Survival Outcomes Associated With First-Line Procarbazine, CCNU, and Vincristine or Temozolomide in Combination With Radiotherapy in IDH-Mutant 1p/19q-Codeleted Grade 3 Oligodendroglioma.

PURPOSE: Patients with IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma (O3IDHmt/Codel) benefit from adding alkylating agent chemotherapy to radiotherapy (RT). However, the optimal chemotherapy regimen between procarbazine, 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and vincristine (PCV) and temozolomide (TMZ) remains unclear given the lack of randomized trial data comparing both regimens. METHODS: The objective was to assess the overall survival (OS) and progression-free survival (PFS) associated with first-line PCV/RT versus TMZ/RT in patients newly diagnosed with O3IDHmt/Codel. We included patients with histologically proven O3IDHmt/Codel (according to WHO criteria) from the French national prospective cohort Prise en charge des OLigodendrogliomes Anaplasiques (POLA). All tumors underwent central pathological review. OS and PFS from surgery were estimated using the Kaplan-Meier method and Cox regression model. RESULTS: 305 newly diagnosed patients with O3IDHmt/Codel treated with RT and chemotherapy between 2008 and 2022 were included, of which 67.9% of patients (n = 207) were treated with PCV/RT and 32.1% with TMZ/RT (n = 98). The median follow-up was 78.4 months (IQR, 44.3-102.7). The median OS was not reached (95% CI, Not reached [NR] to NR) in the PCV/RT group and was 140 months (95% CI, 110 to NR) in the TMZ/RT group (log-rank P = .0033). On univariable analysis, there was a significant difference in favor of PCV/RT in both 5-year (PCV/RT: 89%, 95% CI, 85 to 94; TMZ/RT: 75%, 95% CI, 66 to 84) and 10-year OS (PCV/RT: 72%, 95% CI, 61 to 85; TMZ/RT: 60%, 95% CI, 49 to 73), which was confirmed using the multivariable Cox model adjusted for age, type of surgery, gender, Eastern Cooperative Oncology Group performance status, and CDKN2A homozygous deletion (hazard ratio, 0.53 for PCV/RT, 95% CI, 0.30 to 0.92, P = .025). CONCLUSION: In patients with newly diagnosed O3IDHmt/Codel from the POLA cohort, first-line PCV/RT was associated with better OS outcomes compared with TMZ/RT. Our data suggest that the improved safety profile associated with TMZ comes at the cost of inferior efficacy in this population. Further investigation using prospective randomized studies is warranted.

Characteristics, Patterns of Care and Predictive Geriatric Factors in Elderly Patients Treated for High-Grade IDH-Mutant Gliomas: A French POLA Network Study.

Background: Describe the characteristics, patterns of care, and predictive geriatric factors of elderly patients with IDHm high-grade glioma (HGG) included in the French POLA network. Material and Methods: The characteristics of elderly (≥70 years) patients IDHm HGG were compared to those of younger patients IDHm HGG (<70 years) and of elderly patients IDHwt HGG. Geriatric features were collected. Results: Out of 1433 HGG patients included, 119 (8.3%) were ≥70 years. Among them, 39 presented with IDHm HGG. The main characteristics of elderly IDHm HGG were different from those of elderly IDHwt HGG but similar to those of younger IDHm HGG. In contrast, their therapeutic management was different from those of younger IDHm HGG with less frequent gross total resection and radiotherapy. The median progression-free survival (PFS) and overall survival (OS) were longer for elderly patients IDHm HGG (29.3 months and 62.1 months) than elderly patients IDHwt HGG (8.3 months and 13.3 months) but shorter than those of younger patients IDHm HGG (69.1 months and not reached). Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, body mass index, and autonomy. Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, and body mass index, and autonomy. Conclusion: the outcome of IDHm HGG in elderly patients is better than that of IDHwt HGG. Geriatric assessment may be particularly important to optimally manage these patients.

Expression Analysis of α5 Integrin Subunit Reveals Its Upregulation as a Negative Prognostic Biomarker for Glioblastoma.

