Purpose: The role of repeat resection for recurrent glioblastoma (rGBM) remains equivocal. This s... more Purpose: The role of repeat resection for recurrent glioblastoma (rGBM) remains equivocal. This study aims to assess the overall survival and complications rates of single or repeat resection for rGBM. Methods: A single centre retrospective review of all patients with IDH-wildtype glioblastoma managed surgically, between January 2014 and January 2022, was carried out. Patient survival and factors influencing prognosis were analysed, using Kaplan-Meier and Cox regression methods. Results: 432 patients were included, of whom 329 underwent single resection, 83 had two resections and 20 patients underwent three resections. Median OS (mOS) in the cohort who underwent a single operation was 13.7 months (95% CI:12.7-14.7 months). The mOS was observed to be extended in patients who underwent second or third-time resection, at 22.9 months and 44.7 months respectively (p <0.001). On second operation achieving >95% resection or residual tumour volume of <2.25cc was significantly associated with prolonged survival. There was no significant difference in overall complication rates between primary versus second (p=0.973) or third-time resections (p=0.312). The use of diffusion tensor imaging (DTI) guided resection was associated with reduced post-operative neurological deficit (RR 0.37, p=0.002), as was use of intraoperative ultrasound (iUSS) (RR 0.45, p=0.04). Conclusions: This study demonstrates potential prolongation of survival for GBM patients undergoing repeat resection, without significant increase in complication rates with repeat resections. Achieving a more complete repeat resection improved survival. Moreover, the use of intraoperative imaging adjuncts can maximise tumour resection, whilst minimising the risk of neurological deficit.
Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequent... more Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI. Experimental Design: Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumorbrain interface and to test the efficacy of VCAM-1-targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression. Results: The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the brain metastasis model. T 2 Ã -weighted MRI, following intravenous administration of VCAM-MPIO, highlighted the tumor-brain interface of both tumor models more extensively than gadolinium-DTPA-enhanced T 1 -weighted MRI. Sites of VCAM-MPIO binding, evident as hypointense signals on MR images, correlated spatially with endothelial VCAM-1 upregulation and bound VCAM-MPIO beads detected histologically. These findings were further validated in an orthotopic medulloblastoma model. Finally, the tumor-brain interface in human brain metastasis and glioblastoma samples was similarly characterized by microvascular inflammation, extending beyond the region detectable using conventional MRI. Conclusions: This work illustrates the potential of VCAM-1targeted MRI for improved delineation of the tumor-brain interface in both primary and secondary brain tumors.
intracerebral lesion were included in our study. After patient registration, the lesion outlines ... more intracerebral lesion were included in our study. After patient registration, the lesion outlines were marked on the patient's skin by different participants, consecutively using the Brainlab neuronavigation system and the HoloLens. Each registration on both systems provided a registration transform that was compared for accuracy and consistency. The performance of the participants was measured in terms of duration and accuracy and compared to expert registration and delineation. RESULTS: Both registration and delineation were significantly faster with AR (p=0.02 and p<0.001, respectively, and p<0.001 for the total duration), taking 79.23±17.48 and 39.58±39.10 seconds while neuronavigation required 96.61±24.54 and 90.80±44.09 seconds. AR had a registration offset of 3.3mm and 3.4°, and was more consistent compared to neuronavigation. AR facilitated more accurate and detailed lesion delineation, while neuronavigation often overestimated lesion size. CONCLUSION: Augmented reality provides a faster and more accurate alternative for resection planning. Lesion delineation is more intuitive while remaining high in accuracy. Future research should focus on further intraoperative implementations.
