Immune checkpoint inhibitor treatment of brain metastasis associated with a less invasive growth pattern, higher T-cell infiltration and raised tumor ADC on diffusion weighted MRI.

BACKGROUND: Brain metastases are the most common intracranial tumors with an increasing incidence. They are an important cause of morbidity and mortality in patients with solid organ cancer and a focus of recent clinical research and experimental interest. Immune checkpoint inhibitors are being increasingly used to treat solid organ cancers. METHODS: To determine whether immune checkpoint inhibitors were biologically effective in the brain, we compared melanoma brain metastasis samples where treatment with ipilimumab had occurred preoperatively to those who had not received any immune modulating therapy and looked for histopathological (invasion, vascularity, metastasis inducing proteins, matrix metalloproteinases, immune cell infiltration, tissue architecture) and advanced MRI differences (diffusion weighted imaging). RESULTS: Co-localized tissue samples from the same regions as MRI regions of interest showed significantly lower vascularity (density of CD34 + vessels) in the core and higher T-cell infiltration (CD3 + cells) in the leading edge for ipilimumab-treated brain metastasis samples than for untreated cases and this correlated with a higher tumor ADC signal at post-treatment/preoperative MRI brain. CONCLUSIONS: Treatment of a melanoma brain metastasis with ipilimumab appears to cause measurable biological changes in the tumor that can be correlated with post-treatment diffusion weighted MRI imaging, suggesting both a mechanism of action and a possible surrogate marker of efficacy.

Clinical Presentation and Prognosis.

Over the past three decades, the care for patients with meningioma has steadily improved as a result of a better understanding of the natural history, molecular biology, and classification of these tumors. Surgical frameworks for management have been established and validated with more options for adjuvant and salvage treatment available for patients with residual or recurrent disease. Overall these advances have improved clinical outcomes and prognosis.Alongside the improved clinical management has come an increase in biological understanding of these tumors. The number of publications within the field of meningioma research continues to expand and biological studies identifying molecular factors at the cytogenic and genomic level offer exciting potential for more personalized management strategies. As survival and understanding have increased, treatment outcomes are moving from traditional metrics, which describe the morbidity and mortality to more patient-centered measures. The subjective experiences of patients with meningioma are gaining interest among clinical researchers and it is recognized that even supposedly mild symptoms arising from meningioma can have a significant effect on a patient's quality of life.This chapter reviews the varied clinical presentations of meningioma, which in the modern era of widespread brain imaging must include a discussion of incidental meningioma. The second part examines prognosis and the clinical, pathological, and molecular factors that can be used to predict outcomes.

Genomic profiling using the UltraSEEK panel identifies discordancy between paired primary and breast cancer brain metastases and an association with brain metastasis-free survival.

PURPOSE: Brain metastases (BM) are an increasing clinical problem. This study aimed to assess paired primary breast cancers (BC) and BM for aberrations within TP53, PIK3CA, ESR1, ERBB2 and AKT utilising the MassARRAY® UltraSEEK® technology (Agena Bioscience, San Diego, USA). METHODS: DNA isolated from 32 paired primary BCs and BMs was screened using the custom UltraSEEK® Breast Cancer Panel. Data acquisition and analysis was performed by the Agena Bioscience Typer software v4.0.26.74. RESULTS: Mutations were identified in 91% primary BCs and 88% BM cases. TP53, AKT1, ESR1, PIK3CA and ERBB2 genes were mutated in 68.8%, 37.5%, 31.3%, 28.1% and 3.1% respectively of primary BCs and in 59.4%, 37.5%, 28.1%, 28.1% and 3.1% respectively of BMs. Differences in the mutations within the 5 genes between BC and paired BM were identified in 62.5% of paired cases. In primary BCs, ER-positive/HER2-negative cases harboured the most mutations (70%), followed by ER-positive/HER2-positive (15%) and triple-negatives (13.4%), whereas in BMs, the highest number of mutations was observed in triple-negative (52.5%), followed by ER-positive/HER2-negative (35.6%) and ER-negative/HER2-positive (12%). There was a significant association between the number of mutations in the primary BC and breast-to-brain metastasis-free survival (p = 0.0001) but not with overall survival (p = 0.056). CONCLUSION: These data demonstrate the discordancy between primary BC and BM, as well as the presence of clinically important, actionable mutations in BCBM. The UltraSEEK® Breast Cancer Panel provides a tool for BCBM that can be utilised to direct more tailored treatment decisions and for clinical studies investigating targeted agents.

