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Background Glioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS). Methods Patients were selected from an in-house cohort (GLIOTRAIN-cohort), using defined inclusion criteria (Karnofsky score > 70; age Results Transcriptomic analysis of tumour samples identified cilium gene signatures as enriched in LTS. Moreover, Immunohistochemical analysis confirmed the presence of cilia in the tumours of LTS. Notably, reverse phase protein array analysis (RPPA) demonstrated increased phosphorylated GAB1 (Y627), SRC (Y527), BCL2 (S70) and RAF (S338) protein expression in STS compared to LTS. Next, we identified 25 unique master regulators (MR) and 13 transcription factors (TFs) belonging to ontologies of integrin signalling and cell cycle to be upregulated in STS. Conclusion Overall, comparison of STS and LTS GBM patients, identifies novel biomarkers and potential actionable therapeutic targets for the management of GBM. Graphical abstract

This study aimed to assess the benefit-risk ratio by determining diagnostic yield and safety of brainstem biopsies in adult patients. The secondary objectives were (i) to compare brainstem biopsy safety and postbiopsy patients' outcomes and survival with those of patients biopsied for a brain or cerebellar lesion, and (ii) to assess the impact of brainstem biopsy on final diagnosis and further therapeutic management.Among 1784 stereotactic biopsies performed in adult patients at a tertiary center between April 2009 and October 2020, we retrospectively examined 50 consecutive brainstem biopsies. We compared variables regarding diagnostic yield, safety and post-biopsy outcomes between brainstem biopsy patients and brain/cerebellum biopsy patients.Brainstem biopsy led to a diagnosis in 86% of patients (94.6% in patients with suspected tumor). Lesion contrast enhancement on imaging was the sole predictor of obtaining a diagnosis. Rates of symptomatic complications and mortality were significantly higher in brainstem biopsy patients compared to brain/cerebellum biopsy patients (20% vs 0%; p 0.001 and 6% vs 0%; p = 0.01, respectively). Transfrontal trajectory and prebiopsy swallowing disorders were predictors of brainstem biopsy-related symptomatic complications. Brainstem biopsy findings led to diagnostic change in 22% of patients.Stereotactic biopsy in adult patients with brainstem lesion has a high diagnostic yield. Although stereotactic brainstem biopsy is associated with more functional and fatal complications than biopsies targeting the brain/cerebellum, its safety profile appears acceptable. Thus, the benefit-risk ratio of stereotactic biopsy in patients with brainstem lesion is favorable but should nevertheless be carefully weighted on a case-by-case basis.

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

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Prognosis of GBM patients is poor with median overall survival around 15 months. Temozolomide is the chemotherapeutic agent used in the standard of care of newly diagnosed GBM patients relying on radiotherapy with concurrent chemotherapy followed by chemotherapy alone. Irinotecan has shown some efficacy in recurrent malignant gliomas. Bevacizumab has been combined with irinotecan in the treatment of recurrent GBM and with temozolomide in newly diagnosed GBM. As the efficacy of GBM treatments relies on their brain distribution through the blood brain barrier, the aim of the present preclinical work was to study, in in vivo models, the impact of bevacizumab on brain and tumor distribution of temozolomide and irinotecan. Our results show that bevacizumab pre-treatment was associated with a reduced temozolomide brain distribution in tumor-free mice. In tumor bearing mice, bevacizumab increased temozolomide tumor distribution, although not statistically significant. In both tumor-free and tumor-bearing mice, bevacizumab does not modify brain distribution of irinotecan and its metabolite SN-38. Bevacizumab impacts brain distribution of some anti-tumor drugs and potentially their efficacy in GBM. Further studies are warranted to investigate other therapeutic combination.

Although upfront temozolomide (TMZ) has been widely-used to treat 1p/19q-codeleted diffuse low-grade gliomas (LGG), its long-term impact on the growth kinetics of these tumors has not been determined. Based on serial magnetic resonance images we retrospectively evaluated the evolution of the mean tumor diameter (MTD) in 36 progressive 1p/19q-codeleted LGG treated with upfront TMZ. After TMZ onset, all but two patients (94.4%) presented a progressive MTD decrease that lasted for a median duration of 23 months (range 3–114). In 10 patients (27%) MTD regrowth occurred during TMZ treatment and in 22 patients (66%) after TMZ discontinuation. In these patients, median time to MTD regrowth after TMZ discontinuation was 12 months (range 1–88). The rate of MTD regrowth at 3 and 5 years after TMZ onset was 77 and 94%, respectively. Time to tumor progression (TTP) based on volumetric analysis was shorter than TTP based on Response Assessment in Neuro-Oncology (RANO) bidimensional criteria (23 vs. 35 months, p = 0.05) and shorter than time to next oncological treatment (23 vs. 46 months, p = 0.001). In 10 patients (27%), absence of volumetric analysis led to continue TMZ for a median of 10 cycles after MTD had started to regrow. Volumetric analysis is important to precisely assess chemotherapy efficacy in 1p/19q-codeleted LGG, identify early tumor progression and avoid futile chemotherapy continuation. In the present series, although some long-lasting volumetric responses were observed, most tumors resumed their growth within 3 years after TMZ onset.

