Mechanisms and therapeutic implications of hypermutation in gliomas.

A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.

A threshold for mitotic activity and post-surgical residual volume defines distinct prognostic groups for astrocytoma IDH-mutant.

AIMS: The distinction between CNS WHO grade 2 and grade 3 is instrumental in choosing between observational follow-up and adjuvant treatment for resected astrocytomas IDH-mutant. However, the criteria of CNS WHO grade 2 vs 3 have not been updated since the pre-IDH era. METHODS: Maximal mitotic activity in consecutive high-power fields corresponding to 3 mm2 was examined for 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumour volume, multilobar involvement, post-surgical residual tumour volume and midline involvement) was assessed for tumours with ATRX loss and the absence of CDKN2A homozygous deletion or CDK4 amplification, contrast enhancement, histological necrosis and microvascular proliferation. RESULTS: Seventy-one per cent of the samples had <6 mitoses per 3 mm2 . Mitotic activity, residual volume and multilobar involvement were independent prognostic factors of TTT. The threshold of ≥6 mitoses per 3 mm2 identified patients with a shorter TTT (median 18.5 months). A residual volume ≥1 cm3 also identified patients with a shorter TTT (median 24.5 months). The group defined by <6 mitoses per 3 mm2 and a residual volume <1 cm3 had the longest TTT (median 73 months) and OS (100% survival at 7 years). These findings were confirmed in a validation cohort of 52 tumours. CONCLUSIONS: Mitotic activity and post-surgical residual volume can be combined to evaluate the prognosis for patients with resected astrocytomas IDH-mutant. Patients with <6 mitoses per 3 mm2 and a residual volume <1 cm3 were the best candidates for observational follow-up.

Distinct P2Y Receptors Mediate Extension and Retraction of Microglial Processes in Epileptic and Peritumoral Human Tissue.

Microglia exhibit multiple, phenotype-dependent motility patterns often triggered by purinergic stimuli. However, little data exist on motility of human microglia in pathological situations. Here we examine motility of microglia stained with a fluorescent lectin in tissue slices from female and male epileptic patients diagnosed with mesial temporal lobe epilepsy or cortical glioma (peritumoral cortex). Microglial shape varied from ramified to amoeboid cells predominantly in regions of high neuronal loss or closer to a tumor. Live imaging revealed unstimulated or purine-induced microglial motilities, including surveillance movements, membrane ruffling, and process extension or retraction. At different concentrations, ADP triggered opposing motilities. Low doses triggered process extension. It was suppressed by P2Y12 receptor antagonists, which also reduced process length and surveillance movements. Higher purine doses caused process retraction and membrane ruffling, which were blocked by joint application of P2Y1 and P2Y13 receptor antagonists. Purinergic effects on motility were similar for all microglia tested. Both amoeboid and ramified cells from mesial temporal lobe epilepsy or peritumoral cortex tissue expressed P2Y12 receptors. A minority of microglia expressed the adenosine A2A receptor, which has been linked with process withdrawal of rodent cells. Laser-mediated tissue damage let us test the functional significance of these effects. Moderate damage induced microglial process extension, which was blocked by P2Y12 receptor antagonists. Overall, the purine-induced motility of human microglia in epileptic tissue is similar to that of rodent microglia in that the P2Y12 receptor initiates process extension. It differs in that retraction is triggered by joint activation of P2Y1/P2Y13 receptors.SIGNIFICANCE STATEMENT Microglial cells are brain-resident immune cells with multiple functions in healthy or diseased brains. These diverse functions are associated with distinct phenotypes, including different microglial shapes. In the rodent, purinergic signaling is associated with changes in cell shape, such as process extension toward tissue damage. However, there are little data on living human microglia, especially in diseased states. We developed a reliable technique to stain microglia from epileptic and glioma patients to examine responses to purines. Low-intensity purinergic stimuli induced process extension, as in rodents. In contrast, high-intensity stimuli triggered a process withdrawal mediated by both P2Y1 and P2Y13 receptors. P2Y1/P2Y13 receptor activation has not previously been linked to microglial morphological changes.

Complications after frame-based stereotactic brain biopsy: a systematic review.

