Search

OBJECTIVE The literature shows discrepancies in stereotactic brain biopsy complication rates, severities, and outcomes. Little is known about the timeline of postbiopsy complications. This study aimed to analyze 1) complications following brain biopsies, using a graded severity scale, and 2) a timeline of complication occurrence. The secondary objectives were to determine factors associated with an increased risk of complications and to assess complication-related management and extra costs. METHODS The authors retrospectively examined 1500 consecutive stereotactic brain biopsies performed in adult patients at their tertiary medical center between April 2009 and April 2019. RESULTS Three hundred eighty-one biopsies (25.4%) were followed by a complication, including 88.2% of asymptomatic hemorrhages. Symptomatic complications involved 3.0% of the biopsies, and 0.8% of the biopsies were fatal. The severity grading scale had a 97.6% interobserver reproducibility. Twenty-three (51.1%) of the 45 symptomatic complications occurred within the 1st hour following the biopsy, while 75.6% occurred within the first 6 hours. Age ≥ 65 years, second biopsy procedures, gadolinium-enhanced lesions, glioblastomas, and lymphomas were predictors of biopsy-related complications. Brainstem biopsy-targeted lesions and cerebral toxoplasmosis were predictive of mortality. Asymptomatic hemorrhage was associated with delayed (> 6 hours) symptomatic complications. Symptomatic complications led to extended hospitalization in 86.7% of patients. The average extra cost for management of a patient with postbiopsy symptomatic complication was $35,702. CONCLUSIONS Symptomatic complications from brain biopsies are infrequent but associated with substantial adverse effects and cost implications for the healthcare system. The use of a severity grading scale, as the authors propose in this article, helps to classify complications according to the therapeutic consequences and the patient’s outcome. Because this study indicates that most complications occur within the first few hours following the biopsy, postbiopsy monitoring can be tailored accordingly. The authors therefore recommend systematic monitoring for 2 hours in the recovery unit and a CT scan 2 hours after the end of the biopsy procedure. In addition, they propose a modern algorithm for optimal postoperative management of patients undergoing stereotactic biopsy.

ObjectiveTo assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600–mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort.MethodsWe performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600–mutant GGNTs treated with RAFi/MEKi.ResultsTwenty-eight adults with recurrent or disseminated BRAF V600–mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of −78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score (p = 0.018) and tended to be younger (p = 0.061) and to be treated earlier (p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival.ConclusionsOur study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600–mutant GGNTs and encourages rechallenge in responders.Classification of EvidenceThis study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.

Histiocytoses are heterogeneous hematopoietic diseases characterized by the accumulation of CD68(+) cells with various admixed inflammatory infiltrates. The identification of the pivotal role of the mitogen-activated protein kinase (MAPK) pathway has opened new avenues of research and therapeutic approaches. We review the neurologic manifestations of 3 histiocytic disorders with frequent involvement of the brain and spine: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman-Destombes disease (RDD). Central nervous system (CNS) manifestations occur in 10%-25% of LCH cases, with both tumorous or neurodegenerative forms. These subtypes differ by clinical and radiological presentation, pathogenesis, and prognosis. Tumorous or degenerative neurologic involvement occurs in 30%-40% of ECD patients and affects the hypothalamic-pituitary axis, meninges, and brain parenchyma. RDD lesions are typically tumorous with meningeal or parenchymal masses with strong contrast enhancement. Unlike LCH and ECD, neurodegenerative lesions or syndromes have not been described with RDD. Familiarity with principles of evaluation and treatment both shared among and distinct to each of these 3 diseases is critical for effective management. Refractory or disabling neurohistiocytic involvement should prompt the consideration for use of targeted kinase inhibitor therapies.

Progressive multifocal leukoencephalopathy (PML) is a very rare and opportunistic encephalitis caused by JC polyomavirus that is linked to profound immunosuppression and is usually fatal unless immune function can be restored. Immune checkpoint inhibitors (ICI) are monoclonal antibodies (mAbs) that block either CTLA-4 or PD-1 inhibitor receptors, thus enhancing antiviral T-cell activity. Successful treatment of PML by ICI has recently generated some enthusiasm in case reports/small series of patients. However, the initial enthusiasm was mitigated by some individual case reports that did not show any benefit. More data are thus warranted about efficacy of immune checkpoint inhibitors in the specific context of PML. We report here the outcomes of six PML patients treated by ICI between 2017 and 2019. Underlying causes of immunosuppression consisted in hematologic malignancies (n = 4), primary immune deficiency (n = 1) and use of immunosuppressive therapies for myasthenia gravis (n = 1). Three patients were alive with a mean follow-up of 21 months (14–33) after first ICI infusion, including one patient with frank clinical response, one with stabilization, and one with initial worsening and further stabilization of PML. The three other patients rapidly died from PML. Our data suggest that ICI may be effective for PML treatment but were less impressive than the ones previously reported. Larger studies are thus warranted to confirm this efficacy and to identify the predictive factors of response.

PURPOSE Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation–positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

BackgroundUnderstudied elderly patients comprise a large segment of high-risk patients with glioblastoma (GBM) that are challenging to treat. Tumor Treating Fields (TTFields) is a locoregional, noninvasive, antimitotic therapy delivering low-intensity, intermediate-frequency alternating electric fields to the tumor. In the phase 3 EF-14 clinical trial, TTFields (200 kHz) improved median progression-free survival (PFS) and median overall survival (OS) in patients with newly diagnosed GBM (ndGBM) when added concomitantly to maintenance temozolomide (TMZ). This EF-14 subgroup analysis evaluated the safety and efficacy of TTFields in elderly patients.MethodsAll 134 patients who are ≥65 years of age were included (TTFields/TMZ combination, n=89; TMZ monotherapy, n=45; 2:1 ratio of randomization). PFS and OS were analyzed using Kaplan–Meier methodology (α=0.05). Health-related quality-of-life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire QLQ-C30 supplemented with the brain tumor module (QLQ-BN20). Adverse events (AEs) were evaluated using Common Terminology Criteria for AEs (CTCAE) v4.0.ResultsThe PFS was 6.5 months in patients randomized to the treatment group with TTFields/TMZ combination versus 3.9 months in patients treated with TMZ monotherapy (HR, 0.47; 95% CI, 0.30–0.74; P=0.0236). The OS was 17.4 months in patients treated with TTFields/TMZ combination versus 13.7 months in patients treated with TMZ monotherapy (HR, 0.51; 95% CI, 0.33–0.77; P=0.0204). Annual survival rates with TTFields/TMZ versus TMZ monotherapy were 39% (95% CI, 29–50%) versus 27% (95% CI, 15–41%; P=0.072) at 2 years, 19% (95% CI, 11–29%) versus 11% (95% CI, 4–23%; P=0.135) at 3 years, and 15% (95% CI, 7–25%) versus 0% at 5 years, respectively. There were no significant differences between groups in the preselected items of HRQoL assessment. Grade ≥3 systemic AEs were 46% in the TTFields/TMZ group versus 40% in the TMZ monotherapy group, without statistically significant difference between the two groups. The only TTFields-related AEs were reversible scalp skin reactions, with grades 1–2 and grade 3 skin reactions reported by 51% and 2% of patients, respectively.ConclusionsCombining TTFields with maintenance TMZ significantly improved PFS and OS in elderly patients with ndGBM in the phase 3 EF-14 clinical trial, without significant increases in systemic toxicity or negatively affecting patient HRQoL. TTFields-related skin AEs were low-grade and manageable.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT00916409, identifier: NCT00916409.

