Effectiveness of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin as compared to gemcitabine-based regimens as neoadjuvant chemotherapy for oncologic outcomes in muscle-invasive bladder cancer cases-Single-center study in Japan.

OBJECTIVES: To compare the efficacy and safety of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with gemcitabine-based regimens for neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) patients treated in Japan. METHODS: Data for MIBC patients who received NAC-dd-MVAC followed by a radical cystectomy from June 2019 to May 2023 performed at our hospital were analyzed. For comparisons, data for MIBC patients who received NAC gemcitabine and cisplatin (GC) or gemcitabine and carboplatin (GCarbo) therapy between January 2010 and March 2019 were also obtained. Rates of ypT1N0 or less, progression-free survival (PFS), overall survival (OS), and NAC adverse effects were compared between the GC/GCarbo and dd-MVAC regimens. RESULTS: Results for 32 patients who received dd-MVAC and 30 who received GC/GCarbo NAC therapy were analyzed. ypT1N0 or less was noted in 40.7% of the dd-MVAC and 40.0% of the GC/GCarbo groups, while ypT0N0 rates were 25% and 10%, respectively, with no statistical differences noted. However, Kaplan-Meier analysis of the total cohort demonstrated that dd-MVAC was associated with significantly better PFS and OS rates than GG/GCarbo (hazard ratios: 0.33, p = 0.0237, and 0.23, p = 0.0127, respectively). Propensity-matched models also showed similar results for both PFS and OS. Adverse effects of dd-MVAC were acceptable and the incidence of hematologic toxicity was lower as compared with GC/GCarbo therapy. CONCLUSION: The present study is the first to show that dd-MVAC as NAC can provide better survival as compared with a gemcitabine-based regimen for patients with MIBC treated in Japan.

Swim-up method is superior to density gradient centrifugation for preserving sperm DNA integrity during sperm processing.

Purpose: This study aimed to evaluate the effects of swim-up and density gradient centrifugation methods on sperm DNA fragmentation. Methods: Nineteen normozoospermic patient samples with ≥100 × 106 motile sperms were included in this study. Sperm DNA fragmentation, progressive motility, and progressive motile sperm number were measured before and after the swim-up method or density gradient centrifugation. Results: Sperm DNA fragmentation was not statistically different between swim-up-(14.4 ± 2.1%, p = 0.32) and density gradient centrifugation-processed (25.0 ± 3.0%, p = 0.20) and unprocessed semen samples (19.2 ± 1.9%). Sperm DNA fragmentation was significantly lower in swim-up-than in density gradient centrifugation-processed samples (p < 0.05). Sperm progressive motility was significantly higher (p < 0.05) in swim-up-(92.9 ± 1.0%) and density gradient centrifugation-processed (81.3 ± 2.0%) samples, with the former being higher, than in unprocessed semen samples (53.1 ± 3.7%). The recovery rate of progressive motile sperms was significantly lower in swim-up-(9.7 ± 1.4%) than in density gradient centrifugation-processed samples (17.2 ± 1.8%, p < 0.05). Conclusions: The swim-up method is superior to density gradient centrifugation, evidenced by less sperm DNA fragmentation and higher sperm progressive motility. The recovery rate of progressive motile sperms was better after density gradient centrifugation than after swim-up.

Significant inverse association of testosterone level with penile deformity severity in Japanese males with Peyronie's disease.

OBJECTIVES: We evaluated the relationship between penile curvature and testosterone in Peyronie's disease patients treated in Japan. METHODS: Data were obtained from 109 patients with Peyronie's disease treated with surgery at our hospital between April 2004 and December 2019. Penile deformity assessment was based on findings of a rigid erection induced by intracavernosal injection. Low total testosterone level was defined as <300 ng/dl. Patients were divided into two groups according to curvature severity (I, <60°; II ≥60°), then clinical factors including total testosterone were compared. Uni- and multivariate logistic regression analyses were performed to identify factors predicting severe penile deformity (≥60°). RESULTS: For all patients, mean total testosterone was 469 ng/dl and median curvature was 50°, with a significant inverse correlation found between curvature and testosterone level (p < 0.0001). Group I and II patients numbered 55 and 54, respectively. Mean total testosterone for Group II was 397 ng/dl, significantly lower than Group I (539 ng/dl). Median curvature in 15 patients with a low testosterone level was 80°, significantly higher than those with a normal testosterone range (50°). Univariable and multivariable logistic regression analysis indicated total testosterone, follicle stimulating hormone, and C-reactive protein as significant factors correlated with severe penile deformity, among which total testosterone was most relevant. CONCLUSION: The present findings confirmed that penile deformity severity is correlated with testosterone level in Japanese males with Peyronie's disease.

