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PURPOSE This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

Contains fulltext : 241226.pdf (Publisher’s version ) (Closed access) BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.

Sulfate is currently not regulated by Japanese water quality standards but could pose adverse health effects to dialysis patients if it remains in high concentration (more than 100 mg/L) in dialysis water and dialysis fluid prepared at healthcare facilities (HCFs). In this study, we obtained sulfate levels in raw water and finished water at Japanese drinking water purification plants (DWPPs) from “Statistics on Water Supply (Water Quality)” in FY2012-2014, and then estimated increases in sulfate by water purification processes. Impact of water treatment chemicals containing sulfate (e.g., alum for coagulation and sulfuric acid for pH adjustment) was also evaluated by water sampling at selected three DWPPs. In FY2012-14, sulfate levels in finished water were mostly less than 50 mg/L; however, sulfate at 18 out of 1,497 DWPPs exceeded 100 mg/L. Increases in sulfate level by dosing of the water treatment chemicals were typically less than 10 mg/L, and other part of the sulfate in finished water came from raw water. These information on water quality should be shared with medical professionals conducting the dialysis therapies, and it would be worthwhile to collaborate with them in water quality management at HCFs.

Highlights • LG-ESS is a rare and indolent uterine tumor which has remarkable sensitivity to hormonal agents. • We presented the case of recurrent LG-ESS that was effectively and safely treated with Dienogest. • Dienogest may be useful for the treatment of LG-ESS that is resistant to other progestins., Low-grade endometrial stromal sarcoma (LG-ESS) is a rare uterine tumor that sometimes recurs and advances. Hormonal treatment, especially high-dose progestins and aromatase inhibitors (AIs), has demonstrated efficacy against these tumors. Because the standard treatment period is uncertain and hormonal treatment is effective, hormonal agents are likely to be used long-term, especially when a residual tumor is present. However, the long-term use of high-dose progestins and AIs may cause thromboembolism, as well as musculoskeletal stiffness and pain. Dienogest, a relatively new progestin, has demonstrated safety after long-term administration; it also appears to have a more favorable long-term safety profile compared with other progestins and AIs. We encountered a young patient with recurrent LG-ESS that metastasized to the liver and exhibited resistance to high-dose medroxyprogesterone acetate (MPA). The patient was successfully treated with dienogest monotherapy. This is the first report describing the efficacy of dienogest against recurrent and metastatic LG-ESS that is resistant to MPA and other agents.

This study examined the association between peritoneal cytology and survival in early-stage cervical cancer. This is a nationwide multicenter retrospective study, examining consecutive women with clinical stage IB1-IIB cervical cancer who underwent radical hysterectomy with available peritoneal cytology results from 2004&ndash, 2008. Propensity score inverse probability of treatment weighting was used to assess the impact of malignant peritoneal cytology on survival. Among 1409 analyzed cases, 88 (6.2%) had malignant peritoneal cytology. On weighted models, malignant peritoneal cytology was associated with decreased disease-free survival (hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.36&ndash, 2.32) and overall survival (OS, HR 1.93, 95% CI 1.44&ndash, 2.59). On sensitivity analyses, malignant peritoneal cytology was associated with decreased OS in adenocarcinoma/adenosquamous carcinoma, high-risk early-stage disease and those who received concurrent chemo-radiotherapy. However, among women who received postoperative systemic chemotherapy, malignant peritoneal cytology was not associated with OS (HR 1.21, 95% CI 0.72&ndash, 2.04). A systematic review, including our results, showed that malignant peritoneal cytology was associated with decreased OS (HR 4.03, 95% CI 1.81&ndash, 8.99) and increased recurrence in squamous carcinoma (odds ratio 1.89, 95% CI 1.05&ndash, 3.39) and adenocarcinoma (odds ratio 4.30, 95% CI 2.30&ndash, 8.02). In conclusion, the presence of malignant cells in peritoneal cytology is associated with decreased survival in early-stage cervical cancer. The possible benefit of systemic chemotherapy in this subgroup merits further investigation.

Purpose: A growing number of treatment options and active compounds in treatments have led to better outcomes for patients with advanced or recurrent epithelial ovarian cancer. We examined the association between progression-free survival (PFS), post-progression survival (PPS) and overall survival (OS) in phase III trials of second- and third-line chemotherapy for advanced or recurrent epithelial ovarian cancer. We aim to determine whether PFS or PPS is a surrogate of OS so that we can decide progress of disease is optimal endpoint for ovarian cancer. Methods: We identified 22 trials conducted between January 1, 2000 through December 31, 2014 by literature search. We divided OS into PFS and PPS, and assessed the association between OS and PFS/PPS. We also examined whether the year of trial enrollment completion was associated with any variables. Results: The median PPS was slightly longer in recent trials compared to older trials (10.0 vs. 8.8 months). While PPS was strongly associated with OS (r = 0.88) in all trials, PFS was moderately correlated with OS (r = 0.72). The correlation between OS and PPS in recent trials (r = 0.93) was stronger than in older trials (r = 0.84). Conclusions: Our findings indicate that PPS is highly associated with OS in second/third-line chemotherapy for advanced or recurrent epithelial ovarian cancer, while the association between PFS and OS is moderate. We recommend using OS as primary endpoint for clinical trial of ovarian cancer, however PFS is still an optional endpoint.

