Publications by authors named "Thomas Santarius"

87 Publications

A survey of teaching undergraduate neuroanatomy in the United Kingdom and Ireland.

Br J Neurosurg 2021 Apr 8:1-6. Epub 2021 Apr 8.

Salford Royal Hospital, Salford Royal NHS Foundation Trust, Manchester, United Kingdom.

Background: Medical students' perception of neuroanatomy as a challenging topic has implications for referrals and interaction with specialists in the clinical neurosciences. Given plans to introduce a standardised Medical Licensing Assessment by 2023, it is important to understand the current framework of neuroanatomy education. This study aims to describe how neuroanatomy is taught and assessed in the UK and Ireland.

Methods: A structured questionnaire capturing data about the timing, methods, materials, assessment and content of the 2019/2020 neuroanatomy curriculum in the UK and Ireland medical schools.

Results: We received 24/34 responses. Lectures (96%) were the most widely used teaching method, followed by prosection (80%), e-learning (75%), tutorials/seminars (67%), problem-based learning (50%), case-based learning (38%), and dissection (30%). The mean amount of core neuroanatomy teaching was 29.3 hours. The most common formats of assessing neuroanatomical knowledge were multiple-choice exams, spot tests, and objective structured clinical exams. Only 37.5% schools required demonstration of core clinical competency relating to neuroanatomy.

Conclusions: Our survey demonstrates variability in how undergraduate neuroanatomy is taught and assessed across the UK and Ireland. There is a role for development and standardisation of national undergraduate neuroanatomy curricula in order to improve confidence and attainment.
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http://dx.doi.org/10.1080/02688697.2021.1902942DOI Listing
April 2021

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

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

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

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

Trial of Dexamethasone for Chronic Subdural Hematoma.

N Engl J Med 2020 12 16;383(27):2616-2627. Epub 2020 Dec 16.

From the Divisions of Neurosurgery (P.J.H., E.E., E.P.T., S. Tarantino, K.C., H.M., T.S., C.T., A.G.K.) and Neurology (E.A.W.), Department of Clinical Neurosciences, and the Division of Experimental Medicine and Immunotherapeutics (I.W.), Addenbrooke's Hospital, University of Cambridge, and the Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust (A.A., B.P., C.D.-W., I.W., S.B.), Cambridge, the Faculty of Health: Medicine, Dentistry and Human Sciences, University of Plymouth (E.E.), and the South West Neurosurgical Centre, Derriford Hospital (E.E., P.C.W., M.G.), Plymouth, Wessex Neurological Unit, University Hospital Southampton, Southampton (D.B., A.Z., P.H.), the Department of Neurosurgery, Queen Elizabeth University Hospital, Glasgow (N.S., K.A.), the Department of Neurosurgery, Leeds General Infirmary, Leeds (S. Thomson, I.A.A.), the Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield (Y.Z.A.-T., D.H.), Translational Neurosurgery, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh (P.M.B.), Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich (G.B.), the Department of Neurosurgery, Great Ormond Street Hospital and Institute of Child Health, University College London (A.C.), and the National Hospital for Neurology and Neurosurgery (H.J.M.), London, the Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Salford Royal Hospital, Manchester Academic Health Science Centre, Manchester (A.T.K.), the National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre and Institute of Inflammation and Ageing, University of Birmingham, Birmingham (A.B.), and the Ageing Clinical and Experimental Research Group, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen (P.K.M.) - all in the United Kingdom; and the Department of Neurology, Karolinska University Hospital, Stockholm (E.P.T.).

Background: Chronic subdural hematoma is a common neurologic disorder that is especially prevalent among older people. The effect of dexamethasone on outcomes in patients with chronic subdural hematoma has not been well studied.

Methods: We conducted a multicenter, randomized trial in the United Kingdom that enrolled adult patients with symptomatic chronic subdural hematoma. The patients were assigned in a 1:1 ratio to receive a 2-week tapering course of oral dexamethasone, starting at 8 mg twice daily, or placebo. The decision to surgically evacuate the hematoma was made by the treating clinician. The primary outcome was a score of 0 to 3, representing a favorable outcome, on the modified Rankin scale at 6 months after randomization; scores range from 0 (no symptoms) to 6 (death).

Results: From August 2015 through November 2019, a total of 748 patients were included in the trial after randomization - 375 were assigned to the dexamethasone group and 373 to the placebo group. The mean age of the patients was 74 years, and 94% underwent surgery to evacuate their hematomas during the index admission; 60% in both groups had a score of 1 to 3 on the modified Rankin scale at admission. In a modified intention-to-treat analysis that excluded the patients who withdrew consent for participation in the trial or who were lost to follow-up, leaving a total of 680 patients, a favorable outcome was reported in 286 of 341 patients (83.9%) in the dexamethasone group and in 306 of 339 patients (90.3%) in the placebo group (difference, -6.4 percentage points [95% confidence interval, -11.4 to -1.4] in favor of the placebo group; P = 0.01). Among the patients with available data, repeat surgery for recurrence of the hematoma was performed in 6 of 349 patients (1.7%) in the dexamethasone group and in 25 of 350 patients (7.1%) in the placebo group. More adverse events occurred in the dexamethasone group than in the placebo group.

