Publications by authors named "Michael D Jenkinson"

130 Publications

An International Multicenter Matched Cohort Analysis of Incidental Meningioma Progression During Active Surveillance or After Stereotactic Radiosurgery: The IMPASSE Study.

Neuro Oncol 2021 Jun 9. Epub 2021 Jun 9.

Department of Neurosurgery, University of Liverpool & The Walton Centre NHS Trust, Lower Lane, Liverpool, UK.

Background: The optimal management of patients with an incidental meningiomas remains unclear. The aim of this study was to characterize the radiologic and neurological outcomes of expectant and SRS management of asymptomatic meningioma patients.

Methods: Using data from 14 centers across 10 countries, the study compares SRS outcomes to active surveillance of asymptomatic meningiomas. Local tumor control of asymptomatic meningiomas and development of new neurological deficits attributable to the tumor were evaluated in the SRS and conservatively managed groups.

Results: In unmatched cohorts, 727 meningioma patients underwent SRS and were followed for a mean of 57.2 months. In the conservatively managed cohort, 388 patients were followed for a mean of 43.5 months. Tumor control was 99.0% of SRS and 64.2% of conservatively managed patients (p<0.001; OR 56.860 (95%CI 26.253-123.150))). New neurological deficits were 2.5% in the SRS and 2.8% of conservatively managed patients (p=0.764; OR 0.890 (95% CI 0.416-1.904)). After 1:1 propensity matching for patient age, tumor volume, location, and imaging follow-up, tumor control in the SRS and conservatively managed cohorts was 99.4% and 62.1%, respectively (p<0.001; OR 94.461 (95% CI 23.082-386.568)). In matched cohorts, new neurological deficits were noted in 2.3% of SRS treated and 3.2% of conservatively managed patients (p=0.475; OR 0.700 (95% CI 0.263-1.863)).

Conclusions: SRS affords superior radiologic tumor control compared to active surveillance without increasing the risk of neurological deficits in asymptomatic meningioma patients. While SRS and active surveillance are reasonable options, SRS appears to alter the natural history of asymptomatic meningiomas including tumor progression in the majority of patients treated.
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http://dx.doi.org/10.1093/neuonc/noab132DOI Listing
June 2021

Neuroinflammation preceding primary central nervous system lymphoma (PCNSL) - Case reports and literature review.

J Clin Neurosci 2021 May 31. Epub 2021 May 31.

The Walton Centre Foundation Trust, United Kingdom.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of extra-nodal non-Hodgkin's lymphoma. Corticosteroids cause transient regression of PCNSL at the radiological and histological level. A growing number of case reports describe histologically confirmed neuroinflammation (sentinel lesions) heralding the development of PCNSL. We present two further cases of sentinel lesions contextualised by a review of past literature. Our aims are to collate existing knowledge on sentinel lesions in PCNSL and explore their pathophysiological significance. Two cases were identified (n = 2) from a cohort of 104 patients with PCNSL referred to a tertiary neurosurgery centre. A literature search identified previously reported cases (n = 14). Median age was 57.5 (range; 26-72); pre-biopsy corticosteroid administration was reported in 50% of cases (n = 8); mean time between biopsies was 10 months (range; 3-60). Common MRI features were homogenous enhancement (10;71.4%) and T2-hyperintensity (11;100%). Histochemical analysis of sentinel lesion biopsy revealed inflammatory CD3/4/5/8-positive T-cells (14; 100%), demyelination (13; 81.3%), rare/scattered CD20-postive B-cells (11;78.6%) and CD68-positive macrophages (10;71.4%). Repeat biopsy confirmed PCNSL in all cases. Waxing and waning CNS inflammation has been identified in 16 patients ultimately diagnosed with PCNSL. Neuro-specialists should be aware of this atypical presentation and maintain a high index of suspicion for lymphoma despite histopathology negative for lymphoma when clinical or radiological features indicate PCNSL.
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http://dx.doi.org/10.1016/j.jocn.2021.05.038DOI Listing
May 2021

CovidNeuroOnc: A UK multicenter, prospective cohort study of the impact of the COVID-19 pandemic on the neuro-oncology service.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab014. Epub 2021 Jan 28.

Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, UK.

Background: The COVID-19 pandemic has profoundly affected cancer services. Our objective was to determine the effect of the COVID-19 pandemic on decision making and the resulting outcomes for patients with newly diagnosed or recurrent intracranial tumors.

Methods: We performed a multicenter prospective study of all adult patients discussed in weekly neuro-oncology and skull base multidisciplinary team meetings who had a newly diagnosed or recurrent intracranial (excluding pituitary) tumor between 01 April and 31 May 2020. All patients had at least 30-day follow-up data. Descriptive statistical reporting was used.

Results: There were 1357 referrals for newly diagnosed or recurrent intracranial tumors across 15 neuro-oncology centers. Of centers with all intracranial tumors, a change in initial management was reported in 8.6% of cases ( = 104/1210). Decisions to change the management plan reduced over time from a peak of 19% referrals at the start of the study to 0% by the end of the study period. Changes in management were reported in 16% ( = 75/466) of cases previously recommended for surgery and 28% of cases previously recommended for chemotherapy ( = 20/72). The reported SARS-CoV-2 infection rate was similar in surgical and non-surgical patients (2.6% vs. 2.4%, > .9).

Conclusions: Disruption to neuro-oncology services in the UK caused by the COVID-19 pandemic was most marked in the first month, affecting all diagnoses. Patients considered for chemotherapy were most affected. In those recommended surgical treatment this was successfully completed. Longer-term outcome data will evaluate oncological treatments received by these patients and overall survival.
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http://dx.doi.org/10.1093/noajnl/vdab014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928638PMC
January 2021

Management of pineal and colloid cysts.

Pract Neurol 2021 May 26. Epub 2021 May 26.

Clinical and Academic Neuroscience, Addenbrooke's Hospital, Cambridge, Cambridgeshire, UK.

The widespread use of MRI has led to the increasingly frequent diagnosis of pineal and colloid cysts. While most are small and incidental, do not require long-term monitoring and will never need treatment, they are a cause of patient anxiety and clinician uncertainty regarding the optimal management-particularly for larger cysts or those with an atypical appearance. Occasionally pineal cysts, and more commonly colloid cysts, cause hydrocephalus that requires urgent neurosurgical treatment. More recently the non-hydrocephalic symptomatic pineal cyst has been described in the neurosurgical literature but there is controversy over this entity and its management. This review addresses the difficulties in managing pineal and colloid cysts and provides a pragmatic framework for the practising clinician.
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http://dx.doi.org/10.1136/practneurol-2020-002838DOI Listing
May 2021

Early diagnosis of brain tumours using a novel spectroscopic liquid biopsy.

Brain Commun 2021 30;3(2):fcab056. Epub 2021 Mar 30.

ClinSpec Diagnostics Limited, Royal College Building, Glasgow G1 1XW, UK.

