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Cross-sectional relationships between nocturia and sleep problems have been well evaluated but the risk association for each incidence is scarcely reported. This analysis included 8076 participants of the Nagahama study in Japan (median age 57, 31.0% male) and associations between nocturia and self-reported, sleep-related problems (poor sleep) were evaluated cross-sectionally. Causal effects on each new-onset case were analyzed longitudinally after 5 years. Three models were applied: univariable analysis, adjustment for basic variables (i.e., demographic and lifestyle variables) and full adjustment for basic and clinical variables. The overall prevalences of poor sleep and nocturia were 18.6% and 15.5%, while poor sleep was positively associated with nocturia (OR = 1.85, p < 0.001) and vice versa (OR = 1.90, p < 0.001). Among 6579 good sleep participants, 18.5% developed poor sleep. Baseline nocturia was positively associated with this incident poor sleep (OR = 1.49, p < 0.001, full adjustment). Among 6824 non-nocturia participants, the nocturia incidence was 11.3%. Baseline poor sleep was positively associated with this incident nocturia (OR = 1.26, p = 0.026); such associations were significant only in women (OR = 1.44, p = 0.004) and under-50-year-old groups (OR = 2.82, p < 0.001), after full adjustment. Nocturia and poor sleep associate with each other. Baseline nocturia can induce new-onset poor sleep while baseline poor sleep may induce new-onset nocturia only in women. [ABSTRACT FROM AUTHOR]

Nobiletin and tangeretin (NoT) are flavonoids derived from the peel of Citrus depressa, and they have been found to modulate circadian rhythms. Because nocturia can be considered a circadian rhythm disorder, we investigated the efficacy of NoT for treating nocturia. A randomized, placebo-controlled, double-blind, crossover study was conducted. The trial was registered with the Japan Registry of Clinical Trials (jRCTs051180071). Nocturia patients aged ≥50 years who presented nocturia more than 2 times on a frequency–volume chart were recruited. Participants received NoT or a placebo (50 mg once daily for 6 weeks), followed by a washout period of ≥2 weeks. The placebo and NoT conditions were then switched. Changes in nocturnal bladder capacity (NBC) were the primary endpoint, and changes in nighttime frequency and nocturnal polyuria index (NPi) were secondary endpoints. Forty patients (13 women) with an average age of 73.5 years were recruited for the study. Thirty-six completed the study, while four withdrew. No adverse events directly related to NoT were observed. NoT had little effect on NBC compared with the placebo. In contrast, NoT significantly changed nighttime frequency by −0.5 voids compared with the placebo (p = 0.040). The change in NPi from baseline to the end of NoT was significant (−2.8%, p = 0.048). In conclusion, NoT showed little change in NBC but resulted in decreased nighttime frequency with a tendency toward reduced NPi. [ABSTRACT FROM AUTHOR]

Peripheral clocks function to regulate each organ and are synchronized though various molecular and behavioral signals. However, signals that entrain the bladder clock remain elusive. Here, we show that glucocorticoids are a key cue for the bladder clock in vitro and in vivo. A pBmal1-dLuc human urothelial cell-line showed significant shifts in gene expression after cortisol treatment. In vivo, rhythmic bladder clock gene expression was unchanged by bilateral adrenalectomy but shifted 4 h forward by corticosterone administration at the inactive phase. Moreover, the bladder clock shifted 8–12 h in mice that underwent both bilateral adrenalectomy and corticosterone administration at the inactive phase. These mice showed decreases in the diurnal rhythm of volume voided per micturition, while maintaining diurnal activity rhythms. These results indicate that the diurnal rhythm of glucocorticoid signaling is a zeitgeber that overcomes other bladder clock entrainment factors and coordinates the diurnal rhythm of volume voided per micturition. The diurnal rhythm of glucocorticoid is shown to be a master regulator of the bladder clock in mice. [ABSTRACT FROM AUTHOR]

Ureteral diverticula, especially acquired diverticula, are rare. Surgery is indicated when a diverticulum is accompanied by complications such as stones, pyelonephritis, stenosis, and signs of malignancy. A 59‐year‐old woman visited our urology department with asymptomatic macrohematuria. Enhanced CT scan revealed a right ureteral diverticulum with a 16‐mm diameter that contained two tiny stones inside. After 8 months, the size of these stones increased; therefore, the patient underwent laparoscopic resection of the ureteral diverticulum and end‐to‐end anastomosis of the ureter. Subsequent histopathology of the excised specimen revealed an acquired diverticulum. Follow‐up intravenous pyelography showed adequate urine passage with only minor dilatation of the pelvis at 3 months after the operation. The laparoscopic approach is believed to be feasible for ureteral diverticula cases that require ureteral end‐to‐end anastomosis. [ABSTRACT FROM AUTHOR]

Purpose: There is insufficient understanding of the effects of malignant diseases themselves and chemotherapy on semen quality and final fertility outcomes. Here, the authors focused on the patients with malignant diseases who cryopreserved sperm pre‐ or post‐chemotherapy for future fertility, and revealed how clinical settings can affect semen quality and final outcomes. Methods: The authors reviewed the records of 257 patients with malignant diseases who cryopreserved sperm. Among 257 cases, 113 men with germ cell tumors (GCTs) and 111 men with hematological disorders (HDs) were included in this study. Twenty‐five patients who achieved successful outcomes using cryopreserved sperm were also analyzed. Results: In the men with GCTs and HDs, respectively, differences were observed in age (28 vs 27 years), sperm concentration (32.6 vs 46.1 million/mL, P < 0.05), motility (42.2% vs 41.0%), and the rate of cryopreservation before chemotherapy (90% vs 59%, P < 0.0001). For successful pregnancies and deliveries, age at cryopreservation (30.0 vs 35.3 years, P < 0.05) and disease type (12/16 vs 3/9, P < 0.05) were significant factors. Conclusions: Compared to patients with GCTs, those with HDs have a lower pregnancy and delivery rate, even though semen quality is higher. Disease type and age at cryopreservation are significant factors for successful outcomes. [ABSTRACT FROM AUTHOR]

Background: Although nocturia has been reported to increase mortality in elderly individuals, the particular risk factors that are associated with this event are unclear. Therefore, we evaluated risk factors for death in outpatients with nocturia. Methods: Between October 2002 and December 2009, 250 consecutive patients with nocturia were enrolled in two general hospitals in Japan. Among them, 193 patients were able to be followed for at least 1 year and up to 9 years (median 4.8 years) if the patients did not die. Mortality rates and risk factors were evaluated in the nocturic outpatients. Results: Two- and 5-year survival of the nocturic outpatients was 94.6 % [95 % confidence interval (CI) = 92.2-97.1] and 82.6 % (95 % CI = 75.4-87.8), respectively. Higher Charlson Comorbidity Score, lower body mass index (BMI) and lower Physical Component Summary of Short Form-36 item scores were significantly correlated with mortality (p < 0.0001, p < 0.005 and p < 0.05, respectively) in multivariate analysis. The International Prostate Symptom Score, Pittsburgh Sleep Quality Index, Mental or Role/Social Component Summary of Short Form-36 item scores and Nocturnal Polyuria index were not significantly correlated with mortality. The mortality rate was significantly higher in subjects with an underweight BMI (<18.50) compared with a normal range (18.50-24.99) or overweight (≥25.00) BMI [p < 0.00005, hazard ratio (HR) = 5.84, 95 % CI = 2.03-16.8; p < 0.0005, HR = 5.92, 95 % CI = 1.94-18.0]. Conclusions: Additional attention is required for nocturic outpatients with not only a high Charlson Comorbidity Score but also an underweight BMI because of their high mortality. Large prospective studies are warranted to validate this finding and extend more. [ABSTRACT FROM AUTHOR]

