St Leonards, Australia
St Leonards, Australia

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Hamid O.,Angeles Clinic and Research Institute | Robert C.,Institute Gustave Roussy | Daud A.,University of California at San Francisco | Hodi F.S.,Dana-Farber Cancer Institute | And 22 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. METHODS: We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks. RESULTS: A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. CONCLUSIONS: In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. Copyright © 2013 Massachusetts Medical Society.


Jaiswal R.,University of Sydney | Jaiswal R.,University of Technology, Sydney | Gong J.,University of Sydney | Gong J.,University of Technology, Sydney | And 6 more authors.
FASEB Journal | Year: 2012

Drug resistance is a major cause of cancer treatment failure, with multidrug resistance (MDR) being the most serious, whereby cancer cells display cross-resistance to structurally and functionally unrelated drugs. MDR is caused by overexpression of the efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). These transporters act to maintain sublethal intracellular drug concentrations within the cancer cell, making the population treatment unresponsive. Recently, we discovered a novel nongenetic basis to MDR whereby microparticles (MPs) transfer P-gp intercellularly from MDR donor cells to drug-sensitive recipient cells. MPs isolated from MDR leukemia and breast cancer cells were cocultured with their drug-sensitive counterparts. P-gp transfer was assessed by direct immunolabeling, and acquired transcripts and regulatory microRNAs by quantitative real-time PCR. We show that MDR MPs incorporate nucleic acids; MPs change recipient cells'transcriptional environment to reflect donor MDR phenotype, and distinct pathways exist among cancers of different origin that may be dependent on donor cells'ABCB1 overexpression. We demonstrate that this pathway exists for both hematological and nonhematological malignancies. By conferring MDR and "retemplating"the transcriptional landscape of recipient cells, MPs provide a novel pathway, having implications in the dissemination and acquisition of deleterious traits in clinical oncology. © FASEB.


News Article | November 9, 2016
Site: www.sciencedaily.com

Planned births occur where a considered decision is made to deliver an infant, and in recent years there have been significant changes in clinical practice resulting in an increase in planned births before the ideal time of birth at 39-40 weeks' gestation. This is mostly attributable to the increased use of elective caesarean section and induction of labour. The study of 153,000 Australian children published today in Pediatrics reports that overall, 9.6 per cent of children were developmentally high risk. In particular, infants born following planned birth before the optimal time of birth were more likely to have poor child development. Using the Australian Early Development Census instrument, children in the study were assessed in five domains: physical health and wellbeing, language and cognition, social competence, emotional maturity, and general knowledge and communication. Children scoring in the bottom 10 per cent of these domains were considered 'developmentally vulnerable', and children who were 'developmentally vulnerable' on two or more domains were classified as 'developmentally high risk'. Compared to children born vaginally following spontaneous labor, the combined adjusted relative risk of being 'developmentally high risk' was 26 per cent higher for a planned birth at 37 weeks and 13 per cent higher at 38 weeks. This is after taking account other important factors associated with poor child development such as socioeconomic disadvantage, lower maternal age, maternal smoking in pregnancy and fetal growth restriction. "The timing of planned birth is potentially modifiable, and the benefits of waiting should be communicated to clinicians, mothers and families," says study co-author, Dr Jonathan Morris of the Kolling Institute and the University of Sydney. The study also reports that the risk of being 'developmentally vulnerable' increased with decreasing gestational age. Compared to children with a gestational age of 40 weeks, the adjusted relative risk of being 'developmentally high risk' was 25 per cent higher at 32-33 weeks, 26 per cent higher at 34-36 weeks, 17 per cent higher at 37 weeks, and six per cent higher at 38 weeks. Compared to children born vaginally following spontaneous labor, the adjusted relative risk of being 'developmentally high risk' was seven per cent higher for labor induction or pre-labor cesarean section. The study's senior author, Associate Professor Natasha Nassar from the University of Sydney Menzies Centre for Health Policy said: "While the association between being born earlier -- lower gestational age -- and poorer developmental outcomes is well established, our results revealed that poor development is further exacerbated in the case of planned birth, where a considered decision made to deliver an infant determines gestational age. "Significant changes in clinical practice have seen an increase in planned births before 39-40 completed weeks' gestation from an increased use of primary and repeat cesarean section and a greater use of labor induction. At a population level this has resulted in a decrease in modal gestational age with planned birth accounting for almost half of births before 39-40 weeks. It is of paramount importance to ensure there are no unintended harms from such a significant shift in clinical practice." The study's lead author, Mr Jason Bentley from the Menzies Centre for Health Policy commented: "There is an urgent need for strategies to inform more judicious clinical decision making about the timing of planned birth." "In cases where labor occurs naturally before 39 weeks or planned birth is unavoidable, it is important that there are appropriate interventions and support in early childhood for these potentially vulnerable children."