Early diagnosis of brain tumours is challenging and a major unmet need. Patients with brain tumours most often present with non-specific symptoms more commonly associated with less serious diagnoses, making it difficult to determine which patients to prioritize for brain imaging. Delays in diagnosis affect timely access to treatment, with potential impacts on quality of life and survival. A test to help identify which patients with non-specific symptoms are most likely to have a brain tumour at an earlier stage would dramatically impact on patients by prioritizing demand on diagnostic imaging facilities. This clinical feasibility study of brain tumour early diagnosis was aimed at determining the accuracy of our novel spectroscopic liquid biopsy test for the triage of patients with non-specific symptoms that might be indicative of a brain tumour, for brain imaging. Patients with a suspected brain tumour based on assessment of their symptoms in primary care can be referred for open access CT scanning. Blood samples were prospectively obtained from 385 of such patients, or patients with a new brain tumour diagnosis. Samples were analysed using our spectroscopic liquid biopsy test to predict presence of disease, blinded to the brain imaging findings. The results were compared to the patient's index brain imaging delivered as per standard care. Our test predicted the presence of glioblastoma, the most common and aggressive brain tumour, with 91% sensitivity, and all brain tumours with 81% sensitivity, and 80% specificity. Negative predictive value was 95% and positive predictive value 45%. The reported levels of diagnostic accuracy presented here have the potential to improve current symptom-based referral guidelines, and streamline assessment and diagnosis of symptomatic patients with a suspected brain tumour.
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http://dx.doi.org/10.1093/braincomms/fcab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111062PMC
March 2021

Neurosurgical CSF Diversion in Idiopathic Intracranial Hypertension: A Narrative Review.

Life (Basel) 2021 Apr 26;11(5). Epub 2021 Apr 26.

Department of Paediatric Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool L12 2AP, UK.

The prevalence of idiopathic intracranial hypertension (IIH), a complex disorder, is increasing globally in association with obesity. The IIH syndrome occurs as the result of elevated intracranial pressure, which can cause permanent visual impairment and loss if not adequately managed. CSF diversion via ventriculoperitoneal and lumboperitoneal shunts is a well-established strategy to protect vision in medically refractory cases. Success of CSF diversion is compromised by high rates of complication; including over-drainage, obstruction, and infection. This review outlines currently used techniques and technologies in the management of IIH. Neurosurgical CSF diversion is a vital component of the multidisciplinary management of IIH.
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http://dx.doi.org/10.3390/life11050393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146765PMC
April 2021

The growth rate and clinical outcomes of radiation induced meningioma undergoing treatment or active monitoring.

J Neurooncol 2021 Apr 22. Epub 2021 Apr 22.

Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.

Introduction: Radiation induced meningioma (RIM) incidence is increasing in line with improved childhood cancer survival. No optimal management strategy consensus exists. This study aimed to delineate meningioma growth rates from tumor discovery and correlate with clinical outcomes.

Methods: Retrospective study of patients with a RIM, managed at a specialist tertiary neuroscience center (2007-2019). Tumor volume was measured from diagnosis and at subsequent interval scans. Meningioma growth rate was determined using a linear mixed-effects model. Clinical outcomes were correlated with growth rates accounting for imaging and clinical prognostic factors.

Results: Fifty-four patients (110 meningiomas) were included. Median duration of follow-up was 74 months (interquartile range [IQR], 41-102 months). Mean radiation dose was 41 Gy (standard deviation [SD] = 14.9) with a latency period of 34.4 years (SD = 13.7). Median absolute growth rate was 0.62 cm/year and the median relative growth rate was 72%/year. Forty meningiomas (between 27 patients) underwent surgical intervention after a median follow-up duration of 4 months (IQR 2-35). Operated RIMs were clinically aggressive, likely to be WHO grade 2 at first resection (43.6%) and to progress after surgery (41%). Median time to progression was 28 months (IQR 13-60.5). A larger meningioma at discovery was associated with growth (HR 1.2 [95% CI 1.0-1.5], P = 0.039) but not progression after surgery (HR 2.2 [95% CI 0.7-6.6], P = 0.181). Twenty-seven (50%) patients had multiple meningiomas by the end of the study.

Conclusion: RIMs exhibit high absolute and relative growth rates after discovery. Surgery is recommended for symptomatic or rapidly growing meningiomas only. Recurrence risk after surgery is high.
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http://dx.doi.org/10.1007/s11060-021-03761-3DOI Listing
April 2021

COVID-legal study: neurosurgeon experience in Britain during the first phase of the COVID-19 pandemic - medico-legal considerations.

Br J Neurosurg 2021 Mar 24:1-4. Epub 2021 Mar 24.

Department of Neurosurgery, John Radcliffe Hospital, Nuffield Department of Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

The COVID-19 pandemic has resulted in a significant number of changes to elective and emergency neurosurgical practice. This paper reports the results of an online survey of Society of British Neurological Surgeons (SBNS) members undertaken between 10th and 24th of June 2020 regarding changes in consent practice in response to COVID-19, as well as the physical challenges experienced while operating under higher levels of personal protective equipment (PPE). Despite the real and substantial risks associated with COVID-19, 23% of surgeons reported they were not made any changes to their usual consent process, and 54% of surgeons indicated that they made reference to COVID-19-associated risks in their written consent documentation. 93% of neurosurgeons reported physical difficulties operating using PPE; 62% reported visors/goggles fogging up, 55% experienced 'overheating', 62% reported fatigue, and 82% of surgeons reported difficulty communicating with the theatre staff. This survey highlights discrepancies in the consent practice between neurosurgeons which needs to be addressed at both local and national levels. The PPE being used in neurosurgical operations is not designed for use with specialist equipment (82% of respondents reported having to remove PPE to use the microscope) and the reported physical difficulties using PPE intraoperatively could significantly impact on both neurosurgeon performance and patient outcomes. This requires urgent attention by NHS procurement and management and should be urgently escalated to trust occupational health authorities as a workplace safety concern.
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http://dx.doi.org/10.1080/02688697.2021.1902475DOI Listing
March 2021

A Position Statement on the Utility of Interval Imaging in Standard of Care Brain Tumour Management: Defining the Evidence Gap and Opportunities for Future Research.

Front Oncol 2021 9;11:620070. Epub 2021 Feb 9.

Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.

Objectiv E: To summarise current evidence for the utility of interval imaging in monitoring disease in adult brain tumours, and to develop a position for future evidence gathering while incorporating the application of data science and health economics.

Methods: Experts in 'interval imaging' (imaging at pre-planned time-points to assess tumour status); data science; health economics, trial management of adult brain tumours, and patient representatives convened in London, UK. The current evidence on the use of interval imaging for monitoring brain tumours was reviewed. To improve the evidence that interval imaging has a role in disease management, we discussed specific themes of data science, health economics, statistical considerations, patient and carer perspectives, and multi-centre study design. Suggestions for future studies aimed at filling knowledge gaps were discussed.

