Meningioma: International Consortium on Meningiomas (ICOM) consensus review on scientific advances & treatment paradigms for clinicians, researchers, and patients.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and the rising availability of neuroimaging. While most exhibit non-malignant behaviour, a subset of meningiomas are biologically aggressive and lead to significant neurological morbidity and mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) working group. There also remains clinical equipoise on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas (ICOM) including field-leading experts, have prepared a comprehensive consensus narrative review directed towards clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality of life studies, and management strategies for unique meningioma patient populations. In each section we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Fractionated radiotherapy for surgically resected intracranial meningiomas: A multicentre retrospective cohort study.

BACKGROUND: Aside from surgical resection, the only standard of care treatment modality for meningiomas is radiotherapy (RT). Despite this, few studies have focused on identifying clinical covariates associated with failure of fractionated RT following surgical resection (fRT), and the timing of fRT following surgery still remains controversial (adjuvant versus salvage fRT). We assessed the outcomes of the largest, multi-institutional cohort of surgically resected meningiomas treated with subsequent adjuvant and salvage fRT to identify factors associated with local freedom from recurrence (LFFR) over 3-10 years post-fRT and to determine the optimal timing of fRT. METHODS: Patients with intracranial meningiomas who underwent surgery and fRT between 1997 and 2018 were included. Primary endpoints were radiographic recurrence/progression and time to progression from the completion of fRT. RESULTS: 404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-fRT. Clinical covariates independently associated with worse PFS post-fRT included receipt of previous RT to the meningioma, having a WHO grade 3 meningioma or recurrent meningioma, the meningioma having a higher MIB1-index or brain invasion on pathology, and older patient age at diagnosis. Subgroup analysis identified higher MIB1-index as a histological factor associated with poorer LFFR in WHO grade 2 meningiomas. 179 patients underwent adjuvant RT shortly after surgery whereas 225 patients had delayed, salvage fRT after recurrence/progression. Following propensity score matching, patients that underwent adjuvant fRT had improved LFFR post-fRT compared to those that received salvage fRT. CONCLUSION: There is a paucity of clinical factors that can predict a meningioma's response to fRT following surgery. Adjuvant fRT may be associated with improved PFS post-fRT compared to salvage fRT. Molecular biomarkers of RT-responsiveness are needed to better inform fRT treatment decisions.

Methylation Profiling Identifies Stability of Isocitrate Dehydrogenase Mutation Over Time.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutation status is a key diagnostic and prognostic feature of gliomas. It is thought to occur early in glioma tumorigenesis and remain stable over time. However, there are reports documenting a loss of IDH mutation status in a subset of patients with glioma recurrence. Here, we identified patients with a documented loss of IDH mutation status longitudinally and performed multi-platform analysis in order to determine if IDH mutations are stable throughout glioma evolution. METHODS: We retrospectively identified patients from our institution from 2009 to 2018 with immunohistochemistry (IHC)-recorded IDH mutation status changes longitudinally. Archived formalin-fixed paraffin-embedded and frozen tissue samples from these patients were collected from our institution's tumour bank. Samples were analysed using methylation profiling, copy number variation, Sanger sequencing, droplet digital PCR (ddPCR) and IHC. RESULTS: We reviewed 1491 archived glioma samples including 78 patients with multiple IDH mutant tumour samples collected longitudinally. In all instances of documented loss of IDH mutation status, multi-platform profiling identified a mixture of low tumour cell content and non-neoplastic tissue including perilesional, reactive or inflammatory cells. CONCLUSIONS: All patients with a documented loss of IDH mutation status longitudinally were resolved through multi-platform analysis. These findings support the hypothesis that IDH mutations occur early in gliomagenesis and in the absence of copy number changes at the IDH loci and are stable throughout tumour treatment and evolution. Our study highlights the importance of accurate surgical sampling and the role of DNA methylome profiling in diagnostically uncertain cases for integrated pathological and molecular diagnosis.

A prospective controlled study on the impact of anterior temporal lobectomy on dream content.

