bluuebunny/crossref_metadata_2025 huggingface dataset:
OS4.2 Phase 0 trial of Ceritinib in brain metastasis and recurrent glioblastoma
Authors: Fiorelli R , Li J , Bao X , DeRogatis A , Pennington-Krygier C , Kim S , Mehta S , Sanai N
Published: September 2019

BACKGROUND

Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical data suggest that ceritinib has activity in central nervous system (CNS) malignancies, but to date there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in recurrent glioblastoma and brain metastasis patients.

MATERIALS AND METHODS

Three brain metastasis and seven glioblastoma patients with high expression of pSTAT5b/pFAK/pIGFR1 were enrolled and treated with oral ceritinib daily (750 mg) for 10 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ~ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues.

RESULTS

Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one patient with brain metastasis, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor concentration and CSF concentration as compared to those in glioblastoma patients. In all patients, no changes in PD markers were detected.

CONCLUSION

Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations achieved in brain metastasis and glioblastoma are unlikely sufficient for target modulation.
OS5.5 Characteristics of high-grade gliomas with H3 G34 mutation in adults
Authors: Picart T , Barritault M , Tabouret E , Idbaih A , Izquierdo Gracia C , Poncet D , Honnorat J , Meyronet D , Guyotat J , Ducray F
Published: September 2019

BACKGROUND

H3 G34-mutant high-grade gliomas occur primarily in children but can also be encountered in adults. The aim of the present study was to describe the characteristics of H3 G34-mutant high-grade gliomas in adults.

MATERIAL AND METHODS

We analysed the characteristics of 17 adult H3 G34-mutant high-grade gliomas and compared them with those of adult grade IV gliomas with H3 K27M mutation (n=21), IDH mutation (n=42) and TERT promoter (pTERT) mutation (n=88).

RESULTS

Median age at diagnosis in H3 G34-mutant gliomas was 25 years (range: 19–33 y). All tumors had a hemispheric location. The radiological presentation was suggestive of a high-grade glioma in 6 patients but in 10 patients it initially suggested another diagnosis due to absent or faint contrast enhancement (n=9) or the presence of an initial intratumoral haemorrhage (n=1). In non- or faint contrast-enhancing cases, diffusion-weighted imaging (DWI) was more helpful to suspect an aggressive tumor than MR spectroscopy and perfusion MRI. All H3 G34-mutant gliomas were classified as IDH wildtype glioblastomas. PNET-like foci were observed in 8 cases and most cases were immunonegative for ATRX (92%) and Olig2 (81%) and demonstrated MGMT promoter methylation (82%). The clinical, radiological and histological presentation of H3 G34-mutant gliomas was different from that of midline H3 K27M-mutant diffuse gliomas and from that of IDH-mutant and IDH-wildtype pTERT-mutant glioblastomas. Median overall survival of G34-mutant gliomas was 23.9 months compared to 19.6 months (p=0.16), 13.7 months (p=0.45) and 58 months (p=2.3x10-10) in H3 K27M-mutant diffuse gliomas, IDHwt pTERT-mutant and IDH-mutant glioblastomas, respectively.

CONCLUSION

Adults H3 G34-mutant high-grade gliomas are associated with distinct characteristics and a poor prognosis. DWI seems helpful to identify cases that present as non-contrast enhancing lesions and can wrongly suggest another diagnosis in these young patients.
OS6.4 The hypoxia-induced glioma derived exosome miRNA-199a-3p promotes glioma cells proliferation and increased ischemic injury of the para-tumor neurons by inhibiting mTOR pathway— A pivotal ischemic mechanism in the proliferation and growth of glioma
Authors: Zhao J , Hu J , Xie R
Published: September 2019

BACKGROUND

Growth of glioma cells can be promoted by hypoxia, but its underlying molecular mechanisms are not clear. Exosomes and miRNAs were reported to play crucial roles in tumor progression. Effects of exosomes and exosomal miRNAs, induced by hypoxia, on glioma cells were still unclear.

