bluuebunny/crossref_metadata_2025 huggingface dataset:
PL1.2 Multiparametric assessment of factors influencing 2 HG accumulation in diffuse brain gliomas
Authors: Nichelli L , Branzoli F , Valabregue R , Capelle L , Ottolenghi C , Bielle F , Lerond J , Giry M , Villa C , Galanaud D , Lehéricy S , Marjańska M , Sanson M , Di Stefano A
Published: September 2019

BACKGROUND

2-hydroxyglutarate (2HG) can be detected non-invasively in IDH-mutant gliomas by in vivo magnetic resonance spectroscopy (MRS). We investigated factors affecting 2 HG accumulation and explored the prognostic value of 2 HG detection in IDH mutant gliomas and 2 HG variations during anti-cancer therapies.

MATERIAL AND METHODS

We prospectively scanned by MEGA-PRESS 70 glioma patients (24 before surgery and 46 IDH mutant operated glioma) and measured 2HG. CRLB cut-off was 50%. We followed up 9 IDH mutant patients during radiotherapy and chemotherapy.We analyzed radiological parameters (tumor and cystic/necrotic volumes, fractions of VOI filled with tumor, spectroscopic profile, “infiltrative” versus “expansive” morphology, contrast-enhancement) and genetic profile (IDH1, IDH2, 1p19q codeletion). 2HG concentrations in plasma, urine, and surgical obtained samples were measured by gas chromatography-mass spectrometry (GC-MS).

RESULTS

MEGA-PRESS sequence detected 2HG with a sensitivity of 95% in untreated patients, and of 69% in pre-treated patient. Positive predictive value was 100% in both groups. 2HG was lower in pre-treated IDH mutant gliomas (1.1 versus 2.3 mM, P=0.02) and decreased rapidly during radiotherapy and chemotherapy before any radiological change. 2HG detection was positively correlated with tumor volume (P=0.02), choline measurements (r=0.58 P<0.0001), cellular density (measured by restricted diffusivity, Pearson r -0.40 P=0.01), “expansive” presentation, mutated reads/total reads ratio by NGS and was inversely correlated with Myo-inositol (Pearson R -0.29 P=0.03) and cystic/necrotic areas (P=0.04). 2HG by MRS positively correlated with urine 2HG (r=0.80 P=0.003). 2 HG was higher in IDH2 mutant (4.7 versus 2.4 Mm, P=0.02) and lower in non R132H IDH1 mutant (1.12 mM P=0.004). Among IDH mutant glioma patients, 2 HG detection was associated with longer survival (HR 0.09; 95%CI 0.018–0.52).

CONCLUSION

Tumor volume, cellular density, previous radio- and chemotherapy and genetic features determine 2 HG detection in IDH mutant gliomas. 2 HG detection is associated with better outcome and can be reliably monitored during anti-cancer treatments.
OS1.5 Detection of glioma and prognostic subtypes by non-invasive circulating cell-free DNA methylation markers
Authors: Noushmehr H , Sabedot T , Malta T , Nelson K , Snyder J , Wells M , deCarvalho A , Mukherjee A , Chitale D , Mosella M , Asmaro K , Robin A , Rosenblum M , Mikkelsen T , Rock J , Poisson L , Walbert T , Kalkanis S , Castro A
Published: September 2019

BACKGROUND: Genome-wide DNA methylation profiling has shown that epigenetic abnormalities are biologically important in glioma and can be used to classify these tumors into distinct prognostic groups. Thus far, DNA profiling has required surgically resected glioma tissue; however, gliomas release tumoral material into biofluids providing an opportunity for a minimally invasive testing. While prior studies have shown that molecular markers can be detected in liquid biopsy (LB), there has been low sensitivity for tumor-specific markers. We hypothesize that the low sensitivity is due to the targeted assay methods. METHODS: Genome-wide CpG methylation levels in DNA of tumor tissue and cell-free DNA serum of glioma patients. RESULTS: We defined glioma-specific and IDH-specific epigenetic LB (eLB) signatures (Glioma-eLB and IDH-eLB, respectively) from serum cell-free DNA from patients diagnosed with glioma (N=15 IDH mutant and N=7 IDH wildtype) and with epilepsy (N=3). The epigenetic profiles of the matched tissue demonstrate that these eLB signatures reflected the signature of the tumor. Through cross-validation we show that Glioma-eLB can accurately predict a patient’s glioma from those with other neoplasias (N=6 Colon; N=14 Pituitary; N=3 Breast; N=4 Lung), non-neoplastic immunological conditions (N=22 sepsis; N=9 pancreatic islet transplantation), and from healthy individuals (sensitivity: 98%; specificity: 99%). Finally, IDH-eLB includes promoter methylated markers associated with genes known to be involved in glioma tumorigenesis (PVT1 and CXCR6). CONCLUSIONS: The application of the non-invasive eLB signature discovered in this study has the potential to complement the standard of care for patients harboring glioma.

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)
OS2.1 Incidence patterns for primary spinal cord ependymomas in adults: a Surveillance, Epidemiology, and End Results study
Authors: Man W , Wang G
Published: September 2019

BACKGROUND

Ependymomas are the most common primary spinal cord tumors in adults. However, few population-based studies analyzed the epidemiological features for this tumor type. We explored Surveillance, Epidemiology, and End Results (SEER) database to evaluate the incidence patterns over time with regard to patient gender, race, age at diagnosis, and histological subtype for patients diagnosed with primary malignant spinal cord gliomas between 1973 and 2015.

METHODS

We queried SEER database to identify all adult patients (≥ 20 years of age) diagnosed with primary spinal cord ependymomas during 1973–2015. Variables of interest included gender, race, age at diagnosis, and histological subtype of tumor. The SEER*Stat 8.3.5 program was used to calculate frequencies, age-adjusted incidence rates (IR) with adjustment to the 2000 US Standard population and 95% confidence intervals (CI). An annual percentage change (APC) statistic with a 2-sided p-values was used to assess incidence patterns over time.