OBJECTIVE: Changes of dream ability and content in patients with brain lesions have been addressed in only about 100 case reports. All of these reports lack data regarding prelesional baseline dream content. Therefore, it was the objective of this study to prospectively assess dream content before and after anterior temporal lobectomy. METHODS: Using the Hall and Van de Castle system, 30 dreams before and 21 dreams after anterior temporal lobectomy for drug-resistant epilepsy were analyzed. Fifty-five dreams before and 60 dreams after stereoelectroencephalography served as controls. RESULTS: After anterior temporal lobectomy, patients had significantly less physical aggression in their dreams than preoperatively (p < 0.01, Cohen's h statistic). Dream content of patients undergoing stereoelectroencephalography showed no significant changes. CONCLUSIONS: Within the default dream network, the temporal lobe may account for aggressive dream content. Impact of general anesthesia on dream content, as a possible confounder, was ruled out.

Utility of the spinal instability neoplastic score to identify patients with Gorham-Stout disease requiring spine surgery.

BACKGROUND: Gorham-Stout disease (GSD) is a rare syndrome presenting with progressive osteolysis which in the spine can lead to cord injury, instability, and deformity. Here, the early spine surgery may prevent catastrophic outcomes. CASE DESCRIPTION: A 25-year-old male with GSD involving the T2 to T6 levels presented with acute traumatic kyphoscoliosis at T3 and T4 and left lower extremity paraparesis. The CT scan 4 weeks before this showed progressing osteolysis versus the CT 5 years ago. Unfortunately, the patient underwent delayed treatment resulting in permanent neurological sequelae. Surgery included a laminectomy and vertebrectomy of T3/T4 with instrumented fusion from T1-10. The use of the spinal instability neoplastic score (SINS) is a useful tool to prompt early referral to spine surgeons. CONCLUSION: We recommend using the SINS score in GSD patients who develop spinal lesions to prompt early referral for consideration of surgery.

Radiology reporting of low-grade glioma growth underestimates tumor expansion.

BACKGROUND: An important aspect in the management of patients with diffuse low-grade gliomas (LGGs) involves monitoring the lesions via serial magnetic resonance imaging (MRI). However, radiological interpretations of LGG interval scans are often qualitative and thus difficult to use clinically. METHODS: To contextualize these assessments, we retrospectively compared radiological interpretations of LGG growth or stability to volume change measured by manual segmentation. Tumor diameter was also measured in one, two, and three dimensions to evaluate reported methods for assessment of glioma progression, including RECIST criteria, Macdonald/RANO criteria, and mean tumor diameter/ellipsoid method. RESULTS: Tumors evaluated as stable by radiologists grew a median volume of 5.1 mL (11.1%) relative to the comparison scan, and those evaluated as having grown had a median volume increase of 13.3 mL (23.7%). Diameter-based measurements corresponded well but tended to overestimate gold standard segmented volumes. In addition, agreement with segmented volume measurements improved from 17.6 ± 8.0 to 4.5 ± 5.8 to 3.9 ± 3.6 mm for diameter and from 104.0 ± 96.6 to 25.3 ± 36.8 to 15.9 ± 21.3 mL for volume with radiological measurements in one, two, and three dimensions, respectively. Measurement overestimation increased with tumor size. CONCLUSIONS: Given accumulating evidence that LGG volume and growth are prognostic factors, there is a need for objective lesion measurement. Current radiological reporting workflows fail to appreciate and communicate the true expansion of LGGs. While volumetric analysis remains the gold standard for assessment of growth, careful diametric measurements in three dimensions may be an acceptable alternative.

Impact of Functional Magnetic Resonance Imaging on Clinical Outcomes in a Propensity-Matched Low Grade Glioma Cohort.

BACKGROUND: This study aims to evaluate the impact of preoperative functional magnetic resonance imaging (fMRI) on clinical outcomes in patients with low grade glioma (LGG). METHODS: In a retrospective propensity-matched cohort study, we compared patients with LGG based on whether they underwent fMRI as part of preoperative assessment. Twelve patients with LGG who underwent preoperative fMRI were selected, and a contemporaneous group of 12 control patients with LGG who did not undergo fMRI were matched to the fMRI group based on age, sex, and 1p/19q status. RESULTS: fMRI group subjects tended to have more aggressive surgeries (67% resection, 33% biopsy) than the control group (33% resection, 67% biopsy). There were no significant differences in outcomes between the 2 groups. Time between clinical assessment and surgery tended to be longer in the fMRI group (6.3 ± 4.2 weeks) than in the control group (2.7 ± 2.2 weeks). Extent of resection was similar between the 2 cohorts. fMRI group subjects had lower preoperative functional status and tended to have a greater postoperative functional status improvement than control group subjects. Mean survival was not significantly different (fMRI group 5-year survival: 88.9%, control group 5-year survival: 61.1%). CONCLUSIONS: We evaluated the impact of preoperative fMRI in patients with LGG in this propensity-matched cohort study. This study has not demonstrated any significant difference in outcomes between the fMRI and control groups; however, there were nonsignificant trends for patients who underwent fMRI to undergo more aggressive surgical interventions and have a greater postoperative functional status improvement.

