Protective effects of tadalafil against cisplatin-induced spermatogenic dysfunction.

BACKGROUND: Cisplatin (CDDP) is an effective anticancer drug for the treatment of malignant tumors, such as lung cancer, bladder cancer, and testicular cancer. However, oligozoospermia and azoospermia after administration of CDDP are clinical problems. One of the testicular toxicities of CDDP is known to cause oxidative stress. Tadalafil has been reported to exhibit antioxidant effects and is widely used in clinical practice to treat benign prostatic hyperplasia and erectile dysfunction. Rho-kinase α (ROCK2) regulates cell migration and apoptosis and has been reported to be involved in CDDP-induced nephrotoxicity. The excessive expression of ROCK2 is known to cause oxidative stress. OBJECTIVE: The objective of the current study was to test the effect of tadalafil on the testicular toxicity of CDDP. MATERIAL AND METHODS: Thirty-two rats were used and divided into the following four groups. (1) The control group (CONT), treated with saline on day 1 and saline and dimethyl sulfoxide (DMSO) on days 1-10 intraperitoneally (i.p.) (2) The Tadalafil Group (TAD), treated with saline on day 1, and 0.4 mg/kg tadalafil on days 1-10 i.p. (3) The CDDP group (CD), treated with 7 mg/kg CDDP, saline, and DMSO on days 1-10 i.p. and (4) The CDDP + TAD group (CDT) was treated with 7 mg/kg CDDP on day 1, and 0.4 mg/kg tadalafil on days 1-10 i.p. Testes and epididymides samples were collected on day 11. Biochemical and pathological analyses and quantitative polymerase chain reaction were performed on the excised specimens. RESULTS: CDDP treatment resulted in testicular atrophy, decreased sperm concentration, and atrophy of seminiferous tubules as observed from the testicular histology. Increased apoptosis of seminiferous tubules, oxidative stress, and ROCK2 mRNA expression were observed after CDDP treatment. Treatment with tadalafil improved these adverse effects. CONCLUSION: Tadalafil is a potential drug for reducing CDDP-induced spermatogenic dysfunction. The antioxidant effect of tadalafil may be partly responsible for this phenomenon. ROCK2 and oxidative stress markers may be involved in the possible antioxidant effects of tadalafil. Tadalafil may be considered as one of a treatment option for reducing spermatogenic dysfunction after administration of CDDP.

Separation Effect and Development of Implantation Technique of Hydrogel Spacer for Prostate Cancers.

PURPOSE: The purpose of this study is to improve the placement of a hydrogel spacer in patients with prostate cancer receiving radiation therapy. METHODS AND MATERIALS: A total of 160 patients with prostate cancer were classified into 3 groups: No spacer (group 1; n = 30), spacer placed using conventional technique (group 2; n = 100), and spacer placed using new technique (group 3; n = 30). When placing the spacer, the tip of the needle is placed at the middle of the prostate gland (group 2), or at a level corresponding to a cranial:caudal ratio of 6:4 and as close to the prostate gland as possible (group 3). The separation effect was examined and compared among the groups. RESULTS: The separation in group 2 was larger than that in group 1 from the base to the apex level of the prostate (4 mm), but the separation in group 3 was larger than that in group 2 from the middle to the apex level of the prostate (4 mm). The separation values for the middle to the apex, the spacer thickness from the apex level to the apex (10 mm), the rectal exclusion from the middle to the apex, and the laterality were correlated with the 50 and 60 Gy relative biologic effectiveness (Gy[RBE]) rectal dose (P = 4.1 × 10-9 - .046). The separation vales were strongly correlated with the spacer thickness at the apex (10 mm) and the apex (4 mm; P = 1.1 × 10-18 - 1.8 × 10-17). The rectal volumes at 10 to 60 Gy(RBE) differed among the groups (P = 5.1 × 10-19 - 5.4 × 10-3). The rectal volumes in group 2 were smaller than those in group 1 at all dose levels, but those in group 3 were smaller than those in group 2 at dose levels of 30 to 50 Gy(RBE). CONCLUSIONS: The separation, spacer thickness, and rectal exclusion from the middle to the apex of the prostate and the laterality of the hydrogel spacer affected the reduction in the rectal dose. The rectal dose can be further reduced by implanting a spacer on the caudal and prostate side.

Differentiation of Human Induced Pluripotent Stem Cells Into Testosterone-Producing Leydig-like Cells.