Introduction 5-aminolevulinic acid (5-ALA) is a proagent developed for fluorescent-guided surgery... more Introduction 5-aminolevulinic acid (5-ALA) is a proagent developed for fluorescent-guided surgery for high-grade glioma patients associated with a significant increase in resection conferring survival. 5-ALA was shown to penetrate the blood-brain barrier accumulating in malignant glioma cells with high selectivity, sensitivity and positive predictive value. However, those have yet to be explored aiding diagnosis for tumours of the central nervous system (CNS) other than high-grade gliomas (HGG). No up-to-date systematic review exists reporting the major surgical outcomes and diagnostic accuracy. We sought to conduct a systematic review of the literature summarising surgical outcomes, evaluate the quality of diagnostic accuracy reported in the literature and qualitatively assess the evidence to inform future studies. Methods and analysis We will search electronic databases (Medline, Embase) with subsequent interrogation of references lists of articles reporting the use of 5-ALA for brain tumours other than high-grade glioma adult patients, which also report the extent of resection and/or survival. Prospective and retrospective cohort and case-control studies with more than five patients will be included. Two independent reviewers will screen the abstracts and full articles, with a third reviewer resolving any conflicts. The data will be extracted in a standardised template and outcomes will be reported using descriptive statists. The quality of non-randomised studies will be appraised. Ethics and dissemination The study will summarise the available evidence on the effect of the clinical utility of 5-ALA in achieving resection and improving survival and its diagnostic accuracy for tumours of the CNS other than HGG. The data will be presented nationally and internationally and the manuscript will be published in a peer-reviewed journal. No ethical approvals were needed. The aim is to inform prospective studies minimising reporting bias allowing for more reliable, reproducible and generalisable results. The study has been registered in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PROSPERO registration number CRD42021260542.
Background. Elderly patients with glioblastoma are perceived to face a poor prognosis with percep... more Background. Elderly patients with glioblastoma are perceived to face a poor prognosis with perceptions surrounding older age and a relative lack of randomized data contributing. This study evaluated survival prognosticators in elderly glioblastoma patients to more accurately guide their treatment. Methods. The records of 169 elderly (≥70 years) patients with a new diagnosis of glioblastoma who had undergone neurosurgical intervention were retrospectively examined for patient sex, age, performance status, comorbidities, MGMT promoter methylation, surgical intervention, and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate patient survival at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS). Results. The median overall survival (mOS) of the cohort was 28.8 weeks. Gross-total and subtotal resection were associated with improved survival compared to biopsy alone (respective mOS 65.3 and 28.1 vs 15.7 weeks, P < .001). Hypofractionated radiotherapy (40Gy in 15 fractions) with Temozolomide was noninferior to the Stupp protocol, P = .72. Exploratory subgroup analysis revealed a significant benefit of Temozolomide-based approaches in MGMT-methylated patients as well as a trend towards improved survival in MGMT-unmethylated patients. Our EGSS and EGOS scores successfully estimated survival in this retrospective cohort with 65% and 73% accuracy. Conclusions. Where appropriate and safe, elderly glioblastoma patients may benefit from surgical resection and combined chemoradiotherapy with Temozolomide. The proposed EGSS and EGOS scores take into account important prognostic factors to help guide which patients should receive such treatment. • Elderly glioblastoma (GB) patients require individualized management decisions. • A subgroup of very fit elderly GB patients may benefit from TMZ regardless of their MGMT status. • EGSS and EGOS scores can estimate the survival of elderly GB patients. Surgical and oncological score to estimate the survival benefit of resection and chemoradiotherapy in elderly (≥70 years) glioblastoma patients: A preliminary analysis
bioRxiv (Cold Spring Harbor Laboratory), Mar 5, 2022
Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modu... more Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in two distinct dendritic spineinnervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBC) had columnar "horsetail" axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and non-pyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%) and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine targets. Group III mGluR activation paradoxically increased the frequency of sIPSCs in DBCs (to median 137% of baseline), but suppressed it in PV-DTCs (median 92%), leaving the amplitude unchanged. The facilitation of sIPSCs in DBCs may result from their unique GABAergic input being disinhibited via network effect. We conclude that dendritic spines receive specialised, diverse GABAergic inputs, and group III mGluRs differentially regulate GABAergic synaptic transmission to distinct GABAergic cell types in human cortex.
Purpose Gliomas are the most commonly occurring brain tumour in adults and there remains no cure ... more Purpose Gliomas are the most commonly occurring brain tumour in adults and there remains no cure for these tumours with treatment strategies being based on tumour grade. All treatment options aim to prolong survival, maintain quality of life and slow the inevitable progression from low-grade to high-grade. Despite imaging advancements, the only reliable method to grade a glioma is to perform a biopsy, and even this is fraught with errors associated with under grading. Positron emission tomography (PET) imaging with amino acid tracers such as [18F]fluorodopa (18F-FDOPA), [11C]methionine (11C-MET), [18F]fluoroethyltyrosine (18F-FET), and 18F-FDOPA are being increasingly used in the diagnosis and management of gliomas. Methods In this review we discuss the literature available on the ability of 18F-FDOPA-PET to distinguish low- from high-grade in newly diagnosed gliomas. Results In 2016 the Response Assessment in Neuro-Oncology (RANO) and European Association for Neuro-Oncology (EANO) ...
