Efficacy of Enfortumab Vedotin After Chemotherapy With Anti-programmed Death-Ligand 1 (PD-L1) Maintenance Treatment in a Clear Cell Variant of Invasive Urothelial Carcinoma of the Renal Pelvis: A Case Report.

Among upper urinary tract urothelial carcinoma (UUTUC) cases, there are few reports of the clear cell variant. Systemic chemotherapy will be given according to the usual treatment for urothelial cancer unless lymph nodes or organ metastases make surgical treatment inappropriate. Here, we report a clear cell variant of UUTUC of the left renal pelvis with aortic lymph node metastasis. The patient in this case was treated with systemic chemotherapy, anti-programmed death-ligand 1 (PD-L1) maintenance treatment, radiation therapy, and enfortumab vedotin (EV) therapy. To determine which of the treatments contributed to the therapeutic effect, immunostaining was used. The results indicated that Nectin-4 was expressed in clear cell variant tissues, while programmed cell death protein 1 (PD-1) and PD-L1 expression levels were weak in these tissues. The patient maintained complete remission with these treatments. Two years after the initial treatment, the patient was still alive with no progression or metastasis.

Practical guide for the diagnosis and management of primary ciliary dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a relatively rare genetic disorder that affects approximately 1 in 20,000 people. Approximately 50 genes are currently known to cause PCD. In light of differences in causative genes and the medical system in Japan compared with other countries, a practical guide was needed for the diagnosis and management of Japanese PCD patients. METHODS: An ad hoc academic committee was organized under the Japanese Rhinologic Society to produce a practical guide, with participation by committee members from several academic societies in Japan. The practical guide including diagnostic criteria for PCD was approved by the Japanese Rhinologic Society, Japanese Society of Otolaryngology-Head and Neck Surgery, Japanese Respiratory Society, and Japanese Society of Pediatric Pulmonology. RESULTS: The diagnostic criteria for PCD consist of six clinical features, six laboratory findings, differential diagnosis, and genetic testing. The diagnosis of PCD is categorized as definite, probable, or possible PCD based on a combination of the four items above. Diagnosis of definite PCD requires exclusion of cystic fibrosis and primary immunodeficiency, at least one of the six clinical features, and a positive result for at least one of the following: (1) Class 1 defect on electron microscopy of cilia, (2) pathogenic or likely pathogenic variants in a PCD-related gene, or (3) impairment of ciliary motility that can be repaired by correcting the causative gene variants in iPS cells established from the patient's peripheral blood cells. CONCLUSION: This practical guide provides clinicians with useful information for the diagnosis and management of PCD in Japan.

Renoprotective effects of laxative linaclotide: Inhibition of acute kidney injury and fibrosis in a rat model of renal ischemia-reperfusion.

Ischemia-reperfusion (I/R) leads to tissue damage in transplanted kidneys, resulting in acute kidney injury (AKI) and chronic graft dysfunction, which critically compromises transplant outcomes, such as graft loss. Linaclotide, a guanylate cyclase C agonist clinically approved as a laxative, has recently been identified to exhibit renoprotective effects in a chronic kidney disease (CKD) model. This study evaluates the therapeutic effects of linaclotide on AKI triggered by I/R in a rat model with an initial comparison with other laxatives. Here, we show that linaclotide administration resulted in substantial reduction in serum creatinine levels, reflective of enhanced renal function. Histological examination revealed diminished tubular damage, and Sirius Red staining confirmed less collagen deposition, collectively indicating preserved structural integrity and mitigation of fibrosis. Further analysis demonstrated lowered expression of TGF-ß and associated fibrotic markers, α-SMA, MMP2, and TIMP1, implicating the downregulation of the fibrogenic TGF-ß pathway by linaclotide. Furthermore, one day after I/R insult, linaclotide profoundly diminished macrophage infiltration and suppressed critical pro-inflammatory cytokines such as TNF, IL-1ß, and IL-6, signifying its potential to disrupt initial inflammatory mechanisms integral to AKI pathology. These findings suggest that linaclotide, with its established safety profile, could extend its benefits beyond gastrointestinal issues and potentially serve as a therapeutic intervention for organ transplantation. Additionally, it could provide immediate and practical insights into selecting laxatives for managing patients with AKI or CKD, regardless of the cause, and for those receiving dialysis or transplant therapy.

Evaluation of sexual function after robot-assisted radical prostatectomy: A farewell to IIEF questionnaire.

