Search

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.

Takahira Kuno,1,2 Kenji Tamura,1,3 Nobutaka Shimizu,1 Hideo Fukuhara,1 Satoshi Fukata,1 Shingo Ashida,1 Takashi Karashima,1 Hirofumi Satake,3 Kohji Sawada,4 Ichiro Yamasaki,5 Fumito Komatsu,2 Hajime Kuroiwa,6 Motoaki Saito,7 Keiji Inoue1 1Department of Urology, Kochi Medical School, Kochi University, Nankoku, Japan; 2Department of Urology, Tosa Municipal Hospital, Tosa, Japan; 3Department of Urology, Chikamori Hospital, Kochi, Japan; 4Department of Urology, Kochi Prefectural Hata Kenmin Hospital, Sukumo, Japan; 5Department of Urology, Kubokawa Hospital, Takaoka-gun, Japan; 6Integrated Center for Advanced Medical Technologies (ICAM-Tech), Kochi Medical School, Nankoku, Japan; 7Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, JapanCorrespondence: Kenji Tamura, Email tamurak@kochi-u.ac.jpObjective: The treatment effects of vibegron have not previously been evaluated in a prospective, non-interventional observational study of elderly Japanese patients, particularly those ≥ 80 years old. In addition, no reports have referred to residual urine volume in switching cases. We therefore grouped patients by condition and investigated the treatment effects of vibegron on Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Short Form (OAB-q SF), and residual urine volume in each group.Methods: This multicenter, prospective, non-interventional, observational study consecutively enrolled OAB patients with total OABSS score ≥ 3 and OABSS question 3 score ≥ 2. Sixty-three patients from six centers were recruited. Vibegron 50 mg once daily was administered for 12 weeks as first-line monotherapy (first-line group), monotherapy switching from antimuscarinics or mirabegron due to failure of prior therapy (no washout period), or combination therapy with antimuscarinics (second-line group). OABSS, OAB-q SF, and residual urine volume were collected after 4 and 12 weeks. Adverse events were also recorded at each visit.Results: Of the 63 patients registered, 61 were eligible for analysis (first line, n=36; second line, n=25). The OABSS, excluding daytime frequency scores, and OAB-q SF scale showed significant improvement in all conditions. Switching from mirabegron to vibegron significantly reduced residual urine volume. No serious treatment-related adverse events were encountered.Conclusion: Vibegron 50 mg once daily significantly improved OABSS and OAB-q SF even in patients ≥ 80 years old. Notably, switching from mirabegron to vibegron resulted in significant improvements to residual urine volume.Keywords: selective β 3-adrenoreceptor agonist, overactive bladder, residual urine volume, vibegron, mirabegron

Supplemental Figure S1. Explanation and evaluation of the random forest (RF) classifier. (A) Schematic illustration of the classification of samples by the RF. (B, C) Representative classification trees from the discrimination between malignant and benign tumors. These trees are only representations out of 4,000 trees constructed in the RF classifier. The final class is determined as a result of voting by all 4,000 trees. (D, E) The highest accuracy of prediction (D) and the AUC (E) using different numbers of samples in RF classification between malignant and benign tumors. The mean accuracy and AUC with these 95% confidence intervals were presented for 10 independent sets of randomly selected data of 20%, 40%, 60%, and 80% of patients from the training and test cohorts.

Pretreatment peripheral blood tests of 334 patients with epithelial ovarian cancer and 101 patients with benign ovarian tumor

