Evaluating RB1 and p53 as diagnostic markers in treatment-related neuroendocrine prostate cancer through immunohistochemistry and genomic analysis of RB1 and TP53.

BACKGROUND: The diagnosis of treatment-related neuroendocrine prostate cancer (t-NEPC) often involves a pathological assessment and immunohistochemistry (IHC) for neuroendocrine markers. Genomic alterations in RB1 and TP53 are frequently observed in NEPC and are believed to play a crucial role in the transformation of adenocarcinoma to NEPC. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of patients with t-NEPC to better understand their prognosis and diagnostic utility. METHODS: This retrospective study reviewed the records of patients diagnosed with t-NEPC at Kobe University Hospital between October 2018 and December 2022. Clinical data, including age, serum neuroendocrine marker levels, and treatment history, were collected. IHC was performed for conventional neuroendocrine markers (synaptophysin, chromogranin A, and CD56) and RB1 and p53 expression. Next-generation sequencing (NGS) was conducted using FoundationOne® CDx to identify mutations in RB1 and TP53. RESULTS: This study included 20 patients with t-NEPC. The median time from ADT initiation to development was 42.8 months. IHC revealed RB1 loss in 75% of cases and p53 abnormalities in 75% of cases. NGS identified RB1 mutations in 55% and TP53 mutations in 75% of cases. The concordance between NGS and IHC results was high, with 70% (14/20) agreement for RB1/RB1 and 80% (16/20) for p53/TP53. The immunostaining and genomic analysis of RB1/RB1 and p53/TP53 showed abnormal findings for the four negative cases for conventional neuroendocrine markers. CONCLUSIONS: This study indicated high concordance between IHC and NGS findings for RB1/RB1 and p53/TP53 in t-NEPC. We provide a comprehensive benchmark of NGS performance compared with IHC, and these findings may help increase the diagnostic sensitivity of t-NEPC.

Temporal declines in bone mineral density and trabecular bone score during androgen deprivation therapy.

INTRODUCTION: The trabecular bone score (TBS) has emerged as a convenient measure for assessing the microstructure of trabecular bone in the second through fourth lumbar vertebrae (L2-4) and can be conducted concurrently with bone mineral density (BMD) assessment. This study was performed to evaluate changes in BMD and the TBS during ADT for prostate cancer. MATERIALS AND METHODS: Consecutive patients who had prostate cancer without bone metastases at Kobe University Hospital were studied from March 2020 to December 2021. BMD and TBS were measured every 6 months from the start of treatment using Hologic Horizon devices (Hologic, Inc., Marlborough, MA, USA). RESULTS: Thirty-four patients were followed for 2 years. Significant declines in BMD (-3.8% for femoral neck, -4.2% for total hip, and -6.1% for lumbar spine) and TBS (-16.6%) were noted after 2 years of ADT. Correlation analyses revealed a weak correlation between lumbar spine BMD and TBS at ADT initiation, but this correlation strengthened after 2 years. The multiple regression analysis results suggested that the rate of BMD loss may be slower in patients with a preserved pretreatment TBS. CONCLUSION: In patients without bone metastases undergoing ADT for prostate cancer, notable decreases were found in both BMD and TBS over a 2-year treatment period. Factors influencing the TBS decline remain unclear; however, patients with a lower pretreatment TBS exhibited a more rapid decline in BMD.

Choosing the optimal therapy for metastatic renal cell carcinoma: Insights from a real-world comparative study.

BACKGROUND: The evolution of combination therapies integrating immune checkpoint inhibitors has revolutionized the first-line treatment of metastatic renal cell carcinoma (mRCC). Although these therapies are clinically approved, direct comparisons between dual immune checkpoint inhibitors (IOIO) and immune checkpoint inhibitors combined with tyrosine kinase inhibitors (IOTKI) in clinical trials are lacking. This gap creates uncertainties in selecting the most appropriate treatment based on patient-specific factors. METHODS: This study employed the inverse probability of treatment weighting (IPTW) method to analyze progression-free survival (PFS) and overall survival (OS) for patients with mRCC receiving IOIO or IOTKI treatment regimens. RESULTS: A total of 171 patients were analyzed after applying inclusion criteria and propensity scoring. The study found no significant differences in PFS and OS between the two treatment modalities in the IPTW cohort. However, subgroup analyses revealed that IOTKI therapy was associated with better PFS and OS for patients without bone metastases and better OS for patients with a body mass index (BMI) over 25. IOIO therapy showed better OS for patients with a BMI below 18.5. CONCLUSION: Both IOIO and IOTKI therapies were effective. Therapy selection could be better tailored to patient characteristics by including factors such as the presence of bone metastases and BMI. This study enhances understanding of how patient-specific factors interact with different treatment modalities, potentially guiding more personalized treatment decisions in clinical practice for mRCC.