RESULTS

1224 adult patients with primary spinal cord ependymomas were diagnosed between 1973 and 2015. Of the total population, 55.7% were males (n = 682) and 44.3% were females (n=542). Myxopapillary ependymomas (ICD-O-3 code 9394), papillary ependymomas (9393), ependymomas (9391) and anaplastic ependymomas (9392) accounts for 28.7% (n = 351), 0.5% (n = 6), 69.4% (n = 849) and 1.5% (n = 18) respectively. The overall age-adjusted IR for all adult primary spinal cord ependymomas was 0.16 per 100,000 (95%CI 0.15–0.17). The IR in male was higher than that in female (males 0.19 per 100,000 [95% CI 0.17–0.20], females 0.14 per 100,000 [95% CI 0.13–0.14]. Caucasians experienced higher IR (0.18 per 100,000 [95% CI 0.17–0.19]) compared to African Americans (0.19 per 100,000 [95% CI 0.07–0.12]) and the others (0.10 per 100,000 [95% CI 0.08–0.13]). Patients of age between 40 and 49 years experienced the highest IR (0.25 per 100,000 [95% CI 0.22–0.29]) than patients in the other age ranges. The most common histological subtypes were ependymomas (0.11 per 100,000 [95% CI 0.11–0.12]) and myxopapillary ependymomas (0.047 per 100,000 [95% CI 0.042–0.052]. The overall age-adjusted IR for all adult primary spinal cord ependymomas showed a statistically significant increase over time between 1973 and 2015 (APC=5.15, p<0.01). The same increasing trend was found in Caucasians (APC=5.36, p<0.01) and in both males (APC=5.13, p<0.01) and females (APC=4.95, p<0.01).

CONCLUSION

This study demonstrates an increasing IR of adult primary spinal cord ependymomas over the past four decades. Males, Caucasians and age between 40 and 49 years experienced a higher IR.
OS3.4 Karnofsky and WHO performance scores of brain tumour patients may limit inclusion in protocols though they depend on clinician status
Authors: Frappaz D , Taillandier L , Bonneville Levard A , Sorre J , Ricard D , Carrie S , Schiffler C , Weller M
Published: September 2019

BACKGROUND

Inclusion criteria for oncological protocols often use the Karnofsky performance score (KPS) >=70 or the WHO performance score (PS) 0–2 as a cut-off value. Inclusion of neuro-oncology patients may be hampered, when general condition is preserved, while performance is decreased due to physical handicap. The goal of this study is to compare the KPS and PS assessments according to the status of the clinician.

MATERIAL AND METHODS

A cross-sectional survey was conducted through ANOCEF and EANO networks. Clinicians evaluated KPS and PS in 6 clinical situations concerning neuro oncology patients (from youngest and fittest to oldest, crippled with comorbidities).

RESULTS

The rate of PS <70 or PS> 2 increased significantly from case 1 to 6.

Sex or nationality of the clinicians had no impact when adjusting on clinician characteristics. Conversely, speciality (residents/general practitioner vs neurosurgeons vs neurologists vs oncologists), impacted KPS or PS evaluations (p<.0001 and p=0.0046, respectively). Residents or general practitioner estimate KPS much lower than the others specialities. Neurosurgeons estimate PS more severely. Clinicians who were not used to including patients in clinical trials proposed lower KPS scores (p = 0.0008). This tendancy was not shown on PS. Eldest physicians significantly rated more severely than the youngest (p = 0.0459 and p <.0001 for KPS and PS, respectively).

In a multivariate analysis, age and speciality were correlated with KPS and PS rating even if adjusted on cases.

Discordant decision for protocol inclusion (i:e: (KPS) >=70 vs PS 0–2) showed little discrepancy in case 1 (2.3%), while discrepancy increased to respectively 16, 46, 39, 33 and 43% for cases 2 to 6: in nearly all cases, the KPS would have denied access to a trial, while WHO Ps would have allowed

CONCLUSION

Rating of KP and PS is subjective in neuro oncology patients: influenced by speciality, age and inclusion habit (for KPS) of clinicians, PS 0–2 allows usually more inclusion than KPS>=70 in more severely disabled patients. A Neuro oncology specific KPS and/or PS definition is warranted to allow more widely inclusion of patients with exclusive neurologic handicap.
OS4.3 Feasibility and benefit of Molecular Profiling to Guide Enrollment of Patients with Recurrent Gliomas in Early Phase Trials
Authors: Baldini C , Younan N , Castanon Alvarez E , Bahleda R , Hollebecque A , Dhermain F , Ammari S , Alentorn A , Dumont S , Frenel J , Di Stefano A , Bielle F , Hoang-Xuan K , Delattre J , Soria J , Sanson M , Idbaih A , Massard C , Touat M
Published: September 2019

BACKGROUND

Participation of glioma patients in early phase clinical trials has recently shown to be safe, although clinical benefits reported in this population were marginal. We aimed to evaluate whether an enrichment strategy based on molecular profiling associates with improved outcome in gliomas patients participating in early phase trials.

MATERIAL AND METHODS

Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2017 were analyzed for clinicopathological characteristics, toxicity, response, median progression-free survival (PFS) and overall survival (OS). The primary objective was to evaluate the feasibility and benefit of using molecular profiling to guide enrollment.

RESULTS

Ninety-one patients were enrolled, of whom 47/91 (51.6%) were molecularly oriented. Molecular targets included IDH1/2 (n=15) and BRAF (11) mutations, FGFR1-3 fusions (n= 10) and mutations (n = 4), mismatch repair deficiency (8), and MDM2 amplification (1). Grade 3/4 adverse events were reported in 9/91 (9.9%) patients. In patients with IDH1/2-wild-type high-grade glioma (n=45), the overall response rate (24.0% [95% CI 11.5–43.4] vs 0.0% [95% CI 0.0–16.1], P=0.027) was significantly higher in molecularly-oriented vs non-molecularly-oriented patients. Updated outcome results, and clinical and molecular factors associated with response, PFS and OS in multivariate analyses will be presented at the conference.

