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Background: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration., Patients and Methods: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks., Results: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76)., Conclusions: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected., Competing Interests: Disclosure KEF reports intuitional funding from AstraZeneca (AZ). MF reports institutional funding from AZ, Novartis, and Beigene; consulting fees from AZ, Novartis, GlaxoSimthKline (GSK), Merck Sharp & Dohme (MSD), Takeda, and Lilly; honoraria for lectures from AZ, GSK, and ACT-Genomics; travel support from AZ; and participation in a data advisory role with Australasian Gastro-Intestinal Cancer Trials Group and Independent Data and Safety Monitoring Board. IRC reports personal fees and travel support from AZ, GSK, and Clovis Oncology; and personal fees from Roche, Mersana, Deciphera, Eisai, Amgen, Bristol Myers Squibb, OncXerna, and Aravive. AC reports institutional research funding from AZ; payment from Clovis Oncology for lectures and travel support; and he participates in an advisory role to AZ. RP reports institutional funding from AZ. He participates in an advisory role to AbbVie, AZ, Care4ward (unpaid), Clovis Oncology, Curio Science, Eisai Inc., Genentech, Janssen Oncology (J&J), Merck & Co., Mersana Therapeutics, Inc., NewLink Genetics, Nexus Global Group, Pieris Pharma Inc., Roche, Inc., Sutro Biopharma, Syndax Pharmaceuticals, Tesaro Inc., Vascular Biogenics Ltd. NC reports grants, consulting fees, and personal fees from AZ; consulting fees and personal fees from GSK; and personal fees from Tesaro, Novartis, Clovis, MSD, GSK, EISAI. She participates in an advisory role with Roche, PharmaMar, AZ, Clovis Oncology, MSD, GSK, Tesaro, Pfizer, BIOCAD, ImmunoGen, Mersana, OncXerna, and Eisai. KF reports institutional research funding and honoraria for lectures from AZ. GS reports institutional research funding from AZ, MSD, Novartis, and Roche; and consulting fees paid to the institution from BioViva and Segen. IV reports receiving institutional fees from Oncoinvent AS and Genmab; grant funding from Amgen and Roche; consulting fees from Aksebio, Amgen, GmbH, AZ, Clovis Oncology, Carrick Therapeutics, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Roche, Genmab, GSK, Immunogen Inc., Jazz Pharma, Karyopharm, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Novartis, Octimet Oncology NV, Oncoinvent AS, Sotio a.s., Verastem Oncology, Zentalis; and travel expenses from Amgen, MSD, Tesaro, AZ, Roche. EPL reports medical writing assistance for the primary SOLO2 publication from AZ; institutional grants from AZ and Merck; personal payments for lectures from AZ and GSK; and participation in an advisory role with Incyte, Roche, and Pfizer. He reports other interests including as an employee of ARCAGY GINECO research group. CKL reports institutional payments from Roche, AZ, and Merck KGA; and personal payments for lectures, presentations or travel support from AZ, Amgen, Takeda, Boehringer Ingelheim, Pfizer, Yuhan, Merck KGA, Roche, and MSD. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Ovarian cancer is one of the deadliest gynaecological malignancies and tends to be diagnosed at an advanced stage. Similar to many malignancies, surgery plays a critical role in many aspects of ovarian cancer management. Hyperthermic intraperitoneal chemotherapy (HIPEC) involves the induction of hyperthermia and delivery of intraperitoneal chemotherapy directly into the peritoneal cavity. Combined with cytoreductive surgery, HIPEC is an emerging treatment modality for ovarian cancer. Ovarian cancer survival outcomes can be improved by treatment with surgery and HIPEC in selected patients. Thus, this study aimed to review the current role of surgery and HIPEC in epithelial ovarian cancer. Evidence from the monumental and recent literature will be introduced., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The aim of this study was to evaluate the efficacy of palonosetron, the latest 5-HT3 receptor antagonist, for the prevention of postoperative nausea and vomiting (PONV) during the first 72 h after operation., Methods: In this randomized, double-blinded, placebo-controlled study, 204 healthy inpatients who were undergoing elective surgery with general anaesthesia were enrolled. Patients were divided into two groups: the palonosetron group (palonosetron 0.075 mg i.v.; n=102) and the placebo group (normal saline i.v.; n=102). The treatments were given after the induction of anaesthesia. The incidence of nausea, vomiting, severity of nausea, and the use of rescue anti-emetics during the first 72 h after surgery were evaluated., Results: The incidence of PONV was lower in the palonosetron group compared with the placebo group during the 0-24 h (33% vs 47%) and 0-72 h period (33% vs 52%) (P<0.05), but not during the 24-72 h postoperative period (6% vs 11%). The incidence of nausea was also significantly lower in the palonosetron group than in the placebo group during the 0-24 and 0-72 h period (P<0.05), but not during the 24-72 h postoperative period. However, there were no significant differences in the incidence of vomiting, and the use of rescue anti-emetics between the groups., Conclusions: Palonosetron 0.075 mg i.v. effectively reduced the incidence of PONV during the first 72 h after operation, with most of the reduction occurring in the first 24 h.