Histiocytosis is an uncommon disease characterized by excessive accumulation of histiocytes. Here, we report a rare case of non-Langerhans-cell histiocytosis in a 51-year-old woman who presented with severe symptoms of pericardial effusion. Radiologic investigation also detected multiple bone (lower limbs, vertebrae, ribs, and ilium) lesions. Resected pericardium showed abundant mono- or multi-nucleated non-foamy histiocytes (CD68+/CD163+/S-100+/CD1α−/langerin−) in a fibroinflammatory background. The histiocytes demonstrated emperipolesis of lymphocytes, a hallmark feature of Rosai-Dorfman disease (RDD). However, molecular analysis revealed a BRAF V600E mutation of the proliferating histiocytes, highlighting the neoplastic features frequently observed in another non-Langerhans-cell histiocytosis known as Erdheim-Chester Disease (ECD). We consider this case to be a unique presentation of ECD harboring some RDD-like cells with emperipolesis, but not a case of RDD with a BRAF mutation concerning its clinical manifestation (involvement of the heart and bones) and neoplastic features.

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

Purpose: Myxopapillary ependymoma (MPE) is the most frequent tumor affecting the medullary conus. The surgical therapeutic management is still debated and only few studies have focused on the postoperative clinical outcome of patients. This study aimed to demonstrate long-term postoperative outcome and to assess the predictive factors of recurrence as well as the clinical evolution of these patients.Methods: From 1984 to 2019, in four French centers 101 adult patients diagnosed with MPE were retrospectively included. Results: Median age at surgery was 39 years. Median tumor size was 50mm and lesions were multifocal in 13% of patients. All patients benefited from surgery and one patient received postoperative radiotherapy. Gross total resection was obtained in 75% of cases. Sixteen percent of patients presented recurrence after a median follow-up of 70 months. Progression free survival at 5 and 10 years were respectively estimated at 83% and 79%. After multivariable analysis, sacral localization, and subtotal resection were shown to be independently associated with tumor recurrence. 85% of the patients had a favorable evolution concerning pain. Twelve percent of the patients presented a postoperative deterioration of sphincter function and 4% of motor function. Conclusion: Surgery alone is an acceptable option for MPE patients. Patients with sacral location or incomplete resection are at high risk of recurrence and should be carefully monitored.

Background Little is known about diffuse glioma patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). Methods We performed a descriptive and retrospective analysis of 41 diffuse glioma patients with symptomatic SARS-CoV2 infection during the first wave of the COVID-19 pandemic. Results Confusion with or without fever was the most common neurological symptom (32%) supporting SARS-CoV2 testing in glioma patients with acute and unexplained confusion. Sixteen patients (39%) died after a median delay of 13 days. While multiple clinical, biological, and pathological features, COVID-19- or diffuse glioma-related, at hospital admission appeared to have a pejorative prognostic impact, none was significantly associated with death. Oncological treatments were interrupted at COVID-19 diagnosis and re-initiated with a median delay of 30 days after the end of COVID-19 symptoms. Conclusions Interestingly, our retrospective study describes for the first time the characteristics of a cohort of diffuse glioma patients with symptomatic COVID-19. Diffuse glioma patients with poorly symptomatic COVID-19 did not come to the attention of physicians and were not enrolled in the study skewing the denominator for prognostic analysis. Further studies are warranted to specify prognosis of overall population of diffuse glioma patients with COVID-19, including asymptomatic patients, and interactions of prognostic factors of both COVID-19 and diffuse gliomas.

Background Cancer patients may be at higher risk for severe coronavirus infectious disease-19 (COVID-19); however, the outcome of Primary Central Nervous System Lymphoma (PCNSL) patients with SARS-CoV-2 infection has not been described yet. Methods We conducted a retrospective study within the Lymphomes Oculo-Cérébraux national network (LOC) to assess the clinical characteristics and outcome of SARS-CoV-2 infection in PCNSL patients (positive real-time polymerase chain reaction of nasopharyngeal swab or evocative lung computed tomography scan). We compared clinical characteristics between patients with severe (death and/or intensive care unit admission) and mild disease. Results Between March and May 2020, 13 PCNSL patients were diagnosed with SARS-CoV-2 infection, 11 (85%) of whom were undergoing chemotherapy at the time of infection. The mortality rate was 23% (3/13), and two additional patients (15%) required mechanical ventilation. Two patients (15%) had no COVID-19 symptoms. History of diabetes mellitus was more common in severe patients (3/5 vs 0/8, p = 0.03). Two patients recovered from COVID-19 after mechanical ventilation during more than two weeks and resumed chemotherapy. In all, chemotherapy was resumed after COVID-19 recovery in nine patients (69%) after a median delay of 16 days (range 3–32), none of whom developed unusual chemotherapy complication nor SARS-Cov2 reactivation. Conclusion This preliminary analysis suggests that, while being at higher risk be for severe illness, PCNSL patients with COVID-19 might be treated maximally especially if they achieved oncological response at the time of SARS-CoV-2 infection. Chemotherapy might be resumed without prolonged delay in PCNSL patients with COVID-19. Electronic supplementary material The online version of this article (10.1007/s00415-020-10311-w) contains supplementary material, which is available to authorized users.

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.

Background Isocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined. Methods We searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989–2020). Results Out of 517 grade II gliomas, 47 were “diffuse astrocytomas, IDHwt.” Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%). Conclusions Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.

BackgroundGlioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Leptomeningeal spread (LMS) is a severe complication of GBM, raising diagnostic and therapeutic challenges in clinical routine.MethodsWe performed a review of the literature focused on LMS in GBM. MEDLINE and EMBASE databases were queried from 1989 to 2019 for articles describing diagnosis and therapeutic options in GBM LMS, as well as risk factors and pathogenic mechanisms.ResultsWe retrieved 155 articles, including retrospective series, case reports, and early phase clinical trials, as well as preclinical studies. These articles confirmed that LMS in GBM remains (a) a diagnostic challenge with cytological proof of LMS obtained in only 35% of cases and (b) a therapeutic challenge with a median overall survival below 2 months with best supportive care alone. For patients faced with suggestive clinical symptoms, whole neuroaxis magnetic resonance imaging and cerebrospinal fluid analysis are both recommended. Liquid biopsies are under investigation and may help prompt a reliable diagnosis. Based on the literature, a multimodal and personalized therapeutic approach of LMS, including surgery, radiotherapy, systemic cytotoxic chemotherapy, and intrathecal chemotherapies, may provide benefits to selected patients. Interestingly, molecular targeted therapies appear promising in case of actionable molecular target and should be considered.ConclusionAs the prognosis of glioblastoma is improving over time, LMS becomes a more common complication. Our review highlights the need for translational studies and clinical trials dedicated to this challenging condition in order to improve diagnostic and therapeutic strategies.Implications for PracticeThis review summarizes the diagnostic tools and applied treatments for leptomeningeal spread, a complication of glioblastoma, as well as their outcomes. The importance of exhaustive molecular testing for molecular targeted therapies is discussed. New diagnostic and therapeutic strategies are outlined, and the need for translational studies and clinical trials dedicated to this challenging condition is highlighted.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new virus that has never been identified in humans before. COVID-19 caused at the time of writing of this article, 2.5 million cases of infections in 193 countries with 165,000 deaths, including two-third in Europe. In this context, Oncology Departments of the affected countries had to adapt quickly their health system care and establish new organizations and priorities. Thus, numerous recommendations and therapeutic options have been reported to optimize therapy delivery to patients with chronic disease and cancer. Obviously, while these cancer care recommendations are immediately applicable in Europe, they may not be applicable in certain emerging and low- and middle-income countries (LMICs). In this review, we aimed to summarize these international guidelines in accordance with cancer types, making a synthesis for daily practice to protect patients, staff and tailor anti-cancer therapy delivery taking into account patients/tumour criteria and tools availability. Thus, we will discuss their applicability in the LMICs with different organizations, limited means and different constraints., Highlights • The first recommendations concerned mainly staff and patients with cancer protection. • More than half of the worldwide cancers are diagnosed in low- and middle-income countries (LMICs). • Organization in accordance with available means: main key for anti-cancer strategy in LMICs. • European recommendations applicability for coronavirus disease 2019 (COVID-19) pandemic is questioned in LMICs. • Amplification of pandemic effects on both COVID and cancer is to be feared in LMICs.

