Publications by authors named "Sarah Jefferies"

57 Publications

MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Review.

Neuro Oncol 2021 Apr 30. Epub 2021 Apr 30.

Bristol Medical School: Brain Tumour Research Centre, Population Health Sciences, University of Bristol, Bristol, UK.

Background: The DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT) causes resistance of tumour cells to alkylating agents. It is a predictive biomarker in high grade gliomas treated with temozolomide, however there is no consensus on which test method, methylation sites, and cut-off values to use.

Methods: We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; where MGMT status was determined in tumour tissue, and assessed by one or more technique; and where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios. Two or more methods were compared in 32 independent cohorts with 3474 patients.

Results: Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP.

Conclusions: We cannot draw strong conclusions about use of frozen tissue versus formalin-fixed paraffin embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and Pyrosequencing at CpG sites ranging from 72 to 95. A cut-off threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies. 190 studies were identified presenting hazard ratios from survival analysis in patients in which MGMT methylation was measured by one technique only.
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http://dx.doi.org/10.1093/neuonc/noab105DOI Listing
April 2021

Use of Genomics to Track Coronavirus Disease Outbreaks, New Zealand.

Emerg Infect Dis 2021 05;27(5):1317-1322

Real-time genomic sequencing has played a major role in tracking the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), contributing greatly to disease mitigation strategies. In August 2020, after having eliminated the virus, New Zealand experienced a second outbreak. During that outbreak, New Zealand used genomic sequencing in a primary role, leading to a second elimination of the virus. We generated genomes from 78% of the laboratory-confirmed samples of SARS-CoV-2 from the second outbreak and compared them with the available global genomic data. Genomic sequencing rapidly identified that virus causing the second outbreak in New Zealand belonged to a single cluster, thus resulting from a single introduction. However, successful identification of the origin of this outbreak was impeded by substantial biases and gaps in global sequencing data. Access to a broader and more heterogenous sample of global genomic data would strengthen efforts to locate the source of any new outbreaks.
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http://dx.doi.org/10.3201/eid2705.204579DOI Listing
May 2021

Medullary Thyroid Cancer Patient's Assessment of Quality of Life Tools: Results from the QaLM Study.

Eur Thyroid J 2021 Mar 23;10(1):72-78. Epub 2020 Aug 23.

Centre for Trials Research, Cardiff University, Cardiff, United Kingdom.

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumour and a rare variant of thyroid cancer with different aetiology, presentation and treatment to differentiated thyroid cancer. Currently available thyroid cancer-specific quality of life (QoL) tools focus on issues and treatments more relevant to patients with differentiated thyroid cancer and therefore may not address issues specific to a MTC diagnosis and cancer journey.

Method: This prospective multicentre randomised study involved 204 MTC patients completing four quality of life questionnaires (QOLQ) and stating their most and least preferred. The questionnaires were a general instrument, the EORTC QLQ-C30, two disease-specific tools, the MD Anderson Symptom Inventory (MDASI) thyroid module and the City of Hope Quality of Life Scale/THYROID (amended) and the neuroendocrine questionnaire, EORTC QLQ-GINET21. Patients were randomised to complete the four questionnaires in one of 24 possible orders and then answered questions about which tool they preferred. The primary outcome measure was patients' preferred QoL instrument for describing their concerns and for facilitating communication with their healthcare professional. Secondary analyses looked at differences between preferred QOLQs amongst patient subgroups (WHO performance status [0 and 1+], disease stage: early [T1-3, N0 or N1A], metastatic [T4, any T N1b] and advanced [any T any N M1], and type of MTC [sporadic and inherited]), identification of MTC patients' least preferred questionnaire and clinicians' views on the QoL tools in terms of their ability to highlight problems not otherwise ascertained by a standard clinical review.

Results: No evidence of a difference was observed for most preferred QOLQ ( = 0.650). There was however evidence of a difference in least preferred questionnaire in the cohort of 128 patients who stated their least preferred questionnaire ( = 0.042), with 36% (46/128) of patients choosing the EORTC QLQ-GI.NET21 questionnaire. Subgroup analyses showed that there was no evidence of a difference in patients' most preferred questionnaire in sporadic MTC patients ( = 0.637), patients with WHO PS 0 or 1+ ( = 0.844 and = 0.423) nor when comparing patients with early, advanced local or metastatic disease ( = 0.132, = 0.463 and = 0.506, respectively). Similarly, subgroup analyses on patients' least preferred questionnaires showed no evidence of differences in sporadic MTC patients ( = 0.092), patients with WHO PS 0 or 1+ ( = 0.423 and = 0.276), nor in early or metastatic disease patients ( = 0.682 and = 0.345, respectively). There was however some evidence to suggest a difference in least preferred questionnaire in patients with advanced local stage disease ( = 0.059), with 43% (16/37) of these patients choosing the EORTC QLQ-GI.NET21 questionnaire.

Conclusions: MTC patients regardless of their performance status, disease aetiology and disease burden did not express a preference for any one particular questionnaire suggesting any of the tools studied could be utilized in this patient cohort. The least preferred questionnaire being a gastrointestinal NET specific tool suggests that diarrhoea was not a significant symptom and concern for the population studied.
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http://dx.doi.org/10.1159/000509227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983600PMC
March 2021

Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.

Cochrane Database Syst Rev 2021 03 12;3:CD013316. Epub 2021 Mar 12.

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

Background: Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide.

Objectives: To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide.

Search Methods: We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014.

Selection Criteria: Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis.

Data Collection And Analysis: Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals.

Main Results: We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status.

Authors' Conclusions: PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.
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http://dx.doi.org/10.1002/14651858.CD013316.pub2DOI Listing
March 2021

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand.

Nat Commun 2021 02 12;12(1):1001. Epub 2021 Feb 12.

Regional Public Health, Hutt Valley District Health Board, Wellington, New Zealand.

