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BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases (ClinicalTrials.gov: NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1-50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade >= 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%-28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1-34.1). Seven patients (24.1%, 95% CI: 10.3%-43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.Copyright © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases (ClinicalTrials.gov: NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1-50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade >= 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%-28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1-34.1). Seven patients (24.1%, 95% CI: 10.3%-43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.Copyright © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

The prognostic significance of patients presenting with pulmonary embolism (PE) and elevated International Normalised Ratio (INR) not on anticoagulant therapy has not been described. We investigated whether these patients had higher mortality compared to patients with normal INR. A retrospective study of patients admitted to a tertiary hospital with acute PE from 2000 to 2012 was undertaken, with study outcomes tracked using a state-wide death registry. Patients were excluded if they were taking anticoagulants or had inadequate documentation of their INR and medication status. Of the 1,039 patients identified, 94 (9 %) had an elevated INR (> 1.2) in the absence of anticoagulant use. These patients had higher mortality at six months follow-up (26 % vs 6 %, p< 0.001) compared to controls (INR ≤ 1.2). An INR > 1.2 at diagnosis was an independent predictor of death at six months post-PE (hazard ratio [HR] 2.9, 95 % confidence interval [CI] 1.8–4.7, p< 0.001). The addition of INR to a multivariable model that included the simplified pulmonary embolism severity index (sPESI), chest pain, and serum sodium led to a significant net reclassification improvement estimated at 8.1 %. The final model’s C statistic increased significantly by 0.04 (95 % CI 0.01–0.08, p=0.03) to 0.83 compared to sPESI alone (0.79). In summary, patients presenting with acute PE and elevated INR while not on anticoagulant therapy appear to be at high risk of death. Future validation studies in independent cohorts will clarify if this novel finding can be usefully incorporated into clinical decision making in patients with acute PE.

© 2016 Bing et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Acute pulmonary embolism (PE) carries an increased risk of death. Using transthoracic echocardiography (TTE) to assist diagnosis and risk stratification is recommended in current guidelines. However, its utilization in real-world clinical practice is unknown. We conducted a retrospective observational study to delineate the prevalence of inpatient TTE use following confirmed acute PE, identify predictors for its use and its impact on patient's outcome. Methods Clinical details of consecutive patients (2000 to 2012) from two tertiary-referral hospitals were retrieved from dedicated PE databases. All-cause and cause-specific mortality was tracked from a state-wide death registry. Results In total, 2306 patients were admitted with confirmed PE, of whom 687 (29.8%) had inpatient TTE (39.3% vs 14.4% between sites, P<0.001). Site to which patient presented, older age, cardiac failure, atrial fibrillation and diabetes were independent predictors for inpatient TTE use, while malignancy was a negative predictor. Overall mortality was 41.4% (mean followup 66.5±49.5months). Though inpatient TTE use was not an independent predictor for allcause or cardiovascular mortality in multivariable analysis, in the inpatient TTE subgroup, right ventricle-right atrial pressure gradient (hazard ratio [HR] 1.02 per-1mmHg increase, 95% confidence interval [CI] 1.01-1.03) and moderate/severe aortic stenosis (HR 2.26, 95% CI 1.20-4.27) independently predicted all-cause mortality. Conclusions Inpatient TTE is used infrequently in real-world clinical settings following acute PE despite its usefulness in risk stratification, prognostication and assessing comorbid cardiac pathologies. Identifying patients that will benefit most from a T