MATERIAL AND METHODS

Glioma samples were analyzed by HE and HIF-1α staining. Image data of these patients were also retrospectively analyzed. HT22 and C6 cell lines were co-cultured in both direct and indirect system. Hypoxia (1% oxygen) and oxygen and glucose deprivation (OGD) were applied to evaluate hypoxia effects on the growth and proliferation of cell lines, and such effects were assessed by C6/HT22 ratio, MTT and LDH assay. Hypoxia-induced glioma derived exosomes (HIGDE) and non-HIGDE (NHIGDE) were isolated and were administrated to normal culture medium to evaluate their effects on cell growing. The target miRNA was selected by performing miRNA microarray analysis. MicroRNA mimics and shRNA were constructed to overexpress or inhibit the microRNA expression. MTOR signal pathway was activated by utilizing phosphatidic acid. The RNAs expression were detected by RT-qPCR and the proteins expression was evaluated by western blotting.

RESULTS

Para-tumor hypoxia area shared a same region with cytotoxic edema around the glioma lesion and can be easily detected by PET/CT. The density of positive HIF-1αstaining was higher in tumor area than that in para-tumor and normal parenchyma area. In hypoxia direct co-culture system, the cell number ratio of C6/HT22 was significantly higher than that without hypoxia pretreatment; while in hypoxia mono-culture and indirect co-culture systems, the proliferation ability of HT22 was statistical lower than C6. After applying OGD, neuron cells cultured with HIGDE showed a statistical higher LDH release level than with NHIGDE or normal culture medium. The miRNA microarray analysis revealed that miRNA-199a-3p was the highest expressed in HIGDE than in NHIGDE (p < 0.05; Fold Change > 2). Transfected with mimics or shRNA, it was indicated that upregulation of miR-199a-3p aggravated HIGDE-induced OGD injury in HT22 cells. Moreover, we interfered mTOR signal pathway and the expression of HIF-1αin C6 cells. We found that miRNA-199a-3p aggravated HIGDE-neuron cell injury via suppressing mTOR signal pathway, and hypoxia related upregulation of miRNA-199a-3p in HIGDE was induced by the activation of HIF-1α in C6 cells.

CONCLUSION

The Hypoxia-Induced Glioma Derived Exosome miRNA-199a-3p can be upregulated by the activation of HIF-1α, and is able to promote glioma cells proliferation and increase ischemic injury of the para-tumor neurons via inhibiting mTOR pathway.
OS7.4 Calculating the net clinical benefit in brain tumor clinical trials by combining survival and health-related quality of life data using two methods: quality adjusted survival effect sizes (QASES) and joint modelling (JM)
Authors: Coomans M , Dirven L , Bottomley A , van den Bent M , Sloan J , Stupp R , Weller M , Reijneveld J C , Taphoorn M , Aaronson N , Baumert B G , Brandes A A , Chinot O , Coens C , Gorlia T , Herrlinger U , Keime-Guibert F , Malmström A , Martinelli F , Talacchi A , Wick W
Published: September 2019

BACKGROUND

The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to inform glioma patients and facilitate shared decision making. We applied two methods (i.e. Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM)) that combine survival and health-related quality of life (HRQoL) data into one outcome, to gain insight in the net clinical benefit of a treatment strategy. In addition, we assessed if both methods result in similar interpretations.

MATERIAL AND METHODS

We calculated the net clinical benefit in one randomized controlled trial, EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone, as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. Next, the combined effect size can be determined by weighing the emphasis put on survival or HRQoL (e.g. survival more important). JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting.

RESULTS

288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (difference of 10.8 months). In contrast, the percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. The QASES corresponded to a reduction in the median OS difference from 10.8 months to 6.8 months when adjusted for the HRQoL scales/items, when given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL.

CONCLUSION

Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.
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

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

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

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

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

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

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

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

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

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.
P05.01 the efficacy of donepezil on cognitive function in postoperative brain tumor patients
Authors: Diansari Y , Harun Y , Marisdina S , Felistia Y
Published: September 2019

BACKGROUND

Cognitive impairment is frequently found in brain tumor patients. More than 90% of patients with brain tumor have at least one cognitive domain disturbance. Decline in cognitive function could happen before due to the tumor or after the treatment because of surgery, radiotherapy or chemotherapy. Until now there is no available standard treatment for patients with cognitive impairment due to brain tumor. Moreover, Donepezil is an acetylcholinesterase inhibitor known to be useful for improving cognitive function in patients with dementia. This clinical study aims to determine the cognitive effects of donepezil therapy in patients with brain tumors following surgery.