Purpose:We aimed to develop an ovarian cancer–specific predictive framework for clinical stage, histotype, residual tumor burden, and prognosis using machine learning methods based on multiple biomarkers.Experimental Design:Overall, 334 patients with epithelial ovarian cancer (EOC) and 101 patients with benign ovarian tumors were randomly assigned to “training” and “test” cohorts. Seven supervised machine learning classifiers, including Gradient Boosting Machine (GBM), Support Vector Machine, Random Forest (RF), Conditional RF (CRF), Naïve Bayes, Neural Network, and Elastic Net, were used to derive diagnostic and prognostic information from 32 parameters commonly available from pretreatment peripheral blood tests and age.Results:Machine learning techniques were superior to conventional regression-based analyses in predicting multiple clinical parameters pertaining to EOC. Ensemble methods combining weak decision trees, such as GBM, RF, and CRF, showed the best performance in EOC prediction. The values for the highest accuracy and area under the ROC curve (AUC) for segregating EOC from benign ovarian tumors with RF were 92.4% and 0.968, respectively. The highest accuracy and AUC for predicting clinical stages with RF were 69.0% and 0.760, respectively. High-grade serous and mucinous histotypes of EOC could be preoperatively predicted with RF. An ordinal RF classifier could distinguish complete resection from others. Unsupervised clustering analysis identified subgroups among early-stage EOC patients with significantly worse survival.Conclusions:Machine learning systems can provide critical diagnostic and prognostic prediction for patients with EOC before initial intervention, and the use of predictive algorithms may facilitate personalized treatment options through pretreatment stratification of patients.

Background The development of drugs for Alzheimer’s disease (AD), which is related to the misfolding and aggregation of Amyloid-β (Aβ), is high in demand due to the growing number of AD patients. In this study, we screened 22 kinds of 5-mer synthetic peptides derived from the Box A region of Tob1 protein to find a peptide effective against Aβ aggregation. Methods A Thioflavin T (ThT) assay was performed to evaluate aggregation and screening aggregation inhibitor. Six weeks male ICR mice were administered of saline, 9 nmol Aβ25–35, or a mixture of 9 nmol Aβ25–35 and 9 nmol GSGFK in the right lateral ventricle. The short-term spatial memory assessed using Y-maze. The BV-2 cells were harvested into 24-well plates (4 × 104 cells/well) and incubated for 48 h and then, the cells were treated with 0.01, 0.05, 0.1, 0.2, or 0.5 mM of GSGFK. After incubation for 24 h, bead uptake was evaluated using a laser confocal microscope and Cytation 5. Results We found two kinds of peptides, GSGNR and GSGFK, were not only suppressed aggregation of Aβ25–35 but also resolved the aggregated Aβ25–35. Results obtained from the Y-maze test on an Aβ25-35-induced AD mouse model indicated that GSGFK prevents the deficits in short-term memory induced by Aβ25–35. The effect of GSGFK on phagocytosis in microglia cells (BV-2 cells) proved that GSGFK activates the phagocytic ability of microglia. Conclusions In conclusion, 5-mer peptides prevent short-term memory deficit in Aβ25–35 induced AD mouse model by reducing the aggregated Aβ25–35. They may also upregulate the phagocytic ability of microglia, which makes 5-mer peptides suitable candidates as therapeutic drugs against AD.

BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a slowly progressive syndrome caused by the excessive accumulation of cerebrospinal fluid and is typically characterized by the triad of cognitive, gait, and urinary disturbances and ventricular dilation. In addition to this triad of symptoms, apathy is frequently observed in iNPH and worsens the cognitive impairment and gait disturbance. Although apathy is an important symptom in iNPH, its neurological basis remains unknown.ObjectivesThis study aimed to analyze and elucidate the brain regions associated with apathy in iNPH using statistical imaging analysis and to investigate regional cerebral blood flow and regional gray matter volume, which indicates gray matter compression, in a whole-brain study.MethodsTwenty seven patients with iNPH were assigned to two groups based on their scores on the Neuropsychiatric Inventory items related with apathy; 18 patients were assigned to the group with apathy (iNPH + APA) and 9 to the group without apathy (iNPH - APA). The magnetic resonance images and cerebral blood flow single-photon emission computed tomography data of the two groups were compared using statistical parametric mapping 12. ResultsThe regional gray matter volume of the right precuneus was significantly larger in the iNPH + APA group than in the iNPH − APA group, but the and regional cerebral blood flow in any region of the brain was not significantly different between the two groups.ConclusionThese results suggested that compression of the precuneus might be involved in apathy in iNPH and the importance of brain compression in iNPH symptoms. In addition, this study also shows that VBM is useful for indicating the degree of brain compression.

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.

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 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.