Urothelial cells respond to bladder distension with ATP release, and ATP signaling within the bladder and from the bladder to the CNS is essential for proper bladder function. In other cell types, pannexin 1 (Panx1) channels provide a pathway for mechanically-induced ATP efflux and for ATP-induced ATP release through interaction with P2X7 receptors (P2X7Rs). We report that Panx1 and P2X7R are functionally expressed in the bladder mucosa and in immortalized human urothelial cells (TRT-HU1), and participate in urothelial ATP release and signaling. ATP release from isolated rat bladders induced by distention was reduced by the Panx1 channel blocker mefloquine (MFQ) and was blunted in mice lacking Panx1 or P2X7R expression. Hypoosmotic shock induced YoPro dye uptake was inhibited by MFQ and the P2X7R blocker A438079 in TRT-HU1 cells, and was also blunted in primary urothelial cells derived from mice lacking Panx1 or P2X7R expression. Rinsing-induced mechanical stimulation of TRT-HU1 cells triggered ATP release, which was reduced by MFQ and potentiated in low divalent cation solution (LDPBS), a condition known to enhance P2X7R activation. ATP signaling evaluated as intercellular Ca2+ wave radius was significantly larger in LDPBS, reduced by MFQ and by apyrase (ATP scavenger). These findings indicate that Panx1 participates in urothelial mechanotransduction and signaling by providing a direct pathway for mechanically-induced ATP release and by functionally interacting with P2X7Rs. [ABSTRACT FROM AUTHOR]

Abstract: Rev-erbα, a component of the circadian clock, has also been known as a nuclear receptor that lacks activation function domain 2, functioning as a ligand-dependent transcriptional repressor. However, we recently reported that Rev-erbα activates connexin43 transcription by forming a complex with Sp1. Here we show that heme, a REV-ERB ligand, is dispensable for this novel mechanism and that Rev-erbβ, having homologies with Rev-erbα, does not activate connexin43, but competes with the Rev-erbα/Sp1. The A/B region of Rev-erbα, which is not conserved in Rev-erbβ, is a crucial activating domain, while the ligand binding domain, conserved in Rev-erbβ, functions as a competitor. [Copyright &y& Elsevier]

Overactive bladder is a highly prevalent clinical condition that is often caused by bladder outlet obstruction (BOO). Increased coupling of bladder smooth muscle cells (BSMC) via gap junctions has been hypothesized as a mechanism for myogenic bladder overactivity in BOO, although little is known about the regulatory system underlying such changes. Here, we report the involvement of basic fibroblast growth factor (bFGF) and connexin 43, a bladder gap junction protein, in bladder overactivity. BOO created by urethral constriction in rats resulted in elevated bFGF and connexin 43 levels in the bladder urothelium and muscle layer, respectively, and muscle strips from these bladders were more sensitive than those from sham-operated controls to a cholinergic agonist. In vitro bFGF treatment increased connexin 43 expression in cultured rat BSMC via the ERK 1/2 pathway. This finding was supported by another in vivo model, where bFGF released from gelatin hydrogels fixed on rat bladder walls caused connexin 43 upregulation and gap junction formation in the muscle layer. Bladder muscle strips in this model showed increased sensitivity to a cholinergic agonist that was blocked by inhibition of gap junction function with α-glycyrrhetinic acid. Cystometric analyses of this model showed typical features of detrusor overactivity such as significantly increased micturition frequency and decreased bladder capacity. These findings suggest that bFGF from the urothelium could induce bladder hypersensitivity to acetylcholine via gap junction generation in the smooth muscle, thereby contributing to the myogenic overactivity of obstructed bladders. [ABSTRACT FROM AUTHOR]

Background and Purpose: Worsening lower urinary tract symptoms (LUTS) are a frequent adverse event following proton beam therapy (PBT) for localized prostate cancer. We investigated the differences in worsening LUTS among patients who received PBT at different times of day. Participants and Methods: Among 173 patients who underwent PBT for prostate cancer, 168 patients (median age 68.5 years) completed international prostate symptom score (IPSS) questionnaires and were included. Changes in the IPSS from baseline to the end of PBT were assessed by multiple linear regression analysis for age, National Comprehensive Cancer Network risk classification, androgen deprivation therapy, fractional PBT dose, clinical target volume, severity of IPSS, diabetes, LUTS medication use before PBT, anti-coagulant therapy and radiation time of day (morning (08:30–10:30), around noon (10:31–14:30), and late afternoon (14:31–16:30)). Results: IPSS total score and IPSS-Quality of Life (QoL) score (12 patients were excluded due to missing IPSS-QoL score) increased from eight to 14.9 (p < 0.0001) and from two to four (p < 0.0001), respectively. Time of day (morning) was the only determinant for worsening LUTS (β = −0.24, p < 0.01), voiding subscore (β = −0.22, p < 0.05) and IPSS-QoL (β = −0.27, p < 0.005), and was a determinant in item four (urgency) (β = −0.28, p < 0.005) with age (β = 0.19, p < 0.05). Conclusions: Morning PBT for localized prostate cancer significantly ameliorated worsening LUTS and improved QoL compared with treatment around noon or late afternoon. Chronoradiation therapy for localized prostate cancer may be effective and further research to elucidate the underlying mechanism is warranted. [ABSTRACT FROM AUTHOR]

Post-operative chyloretroperitoneum is a rare complication in urological surgery. We experienced two cases of post-operative chyloretroperitoneum following retroperitoneoscopic left nephroureterectomy. Both cases were treated successfully with drainage, low fat diet, total parenteral nutrition (case 1 only), sclerotherapy and somatostatin analog. Laparoscopic procedures are supposed to have a higher risk of chylous complications, as CO2 pressure appears to make the operator overlook suppressing the lymphatic leakage from the resected lymphatic channels. [ABSTRACT FROM AUTHOR]

We report a case of intravesical tape erosion which occurred 6 months after the tension-free vaginal tape (TVT) procedure, which was successfully treated by partial tape removal. A 75-year-old woman, who had complained of recurrent cystitis after TVT procedure, was referred to Kobe City General Hospital in August 2003. The intravesical tape erosion was revealed by cystoscopy and computed tomography, and the tape was removed with a retropubic approach. The recurrent cystitis has been cured and the stress urinary incontinence has not recurred. The intravesical tape erosion was rare, with only seven reported cases including the present case. [ABSTRACT FROM AUTHOR]

