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Segelov E.,University of New South Wales | Chan D.,Royal North Shore Hospital | Shapiro J.,Monash University | Price T.J.,University of Adelaide | And 3 more authors.
British Journal of Cancer | Year: 2014

Purpose: Biologic agents have achieved variable results in relapsed metastatic colorectal cancer (mCRC). Systematic meta-analysis was undertaken to determine the efficacy of biological therapy.Methods: Major databases were searched for randomised studies of mCRC after first-line treatment comparing (1) standard treatment plus biologic agent with standard treatment or (2) standard treatment with biologic agent with the same treatment with different biologic agent(s). Data were extracted on study design, participants, interventions and outcomes. Study quality was assessed using the MERGE criteria. Comparable data were pooled for meta-analysis.Results: Twenty eligible studies with 8225 patients were identified. The use of any biologic therapy improved overall survival with hazard ratio (HR) 0.87 (95% confidence interval (CI) 0.82-0.91, P<0.00001), progression-free survival (PFS) with HR 0.71 (95% CI 0.67-0.74, P<0.0001) and overall response rate (ORR) with odds ratio (OR) 2.38 (95% CI 2.03-2.78, P<0.00001). Grade 3/4 toxicity was increased with OR 2.34. Considering by subgroups, EGFR inhibitors (EGFR-I) in the second-line setting and anti-angiogenic therapies (both in second-line and third-line and beyond settings) all improved overall survival, PFS and ORR. EGFR-I in third-line settings improved PFS and ORR but not OS.Conclusions: The use of biologic agents in mCRC after first-line treatment is associated with improved outcomes but increased toxicity. © 2014 Cancer Research UK. All rights reserved.

Wilson S.J.,University of Melbourne | Wilson S.J.,Austin HealthVIC | Baxendale S.,University College London
Epilepsy and Behavior | Year: 2014

There has been considerable debate surrounding the benefits and drawbacks of the new approach to classifying the epilepsies released by the ILAE Commission on Classification and Terminology (2005-2009). This new approach has significant implications for the way we conceptualize and assess cognition and behavior in epilepsy; however, as yet, there has been limited discussion of these issues in the field. The purpose of this Targeted Review is to spark this discussion by encouraging researchers and clinicians to think about the changes that the new approach may bring. These may include (i) reframing the way we think about the comorbidities of epilepsy, (ii) more precisely characterizing the cognitive and behavioral phenotypes of electroclinical syndromes, (iii) more carefully mapping the longitudinal trajectory of cognitive and behavioral features relative to the timing of seizures, and (iv) considering the links between cognitive, behavioral, and neurological phenotypes in the new classification scheme. It is hoped that such changes will aid translation of the advances in cognitive and behavioral neuroscience into routine clinical practice by providing purer markers of disease and more targeted treatments. A Special Issue canvassing such issues will be forthcoming that will consider current knowledge of the cognitive and behavioral features of the epilepsies from the view of the new classification scheme. © 2014.

Lasica M.,Austin HealthVIC | Zantomio D.,Austin HealthVIC
Journal of Clinical Apheresis | Year: 2016

We report on the use of red cell exchange in a case of severe intravenous immune globulin induced hemolysis and pigment nephropathy. Renal impairment and hemoglobinuria were not ameliorated by supportive measures including hydration. Partial red cell exchange with group O blood reduced hemoglobinuria and appeared to stabilize renal function. This is the first report on the use of red cell exchange in this clinical setting. J. Clin. Apheresis 31:464–466, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Osadnik C.R.,Monash University | Osadnik C.R.,Institute for Breathing and SleepVIC | Osadnik C.R.,Monash HealthVIC | Borges R.C.,University of Sao Paulo | And 5 more authors.
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2016

The 6-minute walk test (6MWT) is recommended to be performed twice to accurately assess exercise performance in stable chronic obstructive pulmonary disease (COPD) due to the presence of a learning effect. It is unknown whether a learning effect exists when the 6MWT is performed during hospitalisation for acute exacerbation of COPD (AECOPD). This study investigated whether repeat 6MWTs are necessary when conducted in inpatients with AECOPD. Pooled analysis was undertaken of data from two studies (Australia and Brazil) involving 46 participants (25 males, mean age 67.2 years, FEV1 43% predicted) admitted with AECOPD. Two 6MWTs, separated by ≥20 minutes, were performed on the day of discharge. Six-minute walk distance (6MWD; primary outcome), perceived dyspnoea (Borg scale), heart rate and oxyhaemoglobin saturation were recorded. 6MWD data from tests one (T1) and two (T2) were analysed via visual inspection of Bland-Altman plots. Factors associated with test improvement or decline were explored. Mean 6MWD difference between T1 and T2 was 6.2 m, however limits of agreement were wide (−92.2 m to 104.5 m). 32 (70%) participants improved (by any distance) from T1 to T2 by a mean (± standard deviation) of 32 m ± 28 m. Of these, 14 (30%) improved by a distance > 30 m. Fourteen (30%) participants recorded poorer 6MWD at T2 by a mean of 52 m ± 36 m. No factors were able to identify participants who improved or declined upon repeat testing. When performed in patients admitted to hospital with AECOPD, the 6MWT needs to be conducted twice in order to better estimate 6MWD. © 2016 Taylor & Francis Group, LLC.

