bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-22. NIVOLUMAB AND BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA; T-CELL REACTIVITY AGAINST AUTOLOGOUS TUMOR CELLS
Authors: Maarup Simone , Skadborg Signe , Borch Annie , Draghi Arianna , Hasselbalch Benedikte , Østrup Olga , Scheie David , Skjoeth-Rasmussen Jane , Law Ian , Svane Inge Marie , Poulsen Hans , Hadrup Sine , Lassen Ulrik
Published: November 2021

INTRODUCTION

Glioblastoma is an aggressive brain tumor with a median survival of 14.6 months. We have no standard treatment for relapse and known options have limited effect. Novel treatments are necessary to improve survival and quality of life.

METHODS

We present our trial; phase II open label, two-armed translational study of Nivolumab and Bevacizumab for recurrent GBM, who have failed Stupp’s regimen. Patients are included in two arms depending on the possibility of salvage neurosurgical resection. Both arms receive Nivolumab and Bevacizumab administrated every second weekend, and the surgical arm also receive Nivolumab 7 days prior surgery. Forty-four patients were included by January 2021; 20 in each arm (four screen-failures). In the surgical arm, 20 fresh tumor samples as well as paired tissue from primary tumor were available. Tumor infiltrating lymphocytes (TILs) and tumor digest were produced in vitro from recurrent settings. Young TILs were expanded from fresh tumor fragments after minimal-culture, whereas rapidly expanded TILs (REP TILs) were obtained after massive expansion. By intracellular cytokine staining, we investigated the TIL reactivity after exposure to autologous tumor digest in order to evaluate whether the TILs were tumor-reactive, non-reactive or bystanders. RNA and whole exome sequencing were available before and after treatment.

RESULTS

Material from 19 patients was analyzed (one out of the 20 collected biopsies was limited in size, therefore no tumor digest could be produced). Four out of 19 TIL samples showed tumor reactivity after exposure to the autologous tumor digest. Tumor reactivity was ranged between 1,2 to 13,6 tox% in CD8+ TILs and between 2,8 to 10,9 tox% in CD4+ TILs. By flowcytometry we found, IgG4+ CD3+ TILS from tumor biopsies, meaning that Nivolumab were found in the brain. Currently controls are included to evaluate these results.

CONCLUSIONS

Updated results will be presented at SNO.
CTIM-25. A RANDOMIZED PHASE 3 STUDY OF NIVOLUMAB OR PLACEBO COMBINED WITH RADIOTHERAPY PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA WITH METHYLATED MGMT PROMOTER: CHECKMATE 548
Authors: Weller Michael , Lim Michael , Idbaih Ahmed , Steinbach Joachim , Finocchiaro Gaetano , Raval Raju , Ashby Lynn , Ansstas George , Baehring Joachim , Taylor Jennie , Honnorat Jerome , Petrecca Kevin , de Vos Filip , Wick Antje , Sumrall Ashley , Roberts Mustimbo , Slepetis Ruta , Warad Deepti , Lee Michelle , Reardon David , Omuro Antonio
Published: November 2021

BACKGROUND

Novel therapies are needed in newly diagnosed glioblastoma as nearly all patients experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ), including patients with tumors with methylated MGMT promoter, a positive prognostic factor and predictor of benefit with TMZ. Here, we report the final analysis of progression-free survival (PFS), overall survival (OS), and safety from an international randomized, single-blind phase-3 study of nivolumab (NIVO)+RT+TMZ in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter (CheckMate 548; NCT02667587).

METHODS

Patients (N=716) aged ≥ 18y were randomized 1:1 regardless of tumor PD-L1 expression to NIVO (240 mg Q2W×8, then 480 mg Q4W) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 QD during RT, then 4-week break, then 150–200 mg/m2 QD on days 1–5 of every 28-day cycle for 6 cycles) or placebo (PBO)+RT+TMZ. The dual-primary endpoints were PFS by blinded independent central review and OS, both overall and without baseline corticosteroids.

RESULTS

As of December 22, 2020, median PFS was 10.6 months (95% CI, 8.9–11.8) with NIVO+RT+TMZ and 10.3 months (95% CI, 9.7–12.5) with PBO+RT+TMZ (HR, 1.06 [95% CI, 0.90–1.25]). Median OS was 28.9 months (95% CI, 24.4–31.6) with NIVO+RT+TMZ and 32.1 months (95% CI, 29.4–33.8) with PBO+RT+TMZ (HR, 1.10 [95% CI, 0.91–1.33]). Among patients without baseline corticosteroids, median OS was 31.3 months (95% CI, 28.6–34.8) with NIVO+RT+TMZ and 33.0 months (95% CI, 31.0–35.1) with PBO+RT+TMZ (HR, 1.12 [95% CI, 0.87–1.43]). Grade 3–4 treatment-related adverse events were 52.4% and 33.6% with NIVO+RT+TMZ and PBO+RT+TMZ, respectively.