Stereotactic frame-based brain biopsy is one of the most used procedures to obtain brain tissue. This procedure is usually considered as mini-invasive, quick, efficient, and safe even if results of the different studies are widely heterogenous. The objective of this review of the literature is to describe and analyze the complications of stereotactic frame-based brain biopsy. About 132 articles were found after a research in the Medline database. We only considered English references published between 1994 and June 2019. Additional studies were found by using the references from articles identified in the original search. This systematic review was conducted according to PRISMA guidelines. After applying exclusion criteria, we eventually considered 25 relevant studies. The mortality rate varies from 0.7 to 4%. Overall morbidity ranges from 3 to 13%. Most of the complications are revealed by the following symptoms: neurological impairment (transient or permanent), seizure, and unconsciousness. Symptomatic hemorrhage range varies from 0.9 to 8.6%, whereas considering asymptomatic bleeding, the range may be up to 59.8%. Complications were clinically evident within minutes to a few hours after the biopsy. Corrective surgeries are very rare (< 1%). Complications occurring after a frame-based stereotactic brain biopsy are rare but with serious side effects. It rarely leads to death or to permanent neurological impairment. Description and classification of complications are often heterogeneous in the literature. The use of a grading scale could help comparisons between series from around the world. Future studies should establish a score that allows neurosurgeon to predict post-biopsy complications.

Pseudo-continuous arterial spin labelling shows high diagnostic performance in the detection of postoperative residual lesion in hyper-vascularised adult brain tumours.

OBJECTIVES: Our aim was to evaluate the contribution of pseudo-continuous arterial spin labelling (pCASL) in the detection of a postoperative residual lesion in adult brain tumours. METHODS: Seventy-five patients were prospectively included. Following the results of preoperative DSC-PWI assessment, intra-axial lesions, including high-grade gliomas (n = 43) and certain metastases (n = 14), were classified as hyper-vascular (HV+ group, n = 57); other lesions, including low-grade gliomas and certain metastases, were classified as non-hyper-vascular (HV- group, n = 18). To confirm the absence/presence of a residual lesion or disease progression, postoperative MRI including pCASL sequence and follow-up-MRI were performed within 72 h and 1-6 months after the resection, respectively. Two raters evaluated the images. Mean and maximal ASL cerebral blood flow (CBF) values were measured in the perioperative region and normalised to the contralateral tissue. The pCASL-CBF maps and post-contrast T1WI were visually assessed for residual lesion. Quantitative data were analysed with unpaired Student t and Mann-Whitney U tests and the visual diagnostic performance with the McNemar test. RESULTS: In the HV+ group, the mean normalised CBF was 1.97 ± 0.59 and 0.97 ± 0.29 (p < 0.0001, AUC = 0.964, cut-off = 1.27) for patients with or without residual tumours, respectively. The mean normalised CBF was not discriminative for assessing residual tumours in the HV- group (p = 0.454). Visual CBF evaluation allowed 92.98% patients belonging to the HV+ group to be correctly classified (sensitivity 93.02%, specificity 92.86%, p < 0.001). Visual evaluation was correlated with contrast enhancement evaluation and with the mean normalised CBF values (r = 0.505, p < 0.0001 and 0.838, p < 0.0001, respectively). CONCLUSION: Qualitative and quantitative ASL evaluation shows high diagnostic performance in postoperative assessment of hyper-perfused tumours. In this case, postoperative pCASL may be useful, especially if contrast injection cannot be performed or when contrast enhancement is doubtful. KEY POINTS: • Evaluation of postoperative residual lesion in the case of brain tumours is an imaging challenge. • This prospective monocentric study showed that increased normalised cerebral blood flow assessed by pseudo-continuous arterial spin labelling (pCASL) correlates well with the presence of a residual tumour in the case of hyper-vascular tumour diagnosed on preoperative MRI. • Qualitative and quantitative pCASL is an informative sequence for hyper-vascular residual tumour, especially if acquired more than 48 h after brain tumour surgery, when contrast enhancement can give ambiguous results due to blood-brain barrier disruption.

Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations.

BACKGROUND: Astroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined. MATERIALS AND METHODS: We performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM. RESULTS: Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = .021). Mitogen-activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma. CONCLUSION: We suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway. IMPLICATIONS FOR PRACTICE: Astroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.