Female sexual dysfunction and lower urinary tract symptoms associated with vulvovaginal atrophy symptoms: Results of the GENJA study.

OBJECTIVES: To investigate the main symptoms of female sexual dysfunction (FSD) and lower urinary tract symptoms associated with vulvovaginal atrophy (VVA) symptoms as the core symptoms of genitourinary syndrome of menopause. METHODS: We extracted the data of 4134 Japanese women aged 40-79 years who participated in the GENitourinary syndrome of menopause in JApanese women (GENJA) study. All participants responded to web-based questionnaires assessing their health situation, including the Vulvovaginal Symptoms Questionnaire, the Female Sexual Function Index (FSFI), and the Core Lower Urinary Tract Symptom Score. Multivariable regression and multivariable logistic regression analyses were applied to analyze the association between VVA symptoms and FSD, and between VVA symptoms and lower urinary tract symptoms. RESULTS: Multivariable regression analysis revealed that VVA symptoms were associated with lower scores for arousal, lubrication, orgasm, satisfaction, and pain domains in the FSFI in sexually active women (p < 0.01). Regression coefficients were higher for lubrication and pain domains than for the other domains. Multivariable logistic regression analysis revealed that women reporting VVA symptoms were more likely to have increased daytime urinary frequency, nocturia, urgency, slow stream, straining to void, feeling of incomplete emptying, bladder pain, and feeling a bulge/lump from or in the vagina (p < 0.05). Adjusted odds ratios were particularly high for straining to void, feeling of incomplete emptying, and bladder pain. CONCLUSIONS: Vulvovaginal atrophy symptoms were significantly associated with decreased lubrication and dyspareunia in FSD, and urinary symptoms of straining to void, feeling of incomplete emptying, and bladder pain.

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie's Disease.

Peyronie's disease (PD) is a benign condition caused by plaque formation on the tunica albuginea of the penis. It is associated with penile pain, curvature, and shortening, and contributes to erectile dysfunction, which worsens patient quality of life. In recent years, research into understanding of the detailed mechanisms and risk factors involved in the development of PD has been increasing. In this review, the pathological mechanisms and several closely related signaling pathways, including TGF-ß, WNT/ß-catenin, Hedgehog, YAP/TAZ, MAPK, ROCK, and PI3K/AKT, are described. Findings regarding cross-talk among these pathways are then discussed to elucidate the complicated cascade behind tunica albuginea fibrosis. Finally, various risk factors including the genes involved in the development of PD are presented and their association with the disease summarized. The purpose of this review is to provide a better understanding regarding the involvement of risk factors in the molecular mechanisms associated with PD pathogenesis, as well as to provide insight into disease prevention and novel therapeutic interventions.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2.

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 1.

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).

Novel prediction scoring system for simple assessment of stone-free status after flexible ureteroscopy lithotripsy: T.O.HO. score.

OBJECTIVES: To develop a novel simple quantitative scoring model for predicting stone-free status after a flexible ureteroscopy lithotripsy procedure by standardizing the complexity of ureteral stone characteristics. METHODS: We retrospectively reviewed 586 patients with renal or ureteral stones who underwent flexible ureteroscopy lithotripsy at Abiko Toho Hospital, Chiba, Japan, from 2015 to 2018. Multivariate regression was applied to examine the relationship between preoperative descriptors and stone-free status, and a nomogram was developed using significant predictors. Next, the individual components of the nomogram were assigned points to form a simple scoring system. The predictive performance of this new scoring system was compared with the STONE score at optimal cut-off values using receiver operating characteristic curve and area under the curve analyses. RESULTS: Multivariate logistic regression findings showed that factors associated with stone-free status were length, Hounsfield unit and stone location. A nomogram prediction model was developed with an area under the curve value of 0.845, then consequently used to develop a new simple score system termed the T.O.HO. score consisting of three stone characteristics: (T)allness (1-5 points), (O)ccupied lesion (1-3 points) and (HO)unsfield units evaluation (1-3 points). The T.O.HO. score was significantly higher in stone remaining (7.66) than stone-free (5.27; P < 0.001) cases. The area under the curve for the T.O.HO. score was 0.833 at an optimal cut-off value of 7, whereas that for the STONE score was 0.683 at an optimal cut-off value of 9, showing the superiority of this new scoring system. CONCLUSION: The T.O.HO. score is a useful tool for predicting stone-free status in patients who have undergone a flexible ureteroscopy lithotripsy procedure.