Renal artery pseudoaneurysms are a well-documented complication following trauma or percutaneous urological procedures, but are rare after partial nephrectomy. We present the case of a 34-year-old woman who, after undergoing a left nephrectomy in childhood due to Wilms’ tumor, had a pseudoaneurysm in a solitary kidney after laparoscopic right partial nephrectomy with extraperitoneal approach for a renal cell carcinoma. The segmental renal artery feeding the pseudoaneurysm was embolized with coils without significant loss of residual renal function. [ABSTRACT FROM AUTHOR]

A 15-year-old boy, who tumbled from a fourth-floor window, was transported to our hospital. Enhanced computed tomography (CT) 1.5 h after the injury showed a non-contrasted right kidney, and a repeat CT 6 h after the injury showed a growing retroperitoneal hematoma. The angiography showed complete obstruction of the right renal artery and bleeding from the subcapsular artery, which was successfully embolized. Renovascular hypertension developed on the second day after the injury; therefore, simple nephrectomy was performed. [ABSTRACT FROM AUTHOR]

A 77-year-old man visited the Kobe City General Hospital complaining of macroscopic hematuria. A computed tomography scan found a bladder tumor with left iliac and para-aortic lymph node metastasis. Two courses of cisplatin, cyclophosphamide and doxorubicin chemotherapy resulted in a minimal response. Radical cystectomy and a retroperitoneal lymph node dissection with bilateral ureterocutaneostomy reconstruction were then performed. A pathological examination revealed a micropapillary variant of transitional cell carcinoma (Grade 3, pT1pN2M1). The patient died of pelvic recurrence 7 months after the initiation of chemotherapy. Peritonitis carcinomatosa and lung metastases were observed at autopsy. [ABSTRACT FROM AUTHOR]

Background: To identify the prognostic impact of treatment centralization in patients with testicular germ cell tumors (TGCT). Methods: We used a hospital-based cancer registry data in Japan to extract seminoma and non-seminoma cases that were diagnosed in 2013, histologically confirmed, and received the first course of treatment. To compare the 5-years overall survival (OS) rates of patients stratified by institutional care volume, we performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) method to adjust patient backgrounds. Results: A total of 1767 TGCT patients were identified. The 5-years OS rates for stage II and III TGCT patients treated at low-volume institutions (< 7 cases) were significantly worse than high-volume institutions (≥ 7 cases) (91.2% vs. 83.4%, p = 0.012). Histological stratification revealed that 5-year OS rates for stage II and III seminoma patients in the low-volume group were significantly worse than the high-volume group (93.5% vs. 84.5%, p = 0.041). Multivariate OS analysis using an IPTW-matched cohort showed that institutional care volume was an independent prognostic factor (hazard ratio 2.13 [95% confidence interval: 1.23–3.71], p = 0.0072). Conclusion: Our results indicate that stage II and III TGCT patients experience lower survival rates at low-volume institutions and would benefit from treatment centralization. [ABSTRACT FROM AUTHOR]

Background: Genitourinary sarcomas are rare in adults and few large-scale studies on adult genitourinary sarcoma are reported. We aimed to elucidate the clinical characteristics, survival outcomes, and prognostic factors for overall survival of adult genitourinary sarcoma in Japan. Methods: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with genitourinary sarcoma in 2013. The datasets were registered from 121 institutions. Results: A total of 116 men and 39 women were included, with a median age of 66 years. The most common primary site was the kidney in 47 patients, followed by the paratestis in 36 patients. The most common histological type was liposarcoma in 54 patients, followed by leiomyosarcoma in 25 patients. The 5-year overall survival rates were 57.6%. On univariate analysis, male gender, paratestis as primary organ, and histological subtype of liposarcoma were predictive of favorable survival while primary kidney, bladder, or prostate gland location were predictive of unfavorable survival. On multivariate analysis, primary paratestis was an independent predictor of favorable survival while primary kidney, bladder, or prostate gland were independent predictors of unfavorable survival. Conclusions: This is the first report showing the clinical characteristics and survival outcomes of adult genitourinary sarcoma in Japan using a real-world large cohort database. [ABSTRACT FROM AUTHOR]

The article reflects on neurogenic bladder a disease found in patients suffering from multiple sclerosis (MS), a degenerative autoimmune disease of the central nervous system (CNS). A study in mice with experimental autoimmune encephalomyelitis (EAE), found bladder dysfunction to be associated with the pannexin 1 (Panx1) channel. It mentions that a study in hTERT immortalized normal human urothelial cells (TRTHU1) found Panx1-IL-1β loop to be used as the bladder therapeutic approach.

The author reflects on the findings of a research study which revealed that propiverine acted as a noradrenaline re-uptake inhibitor to increase leak point pressure in rats, which was published in the January 2016 issue of the "International Journal of Urology."

Objectives To evaluate the association between nocturia and the incidence of depressive symptoms. Participants and Methods Of 1 127 participants in the HEIJO- KYO population-based cohort, 866 elderly individuals (mean age 71.5 years) without depressive symptoms at baseline were followed for a median period of 23 months. Nocturnal voiding frequency was logged using a standardized urination diary and nocturia was defined as a frequency of ≥2 voids per night. Depressive symptoms were assessed using the Geriatric Depression Scale. Results During the follow-up period, 75 participants reported the development of depressive symptoms (score ≥6). The nocturia group ( n = 239) exhibited a significantly higher hazard ratio ( HR) for incident depressive symptoms than the non-nocturia group ( n = 627) in the Cox proportional hazard model, which was adjusted for age, gender, alcohol consumption, day length and presence of hypertension and chronic kidney disease ( HR 1.69, 95% confidence interval [ CI] 1.05-2.72; P = 0.032]. The significance remained after adjustment for sleep disturbances ( HR 1.68, 95% CI 1.02-2.75; P = 0.040). Analysis stratified by gender showed that the association between nocturia and the incidence of depressive symptoms was significant in men ( HR 2.51, 95% CI 1.27-4.97; P = 0.008) but not in women ( HR 1.12, 95% CI 0.53-2.44; P = 0.74). Conclusions Nocturia is significantly associated with a higher incidence of depressive symptoms in the general elderly population, and gender differences may underlie this association. [ABSTRACT FROM AUTHOR]

Enfortumab vedotin (EV) is an antibody-drug conjugate and a promising agent for metastatic urothelial carcinoma (mUC). However, evaluations in end-stage renal disease patients undergoing hemodialysis are unreported. Here, we report such a case. A 74-year-old woman with mUC, on hemodialysis for complete urinary tract extirpation, was diagnosed with multiple pulmonary metastases after treatment with gemcitabine-carboplatin followed by pembrolizumab. As third-line therapy, she received a standard dose of EV. She achieved complete response after 2 cycles without grade 3 or higher adverse events, demonstrating the utility of EV in this setting. [ABSTRACT FROM AUTHOR]