IntroductionSurgery remains the mainstay for treatment of primary glioblastoma, followed by radio... more IntroductionSurgery remains the mainstay for treatment of primary glioblastoma, followed by radiotherapy and chemotherapy. Current standard of care during surgery involves the intraoperative use of image-guidance and 5-aminolevulinic acid (5-ALA). There are multiple other surgical adjuncts available to the neuro-oncology surgeon. However, access to, and usage of these varies widely in UK practice, with limited evidence of their use. The aim of this trial is to investigate whether the addition of diffusion tensor imaging (DTI) and intraoperative ultrasound (iUS) to the standard of care surgery (intraoperative neuronavigation and 5-ALA) impacts on deterioration free survival (DFS).Methods and analysisThis is a two-stage, randomised control trial (RCT) consisting of an initial non-randomised cohort study based on the principles of the IDEAL (Idea, Development, Exploration, Assessment and Long-term follow-up) stage-IIb format, followed by a statistically powered randomised trial compari...
AIMS Despite evidence of correspondence with intraoperative stimulation, there remains limited da... more AIMS Despite evidence of correspondence with intraoperative stimulation, there remains limited data on MRI diffusion tractography (DT)’s sensitivity to predict morbidity after brain tumour resection. Our aims were: (1) evaluate DT against subcortical stimulation mapping and performance changes during and following awake surgery; (2) evaluate the use of early post-operative DT to predict recovery from post-surgical deficits. METHOD We performed a retrospective review our first 100 awake neurosurgery procedures using DTneuronavigation. Intra-operative stimulation and performance outcomes were assessed to classify DT predictions for sensitivity and specificity calculations. RESULTS Between 2014 and 2019 a total of 91 adult brain tumour patients (mean age 49.2 years) underwent 100 awake surgeries with subcortical stimulation. The sensitivity and specificity of pre-operative DT predictions were 92.2% and 69.2%, varying among tracts. Post-operative deficits occurred after 41 procedures (3...
Background Despite operative and adjuvant therapies, glioblastoma remains incurable, with the ext... more Background Despite operative and adjuvant therapies, glioblastoma remains incurable, with the extent of resection being one of few treatments that can improve survival. To improve resection, operative adjuncts are used, with neuronavigation and 5-aminolevulinic acid (5-ALA) recommended as a standard of care in those aimed for maximal safe resection. Despite the standards, meta-analysis concluded that the impact of 5-ALA on the extent of surgical resection is of low quality due to bias in reporting tumour location and additional image guidance used, factors impacting on extent of resection as well as short-term neurological outcomes being uncertain. Therefore we aimed to evaluate the availability and use of 5-ALA and other adjuncts and compare surgical outcomes of 5-ALA-guided versus non-5-ALA-guided resections. Material and Methods A multicenter prospective observational cohort study was conducted across 27 out of 31 available centres in the UK and Ireland from 6 January until 19 Ma...
IntroductionMeningioma is the most common primary intracranial tumour in adults. The majority are... more IntroductionMeningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two ‘Core Outcome Sets’ (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma.Methods and analysisTwo systematic literature reviews and trial registry searc...
Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequent... more Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI. Experimental Design: Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumor-brain interface and to test the efficacy of VCAM-1–targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression. Results: The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the ...
Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modu... more Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in two distinct dendritic spine-innervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBC) had columnar “horsetail” axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and non-pyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%) and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine ...
Background Elderly patients with glioblastoma are perceived to face a poor prognosis with percept... more Background Elderly patients with glioblastoma are perceived to face a poor prognosis with perceptions surrounding older age and a relative lack of randomized data contributing. This study evaluated survival prognosticators in elderly glioblastoma patients to more accurately guide their treatment. Methods The records of 169 elderly (≥70 years) patients with a new diagnosis of glioblastoma who had undergone neurosurgical intervention were retrospectively examined for patient sex, age, performance status, comorbidities, MGMT promoter methylation, surgical intervention, and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate patient survival at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS). Results The median overall survival (mOS) of the cohort was 28.8 weeks. Gross-to...