Results: Meningioma and glioma were identified as priorities for interval imaging utility analysis. The "monitoring biomarkers" most commonly used in adult brain tumour patients were standard structural MRI features. Interval imaging was commonly scheduled to provide reported imaging prior to planned, regular clinic visits. There is limited evidence relating interval imaging in the absence of clinical deterioration to management change that alters morbidity, mortality, quality of life, or resource use. Progression-free survival is confounded as an outcome measure when using structural MRI in glioma. Uncertainty from imaging causes distress for some patients and their caregivers, while for others it provides an important indicator of disease activity. Any study design that changes imaging regimens should consider the potential for influencing current or planned therapeutic trials, ensure that opportunity costs are measured, and capture indirect benefits and added value.

Conclusion: Evidence for the value, and therefore utility, of regular interval imaging is currently lacking. Ongoing collaborative efforts will improve trial design and generate the evidence to optimise monitoring imaging biomarkers in standard of care brain tumour management.
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http://dx.doi.org/10.3389/fonc.2021.620070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900557PMC
February 2021

Early economic evaluation to guide the development of a spectroscopic liquid biopsy for the detection of brain cancer.

Int J Technol Assess Health Care 2021 Feb 24;37:e41. Epub 2021 Feb 24.

Department of Pure and Applied Chemistry, University of Strathclyde, Technology and Innovation Centre, Glasgow, UK.

Objectives: An early economic evaluation to inform the translation into clinical practice of a spectroscopic liquid biopsy for the detection of brain cancer. Two specific aims are (1) to update an existing economic model with results from a prospective study of diagnostic accuracy and (2) to explore the potential of brain tumor-type predictions to affect patient outcomes and healthcare costs.

Methods: A cost-effectiveness analysis from a UK NHS perspective of the use of spectroscopic liquid biopsy in primary and secondary care settings, as well as a cost-consequence analysis of the addition of tumor-type predictions was conducted. Decision tree models were constructed to represent simplified diagnostic pathways. Test diagnostic accuracy parameters were based on a prospective validation study. Four price points (GBP 50-200, EUR 57-228) for the test were considered.

Results: In both settings, the use of liquid biopsy produced QALY gains. In primary care, at test costs below GBP 100 (EUR 114), testing was cost saving. At GBP 100 (EUR 114) per test, the ICER was GBP 13,279 (EUR 15,145), whereas at GBP 200 (EUR 228), the ICER was GBP 78,300 (EUR 89,301). In secondary care, the ICER ranged from GBP 11,360 (EUR 12,956) to GBP 43,870 (EUR 50,034) across the range of test costs.

Conclusions: The results demonstrate the potential for the technology to be cost-effective in both primary and secondary care settings. Additional studies of test use in routine primary care practice are needed to resolve the remaining issues of uncertainty-prevalence in this patient population and referral behavior.
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http://dx.doi.org/10.1017/S0266462321000143DOI Listing
February 2021

Fibulin-2: A Novel Biomarker for Differentiating Grade II from Grade I Meningiomas.

Int J Mol Sci 2021 Jan 8;22(2). Epub 2021 Jan 8.

Faculty of Health, Medicine, Dentistry and Human Sciences, The Institute of Translational and Stratified Medicine, University of Plymouth, The John Bull Building, Plymouth Science Park, Research Way, Plymouth PL6 8BU, UK.

There is an unmet need for the identification of biomarkers to aid in the diagnosis, clinical management, prognosis and follow-up of meningiomas. There is currently no consensus on the optimum management of WHO grade II meningiomas. In this study, we identified the calcium binding extracellular matrix glycoprotein, Fibulin-2, via mass-spectrometry-based proteomics, assessed its expression in grade I and II meningiomas and explored its potential as a grade II biomarker. A total of 87 grade I and 91 grade II different meningioma cells, tissue and plasma samples were used for the various experimental techniques employed to assess Fibulin-2 expression. The tumours were reviewed and classified according to the 2016 edition of the Classification of the Tumours of the central nervous system (CNS). Mass spectrometry proteomic analysis identified Fibulin-2 as a differentially expressed protein between grade I and II meningioma cell cultures. Fibulin-2 levels were further evaluated in meningioma cells using Western blotting and Real-time Quantitative Polymerase Chain Reaction (RT-qPCR); in meningioma tissues via immunohistochemistry and RT-qPCR; and in plasma via Enzyme-Linked Immunosorbent Assay (ELISA). Proteomic analyses ( < 0.05), Western blotting ( < 0.05) and RT-qPCR ( < 0.01) confirmed significantly higher Fibulin-2 (FBLN2) expression levels in grade II meningiomas compared to grade I. Fibulin-2 blood plasma levels were also significantly higher in grade II meningioma patients compared to grade I patients. This study suggests that elevated Fibulin-2 might be a novel grade II meningioma biomarker, when differentiating them from the grade I tumours. The trend of Fibulin-2 expression observed in plasma may serve as a useful non-invasive biomarker.
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http://dx.doi.org/10.3390/ijms22020560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827565PMC
January 2021

Intraoperative imaging technology to maximise extent of resection for glioma: a network meta-analysis.

Cochrane Database Syst Rev 2021 01 4;1:CD013630. Epub 2021 Jan 4.

Department of Neurosurgery & Institute of Systems Molecular and Integrative Biology, The Walton Centre & University of Liverpool, Liverpool, UK.

Background: Multiple studies have identified the prognostic relevance of extent of resection in the management of glioma. Different intraoperative technologies have emerged in recent years with unknown comparative efficacy in optimising extent of resection. One previous Cochrane Review provided low- to very low-certainty evidence in single trial analyses and synthesis of results was not possible. The role of intraoperative technology in maximising extent of resection remains uncertain. Due to the multiple complementary technologies available, this research question is amenable to a network meta-analysis methodological approach.

Objectives: To establish the comparative effectiveness and risk profile of specific intraoperative imaging technologies using a network meta-analysis and to identify cost analyses and economic evaluations as part of a brief economic commentary.

Search Methods: We searched CENTRAL (2020, Issue 5), MEDLINE via Ovid to May week 2 2020, and Embase via Ovid to 2020 week 20. We performed backward searching of all identified studies. We handsearched two journals, Neuro-oncology and the Journal of Neuro-oncology from 1990 to 2019 including all conference abstracts. Finally, we contacted recognised experts in neuro-oncology to identify any additional eligible studies and acquire information on ongoing randomised controlled trials (RCTs).

Selection Criteria: RCTs evaluating people of all ages with presumed new or recurrent glial tumours (of any location or histology) from clinical examination and imaging (computed tomography (CT) or magnetic resonance imaging (MRI), or both). Additional imaging modalities (e.g. positron emission tomography, magnetic resonance spectroscopy) were not mandatory. Interventions included fluorescence-guided surgery, intraoperative ultrasound, neuronavigation (with or without additional image processing, e.g. tractography), and intraoperative MRI.

Data Collection And Analysis: Two review authors independently assessed the search results for relevance, undertook critical appraisal according to known guidelines, and extracted data using a prespecified pro forma.