Stringent nonpharmaceutical interventions (NPIs) such as lockdowns and border closures are not currently recommended for pandemic influenza control. New Zealand used these NPIs to eliminate coronavirus disease 2019 during its first wave. Using multiple surveillance systems, we observed a parallel and unprecedented reduction of influenza and other respiratory viral infections in 2020. This finding supports the use of these NPIs for controlling pandemic influenza and other severe respiratory viral threats.
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http://dx.doi.org/10.1038/s41467-021-21157-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881137PMC
February 2021

Response to BRAF and MEK1/2 inhibition in a young adult with BRAF V600E mutant epithelioid glioblastoma multiforme: A Case Report and Literature Review.

Curr Probl Cancer 2021 Jan 12:100701. Epub 2021 Jan 12.

Department of Oncology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK. Electronic address:

Epithelioid glioblastoma multiforme (eGBM) is a rare and aggressive variant of glioblastoma multiforme (GBM) that predominantly affects younger patients and can be difficult to distinguish from other gliomas. Data on how patients with eGBM might be best treated are limited, although genomic analyses have shown that almost half of tumours harbour activating BRAF gene mutations. Here we present the case of a young female with BRAF V600E-mutant eGBM who had a prolonged response to targeted therapy with the BRAF and MEK1/2 inhibitors dabrafenib and trametinib. We review current knowledge about eGBM, including the emerging role for BRAF- ± MEK1/2- targeted therapy.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100701DOI Listing
January 2021

Genomic Evidence of In-Flight Transmission of SARS-CoV-2 Despite Predeparture Testing.

Emerg Infect Dis 2021 03 5;27(3):687-693. Epub 2021 Jan 5.

Since the first wave of coronavirus disease in March 2020, citizens and permanent residents returning to New Zealand have been required to undergo managed isolation and quarantine (MIQ) for 14 days and mandatory testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of October 20, 2020, of 62,698 arrivals, testing of persons in MIQ had identified 215 cases of SARS-CoV-2 infection. Among 86 passengers on a flight from Dubai, United Arab Emirates, that arrived in New Zealand on September 29, test results were positive for 7 persons in MIQ. These passengers originated from 5 different countries before a layover in Dubai; 5 had negative predeparture SARS-CoV-2 test results. To assess possible points of infection, we analyzed information about their journeys, disease progression, and virus genomic data. All 7 SARS-CoV-2 genomes were genetically identical, except for a single mutation in 1 sample. Despite predeparture testing, multiple instances of in-flight SARS-CoV-2 transmission are likely.
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http://dx.doi.org/10.3201/eid2703.204714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920679PMC
March 2021

Genomic epidemiology reveals transmission patterns and dynamics of SARS-CoV-2 in Aotearoa New Zealand.

Nat Commun 2020 12 11;11(1):6351. Epub 2020 Dec 11.

Institute of Environmental Science and Research, Wellington, New Zealand.

New Zealand, a geographically remote Pacific island with easily sealable borders, implemented a nationwide 'lockdown' of all non-essential services to curb the spread of COVID-19. Here, we generate 649 SARS-CoV-2 genome sequences from infected patients in New Zealand with samples collected during the 'first wave', representing 56% of all confirmed cases in this time period. Despite its remoteness, the viruses imported into New Zealand represented nearly all of the genomic diversity sequenced from the global virus population. These data helped to quantify the effectiveness of public health interventions. For example, the effective reproductive number, R of New Zealand's largest cluster decreased from 7 to 0.2 within the first week of lockdown. Similarly, only 19% of virus introductions into New Zealand resulted in ongoing transmission of more than one additional case. Overall, these results demonstrate the utility of genomic pathogen surveillance to inform public health and disease mitigation.
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http://dx.doi.org/10.1038/s41467-020-20235-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733492PMC
December 2020

Determinants of Vestibular Schwannoma Growth.

Otol Neurotol 2020 Dec 1. Epub 2020 Dec 1.

Department of Skull Base Surgery, Cambridge University Hospitals.

Objective: Management of vestibular schwannomas (VS) involves surgery, radiotherapy, or surveillance, based on patient and tumor factors. We recently described conditional probability as a more accurate method for stratifying VS growth risk. Building on this, we now describe determinants of VS growth, allowing clinicians to move toward a more personalized approach to growth-risk profiling.

Methods: Retrospective analysis of a prospectively collected database in a tertiary referral skull base unit between 2005 and 2014. Inclusion of patients with unilateral VS managed on surveillance protocol for a minimum of 5 years. Analysis of patient age, sex, tumor location, tumor size, and symptomology using conditional probability.

Results: A total of 340 patients met inclusion criteria. The conditional probability of growth of extracanalicular VS was significantly higher versus intracanalicular (IC) VS (30% versus 13%, p < 0.001) as was small-sized VS versus IC VS (28 versus 13%, p = 0.002), but only in the first year after diagnosis. Sex, age, and presenting symptoms did not significantly affect VS growth.

Conclusion: In our series, extracanalicular VS were more likely to grow than IC VS and small-sized VS more likely to grow than IC VS, but only in the first year after diagnosis. Conversely, sex, age, and presenting symptoms did not affect the conditional probability of VS growth.
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http://dx.doi.org/10.1097/MAO.0000000000003043DOI Listing
December 2020

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand.

medRxiv 2020 Nov 13. Epub 2020 Nov 13.

Regional Public Health, Hutt Valley District Health Board, Wellington, New Zealand.

Stringent nonpharmaceutical interventions (NPIs) such as lockdowns and border closures are not currently recommended for pandemic influenza control. New Zealand used these NPIs to eliminate coronavirus disease 2019 during its first wave. Using multiple surveillance systems, we observed a parallel and unprecedented reduction of influenza and other respiratory viral infections in 2020. This finding supports the use of these NPIs for controlling pandemic influenza and other severe respiratory viral threats.
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http://dx.doi.org/10.1101/2020.11.11.20228692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668762PMC
November 2020

COVID-19 in New Zealand and the impact of the national response: a descriptive epidemiological study.

Lancet Public Health 2020 11 14;5(11):e612-e623. Epub 2020 Oct 14.

Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Background: In early 2020, during the COVID-19 pandemic, New Zealand implemented graduated, risk-informed national COVID-19 suppression measures aimed at disease elimination. We investigated their impacts on the epidemiology of the first wave of COVID-19 in the country and response performance measures.

Methods: We did a descriptive epidemiological study of all laboratory-confirmed and probable cases of COVID-19 and all patients tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in New Zealand from Feb 2 to May 13, 2020, after which time community transmission ceased. We extracted data from the national notifiable diseases database and the national SARS-CoV-2 test results repository. Demographic features and disease outcomes, transmission patterns (source of infection, outbreaks, household transmission), time-to-event intervals, and testing coverage were described over five phases of the response, capturing different levels of non-pharmaceutical interventions. Risk factors for severe outcomes (hospitalisation or death) were examined with multivariable logistic regression and time-to-event intervals were analysed by fitting parametric distributions using maximum likelihood estimation.

Findings: 1503 cases were detected over the study period, including 95 (6·3%) hospital admissions and 22 (1·5%) COVID-19 deaths. The estimated case infection rate per million people per day peaked at 8·5 (95% CI 7·6-9·4) during the 10-day period of rapid response escalation, declining to 3·2 (2·8-3·7) in the start of lockdown and progressively thereafter. 1034 (69%) cases were imported or import related, tending to be younger adults, of European ethnicity, and of higher socioeconomic status. 702 (47%) cases were linked to 34 outbreaks. Severe outcomes were associated with locally acquired infection (crude odds ratio [OR] 2·32 [95% CI 1·40-3·82] compared with imported), older age (adjusted OR ranging from 2·72 [1·40-5·30] for 50-64 year olds to 8·25 [2·59-26·31] for people aged ≥80 years compared with 20-34 year olds), aged residential care residency (adjusted OR 3·86 [1·59-9·35]), and Pacific peoples (adjusted OR 2·76 [1·14-6·68]) and Asian (2·15 [1·10-4·20]) ethnicities relative to European or other. Times from illness onset to notification and isolation progressively decreased and testing increased over the study period, with few disparities and increasing coverage of females, Māori, Pacific peoples, and lower socioeconomic groups.

Interpretation: New Zealand's response resulted in low relative burden of disease, low levels of population disease disparities, and the initial achievement of COVID-19 elimination.

Funding: Ministry of Business Innovation and Employment Strategic Scientific Investment Fund, and Ministry of Health, New Zealand.
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http://dx.doi.org/10.1016/S2468-2667(20)30225-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553903PMC
November 2020

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial.

Neuro Oncol 2020 12;22(12):1840-1850

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ.

Methods: Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines.

Results: Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM.

Conclusion: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.
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http://dx.doi.org/10.1093/neuonc/noaa104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746945PMC
December 2020

Treatment of newly diagnosed glioblastoma in the elderly: a network meta-analysis.

Cochrane Database Syst Rev 2020 03 23;3:CD013261. Epub 2020 Mar 23.

Western General Hospital, Edinburgh Centre for Neuro-Oncology (ECNO), Crewe Road, Edinburgh, Scotland, UK, EH4 2XU.

Background: A glioblastoma is a fatal type of brain tumour for which the standard of care is maximum surgical resection followed by chemoradiotherapy, when possible. Age is an important consideration in this disease, as older age is associated with shorter survival and a higher risk of treatment-related toxicity.

Objectives: To determine the most effective and best-tolerated approaches for the treatment of elderly people with newly diagnosed glioblastoma. To summarise current evidence for the incremental resource use, utilities, costs and cost-effectiveness associated with these approaches.

Search Methods: We searched electronic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase to 3 April 2019, and the NHS Economic Evaluation Database (EED) up to database closure. We handsearched clinical trial registries and selected neuro-oncology society conference proceedings from the past five years.

Selection Criteria: Randomised trials (RCTs) of treatments for glioblastoma in elderly people. We defined 'elderly' as 70+ years but included studies defining 'elderly' as over 65+ years if so reported.

Data Collection And Analysis: We used standard Cochrane methods for study selection and data extraction. Where sufficient data were available, treatment options were compared in a network meta-analysis (NMA) using Stata software (version 15.1). For outcomes with insufficient data for NMA, pairwise meta-analysis were conducted in RevMan. The GRADE approach was used to grade the evidence.