Introduction Only limited data are available regarding the long-term prognosis of patients with high-grade glioma discharged alive from the intensive care unit. We sought to quantify 1-year mortality and evaluate the association between mortality and (1) functional status, and (2) management of anticancer therapy in patients with high-grade glioma discharged alive from the intensive care unit. Patients and methods Retrospective observational cohort study of patients with high-grade glioma admitted to two intensive care units between January 2009 and June 2018. Functional status was assessed by the Karnofsky Performance Status. Anticancer therapy after discharge was classified as (1) continued (unchanged), (2) modified (changed or stopped), or (3) initiated (for newly diagnosed disease). Results Ninety-one high-grade glioma patients (73% of whom had glioblastoma) were included and 78 (86%) of these patients were discharged alive from the intensive care unit. Anticancer therapy was continued, modified, and initiated in 41%, 42%, and 17% of patients, respectively. Corticosteroid therapy at the time of ICU admission [odds ratio (OR) 0.07] and cancer progression (OR 0.09) was independently associated with continuation of anticancer therapy. The mortality rate 1 year after ICU admission was 73%. On multivariate analysis, continuation of anticancer therapy (OR 0.18) and Karnofsky performance status on admission (OR 0.90) were independently associated with lower 1-year mortality. Conclusion The presence of high-grade glioma is not sufficient to justify refusal of intensive care unit admission. Performance status and continuation of anticancer therapy are associated with higher survival after intensive care unit discharge. Previous presentation Preliminary results were presented at the most recent congress of the French Intensive Care Society, Paris, 2019. Electronic supplementary material The online version of this article (10.1007/s00415-020-10191-0) contains supplementary material, which is available to authorized users.

International audience; Overall, tumors of primary central nervous system (CNS) are quite common in adults with an incidence rate close to 30 new cases/100,000 inhabitants per year. Significant clinical and biological advances have been accomplished in the most common adult primary CNS tumors (i.e., diffuse gliomas). However, most CNS tumor subtypes are rare with an incidence rate below the threshold defining rare disease of 6.0 new cases/100,000 inhabitants per year. Close to 150 entities of primary CNS tumors have now been identified by the novel integrated histomolecular classification published by the World Health Organization (WHO) and its updates by the c-IMPACT NOW consortium (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy). While these entities can be better classified into smaller groups either by their histomolecular features and/or by their location, assessing their treatment by clinical trials and improving the survival of patients remain challenging. Despite these tumors are rare, research, and advances remain slower compared to diffuse gliomas for instance. In some cases (i.e., ependymoma, medulloblastoma) the understanding is high because single or few driver mutations have been defined. The European Union has launched European Reference Networks (ERNs) dedicated to support advances on the clinical side of rare diseases including rare cancers. The ERN for rare solid adult tumors is termed EURACAN. Within EURACAN, Domain 10 brings together the European patient advocacy groups (ePAGs) and physicians dedicated to improving outcomes in rare primary CNS tumors and also aims at supporting research, care and teaching in the field. In this review, we discuss the relevant biological and clinical characteristics, clinical management of patients, and research directions for the following types of rare primary CNS tumors: medulloblastoma, pineal region tumors, glioneuronal and rare glial tumors, ependymal tumors, grade III meningioma and mesenchymal tumors, primary central nervous system lymphoma, germ cell tumors, spinal cord tumors and rare pituitary tumors.

BACKGROUND: Glioblastoma relapse is associated with activation of phosphatidylinositol 3-kinase (PI3K) signalling pathway. In preclinical studies, the pan-PI3K inhibitor buparlisib showed antitumour activity in glioma models. METHODS: This was a two-part, multicentre, phase Ib/II study in patients with recurrent glioblastoma pretreated with radiotherapy and temozolomide standard of care. Patients received buparlisib (80 mg or 100 mg once daily) plus carboplatin (area under the curve (AUC)=5 every 3 weeks), or buparlisib (60 mg once daily) plus lomustine (100 mg/m2 every 6 weeks). The primary endpoint was to determine the maximum tolerable dose (MTD) and/or recommended phase II dose of buparlisib plus carboplatin or lomustine. RESULTS: Between 28 February 2014 and 7 July 2016, 35 patients were enrolled and treated with buparlisib plus carboplatin (n=17; buparlisib (80 mg) plus carboplatin, n=3; and buparlisib (100 mg) plus carboplatin, n=14), or buparlisib (60 mg) plus lomustine (n=18). The MTD of buparlisib was determined to be 100 mg per day in combination with carboplatin at an AUC of 5 every 3 weeks. The MTD of buparlisib in combination with lomustine could not be determined as it did not satisfy the MTD criteria per the Bayesian logistic regression model. CONCLUSION: The overall safety profile of buparlisib remained unchanged, and no new or unexpected safety findings were reported in this study. Preliminary assessment for both combinations did not demonstrate sufficient antitumour activity compared with historical data on single-agent carboplatin or lomustine. TRIAL REGISTRATION NUMBER: NCT01934361. ispartof: ESMO OPEN vol:5 issue:4 ispartof: location:England status: published

International audience; Glioblastoma is the most common and aggressive primary malignant brain tumor in adult patients. Despite multimodal treatment with maximal safe surgical resection followed by concurrent radiochemotherapy and adjuvant chemotherapy with temozolomide, the prognosis remains poor with a median survival of 1 year. The survival rate at 5 years is 5% and, theoretically, all glioblastomas relapse [1]. Once tumors progress, treatment options are limited, and the management of recurrent glioblastoma remains challenging. The standard of care for second-line treatment has not been defined; options include surgery, re-irradiation, systemic pharmacotherapy, and, in Europe, mostly lomustine [2,3]. The general and neurological health status of the patient, the molecular findings, the time to first recurrence, the pattern of recurrence, and previous treatment have to be considered. Nitrosoureas or temozolomide rechallenge show limited efficacy. Anti-vascular endothelial growth factor (VEGF) bevacizumab prolonged progression-free survival (PFS), but did not improve overall survival (OS) [4].Because the treatment of recurrent glioblastoma remains a highly unmet clinical need, deeper mechanistic insight into the molecular changes present in these tumors is required. The enrollment of recurrent glioblastoma patients in clinical trials investigating new therapeutic options should be considered carefully whenever possible. In this Special Issue, we present some of the exciting updates on recurrent glioblastomas, which may help shape future treatment options.

Simple Summary Glioblastoma is the most common and aggressive malignant primary brain cancer in adults. The prognosis remains poor following standard-of-care treatment with surgery, radiotherapy and chemotherapy, with a median overall survival of about 15 months. Theoretically, all glioblastoma patients relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. In recent years, new treatments have been tested on recurrent glioblastoma patients. These include immunotherapy, antiangiogenic treatment, targeted therapy and combination regimens. Here, we review these treatment approaches and provide an overview on the molecular characteristics of recurrent glioblastoma. Abstract Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients.