Background: This phase II neoadjuvant trial evaluated bevacizumab-docetaxel and carboplatin in triple-negative breast cancer., Patients and Methods: Women with hormone receptor- and human epidermal growth factor receptor 2 (HER2)-negative, stage II/III breast cancer received six cycles of 75 mg/m(2) docetaxel, carboplatin (AUC = 5) and 15 mg/kg bevacizumab every 21 days. The primary end point was pathological complete response (pCR) in breasts and axillary lymph nodes (ALN)., Results: Forty-five patients were recruited from the Korean Cancer Study Group. The median age was 45 (range 30-72) years. ALNs were positive in 80% of patients (n = 36) at diagnosis. Overall, 98% of patients (n = 44) completed therapy and underwent surgery. The pCR rate was 42% (n = 19); clinical response rate 96% (n = 43); complete 13% (n = 6); partial 82% (n = 37); stable disease 2% (n = 1). Breast-conserving surgery was undertaken in 78% of patients (n = 35). Most frequent grade 3/4 adverse events were neutropenia (84%, n = 38) and febrile neutropenia (9%, n = 4). One patient experienced delayed wound healing after surgery., Conclusions: Neoadjuvant bevacizumab, docetaxel and carboplatin resulted in an encouraging pCR rate and negligible wound healing problems after surgery.

Background: To evaluate the prognostic value of preoperative tumor markers, cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA), in breast cancers., Patients and Methods: Preoperative CA 15-3 and CEA levels of 1681 patients were measured. The association of both tumor markers levels with clinicopathological parameters and outcomes was investigated by univariate and multivariate analyses., Results: Among 1681 patients, elevated preoperative CA15-3 and CEA levels were identified in 176 and 131 patients, respectively. Higher preoperative CA 15-3 and CEA levels were significantly associated with a larger tumor size, axillary node metastases, and advanced stage. Patients with elevated CA 15-3 and CEA levels showed worse survival, even in stage-matched analysis. Patients with normal levels of both CA15-3 and CEA showed better survival than those with one or both markers levels elevated. In multivariate analysis, elevated preoperative CA 15-3 and CEA levels were independent prognostic factors. The statistical significance of elevated preoperative tumor markers levels on survival was solidified with longer follow-up and larger study population., Conclusions: Elevated preoperative CA 15-3 and CEA levels are associated with tumor burden and showed independent prognostic significance. Therefore, new treatment strategies are necessary for patients with elevated preoperative CA 15-3 and CEA levels in clinical practice.