Integrin α5ß1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the expression of integrin α5 and its prognostic impact in a glioblastoma series of patients scheduled to undergo the Stupp protocol as first-line treatment for GBM. The integrin α5 protein expression level was estimated in each tumor by the mean fluorescence intensity (MFI) and allowed us to identify two subpopulations showing either a high or low expression level. The distribution of patients in both subpopulations was not significantly different according to age, gender, recursive partitioning analysis (RPA) prognostic score, molecular markers or surgical and medical treatment. A high integrin α5 protein expression level was associated with a high risk of recurrence (HR = 1.696, 95% CI 1.031-2.792, p = 0.0377) and reduced overall survival (OS), even more significant in patients who completed the Stupp protocol (median OS: 15.6 vs. 22.8 months; HR = 2.324; 95% CI 1.168-4.621, p = 0.0162). In multivariate analysis, a high integrin α5 protein expression level was confirmed as an independent prognostic factor in the subpopulation of patients who completed the temozolomide-based first-line treatment for predicting OS over age, extent of surgery, RPA score and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (p = 0.029). In summary, for the first time, our study validates that a high integrin α5 protein expression level is associated with poor prognosis in GBM and confirms its potential as a therapeutic target implicated in the Stupp protocol resistance.

Temozolomide and Bevacizumab Induction before Chemoradiotherapy in Patients with Bulky Glioblastoma and/or with Severe Neurological Impairment.

Background. New approaches are needed for patients newly diagnosed with bulky glioblastoma (GB) and/or with severe neurological impairment that cannot benefit from first line temozolomide (TMZ)-based chemoradiotherapy. Bevacizumab (BEV), an antiangiogenic anti-VEGF-R monoclonal antibody, has a rapid impact on tumor-related brain edema in recurrent GB. The present study reports the feasibility and efficacy of an induction treatment with TMZ and BEV to alleviate the initial neurological impairment and/or to reduce the tumor volume before a delayed chemoradiotherapy. Methods. We retrospectively analyzed tumor and target volumes and clinical neurological status in 39 patients with bulky GB and/or with severe neurological impairment after an induction treatment combining TMZ and BEV. Neurological and radiological responses were assessed according to RANO criteria. Calculating gross tumor and clinical target volumes (GTV and CTV) was done at diagnosis and before radiotherapy. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan Meier methods. Safety was reported according to NCTCAE. Results. A cohort of 39 patients was analyzed between December 2010 and April 2014. Upfront standard TMZ-based chemoradiotherapy was recused due either to tumor volume or impairment of neurological status and/or performance status. After TMZ/BEV induction (median time of 3 months), 6 (15%) patients achieved a partial response (PR), and 17 (44%) had a stable disease. 24 patients (62%) received a radical-intent chemoradiotherapy. TMZ-BEV induced median reduction of the clinical target volume (CTV) was 25.9% [-84.4%; - 4.8%]. The median PFS and OS were 8.4 months [95% CI: (6.6 - 9.9)] and 11.0 months [95% CI: (9.3 - 13.7)], respectively in the whole cohort and 10.8 [95% CI: (9.3 - 12.9)] and 15.0 [95% CI: (13.2 - 17.8)] for irradiated patients. Induction treatment led to corticosteroid dose reduction or cessation in 21 patients (54%). KPS improvement was observed in 38% of patients. Toxicity was mild with only 7/39 (18%) grade III-IV toxicity, including 1 digestive bleeding and 1 epistaxis. Conclusion. TMZ-BEV induction led to CTV reduction allowing for optimal chemoradiotherapy in a majority (62%) of patients for which radiotherapy was initially recused. A clinical benefit was obtained with improved KPS and a decrease in steroid dose.

Prognostic impact of the 2016 WHO classification of diffuse gliomas in the French POLA cohort.

The new WHO classification of diffuse gliomas has been refined and now includes the 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M mutation. Our objective was to assess the prognostic value of the updated 2016 WHO classification in the French POLA cohort. All cases of high-grade oligodendroglial tumors sent for central pathological review and included into the French nationwide POLA cohort were reclassified according to the updated 4th WHO classification. In total, 1041 patients were included, with a median age at diagnosis of 50.4 years (range 17.1-84.4). Based on the new histomolecular classification, diagnoses included anaplastic oligodendroglioma IDH mutant and 1p/19q-codeleted (32.5 %), anaplastic astrocytoma IDH mutant (IDH (mut)) (11.0 %), anaplastic astrocytoma IDH wild type (IDH (wt)) (5.3 %), glioblastoma IDH (mut) (17.1 %), and glioblastoma IDH (wt) (33.2 %). Ten patients presented with a diffuse midline tumor, H3 K27M mutant. The new WHO classification was prognostic for progression-free survival (PFS) and overall survival (OS) (p < 0.001). We did not find prognosis differences between grades III and IV for IDH (mut) 1p/19q intact and IDH (wt) gliomas in univariate and multivariate analyses. Among anaplastic astrocytoma IDH (wt), cases with chromosome arm 7p gain and 10q loss (55 %) had shorter PFS than the others (p = 0.027). In conclusion, the new WHO histomolecular classification of diffuse gliomas presented with high prognostic value. Grading was not discriminant between grade III and IV high-grade gliomas.

