"Suicide" Gen Therapy for Malignant Central Nervous System Tumors

Despite development in surgical techniques, chemotherapy and radiotherapy, most malignancies of the central nervous system are still devastating tumors with a poor prognosis. For example, median survival of patients with malignant gliomas (astrocytoma, oligodendroglioma or mixed rype) is roughly 12 months and only 5 % of the patients survive more than 5 years after diagnosis. Fifty % of astrocytomas are ryped as glioblastoma multiforme, the most malignant form of glioma. Glioblastoma account for 15-23 % of all intracranial tumors and have a very poor median survival of 6 months with conventional therapy. Metastases account for 15-30 % of all intracranial neoplasm's and develop in 25 to 30 % of all cancer patients. The overall median survival time after surgery followed by radiation therapy in solitary metastatic lesions ranges from 9 to 23 months, depending on the rype of primary cancer. The prognosis in patients with multiple metastases, however, is much worse. Lepto-meningeal metastases from solid tumors are of increasing importance in neuro-oncology, because of the increasing frequency and the severe neurologic disabiliry it causes. About 0.8 to 8 % of patients with cancer develop leptomeningeal metastases and median survival in these patients after radio- and chemotherapy ranges from 7 to 24 weeks

Association Between Supratotal Glioblastoma Resection and Patient Survival: A Systematic Review and Meta-Analysis

- BACKGROUND: Gross total resection (GTR) of the contrast enhancing (CE) area will improve the survival of patients with glioblastoma (GBM). However, GBM can infiltrate into the brain parenchyma, beyond the CE margins. It remains unclear whether resection beyond the CE area (supratotal resection [SPTR]) can improve survival without causing additional neurological deficits. The aim of the present meta-analysis was to study the association between SPTR and overall survival of patients of GBM. - METHODS: Embase, PubMed, and other literature databases were searched for eligible studies until August 2018. Studies involving patients with GBM that had compared SPTR with GTR were included in the present study. The main outcome was overall survival, presented as hazard ratios (HRs) with 95% confidence intervals (CIs) and median overall survival differences with the 95% CIs. - RESULTS: The meta-analysis, which included 6 studies and 1168 unique patients with GBM, showed that compared with GTR, SPTR of GBM resulted in a 53% lower risk of mortality at any time during follow-up (HR, 0.47; 95% CI, 0.31e 0.72; P [ 0.0005). The median overall survival of the SPTR group was 6.4 months (95% CI, 3.2e9.7) longer than the GTR group (P [ 0.0001). Reports on postoperative deficits were limited, and the quality of evidence was moderate to very low. - CONCLUSIONS: Compared with GTR, SPTR of GBM resulted in a lower risk of mortality and longer median overall survival. However, the quality of evidence of the available studies was poor. Therefore, it remains unclear whether SPTR is safe and actually improves the survival of patients with GBM. Future prospective trials and a standardized definition of SPTR are needed

Safe surgery for glioblastoma: recent advances and modern challenges

One of the major challenges during glioblastoma surgery is balancing between maximizing extent of resection and preventing neurological deficits. Several surgical techniques and adjuncts have been developed to help identify eloquent areas both preoperatively (fMRI, nTMS, MEG, DTI) and intraoperatively (imaging (ultrasound, iMRI), electrostimulation (mapping), cerebral perfusion measurements (fUS)), and visualization (5-ALA, fluoresceine)). In this review, we give an update of the state-of-the-art management of both primary and recurrent glioblastomas. We will review the latest surgical advances, challenges, and approaches that define the onco-neurosurgical practice in a contemporary setting and give an overview of the current prospective scientific efforts

Global comparison of awake and asleep mapping procedures in glioma surgery: an international multicenter survey

Background Mapping techniques are frequently used to preserve neurological function during glioma surgery. There is, however, no consensus regarding the use of many variables of these techniques. Currently, there are almost no objective data available about potential heterogeneity between surgeons and centers. The goal of this survey is therefore to globally identify, evaluate and analyze the local mapping procedures in glioma surgery. Methods The survey was distributed to members of the neurosurgical societies of the Netherlands (Nederlandse Vereniging voor Neurochirurgie-NVVN), Europe (European Association of Neurosurgical Societies-EANS), and the United States (Congress of Neurological Surgeons-CNS) between December 2020 and January 2021 with questions about awake mapping, asleep mapping, assessment of neurological morbidity, and decision making. Results Survey responses were obtained from 212 neurosurgeons from 42 countries. Overall, significant differences were observed for equipment and its settings that are used for both awake and asleep mapping, intraoperative assessment of eloquent areas, the use of surgical adjuncts and monitoring, anesthesia management, assessment of neurological morbidity, and perioperative decision making. Academic practices performed awake and asleep mapping procedures more often and employed a clinical neurophysiologist with telemetric monitoring more frequently. European neurosurgeons differed from US neurosurgeons regarding the modality for cortical/subcortical mapping and awake/asleep mapping, the use of surgical adjuncts, and anesthesia management during awake mapping. Discussion This survey demonstrates the heterogeneity among surgeons and centers with respect to their procedures for awake mapping, asleep mapping, assessing neurological morbidity, and decision making in glioma patients. These data invite further evaluations for key variables that can be optimized and may therefore benefit from consensus

Intraoperative B-mode ultrasound guided surgery and the extent of glioblastoma resection: a randomized controlled trial