Purpose Functional magnetic resonance imaging (fMRI) has an established role in neurosurgical pla... more Purpose Functional magnetic resonance imaging (fMRI) has an established role in neurosurgical planning; however, ambiguity surrounds the comparative value of resting and task-based fMRI relative to anatomical localization of the sensorimotor cortex. This study was carried out to determine: 1) how often fMRI adds to prediction of motor risks beyond expert neuroradiological review, 2) success rates of presurgical resting and task-based sensorimotor mapping, and 3) the impact of accelerated resting fMRI acquisitions on network detectability. Methods Data were collected at 2 centers from 71 patients with a primary brain tumor (31 women; mean age 41.9 ± 13.9 years) and 14 healthy individuals (6 women; mean age 37.9 ± 12.7 years). Preoperative 3T MRI included anatomical scans and resting fMRI using unaccelerated (TR = 3.5 s), intermediate (TR = 1.56 s) or high temporal resolution (TR = 0.72 s) sequences. Task fMRI finger tapping data were acquired in 45 patients. Group differences in fMRI...
Experience in the management of COVID-19 vaccine induced thrombosis and thrombocytopenia is curre... more Experience in the management of COVID-19 vaccine induced thrombosis and thrombocytopenia is currently lacking. In this case series we report the presentation and our experience in the management of cerebral venous sinus thrombosis and thrombocytopenia post ChAdOx1 nCoV-19 vaccination. Two of the three cases had confirmed anti-platelet factor 4 antibodies and extracranial thrombosis. In all the cases, plasma exchange, intravenous immunoglobulins and steroids normalised the platelet count and intravenous argatroban was used for initial anticoagulation. Two cases received a platelet transfusion and required decompressive hemicraniectomy due to raised intracranial pressure, secondary to cerebral oedema and haemorrhage. Prompt assessment of a new persistent headache occurring between 5 and 28 days of receiving the ChAdOx1 nCoV-19 vaccine is warranted irrespective of age. In cases with venous thrombosis on imaging or abnormal laboratory findings (thrombocytopenia, abnormal clotting or ele...
Background Over the recent years an increasing number of patients with brain metastasis are being... more Background Over the recent years an increasing number of patients with brain metastasis are being referred to the neuro-oncology multi-disciplinary team (NMDT). Our aim was to determine if referrals of this group of patients to the NMDT in the UK…
Background The molecular genetic classification of gliomas, particularly the identification of is... more Background The molecular genetic classification of gliomas, particularly the identification of isocitrate dehydrogenase (IDH) mutations, is critical for clinical and surgical decision-making. Raman spectroscopy probes the unique molecular vibrations of a sample to accurately characterize its molecular composition. No sample processing is required allowing for rapid analysis of tissue. The aim of this study was to evaluate the ability of Raman spectroscopy to rapidly identify the common molecular genetic subtypes of diffuse glioma in the neurosurgical setting using fresh biopsy tissue. In addition, classification models were built using cryosections, formalin-fixed paraffin-embedded (FFPE) sections and LN-18 (IDH-mutated and wild-type parental cell) glioma cell lines. Methods Fresh tissue, straight from neurosurgical theatres, underwent Raman analysis and classification into astrocytoma, IDH-wild-type; astrocytoma, IDH-mutant; or oligodendroglioma. The genetic subtype was confirmed o...
NEURO-ONCOLOGY • january 2017 apy in 1 and radiotherapy in 1 at time of progression, the other 5 ... more NEURO-ONCOLOGY • january 2017 apy in 1 and radiotherapy in 1 at time of progression, the other 5 patients remain under radiological surveillance CONCLUSION: Tectal plate glioma is a rare tumour in adults that usually presents with hydrocephalus requiring CSF diversion. The majority of these tumours are grade II astrocytoma or grade I pilocytic astrocytoma. Approximately one quarter of patients progressed on radiological follow up. The natural history and course of tectal plate glioma is therefore not entirely benign and patients should remain under close annual MRI surveillance with consideration of biopsy if radiological progression is observed.