Background: The objective of the study was to evaluate the implications of androgen receptor (AR) in breast cancers., Patients and Methods: We investigated immunohistochemical AR expression from the tissue microarrays of 931 patients between 1999 and 2005, and analyzed demographics and outcomes using uni-/multivariate analyses. Tumors with ≥10% nuclear-stained cells were considered positive for AR., Results: AR was expressed in 58.1% of patients. AR was significantly related to older age at diagnosis, smaller size, well-differentiated tumors, higher positivity of hormone receptors, non-triple-negative breast cancers (non-TNBCs), and lower proliferative index. In estrogen receptor (ER)-negative tumors, AR was distinctively associated with human epidermal growth factor receptor type 2 (HER2) overexpression. With a mean follow-up of 72.7 months, AR was positively related to survival in ER-positive but not in ER-negative tumors. In Cox's models, AR was an independent prognostic factor for disease-free survival in ER-positive cancers. Interestingly, molecular apocrine tumors (ER negative and AR positive) with HER2 positive status showed trends of poorer outcome, but AR had no impact on survival in patients with TNBC., Conclusions: AR is significantly associated with favorable features in breast cancers and related to better outcomes in ER-positive not in ER-negative tumors. These results suggest that AR could be an additional marker for endocrine responsiveness in ER-positive cancers and a candidate for therapeutic targeting of ER-negative tumors.

Background: Ramosetron is a new selective 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonist that reportedly has more potent antiemetic effects compared with other 5-HT(3) receptor antagonists. The purpose of this study was to evaluate the efficacy of ramosetron for the prevention of postoperative nausea and vomiting (PONV) with that of ondansetron or placebo in high-risk patients undergoing gynaecological surgery., Methods: In this prospective, randomized, double-blinded, placebo-controlled study, 162 healthy patients who were undergoing gynaecological operation under general anaesthesia using sevoflurane were enrolled. Patients were divided into three groups: the ramosetron group (0.3 mg i.v.; n=54), the ondansetron group (8 mg i.v.; n=54), and the placebo group (normal saline i.v.; n=54). The treatments were given before the end of surgery. The incidence of PONV, severity of nausea, and the use of rescue antiemetic requirements during the first 24 h after surgery were evaluated., Results: The incidence of nausea was lower in the ramosetron (50%) and ondansetron (44%) groups compared with the placebo group (69%) (P<0.05). In addition, the incidence of vomiting was lower in both the ramosetron (17%) and the ondansetron (20%) groups than in the placebo group (44%) during the first 24 h after surgery (P<0.05). The visual analogue scale score for nausea was also lower in the ramosetron and ondansetron groups compared with the placebo group (P<0.05). The proportion of patients requiring rescue antiemetics was significantly lower with ramosetron (15%) when compared with the placebo group (41%) during the 24 h after surgery (P<0.05). However, there were no significant differences in the incidence of nausea and vomiting, severity of nausea, and required rescue PONV between the ramosetron and the ondansetron groups., Conclusions: Ramosetron 0.3 mg i.v. was as effective as ondansetron 8 mg i.v. in decreasing the incidence of PONV and reducing nausea severity in female patients during the first 24 h after gynaecological surgery.

The aniline-assimilating bacterium Acinetobacter lwoffii K24 has two cat gene clusters (cat1 and cat2). In this study, we completely sequenced 10-kb DNA fragment of cat1 genes of A. lwoffii K24, which had been cloned in plasmid pCD1-1. Sequence analysis revealed that the order of genes in the cat1 operon-containing gene cluster was ORF porin, catR1, catB1C1A1D, ORF1, and ORF2. Two ORFs located immediately downstream catD were most similar with two ORFs in cat gene cluster of Acinetobacter calcoaceticus ADP1 but the gene structure of catR1B1C1A1 was closest to that found in Frateurua sp. ANA-18 or Pseudomonas putida PRS2000. CatA1 gene product was significantly overexpressed and detected in SDS-PAGE when four cat1 genes (catB1C1A1D) were placed under the control of a lac promoter in pUC118 while overexpressions of other cat genes were accomplished under the control of a lac promoter in pET vector system. All gene products were verified by N-terminal amino acid sequencing. Gel retardation assay revealed that the putative regulatory gene activator CatR1 for the catB1C1A1 operon could bind the promoter region of catB2 as well as catB1, suggesting that transcription of catB1 or catB2 might be controlled by the putative gene activator CatR1. However, the promoter regions of catA1 and catA2 were found to have no affinity with catR1., (Copyright 2001 Academic Press.)

Background: Dietary fat intake is associated with the incidence of ischemic heart disease (IHD) in Western countries. In populations in which both the average dietary fat consumption and the incidence of IHD are lower than in Western countries, the association of dietary fat intake with IHD incidence remains unknown., Objective: We conducted a case-control study to examine the association of dietary fat with IHD incidence in Korean men., Design: The case group consisted of 108 patients with electrocardiogram-confirmed myocardial infarction or angiographically confirmed (> or =50% stenosis) IHD who were admitted to a university teaching hospital in Seoul, Republic of Korea. The controls were 142 age-matched patients admitted to the departments of ophthalmology and orthopedic surgery at the same hospital. Dietary fat intake was assessed by a nutritionist using a semiquantitative food-frequency questionnaire. Body mass index (BMI), cigarette use, alcohol intake, exercise, and history of disease were determined during an interview and examination., Results: In a univariate analysis, the mean percentages of energy from total fat, saturated fatty acids, and monounsaturated fatty acids were significantly higher in the cases than in the controls. BMI, smoking, and a history of hypertension were associated with the occurrence of IHD. In multiple logistic analyses, total fat intake was a significant risk factor (odds ratio: 1.08 for 1% of energy intake; 95% CI: 1.02, 1.14) after adjustment for BMI and smoking., Conclusion: In a population with a relatively low fat intake (19% of energy intake), a moderate increase in total fat intake may be a risk factor for IHD.

The effect of osmotic pressure on paclitaxel production was investigated in the suspension cell cultures of Taxus chinensis. Paclitaxel production was definitely influenced by the initial sucrose concentration and the highest production yield was achieved at the concentration of 60 g.l(-1) sucrose (300 mOsm.kg(-1)). High osmotic pressure conditions generated by non-metabolic sugar (mannitol and sorbitol) also enhanced paclitaxel production by about two-fold. Kinetic studies revealed that high initial osmotic pressure enhanced paclitaxel production and that high concentration of sucrose was effective for sustaining secondary metabolism after induction of paclitaxel biosynthesis. Stoichiometric analysis with different combinations of sucrose and mannitol confirmed that osmotic pressure was the more important factor for enhancing paclitaxel metabolism. The addition of non-sugar osmotic agent, PEG also enhanced paclitaxel production. In this paper, we showed that high osmotic pressure led to increases in paclitaxel production and proposed that regulation of osmotic pressure may be useful in controlling paclitaxel production.

The objective of this study was to estimate colon-specific delivery of insulin and (Asu(1,7))eel-calcitonin using novel azopolymer-coated pellets. In vitro drug-release experiments from the azopolymer-coated pellets containing fluorescein isothiocyanate dextran (MW 4400; FD-4) were carried out by the Japanese Pharmacopoeia (J.P.) XIII rotating basket method with some slight modifications. Little release of FD-4 from the pellets was observed in phosphate buffered saline. However, the release of FD-4 was markedly increased in the presence of rat cecal contents. The intestinal absorption of insulin and (Asu(1,7))eel-calcitonin after oral administration of the azopolymer-coated pellets containing these peptides with camostat mesilate was evaluated by measuring the hypoglycemic and hypocalcemic effects, respectively. A slight decrease in plasma glucose levels was observed following the oral administration of these pellets containing 12.5 IU of insulin compared with the same dose of insulin solution. Camostat mesilate, a protease inhibitor that is incorporated with insulin in these pellets, further decreased the plasma glucose levels in a dose-dependent manner. Similar results were also obtained with the oral administration of pellets containing (Asu(1,7))eel-calcitonin. These findings suggest that azopolymer-coated pellets may be useful carriers for the colon-specific delivery of peptides including insulin and (Asu(1,7))eel-calcitonin., (Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:89-97, 2001)

In this prospective, randomized, double-blind, placebo-controlled study, the use of continuous subhypnotic propofol infusion as an antiemetic in fentanyl intravenous patient-controlled analgesia (i.v. PCA) was investigated during the first 24 h after surgery. One hundred female patients, ASA I-II, aged 20-71 yr, undergoing major gynaecological or orthopaedic surgery, were included. Either propofol 10 mg or placebo (1 ml of Intralipid) was given and one of the following five regimens was maintained for 24 h: propofol 5, 10, 15 or 20 microg kg(-1) min(-1) or Intralipid 1 ml h(-1) as a placebo. Fentanyl i.v. PCA was started in the postanaesthesia care unit for postoperative analgesia. Significantly more of the patients given propofol 15 and 20 microg kg(-1) min(-1) experienced no nausea or vomiting compared with those given placebo (65% and 70% versus 25%; P<0.05). Patients given propofol 20 microg kg(-1) min(-1) reported more sedation than those in the other groups 4 h after surgery (P<0.05).

