bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS8.2 Risk stratification in chordoid meningioma depends on mutation status and epithelial differentiation
Authors: Georgescu M M , Li Y , Olar A , Mobley B , Faust P , Raisanen J 
Published: September 2019

Abstract

BACKGROUND
Meningiomas are heterogenous tumors and their pathologic classification in the WHO Classification of Tumors of the CNS comprises 13 recognized histologic variants. Chordoid meningioma is a rare and more aggressive histologic variant of meningioma. Due to paucity of cases, the molecular profiling and patient risk stratification were not addressed in this variant.

MATERIAL AND METHODS
We performed an integrated clinical, NHERF1 immunohistochemical (IHC) and next generation sequencing (NGS) analysis of WHO grade II chordoid meningiomas from 30 patients (35 cases), representing the largest study to date. The NGS was performed by using a custom Agilent-generated 295-gene library containing genes with recurrent mutations in adult and pediatric, primary and metastatic brain cancer. Five of these cases cases were confirmed by performing NGS at Tempus on the xT panel containing 596 genes, and an additional 10 atypical (non-chordoid) meningioma, WHO grade II, cases were sequenced at Tempus, for comparison.

RESULTS
The patients with chordoid meningioma have demographic characteristics different from the general population: younger age of onset (45 vs 65), skull base (SB) location for the female patients (6:1), and increased recurrence rate (25% at 5 years). NHERF1 microlumen extent directly correlated with skull base location (p=0.0002), and segregated tumors into three cell differentiation categories -fibroblastic (13.3%), epithelial/poorly-differentiated (26.7%) and epithelial/well-differentiated (60%). NGS identified NF2 and TRAF7, as the most common mutated genes, correlating with the location and epithelial differentiation of the tumors. Mutations in AKT1, KLF4 and MN1 were found in isolated well-differentiated skull base tumors. Mutations in genes not previously involved in meningioma pathogenesis were also found.

CONCLUSION
The integrated tumor analysis stratified the patients into: (1)

HIGH RECURRENCE RISK
, characterized by tumors harboring NF2 mutations and low epithelial differentiation and (2)

LOW RECURRENCE RISK
, characterized by tumors exhibiting either epithelial differentiation, skull base location and TRAF7/AKT1/KLF4 mutations, or fibroblastic differentiation, non-skull base location and other mutations. This is the first study of the integrated mutational landscape of chordoid meningioma with important implications for patient risk stratification and management.
OS8.8 Modified chromatin histone marks at noncoding elements are associated with aggressive meningioma subtype
Authors: Malta T , Sabedot T , Lee I , Wells M , Castro A , Noushmehr H 
Published: September 2019

Abstract
Background: Although most meningiomas are non-malignant, there is a high recurrence rate among atypical and anaplastic (malignant) meningiomas (grades II/III). In addition, malignant meningioma usually progresses after treatment. Recently, based on DNA methylation, two subgroups of meningioma were described with recurrence-free survival differences (favorable and unfavorable). Epigenetic deregulation at distinct genomic elements such as enhancers can drive changes in gene expression and alter the transcriptional profile of the cancer cells. We seek to understand the mechanisms of meningioma recurrence and progression after initial treatment. Material and Methods: Two favorable and two unfavorable meningioma high grade tumor tissue were selected for this pilot study. Immunoprecipitation (Antibodies) for two different histone modifications (H3K4me3 and H3K27ac) were used to generate genome-wide chromatin-IP sequencing. Genome-wide DNA methylation profile was assessed for 90 meningioma cases including the four samples used in this pilot study.
Results: Using a FDR cutoff of 5%, we identified 10,049 H3K27ac and 5,752 H3K4me3 chromatin marks that distinguish favorable from unfavorable meningioma. We dichotomized the results into genomic regions overlapping known gene promoters and non-promoters. Promoter associated chromatin changes (H3K27ac and H3K4me3) coincide with DNA methylation changes in aggressive meningioma. The top 1,000 H3K27ac (sorted by fold difference) without H3K4me3 coincide with highly conserved DNA elements known to be associated with enhancers. These enhancers can drive expression of multiple genes simultaneously. Using DNA methylation differences between favorable and unfavorable meningioma, we will overlap with our unfavorable associated enhancers in order to refine our candidate enhancers for follow up mechanistic studies using aggressive meningioma cell lines.
Conclusion: Our preliminary results are the first to unravel the genome-wide chromatin changes associated with unfavorable or clinically aggressive meningioma. Identification of these candidate enhancers will provide knowledge of the role of epigenomics in the development of malignant meningioma and of opportunities for targeted therapy.
This project is supported by the Henry Ford Health System, Department of Neurosurgery and the Hermelin Brain Tumor Center Foundation (A30935), United States National Institutes of Health (R01CA222146), and United States Department of Defense (CA170278)
OS10.2 Effectiveness and tolerability of lacosamide as add-on therapy in patients with brain tumor-related epilepsy: results from a prospective, non-interventional study in European clinical practice
Authors: Rudà R , Hellot S , De Backer M , Chan J , Joeres L , Leunikava I , Grant R 
Published: September 2019