Effects of modifying hinotori™ surgical robot system on perioperative outcome of robot-assisted radical prostatectomy.

OBJECTIVES: One of the main advantages of the hinotori™ surgical robot system (HSRS) is that it can be easily adjusted. This study aimed to clarify the effects of modifying the HSRS on the perioperative outcomes of robotic-assisted radical prostatectomy (RARP). METHODS: Overall, 158 cases of RARP using the HSRS were classified into three groups based on the modification to the system: group A (no modification, 70 cases), group B (addition of the ability to switch between two types of scopes and to adjust the arm base tilt back and forth, left and right, 42 cases), and group C (reduction of arm floating sensation, mitigation of emergency stop during arm collision, and addition of clutch function via hand switch in addition to foot pedal, 46 cases). The perioperative outcomes of each group were compared. RESULTS: The median of operation time, cockpit time, and cockpit time excluding the time required for lymph node dissection of group C were 223, 146, and 135 min, respectively, where are significantly shorter than those of group A (308, 228, and 208 min, p < 0.0001, respectively) and group B (319, 241, and 214 min, p < 0.0001, respectively). There was no significant difference in the rate of positive margin rates and the pad-free rate before the first follow-up visit among these three groups. The complication rates in groups A, B, and C were 11.4%, 9.4%, and 8.4% (Clavien-Dindo grades I-II), and 4.3%, 2.4%, and 0% (grade III), respectively. CONCLUSIONS: The modifications to the HSRS have enabled smoother surgical procedures for RARP.

Adrenalectomy for pheochromocytoma: Surgical outcomes and preoperative risk factors for hemodynamic instability.

BACKGROUND: Surgical resection for pheochromocytoma (PCC) is still challenging. This study assessed the perioperative outcomes of adrenalectomy for PCC and investigated the risk factors for intraoperative hemodynamic instability (HI). METHODS: This retrospective study included 571 patients with adrenal tumors who underwent adrenalectomy at Kobe University Hospital and other related hospitals between April 2008 and October 2023. The perioperative outcomes of laparoscopic adrenalectomy were compared between PCC (n = 92) and non-PCC (n = 464) groups. In addition, we investigated several potential risk factors for intraoperative HI in patients with PCC (n = 107; open, n = 11; laparoscopic, n = 92; robot-assisted, n = 4). RESULTS: While patients with PCC had a significantly larger amount of blood loss in comparison to those with non-PCC (mean, 70 and 30 mL, respectively; p = 0.004), no significant difference was observed in the rate of perioperative grade ≥III complications (1.1% vs. 0.6%; p = 0.516), and no perioperative mortality was observed in either group. A tumor size of ≥40 mm, with preoperative hypertension and urinary metanephrines at a level ≥3 times the upper limit of the normal value, were found to be significant predictors of HI, with odds ratios of 2.74 (p = 0.025), 3.91 (p = 0.005), and 3.83 (p = 0.004), respectively. CONCLUSIONS: Our data suggest that laparoscopic adrenalectomy for PCC may be as safe as that for other types of adrenal tumors and that large tumors and hormonally active disease may be risk factors for intraoperative HI. The optimal perioperative management for PCC with these risk factors should be established.

Differences in clinical outcomes between men with mosaic Klinefelter syndrome and those with non-mosaic Klinefelter syndrome.

