Prognostic significance of adjuvant chemotherapy in stage I-II endometrial carcinoma patients who underwent lymphadenectomy.

BACKGROUND: Endometrial carcinoma, the most common gynecologic carcinoma, has an excellent prognosis post-surgery when diagnosed early. The role of postoperative adjuvant chemotherapy in stages I-II endometrial carcinoma remains controversial. This study assesses the efficacy of adjuvant chemotherapy in improving prognosis for these patients. METHODS: A retrospective analysis was conducted on 1223 stage I-II endometrial carcinoma patients who underwent surgical treatment including total hysterectomy, bilateral salpingo-oophorectomy, and lymph-node biopsy or dissection across four Jikei University School of Medicine-affiliated facilities between 2001 and 2018. Patients were divided into low intermediate risk (LIR) and high intermediate risk (HIR) groups based on recurrence risk. Propensity score matching adjusted for various covariates was used to compare progression-free survival (PFS) and overall survival (OS) between patients who received adjuvant chemotherapy and those who did not. RESULTS: The study included 443 eligible patients, with 288 in the LIR group and 155 in the HIR group. Post propensity score matching, no significant difference in PFS or OS was observed between the observation and adjuvant chemotherapy groups within both risk categories. Notably, the 5-year OS for LIR was 97.6% in the observation group and 96.7% in the chemotherapy group; for HIR, the 5-year OS was similarly high with no significant difference. CONCLUSIONS: The findings suggest that postoperative adjuvant chemotherapy does not significantly contribute to the improvement of recurrence or prognosis in patients with stage I-II endometrial carcinoma who are categorized outside the low-risk group and have no lymph-node metastasis.

Therapeutic effect of dose-dense paclitaxel plus carboplatin with or without bevacizumab for Japanese patients with epithelial ovarian cancer.

BACKGROUND: Evidence regarding chemosensitivity to different therapeutic regimens in epithelial ovarian cancer (EOC) remains limited. This study aimed to investigate EOC implementation in daily clinical practice and reveal favorable regimens for EOC among Japanese patients. METHODS: We retrospectively collected clinical data of patients newly diagnosed with EOC from 2012 to 2021 at our affiliated institutions. We evaluated overall survival (OS) and progression-free survival (PFS) of conventional paclitaxel plus carboplatin (TC) vs. dose-dense TC (ddTC) according to the eligibility of GOG262 and JGOG3016 and those with bevacizumab (BEV) vs. without BEV based on GOG218. Further, we evaluated OS and PFS of ddTC and ddTC + BEV to TC + BEV among patients with stage III/IV. RESULTS: The ddTC group (n = 402) demonstrated longer PFS and OS than the TC group (n = 165) (adjusted hazard ratios [aHRs] [95% confidential intervals (CIs)]: 0.69 [0.55-0.88] and 0.67 [0.50-0.90], respectively). The group with BEV (n = 158) demonstrated a longer PFS than those without BEV (n = 296) (0.74 [0.57-0.95]), but not for OS (0.84 [0.60-1.17]). The ddTC and ddTC + BEV groups (n = 259 and 117) demonstrated no statistically significant differences in PFS and OS than the TC + BEV group (n = 75) (1.09 [0.79-1.50] and 0.74 [0.52-1.08] for PFS and 0.89 [0.59-1.34] and 0.73 [0.50-1.05] for OS, respectively). CONCLUSION: Our study may indicate ddTC, BEV, and their combination regimen as the promising first-line chemotherapy option among Japanese patients with advanced EOC.

Brain carbon monoxide can suppress the rat micturition reflex through brain γ-aminobutyric acid receptors.