News Article | November 7, 2016
Site: www.eurekalert.org

Planned births occur where a considered decision is made to deliver an infant, and in recent years there have been significant changes in clinical practice resulting in an increase in planned births before the ideal time of birth at 39-40 weeks' gestation. This is mostly attributable to the increased use of elective caesarean section and induction of labour. The study of 153,000 Australian children published today in Pediatrics reports that overall, 9.6 per cent of children were developmentally high risk. In particular, infants born following planned birth before the optimal time of birth were more likely to have poor child development. Using the Australian Early Development Census instrument, children in the study were assessed in five domains: physical health and wellbeing, language and cognition, social competence, emotional maturity, and general knowledge and communication. Children scoring in the bottom 10 per cent of these domains were considered 'developmentally vulnerable', and children who were 'developmentally vulnerable' on two or more domains were classified as 'developmentally high risk'. Compared to children born vaginally following spontaneous labor, the combined adjusted relative risk of being 'developmentally high risk' was 26 per cent higher for a planned birth at 37 weeks and 13 per cent higher at 38 weeks. This is after taking account other important factors associated with poor child development such as socioeconomic disadvantage, lower maternal age, maternal smoking in pregnancy and fetal growth restriction. "The timing of planned birth is potentially modifiable, and the benefits of waiting should be communicated to clinicians, mothers and families," says study co-author, Dr Jonathan Morris of the Kolling Institute and the University of Sydney. The study also reports that the risk of being 'developmentally vulnerable' increased with decreasing gestational age. Compared to children with a gestational age of 40 weeks, the adjusted relative risk of being 'developmentally high risk' was 25 per cent higher at 32-33 weeks, 26 per cent higher at 34-36 weeks, 17 per cent higher at 37 weeks, and six per cent higher at 38 weeks. Compared to children born vaginally following spontaneous labor, the adjusted relative risk of being 'developmentally high risk' was seven per cent higher for labor induction or pre-labor cesarean section. The study's senior author, Associate Professor Natasha Nassar from the University of Sydney Menzies Centre for Health Policy said: "While the association between being born earlier - lower gestational age - and poorer developmental outcomes is well established, our results revealed that poor development is further exacerbated in the case of planned birth, where a considered decision made to deliver an infant determines gestational age. "Significant changes in clinical practice have seen an increase in planned births before 39-40 completed weeks' gestation from an increased use of primary and repeat cesarean section and a greater use of labor induction. At a population level this has resulted in a decrease in modal gestational age with planned birth accounting for almost half of births before 39-40 weeks. It is of paramount importance to ensure there are no unintended harms from such a significant shift in clinical practice." The study's lead author, Mr Jason Bentley from the Menzies Centre for Health Policy commented: "There is an urgent need for strategies to inform more judicious clinical decision making about the timing of planned birth." "In cases where labor occurs naturally before 39 weeks or planned birth is unavoidable, it is important that there are appropriate interventions and support in early childhood for these potentially vulnerable children."


Melrose J.,Kolling Institute | Melrose J.,University of Sydney | Melrose J.,University of New South Wales
Regenerative Medicine | Year: 2016

The intervertebral disc (IVD) is a major weight bearing structure that undergoes degenerative changes with aging limiting its ability to dissipate axial spinal loading in an efficient manner resulting in the generation of low back pain. Low back pain is a number one global musculoskeletal disorder with massive socioeconomic impact. The WHO has nominated development of mesenchymal stem cells and bioscaffolds to promote IVD repair as primary research objectives. There is a clear imperative for the development of strategies to effectively treat IVD defects. Early preclinical studies with mesenchymal stem cells in canine and ovine models have yielded impressive results in IVD repair. Combinatorial therapeutic approaches encompassing biomaterial and cell-based therapies promise significant breakthroughs in IVD repair in the near future. © 2016 Future Medicine Ltd.