Seizure response to perampanel in drug-resistant epilepsy with gliomas: early observations.

Drug-resistant epilepsy (DRE) occurs commonly in gliomas, possibly due to a shared mechanism of AMPA-activation involving both seizure activity and tumor growth. We tested the AMPA-receptor blocker perampanel (PER) in patients with DRE in low- and high-grade gliomas. Seizure response was defined as 50% drop in seizure frequency or as seizure-freedom. Cognitive function was examined by computerized test on cognitive speed (CTCS), which is sensitive to the type of cognitive dysfunction associated with epilepsy and use of anticonvulsants. Treatment policy included reduction of dose or discontinuation of one or more concurrent AEDs, once a seizure-free response was observed. Twelve patients were included patients, median age 41 years, 9 men versus 3 women and 6 months median duration of follow-up. An objective seizure response (75%) was observed in 9 (75%) out of 12 patients: 50%-seizure response in 3, seizure-freedom in 6, which is plainly more than seen with other types of DRE. Side-effects occurred in six patients. Cognitive function as examined by CTCS improved in six out of eight associated withlowering of concurrent AEDs. The final median dose of PER was 8 mg (varying between 2 and 12 mg). These results of an objective seizure response in 9 (75%) out of 12 patients treated by PER in DRE may be interpreted as a surrogate-marker of tumor response secondary to AMPA blockade, advancing confirmation by MR imaging. These results warrant further study of PER on tumor activity in gliomas.

Patterns of relapse and growth kinetics of surgery- and radiation-refractory meningiomas.

Patients with surgery- and radiation-refractory meningiomas have a poor outcome. Due to our lack of knowledge concerning multi-recurrent meningioma natural history, their clinical course is poorly defined. This retrospective study aims at defining patterns of relapse in order to help in the definition of response criteria in future clinical trials. We performed a retrospective review of surgery- and radiotherapy-refractory meningioma cases with interpretable radiological follow-up treated in our department. Tumor volumes were measured on 3D T1 Gadolinium volumetric sequences using a semi-automated algorithm for tumor segmentation. Twenty nine patients with multi-treated meningioma (11 WHO Grade II, 5 de novo WHO Grade III and 13 transformed WHO Grade III), were evaluated. Median PFS was 16 months for patients with Grade II meningiomas. In patients with Grade III meningiomas, the de novo subgroup had a median PFS of 4 months compared with 7 months in patients with malignant transformation. Volumetric analysis of tumor growth concerned 95 tumor nodules in 50 relapses. The mean growth rate of tumor nodules was 10.4 cm(3)/year (95% CI 7.3-14.8 cm(3)/year). Three patterns of tumor growth were described: "classical" for 9 (31%) patients, "local multi-nodular" for 6 (21%) patients and "multi-nodular metastatic" for the last 14 (48%) patients. Considering all tumor nodules, median time to tumor progression (TTP) was 3.7 months. Progressing tumors represent the most frequent histological subgroup of surgery and radiation-refractory meningiomas while tumors with multi-nodular metastatic dissemination are the prominent radiological pattern of progression.

Epileptic seizures in diffuse low-grade gliomas in adults.

Diffuse low-grade gliomas are highly epileptogenic brain tumours. We aimed to explore the natural course of epileptic seizures, their predictors and the prognostic significance of their occurrence in adult patients harbouring a diffuse low-grade glioma. An observational retrospective multicentre study examined 1509 patients with diffuse low-grade gliomas to identify mutual interactions between tumour characteristics, tumour course and epileptic seizures. At diagnosis, 89.9% of patients had epileptic seizures. Male gender (P = 0.003) and tumour location within functional areas (P = 0.001) were independent predictors of a history of epileptic seizures at diagnosis. Tumour volume, growth velocity, cortical location, histopathological subtype or molecular markers did not significantly affect epileptic seizure occurrence probability. Prolonged history of epileptic seizures (P < 0.001), insular location (P = 0.003) and tumour location close to functional areas (P = 0.038) were independent predictors of uncontrolled epileptic seizures at diagnosis. Occurrence of epileptic seizures (P < 0.001), parietal (P = 0.029) and insular (P = 0.002) locations were independent predictors of uncontrolled epileptic seizures after oncological treatment. Patient age (P < 0.001), subtotal (P = 0.007) and total (P < 0.001) resections were independent predictors of total epileptic seizure control after oncological treatment. History of epileptic seizures at diagnosis and total surgical resection were independently associated with increased malignant progression-free (P < 0.001 and P < 0.001) and overall (P < 0.001 and P = 0.016) survivals. Epileptic seizures are independently associated with diffuse low-grade glioma prognosis. Patients diagnosed with epileptic seizures and those with complete and early surgical resections have better oncological outcomes. Early and maximal surgical resection is thus required for diffuse low-grade gliomas, both for oncological and epileptological purposes.

