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We studied the extent of BRCA1/2 genetic testing to help select the surgical approach for patients with breast cancer in Japan remains unclear.The study subjects were female patients with primary unilateral invasive breast cancer considered as candidates for breast-conserving surgery who underwent preoperative BRCA1/2 genetic testing. A retrospective analysis was performed on the results of BRCA1/2 genetic testing and surgical method selection using national registration data from the Japanese Hereditary Breast and Ovarian Cancer Syndrome Consortium.Our study included 318 female patients. Among these patients, 23.7% of patients with BRCA1/2 mutations and 61.8% of patients without these variants underwent breast-conserving surgery (P .01). Among the patients with BRCA1/2 mutations, those who chose breast-conserving surgery tended not to undergo risk-reducing salpingo-oophorectomy (P .05). Among the patients with BRCA1/2 mutations who underwent mastectomy for the affected side, 31.8% received contralateral risk-reducing mastectomy. Patients diagnosed with breast cancer under the age of 50 years were more likely to have contralateral risk-reducing mastectomy than patients over the age 50 years (P .05).Patients with BRCA1/2 mutations tend to choose mastectomy. However, it is speculated that the final surgical method selection is made in consideration of not only the test results but also with careful consideration of the patient, taking into account other factors including individual values for risk-reducing surgeries and the age of breast cancer onset.

Objective The objective of this study is to evaluate the detection rate and diagnostic accuracy of sentinel lymph node (SN) mapping using hysteroscopic sub-endometrial injection of 99m-Technetium labeled phytate (Radio-isotope; RI method) and subserosal Indocyanine green (ICG) injection (Dye method) in patients with endometrial cancer. Methods From April 2009 to December 2012, prospective evaluation of 57 Japanese endometrial cancer patients undergoing SN mapping using RI method combined with Dye method was done. To combine RI method or no was determined by a status of RI supply of the tracer injection day. As for 32 cases, both (RI+Dye) methods were used and 23 cases were performed only in Dye method. The primary endpoint was estimation of sensitivity and negative predictive value (NPV) of SN, and analysis of the distribution of SNs with metastasis. Results At least one SN was detected in 100% and average number of detected SNs was 6.0 in RI+Dye method. Sensitivity and NPV were 100%, 100%, respectively. From results of SN mapping, 62.8% of SNs were present in pelvic and 37.1% in para-aortic lymph nodes (PAN). Total 56.3% of lymph nodes with metastasis were present in pelvic and 43.8% in PAN, and the distribution has no difference with SN mapping results (P=0.602). Among 13 cases with metastatic SNs, 76.9% cases showed metastasis in PAN. Conclusions This SN mapping procedure for endometrial cancer patients revealed high detection rate, sensitivity, NPV, and also indicated the importance of the SN exploration in PAN area.