Main Results: We identified four RCTs, using different intraoperative imaging technologies: intraoperative magnetic resonance imaging (iMRI) (2 trials, with 58 and 14 participants); fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) (1 trial, 322 participants); and neuronavigation (1 trial, 45 participants). We identified one ongoing trial assessing iMRI with a planned sample size of 304 participants for which results are expected to be published around winter 2020. We identified no published trials for intraoperative ultrasound. Network meta-analyses or traditional meta-analyses were not appropriate due to absence of homogeneous trials across imaging technologies. Of the included trials, there was notable heterogeneity in tumour location and imaging technologies utilised in control arms. There were significant concerns regarding risk of bias in all the included studies. One trial of iMRI found increased extent of resection (risk ratio (RR) for incomplete resection was 0.13, 95% confidence interval (CI) 0.02 to 0.96; 49 participants; very low-certainty evidence) and one trial of 5-ALA (RR for incomplete resection was 0.55, 95% CI 0.42 to 0.71; 270 participants; low-certainty evidence). The other trial assessing iMRI was stopped early after an unplanned interim analysis including 14 participants; therefore, the trial provided very low-quality evidence. The trial of neuronavigation provided insufficient data to evaluate the effects on extent of resection. Reporting of adverse events was incomplete and suggestive of significant reporting bias (very low-certainty evidence). Overall, the proportion of reported events was low in most trials and, therefore, issues with power to detect differences in outcomes that may or may not have been present. Survival outcomes were not adequately reported, although one trial reported no evidence of improvement in overall survival with 5-ALA (hazard ratio (HR) 0.82, 95% CI 0.62 to 1.07; 270 participants; low-certainty evidence). Data for quality of life were only available for one study and there was significant attrition bias (very low-certainty evidence).

Authors' Conclusions: Intraoperative imaging technologies, specifically 5-ALA and iMRI, may be of benefit in maximising extent of resection in participants with high-grade glioma. However, this is based on low- to very low-certainty evidence. Therefore, the short- and long-term neurological effects are uncertain. Effects of image-guided surgery on overall survival, progression-free survival, and quality of life are unclear. Network and traditional meta-analyses were not possible due to the identified high risk of bias, heterogeneity, and small trials included in this review. A brief economic commentary found limited economic evidence for the equivocal use of iMRI compared with conventional surgery. In terms of costs, one non-systematic review of economic studies suggested that, compared with standard surgery, use of image-guided surgery has an uncertain effect on costs and that 5-ALA was more costly. Further research, including completion of ongoing trials of ultrasound-guided surgery, is needed.
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http://dx.doi.org/10.1002/14651858.CD013630.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094975PMC
January 2021

Proton Therapy for Intracranial Meningioma for the Treatment of Primary/Recurrent Disease Including Re-Irradiation.

Front Oncol 2020 14;10:558845. Epub 2020 Dec 14.

Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.

Meningeal tumors represent approximately 10-25% of primary brain tumors and occur usually in elderly female patients. Most meningiomas are benign (80-85%) and for symptomatic and/or large tumors, surgery, with or without radiation therapy (RT), has been long established as an effective means of local tumor control. RT can be delivered to inoperable lesions or to those with non-benign histology and for Simpson I-III and IV-V resection. RT can be delivered with photons or particles (protons or carbon ions) in stereotactic or non-stereotactic conditions. Particle therapy delivered for these tumors uses the physical properties of charged carbon ions or protons to spare normal brain tissue (i.e. Bragg peak), with or without or a dose-escalation paradigm for non-benign lesions. PT can substantially decrease the dose delivered to the non-target brain tissues, including but not limited to the hippocampi, optic apparatus or cochlea. Only a limited number of meningioma patients have been treated with PT in the adjuvant or recurrent setting, as well as for inoperable lesions with pencil beam scanning and with protons only. Approximately 500 patients with image-defined or WHO grade I meningioma have been treated with protons. The reported outcome, usually 5-year local tumor control, ranges from 85 to 99% (median, 96%). For WHO grade II or III patients, the outcome of only 97 patients has been published, reporting a median tumor local control rate of 52% (range, 38-71.1). Only 24 recurring patients treated previously with photon radiotherapy and re-treated with PT were reported. The clinical outcome of these challenging patients seems interesting, provided that they presented initially with benign tumors, are not in the elderly category and have been treated previously with conventional radiation dose of photons. Overall, the number of meningioma patients treated or-re-irradiated with this treatment modality is small and the clinical evidence level is somewhat low (i.e. 3b-5). In this review, we detail the results of upfront PT delivered to patients with meningioma in the adjuvant setting and for inoperable tumors. The outcome of meningioma patients treated with this radiation modality for recurrent tumors, with or without previous RT, will also be reviewed.
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http://dx.doi.org/10.3389/fonc.2020.558845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769250PMC
December 2020

Interrogation of Status in Gliomas by Fourier Transform Infrared Spectroscopy.

Cancers (Basel) 2020 Dec 8;12(12). Epub 2020 Dec 8.

WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, 99 George St., Glasgow G1 1RD, UK.

Mutations in the isocitrate dehydrogenase 1 () gene are found in a high proportion of diffuse gliomas. The presence of the mutation is a valuable diagnostic, prognostic and predictive biomarker for the management of patients with glial tumours. Techniques involving vibrational spectroscopy, e.g., Fourier transform infrared (FTIR) spectroscopy, have previously demonstrated analytical capabilities for cancer detection, and have the potential to contribute to diagnostics. The implementation of FTIR microspectroscopy during surgical biopsy could present a fast, label-free method for molecular genetic classification. For example, the rapid determination of status in a patient with a glioma diagnosis could inform intra-operative decision-making between alternative surgical strategies. In this study, we utilized synchrotron-based FTIR microanalysis to probe tissue microarray sections from 79 glioma patients, and distinguished the positive class (-mutated) from the -wildtype glioma, with a sensitivity and specificity of 82.4% and 83.4%, respectively. We also examined the ability of attenuated total reflection (ATR)-FTIR spectroscopy in detecting the biomolecular events and global epigenetic and metabolic changes associated with mutations in the enzyme, in blood serum samples collected from an additional 72 brain tumour patients. Centrifugal filtration enhanced the diagnostic ability of the classification models, with balanced accuracies up to ~69%. Identification of the molecular status from blood serum prior to biopsy could further direct some patients to alternative treatment strategies.
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http://dx.doi.org/10.3390/cancers12123682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762605PMC
December 2020

Impact of COVID-19 pandemic on surgical neuro-oncology multi-disciplinary team decision making: a national survey (COVID-CNSMDT Study).

BMJ Open 2020 08 16;10(8):e040898. Epub 2020 Aug 16.

Department of Neurosurgery, The Walton Centre National Health Service Foundation Trust, Liverpool, UK.

Objectives: Pressures on healthcare systems due to COVID-19 has impacted patients without COVID-19 with surgery disproportionally affected. This study aims to understand the impact on the initial management of patients with brain tumours by measuring changes to normal multidisciplinary team (MDT) decision making.

Design: A prospective survey performed in UK neurosurgical units performed from 23 March 2020 until 24 April 2020.

Setting: Regional neurosurgical units outside London (as the pandemic was more advanced at time of study).