Conclusions: Among adults with symptomatic chronic subdural hematoma, most of whom had undergone surgery to remove their hematomas during the index admission, treatment with dexamethasone resulted in fewer favorable outcomes and more adverse events than placebo at 6 months, but fewer repeat operations were performed in the dexamethasone group. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Dex-CSDH ISRCTN number, ISRCTN80782810.).
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http://dx.doi.org/10.1056/NEJMoa2020473DOI Listing
December 2020

Intraoperative mapping of executive function using electrocorticography for patients with low-grade gliomas.

Acta Neurochir (Wien) 2021 May 22;163(5):1299-1309. Epub 2020 Nov 22.

Department of Neurosurgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Background: Intraoperative functional mapping with direct electrical stimulation during awake surgery for patients with diffuse low-grade glioma has been used in recent years to optimize the balance between surgical resection and quality of life following surgery. Mapping of executive functions is particularly challenging because of their complex nature, with only a handful of reports published so far. Here, we propose the recording of neural activity directly from the surface of the brain using electrocorticography to map executive functions and demonstrate its feasibility and potential utility.

Methods: To track a neural signature of executive function, we recorded neural activity using electrocorticography during awake surgery from the frontal cortex of three patients judged to have an appearance of diffuse low-grade glioma. Based on existing functional magnetic resonance imaging (fMRI) evidence from healthy participants for the recruitment of areas associated with executive function with increased task demands, we employed a task difficulty manipulation in two counting tasks performed intraoperatively. Following surgery, the data were extracted and analyzed offline to identify increases in broadband high-gamma power with increased task difficulty, equivalent to fMRI findings, as a signature of activity related to executive function.

Results: All three patients performed the tasks well. Data were recorded from five electrode strips, resulting in data from 15 channels overall. Eleven out of the 15 channels (73.3%) showed significant increases in high-gamma power with increased task difficulty, 26.6% of the channels (4/15) showed no change in power, and none of the channels showed power decrease. High-gamma power increases with increased task difficulty were more likely in areas that are within the canonical frontoparietal network template.

Conclusions: These results are the first step toward developing electrocorticography as a tool for mapping of executive function complementarily to direct electrical stimulation to guide resection. Further studies are required to establish this approach for clinical use.
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http://dx.doi.org/10.1007/s00701-020-04646-6DOI Listing
May 2021

CSF rhinorrhoea after endonasal intervention to the anterior skull base (CRANIAL): proposal for a prospective multicentre observational cohort study.

Br J Neurosurg 2020 Sep 10:1-10. Epub 2020 Sep 10.

Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, London, UK.

Background: The endonasal transsphenoidal approach (TSA) has emerged as the preferred approach in order to treat pituitary adenoma and related sellar pathologies. The recently adopted expanded endonasal approach (EEA) has improved access to the ventral skull base whilst retaining the principles of minimally invasive surgery. Despite the advantages these approaches offer, cerebrospinal fluid (CSF) rhinorrhoea remains a common complication. There is currently a lack of comparative evidence to guide the best choice of skull base reconstruction, resulting in considerable heterogeneity of current practice. This study aims to determine: (1) the scope of the methods of skull base repair; and (2) the corresponding rates of postoperative CSF rhinorrhoea in contemporary neurosurgical practice in the UK and Ireland.

Methods: We will adopt a multicentre, prospective, observational cohort design. All neurosurgical units in the UK and Ireland performing the relevant surgeries (TSA and EEA) will be eligible to participate. Eligible cases will be prospectively recruited over 6 months with 6 months of postoperative follow-up. Data points collected will include: demographics, tumour characteristics, operative data), and postoperative outcomes. Primary outcomes include skull base repair technique and CSF rhinorrhoea (biochemically confirmed and/or requiring intervention) rates. Pooled data will be analysed using descriptive statistics. All skull base repair methods used and CSF leak rates for TSA and EEA will be compared against rates listed in the literature.

Ethics And Dissemination: Formal institutional ethical board review was not required owing to the nature of the study - this was confirmed with the Health Research Authority, UK.

Conclusions: The need for this multicentre, prospective, observational study is highlighted by the relative paucity of literature and the resultant lack of consensus on the topic. It is hoped that the results will give insight into contemporary practice in the UK and Ireland and will inform future studies.
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http://dx.doi.org/10.1080/02688697.2020.1795622DOI Listing
September 2020

PiggyBac mutagenesis and exome sequencing identify genetic driver landscapes and potential therapeutic targets of EGFR-mutant gliomas.

Genome Biol 2020 07 30;21(1):181. Epub 2020 Jul 30.

The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.

Background: Glioma is the most common intrinsic brain tumor and also occurs in the spinal cord. Activating EGFR mutations are common in IDH1 wild-type gliomas. However, the cooperative partners of EGFR driving gliomagenesis remain poorly understood.

Results: We explore EGFR-mutant glioma evolution in conditional mutant mice by whole-exome sequencing, transposon mutagenesis forward genetic screening, and transcriptomics. We show mutant EGFR is sufficient to initiate gliomagenesis in vivo, both in the brain and spinal cord. We identify significantly recurrent somatic alterations in these gliomas including mutant EGFR amplifications and Sub1, Trp53, and Tead2 loss-of-function mutations. Comprehensive functional characterization of 96 gliomas by genome-wide piggyBac insertional mutagenesis in vivo identifies 281 known and novel EGFR-cooperating driver genes, including Cdkn2a, Nf1, Spred1, and Nav3. Transcriptomics confirms transposon-mediated effects on expression of these genes. We validate the clinical relevance of new putative tumor suppressors by showing these are frequently altered in patients' gliomas, with prognostic implications. We discover shared and distinct driver mutations in brain and spinal gliomas and confirm in vivo differential tumor suppressive effects of Pten between these tumors. Functional validation with CRISPR-Cas9-induced mutations in novel genes Tead2, Spred1, and Nav3 demonstrates heightened EGFRvIII-glioma cell proliferation. Chemogenomic analysis of mutated glioma genes reveals potential drug targets, with several investigational drugs showing efficacy in vitro.

Conclusion: Our work elucidates functional driver landscapes of EGFR-mutant gliomas, uncovering potential therapeutic strategies, and provides new tools for functional interrogation of gliomagenesis.
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http://dx.doi.org/10.1186/s13059-020-02092-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392733PMC
July 2020

Development of a prognostic scoring system to predict risk of reoperation for contralateral hematoma growth after unilateral evacuation of bilateral chronic subdural hematoma.

J Clin Neurosci 2020 Aug 30;78:79-85. Epub 2020 Jun 30.

Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Level 11, Singapore 119228, Singapore; Division of Neurosurgery, Department of Surgery, National University Hospital, National University Health System, 1E Kent Ridge Road, Level 11, Singapore 119228, Singapore. Electronic address:

Bilateral chronic subdural hematoma (bCSDH) is frequently drained unilaterally when the contralateral CSDH is small and asymptomatic. However, reoperation rates for contralateral CSDH growth can be high. We aimed to develop a prognostic scoring system to guide the selection of suitable patients for unilateral drainage of bCSDH. Data were collected retrospectively across three tertiary hospitals from 2010 to 2017 on all consecutive bCSDH patients aged 21 or above. Predictors of reoperation were identified using multivariable logistic regression. A prognostic score was developed and internally validated. 240 bCSDH patients were analyzed. 98 (40.8%) underwent unilateral and 142 (59.2%) underwent bilateral evacuation. Clinical outcomes were comparable between the unilateral and bilateral evacuation groups. Within the unilateral evacuation group, 4 (4.1%) had a reoperation for contralateral CSDH growth. Reoperation for contralateral CSDH was predicted by preoperative use of anticoagulants (OR = 15.0, 95% CI: 1.49-169.15, p = 0.017). Complete resolution of contralateral CSDH was predicted by its preoperative maximum width, with a cut-off of 9 mm producing the highest sensitivity and specificity (OR = 4.17 for ≤9 mm, 95% CI: 1.54-11.11, p = 0.004). Using our prognostic score, reoperation rate for contralateral CSDH was 1.6%, 3.6%, 16.7%, and 50.0% in low-risk, moderate-risk, high-risk and very high-risk patients, respectively. With each increase of 1 in the prognostic score, patients were 4 times as likely to undergo reoperation for contralateral CSDH (OR = 3.98, 95% CI: 1.36-13.53, p = 0.013). Our proposed risk score may be used as an adjunct in clinical decision making for bCSDH patients undergoing unilateral evacuation.
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http://dx.doi.org/10.1016/j.jocn.2020.06.009DOI Listing
August 2020

Malignant meningiomas.

Handb Clin Neurol 2020 ;170:245-250

Department of Neurosurgery, Addenbrooke's Hospital, Cambridge, United Kingdom. Electronic address:

Malignant meningiomas are WHO Grade III meningiomas representing 1% of all meningiomas. They are comprised of three histologic types: anaplastic, rhabdoid, and papillary. They can arise de novo or as a result of biologic progression of meningiomas of lower histologic grades. The overall survival of patients with WHO grade III meningiomas is 2-3 years. Surgery is the main treatment, while radiotherapy is thought to slow tumor growth. Multiple trials have been attempted on chemotherapeutic agents, hormonal therapies, small molecule and anti-angiogenic agents without robust evidence of efficacy. The rarity of these tumors is the main reason for our patchy understanding of the natural history and lack of effective treatment options. There is an urgent need to develop alternative therapies given the significantly increased risk of complication and co-mordibity associated with repeated surgeries in this population.
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http://dx.doi.org/10.1016/B978-0-12-822198-3.00044-6DOI Listing
April 2021

PET-guided repeat transsphenoidal surgery for previously deemed unresectable lateral disease in acromegaly.

Neurosurg Focus 2020 06;48(6):E8

1Cambridge Endocrine Molecular Imaging Group.

Objective: The object of this study was to determine if revision transsphenoidal surgery (TSS), guided by 11C-methionine PET/CT coregistered with volumetric MRI (Met-PET/MRCR), can lead to remission in patients with persistent acromegaly due to a postoperative lateral disease remnant.