CONCLUSIONS

NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter. No new safety signals were observed with NIVO. The role of immunotherapy in this treatment landscape remains an area for further investigation.
CTIM-30. PHASE II TRIAL OF PEMBROLIZUMAB IN RECURRENT AND RESIDUAL HIGH-GRADE MENINGIOMAS
Authors: Brastianos Priscilla , Kim Albert , Giobbie-Hurder Anita , Lee Eudocia Quant , Wang Nancy , Eichler April , Chukwueke Ugonma , Forst Deborah , Arrillaga-Romany Isabel , Dietrich Jorg , Lou Kevin , Larson Juliana , Mora Joana , Nayyar Naema , Loeffler Jay , Oh Kevin , Shih Helen , Curry William , Cahill Daniel , Barker Fred , Gerstner Elizabeth , Santagata Sandro
Published: November 2021

INTRODUCTION

High-grade meningiomas are associated with significant neuro-cognitive morbidity and a poor prognosis. Systemic therapies, to date, have demonstrated minimal efficacy. We recently found that high-grade meningiomas harbor an immunosuppressive tumor microenvironment and that programmed cell death-ligand 1 (PD-L1) expression may contribute to the aggressive phenotype of these tumors. Therefore, we conducted a single-arm, open-label phase II trial evaluating efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 24 patients with recurrent and progressive grade II and III meningiomas.

METHODS

The primary endpoint was the rate of progression-free survival at 6 months. The trial distinguished between 6-month PFS (PFS-6) rates of 26% vs. 52%. If at least 10 patients demonstrated a 6-month PFS, among the 24 patients, the agent would be considered worthy of further study. This design has at least 88% power using an exact binomial test with a one-sided significance level of 0.1.

RESULTS

Between November 2017 to December 2019, twenty-four patients were enrolled. The majority of the patients in our cohort were heavily pre-treated; prior to enrolling to the study, twenty patients underwent more than one surgical resection and twelve patients had received more than one round of radiotherapy. Our study met its primary endpoint and achieved a 6-month progression-free survival rate of 0.50 (90% exact CI: 0.32-0.68) and a median PFS of 8.3 months (90% CI: 4.1-12.9 months). For the twelve patients who achieved the PFS-6 primary endpoint, median PFS from the start of treatment was 17.3 months (90% CI: 9.7 – 24.3 months). Four patients had grade-3 or higher adverse events that were at least possibly treatment-related, including colitis, skin infection, encephalopathy and transaminitis.

CONCLUSION

Our study achieved its primary endpoint. These results suggest that pembrolizumab exerts promising activity on these tumors and results in prolonged PFS compared to historical controls.
CTIM-31. A PHASE II, OPEN-LABEL, SINGLE ARM TRIAL OF PEMBROLIZUMAB FOR REFRACTORY ATYPICAL AND ANAPLASTIC MENINGIOMA AND HEMANGIOPERICYTOMA
Authors: Yust-Katz Shlomit , Amiel Alexandra , Yust-Katz Shlomit , Limon Dror
Published: November 2021

BACKGROUND

Grade II and III meningiomas are invasive tumors which tend to recur following initial treatment and are associated with shorter survival (relative to grade I). Hemangiopericytoma (HPC) is a dural based tumor that originates in the pericytes. Treatment options for these tumors include surgical resection and radiation. There are no defined standard treatments after failure these modalities, and effective systemic treatments are lacking. This trial concept was developed following previous reports of high PD-L1 levels in anaplastic meningioma. We currently report our initial experience with pembrolizumab for refractory atypical/anaplastic meningioma (RAM) and HPC patients.

METHODS

This is a single arm, single institute, phase 2 trial. Inclusion criteria included patients with RAM or HPC whose all previous lines of treatment were exhausted. All patients were treated with pembrolizumab (200mg every 3 weeks) until disease progression. Primary endpoint was 6- and 12-months progression free survival (PFS). The study was planned for 25 patients and we report here preliminary results.

RESULTS

Through February 2021, 12 patients were enrolled to this study (two with HPC, 10 with RAM). After a median follow up of 18.5 months, the 6 and 12 months PFS were 25% and 16.7% respectively, with a median PFS of 2.75 months. Two patients had a partial response while all others progressed, making the overall response rate 16.7%. One of the responders had HPC and has been stable for 30 months, while the second had atypical meningioma and was stable for 13 months. Median survival has not been reached yet; 1 year survival rate was 82.5%. Grade 3 toxicities included hyperglycemia, elevated liver enzymes and fatigue, with no grade 4 or 5 toxicities.

