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.

Cyclophosphamide (CYP), a broad-spectrum anticancer drug, causes serious side effects, such as haemorrhagic cystitis (HC). Hydrogen sulfide (H

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

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.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/mSixty-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.Paclitaxel-carboplatin and bevacizumab therapy is an acceptable and tolerable treatment for advanced or recurrent cervical cancer.

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.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.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.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.

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.

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.

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.

The use of animals for scientific purposes is still a subject of debate. The current regulatory position in most western countries allows regulated animal use to occur because of the perceived benefits in generating new knowledge. The use of animals for scientific purposes engenders a wide range of ethical perspectives, with some people looking for the complete termination of animal use, and others strongly support their continued use. Although regulatory systems vary from country to country, in most jurisdictions, research and teaching institutions are required to ensure that staff and students using animals for scientific purposes are appropriately trained, that animals are well cared for, and that the ethical review process for projects is robust. In the curriculum of the Kochi Medical School, it is mandatory for all medical students to perform laboratory exercises in the class of Pharmacology. For the purpose of this experimental class it is common to use small animals in these exercises. However, in recent years in many countries, alternative methods to replace the use of small animals have been introduced. Such methods are experiment simulations with the use of computers and they have been used in some medical schools. In this manuscript, I will make an introduction on how we perform pharmacological laboratory exercises with the use of small animals in Kochi Medical School. Additionally, I would like to discuss the necessity of the use of small animals in exercises as part of the training of medical students.

Ischemic stroke is one of the most prevalent brain disorders and the major cause of long-term disability. In particularly, hippocampal injury after ischemia-reperfusion is a serious problem as it contributes to vascular dementia. Many researches have revealed that ischemia-reperfusion causes increase in reactive oxygen species production and disruption of neuronal Zn2+ homeostasis in the hippocampus, which induces hippocampal neuron death. Glutathione (GSH) is present in all mammalian cells and plays a crucial role in neuronal cell defense against oxidative stress. On the other hand, thiol group of GSH chemically chelates Zn2+ and functions as a regulator of neuronal Zn2+ homeostasis. These evidences suggest that neuronal GSH levels could be an important factor affecting neuronal surviving. The synthesis of GSH is largely influenced by intracellular cysteine availability. In neurons, excitatory amino acid carrier type 1 (EAAC1) acts as a cysteine transporter and provides cysteine substrate for GSH synthesis. Recently, several animal studies have revealed that promotion of neuronal GSH synthesis through EAAC1 reduces ischemia-induced hippocampal neuron death. This review aims to describe neuroprotective role of GSH against hippocampal injury following ischemia-reperfusion, focusing on EAAC1.

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.

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.

AIM Brain nitric oxide (NO) have been reported in regulation of the sympatho-adrenomedullary system, which can affect voiding and storage functions. Therefore, we investigated effects of intracerebroventricularly (icv) administered 3-(4-morpholinyl)sydnonimine, hydrochloride (SIN-1) (NO donor) on the micturition reflex, focusing on their dependence on the sympatho-adrenomedullary system and on brain N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in urethane-anesthetized (0.8 g/kg, ip) male Wistar rats. METHODS Plasma noradrenaline and adrenaline were measured just before and 5 minutes after SIN-1 administration. Evaluation of urodynamic parameters was started 1 hour before SIN-1 administration or intracerebroventricular pretreatment with other drugs. RESULTS SIN-1 (100 and 250 µg/animal) elevated plasma adrenaline and reduced intercontraction interval ([ICI] values; 110.5% [SIN-1, 0 µg] and 54.9% [SIN-1, 250 µg] during 15 minutes after SIN-1 administration [P

Excessive activation of the sympatho-adrenomedullary system plays a pathogenic role in triggering and sustaining essential hypertension. We previously reported that, in normotensive rats, intracerebroventricularly (i.c.v.) administered neuropeptides, corticotropin-releasing factor and bombesin induced activation of the sympatho-adrenomedullary system, and that brain cannabinoid CB1 receptors negatively regulated this activation. In this study, we investigated the effects of brain CB1 receptor stimulation on blood pressure and the sympatho-adrenomedullary outflow in spontaneously hypertensive rats (SHRs), commonly used animal models of essential hypertension, and in Wistar-Kyoto (WKY) rats, normotensive controls of SHRs. In 18-week-old SHRs and WKY rats under urethane anaesthesia (1.0 g/kg, i.p.), SHRs exhibited significantly higher systolic, mean and diastolic blood pressures and plasma noradrenaline and adrenaline, and a lower heart rate than WKY rats. Single administration of arachidonyl 2'-chloroethylamide (ACEA, CB1 agonist, 1.4 µmol/animal, i.c.v.) significantly but partially reduced mean and diastolic blood pressures and the plasma level of noradrenaline in SHRs compared to vehicle (N,N-dimethylformamide)-treated SHRs. These ACEA-induced reductions were abolished by central pretreatment with rimonabant (CB1 antagonist, 300 nmol/animal, i.c.v.), which alone showed no significant effect on blood pressures or plasma noradrenaline and adrenaline levels of SHRs. On the other hand, ACEA had no significant effect on blood pressure or plasma noradrenaline and adrenaline levels in WKY rats. These results suggest that stimulation of brain CB1 receptors can ameliorate hypertension accompanied by enhanced sympathetic outflow without affecting blood pressure under normotensive conditions.

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.

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.

Aims The goal of this study was to test whether central corticotropin-releasing factor (CRF) was involved in angiotensin II (Ang II) and Ang II type 1 (AT1) receptor-mediated facilitation of micturition reflex and to investigate whether peripherally administered telmisartan, AT1 receptor antagonist, suppresses the central Ang II-induced facilitation of micturition reflex in rats. Methods Urethane anesthetized male Wistar rats were placed under continuous cystometry before and after intracerebroventricular administration of each drug. Rats were intracerebroventricularly administered telmisartan (AT1 receptor antagonist), CP154526 (CRF1 receptor antagonist), or K41498 (CRF2 receptor antagonist) 30 minutes before intracerebroventricular administration of Ang II. Some male Wistar rats were perorally pretreated with either vehicle, AT1 receptor antagonist telmisartan or valsartan, once daily for 8 days, then measured blood pressure. Thereafter, Ang II was intracerebroventricularly administered for continuous cystometry. Results Intracerebroventricularly administered telmisartan or CP154526 dose-dependently suppressed the central Ang II-induced intercontraction interval (ICI) reduction. In contrast, intracerebroventricularly administered K41498 did not affect the central Ang II-induced response compared to vehicle pretreatment. Peripherally administered telmisartan but not valsartan suppressed the central Ang II-induced ICI reduction in rats compared to vehicle administration without altering blood pressure. Conclusions Central Ang II induced facilitation of the micturition reflex through AT1 and CRF1 receptors. Peripherally administered telmisartan suppressed central Ang II-induced facilitation of micturition reflex.

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.