OBJECTIVES: To investigate roles of brain carbon monoxide (CO), an endogenous gasotransmitter, in regulation of the rat micturition reflex. METHODS: In urethane-anesthetized (0.8 g/kg, ip) male rats, evaluation of urodynamic parameters was started 1 h before intracerebroventricular administration of CORM-3 (CO donor) or ZnPP (non-selective inhibitor of heme oxygenase, a CO producing enzyme) and continued for 2 h after the administration. We also investigated effects of centrally pretreated SR95531 (GABAA receptor antagonist) or SCH50911 (GABAB receptor antagonist) on the CORM-3-induced response. RESULTS: CORM-3 significantly prolonged intercontraction intervals (ICIs) without changing maximal voiding pressure (MVP), while ZnPP significantly shortened ICI and reduced single-voided volume and bladder capacity without affecting MVP, post-voided residual volume, or voiding efficiency. The ZnPP-induced ICI shortening was reversed by CORM-3. The CORM-3-induced ICI prolongation was significantly attenuated by centrally pretreated SR95531 or SCH50911, respectively. CONCLUSIONS: Brain CO can suppress the rat micturition reflex through brain γ-aminobutyric acid (GABA) receptors.

Underactive bladder as defined by the International Continence Society in the 2023 Japan Community Health Survey.

OBJECTIVE: To investigate the characteristics of underactive bladder (UAB) in participants of the 2023 Japan Community Health Survey (JaCS 2023). METHODS: The JaCS 2023 was conducted among individuals aged 20-99 years old who had anonymously registered with a Japanese online research company. We divided the 6210 participants of JACS 2023 into UAB and non-UAB groups as defined by the International Continence Society Working Group (ICS-WG) and evaluated the prevalence of UAB as well as concomitant lower urinary tract symptoms. In addition, an association between UAB and vulnerability-related factors, namely participants' characteristics including frailty and comorbidities, was explored by univariable and multivariable analyses. RESULTS: The prevalence of UAB in Japanese community-dwelling men and women aged 20 years or older was 9.3% and 4.0% overall (p < 0.0001), respectively, and when excluding benign prostatic hyperplasia or pelvic organ prolapse, 7.0% and 3.7%, respectively, (p < 0.0001). A significant increase in the prevalence of UAB with age was observed (p < 0.0001). In addition, storage symptoms including overactive bladder were more frequent in the UAB group than the non-UAB group (p < 0.0001). Frailty and several comorbidities were independently associated with UAB. CONCLUSIONS: According to the definition proposed by the ICS-WG, the JaCS 2023 demonstrated that UAB was more prevalent in men than in women and increased in prevalence with age. Storage symptoms including overactive bladder sometimes coexisted with UAB. Vulnerability-related factors were associated with UAB.

Is seated voiding associated with lower urinary tract symptoms, health conditions, or marital status? Findings by age group from the 2023 Japan Community Health Survey.

OBJECTIVES: Seated voiding may be an attempt to obviate voiding dysfunction, improve physical stability during voiding, and prevent messy bathroom contamination. Therefore, we hypothesized that seated voiders had a higher prevalence of lower urinary tract symptoms (LUTS), deteriorating health conditions, and a higher marriage rate than standing voiders. METHODS: Of the participants from the 2023 Japan Community Health Survey conducted by the Japanese Continence Society, 2936 men (mean age: 53.6 years old) were divided into sitting and standing groups based on their posture when voiding at home. Characteristics of the two groups were compared, and factors associated with seated voiding stratified by age were investigated using multivariable logistic regression analysis. RESULTS: One-thousand six-hundred and sixty men (57%) voided in the sitting position at home, and the proportion of seated voiding decreased with age. On multivariable analysis, comorbidities other than benign prostatic hyperplasia were associated with the standing group aged 40-59, and storage symptoms were associated with the seated group aged 60 and older. Being married was significantly and consistently associated with seated voiding across all ages. CONCLUSIONS: Approximately 60% of Japanese men void in the sitting position at home. There are certain differences in the associations of LUTS and health conditions with voiding position by age, while seated voiding is consistently associated with marital status throughout all ages, which implies that sanitation matters.

Prevalence and impact on daily life of lower urinary tract symptoms in Japan: Results of the 2023 Japan Community Health Survey (JaCS 2023).

OBJECTIVES: A large-scale nationwide epidemiological survey of lower urinary tract symptoms (LUTS) was conducted via the Internet in 2023 to clarify the current prevalence of LUTS and evaluate its impact on daily life in Japan. METHODS: The survey was conducted among individuals aged 20-99 years old who had anonymously registered with a Japanese online research company. The survey consisted of 48 questions related to LUTS and daily life. RESULTS: A total of 6210 participants (3088 females and 3122 males), who were selected by probability sampling based on the composition of the Japanese population (age range: 20-99), were recruited. The overall prevalence of LUTS was 77.9% among the subjects aged ≥20 and 82.5% among those aged ≥40. The prevalence of LUTS differed between the sexes and trends toward significant increases in prevalence with age were seen for almost all LUTS. Furthermore, the prevalence of overactive bladder (OAB) was 11.9% among the subjects aged ≥20 and 13.8% among those aged ≥40. This study also showed that LUTS negatively affected daily life. However, the percentage of subjects who visited a physician to receive treatment for LUTS was low, including for participants with a history of treatment for LUTS, although this increased with age. CONCLUSION: The prevalence of LUTS, including OAB, increased with age and negatively affected daily life. However, since the percentage of patients who visit a physician to receive treatment for LUTS remains low, further educational activities regarding LUTS are necessary.

Evaluation of non-hematologic toxicity in patients with cervical cancer after Type 3 radical hysterectomy followed by concurrent chemoradiotherapy: a retrospective study.

OBJECTIVE: To investigate the safety of concurrent chemoradiotherapy after Type 3 radical hysterectomy, focusing on non-hematologic toxicity. METHODS: Between January 2010 and December 2017, 236 patients diagnosed with cervical cancer Stages IB1-II (FIGO2008) and who had undergone Type 3 radical hysterectomy at the Jikei Medical University School-related four hospitals were included. Of these 236 patients, 134 had undergone adjuvant concurrent chemoradiotherapy after Type 3 radical hysterectomy (radical hysterectomy + concurrent chemoradiotherapy group), and 102 received no adjuvant therapy after Type 3 radical hysterectomy (radical hysterectomy group). The frequency of non-hematologic toxicities, especially lymphedema, pelvic infection, renal dysfunction, ileus and diarrhea, was investigated in the radical hysterectomy + concurrent chemoradiotherapy and radical hysterectomy groups using univariate and multivariate analyses. In these analyses, age, extent of lymph node dissection and preoperative clinical stage were included as risk factors for five complications. The risk factors for grade ≤ 2 adverse events were statistically evaluated. RESULTS: The frequency of lower extremity lymphedema (22 vs. 10%), renal dysfunction (13 vs. 3%), and diarrhea (13 vs. 0%) was significantly higher in the radical hysterectomy + CRRT group than that in the radical hysterectomy group. Logistic regression analysis revealed that adjuvant concurrent chemoradiotherapy significantly affected the occurrence of grade ≥ 2 lymphedema (P < 0.01) and renal dysfunction (P < 0.01). CONCLUSIONS: Concurrent chemoradiotherapy after Type 3 radical hysterectomy is associated with a higher incidence of renal dysfunction, lower extremity lymphedema and diarrhea. A more appropriate adjuvant therapy needs to be established.

Genetic characteristics of platinum-sensitive ovarian clear cell carcinoma.

OBJECTIVE: Most ovarian clear cell carcinomas are resistant to platinum-based chemotherapy, while a small subset shows a positive response. The aim of this study was to clarify the clinical, pathological and genetic characteristics of platinum-sensitive ovarian clear cell carcinomas. METHODS: The study included 53 patients with stage III-IV ovarian clear cell carcinoma who had residual tumours after primary surgery and received platinum-based therapy between 2009 and 2018. A retrospective examination of platinum sensitivity was performed using the criterion of ≥6 months from the last day of first-line platinum therapy until recurrence/progression. Cases determined to be platinum-sensitive were subjected to immunohistochemical staining, genomic analyses using target sequencing (i.e. NCC Oncopanel) and homologous recombination deficiency (myChoice® HRD Plus) assays. RESULTS: Of the 53 stage III-IV ovarian clear cell carcinoma cases, 11 (21%) were platinum-sensitive. These cases showed better progression-free and overall survival than platinum-resistant cases (hazard ratio = 0.16, P < 0.001). Among the seven sensitive cases whose tumour tissues were available for molecular profiling, five were pure ovarian clear cell carcinoma based on pathological and genetic features, whereas the remaining two cases were re-diagnosed as high-grade serous ovarian carcinoma. The pure ovarian clear cell carcinomas lacked BRCA1 and BRCA2 mutations, consistent with the absence of the homologous recombination deficiency phenotype, whereas two cases (40%) had ATM mutations. By contrast, the two high-grade serous ovarian carcinoma cases had BRCA1 or BRCA2 mutations associated with the homologous recombination deficiency phenotype. CONCLUSION: The subset of platinum-sensitive ovarian clear cell carcinomas includes a majority with pure ovarian clear cell carcinoma features that lack the homologous recombination deficiency phenotype.

Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury.

This article provides a synopsis of current progress made in fundamental studies of lower urinary tract dysfunction (LUTD) after spinal cord injury (SCI) above the sacral level. Animal models of SCI allowed us to examine the effects of SCI on the micturition control and the underlying neurophysiological processes of SCI-induced LUTD. Urine storage and elimination are the two primary functions of the LUT, which are governed by complicated regulatory mechanisms in the central and peripheral nervous systems. These neural systems control the action of two functional units in the LUT: the urinary bladder and an outlet consisting of the bladder neck, urethral sphincters, and pelvic-floor striated muscles. During the storage phase, the outlet is closed, and the bladder is inactive to maintain a low intravenous pressure and continence. In contrast, during the voiding phase, the outlet relaxes, and the bladder contracts to facilitate adequate urine flow and bladder emptying. SCI disrupts the normal reflex circuits that regulate co-ordinated bladder and urethral sphincter function, leading to involuntary and inefficient voiding. Following SCI, a spinal micturition reflex pathway develops to induce an overactive bladder condition following the initial areflexic phase. In addition, without proper bladder-urethral-sphincter coordination after SCI, the bladder is not emptied as effectively as in the normal condition. Previous studies using animal models of SCI have shown that hyperexcitability of C-fiber bladder afferent pathways is a fundamental pathophysiological mechanism, inducing neurogenic LUTD, especially detrusor overactivity during the storage phase. SCI also induces neurogenic LUTD during the voiding phase, known as detrusor sphincter dyssynergia, likely due to hyperexcitability of Aδ-fiber bladder afferent pathways rather than C-fiber afferents. The molecular mechanisms underlying SCI-induced LUTD are multifactorial; previous studies have identified significant changes in the expression of various molecules in the peripheral organs and afferent nerves projecting to the spinal cord, including growth factors, ion channels, receptors and neurotransmitters. These findings in animal models of SCI and neurogenic LUTD should increase our understanding of pathophysiological mechanisms of LUTD after SCI for the future development of novel therapies for SCI patients with LUTD.

Stimulation of brain corticotropin-releasing factor receptor type1 facilitates the rat micturition via brain glutamatergic receptors.

Corticotropin-releasing factor (CRF), a representative stress-related neuropeptide, in the central nervous system reportedly both facilitates and suppresses the micturition, therefore, roles of central CRF in regulation of the micturition are still controversial. In this study, we investigated (1) effects of intracerebroventricularly (icv)-administered CRF on the micturition, and (2) brain CRF receptor subtypes (CRFR1/CRFR2) and glutamatergic receptors (NMDA/AMPA subtypes) involved in the CRF-induced effects in male Wistar rats under urethane anesthesia. Intercontraction intervals (ICI), and maximal voiding pressure (MVP), were evaluated by continuous cystometry 45 min before CRF administration or intracerebroventricular pretreatment with other drugs as follows and 3 h after CRF administration. Single-voided volume (Vv), post-voiding residual volume (Rv), bladder capacity (BC), and voiding efficiency (VE) were evaluated by single cystometry 60 min before CRF administration and 60-120 min after the administration. Icv-administered CRF reduced ICI, Vv, and BC without changing MVP, Rv, or VE. The CRF-induced ICI reduction was attenuated by icv-pretreated CP154526 (CRFR1 antagonist), MK-801 (NMDA receptor antagonist), and DNQX (AMPA receptor antagonist), but not by K41498 (CRFR2 antagonist). These results indicate that stimulation of brain CRFR1 can be involved in facilitation of the rat micturition via brain NMDA/AMPA receptors.