Longevity with localized prostate cancer (PCa) has been achieved, and the contribution of robot-assisted radical prostatectomy (RARP) to cancer control is evident. The next step to investigate in the treatment of localized PCa is improvement of the quality of life (QOL) after RARP. Erectile dysfunction has been considered a major surgical complication, and patient satisfaction after RARP has not improved despite the development of nerve preservation and penile rehabilitation. To comprehensively understand sexual dysfunction after RARP, we must investigate other complications with regard to sexual health, including low sexual desire, disturbed orgasmic function (i.e., anejaculation, orgasm intensity, painful orgasm, and climacturia), shortening of penile length, penile curvature (Peyronie's disease) and unique psychological alterations after the diagnosis of PCa, which are neglected side effects after prostatectomy. In this context, routine evaluation of erectile function by the International Index of Erectile Function only is not sufficient to understand patients' difficulties. A questionnaire is just one way of enabling patients to evaluate their pre- and postoperative concerns; listening to patients face-to-face is warranted to detect symptoms. Understanding the relationship between symptoms and preserved nerve localization can ultimately provide an individualized nerve-sparing procedure and improve patient satisfaction after RARP. In combination with psychological counseling, including the partner and medical treatment, such as testosterone replacement, it is time to reconsider ways to improve sexual dysfunction after RARP.

Prominin-1 deletion results in spermatogenic impairment, sperm morphological defects, and infertility in mice.

Purpose: Spermatogenesis is a complex process orchestrated by several essential genes. Prominin-1 (Prom1/PROM1) is a gene that is expressed in the testis but with a poorly understood role in spermatogenesis. Methods: We used Prom1 knockout (Prom1 KO) mice to assess the role of Prom1 in spermatogenesis. To this end, we performed immunohistochemistry, immunofluorescence, western blotting, ß-galactosidase staining, and apoptosis assay. Additionally, we analyzed the morphology of sperm and assessed litter sizes. Results: We observed that PROM1 is localized to the dividing spermatocytes in seminiferous epithelial cells, sperm, and columnar epithelium in the epididymis. In the Prom1 KO testis, an aberrant increase in apoptotic cells and a decrease in proliferating seminiferous epithelial cells were observed. Cellular FLICE-like inhibitory protein (c-FLIP) and extracellular signal-regulated kinase 1/2 (ERK1/2) expression were also significantly decreased in Prom1 KO testis. In addition, a significantly increased number of epididymal spermatozoa with abnormal morphology and less motility was found in Prom1 KO mice. Conclusions: PROM1 maintains spermatogenic cell proliferation and survival via c-FLIP expression in the testis. It is also involved in sperm motility and fertilization potential. The mechanism underlying the effect of Prom1 on sperm morphology and motility remains to be identified.

The effect of antiplatelet therapy on outcomes in patients who underwent laparoscopic radical nephrectomy: A Japanese single-center study.

OBJECTIVES: The number of patients receiving antiplatelet therapy (APT) who have undergone laparoscopic radical nephrectomy is increasing. However, it is unclear whether APT affects the outcomes of patients undergoing radical nephrectomy. We investigated the perioperative outcomes of radical nephrectomy in patients with and without APT. METHODS: We retrospectively collected data from 89 Japanese patients who underwent laparoscopic radical nephrectomy for clinically diagnosed renal cell carcinoma (RCC) at Kokura Memorial Hospital between March 2013 and March 2022. We analyzed information related to APT. We divided the patients into two groups: the APT group (patients receiving APT) and the N-APT group (patients not receiving APT). Moreover, the APT group was further divided into the C-APT group (patients with continuous APT) and the I-APT group (patients with interrupted APT). We compared the surgical outcomes of these groups. RESULTS: Among 89 patients eligible for the study, 25 received APT and 10 continued APT. Even though the patients who received APT had a high American Society of Anesthesiologists physical status and many complications, including smoking, diabetes, hypertension, and chronic heart failure, no significant difference in the intra- or postoperative outcomes, including bleeding complications, was observed regardless of whether the patients received APT or continued APT. CONCLUSIONS: We concluded that in laparoscopic radical nephrectomy, continuation of APT is an acceptable strategy for patients with thromboembolic risk caused by interruption of APT.

Risks and benefits of transurethral resection of the bladder tumor using photodynamic diagnosis with oral 5-aminolevulinic acid hydrochloride according to age and history of recurrence in patients with non-muscle invasive bladder cancer.

