Protocol for a prospective multicenter intervention study (URivo study) assessing biomarkers in patients with previously treated advanced clear cell renal cell carcinoma receiving nivolumab

Background:In recent years, immune checkpoint inhibitors have been introduced into routine clinical practice for treating patients with a wide variety of malignant tumors, including advanced renal cell carcinoma (aRCC), resulting in the significant improvement of the prognosis of these patients. However, a reliable biomarker prediciting the clinical course in patients receiving nivolumab has not yet been developed; accordingly, the URivo study was planned to investigate the significance of various candidate biomarkers for aRCC patients treated with nivolumab.Methods:This was designed as a prospective multicenter intervention study, and will include a total of 200 aRCC patients who are scheduled to receive nivolumab followed by treatment with either 1 or 2 tyrosine kinase inhibitors (TKIs). Using resected tumor tissues and serum samples prior to the introduction of nivolumab, the following assessments will be conducted: programmed death ligand-1 (PD-L1) and PD-L2 gene copy number gains by fluorescence in situ hybridization, serum concentrations of PD-L1 and PD-L2 by enzyme-linked immunosorbent assay, and expression ofseveral proteins involved in apoptosis, epithelial-mesenchymal transition, signal transduction and immune reaction by immunohistochemical staining. The outcomes of these assays will be evaluated focusing on the association with the response to nivolumab, overall survival, progression-free survival and disease-specific survival.Conclusions: The significance of various types of candidate biomarker, particularly PD-L1 and PD-L2, will be intensively investigated in this study, and this may offer unique information to determine the optimal indication of nivolumab for aRCC patients following the failure of TKIs.Trial Registration:UMIN000030400; registered April 1, 2018

Recovery of Spermatogenesis Following Cancer Treatment with Cytotoxic Chemotherapy and Radiotherapy

The survival rates of boys and men with cancer have increased due to advances in cancer treatments; however, maintenance of quality of life, including fertility preservation, remains a major issue. Fertile male patients who receive radiation and/or chemotherapy face temporary, long-term, or permanent gonadal damage, particularly with exposure to alkylating agents and whole-body irradiation, which sometimes induce critical germ cell damage. These cytotoxic treatments have a significant impact on a patient's ability to have their own biological offspring, which is of particular concern to cancer patients of reproductive age. Therefore, various strategies are needed in order to preserve male fertility. Sperm cryopreservation is an effective method for preserving spermatozoa. Advances have also been achieved in pre-pubertal germ cell storage and research to generate differentiated male germ cells from various types of stem cells, including embryonic stem cells, induced pluripotent stem cells, and spermatogonial stem cells. These approaches offer hope to many patients in whom germ cell loss is associated with sterility, but are still experimental and preliminary. This review examines the current understanding of the effects of chemotherapy and radiation on male fertility.

Computed Diffusion-Weighted Imaging in Prostate Cancer: Basics, Advantages, Cautions, and Future Prospects

Computed diffusion-weighted MRI is a recently proposed post-processing technique that produces b-value images from diffusion-weighted imaging (DWI), acquired using at least two different b-values. This article presents an argument for computed DWI for prostate cancer by viewing four aspects of DWI: fundamentals, image quality and diagnostic performance, computing procedures, and future uses.

Clinical Outcomes of Varicocele Repair in Infertile Men: A Review

Varicoceles are a major cause of impaired spermatogenesis and the most common correctable cause of male infertility. They are found in approximately 40% of men with primary infertility and 80% of men with secondary infertility, although they also occur in 12% of men with normal semen parameters. The presence of a varicocele does not always affect spermatogenesis, as it has been reported that only 20% of men with documented varicoceles suffer fertility problems. However, varicocele repair appears to have beneficial effects in men with impaired semen parameters and palpable varicoceles. Currently, the main procedures employed for varicocele repair are microsurgical subinguinal or inguinal varicocelectomy, laparoscopic varicocelectomy, and radiological percutaneous embolization. Microsurgical varicocelectomy appears to be the optimal treatment in most cases, whereas the other procedures are useful only in specific cases. After treatment, it typically takes 3 to 6 months for patients' semen parameters to improve; thus, other therapies, including assisted reproductive technology, should be considered if infertility persists after this interval, especially in older couples. Controversies still remain regarding how varicoceles in certain subgroups, such as adolescents or men with azoospermia, should be treated. Due to their relatively high prevalence rate among the general population, varicoceles can occur concomitantly with other conditions that cause impaired spermatogenesis. Further studies are necessary in order to identify the patients who are most likely to benefit from treatment. In this review, we sought to summarize the issues currently associated with varicocele treatment in infertile men.