Direct oral anticoagulants (DOACs) are increasingly being used for the treatment of cancer-associated venous thromboembolism (CAT). However, there is limited evidence of the efficacy of DOACs for the treatment of gynecological CAT. Thus, this study aimed to investigate the efficacy and safety of edoxaban for the treatment of gynecological CAT using Japanese real-world data.We reviewed the medical records of patients with 371 gynecological cancer who received edoxaban or vitamin K antagonist (VKA) between January 2011 and December 2018.Altogether, 211 and 160 patients were treated with edoxaban and VKA, respectively. Fourteen patients (6.8%) in the edoxaban group and 22 (13.8%) in the VKA group showed recurrence of venous thromboembolism (VTE). Cumulative VTE recurrence was not significantly different between the 2 groups (p=0.340). Adverse events occurred in 15 (7.1%) and 11 (6.9%) patients in the edoxaban and VKA groups, respectively (p=0.697). Subgroup analysis of the edoxaban and VKA groups according to different tumor types, including ovarian, endometrial, and cervical cancer, showed equivalent outcomes in terms of VTE recurrence and adverse events. Patients without pulmonary embolism (PE) were mostly omitted from initial unfractionated heparin (UFH) therapy prior to administration of edoxaban. However, this did not increase the recurrence of VTE.This study confirmed that edoxaban is effective and safe for the treatment of gynecological CAT. This finding was consistent for different types of gynecological cancer. Additionally, initial UFH therapy prior to the administration of edoxaban may be unnecessary for patients without PE.

We investigated the predictive value of scoring systems of peritoneal disseminations for complete surgery (CS) at primary debulking surgery (PDS) in advanced ovarian cancer.We retrospectively enrolled eligible patients with clinical stages III or IVA selected for PDS from January 2015 to December 2019. Concern variables were predictive index value (PIV) and peritoneal cancer index (PCI) from operative and pathological reports. Primary endpoints were cutoffs to predict operative completeness using the receiver operating characteristic curve.Among 111 patients, PIV ≥8 and PCI ≥13 were the best predictors of incomplete PDS, including optimal and suboptimal surgeries (AUC=0.821 and 0.855, respectively). CS rates in PIV ≤6 and PCI ≤12 were significantly higher than in PIV ≥8 (89.3% vs. 47.2%; p0.05) and PCI ≥13 (90.9% vs. 41.2%: p0.05).PIV and PCI are potential predictors for CS at PDS.

INTRODUCTION AND OBJECTIVE:Although aging or severe bladder ischemia could be involved in progression of detrusor underactivity (DU), the pathophysiological mechanism of DU is not well clarified. H...

Stroke is a major cause of death worldwide, leading to serious disability. Post-ischemic injury, especially in the cerebral ischemia-prone hippocampus, is a serious problem, as it contributes to vascular dementia. Many studies have shown that in the hippocampus, ischemia/reperfusion induces neuronal death through oxidative stress and neuronal zinc (Zn2+) dyshomeostasis. Glutathione (GSH) plays an important role in protecting neurons against oxidative stress as a major intracellular antioxidant. In addition, the thiol group of GSH can function as a principal Zn2+ chelator for the maintenance of Zn2+ homeostasis in neurons. These lines of evidence suggest that neuronal GSH levels could be a key factor in post-stroke neuronal survival. In neurons, excitatory amino acid carrier 1 (EAAC1) is involved in the influx of cysteine, and intracellular cysteine is the rate-limiting substrate for the synthesis of GSH. Recently, several studies have indicated that cysteine uptake through EAAC1 suppresses ischemia-induced neuronal death via the promotion of hippocampal GSH synthesis in ischemic animal models. In this article, we aimed to review and describe the role of GSH in hippocampal neuroprotection after ischemia/reperfusion, focusing on EAAC1.