BACKGROUND: Patient selection for transurethral resection of the bladder tumor using photodynamic diagnosis (PDD-TURBT) with oral 5-aminolevulinic acid (5-ALA) hydrochloride for non-muscle-invasive bladder cancer (NMIBC) is still unclear as to the best balance of risks (adverse events including hypotension) and benefits (reduction of intravesical recurrence). METHODS: This single-center retrospective study between April 2013 and March 2022, compared the intravesical recurrence-free survival between patients who underwent PDD-TURBT and WL-TURBT using propensity score matching. RESULTS: A total of 222 patients who underwent PDD-TURBT and 177 patients who underwent WL-TURBT for NMIBC were included. Propensity score matching was used to compare intravesical recurrence-free survival in 119 NMIBC patients in the both treatment groups. The intravesical recurrence-free survival within 500 days was significantly higher in the PDD-TURBT group than in the WL-TURBT group (P = 0.039; hazard ratio [HR] 0.48 [0.23-0.98]). Subgroup analysis showed that PDD-TURBT contributed to the reduction of short-term intravesical recurrence in patients aged < 75 years (P = 0.02; HR 0.22 [0.06-0.79]) and primary disease (P = 0.038; HR 0.35 [0.13-0.94]). Hypotension with a systolic blood pressure of < 80 mmHg was observed in 79 patients (35.6%) during PDD-TURBT surgery. In particular, age ≥75 years and general anesthesia were independent prognostic factors for predicting intraoperative hypotension. CONCLUSIONS: PDD-TURBT reduced short-term intravesical recurrence in NMIBC, whereas a higher frequency of hypotension was found in patients aged ≥ 75 years. These results suggest that the risks and benefits of PDD-TURBT are well balanced in younger patients (< 75 years) and those with primary disease.

Novel compound heterozygous mutations in the PLEC gene in a neonate with epidermolysis bullosa simplex with pyloric atresia.

Epidermolysis bullosa (EB) is a heterogeneous group of inherited disorders characterized by the blistering of the skin and mucous membranes. Although the molecular basis of EB has been significantly elucidated, the precise phenotypes of the lethal types of EB have not been completely characterized. Herein, we report a severe case of EB with pyloric atresia (PA). The patient was a Japanese boy who not only had skin lesions but also various complications such as PA, dysphagia, hypotonia, infectious keratitis with corneal ulcer, obstructive uropathy and protein-losing enteropathy. Genetic analysis led to the identification of two novel compound heterozygous mutations in the last exon of the plectin (PLEC) gene. Based on this finding, EB simplex with PA was diagnosed. Immunostaining with anti-plectin antibodies revealed truncated plectin proteins lacking the C-terminus in the patient's skin. We also conducted a prenatal diagnosis in subsequent pregnancy. Our report further highlights the crucial role of plectin in many organs and provides valuable information regarding the phenotypes resulting from mutations in the PLEC gene.

Heat stress upregulates aromatases expression through nuclear DAX-1 deficiency in R2C Leydig tumor cells.

An appropriate balance between testicular testosterone and estradiol is required for spermatogenesis. Excess estradiol is often identified in the semen and serum of infertile men; however, the mechanisms behind this observation remain unclear. This study indicates the relationship between heat stress and aromatase synthesis in Leydig cells. We used R2C rat Leydig tumor cells, which can synthesize both testosterone and estradiol. Aromatase transcription was regulated by the PⅡ promoter with or without heat stress. Heat stress at 40 °C increased aromatase expression and decreased testosterone to estradiol ratio and nuclear DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), which is a suppressor of steroidogenic factor 1 (SF-1). Leptomycin B and KPT-185, a nuclear export inhibitor, prevented nuclear DAX-1 deficiency induced by heat stress and inhibited aromatase transcription. These results indicate that heat stress interferes with DAX-1-SF-1 interaction and induces SF-1-dependent aromatase transcription.

Mucin-producing urothelial-type adenocarcinoma of the prostate diagnosed after robot-assisted radical prostatectomy.

INTRODUCTION: Mucin-producing adenocarcinoma of the prostate is a rare disease that includes prostate adenocarcinoma with mucus production, secondary adenocarcinoma from the bladder or colorectum, and adenocarcinoma from the urothelium of the prostatic urethra. We describe prostate-specific antigen-negative mucin-producing urothelial-type adenocarcinoma of the prostate. CASE PRESENTATION: The patient had urinary retention and a serum prostate-specific antigen level of 0.74 ng/mL. Computed tomography and magnetic resonance imaging revealed a prostate tumor with a mucous component. We diagnosed adenocarcinoma by prostate biopsy and subsequently performed robot-assisted radical prostatectomy. Mucin-producing urothelial-type adenocarcinoma of the prostate was diagnosed by pathological examinations. Lung metastasis, developing within 3 months after surgery, was treated using chemotherapy. CONCLUSION: Endocrine therapy is ineffective for mucin-producing urothelial-type adenocarcinoma of the prostate. Mucin-producing urothelial-type adenocarcinoma of the prostate diagnosis requires pathological and immunohistochemical analyses. It is important to surgically remove the primary lesion, and robot-assisted radical prostatectomy may provide an effective approach. Multimodal therapy is essential to treat for mucin-producing urothelial-type adenocarcinoma of the prostate.