CONCLUSION

Using molecular profiling to guide enrollment in early phase trials is feasible and offers potential benefit to gliomas patients. Further studies are warranted to identify the population most likely to benefit from this approach.
OS6.3 The complex role of lactate dehydrogenases in glioblastoma development
Authors: Daubon T , Guyon J , Chouleur T , Espedal H , Leon C , Bjerkvig R , Bikfalvi A
Published: September 2019

BACKGROUND

Glioblastomas are among the most malignant primary brain tumors. GBMs are highly angiogenic, exhibit invasive growth, and elevated glycolysis. Under glycolytic conditions, glucose from the blood is metabolized in astrocytes into lactate by LDHA, and exported by MCT4 into the extracellular compartment, inducing a concomitant acidification of the microenvironment. LDHB, generally expressed in oligodendrocytes or neurons, metabolizes lactate into pyruvate for generating ATP in mitochondria. LDH expression was reported to be linked to phenotypic modifications in vitro in GBMs but the mechanisms and the precise role in vivo have not yet been investigated.

MATERIAL AND METHODS

We designed LDHA and LDHB Crispr-Cas9 constructs for infecting glioblastoma stem-like cells. Results: In vitro tumor cell invasion was not significantly impaired in sgLDHA glioblastoma cells, even under extreme hypoxic conditions. Tumor development was moderately impacted in terms of invasion or vascular density. We then explored the role of LDHB in these processes. LDHB knock-out cells had decreased invasive properties in vitro but surprisingly tumors were highly hemorrhagic and angiogenic, supporting a role of tumor-derived LDHB in blood vessel development. We furthermore evaluated the consequences of a double LDHA and LDHB knock-out in the glioma cells. Under hypoxic conditions, sgLDHA/B cell invasion was dramatically decreased in comparison to control cells, and apoptosis was also increased. Tumor development was dramatically impaired for LDHA/LDHB knockout tumors.

CONCLUSION

These results indicate the complex role of LDH enzymes in glioblastoma development. It constitutes the basis for further mechanistical studies linking lactate metabolism to brain tumor development and perturbation of the neuro-vascular microenvironment.
OS7.1 Impact of the addition of Rituximab to standard therapy with high dose methotrexate on health-related quality of life in primary central nervous system lymphoma patients
Authors: van der Meulen M , Dirven L , Bakunina K , Taphoorn M J B , van den Bent M J , Issa S , Doorduijn J K , Bromberg J E C
Published: September 2019

BACKGROUND

Data on the impact of treatment with Rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma (PCNSL) patients are scarce. To determine the net clinical benefit of a new treatment, analyzing the effect on HRQoL is warranted.

MATERIAL AND METHODS

Patients from a phase III trial (HOVON 105/ ALLG NHL 24), randomized to standard chemotherapy with or without Rituximab, were asked to fill in the EORTC QLQ-C30 and QLQ-BN20 questionnaires before and during treatment, and up to 2 years follow-up or progression. Five predetermined scales were selected for primary analyses: global health status (GH), role (RF) and social functioning (SF), fatigue (FA), and motor dysfunction (MD). A difference ≥10 points was defined as clinically relevant. Cross-sectional analyses were performed comparing changes in HRQoL scores from baseline between the two arms at 12 and 24 months after treatment. Effect of whole brain radiotherapy (WBRT) was analyzed in irradiated patients only. Differences in HRQoL over time between the treatment arms, i.e. the primary outcome, were assessed using linear mixed models (LMM).

RESULTS

175/199 patients completed at least one HRQoL questionnaire, and compliance was >60% at all evaluation points. Median age was 61 (IQR 55–66), 74% had a WHO performance score <2, and 38% received WBRT, similar to the total trial population. HRQoL scores on all five scales were significantly and to a clinically relevant extent improved at 12 and 24 months follow-up when compared to baseline in both arms (range: 11.6–42.4), except for FA and MD at 12 months (both -7.2). Differences in HRQoL changes from baseline to 12 and 24 months between the two arms were not statistically significant (range: 3.6–10.9). In the irradiated patients (n=52), HRQoL scores remained stable up to 24 months compared to shortly after WBRT for GH, SF, FA and MD (range -8.1 - 7.6). A clinically relevant and statically significant improvement was seen in RF for both arms at 12 and 24 months compared to ‘after WBRT’(range: +16.7 - +22.2). After correction for multiple testing, LMM analyses showed no statistically significant and clinically relevant differences between the arms for any of the scales over time (range: -3.8 to +4.0).

CONCLUSION

Treatment resulted in improved HRQoL, but the addition of Rituximab to standard chemotherapy did not further impact HRQoL over time. WBRT did not result in deterioration of HRQoL up to 2 years of follow-up.
OS7.2 Measuring change in health-related quality of life: the added value of analysis on the individual patient level in glioma patients in clinical decision making
Authors: Coomans M , Taphoorn M J B , Aaronson N , Baumert B G , van den Bent M , Bottomley A , Brandes A A , Chinot O , Coens C , Gorlia T , Herrlinger U , Keime-Guibert F , Malmström A , Martinelli F , Stupp R , Talacchi A , Weller M , Wick W , Reijneveld J C , Dirven L
Published: September 2019

BACKGROUND

Health-related quality of life (HRQoL) is often used as an outcome in glioma research, reflecting the impact of disease and treatment on a patient’s functioning and wellbeing. Data on changes in HRQoL scores may provide important information for clinical decision-making, but different analytical methods may lead to different interpretations of the impact of treatment on HRQoL. This study aimed to examine three different methods to evaluate change in HRQoL, and to study whether these methods result in different interpretations.