Participants: Representatives from all units were invited to collect data on new patients discussed at their MDT meetings during the study period. Each unit decided if management decision for each patient had changed due to COVID-19.

Primary And Secondary Outcome Measures: Primary outcome measures included number of patients where the decision to undergo surgery changed compared with standard management usually offered by that MDT. Secondary outcome measures included changes in surgical extent, numbers referred to MDT, number of patients denied surgery not receiving any treatment and reasons for any variation across the UK.

Results: 18 units (75%) provided information from 80 MDT meetings that discussed 1221 patients. 10.7% of patients had their management changed-the majority (68%) did not undergo surgery and more than half of this group not undergoing surgery had no active treatment. There was marked variation across the UK (0%-28% change in management). Units that did not change management could maintain capacity with dedicated oncology lists. Low volume units were less affected.

Conclusion: COVID-19 has had an impact on patients requiring surgery for malignant brain tumours, with patients receiving different treatments-most commonly not receiving surgery or any treatment at all. The variations show dedicated cancer operating lists may mitigate these pressures.

Study Registration: This study was registered with the Royal College of Surgeons of England's COVID-19 Research Group (https://www.rcseng.ac.uk/coronavirus/rcs-covid-research-group/).
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http://dx.doi.org/10.1136/bmjopen-2020-040898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430412PMC
August 2020

Stratifying Brain Tumour Histological Sub-Types: The Application of ATR-FTIR Serum Spectroscopy in Secondary Care.

Cancers (Basel) 2020 Jun 27;12(7). Epub 2020 Jun 27.

WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, 99 George St, Glasgow G1 1RD, UK.

Patients living with brain tumours have the highest average years of life lost of any cancer, ultimately reducing average life expectancy by 20 years. Diagnosis depends on brain imaging and most often confirmatory tissue biopsy for histology. The majority of patients experience non-specific symptoms, such as headache, and may be reviewed in primary care on multiple occasions before diagnosis is made. Sixty-two per cent of patients are diagnosed on brain imaging performed when they deteriorate and present to the emergency department. Histological diagnosis from invasive surgical biopsy is necessary prior to definitive treatment, because imaging techniques alone have difficulty in distinguishing between several types of brain cancer. However, surgery itself does not necessarily control tumour growth, and risks morbidity for the patient. Due to their similar features on brain scans, glioblastoma, primary central nervous system lymphoma and brain metastases have been known to cause radiological confusion. Non-invasive tests that support stratification of tumour subtype would enhance early personalisation of treatment selection and reduce the delay and risks associated with surgery for many patients. Techniques involving vibrational spectroscopy, such as attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, have previously demonstrated analytical capabilities for cancer diagnostics. In this study, infrared spectra from 641 blood serum samples obtained from brain cancer and control patients have been collected. Firstly, we highlight the capability of ATR-FTIR to distinguish between healthy controls and brain cancer at sensitivities and specificities above 90%, before defining subtle differences in protein secondary structures between patient groups through Amide I deconvolution. We successfully differentiate several types of brain lesions (glioblastoma, meningioma, primary central nervous system lymphoma and metastasis) with balanced accuracies >80%. A reliable blood serum test capable of stratifying brain tumours in secondary care could potentially avoid surgery and speed up the time to definitive therapy, which would be of great value for both neurologists and patients.
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http://dx.doi.org/10.3390/cancers12071710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408619PMC
June 2020

Management evaluation of metastasis in the brain (MEMBRAIN)-a United Kingdom and Ireland prospective, multicenter observational study.

Neurooncol Pract 2020 Jun 6;7(3):344-355. Epub 2019 Dec 6.

Department of Neurosurgery, King's College Hospital, London, UK.

Background: In recent years an increasing number of patients with cerebral metastasis (CM) have been referred to the neuro-oncology multidisciplinary team (NMDT). Our aim was to obtain a national picture of CM referrals to assess referral volume and quality and factors affecting NMDT decision making.

Methods: A prospective multicenter cohort study including all adult patients referred to NMDT with 1 or more CM was conducted. Data were collected in neurosurgical units from November 2017 to February 2018. Demographics, primary disease, KPS, imaging, and treatment recommendation were entered into an online database.

Results: A total of 1048 patients were analyzed from 24 neurosurgical units. Median age was 65 years (range, 21-93 years) with a median number of 3 referrals (range, 1-17 referrals) per NMDT. The most common primary malignancies were lung (36.5%, n = 383), breast (18.4%, n = 193), and melanoma (12.0%, n = 126). A total of 51.6% (n = 541) of the referrals were for a solitary metastasis and resulted in specialist intervention being offered in 67.5% (n = 365) of cases. A total of 38.2% (n = 186) of patients being referred with multiple CMs were offered specialist treatment. NMDT decision making was associated with number of CMs, age, KPS, primary disease status, and extent of extracranial disease (univariate logistic regression, < .001) as well as sentinel location and tumor histology ( < .05). A delay in reaching an NMDT decision was identified in 18.6% (n = 195) of cases.

Conclusions: This study demonstrates a changing landscape of metastasis management in the United Kingdom and Ireland, including a trend away from adjuvant whole-brain radiotherapy and specialist intervention being offered to a significant proportion of patients with multiple CMs. Poor quality or incomplete referrals cause delay in NMDT decision making.
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http://dx.doi.org/10.1093/nop/npz063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274191PMC
June 2020

Rapid analysis of disease state in liquid human serum combining infrared spectroscopy and "digital drying".

J Biophotonics 2020 09 23;13(9):e202000118. Epub 2020 Jun 23.

WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow, UK.

In recent years, the diagnosis of brain tumors has been investigated with attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy on dried human serum samples to eliminate spectral interferences of the water component, with promising results. This research evaluates ATR-FTIR on both liquid and air-dried samples to investigate "digital drying" as an alternative approach for the analysis of spectra obtained from liquid samples. Digital drying approaches, consisting of water subtraction and least-squares method, have demonstrated a greater random forest (RF) classification performance than the air-dried spectra approach when discriminating cancer vs control samples, reaching sensitivity values higher than 93.0% and specificity values higher than 83.0%. Moreover, quantum cascade laser infrared (QCL-IR) based spectroscopic imaging is utilized on liquid samples to assess the implications of a deep-penetration light source on disease classification. The RF classification of QCL-IR data has provided sensitivity and specificity amounting to 85.1% and 75.3% respectively.
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http://dx.doi.org/10.1002/jbio.202000118DOI Listing
September 2020

Silver-impregnated, antibiotic-impregnated or non-impregnated ventriculoperitoneal shunts to prevent shunt infection: the BASICS three-arm RCT.

Health Technol Assess 2020 03;24(17):1-114

Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK.

Background: Insertion of a ventriculoperitoneal shunt to treat hydrocephalus is one of the most common neurosurgical procedures worldwide. Shunt infection affects up to 15% of patients, resulting in long hospital stays, multiple surgeries and reduced cognition and quality of life.