Simple Summary: Some metastatic renal cell carcinoma (mRCC) patients do not respond to immune checkpoint inhibitor (ICI) therapy. However, since predicting who will be a poor responder is difficult, a non-invasive, high-resolution genomic biomarker to accurately predict clinical responses to ICIs is urgently required. We found a minimum set of 14 genes that change in response to treatment and this panel can be used to accurately classify responder patients. Our results suggest that the gene signatures identified from a whole-blood transcriptome approach are clinically useful biomarkers for predicting ICI responses in patients with mRCC. In metastatic renal cell carcinoma (mRCC), the clinical response to immune checkpoint inhibitors (ICIs) is limited in a subset of patients and the need exists to identify non-invasive, blood-based, predictive biomarkers for responses. We performed RNA sequencing using whole-blood samples prospectively collected from 49 patients with mRCC prior to the administration of ipilimumab (IPI) and/or nivolumab (NIVO) to determine whether gene expression profiles were associated with responses. An analysis from 33 mRCC patients with complete responses (n = 5), partial responses (n = 14), and progressive disease (n = 14) showed 460 differentially expressed genes (DEGs) related to immune responses between the responder and non-responder groups with significant differences. A set of 14 genes generated from the initial 460 DEGs accurately classified responders (sensitivity 94.7% and specificity 50.0%) while consensus clustering defined clusters with significantly differing response rates (92.3% and 35.0%). These clustering results were replicated in a cohort featuring 16 additional SD patients (49 total patients): response rates were 95.8% and 48.0%. Collectively, whole-blood gene expression profiles derived from mRCC patients treated with ICIs clearly differed by response and hierarchical clustering using immune response DEGs accurately classified responder patients. These results suggest that such screening may serve as a predictor for ICI responses in mRCC patients. [ABSTRACT FROM AUTHOR]

Objectives: Most testicular cancer (TC) survivors have long‐term survival. However, the association between financial toxicity (FT), which is an economic side effect of cancer treatment, and the quality of life (QOL) of TC survivors is still unclear. Thus, the impact of FT on the QOL of TC survivors was examined in a multi‐institutional cross‐sectional study. Methods: We recruited TC survivors from eight high‐volume institutions in Japan between January 2018 and March 2019. A total of 562 participants completed the EORTC QLQ‐C30, EORTC QLQ‐TC26 and the questionnaires on demographics, including annual income. Financial difficulty in the EORTC QLQ‐C30 and low income were used to assess financial distress (FD) and financial burden (FB), respectively. FT was defined as FD and FB. The QOL scores were compared, and a multivariate logistic regression analysis for FT was performed. Results: With severe FD, TC survivors had more treatment side effects, physical limitations, and anxiety concerning employment and future. The TC survivors who reported low income were worried about their jobs and the future. The QOL of the survivors with FT exhibited high impairment, except for sexual activity. In particular, the TC survivors with FT were physically limited and anxious concerning the future. The multivariate logistic regression analysis revealed that four or more chemotherapy cycles were substantial risk factors for FT (4 cycles, odds ratio (OR) = 4.17; ≥5 cycles, OR = 6.96). Conclusions: TC survivors who received multi‐cycle chemotherapy were prone to experience FT, resulting in a decline in their health‐related QOL. [ABSTRACT FROM AUTHOR]

Objective: To identify the clinicopathological features of adrenal malignancies and analyze the prognoses of patients with adrenal cortical carcinoma (ACC) and malignant pheochromocytoma (MPCC). Patients and methods: We used a hospital‐based cancer registry data in Japan to extract cases of adrenal malignancies that were histologically confirmed, diagnosed, and initially treated from 2012–2015. For survival analysis, we used data from the 2008–2009 cohort to estimate 5‐year overall survival (OS) by the Kaplan–Meier method. Results: A total of 989 adrenal malignancies were identified in the 2012–2015 cohort. The most common histologies were ACC (26.4%), diffuse large B‐cell lymphoma (DLBCL; 25.4%), neuroblastoma (22.2%), and MPCC (11.9%). While most ACC and MPCC patients were in their 60s, DLBCL patients accounted for 61.5% of adrenal malignancies in the over‐70 cohort. Among ACC patients with clinical staging data, 46.3% of patients were stage IV. Although surgery was a chief strategy for all stages, younger patients tended to receive combination therapy, including surgery and chemotherapy or hormone therapy. In the 2008–2009 cohort, the 5‐year OS rates of ACC (n = 49) and MPCC (n = 23) patients were 56.2% and 86.4% while ACC patients without surgery had 1‐ and 2‐year OS rates of 25.0% and 12.5%. Conclusion: In Japan, DLBCL accounted for the majority of adrenal malignancies in older patients. Despite advanced staging, ACC patients were mainly treated with surgery and their prognosis was not satisfactory. Such epidemiological data may be useful in considering initial management strategies. [ABSTRACT FROM AUTHOR]

The authors discuss the method they developed used in analyzing mouse micturition known as automated Voided Stain on Paper (aVOSP). The method uses a rolled, processed filter paper whose color changes by water drops in which the voided per micturition (VV) of mice are calculated. Using aVOSP, VV and total urine volume (UV) increased in mice until six weeks of age. Frequency and micturition rhythm in male adolescent mice were found to be similar at five to six weeks.

The circadian clock system exists in most organs and regulates diverse physiological processes, including growth. Here, we used a prostate-specific Bmal1-knockout mouse model (pBmal1 KO: PbsnCre+; Bmal1fx/fx) and immortalized human prostate cells (RWPE-1 and WPMY-1) to elucidate the role of the peripheral prostate clock on prostate growth. Bmal1 KO resulted in significantly decreased ventral and dorsolateral lobes with less Ki-67-positive epithelial cells than the controls. Next, the cap analysis of gene expression revealed that genes associated with cell cycles were differentially expressed in the pBmal1 KO prostate. Cdkn1a (coding p21) was diurnally expressed in the control mouse prostate, a rhythm which was disturbed in pBmal1 KO. Meanwhile, the knockdown of BMAL1 in epithelial RWPE-1 and stromal WPMY-1 cell lines decreased proliferation. Furthermore, RWPE-1 BMAL1 knockdown increased G0/G1-phase cell numbers but reduced S-phase numbers. These findings indicate that core clock gene Bmal1 is involved in prostate growth via the modulation of the cell cycle and provide a rationale for further research to link the pathogenesis of benign prostatic hyperplasia or cancer with the circadian clock. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to develop models to predict new‐onset overactive bladder in 5 years using a large prospective cohort of the general population. Methods: This is a secondary analysis of a longitudinal cohort study in Japan. The baseline characteristics were measured between 2008 and 2010, with follow‐ups every 5 years. We included subjects without overactive bladder at baseline and with follow‐up data 5 years later. Overactive bladder was assessed using the overactive bladder symptom score. Baseline characteristics (demographics, health behaviors, comorbidities, and overactive bladder symptom scores) and blood test data were included as predictors. We developed two competing prediction models for each sex based on logistic regression with penalized likelihood (LASSO). We chose the best model separately for men and women after evaluating models' performance in terms of discrimination and calibration using an internal validation via 200 bootstrap resamples and a temporal validation. Results: We analyzed 7218 participants (male: 2238, female: 4980). The median age was 60 and 55 years, and the number of new‐onset overactive bladder was 223 (10.0%) and 288 (5.8%) per 5 years in males and females, respectively. The in‐sample estimates for C‐statistic, calibration intercept, and slope for the best performing models were 0.77 (95% confidence interval 0.74–0.80), 0.28 and 1.15 for males, and 0.77 (95% confidence interval 0.74–0.80), 0.20 and 1.08 for females. Internal and temporal validation gave broadly similar estimates of performance, indicating low optimism. Conclusion: We developed risk prediction models for new‐onset overactive bladder among men and women with good predictive ability. [ABSTRACT FROM AUTHOR]