Purpose: We aimed to develop an ovarian cancer–specific predictive framework for clinical stage, histotype, residual tumor burden, and prognosis using machine learning methods based on multiple biomarkers. Experimental Design: Overall, 334 patients with epithelial ovarian cancer (EOC) and 101 patients with benign ovarian tumors were randomly assigned to “training” and “test” cohorts. Seven supervised machine learning classifiers, including Gradient Boosting Machine (GBM), Support Vector Machine, Random Forest (RF), Conditional RF (CRF), Naïve Bayes, Neural Network, and Elastic Net, were used to derive diagnostic and prognostic information from 32 parameters commonly available from pretreatment peripheral blood tests and age. Results: Machine learning techniques were superior to conventional regression-based analyses in predicting multiple clinical parameters pertaining to EOC. Ensemble methods combining weak decision trees, such as GBM, RF, and CRF, showed the best performance in EOC prediction. The values for the highest accuracy and area under the ROC curve (AUC) for segregating EOC from benign ovarian tumors with RF were 92.4% and 0.968, respectively. The highest accuracy and AUC for predicting clinical stages with RF were 69.0% and 0.760, respectively. High-grade serous and mucinous histotypes of EOC could be preoperatively predicted with RF. An ordinal RF classifier could distinguish complete resection from others. Unsupervised clustering analysis identified subgroups among early-stage EOC patients with significantly worse survival. Conclusions: Machine learning systems can provide critical diagnostic and prognostic prediction for patients with EOC before initial intervention, and the use of predictive algorithms may facilitate personalized treatment options through pretreatment stratification of patients.

Gastric-type mucinous carcinoma (GAS) is a novel variant of mucinous carcinoma of the uterine cervix. As shown in the original Japanese group description, in recent studies, GAS represents a more aggressive disease than the usual-type endocervical adenocarcinoma (UEA). Detailed clinicopathological features of this variant remain to be elucidated in a larger series of patients.Patients were enrolled by the Gynecologic Cancer Study Group of the Japan Clinical Oncology Group after receiving the approval of each Institutional Review Board. The study population comprised of women with stage I to II endocervical adenocarcinomas who underwent surgery between 2000 and 2009. Representative slides were evaluated by central pathological review (CPR), categorized into either GAS or UEA, and correlated with clinicopathological features and outcome.Among the 393 enrolled patients with endocervical adenocarcinoma, 328 patients met the criteria for CPR and the study eligibility criteria and were included in further analysis. A total of 95 of the 328 tumors were classified as GAS. Compared with UEA, GAS was more significantly associated with bulky mass, deep stromal invasion, lymphovascular space invasion, parametrial invasion, ovarian metastasis, positive ascitic fluid cytology, pelvic lymph node metastasis, and pathological (p) T stage but was not related to the degree of histological differentiation. Disease-free survival (P 0.0001) and overall survival (P 0.0001) were poorer in patients with GAS than in those with UEA.GAS showed aggressive behavior with ominous histopathological predictors as well as decreased survival. GAS is therefore considered a distinct entity that should be distinguished from UEA.UMIN Clinical Trials Registry: UMIN000007987.

Background: Children with spinal cord disorders can present with neurogenic bladder, a condition in which the bladder partly or completely loses its ability to store urine and void at low pressure. A bladder with low compliance may cause urinary incontinence, which negatively impacts quality of life and renal function. Long-term high pressure neurogenic bladder can increase the risk of deterioration in renal function. Antimuscarinic pharmacotherapy with clean intermittent catheterization is currently considered one of the most effective treatments for these patients. However, some patients do not respond to oral medication or have unacceptable adverse events (AEs), which may result in medical withdrawal for these patients. Intravesical oxybutynin is an effective treatment with less AEs compared with oral medication. However, an important issue with this treatment is retention of the solution in the bladder. Moreover, as yet no data are available on the very long-term use and outcome of modified intravesical oxybutynin therapy. In the present study, we report on the efficacy, safety, and side effects of long-term modified intravesical oxybutynin therapy in children with neurogenic bladder. Methods: Modified intravesical oxybutynin (1.25 mg/5 mL, twice a day) was administered to four children (three boys and one girl) with neurogenic bladder (detrusor overactivity and/or low compliance bladder), who were previously unresponsive to or experienced intolerable AEs from oral medications. Results of pretreatment cystometrograms were compared to those from follow-up urodynamic studies. Anticholinergic AEs, occurrence of urinary tract infection, and degree of incontinence during this treatment were also evaluated. Results: After 1 year, bladder compliance improved in three of the four patients. After 3 years, detrusor overactivity was undetectable in all patients. Bladder compliance at 3 years and 10 years after initiation of therapy was similar for three patients, and they are continuing modified intravesical oxybutynin therapy. One patient discontinued therapy at 118 months due to worsening of bladder compliance and upper urinary tract infection. No anticholinergic systemic AEs were observed in any of the patients. Conclusions: These results suggest that modified intravesical oxybutynin is an effective and relatively safe long-term therapeutic option for children with neurogenic bladder. J Clin Med Res. 2019;11(4):256-260 doi: https://doi.org/10.14740/jocmr3752