Primary Central Nervous System Lymphoma (PCNSL) is most often non-Hodgkin lymphoma diffuse large B cell lymphoma (NHL-DLBCL) confined exclusively to the central nervous system. Its pathogenesis remains unknown in immunocompromised patients. Recent studies pointed out that systemic NHL, especially B cell NHL, might be associated with Hepatitis B virus (HBV) [1, 2]. We thus reported the prevalence of HBV in immunocompetent patients with PCNSL and search for a possible association. We included 109 patients treated for PCNSL in our department in Paris, France, from 2002 to 2012. The inclusion criteria were: (i) aged C18 years, (ii) pathologically documented diagnosis of ocular or cerebral DLBC-PCNSL, (iii) HIV seronegative and (iv) available HBV serology. The control population included 319 patients treated in the same Department, from 1993 to 2011, for other primary brain tumors (PBT) and with available HBV serology. We compared prevalence of HBsAg, anti-HBc and anti-HBs between these populations using a Fischer’s test (STATA 8.0, Woolf test). We also compared prevalence of HBsAg and anti-HBc in the PCNSL group to the French and greater Paris’ area (GPA) populations using an exact test based on binomial probability function [3]. The characteristics of the PCNSL and the PBT populations are reported in Table 1. Prevalence of HBsAg was greater among the PCNSL patients than within the French population (p = 0.01) and the GPA population (p = 0.02). In addition, prevalence of anti-HBc in the PCNSL patients was higher than within the French population (p = 0.01). Although no statistically significant difference was found between PCNSL and PBT patients (p = 0.49 regarding HBsAg, p = 0.10 regarding anti-HBc and p = 0.23 regarding anti-HBs), a trend for a positive association between HBV and PCNSL was highlighted. Regarding active (p = 0.49) and past infections (p = 0.10) and Electronic supplementary material The online version of this article (doi:10.1007/s11060-015-1879-x) contains supplementary material, which is available to authorized users.

Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify new genomic regions associated with prognosis, 60 AOTs from the EORTC trial 26951 were analyzed retrospectively using BAC-array-based comparative genomic hybridization. The data were processed using a binary tree method. Thirty-three BACs with prognostic value were identified distinguishing four genomic subgroups of AOTs with different prognosis (p

Optimal treatment of anaplastic oligodendrog- lial tumors (AOT) in elderly patients is debatable. We report a retrospective study of 44 consecutive patients aged 70 years or older (median age: 74 years; median Karnofsky performance status (KPS): 70) treated with up-front che- motherapy using temozolomide (TMZ) at conventional doses until tumor progression. O 6 -methylguanine-DNA methyltransferase promoter (MGMTP) methylation was assessed in 38 patients. Of the 41 evaluable patients, partial response (PR) was seen in 13 (32%) patients, 17 (41%) patients achieved stable disease, while the disease pro- gressed in 11 (27%) patients. Median progression-free survival (PFS) and overall survival (OS) were 6.9 and 12.4 months, respectively. Hematoxicity grades 3-4 occurred in nine patients (20%). MGMTP was methylated in 50% of patients and was associated with both longer PFS (8.7 versus 5.7 months, P = 0.01) and longer OS (16.1 versus 12.4 months, P = 0.05). The rate of responders to chemotherapy was similar in MGMTP-methylated (38%) and in MGMTP-unmethylated patients (31%), but duration of response was significantly longer in responders with methylated MGMTP than in responders with unmethylated MGMTP (16.1 versus 9.6 months, P = 0.0004). This study demonstrates that a substantial number of elderly patients with AOT can achieve prolonged survival with up-front chemotherapy using TMZ. Further investigation is needed to determine whether this treatment is preferable to initial radiation therapy.

The names of authors Marc Sanson and Jean-Yves Delattre were incorrectly presented in the initial online publication. The original article has been corrected.