CONCLUSIONS

Pembrolizumab induced a low response rate for RAM and HPC. However, a subset of patients might benefit from this treatment with a prolonged response period.
CTNI-09. TRIDENT PHASE 3 TRIAL (EF-32): FIRST-LINE TUMOR TREATING FIELDS (TTFields; 200 KHZ) CONCOMITANT WITH CHEMO-RADIATION, FOLLOWED BY MAINTENANCE TTFIELDS/TEMOZOLOMIDE IN NEWLY-DIAGNOSED GLIOBLASTOMA
Authors: Shi Wenyin , Kleinberg Lawrence , Jeyapalan Suriya , Goldlust Samuel , Nagpal Seema , Combs Stephanie , Roberge David , Nishikawa Ryo , Reardon David , Grossman Rachel , Glas Martin
Published: November 2021

INTRODUCTION

Tumor Treating Fields (TTFields; 200 kHz; non-invasive, loco-regional antimitotic treatment) is approved for newly-diagnosed glioblastoma (ndGBM). In the Phase 3 EF-14 trial, post-surgical radiotherapy/temozolomide, followed by maintenance TTFields/temozolomide significantly increased overall survival (OS) and progression-free survival (PFS) in patients with ndGBM versus TMZ alone. Addition of maintenance TTFields did not increase systemic toxicity; and related adverse events (AEs) were mainly dermatological. In preclinical models, addition of TTFields increased the benefit of radiotherapy. Two pilot studies showed that TTFields concomitant with radiotherapy/temozolomide is feasible and well-tolerated. The benefit of TTFields concomitant with radiotherapy/temozolomide will be investigated in the TRIDENT trial.

METHODS

TRIDENT (EF-32; NCT04471844) is an international, pivotal, phase 3 randomized trial comparing triple-combination of TTFields/radiotherapy/temozolomide versus standard radiotherapy/temozolomide. Patients in both arms will receive maintenance TTFields/TMZ. Arrays of the Optune® System will be used to deliver TTFields (200 KHz) for ≥18 hours/day concomitant with radiotherapy. TTFields treatment will be continued until second disease progression (RANO) or 24 months, whichever occurs first. Patients with pathologically-confirmed ndGBM, ≥ 18 years of age (≥ 22 years of age; US), KPS ≥ 70, post-surgery/biopsy, and amenable for radiotherapy/temozolomide will be stratified by extent-of-resection and MGMT promoter methylation status. The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1-year and 2-year survival rates, overall radiological response (ORR; RANO), PFS (PFS-6M, PFS-12M, PFS-2Y), severity and frequency of AEs (CTCAE V5.0), pathological post-treatment changes in resected GBM tumors, quality-of-life (EORTC QLQ-C30), and OS correlation to TTFields duration-of-usage. The hypothesis is that first-line TTFields/RT/TMZ triple-combination will significantly improve OS compared to radiotherapy/temozolomide; each followed by maintenance TTFields/temozolomide. Sample size (N=950; 475/arm) was powered for a HR < 0.8 with 5% type I error. Survival will be measured from time-of-randomization. The TRIDENT trial is currently enrolling patients.

RESULTS/CONCLUSIONS

N/A TiP.
CTNI-10. ADVANCES IN MANAGEMENT OF LOW-GRADE GLIOMAS
Authors: Raval Ruchi , Pandya Aadi , Behl Jaspreet , Raval Sumul
Published: November 2021

BACKGROUND

Low-grade gliomas (LGGs) are common benign brain tumors that arise from glial cells of the brain. The complex and variable backgrounds of LGGs cause difficulties in assigning therapies. In this report, we compile findings relating to LGG genetics and treatment options in order to create a coherent summary for referential use.

METHODS

We compiled 70 articles from the past ten years that cover a broad range of topics pertaining to LGGs, including molecular, genetic, epigenetic, morphological, and other diagnostic factors, as well as prognosis and treatment options.

RESULTS

In order to provide proper treatment, the molecular basis and histology of the tumor must be addressed. The 1p/19q co-deletion indicator has been considered the gold standard of glioma diagnosis, but oft-sighted mutations in the IDH1 and IDH2 genes have given rise to three subgroups of 1p/19q co-deleted tumors, each associated with specific patterns of nervous cells. Other molecular markers and microRNA expression patterns have been studied for possible diagnostic and prognostic methods. Microsurgical resection is the singular treatment with highest overall survival (OS) and quality of life (QOL). Total gross resection is optimal, with patients having a 5-year OS of 100% with 90% tumor resection. Low doses of radiation are as effective as high doses and are better tolerated (with less cognitive deficits). Chemotherapy, specifically temozolomide, offers a favorable toxicity profile and QOL; additionally, seizure reduction is an early and consistent prognostic marker for survival after treatment with temozolomide.

CONCLUSIONS

The “wait and see” approach for treatment is no longer the standard for LGGs. Immediate treatment after diagnosis is recommended. Gross total resection (if achievable) is the most favorable treatment, with the highest OS and QOL. The use of temozolomide and radiotherapy is recommended. Histological background and genetic markers are vital for determining a treatment plan.
CTNI-28. VOLUMETRIC AND DOSIMETRIC PATTERNS OF FAILURE ANALYSIS OF A PHASE II CLINICAL TRIAL OF 18F-DOPA-PET DIRECTED DOSE ESCALATED RADIOTHERAPY FOR GLIOBLASTOMA
Authors: Breen William , Anderson S Keith , Pafundi Deanna , Kaufmann Timothy , Hunt Christopher , Lowe Val , Vogen Diane , Yan Elizabeth , Sarkaria Jann , Brown Paul , Kizilbash Sani , Uhm Joon , Ruff Michael , Zakhary Mark , Zhang Yan , Seaberg Maasa , Rehim Abdou Abdel , Tseung Hok Seum Wan Chan , Qian Jing , Kabat Brian , Kemp Bradley , Laack Nadia , Brinkmann Debra
Published: November 2021

While dose escalation of radiotherapy (DERT) has failed to improve overall survival (OS) or progression-free survival (PFS) for glioblastoma in previous studies, a recent phase II clinical trial utilizing 18F-DOPA-PET-directed DERT demonstrated improved PFS in MGMT-unmethylated patients and OS in MGMT-methylated patients compared to historical controls. This planned secondary analysis sought to determine 1) how 18F-DOPA-PET changes RT volumes beyond standard MRI-planning, 2) which patients benefit most and least from this protocol, 3) which are mostly likely to experience clinically significant radionecrosis after DERT, and 4) patterns of failure after DERT. For 69 evaluable patients, median MRI-defined, PET-defined, and combined low-dose gross tumor volumes (GTV51) were 54 cc (range 9-248), 23 cc (0.4-179), and 62 cc (10-260), respectively. Median MRI-defined, PET-defined, and combined high-dose GTVs (GTV76) were 32 cc (range 4-136), 6 cc (0.1-138), and 34 cc (4-162), respectively. 18F-DOPA-PET resulted in a median volumetric expansion of 13% (0-243%) and 5% (0-217%) from MRI-defined low-dose and high-dose GTV’s, respectively. Central failures ( >95% of recurrence tumor volume) occurred within the 76 Gy, 60 Gy, and 51 Gy isodose lines in 32 (46%), 60 (87%), and 64 (93%) patients, respectively. Recursive partitioning analysis stratified patients by OS and PFS. Patients with 18F-DOPA-PET-defined GTV76 > 7.8cc, MRI-defined GTV76 > 42.7cc, and MGMT promotor-unmethylated tumors had the shortest OS, while patients with smaller PET and MRI-defined tumors had the longest OS (median 10.4 vs. 64.6 months, p< 0.001). Similarly, PFS was worst in patients with 18F-DOPA-PET-defined GTV76 > 2.17 cc who had biopsy only (median PFS 3.2 months, p< 0.001). Patients with 18F-DOPA-PET-defined GTV51 > 50 cc had the highest risk of grade 3+ radionecrosis (p< 0.001). In conclusion, larger 18F-DOPA-PET and MRI-defined tumor volumes were associated with worse outcomes, and 18F-DOPA-PET-directed DERT appears to reduce risk of central recurrence in high-dose volumes.
CTNI-30. A SNAPSHOT OF “REAL WORLD” CURRENT NEURO-ONCOLOGY PRACTICE IN TEN UK CENTRES AND RATIONALE FOR THE TESSA JOWELL BRAIN MATRIX (TJBM) PLATFORM STUDY
Authors: Wykes Victoria , Apps John , Savage Joshua , Meade Sara , Pohl Ute , Sawlani Vijay , Patel Amit , Billingham Lucinda , Thompson Gerard , Waldman Adam , Ansorge Olaf , Watts Colin
Published: November 2021

OVERVIEW

The TJBM Platform Study (https://www.birmingham.ac.uk/research/crctu/trials/brain-matrix) is a programme of work aimed at improving the knowledge of, and treatment for, glioma. We present the feasibility data collected from the initial ten UK centres.

METHOD

The UK TJBM centres completed a multi-disciplinary feasibility questionnaire to facilitate participation and collaboration across centres. Data were collected from hospital electronic board review records, clinic letters, operative and imaging notes, MDT or personal experience.

RESULTS

Work load: Between 2016-2018 service provision redistribution reflects a trend towards higher volume centres. Overall, glioma workload within ten TJBM centres has remained stable. Imaging: All TJBM centres have good access to imaging techniques and neuroradiology expertise, including relevant ‘advanced’ imaging. All have RANO capability, although not widely used clinically. Neurosurgery: All centres have access to 5 ALA, perform awake craniotomy for language assessment and motor/sensory mapping are typically performed asleep, with subtle variation in techniques. Pathology: Despite molecular analysis advances, current practice is limited to the evaluation of formalin embedded tissue by traditional morphology/ immunohistochemically staining, with limited targeted testing of specific genetic changes. Clinical oncology: Oncology treatments for glioma were as per NICE guidance with some minor local variation. A relative lack of linking treatments to detailed clinical, treatment, toxicity, and quality of life data making communication of significance of findings to patients challenging.

CONCLUSION

Through systematic real-world data collection the TJBM platform study will provide a detailed understanding of practice within the UK, linked to molecular tumour genotype, treatment response outcome measures, and regular quality of life assessments. This infrastructure will help establish a trial-competent network for future collaborative research. Academic and industry partners will be able to use the TJBM platform through collaboration, overseen by a strong governance framework. This will maximise the opportunities and abilities to translate advances into trials and patient benefit.
CTNI-31. RESECTION AND SURGICALLY TARGETED RADIATION THERAPY FOR TREATMENT OF LOCALLY RECURRENT GBM IN 28 PROSPECTIVELY TREATED PATIENTS
Authors: Smith Kris , Nakaji Peter , Thomas Theresa , Pinnaduwage Dilini , Wallstrom Garrick , Brachman David
Published: November 2021

INTRODUCTION

Recurrent GBM is a diffuse disease and resection (R) alone does not routinely provide durable local control (LC) or prolonged overall survival (OS). We hypothesized R plus immediate radiation (RT) utilizing a novel brachytherapy device might achieve more durable LC and thereby secondarily improve OS.