Tumor growth dynamics in serially-imaged low-grade glioma patients.

BACKGROUND: Diffuse low-grade gliomas (LGGs) are infiltrative, slow-growing primary brain tumors that remain relatively asymptomatic for long periods of time before progressing into aggressive and fatal high-grade gliomas. METHODS: We retrospectively identified LGG patients with numerous (≥ 8) serial magnetic resonance imaging (MRI) studies. Tumor volumes were measured by manual segmentation on serial imaging to study the natural history and growth of the lesion. Patient demographic information, tumor characteristics, and histological data were collected from electronic medical records and paper charts. RESULTS: Out of 74 LGG patients, 10 patients (13.5%) were identified to meet the study criteria with number of MRIs acquired ranging from 8 to 18 (median, 11.5) over a median of 79.7 months (range 39.8-113.8 months). Tumor diameter increased at a median of 2.17 mm/year in a linear trajectory. Cox regression analysis revealed that initial tumor volume was an independent predictor of time to clinical intervention, and Mann-Whitney U test found that patients younger than 50 years old had significantly slower-growing tumors. Clinical intervention was more likely for tumors above a volume threshold of 73.6 mL. CONCLUSION: We retrospectively analyzed the natural history of LGGs of patients managed at a single institution with numerous serial MRI scans. Comparisons of our cohort to the literature suggest that this is a subset of particularly slow-growing and low-risk tumors.

Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy.

Expression of thioredoxin-interacting protein (TxNIP), an endogenous inhibitor of the thiol oxidoreductase thioredoxin, is augmented by high glucose (HG) and promotes oxidative stress. We previously reported that TxNIP-deficient mesangial cells showed protection from HG-induced reactive oxygen species, mitogen-activated protein kinase phosphorylation, and collagen expression. Here, we investigated the potential role of TxNIP in the pathogenesis of diabetic nephropathy (DN) in vivo. Wild-type (WT) control, TxNIP(-/-), and TxNIP(+/-) mice were rendered equally diabetic with low-dose streptozotocin. In contrast to effects in WT mice, diabetes did not increase albuminuria, proteinuria, serum cystatin C, or serum creatinine levels in TxNIP(-/-) mice. Whereas morphometric studies of kidneys revealed a thickened glomerular basement membrane and effaced podocytes in the diabetic WT mice, these changes were absent in the diabetic TxNIP(-/-) mice. Immunohistochemical analysis revealed significant increases in the levels of glomerular TGF-ß1, collagen IV, and fibrosis only in WT diabetic mice. Additionally, only WT diabetic mice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (IL-1ß mRNA, F4/80 immunohistochemistry). Expression levels of Nox4-encoded mRNA and protein increased only in the diabetic WT animals. A significant loss of podocytes, assessed by Wilms' tumor 1 and nephrin staining and urinary nephrin concentration, was found in diabetic WT but not TxNIP(-/-) mice. Furthermore, in cultured human podocytes exposed to HG, TxNIP knockdown with siRNA abolished the increased mitochondrial O2 (-) generation and apoptosis. These data indicate that TxNIP has a critical role in the progression of DN and may be a promising therapeutic target.

The p38 pathway regulates oxidative stress tolerance by phosphorylation of mitochondrial protein IscU.

The p38 pathway is an evolutionarily conserved signaling pathway that responds to a variety of stresses. However, the underlying mechanisms are largely unknown. In the present study, we demonstrate that p38b is a major p38 MAPK involved in the regulation of oxidative stress tolerance in addition to p38a and p38c in Drosophila. We further show the importance of MK2 as a p38-activated downstream kinase in resistance to oxidative stresses. Furthermore, we identified the iron-sulfur cluster scaffold protein IscU as a new substrate of MK2 both in Drosophila cells and in mammalian cells. These results imply a new mechanistic connection between the p38 pathway and mitochondria iron-sulfur clusters.