Comparison of Predictive Factors for Postoperative Incontinence of Holmium Laser Enucleation of the Prostate by the Surgeons' Experience During Learning Curve / 대한배뇨장애요실금학회지

PURPOSE: To detect predictive factors for postoperative incontinence following holmium laser enucleation of the prostate (HoLEP) according to surgeon experience (beginner or experienced) and preoperative clinical data. METHODS: Of 224 patients, a total of 203 with available data on incontinence were investigated. The potential predictive factors for post-HoLEP incontinence included clinical factors, such as patient age, and preoperative urodynamic study results, including detrusor overactivity (DO). We also classified the surgeons performing the procedure according to their HoLEP experience: beginner (<21 cases) and experienced (≥21 cases). RESULTS: Our statistical data showed DO was a significant predictive factor at the super-short period (the next day of catheter removal: odds ratio [OR], 3.375; P=0.000). Additionally, patient age, surgeon mentorship (inverse correlation), and prostate volume were significant predictive factors at the 1-month interval after HoLEP (OR, 1.072; P=0.004; OR, 0.251; P=0.002; and OR, 1.008; P=0.049, respectively). With regards to surgeon experience, DO and preoperative International Prostate Symptom Score (inverse) at the super-short period, and patient age and mentorship (inverse correlation) at the 1-month interval after HoLEP (OR, 3.952; P=0.002; OR, 1.084; P=0.015; and OR,1.084; P=0.015; OR, 0.358; P=0.003, respectively) were significant predictive factors for beginners, and first desire to void (FDV) at 1 month after HoLEP (OR, 1.009; P=0.012) was a significant predictive factor for experienced surgeons in multivariate analysis. CONCLUSIONS: Preoperative DO, IPSS, patient age, and surgeon mentorship were significant predictive factors of postoperative patient incontinence for beginner surgeons, while FDV was a significant predictive factors for experienced surgeons. These findings should be taken into account by surgeons performing HoLEP to maximize the patient's quality of life with regards to urinary continence.

Nerves and fasciae in and around the paracolpium or paravaginal tissue: an immunohistochemical study using elderly donated cadavers / 대한해부학회지

The paracolpium or paravaginal tissue is surrounded by the vaginal wall, the pubocervical fascia and the rectovaginal septum (Denonvilliers' fascia). To clarify the configuration of nerves and fasciae in and around the paracolpium, we examined histological sections of 10 elderly cadavers. The paracolpium contained the distal part of the pelvic autonomic nerve plexus and its branches: the cavernous nerve, the nerves to the urethra and the nerves to the internal anal sphincter (NIAS). The NIAS ran postero-inferiorly along the superior fascia of the levator ani muscle to reach the longitudinal muscle layer of the rectum. In two nulliparous and one multiparous women, the pubocervical fascia and the rectovaginal septum were distinct and connected with the superior fascia of the levator at the tendinous arch of the pelvic fasciae. In these three cadavers, the pelvic plexus and its distal branches were distributed almost evenly in the paracolpium and sandwiched by the pubocervical and Denonvilliers' fasciae. By contrast, in five multiparous women, these nerves were divided into the anterosuperior group (bladder detrusor nerves) and the postero-inferior group (NIAS, cavernous and urethral nerves) by the well-developed venous plexus in combination with the fragmented or unclear fasciae. Although the small number of specimens was a major limitation of this study, we hypothesized that, in combination with destruction of the basic fascial architecture due to vaginal delivery and aging, the pelvic plexus is likely to change from a sheet-like configuration to several bundles.

Topohistology of sympathetic and parasympathetic nerve fibers in branches of the pelvic plexus: an immunohistochemical study using donated elderly cadavers / 대한해부학회지

Although the pelvic autonomic plexus may be considered a mixture of sympathetic and parasympathetic nerves, little information on its composite fibers is available. Using 10 donated elderly cadavers, we investigated in detail the topohistology of nerve fibers in the posterior part of the periprostatic region in males and the infero-anterior part of the paracolpium in females. Neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP) were used as parasympathetic nerve markers, and tyrosine hydroxylase (TH) was used as a marker of sympathetic nerves. In the region examined, nNOS-positive nerves (containing nNOS-positive fibers) were consistently predominant numerically. All fibers positive for these markers appeared to be thin, unmyelinated fibers. Accordingly, the pelvic plexus branches were classified into 5 types: triple-positive mixed nerves (nNOS+, VIP+, TH+, thick myelinated fibers + or -); double-positive mixed nerves (nNOS+, VIP-, TH+, thick myelinated fibers + or -); nerves in arterial walls (nNOS-, VIP+, TH+, thick myelinated fibers-); non-parasympathetic nerves (nNOS-, VIP-, TH+, thick myelinated fibers + or -); (although rare) pure sensory nerve candidates (nNOS-, VIP-, TH-, thick myelinated fibers+). Triple-positive nerves were 5-6 times more numerous in the paracolpium than in the periprostatic region. Usually, the parasympathetic nerve fibers did not occupy a specific site in a nerve, and were intermingled with sympathetic fibers. This morphology might be the result of an "incidentally" adopted nerve fiber route, rather than a target-specific pathway.

Significance of Neoadjuvant Hormonal Therapy in Radical Retropubic Prostatectomy: A Retrospective Single-Surgeon Study

PURPOSE: The purpose of this study was to evaluate whether neo-adjuvant hormonal therapy (NHT) prior to radical retropubic prostatectomy (RRP) for prostate cancer (PCa) is beneficial in terms of surgical outcomes and for preventing or delaying biochemical recurrence via single-surgeon case series study. MATERIALS AND METHODS: Fifty-three men underwent RRP by a single surgeon. The patients were divided into two groups according to whether or not NHT was performed prior to RRP. The study was analyzed retrospectively. We evaluated clinical parameters, surgical parameters, and biochemical recurrence rate. Group 1 (n=34) was treated with RRP only, while Group 2 (n=19) underwent RRP along with NHT. RESULTS: There were no significant differences in clinical, operation-related and pathological factors between the two groups (p>0.05). There was also no significant difference in biochemical recurrence rate between the two groups at the last follow-up, although Group 2 tended to have a lower PCa recurrence rate than Group 1 and the initial prostate-specific antigen (PSA) level was significantly higher in Group 2 than Group 1 (p=0.0496). CONCLUSION: The present single-surgeon case series study revealed a trend toward a lower rate of PCa recurrence in NHT+RRP treated patients compared to those treated with RRP alone, but this did not reach statistical significance, despite the fact that NHT+RRP patients exhibited higher serum PSA levels preoperatively. Prospective studies with a longer duration of observation and a greater number of patients would be helpful in evaluating NHT more definitively.

Possible Role of Sonic Hedgehog and Epithelial-Mesenchymal Transition in Renal Cell Cancer Progression

PURPOSE: Sonic hedgehog (Shh) signaling and epithelial-mesenchymal transition (EMT) are both known to relate to cancer progression. The purpose of this study was to investigate the role of Shh signaling and EMT in renal cell carcinoma (RCC). MATERIALS AND METHODS: Cell proliferation was assayed in RCC cell lines in the presence or absence of a Shh signaling stimulator, recombinant Shh (r-Shh) protein, or a Shh signaling inhibitor, cyclopamine. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed to study the expression of EMT markers (E-cadherin, N-cadherin, and vimentin) and osteonectin. The expression of Ki-67, Gli-1, osteonectin, and EMT markers in nephrectomy specimens from RCC patients was also measured by immunohistochemical (IHC) staining. RESULTS: RCC cells showed enhanced cell proliferation by r-Shh protein, whereas cell proliferation was suppressed by the addition of cyclopamine in RenCa cells. Real-time RT-PCR showed that r-Shh suppressed the expression of E-cadherin and that this suppression was partly blocked by cyclopamine alone in RenCa cells. In the IHC results, osteonectin significantly correlated with vein sinus invasion (p=0.0218), and the expression of vimentin significantly correlated with lymphatic invasion (p=0.0392). CONCLUSIONS: Shh signaling and EMT play roles in RCC progression, and the Shh signaling inhibitor cyclopamine might be a possible molecular targeted therapeutic strategy for RCC.

Efficacy of Using Three-Tesla Magnetic Resonance Imaging Diagnosis of Capsule Invasion for Decision-Making About Neurovascular Bundle Preservation in Robotic-Assisted Radical Prostatectomy

PURPOSE: To evaluate the efficacy of using 3-tesla (T) magnetic resonance imaging (MRI) diagnosis of extracapsular extension (ECE) for decision-making about neurovascular bundle (NVB) preservation in robot-assisted radical prostatectomy (RARP) for prostate cancer (PC). MATERIALS AND METHODS: We prospectively collected data on PC patients (n=67) who underwent preoperative 3-T MRI before RARP. The choice between nerve sparing or resection was based on 3-T MRI findings of ECE. We compared the MRI findings with the pathological data on surgical margins. Our clinical staging in this study was defined only by MRI. RESULTS: When the data were divided by prostate lobe (right lobe or left lobe, n=134), 3-T MRI showed 28 positive cases of ECE in 134 prostate lobes, allowing NVB preservation in 42 cases (31.3%). Nerve-sparing surgery was achieved in 38.7% of cases in which clinical T2 staging by MRI was reported. The pathological data revealed that 10 of 134 prostate lobes had positive ECE. The overall sensitivity, specificity, positive predictive value, and negative predictive value for predicting stage T3 (positive ECE) by side were 60.0% (12 of 20 sides), 86.0% (98 of 114 sides), 42.9% (12 of 28 sides), and 92.5% (98 of 106 sides), respectively. CONCLUSIONS: Three-T MRI prior to RARP enables the use of ECE diagnosis to guide decision-making about NVB preservation, with comparatively high specificity and negative predictive value. Further prospective studies are underway to reach more definitive conclusions.

Postoperative Infectious Complications in Our Early Experience With Holmium Laser Enucleation of the Prostate for Benign Prostatic Hyperplasia

PURPOSE: The objective of this study was to retrospectively investigate postoperative infectious complications (PICs) in our early experience with holmium laser enucleation of the prostate (HoLEP) followed by mechanical morcellation for symptomatic benign prostatic hyperplasia. MATERIALS AND METHODS: A retrospective review was performed of the clinical data for 90 consecutive patients who underwent HoLEP at our institution between February 2008 and March 2011. All patients were evaluated for the emergence of PICs, including prophylactic antibiotic administration (PAA) and the influence of the kind or duration of PAA on PIC. The details of cases with PICs were also examined. RESULTS: The patients' mean age was 71 years (range, 50 to 95 years), and their mean prostate volume was 60 mL (range, 2 to 250 mL). There were 7 cases (7.78%) with PICs; in detail, 3 patients were diagnosed with prostatitis, 2 with pyelonephritis, and 2 with epididymitis. Three patients had positive urine cultures: 1 had Serratia marcescens/Proteus mirabilis, 1 had S. marcescens, and 1 had Klebsiella pneumonia; only one case had urological sepsis. Our statistical data showed no significant differences between 2 or fewer days and 3 or more days of PAA and PIC occurrence. There was also no significant effect on PIC occurrence of sulbactam/ampicillin compared with other antibiotics. CONCLUSIONS: The results of this retrospective study showed that PIC occurrence did not depend on the duration or the kind of PAA. Further prospective study is necessary for the evaluation and establishment of prophylactic measures for PICs.

Efficacy of Combination Use of Beta-Lactamase Inhibitor with Penicillin and Fluoroquinolones for Antibiotic Prophylaxis in Transrectal Prostate Biopsy

PURPOSE: To investigate the efficacy of tazobactam/piperacillin (TAZ/PIPC) plus levofloxacin (LVFX) as a prophylactic administration in transrectal prostate biopsy (TPBX). MATERIALS AND METHODS: We investigated 201 consecutive patients who underwent TPBX in one Japanese hospital during the period of 2009-2010. The patients received TAZ/PIPC 4.5 g i.v. once just before and 3 hours after TPBX, plus oral LVFX 300 mg or 500 mg daily for 3 days. We examined the infectious adverse events and laboratory data (serum white blood cell [WBC] count and C-reactive protein [CRP]) before and 1 day after TPBX. RESULTS: Only one patient (0.50%) in 201 cases had febrile complications after TPBX. Serum WBC and CRP did not rise significantly on the day after TPBX compared with before TPBX (p>0.05). There was no significant difference in the rise of serum WBC and CRP before and after TPBX in the comparison of LVFX 500 mg with LVFX 300 mg in the TAZ/PIPC plus LVFX regimen. CONCLUSIONS: TAZ/PIPC plus LVFX can be considered as a prophylactic regimen for preventing infectious complications in TPBX.

Erythropoietin gene transfer into rat testes by in vivo electropo-ration may reduce the risk of germ cell loss caused by cryptorchidism / 亚洲男科学杂志(英文版)

<p><b>AIM</b>To investigate the effects of rat Erythropoietin (Epo) on spermatogenesis by transferring rat Epo gene into cryptorchid testes by means of in vivo electroporation.</p><p><b>METHODS</b>Sprague-Dawley rats with surgically-induced unilateral cryptorchidism were divided into three groups: the first group was given intratesticular injections of pCAGGS-Epo (pCAGGS-Epo group), the second group was given intratesticular injections of pCAGGS (pCAGGS group), and the third group were given intratesticular injections of phosphate-buffered saline (PBS group). At the same time, square electric pulses of 30 V were applied six times with a time constant of 100 ms. One or two weeks after injection, each testis was weighed and the ratio of the total number of germ cells to that of Sertoli cells (G/S ratio) was calculated to evaluate the impairment of spermatogenesis. Ten testes taken from each of the three groups were examined at each time point.</p><p><b>RESULTS</b>The testicular weight after the injection of pCAGGS-Epo or pCAGGS control plasmid was (0.85+/-0.08) g and (0.83+/-0.03) g, respectively, at week 1 (P = 0.788) and (0.62+/-0.06) g and (0.52+/-0.02) g, respectively, at week 2 (P = 0.047). At week 1, spermatids and sperm were more abundant in testes with pCAGGS-Epo than those in the control testes. At week 2, spermatids and sperm were hardly detected in either group. The G/S ratio was 23.27 +/-6.80 vs. 18.63+/-5.30 at week 1 (P = 0.0078) and 7.16+/-3.06 vs. 6.05+/-1.58 at week 2 (P = 0.1471), respectively.</p><p><b>CONCLUSION</b>The transfer of Epo to rat testes by in vivo electroporation may reduce the risk of the germ cell loss caused by cryptorchidism.</p>

Distribution of intracellular and extracellular expression of transforming growth factor-beta1 (TGF-beta1) in human testis and their association with spermatogenesis / 亚洲男科学杂志(英文版)

<p><b>AIM</b>Spermatogenic dysfunction may result from thickening of seminiferous tubular basement membrane (BM) with tubular sclerosis. Transforming growth factor beta1 (TGF-beta1) plays an important role in fibrogenesis. The intracellular and extracellular expression of TGF-beta1 in the testis were immunohistochemically determined, using LC antibody (LC) for intracellular TGF-beta1 and CC antibody (CC) for extracellular TGF-beta1.</p><p><b>METHODS</b>Twenty-three testicular biopsy specimens were obtained from varicocele and five from Sertoli-cell-only (SCO) patients, and five from normal volunteers. The relative area involved by the expression of TGF-beta1 for CC or LC (TGF-beta1 index for CC or LC) was examined, and semen parameters and serum hormonal levels and TGF-beta1 were analyzed. The Johnson score (JS), the BM thickness, and the tubular diameter were also determined.</p><p><b>RESULTS</b>Immunoreactivity for CC was hardly detected. That for LC was detected in the Sertoli and germ cells. The TGF-beta1 index for LC was significantly higher in the varicoceles than in the normal testes. Interestingly, that for LC was significantly higher in the varicoceles than in the SCO. The level of serum TGF-beta1 was significantly higher in varicoceles than in the normal testes.</p><p><b>CONCLUSION</b>The distribution of the intracellular and extracellular expression of TGF-beta1 in human testis was demonstrated. It suggests that TGF-beta1 is related to fibrosis of seminiferous tubules and may lead to spermatogenic disruption.</p>