MATERIAL AND METHODS

HRQoL and sociodemographical/clinical data from 15 randomized clinical trials were combined. Change in HRQoL scores was analyzed in three ways: (1) at the group level, comparing mean changes in scale/item scores between treatment arms over time, (2) at the patient level per scale/item by calculating the percentage of patients that deteriorated, improved or remained stable on a scale/item per scale/item, and (3) at the individual patient level combining all scales/items.

RESULTS

Baseline and first follow-up HRQoL data were available for 3727 patients. At the group scale/item level (method 1), only the item ‘hair loss’ showed a significant and clinically relevant change (i.e. ≥10 points) over time, whereas change scores on the other scales/items showed a statistically significant change only (all p<.001, range in change score: 0.1–6.2). Analyses on the patient level per scale (method 2) indicated that, while a large proportion of patients had stable HRQoL over time (range 27–84%), many patients deteriorated (range: 6–43%) or improved (range: 8–32%) on a specific scale/item. At the individual patient level (method 3), the majority of patients (86%) showed both deterioration and improvement, while only 1% of the patients remained stable on all scales. Clustering on clinical characteristics (WHO performance status, sex, tumor type, type of resection, newly diagnosed versus recurrent tumor and age) did not identify subgroups of patients with a specific pattern of change in their HRQoL score.

CONCLUSION

Different analytical methods of changes in HRQoL result in distinct interpretations of treatment effects, all of which may be relevant for clinical decision-making. Additional information about the joint impact of treatment on all outcomes, showing that most patients experience both deterioration and improvement, may help patients and physicians to make the best treatment decision.
OS8.7 Targeting Pi3k-Akt-mTOR and MAPKinase pathways in aggressive meningiomas: in vitro study
Authors: Mondielli G , Darriet F , Roche C , Lisbonis C , Querdray A , Figarella-Branger D , Dufour H , Barlier A , Graillon T
Published: September 2019

BACKGROUND

Recurrent and aggressive meningiomas remain an unmet medical need in neuro-oncology. In our preclinical model on meningioma primary cell culture, the combination of the mTOR inhibitor, everolimus and the somatostatin analog, octreotide decreased cell viability and proliferation without inducing apoptosis. The interest of the combined treatment everolimus plus octreotide were clinically validated by the CEVOREM clinical trial demonstrating a decrease in growth rate of meningiomas in most treated patients.

Nevertheless, everolimus induced an increase in Akt activity in vitro, which probably limited everolimus efficiency. We hypothesized that targeting Pi3K could prevent this positive feedback on Akt phosphorylation, induced by mTOR inhibition. The involvement of MAPKinase pathway in meningioma tumorigenesis was recently demonstrated. Our aim was to decipher the effect of the Pi3k α inhibitor Alpelisib (BYL719) and the specific inhibitor of MEK1,2 Mekinist (Trametinib) alone or in combination, in comparison to the mTor inhibitor everolimus on human meningioma primary cell cultures.

MATERIAL AND METHODS

The impact of the drugs was studied on 40 meningiomas, well characterized at clinical, histological and molecular level. The cell viability, cell proliferation and apoptosis were analyzed under drugs.

RESULTS

BYL719 induced a dose dependent decrease in cell viability (maximal effect -90%, IC50 10-6M) in all tested meningiomas (n=30). This effect was stronger than those of everolimus (maximal effect -50%, n=24, IC50 10-8M). 22 tumors were sensitive to Trametinib (maximal effect <-50%, IC50 10–5 M), 14 were partially sensitive (maximal effect between -20 and -40% IC50 10–5 M) and 3 were resistant. An apoptotic effect was observed under BYL719 in 6/18 tested tumors whereas no apoptosis was observed under Trametinib and Everolimus. Combination of BYL719 and Trametinib induced a significant stronger decrease in cell viability than each drug alone. Correlation analysis between these functional results, the tumor genomic profile and the activation of ERK/MEK kinase pathway is ongoing.

CONCLUSION

PI3K-Akt-mTOR and ERK/MEK kinase pathways constitute relevant targets in aggressive meningioma therapy. In our preclinical model, previously validated by CEVOREM clinical trial, co-targeting Pi3k-Akt-mTOR and MAPkinase pathways improved cell proliferation inhibition in comparison to the target of each pathway alone. BYL719 induced apoptosis which was not achieved by everolimus. These results support the ongoing clinical trial ALTREM combining Alpelisib and Trametinib on patients harboring aggressive recurrent meningiomas.
OS9.7 Telomere length, TERTp mutation and ALT status in adult diffuse gliomas
Authors: Birzu C , Hillairet A , Giry M , Grandin N , Verrelle P , Mokhtari K , Marie Y , Hoang-Xuan K , Delattre J , Idbaih A , Charbonneau M , Sanson M , Alentorn A
Published: September 2019

BACKGROUND

The current classification of adult diffuse gliomas integrates two alternative telomere maintenance mechanisms: reactivation of telomerase activity by TERT promoter (TERTp) mutations or ATRX mutations associated with alternative length telomere (ALT). We investigated here the relation between these two mechanisms, telomere length, and outcome in a large series of diffuse gliomas.

MATERIAL AND METHODS

We performed C-circle assay (CCA) to determine ALT status, determined telomere length in tumor (RTLt) and leukocyte (RTLl) in a cohort of 354 adult diffuse gliomas, and sequenced ATRX gene. We calculated an age-adjusted telomere score considering tumor and leukocyte (blood) telomere length and corrected by age. This score was used in univariate and multivariate survival analyses to evaluate the potential impact of telomere length on the prognosis of gliomas. We used the TCGA LGG-GBM dataset to validate our findings in an independent cohort.