Main Results: We included 12 RCTs involving approximately 1818 participants. Six were conducted exclusively among elderly people (either defined as 65 years or older or 70 years or older) with newly diagnosed glioblastoma, the other six reported data for an elderly subgroup among a broader age range of participants. Most participants were capable of self-care. Study quality was commonly undermined by lack of outcome assessor blinding and attrition. NMA was only possible for overall survival; other analyses were pair-wise meta-analyses or narrative syntheses. Seven trials contributed to the NMA for overall survival, with interventions including supportive care only (one trial arm); hypofractionated radiotherapy (RT40; four trial arms); standard radiotherapy (RT60; five trial arms); temozolomide (TMZ; three trial arms); chemoradiotherapy (CRT; three trial arms); bevacizumab with chemoradiotherapy (BEV_CRT; one trial arm); and bevacizumab with radiotherapy (BEV_RT). Compared with supportive care only, NMA evidence suggested that all treatments apart from BEV_RT prolonged survival to some extent. Overall survival High-certainty evidence shows that CRT prolongs overall survival (OS) compared with RT40 (hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.56 to 0.80) and low-certainty evidence suggests that CRT may prolong overall survival compared with TMZ (TMZ versus CRT: HR 1.42, 95% CI 1.01 to 1.98). Low-certainty evidence also suggests that adding BEV to CRT may make little or no difference (BEV_CRT versus CRT: HR 0.83, 95% CrI 0.48 to 1.44). We could not compare the survival effects of CRT with different radiotherapy fractionation schedules (60 Gy/30 fractions and 40 Gy/15 fractions) due to a lack of data. When treatments were ranked according to their effects on OS, CRT ranked higher than TMZ, RT and supportive care only, with the latter ranked last. BEV plus RT was the only treatment for which there was no clear benefit in OS over supportive care only.   One trial comparing tumour treating fields (TTF) plus adjuvant chemotherapy (TTF_AC) with adjuvant chemotherapy alone could not be included in the NMA as participants were randomised after receiving concomitant chemoradiotherapy, not before. Findings from the trial suggest that the intervention probably improves overall survival in this selected patient population. We were unable to perform NMA for other outcomes due to insufficient data. Pairwise analyses were conducted for the following. Quality of life Moderate-certainty narrative evidence suggests that overall, there may be little difference in QoL between TMZ and RT, except for discomfort from communication deficits, which are probably more common with RT (1 study, 306 participants, P = 0.002). Data on QoL for other comparisons were sparse, partly due to high dropout rates, and the certainty of the evidence tended to be low or very low. Progression-free survival High-certainty evidence shows that CRT increases time to disease progression compared with RT40 (HR 0.50, 95% CI 0.41 to 0.61); moderate-certainty evidence suggests that RT60 probably increases time to disease progression compared with supportive care only (HR 0.28, 95% CI 0.17 to 0.46), and that BEV_RT probably increases time to disease progression compared with RT40 alone (HR 0.46, 95% CI 0.27 to 0.78). Evidence for other treatment comparisons was of low- or very low-certainty. Severe adverse events Moderate-certainty evidence suggests that TMZ probably increases the risk of grade 3+ thromboembolic events compared with RT60 (risk ratio (RR) 2.74, 95% CI 1.26 to 5.94; participants = 373; studies = 1) and also the risk of grade 3+ neutropenia, lymphopenia, and thrombocytopenia. Moderate-certainty evidence also suggests that CRT probably increases the risk of grade 3+ neutropenia, leucopenia and thrombocytopenia compared with hypofractionated RT alone. Adding BEV to CRT probably increases the risk of thromboembolism (RR 16.63, 95% CI 1.00 to 275.42; moderate-certainty evidence). Economic evidence There is a paucity of economic evidence regarding the management of newly diagnosed glioblastoma in the elderly. Only one economic evaluation on two short course radiotherapy regimen (25 Gy versus 40 Gy) was identified and its findings were considered unreliable.

Authors' Conclusions: For elderly people with glioblastoma who are self-caring, evidence suggests that CRT prolongs survival compared with RT and may prolong overall survival compared with TMZ alone. For those undergoing RT or TMZ therapy, there is probably little difference in QoL overall. Systemic anti-cancer treatments TMZ and BEV carry a higher risk of severe haematological and thromboembolic events and CRT is probably associated with a higher risk of these events. Current evidence provides little justification for using BEV in elderly patients outside a clinical trial setting. Whilst the novel TTF device appears promising, evidence on QoL and tolerability is needed in an elderly population. QoL and economic assessments of CRT versus TMZ and RT are needed. More high-quality economic evaluations are needed, in which a broader scope of costs (both direct and indirect) and outcomes should be included.
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http://dx.doi.org/10.1002/14651858.CD013261.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086476PMC
March 2020

The Conditional Probability of Vestibular Schwannoma Growth at Different Time Points After Initial Stability on an Observational Protocol.

Otol Neurotol 2020 02;41(2):250-257

Department of Skull Base Surgery, Cambridge University Hospitals.

Objective: The natural history of vestibular schwannomas (VS) is well documented in the literature, with tumour growth being paramount to decision making for both surveillance and treatment of these patients. Most previous studies refer to the risk of VS growth over a given period of time; however, this is not useful for counselling patients at different stages of their follow-up, as the risk of tumour growth is likely to be less following each subsequent year that a tumour does not grow. Accordingly, we investigated the conditional probability of VS growth at particular time-points, given a patient has not grown thus far. This Bayesian method of risk stratification allows for more tailored and accurate approximations of the risk of growth versus nongrowth of VS.

Methods: Retrospective analysis of a prospectively collected database in a tertiary referral skull base unit, containing all patients diagnosed between 2005 and 2014 with sporadic unilateral VS and a minimum of 5-year surveillance.

Results: A total of 341 patients met the inclusion criteria. The mean age at diagnosis was 67 years, the sizes of the VS at diagnosis were intracanalicular in 49%, small in 39%, medium in 11%, and large in 1%. Over the entire 5-year surveillance period, a total of 139 tumours were seen to grow (41%) and 202 did not grow (59%). At 1 year, the probability of growth given that the tumour had not grown to date was seen to be 21%, at 2 years 12%, at 3 years 9%, at 4 years 3%, and at 5 years 2%. The conditional probability of growth of extracanalicular VS was significantly higher in the first year when compared with intracanalicular VS (29% versus 13%, p = 0.01), but there was no such difference in years 2, 3, 4 or 5 (p = 0.60, 0.69, 0.36, 0.39, respectively).

Conclusion: This is the first study in the literature concerned specifically with the conditional probability of VS growth. The data presented here can be used to better inform VS patients of their risk of growth at particular time points in their disease-the longer VS have been observed to be stable, the lower the risk of subsequent growth in a given year. Further, an extracanalicular vestibular schwannoma is more likely to grow in the first year compared with an intracanalicular vestibular schwannoma. Our data also adds support to surveillance protocols with increasingly infrequent MRI scans, as after 4 years of not growing, the risk of growth in year 5 falls to <2%.
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http://dx.doi.org/10.1097/MAO.0000000000002448DOI Listing
February 2020

A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma.

Clin Cancer Res 2019 05 22;25(9):2708-2716. Epub 2019 Feb 22.

Department of Oncology, Barts Health NHS Trust, London, United Kingdom.

Purpose: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase () and/or argininosuccinate lyase (). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed.

Patients And Methods: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16-06/17) to receive weekly ADI-PEG20 36 mg/m intramuscularly plus pemetrexed 500 mg/m and cisplatin 75 mg/m intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy.

Results: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5-20.8) and overall survival was 6.3 months (95% CI, 1.8-9.7).