Objectives: The aim of this trial was to determine whether or not antibiotic-impregnated ventriculoperitoneal shunts (hereafter referred to as antibiotic shunts) (e.g. impregnated with rifampicin and clindamycin) or silver-impregnated ventriculoperitoneal shunts (hereafter referred to as silver shunts) reduce infection compared with standard ventriculoperitoneal shunts (hereafter referred to as standard shunts).

Design: This was a three-arm, superiority, multicentre, parallel-group randomised controlled trial. Patients and a central primary outcome review panel, but not surgeons or operating staff, were blinded to the type of ventriculoperitoneal shunt inserted.

Setting: The trial was set in 21 neurosurgical wards across the UK and the Republic of Ireland.

Participants: Participants were patients with hydrocephalus of any aetiology who were undergoing insertion of their first ventriculoperitoneal shunt.

Interventions: Participants were allocated 1 : 1 : 1 by pressure-sealed envelope to receive a standard non-impregnated, silver-impregnated or antibiotic-impregnated ventriculoperitoneal shunt at the time of insertion. Ventriculoperitoneal shunts are medical devices, and were used in accordance with the manufacturer's instructions for their intended purpose.

Main Outcome Measures: The primary outcome was time to ventriculoperitoneal shunt failure due to infection. Secondary outcomes were time to failure for any cause, reason for failure (infection, mechanical), types of ventriculoperitoneal shunt infection, rate of infection after first clean (non-infected) revision and health economics. Outcomes were analysed by intention to treat.

Results: Between 26 June 2013 and 9 October 2017, 1605 patients from neonate to 91 years of age were randomised to the trial:  = 36 to the standard shunt,  = 538 to the antibiotic shunt and  = 531 to the silver shunt. Patients who did not receive a ventriculoperitoneal shunt ( = 4) or who had an infection at the time of insertion ( = 7) were not assessed for the primary outcome. Infection occurred in 6.0% ( = 32/533) of those who received the standard shunt, in 2.2% ( = 12/535) of those who received the antibiotic shunt and in 5.9% ( = 31/526) of those who received the silver shunt. Compared with the standard shunt, antibiotic shunts were associated with a lower rate of infection (cause-specific hazard ratio 0.38, 97.5% confidence interval 0.18 to 0.80) and a decreased probability of infection (subdistribution hazard ratio 0.38, 97.5% confidence interval 0.18 to 0.80). Silver shunts were not associated with a lower rate of infection than standard shunts (cause-specific hazard ratio 0.99, 97.5% confidence interval 0.56 to 1.74). The ventriculoperitoneal shunt failure rate attributable to any cause was 25.0% overall and did not differ between arms. Antibiotic shunts save £135,753 per infection avoided. There were no serious adverse events.

Limitations: It was not possible to blind treating neurosurgeons to the ventriculoperitoneal shunt type. The return rate for patient-reported outcomes was low. Limitations to the economic evaluation included failure to obtain Hospital Episode Statistics data from NHS Digital, as per protocol. Reliance on patient-level information and costing systems data mitigated these limitations.

Conclusions: Antibiotic shunts have a reduced infection rate compared with standard shunts, whereas silver shunts do not. Antibiotic shunts are cost-saving.

Future Work: A sample collection has been established that will enable the study of surrogate markers of ventriculoperitoneal shunt infection in cerebrospinal fluid or blood using molecular techniques. A post hoc analysis to study factors related to shunt failure will be performed as part of a future study. An impact analysis to assess change in practice is planned.

Trial Registration: Current Controlled Trials ISRCTN49474281.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 17. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184313PMC
March 2020

Treatment Outcomes of Incidental Intracranial Meningiomas: Results from the IMPACT Cohort.

World Neurosurg 2020 06 19;138:e725-e735. Epub 2020 Mar 19.

Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.

Background: Incidental findings such as meningioma are becoming increasingly prevalent. There is no consensus on the optimal management of these patients. The aim of this study was to examine the outcomes of patients diagnosed with an incidental meningioma who were treated with surgery or radiotherapy.

Methods: Single-center retrospective cohort study of adult patients diagnosed with an incidental intracranial meningioma (2007-2015). Outcomes recorded were postintervention morbidity, histopathologic diagnosis, and treatment response.

Results: Out of 441 patients, 44 underwent treatment. Median age at intervention was 56.1 years (interquartile range [IQR], 49.6-66.5); patients included 35 women and 9 men. The main indication for imaging was headache (25.9%). Median meningioma volume was 4.55 cm (IQR, 1.91-8.61), and the commonest location was convexity (47.7%). Six patients underwent surgery at initial diagnosis. Thirty-eight had intervention (34 with surgery and 4 with radiotherapy) after a median active monitoring duration of 24 months (IQR, 11.8-42.0). Indications for treatment were radiologic progression (n = 26), symptom development (n = 6), and patient preference (n = 12). Pathology revealed World Health Organization (WHO) grade 1 meningioma in 36 patients and WHO grade 2 in 4 patients. The risk of postoperative surgical and medical morbidity requiring treatment was 25%. Early and late moderate adverse events limiting activities of daily living occurred in 28.6% of patients treated with radiotherapy. Recurrence rate after surgery was 2.5%. All meningiomas regressed or remained radiologically stable after radiotherapy.

Conclusions: The morbidity after treatment of incidental intracranial meningioma is not negligible. Considering most operated tumors are WHO grade 1, treatment should be reserved for those manifesting symptoms or demonstrating substantial growth on radiologic surveillance.
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http://dx.doi.org/10.1016/j.wneu.2020.03.060DOI Listing
June 2020

Biofluid diagnostics by FTIR spectroscopy: A platform technology for cancer detection.

Cancer Lett 2020 05 26;477:122-130. Epub 2020 Feb 26.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Technology and Innovation Centre, 99 George Street, Glasgow, G1 1RD, UK; ClinSpec Diagnostics Ltd., Technology and Innovation Centre, 99 George Street, Glasgow, G1 1RD, UK. Electronic address:

Fourier Transform Infrared Spectroscopy (FTIR) has been largely employed by scientific researchers to improve diagnosis and treatment of cancer, using various biofluids and tissues. The technology has proved to be easy to use, rapid and cost-effective for analysis on human blood serum to discriminate between cancer versus healthy control samples. The high sensitivity and specificity achievable during samples classification aided by machine learning algorithms, offers an opportunity to transform cancer referral pathways, as it has been demonstrated in a unique and recent prospective clinical validation study on brain tumours. We herein highlight the importance of early detection in cancer research using FTIR, discussing the technique, the suitability of serum for analysis and previous studies, with special focus on pre-clinical factors and clinical translation requirements and development.
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http://dx.doi.org/10.1016/j.canlet.2020.02.020DOI Listing
May 2020

Challenges Conveying Clinical Equipoise and Exploring Patient Treatment Preferences in an Oncology Trial Comparing Active Monitoring with Radiotherapy (ROAM/EORTC 1308).

Oncologist 2020 04 11;25(4):e691-e700. Epub 2020 Feb 11.

Institute of Population Health Sciences, University of Liverpool, United Kingdom.