RESULTS

RTLl and RTLt were associated with ATRX mutation and ALT phenotype, and negatively associated with age and TERTp mutations. ATRX mutations (found in 52% (64/123) of samples) were mostly transitions (C>T or T>C), and were associated with ALT phenotype. None of 1p/19q co-deleted oligodendrogliomas harbored an ALT phenotype. No patients with TERTp mutations had ALT phenotype except for a very small subgroup of patients (3/87, 3.4%) suggesting that multiple ways of telomere maintenance, may co-exist in a single tumor, probably expressed in different clones. Telomere age-adjusted score was independently associated with better outcome (HR= 0.73 [95% CI 0.56–0.97], p-value 0.03 adjusted for age, TERTp mutation, IDH mutation, 1p/19q co-deletion and WHO grade). These results were validated using the LGG-GBM TCGA dataset.

CONCLUSION

We unravel the relation between RTLl and RTLt, TERTp mutation and ALT phenotype and describe a novel telomere age-adjusted score independently associated with better prognosis in adult diffuse gliomas.
OS10.6 Infigratinib (BGJ398) in patients with recurrent gliomas with fibroblast growth factor receptor (FGFR) alterations: a multicenter phase II study
Authors: Lassman A B , Sepúlveda-Sánchez J M , Cloughesy T , Gil-Gil J M , Puduvalli V K , Raizer J , De Vos F Y , Wen P Y , Butowski N , Clement P , Groves M D , Belda-Iniesta C , Steward K , Moran S , Ye Y , Roth P
Published: September 2019

BACKGROUND

FGFR mutations and translocations occur in approximately 10% of glioblastomas (GBMs). FGFR3-TACC3 fusion has been reported as predictive of response to FGFR tyrosine kinase inhibitor therapy both pre-clinically and clinically. Infigratinib (BGJ398) is a selective small-molecule pan-FGFR kinase inhibitor that has demonstrated anti-tumor activity in several solid tumors with FGFR genetic alterations. Therefore, we conducted a phase II trial to test the efficacy of infigratinib in FGFR-altered recurrent GBM (NCT01975701).

METHODS

This open-label trial accrued adults with recurrent high-grade gliomas following failure of initial therapy that harbored FGFR1-TACC1 or FGFR3-TACC3 fusions; activating mutations in FGFR1, 2 or 3; or FGFR1, 2, 3, or 4 amplification. Oral infigratinib was administered 125 mg on days 1–21 every 28 days. Prophylaxis for hyperphosphatemia, a common toxicity, was recommended. The primary endpoint was the 6-month progression-free survival (6mPFS) rate by RANO (locally assessed, estimated by K-M method), with a goal of >40%.

RESULTS

As of the Sep 2017 data cut-off, 26 patients (16 men, 10 women; median age 55 years, range 20–76 years; 50% with ≥2 prior regimens) were treated, and 24 (92.3%) discontinued for disease progression (n=21) or other reasons (n=3). All patients had FGFR1 or FGFR3 gene alterations, and 4 had >1 gene alteration. The estimated 6mPFS rate was 16% (95% CI 5.0–32.5%); median PFS was 1.7 months (95% CI 1.1–2.8 months); median OS was 6.7 months (95% CI 4.2–11.7 months); ORR was 7.7% (95% CI 1.0–25.1%). The best overall response was: partial response 7.7% (FGFR1 mutation n=1; FGFR3 amplification n=1); stable disease 26.9%; progressive disease 50.0%; missing/unknown 15.3%. The most common (>15%) all-grade treatment-related adverse events (AEs) were hyperphosphatemia, fatigue, diarrhea, hyperlipasemia, and stomatitis. There were no grade 4 treatment-related AEs. Eleven patients (42.3%) had treatment-related AEs requiring dose interruptions or reductions (most commonly hyperphosphatemia).

CONCLUSIONS

Infigratinib induced partial response or stable disease in approximately one-third of patients with recurrent GBM and/or other glioma subtypes harboring FGFR alterations. Most AEs were reversible and manageable. Further potential combinations are being explored in patients with proven FGFR-TACC fusion genes and analysis of biomarker data is ongoing.
OS12.5 Small GTPase RHOE/RND3, a new critical regulator of NF-êB signaling in glioblastoma multiforme?
Authors: Liu B , Chen Q
Published: September 2019

Background

Abnormal activation of NF-κB signaling is a major mechanism of apoptosis resistance in glioblastoma multiforme (GBM). Therefore, better understanding of the regulation of NF-κB signaling has a significant impact for GBM therapy. Here, we uncovered a critical role of the small GTPase RND3 in regulating the p65 subunit of NF-κB and NF-κB signaling in GBM.

MATERIALS AND METHODS

Human GBM samples, GBM cells and a human orthotopic GBM-xenografted animal model were used. The mechanisms of RND3 in regulation of NF-κB signaling and GBM cell apoptosis were examined by luciferase assay, quantitative PCR, immunostaining, immunoblotting, immunofluorescence, co-immunoprecipitation, TUNEL staining, JC-1 analysis and flow cytometry.

RESULTS

Overexpression of RND3 led to reduced p65 activity in GBM cultured cells and a GBM animal model, indicating that the NF-κB pathway is negatively regulated by RND3 in GBM. Mechanistically, we found that RND3 bound p65 and promoted p65 ubiquitination, leading to decreased p65 protein levels. Furthermore, RND3 enhanced cleaved-caspase 3 levels and promoted apoptosis in GBM cells, and RND3 expression was positively correlated with cleaved-caspase 3 and IL-8 in human GBM samples. The effect of RND3 on promoting apoptosis disappeared when p65 ubiquitination was blocked by protease inhibitor carfilzomib or upon co-expression of ectopic p65.