Purpose: The role of repeat resection for recurrent glioblastoma (rGBM) remains equivocal. This s... more Purpose: The role of repeat resection for recurrent glioblastoma (rGBM) remains equivocal. This study aims to assess the overall survival and complications rates of single or repeat resection for rGBM. Methods: A single centre retrospective review of all patients with IDH-wildtype glioblastoma managed surgically, between January 2014 and January 2022, was carried out. Patient survival and factors influencing prognosis were analysed, using Kaplan-Meier and Cox regression methods. Results: 432 patients were included, of whom 329 underwent single resection, 83 had two resections and 20 patients underwent three resections. Median OS (mOS) in the cohort who underwent a single operation was 13.7 months (95% CI:12.7-14.7 months). The mOS was observed to be extended in patients who underwent second or third-time resection, at 22.9 months and 44.7 months respectively (p <0.001). On second operation achieving >95% resection or residual tumour volume of <2.25cc was significantly associated with prolonged survival. There was no significant difference in overall complication rates between primary versus second (p=0.973) or third-time resections (p=0.312). The use of diffusion tensor imaging (DTI) guided resection was associated with reduced post-operative neurological deficit (RR 0.37, p=0.002), as was use of intraoperative ultrasound (iUSS) (RR 0.45, p=0.04). Conclusions: This study demonstrates potential prolongation of survival for GBM patients undergoing repeat resection, without significant increase in complication rates with repeat resections. Achieving a more complete repeat resection improved survival. Moreover, the use of intraoperative imaging adjuncts can maximise tumour resection, whilst minimising the risk of neurological deficit.
Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequent... more Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI. Experimental Design: Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumorbrain interface and to test the efficacy of VCAM-1-targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression. Results: The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the brain metastasis model. T 2 Ã -weighted MRI, following intravenous administration of VCAM-MPIO, highlighted the tumor-brain interface of both tumor models more extensively than gadolinium-DTPA-enhanced T 1 -weighted MRI. Sites of VCAM-MPIO binding, evident as hypointense signals on MR images, correlated spatially with endothelial VCAM-1 upregulation and bound VCAM-MPIO beads detected histologically. These findings were further validated in an orthotopic medulloblastoma model. Finally, the tumor-brain interface in human brain metastasis and glioblastoma samples was similarly characterized by microvascular inflammation, extending beyond the region detectable using conventional MRI. Conclusions: This work illustrates the potential of VCAM-1targeted MRI for improved delineation of the tumor-brain interface in both primary and secondary brain tumors.
intracerebral lesion were included in our study. After patient registration, the lesion outlines ... more intracerebral lesion were included in our study. After patient registration, the lesion outlines were marked on the patient's skin by different participants, consecutively using the Brainlab neuronavigation system and the HoloLens. Each registration on both systems provided a registration transform that was compared for accuracy and consistency. The performance of the participants was measured in terms of duration and accuracy and compared to expert registration and delineation. RESULTS: Both registration and delineation were significantly faster with AR (p=0.02 and p<0.001, respectively, and p<0.001 for the total duration), taking 79.23±17.48 and 39.58±39.10 seconds while neuronavigation required 96.61±24.54 and 90.80±44.09 seconds. AR had a registration offset of 3.3mm and 3.4°, and was more consistent compared to neuronavigation. AR facilitated more accurate and detailed lesion delineation, while neuronavigation often overestimated lesion size. CONCLUSION: Augmented reality provides a faster and more accurate alternative for resection planning. Lesion delineation is more intuitive while remaining high in accuracy. Future research should focus on further intraoperative implementations.
Introduction 5-aminolevulinic acid (5-ALA) is a proagent developed for fluorescent-guided surgery... more Introduction 5-aminolevulinic acid (5-ALA) is a proagent developed for fluorescent-guided surgery for high-grade glioma patients associated with a significant increase in resection conferring survival. 5-ALA was shown to penetrate the blood-brain barrier accumulating in malignant glioma cells with high selectivity, sensitivity and positive predictive value. However, those have yet to be explored aiding diagnosis for tumours of the central nervous system (CNS) other than high-grade gliomas (HGG). No up-to-date systematic review exists reporting the major surgical outcomes and diagnostic accuracy. We sought to conduct a systematic review of the literature summarising surgical outcomes, evaluate the quality of diagnostic accuracy reported in the literature and qualitatively assess the evidence to inform future studies. Methods and analysis We will search electronic databases (Medline, Embase) with subsequent interrogation of references lists of articles reporting the use of 5-ALA for brain tumours other than high-grade glioma adult patients, which also report the extent of resection and/or survival. Prospective and retrospective cohort and case-control studies with more than five patients will be included. Two independent reviewers will screen the abstracts and full articles, with a third reviewer resolving any conflicts. The data will be extracted in a standardised template and outcomes will be reported using descriptive statists. The quality of non-randomised studies will be appraised. Ethics and dissemination The study will summarise the available evidence on the effect of the clinical utility of 5-ALA in achieving resection and improving survival and its diagnostic accuracy for tumours of the CNS other than HGG. The data will be presented nationally and internationally and the manuscript will be published in a peer-reviewed journal. No ethical approvals were needed. The aim is to inform prospective studies minimising reporting bias allowing for more reliable, reproducible and generalisable results. The study has been registered in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PROSPERO registration number CRD42021260542.