Background TAS-117 is a novel highly potent and selective oral allosteric AKT inhibitor. This study investigated the safety, efficacy, pharmacokinetics, pharmacodynamics, and pharmacogenomics profiles of TAS-117 in patients (pts) with advanced solid tumors, for whom no standard treatment remains. Methods The primary objective was to evaluate the safety profile of TAS-117, including the identification of the maximum tolerated dose (MTD) and the recommended dose (RD) with regimen (RR) in a 21-day cycle. Dose escalation was assessed in a once-daily repeated dosing regimen (QD), starting at 4 mg/day, with an accelerated titration design. Dose-limiting toxicity (DLT) was evaluated in a first cycle. After RD and RR were determined, pts with endometrial cancer (EC) harboring PIK3CA or AKT gene alterations or ovarian clear cell carcinoma (OCC) were enrolled for further safety evaluation. Results TAS-117 was administered QD (n = 12) and in a 4 days on/3 days off regimen (4d/3d) (n = 10). The dose was escalated to 24 mg/day in QD dosing and 32 mg/day in 4d/3d; the MTD was not reached. The DLT was a grade 3 rash maculo-papular at 32 mg/day in 4d/3d dosing. The RD and RR were determined as TAS-117 24 mg/day and 4d/3d. As of 24 Apr 2019, 42 pts (15 with PIK3CA-mutated (mt) EC, 7 with AKT-altered EC, and 20 with OCC) were enrolled, and safety profiles were investigated. The common (≥30%) treatment-related adverse events (TRAEs) were rash maculo-papular (grade 3, observed in 42.5% of pts), stomatitis, hyperglycemia, white blood cell decrease, and neutrophil count decreased. Common TRAEs, especially rash maculo-papular, were manageable with dose reduction, dose interruption, or symptomatic therapy. TAS-117 exposure tended to increase in a dose-dependent matter. In efficacy-evaluable pts, objective responses were observed in 1 pt with PIK3CA-mt EC and 5 pts with OCC. The disease control rate was 61.5% in 13 pts with PIK3CA-mt EC, 80.0% in 5 pts with AKT-altered EC, and 37.5% in 16 pts with OCC. Conclusions TAS-117 had a manageable safety profile with clinical antitumor activity in pts with advanced solid tumors. Further investigation of the drug in a combination therapy is in preparation. Clinical trial identification JapicCTI-152780. Legal entity responsible for the study Taiho Pharmaceutical Co., Ltd. Funding Has not received any funding. Disclosure S. Takahashi: Honoraria (self), Research grant / Funding (self): Eisai; Honoraria (self): Bristol-Myers-Squibb; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self): Bayer; Research grant / Funding (self): MSD; Research grant / Funding (self): Astrazeneka; Research grant / Funding (self): Quintiles; Research grant / Funding (self): IQVIA; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Ono pharmaceutical. D. Aoki: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy: AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy: MSD K.K.. K. Yonemori: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Ono; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): ICON Japan; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Nippon Kayaku; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): 3D MATRIX. H. Hara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Incyte. K. Hasegawa: Honoraria (self), Research grant / Funding (self): Daiichi-Sankyo; Honoraria (self): Chugai; Honoraria (self): Nippon Kayaku; Honoraria (self): Bayer; Honoraria (self): AstraZeneca; Advisory / Consultancy: MSD; Research grant / Funding (self): OncoTherapy Science; Research grant / Funding (self): Yakult Honsha. K. Takehara: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Kyowa Kirin; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Nippon Kayaku; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Treumo; Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Chugai Pharma; Speaker Bureau / Expert testimony: Eisai. K. Harano: Honoraria (self): Eisai; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self): AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Chugai; Advisory / Consultancy: Takeda. E. Noguchi: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Nippon Kayaku; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Chugai; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): ICON Japan; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): 3D MATRIX. T. Doi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy: Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Kyowa Hakko Kirin; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: AstraZeneka; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Daiichisankyo; Advisory / Consultancy, Research grant / Funding (institution): Dainippon Sumitomo; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Taiho, Zenyaku Kogyo, Astellas; Research grant / Funding (institution): Janssen, Eisai, Sanofi; Research grant / Funding (institution): NanoCarrier, Quintiles, Pfizer; Research grant / Funding (institution): Bristol-myers; Research grant / Funding (institution): Bristol-Myers-Squibb. All other authors have declared no conflicts of interest.