BackgroundIntraoperative MRI and 5-aminolaevulinic acid guided surgery are useful to maximize the extent of glioblastoma resection. Intraoperative ultrasound is used as a time-and cost-effective alternative, but its value has never been assessed in a trial. The goal of this randomized controlled trial was to assess the value of intraoperative B-mode ultrasound guided surgery on the extent of glioblastoma resection.Materials and MethodsIn this randomized controlled trial, patients of 18 years or older with a newly diagnosed presumed glioblastoma, deemed totally resectable, presenting at the Erasmus MC (Rotterdam, The Netherlands) were enrolled and randomized (1:1) into intraoperative B-mode ultrasound guided surgery or resection under standard neuronavigation. The primary outcome of this study was complete contrast-enhancing tumor resection, assessed quantitatively by a blinded neuroradiologist on pre- and post-operative MRI scans. This trial was registered with ClinicalTrials.gov (NCT03531333).ResultsWe enrolled 50 patients between November 1, 2016 and October 30, 2019. Analysis was done in 23 of 25 (92%) patients in the intraoperative B-mode ultrasound group and 24 of 25 (96%) patients in the standard surgery group. Eight (35%) of 23 patients in the intraoperative B-mode ultrasound group and two (8%) of 24 patients in the standard surgery group underwent complete resection (p=0.036). Baseline characteristics, neurological outcome, functional performance, quality of life, complication rates, overall survival and progression-free survival did not differ between treatment groups (p>0.05).ConclusionsIntraoperative B-mode ultrasound enables complete resection more often than standard surgery without harming patients and can be considered to maximize the extent of glioblastoma resection during surgery.Neurolog

Isocitrate dehydrogenase 1R132H mutation in microglia/macrophages in gliomas: Indication of a significant role of microglia/macrophages in glial tumorigenesis

Somatic mutation of Isocitrate dehydrogenase 1 (IDH1) at the locus of R132 (IDH1R132H) occurs in > 70% of WHO grades II-III gliomas and secondary glioblastomas. To date it remains unknown whether the mutation is restricted to glial tumor cells. Microglial cells are the resident macrophages in the central nervous system. Tumor-infiltrating microglial cells/macrophages are major stromal cellular components of malignant gliomas and substantially contribute to the tumor mass. Differential identification of the IDH1 R132H mutant cellular components is of particular importance for understanding of the mutation-associated tumor biology. Here we discovered that a significant portion of CD68+, Iba1+, CX3CR1+ microglial cells/macrophages also harbor the IDH1R132H mutation. The findings provide novel insights for understanding the mutation-associated tumor biology relevant to clinical applications as a predictive and/or prognostic marker or therapeutic target

Monocytes carrying GFAP detect glioma, brain metastasis and ischaemic stroke, and predict glioblastoma survival

Diagnosis and monitoring of primary brain tumours, brain metastasis and acute ischaemic stroke all require invasive, burdensome and costly diagnostics, frequently lacking adequate sensitivity, particularly during disease monitoring. Monocytes are known to migrate to damaged tissues, where they act as tissue macrophages, continuously scavenging, phagocytizing and digesting apoptotic cells and other tissue debris. We hypothesize that upon completion of their tissue-cleaning task, these tissue macrophages might migrate via the lymph system to the bloodstream, where they can be detected and evaluated for their phagolysosomal contents. We discovered a blood monocyte subpopulation carrying the brain-specific glial fibrillary acidic protein in glioma patients and in patients with brain metastasis and evaluated the diagnostic potential of this finding. Blood samples were collected in a cross-sectional study before or during surgery from adult patients with brain lesions suspected of glioma. Together with blood samples from healthy controls, these samples were flowing cytometrically evaluated for intracellular glial fibrillary acidic protein in monocyte subsets. Acute ischaemic stroke patients were tested at multiple time points after onset to evaluate the presence of glial fibrillary acidic protein-carrying monocytes in other forms of brain tissue damage. Clinical data were collected retrospectively. High-grade gliomas (N = 145), brain metastasis (N = 21) and large stroke patients (>100 cm(3)) (N = 3 versus 6; multiple time points) had significantly increased frequencies of glial fibrillary acidic protein+CD16+ monocytes compared to healthy controls. Based on both a training and validation set, a cut-off value of 0.6% glial fibrillary acidic protein+CD16+ monocytes was established, with 81% sensitivity (95% CI 75-87%) and 85% specificity (95% CI 80-90%) for brain lesion detection. Acute ischaemic strokes of >100 cm(3) reached >0.6% of glial fibrillary acidic protein+CD16+ monocytes within the first 2-8 h after hospitalization and subsided within 48 h. Glioblastoma patients with >20% glial fibrillary acidic protein+CD16+ non-classical monocytes had a significantly shorter median overall survival (8.1 versus 12.1 months). Our results and the available literature, support the hypothesis of a tissue-origin of these glial fibrillary acidic protein-carrying monocytes. Blood monocytes carrying glial fibrillary acidic protein have a high sensitivity and specificity for the detection of brain lesions and for glioblastoma patients with a decreased overall survival. Furthermore, their very rapid response to acute tissue damage identifies large areas of ischaemic tissue damage within 8 h after an ischaemic event. These studies are the first to report the clinical applicability for brain tissue damage detection through a minimally invasive diagnostic method, based on blood monocytes and not serum markers, with direct consequences for disease monitoring in future (therapeutic) studies and clinical decision making in glioma and acute ischaemic stroke patients.Stemcel biology/Regenerative medicine (incl. bloodtransfusion

Multicentre comparison of a diagnostic assay: Aquaporin-4 antibodies in neuromyelitis optica

Objective Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). Methods Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). Results Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. Conclusions The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology