Background and purpose: Brain metastases originating from gynaecological tumours are a rare phenomenon, but have an increasing incidence due to better targeted therapies. This study aimed to... Show moreBackground and purpose: Brain metastases originating from gynaecological tumours are a rare phenomenon, but have an increasing incidence due to better targeted therapies. This study aimed to identify factors that predict survival in these patients, which can be used in creating a robust prognostic tool for shared decision making.Materials and methods: We identified a consecutive cohort of 73 patients treated for gynaecological brain metastases in two tertiary institutions. Baseline demographics, pathology and serum CA-125 were included in a multivariable Cox proportional hazards model.Results: Median overall survival in our cohort was 14.4 months, with a one-year survival of 56.4% and a two-year survival of 39.1%. Thirty-eight patients (52.1%) had ovarian carcinoma as the primary malignancy. The following factors were significantly associated with survival: age (HR 1.05 per year), CA-125 (HR 1.02 par 50 U/ml), and uterine and vulvar primary tumours (when compared to ovarian carcinoma, with HRs 3.07 and 8.70). A post-hoc analysis with primary tumour site reclassified into ovary versus non-ovary showed a HR of 0.50 for ovarian primary tumour type.Conclusion: We have found that age, pathology and CA-125 are prognostic factors for survival in patients with brain metastases from gynaecological tumours. Our findings may provide a foundation for future development of prediction models, for the benefit of both patients and physicians. (c) 2020 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. Show less
Background. Breast cancer (BC) brain metastases (BM) can have discordant hormonal or human epidermal growth factor receptor 2 (HER2) expression compared with corresponding primary tumors. This... Show moreBackground. Breast cancer (BC) brain metastases (BM) can have discordant hormonal or human epidermal growth factor receptor 2 (HER2) expression compared with corresponding primary tumors. This study aimed to describe incidence, predictors, and survival outcomes of discordant receptors and associated subtype switching in BM.Methods. BCBM patients seen at 4 tertiary institutions who had undergone BM resection or biopsy were included. Surgical pathology reports were retrospectively assessed to determine discordance between the primary tumor and the BCBM. In discordant cases, expression in extracranial metastases was also assessed.Results. In BM from 219 patients, prevalence of any discordance was 36.3%; receptor-specific discordance was 16.7% for estrogen, 25.2% for progesterone, and 10.4% for HER2. Because estrogen and progesterone were considered together for hormonal status, 50 (22.8%) patients switched subtype as a result; 20 of these switches were HER2 based. Baseline subtype predicted switching, which occurred in up to 37.5% of primary HR+ patients. Moreover, 14.8% of initially HER2-negative patients gained HER2 in the BM. Most (63.6%) discordant patients with extracranial metastases also had discordance between BM and extracranial subtype. Loss of receptor expression was generally associated with worse survival, which appeared to be driven by estrogen loss (hazard ratio = 1.80, P= 0.03). Patients gaining HER2 status (n =8) showed a nonsignificant tendency toward improved survival (hazard ratio = 0.64, P= 0.17).Conclusions. In this multicenter study, we report incidence and predictors of subtype switching, the risk of which varies considerably by baseline subtype. Switches can have clinical implications for prognosis and treatment choice. Show less
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or Covid-19), which began as an epidemic in China and spread globally as a pandemic, has necessitated resource management to... Show moreBackground Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or Covid-19), which began as an epidemic in China and spread globally as a pandemic, has necessitated resource management to meet emergency needs of Covid-19 patients and other emergent cases. We have conducted a survey to analyze caseload and measures to adapt indications for a perception of crisis. Methods We constructed a questionnaire to survey a snapshot of neurosurgical activity, resources, and indications during 1 week with usual activity in December 2019 and 1 week during SARS-CoV-2 pandemic in March 2020. The questionnaire was sent to 34 neurosurgical departments in Europe; 25 departments returned responses within 5 days. Results We found unexpectedly large differences in resources and indications already before the pandemic. Differences were also large in how much practice and resources changed during the pandemic. Neurosurgical beds and neuro-intensive care beds were significantly decreased from December 2019 to March 2020. The utilization of resources decreased via less demand for care of brain injuries and subarachnoid hemorrhage, postponing surgery and changed surgical indications as a method of rationing resources. Twenty departments (80%) reduced activity extensively, and the same proportion stated that they were no longer able to provide care according to legitimate medical needs. Conclusion Neurosurgical centers responded swiftly and effectively to a sudden decrease of neurosurgical capacity due to relocation of resources to pandemic care. The pandemic led to rationing of neurosurgical care in 80% of responding centers. We saw a relation between resources before the pandemic and ability to uphold neurosurgical services. The observation of extensive differences of available beds provided an opportunity to show how resources that had been restricted already under normal conditions translated to rationing of care that may not be acceptable to the public of seemingly affluent European countries. Show less
The original version of the article unfortunately contained an error in Figure 2. The term 'Refer within 3 days' should read 'Refer as soon as possible'. Corrected version of Figure 2 is given below.