Objectives: Germ cell tumors are highly susceptible to chemotherapy; however, there is a lack of established treatments for consistently relapsing germ cell tumor. Therefore, in this phase II study, we evaluated the efficacy and safety of nivolumab for relapsed germ cell tumor. Methods: Seventeen adult patients (median age 34 years) with refractory primary germ cell tumor after second‐line or higher chemotherapy were enrolled. Nivolumab was administered over 30 min at 240 mg/body every 2 weeks until disease progression or intolerable adverse event occurrence. The primary endpoint was the overall response rate. Result: We performed a biomarker analysis of programmed death ligand‐1 expression and genomic sequencing. Tumor histology revealed nonseminoma and seminoma in 14 and three patients, respectively. Patients were pretreated with a median of three chemotherapy lines, and three patients received high‐dose chemotherapy. The median number of nivolumab doses was 3 (range 2–46). One patient showed a partial response and three showed stable disease. Responses were durable in one patient with a partial response and one patient with stable disease (median 90 and 68 weeks, respectively). Nivolumab was well‐tolerated, with only two Grade 3 adverse events observed. Programmed death ligand‐1 expression was not associated with objective responses. Genomic sequencing revealed a high tumor mutation burden in a patient with a durable partial response. While a small subset of chemorefractory germ cell tumors may respond to nivolumab, programmed death ligand‐1 is unreliable to measure response. Conclusions: Tumor mutation burden is a potential biomarker for future testing of germ cell tumor response. [ABSTRACT FROM AUTHOR]

Introduction: No standard procedure has been established for laparoendoscopic single‐site surgery for urachal remnants (LESS‐U). This study aimed to report the novel surgical techniques and initial outcomes of laparoendoscopic single‐site surgery with an extraperitoneal approach through a suprapubic port for urachal remnants (spLESS). Methods: Fifty‐five patients (median age, 27 years; range, 15–69 years) who underwent LESS‐U were analyzed. To overcome the limitations inherent in the conventional procedure (LESS‐U through an umbilical port: uLESS), we modified the port placement and approached via the extraperitoneal space. spLESS is a novel procedure which reduces intestinal damage caused by the extraperitoneal approach and overcomes incomplete resection of the urachal remnant, especially in the bladder dome. Three trocars are inserted into the extraperitoneal space through a suprapubic port in spLESS, and complete resection of the urachal remnant from the umbilicus to the bladder is performed with an appropriate incision line. Patient characteristics and perioperative results were retrospectively collected. Cosmetic outcomes were prospectively evaluated using self‐administered questionnaires (body image and photo‐series questionnaire). Results: spLESS and uLESS were performed in 43 and 12 patients, respectively. No differences were observed between the perioperative results. The cosmetic outcomes were compared between the groups using body image and photo‐series questionnaires. No patient developed major complications; there was no recurrence in either group. Conclusions: spLESS is a novel procedure which can completely resect the urachal remnant and reduce the risk of intestinal damage. spLESS is a safe, effective, and feasible procedure with high postoperative cosmesis. [ABSTRACT FROM AUTHOR]

Bladder inflammatory diseases cause various urinary symptoms, such as urinary frequency and painful urination, that impair quality of life. In this study, we used a mouse model of cyclophosphamide (CYP)-induced bladder inflammation and immortalized human urothelial (TRT-HU1) cells to explore the preventive potential of nobiletin (NOB), a polymethoxylated flavone enriched in citrus fruit peel, and investigate its mechanism of action in the bladder. Prophylaxis with PMF90 (60% NOB) attenuated the development of bladder inflammation and urinary symptoms in CYP-treated mice. PMF90 also reduced the upregulation of connexin 43 (Cx43), a major component of gap junction channels, in the bladder mucosa of CYP-treated mice. Stimulation of TRT-HU1 cells with the pro-inflammatory cytokine IL-1β increased Cx43 mRNA and protein expression and enhanced gap junction coupling—responses that were prevented by pre-treatment with NOB. In urothelium-specific Cx43 knockout (uCx43KO) mice, macroscopic signs of bladder inflammation and changes in voiding behavior induced by CYP treatment were significantly attenuated when compared to controls. These findings indicate the participation of urothelial Cx43 in the development of bladder inflammation and urinary symptoms in CYP-treated mice and provide pre-clinical evidence for the preventive potential of NOB through its anti-inflammatory effects on IL-1β signaling and urothelial Cx43 expression. [ABSTRACT FROM AUTHOR]

Background: The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have published guidelines on the use of cancer treatments in young people of reproductive potential. However, no such guideline is available in Japan. Therefore, this project aimed to gather relevant data and draft a respective guidance paper. Methods: From April 2019 to March 2021, the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential at the Japan Agency for Medical Research and Development gathered opinions from experts in reproductive medicine, toxicology, and drug safety measures. The group considered these opinions, the FDA and EMA guidelines, and relevant Japanese guidelines and prepared a guidance paper, which they sent to 19 related organizations for comment. Results: By November 2020, the draft guidance paper was completed and sent to the related organizations, 17 of which provided a total of 156 comments. The study group finalized the guidance paper in March 2021. Conclusions: The "Guidance on the Need for Contraception Related to Use of Pharmaceuticals" (The report of the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential, Research on Regulatory Science of Pharmaceuticals and Medical Devices, Japan Agency for Medical Research and Development: JP20mk0101139) is expected to help Japanese healthcare professionals provide fertility-related care and advice to adolescents, and young adults with cancer and their families. [ABSTRACT FROM AUTHOR]

Intravesical Bovis bacillus Calmette-Guérin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6′-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8+ T cells, and those with knockout of macrophage-inducible C-type lectin (Mincle) which recognize TDM. Lip-TDM treatment enhanced the maturation and migration of dendritic cells in the tumor microenvironment in a Mincle-dependent manner. Our results elucidate mechanisms that underlie Lip-TDM treatment and suggest that Lip-TDM has potential as a safe and effective treatment for various cancers. [ABSTRACT FROM AUTHOR]

Invasion of bladder cancer (BC) cells from the mucosa into the muscle layer is canonical for BC progression while phospholipase D isoform 1 (PLD1) is known to mediate development of cancer through phosphatidic acid (PA) production. We therefore used in silico, in vitro and in vivo approaches to detail the effect of PLD1 on BC invasion. In BC patients, higher levels of PLD1 expression were associated with poor prognoses. PLD1 knockdown significantly suppressed cellular invasion by human BC cells and matrix metalloproteinase-13 (MMP-13) was observed to mediate this effect. In our mouse bladder carcinogenesis model, the development of invasive BCs was suppressed by PLD1 knockout and a global transcriptomic analysis in this model indicated MMP-13 as a potential tumor invasion gene with NF-κB (nuclear factor-kB) as its transcriptional regulator. Furthermore, PA administration increased MMP-13 expression in line with NF-κB p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression through the NF-κB signaling pathway and that PLD1 might be a potential therapeutic target to prevent clinical progression in BC patients. [ABSTRACT FROM AUTHOR]