The aim of the study was to investigate the ability of (1)HMRS to reflect proliferative activity of diffuse low-grade gliomas (WHO grade II). Between November 2002 and March 2007, a prospective study was performed on consecutive patients with suspected supratentorial hemispheric diffuse low-grade tumors. All the patients underwent MR examination using uniform procedures, and then surgical resection or biopsy within 2 weeks of the MR examination. Proliferative activity of the tumors was assessed by Ki-67 immunochemistry (Mb-1) on paraffin embedded tumor sections. Spectroscopic data was compared with Ki-67 labeling index and other histologic data such as histological subtype, cellular atypia, cellular density using univariate and multivariate analysis. 82 of 97 consecutive patients had histologically confirmed WHO grade 2 gliomas. Ki-67 proliferation index (PI) was correlated with specific spectral patterns: (1) low PI (4%) was associated with increased Cho/Cr and absence of both free lipids or lactates; (2) intermediate PI (4-8%) was associated with resonance of lactates; and (3) high PI (8%) was characterized by a resonance of free lipids. On multivariate analysis, resonance of lactates and resonance of free lipids appeared as independent predictors of intermediate PI (P0.001) and high PI (P0.001), respectively; moreover, free lipids resonance was correlated with cellular atypia (P0.05). This study suggests that (1)HMRS is a reliable tool to evaluate the proliferation activity of WHO grade 2 glioma and to identify potentially more aggressive clinical behavior.

DNA and histone methylation are post-transcriptional modifications that have been recently described in gliomas. Indeed, glioma CpG island hypermethylated phenotype has been identified as prognostic biomarker and as a surrogate marker of IDH1/2 mutations. However, the role of DNA methylation in glioblastoma progression is unknown. We sought to analyze DNA methylation levels in paired (initial and recurrent) primary glioblastoma samples to identify candidate pathways that may prone to glioblastoma progression. We have analyzed 12 samples (5 paired samples, two of them with three surgeries) using methylation arrays. We have analyzed differential methylation at probe and at gene region level. Finally, pathway analysis has been performed using differentially methylated regions. All analysis has been performed with R and Bioconductor packages. Mean methylation level at initial sample compared to recurrence was strongly positively correlated (R(2) = 0.98). There was no differentially methylation at probe level. However, at gene level 3080 regions were differentially methylated. Interestingly, pathways analysis showed that the most differentially methylated genes are involved in cellular response to macrophage colony-stimulating factor stimulus (GO:0036006). Methylation levels were strongly conserved when comparing initial to recurrence in primary glioblastomas. Interestingly, differentially methylated pathway analysis suggests that a modulation of methylation in immune response genes may play a role in glioblastoma progression. Further studies are needed to validate the role of methylation of glioblastoma immune response genes in tumor progression.

Diffuse intrinsic brainstem gliomas (DIBG) account for 1–2 % of adult gliomas. Their biological characteristics are scarcely understood and whether DIBG are biologically different from supratentorial gliomas remains to be established. We analyzed 17 DIBG samples for IDH1 R132H, alpha internexin, p53, and Ki67 expression, and, in a subset with sufficient DNA amount, for IDH1 and histone H3 mutational status, genomic profiling and MGMT promoter methylation status. A series of 738 adult supratentorial gliomas was used for comparison. Median age at diagnosis was 41 years (range 18.9–65.3 years). Median overall survival was 48.7 months (57 months for low-grade vs. 16 months for high-grade gliomas, p

The role of prophylactic intrathecal chemotherapy in the treatment of primary central nervous system lymphoma remains controversial. We report a retrospective single center study of a cohort of 69 patients with primary central nervous system lymphoma who had been treated with a regimen that combined high intravenous doses of Methotrexate, CCNU, procarbazine and methylprednisolone. Before 2000, patients systematically received intrathecal prophylaxis including Methotrexate, cytarabine, and hydrocortisone delivered either by intraventricular or lumbar injection along with the systemic chemotherapy (group A, n = 39). After this date, the procedure was changed and intrathecal chemotherapy was withdrawn from the protocol (group B, n = 30). The median age and Karnofsky index were comparable in both groups. At the time of analysis, we found no significant difference between patients with and without intrathecal prophylaxis in terms of objective response rate, patterns of relapse, progression-free survival or overall survival. In our study, intrathecal prophylaxis withdrawal from a high dose intravenous Methotrexate-based chemotherapy regimen did not influence disease control and outcome of primary central nervous system lymphoma. Further studies prospectively investigating the role of intrathecal chemoprophylaxis are warranted for this disease.

