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.

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.

Improvement in gait velocity variability after cerebrospinal fluid elimination and its relationship to clinical symptoms in patients with idiopathic normal pressure hydrocephalus.

AIM: This study aimed to investigate the improvement in gait velocity variability after cerebrospinal fluid (CSF) elimination, and the association between gait velocity variability and gait and cognitive impairment in patients with idiopathic normal pressure hydrocephalus. METHODS: The gait velocity of 44 patients with idiopathic normal pressure hydrocephalus was measured using the Timed Up and Go Test (TUG) for a total of 10 times over 3 days each before and after CSF elimination. The coefficient of variation (CV) in the time required for the sequence of actions in TUG (TUG-CV) was calculated using 10 TUG data, and used for measuring intraindividual gait velocity variability. Gait quality was evaluated with the Gait Status Scale Revised (GSSR), and cognitive function was evaluated with the Mini-Mental State Examination and the Frontal Assessment Battery. RESULTS: The TUG, TUG-CV, GSSR and Frontal Assessment Battery results improved significantly after CSF elimination. The analyses using pre-CSF elimination results showed that the TUG-CV significantly and positively correlated with the TUG and GSSR results, and negatively with Mini-Mental State Examination results, but not with age and the Frontal Assessment Battery results. The stepwise multiple regression analysis indicates that the TUG, GSSR and Mini-Mental State Examination results were significant predictors of the TUG-CV. The analysis using data of change after CSF elimination showed that ΔTUG and ΔGSSR were significant predictors of ΔTUG-CV. CONCLUSIONS: Gait velocity variability improved after CSF elimination, and gait velocity variability was associated with gait disturbances and cognitive impairment in patients with idiopathic normal pressure hydrocephalus. Geriatr Gerontol Int 2024; 24: 693-699.

SKGQA, a Peptide Derived from the ANA/BTG3 Protein, Cleaves Amyloid-ß with Proteolytic Activity.

Despite the extensive research conducted on Alzheimer's disease (AD) over the years, no effective drug for AD treatment has been found. Therefore, the development of new drugs for the treatment of AD is of the utmost importance. We recently reported the proteolytic activities of JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMA), synthetic peptides of nine amino acids each, derived from the Box A region of Tob1 and ANA/BTG3 proteins, respectively. Furthermore, two components of ANA-TA9, ANA-YA4 (YRMI) at the C-terminus end and ANA-SA5 (SKGQA) at the N-terminus end of ANA-TA9, exhibited proteolytic activity against amyloid-ß (Aß) fragment peptides. In this study, we identified the active center of ANA-SA5 using AEBSF, a serine protease inhibitor, and a peptide in which the Ser residue of ANA-SA5 was replaced with Leu. In addition, we demonstrate the proteolytic activity of ANA-SA5 against the soluble form Aß42 (a-Aß42) and solid insoluble form s-Aß42. Furthermore, ANA-SA5 was not cytotoxic to A549 cells. These results indicate that ANA-SA5 is a promising Catalytide and a potential candidate for the development of new peptide drugs targeting Aß42 for AD treatment.

A retrospective study of dose-dense paclitaxel and carboplatin plus bevacizumab as first-line treatment of advanced epithelial ovarian cancer.

OBJECTIVE: This study compared the effectiveness, safety, and tolerability of dose-dense paclitaxel and carboplatin plus bevacizumab (ddTC+Bev) with ddTC for advanced ovarian cancer. METHODS: We retrospectively analyzed the clinical records of 134 patients who received ddTC+Bev or ddTC as first-line chemotherapy for stage III-IV ovarian cancer. Progression-free survival as primary endpoint of this study was compared using the log-rank test. Cox proportional hazards model and propensity score matching (PSM) were used to analyze prognostic factors, and the frequency of adverse events was examined using the χ² test. RESULTS: We categorized 134 patients in the ddTC+Bev (n=57) and ddTC (n=77) groups who started treatment at four related institutions from November 2013 to December 2017. No patients used poly (ADP-ribose) polymerase inhibitors as the first line maintenance therapy. The progression-free survival (PFS) of the ddTC+Bev group had a significantly better prognosis than that of the ddTC group (hazard ratio [HR]=0.50; 95% confidence interval [CI]=0.32-0.79; p<0.003). Multivariate analysis showed that ddTC+Bev regimen was a prognostic factor. However, intergroup comparison using PSM revealed that the PFS of the ddTC+Bev group had a nonsignificantly better prognosis than that of the ddTC group (HR=0.70; 95% CI=0.41-1.20; p=0.189). Few adverse events above G3 were noted for ddTC+Bev, which were sufficiently tolerable. CONCLUSION: This study could not demonstrate that adding Bev to ddTC improves prognosis. Further studies with more cases are warranted.

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.

Intraperitoneal Carboplatin for Ovarian Cancer - A Phase 2/3 Trial.

BACKGROUND: Intraperitoneal chemotherapy has been shown to be effective at reducing mortality for patients with advanced epithelial ovarian cancer but is not widely used in practice. METHODS: We performed the Intraperitoneal Therapy for Ovarian Cancer with Carboplatin (iPocc) trial as an open-label, international, multi-institutional, randomized phase 2/3 clinical trial in women with newly diagnosed epithelial ovarian cancer who underwent laparotomy or laparoscopy. All patients received intravenous paclitaxel (80 mg/m2 on days 1, 8, and 15 of a 21-day cycle). In addition, patients in the control group received intravenous carboplatin (dose-dense intravenous paclitaxel plus intravenous carboplatin [dd-TCiv]), whereas patients in the experimental group received dose-dense intravenous paclitaxel plus intraperitoneal carboplatin (dd-TCip). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response, treatment completion rate, and incidence of adverse events (AEs). RESULTS: Among 655 patients randomized to treatment, median (95% confidence interval [CI]) PFS was 20.7 (18.1 to 22.8) months for dd-TCiv (n=328) and 23.5 (20.5 to 26.9) months for dd-TCip (n=327; hazard ratio, 0.83; 95% CI, 0.69 to 0.99; P=0.04). The PFS benefit with dd-TCip was consistent in patients with different baseline characteristics, stage, size of residual tumor, age, and performance status. The treatment completion rates were 68.3 and 59.9% in the dd-TCiv and dd-TCip groups, respectively. The incidence of intraperitoneal catheter-related AEs in the dd-TCip group was 10.1%; there were no such AEs in the dd-TCiv group. CONCLUSIONS: In the first-line treatment of advanced epithelial ovarian cancer, intraperitoneal carboplatin resulted in a modest prolongation of PFS when given with dose-dense weekly paclitaxel regardless of residual tumor size, with no impact on noncatheter-related toxicities. (Funded by the Japan Agency for Medical Research and Development, and others; Japan Registry of Clinical Trials number, jRCTs031180141.)