Ginsenoside Rh1 or Rh2 differentiated B16 melanoma or F9 teratocarnoma to phenotypic normal melanocyte-like cells or parietal endoderm-like cells. Ginsenoside Rh3 and Rh4 were recently isolated from Panax ginseng, but their biochemical and pharmacological effects remain unidentified. The present study investigated whether the ginsenoside Rh group (G-Rh1, -Rh2, -Rh3 and -Rh4) having similar structures induce differentiation of HL-60 cells and whether protein kinase C (PKC) is involved in differentiation by ginsenoside. Differentiation was assessed by Wright-Giemsa stain and nitroblue tetrazolium reduction. G-Rh2 and G-Rh3 induced differentiation of HL-60 cells into morphologically and functionally granulocytes but G-Rh1 and G-Rh4 did not. G-Rh2 and G-Rh3 arrested the cell cycle at the G1/S phase, consistent with the ability to induce differentiation in a decreasing order of retinoic acid > G-Rh2 > G-Rh3. During differentiation by G-Rh2, Ca2+/phospholipid-dependent PKC activity was increased in both the cytosol and total cell extract and Ca2+/phospholipid-dependent phosphorylation of 38 and 200 kDa endogenous proteins increased, while phosphorylation of 60, 64, 66 and 97 kDa proteins was Ca2+/phospholipid-independent. When cytosolic PKC isoforms were analyzed by immunoblotting, no significant change was observed in the alpha level, however, the immunoreactive 60 kDa band of a similar mass to the PKC catalytic fragment appeared following treatment with G-Rh2. The beta isoform was gradually increased with prolonged treatment. The gamma isoform was not detected in the cytosol of untreated cells, whereas a small amount was detected 5 days after treatment. It is concluded that G-Rh2 and G-Rh3 can induce differentiation of HL-60 cells into granulocytes and modulation of PKC isoform levels may contribute to differentiation of HL-60 cells by G-Rh2.

Previously, we have reported that two clustered cat genes from Acenitobacter lwoffi K24 had different arrangements, catB1C1A1 and catB2A2C2 (Kim, S.I., S.-H. Leem, J.-S. Choi, Y.H. Chung, S. Kim, Y.-M. Park, Y.K. Park, Y.N. Lee, and K.-S. Ha. 1997, J. Bacteriol. 179, 5226-5231). By further analysis of the organization of the cat1 gene cluster, we obtained a complete sequence of the catB1 gene, which encoded 40.8-kDa polypeptide containing 379 amino acids, and found a open reading frame (ORF) coding a putative regulatory protein in upstream region of catB1 on plasmid pCD1-1. This ORF encoded 34.2-kDa polypeptide containing 379 amino acids and had more than 40% identity with catR, LysR family regulatory protein of Pseudomonas putida. RT-PCR, Northern blot analysis and primer extension assay for transcriptional analysis of the cat1 gene cluster revealed that the catB1C1 genes were cotranscribed and the catA1 gene was independently transcribed.

The anticomplementary activity of ginseng saponins and their degradation products obtained by chemical treatment of Korean red ginseng saponins was investigated. The total saponin and its major components showed strong anticomplementary activity and their structure-activity relationship was evaluated.

Glycosylation of 12beta-acetoxy-dammar-24-en-3beta,20(S)-diol (4), with hepta-O-acetyl-alpha-sophorosyl bromide (5) under catalysis by Ag2CO3 or Ag2O afforded a chromatographically unseparated mixture of the alpha- and beta-linked octaacetates 6 and 7 in an approximately 2.5:1 ratio. After deprotection and chromatographic purification, the free alpha- (8) and beta-glycosides (9) were obtained. Sophoroside 9 was identical in all respects with ginsenoside Rg3, the minor component of Ginseng Radix rubra. All compounds were fully characterized by 1H and 13C NMR spectroscopy.