ObjectiveCNS involvement in Erdheim-Chester disease (ECD) leads to substantial morbidity and mortality. To assess CNS manifestations in a French cohort of 253 patients with ECD, we determined clinical characteristics and outcomes, including those under targeted therapies.MethodsThis was a retrospective longitudinal study. CNS manifestations were determined by clinical examination and brain or spine MRI. Targeted therapy efficacy was assessed using global assessment from a physician and a radiologist. The study was approved by the ethics committee Comité de Protection des Personnes Ile de France III.ResultsNinety-seven of 253 patients (38%) with ECD had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptom onset (mean 50.5 years), as well as with the presence of the BRAFV600E mutation (in 77% of cases), xanthelasma (34%), and diabetes insipidus (36%). Median survival among patients with CNS involvement was significantly lower than that of patients with ECD without CNS involvement (124 months vs 146 months, p = 0.03). Seventy-four CNS MRIs were centrally reviewed, which showed 3 patterns: tumoral in 66%, pseudo-degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF or MEK inhibitors) was associated with improved symptoms in 43% of patients and MRI improvement in 45%.ConclusionsCNS manifestations are typically associated with poor prognosis in patients with ECD. Three distinct patterns can be recognized: tumoral, pseudodegenerative, and vascular.Classification of evidenceThis study provides Class III evidence that targeted therapy leads to clinical or imaging improvement in almost 50% of patients.

The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. The guideline is based on the 2016 WHO classification of tumours of the CNS and on scientific developments published since 1980. It aims to provide direction for diagnostic and management decisions, and for limiting unnecessary treatments and cost. In view of the scarcity of data in adults with medulloblastoma, we base our recommendations on adult data when possible, but also include recommendations derived from paediatric data if justified. Our recommendations are a resource for professionals involved in the management of post-pubertal and adult patients with medulloblastoma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.

Summary Background Bevacizumab is frequently used in the treatment of recurrent WHO grade II and III glioma, but without supporting evidence from randomised trials. Therefore, we assessed the use of bevacizumab in patients with first recurrence of grade II or III glioma who did not have 1p/19q co-deletion. Methods The TAVAREC trial was a randomised, open-label phase 2 trial done at 32 centres across Europe in patients with locally diagnosed grade II or III glioma without 1p/19q co-deletion, with a first and contrast-enhancing recurrence after initial radiotherapy or chemotherapy, or both. Previous chemotherapy must have been stopped at least 6 months before enrolment and radiotherapy must have been stopped at least 3 months before enrolment. Random group assignment was done electronically through the European Organisation for Research and Treatment of Cancer web-based system, stratified by a minimisation procedure using institution, initial histology (WHO grade II vs III), WHO performance status (0 or 1 vs 2), and previous treatment (radiotherapy, chemotherapy, or both). Patients were assigned to receive either temozolomide (150–200 mg/m2, orally) monotherapy on days 1–5 every 4 weeks for a maximum of 12 cycles, or the same temozolomide regimen in combination with bevacizumab (10 mg/kg, intravenously) every 2 weeks until progression. The primary endpoint was overall survival at 12 months in the per-protocol population. Safety analyses were done in all patients who started their allocated treatment. The study is registered at EudraCT (2009–017422–39) and ClinicalTrials.gov ( NCT01164189 ), and is complete. Findings Between Feb 8, 2011, and July 31, 2015, 155 patients were enrolled and randomly assigned to receive either monotherapy (n=77) or combination therapy (n=78). Overall survival in the per-protocol population at 12 months was achieved by 44 (61% [80% CI 53–69]) of 72 patients in the temozolomide group and 38 (55% [47–69]) of 69 in the combination group. The most frequent toxicity was haematological: 17 (23%) of 75 patients in the monotherapy group and 25 (33%) of 76 in the combination group developed grade 3 or 4 haematological toxicity. Other than haematological toxicities, the most common adverse events were nervous system disorders (59 [79%] of 75 patients in the monotherapy group vs 65 [86%] of 76 in the combination group), fatigue (53 [70%] vs 61 [80%]), and nausea (39 [52%] vs 43 [56%]). Infections were more frequently reported in the combination group (29 [38%] of 76 patients) than in the monotherapy group (17 [23%] of 75). One treatment-related death was reported in the combination group (infection after intratumoral haemorrhage during a treatment-related grade 4 thrombocytopenia). Interpretation We found no evidence of improved overall survival with bevacizumab and temozolomide combination treatment versus temozolomide monotherapy. The findings from this study provide no support for further phase 3 studies on the role of bevacizumab in this disease. Funding Roche Pharmaceuticals.

International audience; Background: Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma.Methods: We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive lomustine plus bevacizumab (combination group, 288 patients) or lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival.Results: A total of 437 patients underwent randomization. The median number of 6-week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P

2004 Background: Patients with newly diagnosed glioblastoma receive postoperative standard therapy with radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor with encouraging findings in preclinical models and early-stage clinical trials for patients with newly diagnosed and recurrent glioblastoma. Therefore, a phase 3 trial was designed to explore the activity of marizomib in addition to TMZ/RT→TMZ. ClinicalTrials.gov Identifier: NCT03345095 Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase 3 superiority trial. Eligibility criteria included histologically confirmed newly diagnosed glioblastoma and a Karnofsky performance status (KPS) > 70. Eligible patients were stratified for institution, age, KPS as well as extent of surgery, and centrally randomized in a 1:1 ratio. The primary objective of this study is to compare overall survival (OS) in patients receiving marizomib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include progression-free survival (PFS), safety, neurocognitive function, and quality of life. Results: The study was opened at 49 EORTC sites in Europe, 23 CCTG sites in Canada, and 8 sites in the US. Patient enrolment started in June 2018 and was close to completion at the time of a planned interim analysis in September 2020. A total of 749 patients (of the planned 750) were randomized when the IDMC recommended to discontinue enrollment. Age, KPS and extent of resection were well balanced between the 2 study arms. No difference in median OS was observed between the standard arm (15.9 months) and the marizomib arm (15.7 months; HR = 0.99). Median PFS was 6.1 vs. 6.2 months (HR = 1.02). Patients in the marizomib group had more often grade 3/4 treatment-emergent adverse events (TEAE) compared to the standard therapy group (42.6% vs. 20.5%), including ataxia, hallucinations and headache. Conclusions: The addition of marizomib to standard radiochemotherapy did not improve OS or PFS in patients with newly diagnosed glioblastoma. Final survival analyses including determination of MGMT promoter methylation status and analyses of other secondary endpoints are ongoing. Clinical trial information: NCT03345095.

Introduction: Glioblastoma (GBM) is the most aggressive primary brain cancer in adults. The standard of care of newly diagnosed GBM, including radiotherapy with concurrent and adjuvant chemotherapy with temozolomide, was established more than 10 years ago. Despite this very intensive and multimodal therapeutic regimen, the prognosis of GBM patients remains grim. New treatments are urgently needed. Immunotherapy is changing perspectives in oncology and has raised of lot of hope for brain tumor patients.Areas covered: We will review molecular and cellular actors involved in immune response against GBM cells. Then, we will discuss the drugs modulating these immune molecular and cellular targets including passive and active immunotherapies.Expert commentary: Results obtained from studies using immunotherapy in GBM are encouraging and multiple promising phase III clinical trials are ongoing. Better outcomes with immunotherapies, alone or in combination, are expected in at least subpopulations of patien...