Gestational choriocarcinoma is a malignant trophoblastic tumor that usually occurs in the uterus after pregnancy. The tumor is curable with advanced chemotherapy, but the molecular mechanism of choriocarcinoma tumorigenesis remains unclear. This is partly because the low incidence makes it difficult to obtain clinical samples for investigation and because an appropriate choriocarcinoma cell model to study the tumorigenesis has not been developed. We have established a new choriocarcinoma cell line, induced choriocarcinoma cell-1 (iC(3)-1), that possesses unique characteristics compared to other choriocarcinoma cell lines, including production of tumors that consist of the two types of cells commonly found in choriocarcinoma and mimicking of the clinical pathology. Existing trophoblast cell lines utilized in previous choriocarcinoma studies have had significantly dissimilar gene expression profiles. Therefore, it is important to choose an appropriate cell line for a particular study based on the characteristics of the cell line. In this study, to clarify the genetic characteristics of iC(3)-1 and to explore the tumorigenesis mechanism, we examined the gene profile of iC(3)-1 compared to those of existing cell lines and normal placental tissue. Bioinformatics analysis showed that several characteristic genes, IGF1R, CHFR, MUC3A, TAF7, PARK7, CDC123 and PSMD8, were significantly upregulated in iC(3)-1 compared to BeWo and JEG3 cells. Interestingly, HAS2, CD44 and S100P were significantly upregulated in iC(3)-1 compared to parental HTR8/SVneo cells and normal third trimester placenta. Choriocarcinoma samples also showed immunoreactivity to HAS2, CD44 and S100. In summary, the gene expression profile of iC(3)-1 suggests that studies using this cell line can make an important contribution to improved understanding of choriocarcinoma tumorigenesis.

The aim of this study was to examine the relation between cofilin 1 expression and progression-free survival in advanced epithelial ovarian cancer. We performed quantitative reverse transcriptase polymerase chain reaction and immunohistochemical analysis in 78 patients with advanced epithelial ovarian cancer (excluding those with mucinous and clear-cell types). All patients received the standard therapy, including staging laparotomy and adjuvant chemotherapy consisting of carboplatin and paclitaxel. Of 78 samples, RNA from 62 samples was available for reverse transcriptase polymerase chain reaction analysis. We defined cofilin 1 high expression as relative gene expression equal to or higher than the median and low expression as gene expression lower than median. The progression-free survival was longer in cofilin 1 low-expression cases than in high-expression cases (P = .039). Multivariate analysis demonstrated that stage and cofilin 1 expression were significant predictors of progression-free survival. Of the 78 samples, 54 were appropriate for immunohistochemical study. In 35 of those 54 cases, cofilin 1 protein expression was detected. The progression-free survival was longer in cofilin 1 protein-negative cases than in protein-positive cases (P = .042). Expression of cofilin 1 may predict the progression-free survival of patients with advanced epithelial ovarian cancer receiving standard therapy.

Background: The purpose of this study is to assess the efficacy and safety of treatment with taxane plus platinum in combination therapies for advanced or recurrent endometrial carcinoma. Patients and methods: Patients with measurable disease derived from histologically confirmed stage III/IV or recurrent endometrial carcinoma were randomly assigned to receive docetaxel plus cisplatin (DP), docetaxel plus carboplatin (DC), or paclitaxel plus carboplatin (TC) every 3 weeks until disease progression or adverse events prohibited further therapy. Among these regimens, the study evaluated the tumor response rate as the primary end point as well as toxicity. Results: Ninety patients were enrolled. Of them, 88 were eligible and consequently 29, 29, and 30 patients were randomly assigned to DP, DC, and TC, respectively. Tumor response rates were 51.7%, 48.3%, and 60.0% in DP, DC, and TC, respectively (P = 0.65). The following toxic effects were observed: grade 3/4 neutropenia in 83.3%, 90.0%, and 76.6%; febrile neutropenia in 10.0%, 6.7%, and 3.3%; grade 3/4 thrombocytopenia in 6.7%, 10.0%, and 10.0%; grade 3/4 diarrhea in 13.3%, 3.3%, and 0%, respectively; and grade 3 neurotoxicity in 10.0% of TC. These toxicity profiles were not significantly different. Conclusion: The taxane plus platinum combination therapies could be candidates in further phase III trials for endometrial carcinoma.

Newly designed pressure infiltration technique was developed to clarify the molten metal flow through solid network, aiming to obtain property materials and, simultaneously, the purified matrix as a filtrated metal. An experimental apparatus was constructed to control the microstructure morphology for varied fraction of solid and applied pressure. A sample, Al-7 wt.% Si-20 vol.% SiCp was squeezed on the double layers of semi-solid aluminum alloy cake and alumina porous medium by using argon gas pressure. Permeability values were estimated by Darcy's law in order to know the molten metal flow characteristics through solid network in the semi-solid range. It was found that the permeability suddenly decreased with increasing fraction of solid, and filtration mechanism was changed between depth and cake filtration near fraction of solid 0.25 due to much difference of the flow resistance between the two. Increasing applied pressure decreased the permeability due to the consolidation of solid grains. For pressurized sample on the filter and filtrated metal, SiCp content became to as high as 38 and less than 0.4 in volume percentage depending on fraction of solid, respectively. The pressurized samples with high SiCp content showed low wear rate and high hardness, when compared with original composite sample.

Semi-solid processing using cooling plate technique was developed to produce a high quality ultrahigh-carbon steel (UHCS) components. Microstructure and mechanical properties were investigated as a function of fraction of solid. The microstructure of UHCS was improved using semi-solid processing. A unique homogenized microstructure comprised of fine particles grain size (200–100 μm) was obtained which totally differs from that obtained by ordinary UHCS casting (520 μm particle grain size). Tensile strength of as-cast and heat treated semi-solid processed UHCS is relatively high compared with ordinary one. Both the tensile strength and elongation closely connect with the particle grain size and cementite network changed with fraction of solid. Increasing fraction of solid increases hardness values, which is attributed to the fine and homogenous structure by semi-solid processing.

The processing of metals in the semi-solid state is becoming an innovative technology for the production of globular structure and high quality cast parts. This research is directed towards studying the effect of semi-solid processing (using cooling plate technique) on the microstructure and the strength of gray cast iron. The charge material used for all trials was hypoeutectic gray cast iron with 3.59% carbon equivalent. The results indicated that by increasing fraction of solid microstructure becomes finer and more globular. Increasing primary fraction of solid causes an increment of undercooling and changes graphite morphology. Tensile strength of semi-solid processed gray cast iron is relatively high compared with ordinary one. The values of both the tensile strength and the elongation depend on the fraction of solid. It is found that graphite morphology (size and type), primary solid agglomeration and cutting graphite network have a large influence on both the properties in semi-solid processing. The total fracture strength is observed to depend on the graphite morphology as well as the matrix contribution that mainly depends on fraction of solid. Increasing fraction of solid increases hardness values, which is attributed to the homogenous structure by semi-solid processing.

A three-dimensional simulation model for green sand molding analysis is developed using a typical discontinuous model, the distinct element method (DEM). This model is combined with a new algorithm and the characteristics of bonded sand and the particle size distribution are taken into consideration in the simulation. The model is applied to squeeze process simulation using several kinds of green sand. Laboratory experiments are carried out to test the validity of the model. The effect of the particle size distribution on the sand compacting behavior is clarified by both the experiment and simulation. The mold properties obtained by the simulation almost agree with the experimental ones. The present study provides new and useful information on the compacting behavior in green sand molding processes.

In order to clarify the mechanism such as makes the cavity filling optimize by one-time's switching of the injection velocity in a die casting process, a series of experiments and computer simulation have been done using the water or the low melting-temperature alloy. SOLA-MAC simulation method using both continuity and Navier-Stokes equations is applied to analyze the cavity filling behavior for switching the injection velocity during the injection. The validity of model is clarified. A perfomance index to obtain the appropriate filling behavior with the defects-free of casting products is proposed. Good conditions to switch the injection velocity from a low speed to a high speed are obtained by computer simulations.

In Xenopus oocytes, lysophosphatidic acid (LPA) evoked inward currents at the holding potential of −60 mV, which were quickly desensitized upon repeated challenges of the compound at 10 nM or 1 μM. This desensitization was prevented by pretreatment with protein kinase A inhibitor or recovered by its post-treatment, but not by the pretreatment with an inhibitor of protein kinase C or calmodulin kinase II. From pharmacological studies, the LPA-evoked currents were found to be mediated by phospholipase C, calcium-mobilization from thapsigargin-sensitive Ca2+ stores, araguspongine E-sensitive inositol trisphosphate receptor, and calcium-dependent chloride channels.

