Publications by authors named "Helen Wheeler"

69 Publications

A randomized phase II trial of veliparib, radiotherapy and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study.

Neuro Oncol 2021 May 13. Epub 2021 May 13.

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.

Background: Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O 6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly ADP-ribose polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.

Methods: VERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the 6-month progression-free survival (PFS-6m) in the experimental arm.

Results: A total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36-57%) in the experimental arm and 31% (95% CI: 18-46%) in the standard arm. Median OS was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.

Conclusion: The veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.
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http://dx.doi.org/10.1093/neuonc/noab111DOI Listing
May 2021

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.

Acta Neuropathol 2021 Jun 19;141(6):945-957. Epub 2021 Mar 19.

Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1 mutations. Patients harbouring IDH1 mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1 have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1 mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.
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http://dx.doi.org/10.1007/s00401-021-02291-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113211PMC
June 2021

Are In Vitro Human Blood-Brain-Tumor-Barriers Suitable Replacements for In Vivo Models of Brain Permeability for Novel Therapeutics?

Cancers (Basel) 2021 Feb 25;13(5). Epub 2021 Feb 25.

Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW 2065, Australia.

Background: High grade gliomas (HGG) are incapacitating and prematurely fatal diseases. To overcome the poor prognosis, novel therapies must overcome the selective and restricted permeability of the blood-brain barrier (BBB). This study critically evaluated whether in vitro human normal BBB and tumor BBB (BBTB) are suitable alternatives to "gold standard" in vivo models to determine brain permeability.

Methods: A systematic review utilizing the PRISMA guidelines used English and full-text articles from the past 5 years in the PubMed, Embase, Medline and Scopus databases. Experimental studies employing human cell lines were included.

Results: Of 1335 articles, the search identified 24 articles for evaluation after duplicates were removed. Eight in vitro and five in vivo models were identified with the advantages and disadvantages compared within and between models, and against patient clinical data where available. The greatest in vitro barrier integrity and stability, comparable to in vivo and clinical permeability data, were achieved in the presence of all cell types of the neurovascular unit: endothelial cells, astrocytes/glioma cells, pericytes and neurons.

Conclusions: In vitro co-culture BBB models utilizing stem cell-derived or primary cells are a suitable proxy for brain permeability studies in order to reduce animal use in medical research.
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http://dx.doi.org/10.3390/cancers13050955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956470PMC
February 2021

Clinical impact of molecular point-of-care testing for suspected COVID-19 in hospital (COV-19POC): a prospective, interventional, non-randomised, controlled study.

Lancet Respir Med 2020 12 8;8(12):1192-1200. Epub 2020 Oct 8.

School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK. Electronic address:

Background: The management of the COVID-19 pandemic is hampered by long delays associated with centralised laboratory PCR testing. In hospitals, these delays lead to poor patient flow and nosocomial transmission. Rapid, accurate tests are therefore urgently needed in preparation for the next wave of the pandemic.

Methods: We did a prospective, interventional, non-randomised, controlled study of molecular point-of-care testing in patients aged 18 years or older presenting with suspected COVID-19 to the emergency department or other acute areas of Southampton General Hospital during the first wave of the pandemic in the UK. Nose and throat swab samples taken at admission from patients in the point-of-care testing group were tested with the QIAstat-Dx Respiratory SARS-CoV-2 Panel. Samples taken from patients in a contemporaneous control group were tested by laboratory PCR. The primary outcome was time to results in the full cohort. This study is registered with ISRCTN (ISRCTN14966673) and is completed.

Findings: Between March 20 and April 29, 2020, 517 patients were assessed for eligibility, of whom 499 were recruited to the point-of-care testing group and tested by the QIAstat-Dx Respiratory SARS-CoV-2 Panel. 555 contemporaneously identified patients were included in the control group and tested by laboratory PCR. The two groups were similar with regard to the distribution of sex, age, and ethnicity. 197 (39%) patients in the point-of-care testing group and 155 (28%) in the control group tested positive for COVID-19 (difference 11·5% [95% CI 5·8-17·2], p=0·0001). Median time to results was 1·7 h (IQR 1·6-1·9) in the point-of-care testing group and 21·3 h (16·0-27·9) in the control group (difference 19·6 h [19·0-20·3], p<0·0001). A Cox proportional hazards regression model controlling for age, sex, time of presentation, and severity of illness also showed that time to results was significantly shorter in the point-of-care testing group than in the control group (hazard ratio 4023 [95% CI 545-29 696], p<0·0001).

Interpretation: Point-of-care testing is associated with large reductions in time to results and could lead to improvements in infection control measures and patient flow compared with centralised laboratory PCR testing.

Funding: University Hospitals Southampton NHS Foundation Trust.
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http://dx.doi.org/10.1016/S2213-2600(20)30454-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544498PMC
December 2020

Clinical characteristics, symptoms and outcomes of 1054 adults presenting to hospital with suspected COVID-19: A comparison of patients with and without SARS-CoV-2 infection.

J Infect 2020 12 28;81(6):937-943. Epub 2020 Sep 28.

School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS, Foundation Trust, Southampton, UK; NIHR Post Doctoral Fellowship Programme, UK.

Objectives: Most reports describing the characteristics of patients hospitalised with COVID-19 lack a comparator group. We compared clinical characteristics, symptoms, and outcomes of adults presenting to hospital during the pandemic first wave, who tested positive and negative for SARS-CoV-2.

Methods: Detailed patient data was obtained from a large, controlled, non-randomised trial of molecular point-of-care testing versus laboratory RT-PCR for SARS-CoV-2 in adults presenting to a large UK hospital with suspected COVID-19.

Results: 1054 patients were included: 352 (33.4%) tested positive and 702 (66.6%) negative. 13.4% (47/352) COVID-19-positive patients had COPD versus 18.7% (131/702) of COVID-19-negative patients (difference=5.3% [95%CI -9.7% to -0.5%], p = 0.0297). 5.7% (20/352) of COVID-19-positive patients were smokers versus 16.5% (116/702) of negative patients (difference=-10.8% [-14.4% to -7.0%], p = 0.0001). 70.5% (248/352) of COVID-19-positive patients were White-British versus 85.5% (600/702) of negative patients (difference=-15.0% [-20.5% to -9.7%], p<0.0001). 20.9% (39/187) of COVID-19-positive patients were healthcare workers versus 5.2% (15/287) of negative patients (p<0.0001). Anosmia was reported in 33.1% (47/142) versus 8.8% (19/216) of COVID-19-positive and negative patients respectively (p<0.0001). Non-SARS-CoV-2 respiratory viruses or atypical bacteria were detected in 2.5% (5/197) of COVID-19 patients versus 7.9% (24/302) of COVID-19-negative patients (p = 0.0109). Hospitalisation duration and 30-day-mortality were higher in COVID-19 patients and invasive ventilation was more frequent (11.1% vs 2.8%, p<0.0001), and longer (14.5 vs 4.7 days, p = 0.0015).

Conclusions: There were substantial differences between patients with and without COVID-19 in terms of ethnicity, healthcare worker-status, comorbidities, symptoms, and outcomes. These data can inform healthcare planning for the next phase of the pandemic.
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http://dx.doi.org/10.1016/j.jinf.2020.09.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521430PMC
December 2020

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Cell Rep Med 2020 Jun;1(3)

Departments of Pediatrics, Anatomy, and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA.

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
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http://dx.doi.org/10.1016/j.xcrm.2020.100038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394286PMC
June 2020

Modelling patient flows and resource use within a sexual health clinic through discrete event simulation to inform service redesign.

BMJ Open 2020 07 8;10(7):e037084. Epub 2020 Jul 8.

Population Health Sciences, University of Bristol, Bristol, UK.

Objectives: Continuous improvement in the delivery of health services is increasingly being demanded in the UK at a time when budgets are being cut. Simulation is one approach used for understanding and assessing the likely impact of changes to the delivery of health services. However, little is known about the usefulness of simulation for analysing the delivery of sexual health services (SHSs). We propose a simulation method to model and evaluate patient flows and resource use within an SHS to inform service redesign.

Methods: We developed a discrete event simulation (DES) model to identify the bottlenecks within the Unity SHS (Bristol, UK) and find possible routes for service improvement. Using the example of the introduction of an online service for sexually transmitted infection (STI) and HIV self-sampling for asymptomatic patients, the impact on patient waiting times was examined as the main outcome measure. The model included data such as patient arrival time, staff availability and duration of consultation, examination and treatment. We performed several sensitivity analyses to assess uncertainty in the model parameters.

Results: We identified some bottlenecks under the current system, particularly in the consultation and treatment queues for male and female walk-in patients. Introducing the provision of STI and HIV self-sampling alongside existing services decreased the average waiting time (88 vs 128 min) for all patients and reduced the cost of staff time for managing each patient (£72.64 vs £88.74) compared with the current system without online-based self-sampling.

Conclusions: The provision of online-based STI and HIV self-sampling for asymptomatic patients could be beneficial in reducing patient waiting times and the model highlights the complexities of using this to cut costs. Attributing recognition for any improvement requires care, but DES modelling can provide valuable insights into the design of SHSs ensuing in quantifiable improvements. Extension of this method with the collection of additional data and the construction of more informed models seems worthwhile.
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http://dx.doi.org/10.1136/bmjopen-2020-037084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348479PMC
July 2020

Diagnostic accuracy of the FebriDx host response point-of-care test in patients hospitalised with suspected COVID-19.

J Infect 2020 10 21;81(4):607-613. Epub 2020 Jun 21.

Southampton Clinical Trials Unit, University of Southampton, UK.

Introduction: Management of the COVID-19 pandemic is hampered by long delays associated with centralised laboratory PCR testing. In hospitals this leads to poor patient flow and nosocomial transmission and so rapid, accurate diagnostic tests are urgently required. The FebriDx is a point-of-care test that detects an antiviral host response protein in finger prick blood within 10 min, but its accuracy for the identification of COVID-19 is unknown.

Methods: We performed a real-world diagnostic accuracy study of FebriDx in hospitalised patients during the first wave of the pandemic. Measures of diagnostic accuracy were calculated based on FebriDx results compared to the reference standard of SARS-CoV-2 PCR on combined nose and throat swabs. A multivariable predictive model including FebriDx, age, sex, and clinical characteristics was developed and underwent internal validation.

Results: FebriDx was performed on 251 patients and gave a valid result in 248. 118 of 248 (48%) were PCR positive for COVID-19. FebriDx results were available after 10 min compared with 1.7 (1.6 to 2.1) hours with point-of-care PCR testing and 23.4 (17.2 to 31.1) hours with laboratory PCR testing. Sensitivity of FebriDx for the identification of COVID-19 was 93% (110/118; 95% CI 87 to 97%) and specificity was 86% (112/130; 95%CI 79 to 92%). Positive and negative likelihood ratios were 6.73 (95%CI 4.37 to 10.37) and 0.08 (95%CI 0.04 to 0.15) respectively. In the multivariate model age, sex and other clinical features did not contribute significantly to the effect of the FebriDx result in distinguishing patients with and without COVID-19.

Conclusions: During the first wave of the pandemic, FebriDx had high accuracy for the identification of COVID-19 in hospitalised adults and could be deployed as a front door triage tool.

Trial Registration: ISRCTN14966673.
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http://dx.doi.org/10.1016/j.jinf.2020.06.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306108PMC
October 2020

Anti-epidermal growth factor receptor therapy for glioblastoma in adults.

Cochrane Database Syst Rev 2020 May 12;5:CD013238. Epub 2020 May 12.

Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia.

Background: Glioblastoma is an uncommon but highly aggressive type of brain tumour. Significant gains have been achieved in the molecular understanding and the pathogenesis of glioblastomas, however clinical improvements are difficult to obtain for many reasons. The current standard of care involves maximal safe surgical resection followed by chemoradiation and then adjuvant chemotherapy European Organisation for Research and Treatment of Cancer and the NCIC Clinical Trials Group (EORTC-NCIC) protocol with a median survival of 14.6 months. Successive phase III international randomised controlled studies have failed to significantly demonstrate survival advantage with newer drugs. Epidermal growth factor receptor (EGFR) is observed to be aberrant in 30% to 60% of glioblastomas. The receptor aberrancy is driven by abnormal gene amplification, receptor mutation, or both, in particular the extracellular vIII domain. EGFR abnormalities are common in solid tumours, and the advent of anti-EGFR therapies in non-small cell lung cancer and colorectal adenocarcinomas have greatly improved clinical outcomes. Anti-EGFR therapies have been investigated amongst glioblastomas, however questions remain about its ongoing role in glioblastoma management. This review aimed to report on the available evidence to date and perform a systematic analysis on the risks and benefits of use of anti-EGFR therapies in glioblastomas.

Objectives: To evaluate the efficacy and harms of anti-EGFR therapies for glioblastoma in adults.

Search Methods: We searched CENTRAL, MEDLINE, Embase, EBM Reviews databases, with supplementary handsearches to identify all available and relevant studies to 20 April 2020.

Selection Criteria: All randomised controlled trials (RCTs) using anti-EGFR therapies in adults with glioblastoma were eligible for inclusion. Anti-EGFR therapies included tyrosine kinase inhibitors, monoclonal antibodies, or vaccines. The comparison included investigational product added to standard of care versus standard of care or placebo, or investigational product against standard of care or placebo.