Introduction: Providing balanced information that emphasizes clinical equipoise (i.e., uncertainty regarding the relative merits of trial interventions) and exploring patient treatment preferences can improve informed consent and trial recruitment. Within a trial comparing adjuvant radiotherapy versus active monitoring following surgical resection for an atypical meningioma (ROAM/EORTC-1308), we explored patterns in communication and reasons why health practitioners may find it challenging to convey equipoise and explore treatment preferences.

Materials And Methods: Qualitative study embedded within ROAM/EORTC-1308. Data were collected on 40 patients and 18 practitioners from 13 U.K. sites, including audio recordings of 39 patients' trial consultations, 23 patient interviews, and 18 practitioner interviews. Qualitative analysis drew on argumentation theory.

Results: Practitioners acknowledged the importance of the research question that the trial aimed to answer. However, they often demonstrated a lack of equipoise in consultations, particularly with eligible patients who practitioners believed to be susceptible to side effects (e.g., cognitive impairment) or inconvenienced by radiotherapy. Practitioners elicited but rarely explored patient treatment preferences, especially if a patient expressed an initial preference for active monitoring. Concerns about coercing patients, loss of practitioner agency, and time constraints influenced communication in ways that were loaded against trial participation.

Conclusions: We identified several challenges that practitioners face in conveying equipoise and exploring patient treatment preferences in oncology, and particularly neuro-oncology, trials with distinct management pathways. The findings informed communication about ROAM/EORTC-1308 and will be relevant to enhancing trial communication in future oncology trials. Qualitative studies embedded within trials can address difficulties with communication, thus improving informed consent and recruitment. ROAM/EORTC-1308 RCT: ISRCTN71502099.

Implications For Practice: Oncology trials can be challenging to recruit to, especially those that compare treatment versus monitoring. Conveying clinical equipoise and exploring patient treatment preferences can enhance recruitment and patient understanding. This study focused on the challenges that practitioners encounter in trying to use such communication strategies and how practitioners may inadvertently impede patient recruitment and informed decision making. This article provides recommendations to support practitioners in balancing the content and presentation of trial management pathways. The results can inform training to optimize communication, especially for neuro-oncology trials and trials comparing markedly different management pathways.
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http://dx.doi.org/10.1634/theoncologist.2019-0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160418PMC
April 2020

Ketogenic diets as an adjuvant therapy for glioblastoma (KEATING): a randomized, mixed methods, feasibility study.

J Neurooncol 2020 Mar 8;147(1):213-227. Epub 2020 Feb 8.

Institute of Translational Medicine, University of Liverpool, Brownlow Hill, Liverpool, L69 3BX, UK.

Purpose: We conducted a feasibility study to investigate the use of ketogenic diets (KDs) as an adjuvant therapy for patients with glioblastoma (GBM), investigating (i) trial feasibility; (ii) potential impacts of the trial on patients' quality of life and health; (iii) patients' perspectives of their decision-making when invited to participate in the trial and (iv) recommending improvements to optimize future phase III trials.

Methods: A single-center, prospective, randomized, pilot study (KEATING), with an embedded qualitative design. Twelve newly diagnosed patients with GBM were randomized 1:1 to modified ketogenic diet (MKD) or medium chain triglyceride ketogenic diet (MCTKD). Primary outcome was retention at three months. Semi-structured interviews were conducted with a purposive sample of patients and caregivers (n = 15). Descriptive statistics were used for quantitative outcomes and qualitative data were analyzed thematically aided by NVivo.

Results: KEATING achieved recruitment targets, but the recruitment rate was low (28.6%). Retention was poor; only four of 12 patients completed the three-month diet (MCTKD n = 3; MKD n = 1). Participants' decisions were intuitive and emotional; caregivers supported diet implementation and influenced the patients' decision to participate. Those who declined made a deliberative and considered decision factoring diet burden and quality of life. A three-month diet was undesirable to patients who declined and withdrew.

Conclusion: Recruitment to a KD trial for patients with GBM is possible. A six-week intervention period is proposed for a phase III trial. The role of caregivers should not be underestimated. Future trials should optimize and adequately support the decision-making of patients.
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http://dx.doi.org/10.1007/s11060-020-03417-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076054PMC
March 2020

Does the application of diffusion weighted imaging improve the prediction of survival in patients with resected brain metastases? A retrospective multicenter study.

Cancer Imaging 2020 Feb 7;20(1):16. Epub 2020 Feb 7.

Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.

Background: Brain metastases are common in clinical practice. Many clinical scales exist for predicting survival and hence deciding on best treatment but none are individualised and none use quantitative imaging parameters. A multicenter study was carried out to evaluate the prognostic utility of a simple diffusion weighted MRI parameter, tumor apparent diffusion coefficient (ADC).

Methods: A retrospective analysis of imaging and clinical data was performed on a cohort of 223 adult patients over a ten-year period 2002-2012 pooled from three institutions. All patients underwent surgical resection with histologically confirmed brain metastases and received adjuvant whole brain radiotherapy and/or chemotherapy. Survival was modelled using standard clinical variables and statistically compared with and without the addition of tumor ADC.

Results: The median overall survival was 9.6 months (95% CI 7.5-11.7) for this cohort. Greater age (p = 0.002), worse performance status (p < 0.0001) and uncontrolled extracranial disease (p < 0.0001) were all significantly associated with shorter survival in univariate analysis. Adjuvant whole brain radiotherapy (p = 0.007) and higher tumor ADC (p < 0.001) were associated with prolonged survival. Combining values of tumor ADC with conventional clinical scoring systems such as the Graded Prognostic Assessment (GPA) score significantly improved the modelling of survival (e.g. concordance increased from 0.5956 to 0.6277 with Akaike's Information Criterion reduced from 1335 to 1324).

Conclusions: Combining advanced MRI readings such as tumor ADC with clinical scoring systems is a potentially simple method for improving and individualising the estimation of survival in patients having surgery for brain metastases.
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http://dx.doi.org/10.1186/s40644-020-0295-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006156PMC
February 2020

Interval brain imaging for adults with cerebral glioma.

Cochrane Database Syst Rev 2019 12 24;12:CD013137. Epub 2019 Dec 24.

Institute of Translational Medicine, University of Liverpool & Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, Merseyside, UK.

Background: Clinical practice guidelines suggest that magnetic resonance imaging (MRI) of the brain should be performed at certain time points or intervals distant from diagnosis (interval or surveillance imaging) of cerebral glioma, to monitor or follow up the disease; it is not known, however, whether these imaging strategies lead to better outcomes among patients than triggered imaging in response to new or worsening symptoms.

Objectives: To determine the effect of different imaging strategies (in particular, pre-specified interval or surveillance imaging, and symptomatic or triggered imaging) on health and economic outcomes for adults with glioma (grades 2 to 4) in the brain.

Search Methods: The Cochrane Gynaecological, Neuro-oncology and Orphan Cancers (CGNOC) Group Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase up to 18 June 2019 and the NHS Economic Evaluation Database (EED) up to December 2014 (database closure).