Methods: The authors identified 9 patients with persistent acromegaly following primary intervention (TSS ± medical therapy ± radiotherapy) in whom further surgery had initially been discounted because of equivocal MRI findings with suspected lateral sellar and/or parasellar disease (cases with clear Knosp grade 4 disease were excluded). All patients underwent Met-PET/MRCR. Scan findings were used by the pituitary multidisciplinary team to inform decision-making regarding repeat surgery. Revision TSS was performed with wide lateral exploration as guided by the PET findings. Endocrine reassessment was performed at 6-10 weeks after surgery, with longitudinal follow-up thereafter.

Results: Met-PET/MRCR revealed focal tracer uptake in the lateral sellar and/or parasellar region(s) in all 9 patients, which correlated with sites of suspected residual tumor on volumetric MRI. At surgery, tumor was identified and resected in 5 patients, although histological analysis confirmed somatotroph tumor in only 4 cases. In the other 4 patients, no definite tumor was seen, but equivocal tissue was removed. Despite the uncertainty at surgery, all patients showed immediate significant improvements in clinical and biochemical parameters. In the 8 patients for whom long-term follow-up data were available, insulin-like growth factor 1 (IGF-1) was ≤ 1.2 times the upper limit of normal (ULN) in all subjects and ≤ 1 times the ULN in 6 subjects, and these findings have been maintained for up to 28 months (median 8 months, mean 13 months) with no requirement for adjunctive medical therapy or radiotherapy. No patient suffered any additional pituitary deficit or other complication of surgery.

Conclusions: This study provides proof of concept that Met-PET/MRCR can be helpful in the evaluation of residual lateral sellar/parasellar disease in persistent acromegaly and facilitate targeted revision TSS in a subgroup of patients.
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http://dx.doi.org/10.3171/2020.3.FOCUS2052DOI Listing
June 2020

Connections, Tracts, Fractals, and the Rest: A Working Guide to Network and Connectivity Studies in Neurosurgery.

World Neurosurg 2020 08 2;140:389-400. Epub 2020 Apr 2.

Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.

Brain mapping and connectomics can probe networks that span the entire brain, producing a diverse range of outputs for probing specific clinically relevant questions. The potential for understanding the effect of focal lesions on brain function, cognition, and plasticity abounds, any one of which would likely yield more effective and safer neurosurgical strategies. However, the possibilities of advanced magnetic resonance imaging and connectomics have been somewhat underused in neurosurgery, arising from actual or perceived difficulties in either application or analysis. The present review builds on previous work describing the theoretical attractions of connectomics to deliberate on the practical details of performing high-quality connectomics studies in neurosurgery. First, the data and methods involved in deriving connectomics models will be considered, specifically for the purpose of determining the nature of inferences that can be made subsequently. Next, a selection of key analysis methods will be explored using practical examples that illustrate their effective implementation and the insights that can be gleaned. The principles of study design will be introduced, including analysis tips and methods for making efficient use of available resources. Finally, a review of the best research practices for neuroimaging studies will be discussed, including principles of open access data sharing, study preregistration, and methods for improving replicability. Ultimately, we hope readers will be better placed to appraise the current connectomics studies in neurosurgery and empowered to develop their own high-quality studies, both of which are key steps in realizing the true potential of connectomics and advanced neuroimaging analyses in general.
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http://dx.doi.org/10.1016/j.wneu.2020.03.116DOI Listing
August 2020

Practical Application of Networks in Neurosurgery: Combined 3-Dimensional Printing, Neuronavigation, and Preoperative Surgical Planning.

World Neurosurg 2020 05 17;137:e126-e137. Epub 2020 Jan 17.

Division of Neurosurgery, Department of Clinical Neurosciences, Cambridge Biomedical Campus, Cambridge, England, United Kingdom. Electronic address:

Background: A plethora of cutting-edge neuroimaging analyses have been developed and published, yet they have not hitherto been realized as improvements in neurosurgical outcomes. In this paper we propose a novel interface between neuroimaging and neurosurgery for aiding translational research. Our objective is to create a method for applying advanced neuroimaging and network analysis findings to neurosurgery and illustrate its application through the presentation of 2 detailed case vignettes.

Methods: This interface comprises a combination of network visualization, 3-dimensional printing, and ex-vivo neuronavigation to enable preoperative planning according to functional neuroanatomy. Clinical cases were selected from a prospective cohort study.

Results: The first case vignette describes a low-grade glioma with potential language and executive function network involvement that underwent a successful complete resection of the lesion with preservation of network features. The second case describes a low-grade glioma in an apparently noneloquent location that underwent a subtotal resection but demonstrated unexpected and significant impairment in executive function postoperatively that subsequently abated during follow-up. In both examples the neuroimaging and network data highlight the complexity of the surrounding functional neuroanatomy at the individual level, beyond that which can be perceived on standard structural sequences.

Conclusions: The described interface has widespread applications for translational research including preoperative planning, neurosurgical training, and detailed patient counseling. A protocol for assessing its effectiveness and safety is proposed. Finally, recommendations for effective translation of findings from neuroimaging to neurosurgery are discussed, with the aim of making clinically meaningful improvements to neurosurgical practice.
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http://dx.doi.org/10.1016/j.wneu.2020.01.085DOI Listing
May 2020

Quality improvement of neuro-oncology services: integrating the routine collection of patient-reported, health-related quality-of-life measures.