Data Collection And Analysis: The authorship team screened the search results and recorded the extracted data for analysis. We used standard Cochrane methodology to performed quantitative meta-analysis if two or more studies had appropriate and available data. Otherwise, we conducted a qualitative and descriptive analysis. We used the GRADE system to rate the certainty of the evidence. The analysis was performed along the two clinical settings: first-line (after surgery) and recurrent disease (after failure of first line treatment). Where information was available, we documented overall survival, progression-free survival, adverse events, and quality of life data from eligible studies.

Main Results: The combined searches initially identified 912 records (after removal of duplicates), and further screening resulted in 19 records for full consideration. We identified nine eligible studies for inclusion in the review. There were three first-line studies and six recurrent studies. Five studies used tyrosine kinase inhibitors (TKIs); two studies used monoclonal antibodies; and two studies used targeted vaccines. More recent studies presented greater detail in the conduct of their studies and thus had a lower risk of bias. We observed no evidence benefit in overall survival with the use of anti-EGFR therapy in the first-line or recurrent setting (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76 to 1.04; 3 RCTs, 1000 participants, moderate-certainty evidence; and HR 0.79, 95% CI 0.51 to 1.21, 4 RCTs, 489 participants, low-certainty evidence, respectively). All the interventions were generally well tolerated with low-certainty evidence for lymphopenia (odds ratio (OR) 0.97, 95% CI 0.19 to 4.81; 4 RCTs, 1146 participants), neutropenia (OR 1.29, 95% CI 0.82 to 2.03; 4 RCTs, 1146 participants), and thrombocytopenia (OR 3.69, 95% CI 0.51 to 26.51; 4 RCTs, 1146 participants). A notable toxicity relates to ABT-414, where significant ocular issues were detected. The addition of anti-EGFR therapy showed no evidence of an increase in progression-free survival (PFS) in the first-line setting (HR 0.94, 95% CI 0.81 to 1.10; 2 RCTs, 894 participants, low-certainty evidence). In the recurrent setting, there was an increase in PFS with the use of anti-EGFR therapy (HR 0.75, 95% CI 0.58 to 0.96, 3 RCTs, 275 participants, low-certainty evidence). The available quality of life assessment data showed that anti-EGFR therapies were neither detrimental or beneficial when compared to standard care (not estimable).

Authors' Conclusions: In summary, there is no evidence of a demonstrable overall survival benefit with the addition of anti-EGFR therapy in first-line and recurrent glioblastomas. Newer drugs that are specially designed for glioblastoma targets may raise the possibility of success in this population, but data are lacking at present. Future studies should be more selective in pursuing people displaying specific EGFR targets.
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http://dx.doi.org/10.1002/14651858.CD013238.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389448PMC
May 2020

Ongoing improvements in postoperative survival of glioblastoma in the temozolomide era: a population-based data linkage study.

Neurooncol Pract 2020 Jan 6;7(1):22-30. Epub 2019 Jul 6.

Cancer Institute NSW, Sydney, Australia.

Background: Translating outcomes achieved by clinical trials into routine care is crucial to improving outcomes of glioblastoma (GBM). This study examines the extent to which an advance in treatment for GBM has translated into meaningful, population-level survival benefits in New South Wales (NSW), Australia.

Methods: This retrospective cohort study used linked population-based cancer registry, admitted patient, and mortality datasets. The cohort (n = 2604) included NSW residents aged ≥18 years with a histologically confirmed GBM and a surgical resection between July 2001 and December 2012. The study outcome was all-cause survival, examined using multivariable proportional hazard models. The main study factor was period of surgery, categorized into 4 periods corresponding to different eras in temozolomide (TMZ) use. Survival was examined over time by age (≤70 and >70 years) and for a subcohort selected to approximate the seminal European Organisation for Research and Treatment of Cancer (Stupp) protocol trial cohort. TMZ use was estimated using aggregate prescription claims data.

Results: Median survival in 2001-2003, 2004-2006, 2007-2009, and 2010-2012 was 7.4, 9.0, 9.8, and 10.6 months, and risk-adjusted 2-year survival was 8.2%, 13.8%, 15.5%, and 18.3%, respectively. Survival improved for those aged ≤70 years and those aged >70 years. In the proxy trial subcohort, median and 2-year survival were 14.3 months and 27.3%, respectively. The volume of TMZ prescribed annually increased rapidly from 2005.

Conclusions: Introduction of TMZ into standard care in 2005 coincided with improvements in survival and a rapid increase in TMZ prescribing. Optimization of care has continued to improve survival of people with GBM in subsequent years.
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http://dx.doi.org/10.1093/nop/npz021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104886PMC
January 2020

Temporal and spatial modulation of the tumor and systemic immune response in the murine Gl261 glioma model.

PLoS One 2020 2;15(4):e0226444. Epub 2020 Apr 2.

Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, The University of Sydney Northern Clinical School and Northern Sydney Local Health District, St Leonards, NSW, Australia.

Glioblastoma, the most aggressive form of glioma, has a 5-year survival rate of <5%. While radiation and immunotherapies are routinely studied in the murine Gl261 glioma model, little is known about its inherent immune response. This study quantifies the temporal and spatial localization of immune cell populations and mediators during glioma development. Eight-week old male C57Bl/6 mice were orthotopically inoculated with 1x106 Gl261 cells and tumor morphology, local and systemic immune cell populations, and plasma cytokines/chemokines assessed at day 0, 1, 3, 7, 14, and 21 post-inoculation by magnetic resonance imaging, chromogenic immunohistochemistry, multiplex immunofluorescent immunohistochemistry, flow cytometry and multiplex immunoassay respectively. From day 3 tumors were distinguishable with >30% Ki67 and increased tissue vascularization (p<0.05). Increasing tumor proliferation/malignancy and vascularization were associated with significant temporal changes in immune cell populations within the tumor (p<0.05) and systemic compartments (p = 0.02 to p<0.0001). Of note, at day 14 16/24 plasma cytokine/chemokines levels decreased coinciding with an increase in tumor cytotoxic T cells, natural killer and natural killer/T cells. Data derived provide baseline characterization of the local and systemic immune response during glioma development. They reveal that type II macrophages and myeloid-derived suppressor cells are more prevalent in tumors than regulatory T cells, highlighting these cell types for further therapeutic exploration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226444PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117758PMC
July 2020

The role of large volume re-irradiation with Bevacizumab in chemorefractory high grade glioma.

Clin Transl Radiat Oncol 2020 May 9;22:33-39. Epub 2020 Mar 9.

Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, Australia.

Background And Purpose: Current practice in re-irradiation (reRT) of previously treated high-grade gliomas (HGG) has generally been limited to small volume reRT with stereotactic procedures. Less evidence exists for large volume reRT involving treatment volumes equivalent to that used at initial diagnosis. The primary aim of this study was to investigate the outcome of large volume reRT delivered in combination with Bevacizumab (BEV) in patients with recurrent chemorefractory HGG.

Methods And Materials: Patients with HGG managed with reRT were entered prospectively into a database. Clinicopathological features were recorded including timing of reRT, use of BEV and Dosimetric data. Median survival following reRT was the primary endpoint and association with clinicopathological factors was assessed with cox regression models.