METHODS

From 2/2013-2/2018, locally recurrent GBM were treated in a single arm trial (ClinicalTrials.gov, NCT#03088579) of R plus immediate implantation of a surgically targeted radiation therapy (STaRT) device utilizing Cs-131 in bioresorbable collagen tiles (GammaTile, GT Medical Technologies, Tempe AZ USA).

RESULTS

28 patients (pts) were treated, 20 at first recurrence (range 1-3). Median age 58 (range 21-80), KPS 80 (60-100), female:male ratio 10:18. Median OS was 10.7 mo., radiographic LC 8.8 mo., and no first failure was local. MGMT, KPS, and sex were non-predictive. Post hoc analysis disclosed after R+STaRT, 17 pts (54%) received > 1 cycle of Sys (“Sys+”) and 13 (46%) did not (“Sys- “). Sys was given as adjuvant, salvage, or both, either alone or in combination. 15 pts received bevacizumab (BEV), 12 temozolomide (TMZ) and 8 lomustine (CCNU). Median OS (mo.) for Sys+ vs. Sys- was 15.1/6.5 (hazard ratio (HR) .38, p=.017); OS for BEV+ vs. BEV- was 16.7/4.5 (HR .38, p=.017), TMZ+ vs. TMZ- 17.5/6.7 (HR .40, p=.025) and for CCNU+ vs. CCNU- 17.5/7.9 (HR .61, p=.25), respectively. LC was 11.4 mo. for Sys+ vs. 2.1 mo. for Sys- (HR .44; p=.16). Three attributed AE occurred, 1 wound infection requiring surgery and 2 radiation brain effects, managed medically.

CONCLUSION

Post hoc analysis suggests R+STaRT+Sys may have the potential to impact OS in locally recurrent GBM, possibly by allowing sufficient time for effective but biologically slower treatments to have an impact. FDA clearance was received in 2018 for recurrent intracranial neoplasms and in 2020 for newly-diagnosed malignant brain tumors.
CTNI-33. METRONOMIC TEMOZOLOMIDE THERAPY IN HEAVILY PRETREATED PATIENTS WITH RECURRENT GLIOBLASTOMA: A LARGE MONO-INSTITUTIONAL RETROSPECTIVE STUDY
Authors: Bosio Alberto , Cerretti Giulia , Padovan Marta , Caccese Mario , Guarneri Valentina , Zagonel Vittorina , Lombardi Giuseppe
Published: November 2021

BACKGROUND

Despite advances in surgical and first-line treatment, all glioblastoma pts relapse. The aim of this study is to evaluate the benefit of metronomic temozolomide (mTMZ) for recurrent glioblastoma.

METHODS

120 pts treated at Veneto Institute of Oncology from September 2013 to March 2021 were retrospectively reviewed. Major inclusion criteria were: first-line therapy with Stupp protocol, relapse after first or subsequent line of therapy, treatment with mTMZ schedule (50mg/m2 continuously), hystologically confirmed diagnosis.

RESULTS

mFollow-up was 15.6ms, mAge 59ys (range 18-81), ECOG PS 0-2 in 107pts (89%) and 3 in 11 (9%). MGMT was methylated in 66 of 105 (62%) evaluable pts, IDH mutated in 9 of 106 (8%). mNumber of prior lines of treatment was 2 (range 1-7); 41% of pts received mTMZ beyond the third line. mTime between last standard TMZ (sTMZ) cycle and mTMZ administration was 6ms (range 1-50); 40% of pts started mTMZ after 3ms from sTMZ. All pts were evaluable for response: 3 (2%) and 48 (40%) showed PR and SD. mOS from the start of mTMZ was 5.4ms (95% CI 4.3-6.4), mPFS 2.6ms (95% CI 2.3-2.8). On univariate analysis, MGMTmet and MGMTunmet pts had a mOS of 5.6 and 4.4ms (p= 0.03); mOS for pts with ECOG PS > or ≤ 2 was 2.3 and 6.0ms (p< 0.001). On multivariate analysis, MGMTmet status (HR= 2.3, 95% CI, p= 0.004) and ECOG PS (HR= 0.5, 95% CI, p= 0.017) remained significant for PFS; ECOG PS (HR= 0.4, 95% CI, p= 0.001) was the only factor significantly associated with OS. The most common grade 3-4 hematologic toxicities were lymphopenia (10%) and thrombocytopenia (3%). Grade 3-4 nonhematologic toxicities were uncommon.