Purpose: This study compared the clinical outcomes of men with Klinfelter syndrome based on karyotype. Methods: The authors analyzed the outcomes of microdissection testicular sperm extraction (micro-TESE) performed on 57 patients with Klinfelter syndrome (KS) at our clinic. Results: The average ages of the non-mosaic and mosaic KS groups were 32.2 ± 4.8 and 45.9 ± 13.1 years, respectively. The sperm retrieval rates of the non-mosaic and mosaic KS groups were 46.5% (20/43) and 50.0% (7/14), respectively. The fertilization rates after intracytoplasmic sperm injection did not significantly differ between the non-mosaic and mosaic KS groups. The mosaic KS group had higher cleavage and blastocyst development rates than the non-mosaic KS group (72.2% vs. 96.2% and 30.5% vs. 44.7%, respectively). The group using motile sperm had better outcomes than the group using immotile sperm. The embryo transfer outcomes of the non-mosaic and mosaic KS groups did not significantly differ (clinical pregnancy rate: 28.0% vs. 20.7%, miscarriage rate: 14.3% vs. 33.3%, production rate per transfer: 22.0% vs. 13.8%, and production rate per case: 58.8% vs. 57.1%). Conclusions: Compared with the non-mosaic KS group, the mosaic KS group had significantly better intracytoplasmic sperm injection outcomes because of the higher utilization rate of motile sperm.

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.

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.

Transplacental Pharmacokinetic Model of Digoxin Based on Ex Vivo Human Placental Perfusion Study.

Digoxin is used as first-line therapy to treat fetal supraventricular tachycardia; however, because of the narrow therapeutic window, it is essential to estimate digoxin exposure in the fetus. The data from ex vivo human placental perfusion study are used to predict in vivo fetal exposure noninvasively, but the ex vivo fetal-to-maternal concentration (F:M) ratios observed in digoxin perfusion studies were much lower than those in vivo. In the present study, we developed a human transplacental pharmacokinetic model of digoxin using previously reported ex vivo human placental perfusion data. The model consists of maternal intervillous, fetal capillary, non-perfused tissue, and syncytiotrophoblast compartments, with multidrug resistance protein (MDR) 1 and influx transporter at the microvillous membrane (MVM) and influx and efflux transporters at the basal plasma membrane (BM). The model-predicted F:M ratio was 0.66, which is consistent with the mean in vivo value of 0.77 (95% confidence interval: 0.64-0.91). The time to achieve the steady state from the ex vivo perfusion study was estimated as 1,500 minutes, which is considerably longer than the reported ex vivo experimental durations, and this difference is considered to account for the inconsistency between ex vivo and in vivo F:M ratios. Reported digoxin concentrations in a drug-drug interaction study with MDR1 inhibitors quinidine and verapamil were consistent with the profiles simulated by our model incorporating inhibition of efflux transporter at the BM in addition to MVM. Our modeling and simulation approach should be a powerful tool to predict fetal exposure and DDIs in human placenta. SIGNIFICANCE STATEMENT: We developed a human transplacental pharmacokinetic model of digoxin based on ex vivo human placental perfusion studies in order to resolve inconsistencies between reported ex vivo and in vivo fetal-to-maternal concentration ratios. The model successfully predicted the in vivo fetal exposure to digoxin and the drug-drug interactions of digoxin and P-glycoprotein/multidrug resistance protein 1 inhibitors in human placenta.

Development of a Pharmacokinetic Model of Transplacental Transfer of Metformin to Predict In Vivo Fetal Exposure.