Background. Elderly patients with glioblastoma are perceived to face a poor prognosis with percep... more Background. Elderly patients with glioblastoma are perceived to face a poor prognosis with perceptions surrounding older age and a relative lack of randomized data contributing. This study evaluated survival prognosticators in elderly glioblastoma patients to more accurately guide their treatment. Methods. The records of 169 elderly (≥70 years) patients with a new diagnosis of glioblastoma who had undergone neurosurgical intervention were retrospectively examined for patient sex, age, performance status, comorbidities, MGMT promoter methylation, surgical intervention, and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate patient survival at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS). Results. The median overall survival (mOS) of the cohort was 28.8 weeks. Gross-total and subtotal resection were associated with improved survival compared to biopsy alone (respective mOS 65.3 and 28.1 vs 15.7 weeks, P < .001). Hypofractionated radiotherapy (40Gy in 15 fractions) with Temozolomide was noninferior to the Stupp protocol, P = .72. Exploratory subgroup analysis revealed a significant benefit of Temozolomide-based approaches in MGMT-methylated patients as well as a trend towards improved survival in MGMT-unmethylated patients. Our EGSS and EGOS scores successfully estimated survival in this retrospective cohort with 65% and 73% accuracy. Conclusions. Where appropriate and safe, elderly glioblastoma patients may benefit from surgical resection and combined chemoradiotherapy with Temozolomide. The proposed EGSS and EGOS scores take into account important prognostic factors to help guide which patients should receive such treatment. • Elderly glioblastoma (GB) patients require individualized management decisions. • A subgroup of very fit elderly GB patients may benefit from TMZ regardless of their MGMT status. • EGSS and EGOS scores can estimate the survival of elderly GB patients. Surgical and oncological score to estimate the survival benefit of resection and chemoradiotherapy in elderly (≥70 years) glioblastoma patients: A preliminary analysis
bioRxiv (Cold Spring Harbor Laboratory), Mar 5, 2022
Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modu... more Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in two distinct dendritic spineinnervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBC) had columnar "horsetail" axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and non-pyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%) and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine targets. Group III mGluR activation paradoxically increased the frequency of sIPSCs in DBCs (to median 137% of baseline), but suppressed it in PV-DTCs (median 92%), leaving the amplitude unchanged. The facilitation of sIPSCs in DBCs may result from their unique GABAergic input being disinhibited via network effect. We conclude that dendritic spines receive specialised, diverse GABAergic inputs, and group III mGluRs differentially regulate GABAergic synaptic transmission to distinct GABAergic cell types in human cortex.
Purpose Gliomas are the most commonly occurring brain tumour in adults and there remains no cure ... more Purpose Gliomas are the most commonly occurring brain tumour in adults and there remains no cure for these tumours with treatment strategies being based on tumour grade. All treatment options aim to prolong survival, maintain quality of life and slow the inevitable progression from low-grade to high-grade. Despite imaging advancements, the only reliable method to grade a glioma is to perform a biopsy, and even this is fraught with errors associated with under grading. Positron emission tomography (PET) imaging with amino acid tracers such as [18F]fluorodopa (18F-FDOPA), [11C]methionine (11C-MET), [18F]fluoroethyltyrosine (18F-FET), and 18F-FDOPA are being increasingly used in the diagnosis and management of gliomas. Methods In this review we discuss the literature available on the ability of 18F-FDOPA-PET to distinguish low- from high-grade in newly diagnosed gliomas. Results In 2016 the Response Assessment in Neuro-Oncology (RANO) and European Association for Neuro-Oncology (EANO) ...