Benign prostatic hyperplasia/benign prostatic enlargement (BPH/BPE) is a common proliferative disease, and giving rise to associate with lower urinary tract symptoms (LUTS). However, the pathogenesis is not well clarified, and thought to be multifactorial. There are some lines of evidence that impairment in the blood supply of the lower urinary tract causes development of BPH/BPE. Clinical data showed an association between the development of BPH/BPE and atherosclerotic disease such as hypertension, diabetes and hyperlipidemia. The spontaneously hypertensive rat (SHR) has been used as model of genetic hypertension. SHR also shows decreased blood flow and hyperplastic morphological abnormalities in the ventral prostate. Our previous studies demonstrated that chronic treatment with vasodilative drugs nicorandil (ATP sensitive potassium channel opener) and silodosin (alpha1 adrenoceptor antagonist) increased blood flow and suppressed the growth factor and morphological abnormalities in the SHR ventral prostate. These data suggested that prostatic blood flow could be therapeutic targets for BPH/LUTS.

Highlights • High recurrence rate is one of the most difficult problems in treating advanced ovarian cancer today. • The most common site of recurrence is the peritoneum, which may be due to microscopically residual tumor on the peritoneum. • We performed total parietal peritonectomy (TPP) in primary debulking surgery to reduce those invisible tumors. • TPP may increase the incidence of intraoperative and postoperative complications. • TPP may provide better prognosis by adding to complete surgery., The object of this study is to evaluate the clinical safety and efficacy of total parietal peritonectomy (TPP) in primary debulking surgery (PDS) for advanced ovarian cancer. This retrospective single-center study analyzed 16 patients with FIGO stages IIIC-IVB epithelial ovarian cancer who underwent TPP in PDS and achieved macroscopically complete resection between April 2015 and June 2016. The median age of 16 patients was 52.5 years old. 12 were in stage IIIC and 4 were in stage IV. Regarding intraoperative complications, unintended diaphragm perforation was observed in two patients. Regarding postoperative complications (Clavien–Dindo classification grade 3–5) before the adjuvant chemotherapy, lymph cysts occured in 3 patients, intra-abdominal abscess in 3, ileus in 2, pancreatic fistula in 1 and temporary kidney failure in 1. Regarding postoperative complications (grade 3–5) after the initiation of adjuvant chemotherapy, diaphragmatic hernia occured in 1 patient, ileus in 2 and intra-abdominal abscess in 2. Except 1 patient who relapsed approximately one month from surgery and died, the other 15 patients overcamed complications and recovered without problems in daily life. This analysis was conducted 3 years after all patients underwent PDS, with the 3-year progression-free and overall survival of 62.5% (95% confidence interval [CI], 34.9–81.1) and 87.5% (95 %CI, 58.6–96.7), respectively. Based on the above results, TPP in PDS may improve the prognosis compared to previous reports such as LION trial. On the other hand, complications may increase. Therefore, further studies are necessary on its safety and efficacy.

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.

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-β-erythroidine (selective α4β2-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.

Introduction We recently discovered a short synthetic peptide derived from the ANA/BTG3 protein Box A region called ANA‐TA9 (SKGQAYRMI), which possesses catalytic activity. Herein we demonstrated the proteolytic activity of ANA‐TA9 against amyloid beta 42 (Aβ42). Methods The proteolytic activity of ANA‐TA9 against both the authentic soluble form Aβ42 (a‐Aβ42) and the solid insoluble form Aβ42 (s‐Aβ42) was analyzed by high‐performance liquid chromatography and mass spectrometry. Plasma clearance, brain uptake, and cell viability were examined. Results ANA‐TA9 cleaved not only a‐Aβ42 but also s‐Aβ42. Proteolytic activity was partially inhibited by 4‐(2‐aminoethyl) benzenesulfonyl fluoride hydrochloride, a serine protease inhibitor. Plasma clearance was very rapid, and the brain concentration indicated efficient brain delivery of ANA‐TA9 via nasal application. Cell viability analysis indicated that ANA‐TA9 did not display toxicity. Discussion ANA‐TA9 is an attractive potential candidate for the development of novel peptide drugs in Alzheimer's disease treatment.