Diagnostic and prognostic value of preoperative combined GFAP, IGFBP-2, and YKL-40 plasma levels in patients with glioblastoma.

BACKGROUND: Circulating proteins released by tumor cells have recently been investigated as potential single surrogate biomarkers for glioblastoma multiforme (GBM). The aim of the current hypothesis-generating study was to evaluate the diagnostic and prognostic role of preoperative insulin-like growth factor-binding protein 2 (IGFBP-2), chitinase-3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) plasma levels in patients with GBM, both as single markers and as a combined profile. METHODS: Plasma samples from 111 patients with GBM and a subset of 40 patients with nonglial brain tumors were obtained preoperatively. Plasma from 99 healthy controls was also analyzed. IGFBP-2, YKL-40, and GFAP levels were determined using enzyme-linked immunoadsorbent assay tests. Their association with histological and radiological variables was assessed. RESULTS: Circulating levels of all 3 proteins were found to be significantly higher in patients with GBM compared with healthy controls (P < .01). Only YKL-40 and GFAP were found to demonstrate significant differences between patients with GBM and nonglial brain tumors (P = .04). GFAP was undetectable (<0.02 ng/mL) in all patients without GBM. A receiver operating characteristic analysis accounting for a 2-step diagnostic procedure including the 3 biomarkers afforded an area under the curve of 0.77 for differentiating patients with GBM from those with nonglial brain tumors. There was a significant correlation between tumor volume and plasma IGFBP-2 level (Spearman Rho correlation coefficient, 0.22; P = .025) and GFAP (Spearman Rho correlation coefficient, 0.36; P < .001) among patients with GBM. Preoperative plasma IGFBP-2 levels were found to be independently associated with worse overall survival among patients with GBM (hazard ratio, 1.3; P = .05). CONCLUSIONS: A combined profile of preoperative IGFBP-2, GFAP, and YKL-40 plasma levels could serve as an additional diagnostic tool for patients with inoperable brain lesions suggestive of GBM. In addition, IGFBP-2 levels appear to constitute an independent prognostic factor in patients with GBM.

Significant heterogeneity in the geographical distribution of diffuse grade II/III gliomas in France.

Diffuse WHO grade II and III gliomas (DGII/IIIG) are rare tumors, with few specific epidemiological studies. We aimed at describing the geographical distribution of a homogeneous series of histologically confirmed DGII/IIIG, over a four-year period (2006-2009), at a national level. The methodology is based on a multidisciplinary national network already established by the French Brain Tumor DataBase and data collected directly from every neuropathology department. Personal home addresses were collected for confirmed cases. For each region, the incidence of DGII/IIIG was analyzed and standardized on the age and sex distribution of the French population. The number of patients with newly diagnosed, histologically confirmed DGII/IIIG was 4,790. The overall crude rate was 19.4/10(6). To enable international comparisons, standardized rates were calculated as follows: 19.8/10(6), 18.8/10(6) and 16.0/10(6) (reference population, Europe, US and world, respectively). The geographical distribution by region showed significant differences, with higher incidence rates in Northeast and central parts of France. This work is the first studying the geographical distribution of a pure series of DGII/IIIG at a national level. It demonstrates significant heterogeneity in the distribution, and raises the question of the role of environmental and/or genetic risk(s) factor(s) for DGII/IIIG.

Atypical crossmodal emotional integration in patients with gliomas.