Abels, E.R.; Maas, S.L.N.; Tai, E.; Ting, D.T.; Broekman, M.L.D.; Breakefield, X.O.; Khoury, J. el 2020
Monocytes, macrophages and microglia make up a large part of the glioma environment and have an important role in maintaining and propagating glioma progression. Targeting these cells to inhibit... Show moreMonocytes, macrophages and microglia make up a large part of the glioma environment and have an important role in maintaining and propagating glioma progression. Targeting these cells to inhibit their tumor-promoting effect and reprogramming them into an anti-tumor phenotype is a potential therapeutic approach for glioma. In this study we analyzed the transcriptomes of eight different monocyte subgroups derived from the brain and the blood of glioma-bearing mice. We compared the expression profile of blood-derived monocytes versus tumor-infiltrating monocytes and found increased expression of both pro- and anti-inflammatory pathways in tumor infiltrating monocytes. To help disseminate these datasets, we created a user-friendly web-based tool accessible at www.glioma-monocytes.com. This tool can be used for validation purposes and to elucidate gene expression profiles of tumor-interacting monocytes and macrophages as well as blood-derived circulating monocytes. This tool can also be used to identify new markers and targets for therapy in these different cell populations. Show less
Background The COVID-19 pandemic confronts healthcare workers, including neurosurgeons, with difficult choices regarding which patients to treat. Methods In order to assist ethical triage, this... Show moreBackground The COVID-19 pandemic confronts healthcare workers, including neurosurgeons, with difficult choices regarding which patients to treat. Methods In order to assist ethical triage, this article gives an overview of the main considerations and ethical principles relevant when allocating resources in times of scarcity. Results We discuss a framework employing four principles: prioritizing the worst off, maximizing benefits, treating patients equally, and promoting instrumental value. We furthermore discuss the role of age and comorbidity in triage and highlight some principles that may seem intuitive but should not form a basis for triage. Conclusions This overview is presented on behalf of the European Association of Neurosurgical Societies and can be used as a toolkit for neurosurgeons faced with ethical dilemmas when triaging patients in times of scarcity. Show less
Maas, S.L.N.; Abels, E.R.; Haar, L.L. van de; Zhang, X.; Morsett, L.; Sil, S.; ... ; Khoury, J. el 2020
Background: Glioblastomas are the most common and lethal primary brain tumors. Microglia, the resident immune cells of the brain, survey their environment and respond to pathogens, toxins, and... Show moreBackground: Glioblastomas are the most common and lethal primary brain tumors. Microglia, the resident immune cells of the brain, survey their environment and respond to pathogens, toxins, and tumors. Glioblastoma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Despite the presence of large numbers of microglia in glioblastoma, the tumors continue to grow, and these neuroimmune cells appear incapable of keeping the tumor in check. To understand this process, we analyzed gene expression in microglia interacting with glioblastoma cells.Methods: We used RNASeq of isolated microglia to analyze the expression patterns of genes involved in key microglial functions in mice with glioblastoma. We focused on microglia that had taken up tumor-derived EVs and therefore were within and immediately adjacent to the tumor.Results: We show that these microglia have downregulated expression of genes involved in sensing tumor cells and tumor-derived danger signals, as well as genes used for tumor killing. In contrast, expression of genes involved in facilitating tumor spread was upregulated. These changes appear to be in part EV-mediated, since intracranial injection of EVs in normal mice led to similar transcriptional changes in microglia. We observed a similar microglial transcriptomic signature when we analyzed datasets from human patients with glioblastoma.Conclusion: Our data define a microgliaGlioblastoma specific phenotype, whereby glioblastomas have hijacked gene expression in the neuroimmune system to favor avoiding tumor sensing, suppressing the immune response, clearing a path for invasion, and enhancing tumor propagation. For further exploration, we developed an interactive online tool at http://www.glioma-microglia.com with all expression data and additional functional and pathway information for each gene. Show less