Ultrasound-guided laparotomic oocyte retrieval during surgery for fertility preservation in a case of tumor recurrence after a unilateral salpingo-oophorectomy.

Case: A 28 year old unmarried woman underwent a unilateral salpingo-oophorectomy and was suspected of having a malignant tumor in the remaining ovary. After consultation with the patient and her family, it was decided to cryopreserve the unfertilized oocytes. In order to reduce the risk of puncturing or rupturing the tumor when performing the oocyte retrieval from the ovary that was affected by the malignant tumor, it was chosen to use direct laparotomic oocyte retrieval during surgery, instead of conventional transvaginal retrieval. In order to further reduce the risk of tumor rupture, an ultrasound was used in the laparotomy field to precisely puncture only the follicle and thus avoid the tumor. A total of 11 oocytes was retrieved and 10 of them were cryopreserved in the MII phase. Outcome: By using an ultrasound at the same time as the oocyte retrieval, it was possible to avoid the ovarian tumor site. Furthermore, by checking and puncturing the follicles, it became possible to retrieve oocytes from the healthy parts of the ovary with greater precision. The combined use of an ultrasound with oocyte retrieval can be considered to be an effective method because it can be performed relatively easily. Conclusion: The authors believe that not only macroscopic, but also ultrasonic, methods are useful to reduce the risk of tumor rupture.

Long-term clinical outcomes of testicular sperm extraction and intracytoplasmic sperm injection for infertile men.

Purpose: To find the best methods to achieve the highest pregnancy and birth rates for couples needing testicular sperm extraction (TESE)-intracytoplasmic sperm injection (ICSI). Methods: Retrospectively studied were 801 patients with male factor infertility who had undergone TESE-ICSI between April, 1996 and July, 2016 and who had been categorized into four groups: obstructive azoospermia (OA); non-obstructive azoospermia (NOA); Klinefelter syndrome (KS); and cryptozoospermia (Crypt). The sperm retrieval rate, hormone levels, fertilization rate (FR), pregnancy rate (PR), and birth rate (BR) after ICSI among three groups were compared: fresh testicular sperm (FS)-fresh oocytes (FO) (Group I); frozen-thawed testicular sperm-FO (Group II); and FS-vitrified-warmed oocytes (Group III). Results: The testicular sperm recovery rate was 57.8% (463/801): 89.6% in the Crypt, 97.1% in the OA, 28.9% in the NOA, and 42.2% in the KS groups. The follicle-stimulating hormone levels were significantly higher in the NOA and KS groups and the testosterone levels were significantly lower in the KS group. The FR, PR, and BR were: 65.2%, 43.2%, and 28.5% in group I; 59.2%, 33.4%, and 18.7% in group II; and 56.4%, 33.8%, and 22.1% in group III. Conclusion: Intracytoplasmic sperm injection with FS-FO achieved the best PR and BR. It should be considered what to do in cases with no testicular sperm by TESE. The authors hope that ICSI with donor sperm will be allowed in Japan in the near future.

Randomized Crossover Trial of Amoxapine Versus Vitamin B12 for Retrograde Ejaculation.

OBJECTIVE: To compare the efficacy and safety of amoxapine and vitamin B12 for treating retrograde ejaculation (RE). MATERIALS AND METHODS: Between May 2009 and November 2012, this open-label, randomized, crossover study enrolled 26 men suffering with RE at Department of Reproductive Medicine, Omori Hospital. Patients were randomly allocated into two groups (n=13 each). The amoxapine-B12 group received amoxapine (50 mg daily for 4 weeks, orally) followed (after a 1-week washout period) by vitamin B12 (500 µg three-times daily for 4 weeks). The B12-amoxapine group received the opposite regimen. All pa-tients masturbated to ejaculation at least twice during each treatment period. The primary outcome was antegrade ejaculation of semen, as reported by the patient, on more than one occasion during either treatment period (defined as treatment success). Any adverse events were noted. Success rates were compared between treatments using Fisher's exact test. RESULTS: One patient (B12-amoxapine group) withdrew for personal reasons (breakdown of marital relations); all other patients completed the study. Overall success rate was 88% (22/25). Success rate was higher for amoxapine than for vitamin B12 (80%, 20/25 vs 16%, 4/25; P<0.0001). 18 patients were responsive to amoxapine but not to vitamin B12, 2 patients were responsive to vitamin B12 but not amoxapine, 2 patients were responsive to both drugs, and 3 patients had no response to either drug. One patient (4%) reported sleepiness and 2 (8%) reported constipation while receiving amoxapine. No adverse events were reported during vitamin B12 treatment. CONCLUSIONS: Amoxapine may be an effective, safe and well-tolerated therapy for RE.