Selection Criteria: We included randomised controlled trials, non-randomised controlled trials, and controlled before-after studies with concurrent comparison groups comparing the effect of different imaging strategies on survival and other health outcomes in adults with cerebral glioma; and full economic evaluations (cost-effectiveness analyses, cost-utility analyses and cost-benefit analyses) conducted alongside any study design, and any model-based economic evaluations on pre- and post-treatment imaging in adults with cerebral glioma.

Data Collection And Analysis: We used standard Cochrane review methodology with two authors independently performing study selection and data collection, and resolving disagreements through discussion. We assessed the certainty of the evidence using the GRADE approach.

Main Results: We included one retrospective, single-institution study that compared post-operative imaging within 48 hours (early post-operative imaging) with no early post-operative imaging among 125 people who had surgery for glioblastoma (GBM: World Health Organization (WHO) grade 4 glioma). Most patients in the study underwent maximal surgical resection followed by combined radiotherapy and temozolomide treatment. Although patient characteristics in the study arms were comparable, the study was at high risk of bias overall. Evidence from this study suggested little or no difference between early and no early post-operative imaging with respect to overall survival (deaths) at one year after diagnosis of GBM (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.61 to 1.21; 48% vs 55% died, respectively; very low certainty evidence) and little or no difference in overall survival (deaths) at two years after diagnosis of GBM (RR 1.06, 95% CI 0.91 to 1.25; 86% vs 81% died, respectively; very low certainty evidence). No other review outcomes were reported. We found no evidence on the effectiveness of other imaging schedules. In addition, we identified no relevant economic evaluations assessing the efficiency of the different imaging strategies.

Authors' Conclusions: The effect of different imaging strategies on survival and other health outcomes remains largely unknown. Existing imaging schedules in glioma seem to be pragmatic rather than evidence-based. The limited evidence suggesting that early post-operative brain imaging among GBM patients who will receive combined chemoradiation treatment may make little or no difference to survival needs to be further researched, particularly as early post-operative imaging also serves as a quality control measure that may lead to early re-operation if residual tumour is identified. Mathematical modelling of a large glioma patient database could help to distinguish the optimal timing of surveillance imaging for different types of glioma, with stratification of patients facilitated by assessment of individual tumour growth rates, molecular biomarkers and other prognostic factors. In addition, paediatric glioma study designs could be used to inform future research of imaging strategies among adults with glioma.
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http://dx.doi.org/10.1002/14651858.CD013137.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953319PMC
December 2019

A novel panel of differentially-expressed microRNAs in breast cancer brain metastasis may predict patient survival.

Sci Rep 2019 12 6;9(1):18518. Epub 2019 Dec 6.

Institute of Translational Medicine, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.

Breast cancer brain metastasis (BCBM) is an area of unmet clinical need. MicroRNAs (miRNAs) have been linked to the metastatic process in breast cancer (BC). In this study, we aim to determine differentially-expressed miRNAs utilising primary BCs that did not relapse (BCNR, n = 12), primaries that relapsed (BCR) and their paired (n = 40 pairs) brain metastases (BM) using the NanoString™ nCounter™ miRNA Expression Assays. Significance analysis of microarrays identified 58 and 11 differentially-expressed miRNAs between BCNR vs BCR and BCR vs BM respectively and pathway analysis revealed enrichment for genes involved in invasion and metastasis. Four miRNAs, miR-132-3p, miR-199a-5p, miR-150-5p and miR-155-5p, were differentially-expressed within both cohorts (BCNR-BCR, BCR-BM) and receiver-operating characteristic curve analysis (p = 0.00137) and Kaplan-Meier survival method (p = 0.0029, brain metastasis-free survival; p = 0.0007, overall survival) demonstrated their potential use as prognostic markers. Ingenuity pathway enrichment linked them to the MET oncogene, and the cMET protein was overexpressed in the BCR (p < 0.0001) and BM (p = 0.0008) cases, compared to the BCNRs. The 4-miRNAs panel identified in this study could be potentially used to distinguish BC patients with an increased risk of developing BCBM and provide potential novel therapeutic targets, whereas cMET-targeting warrants further investigation in the treatment of BCBM.
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http://dx.doi.org/10.1038/s41598-019-55084-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897960PMC
December 2019

Longitudinal molecular trajectories of diffuse glioma in adults.

Nature 2019 12 20;576(7785):112-120. Epub 2019 Nov 20.

Fondazione IRCCS Istituto Neurologico Besta, Milano, Italy.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
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http://dx.doi.org/10.1038/s41586-019-1775-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897368PMC
December 2019

'Meningiomics'-an integration of data on the patient, tumour, extent of resection and molecular pathology to optimise the management and follow-up for meningiomas.

Acta Neurochir (Wien) 2019 12 28;161(12):2551-2552. Epub 2019 Oct 28.

Institute of Translational Medicine, University of Liverpool, L9 7LJ, Liverpool, UK.

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http://dx.doi.org/10.1007/s00701-019-04102-0DOI Listing
December 2019

Developing infrared spectroscopic detection for stratifying brain tumour patients: glioblastoma multiforme vs. lymphoma.

Analyst 2019 Nov;144(22):6736-6750

WestCHEM, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, 99 George St, Glasgow, G1 1RD, UK.

Over a third of brain tumour patients visit their general practitioner more than five times prior to diagnosis in the UK, leading to 62% of patients being diagnosed as emergency presentations. Unfortunately, symptoms are non-specific to brain tumours, and the majority of these patients complain of headaches on multiple occasions before being referred to a neurologist. As there are currently no methods in place for the early detection of brain cancer, the affected patients' average life expectancy is reduced by 20 years. These statistics indicate that the current pathway is ineffective, and there is a vast need for a rapid diagnostic test. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy is sensitive to the hallmarks of cancer, as it analyses the full range of macromolecular classes. The combination of serum spectroscopy and advanced data analysis has previously been shown to rapidly and objectively distinguish brain tumour severity. Recently, a novel high-throughput ATR accessory has been developed, which could be cost-effective to the National Health Service in the UK, and valuable for clinical translation. In this study, 765 blood serum samples have been collected from healthy controls and patients diagnosed with various types of brain cancer, contributing to one of the largest spectroscopic studies to date. Three robust machine learning techniques - random forest, partial least squares-discriminant analysis and support vector machine - have all provided promising results. The novel high-throughput technology has been validated by separating brain cancer and non-cancer with balanced accuracies of 90% which is comparable to the traditional fixed diamond crystal methodology. Furthermore, the differentiation of brain tumour type could be useful for neurologists, as some are difficult to distinguish through medical imaging alone. For example, the highly aggressive glioblastoma multiforme and primary cerebral lymphoma can appear similar on magnetic resonance imaging (MRI) scans, thus are often misdiagnosed. Here, we report the ability of infrared spectroscopy to distinguish between glioblastoma and lymphoma patients, at a sensitivity and specificity of 90.1% and 86.3%, respectively. A reliable serum diagnostic test could avoid the need for surgery and speed up time to definitive chemotherapy and radiotherapy.
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http://dx.doi.org/10.1039/c9an01731cDOI Listing
November 2019