OBJECTIVE: Outcome prediction in severe traumatic brain injury (sTBI) has been studied using clinical and radiographic measurements and by using biomarkers such as glial fibrillary acidic protein,... Show moreOBJECTIVE: Outcome prediction in severe traumatic brain injury (sTBI) has been studied using clinical and radiographic measurements and by using biomarkers such as glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, and tau. Routine blood tests are regularly performed in patients with sTBI and could be used to predict outcomes. This study aims to investigate whether routine blood tests on admission can be predictive of outcome in patients with sTBI.METHODS: Patients with sTBI were selected from 2 institutional databases based on International Classification of Diseases Ninth and Tenth Revision codes for traumatic brain injury (TBI), ventilatory assistance >24 hours, intracranial pressure monitoring, and Glasgow Coma Score (GCS) score =8. Laboratory parameters included blood urea nitrogen, creatinine, glucose, hematocrit, hemoglobin, red blood cells, white blood cells, monocytes, lymphocytes, neutrophils, neutrophil lymphocyte ratio, platelets, international normalized ratio, prothrombin time, sodium, and potassium. Clinical outcome was measured as hospital length of stay, 30-day mortality, and favorable versus unfavorable outcome based on Glasgow Outcome Scale at 3 months.RESULTS: A total of 255 adult patients were selected. Median Injury Severity Score was 14.00 (interquartile range, 9.00-22.00). Of patients, 25.9% died within 30 days and 56.1% had an unfavorable outcome at 3 months. On multivariate analysis, low sodium level was significant for 30-day mortality and high sodium level was significant for unfavorable outcome at 3 months. However, after correction for multiple testing, no routine blood test remained significant.CONCLUSIONS: No routine blood tests measured on admission were significant predictors of outcome in patients with sTBI. Other clinical and radiologic factors may be better suited to predicting outcomes in this patient population. Show less
Given the median survival of 15 months after diagnosis, novel treatment strategies are needed for glioblastoma. Beta-blockers have been demonstrated to inhibit angiogenesis and tumor cell... Show moreGiven the median survival of 15 months after diagnosis, novel treatment strategies are needed for glioblastoma. Beta-blockers have been demonstrated to inhibit angiogenesis and tumor cell proliferation in various cancer types. The aim of this study was to systematically review the evidence on the effect of beta-blockers on glioma growth. A systematic literature search was performed in the PubMed, Embase, Google Scholar, Web of Science, and Cochrane Central to identify all relevant studies. Preclinical studies concerning the pharmacodynamic effects of beta-blockers on glioma growth and proliferation were included, as well as clinical studies that studied the effect of beta-blockers on patient outcomes according to PRISMA guidelines. Among the 980 citations, 10 preclinical studies and 1 clinical study were included after title/abstract and full-text screening. The following potential mechanisms were identified: reduction of glioma cell proliferation (n = 9), decrease of glioma cell migration (n = 2), increase of drug sensitivity (n = 1), induction of glioma cell death (n = 1). Beta-blockers affect glioma proliferation by inducing a brief reduction of cAMP and a temporary cell cycle arrest in vitro.Contrasting results were observed concerning glioma cell migration. The identified clinical study did not find an association between beta-blockers and survival in glioma patients. Although preclinical studies provide scarce evidence for the use of beta-blockers in glioma, they identified potential pathways for targeting glioma. Future studies are needed to clarify the effect of beta-blockers on clinical endpoints including survival outcomes in glioma patients to scrutinize the value of beta-blockers in glioma care. Show less
Glioblastoma the most aggressive form of brain cancer, comprises a complex mixture of tumor cells and nonmalignant stromal cells, including neurons, astrocytes, microglia, infiltrating monocytes... Show moreGlioblastoma the most aggressive form of brain cancer, comprises a complex mixture of tumor cells and nonmalignant stromal cells, including neurons, astrocytes, microglia, infiltrating monocytes/macrophages, lymphocytes, and other cell types. All nonmalignant cells within and surrounding the tumor are affected by the presence of glioblastoma. Astrocytes use multiple modes of communication to interact with neighboring cells. Extracellular vesicle-directed intercellular communication has been found to be an important component of signaling between astrocytes and glioblastoma in tumor progression. In this review, we focus on recent findings on extracellular vesicle-mediated bilateral crosstalk, between glioblastoma cells and astrocytes, highlighting the protumor and antitumor roles of astrocytes in glioblastoma development. Show less