CONCLUSIONS

Rechallenge with mTMZ can be a well tolerated treatment option for recurrent glioblastoma, even in heavily pretreated pts. Pts with MGMTmet and good ECOG PS might report the major benefit.
CTNI-34. TOXICITY PROFILE AND COMPLIANCE OF PATIENTS WITH HIGH RISK GRADE 2 OR GRADE 3 GLIOMAS RECEIVING ADJUVANT PCV VERSUS ADJUVANT TEMOZOLOMIDE
Authors: Menon Nandini , Chatterjee Abhishek , Gupta Tejpal , Goda Jayant Sastri , Sridhar Epari , Sahay Ayushi , Janu Amit , Mahajan Abhishek , Puranik Ameya , Moiyadi Aliasgar , Shetty Prakash , Singh Vikas , Jalali Rakesh , Patil Vijay
Published: November 2021

INTRODUCTION

The NCCN recommends either PCV (Procarbazine, CCNU and vincristine) or Temozolomide (TMZ) as adjuvant therapy in high-risk grade 2 & grade 3 gliomas. In this ongoing study we are comparing PCV with TMZ as adjuvant therapy in this setting.

METHODS

This is a randomised phase 3 study that includes patients with high risk (as per RTOG) grade 2 gliomas and grade 3 gliomas after surgery. Patient are randomly assigned in 1: 2 to receive either adjuvant PCV or TMZ after adjuvant RT. The primary end-point is progression-free survival & key secondary end points are overall survival, toxicity and quality of life. The current analysis focuses on the compliance and adverse events seen in patients enrolled till 30th April 2020.

RESULTS

46 patients were enrolled, with 30 patients in TMZ arm. The median age of patients was 37 years (range 23-64). The ECOG PS was 1 in 45 (97.8%) patients and 2 in 1(2.2%) patient at enrolment. The number of patients who have completed all planned cycles of chemotherapy in the PCV arm is 62.5% (10, n=16) as compared to 90% (27, n=30) in the TMZ arm (P=0.047). The incidence of grade 3 or higher adverse events is 68.8% (n=11) in the PCV arm and 16.7% (n=5) in the TMZ arm (P=0.001). The most common grade 3 or higher toxicities noted are lymphopenia in 50% (n=8), neutropenia in 37.5% (n=6), and thrombocytopenia in 25% (n=4) in the PCV arm; while the corresponding numbers in the TMZ arm are 13.3% (n=4), 3.3% (n=1) and 10% (n=3) respectively.

CONCLUSION

In the current study the chemotherapy completion rates are higher with TMZ and it is associated with lower grade 3-4 events, whether this will lead to an improvement in outcomes remains to be seen.
CTNI-35. UPDATE ON THE FEASIBILITY STUDY OF OKN-007 IN COMBINATION WITH TEMOZOLOMIDE AND RADIATION IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Battiste James , Wright Deborah , Glenn Chad , Dunn Ian , Algan Ozer , Gunter Tyler , Zhao Daniel , Cohoon Andrew , Sung Sarah , Towner Rheal , Kim Hyon sook
Published: November 2021

BACKGROUND

Temozolomide (TMZ) with concurrent radiation is the traditional standard of care for newly diagnosed glioblastoma. Unfortunately, this combination has limited efficacy and resistance can render TMZ ineffective. The novel anti-cancer agent OKN-007 plus TMZ increased survival in preclinical studies. Therefore, we initiated a phase Ib/feasibility clinical trial (NCT03587038) of OKN-007 in combination with TMZ and radiation therapy (RT). We report the safety and tolerability findings of this trial in-progress.

METHODS

Adults with newly-diagnosed GBM were eligible. OKN-007 was administered by IV at 60 mg/kg. There were three treatment phases: Concomitant, Pre-Maintenance, and Maintenance. In the Concomitant Phase, patients received OKN-007 three times per week (Cohort A) or five times per week (Cohort B); all patients receive TMZ at 75 mg/m2 daily and RT at 60 Gy over 30 fractions. In the 28-day Pre-Maintenance Phase, all patients receive OKN-007 thrice weekly. In the Maintenance Phase (MP), comprising up to eighteen 28-day cycles, TMZ was dosed at 150-200 mg/m2 on days 1-5 of each cycle for six cycles. OKN-007 was administered thrice weekly for six cycles, then twice weekly for three cycles, then once weekly for nine cycles. Each cohort was evaluated for safety with 3-6 patients followed by an expansion of cohorts if safety parameters were met.

RESULTS

Three patients completed Cohort A without dose-limiting toxicity (DLT). In Cohort B, two DLT’s (hematologic toxicities deemed to be related to TMZ) occurred, and this cohort was stopped. Currently, median PFS and OS have not been reached due to lack of events, but preliminary data indicate improved median PFS and OS compared to standard of care.

CONCLUSIONS

The treatment plan appears safe and well-tolerated at the Cohort A combination dosing level and may increase favorable treatment outcomes suggesting that the OKN-007 warrants further study.
CTNI-39. IDENTIFICATION OF AN AUTOPHAGY-RELATED GENE SIGNATURE AND ESTABLISHMENT OF A NOMOGRAM PREDICTING SURVIVAL OF LOWER-GRADE GLIOMA
Authors: Wen Lei , Wang hui , Lai Mingyao , Shan Changguo , Cai Linbo
Published: November 2021

OBJECTIVE

The aim of our study was to establish an autophagy-related signature for individualized risk stratification and prognosis prediction in LGG.