Results: Sixty seven patients in total were managed with reRT, 51 patients had glioblastoma and 16 had anaplastic glioma. The median PTV was 145.3 cm. Median OS post reRT was 7.8 months (95% CI 6.3-9.2 months) in the total cohort and 7.5 months (95% CI: 6.6-8.3 months) for GBM patients. In multivariate analysis of the whole cohort, IDH1 mutation status (p = 0.041) and ECOG status prior to reRT (<0.001) were significantly associated with OS. In terms of safety and toxicity, the majority of patients (66.5%) were ECOG 0-2 three months after treatment. In total, four episodes of suspected radiation necrosis occurred, all in patients treated without upfront BEV.

Conclusion: Large volume reRT with bevacizumab is a feasible late salvage option in patients with recurrent HGG and offers meaningful prolongation of survival with low toxicity.
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http://dx.doi.org/10.1016/j.ctro.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075764PMC
May 2020

Sub-acute Toxicity in Non-cancerous Tissue and Immune-Related Adverse Events of a Novel Combination Therapy for Cancer.

Front Oncol 2019 14;9:1504. Epub 2020 Jan 14.

Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, The University of Sydney Northern Clinical School and Northern Sydney Local Health District, St Leonards, NSW, Australia.

Brain, lung, and colon tissue experience deleterious immune-related adverse events when immune-oncological agents or radiation are administered. However, there is a paucity of information regarding whether the addition of radiation to immuno-oncological regimens exacerbates the tissue inflammatory response. We used a murine model to evaluate sub-acute tissue damage and the systemic immune response in C57Bl/6 mice when administered systemic anti-programmed cell death protein 1 (αPD-1) immunotherapy alone or in combination with stereotactic fractionated 10 gray/5 X-ray radiation to normal brain, lung or colon tissue. The model indicated that combinatorial αPD-1 immunotherapy and radiation may alter normal colon cell proliferation and cerebral blood vasculature, and induce systemic thrombocytopenia, lymphopenia, immune suppression, and altered immune repertoire (including interleukin-1β). Therein our data supports close monitoring of hematological and immune-related adverse events in patients receiving combination therapy.
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http://dx.doi.org/10.3389/fonc.2019.01504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971197PMC
January 2020

Molecular and clonal evolution in recurrent metastatic gliosarcoma.

Cold Spring Harb Mol Case Stud 2020 02 3;6(1). Epub 2020 Feb 3.

Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, New South Wales 2065, Australia.

We discuss the molecular evolution of gliosarcoma, a mesenchymal type of glioblastoma (GBM), using the case of a 37-yr-old woman who developed two recurrences and an extracranial metastasis. She was initially diagnosed with isocitrate dehydrogenase (IDH) wild-type gliosarcoma in the frontal lobe and treated with surgery followed by concurrent radiotherapy with temozolomide. Five months later the tumor recurred in the left frontal lobe, outside the initially resected area, and was treated with further surgery and radiotherapy. Six months later the patient developed a second left frontal recurrence and was again treated with surgery and radiotherapy. Six weeks later, further recurrence was observed in the brain and bone, and biopsy confirmed metastases in the pelvic bones. To understand the clonal relationships between the four tumor instances and the origin of metastasis, we performed whole-genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. We compared their mutational and copy-number profiles and inferred the clonal phylogeny. The tumors harbored shared alterations in GBM driver genes, including mutations in , , and , and deletion. Whole-genome doubling was identified in the first recurrence and the extracranial metastasis. Comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profile but contrasting evidence regarding the origin of the metastasis. Subclonal reconstruction suggested a parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. We conclude that metastasis in glioma can be a late event in tumorigenesis.
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http://dx.doi.org/10.1101/mcs.a004671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996521PMC
February 2020

Reflecting on survivorship outcomes to aid initial decision making in patients treated for IDH-mutated anaplastic glioma.

Cancer 2019 Oct 28;125(19):3457-3466. Epub 2019 Jun 28.

Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales, Australia.

Background: Patients with anaplastic glioma (AG) harboring an isocitrate dehydrogenase mutation have potential durable survival after intensity-modulated radiotherapy (IMRT) and chemotherapy. Understanding long-term functioning, and the factors that have an impact on later effects, is important for decision making.

Methods: Consecutive patients with AG who received IMRT were reviewed with regard to 6 survivorship domains, including Eastern Cooperative Oncology Group (ECOG) performance status, Medical Research Council (MRC) neurological status, late toxicity, comorbidity, functional status (employment/driving), and psychosocial events. Assessments were performed at baseline before RT; at month +6; and at years +1, +3, and +5 after RT. The primary endpoints were ECOG at year +3 and employment at year +3.

Results: A total of 146 patients were included, with a median follow-up of 5.1 years. The 6-year overall survival rate was 78.7% (95% CI, 71.1%-87.0%). Baseline ECOG performance status was 0 to 1 in 82.2% of patients but improved at year +1 (95.7%) and year +3 (97.2%). Employment rates at year +3 and year +5 were 70.1% and 76.5%, respectively, compared with 61.6% at baseline. Worse ECOG performance status at year +3 was related to the anaplastic astrocytoma subtype (P = .001), delayed RT (P = .081), multiple craniotomies performed before RT (P = .002), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), seizures (P = .038), neurocognitive disturbance (P < .001), and the presence of recurrent disease (P = .004). Absent or impaired employment at year +3 was found to be related to older age (P = .007), delayed timing of RT (P = .023), multiple craniotomies prior to RT (P = .005), worse ECOG performance status before RT (P < .001), worse MRC neurological status before RT (P < .001), and neurocognitive disturbance (P < .001).

Conclusions: Patients with AG with an isocitrate dehydrogenase mutation have the potential for prolonged survival. Functional status appears to be good in patients who are free of disease progression at 3 to 5 years after IMRT, with >95% of patients having high ECOG performance status and >75% being employed.
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http://dx.doi.org/10.1002/cncr.32352DOI Listing
October 2019

Role of delayed salvage bevacizumab at symptomatic progression of chemorefractory glioblastoma.

BMC Cancer 2019 May 14;19(1):445. Epub 2019 May 14.

Central Coast Cancer Centre, Gosford Hospital, Gosford, NSW, 2250, Australia.

Background: Assess benefit of salvage bevacizumab (BEV) at time of symptomatic progression in patients with refractory glioblastoma (GBM).

Methods: Patients managed with adjuvant long course chemo-radiation therapy for GBM were entered into a prospective database. At chemorefractory symptomatic progression, patients were offered BEV or best supportive care. Re-irradiation (ReRT) was used with BEV in selected patients. BEV continued indefinitely until deterioration limited hospital based infusion. The primary endpoint was median survival calculated from date of decision for BEV to proceed (BEVstart), or decision to decline BEV (BEVreject).

