonance imaging showed a heterogeneous mass with a diameter of 7 cm at the left adrenal grand. We carried out open adrenalectomy and pathological findings were a metastatic adrenal tumor from uterine leiomyosarcoma. No signs of recurrence or metastasis have been observed for 6 months after the operation.

[Brain tumor (germinoma) diagnosed after assessment for male late-onset hypogonadism syndrome: a case report].

A 44-year-old man suffered from sleep disturbance, headache, lack of energy and appetite loss. His local doctor recommended he consult our clinic for further examination of late-onset hypogonadism. His aging males' symptoms (AMS) and international index of erectile function (IIEF-5) scores were 62 and 1, respectively. His biochemistry revealed 0.29 mIU/ml luteinizing hormone (LH), 1.36 mIU/ml follicular stimulating hormone (FSH), 0.16 ng/ml total testosterone (TT) and＜0.6 pg/ml free testosterone (FT). Male hypogonadotropic hypogonadism was suspected from these results, He was then referred to a neurosurgeon for discrimination of intracranial disease where magnetic resonance imaging (MRI) revealed multiple intracranial tumors. An open brain biopsy was performed, and germinoma was diagnosed. After 4 courses of anti-cancer chemotherapy, complete remission was achieved. He was followed up endocrinologically by administration of testosterone injections along with other endocrinology replacement treatments. However, MRI 3 months later revealed tumor recurrence in the left lateral ventricle, and he has been receiving radiation therapy.