Glioblastomas are the most frequent and aggressive primary brain tumors which are expressing various evolutions, aggressiveness, and prognosis. Thus, the 2007 World Health Organization classification based solely on the histological criteria is no longer sufficient. It should be complemented by molecular analysis for a true histomolecular classification. The new 2016 WHO classification of tumors of the central nervous system uses molecular parameters in addition to histology to reclassify these tumors and reduce the interobserver variability. The aim of this study is to determine the prevalence ofIDHmutations andEGFRamplifications in the population of the northeast region of Morocco and then to compare the results with other studies.Methods.IDH1codon 132 andIDH2codon 172 were directly sequenced and the amplification of exon 20 ofEGFRgene was investigated by qPCR in 65 glioblastoma tumors diagnosed at the University Hospital of Fez between 2010 and 2014.Results. The R132HIDH1mutation was observed in 8 of 65 tumor samples (12.31%). No mutation ofIDH2was detected.EGFRamplification was identified in 17 cases (26.15%).Conclusion. A systematic search of both histological and molecular markers should be requisite for a good diagnosis and a better management of glioblastomas.

The blood-brain barrier (BBB) limits penetration of systemically administered therapies to brain tumors and peritumoral tissue and may be responsible for the failure of numerous drugs in recent clinical trials for glioblastoma (GBM). Low intensity pulsed ultrasound (LIPU), with concomitant intravenous microbubble injection (DEFINITY®), can temporarily disrupt the BBB for 6–24 hours and allow for enhanced delivery of drugs to the brain. In previous clinical studies, a 1-cm ultrasound (US) device, SonoCloud-1, was implanted in a burr hole of recurrent GBM patients (n=27) and used to disrupt the BBB prior to carboplatin infusion at AUC5. This ongoing pilot phase 1/2 study (NCT03744026) aims to evaluate the safety and efficacy of transient opening of the BBB by LIPU in rGBM with the SonoCloud-9, a larger nine-emitter implantable device, designed to cover the tumor and surrounding infiltrative regions. The ultrasound device is implanted in a 6 cm x 6 cm bone flap window after tumor debulking surgery. Patients receive a 270-second sonication every month with concomitant microbubble injection to disrupt the BBB followed by carboplatin infusion at AUC4-6. Magnetic resonance imaging (MRI) is performed to verify safety and extent of BBB disruption. This study began enrollment in early 2019 and is an international, open-label, single arm, multi-site, dose-escalation and expansion trial to evaluate the safety of escalating sonication volume (“dose”) with concurrent carboplatin. The number of activated emitters in the implant (3, 6, 9) is increased using a 3 + 3 dose escalation design. Safety data of the escalation phase of the study will be presented.

BACKGROUND The blood-brain barrier (BBB) limits penetration of drug therapies to the brain and may account for the limited effectiveness of chemotherapies in patients with primary brain cancer. An implantable ultrasound (US) device, SonoCloud, was developed to temporarily disrupt the BBB in patients with recurrent glioblastoma (rGBM) prior to carboplatin chemotherapy administration to enhance brain drug concentrations. BBB disruption was investigated with a single emitter device, SonoCloud-1 (SC1) and a three-emitter device, SonoCloud-3 (SC3) in a safety and feasibility study in rGBM patients at the Hôpitaux Universitaires La Pitié Salpêtrière in Paris, France (NCT02253212). MATERIAL AND METHODS The SC1 implant consisted of a 1 MHz, 10-mm diameter ultrasound transducer encapsulated in a biocompatible housing while the SC3 consisted of (3) separate SC1 emitters implanted in a triangular pattern to disrupt the BBB over a 3x larger volume. Patients were implanted with the SonoCloud device during tumor debulking or in a dedicated surgical procedure. The devices were activated monthly by connecting the device to an external generator via a transdermal needle. Intravenous injection of SonoVue® microbubbles was performed with device activation to temporarily disrupt the BBB. Magnetic resonance imaging (MRI) was performed after sonications with gadolinium contrast to verify BBB disruption followed by carboplatin infusion at AUC4-6. Patients received treatments until disease progression. RESULTS Between 2014 and 2016, 21 patients were registered for the study and implanted with the SC1; 19 patients received at least one sonication. Six additional patients were implanted and received sonications with the SC3. A total of 89 US sessions were performed to disrupt the BBB - 65 with the SC1 and 24 with the SC3. Treatment-related adverse events observed were transient and manageable. No carboplatin-related neurotoxicity was observed. SC1 patients with no or poor BBB disruption (n=8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. SC1 patients with clear BBB disruption (n=11) had a median PFS of 4.11 months, and a median OS of 12.94 months. The SC3 device was as well-tolerated as the SC1 device, with SC3 patients receiving between 1–12 monthly sonications. CONCLUSION These results provide the first safety data on the effects of disrupting the BBB in rGBM patients prior to carboplatin chemotherapy using an implantable low intensity pulsed ultrasound device on enlarged areas of brain. This study has now been completed. A new safety study with a larger device, SonoCloud-9, that covers the tumor and surrounding infiltrative regions, has started in France in early 2019 (NCT03744026). Work supported by CarThera and APHP.

Purpose: Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas. Patients and Methods: Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety. Results: A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003). Conclusions: The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.

Background. Langerhans Cell Histiocytosis (LCH) is a rare inflammatory neoplasm characterized by an infiltration of organs by Langerin + (CD207+) and CD1a+ histiocytes. Diabetes insipidus is a frequent manifestation of the disease, while diabetes mellitus is very rare. We report the first case of a 20-year-old man suffering from hypothalamopituitary histiocytosis and diabetes mellitus with serum anti-insulin receptor antibodies. Case Presentation. A 20-year-old patient was admitted for the evaluation of growth delay and hyperphagia. HbA1c level and fasting blood glucose were in the normal range. The diagnosis of hypothalamopituitary histiocytosis was based on histological features after biopsy of a large suprachiasmatic lesion identified on magnetic resonance imaging (MRI). Association of vinblastine and purinethol was started followed by a second-line therapy by cladribine. During the follow-up, the patient was admitted for recurrence of hyperglycemic states and extreme insulin resistance. The screening for serum anti-insulin receptor antibodies was positive. Each episode of hyperglycemia appeared to be correlated with tumoral activity and increase in serum anti-insulin receptor antibodies and appeared to be improved when the disease was controlled by chemotherapy. Conclusion. We report the first description of a hypothalamopituitary histiocytosis associated with serum anti-insulin receptor antibodies, extreme insulin resistance, and diabetes. Parallel evolution of glucose levels and serum anti-insulin receptor antibodies seemed to be the consequence of immune suppressive properties of cladribine.

ObjectiveImaging necrosis on MRI scans was assessed and compared to outcome measures of the European Organisation for Research and Treatment of Cancer 26101 phase III trial that compared single-agent lomustine with lomustine plus bevacizumab in patients with progressive glioblastoma.MethodsMRI in this post hoc analysis was available for 359 patients (lomustine = 127, lomustine + bevacizumab = 232). First, imaging necrosis at baseline being formally measurable (>10 × 10 mm, given 2 slices) was assessed. At weeks 6 and 12 of treatment, it was analyzed whether this necrosis remained stable or increased >25% calculated by 2 perpendicular diameters or whether necrosis developed de novo. Univariate and multivariate associations of baseline necrosis with overall survival (OS) and progression-free survival (PFS) were tested by log-rank test. Hazard ratios (HR) with 95% confidence interval were calculated by Cox model.ResultsImaging necrosis at baseline was detected in 191 patients (53.2%) and was associated with worse OS and PFS in univariate, but not in multivariate analysis. Baseline necrosis was predictive for OS in the lomustine-only group (HR 1.46, p = 0.018). At weeks 6 and 12 of treatment, increase of baseline necrosis and de novo necrosis were strongly associated with worse OS and PFS in univariate and multivariate analysis (PFS both p < 0.001, OS univariate p < 0.001, multivariate p = 0.0046).ConclusionIncrease of and new development of imaging necrosis during treatment is a negative prognostic factor for patients with progressive glioblastoma. These data call for consideration of integrating the assessment of imaging necrosis as a separate item into the MRI response assessment criteria.