[OVERALL SURVIVAL EVALUATION OF PROSTATE CANCER PATIENTS TREATED WITH ANDROGEN DEPRIVATION THERAPY BY ESTIMATING FLUCTUANT PATTERNS OF METABOLIC FACTOR SERUM LEVELS].

(Background) The effects of fluctuant patterns of serum alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels on overall survival of patients with prostate cancer (PC) treated with androgen deprivation therapy (ADT) remain unclear. (Methods) We enrolled 236 patients with PC and divided into 3 cohorts by fluctuant patterns of serum levels of ALP and LDH between at baseline and at 1 year later, or at diagnosis of castration-resistant prostate cancer (CRPC): intermediate, within interquartile range (IQR) [I]; lower than IQR [L]; higher than IQR [H]. (Results) In the 1 year later ALP cohort, all parameters except age were significantly different. In the L cohort, 75% of patients had bone metastasis and > 50% developed CRPC or died. In the 1 year later LDH cohort, Eastern Cooperative Oncology Group-performance status (ECOG-PS) and clinical metastasis classification were significantly different among the cohorts. In the CRPC/ALP cohorts, baseline prostate-specific antigen values and clinical metastasis classification were significantly different among the cohorts, and all cases had metastasis in the L cohort. In the CRPC/LDH cohort, the L cohort had higher ECOG-PS and shorter time to CRPC. In the 1 year later ALP cohort, the hazard ratio (HR) for death of the L and H cohort to the I cohort was 3.77 and 2.27, respectively and both were significant. In the CRPC/LDH cohort, the HR for death of L cohort to I cohort was 1.99. (Conclusions) Larger fluctuations in serum ALP and LDH levels were a sign of poorer prognosis, especially for patients in the L cohort.

Genome medicine in male infertility: From karyotyping to single-cell analysis.

Male infertility is a multifactorial pathological condition that affects half of infertile couples. The majority of cases are categorized as idiopathic, especially in cases of nonobstructive azoospermia (NOA). An increasing number of genetic abnormalities have been shown to cause spermatogenic impairment with the development of microarray technologies and next-generation sequencing (NGS), moving beyond classical karyotype and polymerase chain reaction analyses of targeted genes. However, the majority of gene mutations, such as Klinefelter syndrome, azoospermia factor microdeletion, or congenital bilateral absence of the vas deferens, fail to function in a one gene-one phenotype manner. Single-cell transcriptome analysis performed using human testicular samples has begun to be published, which has brought about a more comprehensive understanding of testicular pathology. NGS also enables omics approaches, which provide more powerful tools to interrogate the genome, epigenome, transcriptome, and proteome. Simultaneously, the involvement of environmental factors and comorbidities, which may potentially regulate epigenetic factors, has been shown, resulting in a more complex understanding of the pathophysiology of spermatic disorders, especially NOA. The combination of phenotypic data and large amounts of bioinformatical data obtained by NGS may provide a more comprehensive understanding of the pathophysiology of male infertility, which will contribute not only to a diagnosis but also to the proper selection of infertility treatment and the development of new treatment modalities for male infertility.

Testicular localization of activating transcription factor 1 and its potential function during spermatogenesis†.

Activating transcription factor 1 (ATF1), belonging to the CREB/ATF family of transcription factors, is highly expressed in the testes. However, its role in spermatogenesis has not yet been established. Here, we aimed to elucidate the impact of ATF1 in spermatogenesis by examining the expression pattern of ATF1 in mice and the effect of ATF1 knockdown in the mouse testes. We found that ATF1 is expressed in various organs, with very high levels in the testes. Immunohistochemical staining showed that ATF1 was localized in the nuclei of spermatogonia and co-localized with proliferating cell nuclear antigen. In ATF1-deficient mice, the seminiferous tubules of the testis contained cells at all developmental stages; however, the number of spermatocytes was decreased. Proliferating cell nuclear antigen expression was decreased and apoptotic cells were rare in the seminiferous tubules. These results indicate that ATF1 plays a role in male germ cell proliferation and sperm production.

Testicular Temperature and the Effects of Orchiopexy in Infants with Cryptorchidism.