The relevance of emotional perception in interpersonal relationships and social cognition has been well documented. Although brain diseases might impair emotional processing, studies concerning emotional recognition in patients with brain tumours are relatively rare. The aim of this study was to explore emotional recognition in patients with gliomas in three conditions (visual, auditory and crossmodal) and to analyse how tumour-related variables (notably, tumour localisation) and patient-related variables influence emotion recognition. Twenty six patients with gliomas and 26 matched healthy controls were instructed to identify 5 basic emotions and a neutral expression, which were displayed through visual, auditory and crossmodal stimuli. Relative to the controls, recognition was weakly impaired in the patient group under both visual and auditory conditions, but the performances were comparable in the crossmodal condition. Additional analyses using the 'race model' suggest differences in multisensory emotional integration abilities across the groups, which were potentially correlated with the executive disorders observed in the patients. These observations support the view of compensatory mechanisms in the case of gliomas that might preserve the quality of life and help maintain the normal social and professional lives often observed in these patients.

Oncological patterns of care and outcomes for 265 elderly patients with newly diagnosed glioblastoma in France.

The incidence of glioblastoma (GBM) has increased in patients aged 70 years or older, and will continue to grow. Elderly GBM patients have been excluded from most clinical trials; furthermore, optimal care management as well as benefit/risk ratio of GBM treatments are still being debated. This study describes oncological patterns of care, prognostic factors, and survival for patients ≥ 70 years in France. We identified patients over 70 with newly diagnosed and histologically confirmed GBM on data previously published by the French Brain Tumor DataBase. We included 265 patients. Neurological deficits and mental status disorders were the most frequent symptoms. The surgery consisted of resection (RS n = 95) or biopsy (B n = 170); 98 patients did not have subsequent oncological treatment. After surgery, first-line treatment consisted of radiotherapy (RT n = 76), chemotherapy (CT n = 52), and concomitant radiochemotherapy (CRC n = 39). The median age at diagnosis was 76, 74, and 73 years, respectively, for the untreated, B + RT and/or CT, RS ± RT and/or CT groups. Median survival (in days, 95 % CI) with these main strategies, when analyzed according to surgical groups, was: B-CT n = 41, 199[155-280]; B-CRC n = 21, 318[166-480]; B-RT n = 37, 149[130-214]; RS-CT n = 11, 245[211-na]; RS-CRC n = 18, 372[349-593]; RS-RT n = 39, 269[218-343]. This population study for elderly GBM patients is one of the most important in Europe, and could be considered as a historical cohort to compare future treatments. Moreover, we can hypothesize that elderly patients (versus patients <70 years) are undertreated. Karnofsky performance status seems to be the most relevant clinical predictive factor, and RS and CRC have a positive impact on survival for elderly GBM patients in the general population, at least when feasible.

Tumoral epileptogenicity: how does it happen?

Gliomas are the most frequent primary brain tumors and most glioma patients have seizures. The origin and mechanisms of human glioma-related epilepsy are multifactorial and an intermix of oncologic and neuronal processes. In this brief review, we show that the infiltrated peritumoral neocortex appears to be the key structure for glioma-related epileptic activity, which depends on the interactions between the tumor per se and the surrounding brain. We shed light on the underlying mechanisms from two different "tumorocentric" and "epileptocentric" approaches, with a special emphasis on the glioma-related glutamatergic and γ-aminobutyric acid (GABA)ergic changes leading to epileptogenicity. Because gliomas use the neurotransmitter glutamate as a "tumor growth factor" to enhance glioma cell proliferation and invasion with neurotoxic, proinvasive, and proliferative effects, glutamate homeostasis is impaired, with elevated extracellular glutamate concentrations. Such excitatory effects contribute to the generation of epileptic activity in the peritumoral neocortex. GABAergic signaling is also involved both in tumor growth and in paradoxical excitatory effects mediated by alterations in neuronal and tumor cell Cl(-) homeostasis related to cotransporter changes. Local excitability may also be affected by an increase in extracellular K(+) concentration, the alkalization of peritumoral neocortex, and alterations of gap-junction functioning. Finally, the tumor itself may mechanically affect locally neuronal behavior, connections, and networks. Better understanding of glioma-related oncologic and epileptologic processes are crucial for development of combined therapeutic strategies, but so far, the surgical management of gliomas should comprise a maximally safe surgical resection encompassing peritumoral neocortex.

Strengths and weaknesses of multimodal processing in a group of adults with gliomas.