Objective Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm which can infiltrate any organ or tissue. Endocrine involvement has mostly been described in case reports and small retrospective studies. We aimed to describe endocrine manifestations in a large cohort of adulthood onset (AO) and childhood onset (CO) patients with LCH. Design Single-center observational study conducted between January 2002 and December 2017 at Pitié-Salpêtrière University Hospital (Paris, France), a tertiary care hospital. Method Clinical, biological and morphological evaluations of pituitary, gonadal, adrenal and thyroid function evaluations performed in 63 consecutive patients with LCH (AO patients: 40, CO patients: 23). Fifty-eight patients underwent follow-up assessments. Results Complete pituitary evaluation was performed in 38/63 patients (60.3%); at least one anterior pituitary dysfunction (APD) was found in 63.2% of them. In this subgroup of patients, the most prevalent deficiencies were diabetes insipidus (DI) and GHD (55.3% each), followed by gonadotropin deficiency (34.2%) and thyrotropin deficiency (23.7%). In the subgroup of the 25 incompletely evaluated patients, we found DI in 44%, GHD in 50%, gonadotropin deficiency in 30.4% and thyrotropin deficiency in 16%. APD was more common in CO patients (P = 0.003) but was not systematically associated with DI regardless of the age of onset. Endocrine dysfunction was most often permanent; moreover, occurrence of new deficiencies has been described during follow-up. Conclusion The spectrum of endocrine disorders appears to be large in LCH (both in AO and CO patients) and should be evaluated carefully at diagnosis and during follow-up. APD was not always associated with DI.

Purpose: The blood–brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations. Patients and Methods: A first-in-man, single-arm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy. Results: Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n = 11) had a median PFS of 4.11 months, and a median OS of 12.94 months. Conclusions: SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity. See related commentary by Sonabend and Stupp, p. 3750

BACKGROUND: MMR deficiency (MMRd) is found in a subset of gliomas. Emerging evidence indicates that MMRd could serve as predictive biomarker for both response to immunotherapy and resistance to alkylating agents. However, the molecular epidemiology, outcome, and the optimal diagnostic method of MMRd are poorly defined in gliomas. METHODS: A cohort of 350 adult gliomas was characterized as to WHO 2016 diagnosis, IDH1/2 sequencing, MGMT promoter methylation, prior treatment and outcome. Immunohistochemistry of MMR proteins (MSH2, MSH6, MLH1, PMS2) was performed in 260 tumors with available tissue. 100 tumors were analyzed with next generation targeted exome sequencing (NGS, Oncopanel) of 447 cancer genes, including full exon coverage of MMR genes. Comparisons between results from IHC, NGS and microsatellite instability (MSI) testing using pentaplex PCR amplification testing were incorporated to inform best practices. RESULTS: 53/260 tumors showed immunohistochemical (ie MMR protein staining loss) and/or molecular (ie presence of MMR pathogenic mutation with hypermutation) evidence of MMRd. No MSI was found by pentaplex PCR. 38/260 tumors harbored loss of protein expression of one or two MMR proteins: 15 showed loss of MSH6 protein (with/without concomitant MSH2 loss) and 23 had loss of PMS2 (with/without MLH1 loss). Analysis of 201 consecutive recurrent tumors from alkylator pre-treated patients showed significant association between MMRd and the presence of IDH1/2 mutation: MMRd in 20/90 (22.2%) of IDH1/2-mutant tumors vs 2/111 (1.8%) of IDH1/2-wild-type tumors (p

Acute respiratory failure (ARF) is common and potentially fatal in patients with primary malignant brain tumors (PMBT). However, few data are available regarding its precipitating factors and prognosis. We sought to: (1) compare the causes of ARF and the outcome between patients with PMBT and patients with other peripheral solid tumors (PST), (2) identify the factors influencing ICU survival in PMBT patients. Two-center retrospective case-control study from March 1996 to May 2014. Primary central nervous system lymphomas were also included. Eighty-four patients with PMBT and 133 patients with PST were included. Acute infectious pneumonia was more frequent in PMBT than PST patients (77 vs. 36%, p

Low intensity pulsed ultrasound (LIPU), in combination with systemic injection of microbubbles, can be used to transiently disrupt the blood-brain barrier (BBB) and increase brain-drug concentrations. In pre-clinical models, carboplatin can be enhanced by a factor of 5x in the brain using LIPU and increase the survival of GBM-bearing mice. In clinical studies, a single emitter, implantable ultrasound device (SonoCloud-1) was used to disrupt the BBB in 19 rGBM patients prior to carboplatin chemotherapy (NCT02253212). The feasibility of this approach was demonstrated, and safe acoustic parameters were determined. The primary objective of this subsequent Phase 1/2a study (NCT03744026) was to demonstrate the safety of BBB disruption over a larger volume, including the tumor and surrounding peritumoral region using a nine-emitter version of the device (SonoCloud-9). This study was a 3 + 3 design using escalating numbers of activated 1-cm diameter emitters (3, 6, 9). GBM patients at any recurrence, with a maximum tumor size of < 70 mm were included. The SonoCloud-9 device was implanted during tumor debulking/resection surgery and replaced the bone flap. The device was activated every four weeks for 270 seconds, concomitantly with DEFINITY® microbubbles to disrupt the BBB prior to administration of carboplatin. Magnetic resonance imaging was performed to verify safety and the extent of BBB disruption. As of June 2020, the escalation phase of the study (9 patients) was complete, with a median of four monthly cycles of sonication and carboplatin chemotherapy per patient. No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with only a few, transient, and manageable related adverse events. The safety of administration of multiple repeat treatments of BBB opening using nine emitters of the device at an acoustic pressure of 1.03 MPa will be confirmed in an additional 12 patients to be included in the ongoing expansion phase.

Introduction: Glioblastoma (GBM) is a primary central nervous system tumor associated with a poor prognosis. Radiotherapy in combination with chemotherapy with temozolomide has been proven to increase survival, but traditional treatments remain of limited efficacy in this disease. Other approaches, increasingly complex, are emerging.Areas covered: We will review molecules targeting angiogenesis and microtumor environment, cell surface receptors, and signal transduction pathways, as well as immune checkpoint inhibitors. We conducted a non-systematic search to identify past and planned human trials using those drugs.Expert commentary: Results from studies using targeted therapy in GBM have been under expectations. This could signal a need for a more tailored approach or the simultaneous use of drugs with different targets.

International audience

Glioblastoma is the most common primary malignant brain tumor in adults. Despite very intensive treatments (i.e. maximal safe surgery, radiotherapy and cytotoxic chemotherapy), the prognosis of glioblastoma patients remains dismal with a median overall survival below 2 years. More effective and better tolerated treatments are needed. Over the last years, major advances have been accomplished in the molecular characterization of glioblastoma mainly thanks to high throughput molecular biology techniques. In parallel to these biological advances, pharmacological progresses have been made with the development of molecular targeted therapies or precision medicine or smart drugs targeting these molecular alterations detected in cancer cells but absent in normal cells of the body. These targeted molecular therapies, more effective and less toxic, have already revolutionized the prognosis of several systemic cancers (e.g., melanoma, lung cancer). On the basis of our knowledge of glioblastoma molecular biology, these molecular targeted therapies also appear promising in glioblastomas. Anti-angiogenic drugs are the most advanced molecular targeted therapies in their evaluation. Promising results were observed in recurrent glioblastoma patients. Other molecular targeted therapies are currently under preclinical or clinical evaluations. Similarly, to several systemic cancers, molecular targeted therapies will most likely find quickly their place in the therapeutic arsenal directed against glioblastomas to improve survival and quality of ife of patients suffering from this cancer type.