MATERIAL AND METHODS

This is a pilot study with total of 20 adult brain tumor patients were double blinded randomly assigned to receive a single daily dose (5mg for 12 weeks) of donepezil or placebo. The inclusion criteria were patients with primary brain tumor who had undergone surgery with cognitive impairment at the initial evaluation and age range 18 to 65 years old. Patients with previous cognitive problem, other diseases that can cause cognitive decline e.g. stroke and history of taking donepezil, memantine, methylphenidate, ginkgo biloba, and modafinil were excluded. A cognitive test using Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment Indonesia Version (MoCA-INA) assessing memory, attention, language, visuospatial, verbal fluency, and executive functions were administered before random assignment and at 4, 8 and 12 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated. Furthermore, side effects and adverse events were also recorded.

RESULTS

Of this mostly middle-age (30–60 years old), female, meningioma as primary brain tumor with frontal and temporal lobe are the most frequent locations. After 12 weeks of treatment, the composite scores did differ significantly between groups (MMSE P=0.027, MoCA-INA P=0.024). Furthermore, the significant differences favouring donepezil were observed for orientation and recall domains using MMSE with p value 0.017 and 0.006 respectively. Visuospatial (P=0.034) and delayed recall domains (P=0.004) were significant through MoCA-INA evaluation. In addition, Mean MMSE score for pre-donepezil administration was 14.60 ± 4.47 and after 3 months was 20.40 ± 4.24 (P=0.000). Mean MoCA-INA score for pre-donepezil administration was 9.30 ± 3.65 and after 3 months was 15.30 ± 4.24 (P=0.000). However, there was no differences in the placebo group (MMSE P= 0.066, MoCA-INA P=0.313).

CONCLUSION

Three months treatment with donepezil significantly improve the cognitive functions among post-operative brain tumor patients with no reported side effect. Moreover, further research is needed for longer duration of follow-up and possibility of increased doses.
P05.08 High-grade gliomas and immunotherapeutic early phase clinical trials: a single-center experience
Authors: Simonelli M , Persico P , Dipasquale A , Lorenzi E , Giordano L , Pessina F , Navarria P , Scorsetti M , Bello L , Santoro A
Published: September 2019

BACKGROUND

Patients with high-grade gliomas (HGGs) have historically been excluded from immunotherapeutic early-phase clinical trials (ieCTs) due to unavailability of serial bioptic sampling, the frequent need of corticosteroids, concerns regarding activity of immunotherapy in central nervous system, and rapid clinical deterioration.

MATERIAL AND METHODS

We retrospectively reviewed data of all recurrent HGG patients enrolled in ieCTs at Humanitas Cancer Center Phase I Unit between 2014 and 2019. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard treatments (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for sex, age, line of treatment, MGMT methylation status, and IDH mutational status, was selected for comparison. A series of clinical parameters with an established prognostic value for patients with solid tumors treated into ieCTs were correlated with survivals through an univariate analysis. These include: use of steroids, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, lactate dehydrogenase, albumin, total protein.

RESULTS

Five among the 23 ieCTs conducted at our Phase I Unit allowed inclusion of HGG patients. 25 patients were enrolled in the experimental cohort (EC): 22 (88%) glioblastoma, 3 (12%) anaplastic astrocytoma. Median age was 50 years (range 25–71); 16 patients (64%) were men, 9 (36%) women; 17 pts (68%) required steroid therapy, with a median baseline dexamethasone dose of 2 mg (range 1–6). The median number of prior systemic therapies was 1 (range 1–2). Twelve patients (48%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-ß, anti cereblon), 13 (52%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 40% (1 CR + 2 PR + 7 SD) and 37% (9 SD), in EC and CC, respectively. Four patients (16%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up of 14 months PFS-6 were 35% and 16% (p=0.075), in EC and CC respectively, while OS-6 was significantly improved in the EC (82% vs 44%, p=0.004). In our small series, none of clinical factors resulted prognostic.