Results: Fifty-five patients were managed of which 48 patients have relapsed disease. The median survival post relapse was 6 months (95%CI: 4.6-7.4). At relapse, 28 patients received BEV with only 14% delivered at first relapse. The median number of BEV cycles was 8 (range 1-25). ReRT was subsequently used in 16 (33%) relapsed patients. BEV treated patients were associated with improved median survival post relapse with 9 months vs 3 months (p < 0.01). The median survival from BEV related decision-making at symptomatic refractory progression to death was 4 months (95%CI: 2.0-6.0). BEVstart was associated with improved survival from this date with median survival of 6 months vs 1 month with BEVreject (p < 0.01). Median survival with ReRT from this date was 8 months vs 3 months without ReRT (p = 0.01). In the BEV patients at eventual progression, death occurred at a median of 30 days post BEV cessation.

Conclusion: In this clinic managing selected patients with chemorefractory progressive glioblastoma, delayed salvage bevacizumab, often in combination with re-irradiation, may provide an increase in survival duration compared with best supportive care.
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http://dx.doi.org/10.1186/s12885-019-5678-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518639PMC
May 2019

Rewilding complex ecosystems.

Science 2019 04;364(6438)

Department of Biology, Anglia Ruskin University, Cambridge, UK.

The practice of rewilding has been both promoted and criticized in recent years. Benefits include flexibility to react to environmental change and the promotion of opportunities for society to reconnect with nature. Criticisms include the lack of a clear conceptualization of rewilding, insufficient knowledge about possible outcomes, and the perception that rewilding excludes people from landscapes. Here, we present a framework for rewilding that addresses these concerns. We suggest that rewilding efforts should target trophic complexity, natural disturbances, and dispersal as interacting processes that can improve ecosystem resilience and maintain biodiversity. We propose a structured approach to rewilding projects that includes assessment of the contributions of nature to people and the social-ecological constraints on restoration.
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http://dx.doi.org/10.1126/science.aav5570DOI Listing
April 2019

Influence of molecular classification in anaplastic glioma for determining outcome and future approach to management.

J Med Imaging Radiat Oncol 2019 Apr 24;63(2):272-280. Epub 2019 Jan 24.

Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales, Australia.

Introduction: Assess survival of patients with anaplastic glioma (AG) and the relationship to molecular subtype.

Methods: Patients with AG managed with IMRT between 2008 and 2014 were entered into a prospective database assessing relapse-free survival (RFS) and overall survival (OS). Isocitrate dehydrogenase (IDH) mutations were assessed prospectively from 2011, and subsequent testing of historical patients allowing categorisation under WHO 2016 classification as anaplastic astrocytoma IDH wild type (AAwt), anaplastic astrocytoma IDH mutated (AAmut), anaplastic oligodendroglioma (AOD) or other glial tumour (OTH). Kaplan-Meier estimates of survival distribution were calculated for the primary endpoint of overall survival and Log-rank test used to determine associated factors.

Results: One hundred and fifty-six patients were included with median follow-up for survivors of 4.7 years. Fifty-six per cent were managed after initial diagnosis, whilst 18% received IMRT at second or later relapse. Seventy-three per cent had temozolomide as part of initial therapy. A total of 118 or 75% of patients had IDH mutated glioma, of which 61 were AOD and 57 AAmut. There were 68 relapses and 52 deaths for a 6yrRFS of 51.2% and 6yrOS of 62.5%. AAwt was associated with worse survival (P < 0.001); and delay of RT until second or later relapse (P = 0.03). Within the 118 patients with IDH mutated tumours, 6yrOS for AOD and AAmut were 90.0% and 62.5%, respectively (P = 0.003). Also two or more craniotomies (P < 0.001), delayed RT (P = 0.006) and age <40 years (P = 0.022) were associated with worse survival on univariate analysis but only AAmut subtype and number of craniotomies on multivariate analysis.

Conclusion: Within AG, molecular classification predicts for survival, and should influence current decision-making.
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http://dx.doi.org/10.1111/1754-9485.12850DOI Listing
April 2019

Anti-angiogenic therapy for high-grade glioma.

Cochrane Database Syst Rev 2018 11 22;11:CD008218. Epub 2018 Nov 22.

Medical Oncology, Alfred Hospital, Commercial Road, Melbourne, Victoria, Australia, 3004.

Background: This is an updated version of the original Cochrane Review published in September 2014. The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma and carries a median survival in treated patients of about 15 months. Glioblastomas are rich in blood vessels (i.e. highly vascular) and also rich in a protein known as vascular endothelial growth factor (VEGF) that promotes new blood vessel formation (the process of angiogenesis). Anti-angiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several anti-angiogenic agents have been investigated in clinical trials, both in newly diagnosed and recurrent HGG, showing preliminary promising results. This review was undertaken to report on the benefits and harms associated with the use of anti-angiogenic agents in the treatment of HGGs.

Objectives: To evaluate the efficacy and toxicity of anti-angiogenic therapy in people with high-grade glioma (HGG). The intervention can be used in two broad groups: at first diagnosis as part of 'adjuvant' therapy, or in the setting of recurrent disease.

Search Methods: We conducted updated searches to identify published and unpublished randomised controlled trials (RCTs), including the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE and Embase to October 2018. We handsearched proceedings of relevant oncology conferences up to 2018. We also searched trial registries for ongoing studies.

Selection Criteria: RCTs evaluating the use of anti-angiogenic therapy to treat HGG versus the same therapy without anti-angiogenic therapy.

Data Collection And Analysis: Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles.

Main Results: After a comprehensive literature search, we identified 11 eligible RCTs (3743 participants), of which 7 were included in the original review (2987 participants). There was significant design heterogeneity in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to glioblastomas and there were no eligible studies evaluating other HGGs. Ten studies were available as fully published peer-reviewed manuscripts, and one study was available in abstract form. The overall risk of bias in included studies was low. This risk was based upon low rates of selection bias, detection bias, attrition bias and reporting bias. The 11 studies included in this review did not show an improvement in overall survival with the addition of anti-angiogenic therapy (pooled hazard ratio (HR) of 0.95, 95% confidence interval (CI) 0.88 to 1.02; P = 0.16; 11 studies, 3743 participants; high-certainty evidence). However, pooled analysis from 10 studies (3595 participants) showed improvement in progression-free survival with the addition of anti-angiogenic therapy (HR 0.73, 95% CI 0.68 to 0.79; P < 0.00001; high-certainty evidence).We carried out additional analyses of overall survival and progression-free survival according to treatment setting and for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone. Pooled analysis of overall survival in either the adjuvant or recurrent setting did not show an improvement (HR 0.93, 95% CI 0.86 to 1.02; P = 0.12; 8 studies, 2833 participants; high-certainty evidence and HR 0.99, 95% CI 0.85 to 1.16; P = 0.90; 3 studies, 910 participants; moderate-certainty evidence, respectively). Pooled analysis of overall survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy also did not clearly show an improvement (HR 0.92, 95% CI 0.85 to 1.00; P = 0.05; 11 studies, 3506 participants; low-certainty evidence). The progression-free survival in the subgroups all showed findings that demonstrated improvements in progression-free survival with the addition of anti-angiogenic therapy. Pooled analysis of progression-free survival in both the adjuvant and recurrent setting showed an improvement (HR 0.75, 95% CI 0.69 to 0.82; P < 0.00001; 8 studies, 2833 participants; high-certainty evidence and HR 0.64, 95% CI 0.54 to 0.76; P < 0.00001; 2 studies, 762 participants; moderate-certainty evidence, respectively). Pooled analysis of progression-free survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone showed an improvement (HR 0.72, 95% CI 0.66 to 0.77; P < 0.00001; 10 studies, 3464 participants). Similar to trials of anti-angiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing, and the potential for thromboembolic events, although generally, the rate of grade 3 and 4 adverse events was low (< 14.1%) and in keeping with the literature. The impact of anti-angiogenic therapy on quality of life varied between studies.