International audience; Objective: IDH wild-type glioblastoma is the most common and aggressive primary brain cancer in adults. At tumor recurrence, treatment decision-making is not standardized; several options include second surgery, reirradiation, and a second line of chemotherapy. In this retrospective monocentric study conducted at the era of WHO 2016 classification, we investigated IDH wild-type glioblastoma patients below the age of 70 to see (i) the clinical benefit of second surgery at recurrence and (ii) the prognostic factors in resected recurrent glioblastoma patients.Methods: 229 newly diagnosed IDH wild-type glioblastoma patients below the age of 70 treated with the standard of care (SOC) were enrolled in the current study and stratified into two subgroups according to treatment at recurrence: re-resection and no re-resection.Results: All experienced tumor recurrence with a median progression-free survival of 11 months. 25 % of patients were reoperated. Patients reoperated at recurrence had longer post-progression median overall survival compared to their non-reoperated counterparts (14 versus 9 months, p < .05). Initial surgical resection and a long time from the initial diagnosis to the first recurrence were independent prognostic factors for good outcomes in resected recurrent IDH-wild-type glioblastoma patients; however, tumor size before and after surgery did not impact post-surgical survival.Conclusion: Our study supports surgical resection at recurrence as therapeutic in IDH wild-type glioblastoma patients aged below 70 and in good clinical condition regardless of preoperative tumor size, particularly in patients who experienced a longer time before first recurrence and surgery at initial diagnosis. Further prospective and larger studies are warranted to validate our findings.

7560 Background: Erdheim–Chester disease (ECD), an inflammatory myeloid neoplasm from the L group, is an histiocytosis associated with multisystem infiltration. Around 1500 cases have been reported worldwide since 1930. In 15% of cases, ECD is associated with another histiocytosis corresponding to mixed histiocytosis. Before 2004, 60% of patients died within 3 years after diagnosis. The targetable BRAFV600Emutation is present in as much as 70% of all ECD cases. Targeted therapies (BRAF inhibitors in April 2012, followed by MEK inhibitors after 2015) have revolutionized the therapeutic options and prognosis of refractory ECD and mixed histiocytosis. Methods: This retrospective study was conducted between April 2012 and December 2019 on 117 ECD patients who received targeted therapies in the French National Referral Center for Histiocytosis at Pitié-Salpêtrière Hospital in Paris, France. 28 patients (pts) (24%) had a mixed histiocytosis. Results: 43 (36.7%) pts were female and 95/116 exploitable pts (81.9%) had a BRAF V600E mutation. 12 (10.3%) pts had a co-ocurring hemopathy (myeloproliferative neoplasm or myelodysplastic syndrom). Age at diagnosis was 57.2 yr (+/- 13.8). The main sites of involvement were: vascular (“coated aorta”) in 85 pts (73%), heart in 83 pts (71%), xanthelasma in 30 pts (26%), central nervous system in 56 pts (48%) and peri-renal (“hairy kidney”) in 84 pts (72%). 34 pts (29%) had previously received corticosteroids, and 63 pts (54%) interferon alpha regimen (mainly PEG interferon). 86 (74%) pts received the BRAF inhibitor vemurafenib, and 42 (36%) pts the MEK inhibitor cobimetinib (some patients receiving both). 25 pts died during follow-up. The median survival of patients with targeted therapies in december 2019 was undefined, whereas the patients with no targeted therapies had a median survival of 133 months (HR 0.64 (0.42-0.99); p = 0.04). Among the 117 pts, only 2 had a progression of VAF of mutations within genes frequently mutated in myeloid neoplasms. The most serious adverse events were cutaneous (squamous cell carcinoma, basocellular carcinoma, DRESS) and acute pancreatitis with BRAF inhibitors, whereas chorioretinitis and left ventricular dysfunction were seen with MEK inhibitors. None of the patients receiving targeted therapies progressed. Conclusions: Targeted therapies (BRAF and/or MEK inhibitors) were found dramatically efficacious in 117 patients with severe and refractory ECD and mixed histiocytosis, improving survival of patients.

Background: Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis, characterized by the infiltration of tissues by foamy CD68+CD1a- histiocytes, with 1500 known-cases since 90 years. Mutations activating the MAPK pathway are found in more than 80% of ECD patients, mainly the BRAFV600E in 57 to 70%. Central nervous system (CNS) involvement during ECD lead to significant morbidity and mortality. We assessed CNS manifestations in a French cohort of 253 ECD patients. Since 2012, close to 200 patients worldwide with multi-systemic and refractory ECD (e.g. heart and/or CNS involvements) have benefited from BRAF and MEK inhibitors, which have proven highly beneficial. Methods: CNS manifestations were determined by clinical examination and brain and/or spine magnetic resonance imaging (MRI). Targeted therapy efficacy was assessed using physician and radiologist global assessment. Results: Ninety-seven (38%) among the 253 of the whole cohort of ECD patients had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptoms onset (mean 50.5 years), and also with the presence of the BRAFV600E mutation (in 77% of cases), xanthelasma (34%), and diabetes insipidus (36%). Median survival among patients with CNS involvement was significantly lower than in ECD patients without CNS involvement (124 months versus 146 months, p=0.03). Seventy-four CNS MRI were centrally reviewed, corresponding to 3 patterns: tumoral in 66%, degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF and/or MEK inhibitors) was associated with improvement of symptoms in 43% of patients, and MRI improvement in 45%. Conclusions: CNS manifestations are typically associated with a poor prognosis in ECD. Three distinct patterns may be recognized: tumoral, degenerative, and vascular. Targeted therapy leads to clinical and/or imaging improvement in almost 50% of patients. OffLabel Disclosure: Targeted therapies such as BRAF inhibitor (vemurafenib) and MEK inhibitor (cobimetinib) are used in severe histiocytosis in EU but are off label

ObjectiveTo characterize the prevalence and prognostic significance of major driver molecular alterations in adult midline diffuse gliomas (MLG).MethodsAdults with histologically proven MLG diagnosed between 1996 and 2017 were identified from our tumor bank, systematically reviewed, and reclassified according to WHO 2016. Targeted sequencing was performed, including determination ofH3F3A,HIST1H3B,TERTp,IDH1/2,FGFR1,p16/CDKN2A, andEGFRstatus.ResultsA total of 116 adult patients (M/F 71/45, median age 46.5 years) with MLG (17 cerebellar, 8 spinal, 30 brainstem, 57 thalamic, and 4 diencephalic nonthalamic) were identified. Most patients had high-grade disease at presentation (grade II: 11%, grade III: 15%, grade IV: 75%). Median overall survival was 17.3 months (14.5–23.8 months). Main molecular alterations observed wereTERTpromoter,H3F3A, and hotspotFGFR1(N546 and K656) mutations, in 37%, 34%, and 18% of patients, respectively.IDH1mutations only affected brainstem gliomas (6/24 vs 0/78;p= 7.5 × 10−5), were mostly non-R132H (contrasting with hemispheric gliomas,p= 0.0001), and were associated with longer survival (54 vs 12 months).TERTpromoter mutation (9.1 vs 24.2 months),CDKN2Adeletion (9.9 vs 23.8 months), and EGFR amplification (4.3 vs 23.8 months) were associated with shorter survival. Of interest, in contrast with pediatric MLG, H3K27M mutations were not associated with worse prognosis (23 vs 15 months).ConclusionsPatients with adult MLG present with unique clinical and molecular characteristics, differing from their pediatric counterparts. The identification of potentially actionableFGFR1mutations in a subset of adult MLG highlights the importance of comprehensive genomic analysis in this rare affection.