Academic neurosurgery in the UK: present and future directions.

Academic neurosurgery encompasses basic science and clinical research efforts to better understand and treat diseases of relevance to neurosurgical practice, with the overall aim of improving treatment and outcome for patients. In this article, we provide an overview of the current and future directions of British academic neurosurgery. Training pathways are considered together with personal accounts of experiences of structured integrated clinical academic training and unstructured academic training. Life as an academic consultant is also described. Funding is explored, for the specialty as a whole and at the individual level. UK academic neurosurgical organisations are highlighted. Finally, the UK's international standing is considered.

Extent of resection predicts risk of progression in adult pilocytic astrocytoma.

Object: Pilocytic astrocytomas are rare tumours in adults. Presentation, management and prognostic factors are poorly characterised. Methods: Retrospective single centre study from 2000 to 2016. Results: 50 cases were identified (median age 29 years; range 16-76). Symptoms at presentation were neurological deficit (n = 21), headache (n = 18) and seizures (n = 6). Five were incidental findings. Five patients had hydrocephalus at presentation and required emergent management, two by endoscopic third ventriculostomy and three by external ventricular drain. Symptoms were present for a median of 16 weeks (range 1 week to 34 years). Surgery consisted of gross total resection (n = 23), subtotal resection (n = 21) or biopsy (n = 6). Progression occurred in 20 patients at a median time of 7 years following surgery and was asymptomatic in just over half of these cases. A greater degree of resection (complete vs. subtotal) was associated with longer time to progression (Kaplan-Meier analysis, log rank test = 3.58, p = 0.059). At their first progression 12 patients underwent re-resective surgery and the remainder received radiotherapy. The median 5-year survival was 80%. Conclusions: In adult patients with a pilocytic astrocytoma, a macroscopic resection should be the aim at the first resective operation. Emergency management of hydrocephalus may be required in the first instance.

Use of diffusion-weighted MRI to modify radiosurgery planning in brain metastases may reduce local recurrence.

Stereotactic radiosurgery (SRS) is an effective and well tolerated treatment for selected brain metastases; however, local recurrence still occurs. We investigated the use of diffusion weighted MRI (DWI) as an adjunct for SRS treatment planning in brain metastases. Seventeen consecutive patients undergoing complete surgical resection of a solitary brain metastasis underwent image analysis retrospectively. SRS treatment plans were generated based on standard 3D post-contrast T1-weighted sequences at 1.5T and then separately using apparent diffusion coefficient (ADC) maps in a blinded fashion. Control scans immediately post operation confirmed complete tumour resection. Treatment plans were compared to one another and with volume of local recurrence at progression quantitatively and qualitatively by calculating the conformity index (CI), the overlapping volume as a proportion of the total combined volume, where 1 = identical plans and 0 = no conformation whatsoever. Gross tumour volumes (GTVs) using ADC and post-contrast T1-weighted sequences were quantitatively the same (related samples Wilcoxon signed rank test = -0.45, p = 0.653) but showed differing conformations (CI 0.53, p < 0.001). The diffusion treatment volume (DTV) obtained by combining the two target volumes was significantly greater than the treatment volume based on post contrast T1-weighted MRI alone, both quantitatively (median 13.65 vs. 9.52 cm3, related samples Wilcoxon signed rank test p < 0.001) and qualitatively (CI 0.74, p = 0.001). This DTV covered a greater volume of subsequent tumour recurrence than the standard plan (median 3.53 cm3 vs. 3.84 cm3, p = 0.002). ADC maps may be a useful tool in addition to the standard post-contrast T1-weighted sequence used for SRS planning.

A national survey of the management of patients with incidental meningioma in the United Kingdom.