The Water and Environment Technology Conference 2019 (WET 2019)；2019.7.13-14；Osaka, Japan

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published

Two spin crossover (SCO) coordination polymers assembled by combining FeII octahedral ion, 4-cyanopyridine (4-CNpy) and [Au(CN)2]&minus, liner unit are described. These compounds, Fe(4-CNpy)2[Au(CN)2]2&middot, 1/2(4-CNpy) (1a) and {Fe(4-CNpy)2[Au(CN)2]2}-{Fe(H2O)2[Au(CN)2]2} (1b), present quite different supramolecular networks that show different magnetic behaviors. Compound 1a crystallizes in the centrosymmetric space group Pbcn. The asymmetric unit contains two 4-CNpy, one type of Fe2+, and two types of crystallographically distinct [Au(CN)2]&minus, units which form Hofmann-like two dimensional layer structures with guest spaces. The layers are combined with another layer by strong gold-gold intermetalic interactions. Compound 1b crystallizes in the centrosymmetric space group Pnma. The bent bismonodentate [AuI(CN)2] units and FeII ions form a complicated interpenetrated three dimensional structure. In addition, 1b exhibits ferromagnetic interaction.

Background Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib. Methods This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6–12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients. Findings Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months [95% CI 16·3–25·7]) than with placebo (5·5 months [5·2–5·8]; hazard ratio [HR] 0·30 [95% CI 0·22–0·41], p

This correlation study investigated outpatients with early stage uterine cervical cancer. The subjects' mental health and its' relationship with demographic characteristics, clinical characteristics, and quality of life were examined. One hundred and seventy six patients from three major hospitals in the Fukuoka area were surveyed with a structured questionnaire. The status of mental health measured by CES-D (Center for Epidemiologic Studies Depression Scale) indicated an average score of 13 ±8 (mean± SD). No clinical parameters were found to have significant correlation to CES-D. However, increased pain (p < 0.001) and the absence of a husband or a partner (p, 本研究は,初期の子宮頸がんの通院患者の精神的健康に関連する要因構造を,単に臨床的な視点からのみならず,個人の属性や生活の質という全人的な視点から分析することを目的とした.対象者は,福岡市内の医療機関に通院する176名の子宮頸がん患者である.精神的健康度は,CES-D自記式抑うつ尺度を使って測定され,平均値は13±8(平均±標準偏差)点であった.CES-D得点との有意な関連の見られる項目として,「痛みの程度」と「夫(恋人)の有無」があり,痛みが激しいほど,また夫が有る者に比べ無い者においてCES-D得点が高く,抑うつ傾向が強いことが明らかになった.生活の質に関する項目は,因子分析の結果4因子が抽出され,それぞれ,「生活満足度」(r=-.526,p

A large Faraday rotation is reported for Rh 4+ -substituted magnetic garnets in the near infrared wavelength region. The Faraday rotation at 0.9 μ m reaches at about seven times as large as that in YIG by substituting Rh 4+ ions of only 0.13 per formula unit at room temperature. From the electronic state calculations of a @h ' + (Rh 4+ O 6 ) 8- octahedal cluster performed by using an SCF-Unrestricted-SW X α method, the large Faraday rotation is assigned to the charge transfer transitions of an electron from O 2p to Rh 4d orbitals, or t 1 u n (2p) → t 2 s * (4d) and t 2 u n (2p) → t 2 s * (4d) transitions.

We element specifically studied the electronic and magnetic states of epitaxially grown full-Heusler alloy Co2MnSi (CMS) 1.1 nm (4 ML) thick ultrathin films facing an epitaxial MgO(001) tunnel barrier by means of x-ray absorption spectroscopy (XAS) and x-ray magnetic circular dichroism (XMCD). In situ reflection high-energy electron-diffraction observations indicated that the CMS films grew into the L21 structure. The observed XAS and XMCD spectra revealed that the CMS ultrathin film was not oxidized. The ratio of Mn and Co spin magnetic moments obtained by applying the sum rules was about 2.7, close to a theoretical value of 2.8 for CMS with the L21 structure.