International audience; Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late-onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND-LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND-LCH. The 10-year cumulative incidence of cND-LCH was 4·1%. cND-LCH typically affected patients previously treated for a multisystem, risk organ-negative LCH, represented in 69·4% of cND-LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND-LCH patients compared to those without cND-LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The 'cND susceptible patients' (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10-year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV 600E status added important information among these cND susceptible patients, with the 10-year cND risk of 33·1% if a BRAFV 600E mutation was present compared to 2·9% if it was absent (P = 0·002).

Tumor-treating fields (TTFields) therapy improves both progression-free and overall survival in patients with glioblastoma. There is a need to assess the influence of TTFields on patients' health-related quality of life (HRQoL).To examine the association of TTFields therapy with progression-free survival and HRQoL among patients with glioblastoma.This secondary analysis of EF-14, a phase 3 randomized clinical trial, compares TTFields and temozolomide or temozolomide alone in 695 patients with glioblastoma after completion of radiochemotherapy. Patients with glioblastoma were randomized 2:1 to combined treatment with TTFields and temozolomide or temozolomide alone. The study was conducted from July 2009 until November 2014, and patients were followed up through December 2016.Temozolomide, 150 to 200 mg/m2/d, was given for 5 days during each 28-day cycle. TTFields were delivered continuously via 4 transducer arrays placed on the shaved scalp of patients and were connected to a portable medical device.Primary study end point was progression-free survival; HRQoL was a predefined secondary end point, measured with questionnaires at baseline and every 3 months thereafter. Mean changes from baseline scores were evaluated, as well as scores over time. Deterioration-free survival and time to deterioration were assessed for each of 9 preselected scales and items.Of the 695 patients in the study, 639 (91.9%) completed the baseline HRQoL questionnaire. Of these patients, 437 (68.4%) were men; mean (SD) age, 54.8 (11.5) years. Health-related quality of life did not differ significantly between treatment arms except for itchy skin. Deterioration-free survival was significantly longer with TTFields for global health (4.8 vs 3.3 months; P .01); physical (5.1 vs 3.7 months; P .01) and emotional functioning (5.3 vs 3.9 months; P .01); pain (5.6 vs 3.6 months; P .01); and leg weakness (5.6 vs 3.9 months; P .01), likely related to improved progression-free survival. Time to deterioration, reflecting the influence of treatment, did not differ significantly except for itchy skin (TTFields worse; 8.2 vs 14.4 months; P .001) and pain (TTFields improved; 13.4 vs 12.1 months; P .01). Role, social, and physical functioning were not affected by TTFields.The addition of TTFields to standard treatment with temozolomide for patients with glioblastoma results in improved survival without a negative influence on HRQoL except for more itchy skin, an expected consequence from the transducer arrays.clinicaltrials.gov Identifier: NCT00916409.

International audience; 716 IDH2 mutations are commonly associated with 1p/19q codeletion in diffuse adult gliomas Diffuse gliomas are classified according to the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System, 1 which combines histological and molecular features. Diagnosis requires the assessment of mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2), key genetic alterations characterizing gliomas with favorable outcome. 2 Because IDH1 and IDH2 are highly similar enzymes, the WHO classification, as most of the current studies, combines these mutations into the same molecular group; however, it is unclear whether these tumors share the same characteristics. We analyzed data from 1517 patients included in the French POLA Network to investigate differences between IDH1-and IDH2-mutant gliomas. Inclusion criteria were the written consent of the patient for clinical data collection and genetic analysis and sufficient material for molecular studies allowing classification according to the 2016 WHO classification. IDH1-R132H mutational status was evaluated using automated immunohistochemistry in all cases (n = 1517). Direct sequencing 3 was performed in 978 cases and demonstrated IDH mutation in 573 cases (this includes confirmation of IDH1-R132H mutation in 468 cases, other IDH1 mutations in 61 cases, and IDH2 mutation in 44 cases). The 1p/19q codeletion status was determined based on single nucleotide polymor-phism arrays, comparative genomic hybridization arrays, and/ or microsatellite marker analysis. 3 The following data were recorded: age, sex, follow-up, and MRI features (tumor location , extension, contrast enhancement, edema). All statistical analysis was done using IBM SPSS statistics software version 23. Chi-square test was used to compare qualitative variables. Continuous variables were compared using the Mann– Whitney U-test, and the Kaplan–Meier method was used to estimate survival distributions. Among the 1517 patients, 1025 had an IDH-mutant tumor: 96% were IDH1-mutant and 4% IDH2-mutant. Integrated diagnoses are summarized in Fig. 1. The frequency of 1p/19q code-letion was higher in the IDH2-mutant group compared with the IDH1-mutant group (91% vs 48%, P < 0.001). Wang and coworkers previously reported higher frequency of 1p/19q codeletion in IDH2-mutant gliomas (9/18 samples) compared with IDH1-mutant. 4 The percentage of each category in our study does not reflect the normal distribution of glioma because of the inclusion criteria in the POLA Network (ie, high-grade glioma with oligodendroglial component). However, the higher proportion of 1p/19q codeleted glioma in the IDH2-mutant group cannot be attributed to the inclusion criteria. Because the main population of glioma associated with IDH2 mutation was 1p/19q codeleted anaplastic oligodendroglioma, we focused on this subgroup to search for differences compared with IDH1 mutation. Among these patients (n = 474), we did not observe any difference in terms of age, sex, progression free survival, or overall survival between IDH1-and IDH2-mutant tumors. However, IDH2-mutant anaplastic oli-godendrogliomas presented more frequently with multilobar extension (56% of the IDH2-mutant vs 35% of the IDH1-mutant, P = 0.015) and edema (79% vs 57%, P = 0.02). Furthermore, bifrontal location with corpus callosum involvement was more frequent in IDH2-mutant compared with IDH1-mutant tumors (41% vs 16%, P < 0.001). IDH mutation is supposed to be one of the first " hits " of gliomagenesis, 5 resulting in production of an oncome-tabolite, D-2-hydroxyglutarate (D-2HG), which impacts the α-ketoglutarate–dependent dioxygenase functions. Previous studies demonstrated that the potential for IDH-mutant enzymes to produce D-2HG depends on the mutation type. 6 Based on our observations, we could hypothesize that the higher D-2HG accumulation induced by IDH2 mutation may lead to a phenotype that is favorable to 1p/19q chromosomal loss. It may also impact distinct cellular pathways that promote a more invasive phenotype. Whether IDH1 or IDH2 mutations impact distinct glial precursor cells with differential invasive properties remains to be elucidated. In conclusion, our results illustrate that IDH2-mutant glio-mas are commonly associated with 1p/19q codeletion. Most of IDH2-mutant anaplastic oligodendroglioma 1p/19q codeleted are multilobar. Understanding the genomic events involved in these specificities may represent a step forward for therapeutic development.

Personalized medicine is a challenge to improve survival and quality of life of patients suffering from primary malignant brain tumor. Molecular biology is integrated in initial diagnosis and relapse, and, in the nearest future, over treatment schedule and monitoring. Liquid biopsy is a minimally invasive way to obtain tumor material. Over the past years, three fluids have been explored to provide tumor information in primary malignant brain tumor: blood, cerebrospinal fluid, and vitreous liquid. Different tumor components were identified: (1) circulating tumor cells, (2) circulating tumor DNA, (3) RNA and non-coding miRNA, and (4) extracellular vesicles. The performance of the liquid biopsy depends on the tumor type and on the method of detection. Liquid biopsy could be a valuable tool to improve patient care in primary malignant brain tumor. Improvement of its sensitivity is the major challenge to generalize its use in daily practice.