Conclusions: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3729DOI Listing
May 2019

Incidence of second and higher order smoking-related primary cancers following lung cancer: a population-based cohort study.

Thorax 2019 05 18;74(5):466-472. Epub 2019 Feb 18.

Department of Oncology, University of Cambridge, Cambridge, UK.

Background: Lung cancer 5-year survival has doubled over 15 years. Although the risk of second primary cancer is recognised, quantification over time is lacking. We describe the incidence of second and higher order smoking-related primary cancers in lung cancer survivors, identifying high-incidence groups and how incidence changes over time from first diagnosis.

Methods: Data on smoking-related primary cancers (lung, laryngeal, head and neck, oesophageal squamous cell carcinoma and bladder) diagnosed in England between 2000 and 2014 were obtained from Public Health England National Cancer Registration and Analysis Service. We calculated absolute incidence rates and standardised incidence rate ratios, both overall and for various subgroups of second primary cancer for up to 10 years from the initial diagnosis of lung cancer, using Poisson regression.

Results: Elevated incidence of smoking-related second primary cancer persists for at least 10 years from first lung cancer diagnosis with those aged 50 and 79 at first diagnosis at particularly high risk. The most frequent type of second malignancy was lung cancer although the highest standardised incidence rate ratios were for oesophageal squamous cell carcinoma (2.4) and laryngeal cancers (2.8) and consistently higher in women than in men. Over the last decade, the incidence of second primary lung cancer has doubled.

Conclusion: Lung cancer survivors have increased the incidence of subsequent lung, laryngeal, head and neck and oesophageal squamous cell carcinoma for at least a decade from the first diagnosis. Consideration should be given to increasing routine follow-up from 5 years to 10 years for those at highest risk, alongside surveillance for other smoking-related cancers.
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http://dx.doi.org/10.1136/thoraxjnl-2018-212456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475108PMC
May 2019

Uncommon low-grade brain tumors.

Neuro Oncol 2019 02;21(2):151-166

Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.

The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I-II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management.
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http://dx.doi.org/10.1093/neuonc/noy151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374757PMC
February 2019

Anatomical change during radiotherapy for head and neck cancer, and its effect on delivered dose to the spinal cord.

Radiother Oncol 2019 01 23;130:32-38. Epub 2018 Jul 23.

University of Manchester, Manchester Academic Health Science Centre and The Christie NHS Foundation Trust, Manchester, UK.

Background And Purpose: The impact of weight loss and anatomical change during head and neck (H&N) radiotherapy on spinal cord dosimetry is poorly understood, limiting evidence-based adaptive management strategies.

Materials And Methods: 133 H&N patients treated with daily mega-voltage CT image-guidance (MVCT-IG) on TomoTherapy, were selected. Elastix software was used to deform planning scan SC contours to MVCT-IG scans, and accumulate dose. Planned (D) and delivered (D) spinal cord D (SCD) were compared. Univariate relationships between neck irradiation strategy (unilateral vs bilateral), T-stage, N-stage, weight loss, and changes in lateral separation (LND) and CT slice surface area (SSA) at C1 and the superior thyroid notch (TN), and ΔSCD [(D - D) D] were examined.

Results: The mean value for (D - D) D was -0.07 Gy (95%CI -0.28 to 0.14, range -5.7 Gy to 3.8 Gy), and the mean absolute difference between D and D (independent of difference direction) was 0.9 Gy (95%CI 0.76-1.04 Gy). Neck treatment strategy (p = 0.39) and T-stage (p = 0.56) did not affect ΔSCD. Borderline significance (p = 0.09) was seen for higher N-stage (N2-3) and higher ΔSCD. Mean reductions in anatomical metrics were substantial: weight loss 6.8 kg; C1LND 12.9 mm; C1SSA 12.1 cm; TNLND 5.3 mm; TNSSA 11.2 cm, but no relationship between weight loss or anatomical change and ΔSCD was observed (all r < 0.1).

Conclusions: Differences between delivered and planned spinal cord D are small in patients treated with daily IG. Even patients experiencing substantial weight loss or anatomical change during treatment do not require adaptive replanning for spinal cord safety.
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http://dx.doi.org/10.1016/j.radonc.2018.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358720PMC
January 2019

Adjuvant postoperative high-dose radiotherapy for atypical and malignant meningioma: A phase-II parallel non-randomized and observation study (EORTC 22042-26042).

Radiother Oncol 2018 08 28;128(2):260-265. Epub 2018 Jun 28.

EORTC Headquarters, Brussels, Belgium.

Purpose: The therapeutic strategy for non-benign meningiomas is controversial. The objective of this study was to prospectively investigate the impact of high dose radiation therapy (RT) on the progression-free survival (PFS) rate at 3 years in WHO grade II and III meningioma patients.

Materials And Methods: In this multi-cohorts non-randomized phase II and observational study, non-benign meningioma patients were treated according to their WHO grade and Simpson's grade. Patients with atypical meningioma (WHO grade II) and Simpson's grade 1-3 [Arm 1] entered the non-randomized phase II study designed to show a 3-year PFS > 70% (primary endpoint). All other patients entered the 3 observational cohorts: WHO grade II Simpson grade 4-5 [Arm 2] and Grade III Simpson grade 1-3 or 4-5 [Arm 3&4] in which few patients were expected.

Results: Between 02/2008 and 06/2013, 78 patients were enrolled into the study. This report focuses on the 56 (median age, 54 years) eligible patients with WHO grade II Simpson's grade 1-3 meningioma who received RT (60 Gy). At a median follow up of 5.1 years, the estimated 3-year PFS is 88.7%, hence significantly greater than 70%. Eight (14.3%) treatment failures were observed. The 3-year overall survival was 98.2%. The rate of late signs and symptoms grade 3 or more was 14.3%.

Conclusions: These data show that 3-year PFS for WHO grade II meningioma patients undergoing a complete resection (Simpson I-III) is superior to 70% when treated with high-dose (60 Gy) RT.
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http://dx.doi.org/10.1016/j.radonc.2018.06.018DOI Listing
August 2018

Identifying risk factors for L'Hermitte's sign after IMRT for head and neck cancer.