Allelic loss of 9p21.3 is a prognostic factor in 1p/19q codeleted anaplastic gliomas.

OBJECTIVES: We aimed to study the potential clinical relevance of 9p allelic loss, with or without copy number variation, in 1p/19q codeleted anaplastic oligodendroglial tumors (AOTs). METHODS: This study enrolled 216 patients with 1p/19q codeleted AOT. The prognostic value of 9p allelic loss was investigated using a French nation-wide prospective registry, POLA (prise en charge des tumeurs oligodendrogliales anaplasiques) and high-density single nucleotide polymorphism arrays. We validated our results using the Repository of Molecular Brain Neoplasia Data (REMBRANDT) dataset. RESULTS: The minimal common region of allelic loss in chromosome arm 9p was 9p21.3. Allelic loss of 9p21.3, detected in 41.7% of tumors, was associated with shorter progression-free and overall survival rates in univariate (p = 0.008 and p < 0.001, respectively) and multivariate analyses (p = 0.009 and p = 0.009, respectively). This finding was validated in the REMBRANDT dataset in univariate and multivariate analysis (p = 0.01 and p = 0.01, respectively). CONCLUSION: Our study highlights a novel potential prognostic biomarker in 1p/19q codeleted AOT. Further prospective studies are warranted to investigate our finding.

Frameless robotic stereotactic biopsies: a consecutive series of 100 cases.

OBJECT: Stereotactic biopsy procedures are an everyday part of neurosurgery. The procedure provides an accurate histological diagnosis with the least possible morbidity. Robotic stereotactic biopsy needs to be an accurate, safe, frameless, and rapid technique. This article reports the clinical results of a series of 100 frameless robotic biopsies using a Medtech ROSA device. METHODS: The authors retrospectively analyzed their first 100 frameless stereotactic biopsies performed with the robotic ROSA device: 84 biopsies were performed by frameless robotic surface registration, 7 were performed by robotic bone fiducial marker registration, and 9 were performed by scalp fiducial marker registration. Intraoperative flat-panel CT scanning was performed concomitantly in 25 cases. The operative details of the robotic biopsies, the diagnostic yield, and mortality and morbidity data observed in this series are reported. RESULTS: A histological diagnosis was established in 97 patients. No deaths or permanent morbidity related to surgery were observed. Six patients experienced transient neurological worsening. Six cases of bleeding within the lesion or along the biopsy trajectory were observed on postoperative CT scans but were associated with transient clinical symptoms in only 2 cases. Stereotactic surgery was performed with patients in the supine position in 93 cases and in the prone position in 7 cases. The use of fiducial markers was reserved for posterior fossa biopsy via a transcerebellar approach, via an occipital approach, or for pediatric biopsy. CONCLUSIONS: ROSA frameless stereotactic biopsies appear to be accurate and safe robotized frameless procedures.

The impact of the reference imaging modality, registration method and intraoperative flat-panel computed tomography on the accuracy of the ROSA® stereotactic robot.

OBJECTIVE: To establish the impact of the imaging modality, registration method and use of intraoperative computed tomography (CT) scan on the accuracy of the ROSA® stereotactic robot. METHODS: Using a dedicated phantom device, we measured the accuracy of the stereotactic robot for 20 targets as a function of the registration method (frameless, FL, or frame-based, FB) and the reference imaging modality (3T magnetic resonance imaging, MRI, CT scanner or flat-panel CT, fpCT). We performed a retrospective study of the accuracy of the first 26 FB and 31 FL robotized stereotactic surgeries performed in our department. RESULTS: In a phantom study, the mean target accuracy was 1.59 mm for 3T MRI-guided FL surgery, 0.3 mm for fpCT-guided FL surgery and 0.3 mm for CT-guided FB surgery. In our retrospective series, the mean accuracy was 0.81 mm for FB stereotactic surgery, 1.22 mm for our 24 stereotactic surgery procedures with FL (surface recognition) registration and 0.7 mm for our 7 stereotactic surgery procedures with FL fiducial marker registration. Intraoperative fpCT fully corrected all the registration errors. CONCLUSIONS: The ROSA stereotactic robot is highly accurate. Robotized FB stereotactic surgery is more accurate than robotized FL stereotactic surgery.

SNP array analysis reveals novel genomic abnormalities including copy neutral loss of heterozygosity in anaplastic oligodendrogliomas.

Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations).To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named "Prise en charge des OLigodendrogliomes Anaplasiques (POLA)," has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively.At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD.Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.