CONCLUSION

RND3 binds p65 protein and promotes its ubiquitination, resulting in reduced p65 protein expression and inhibition of NF-κB signaling to induce GBM cell apoptosis.
P03.05 Could suspected Glioblastomas be Treated without Hystological Diagnosis?
Authors: Cortés Mateus K , Valduvieco Ruíz I , Verger Fransoy E , Pineda Losada E , Oleaga Zufiria L , Pujol Farre T , González Sánchez J , Pedrosa Eguílaz L , Graus Ribas F , Barreto Zambrano T , Muñoz Guglielmetti D , Castro Cuevas C , Escudero López E , Lloret Puerto A , Sáez Beltrán J , Camacho López C , Conill Llobet C , Oses González G , Garrido Alcantud S , Mollà Armada M
Published: September 2019

BACKGROUND

Probable unresectable Glioblastomas (GB) diagnosed by imaging techniques withouth anatomo-pathological (ap) confirmation could be treated under standard treatment. We reported the outcomes from this strategy in our center after tumor board evaluation.

MATERIAL AND METHODS

From January/10 to September/16, 303 patients (pt) with GB were assessed by tumor board, during the same period 66 patients were consecutive analyzed with suspected GB by radiological criteria without histological diagnosis. We focus in the last group and analyzed the demographic/radiological data, non-biopsy causes, treatment type (concomitant Radio-Chemotherapy (RT/Ch), exclusive RT or Ch or Best supportive care (BSC)), Karnofsky index (KI) and degree of comorbidity (Charlson index (CI)).

RESULTS

Sixty six patients, 17.88% of the total GB cases (with/without ap). Average age: 77 years (33–91). Biopsy: non-diagnostic in 4pt. No biopsy: 62pt; due to non medical indication (71%), localization (22.7%), voluntary (4.5%). Treatment Type: Active: 43.93%, without biopsy due to non-medical indication (44.8%) and localization (41.37%). BSC: 53.03%, without biopsy due to non-medical indication 82.85%, localization 8.5%, voluntary 5.7%. Overall survival: 11.65 months in patients with active treatment and 4.8 months in BSC, greater benefit in <70 years and KI≥ 70 with statistical signification.

CONCLUSION

The diagnosis of GB by radiological criteria with the new imaging techniques has a good diagnostic-therapeutic correlation. In cases where surgical intervention is not possible, standard treatment offers good results. Age and KPS are variables that allow predicting a better evolution course. Although it was not possible to obtain a histological diagnosis, in this type of cases liquid biopsy could contribute to diagnosis this type of lesions inaccessible to biopsy.
P03.09 Real world management and prognosis of glioma patients:SYSUCC report from China
Authors: Li D , Chen Y , Guo C , Yang Q , Wu S , Xia Y , Zeng J , zhang X , Ke C , Sai K , Wang J , Mou Y , Chen Z
Published: September 2019

Background: The conventional way of patient treatment should be following guidelines. While in clinical practice, patients received treatments very often away from suggested guideline. In this report, we reviewed glioma patients received real world treatment at Sun Yat-sen University Cancer Center (SYSUCC) and results of this patient series.

Methods: Total of 1215 glioma patients received surgery at SYSUCC from 2000 to 2017 were enclosed for analysis. The pathologic diagnosis of patients has followed WHO classification (initially 2007 standard, than 2016 standard).

Results: A total of 1001 newly diagnosed brain glioma patients were analyzed, including 90 cases WHO grade I, 307 grade II, 239 grade III and 365 grade IV. The median age of onset was 14 (1–75), 35 (2–69), 41 (8–82) and 50 (2–86) years old, respectively, for grade I, II, III and IV glioma patients. Tumor total resection was achieved in 567 patients (57.5%). Among all patients, 331 high-grade gliomas (54.8%) and 159 low-grade glioma (40.1%) received radiotherapy, whereas 285 high-grade gliomas (47.1%) and 80 low-grade tumors (20.2%) received chemotherapy. Among high-grade gliomas, the median OS of glioblastoma, anaplastic astrocytoma and anaplastic oligodendroglial tumors were 17.7 months (15.7–19.7 months), 33.7 months (24.0–43.4 months) and 110.6 months (43.5–177.7 months), respectively, whereas the median OS of low-grade gliomas was not reach. The 5-year survival rate of grade I, II, III and IV gliomas was 94.7%, 73.7%, 45.1% and 18.6%, respectively. Multivariate analysis identified that onset age, Karnofsky performance status, tumor location, preoperative seizure, pathological subtype, resection extent and post-surgical treatment were independent predictors of OS for patients with high-grade gliomas. Patients received post-surgical radiotherapy and (or) chemotherapy had better survival than those without adjuvant treatment (grade III: 53.3 vs. 20.6 months, p =0.012; grade IV: 22.9 vs. 12.3 months, p < 0.001). For low-grade gliomas, patients’ age, Ki-67 index, tumor subtype and resection extent were associated with clinical outcomes.

Conclusions: Glioma patients received treatments do not always following guidelines in clinical practice. Although standard care for patients may beneficial for prognosis, personalized treatment may more acceptable for patients and even resulting better outcome which should keep in mind in routine clinical practice.
P03.14 New features of modern 3D conformal external radiotherapy (RT) of benign head tumors in children
Authors: Antonenko F , Slobina E , Abbasova E , Smyslov A , Dykina A , Sidibe N , Abdullaeva S , Vasilyev V
Published: September 2019

BACKGROUND

demonstrate the possibilities of radiation therapy (LT) in children with benign head tumors using IMRT, VMAT, IGRT techniques - high-precision modern 3D conformal radiation therapy

MATERIAL AND METHODS

From 1990 to 2007 for the first time in Russia, 88 children with juvenile angiofibromas were treated in Russian Scientific Center of Roentgenoradiology. The studies were carried out on the gamma-therapeutic apparatus “AGAT-P1” and on the linear accelerator “Phillips SL75” Total dose was 35–45 Gy. In 2014–2018 we treated 29 patients aged 3–17 years with benign tumors of the skull base and brain (angiofibromas, craniopharyngiomas, hemangiomas) using high-precision techniques (IMRT, VMAT, IGRT). 15 of 29 patients were repeatedly operated in various domestic and foreign clinics and were admitted to RT with the threat of bleeding, with recurrent growth of tumors, including after multiple selective angioembolization.