Background: Nonmuscle-invasive bladder cancer is diagnosed, treated, and monitored using cystoscopy. Artificial intelligence (AI) is increasingly used to augment tumor detection, but its performance is hindered by the limited availability of cystoscopic images required to form a large training data set. This study aimed to determine whether stepwise transfer learning with general images followed by gastroscopic images can improve the accuracy of bladder tumor detection on cystoscopic imaging. Materials and Methods: We trained a convolutional neural network with 1.2 million general images, followed by 8728 gastroscopic images. In the final step of the transfer learning process, the model was additionally trained with 2102 cystoscopic images of normal bladder tissue and bladder tumors collected at the University of Tsukuba Hospital. The diagnostic accuracy was evaluated using a receiver operating characteristic curve. The diagnostic performance of the models trained with cystoscopic images with or without stepwise organic transfer learning was compared with that of medical students and urologists with varying levels of experience. Results: The model developed by stepwise organic transfer learning had 95.4% sensitivity and 97.6% specificity. This performance was better than that of the other models and comparable with that of expert urologists. Notably, it showed superior diagnostic accuracy when tumors occupied >10% of the image. Conclusions: Our findings demonstrate the value of stepwise organic transfer learning in applications with limited data sets for training and further confirm the value of AI in medical diagnostics. Here, we applied deep learning to develop a tool to detect bladder tumors with an accuracy comparable with that of a urologist. To address the limitation that few bladder tumor images are available to train the model, we demonstrate that pretraining with general and gastroscopic images yields superior results. [ABSTRACT FROM AUTHOR]

In humans, most renal functions, including urine volume and electrolyte excretions, have a circadian rhythm. Light is a strong circadian entrainment factor and daytime-light exposure is known to affect the circadian rhythm of rectal temperature (RT). The effects of daytime-light exposure on the diurnal rhythm of urinary excretion have yet to be clarified. The aim of this study was to clarify whether and how daytime exposure to bright-light affects urinary excretions. Twenty-one healthy men (21–27 years old) participated in a 4-day study involving daytime (08:00–18:00 h) exposure to two light conditions, Dim (< 50 lx) and Bright (~ 2500 lx), in a random order. During the experiment, RT was measured continuously. Urine samples were collected every 3 ~ 4 h. Compared to the Dim condition, under the Bright condition, the RT nadir time was 45 min earlier (p = 0.017) and sodium (Na), chloride (Cl), and uric acid (UA) excretion and urine volumes were greater (all p < 0.001), from 11:00 h to 13:00 h without a difference in total daily urine volume. The present results suggest that daytime bright light exposure can induce a phase shift advance in urine volume and urinary Na, Cl, and UA excretion rhythms. [ABSTRACT FROM AUTHOR]

Objectives: Drug‐resistant overactive bladder (OAB) represents an unmet medical need in that treatment options are limited. We developed a treatment model based on cognitive behavioral therapy and evaluated its feasibility and acceptability for drug‐resistant OAB in women. Methods: This was an open‐label, single‐arm, multicenter pilot study. We defined drug‐resistant OAB as OAB with moderate to severe symptoms despite pharmacotherapy for more than 12 weeks. A face‐to‐face intervention was prescribed as six sessions (30 minutes each) over 6 to 12 weeks according to a treatment manual. The effects were assessed by self‐reported questionnaires and frequency voiding charts (FVC) at baseline, during intervention, immediately after intervention, and at follow‐up. Results: Ten patients participated in this study. Median age was 72 years, median OAB Symptom Score was nine points, and median duration of prior treatment for OAB was 5.5 years at baseline. Two participants dropped out of the study. Among the remaining patients, the scores of the OAB Questionnaire subscales improved (effect size: 0.75‐1.73), and the mean urinary frequency in the FVC also improved from baseline (9.0 times, SD: 2.1) to follow‐up (6.2 times, SD: 1.2). All participants were satisfied with the intervention. There were no adverse events during this study. Conclusions: The new treatment based on cognitive behavioral therapy was well tolerated and feasible in women with drug‐resistant OAB. Further randomized research is needed to rigorously evaluate the efficacy of the treatment. [ABSTRACT FROM AUTHOR]

Background: Microdissection testicular sperm extraction (microTESE) is considered the gold standard method of sperm retrieval from patients with non‐obstructive azoospermia (NOA). For careful and thorough examination of seminiferous tubules during microTESE, maximizing surface area of the testicles which we are able to search is essential. Objectives: To develop a systematic procedure for microTESE to maximize surface area and to achieve high sperm retrieval rate (SRR) in microTESE. Materials and methods: We simulated microTESE using three‐dimensional (3D) simulation model and analyzed mathematically the sum of the surface area in various methods. The best method obtained from this simulation model was applied to 102 patients with NOA from 2014 to 2018. These new clinical results were compared with those of 56 patients who underwent a previous method of microTESE from 2011 to 2014. Results: The mathematical 3D simulation model of microTESE indicated that a longitudinal incision on the tunica albuginea and following transverse slicing incisions of testicular parenchyma maximized the surface area coverage. Forty‐six (45%) out of 102 patients who underwent microTESE with the new method had successful retrieval of testicular spermatozoa compared with 16 (29%) of 56 patients with the previous method of microTESE (P =.04). Discussion: Transverse resections of parenchyma in our method run parallel to the courses of intratesticular arteries and do not interfere with the blood supply. The small amount of extracted seminiferous tubules was equivalent to that of the previous method, and no patients exhibited post‐operative symptoms of androgen deficiency in our study. As for post‐operative pain, our new method was comparable with the previous method. Although our study needs a longer follow‐up, there will be limited effects on testicular functions. Conclusion: Longitudinal incision on the tunica albuginea and following transverse slicing incisions in the testicular parenchyma maximized the surface area and improved the SRR of microTESE. [ABSTRACT FROM AUTHOR]