Abeyrathne C.D.,University of Melbourne | Huynh D.H.,University of Melbourne | McIntire T.W.,University of Melbourne | Nguyen T.C.,University of Melbourne | And 9 more authors.
Analyst | Year: 2016

The Gram-positive bacterium, Staphylococcus aureus (S. aureus), is a major pathogen responsible for a variety of infectious diseases ranging from cellulitis to more serious conditions such as septic arthritis and septicaemia. Timely treatment with appropriate antibiotic therapy is essential to ensure clinical defervescence and to prevent further complications such as infective endocarditis or organ impairment due to septic shock. To date, initial antibiotic choice is empirical, using a "best guess" of likely organism and sensitivity- an approach adopted due to the lack of rapid identification methods for bacteria. Current culture based methods take up to 5 days to identify the causative bacterial pathogen and its antibiotic sensitivity. This paper provides proof of concept for a biosensor, based on interdigitated electrodes, to detect the presence of S. aureus and ascertain its sensitivity to flucloxacillin rapidly (within 2 hours) in a cost effective manner. The proposed method is label-free and uses non-faradic measurements. This is the first study to successfully employ interdigitated electrodes for the rapid detection of antibiotic resistance. The method described has important potential outcomes of faster definitive antibiotic treatment and more rapid clinical response to treatment. © 2016 The Royal Society of Chemistry.

Malpas C.B.,Royal Melbourne HospitalVIC | Malpas C.B.,University of Melbourne | Malpas C.B.,Royal Melbourne Hospital | Malpas C.B.,Murdoch Childrens Research Institute | And 12 more authors.
Journal of Clinical Neuroscience | Year: 2016

There is growing interest in the neurobiological substrate of general intelligence. Psychometric estimates of general intelligence are reduced in a range of neurological disorders, leading to practical application as sensitive, but non-specific, markers of cerebral disorder. This study examined estimates of general intelligence in neurotypical adults using diffusion tensor imaging and resting-state functional connectivity analysis. General intelligence was related to white matter organisation across multiple brain regions, confirming previous work in older healthy adults. We also found that variation in general intelligence was related to a large functional sub-network involving all cortical lobes of the brain. These findings confirm that individual variance in general intelligence is related to diffusely represented brain networks. © 2015 Elsevier Ltd.

Ameratunga M.,Austin Health | Asadi K.,Austin HealthVIC | Lin X.,Ontario Cancer Institute | Murone C.,Austin HealthVIC | And 7 more authors.
PLoS ONE | Year: 2016

Introduction Immune checkpoint inhibition has shifted treatment paradigms in non-small cell lung cancer (NSCLC). Conflicting results have been reported regarding the immune infiltrate and programmed death-ligand 1 (PD-L1) as a prognostic marker. We correlated the immune infiltrate and PD-L1 expression with clinicopathologic characteristics in a cohort of resected NSCLC. Methods A tissue microarray was constructed using triplicate cores from consecutive resected NSCLC. Immunohistochemistry was performed for CD8, FOXP3 and PD-L1. Strong PD-L1 expression was predefined as greater than 50% tumor cell positivity. Matched nodal samples were assessed for concordance of PD-L1 expression. Results Of 522 patients, 346 were node-negative (N0), 72 N1 and 109 N2; 265 were adenocarcinomas (AC), 182 squamous cell cancers (SCC) and 75 other. Strong PD-L1 expression was found in 24% cases. In the overall cohort, PD-L1 expression was not associated with survival. In patients with N2 disease, strong PD-L1 expression was associated with significantly improved disease-free (DFS) and overall survival (OS) in multivariate analysis (HR 0.49, 95%CI 0.36-0.94, p = 0.031; HR 0.46, 95%CI 0.26-0.80, p = 0.006). In this resected cohort only 5% harboured EGFR mutations, whereas 19% harboured KRAS and 23% other. KRAS mutated tumors were more likely to highly express PD-L1 compared to EGFR (22% vs 3%). A stromal CD8 infiltrate was associated with significantly improved DFS in SCC (HR 0.70, 95%CI 0.50-0.97, p = 0.034), but not AC, whereas FOXP3 was not prognostic. Matched nodal specimens (N = 53) were highly concordant for PD-L1 expression (89%). Conclusion PD-L1 expression was not prognostic in the overall cohort. PD-L1 expression in primary tumor and matched nodal specimens were highly concordant. The observed survival benefit in N2 disease requires confirmation. © 2016 Ameratunga 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.