RESULTS

Up to 80% of patients had a 5-year stable remission, and the optimal total dose for radiation therapy of benign head tumors in children was scientifically substantiated. It was found that there is a high risk of continued growth after RT in children under 8 years of age, complications in 10% of patients in the coming years after RT and in 100% of those reirradiated. In all 29 cases of RT in children, we observed a positive clinical effect - stopping bleeding from the nasopharynx after 1–3 sessions of 3D conformal RT (Dose per fraction 1.8 Gy, total dose 45–54 Gy), positive clinical symptoms under the supervision of an Head and Neck surgeon. The effect of hardening and stopping the growth of tumors according to MRI data were followed up after 3 months, 6 months, 1 year.

CONCLUSION

The development of navigational, endosurgical and fibro-endoscopic minimally invasive technologies in the last 30 years has allowed to expand the indications for surgical methods of treatment for benign head tumors in children, which has reduced their flow to RT. However, after modern surgical interventions, 6–10% of these patients experience recurrences and bleeding, the number of which can be reduced with timely RT. New technologies in LT provide minimal impact on surrounding healthy tissues and allow wider use of RT in recurrent and difficult-to-reach benign skull base tumors in children
P04.02 Postponing the medical treatment is possible in selected cases of diffuse low-grade glioma with foci of WHO grade III-IV after total or subtotal resection
Authors: Darlix A , Rigau V , Fraisse J , Gozé C , Fabbro M , Duffau H
Published: September 2019

BACKGROUND

Diffuse low-grade gliomas (DLGG) are defined by a continuous growth and an unavoidable malignant transformation. Foci of malignant transformation may be found within DLGG samples obtained from surgical resections. As the medical management is classically based on the higher tumor grade, an immediate adjuvant treatment is usually proposed (radiotherapy [RT] with Temozolomide or PCV), whatever the extent of resection. Yet, early RT has no impact on overall survival compared with late RT, and is associated with cognitive toxicity. An alternative approach consists in postponing the medical treatment in selected patients.

MATERIAL AND METHODS

We conducted a monocentric retrospective analysis of a consecutive series of patients managed with this conservative approach. Inclusion criteria were: DLGG (WHO 2016 grade II) with at least one focus of malignant transformation (grade III-IV); no previous chemotherapy or RT; no less than a subtotal resection of the FLAIR tumor volume; no intention of treating with immediate adjuvant therapy; at least two years of postoperative follow-up. The time interval to the next medical treatment (chemotherapy and/or radiotherapy) was assessed, as well as the functional and survival results.

RESULTS

Forty-five DLGG patients, of median age 36.5 years, were included in the analysis (median time interval from diagnosis: 7.3 months). The histo-molecular diagnosis was diffuse astrocytoma, IDH mutant in 46.7% of cases, astrocytoma, IDH wild-type in 13.3% and oligodendroglioma, IDH mutant and 1p/19q codeleted in 40.0%. Ten tumors presented with grade IV foci. The quality of resection was subtotal (FLAIR tumor residue ≤15 cm3) in 73.3%, total (no FLAIR tumor residue) in 24.4% and supratotal in 2.2%. After surgery, patients were managed with regular clinical and radiological follow-up. With a median postoperative follow-up of 6.3 years, 75.5% of patients received a subsequent medical treatment, after a median time interval of 3.7 years. The first treatment after surgery consisted of repeated surgery in 11 patients, Temozolomide in 28 patients, RT in one patient. At the time of analysis, 19 patients (42.2%) had been treated with RT, after a median time interval of 9.5 years. Nine patients (20.0%) had died (median overall survival not reached, 5-years and 7-years survival rates: 95.2% and 67.0%). Most surviving patients were still active professionally (69.4%), with a median Karnofsky performance status of 90, and no or rare seizures.

CONCLUSION

In this series, total or subtotal resection of DLGG with a least one focus of grade III-IV glioma radically changed the natural history of these tumors and allowed delaying the following medical treatment by several years. This strategy is feasible in selected patients and should be considered on a case-by-case basis in patients with foci of malignant transformation following total or subtotal resection.
P04.08 The role of SCN1A in glioblastomas and mixed neuronal glial tumors of pediatric age
Authors: Giunti L , Cetica V , De Gregorio V , Mei D , Barba C , Buccoliero A , Genitori L , Guerrini R , Giglio S , Sardi I , Guidi M , Censullo M
Published: September 2019

BACKGROUND

Low and high grade gliomas, are the most common pediatric central nervous system (CNS) tumors and they show an extremely broad range of clinical behavior. Pediatric glioma is distinct from its adult counterpart with different genetic/epigenetic profile and biological features. Recently, several studies have shown the involvement of voltage-gated Na+ channels (VGSC) in different types of cancer, including gliomas. VGSC are multimeric transmembrane complexes, responsible for membrane depolarization in excitable cells playing an important role also in cell proliferation, migration, apoptosis and differentiation. VGSC are therapeutic targets in cardiovascular and neurological disorders and, in cancers, they could be a novel target for the development of promising anticancer therapy

MATERIAL AND METHODS

Firstly, we explored the genetic background of 9 pediatric glioblastomas (1–9 pGBMs), through whole-exome sequencing (WES) using HiSeq1000 platform (Illumina) with paired-end approach. On the basis of our results, we extended our study in another group of 16 epileptogenic mixed neuronal-glial tumors of pediatric age, (WHO grade I and II), through an amplicon approach (TSCA) using MiniSeq System platform (Illumina)