Authors' Conclusions: The use of anti-angiogenic therapy does not significantly improve overall survival in newly diagnosed people with glioblastoma. Thus, there is insufficient evidence to support the use of anti-angiogenic therapy for people with newly diagnosed glioblastoma at this time. Overall there is a lack of evidence of a survival advantage for anti-angiogenic therapy over chemotherapy in recurrent glioblastoma. When considering the combination anti-angiogenic therapy with chemotherapy compared with the same chemotherapy alone, there may possibly be a small improvement in overall survival. While there is strong evidence that bevacizumab (an anti-angiogenic drug) prolongs progression-free survival in newly diagnosed and recurrent glioblastoma, the impact of this on quality of life and net clinical benefit for patients remains unclear. Not addressed here is whether subsets of people with glioblastoma may benefit from anti-angiogenic therapies, nor their utility in other HGG histologies.
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http://dx.doi.org/10.1002/14651858.CD008218.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516839PMC
November 2018

Identifying key needs for the integration of social-ecological outcomes in arctic wildlife monitoring.

Conserv Biol 2019 08 25;33(4):861-872. Epub 2019 Jan 25.

Centre d'Ecologie Fonctionnelle et Evolutive, UMR 5175, Centre National de la Recherche Scientifique - Université de Montpellier - Université Paul-Valéry Montpellier - EPHE, 1919 route de Mende, Montpellier, 34090, France.

For effective monitoring in social-ecological systems to meet needs for biodiversity, science, and humans, desired outcomes must be clearly defined and routes from direct to derived outcomes understood. The Arctic is undergoing rapid climatic, ecological, social, and economic changes and requires effective wildlife monitoring to meet diverse stakeholder needs. To identify stakeholder priorities concerning desired outcomes of arctic wildlife monitoring, we conducted in-depth interviews with 29 arctic scientists, policy and decision makers, and representatives of indigenous organizations and nongovernmental organizations. Using qualitative content analysis, we identified and defined desired outcomes and documented links between outcomes. Using network analysis, we investigated the structure of perceived links between desired outcomes. We identified 18 desired outcomes from monitoring and classified them as either driven by monitoring information, monitoring process, or a combination of both. Highly cited outcomes were make decisions, conserve, detect change, disseminate, and secure food. These reflect key foci of arctic monitoring. Infrequently cited outcomes (e.g., govern) were emerging themes. Three modules comprised our outcome network. The modularity highlighted the low strength of perceived links between outcomes that were primarily information driven or more derived (e.g., detect change, make decisions, conserve, or secure food) and outcomes that were primarily process driven or more derived (e.g., cooperate, learn, educate). The outcomes expand monitoring community and disseminate created connections between these modules. Key desired outcomes are widely applicable to social-ecological systems within and outside the Arctic, particularly those with wildlife subsistence economies. Attributes and motivations associated with outcomes can guide development of integrated monitoring goals for biodiversity conservation and human needs. Our results demonstrated the disconnect between information- and process-driven goals and how expansion of the monitoring community and improved integration of monitoring stakeholders will help connect information- and process-derived outcomes for effective ecosystem stewardship.
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http://dx.doi.org/10.1111/cobi.13257DOI Listing
August 2019

Tumour volume reduction following PET guided intensity modulated radiation therapy and temozolomide in IDH mutated anaplastic glioma.

J Clin Neurosci 2019 Jan 14;59:68-74. Epub 2018 Nov 14.

Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Sydney NeuroOncology Group, Sydney, Australia.

The role of maximal surgical debulking in isocitrate dehydrogenase (IDH) mutated anaplastic glioma prior to adjuvant radiation therapy remains uncertain. This study assessed the reduction in tumour volume following intensity modulated radiation therapy (IMRT) and temozolomide in this favourable and more responsive tumour pathology. 56 patients were managed from 2011 to 2014 and 53 had residual disease. To assess radiological response, tumour volumes were created on representative T1/T2Flair MRI sequences using identical slice-levels in three planes for pre-IMRT, month + 3 and month + 12 post-IMRT scans. Change in volumes was assessed between time periods. Progression-free survival (PFS) was calculated from start of radiotherapy. Median follow-up for survivors is 48.2 months. Pathology was anaplastic oligodendroglioma (AOD) and anaplastic astrocytoma IDH-mutated (AAmut) in 32 and 21 patients respectively. 93% received sequential chemotherapy. The median residual disease on T1 and T2Flair imaging was 9.7 cm and 20.6 cm. 17 patients relapsed for projected 5 year PFS of 74.9%; with 8 isolated relapses within initial surgical site. On MRI at month + 3, the median volume for T1 and T2Flair reduced by 69.4% and 67.3% respectively; which further decreased to 82.4% and 81.3% at month + 12. By month + 12, 69.2% and 62.2% of patients had >75% volume reduction. Patients with AOD had superior reduction at month + 3 compared with AAmut (p = 0.02); but equivalent reduction at month + 12 (p = 0.14). Thus, in patients with anaplastic glioma harbouring an IDH mutation, where an attempt at near-total resection may be associated with unacceptable morbidity, this data suggests that the radiation therapy may provide effective cytoreduction of residual disease.
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http://dx.doi.org/10.1016/j.jocn.2018.11.005DOI Listing
January 2019

Optimising Outcomes for Glioblastoma through Subspecialisation in a Regional Cancer Centre.

Brain Sci 2018 Oct 15;8(10). Epub 2018 Oct 15.

Central Coast Cancer Centre, Gosford Hospital, Gosford, NSW 2250, Australia.