BACKGROUND: Incidental meningiomas are increasingly being diagnosed due to widespread use of brain imaging. Treatment options include surveillance, surgery and stereotactic radiosurgery, but the natural history of these tumours is not fully understood and there are no accepted management guidelines to aid clinical decision-making. The aim of this study was to assess current practice in the United Kingdom and identify areas of variation for further study. METHODS: A questionnaire was distributed to all members of the Society of British Neurosurgeons (SBNS). The main components of the survey included the assessment of which factors and tumour characteristics are considered in the management and follow-up of incidental meningiomas. Two case scenarios were also presented. RESULTS: The response rate was 12.5% (44 completed surveys) with 74% (25/34) of neurosurgical centres represented. Absence of calcification was only considered by 36% (16/44) of neurosurgeons. Most neurosurgeons opt for surveillance at initial presentation, and the length of follow-up was 5 years (14/33) and 10 years (11/33). The case scenarios highlighted that tumour growth at follow-up resulted in a preference to change from surveillance to treatment with surgery or SRS. SRS was preferred in skull-base (23/36) and medial sphenoid wing (16/39) tumours. CONCLUSIONS: This survey has demonstrated that certain aspects of incidental meningioma management show variation and remain controversial. Further research through prospective cohort studies is required to provide evidence to support guidelines for the management of incidental meningiomas.

Metastasis-inducing proteins are widely expressed in human brain metastases and associated with intracranial progression and radiation response.

BACKGROUND: Understanding the factors that drive recurrence and radiosensitivity in brain metastases would improve prediction of outcomes, treatment planning and development of therapeutics. We investigated the expression of known metastasis-inducing proteins in human brain metastases. METHODS: Immunohistochemistry on metastases removed at neurosurgery from 138 patients to determine the degree and pattern of expression of the proteins S100A4, S100P, AGR2, osteopontin (OPN) and the DNA repair marker FANCD2. Validation of significant findings in a separate prospective series with the investigation of intra-tumoral heterogeneity using image-guided sampling. Assessment of S100A4 expression in brain metastatic and non-metastatic primary breast carcinomas. RESULTS: There was widespread staining for OPN, S100A4, S100P and AGR2 in human brain metastases. Positive staining for S100A4 was independently associated with a shorter time to intracranial progression after resection in multivariate analysis (hazard ratio for negative over positive staining=0.17, 95% CI: 0.04-0.74, P=0.018). S100A4 was expressed at the leading edge of brain metastases in image guided sampling and overexpressed in brain metastatic vs non-brain metastatic primary breast carcinomas. Staining for OPN was associated with a significant increase in survival time after post-operative whole-brain radiotherapy in retrospective (OPN negative 3.43 months, 95% CI: 1.36-5.51 vs OPN positive, 11.20 months 95% CI: 7.68-14.72, Log rank test, P<0.001) and validation populations. CONCLUSIONS: Proteins known to be involved in cellular adhesion and migration in vitro, and metastasis in vivo are significantly expressed in human brain metastases and may be useful biomarkers of intracranial progression and radiosensitivity.

Surgical management of posterior fossa metastases.

The diagnosis of brain metastases is associated with a poor prognosis reflecting uncontrolled primary disease that has spread to the relative sanctuary of the central nervous system. 20 % of brain metastases occur in the posterior fossa and are associated with significant morbidity. The risk of acute hydrocephalus and potential for sudden death means these metastases are often dealt with as emergency cases. This approach means a full pre-operative assessment and staging of underlying disease may be neglected and a proportion of patients undergo comparatively high risk surgery with little or no survival benefit. This study aimed to assess outcomes in patients to identify factors that may assist in case selection. We report a retrospective case series of 92 consecutive patients operated for posterior fossa metastases between 2007 and 2012. Routine demographic data was collected plus data on performance status, primary cancer site, details of surgery, adjuvant treatment and survival. The only independent positive prognostic factors identified on multivariate analysis were good performance status (if Karnofsky performance score >70, hazard ratio (HR) for death 0.36, 95 % confidence interval (CI) 0.18-0.69), adjuvant whole brain radiotherapy (HR 0.37, 95 % CI 0.21-0.65) and adjuvant chemotherapy where there was extracranial disease and non-synchronous presentation (HR 0.51, 95 % CI 0.31-0.82). Patients presenting with posterior fossa metastases may not be investigated as thoroughly as those with supratentorial tumours. Staging and assessment is essential however, and in the meantime emergencies related to tumour mass effect should be managed with steroids and cerebrospinal fluid diversion as required.