IntroductionSurgery remains the mainstay for treatment of primary glioblastoma, followed by radio... more IntroductionSurgery remains the mainstay for treatment of primary glioblastoma, followed by radiotherapy and chemotherapy. Current standard of care during surgery involves the intraoperative use of image-guidance and 5-aminolevulinic acid (5-ALA). There are multiple other surgical adjuncts available to the neuro-oncology surgeon. However, access to, and usage of these varies widely in UK practice, with limited evidence of their use. The aim of this trial is to investigate whether the addition of diffusion tensor imaging (DTI) and intraoperative ultrasound (iUS) to the standard of care surgery (intraoperative neuronavigation and 5-ALA) impacts on deterioration free survival (DFS).Methods and analysisThis is a two-stage, randomised control trial (RCT) consisting of an initial non-randomised cohort study based on the principles of the IDEAL (Idea, Development, Exploration, Assessment and Long-term follow-up) stage-IIb format, followed by a statistically powered randomised trial compari...
AIMS Despite evidence of correspondence with intraoperative stimulation, there remains limited da... more AIMS Despite evidence of correspondence with intraoperative stimulation, there remains limited data on MRI diffusion tractography (DT)’s sensitivity to predict morbidity after brain tumour resection. Our aims were: (1) evaluate DT against subcortical stimulation mapping and performance changes during and following awake surgery; (2) evaluate the use of early post-operative DT to predict recovery from post-surgical deficits. METHOD We performed a retrospective review our first 100 awake neurosurgery procedures using DTneuronavigation. Intra-operative stimulation and performance outcomes were assessed to classify DT predictions for sensitivity and specificity calculations. RESULTS Between 2014 and 2019 a total of 91 adult brain tumour patients (mean age 49.2 years) underwent 100 awake surgeries with subcortical stimulation. The sensitivity and specificity of pre-operative DT predictions were 92.2% and 69.2%, varying among tracts. Post-operative deficits occurred after 41 procedures (3...
Background Despite operative and adjuvant therapies, glioblastoma remains incurable, with the ext... more Background Despite operative and adjuvant therapies, glioblastoma remains incurable, with the extent of resection being one of few treatments that can improve survival. To improve resection, operative adjuncts are used, with neuronavigation and 5-aminolevulinic acid (5-ALA) recommended as a standard of care in those aimed for maximal safe resection. Despite the standards, meta-analysis concluded that the impact of 5-ALA on the extent of surgical resection is of low quality due to bias in reporting tumour location and additional image guidance used, factors impacting on extent of resection as well as short-term neurological outcomes being uncertain. Therefore we aimed to evaluate the availability and use of 5-ALA and other adjuncts and compare surgical outcomes of 5-ALA-guided versus non-5-ALA-guided resections. Material and Methods A multicenter prospective observational cohort study was conducted across 27 out of 31 available centres in the UK and Ireland from 6 January until 19 Ma...
IntroductionMeningioma is the most common primary intracranial tumour in adults. The majority are... more IntroductionMeningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two ‘Core Outcome Sets’ (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma.Methods and analysisTwo systematic literature reviews and trial registry searc...
Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequent... more Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI. Experimental Design: Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumor-brain interface and to test the efficacy of VCAM-1–targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression. Results: The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the ...
Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modu... more Diverse neocortical GABAergic neurons specialise in synaptic targeting and their effects are modulated by presynaptic metabotropic glutamate receptors (mGluRs) suppressing neurotransmitter release in rodents, but their effects in human neocortex are unknown. We tested whether activation of group III mGluRs by L-AP4 changes GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in two distinct dendritic spine-innervating GABAergic interneurons recorded in vitro in human neocortex. Calbindin-positive double bouquet cells (DBC) had columnar “horsetail” axons descending through layers II-V innervating dendritic spines (48%) and shafts, but not somata of pyramidal and non-pyramidal neurons. Parvalbumin-expressing dendrite-targeting cell (PV-DTC) axons extended in all directions innervating dendritic spines (22%), shafts (65%) and somata (13%). As measured, 20% of GABAergic neuropil synapses innervate spines, hence DBCs, but not PV-DTCs, preferentially select spine ...
Background Elderly patients with glioblastoma are perceived to face a poor prognosis with percept... more Background Elderly patients with glioblastoma are perceived to face a poor prognosis with perceptions surrounding older age and a relative lack of randomized data contributing. This study evaluated survival prognosticators in elderly glioblastoma patients to more accurately guide their treatment. Methods The records of 169 elderly (≥70 years) patients with a new diagnosis of glioblastoma who had undergone neurosurgical intervention were retrospectively examined for patient sex, age, performance status, comorbidities, MGMT promoter methylation, surgical intervention, and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate patient survival at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS). Results The median overall survival (mOS) of the cohort was 28.8 weeks. Gross-to...