Abstract

BACKGROUND
Data on the use of lacosamide (LCM) for the treatment of brain tumor-related epilepsy (BTRE) are limited. The objective of this study was to evaluate the effectiveness and tolerability of LCM added to 1 or 2 antiepileptic drugs (AEDs) in the treatment of patients with epilepsy due to low-grade primary brain tumor.

MATERIAL AND METHODS
Prospective, multicenter, single-arm, non-interventional study with a 6-month observation period (EP0045; NCT02276053). LCM was added to existing treatment with 1 or 2 AEDs. Patients aged ≥16 years with BTRE secondary to low-grade glioma (WHO Grade I-II) were eligible. Primary endpoints: patients experiencing a ≥50% reduction in seizure frequency from Baseline to Month 6; Patient’s Global Impression of Change (PGIC) rating at Month 6. Secondary endpoints: Kaplan-Meier estimated retention rate and change from Baseline in quality-of-life to Month 6 (EQ-5D-5L and MDASI-BT). Safety variables: occurrence of adverse drug reactions (ADRs) and ADRs leading to discontinuation. The present analysis was performed for the safety set: all patients who took ≥1 dose of lacosamide.

RESULTS
The study was conducted between November 2014 and December 2017. Patients were enrolled from 24 sites in Italy, the United Kingdom, the Netherlands, Germany, France, and Spain. 93 patients started LCM (mean [SD] age: 44.5 [14.7] years; 50 [53.8%] male); 14 (15.1%) withdrew from the study by 6 months. 85 (91.4%) patients had low-grade glioma, 3 (3.2%) had suspected glioma, 3 (3.2%) had meningioma, 1 (1.1%) had craniopharyngioma, and 1 (1.1%) had a histologically unverified tumor. At 6-months, 66 (71.0%) patients reported a ≥50% reduction in seizure frequency, 30 (32.3%) of whom were seizure-free. Improvements on PGIC were reported by 49 (52.7%) patients. The Kaplan-Meier estimated 6-month retention rate was 86.0%. Quality of life (EQ-5D-5L) and symptoms outcome measures (MDASI-BT) remained stable. ADRs leading to discontinuation occurred in 4 (4.3%) patients, most commonly vertigo (2 [2.2%] patients).

CONCLUSION
This is the first prospective, multicenter study focusing on epilepsy due to slow-growing tumors (mainly low-grade gliomas), treated with LCM. The results suggest that LCM reduces seizures in patients with resistant BTRE. The majority of patients noticed a clinical improvement with the addition of LCM. Observed ADRs were consistent with the known safety profile of LCM. STUDY SUPPORTED BY: UCB Pharma.
OS10.4 Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for leptomeningeal metastasis from breast cancer - a randomized study. Final results
Authors: Le Rhun E , Wallet J , Mailliez A , Le Deley M , Rodrigues I , Boulanger T , Lorgis V , Barriere J , Robin Y , Weller M , Bonneterre J 
Published: September 2019

Abstract

BACKGROUND
Leptomeningeal metastasis (LM) is a common manifestation in metastatic breast cancer. Standards of care remain controversial, notably intrathecal pharmacotherapy.