CONCLUSION

Survival outcomes of ourHGG patients treated into ieCTs compared very favorably with a matched CC. Inclusion of HGGs patients into ieCTs should be strongly encouraged. Identification of clinical factors to select who may benefit from ieCTs still remains crucial.
P07.01 Functional role of N-Myc in SHH type TP53 mutated MB’s metabolism
Authors: Yokogami K
Published: September 2019

BACKGROUND

Medulloblastoma is classified in 4 subgroups. Prognosis and therapeutic option was different from each subgroups. Thus, we need subgroup-specific in vitro models for investigating new therapeutic targets. Little established medulloblastoma cell-lines, which have been subgrouped is available. Especially, commercially available SHH type TP53 mutated cell-line is only DAOY. We established new cell lines 505CSC / 507FBS from the patient with SHH type with TP53 mutated MB. This matched pair cell line showed high expression of N-MYC in serum free conditioned medium. To know the functional role of N-MYC in MB, we used 507CSC and DAOY.

MATERIAL AND METHODS

Using chemical inhibitor of N-Myc in 507CSC and DAOY, proliferation assay, mRNA expression and measurements of ex-vivo metabolic phenotype were performed.

RESULTS

N-MYC inhibition leads to cell death in both cell lines. N-MYC regulated glucose, glutamine and methionine metabolism. Especially the targets were PKM2, GLS2, MAT2A, DNMT1 and 3A.

CONCLUSION

N-MYC is a target of therapy in a patient with SHH type TP53 mutated medulloblastoma.
P08.04 Glioblastoma and Alzheimer pathology: lessons from a single case with practical implications and need for further research
Authors: Gállego Pérez-Larraya J , Esparragosa I , Puigdelloses M , Idoate M , Alonso M
Published: September 2019

BACKGROUND

Glioblastoma (GBM) and Alzheimer’s disease (AD) are frequent among the elderly: about 50% of all GBM patients are 65 years or older, and 5–10% of people above this age threshold suffer from AD.

MATERIAL AND METHODS

We describe the case of an elderly patient with newly diagnosed GBM who developed a rapidly progressive severe dementia immediately following concomitant radio-chemotherapy. A purposed retrospective analysis of the surgical sample revealed Alzheimer pathology.

RESULTS

A 69-year old woman with no relevant past-medical history was diagnosed with a right temporo-parietal GBM on May 2017, with wild-type IDH1R132H gene and methylated MGMTP. After complete resection she received radiotherapy (60 Gy in 30 fractions) and concomitant chemotherapy with Temozolomide 75 mg/m2/day. During the last weeks of concomitant radio-chemotherapy and further on the patient developed a progressive neurological worsening with severe cognitive dysfunction, gait impairment and sphincter incontinence, becoming severely disabled and requiring continuous assistance. Brain MRI exams showed no signs of tumor recurrence, with focal white matter changes consisting on T2/FLAIR hyperintensities within the radiation field, enlarged sulci and ventriculomegaly. Underlying infectious and metabolic disorders, non-convulsive epileptic status and normal-pressure hydrocephalus were ruled out. Facing this situation the patient relatives were purposely asked for previous cognitive symptoms, and described very mild complaints of short-term memory loss during the previous year. Aiming at investigating the possibility of an underlying AD, focused examination of the surgical sample revealed the presence of frequent neuritic plaques, a neuropathological hallmark of AD. The patient developed a severe dementia with akinetic mutism by September 2017. Without evidence of tumor recurrence despite lack of adjuvant chemotherapy, she died of aspiration pneumonia on January 2019.

CONCLUSION

A unique retrospective study including elderly GBM patients treated only with surgery revealed that Alzheimer disease pathology was present in 42% of them. This case illustrates the need for actively addressing the previous cognitive status of elderly patients with GBM. Histopathological assessment of Alzheimer pathology might also be considered in this specific population. In positive cases, particularly in those with methylated MGMTP, radiotherapy should be avoided and treatment alone with Temozolomide might be considered.
P11.08 Defining EGFR amplification status for clinical trial inclusion
Authors: French P , Eoli M , Sepulveda J , de Heer I , Kros J M , Walenkamp A , Frenel J , Franceschi E , Clement P , Weller M , Ansell P , Looman J , Bain E , Morfouace M , Gorlia T , van den Bent M
Published: September 2019

BACKGROUND

Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no golden standard in determining the amplification status of EGFR or EGFRvIII expression. Here, we aimed to determine which technique and which cut-offs are suitable to determine EGFR amplification status.

