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.

Potential for artificial intelligence in medicine and its application to male infertility.

Background: The third AI boom, which began in 2010, has been characterized by the rapid evolution and diversification of AI and marked by the development of key technologies such as machine learning and deep learning. AI is revolutionizing the medical field, enhancing diagnostic accuracy, surgical outcomes, and drug production. Methods: This review includes explanations of digital transformation (DX), the history of AI, the difference between machine learning and deep learning, recent AI topics, medical AI, and AI research in male infertility. Main Findings Results: In research on male infertility, I established an AI-based prediction model for Johnsen scores and an AI predictive model for sperm retrieval in non-obstructive azoospermia, both by no-code AI. Conclusions: AI is making constant progress. It would be ideal for physicians to acquire a knowledge of AI and even create AI models. No-code AI tools have revolutionized model creation, allowing individuals to independently handle data preparation and model development. Previously a team effort, this shift empowers users to craft customized AI models solo, offering greater flexibility and control in the model creation process.

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.

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.

Bone biopsy findings in patients receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis.

INTRODUCTION: Bisphosphonates (BPs) have been shown to reduce the incidence of vertebral fractures during the first year or two of glucocorticoid (GC) treatments and are therefore recommended as a first-line treatment for GC-induced osteoporosis (GIO). However, there are theoretical concerns about the long-term use of BPs in low-turnover osteoporosis caused by chronic GC therapy. MATERIALS AND METHODS: We analyzed the trabecular microarchitecture, bone metabolism, and material strength of iliac crest bone biopsy samples from 10 female patients with rheumatoid arthritis who received an average of 6.7 years of BP therapy for GIO (GIOBP group), compared with those of 10 age- and bone mineral density (BMD)-matched non-rheumatoid arthritis postmenopausal women (reference group). RESULTS: Patients in the GIOBP group had a significantly greater fracture severity index, as calculated from the number and the extent of vertebral fractures compared with the reference patients. Micro-computed tomography analysis showed that the degree of mineralization and trabecular microarchitecture were significantly lower in the GIOBP group than in the reference patients. Patients in the GIOBP group exhibited lower bone contact stiffness, determined by micro-indentation testing, than in the reference group. The contact stiffness of the bone was negatively correlated with the fracture severity index and the daily prednisolone dosage. Immunohistochemistry and serum bone turnover markers showed decreased osteoclastic activity, impaired mineralization, and an increased fraction of empty lacunae in the GIOBP group. CONCLUSION: Our findings indicate that patients receiving long-term BP for GIO are still at high risk for fragility fractures because of poor bone quality.

Comparison of the Efficacy and Renal Safety of Bisphosphonate Between Low-Dose/High-Frequency and High-Dose/Low-Frequency Regimens in a Late-Stage Chronic Kidney Disease Rat Model.

The efficacy and renal safety of low-dose/high-frequency (LDHF) dosing and high-dose/low-frequency (HDLF) dosing of bisphosphonates (BPs) are comparable in patients with normal kidney function but might be different in patients with late-stage chronic kidney disease (CKD). This study aimed to compare the efficacy and renal safety of two different dosage regimens of a BP, alendronate (ALN), in stage 4 CKD using a rat model. Male, 10-week-old Sprague-Dawley rats were subjected to either 5/6 nephrectomy or sham surgery. The animals received subcutaneous administration of vehicle (daily) or ALN in LDHF dosage regimen (LDHF-ALN: 0.05 mg/kg/day) or HDLF dosage regimen (HDLF-ALN: 0.70 mg/kg/2 weeks). Medications commenced at 20 weeks of age and continued for 10 weeks. Micro-computed tomography, histological analysis, infrared spectroscopic imaging, and serum and urine assays were performed to examine the efficacy and renal safety of the ALN regimens. Both LDHF-ALN and HDLF-ALN increased bone mass, improved micro-structure, and enhanced mechanical properties, without causing further renal impairment in CKD rats. Histologically, however, HDLF-ALN more efficiently suppressed bone turnover, leading to more mineralized trabecular bone, than LDHF-ALN in CKD rats, whereas such differences between LDHF-ALN and HDLF-ALN were not observed in sham rats. Both LDHF-ALN and HDLF-ALN showed therapeutic effects on high bone turnover osteoporosis in CKD stage 4 rats without causing further renal impairment. However, as HDLF-ALN more efficiently suppressed bone turnover than LDHF-ALN in late-stage CKD, HDLF-ALN might be more appropriate than LDHF-ALN for fracture prevention in high bone turnover osteoporosis patients with late-stage CKD.