The JGOG 3016 showed that dose-dense paclitaxel and carboplatin (ddTC) improved progression-free survival (PFS) and overall survival (OS) in advanced ovarian cancer (AOC). ICON7 and GOG-0218 showed that bevacizumab (Bev) improved PFS. GOG-0262 suggested that ddTC+Bev showed no superiority in PFS. The aim of this study is to evaluate the efficacy and safety of ddTC+Bev compared with ddTC in AOC. We retrospectively investigated patients with FIGO stage III-IV OC who received ddTC or ddTC+Bev as first-line chemotherapy. PFS was investigated about ddTC+Bev compared with ddTC using log-rank test. Age ( A total of 134 patients were enrolled. Median follow up periods was 30.5 months. 80.1% of patients had stage III disease. 76.7% had serous/endometrioid histologic findings. 59.7% received PDS. 61.9% received complete surgery. Compared with ddTC, ddTC+Bev improved PFS (p ddTC+Bev significantly prolonged PFS. Although the frequency of AE of ddTC+Bev is higher than ddTC, it is totally tolerable. ddTC+Bev is an effective 1st line regimen for AOC.

Objective Venous thromboembolism (VTE) is increasingly being treated with oral direct Xa inhibitors, including edoxaban. However, direct evidence supporting the use of edoxaban for thrombosis associated with gynecological cancer is limited. Thus, we compared edoxaban to warfarin with regard to their efficacy, safety and convenience in gynecological cancer patients with VTE. Method We reviewed the medical records of 317 gynecological cancer patients who received edoxaban or warfarin treatment for VTE between January 2011 and December 2018. Result The median follow-up period was 712 days (16–2868). Of the 317 patients, 180 and 137 were treated with edoxaban or warfarin, respectively. Details of cancer types were as follows: ovarian cancer 110 (62%), endometrial cancer 40 (22%), cervical cancer 22 (12%) and others 8 (4%) in edoxaban group and 81 (59%), 37 (27%), 16 (12%), 3 (2%) in warfarin group. There was no significant difference between two treatments groups in terms of BMI, VTE site, cancer type, histological subtype and stage. Recurrence of VTE occurred in 16 patients (8.9%) in edoxaban group and 18 (13.1%) in warfarin group (p=0.31). Adverse events that required discontinuation of anticoagulation occurred in 1 patient (0.6%) with edoxaban and 6 patients (4.4%) with warfarin (p=0.06), and no fatal events in either group. Initial heparin bridge was employed in 63 patients (37.7%) and 115 patients (92.0%) of edoxaban and warfarin group, respectively (p Conclusion Edoxaban is effective, safe and convenient for VTE patients with gynecological cancers.

Objective Ovarian clear cell carcinoma (OCCC) is a rare type of epithelial ovarian cancer that behaves comparable to a distinct entity. Novel genomic and immunological profiling-based strategies targeting OCCC remain unavailable. ARID1A, which is one of the most frequently mutated genes in OCCC, could be a druggable target as well as a regulator of mismatch repair (MMR). Most of the mutated neoantigens in MMR-deficient cancers sensitize them to immune checkpoint blockade. However, the role and frequency of MMR deficiency in OCCC are still poorly understood. We aimed to evaluate the abnormal expression frequency of MMR and PD-L1 proteins in OCCC for identifying the effective OCCC population with immune checkpoint blockade. Methods The study cohort comprised 113 patients with OCCC treated at a single institution. Protein expression levels in ARID1A, MLH1, PMS2, MSH2, MSH6, and PD-L1 were evaluated by immunohistochemistry (IHC). We investigated the correlations between immunoreactivity for MMR/PD-L1 and clinicopathological parameters including ARID1A status. Results MMR proteins disappeared in two cases (1.8%), specifically those who had synchronous double cancer with endometrial carcinoma and a family history of Lynch syndrome-related tumor. PD-L1 expression was diffused in 17 cases (15.0%). The diffused PD-L1 expression was significantly associated with ARID1A expression loss (p = 0.003), but no other correlations existed between PD-L1 expression and clinical parameter. Conclusions Although only few Japanese OCCC cases showed MMR deficiency as evaluated by IHC, immune checkpoint signals were activated even in MMR-intact OCCC, possibly through ARID1A interaction.