Two types of systems are used in ex vivo human placental perfusion studies to predict fetal drug exposures, that is, closed systems with recirculation of the maternal and fetal buffer and open systems using a single-pass mode without recirculation. The in vivo fetal/maternal (F:M) ratio of metformin, a cationic drug that crosses the placenta, is consistent with that reported in an open system ex vivo but not with that in a closed system. In the present study, we aimed to develop a pharmacokinetic (PK) model of transplacental transfer of metformin to predict in vivo fetal exposure to metformin and to resolve the apparent inconsistency between open and closed ex vivo systems. The developed model shows that the difference between open and closed systems is due to the difference in the time required to achieve the steady state. The model-predicted F:M ratio (approx. 0.88) is consistent with reported in vivo values [mean (95% confidence interval): 1.10 (0.69-1.51)]. The model incorporates bidirectional transport via organic cation transporter 3 (OCT3) at the basal plasma membrane, and simulations indicate that the use of trimethoprim (an OCT3 inhibitor) to prevent microbial growth in the placenta ex vivo has a negligible effect on the overall maternal-to-fetal and fetal-to-maternal clearances. The model could successfully predict in vivo fetal exposure using ex vivo human placental perfusion data from both closed and open systems. This transplacental PK modeling approach is expected to be useful for evaluating human fetal exposures to other poorly permeable compounds, besides metformin. SIGNIFICANCE STATEMENT: We developed a pharmacokinetic model of transplacental transfer of metformin, used to treat gestational diabetes mellitus, in order to predict in vivo fetal exposure and resolve the discrepancy between reported findings in open and closed ex vivo perfusion systems. The discrepancy is due to a difference in the time required to reach the steady state. The model can predict in vivo fetal exposure using data from both closed and open systems.

Sperm retrieval from a male with the rare 47, XXYqs variant of Klinefelter syndrome for intracytoplasmic sperm injection: A case report.

A 27-year-old man with nonobstructive azoospermia was diagnosed with Klinefelter syndrome (KS) with a satellite Y chromosome (47, XXYqs) by karyotyping. Genetic analysis revealed azoospermia factor c (AZFc) microdeletion of gr/gr deletion in the Y chromosome. Microdissection testicular sperm extraction (micro-TESE) was performed in bilateral testes. Very few seminiferous tubules were bilaterally observed, and a minute number of spermatozoa obtained from the left testis were cryopreserved. Histologic examination of the left testicular tissue revealed severe tubular atrophy with only Sertoli cells accompanied by Leydig cell hyperplasia. Oocyte harvest was conducted in his wife in two different cycles after ovarian stimulation, and intracytoplasmic sperm injection was performed for 24 oocytes (8 and 16 oocytes respectively) using thawed spermatozoa. Fertilisation was confirmed in total of 19 oocytes (79.2%), with 15 cleaved embryos (62.5%). Two cleavage-stage embryos were cryopreserved at day 2, but no blastocysts developed. Frozen-thawed embryo transfer was performed using two cleavage-stage (day 2) embryos; however, the wife did not conceive. In conclusion, spermatozoa were successfully obtained by micro-TESE from a patient with 47, XXYqs. Despite failure of conception, the fertilisation and cleavage rates were comparable or better than those reported in patients with "typical" KS.

Application of hyaluronic acid/carboxymethyl cellulose membrane for early continence after nerve-sparing robot-assisted radical prostatectomy.

BACKGROUND: To assess whether application of a hyaluronic acid-carboxymethyl cellulose membrane (HA/CMC) to the prostate bed and neurovascular plate facilitated early return of continence after nerve-sparing robot-assisted radical prostatectomy (RARP). METHODS: The subjects were 183 consecutive patients with organ-confined prostate cancer who underwent unilateral or bilateral nerve-sparing RARP. After vesicourethral anastomosis, HA/CMC was placed to cover Denonvilliers' fascia (behind the anastomotic suture) and the preserved neurovascular plate. The time until complete continence after RARP and perioperative complications were compared between patients with or without HA/CMC. RESULTS: HA/CMC was applied in 13/46 patients (28.3%) receiving bilateral nerve-sparing surgery and 40/137 patients (29.2%) receiving unilateral nerve-sparing surgery. After bilateral nerve-sparing RARP, the median time until continence was significantly shorter in patients with HA/CMC than in those without HA/CMC (3.2 vs. 9.3 months, respectively, p < 0.01). After unilateral nerve-sparing RARP, the median time until continence was also significantly shorter in patients with HA/CMC than in those without HA/CMC (3.2 vs. 12.0 months, respectively, p < 0.01). Multivariate Cox proportional hazards regression analysis showed that an age < 70 years (hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.12-2.80), institutional caseload > 200, (HR: 1.64, 95%CI: 1.10-2.47), and use of HA/CMC (HR: 1.84, 95%CI: 1.22-2.76) were independent predictors of early postoperative continence. Complication rates, including urinary leakage, did not differ significantly between patients with or without HA/CMC. CONCLUSION: Application of HA/CMC to the prostate bed and neurovascular plate resulted in significantly faster postoperative return of continence after both unilateral and bilateral nerve-sparing RARP.