Background: Aurora kinases A and B are oncogenic serine/threonine kinases with distinct, crucial functions in regulation of mitosis and control of the G2 checkpoint. Aurora kinases are amplified and/or over-expressed in many solid tumors and associated with poor prognosis and therapeutic resistance. AMG 900 is an investigational, orally administered, highly potent, selective small molecule pan-aurora inhibitor that has shown activity in taxane-resistant human tumor xenograft models. An open-label, first-inhuman study evaluated the safety, tolerability, pharmacokinetics (PK), and clinical activity of AMG 900 in patients with advanced, treatment-refractory solid tumors. In the dose-escalation phase, AMG 900 showed activity in ovarian and endometrial carcinoma. Here, we present interim results of the dose-expansion phase in ovarian carcinoma (OC), triple-negative breast cancer (TNBC), and castration-resistant prostate cancer (PC). Method(s): Eligibility criteria included age >=18 years, measurable disease, ECOG <=2, adequate organ function, and diagnosis of platinum- and taxane-resistant epithelial OC, taxane-resistant TNBC, or taxane- or cisplatin-etoposide-resistant stage IV PC with neuroendocrine features. AMG 900 was administered at 40 mg daily for 4 consecutive days every 2 weeks with prophylactic G-CSF support (maximum tolerated dose defined in the dose-escalation phase). PK parameters were estimated using data from the dose-escalation and dose-expansion phases of this study. Tumor response was measured per RECIST guidelines for all patients and by Rustin criteria (RECIST + CA-125) for OC patients. Aurora A and B amplification/over-expression and p53 mutational status/amplification were investigated in archival tissue when available. This Amgen-sponsored study (NCT00858377) has completed enrollment. Result(s): As of April 21, 2014, the dose-expansion phase of this study included 46 patients (OC = 24, TNBC = 10, PC = 12). Table 1 shows demographics, treatment-emer

Background: Aurora kinases A and B are oncogenic serine/threonine kinases with distinct, crucial functions in regulation of mitosis and control of the G2 checkpoint. Aurora kinases are amplified and/or over-expressed in many solid tumors and associated with poor prognosis and therapeutic resistance. AMG 900 is an investigational, orally administered, highly potent, selective small molecule pan-aurora inhibitor that has shown activity in taxane-resistant human tumor xenograft models. An open-label, first-inhuman study evaluated the safety, tolerability, pharmacokinetics (PK), and clinical activity of AMG 900 in patients with advanced, treatment-refractory solid tumors. In the dose-escalation phase, AMG 900 showed activity in ovarian and endometrial carcinoma. Here, we present interim results of the dose-expansion phase in ovarian carcinoma (OC), triple-negative breast cancer (TNBC), and castration-resistant prostate cancer (PC). Method(s): Eligibility criteria included age >=18 years, measurable disease, ECOG <=2, adequate organ function, and diagnosis of platinum- and taxane-resistant epithelial OC, taxane-resistant TNBC, or taxane- or cisplatin-etoposide-resistant stage IV PC with neuroendocrine features. AMG 900 was administered at 40 mg daily for 4 consecutive days every 2 weeks with prophylactic G-CSF support (maximum tolerated dose defined in the dose-escalation phase). PK parameters were estimated using data from the dose-escalation and dose-expansion phases of this study. Tumor response was measured per RECIST guidelines for all patients and by Rustin criteria (RECIST + CA-125) for OC patients. Aurora A and B amplification/over-expression and p53 mutational status/amplification were investigated in archival tissue when available. This Amgen-sponsored study (NCT00858377) has completed enrollment. Result(s): As of April 21, 2014, the dose-expansion phase of this study included 46 patients (OC = 24, TNBC = 10, PC = 12). Table 1 shows demographics, treatment-emer

© 2015 Bentham Science Publishers. Burkholderia pseudomallei is the causative agent of melioidosis and represents a potential bioterrorism threat. In this study, the transcriptomic responses of B. pseudomallei infection of a human macrophage cell model were investigated using whole-genome microarrays. Gene expression profiles were compared between infected THP-1 human monocytic leukemia cells with or without treatment with Daboia russelli russelli daboiatoxin (DRRDbTx) or ceftazidime (antibiotic control). Microarray analyses of infected and treated cells revealed differential upregulation of various inflammatory genes such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-a), cyclooxygenase (COX-2), vascular endothelial growth factor (VEGF), chemokine C-X-C motif ligand 4 (CXCL4), transcription factor p65 (NF-kB); and several genes involved in immune and stress responses, cell cycle, and lipid metabolism. Moreover, following DRR-DbTx treatment of infected cells, there was enhanced expression of the tolllike receptor 2 (TLR-2) mediated signaling pathway involved in recognition and initiation of acute inflammatory responses. Importantly, we observed that highly inflammatory cytokine gene responses were similar in infected cells exposed to DRR-DbTx or ceftazidime after 24 h. Additionally, there were increased transcripts associated with cell death by caspase activation that can promote host tissue injury. In summary, the transcriptional responses during B. pseudomallei infection of macrophages highlight a broad range of innate immune mechanisms that are activated within 24 h post-infection. These data provide insights into the transcriptomic kinetics following DRR-DbTx treatment of human macrophages infected with B. pseudomallei.