Neurooncol Pract 2019 May 17;6(3):226-236. Epub 2018 Oct 17.

Neurosurgery Department, Cambridge University Hospitals NHS Trust, Addenbrookes Hospital, UK.

Background: Brain cancer has a strong impact on health-related quality of life (HRQoL), and its evaluation in clinical practice can improve the quality of care provided. The aim of this project was to integrate routine collection of HRQoL information from patients with brain tumor or metastasis in 2 specialized United Kingdom tertiary centers, and to evaluate the implementation process.

Methods: Since October 2016, routine collection of electronic self-reported HRQoL information has been progressively embedded in the participating centers using standard questionnaires. During the first year, the project was implemented, and the process evaluated, through regular cycles of process evaluation followed by an action plan, monitoring of questionnaire completion rates, and assessment of patient views.

Results: Main challenges encountered included reluctance to change usual practice and limited resources. Key measures for success included strong leadership of senior staff, involvement of stakeholders in project design and evaluation, and continuous strategic support to professionals. Final project workflow included 6 process steps, 1 decision step, and 4 outputs. Questionnaires were mostly self-completed (75.1%), and completion took 6-9 minutes. Most patients agreed that the questionnaire items were easy to understand (97.0%), important for them (93.0%), and helped them think what they wanted to discuss in their clinical consultation (75.4%).

Conclusions: Integrating HRQoL information as a routine part of clinical assessments has the potential to enhance individually tailored patient care in our institutions. Challenges involved in innovations of this nature can be overcome through a systematic approach involving strong leadership, wide stakeholder engagement, and strategic planning.
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http://dx.doi.org/10.1093/nop/npy040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656295PMC
May 2019

Outcomes of Subdural Versus Subperiosteal Drain After Burr-Hole Evacuation of Chronic Subdural Hematoma: A Multicenter Cohort Study.

World Neurosurg 2019 Nov 30;131:e392-e401. Epub 2019 Jul 30.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Neurosurgery, Department of Surgery, National University Hospital, National University Health System, Singapore.

Background: Although the use of a postoperative drain after burr-hole evacuation of chronic subdural hematoma (CSDH) is known to improve surgical outcomes, the superiority of subdural over subperiosteal drains has not been firmly established. Evidence comparing these 2 drain types is largely restricted to single-center series with limited numbers. Using a multicenter cohort study, we aimed to show noninferiority of subperiosteal drains vis-à-vis subdural drains after burr-hole evacuation of CSDH.

Methods: We performed a retrospective analysis of all consecutive patients with CSDH aged 21 years and older who had undergone burr-hole craniostomy across 3 tertiary hospitals from 2010 to 2017. Primary outcome measures included CSDH recurrence and modified Rankin Scale (mRS) score at 6 months. Outcomes of patients in the subdural and subperiosteal drain groups were analyzed and confounders were adjusted for using multivariate logistic regression.

Results: Of the 570 cases analyzed, 329 (57.7%) received a subdural drain and 241 (42.3%) received a subperiosteal drain. There was no significant difference between the 2 drain groups in CSDH recurrence (13.1% in the subdural group vs. 11.2% in the subperiosteal group; P = 0.502) or 6-month mRS score (27.2% with mRS 4-6 in the subdural group vs. 20.4% in the subperiosteal group; P = 0.188). Independent predictors of CSDH recurrence identified on multivariate analysis included premorbid mRS score 0-3 (P = 0.021), separated CSDH type on preoperative computed tomography scan (P = 0.002), and postoperative pneumocephalus of ≥15 mm (P = 0.005).

Conclusions: Outcomes of subdural and subperiosteal drains after burr-hole craniostomy for CSDH are largely equivalent based on our findings.
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http://dx.doi.org/10.1016/j.wneu.2019.07.168DOI Listing
November 2019

Infratentorial Supracerebellar Approach for Resection of Midbrain Cavernous Malformation: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2020 Feb;18(2):E44

Division of Neurosurgery, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.

Cavernous malformations (cavernomas) of the brain stem with recurrent hemorrhage may be amenable to microsurgical resection if they are present close to the surface. The risks of surgery need to be balanced with the natural history of the lesion and the accumulation of neurological deficits and risk to life with multiple hemorrhages. In this 3D operative video, we illustrate the technique for the resection of a dorsally located midbrain cavernous malformation. Informed consent was obtained for this procedure. The cavernoma is accessed with the use of a supracerebellar infratentorial approach. The infratentorial craniotomy and coagulation of the superior vermian veins is shown. A description is provided of the use of hemosiderin staining and the intercollicular relative "safe zone"1 as landmarks for the neurotomy. The technique of cavernoma dissection from the surrounding gliotic plane is shown and described. In this case, the patient required prolonged rehabilitation but fully recovered without residual deficit 1 yr following surgery.
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http://dx.doi.org/10.1093/ons/opz114DOI Listing
February 2020

Utilization of volumetric magnetic resonance imaging for baseline and surveillance imaging in Neuro-oncology.

Br J Radiol 2019 Jun 8;92(1098):20190059. Epub 2019 May 8.

2 National Cancer Research Institute Metastases and Meningioma subgroup of the Brain Clinical Studies Group , London , United Kingdom.