Effect of mirabegron on tight junction molecules in primary cultured rat Sertoli cells.

Mirabegron is a selective beta3-adrenoceptor (ß3 -AR) agonist, which is commonly used for the treatment of overactive bladder. This medicine is associated with atrophy of reproductive organs in rats. However, no study has examined the detailed action and mechanism of its toxicity in reproductive cells. In this study, we examined the effect of mirabegron on primary cultured rat Sertoli cells. Firstly, RT-PCR and immunocytochemistry revealed that ß3 -AR was present in rat Sertoli cells. Then, primary cultured rat Sertoli cells were treated with mirabegron. Quantitative real-time PCR revealed that mirabegron treatment induced a significant increase in claudin-11 mRNA, which is crucial for spermatogenesis. Western blot analysis also showed that mirabegron treatment significantly activated p44/42 mitogen-activated protein kinase (MAPK). After additional treatment with U0126, a specific noncompetitive inhibitor of mitogen-activated protein kinase kinase (MAPKK), the upregulation of claudin-11 mRNA induced by mirabegron was reduced. At the same time, immunocytochemistry showed mirabegron treatment disturbed claudin-11 localisation to tight junction, which was recovered when treated with mirabegron in the presence of U0126. These results suggest that mirabegron treatment is associated with assembly of the blood-testis barrier through p44/42 MAPK pathway. These findings could explain one of the underlying mechanisms of reproductive toxicity induced by mirabegron.

Two cases of reversible male infertility due to congenital adrenal hyperplasia combined with testicular adrenal rest tumor.

Cases: Testicular adrenal rest tumor (TART) is one of the possible causes of male infertility, accompanied by congenital adrenal hyperplasia (CAH). Here are reported two cases of TARTs that were referred to Kobe City Medical Center West Hospital for the treatment of infertility and testicular tumors. Outcome: In one case, the semen analysis was improved from oligoasthenozoospermia to normozoospermia after taking oral glucocorticoid supplementation. The other case of original azoospermia showed that sperm had ejaculated into the semen after taking oral glucocorticoid supplementation. Conclusion: Although the prevalence of TARTs in male infertility is very rare, it is important to know how to approach this disease, considering the curable pathology of spermatogenesis and tumors resembling an appearance to germ cell tumors.

Nationwide survey of urological specialists regarding male infertility: results from a 2015 questionnaire in Japan.

Purpose: To investigate the incidence, etiology, treatment indications, and outcomes regarding infertile male patients in Japan. Methods: Between April, 2014 and March, 2015, the authors contacted 47 clinical specialists in male infertility who had been certified by the Japan Society for Reproductive Medicine. The participating clinicians were sent a questionnaire regarding information on their infertile patients, according to etiology and the number and success rates of male infertility operations that had been performed in their practice. Results: Thirty-nine specialists returned the questionnaire and provided information regarding 7268 patients. The etiology of infertility included testicular factors, sexual disorders, and seminal tract obstruction. During the study year, the clinicians performed varicocelectomies, testicular sperm extractions (TESEs), and re-anastomoses of the seminal tract. The rate of successful varicocelectomies was >70%. The sperm retrieval rates with conventional TESE and microdissection TESE were 98.3% and 34.0%, respectively, while the patency rates with vasovasostomy and epididymovasostomy were 81.8% and 61.0%, respectively. Conclusion: Surgical outcomes for infertile male patients are favorable and can be of great clinical benefit for infertile couples. To achieve this, urologists should work in collaboration with gynecological specialists in order to optimize the treatment of both partners.

An Empirical Study of the Prescription Pattern of Drugs for Hematological Malignancies in Japan from 2010-2014.