Chan D.L.,University of Sydney | Pavlakis N.,University of Sydney | Shapiro J.,Monash University | Price T.J.,University of Adelaide | And 3 more authors.
PLoS ONE | Year: 2015

Importance The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC. Objective To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC. Data sources: MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ ESMO conference abstracts. Study Selection Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1) chemotherapy with or without a biological agent or 2) different chemotherapy regimens with the same biological agent. EGFR-I trials were restricted to KRAS exon 2 wild-type (WT) populations. Data Extraction and Synthesis Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria. The primary outcome was overall survival with secondary endpoints progression free survival (PFS), overall response rate (ORR) and toxicity. Results EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81-1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69-0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87-1.09) and PFS HR 0.92 (95% CI 0.83-1.02)). Significant oxaliplatin- irinotecan subgroup interactions were present for PFS with I2 = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72-0.94) compared to capecitabine (HR 1.09; 95% CI 0.91-1.30) and bolus 5FU (HR 1.07; 95% CI 0.79-1.45); subgroup interaction was present with I2 = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan- based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I2 = 89.7%, p = 0.002). Conclusion and Relevance The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs. © 2015 Chan et al.

Villemagne V.L.,Austin HealthVIC | Villemagne V.L.,University of Melbourne | Fodero-Tavoletti M.T.,Austin HealthVIC | Fodero-Tavoletti M.T.,University of Melbourne | And 3 more authors.
The Lancet Neurology | Year: 2015

Use of selective in-vivo tau imaging will enable improved understanding of tau aggregation in the brain, facilitating research into causes, diagnosis, and treatment of major tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. Neuropathological studies of Alzheimer's disease show a strong association between tau deposits, decreased cognitive function, and neurodegenerative changes. Selective tau imaging will allow the in-vivo exploration of such associations and measure the global and regional changes in tau deposits over time. Such imaging studies will comprise non-invasive assessment of the spatial and temporal pattern of tau deposition over time, providing insight into the role tau plays in ageing and helping to establish the relation between cognition, genotype, neurodegeneration, and other biomarkers. Once validated, selective tau imaging might be useful as a diagnostic, prognostic, and progression biomarker, and a surrogate marker for the monitoring of efficacy and patient recruitment for anti-tau therapeutic trials. © 2015 Elsevier Ltd.

Sowerby R.J.,University of Toronto | Gani J.,Austin HealthVIC | Yim H.,University of Toronto | Radomski S.B.,University of Toronto | Catton C.,University of Toronto
Journal of the Canadian Urological Association | Year: 2014

Introduction: Choosing adjuvant radiotherapy (RT) or salvage RT after radical prostatectomy (RP) for locally advanced prostate cancer is controversial. Performing RT early after RP may increase the risk of urinary complications compared to RT performed later. We evaluated the urinary complication rates of men treated with surgery followed by early or late RT. Methods: Using a retrospective chart review, we compared rates of urinary incontinence (UI), bladder neck contracture (BNC), or urethral stricture in men with prostate cancer treated with early RT (<6 months after RP) or late RT (≥6 months after RP), 3 years after RT. Results: In total, 652 patients (between 2000 and 2007) underwent early RT (162, 24.8%) or late RT (490, 75.2%) after RP. The mean time to early RT was 3.6 months (range: 1-5 months) and to late RT was 30.1 months (range: 6-171 months). At 3 years post-RT, UI rates were similar in the early RT and the late RT groups (24.5% vs. 23.3%, respectively, p = 0.79). Prior to RT, 27/652 (4%) patients had a BNC and 11/652 (1.7%) had a urethral stricture, of which only 1 BNC persisted at 3 years post-RT. After RT, 17/652 (2.6%) BNC and 4/652 (0.6%) urethral stricture developed; of these, 6 BNC and 2 urethral strictures persisted at 3 years. Conclusion: Rates of UI, BNC, and urethral stricture were similar with early and late RT at 3 years post-RT. These findings suggest that the timing of RT after RP does not alter the incidences of these urinary complications and can aid in the decision-making process regarding adjuvant RT versus salvage RT. © 2014 Canadian Urological Association.

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