Delivery of highly sophisticated, and subspecialised, management protocols for glioblastoma in low volume rural and regional areas creates potential issues for equivalent quality of care. This study aims to demonstrate the impact on clinical quality indicators through the development of a novel model of care delivering an outsourced subspecialised neuro-oncology service in a regional centre compared with the large volume metropolitan centre. Three hundred and fifty-two patients with glioblastoma were managed under the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada Clinical Trials Group (EORTC-NCIC) Protocol, and survival outcome was assessed in relation to potential prognostic factors and the geographical site of treatment, before and after opening of a regional cancer centre. The median overall survival was 17 months (95% CI: 15.5⁻18.5), with more favourable outcome with age less than 50 years ( < 0.001), near-total resection ( < 0.001), Eastern Cooperative Oncology Group (ECOG) Performance status 0, 1 ( < 0.001), and presence of O-6 methylguanine DNA methyltransferase (MGMT) methylation ( = 0.001). There was no difference in survival outcome for patients managed at the regional centre, compared with metropolitan centre ( = 0.35). Similarly, no difference was seen with clinical quality process indicators of clinical trial involvement, rates of repeat craniotomy, use of bevacizumab and re-irradiation. This model of neuro-oncology subspecialisation allowed equivalent outcomes to be achieved within a regional cancer centre compared to large volume metropolitan centre.
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http://dx.doi.org/10.3390/brainsci8100186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210056PMC
October 2018

FET PET in the evaluation of indeterminate brain lesions on MRI: Differentiating glioma from other non-neoplastic causes - A pilot study.

J Clin Neurosci 2018 Dec 19;58:130-135. Epub 2018 Sep 19.

Department of Radiation Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia.

We aimed to determine the utility of FET PET in the management of indeterminate CNS lesions found on MRI. We performed a retrospective analysis of patients with FET PET at a single tertiary institution from 2011 to 2015. FET PET images were processed using usual methods and measurements taken including SUVmax, TBRmax, and analysis of dynamic series where available (Kipeak, Vdpeak, as well as tumor:background ratio for these variables). Correlation studies were performed using ANOVA between cohorts of high-grade histology, low-grade histology, and benign histology/stable on observation. Thirty-five patients were included, of whom 34 were suitable for analysis with median follow-up of 5 months. The positive predictive value of FET PET in this cohort was 83.3%. FET SUVmax differentiated between patients with high-grade (mean SUV 3.38, 95% CI 2.21-4.55), low-grade (1.88, 95% CI 1.33-2.43) and benign/observation (1.42, 95% CI 1.13-1.71) cohorts (p = 0.0003). Similarly, tumour to brain ratio was significant (p < 0.0001). Kipeak distinguished between high grade and observation cohorts (p = 0.036), as did KiTBR (p = 0.025). Vd peak was not significantly different in these two cohorts (p = 0.057) but Vd TBR was (p = 0.041). In conclusion, FET PET demonstrated a high positive predictive value for glioma in patients with indeterminate brain lesions on MRI. The combination of negative FET and negative FDG PET scans may predict an indolent clinical course. Confirmatory trials are needed to establish the potential value of FET PET in guiding surgical management in this cohort.
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http://dx.doi.org/10.1016/j.jocn.2018.09.009DOI Listing
December 2018

Glioblastoma Recurrence Correlates With Increased APE1 and Polarization Toward an Immuno-Suppressive Microenvironment.

Front Oncol 2018 13;8:314. Epub 2018 Aug 13.

The Brain Cancer Group, Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, St Leonards, NSW, Australia.

While treatment with surgery, radiotherapy and/or chemotherapy may prolong life for patients with glioblastoma, recurrence is inevitable. What is still being discovered is how much these treatments and recurrence of disease affect the molecular profiles of these tumors and how these tumors adapt to withstand these treatment pressures. Understanding such changes will uncover pathways used by the tumor to evade destruction and will elucidate new targets for treatment development. Nineteen matched pre-treatment and post-treatment glioblastoma tumors were subjected to gene expression profiling (Fluidigm, TaqMan assays), promoter methylation analysis (pyrosequencing) and protein expression analysis of the DNA repair pathways, known to be involved in temozolomide resistance (immunohistochemistry). Gene expression profiling to molecularly subtype tumors revealed that 26% of recurrent post-treatment specimens did not match their primary diagnostic specimen subtype. Post-treatment specimens had molecular changes which correlated with known resistance mechanisms including increased expression of APEX1 ( < 0.05) and altered methylation status. In addition, genes associated with immune suppression, invasion and aggression () and polarization toward an M2 phenotype ( and ) were up-regulated in post-treatment tumors, demonstrating an overall change in the tumor microenvironment favoring aggressive tumor growth and disease recurrence. This was confirmed by studies that determined that glioma cell migration was enhanced in the presence of M2 polarized macrophage conditioned media. Further, M2 macrophage-modulated migration was markedly enhanced in post-treatment (temozolomide resistant) glioma cells. These findings highlight the ability of glioblastomas to evade not only the toxic onslaught of therapy but also to evade the immune system suggesting that immune-altering therapies may be of value in treating this terrible disease.
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http://dx.doi.org/10.3389/fonc.2018.00314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099184PMC
August 2018

Predicting patterns of failure in temporal lobe GBMs: possible implications on radiotherapy treatment portals.

Radiat Oncol 2018 Jul 20;13(1):133. Epub 2018 Jul 20.

Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia.

Background: Characterise patterns of failure of Temporal Lobe (TL) Glioblastoma (GBM) following treatment with relation to normal temporal lobe anatomy and neural pathways.

Methods: 335 GBM patients received radiotherapy between 03/2007 and 07/2014, 100 were located in TL. Site of initial tumour and subsequent relapse were subdivided into 5 local TL sites (anterior, lateral, medial, posterior and superior); 5 adjacent regional sites (occipital lobe, inferior frontal lobe, caudate/thalamus/internal/external capsules, fornix/ventricular trigone), and 5 distant failure sites (ventricles, contralateral hemisphere, brainstem, leptomeninges and spine). Extension along major neuroanatomical pathways at initial presentation and at first documented Magnetic Resonance Imaging (MRI) failure were categorised into anterior, superior, medial and posterior pathways.

Results: Of the 100 patients, 86 had radiological progress with a median survival of 17.3 months. At initial diagnosis, 74% of tumours were linked to one TL site and 94% were confined to the TL. 19% had neural pathway disease at initial pre-treatment MRI. At first recurrence locoregional site failure was 74%. 26% failed within distant sites and 53% patients were noted to have neural pathway involvement. Initial tumour location predicted for local site recurrence (p < 0.0001), regional site recurrence (p = 0.004) and neural pathway recurrence pattern (p = 0.005), but not for distant sites (p = 0.081).

Conclusion: Most GBMs fail at local or adjacent regional sites. Many of the recurrences occurred in a predictable pattern within a local or regional site, unique to initial TL site with more than half involving neural pathways. Knowledge of tumour infiltration and failure may improve target definition and radiotherapy.
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http://dx.doi.org/10.1186/s13014-018-1078-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053721PMC
July 2018

Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial.