Background: To elucidate the clinicopathological features, hospital-based care volume and prognoses associated with primary retroperitoneal sarcoma (PRS). Methods: Clinical data on PRS cases, diagnosed from 2008 to 2009 (cohort A) and from 2012 to 2015 (cohort B), were obtained from the national hospital-based cancer registry in Japan. Since data on survival, 5 years after PRS diagnosis, were available only for cohort A, patient prognoses were analyzed in this group alone. Results: The numbers of participating hospitals were 154 in cohort A and 537 in cohort B. In total, 380 and 2011 patients with PRS were identified in cohorts A and B, respectively. The incidence of PRS among all the registered urogenital malignancies was 0.52% (2391/462,866). Liposarcoma was the most commonly observed PRS subtype (55.8%), followed by leiomyosarcoma (19.0%). In cohort A, the 5-year overall survival (OS) was 40.4%. The 5-year OS associated with stage I (n = 107), stages II and III (n = 61), and stage IV (n = 59) disease were 59%, 39%, and 6%, respectively. Only two institutions treated over ten patients per year in each cohort. When institutions were divided by hospital care volume (8 hospitals with ≥ = 3 cases and 149 with < 3 cases/year), there were any statistic differences in the OS. Conclusions: We presented the distribution and prognoses associated with PRS using a real-world large cohort database. Centralization for PRS management was not established in Japan, while the prognosis did not significantly depend on the treatment volume of hospitals. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate barriers to sperm cryopreservation for patients with advanced germ cell tumors. Methods: We reviewed data collected from patients who underwent chemotherapy for advanced germ cell tumors in our institutions from 1996 to 2016. We divided sperm cryopreservation procedures into three steps: offering information about sperm cryopreservation, patients' decision making and sperm collection, and investigating the barriers in each step. Results: Of the 91 patients, 43 (47%) successfully completed sperm cryopreservation. Thirty (33%) patients were not offered information about sperm cryopreservation from the doctors. Nine patients (9.9%) were offered but declined preservation. Nine patients (9.9%) were not able to provide sperm because of azoospermia (5) and anejaculation (4). Among 43 patients who successfully provided sperm, 10 (23%) had their cryopreserved sperm used for 21 cycles of in vitro fertilization. Ten pregnancies and 7 fatherhoods were achieved. Thirteen patients (30%) had their cryopreserved sperm discarded without use, whereas 20 (47%) continued preserving their sperm for a median 12.5 years. Conclusions: Not only offering proper information about sperm cryopreservation, but also shared decision making prior to chemotherapy, and considering fertility preservation before orchiectomy are imperative. The rate of use of preserved sperm was relatively high, but decision making for sperm disposal should also be supported. [ABSTRACT FROM AUTHOR]

Prognoses for patients with metastatic urothelial carcinoma (mUC) have improved with pembrolizumab treatment, an immune checkpoint inhibitor, but clinical benefits are limited to a subset of patients. Therefore, a non-invasive biomarker to predict pembrolizumab response is required. The present study retrospectively examined genomic alterations in 25 plasma circulating tumor DNA (ctDNA) samples using targeted sequencing of 77 genes from 16 patients with mUC during pembrolizumab treatment. A total of 11 (68.8%) patients demonstrated ≥2 genomic alterations, including TP53 mutations (as defined by ctDNA-positive status). The proportion of responders to pembrolizumab in the ctDNA-positive group was higher compared with that in the ctDNA-negative group (72.7 vs. 20.0%). Furthermore, among all detected genomic alterations, variant allele frequency decreases in TP53 during pembrolizumab treatment were mainly associated with therapeutic response. Collectively, these data suggest that profiling of ctDNA in plasma, particularly TP53, may be useful for predicting and monitoring therapeutic responses to pembrolizumab in patients with mUC. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the predictive factors for comorbidity of Hunner‐type interstitial cystitis in patients with chronic prostatitis/chronic pelvic pain syndrome using urethrocystoscopy. Methods: Thirty‐two male patients were included in this study. Between April 2012 and April 2016; they were diagnosed with chronic prostatitis/chronic pelvic pain syndrome according to the National Institutes of Health classification. Their symptoms were not improved by 3 months of behavioral and pharmacological therapies. They all underwent narrow band imaging‐assisted urethrocystoscopy to assess whether the presence of Hunner's lesions correlated with other variables. Results: Thirteen out of 32 patients (41%) had Hunner's lesions. Of the variables, maximal voided volume per micturition (106 ± 29 mL vs 171 ± 61 mL) and bladder capacity (267 ± 121 mL vs 407 ± 137 mL) were significantly smaller in patients with Hunner's lesions compared to those without. Other variables, apart from age, were not significantly different. Furthermore, patients with voided volume less than 150 mL were more likely to have Hunner's lesions than those with voided volume exceeding 150 mL. Conclusions: Hunner‐type interstitial cystitis is a common comorbidity among patients with refractory chronic prostatitis/chronic pelvic pain syndrome. In cases where voided volume is small, performing narrow band imaging‐assisted urethrocystoscopy would be very helpful for detecting bladder mucosal changes such as Hunner's lesions. [ABSTRACT FROM AUTHOR]

Bladder cancer usually forms a papillary structure. Progression along the cavity or membranous structures surrounding the bladder, rectum, or retroperitoneum without formation of a discrete mass is rare. We here present two patients with duodenal obstruction caused by retroperitoneal progression of bladder cancer, in both of whom computed tomography revealed bladder and rectal wall thickening with a malignant target sign, thickened mesorectal fascia with abnormal tissue stranding, and increased perirectal fat density. Both cancers progressed despite treatment, as indicated by faint abnormal tissue stranding and increased retroperitoneal fat density along the retromesenteric plane from the pelvis to the duodenum. Subsequently, both patients developed obstruction in the horizontal portion of the duodenum, still without formation of a mass lesion. These two patients highlight the challenges associated with retroperitoneal invasion by bladder cancer in the absence of a mass lesion and underscore the importance of considering cancer progression in patients with bowel obstruction, even when there is no obvious mass lesion and/or only minor retroperitoneal findings. Progression along the retromesenteric plane may be the key pathway via which progressive bladder cancer results in duodenal obstruction without or with a minor mass lesion. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether sodium restriction alters the nocturnal urine volume (NUV) and the ratio of NUV to 24-hour urine of renal allograft recipients (RARs).Materials and Methods: This prospective, single-center study analyzed 38 of the 59 RARs who were followed up for more than 6 months in our hospital. All patients underwent 3 sessions of dietary counseling performed by a board-certified dietitian. Before and after these 3 sessions, 24-hour urine samples were collected, along with voiding frequency volume charts.Results: Of the 38 included RARs, 23 (60.5%) were diagnosed as having nocturnal polyuria (NP, NUV >10 mL/kg). After counseling the RARs with NP, their 24-hour sodium excretion was reduced from 169.5 to 125.6 mEq (P = .0066), their NUV from 862 to 709 mL (P = .021), and the ratio of NUV to 24-hour urine volume from 38.9% to 33.0% (P = .023). In contrast, these parameters were not significantly changed by dietary counseling in RARs without NP. Reduced sodium excretion and decreased NUV were significantly correlated (Spearman rho = 0.45, P = .005).Conclusion: Excess intake of sodium is considered a cause of NP in RARs. Dietary counseling on sodium restriction is effective in reducing NUV in RARs. Prospective studies are needed to evaluate the general population with NP. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate the factors predicting efficacy and adverse effects of enzalutamide in patients with castration-resistant prostate cancer. Methods: We retrospectively evaluated data on 345 patients who had received enzalutamide for castration-resistant prostate cancer in 20 hospitals (Kyoto University Hospital and other satellite hospitals). Cox proportional hazards regression analysis was performed to identify factors predicting prostate-specific antigen (PSA) progression after enzalutamide treatment and logistic regression analysis for those associated with development of adverse effects. Results: PSA titers decreased by >50 % in 197 patients (57 %). The median PSA progression free survival was 163 days. Gleason score >8 (HR 2.078, 95 % CI 1.37-3.153, P = 0.00058), performance status ≥1 (HR 2.292, 95 % CI 1.463-3.592, P = 0.000296), presence of bone metastasis (HR 1.774, 95 % CI 1.019-3.090, P = 0.0429), visceral metastasis (HR 2.127, 95 % CI 1.215-3.722, P = 0.00823), previous steroid treatment (HR 1.780, 95 % CI 1.207-2.626, P = 0.00361) and docetaxel treatment (HR 1.602, 95 % CI 1.051-2.442, P = 0.0284) significantly predicted the efficacy of enzalutamide. Adverse effects, including fatigue or appetite loss, occurred in 169 patients (49 %), 48 (18 %) of whom stopped enzalutamide. Age >75 years (HR 1.980, 95 % CI 1.270-3.09, P = 0.00246) and lower enzalutamide dose (HR 0.437, 95 % CI 0.255-1.270, P = 0.00249) were significantly associated with development of adverse effects. Conclusions: Enzalutamide treatment is effective in patients with castration-resistant prostate cancer with low Gleason scores, good performance status, without bone or visceral metastasis and no prior steroid or docetaxel treatment. Lower doses of enzalutamide decrease the incidence of adverse effects, especially in older patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is commonly associated with bladder dysfunction resulting in a progressive loss of voluntary control for urination over time. Here, we used the voided stain on paper (VSOP) method to investigate bladder function in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Using the VSOP test, we show that bladder dysfunction reflects pro-inflammatory processes of EAE and severity of clinical EAE symptoms, as characterized by increased urine voided volume per micturition (UVVM) on post-induction day 7 and decreased UVVM on post-induction day 14. The UVVM was closely related to a clinical disease index of EAE symptoms and plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine levels. UVVM was also sensitive to early life stress caused by animal transportation, which diminished UVVM at the peak of symptoms on post-induction day 14 in EAE mice. The results indicate that symptoms and progression of EAE can be reliably measured by VSOP as a non-motor function assessment. • Early life stress does not affect the severity of bladder dysfunction in EAE mice. • EAE severity is associated with an inflammatory response by GM-CSF cytokine. • Bladder dysfunction in terms of impaired micturition can be detectable in the EAE model. • EAE severity can be predicted by loss of bladder control in mice. • Progression of EAE can be reliably measured by VSOP. [ABSTRACT FROM AUTHOR]