METHODS

RNA-sequencing data from The Cancer Genome Atlas (TCGA), Genome Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) were used. The 232 ARGs were obtained from the Human Autophagy Database (HADb). Univariate and Lasso regression were employed to identify differentially expressed autophagy-related genes (ARGs) and establish a prognostic signature whose performance was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell’s concordance index (C-index) and calibration curve.

RESULTS

Fifty-three autophagy-related DEGs were identified. Four autophagy-related genes (DIRAS3, GNAI3, PTK6, and BIRC5) were selected to establish the prognostic signature and verified in the CGGA validation cohorts. Univariate and multivariate Cox regression indicated that the autophagy signature (HR, 95%CI, P) was an independent predictor of prognosis in LGG. Finally, a prognostic nomogram incorporating age, grade, targeted therapy, new event, tumor status and autophagy signature achieved excellent predicative performance (AUC 0.907, 0.865 and 0.858 for 1-year, 3-year and 5-year survival, respectively) verified by Time-dependent ROC, C-index (0.844, 95% CI, 0.799 to 0.889; P = 1.01e-12) and calibration plots.

CONCLUSION

The present study constructed a robust four autophagy-related gene signature. A prognostic nomogram in risk stratification and prediction of overall survival in LGG was established. The findings may be beneficial to individualized survival prediction and medical decision-making for LGG.
CTNI-50. REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: A LARGE REAL-LIFE EXPERIENCE
Authors: Caccese Mario , Cerretti Giulia , Padovan Marta , Zagonel Vittorina , Lombardi Giuseppe
Published: November 2021

INTRODUCTION

Regorafenib (REG), an oral multikinase inhibitor, showed benefit in recurrent GBM (recGBM) patients in the REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recGBM patients treated at Veneto Institute of Oncology as off-label use.

MATERIAL AND METHODS

Patients receiving REG were entered prospectively on a clinical database. Data were retrospectively analyzed. The primary endpoints were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression by RANO criteria after Stupp protocol, ECOG PS ≤ 2. Patients received REG 160 mg per day for the first 3 weeks in a 4-week cycle. Kaplan-Meier method was used to estimate the survival, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events.

RESULTS

54 patients were enrolled: median age was 56, ECOG PS 0-1 in 91%, MGMTmet in 53%, second surgery at the time of relapse in 30%. Median follow-up was 11.1ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. MedianOS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; medianPFS was 2.3 ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. Disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT(2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%.

CONCLUSIONS

We reported a “real-world” experience of REG in recGBM patients. Results are close to those reported in REGOMA trial; we showed a longer OS. Toxicity was manageable. Encouraging clinical benefits of REG in recGBM population were confirmed.
CTNI-57. MATRix REGIMEN FOR NEWLY DIAGNOSED PRIMARY DIFFUSE B-CELL LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM
Authors: Green Richard , Guzman-Marin Ruben , Lam Keng , Thornton Colleen
Published: November 2021

We report our experience treating 20 patients with newly diagnosed primary diffuse B-cell lymphoma of the central nervous system with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 65 y; 8 patients were men and 12 were women. Eighteen had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 14 patients completed initial chemotherapy. Twelve of these 14 went on to transplantation; one patient had early disease progression, and in one no stem cells could be collected. All 4 patients over 70 y died early after 1-2 cycles; the median age of these was 80 y, and the causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One patient who completed the entire regimen including transplantation died of fungal pneumonia; the other 13 experienced no serious acute toxicity. One patient had late disease progression; one developed symptomatic leukoencephalopathy. Thirteen of the 20 patients remain alive. Median OS for the cohort is 698 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 70 y suggests that the regimen may be too toxic for elderly individuals.
DDRE-02. PATIENTS WITH LEPTOMENINGEAL METASTASES FROM NSCLC BENEFITED FROM INTRATHECAL PEMETREXED AFTER FAILURE TO TYROSINE KINASE INHIBITORS: TWO CASE REPORTS
Authors: Ye Minting , Wen Lei , Zhou Jiangfen , Cai Linbo
Published: November 2021

BACKGROUND

The incidence of leptomeningeal metastasis (LM) is 3%-5% in NSCLC patients; the incidence is even higher in patients with EGFR mutations or ALK gene rearrangement. The prognosis of NSCLC patients with LM is poor with an overall survival (OS) of 3 months with contemporary treatment.

METHODS

Here we report two cases of patients with leptomeningeal metastases from NSCLC who benefited from intrathecal pemetrexed after failure to tyrosine kinase inhibitors(TKIs).