Glioblastoma is the most aggressive brain malignancy, for which immunotherapy has failed to prolong survival. Glioblastoma-associated immune infiltrates are dominated by tumor-associated... Show moreGlioblastoma is the most aggressive brain malignancy, for which immunotherapy has failed to prolong survival. Glioblastoma-associated immune infiltrates are dominated by tumor-associated macrophages and microglia (TAMs), which are key mediators of immune suppression and resistance to immunotherapy. We and others demonstrated aberrant expression of glycans in different cancer types. These tumor-associated glycans trigger inhibitory signaling in TAMs through glycan-binding receptors. We investigated the glioblastoma glycocalyx as a tumor-intrinsic immune suppressor. We detected increased expression of both tumor-associated truncated O-linked glycans and their receptor, macrophage galactose-type lectin (MGL), on CD163+ TAMs in glioblastoma patient-derived tumor tissues. In an immunocompetent orthotopic glioma mouse model overexpressing truncated O-linked glycans (MGL ligands), high-dimensional mass cytometry revealed a wide heterogeneity of infiltrating myeloid cells with increased infiltration of PD-L1+ TAMs as well as distant alterations in the bone marrow (BM). Our results demonstrate that glioblastomas exploit cell surface O-linked glycans for local and distant immune modulation. Show less
Solinge, T.S. van; Muskens, I.S.; Kavouridis, V.K.; Gormley, W.B.; Mekary, R.A.; Broekman, M.L.D.; Arnaout, O. 2020
Intraventricular hemorrhage (IVH) is an independent poor prognostic factor in subarachnoid and intra-parenchymal hemorrhage. The use of intraventricular fibrinolytics (IVF) has long been debated,... Show moreIntraventricular hemorrhage (IVH) is an independent poor prognostic factor in subarachnoid and intra-parenchymal hemorrhage. The use of intraventricular fibrinolytics (IVF) has long been debated, and its exact effects on outcomes are unknown. A systematic review and meta-analysis were performed in accordance with the PRISMA guidelines to assess the impact of IVF after non-traumatic IVH on mortality, functional outcome, intracranial bleeding, ventriculitis, time until clearance of third and fourth ventricles, obstruction of external ventricular drains (EVD), and shunt dependency. Nineteen studies were included in the meta-analysis, totaling 1020 patients. IVF was associated with lower mortality (relative risk [RR] 0.58; 95% confidence interval [CI] 0.47-0.72), fewer EVD obstructions (RR 0.41; 95% CI 0.22-0.74), and a shorter time until clearance of the ventricles (median difference [MD] - 4.05 days; 95% CI - 5.52 to - 2.57). There was no difference in good functional outcome, RR 1.41 (95% CI 0.98-2.03), or shunt dependency, RR 0.93 (95% CI 0.70-1.22). Correction for publication bias predicted an increased risk of intracranial bleeding, RR 1.67 (95% CI 1.01-2.74) and a lower risk of ventriculitis, RR 0.68 (95% CI 0.45-1.03) in IVH patients treated with IVF. IVF was associated with improved survival, faster clearance of blood from the ventricles and fewer drain obstructions, but further research is warranted to elucidate the effects on ventriculitis, long-term functional outcomes, and re-hemorrhage. Show less
PURPOSE The aim of this study was to develop an open-source natural language processing (NLP) pipeline for text mining of medical information from clinical reports. We also aimed to provide insight... Show morePURPOSE The aim of this study was to develop an open-source natural language processing (NLP) pipeline for text mining of medical information from clinical reports. We also aimed to provide insight into why certain variables or reports are more suitable for clinical text mining than others.MATERIALS AND METHODS Various NLP models were developed to extract 15 radiologic characteristics from free-text radiology reports for patients with glioblastoma. Ten-fold cross-validation was used to optimize the hyperparameter settings and estimate model performance. We examined how model performance was associated with quantitative attributes of the radiologic characteristics and reports.RESULTS In total, 562 unique brain magnetic resonance imaging reports were retrieved. NLP extracted 15 radiologic characteristics with high to excellent discrimination (area under the curve, 0.82 to 0.98) and accuracy (78.6% to 96.6%). Model performance was correlated with the inter-rater agreement of the manually provided labels (rho = 0.904; P<.001) but not with the frequency distribution of the variables of interest (rho = 0.179; P =.52). All variables labeled with a near perfect inter-rater agreement were classified with excellent performance (area under the curve > 0.95). Excellent performance could be achieved for variables with only 50 to 100 observations in the minority group and class imbalances up to a 9:1 ratio. Report-level classification accuracy was not associated with the number of words or the vocabulary size in the distinct text documents.CONCLUSION This study provides an open-source NLP pipeline that allows for text mining of narratively written clinical reports. Small sample sizes and class imbalance should not be considered as absolute contraindications for text mining in clinical research. However, future studies should report measures of inter-rater agreement whenever ground truth is based on a consensus label and use this measure to identify clinical variables eligible for text mining. Show less