Protective effects of hydrogen sulfide pretreatment on cyclophosphamide-induced bladder dysfunction in rats via suppression of bladder afferent nerves.

Cyclophosphamide (CYP), a broad-spectrum anticancer drug, causes serious side effects, such as haemorrhagic cystitis (HC). Hydrogen sulfide (H2S), an endogenous gasotransmitter, has physiological properties, including anti-inflammation, anti-oxidation, and neuromodulation. In this study, we investigated the effects of NaHS (H2S donor) pretreatment on bladder dysfunction in CYP-treated rats. Male Wistar rats were intraperitoneally pretreated with NaHS (3 or 10 µmol/kg) or vehicle once daily for 7 days before cystometry, and CYP (150 mg/kg) or saline was intraperitoneally administered 2 days before cystometry. After cystometry, the bladder tissues were collected for haematoxylin and eosin staining. In some rats, capsaicin (CAP), which can desensitise CAP-sensitive afferent nerves, was subcutaneously injected at 125 mg/kg 4 days before cystometry. CYP reduced intercontraction intervals (ICI) and bladder compliance (Comp) and increased the number of non-voiding contractions (NVCs) compared with the saline-treated control group. NaHS pretreatment dose-dependently improved the CYP-induced these changes. In bladder tissues, CYP increased histological scores of neutrophil infiltration, haemorrhage, and oedema, while NaHS had no effect on these CYP-induced changes. CAP showed a tendency to suppress CYP-induced changes in ICI. NaHS-induced improvement in CYP-induced changes in urodynamic parameters were not detected in CAP-treated rats. These findings suggest that NaHS pretreatment prevented bladder dysfunction in CYP-treated rats by suppressing CAP-sensitive bladder afferent nerves, but not by suppressing bladder inflammation. Therefore, H2S represents a new candidate as a protective drug for bladder dysfunction induced by HC, a side effect of CYP chemotherapy.

Paclitaxel-carboplatin and bevacizumab combination with maintenance bevacizumab therapy for metastatic, recurrent, and persistent uterine cervical cancer: An open-label multicenter phase II trial (JGOG1079).

OBJECTIVE: This multicenter, open-label, phase II study aimed to evaluate the efficacy and safety of paclitaxel-carboplatin, bevacizumab, and bevacizumab-based maintenance therapy for metastatic, recurrent, and persistent uterine cervical cancer. METHODS: Patients with measurable diseases that were not adapted to regional therapies, such as surgery or radiotherapy, and were systematic chemotherapy-naïve were eligible. The participants received paclitaxel (175 mg/m2), carboplatin (AUC 5), and bevacizumab (15 mg/m2) every three weeks until disease progression or unacceptable adverse events occurred. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall response rate (ORR), overall survival (OS), safety, and time to treatment failure. RESULTS: Sixty-nine patients were analyzed using our protocol. The median paclitaxel- carboplatin therapy duration was six cycles; 40% of patients received bevacizumab maintenance therapy. The median PFS was 11.3 months. The median OS was not reached; the median time to treatment failure was 5.9 months. The ORR was 79.7% [95% confidence interval (CI) 63.8-88.4]; 16 patients (23.2%) showed complete response (CR) and 39 patients (56.5%) showed partial response (PR). The median PFS was 14.3 months (95% CI 7.3-17 months) for the 25 patients who received maintenance therapy and 7.4 months (95% CI 6.1-11 months) for nonrecipients (p = 0.0449). Gastrointestinal perforation/fistulas occurred in four patients (5.6%), all of whom had a history of radiation therapy. CONCLUSIONS: Paclitaxel-carboplatin and bevacizumab therapy is an acceptable and tolerable treatment for advanced or recurrent cervical cancer.