Semen cryopreservation as an oncofertility treatment in 122 Japanese men with cancer: A decade-long study.

Purpose: Oncofertility is a subspecialty that is concerned with helping patients with cancer preserve their ability to have children in the future. For men, sperm banking is an established way to preserve fertility. The aim was to determine the prefreeze semen characteristics and reproductive outcomes according to cancer type for men who chose semen cryopreservation. Methods: The records of 122 men with cancer who requested semen cryopreservation at the authors' hospital from 2006 to 2015 were reviewed. The mean patient age when the semen was cryopreserved was 33.6 years. Results: The 122 men who banked sperm during the study period had the following types of cancer: testicular (44.3%), hematological (31.1%), digestive (8.2%), and other types (16.4%). The mean sperm concentration by cancer type was 30.5 × 106/mL for testicular, 45.0 × 106/mL for hematological, 40.5 × 106/mL for digestive, and 68.4 × 106/mL for the other types. The mean sperm motility by cancer type was 59.6% for testicular, 50.1% for hematological, 43.0% for digestive, and 44.8% for the other types. For 12 (9.8%) men who used the banked semen, there were five (41.7%) clinical pregnancies. Conclusion: Semen cryopreservation is a simple procedure that can be accomplished quickly and can preserve fertility.

Contemporary outcomes of seminal tract re-anastomoses for obstructive azoospermia: a nationwide Japanese survey.

OBJECTIVES: To evaluate current outcomes of seminal tract re-anastomoses in Japan, and to compare them with historical data. METHODS: A total of 213 patients with obstructive azoospermia who underwent seminal tract re-anastomosis from April 2008 to March 2012 at 25 institutions were enrolled in the present study. The outcomes of the procedure were compared with those reported in a previous multi-institutional study carried out in 2000. RESULTS: The percentage of partners aged over 35 years was 37%. A microsurgical double-layer anastomosis was carried out 83.0% of the time. Sperm were observed in ejaculate postoperatively in 68.9% and 41.5% of patients who underwent a vasovasostomy or a vasoepididymostomy, respectively. Natural conception occurred in 27.5% of patients after a vasectomy and 32.3% of patients with an epididymal obstruction. Except for the ratio of natural conception in patients with vasal obstruction after herniorrhaphies, there were no significant differences in final ratios of sperm appearance and natural conception between the previously reported study and the present study. CONCLUSIONS: Compared with historical data, contemporary seminal tract re-anastomosis in Japan seems to provide equivalent or better outcomes, depending on the cause of obstruction. Seminal tract re-anastomosis is a valid treatment option for patients with obstructive azoospermia.

Gaps between actual and desired sex life: web survey of 5,665 Japanese women.

To explore issues that heterosexual women have concerning their sex life and desire toward their male partner, the authors conducted an online survey on actual sex life and sexual quality of life. Survey participants included 5,665 women who were 20 years of age and older who (a) lived in or near Tokyo, (b) had a male sex partner, and (c) intended to have sexual activity. Participants were asked to respond to a wide range of questions regarding their sexual fulfillment and desires. Differences between actual and desired duration of sexual activities (foreplay, intercourse, and afterplay) and number of sexual positions were calculated. The authors performed subgroup analyses regarding pain during sexual intercourse and by degree of partner's unilateral action. In addition, the authors investigated the relation between sexual quality of life and each subgroup. Women who participated in this survey tended to desire a longer duration of foreplay and afterplay than was experienced. The greater the pain during sexual intercourse, the percentage of respondents who desired a shorter duration of intercourse and fewer numbers of sexual positions increased and the sexual quality of life decreased. The degree of partner's unilateral action during sexual activity negatively affected the woman's sexual quality of life. The present study suggests the importance of establishing good communication between sex partners.

Role of varicocele repair for male infertility in the era of assisted reproductive technologies.

