Objective: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. Methods: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. Results: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). Conclusion The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE.Trial Registration: JRCT Identifier: jRCTs031180124

Objective: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. Methods: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. Results: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). Conclusion The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE.Trial Registration: JRCT Identifier: jRCTs031180124

Objective: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. Methods: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. Results: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). Conclusion The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE.Trial Registration: JRCT Identifier: jRCTs031180124

Objective: The addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1. Methods: PAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint). Results: Of 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11–1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16–2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab. Conclusion: Results in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer.

Objective: By using human liver microsomes (HLM), we analyzed the effects of 14 known components of A.senticosus Harms on the activities of CYP2C9 and CYP3A4.
Methods and Results: Sesamin and quercetin inhibited both enzyme activities, whereas quercitrin strongly inhibited CYP3A4 activity. The 50% inhibitory concentrations (IC₅₀s) of sesamin and quercetin on CYP2C9 activity were approximately 124- and 59-fold higher and the IC₅₀s of sesamin, quercetin, and quercitrin on CYP3A4 activity were approximately 427-, 135-, and 22-fold higher than that of A. senticosus Harms extract (ASE), respectively. All these components inhibited both CYP3A4 and CYP2C9 in a non-competitive manner. However, these components are present in small amounts in ASE.
Conclusion: Therefore, the food-drug interactions caused by A. senticosus Harms are presumed to be due to the additive or synergistic interaction of these components or the other existing components, including their metabolites.

The inhibitory effects of the freeze-dried powder of the aqueous extract of black tea leaf (JAT) on α-glucosidase activity were investigated. We initially examined the effects of JAT addition on yeast α-glucosidase activity. JAT significantly and dose-dependently inhibited α-glucosidase activity and more strongly inhibited the activity than acarbose, the positive control. Then, we examined the effects of oral administration of JAT on sucrose tolerance in type 2 diabetes mellitus model db/db mice. Both JAT and acarbose administered groups showed a dose-dependent decrease in plasma glucose levels after the sucrose loading compared with the control group. Notable was that the plasma glucose levels of the 500 mg/kg JAT administered group exhibited a significant decrease 30 min or longer after the sucrose loading. On the other hand, no significant difference in plasma insulin levels was seen between the JAT administered group and the control group. We also measured small intestinal sucrase activity in db/db mouse at 30 min after JAT oral administration. Compared to control mice, small intestinal sucrase activity was significantly decreased in the 500 mg/kg JAT administered mice. These findings indicate that JAT may be a useful natural material for the prevention and therapy of type 2 diabetes mellitus.

Objective: Acanthopanax senticosus Harms extract (ASE) is an ingredient of functional foods, such as health supplements, in Japan. We investigated the effects of ASE on CYP2C9 activity.
Methods and Results: CYP2C9-catalyzed diclofenac 4′-hydroxylase activities in human intestinal and liver microsomes (abbreviated as HIM and HLM, respectively) were significantly decreased by the addition of ASE in a concentration-dependent manner. Kinetic studies of diclofenac 4′-hydroxylase in HLM revealed that ASE addition significantly decreased V_max but had no effect on K_m. These results suggest that diclofenac 4′-hydroxylase activity is suppressed by ASE addition in a non-competitive manner. Then, we investigated the time courses of diclofenac 4′-hydroxylase activity in rat liver microsomes after ASE oral administration (50 to 400 mg/kg). Diclofenac 4′-hydroxylase activities were significantly lowered by the administration of 200 and 400 mg/kg ASE at 0.5 to 4 hr compared with control (0 hr). Furthermore, we investigated the effects of ASE oral administration on the pharmacokinetics of tolbutamide (substrate for CYP2C9) in rats. The area under the concentration-time curve of tolbutamide after ASE oral administration (400 mg/kg) was enhanced by approximately 1.6 times compared with that without ASE oral administration.
Conclusion: These findings indicated that ASE inhibits human intestinal and hepatic CYP2C9 activities.

Emergency coronary artery bypass grafting (CABG) in patients with acute coronary syndrome (ACS) is still associated with high mortality and morbidity, and early outcome is poor compared with outcome in patients with stable angina. The purpose of this study was to examine the clinical results of on-pump beating heart CABG vs. off-pump coronary artery bypass (OPCAB) for ACS patients. From a total of 432 CABG patients, we retrospectively analyzed 72 (16.7%) patients who underwent emergency CABG between 2004 and 2008. Emergency CABG cases were divided into 2 operative groups : an on-pump beating-heart CABG group (on, n=31) and an OPCAB group (off, n=41). A preoperative history of acute myocardial infarction (AMI), detection of troponin T, preoperative creatine phosphokinase (CPK) value, low ejection fraction, presence of mitral regurgitation (MR) (>II) and cardiomegaly were markedly higher in the on group. There were no statistically significant differences in intraoperative factors. In-hospital mortality was 3.2% (1 patient) in the on group and 7.3% (3 patients) in the off group. Furthermore, statistically significant differences were found between the 2 groups in incidence of all-cause morbidity (on=71.0% : off=41.5%, p=0.01), respiratory failure (on=58.1% : off=29.3%, p=0.01), ICU stay (on=6.5±4.6 days : off=4.1±3.2 days, p=0.01), and necessary inotropic support (on=51.6% : off=17.1%, p=0.02). Multivariate regression analysis of preoperative and intraoperative factors was performed to identify independent factors for in-hospital mortality and morbidity. On multivariate analysis of preoperative factors, only the pre-CPK value reached statistical significance as an independent factor for in-hospital mortality and morbidity.

A 72-year-old woman was admitted with a sensation of compression and shortness of breath. A mass was detected in the right atrium (RA) by transthoracic echocardiography. Preoperative chest computed tomography showed an RA tumor measuring 30×24 mm in the lateral wall. We performed resection under the cardiopulmonary bypass. Histopathological examination confirmed that this tumor was a lipoma.

Recent studies showed that high biocompatibility and reduction of uremic toxin contributed to the improvement of freatment outcome in hemodialysis patients.Therefore, a high-flux membrane dialyzer, especially polysulfone (PS) membrane, was generally used in dialysis. However, it was suggested that the higher efficiency of reduction in uremic toxins might cause an increase in the albumin leakage through the dialyzer membrane during dialysis, resulting in a decrease in serum albumin concentration. In this study, we used two different dialyzer membranes with high biocompatibility, namely, ethylenevinylalcohol (EVAL) membrane and improved PS membrane with a very lower leakage of serum albumin. After using these two types of mambrane of six straight months, we examined the effect of each dialyzer membrane characteristic on the serum total protein and albumin concentration. The reduction rates of each uremic solute and serum total protein concentration were significantly higher. The serum albumin concentration and its rate of change with the passing of time tended to increase in the case of the PS membrane. But in the case of EVAL membrane, these values tended to decrease. These results suggested that the differences in the changes in the serum total protein and albumin concentration might result from the differences in the efficiency of the reduction of uremic toxins. Therefore, it is necessary to consider the usage of the dialyzer membrane with a higher reduction of uremic solutes and a lower leakage of serum albumin to add to the higher biocompatibility specially in hemodialysis patients with hypoproteinemia.
Membranes ; Concentration ; Reduction (chemical) ; Serum Albumin ; Hemodialysis