RESULTS

We identified variants in SCN1A gene in 3/9 pGBMs: case 3 had c.5782C>G in tumor and blood; case 5 showed c.2278G>T and two mosaic variants (c.5933C>T, 22% and c.4942C>T, 14%); case 6 showed c.667G>T variant only in tumor, and not in other non tumoral tissues (blood, urine and buccal swab). No variants in SCN1A were identified in a group of 16 pediatric mixed gliomas

CONCLUSION

In this study, we explore the genetic background of two groups of pediatric neuroepithelial brain tumors, through Next generation sequencing approach. We identified only in pGBMs variants in SCN1A gene that encoded for VGSCs and is involved in a spectrum of early-onset epileptic encephalopathies. None of our mutated patients showed history of epilepsy. Now, it is not clear the significance of these variants in pGBMs but interestingly, these variants are present in pGBM and not in mixed gliomas. Further studies on a big cohort of patients are needed to establish if they could play a role in pGBMs aggressiveness, migration and progression. Moreover, VGSCs could be a pharmacological target in pGBMs treatment
P04.11 Voxelwise correlation between vascular MRI parameters obtained with ASL and DSC is decreased in IDH-wt non-enhancing glioma
Authors: Warnert E A H , Incekara F , Vincent A J P E , Schouten J W , van den Bent M J , French P J , Dubbink H J , Kros J M , Hernandez-Tamames J A , Smits M
Published: September 2019

BACKGROUND

Comparative studies of dynamic susceptibility contrast (DSC) based measurement of cerebral blood volume (CBV) or cerebral blood flow (CBF) and arterial spin labelling (ASL) based measurement of CBF have previously shown good correlation of these parameters in human glioma. However, these studies were mostly done before inclusion of the mutation status of the isocitrate dehydrogenase (IDH) encoding gene in brain tumour classification. In light of the call for gadolinium-free imaging, here we investigate the effect of IDH-mutation status on the correlation between ASL and DSC-based perfusion measurements in non-enhancing glioma.

MATERIAL AND METHODS

Twenty-two patients with non-enhancing glioma and confirmed IDH-mutation status (next generation sequencing, 6 IDH-wildtype and 16 IDH-mutated) underwent 3T MRI scanning (GE, Milwaukee, WI, USA). Image acquisition included a 3D spiral pseudocontinuous ASL with time-encoded labelling (7 effective label delays from 0.8 to 2 s, reconstruction matrix 128x128x42, resolution 1.9x1.9x3.5 mm3), and 2D DSC imaging (122 TRs, TR/TE 1500m/18.6ms, 15 slices, voxel size: 1.88x1.88x4 mm3) in which a bolus of 7.5ml of gadolinium-based contrast agent (Gadovist, Bayer, Leverkussen, GE) was injected. A pre-load bolus of equal size was given 5 minutes prior to DSC imaging. DSC and ASL images were motion corrected and linearly registered to high resolution FLAIR images (FSL, version 5.0.9, Oxford, UK). DSC-relative CBV (rCBV), DSC-relative CBF (rCBF), and ASL-CBF maps were calculated via previously described methods. The glioma region of interest (ROI) was determined via manual segmentation on the FLAIR images. Voxel-wise Pearson’s linear correlation coefficients (ρ) within this ROI were calculated between ASL-CBF and DSC-rCBV, and between ASL-CBF and DSC-rCBF.

RESULTS

Normalised histograms indicate that IDH-wt glioma has higher values for ASL-CBF, DSC-rCBV, and DSC-rCBF than IDH-mutated glioma. IDH-wildtype glioma has a significantly lower ρ ASL-CBF vs DSC-rCBV and ρ ASL-CBF vs DSC-rCBF than IDH-mutated glioma (two-sample t-tests p < 0.05).

CONCLUSION

IDH-mutation status of non-enhancing glioma potentially affects the correlation between ASL-CBF and DSC-rCBF/rCBV and should be taken into account when moving towards ASL-only imaging. The decreased correlation between ASL and DSC-based vascular parameters in IDH-wt gliomas may be due to more aggressive vasculature in subtypes of IDH-wt tumours. Future work includes expansion of the current patient cohort (part of the ongoing iGENE study).
P04.13 Prognostic role of single stranded DNA binding protein 2 in IDH wild type lower grade glioma
Authors: Chai Y , Liu W , Hu L , Zhang Y , Liang P
Published: September 2019

Comprehensive and integrative characterizations of genomic analysis including somatic alterations and molecular subtypes of glioma have been established. However, diffuse gliomas (World Health Organization grades II and III, hereafter referred to collectively as lower-grade gliomas,LGG) consist of highly variable clinical behaviors, leading to emerging studies to identify prognostic factors. Through comparative analyses of 516 cases of primary LGG patients from The Cancer Genome Atlas (TCGA) dataset, we reported that the expression level and methylation level of SSBP2 (encoding single stranded DNA-binding protein 2) gene vary among LGG patients and SSBP2 expression or gene body methylation can be served as prognostic biomarkers for LGG survival. Cox regression results confirmed that SSBP2 as an independent predictor of survival in LGG, with a cox coefficient of 0.534 indicating a worse prognosis. Furthermore, lower-grade glioma was statistically ranked first among 21 different cancer types according to the FDR correction. We further investigated the combination of SSBP2 with other known genetic prognostic factors(IDH mutation and 1p19q co-deletion) of LGG. By matching gene expression profile of LGG patients, IDH-mutant gliomas had decreased expression of SSBP2 compared with IDH-wildtype gliomas and 1p19q intact gliomas had increased expression of SSBP2 compared with 1p19q codeletion gliomas. Moreover, we found that the combination of IDH or 1p19q status with SSBP2 identified LGG subsets with significantly diverse survival effects. Patients with low SSBP2 expression had significantly better 5-, 10-, and 15-year OS in IDH wild type, but not in the cohorts of IDH mutant. Our findings offer an explanation for the specificity of SSBP2 effect on survival rate in IDH wild type LGG patients.