Late-onset hypogonadism (LOH) syndrome, due to a partial lack of testosterone, decreases the quality of life of older men. Testosterone is mainly secreted by Leydig cells in the testes. Leydig cell transplantation is expected to be a promising alternative to conventional testosterone replacement therapy for LOH syndrome. We herein report a simple and robust protocol for directed differentiation of human induced pluripotent stem cells (hiPSCs) into Leydig-like cells by doxycycline-inducible overexpression of NR5A1 and treatment with a combination of 8-bromoadenosine-3',5'-cyclic monophosphate (8-Br-cAMP) and forskolin. The differentiated cells expressed the steroidogenic enzyme genes STAR, CYP11A1, CYP17A1, and HSD3B2 and the specific markers of adult Leydig cells HSD17B3, INSL3, and LHCGR. Furthermore, we confirmed the secretion of functional testosterone from the cells into the culture supernatant by a testosterone-sensitive cell proliferation assay. These findings showed that the hiPSCs were able to be differentiated into Leydig-like cells, supporting the expectation that hiPSC-derived Leydig-like cells can be novel tools for treating LOH syndrome.

Improved Lower Urinary Tract Symptoms Associated With Testosterone Replacement Therapy in Japanese Men With Late-Onset Hypogonadism.

This study aimed to investigate the effects of testosterone replacement therapy (TRT) on lower urinary tract symptoms (LUTS) in men with late-onset hypogonadism (LOH) and to identify parameters predicting the efficacy of TRT in improving LUTS. This study included 60 consecutive Japanese men who were diagnosed with LOH and subsequently received TRT between January 2009 and December 2014. In this series, 250 mg of testosterone was injected intramuscularly every 3 or 4 weeks in all patients. The following parameters were retrospectively reviewed: body mass index (BMI), Aging Male Symptom (AMS) score, International Prostate Symptom Score (IPSS), International Index of Erectile Function-5 (IIEF-5) score, residual urine volume, prostate volume, serum levels of the prostate-specific antigen (PSA), and total- and free-testosterone levels before and 6 months after TRT. No significant differences were observed in BMI, residual urine volume, or prostate volume between surveys before and after TRT. The AMS score, IPSS, and IIEF-5 score were significantly improved and significant increases were noted in the serum levels of PSA and total- and free-testosterone levels after TRT. An analysis of IPSS subscores documented the significant improvement in storage symptom scores, but not in voiding symptom scores after TRT. Multivariate analyses of parameters assessed in this study identified the pretreatment AMS score, posttreatment IIEF-5 score, and prostate volume as independent predictors of improvements in IPSS following TRT. This study revealed that TRT appeared to have considerable therapeutic effects on LUTS, particularly on storage symptoms, in men with LOH.

[Clinical Outcome of Laparoscopic Partial Nephrectomy].

The purpose of this study was to evaluate the safety and feasibility of laparoscopic partial nephrectomy with a small renal tumor. Between September 2004 and October 2014, 69 patients who underwent laparoscopic partial nephrectomy in Kansai Rosai Hospial were examined. The mean patient age was 60.3 years, and the mean tumor size was 24.5 mm. The mean estimated blood loss was 111 cc. The mean cold ischemic time was 59.7 minutes, and the mean warm ischemic time was 31.3 minutes. There were 5 complications : intraoperative ureteral injury, blood transfusion, postoperative perinephric hematoma, portsite bleeding, urinary fistula, respectively. All of the cases were cured with non-surgical treatment except ureteral injury which was repaired intraoperatively. The postoperative eGFR loss was 11%. At present, no patients have developed local recurrence or distant metastasis. The initial outcome of laparoscopic partial nephrectomy in our hospital was satisfactory in terms of safety, renal function and cancer control.

An inflammatory myofibroblastic tumor exhibiting immunoreactivity to KIT: a case report focusing on a diagnostic pitfall.

Inflammatory myofibroblastic tumors (IMTs) and gastrointestinal stromal tumors (GISTs) are both spindle cell tumors, and occur rarely in the wall of the urinary bladder. In general, immunostaining allows differentiation of IMTs and GISTs. Most IMTs are positive for anaplastic lymphoma kinase (ALK) and negative for KIT, whereas most GISTs are ALK-negative and KIT-positive. Here, we describe a case of a spindle cell tumor in the wall of the urinary bladder. The spindle cells were positive for both ALK and KIT, and it was thus difficult to determine whether the tumor was an IMT or a GIST. We eventually diagnosed an IMT, because ALK gene rearrangement was confirmed by fluorescent in-situ hybridization. Cytoplasmic staining for KIT and the absence of other GIST markers, including DOG1 and platelet-derived growth factor α, indicated that the tumor was not a GIST. Therefore, IMTs should be included in the differential diagnosis of spindle cell tumors, even those that are KIT-positive.