Purpose Functional magnetic resonance imaging (fMRI) has an established role in neurosurgical pla... more Purpose Functional magnetic resonance imaging (fMRI) has an established role in neurosurgical planning; however, ambiguity surrounds the comparative value of resting and task-based fMRI relative to anatomical localization of the sensorimotor cortex. This study was carried out to determine: 1) how often fMRI adds to prediction of motor risks beyond expert neuroradiological review, 2) success rates of presurgical resting and task-based sensorimotor mapping, and 3) the impact of accelerated resting fMRI acquisitions on network detectability. Methods Data were collected at 2 centers from 71 patients with a primary brain tumor (31 women; mean age 41.9 ± 13.9 years) and 14 healthy individuals (6 women; mean age 37.9 ± 12.7 years). Preoperative 3T MRI included anatomical scans and resting fMRI using unaccelerated (TR = 3.5 s), intermediate (TR = 1.56 s) or high temporal resolution (TR = 0.72 s) sequences. Task fMRI finger tapping data were acquired in 45 patients. Group differences in fMRI...
Experience in the management of COVID-19 vaccine induced thrombosis and thrombocytopenia is curre... more Experience in the management of COVID-19 vaccine induced thrombosis and thrombocytopenia is currently lacking. In this case series we report the presentation and our experience in the management of cerebral venous sinus thrombosis and thrombocytopenia post ChAdOx1 nCoV-19 vaccination. Two of the three cases had confirmed anti-platelet factor 4 antibodies and extracranial thrombosis. In all the cases, plasma exchange, intravenous immunoglobulins and steroids normalised the platelet count and intravenous argatroban was used for initial anticoagulation. Two cases received a platelet transfusion and required decompressive hemicraniectomy due to raised intracranial pressure, secondary to cerebral oedema and haemorrhage. Prompt assessment of a new persistent headache occurring between 5 and 28 days of receiving the ChAdOx1 nCoV-19 vaccine is warranted irrespective of age. In cases with venous thrombosis on imaging or abnormal laboratory findings (thrombocytopenia, abnormal clotting or ele...
Background Over the recent years an increasing number of patients with brain metastasis are being... more Background Over the recent years an increasing number of patients with brain metastasis are being referred to the neuro-oncology multi-disciplinary team (NMDT). Our aim was to determine if referrals of this group of patients to the NMDT in the UK…
Background The molecular genetic classification of gliomas, particularly the identification of is... more Background The molecular genetic classification of gliomas, particularly the identification of isocitrate dehydrogenase (IDH) mutations, is critical for clinical and surgical decision-making. Raman spectroscopy probes the unique molecular vibrations of a sample to accurately characterize its molecular composition. No sample processing is required allowing for rapid analysis of tissue. The aim of this study was to evaluate the ability of Raman spectroscopy to rapidly identify the common molecular genetic subtypes of diffuse glioma in the neurosurgical setting using fresh biopsy tissue. In addition, classification models were built using cryosections, formalin-fixed paraffin-embedded (FFPE) sections and LN-18 (IDH-mutated and wild-type parental cell) glioma cell lines. Methods Fresh tissue, straight from neurosurgical theatres, underwent Raman analysis and classification into astrocytoma, IDH-wild-type; astrocytoma, IDH-mutant; or oligodendroglioma. The genetic subtype was confirmed o...
NEURO-ONCOLOGY • january 2017 apy in 1 and radiotherapy in 1 at time of progression, the other 5 ... more NEURO-ONCOLOGY • january 2017 apy in 1 and radiotherapy in 1 at time of progression, the other 5 patients remain under radiological surveillance CONCLUSION: Tectal plate glioma is a rare tumour in adults that usually presents with hydrocephalus requiring CSF diversion. The majority of these tumours are grade II astrocytoma or grade I pilocytic astrocytoma. Approximately one quarter of patients progressed on radiological follow up. The natural history and course of tectal plate glioma is therefore not entirely benign and patients should remain under close annual MRI surveillance with consideration of biopsy if radiological progression is observed.
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Papers by Puneet Plaha