The impact of MGMT methylation and IDH-1 mutation on long-term outcome for glioblastoma treated with chemoradiotherapy.

BACKGROUND: Increasingly, biomarkers have been identified that correlate with improved overall and progression-free survival (OS and PFS) in glioblastoma, including MGMT methylation status and mutations in the IDH1 gene. In this study, we investigated the clinical and biological factors associated with long-term survival in glioblastoma patients treated with chemoradiotherapy. METHOD: Demographic and clinical data were collected for all patients with glioblastoma diagnosed between May 2004 and September 2007, treated with chemoradiotherapy and with associated tissue samples available for biomarker analysis. MGMT methylation was determined by pyrosequencing. IDH1 mutation was identified by R132H immunohistochemistry. Univariate Cox regression analysis of factors associated with survival and Kaplan-Meier survival analysis was performed using the SPSS statistics package. RESULTS: One hundred patients were included in the study. Median follow-up was 12.2 months (range 1.6-102.4). Median OS was 12.1 months (95 % CI: 10.8-13.3) and median PFS was 8.2 months (95 % CI: 6.8-9.5). The 2-, 3- and 5-year survival was 18, 9 and 6 % respectively. Three patients are still alive at 7.4, 8.3 and 8.5 years after diagnosis. Cox proportional-hazards regression identified independent prognostic factors for OS, female (p = 0.019), MGMT methylation (p < 0.0001) and IDH1 mutation (p = 0.023), and for PFS, MGMT methylation (p = 0.001) and IDH1 mutation (p = 0.018). Kaplan-Meier survival analysis showed that MGMT(methylated)/IDH1(+ve) was associated with a significantly longer OS 66.8 months (95 % CI: 0.0-167.8) and PFS 16.9 months (95 % CI: 11.1-22.7) when compared with MGMT(methylated)/IDH1(-ve) OS 15.5 months (95 % CI: 11.6-19.4) and PFS 9.4 months (95 % CI: 8-10.8) (log-rank, P = 0.000) and MGMT(unmethylated)/IDH1(-ve) OS 11.1 months (95 % CI: 8.5-13.7) and PFS 6.3 months (95 % CI: 4.4-8.3) (log-rank, p = 0.000). CONCLUSIONS: While the importance of MGMT methylation is well established, we demonstrate that the combination of MGMT(methylated)/IDH1(+ve) is associated with considerably longer OS and PFS in this series of chemoradiotherapy-treated glioblastoma tumours. The long-term cognitive function and quality of life in these long-term survivors warrant investigation.

Atypical meningoma: current management dilemmas and prospective clinical trials.

Atypical meningioma is an intermediate grade tumour with a greater risk of recurrence following surgical resection. Changes to the WHO classification have resulted in an increased reporting of these tumours. The role of early adjuvant radiotherapy after gross total resection has not been clearly defined and the literature evidence is of poor quality providing conflicting information. This review assesses the evidence for current clinical practice, management dilemmas and the need for prospective clinical trials for atypical meningioma.

Conservative management of type II and III odontoid fractures in the elderly at a regional spine centre: A prospective and retrospective cohort study.

BACKGROUND: The optimal management of odontoid fractures in the elderly population is unclear and management of this group of patients is complicated by multiple co-morbidities. This study aimed to determine the outcomes after conservative management strategies were applied in this patient group. METHODS: We carried out retrospective and prospective analyses of all patients with axial cervical spine injuries, at a single centre. We included patients aged over 60 years with type II and III odontoid fractures. Information was gathered on demographics, ASA grading-associated injuries and complications. The outcome measures were rates and type of union, pain and neurological functions, specifically ambulation. RESULTS: Fifty-seven adult patients with a median age of 78 years (range 60-92 years) were included. There were 42 type II and 15 type III odontoid fractures. Three patients required surgical fixation due to displaced fractures, which could not be reduced with manual traction. Twenty-four (41%) patients were managed with a rigid pinned halo orthosis to obtain adequate reduction and immobilisation. The remaining 30 (53%) were managed in a hard cervical collar. Patients managed with a halo were significantly younger and had more associated injuries than patients managed in a collar (age: t-test=4.05, p<0.01, associated injuries: Chi-square=4.38, p<0.05). At a mean follow-up of 25 weeks, 87% of type II and 100% of type III fractures had achieved bony union or stable, fibrous non-union. There were no statistical differences in fracture type, follow-up or neurological outcomes between the halo and collar groups. However, overall more patients managed in a collar developed stable fibrous non-union than bony fusion (Fisher's exact test, p<0.05), although this was not significant when analysed by each fracture type individually. A regression model was constructed and identified fracture type as the only independent predictor of time to union, with type III fractures healing faster than type II. CONCLUSIONS: High rates of bony union and stable fibrous non-union with a good functional outcome can be achieved in the elderly population sustaining type II or III odontoid fractures, when managed non-surgically. Halo orthosis may not offer any clear advantage over hard collar in this group. Close follow-up is needed for late complications and there must be a willingness to perform surgery if conservative measures fail.