Right ventricular overloading is attenuated in monocrotaline-induced pulmonary hypertension model rats with a disrupted Gpr143 gene, the gene that encodes the 3,4-l-dihydroxyphenyalanine (l-DOPA) receptor.

Pulmonary hypertension (PH) is a severe and progressive disease that causes elevated right ventricular systolic pressure, right ventricular hypertrophy and ultimately right heart failure. However, the underlying pathophysiologic mechanisms are poorly understood. We previously showed that 3,4-l-dihydroxylphenyalanine (DOPA) sensitizes vasomotor response to sympathetic tone via coupling between the adrenergic receptor alpha1 (ADRA1) and a G protein-coupled receptor 143 (GPR143), a DOPA receptor. We investigated whether DOPA similarly enhances ADRA1-mediated contraction in pulmonary arteries isolated from rats, and whether GPR143 is involved in the PH pathogenesis. Pretreating the isolated pulmonary arteries with DOPA 1 µM enhanced vasoconstriction in response to phenylephrine, an ADRA1 agonist, but not to U-46619, a thromboxane A2 agonist or endothelin-1. We generated Gpr143 gene-deficient (Gpr143-/y) rats, and confirmed that DOPA did not augment phenylephrine-induced contractile response in Gpr143-/y rat pulmonary arteries. We utilized a rat model of monocrotaline (MCT)-induced PH. In the MCT model, the right ventricular systolic pressure was attenuated in the Gpr143-/y rats than in WT rats. Phenylephrine-induced cell migration and proliferation were also suppressed in Gpr143-/y pulmonary artery smooth muscle cells than in WT cells. Our result suggests that GPR143 is involved in the PH pathogenesis in the rat models of PH.

Tadalafil 5 mg Once Daily Improved Each IPSS Subscore, QOL, and Nocturia in Elderly BPH Patients over 70 Years Old in a Real-World Clinical Setting.

OBJECTIVE: No reports have evaluated the treatment effects of tadalafil by age group in a positive, noninterventional observational study of Japanese men. The present study aimed to evaluate the treatment effects of tadalafil by age group in a positive, noninterventional observational study of Japanese men. We therefore divided patients into 2 groups about the age of 70 years and investigated the treatment effects of tadalafil regarding voiding and storage functions by age group. METHODS: Changes from baseline in each parameter (International Prostate Symptom Score [IPSS], quality of life [QOL] score, Overactive Bladder Symptom Score [OABSS], and residual urine volume) at 4, 12, and 24 weeks after initiating tadalafil for benign prostatic hyperplasia (BPH) patients were compared between groups (50-69 years vs. ≥70 years). In addition, side effects of tadalafil were investigated by age group. RESULTS: In the 50-69 years group, significant improvements from baseline were seen in IPSS total and QOL score for all time points. In addition, significant improvements in IPSS storage subscore from baseline were observed at the 4- and 24-week time points. In the ≥70 years group, significant improvements from baseline were seen in IPSS total, IPSS voiding and storage subscores, and QOL score at each time point. CONCLUSIONS: Tadalafil 5 mg once daily appeared effective in clinical settings for elderly BPH patients even over 70 years old.

5-Aminolevulinic acid has the potential to prevent bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis.

OBJECTIVES: To investigate the effects of pretreatment with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate on bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis in rats. METHODS: Male Wistar rats (340-460 g) were pretreated with vehicle or with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (100/157 or 300/471 mg/kg/day, po) once daily for 7 days before cystometry. Saline or cyclophosphamide (150 mg/kg, ip) was administered 2 days before cystometry. Cystometry was performed under urethane anesthesia (0.8 g/kg, ip) via a catheter inserted into the bladder. After cystometry, bladder tissues were collected to perform hematoxylin and eosin staining for pathological evaluation (neutrophil infiltration, edema, and bleeding scores), and for enzyme-linked immunosorbent assay and real-time polymerase chain reaction for investigating tissue levels of myeloperoxidase, and mRNA levels of haem oxygenase-1 as a cytoprotective molecule. RESULTS: Compared to controls, cyclophosphamide induced a shorter intercontraction interval, lower bladder compliance, increased number of non-voiding contractions, and increased pathological scores and myeloperoxidase expression in the bladder. Pretreatment with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (300/471 mg/kg/day) significantly improved cyclophosphamide-induced intercontraction interval shortening and increases in number of non-voiding contractions and neutrophil infiltration/bleeding scores and enhanced haem oxygenase-1 expression in the bladder. In addition, cyclophosphamide-induced decreases in bladder compliance and increases in myeloperoxidase were not detected with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate pretreatment. CONCLUSIONS: Pretreatment with 5-aminolevulinic acid expects protective effects on bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis by improving inflammatory changes in bladder tissues perhaps via up-regulation of haem oxygenase-1.