Goncalves-Bradley D.C.,University of Oxford | Lannin N.A.,Alfred Health | Clemson L.M.,University of Sydney | Cameron I.D.,Kolling Institute | Shepperd S.,University of Oxford
Cochrane Database of Systematic Reviews | Year: 2016

Background: Discharge planning is a routine feature of health systems in many countries. The aim of discharge planning is to reduce hospital length of stay and unplanned readmission to hospital, and to improve the co-ordination of services following discharge from hospital.This is the third update of the original review. Objectives: To assess the effectiveness of planning the discharge of individual patients moving from hospital. Search methods: We updated the review using the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE, EMBASE, CINAHL, the Social Science Citation Index (last searched in October 2015), and the US National Institutes of Health trial register (ClinicalTrials.gov). Selection criteria: Randomised controlled trials (RCTs) that compared an individualised discharge plan with routine discharge care that was not tailored to individual participants. Participants were hospital inpatients. Data collection and analysis: Two authors independently undertook data analysis and quality assessment using a pre-designed data extraction sheet. We grouped studies according to patient groups (elderly medical patients, patients recovering from surgery, and those with a mix of conditions) and by outcome. We performed our statistical analysis according to the intention-to-treat principle, calculating risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous data using fixed-effect meta-analysis. When combining outcome data was not possible because of differences in the reporting of outcomes, we summarised the reported data in the text. Main results: We included 30 trials (11,964 participants), including six identified in this update. Twenty-one trials recruited older participants with a medical condition, five recruited participants with a mix of medical and surgical conditions, one recruited participants from a psychiatric hospital, one from both a psychiatric hospital and from a general hospital, and two trials recruited participants admitted to hospital following a fall. Hospital length of stay and readmissions to hospital were reduced for participants admitted to hospital with a medical diagnosis and who were allocated to discharge planning (length of stay MD - 0.73, 95% CI - 1.33 to - 0.12, 12 trials, moderate certainty evidence; readmission rates RR 0.87, 95% CI 0.79 to 0.97, 15 trials, moderate certainty evidence). It is uncertain whether discharge planning reduces readmission rates for patients admitted to hospital following a fall (RR 1.36, 95% CI 0.46 to 4.01, 2 trials, very low certainty evidence). For elderly patients with a medical condition, there was little or no difference between groups for mortality (RR 0.99, 95% CI 0.79 to 1.24, moderate certainty). There was also little evidence regarding mortality for participants recovering from surgery or who had a mix of medical and surgical conditions. Discharge planning may lead to increased satisfaction for patients and healthcare professionals (low certainty evidence, six trials). It is uncertain whether there is any difference in the cost of care when discharge planning is implemented with patients who have a medical condition (very low certainty evidence, five trials). Authors' conclusions: A discharge plan tailored to the individual patient probably brings about a small reduction in hospital length of stay and reduces the risk of readmission to hospital at three months follow-up for older people with a medical condition. Discharge planning may lead to increased satisfaction with healthcare for patients and professionals. There is little evidence that discharge planning reduces costs to the health service. © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


Malhi G.S.,Kolling Institute | Malhi G.S.,University of Sydney | Malhi G.S.,Royal North Shore Hospital
Evidence-Based Mental Health | Year: 2015

Antidepressants are widely used in the treatment of bipolar depression despite relatively meagre evidence for their efficacy and significant concerns that their prescription can precipitate an acute affective switch into mania/hypomania and that long-term administration can lead to mood instability. Therefore, the use of antidepressants to treat bipolar depression is an important but contentious issue that two recent studies, which provide important new evidence, attempt to inform. One study suggests that long-term continuation of antidepressants in patients with rapid-cycling bipolar disorder leads to a threefold increase in mood episodes during the first year of follow-up—supporting the notion that antidepressants can cause more harm than good, and that they should be used sparingly. However, this is countered by findings from the other study, which suggests that continuation antidepressant monotherapy provides patients with bipolar II disorder reasonable prophylaxis, and that the risk of switching into mania/ hypomania is actually quite low. In addition to contrary findings both studies are modest in sample sizes and have significant design limitations and hence the debate remains unresolved. This brief perspective presents both views in the context of evidence and provides some key insights into the complexity of this challenging but common clinical issue. © 2015, BMJ Publishing Group. All rights reserved.