PURPOSE: Testicular temperature should remain low to maintain optimal function of germ cells; however, information regarding testicular temperature in infants and the effect of cryptorchidism and its correction, including laparoscopic staged Fowler-Stephens orchiopexy (LSFSO), is limited. MATERIALS AND METHODS: A total of 82 infants with unilateral palpable cryptorchidism, 24 with nonpalpable testes who underwent unilateral LSFSO and 20 with scrotal hydrocele were included. Ultrasonographic determination of testicular volume and measurement of testicular temperature but not scrotal surface temperature using a Coretemp CTM204® (Terumo, Tokyo) were performed before and 12 months after orchiopexy. The effects of the route of testicular delivery, conventionally through a new hiatus medial to the inferior epigastric vessels or through the transinguinal approach, were investigated in the LSFSO cases. RESULTS: Undescended testicular volume was significantly increased after orchiopexy (0.80 ml to 0.92 ml, p <0.0001). The preoperative testicular temperature (35.1C) was significantly higher than that of the control (34.4C, p <0.0001), and significant decreases in testicular temperature occurred after orchiopexy (34.3C, p <0.0001). A multivariate analysis showed that a decrease in testicular temperature was a factor associated with postoperative testicular development. Twelve months after LSFSO, transinguinal approach was shown to be more effective in decreasing the testicular temperature than the conventional approach (34.4 and 35.3C, respectively, p <0.05). CONCLUSIONS: Orchiopexy is effective in correcting the high-temperature environment caused by cryptorchidism. In the case of nonpalpable testes treated by LSFSO, transinguinal fixation is more effective than the conventional approach in reducing testicular temperature, but a longer followup period is necessary to draw a final conclusion.

[ADVERSE EFFECTS OF ANDROGEN DEPRIVATION THERAPY ON PATIENTS WITH PROSTATE CANCER AND ITS EFFECT ON OVERALL SURVIVAL].

(Background) Patients with prostate cancer, which progresses slowly compared with other cancers, are generally older, and not a few are solely treated with androgen-deprivation therapy (ADT). The physical effects of ADT on bone health, body composition, and hematological parameters must be carefully considered. (Methods) We collected the clinical records of 185 men with pathologically diagnosed prostate cancer who were treated with ADT at our hospital. The primary aim of the study was to determine the prevalence and severity of adverse effects caused by ADT. The second aim was to analyze the effect of fluctuation in the rate of these adverse effects on overall survival (OS). (Results) The median age of patients was 75 years. After ADT for 1 or 2 years, evaluation of bone mineral density revealed median losses of 3% and 6%, respectively. After ADT for 1 year, body mass index was significantly increased by a median 2.1%, and total cholesterol and hemoglobin levels were significantly increased and decreased, respectively. The local and systemic symptoms of subcutaneous granuloma and hot flashes were experienced by 39% and 21.6% patients, respectively. Mono- and multivariate analysis revealed that significant fluctuation in the rate of adverse events after 1-year ADT did not affect OS. (Conclusion) Prevalence and severity of adverse effects caused by ADT were acceptable and almost all patients could be treated in the outpatient clinic, and significant fluctuation in the rate of adverse effects had no effect on OS.

[EFFECT OF NEW ANDROGEN RECEPTOR AXIS-TARGETED AGENTS ON SURVIVAL OF CASTRATION-RESISTANT PROSTATE CANCER].

(Background)The real world's effect of new androgen receptor axis-targeted agents (ARATs) on survival of castration-resistant prostate cancer (CRPC) remains unclear in Japan. (Aims)The primary aim was to determine the clinical benefit of ARATs on survival of CRPC patients. The secondary aim was to evaluate predictive factors affecting the survival of CRPC patients. (Patients and results)Among 236 patients treated with androgen deprivation therapy (ADT), 68 patients developed CRPC; two groups of 34 patients were treated with ARATs (A cases) or conventional ADT (V cases). In a median follow-up of 61.5 months, 20 A and 22 V cases died of cancer. Median survival time (MST) from diagnosis was 99 and 66 months for A and V cases, respectively, and MST from CRPC to death were 50.5 and 44.5 months, respectively. There were no significant differences between both cases. The hazard ratio for death from diagnosis or CRPC progression of the A cases to V cases was 0.711; 95% confidence interval (CI), 0.371 to 1.362; P = 0.3037, or 0.805; 95% CI, 0.434 to 1.491; P=0.4899, respectively. Multivariable analysis revealed that a unique and significant independent prognostic factor from diagnosis was time to CRPC. (Conclusions)In this small retrospective study, we could not determine the clinical benefit of new ARATs compared with conventional ADT on survival of CRPC patients, and a unique and significant independent prognostic factor from diagnosis was time to CRPC. We need to validate these results in a future multi-institutional study.