Stimulation of brain α7-nicotinic acetylcholine receptors suppresses the rat micturition through brain GABAergic receptors.

Brain nicotinic acetylcholine receptors (nAChRs) reportedly suppress the micturition, but the mechanisms responsible for this suppression remain unclear. We previously reported that intracerebroventricularly administered (±)-epibatidine (non-selective nAChR agonist) activated the sympatho-adrenomedullary system, which can affect the micturition. Therefore, we investigated (1) whether intracerebroventricularly administered (±)-epibatidine-induced effects on the micturition were dependent on the sympatho-adrenomedullary system, and (2) brain nAChR subtypes involved in the (±)-epibatidine-induced effects in urethane-anesthetized male Wistar rats. Plasma noradrenaline and adrenaline (catecholamines) were measured just before and 5 min after (±)-epibatidine administration. Evaluation of urodynamic parameters, intercontraction intervals (ICI) and maximal voiding pressure (MVP) by cystometry was started 1 h before (±)-epibatidine administration or intracerebroventricular pretreatment with other drugs and continued 1 h after (±)-epibatidine administration. Intracerebroventricularly administered (±)-epibatidine elevated plasma catecholamines and prolonged ICI without affecting MVP, and these changes were suppressed by intracerebroventricularly pretreated mecamylamine (non-selective nAChR antagonist). Acute bilateral adrenalectomy abolished the (±)-epibatidine-induced elevation of plasma catecholamines, but had no effect on the (±)-epibatidine-induced ICI prolongation. The latter was suppressed by intracerebroventricularly pretreated methyllycaconitine (selective α7-nAChR antagonist), SR95531 (GABAA antagonist), and SCH50911 (GABAB antagonist), but not by dihydro-ß-erythroidine (selective α4ß2-nAChR antagonist). Intracerebroventricularly administered PHA568487 (selective α7-nAChR agonist) prolonged ICI without affecting MVP, similar to (±)-epibatidine. These results suggest that stimulation of brain α7-nAChRs suppresses the rat micturition through brain GABAA/GABAB receptors, independently of the sympatho-adrenomedullary outflow modulation.

Re-thinking the prognostic significance of positive peritoneal cytology in endometrial cancer.

BACKGROUND: Whether abnormal peritoneal cytology (PC) is an independent prognostic factor in endometrial cancer (EC) remains controversial. This study aimed to re-think the prognostic significance of PC in not only all EC patients but also in various subgroups with similar clinicopathological and biological characteristics. METHODS: EC patients who underwent primary surgery of at least a hysterectomy and were pathologically diagnosed with EC in four hospitals affiliated with the Jikei University School of Medicine were retrospectively reviewed. The prognostic significance of PC was evaluated with univariate and multivariate analyses in the entire cohort and subgroups stratified by surgical stages (early/advanced stages), tumor types (types 1/2), and risk classifications (low/intermediate/high). RESULTS: Of 1963 EC cases, 1616 met the inclusion criteria. Positive PC was identified as an adverse prognostic factor in analyses of all EC cases and in all subgroup analyses stratified by surgical stages and tumor types. In survival curve comparisons, the progression-free survival (PFS) and disease-specific survival in early-stage patients with positive PC were clearly located between those of stage II patients with negative PC and stage III patients. In the subgroup analyses stratified by risk classification in early-stage EC, positive PC was related to poorer PFS in the intermediate- and high-risk groups but not in the low-risk group. CONCLUSION: PC status was an independent prognostic factor of EC in all stages and tumor types. Early PC-positive cases, except for the low-risk group, may be recommended for upstaging and should be carefully managed compared with PC-negative cases.