MATERIAL AND METHODS
DEPO-SEIN was a randomized open-label phase III study to explore the addition of intrathecal liposomal cytarabine to systemic therapy for the treatment of newly diagnosed LM from breast cancer. Patients diagnosed with LM based on the detection of tumor cells in the cerebrospinal fluid or typical clinical and neuroimaging signs of LM were randomly assigned to receive systemic therapy alone (control group) or systemic therapy plus intrathecal liposomal cytarabine (five injections of 50 mg every two weeks, followed by one monthly injection of 50 mg until progression, unacceptable toxicity or for one year) (experimental group). Progression-free survival related to LM (LM-PFS) was the primary endpoint.

RESULTS
Thirty-seven and 36 patients were assigned to the control and the experimental groups. The median number of liposomal cytarabine injections in the experimental group was five (range 1–20). Focal radiotherapy was performed in six patients (16%) and three patients (8%) in the control and experimental groups. In the intent-to-treat population, median LM-PFS was 2·2 months (95% confidence interval (CI) 1·3-3·1) in the control versus 3·8 months (95% CI 2·3–6·8) in the experimental group (hazard ratio 0·61, 95% CI 0·38-0·98) (p=0·04). Seventy-one patients have died. Median OS was 4·0 months (95% CI 2·2–6·3) in the control versus 7·3 months (95% CI 3·9-9·6) in the experimental group (hazard ratio 0·85, 95% CI 0·53-1·36) (p=0·51). Serious adverse events were reported in 22 and 30 patients in the control and experimental groups. Quality of life until progression did not differ between groups.

CONCLUSION
Intrathecal liposomal cytarabine improves LM-related PFS. A larger confirmatory trial with optimized patient selection criteria may be required to demonstrate a survival benefit from intrathecal pharmacotherapy.
P01.02 Serum-derived DNA methylation markers distinguish functional and invasiveness subtypes in patients harboring pituitary tumors
Authors: Castro A V , Wells M , Asmaro K , Sabedot T S , Mosella M S , Malta T M , Nelson K , Snyder J , deCarvalho A , Mukherjee A , Chitale D , Robin A , Rosenblum M , Mikkelsen T , Poisson L M , Lee I , Walbert T , Bhan A , Kalkanis S , Rock J , Noushmehr H 
Published: September 2019

Abstract

BACKGROUND
Molecular profiling of circulating biomarkers released by tumors has a relevant clinical value in central nervous system (CNS) tumors, but its feasibility has not been investigated in pituitary tumors (PT) despite being the second common intraaxial tumors of the CNS (~15%). Although usually benign and slow-growing, they can be nonfunctioning and invade surrounding structures resulting in significant comorbidities. DNA methylation aberrations distinguish PT according to their functional status but their role in invasiveness is still unclear. Pre-surgical detection of clinically relevant molecular markers associated with tumor behavior can address current diagnostic and therapeutic challenges. We hypothesized that PT release cell-free DNA (cfDNA) into the bloodstream allowing for the profiling of epigenetic markers associated with relevant clinicopathological features.

MATERIAL AND METHODS
Genome-wide methylome profile of paired serum cfDNA (EPIC array) and tissue from 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 NFPT, 6 invasive) and 3 controls serum (patients with epilepsy).

RESULTS
Unsupervised analysis of the serum methylome from patients harboring PT was distinct from controls and other diseases (hypopituitarism, glioma and colorectal cancer) and supervised analysis (Wilcoxon Rank-sum Test) identified significant differentially methylated probes (DMP) that segregated PT from control serum specimens. Nonfunctioning and invasive-specific DMPs identified in the serum also defined functional, and less prominently invasive status, in the tissue of an independent cohort of PT.

CONCLUSION
This is the first study to show the feasibility to profile the methylome in the serum of patients with PT using cfDNA. In addition, we identified unique methylation signatures that distinguished PT according to functional and invasiveness subtypes. These results underpin the potential role of methylation profile and liquid biopsy as a noninvasive approach to assess clinically relevant molecular features in the serum of patients harboring PT.
P03.10 Analyzing the role of reoperation in high grade gliomas: a retrospective study
Authors: González V , Ibáñez J , Fuster J , Brell M 
Published: September 2019

Abstract

BACKGROUND
Primary treatment of high grade glioma consists in a standard therapeutic regimen that involves maximal surgical safe resection followed by chemoradiotherapy. Unfortunately, due to its aggressive behavior, relapse is the rule in all patients. When this situation arises, treatment strategy is less clear and reintervention in selected cases is controversial and still a reason for debate.