The acquisition of volumetric post-contrast MRI has clear advantages in the interpretation of neuro-oncology studies but has yet to find its way into routine clinical practice beyond planning scans for surgery and radiotherapy. This commentary briefly highlights the benefits of these techniques whilst dispelling some of the perceived disadvantages.
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http://dx.doi.org/10.1259/bjr.20190059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592091PMC
June 2019

Life after surgical resection of a meningioma: a prospective cross-sectional study evaluating health-related quality of life.

Neuro Oncol 2019 01;21(Suppl 1):i32-i43

Department of Neurosurgery, Royal Melbourne Hospital, Parkville, Victoria, Australia.

Background: Few studies have evaluated the health-related quality of life (HRQoL) of patients with meningiomas. Here, we report the largest prospective, longitudinal cross-sectional cohort study of HRQoL in meningiomas to date, in order to identify possible actionable determinants of global HRQoL.

Methods: Adults who had undergone resection of a grade I intracranial meningioma and were in routine follow-up at a single large tertiary center underwent HRQoL assessment using the QLQ-C30 questionnaire administered opportunistically at follow-up visits. Averaged transformed QLQ-C30 scores at 12-month intervals were compared with scores from a normative reference population, with reference to known minimal clinically meaningful difference (CMD) in scores. To evaluate for possible determinants of changes in global HRQoL, global HRQoL scores were correlated (Spearman's Rho) with subdomain and symptom scores and with interval time from surgical resection.

Results: A total of 291 postoperative patients with histologically confirmed and surgically treated grade I meningiomas consented to participation and a total of 455 questionnaires were included for analysis. Patients with meningiomas reported reduced global HRQoL at nearly every 12-month interval with clinically and statistically significant impairments at 12, 48, 108, and 120 months postoperative compared with the normative population (P < 0.05). Meningioma patients at the 12-month interval also reported a reduction of each subdomain of HRQoL assessment (P < 0.05); however, a CMD was only seen in cognitive functioning. Physical, emotional, cognitive, and social subdomains, as well as fatigue and sleep/insomnia, were significantly associated with global HRQoL at the first 12-month interval. Overall, there was no significant correlation between time from surgery and global HRQoL or the subdomain functional or symptom sections of the QLQ-C30.

Conclusions: Meningioma patients report considerable limitations in HRQoL for more than 120 months after surgery, particularly in cognitive, emotional, and social function, as well as suffering significant fatigue and sleep impairment compared with a normative reference population. The majority of these reported functional impairments and symptoms are strongly associated with global HRQoL and thus can be considered determinants of global HRQoL that if treated, have the potential to improve HRQoL for our meningioma patients. This hypothesis requires future study of targeted interventions to determine their efficacy.
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http://dx.doi.org/10.1093/neuonc/noy152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347082PMC
January 2019

Awake Craniotomy for Resection of Left Temporal Cavernoma: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2019 Sep;17(3):E102

Division of Neurosurgery, Cambridge University Hospital's NHS Foundation Trust, Cambridge, United Kingdom.

Cavernomas presenting with seizures refractory to medical treatment may require surgical excision for seizure control. If superficial, they can be surgically accessible but can pose additional risks when located in or near eloquent cortex. In this 3D operative video we illustrate the technique for the resection of a left temporal cavernoma located near eloquent cortex for speech with awake surgery and cortical mapping to avoid a speech deficit postoperatively. Informed consent was obtained for this procedure. Navigation is used to localize the cavernoma following which a large craniotomy is performed exposing the temporal lobe, frontal lobe, and sylvian vein. Bipolar stimulation is used to localize speech with the patient awake until speech arrest occurs. The cavernoma is situated immediately inferior to the sulcus over which speech arrest occurs. The sulcus immediately above the cavernoma is opened and adjacent arteries are carefully preserved. The glial plane around the cavernoma is used to dissect the cavernoma from the surrounding cortex. Care is taken to remove the haemosiderin as this can act as a precipitant for ongoing seizures. In this case the patient had no neurological deficits following surgery and was seizure free.
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http://dx.doi.org/10.1093/ons/opy381DOI Listing
September 2019

Exophytic Brainstem Cavernoma in the Floor of the Fourth Ventricle Midline Suboccipital Approach: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2019 Sep;17(3):E109

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

This 3-dimensional operative video covers the suboccipital approach to a brainstem cavernoma of the floor of the fourth ventricle. Brainstem cavernomas are low-flow vascular lesions associated with a 2% to 6% annual bleed rate. Repeated bleeds typically result in progressive neurological deficit, and especially for exophytic lesions surgery may arrest this progression without significantly exacerbating pre-existing deficits. The approach to these lesions may be via any standard skull base approach, dictated in each lesion by the presentation to the pial surface. Here, we describe a suboccipital approach to an exophytic cavernoma of the floor of the fourth ventricle, arising caudal to the medial longitudinal fasciculus and facial colliculus. The 38-yr-old male patient had suffered a stepwise neurological deterioration secondary to repeated bleeds, and complete resection of the cavernoma demonstrated here arrested this progression. The patient has provided signed consent to video acquisition and storage at operation, and to publication of this material.
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http://dx.doi.org/10.1093/ons/opy384DOI Listing
September 2019

An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures.