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.

Temporary pacemaker insertion for severe bradycardia following pneumoperitoneum during robot-assisted radical prostatectomy: a case report.

BACKGROUND: Pneumoperitoneum to maintain a constant gas flow to assist various surgeries is known to cause severe bradycardia and has been linked to heart failure;; however, a recent study demonstrated that it is not linked to poorer surgical outcomes; accordingly, it does not require routine preventive measures. Thus, whether there is a link between sudden bradycardia development and surgical procedures is controversial. We report the case of severe bradycardia that occurred along with a complete atrioventricular block (CAVB) during peritoneum creation in robot-assisted radical prostatectomy (RARP). CASE PRESENTATION: A 72-year-old man presented at our hospital with prostate cancer and underwent RARP. After pneumoperitoneum, severe bradycardia and CAVB were observed; thus, the surgery was extended by inserting a temporary pacemaker (TPM). CONCLUSION: Because of the difficulty in performing emergency procedures in robot-assisted surgeries, the current case is reported to provide an awareness that surgeons should be cautious of the possible complication of bradycardia and CAVB during such operations, and thus should take steps necessary for managing induction of such conditions.

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.

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.

Bizarre parosteal osteochondromatous proliferation (Nora's lesion) affecting the distal end of the ulna: a case report.

BACKGROUND: Bizarre parosteal osteochondromatous proliferation (BPOP), first described by Nora et al. in 1983 and therefore termed "Nora's lesion", is a rare lesion that occurs in the short bones of the hands and feet and eventually presents as a parosteal mass. Reports of BPOP in the long bones are very rare. A benign disease, BPOP does not become malignant, although a high rate of recurrence following surgical resection is reported. Because of its atypical imaging findings and histopathological appearance, a BPOP might be misdiagnosed as a malignant tumor such as an osteochondroma with malignant transformation, a parosteal osteosarcoma, or a periosteal osteosarcoma. CASE PRESENTATION: A 58-year-old woman complained of left ulnar wrist pain at the time of her initial presentation. Plain x-rays showed ectopic calcifications in and around the distal radioulnar joint, which supported the diagnosis of subacute arthritis with hydroxyapatite crystal deposition. She was initially given a wrist brace and directed to follow-up, but her persistent pain required the administration of corticosteroid injections into the distal radioulnar joint. Increasing ulnar wrist joint pain and limited forearm pronation and wrist flexion necessitated computed tomography and contrast-enhanced magnetic resonance imaging. BPOP was diagnosed based on the preoperative imaging studies, and a resection of the lesion was performed along with the decortication of the underlying the cortical bone to reduce recurrence rates. The diagnosis of BPOP was confirmed by pathologic examination. Two years after surgery, the patient has no subsequent pain complaints and an improved range of motion. CONCLUSIONS: BPOP affecting the distal end of the ulna is exceedingly rare. Because BPOP was diagnosed primarily based upon preoperative imaging findings in our patient, decortication of the underlying cortical bone was performed to reduce recurrence rates. Further careful follow-up in these patients is essential, despite the non-recurrence of the lesion.

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.

Time course of histopathology of bleomycin-induced pulmonary fibrosis using an intratracheal sprayer in mice.

Idiopathic pulmonary fibrosis (IPF) is a poor prognosis disease that affects approximately 5 million people worldwide, and the detailed mechanisms underlying the pathogenesis of IPF remain unclear. Bleomycin-induced pulmonary fibrosis has been widely used as a representative animal model of IPF that induces fibrosis in lung tissue. The lungs of rodent consist of five lobes and each bronchus enters each lobe of the lung at a different bifurcation angle, path length, and diameter. The method of administration of bleomycin is considered as important thing to establish appropriate animal models. We conducted a time-dependent histopathological study to examine how pulmonary fibrosis develops in each lung lobe when bleomycin was intratracheally sprayed in ICR mice. And we then explored the suitable points for evaluation of anti-fibrotic agents in this model. As a result, we found that homogeneous fibrosis was induced in the 5 lobes of the lungs following initial inflammation. The expression of transforming growth factor (TGF)-ß1 and phospho-Smad2 (pSmad2) was observed from Day 1, and their positivity increased until Day 21. In conclusion, we have observed a detailed time course of histological changes in bleomycin-induced pulmonary fibrosis in ICR mice using the aerosolization technique. We found that our protocol can induce a highly homogeneous lesion in the lung and that the most suitable time point to assess anti-fibrotic agents is 14 days after treatment in this model.