Diagnostic challenges, management and outcomes of midline low-grade gliomas.

INTRODUCTION: Low-grade gliomas (LGGs) are slow-growing and diffusely infiltrating tumours constituting 25-30 % of adult gliomas. Rarely, these tumours may arise in the cerebral midline, including the thalamus, hypothalamus, tectum and brainstem. Here we present a contemporary experience with midline LGGs. METHODS: Midline LGGs were identified from a retrospective database of adult patients who received a histological diagnosis of WHO grade II glioma between 2006 and 2012 at a single institution. Location, radiological data and clinical outcomes were collected. IDH1 status was assessed by immunohistochemistry. RESULTS: Eighteen patients with midline LGGs were identified, with a median age of 45. Most received biopsy upon diagnosis, though asymptomatic patients with tectal tumours underwent active surveillance. Oligodendroglial tumours were much less common than in a comparable group of lobar tumours (6 vs. 38 %, Fisher's exact test, p = 0.007). Only one tumour was immunopositive for IDH1 (1/17). Radiological diagnosis correlated with histology in only 71 % of patients. Median survival of midline LGGs was 48 months (3-90 months) and radiological features such as contrast enhancement, size and radiological diagnosis did not predict survival in this cohort. Median overall survival of midline LGGs was less than lobar LGGs (log-rank, p = 0.006), though differences became insignificant when considering only biopsied astrocytomas in both locations (log-rank, p = 0.491). CONCLUSIONS: Diagnosis of midline LGGs is complicated by both limitations of biopsy and imaging. Midline tumours have a poorer prognosis compared to lobar equivalents and survival differences are probably due to the absence of significant surgical intervention in midline locations.

Diffusion-weighted MRI characteristics of the cerebral metastasis to brain boundary predicts patient outcomes.

BACKGROUND: Diffusion-weighted MRI (DWI) has been used in neurosurgical practice mainly to distinguish cerebral metastases from abscess and glioma. There is evidence from other solid organ cancers and metastases that DWI may be used as a biomarker of prognosis and treatment response. We therefore investigated DWI characteristics of cerebral metastases and their peritumoral region recorded pre-operatively and related these to patient outcomes. METHODS: Retrospective analysis of 76 cases operated upon at a single institution with DWI performed pre-operatively at 1.5T. Maps of apparent diffusion coefficient (ADC) were generated using standard protocols. Readings were taken from the tumor, peritumoral region and across the brain-tumor interface. Patient outcomes were overall survival and time to local recurrence. RESULTS: A minimum ADC greater than 919.4 × 10(-6) mm(2)/s within a metastasis predicted longer overall survival regardless of adjuvant therapies. This was not simply due to differences between the types of primary cancer because the effect was observed even in a subgroup of 36 patients with the same primary, non-small cell lung cancer. The change in diffusion across the tumor border and into peritumoral brain was measured by the "ADC transition coefficient" or ATC and this was more strongly predictive than ADC readings alone. Metastases with a sharp change in diffusion across their border (ATC >0.279) showed shorter overall survival compared to those with a more diffuse edge. The ATC was the only imaging measurement which independently predicted overall survival in multivariate analysis (hazard ratio 0.54, 95% CI 0.3 - 0.97, p = 0.04). CONCLUSIONS: DWI demonstrates changes in the tumor, across the tumor edge and in the peritumoral region which may not be visible on conventional MRI and this may be useful in predicting patient outcomes for operated cerebral metastases.