MATERIAL AND METHODS

We compared fluorescent in-situ hybridization (FISH) and RT-qPCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA).

RESULTS

By using data from >1000 samples, we show which cut-offs are optimal to determine EGFR gene amplification by FISH. Our data also show that gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with ROC analysis showing an under the curve area of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data shows that EGFR copy numbers can strongly vary between tumors with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII.

CONCLUSION

Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help defining the optimal cut-off for various techniques to determine EGFR amplification for diagnostic purposes.
P11.09 Pan-RTK inhibition of sLRIG1 mediates AXL downregulation in Glioblastoma
Authors: Neirinckx V , Hau A , Schuster A , Fritah S , Chevigné A , Schmidt M H H , Niclou S P
Published: September 2019

INTRODUCTION

Aberrant regulation of receptor tyrosine kinase (RTK) activity is characteristic of Glioblastoma (GBM). However, RTK-based targeted therapies have been largely unsuccessful in GBM patients, partially due to the complexity and redundance of RTK signaling. LRIG1 (Leucine-rich Repeats and ImmunoGlobulindomains protein 1) is known as an endogenous inhibitor of epidermal growth factor receptor (EGFR) during health and disease, however its mechanism of action is poorly understood. We previously showed that the soluble form of LRIG1 potently inhibits of GBM growth in vivo, irrespective of EGFR expression level and status, suggesting the involvement of other RTKs. Here, we aimed to shed light on the molecular mechanisms underlying its anti-cancer activity.

MATERIAL AND METHODS

We generated a recombinant human soluble LRIG1 protein by expressing LRIG1 ectodomain in insect cells via baculovirus infection and subsequent His-tag purification. rh-sLRIG1 was applied in the medium of classical GBM cell lines, patient-derived GBM stem-like cells and patient-derived 3D tumor organoids. Using different cell-based assays, cell proliferation, invasion, cell morphology, as well as protein expression and protein-protein interactions were investigated.

RESULTS

We find that recombinant sLRIG1 efficiently reduces proliferation, invasion and viability of GBM cells and patient-derived organoids, and modulates cytoskeleton proteins and cell shape. In line with previous data, the effect of recombinant sLRIG1 is independent of EGFR expression. Interestingly sLRIG1 regulates several RTKs by direct protein downregulation, including AXL, while EGFR expression is not affected. At the molecular level, we find that sLRIG1 interferes with AXL dimerization, while no protein interaction with EGFR is detected.

CONCLUSION

We identify AXL as a novel LRIG1 target and provide evidence that sLRIG1-mediated RTK downregulation requires direct protein-protein interaction. These data pave the way for a potential therapeutic application of recombinant sLRIG1 in the inhibition of growth factor signaling in GBM.
P11.12 Periostin is expressed by pericytes and is crucial for angiogenesis in glioma
Authors: Huizer K , Kros J M , Zhu C , Chirifi I , Krist B , Cheng C , Mustafa D
Published: September 2019

BACKGROUND

The expression of the matricellular protein periostin has recently been associated with glioma progression and angiogenesis. The aim of the present study was to identify the cellular source of periostin expression in human gliomas and to study the role of periostin in an in vitro model for angiogenesis.

MATERIAL AND METHODS

The expression of periostin in various types and grades of brain tumors was investigated at the genetics level by RT-PCR and at the protein level by immunohistochemistry. In addition, the expression of periostin in glioma samples was studied by double labeling and in situ RNA techniques. Subsequently, by silencing periostin in a 3D in vitro angiogenesis model, its effects on angiogenesis were studied.

RESULTS

Periostin RNA and protein expression was found to be elevated in pilocytic astrocytoma and glioblastoma, but not in grade II/III astrocytomas. The expression of periostin co-localized with PDGFRβ + cells, but not with Olig2+ / Sox2+ glioma stem cells. Silencing of periostin in pericytes resulted in the attenuation of the number and the length of the vessels, and in decrease in the number of vessel junctions formed.

CONCLUSION

The results prove that pericytes are the main source of periostin in human gliomas. We demonstrate that periostin plays an essential role in the growth and branching of blood vessels. Therefore, periostin and / or its molecular interactions should be explored as a novel target for developing a new anti-angiogenic therapy for glioma.