Radiat Oncol 2018 May 4;13(1):84. Epub 2018 May 4.

VoxTox Research Group, Cambridge University Dept. of Oncology, Hutchison/MRC Research Centre, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.

Background: L'Hermitte's sign (LS) after chemoradiotherapy for head and neck cancer appears related to higher spinal cord doses. IMRT plans limit spinal cord dose, but the incidence of LS remains high.

Methods: One hundred seventeen patients treated with TomoTherapy™ between 2008 and 2015 prospectively completed a side-effect questionnaire (VoxTox Trial Registration: UK CRN ID 13716). Baseline patient and treatment data were collected. Radiotherapy plans were analysed; mean and maximum spinal cord dose and volumes receiving 10, 20, 30 and 40 Gy were recorded. Dose variation across the cord was examined. These data were included in a logistic regression model.

Results: Forty two patients (35.9%) reported LS symptoms. Concurrent weekly cisplatin did not increase LS risk (p = 0.70, OR = 1.23 {95% CI 0.51-2.34}). Of 13 diabetic participants (9 taking metformin), only 1 developed LS (p = 0.025, OR = 0.13 {95% CI 0.051-3.27}). A refined binary logistic regression model showed that patients receiving unilateral radiation (p = 0.019, OR = 2.06 {95% CI 0.15-0.84}) were more likely to develop LS. Higher V (p = 0.047, OR = 1.06 {95% CI 1.00-1.12}), and younger age (mean age 56.6 vs 59.7, p = 0.060, OR = 0.96 {95% CI 0.92-1.00}) were associated with elevated risk of LS, with borderline significance.

Conclusions: In this cohort, concomitant cisplatin did not increase risk, and LS incidence was lower in diabetic patients. Patient age and dose gradients across the spinal cord may be important factors.
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http://dx.doi.org/10.1186/s13014-018-1015-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936022PMC
May 2018

PARADIGM-2: Two parallel phase I studies of olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma, with treatment stratified by MGMT status.

Clin Transl Radiat Oncol 2018 Jan 21;8:12-16. Epub 2017 Nov 21.

Institute of Cancer Sciences, University of Glasgow, UK.

Glioblastoma has a dismal prognosis and molecular targeted agents have failed to improve outcomes to date. PARADIGM-2 is a phase I dose escalation study evaluating olaparib plus radiotherapy ± temozolomide in newly diagnosed glioblastoma, using MGMT methylation status to stratify patients and inform treatment schedules.
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http://dx.doi.org/10.1016/j.ctro.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862667PMC
January 2018

Brain tumor research in the United Kingdom: current perspective and future challenges. A strategy document from the NCRI Brain Tumor CSG.

Neurooncol Pract 2018 Mar 30;5(1):10-17. Epub 2017 Aug 30.

Department of Clinical Neurosciences, Division of Neurosurgery, University of Cambridge, UK.

The National Cancer Research Institute (NCRI) is a partnership of charity and government research funders whose purpose is to improve health and quality of life by accelerating progress in cancer-related research through collaboration. Under this umbrella, the NCRI Brain Tumor Clinical Studies Group is focused on improving clinical outcomes for adult patients with brain and central nervous system tumors, including those with brain metastasis from other primary sites. This document discusses the current state of clinical brain tumor research in the United Kingdom and the challenges to increasing study and trial opportunities for patients. The clinical research priorities are defined along with a strategy to strengthen the existing brain tumor research network, improve access to tissue and imaging and to develop the future leadership for brain tumor research in the United Kingdom. This strategy document may serve as a framework for other organizations and countries.
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http://dx.doi.org/10.1093/nop/npx022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6655398PMC
March 2018

Aspirin does not prevent growth of vestibular schwannomas: A case-control study.

Laryngoscope 2018 09 6;128(9):2139-2144. Epub 2018 Feb 6.

Department of Otolaryngology, Addenbrooke's Hospital, Cambridge, United Kingdom.

Objectives/hypothesis: To determine if aspirin intake is associated with reduced growth of vestibular schwannomas (VS). To determine the prevalence of contraindications to regular aspirin in patients with VS.

Study Design: Retrospective, observational case-control study.

Methods: The study utilized a postal questionnaire and telephone interviews to determine aspirin exposure. Propensity score matching was used to control for age, sex, and tumor size. Cases were defined as patients with VS proven to have grown on serial magnetic resonance imaging (MRI). Controls were defined as patient with VS stable on serial MRI. Prevalence of regular aspirin use was compared in patients with growing VS versus stable VS. Absolute and relative contraindications to aspirin intake were recorded.

Results: Six hundred fifty-three patients with VS were contacted, and responses were received by 67% (220 cases and 217 controls). The mean tumor size was 11.3 mm (9.0 mm and 13.3 mm in controls and cases, respectively). Aspirin exposure was more common in stable VS than growing VS (22.1% vs. 17.3%). However, following matching to control for covariates, aspirin was not found to be associated with VS stability (P = .475). Multiple logistic regression (analysis of variance) found tumor size to be the only factor strongly associated with tumor growth (P < .0001). Ninety-two percent of patients were able to take aspirin, with the majority being at low risk of complications from regular use.

Conclusions: This study aimed to examine the relationship between aspirin intake and VS stability. In contrast to previous reports, after controlling for covariates, the findings do not demonstrate an association. Only tumor size at diagnosis appears predictive of risk of VS growth.

Level Of Evidence: 3b. Laryngoscope, 128:2139-2144, 2018.
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http://dx.doi.org/10.1002/lary.27114DOI Listing
September 2018

Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary 'VoxTox' research programme.

CERN Ideasq J Exp Innov 2017 Jun;1(1):3-12

Cancer Research UK VoxTox Research Group, University of Cambridge Department of Oncology, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.
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http://dx.doi.org/10.23726/cij.2017.457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701740PMC
June 2017

Local alkylating chemotherapy applied immediately after 5-ALA guided resection of glioblastoma does not provide additional benefit.