Sci Rep 2018 09 10;8(1):13537. Epub 2018 Sep 10.

Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, Devon, PL4 8AA, UK.

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.
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http://dx.doi.org/10.1038/s41598-018-31659-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131140PMC
September 2018

Results of Transcranial Resection of Olfactory Groove Meningiomas in Relation to Imaging-Based Case Selection Criteria for the Endoscopic Approach.

Oper Neurosurg (Hagerstown) 2019 05;16(5):539-548

Division of Neurosurgery, Addenbrookes Hospital, University of Cambridge, Cambridge, United Kingdom.

Background: Endoscopic endonasal surgery (EES) is increasingly used for olfactory groove meningiomas (OGMs). The role of EES for large (≥4 cm) or complex OGMs is debated. Specific imaging features have been reported to affect the degree of gross total resection (GTR) and complications following EES for OGMs. The influence of these factors on transcranial resection (TCR) is unknown.

Objective: To examine the impact of specific imaging features on outcome following TCR to provide a standard for large and endoscopically less favorable OGMs against which endoscopic outcomes can be compared.

Methods: Retrospective study of patients undergoing TCR for OGMs 2002 to 2016.

Results: Fifty patients (mean age 62.1 yr, mean maximum tumor diameter 5.04 cm and average tumor volume of 48.8 cm3) were studied. Simpson grade 1 and 2 resections were achieved in 80% and 12%, respectively. A favorable functional outcome (modified Rankin Scale [mRS] 0-2) was attained in 86%. The degree of resection, mRS, mortality (4%), recurrence (6%), infection (8%), and cerebrospinal fluid leak requiring intervention (12%) were not associated with tumor calcification, absence of cortical cuff, T2 hyperintensity, tumor configuration, tumor extension beyond midpoint of superior orbital roof, or extension to posterior wall of frontal sinus. There was no difference in resection rates but a trend towards greater complications between 3 arbitrarily divided groups of large meningiomas of increasing complexity based on extensive extension or vascular adherence.

Conclusion: Favorable outcomes can be achieved with TCR for large and complex OGMs Factors that may preclude endoscopic resection do not negatively affect outcome following TCR.
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http://dx.doi.org/10.1093/ons/opy191DOI Listing
May 2019

Effectiveness of Cadaveric Simulation in Neurosurgical Training: A Review of the Literature.

World Neurosurg 2018 Oct 11;118:88-96. Epub 2018 Jul 11.

Division of Neurosurgery, Addenbrooke's Hospital, Cambridge, United Kingdom. Electronic address:

Objective: Increased restrictions on working hours and the resultant decrease in theater time coupled with greater scrutiny to demonstrate proficiency at surgical tasks has resulted in the incorporation of simulators for surgical training. This literature review describes the use of cadaveric simulators in postgraduate neurosurgical training, with the aim to analyze their effectiveness in improving surgical performance.

Methods: An electronic literature search of the MEDLINE, Embase, and Cochrane Library databases was conducted to identify studies that look at the efficacy of cadaveric simulation in neurosurgical training. Studies that were eligible were those that assessed either objectively or subjectively the effectiveness of human cadaver models in cranial or spinal neurosurgical training. Studies that did not assess efficacy on training, looked at animal cadavers, or noncadaveric simulators were excluded.

Results: Twelve studies were deemed to meet the eligibility criteria. Only 4 of the studies used objective measures to assess the effectiveness of cadaveric simulators on training. Most studies reported a positive impact of cadaveric simulators on training.

Conclusions: Most studies identified in this review failed to provide strong objective evidence for effectiveness in achieving competency and good outcomes in the theatres. Lack of use of validated skills assessment tools prevented studies from associating cadaveric training with improvement in operating skills. Future studies should aim to address these shortcomings and focus on validating cadaveric simulation, ensuring only those that improve performance of both technical and nontechnical skills are pursued.
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http://dx.doi.org/10.1016/j.wneu.2018.07.015DOI Listing
October 2018

Imaging practice in low-grade gliomas among European specialized centers and proposal for a minimum core of imaging.

J Neurooncol 2018 Sep 10;139(3):699-711. Epub 2018 Jul 10.

VU University Medical Center, Amsterdam, The Netherlands.

Objective: Imaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers.

Methods: An online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery.

Results: A total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI.

Conclusion: A minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of ≤ 3 mm. No common standard could be obtained regarding advanced MRI protocols and PET.

Importance Of The Study: We believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed "minimal core of imaging" in clinical routine will facilitate future cooperative studies.
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http://dx.doi.org/10.1007/s11060-018-2916-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132968PMC
September 2018

Predictors of early progression of surgically treated atypical meningiomas.

Acta Neurochir (Wien) 2018 09 30;160(9):1813-1822. Epub 2018 Jun 30.

Division of Neurosurgery, Cambridge Biomedical Campus, Addenbrooke's Hospital, University of Cambridge, Box 167, Cambridge, CB2 0QQ, UK.

Background: Clinical behaviour of atypical meningiomas is not uniform. While, as a group, they exhibit a high recurrence rate, some pursue a more benign course, whereas others progress early. We aim to investigate the imaging and pathological factors that predict risk of early tumour progression and to determine whether early progression is related to outcome.