Neuro Oncol 2019 01;21(1):106-114

NorthShore University Health System, Evanston, Illinois, USA.

Background: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM.

Methods: M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve.

Results: There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%.

Conclusions: Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).
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http://dx.doi.org/10.1093/neuonc/noy091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303422PMC
January 2019

ROS1-Rearranged Non-Small-Cell Lung Cancer, Factor V Leiden, and Recurrent Venous Thromboses.

Clin Lung Cancer 2018 09 5;19(5):457-459. Epub 2018 Jun 5.

Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, Australia; Northern Sydney Cancer Centre, Northern Sydney Local Health District, Royal North Shore Hospital, St Leonards, Australia; Sydney Medical School, Northern Clinical School, University of Sydney, Sydney, Australia.

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http://dx.doi.org/10.1016/j.cllc.2018.05.015DOI Listing
September 2018

The development of a district nursing caseload review tool.

Br J Community Nurs 2018 Jun;23(6):272-278

District Nurse and Operational Manager, SSOTP.

District Nursing (DN) caseloads are increasingly unwieldy. ( Queen's Nursing Institute, 2016 ). They can also be difficult to manage due to the unpredictability and increasing complexity of the patient's needs. It is an essential component of DN teams that caseloads are reviewed on a regular basis to support the delivery of efficient, effective and safe patient care. This article illustrates how a caseload review tool was developed, which would standardise the process in all teams, analyse and monitor the outcomes, identify any trends and themes and give assurance that DN caseloads were productive and safe. The testing, piloting and evaluation of the DN caseload review tool was over a period of 12 months and included 35 DN teams across the Trust. The method used was standardised and systematic, in order to ensure that the results were consistent across the pilot site. It also allowed for standardised challenges to be made by the reviewers, ensuring that the process was efficient and meaningful, the outcomes measured and documented and the clinical systems updated appropriately. Results from the initial reviews have been positive. They have produced both qualitative and quantitative data, which has supported further development of the tool. In addition, actions and outcomes identified for individual patients have been documented and addressed, where possible, at local level. A governance process is in place which supports unaddressed challenges, themes and trends. The conclusion of the pilot has confirmed that this process is valid and will continue to be used within the organisation.
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http://dx.doi.org/10.12968/bjcn.2018.23.6.272DOI Listing
June 2018

The development of a district nursing caseload review tool.

Br J Community Nurs 2018 Jun;23(6):220-226

District Nurse and Operational Manager, SSOTP.

District Nursing (DN) caseloads are increasingly unwieldy. ( Queen's Nursing Institute, 2016 ). They can also be difficult to manage due to the unpredictability and increasing complexity of the patient's needs. It is an essential component of DN teams that caseloads are reviewed on a regular basis to support the delivery of efficient, effective and safe patient care. This article illustrates how a caseload review tool was developed, which would standardise the process in all teams, analyse and monitor the outcomes, identify any trends and themes and give assurance that DN caseloads were productive and safe. The testing, piloting and evaluation of the DN caseload review tool was over a period of 12 months and included 35 DN teams across the Trust. The method used was standardised and systematic, in order to ensure that the results were consistent across the pilot site. It also allowed for standardised challenges to be made by the reviewers, ensuring that the process was efficient and meaningful, the outcomes measured and documented and the clinical systems updated appropriately. Results from the initial reviews have been positive. They have produced both qualitative and quantitative data, which has supported further development of the tool. In addition, actions and outcomes identified for individual patients have been documented and addressed, where possible, at local level. A governance process is in place which supports unaddressed challenges, themes and trends. The conclusion of the pilot has confirmed that this process is valid and will continue to be used within the organisation.
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http://dx.doi.org/10.12968/bjcn.2018.23.6.220DOI Listing
June 2018

Utilizing 18F-fluoroethyltyrosine (FET) positron emission tomography (PET) to define suspected nonenhancing tumor for radiation therapy planning of glioblastoma.

Pract Radiat Oncol 2018 Jul - Aug;8(4):230-238. Epub 2018 Jan 31.

Sydney Vital, Northern Translational Cancer Research Centre, St Leonards, NSW, Australia; Department of Radiation Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Sydney Neuro-Oncology Group, North Shore Private Hospital, St Leonards, NSW, Australia.

Aim: The authors sought to evaluate the impact of 18F-fluoroethyltyrosine (FET) positron emission tomography (PET) on radiation therapy planning for patients diagnosed with glioblastoma (GBM) and the presence of suspected nonenhancing tumors compared with standard magnetic resonance imaging (MRI).

Methods And Materials: Patients with GBM and contrast-enhanced MRI scans showing regions suspicious of nonenhancing tumor underwent postoperative FET-PET before commencing radiation therapy. Two clinical target volumes (CTVs) were created using pre- and postoperative MRI: MRI fluid-attenuated inversion recovery (FLAIR) sequences (CTV) and MRI contrast sequences with an expansion on the surgical cavity (CTV). FET-PET was used to create biological tumor volumes (BTVs) by encompassing FET-avid regions, forming BTV and BTV. Volumetric analyses were conducted between CTVs and respective BTVs using Wilcoxon signed-rank tests. The volume increase with addition of FET was analyzed with respect to BTV and BTV. Presence of focal gadolinium contrast enhancement within previously nonenhancing tumor or within the FET-avid region was noted on MRI scans at 1 and 3 months after radiation therapy.

Results: Twenty-six patients were identified retrospectively from our database, of whom 24 had demonstrable FET uptake. The median CTV, CTV, BTV, and BTV were 57.1 mL (range, 1.1-217.4), 83.6 mL (range, 27.2-275.8), 62.8 mL (range, 1.1-307.3), and 94.7 mL (range, 27.2-285.5), respectively. When FET-PET was used, there was a mean increase in volume of 26.8% from CTV to BTV and 20.6% from CTV to BTV. A statistically significant difference was noted on Wilcoxon signed-rank test when assessing volumetric change between CTV and BTV (P < .0001) and CTV and BTV (P < .0001). Six of 24 patients (25%) with FET avidity before radiation therapy showed focal gadolinium enhancement within the radiation therapy portal.

Conclusions: FET-PET may help improve delineation of GBM in cases with a suspected nonenhancing component. This may result in improved radiation therapy target delineation and reduce the risk of potential geographical miss.

Summary: We investigated the impact of 18F-fluoroethyltyrosine (FET) positron emission tomography (PET) on radiation therapy planning for patients diagnosed with glioblastoma (GBM) and a suspected nonenhancing tumor compared with standard magnetic resonance imaging. We performed volumetric analyses between clinical target volumes and respective biological target volumes using Wilcoxon signed-rank tests. FET-PET may help improve delineation of GBM in cases with a suspected nonenhancing component and reduce the risk of potential geographical miss.
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http://dx.doi.org/10.1016/j.prro.2018.01.006DOI Listing
December 2018