Varicocele is an abnormal condition characterized by dilatation of the pampiniform plexus veins draining the testis and is present in 15 % of men. Varicoceles have an adverse effect on spermatogenesis and are the most common cause of male infertility. Approximately 35 % of infertile men and more than 70 % of men with secondary infertility were reported to have varicoceles. Although data on methods of varicocele repair are accumulating, there remains controversy regarding the indications and techniques for varicocele repair. In addition, the role of varicocele repair in this era of assisted reproductive technologies continues to be debated. In this study, we performed a comprehensive PubMed search in order to review the current status of varicocele repair for male infertility. We reviewed English-language studies published from 1992 through 2013. After reviewing the articles, we identified a recent meta-analysis of four randomized controlled trials, which found that varicocele repair for oligozoospermic men was associated with better pregnancy rates as compared with observation. Our review of prospective studies showed that all semen parameters, including sperm concentration, motility, and progressive motility, were significantly improved after varicocele repair. We also summarize the findings of recent studies reporting beneficial effects of varicocele repair, i.e., decreased oxidative stress and sperm DNA fragmentation after varicocele repair and superior cost effectiveness versus in vitro fertilization/intracytoplasmic sperm injection alone, which may be important in the era of assisted reproductive technologies. Varicocele repair is a widespread, well-established procedure that can improve semen parameters in men with infertility. The effect of such treatment on the pregnancy rate is unclear because evidence is limited due to difficulties in recruiting patients for studies. Among the repair techniques, microsurgical repair using a subinguinal approach is potentially the best practice, although this procedure requires training in microsurgery. All these topics require further research in studies with sufficient patient enrollment and follow-up.

[Linguistic validation of Japanese version of Prolapse/Urinary Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR)].

PURPOSE: To translate the Prolapse/Urinary Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR) into Japanese and evaluate the linguistic validation of the translated PISQ-IR. METHODS: The translation and evaluation of PISQ-IR were performed through 3 steps: forward translation based on 2 urologists and discussed by another 4 urologists, 1 pharmacoeconomist and 1 nurse; the community review process consists of conducting one-on-one cognitive interviews with 20 patients by a professional interviewer; backward translation by a native English speaker, which was negotiated with the PISQ-IR Working Group comprised original authors in International Urogynecological Association (IUGA). RESULTS: The PISQ-IR Working Group generally approved our translation and had 2 major concerns in the Japanese version; 1) "disagree" in every sentence of English version was not translated into Japanese, and 2) the Japanese expression in "sexual desire" should be more emotional. The former concern was approved by explaining that Japanese does not have the word which is the equivalent of "disagree", and "don't agree" is always used instead of "disagree". The latter concern was compromised by switching to a translation using emotional words. CONCLUSION: The Japanese version of PISQ-IR was translated in a linguistically valid manner. It would be equivalent to the original English questionnaire. It may provide a tool to assess sexual function for Japanese women with prolapse, urinary incontinence and/or fecal incontinence in an internationally harmonized fashion.

Endometrial congestion is the only hysteroscopic finding indicative of chronic endometritis.

Chronic endometritis (CE), an inflammatory condition characterized by plasma cell infiltration within the endometrial stroma, is prevalent among women experiencing unexplained infertility or recurrent miscarriages. CE is traditionally diagnosed by endometrial biopsy using CD138 immunohistochemistry staining. Despite some studies suggesting hysteroscopy as an alternative diagnostic tool, its reliability compared with biopsy remains controversial. This study evaluated the diagnostic accuracy of hysteroscopy for CE by examining endometrial features, such as congestion, micropolyps, edema, and polyps, and comparing these with biopsy-confirmed cases of CE. This retrospective observational study was conducted at Toho University Omori Medical Center between June 2017 and November 2019 and included patients undergoing both hysteroscopy and histopathological examination. Endometrial congestion was identified as the only hysteroscopic finding significantly associated with CE, showing a moderate diagnostic agreement with biopsy results. These findings highlight the importance of further investigating hysteroscopic features of CE and their diagnostic implications and identify endometrial congestion as a potential predictive marker for CE.

[Role of androgen in the elderly. Male sexual dysfunction and androgen].

Testosterone enhances DA release in the MPOA at rest and with sexual challenge, possibly by upregulating NOS, which increases NO and thereby increases DA release. Androgens have beneficial effects on endothelial cells and smooth-muscle cells. Testosterone and dihydrotestosterone may also relax penile artery and cavernous smooth muscle through their nongenomic effects. In rats, castration has been reported to decrease arterial flow, induce venous leakage, and reduce the erectile response to stimulation of the cavernous nerve. Hypogonadal patients in whom PDE5 inhibitor failed could be rescued by the administration of testosterone.