Gliomatosis cerebri (GC) constitutes a heterogeneous group of conditions involving diffuse neoplastic glial cell infiltration of the brain. Management is difficult and an obvious challenge is to identify prognostic factors. Alpha-internexin (INA) expression, which is closely related to the 1p19q codeletion, is a strong prognostic marker in oligodendroglial tumors. Similarly, the R132H isocitrate dehydrogenase 1 IDH1 mutation, which can now be detected by use of a specific antibody, predicts better outcome in gliomas. In a retrospective series of 40 GC treated with up-front chemotherapy, we analyzed IDH1(R132H) mutant protein and INA immunohistochemical expression and correlated it with outcome; 17/40 GC expressed IDH1(R132H) and 10/40 GC expressed INA. IDH1(R132H) staining was strongly related to progression-free survival (42.3 vs. 15.5 months for positive IDH1(R132H) vs. negative tumors; P0.0001) and overall survival (73.9 vs. 23.6 months; P0.0001). This effect was independent of grade, histologic subtype, and INA expression (P0.001). Combined expression of IDH1(R132H) and INA was strongly associated with response to chemotherapy (100% vs. 36%; P = 0.003). These data strongly suggest that INA and IDH1(R132H) mutant protein immunohistochemical analysis is of a great prognostic value in biopsied GC.

There is a growing evidence of using Temozolomide as upfront therapy for progressive low grade gliomas. No data exist on the efficacy of nitrosoureas as an alternative to radiotherapy in those patients who progress after Temozolomide. We retrospectively reviewed 30 patients with median age of 46 years. Twenty-one patients had pure oligodendrogliomas. Thirteen patients had a non-enhancing tumor at progression after Temozolomide. The chromosomes 1p/19q were co-deleted in 5 cases and retained in 10 cases. Response rate was 10% (3 minor responses achieved in non-enhancing tumors). Tolerance was acceptable (17% grade III and IV myelosupression). Median PFS was 6.5 months. Median OS from start of salvage treatment was 23.4 months. Tumors without contrast enhancement demonstrated a better prognosis than those with contrast enhancement both in term of PFS (P = 0.0003) and OS (P = 0.0006). Chromosomes 1p/19q codeletion was not predictive for objective response to salvage treatment but correlated with a better PFS (P = 0.02). In conclusion, salvage NU chemotherapy provide disappointing results in TMZ-pretreated low grade gliomas (LGG), which should be treated in priority by conventional radiotherapy especially in LGG that display contrast enhancement at progression.

Ependymomas are glial neoplasms originating from the wall of the ventricles or from the spinal canal. The significance of histopathological features in accurately predicting biological behavior is still debated. Moreover, key molecular events in the pathogenesis of ependymoma are yet to be defined. The main objective of the present study was to identify specific patterns of chromosomal aberrations that correlate with tumor location, histological subtype and grade. Forty-five ependymoma samples were analyzed by 1-megabase resolution array comparative genomic hybridization (CGH). Association between clinical or histopathological parameters and the genomic alterations identified was evaluated. The most frequently detected chromosome (chr) abnormalities were gain of chr 7, 9, 12 and 15 and loss of chr 22. Co-occurrence of those five alterations characterized spinal ependymomas (P = 0.01). Myxopapillary ependymomas displayed a specific genomic profile defined by concurrent gain of chr 5, 7, 9, 16 and 18 (P = 0.0007). Overall, the number of chromosomal abnormalities detected was inversely correlated with the malignancy grade. Gain of chr 1q correlated with intracranial high-grade tumors (P = 0.002). Loss of chr 6q was mainly observed in infratentorial (P = 0.02) and World Health Organization (WHO) grade III (P = 0.04) lesions. Chr 10q loss was associated with high-grade ependymomas (P = 0.01). The +7/+9/+12/+15/−22 genomic profile is significantly associated with WHO grade II spinal ependymomas, whereas the +5/+7/+9/+16/+18 genomic pattern is specific of myxopapillary ependymomas. Identification of specific genomic imbalances at a given tumor location suggests that ependymomas from different central nervous system (CNS) regions represent genetically distinct diseases. Detecting genomic alterations associated with aggressive biological behavior may help stratify patients in high- and low-risk disease.

There is no standard of care for elderly patients with glioblastoma (GBM) and poor performance status. A 79-year-old woman with GBM, aphasia, and hemiplegia achieved a complete response after only one cycle of temozolomide (TMZ) (150 mg/m2/day over 5 days). Genomic profiling of the tumor demonstrated loss of chromosome 10 and MDM2 amplification, which are predictive of poor outcome. The MGMT promoter was methylated, and it is likely that this at least partially explains the exquisite chemosensitivity in our patient. This unusual case report suggests that TMZ warrants further investigation in elderly patients with poor performance status.