Nippita T.A.,Kolling Institute | Nippita T.A.,University of Sydney | Nippita T.A.,Royal North Shore Hospital | Lee Y.Y.,Kolling Institute | And 7 more authors.
BJOG: An International Journal of Obstetrics and Gynaecology | Year: 2015

Objective To explore the variation in hospital caesarean section (CS) rates for nulliparous women, to determine whether different case-mix, labour and delivery, and hospital factors can explain this variation and to examine the association between hospital CS rates and outcomes. Design Population-based cohort study. Setting New South Wales, 2009-2010. Population Nulliparous women with singleton cephalic live births at term. Methods Random effect multilevel logistic regression models using linked hospital discharge and birth data. Main outcome measures Prelabour and intrapartum CS rates following spontaneous labour or labour induction; maternal and neonatal severe morbidity rates. Results Of 67 239 nulliparous women, 4902 (7.3%) had a prelabour CS, 39 049 (58.1%) laboured spontaneously, and 23 288 (34.6%) had labour induced. Overall, there were 18 875 (28.1%) CSs, with labour inductions twice as likely to result in an intrapartum CS compared with women with a spontaneous onset of labour (34.0% versus 15.5%). After adjusting for differences in case-mix, labour and delivery, and hospital factors, the overall variation in CS rates decreased by 78% for prelabour CSs, 52% for intrapartum CSs following spontaneous labour and 9% following labour induction. Adjusting for labour and delivery practices increased the unexplained variation in intrapartum CSs. The adjusted rates of severe maternal and neonatal morbidity were not significantly different across CS rate quintile groups, except for women in spontaneous labour, where the hospitals in the lowest CS quintile had the lowest neonatal morbidity rate. Conclusions Differences in clinical practice were substantial contributors to variation in intrapartum CS rates. Our findings suggest that CS rates in some hospitals could be lowered without adversely affect pregnancy outcomes. © 2015 Royal College of Obstetricians and Gynaecologists.


Harkness L.M.,University of Sydney | Ashton A.W.,Kolling Institute | Burgess J.K.,University of Sydney
Pharmacology and Therapeutics | Year: 2015

Multiple studies have identified an expansion and morphological dysregulation of the bronchial vascular network in the airways of asthmatics. Increased number, size and density of blood vessels, as well as vascular leakage and plasma engorgement, have been reported in the airways of patients with all grades of asthma from mild to fatal. This neovascularisation is an increasingly commonly reported feature of airway remodelling; however, the pathophysiological impact of the increased vasculature in the bronchial wall and its significance to pulmonary function in asthma are unrecognised at this time. Multiple factors capable of influencing the development and persistence of the vascular network exist within asthmatic airway tissue. These include structural components of the altered extracellular matrix (ECM), imbalance of proteases and their endogenous inhibitors, release of active matrikines and the dysregulated levels of both soluble and matrix sequestered growth factors. This review will explore the features of the asthmatic airway which influence the development and persistence of the increased vascular network, as well as the effect of enhanced tissue perfusion on chronic inflammation and airway dynamics. The response of cells of the airways to the altered vascular profile and the subsequent influence on the features of airway remodelling will also be highlighted. We will explore the failure of current asthma therapeutics in "normalising" this vascular remodelling. Finally, we will summarize the outcomes of recent clinical trials which provide hope that anti-angiogenic therapies may be a potent asthma-resolving class of drugs and provide a new approach to asthma management in the future. © 2014 Elsevier Inc.


McLean A.K.,University of Sydney | Stewart C.,University of Sydney | Kerridge I.,University of Sydney | Kerridge I.,Royal North Shore Hospital | Kerridge I.,Kolling Institute
Stem Cell Research and Therapy | Year: 2015

An increasing number of private clinics in Australia are marketing and providing autologous stem cell therapies to patients. Although advocates point to the importance of medical innovation and the primacy of patient choice, these arguments are unconvincing. First, it is a stark truth that these clinics are flourishing while the efficacy and safety of autologous stem cell therapies, outside of established indications for hematopioetic stem cell transplantation, are yet to be shown. Second, few of these therapies are offered within clinical trials. Third, patients with chronic and debilitating illnesses, who are often the ones who take up these therapies, incur significant financial burdens in the expectation of benefiting from these treatments. Finally, the provision of these stem cell therapies does not follow the established pathways for legitimate medical advancement. We argue that greater regulatory oversight and professional action are necessary to protect vulnerable patients and that at this time the provision of unproven stem cell therapies outside of clinical trials is unethical. © 2015 McLean et al.; licensee BioMed Central.

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