The number of elderly patients with hematologic malignancies has been steadily increasing with the aging of society. However, little research has been conducted to evaluate the prescription status of drugs for such diseases in Japan. Therefore, the aims of this study were to identify the patient population currently being prescribed drugs for hematologic malignancies in Japan and the direction of drug development. To examine the prescription pattern of drugs for the treatment of hematological malignancies in Japan from 2010-2014, we used the IMS Japan Pharmaceutical Market database and the Japanese Society of Hematology Clinical Practice Guidelines, and for drug development status, we used ClinicalTrials.gov and the University Hospital Medical Information Network Clinical Trials Registry. We found a significant upward trend in prescriptions for molecular-targeted agents, which are typically prescribed over the long term, and a significant downward trend in chemotherapeutic agents, which are usually prescribed for the short term. We also found that recent drug development in hematological malignancies has focused on molecular-targeted agents. These results suggest that drug development should be directed toward anti-tumor agents in hematological malignancies that can help maintain and improve patients' QOL.

LOH (late-onset hypogonadism) syndrome.

Testosterone deficiency has recently drawn wide attention due to the high prevalence of hypo-gonadal symptoms in the aging male population. A number of studies have reported the beneficial effects of testosterone replacement therapy for men with late-onset hypogonadism (LOH) syndrome. Based on the study evaluating the age distribution of serum testosterone concentration, serum free testosterone less than 8.5 pg/mL is considered as a good indica- tion for testosterone replacement therapy among the Japanese population. However, at present, testosterone enanthate is the only drug that is covered by health insurance in Japan. Further studies are needed to establish more suitable treatment in men with LOH syndrome among Japanese population.

Characterization of urocortin as an anti-apoptotic protein in experimental ischemia-reperfusion model of the rat testis.

The objective of this study was to investigate the role of urocortin in testicular apoptosis using an experimental ischemia-reperfusion rat model. To evaluate the change in urocortin expression and apoptotic status in the testes following ischemia-reperfusion, the left testes of rats were rotated clockwise by 720° for 1 h, and were then harvested at 0, 1, 3, 6 and 24 h after detorsion (n = 5 in each group). A time-dependent increase in the expression levels of urocortin was noted until 6 h after reperfusion, but the expression of urocortin was markedly decreased 24 h after reperfusion. However, a TUNEL assay showed that the proportion of germ cells undergoing apoptosis significantly increased 24 h after reperfusion compared with that of 6 h after reperfusion. To clarify whether or not urocortin directly regulates the testicular apoptosis induced by ischemia-reperfusion, either astressin, an antagonist of urocortin, or normal saline was injected into the rat testes 15 min before detorsion, followed by the testicular torsion. The testes were then removed 3 h after detorsion (n = 5 in each group). The testicular injection of astressin significantly increased the proportion of TUNEL-positive germ cells, and significantly decreased expression of Bcl-2 and Bcl-xL. In addition, the level of phosphorylated ERK 1/2, but not that of phosphorylated Akt, was significantly reduced by the intratesticular administration of astressin. These findings suggest that urocortin may play a cytoprotective role in the germ cells in response to ischemia-reperfusion injury through the activation of major anti-apoptotic proteins, as well as by the mitogen-activated protein kinase signaling pathway activation.

The development of surgical sperm extraction and new challenges to improve the outcome.

Surgical sperm extraction with intracytoplasmic sperm injection has become widespread worldwide and is regarded as the sole option for patients with azoospermia. However, the sperm retrieval rate remains unsatisfactorily low, particularly for men with non-obstructive azoospermia (NOA). Therefore, the technical challenges associated with improving the sperm retrieval rate for men with NOA are being addressed. The most successful method developed to date is microdissection testicular sperm extraction (micro-TESE), which is rapidly becoming recognized as a useful technique due to its relatively high sperm retrieval rate and low complication rate. However, even with micro-TESE, the sperm retrieval rate for men with NOA remains at 30-60 %, with an even lower birth rate. The technical challenges associated with improving the outcomes of surgical sperm extraction are being approached through the use of ultrasound and optimal surgical devices such as narrow band imaging, multiphoton microscopy, and optical coherent tomography. In addition to the difficulties related to searching for sperm, medical treatments that induce spermatogenesis remain controversial. For example, varicocele repair prior to surgical sperm extraction and hormonal therapy before and after TESE have been extensively examined. We herein briefly summarized the development process in surgical sperm extraction up to the present and technical challenges to improve the outcomes of surgical sperm extraction.