The present study aimed to analyze the multimodal skills that would be spared, altered, or impaired by gliomas that slowly infiltrate various and diversely localized areas in the cerebral hemispheres. Ten patients and 60 healthy controls were evaluated using four multimodal processing paradigms across 11 tasks. Our objectives were as follows: (a) to describe the strengths and weaknesses of the glioma patients' multimodal processing performance after accounting for task specificity and their individual performances compared to those of the control group; (b) to determine the correlation between lesion localization and impairments; and (c) to identify the tasks that were most sensitive to tumor infiltration and plasticity limits. Our results show that patients as a whole were efficient at most tasks; however, the patients exhibited difficulties in the productive picture-naming task, the receptive verbal judgment task, and the visual/graphic portion of the dual-attention task. The individual case reports show that the difficulties were distributed across the patients and did not correlate with lesion localization and tumor type.

The silent phase of diffuse low-grade gliomas. Is it when we missed the action?

BACKGROUND: It is commonly believed that, before being diagnosed after onset of symptoms, diffuse low-grade glioma evolve silently for a long time. The present study aimed to estimate for the first time the exact duration of this silent phase, during which the glioma is radiologically visible but undiscovered. METHODS: We retrospectively reviewed our French national database of diffuse low-grade glioma, searching for patients with an MRI-based assessment of their velocity of diameter growth at diagnosis and before any treatment (at least three MRIs over more than 6 months). For each patient, the duration of the silent phase was estimated by the formula: duration = initial diameter / initial velocity of growth. RESULTS: A total of 148 patients were included in the study. The mean lead-time duration (i.e., duration of the silent phase) was 14.0 ± 7.8 years (median, 11.6 ; range, 1.6-39.4). The lead-time is statistically not correlated to the tumor volume. It is markedly decreasing with the velocity of diameter expansion. CONCLUSIONS: Diffuse low-grade glioma are radiologically detectable but clinically silent for more than a decade. Such a long period of silent evolution could explain our current failure to cure these tumors. It can also be viewed as a window of opportunity to detect these tumors earlier, suggesting the need to set up a screening program.

Combined Angio-Seal™ and stenting rescue treatment in a case of iatrogenic common carotid artery dissection during direct puncture for ruptured intracranial aneurysm embolization: a technical note.

BACKGROUND AND IMPORTANCE: Direct puncture may offer an alternative access for embolization of intracranial aneurysms in patients presenting with tortuous vessels. Nevertheless, major complications such as compressive hematoma and arterial dissection can occur with this technique. CLINICAL PRESENTATION: A tight common carotid artery (CCA) dissection was seen secondary to direct puncture in a 72-year-old patient who presented with a ruptured anterior communicating artery (ACom) aneurysm. After regular coiling of the aneurysm and using a femoral approach, an Angio-Seal™ device (St Jude Medical, Saint Paul, MN, USA) was placed and a carotid wallstent (Stryker Neurovascular, Fremont, CA, USA) successfully deployed at the dissected CCA, which was followed by good clinical and angiographic outcomes. CONCLUSION: A combined rescue technique combining Angio-Seal insertion and stent deployment was safe and effective for managing iatrogenic carotid artery dissection.

Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells are identified in patient and mouse GBMs. Partial removal of p16Ink4a-expressing malignant senescent cells, which make up less than 7 % of the tumor, modifies the tumor ecosystem and improves the survival of GBM-bearing female mice. By combining single cell and bulk RNA sequencing, immunohistochemistry and genetic knockdowns, we identify the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM.

In Vivo 2-Hydroxyglutarate Monitoring With Edited MR Spectroscopy for the Follow-up of IDH-Mutant Diffuse Gliomas: The IDASPE Prospective Study.

BACKGROUND AND OBJECTIVES: D-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels. METHODS: MEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS). RESULTS: MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p = 0.03) and total choline levels (p < 0.001) and were higher in IDH2-mutant compared with IDH1 R132H-mutant and non-R132H IDH1-mutant patients (p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities. DISCUSSION: MEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: A POLA network study.

BACKGROUND: Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described. METHODS: We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression. RESULTS: In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions. CONCLUSION: In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after RT, the possibility of a pseudoprogression should be carefully considered.