Objective The association between muscle mass and strength decrease by aging (Sarcopenia) and adverse events of chemotherapy and prognosis has been reported in several solid cancers. Skeletal muscle mass has also been shown to be a prognostic factor in elderly epithelial ovarian cancer, it has been unclear in the Japanese population. Furthermore, the association between more easily calculated iliopsoas muscle mass and prognosis of elderly epithelial ovarian cancer patients has not been clarified. This study aimed to evaluate association between iliopsoas muscle mass and prognosis of elderly ovarian cancer patients in the Japanese population. Method Medical charts of 110 epithelial ovarian cancers aged 60 years and older at our hospitals between 2013 and 2014 were retrospectively reviewed. Muscle areas of bilateral psoas major muscles at the third lumbar vertebra were measured using images obtained by computed tomography tested before treatment. Psoas muscle index (PMI) was calculated as the psoas muscle area divided by the height squared. Cox-regression Hazard Models were applied. Results Median follow-up period was 40 months, average age was 67.8 years, and median PMI was 313 mm2/m2 (range 137–572). 44 patients (40.0%) with less than 300 mm2/m2 PMI were found to be statistically significant poor prognosis in multivariate analysis (Hazard Ratio: 2.896, 95% Confidence Interval: 1.1510–7.287, P value: 0.024). Conclusions Low PMI was a statistically significant poor prognostic factor in Japanese elderly patients with epithelial ovarian cancer. It suggests that low PMI can be a biomarker that predicts poor prognosis in elderly patients with epithelial ovarian cancer.

INTRODUCTION AND OBJECTIVE:In the lower urinary tract, nitric oxide (NO) is well known as a relaxation factor in the urethra. On the other hand, in the central nervous system, NO is reported to hav...

Recently, hydrogen sulfide (H2S) has been recognized as the third gasotransmitter besides nitric oxide and carbon monoxide, and it has been reported that H2S exhibits various physiological functions such as neuromodulation and vasorelaxation. In the lower urinary tract (bladder and prostate), it is reported that donors of H2S induce contraction of the rat detrusor and relaxation of the pig bladder neck. These reports suggest a possibility that H2S may have site-specific effects on the bladder. However, the detailed functions of H2S in each part of the bladder are still unclear. In addition, there is no report showing physiological roles of H2S in the prostate. In this article, we will review the distribution of enzymes related to H2S biosynthesis and physiological roles of H2S in the lower urinary tract based on reports from our and other groups. We will also introduce a possibility that H2S can be a new therapeutic target against lower urinary tract symptoms (LUTS) based on our data from spontaneously hypertensive rats (SHRs), which develop hypertension-mediated LUTS.

Psychological stress can induce not only frequent urination but also exacerbation of bladder dysfunctions. However, the brain pathophysiological mechanisms underlying stress-induced effects on the micturition reflex are still unknown. Bombesin (BB)-related peptides and BB receptors in the brain have been reported to mediate and integrate stress responses. We have found that centrally administered BB induced frequent urination in rats through brain BB1 and BB2 receptors, serotoninergic nervous system/5-HT7 receptors and corticotropin-releasing factor (CRF) type1 (CRF1) receptors. Interestingly, the BB-induced frequent urination was independent of the BB-induced activation of the sympatho-adrenomedullary outflow, a representative response to stress. Because the outflow is well known to regulate micturition, the finding was very surprising. These findings indicate that brain BB1, BB2, 5-HT7 and CRF1 receptors could be new therapeutic targets for bladder dysfunction exacerbated by stress exposure.

We identified that JAL-TA9, a 9-mer synthetic peptide derived from Tob1 protein, possesses catalytic activity and cleaves Aβ42. We also determined that the C-terminal end of Prion protein (PrP) is an essential region for aggregation of PrP using PrP fragment peptides. We investigated the effect of JAL-TA9 on hPrP180-192, which is a fragment peptide derived from human prion protein. Conformational studies were performed using CD analysis. The cleavage reaction was identified using HPLC and MS analyses. JAL TA9 inhibited the formation of aggregated hPrP180-192 and decreased the aggregated hPrP180-192 level through the cleavage reaction. These results indicate that JAL-TA9 could be a promising candidate for developing novel drugs against prion diseases and Alzheimer’s disease.

Background and purpose We have demonstrated that i.c.v.-administered (±)-epibatidine, a nicotinic ACh receptor (nAChR) agonist, induced secretion of noradrenaline and adrenaline (catecholamines) from the rat adrenal medulla with dihydro-β-erythroidin (an α4β2 nAChR antagonist)-sensitive brain mechanisms. Here, we examined central mechanisms for the (±)-epibatidine-induced responses, focusing on brain NOS and NO-mediated mechanisms, soluble GC (sGC) and protein S-nitrosylation (a posttranslational modification of protein cysteine thiol groups), in urethane-anaesthetized (1.0 g·kg-1 , i.p.) male Wistar rats. Experimental approach (±)-Epibatidine was i.c.v. treated after i.c.v. pretreatment with each inhibitor described below. Then, plasma catecholamines were measured electrochemically after HPLC. Immunoreactivity of S-nitrosylated cysteine (SNO-Cys) in α4 nAChR subunit (α4)-positive spinally projecting neurones in the rat hypothalamic paraventricular nucleus (PVN, a regulatory centre of adrenomedullary outflow) after i.c.v. (±)-epibatidine administration was also investigated. Key results (±)-Epibatidine-induced elevation of plasma catecholamines was significantly attenuated by L-NAME (non-selective NOS inhibitor), carboxy-PTIO (NO scavenger), BYK191023 [selective inducible NOS (iNOS) inhibitor] and dithiothreitol (thiol-reducing reagent), but not by 3-bromo-7-nitroindazole (selective neuronal NOS inhibitor) or ODQ (sGC inhibitor). (±)-Epibatidine increased the number of spinally projecting PVN neurones with α4- and SNO-Cys-immunoreactivities, and this increment was reduced by BYK191023. Conclusions and implications Stimulation of brain nAChRs can induce elevation of plasma catecholamines through brain iNOS-derived NO-mediated protein S-nitrosylation in rats. Therefore, brain nAChRs (at least α4β2 subtype) and NO might be useful targets for alleviation of catecholamines overflow induced by smoking.

Background and purpose We investigated the effects of centrally administered stress-related neuropeptide, angiotensin II, on the micturition reflex and the downstream signalling pathways in rats. Experimental approach Male Wistar rats were anaesthetized with urethane for cystometry before and after i.c.v. administration of vehicle or angiotensin II (30 pmol). Muscimol (a GABAA receptor agonist) or baclofen (a GABAB receptor agonist) was i.c.v. administered 30 min before or 15 min after central angiotensin II administration. Telmisartan [an angiotensin II type 1 (AT1 ) receptor antagonist], valsartan (an AT1 receptor antagonist), PD123319 (an AT2 receptor antagonist), U-73122 (a PLC inhibitor), chelerythrine chloride (a PKC inhibitor), apocynin (a NADPH oxidase inhibitor) or tempol (an antioxidant) was centrally administered 30 min before central angiotensin II administration. Key results Centrally administered angiotensin II significantly shortened the intercontraction interval and decreased the voided volume and bladder capacity without altering the maximum voiding pressure, post-voiding residual urine volume or voiding efficacy. Muscimol, baclofen, telmisartan, valsartan, U-73122, chelerythrine chloride, apocynin or tempol pretreatment significantly suppressed the reduction in intercontraction interval induced by central angiotensin II. Post-treatment with muscimol or baclofen also ameliorated the decrease in intercontraction interval induced by central angiotensin II. Conclusions and implications Angiotensin II in the CNS facilitates micturition reflex by inhibiting central GABAergic activity and activating the AT1 receptor/PLC/PKC/NADPH oxidase/superoxide anion pathway.