Letter: Estimating the baseline local recurrence rate for a brain metastasis after neurosurgical resection.

Brain metastases represent a growing healthcare challenge with a rising incidence attributed to earlier detection and improved systemic cancer treatments. We conducted a systematic review and meta-analysis to investigate the local recurrence rate following surgical resection of a brain metastasis without adjuvant therapy. The analysis included four studies with a total of 235 cases. It was found that the rate of local recurrence by 12-months was 48.1% (95% CI 41.2-58.9). These findings underscore the high rate of patients who will experience local recurrence within 12-months of surgery, emphasising the need for vigilant surveillance when omitting adjuvant radiotherapy in favour of systemic treatments with potential but unproven CNS penetrance. The analysis highlights unmet needs in this patient population.

BMScope: A scoping review to chart the evolving clinical study landscape in brain and leptomeningeal metastasis.

BACKGROUND: Recent studies have challenged the notion that patients with brain metastasis (BM) or leptomeningeal metastasis (LM) should be excluded from systemic therapy clinical trials. This scoping study summarises the BM/LM clinical studies published between 2010 and 2023. METHODS: MEDLINE, CINAHL, CAB Abstracts, PsycINFO, Cochrane Library, HINARI, International Pharmaceutical Abstracts, PubMed, Scopus, Web of Science, and EMBASE electronic databases were searched on 21 June 2021. An updated search was performed on 21 February 2023. Eligible studies should involve investigation of a therapeutic intervention in solid tumour patients with BM and/or LM and a reported patient outcome. Extracted study-level data, included study type, publication date, geographical location, number of BM/LM patients in study, primary tumour type and type of therapeutic intervention. RESULTS: 4921 unique studies were eligible for analysis. The key finding is that BM/LM clinical research is expanding globally, both observational studies and clinical trials. Despite the shift over time towards a higher proportion of systemic therapy trials, the majority still do not include patients with symptomatic disease and lack reporting of BM/LM specific endpoints. Globally, there has been a trend to more international collaboration in BM/LM clinical studies. CONCLUSIONS: This analysis of the BM/LM literature charts the evolving landscape of studies involving this previously excluded population. Given the increasing clinical research activity, particularly involving late-stage systemic therapy trials, it is imperative that due consideration is given to the intracranial activity of new investigational agents. Wider adoption of standardised reporting of intracranial-specific endpoints will facilitate evaluation of relative intracranial efficacy.

A decision analysis tool for the assessment of posterior fossa tumour surgery outcomes in children--the "Liverpool Neurosurgical Complication Causality Assessment Tool".

INTRODUCTION: Complications may occur following posterior fossa tumour surgery in children. Such complications are subjectively and inconsistently reported even though they may have significant long-term behavioural and cognitive consequences for the child. This makes comparison of surgeons, programmes and treatments problematic. MATERIALS AND METHODS: We have devised a causality tool for assessing if an adverse event after surgery can be classified as a surgical complication using a series of simple questions, based on a tool used in assessing adverse drug reactions. This tool, which we have called the "Liverpool Neurosurgical Complication Causality Assessment Tool", was developed by reviewing a series of ten posterior fossa tumour cases with a panel of neurosurgery, neurology, oncology and neuropsychology specialists working in a multidisciplinary paediatric tumour treatment programme. DISCUSSION AND CONCLUSION: We have demonstrated its use and hope that it may improve reliability between different assessors both in evaluating the outcomes of existing programmes and treatments as well as aiding in trials which may directly compare the effects of surgical and medical treatments.

Posterior spinal cord herniation: a novel occurrence following surgery for an intramedullary cyst at the thoracolumbar junction.

BACKGROUND: Dorsal herniation of the spinal cord through the dura is an uncommon phenomenon and this is only the fifth reported case in the thoracolumbar spine, the first following surgery at the thoracolumbar junction. CASE: A 57-year-old male underwent marsupialisation of a benign intramedullary cyst at the T12-L1 level and subsequently returned with symptoms of dorsal column compromise. He was found to have a posterior herniation of the cord into a pseudomeningocele at the level of the previous surgery. CONCLUSION: The hernia was reduced surgically and the defect closed directly without the need for a dural patch leading to a full recovery. Posterior cord herniation, its possible aetiologies and management strategies are discussed.