J Neurooncol 2018 Jan 14;136(2):273-280. Epub 2017 Nov 14.

Division of Neurosurgery, Addenbrookes Hospital, Cambridge University NHS Foundation Trust, Cambridge, UK.

Grade IV glioma is the most common and aggressive primary brain tumour. Gross total resection with 5-aminolevulinic acid (5-ALA) guided surgery combined with local chemotherapy (carmustine wafers) is an attractive treatment strategy in these patients. No previous studies have examined the benefit carmustine wafers in a treatment programme of 5-ALA guided resection followed by a temozolomide-based chemoradiotherapy protocol. The objective of this study was to examine the benefit of carmustine wafers on survival in patients undergoing 5-ALA guided resection. A retrospective cohort study of 260 patients who underwent 5-ALA resection of confirmed WHO 2007 Grade IV glioma between July 2009 and December 2014. Survival curves were calculated using the Kaplan-Meier method from surgery. The log-rank test was used to compare survival curves between groups. Cox regression was performed to identify variables predicting survival. A propensity score matched analysis was used to compare survival between patients who did and did not receive carmustine wafers while controlling for baseline characteristics. Propensity matched analysis showed no significant survival benefit of insertion of carmustine wafers over 5-ALA resection alone (HR 0.97 [0.68-1.26], p = 0.836). There was a trend to higher incidence of wound infection in those who received carmustine wafers (15.4 vs. 7.1%, p = 0.064). The Cox regression analysis showed that intraoperative residual fluorescent tumour and residual enhancing tumour on post-operative MRI were significantly predictive of reduced survival. Carmustine wafers have no added benefit following 5-ALA guided resection. Residual fluorescence and residual enhancing disease following resection have a negative impact on survival.
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http://dx.doi.org/10.1007/s11060-017-2649-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770495PMC
January 2018

High flow or titrated oxygen for obese medical inpatients: a randomised crossover trial.

Med J Aust 2017 Nov;207(10):430-434

Medical Research Institute of New Zealand, Wellington, New Zealand.

Objective: To compare the effects on transcutaneous carbon dioxide tension (Ptco2) of high concentration and titrated oxygen therapy in medical inpatients with morbid obesity who were not selected for a pre-existing diagnosis of obesity hypoventilation syndrome.

Design: A randomised, crossover trial undertaken between February and September 2015.

Setting: Internal medicine service, Wellington Regional Hospital, New Zealand.

Participants: 22 adult inpatients, aged 16 years or more, with a body mass index exceeding 40 kg/m2.

Interventions: Participants received in random order two 60-minute interventions, with a minimum 30-minute washout period between treatments: titrated oxygen therapy (oxygen delivered, if required, via nasal prongs to achieve peripheral oxygen saturation [Spo2] of 88-92%), and high concentration oxygen therapy (delivered via Hudson mask at 8 L/min, without regard to Spo2). Ptco2 and Spo2 were recorded at 10-minute intervals.

Main Outcome Measure: Ptco2 at 60 minutes, adjusted for baseline.

Results: Baseline Ptco2 was 45 mmHg or lower for 16 participants with full data (73%). The mean difference in Ptco2 between high concentration and titrated oxygen therapy at 60 minutes was 3.2 mmHg (95% CI, 1.3-5.2 mmHg; P = 0.002).

Conclusion: High concentration oxygen therapy increases Ptco2 in morbidly obese patients. Our findings support guidelines that advocate oxygen therapy, if required in patients with morbid obesity, be titrated to achieve a target Spo2 of 88-92%.

Clinical Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12610000522011.
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http://dx.doi.org/10.5694/mja17.00270DOI Listing
November 2017

Analysis of heterogeneity in T2-weighted MR images can differentiate pseudoprogression from progression in glioblastoma.

PLoS One 2017 17;12(5):e0176528. Epub 2017 May 17.

Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.

Purpose: To develop an image analysis technique that distinguishes pseudoprogression from true progression by analyzing tumour heterogeneity in T2-weighted images using topological descriptors of image heterogeneity called Minkowski functionals (MFs).

Methods: Using a retrospective patient cohort (n = 50), and blinded to treatment response outcome, unsupervised feature estimation was performed to investigate MFs for the presence of outliers, potential confounders, and sensitivity to treatment response. The progression and pseudoprogression groups were then unblinded and supervised feature selection was performed using MFs, size and signal intensity features. A support vector machine model was obtained and evaluated using a prospective test cohort.

Results: The model gave a classification accuracy, using a combination of MFs and size features, of more than 85% in both retrospective and prospective datasets. A different feature selection method (Random Forest) and classifier (Lasso) gave the same results. Although not apparent to the reporting radiologist, the T2-weighted hyperintensity phenotype of those patients with progression was heterogeneous, large and frond-like when compared to those with pseudoprogression.

Conclusion: Analysis of heterogeneity, in T2-weighted MR images, which are acquired routinely in the clinic, has the potential to detect an earlier treatment response allowing an early change in treatment strategy. Prospective validation of this technique in larger datasets is required.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176528PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435159PMC
September 2017

Effect of Heat Exposure and Simulated Physical Firefighting Work on Acute Inflammatory and Cortisol Responses.

Ann Work Expo Health 2017 Jun;61(5):600-603

Institute for Physical Activity and Nutrition (IPAN), Deakin University, 1 Gheringhap Street, Geelong, Victoria 3220, Australia.

Objective: To examine firefighters' hormonal and immune markers during consecutive days of physical firefighting work performed in hot compared to mild ambient temperatures.

Methods: Firefighters completed 3 days of simulated physical firefighting work in either hot (HOT condition; n = 19; 33°C) or mild temperature conditions (CON condition; n = 18; 19°C). Participants provided regular daily samples for the determination of salivary cortisol and plasma cytokine levels (IL-6, IL-8, IL-1β, TNF-α, IL-4, and IL-10).