Analysis of risk factors for patients with early-stage cervical cancer: A study of 374 patients.

AIM: This study aimed to identify the postoperative histological features affecting the prognosis of patients with early-stage cervical cancer who underwent open radical hysterectomy. METHODS: This retrospective study enrolled 374 patients with pT1a, 1b1 and 2a1 early-stage cervical cancer who underwent open radical hysterectomy between 2001 and 2018. Survival outcomes were analyzed by Kaplan-Meier method and compared with log-rank test. Using the Cox proportional hazards regression test, we conducted a multivariate analysis for disease-free survival and overall survival. RESULTS: Others histology, including other epithelial tumors and neuroendocrine tumors, had a significantly worse prognosis in both disease-free survival and overall survival than those of squamous cell carcinoma and adenocarcinoma (hazard ratio, 4.37 and 11.76; P = 0.006 and P = 0.002, respectively), along with lymph node metastasis (hazard ratio, 2.99 and 7.03; P = 0.009 and P = 0.001, respectively). CONCLUSION: Others histology including adenosquamous carcinoma had a poor prognosis in early-stage cervical cancer as with high-risk factors.

Psychological/mental stress-induced effects on urinary function: Possible brain molecules related to psychological/mental stress-induced effects on urinary function.

Exposure to psychological/mental stress can affect urinary function, and lead to and exacerbate lower urinary tract dysfunctions. There is increasing evidence showing stress-induced changes not only at phenomenological levels in micturition, but also at multiple levels, lower urinary tract tissues, and peripheral and central nervous systems. The brain plays crucial roles in the regulation of the body's responses to stress; however, it is still unclear how the brain integrates stress-related information to induce changes at these multiple levels, thereby affecting urinary function and lower urinary tract dysfunctions. In this review, we introduce recent urological studies investigating the effects of stress exposure on urinary function and lower urinary tract dysfunctions, and our recent studies exploring "pro-micturition" and "anti-micturition" brain molecules related to stress responses. Based on evidence from these studies, we discuss the future directions of central neurourological research investigating how stress exposure-induced changes at peripheral and central levels affect urinary function and lower urinary tract dysfunctions. Brain molecules that we explored might be entry points into dissecting the stress-mediated process for modulating micturition.

Age-related differences in responses to hydrogen sulfide in the bladder of spontaneously hypertensive rats.

OBJECTIVES: To investigate whether a response to hydrogen sulfide donors (GYY4137 and sodium hydrosulfide) and the endogenous hydrogen sulfide system (hydrogen sulfide level and expression of cysteine aminotransferase, cystathionine ß-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase) in the spontaneously hypertensive rat bladder differ with age, we compared the responses of hydrogen sulfide donors to micturition and bladder relaxation, and the endogenous hydrogen sulfide system in the bladder of 18-week versus 12-week-old spontaneously hypertensive rats. METHODS: GYY4137 was intravesically administered and cystometry was performed in anesthetized rats. The responses of sodium hydrosulfide were evaluated in carbachol-mediated precontracted bladder strips. Bladder hydrogen sulfide levels and expression levels of each enzyme were investigated using the methylene blue method and Western blotting, respectively. RESULTS: GYY4137 treatment significantly prolonged intercontraction intervals only in 12-week-old rats. Sodium hydrosulfide-induced bladder relaxation was significantly attenuated in the strips of 18-week-old rats compared with that in 12-week-old rats. In the bladder dome, significant increases in hydrogen sulfide levels and in the expression of cystathionine ß-synthase, 3-mercaptopyruvate sulfurtransferase, and cysteine aminotransferase were observed in 18-week-old rats compared with 12-week-old rats. However, cystathionine γ-lyase bands were not detected in bladder tissues of either group. CONCLUSIONS: Bladder relaxation induced by hydrogen sulfide may be attenuated in spontaneously hypertensive rats in an age-dependent manner.