It is unclear if clinician risk stratification has changed with time. The aim of this study was to assess the temporal change in the concordance between patient presenting risk and the intensity of evidence-based therapies received for nonST-segment elevation acute coronary syndromes over a 9-year period. Data from 3,562 patients with nonST-segment elevation acute coronary syndromes enrolled in the Australian and New Zealand population of the Global Registry of Acute Coronary Events (GRACE) from 1999 to 2007 were analyzed. Patients were stratified to risk groups on the basis of the GRACE risk score for in-hospital mortality. Main outcome measures included in-hospital use of widely accepted evidence-based medications, investigations, and procedures. Invasive management was consistently higher in low-risk patients than in intermediate- or high-risk patients (coronary angiography 66.7% vs 63.5% vs 35.3%, p <0.001; percutaneous coronary intervention 31.1% vs 22.0% vs 12.9%, p <0.001). Absolute rates of angiography and percutaneous coronary intervention in the high-risk group remained 24% and 15% lower compared to the low-risk group in the most recent time period (2005 to 2007). In-hospital use of thienopyridine, lowmolecular weight heparin, and glycoprotein IIb/IIIa inhibitors showed a similar inverse relation with risk. Prescription of aspirin, beta blockers, statins, and angiotensin receptor blockers was inversely related to risk before 2004, although this inverse relation was no longer present in the most recent time period (2005 to 2007). Only in-hospital use of unfractionated heparin showed use concordant with patient risk status. In conclusion, despite an overall increase in the uptake of evidence-based therapies, most investigations and treatments are not targeted on the basis of patient risk. Clinician risk stratification remains suboptimal compared to objective measures of patient risk. © 2011 Elsevier Inc. All rights reserved.

It is unclear if clinician risk stratification has changed with time. The aim of this study was to assess the temporal change in the concordance between patient presenting risk and the intensity of evidence-based therapies received for nonST-segment elevation acute coronary syndromes over a 9-year period. Data from 3,562 patients with nonST-segment elevation acute coronary syndromes enrolled in the Australian and New Zealand population of the Global Registry of Acute Coronary Events (GRACE) from 1999 to 2007 were analyzed. Patients were stratified to risk groups on the basis of the GRACE risk score for in-hospital mortality. Main outcome measures included in-hospital use of widely accepted evidence-based medications, investigations, and procedures. Invasive management was consistently higher in low-risk patients than in intermediate- or high-risk patients (coronary angiography 66.7% vs 63.5% vs 35.3%, p <0.001; percutaneous coronary intervention 31.1% vs 22.0% vs 12.9%, p <0.001). Absolute rates of angiography and percutaneous coronary intervention in the high-risk group remained 24% and 15% lower compared to the low-risk group in the most recent time period (2005 to 2007). In-hospital use of thienopyridine, lowmolecular weight heparin, and glycoprotein IIb/IIIa inhibitors showed a similar inverse relation with risk. Prescription of aspirin, beta blockers, statins, and angiotensin receptor blockers was inversely related to risk before 2004, although this inverse relation was no longer present in the most recent time period (2005 to 2007). Only in-hospital use of unfractionated heparin showed use concordant with patient risk status. In conclusion, despite an overall increase in the uptake of evidence-based therapies, most investigations and treatments are not targeted on the basis of patient risk. Clinician risk stratification remains suboptimal compared to objective measures of patient risk. © 2011 Elsevier Inc. All rights reserved.

The Trail smelter uses an oxygen softening process for partial removal of arsenic and antimony from lead bullion by oxygen injection to form an oxide slag. Levels are reduced to those suitable for input to the Betts electrorefining process. Recent increases in the arsenic content of the feed requiring better arsenic removal and the concomitant need to improve bullion flow rates to maintain heat balance have prompted a study of the thermochemistry and kinetics of the process followed by in-plant trials. The latter showed that increases of 60% in arsenic removal were possible with proper control of the process heat balance., The Trail smelter uses an oxygen softening process for partial removal of arsenic and antimony from lead bullion by oxygen injection to form an oxide slag. Levels are reduced to those suitable for input to the Betts electrorefining process. Recent increases in the arsenic content of the feed requiring better arsenic removal and the concomitant need to improve bullion flow rates to maintain heat balance have prompted a study of the thermochemistry and kinetics of the process followed by in-plant trials. The latter showed that increases of 60% in arsenic removal were possible with proper control of the process heat balance.