Results: The HOT condition elicited higher IL-4 and a trend towards elevated afternoon and evening cortisol when compared to the CON trial. The HOT condition also produced lower levels of IL-1β compared to the CON across time points and a decrease in IL-1β between days of work. IL-6 increased across time points and between work days, but this finding was not different between mild and hot conditions. Immune-endocrine interactions revealed a rise in morning IL-6 that was related to elevated daily cortisol levels, independent of condition.

Conclusion: Findings demonstrate the possibility that firefighters are able to regulate normal acute immune and hormonal responses to multiple days of simulated physical work in hot and mild ambient temperatures. Further research is necessary to determine if the responses continue under non-simulated conditions and in response to more extreme temperatures possible on the fire-ground.
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http://dx.doi.org/10.1093/annweh/wxx029DOI Listing
June 2017

Prevention of radiotherapy-induced neurocognitive dysfunction in survivors of paediatric brain tumours: the potential role of modern imaging and radiotherapy techniques.

Lancet Oncol 2017 02;18(2):e91-e100

Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.

Neurocognitive dysfunction is the leading cause of reduced quality of life in long-term survivors of paediatric brain tumours. Radiotherapy is one of the main contributors to neurocognitive sequelae. Current approaches for prevention and reduction of neurocognitive dysfunction include avoidance of radiotherapy in young children and reduction of the radiotherapy dose and volume of brain irradiated. Substantial advances have been made in brain imaging, especially with functional imaging and fibre tracking with the use of diffusion tensor imaging. Radiotherapy techniques for photon therapy have also evolved, with widespread use of techniques such as image-guided radiotherapy, volumetric modulated arc therapy, helical tomotherapy, and adaptive radiotherapy. The number of proton beam and heavy ion therapy facilities is increasing worldwide and there is great enthusiasm for clinical use of advanced MRI-guided radiotherapy systems. Here, we review the potential role of modern imaging and innovative radiotherapy techniques in minimisation of neurocognitive sequelae in children with brain tumours, and discuss various strategies to integrate these advances to drive further research.
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http://dx.doi.org/10.1016/S1470-2045(17)30030-XDOI Listing
February 2017

Minimally invasive surgery versus radiotherapy/chemoradiotherapy for small-volume primary oropharyngeal carcinoma.

Cochrane Database Syst Rev 2016 12 11;12:CD010963. Epub 2016 Dec 11.

Head and Neck Unit, Royal Marsden Hospital, Fulham Road, London, UK, SW3 6JJ.

Background: More than 400,000 cases of oropharyngeal squamous cell carcinoma (OPSCC) are diagnosed each year worldwide and the incidence is rising, partly as a result of human papillomavirus. Human papillomavirus-associated OPSCC affects younger patients and often presents at a higher stage; however, it is associated with a better prognosis.Until recently, first-line management of OPSCC involved chemoradiotherapy, as research had demonstrated comparable survival outcomes when compared with open surgery, with significantly decreased morbidity. However, interventions have now evolved with computerised planning and intensity-modulated radiotherapy, and the advent of endoscopic head and neck surgery, which provide the potential for decreased treatment-associated morbidity.The oropharynx plays an essential role in swallowing, speech and protecting the airway as it is situated at the bifurcation of the respiratory and digestive tracts. Treatment modality recommendations are based on survival outcomes. Given the younger patient demographic, establishing the safety of modalities that potentially have better functional outcome is becoming increasingly important.

Objectives: To assess the efficacy of endoscopic head and neck surgery (transoral robotic surgery or transoral laser microsurgery) for small-volume, primary (T1-2, N0-2) oropharyngeal squamous cell carcinoma (OPSCC) in comparison to radiotherapy/chemoradiotherapy.

Search Methods: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2016, Issue 10); PubMed; EMBASE; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 8 November 2016.

Selection Criteria: Randomised controlled trials in patients with carcinoma in the oropharynx subsite (as defined by the World Health Organization classification C09, C10). Cancers included were primary squamous cell carcinomas arising from the oropharyngeal mucosa. The tumours were classified as T1-T2 with or without nodal disease and with no evidence of distant metastatic spread. The intervention was transoral, minimally invasive surgery with or without adjuvant radiotherapy or adjuvant chemoradiotherapy. The comparator was primary radiotherapy with or without induction or concurrent chemotherapy for the tumour. The treatments received and compared were of curative intent and patients had not undergone prior intervention, other than diagnostic biopsy.

Data Collection And Analysis: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival (disease-related mortality was to be studied where possible), locoregional control, disease-free survival and progression-free survival or time to recurrence. All outcomes were to be measured at two, three and five years after diagnosis. Our secondary outcomes included quality of life, harms associated with treatment, patient satisfaction and xerostomia score.

Main Results: No completed studies met the inclusion criteria for the review. Two ongoing trials fulfilled the selection criteria, however neither are complete.'Early-stage squamous cell carcinoma of the oropharynx: radiotherapy versus trans-oral robotic surgery (ORATOR)' is a phase II randomised controlled trial comparing primary radiation therapy with primary transoral robotic surgery for small-volume primary (T1-2, N0-2) OPSCC. It is currently in progress with an estimated completion date of June 2021.'European Organisation for Research and Treatment of Cancer 1420 (EORTC 1420-HNCG-ROG)' is a phase III, randomised study assessing the "best of" radiotherapy compared to transoral robotic surgery/transoral laser microsurgery in patients with T1-T2, N0 squamous cell carcinoma of the oropharynx and base of tongue. It was due to start accrual mid-2016.

Authors' Conclusions: The role of endoscopic head and neck surgery in the management of OPSCC is clearly expanding as evidenced by its more overt incorporation into the current National Comprehensive Cancer Network guidelines. Data are mounting regarding its outcomes both in terms of survival and lower morbidity. As confidence increases, it is being used in the management of more advanced OPSCC.Based on this review, there is currently no high-quality evidence from randomised controlled trials regarding clinical outcomes for patients with oropharyngeal cancer receiving endoscopic head and neck surgery compared with primary chemoradiotherapy.
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http://dx.doi.org/10.1002/14651858.CD010963.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463943PMC
December 2016