Bilateral abducens paralysis revealing bipartite spheno-occipital synchondrosis fracture in a child: case based update.

BACKGROUND: After reviewing the literature about sella turcica and spheno-occipital synchondrosis fracture, we present the case of a 6-year-old girl who suffered complex sphenoid bone fracture produced by an indirect mechanism. METHODS: The girl fell from her height after a blunt head injury due to a falling lamppost. RESULTS: Computer tomography (CT) scan showed occipital, sellar and clival fractures with pneumatocephalus. The probable fracture mechanism is contre-coup injury linked to osseous and brain oscillations after head trauma. CONCLUSION: Two complications, abducens nerve palsy and cerebrospinal fluid fistula, are observed and discussed.

Effect of transcranial magnetic stimulation on four types of pressure-programmable valves.

BACKGROUND: Exposure to powerful magnetic fields may alter the settings of programmable ventriculoperitoneal shunt valves or even cause permanent damage to these devices. Transcranial magnetic stimulation (TMS) and magnetic resonance imaging both generate a high-intensity, focal magnetic field. To the best of our knowledge, there is no literature data on the compatibility of TMS with neurosurgical implants. The aim of the present in vitro study was to investigate the effects of TMS on four types of pressure-programmable valves (the Strata 2 from Medtronic, the Polaris from Sophysa, the ProGAV from Miethke, and a cylindrical valve from Codman-Hakim). METHODS: We used a Magpro X100 stimulator (Medtronic) for monophasic or biphasic TMS via a circular or a figure-of-eight coil. Each valve setting was tested before and after exposure to TMS. Experiment 1: The effect of the coil-valve distance (10, 5, 2.5, and 1 cm) was assessed. Experiment 2: We mimicked in situ stimulation with a human mannequin by placing the valve in a retroauricular position, the TMS circular coil on the apex, and figure-of-eight coil centered over the primary motor area site. Temperature changes were monitored throughout the experiments. Experience 3: TMS-induced valve movements were assessed by using an in-house accelerometric setup. RESULTS: Our results primarily demonstrated that the Strata 2 and Codman-Hakim valves' settings were perturbed by TMS. There was no heating effect for any of the valves. However, TMS induced movements of the Strata 2, Polaris, and ProGAV valves. Experiment 1: The unsetting frequencies observed for the Strata 2 and the Codman-Hakim valve showed an influence of the distance, the coil model, and the magnetic field characteristics, whereas the Polaris and ProGAV's settings remained unchanged. Experiment 2: Unsetting occurred for Strata 2 valve with the circular coil only, whereas the Polaris, ProGAV, and Codman-Hakim valves' settings remained stable. Experiment 3: The Strata 2, Polaris, and ProGAV valves showed high-amplitude oscillations during TMS under all stimulation conditions, whereas the Codman-Hakim valve did not move. CONCLUSIONS: Our in vitro experiments showed that TMS can interfere with programmable shunt valves by inducing unsetting or movement. This finding suggests that great care must be taken if applying TMS in hydrocephalic, shunted patients.

Additional familial case of subtotal leukonychia and sebaceous cysts (Bauer syndrome): belong the nervous tumours to the phenotype?

Familial leukonychia with sebaceous cysts is a rare autosomal dominant genetic condition, previously reported in four families. Molecular basis of the disorder is unknown. We report on a five-generation family with subtotal leukonychia and sebaceous cysts. Six individuals were affected, five women and one boy. One of the women exhibited a cervical ependymoma and bilateral multiple inoperable acoustic neuromas. These tumours have never been reported in association with leukonychia and may represent an uncommon severe complication of the syndrome.

Odontoid fracture complicating Jaffe-Lichtenstein disease. Case report.

The authors report the case of a 31-year-old man with polyostotic fibrous dysplasia who suffered a traumatic odontoid fracture in an area of a preexisting bone lesion. Conservative treatment was successfully performed. Jaffe-Lichtenstein disease is discussed along with differential diagnoses and alternative methods of treatment.

Cerebral venous angioma of the pons complicated by nonhemorrhagic infarction. Case report.

The authors emphasize an unusual complication of venous angiomas in the brain: venous infarction. The patient in this case is a 32-year-old man who presented with a clinical history of headache followed by a worsening of his neurological status. Neuroimaging studies demonstrated a brain infarct in the posterior fossa, which was related to thrombosis of the draining vein of a cerebral venous angioma. A conservative treatment approach without anticoagulation therapy was followed and the patient completely recovered. Nonhemorragic venous infarction caused by thrombosis of a venous angioma is exceptional and only nine previous cases have been reported in the literature.