Tremor reduction and quality of life after deep brain stimulation for multiple sclerosis-associated tremor.

BACKGROUND: Tremor is an important cause of disability and poor quality of life amongst multiple sclerosis (MS) patients. We assessed the outcomes of ventral intermediate (VIM) nucleus deep brain stimulation for the treatment of multiple sclerosis (MS)-associated tremor at a single centre in a prospective fashion. METHODS: Sixteen patients (9 female, 7 male) with a mean age of 41.7 years (range 24-59) underwent surgery. The median duration of MS prior to surgery was 6.5 years and median duration of tremor prior to surgery was 4 years. Case selection was by multidisciplinary assessment with carers, therapists, neurosurgeons and movement disorder neurologists. Tremor was scored pre-operatively and at 6 to 12 months post operatively using Bain and/or Fahn-Tolosa-Marin systems. The Euro-Qol 5D tool was used to assess quality of life before and after surgery. RESULTS: The mean tremor reduction was 39 % with a range between 0 and 87 %. Five of 16 patients achieved at least 50 % tremor reduction and 11 of 16 achieved at least 30 % tremor reduction at last follow up, mean 11.6 months (range 3-80). Tremor was significantly reduced as rated by Bain scores (Wilcoxon matched pairs, Z = 3.07, p = .002) and tended to significance as rated by Fahn scores (Wilcoxon matched pairs, Z = 1.85, p = 0.06). Sub-analysis of activities of daily living measures from the Fahn system showed post operative improvement in feeding (statistically significant), hygiene, dressing, writing and working. Mean visual analogue scores (0-100) of patient reported well-being increased from 54.6 to 57.4 post operatively with a trend to significance (Student's t-test, t = 1.26, p = 0.2). Euro-Qol 5D utility values increased following surgery with a trend to significance which was greater in the group with at least 50 % tremor reduction than in those with none or at least 30 % tremor reduction. CONCLUSIONS: VIM DBS may reduce severe, disabling tremor in patients with MS. This tremor reduction tends to be associated with improved quality of life and function in those who respond. Patient reported outcome measures may not correlate with physician rated clinical outcome such as tremor scoring systems and more subtle assessment of these patients is required.

Genomic Alterations and the Incidence of Brain Metastases in Advanced and Metastatic NSCLC: A Systematic Review and Meta-Analysis.

INTRODUCTION: Brain metastases (BMs) in patients with advanced and metastatic NSCLC are linked to poor prognosis. Identifying genomic alterations associated with BM development could influence screening and determine targeted treatment. We aimed to establish prevalence and incidence in these groups, stratified by genomic alterations. METHODS: A systematic review and meta-analysis compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses were conducted (PROSPERO identification CRD42022315915). Articles published in MEDLINE, EMBASE, and Cochrane Library between January 2000 and May 2022 were included. Prevalence at diagnosis and incidence of new BM per year were obtained, including patients with EGFR, ALK, KRAS, and other alterations. Pooled incidence rates were calculated using random effects models. RESULTS: A total of 64 unique articles were included (24,784 patients with NSCLC with prevalence data from 45 studies and 9058 patients with NSCLC having incidence data from 40 studies). Pooled BM prevalence at diagnosis was 28.6% (45 studies, 95% confidence interval [CI]: 26.1-31.0), and highest in patients that are ALK-positive (34.9%) or with RET-translocations (32.2%). With a median follow-up of 24 months, the per-year incidence of new BM was 0.13 in the wild-type group (14 studies, 95% CI: 0.11-0.16). Incidence was 0.16 in the EGFR group (16 studies, 95% CI: 0.11-0.21), 0.17 in the ALK group (five studies, 95% CI: 0.10-0.27), 0.10 in the KRAS group (four studies, 95% CI: 0.06-0.17), 0.13 in the ROS1 group (three studies, 95% CI: 0.06-0.28), and 0.12 in the RET group (two studies, 95% CI: 0.08-0.17). CONCLUSIONS: Comprehensive meta-analysis indicates a higher prevalence and incidence of BM in patients with certain targetable genomic alterations. This supports brain imaging at staging and follow-up, and the need for targeted therapies with brain penetrance.