Methods: Adult patients with WHO grade II meningioma treated in three regional referral centres between 2007 and 2014 were included. MRI and pathology characteristics were assessed. Gross total resection (GTR) was defined as Simpson 1-3. Recurrence was classified into early and late (≤ 24 vs. > 24 months).

Results: Among the 220 cases, 37 (16.8%) patients progressed within 24 months of operation. Independent predictors of early progression were subtotal resection (STR) (p = 0.005), parafalcine/parasagittal location (p = 0.015), peritumoural oedema (p = 0.027) and mitotic index (MI) > 7 (p = 0.007). Adjuvant radiotherapy was negatively associated with early recurrence (p = 0.046). Thirty-two per cent of patients with residual tumour and 26% after GTR received adjuvant radiotherapy. There was a significantly lower proportion of favourable outcomes at last follow-up (mRS 0-1) in patients with early recurrence (p = 0.001).

Conclusions: Atypical meningiomas are a heterogeneous group of tumours with 16.8% patients having recurrence within 24 months of surgery. Residual tumour, parafalcine/parasagittal location, peritumoural oedema and a MI > 7 were all independently associated with early recurrence. As administration of adjuvant radiotherapy was not protocolised in this cohort, any conclusions about benefits of irradiation of WHO grade II meningiomas should be viewed with caution. Patients with early recurrence had worse neurological outcome. While histological and imaging characteristics provide some prognostic value, further molecular characterisation of atypical meningiomas is warranted to aid clinical decision making.
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http://dx.doi.org/10.1007/s00701-018-3593-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105233PMC
September 2018

Anterolateral Approach for Central Thoracic Disc Prolapse-Surgical Strategies Used to Tackle Differing Operative Findings: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2019 Jan;16(1):E5-E6

Department of Neurosurgery, Cambridge University Hospital's NHS Foundation Trust, Cambridge, UK.

Thoracic disc prolapses causing cord compression can be challenging. For compressive central disc protrusions, a posterior approach is not suitable due to an unacceptable level of cord manipulation. An anterolateral transthoracic approach provides direct access to the disc prolapse allowing for decompression without disturbing the spinal cord. In this video, we describe 2 cases of thoracic myelopathy from a compressive central thoracic disc prolapse. In both cases, informed consent was obtained. Despite similar radiological appearances of heavy calcification, intraoperatively significant differences can be encountered. We demonstrate different surgical strategies depending on the consistency of the disc and the adherence to the thecal sac. With adequate exposure and detachment from adjacent vertebral bodies, soft discs can be, in most instances, separated from the theca with minimal cord manipulation. On the other hand, largely calcified discs often present a significantly greater challenge and require thinning the disc capsule before removal. In cases with significant adherence to dura, in order to prevent cord injury or cerebrospinal fluid leak a thinned shell can be left, providing total detachment from adjacent vertebrae can be achieved. Postoperatively, the first patient, with a significantly calcified disc, developed a transient left leg weakness which recovered by 3-month follow-up. This video outlines the anatomical considerations and operative steps for a transthoracic approach to a central disc prolapse, whilst demonstrating that computed tomography appearances are not always indicative of potential operative difficulties.
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http://dx.doi.org/10.1093/ons/opy063DOI Listing
January 2019

Type I Spinal Dural Fistula Treated Using a Minimally Invasive Approach With a 20-mm Nonexpandable Tubular Retractor: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2018 Nov;15(5):E52

Division of Neurosurgery, Cambridge University Hospital's NHS Foundation Trust, Cambridge, United Kingdom.

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http://dx.doi.org/10.1093/ons/opy032DOI Listing
November 2018

Microsurgical Clipping of an Ophthalmic Artery Aneurysm With a Limited Intradural Anterior Clinoidectomy: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2018 Nov;15(5):604

Division of Neurosurgery, Cambridge University Hospital's NHS Foundation Trust, Cambridge, United Kingdom.

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http://dx.doi.org/10.1093/ons/opy021DOI Listing
November 2018

Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma.

NPJ Genom Med 2017 13;2. Epub 2017 Mar 13.

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

Aberrant genetic and epigenetic variations drive malignant transformation and are hallmarks of cancer. Using PCR-free sample preparation we achieved the first in-depth whole genome (hydroxyl)-methylcytosine, single-base-resolution maps from a glioblastoma tumour/margin sample of a patient. Our data provide new insights into how genetic and epigenetic variations are interrelated. In the tumour, global hypermethylation with a depletion of 5-hydroxymethylcytosine was observed. The majority of single nucleotide variations were identified as cytosine-to-thymine deamination products within CpG context, where cytosine was preferentially methylated in the margin. Notably, we observe that cells neighbouring tumour cells display epigenetic alterations characteristic of the tumour itself although genetically they appear "normal". This shows the potential transfer of epigenetic information between cells that contributes to the intratumour heterogeneity of glioblastoma. Together, our reference (epi)-genome provides a human model system for future studies that aim to explore the link between genetic and epigenetic variations in cancer progression.
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http://dx.doi.org/10.1038/s41525-017-0007-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677956PMC
March 2017