MATERIAL AND METHODS
We retrospectively analysed (n=393) patients affected with high grade glioma in our institution during a period of 14 years (from January 2005 to March 2019). Treatment modality at diagnosis and recurrence, overall and progression-free survival were reviewed.

RESULTS
There were 320 grade IV and 73 grade III gliomas. Regarding to the modality of treatment, more procedures with radical intention (n=227) than biopsies (n=166) were performed. At progression, glioblastoma patients were treated in (n=118) cases. We decided to reoperate (n=30) cases who also received second-line chemotherapies.The other group (n=88) received only systemic treatment. Median overall survival assessed from initial diagnosis was 23 months(95% CI 17–28.9) versus 17 months (95% CI 15.7–18.2) in patients with surgery at recurrence comparing to those who did not undergo second surgery, (p< 0.05). In addition, clinical condition of most patients did not worsen after the second surgery.

CONCLUSION
Second surgery for recurrent glioblastoma was associated with a survival advantage. Reoperation should be considered in patients with tumours located in low eloquence areas and good clinical condition.
P04.10 IDH-wildtype low grade gliomas: overall survival and prognostic indicators
Authors: Berzero G , Di Stefano A , Ronchi S , Villa C , Marie Y , Hoang-Xuan K , Delattre J , Mokhtari K , Sanson M 
Published: September 2019

Abstract

BACKGROUND
IDH-wildtype WHO grade II diffuse gliomas represent a rare subgroup of low grade tumors characterized by poor prognosis. The clinical and molecular profile associated with these tumors has not been fully elucidated yet, and the ongoing uncertainties regarding their biological behavior hamper to establish a standard of treatment. The aim of this study is to define the median overall survival and the main prognostic factors associated with this rare tumor entity.

MATERIALS AND METHODS
We performed a retrospective research in our center for all patients diagnosed with diffuse WHO grade II and III gliomas from 1976 to 2018. WHO grade II and III gliomas were divided into three molecular subgroups according to the IDH1/2 mutation and the 1p/19q codeletion status (1: IDH-mutant, 1p/19q codeleted; 2: IDH-mutant, 1p/19q non codeleted; 3: IDH-wildtype). We analyzed the clinical and molecular characteristics of the three subgroups, and then the clinical, radiological, histological and molecular features of IDH-wildtype WHO grade II gliomas.

RESULTS
We identified 445 patients with diffuse WHO grade II gliomas, including 59 IDH1/2-wildtype tumors. IDH-wildtype grade II gliomas affected more frequently male (75% vs. 55%, p = 0.004) and older (mean age: 50.0 vs. 39.6 years, p<0.0001) patients, had frequent fronto-temporo-insular location (41%) and commonly underwent biopsy (53%) rather than resection. We found TERT promoter mutations (18/42, 43%), chromosome 7q gains (12/30, 40%), chromosome 10q losses (12/44, 27%), chromosome 9p losses (7/47, 15%), EGFR amplifications (5/51, 10%) and p16 deletions (4/50, 8%) but no P53 (0/16) mutations. Median overall survival was 46 months (vs. 98 for IDH-mutant non codeleted and 175 for IDH-mutant codeleted WHO grade II gliomas (p<0.0001); vs. 20 months for IDH-wildtype WHO grade III gliomas (p = 0.001)). Survival was not significantly influenced by age, preoperative KPS, tumor location, extent of resection or adjuvant treatment schemes. Chromosome 9p loss had a strong negative impact on overall survival (p=0.002).

CONCLUSION
The median overall survival associated with IDH-wildtype WHO grade II gliomas does not exceed 4 years from diagnosis. As some genetic alterations seem to have a strong prognostic impact, an exhaustive genetic assessment can be helpful in this rare tumor group for purposes of prognostic stratification and treatment decision.
P04.12 Characteristics of IDH-mutant gliomas with non-canonical IDH mutations
Authors: Poetsch L , Dehais C , Frénel J , Siegfried A , Lacomme S , Seizeur R , Larrieu-Ciron D , Cappellen D , Loussouarn D , Ferec C , Eimer S , Carpentier C , Sanson M , Delattre J , Figarella-Branger D , Ducray F ,   POLA network, Bronnimann C 
Published: September 2019

Abstract

BACKGROUND
About 10% of IDH-mutant gliomas harbor non-canonical IDH mutations (non-R132H IDH1 and IDH2 mutations). The aim of the present study was to analyze the characteristics of these gliomas in comparison to those of IDH1 R132H mutant gliomas.