Lower urinary tract symptoms (LUTS) include storage, voiding and post-micturition symptoms, featuring many urological diseases. Storage symptoms are the most frequent among these and associated with overactive bladder and non-bacterial bladder inflammation such as interstitial cystitis/bladder pain syndrome (IC/BPS). Gap junction, a key regulator of hyperactive conditions in the bladder, has been reported to be involved in pathological bladder inflammation. Here we report involvement of gap junction in the etiology of storage symptoms in bladder inflammation. In this study, cyclophosphamide-induced cystitis was adapted as a model of bladder inflammation. Cyclophosphamide-treated mice showed typical storage symptoms including increased urinary frequency and reduced bladder capacity, with concurrent up-regulation of connexin 43 (GJA1), one of the major gap junction proteins in the bladder. In isometric tension study, bladder smooth muscle strips taken from the treated mice showed more pronounced spontaneous contraction than controls, which was attenuated by carbenoxolone, a gap junction inhibitor. In voiding behavior studies, the storage symptoms in the treated mice characterized by frequent voiding were alleviated by 18α-glycyrrhetinic acid, another gap junction inhibitor. These results demonstrate that cyclophosphamide-induced mouse model of cystitis shows clinical storage symptoms related with bladder inflammation and that gap junction in the bladder may be a key molecule of these storage symptoms. Therefore, gap junction in the bladder might be an alternative therapeutic target for storage symptoms in bladder inflammation. [ABSTRACT FROM AUTHOR]

Pannexin1 (Panx1) is a plasma membrane channel permeable to relatively large molecules, such as ATP. In the central nervous system (CNS) Panx1 is found in neurons and glia and in the immune system in macrophages and T-cells. We tested the hypothesis that Panx1-mediated ATP release contributes to expression of Experimental Autoimmune Encephalomyelitis (EAE), an animal model for multiple sclerosis, using wild-type (WT) and Panx1 knockout (KO) mice. Panx1 KO mice displayed a delayed onset of clinical signs of EAE and decreased mortality compared to WT mice, but developed as severe symptoms as the surviving WT mice. Spinal cord inflammatory lesions were also reduced in Panx1 KO EAE mice during acute disease. Additionally, pharmacologic inhibition of Panx1 channels with mefloquine (MFQ) reduced severity of acute and chronic EAE when administered before or after onset of clinical signs. ATP release and YoPro uptake were significantly increased in WT mice with EAE as compared to WT non-EAE and reduced in tissues of EAE Panx1 KO mice. Interestingly, we found that the P2X7 receptor was upregulated in the chronic phase of EAE in both WT and Panx1 KO spinal cords. Such increase in receptor expression is likely to counterbalance the decrease in ATP release recorded from Panx1 KO mice and thus contribute to the development of EAE symptoms in these mice. The present study shows that a Panx1 dependent mechanism (ATP release and/or inflammasome activation) contributes to disease progression, and that inhibition of Panx1 using pharmacology or gene disruption delays and attenuates clinical signs of EAE. [ABSTRACT FROM AUTHOR]

Connexin43 (Cx43), the main gap junction and hemichannel forming protein in the urinary bladder, participates in the regulation of bladder motor and sensory functions and has been reported as an important modulator of day–night variations in functional bladder capacity. However, because Cx43 is expressed throughout the bladder, the actual role played by the detrusor and the urothelial Cx43 is still unknown. For this purpose, we generated urothelium-specific Cx43 knockout (uCx43KO) mice using Cre-LoxP system. We evaluated the day–night micturition pattern and the urothelial Cx43 hemichannel function of the uCx43KO mice by measuring luminal ATP release after bladder distention. In wild-type (WT) mice, distention-induced ATP release was elevated, and functional bladder capacity was decreased in the animals' active phase (nighttime) when Cx43 expression was also high compared to levels measured in the sleep phase (daytime). These day–night differences in urothelial ATP release and functional bladder capacity were attenuated in uCx43KO mice that, in the active phase, displayed lower ATP release and higher functional bladder capacity than WT mice. These findings indicate that urothelial Cx43 mediated ATP signaling and coordination of urothelial activity are essential for proper perception and regulation of responses to bladder distension in the animals' awake, active phase. [ABSTRACT FROM AUTHOR]

Chronic expanding hematoma is defined as a structure with central mass of blood and granulation tissue encapsulated with dense fibrous membrane that slowly grows over a month. We report a case of a 67-year-old man with left adrenal chronic expanding hematoma who underwent surgical resection after 7-year surveillance, presenting natural history of an adrenal chronic expanding hematoma. [ABSTRACT FROM AUTHOR]