Aim: We previously reported results from AGO-OVAR16 (NCT00866697), a randomized, double-blind, placebo-controlled phase 3 trial that evaluated the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients without disease progression after first-line chemotherapy for AEOC (du Bois et al, ASCO 2013; abstract LBA5503). Patients in the pazopanib arm had longer progression-free survival (PFS) versus those in the placebo arm (HR = 0.766; 95% CI: 0.643, 0.911; P = .0021; medians 17.9 vs 12.3 months, respectively). The first interim analysis for overall survival (OS) after 190 deaths (20% of the study population) revealed no difference between arms (HR = 0.994; 95% CI: 0.747, 1.321). In this report we present updated results from the planned second interim OS analysis after 335 events (36% of the study population; 61% of events required for the final OS analysis, which will be performed after 551 events). Methods: Eligible patients had histologically confirmed AEOC, FIGO stage II-IV, and no evidence of disease progression after surgery and ≥ 5 cycles of platinum-taxane chemotherapy. Patients were randomized 1:1 to receive pazopanib 800 mg once daily or placebo for up to 24 months. The primary endpoint was PFS by RECIST. Secondary endpoints included OS, safety, and quality of life. Results: A total of 940 patients were randomized. At this second interim analysis of OS, 172 patients (36%) in the pazopanib arm and 163 patients (35%) in the placebo arm had died (HR = 1.076; 95% CI: 0.868, 1.333; P = .4985). The majority of deaths in each arm were attributed to the cancer under study. Additional subgroup analyses are ongoing and will be presented. Conclusions: Results from this updated OS analysis are consistent with the first interim analysis. Although maintenance therapy with pazopanib in AEOC significantly prolonged PFS in the overall study population, no difference in OS was observed in the planned second interim OS analysis. Disclosure: J.A. Arranz Arija: I have received honorarium for participating in advisory boards organized by GSK. I have received honorarium for participating as speaker in meetings organized by GSK. I do not have other economic relationships nor interest with GSK; N. Colombo: I have to declare participation in advisory boards; B.J. Monk: I have received honoraria for Advisory Boards. GSK supports research done at my institution and the payments do not go to me; T. Herzog: Consultant via advisory boards: Az, Roche, merk, morphotek No other as no speaker bureaus stock etc; C. Barrett and M. Jobanputra: I am employed by GlaxoSmithKline and hold GSK stock; Q. Wang: I'm a GSK employee and own GSK stocks. I do not have anything else to disclose; A. Du Bois: Consultant/advisor for Roche, Pharmamar, Amgen, and MSD Honoraria received from Roche, Johnson & Johnson, Pharmamar and MSD. All other authors have declared no conflicts of interest.

In this paper, an optimal control system is presented for the foundry sand cooling process using a fluidised bed. A mathematical model based on heat and mass transfer is constructed for cooling process in fluidised bed. Two effective manipulated variables, air flow rate and water addition content, are proposed for the present controlled variables, discharged sand temperature and moisture content. LQI control approach with finite settling time observer is applied, and simulation studies have been done concerning disturbance compensation problem, tracking problem for the shift of reference input and so on. A series of experiments are conducted to show the usefulness of LQI control approach.

In order to establish the optimum control system of hot sand cooling in foundry, a mathematical model for cooling process has been studied, The present study is especially directed towards modelling on dynamical behavior of the process in onepass fluidized bed. The model includes linear differential equations for phase-to-phase heat transfer, Computer simulations on both transient and steady-state temperatures of the bed are provided and compared with the experimental results Sensitivity analysis of the cooling model has been carried out. A special interest is in the variation of steady-state bed temperature owing to the change of inlet sand temperature. The results of computer simulation are presented and comparison with the experiments is done. The proposed model is shown useful in predicting process characteristics of sand cooling system and in designing the optimum cooling system.