MATERIAL AND METHODS
We retrospectively analyzed the characteristics of a multicentric series of 161 gliomas with non-canonical IDH mutations and compared them to those of consecutive series of 109 IDH1 R132H mutant gliomas. Medical, radiological and pathological were reviewed.

RESULTS
Median age at diagnosis was 35 years in gliomas with a non-canonical IDH1 mutation, 42 years in those with an IDH2 mutation and 44 years in those with an IDH1R132H mutation. A familial history of cancer was more frequent in gliomas with a non-canonical IDH mutation than in those with an IDH1 R132H mutation (22,3% vs 5,5%, p<0.05). In both IDH1 R132H-mutant and non-canonical IDH-mutant gliomas the most frequent location was the frontal lobe. Yet, compared to IDH1R132H-mutant gliomas those with a non-canonical IDH mutation had more frequently an infratentorial location (5,5% vs 0% p<0,05) and were more frequently multicentric (4,9%, versus 0.9%, p<0.05). Compared to IDH1R132H-mutant gliomas, gliomas with a non-canonical IDH1 mutation were more frequently astrocytomas (65.7% vs 45%, p<0.05) while those with an IDH2 mutation were more frequently oligodendrogliomas (82% vs 55%, p<0.05). The median overall survival in IDH1 R132H-mutant and non-canonical IDH-mutant gliomas was similar (122 versus 120 months).

CONCLUSION
Gliomas with non-canonical IDH mutations are associated with distinct clinical, radiological and histological characteristics. Their prognosis, however, is similar to that of gliomas with canonical IDH mutations.
P04.18 Management of diffuse gliomas using hypnosis-aided awake surgery: oncological and functional preliminary results in a series of 16 cases
Authors: Picart T , Pardey Bracho G , Ameli R , Berner L , Thomas L , Cartalat S , Honnorat J , Ducray F , Guyotat J 
Published: September 2019

Abstract

BACKGROUND
Awake resection of diffuse gliomas aims to find a tailored onco-functional balance for each patient. Hypnosis represents an innovative technique able to optimize the comfort and well-being of the patient during such procedures. The aim of the present study is to analyse the oncological and functional outcome in a cohort of patients operated on with hypnosis-aided awake surgery.

MATERIAL AND METHODS
All consecutive adult patients that underwent hypnosis-aided resection for a diffuse glioma between January 2018 and January 2019 were recorded. Neurological and cognitive status were assessed preoperatively and at 3 months postoperatively. Extent of tumor resection was quantified by a radiologist on magnetic resonance imaging.

RESULTS
Sixteen patients (6 males and 10 females), with a mean age of 39 years, were included. Gliomas were revealed by epileptic seizures (62.5%), motor deficit (6.25%) or incidentally discovered (31.25%) and were either located in the right hemisphere (50%) or in the left hemisphere (50%), with a mean initial volume of 42 mL. Histologically, there were six grade II-astrocytomas, three grade III-astrocytomas, five grade II-oligodendroglioma, one grade III-oligodendroglioma and one ganglioglioma. Under HAS, the awake-time after the anaesthesia drugs stop was short, because low doses of drugs were required thanks to the hypnotic state. All patients were able to reliably performed the different tests until functional subcortical limits were reached. Postoperative magnetic resonance imaging showed complete resection in 8 cases (50%), subtotal resection in 2 cases (12.5%) and partial resection in 6 cases (37.5%), with a mean resection rate of 84.6%. At 3 months after surgery, there was only a new motor deficit (6.25%). The language and neuropsychological assessments were improved in 7 patients (43.75%), stable in 7 patients (43.75%) and deteriorated in some tests in 2 patients (12.5%). After surgery, no patient reported negative emotion concerning the awake glioma resection and all patient declared being ready for a second awake resection in the future, if indicated.

CONCLUSION
According to these preliminary results, hypnosis-aided awake resection of diffuse gliomas appears to be safe and effective from an onco-functional viewpoint and parallelly contributes to decrease intra-operative pain, anxiety and major discomfort.