Involvement of Siglec-15 in regulating RAP1/RAC signaling in cytoskeletal remodeling in osteoclasts mediated by macrophage colony-stimulating factor.

DNAX-associated protein 12 kD size (DAP12) is a dominant immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptor that activates costimulatory signals essential for osteoclastogenesis. Although several DAP12-associated receptors (DARs) have been identified in osteoclasts, including triggering receptor expressed on myeloid cells 2 (TREM-2), C-type lectin member 5 A (CLEC5A), and sialic acid-binding Ig-like lectin (Siglec)-15, their precise role in the development of osteoclasts and bone remodeling remain poorly understood. In this study, mice deficient in Trem-2, Clec5a, Siglec-15 were generated. In addition, mice double deficient in these DAR genes and FcεRI gamma chain (FcR)γ, an alternative ITAM adaptor to DAP12, were generated. Bone mass analysis was conducted on all mice. Notably, Siglec-15 deficient mice and Siglec-15/FcRγ double deficient mice exhibited mild and severe osteopetrosis respectively. In contrast, other DAR deficient mice showed normal bone phenotype. Likewise, osteoclasts from Siglec-15 deficient mice failed to form an actin ring, suggesting that Siglec-15 promotes bone resorption principally by modulating the cytoskeletal organization of osteoclasts. Furthermore, biochemical analysis revealed that Sigelc-15 activates macrophage colony-stimulating factor (M-CSF)-induced Ras-associated protein-1 (RAP1)/Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway through formation of a complex with p130CAS and CrkII, leading to cytoskeletal remodeling of osteoclasts. Our data provide genetic and biochemical evidence that Siglec-15 facilitates M-CSF-induced cytoskeletal remodeling of the osteoclasts.

Micronutrient Antioxidants for Men (Menevit®) Improve Sperm Function by Reducing Oxidative Stress, Resulting in Improved Assisted Reproductive Technology Outcomes.

Oxidative stress (OS) affects men's health and impairs spermatogenesis. Micronutrient antioxidants are available for male infertility as complemental support; however, their efficacy remains debatable. This study aimed to investigate whether antioxidants can help to reduce sperm OS and improve semen analysis and quality. We included 171 male partners of couples planning to undergo assisted reproductive technology (ART). Male partners, aged 29-41 years, of couples intending to conceive were self-selected to take daily antioxidants (n = 84) containing folic acid and zinc, or not to take antioxidants (n = 52) for 6 months. We analyzed the alterations in serum oxidant levels, sperm parameters, OS, and deoxyribonucleic acid fragmentation after 3 and 6 months. Additionally, implantation, clinical pregnancy, and miscarriage rates after vitrified-warmed embryo transfer were compared between those taking antioxidants and those not taking them after 6 months. In men with high static oxidation-reduction potential (sORP), we observed a significant improvement in sperm concentration and sORP. The high-quality blastocyst rate tended to increase, and implantation and clinical pregnancy rates also significantly increased after 6 months of intervention. The micronutrient antioxidants could improve sperm function by reducing OS and improving ART outcomes. Therefore, micronutrient antioxidants may be a viable treatment option for male infertility.

Proposal for effective treatment of Shiga toxin-producing Escherichia coli infection in mice.

Previously, we reported that minocycline, kanamycin and norfloxacin improved the survival rate in the E32511 model that we developed (FEMS Immunol Med Microbiol 26, 101-108, 1999), but fosfomycin did not. In this study, we investigated the effectiveness of azithromycin (AZM) against Stx2d-producing EHEC O91:H21 strain B2F1 or Stx2c-producing Escherichia coli strain E32511 treated with mitomycin C in vivo. Recently, we reported the effectiveness of AZM in our model and AZM strongly inhibited the release of Stx2c from E32511 in vitro (PLOS ONE e58959, 2013). However, it was very difficult to completely eliminate E32511 in the mouse feces by treatment with AZM alone. In this report, only AZM or Daio effectively promoted survival of mice infected with B2F1 compared to untreated mice. Furthermore, Daio inhibited the colonization of GFP-expressing B2F1 in the mouse intestine. Similarly, a combination of AZM and Daio in the E32511-infected mice reduced E32511 in the mouse feces and significantly improved survival.

[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.