Rationale The health care landscape is changing: it has become the largest part of the economy and changes in public management systems will greatly affect how we practice medicine in the future.... Show moreRationale The health care landscape is changing: it has become the largest part of the economy and changes in public management systems will greatly affect how we practice medicine in the future. Medical education will be more important than ever to ensure patients get the best care with empathy. However, new public management systems implemented without thorough analysis might challenge medical education. An increasing number of public health care institutions provide services based on competitive market rules and express their goals in financial terms and have set financial gains as their main goal, which contradicts the fundamental nature of medical ethics and practice. Aims and objectives To explore new public management to identify potential problems and offer possible solutions for medical education and health care institutions. Methods A scoping review of the literature on public administration, hospital management, professionalism, ethics, and medical education was undertaken to map evidence on the topic and identify main concepts and knowledge gaps in the influence of management systems on the quality of medical educational practices. Results If the accelerating changes in public management are cursorily analysed, medical education may lose the esteem in which it has long been held globally. Without precautions, the so-called new public management medical faculties will-at best-generate economic benefit, following a business model with strict quality rules, regulations, standardized products, and complex analysis and measurement systems. However, these faculties will function at a level far below the ideal of teaching institutions distinguished for their outstanding components, creativity, and ambience. Conclusions Patients and teaching values are not reducible to financial terms only and the acknowledgement of non-financial values is fundamental to achieve quality in health care and education. The most essential step could be selecting managers who will implement public management principles while taking into account both business requirements and medical ethics. Show less
Purpose To describe practice patterns and patient outcomes with respect to the use of postoperative systemic therapy (ST) after resection of a solitary breast cancer brain metastasis (BCBM).... Show morePurpose To describe practice patterns and patient outcomes with respect to the use of postoperative systemic therapy (ST) after resection of a solitary breast cancer brain metastasis (BCBM). Methods A multi-institutional retrospective review of consecutive patients undergoing resection of a single BCBM without extracranial metastases was performed to describe subtype-specific postoperative outcomes and assess the impact of types of ST on site of recurrence, progression-free survival (PFS), and overall survival (OS). Results Forty-four patients were identified. Stratified estimated survival was 15, 24, and 23 months for patients with triple negative, estrogen receptor positive (ER+), and HER2+ BCBMs, respectively. Patients receiving postoperative ST had a longer median PFS (8 versus 4 months, adjusted p-value 0.01) and OS (32 versus 15 months, adjusted p-value 0.21). Nine patients (20%) had extracranial progression, 23 (52%) had intracranial progression, three (8%) had both, and nine (20%) did not experience progression at last follow-up. Multivariate analysis showed that postoperative hormonal therapy was associated with longer OS (HR 0.26; 95% CI 0.08-0.89; p = 0.03) but not PFS (HR 0.35, 95% CI 0.08-1.47, p = 0.15) in ER+ patients. Postoperative HER2-targeted therapy was not associated with longer OS or PFS in HER2+ patients. Conclusions Disease progression occurred intracranially more often than extracranially following resection of a solitary BCBM. In ER+ patients, postoperative hormonal therapy was associated with longer OS. Postoperative HER2-targeted therapy did not show survival benefit in HER2+ patients. These results should be validated in larger cohorts. Show less