RESULTS

A 53-year-old woman, diagnosed with adenocarcinoma of the lung with ALK rearrangement, suffered form right limb weakness, dysphagia after multi-line targeted therapy and radiotherapy for brain metastases. Evaluation revealed a rapidly progressing right brainstem mass and diffuse leptomeningeal enhanced. And cytological examination of CSF showed neoplastic cells, which definitely diagnosed as LM. After first intrathecal injection of 30mg pemetrexed every three weeks, the patient's symptoms improved. There were no significant treatment side effects and the quality of life was not affected during the five subsequent treatments. Another patient was a 32-year-old man, diagnosed with adenocarcinoma of the lung with EGFR E24-RAD51E4 fusion mutation with KPS score 30. LM was confirmed after multiline therapy. He suffered form blurred vision and drooping eyelid. Similarly, after first intrathecal injection of 20mg pemetrexed every week, the patient's symptoms improved and KPS score increased gradually. And level II leukopenia was detected during subsequent treatments. Combined with intrathecal pemetrexed progression-free survival (PFS) were 3 months in two NSCLC patients with LM harboring ALK/EGFR mutation . And the quality of life of patients were effectively increased.

CONCLUSION

Combination therapy third generation EGFR/ALK agents with intrathecal chemotherapy might be benefited in overall survival.
DDRE-06. TARGETING THE SPHINGOLIPID BALANCE VIA ACID CERAMIDASE INHIBITION TO DECREASE GROWTH OF TMZ-RESISTANT GLIOBLASTOMA AND BLOCK MIGRATION
Authors: Hawkins Cyntanna , Jones Amber , Ziebro Julia , Gordon Emily , Libby Catherine , Williford Sarah , Allegood Jeremy , Cooper Sara , Ramanadham Sasanka , Doan Ninh , Hjelmeland Anita
Published: November 2021

Dysregulated sphingolipid metabolism is associated with many cancers; allowing cells to evade apoptosis through increases in sphingosine-1-phosphate (S1P) and decreases in ceramides. Ceramides can be hydrolyzed by ceramidases to sphingosine, which can then be phosphorylated by sphingosine kinases to S1P. S1P allows cells to evade apoptosis and increase migration, while shifts toward ceramides favor cell death. Glioblastoma (GBM) exhibits shifts in the sphingolipid balance towards S1P, contributing to chemoresistance and migration. Understanding of sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target the dysregulation. Acid ceramidase (ASAH1), a key enzyme in the production of S1P, is highly expressed in GBM and is associated with worse survival of GBM patients, as per The Cancer Genome Atlas data. To address the altered sphingolipid metabolism and therapeutic resistance in GBM, we explored the efficacy of pharmacologic and genetic inhibition of ASAH1 in both parental and temozolomide (TMZ)-resistant patient-derived xenografts. Cells were infected with ASAH1 shRNA or treated with ASAH1 inhibitors and assessed for cell growth and migration. Our work suggests that pharmacologic inhibition of ASAH1 induces cell death and that this effect is maintained in TMZ-resistant cells. Furthermore, we find a novel role for carmofur, an ASAH1 inhibitor, in the inhibition of GBM migration. Together, these data suggest the potential utility of normalizing the sphingolipid balance in the context of GBM TMZ resistance.
DDRE-15. Sema3C SIGNALING CONFERS RESISTANCE TO Wnt INHIBITION IN GLIOBLASTOMA
Authors: Hao Jing , Han Xiangzi , Huang Haidong , yu xingjiang , Bao Shideng , Prayson Richard , Yu Jennifer
Published: November 2021

BACKGROUND

Wnt signaling is widely dysregulated in cancer. The therapeutic potential of Wnt inhibitors appears promising in preclinical studies. However, they have uniformly failed clinical trials. How cancer cells develop Wnt inhibitor resistance is poorly understood. Current Wnt inhibitors are designed targeting either ligand or receptor. We hypothesized cancer cells will bypass ligand-receptor interaction through an unknown mechanism. We focused on the neurodevelopmental signaling program of Semaphorin 3C (Sema3C) that is upregulated in 85% of GBM and regulates glioma stem-cell-driven tumor progression.

RESULTS

Porcupine inhibitor LGK974 reduced TCF1 expression in the GBM tumor mouse models, suggesting successful target engagement in vivo. However, it failed to prolong the overall survival. Sema3C expression strongly correlated with TCF1 expression in human GBM samples by immunohistochemical analysis. Genetic inhibition of Sema3C and TCF1 together prolonged animal survival more than either alone, indicating better control of Wnt pathway signaling with dual pathway blockade. Immunofluorescence and cell fractionation studies revealed that Sema3C signaling drove β-catenin nuclear accumulation. Sema3C regulates transactivation of Wnt target genes including TCF1, c-Myc and c-Met. Sema3C pathway activates Rac1. It is reported that Rac1 activates β-catenin and promotes β-catenin nuclear accumulation. In GSCs, constitutively active Rac1 restored β-catenin nuclear localization and rescued TCF1 and c-Myc down-regulation in the setting of Sema3C silencing. Sema3C can drive canonical Wnt signaling even when Wnt ligand secretion is blocked. Together, the data support that GSCs can escape Wnt inhibition through Sema3C and Rac1.

CONCLUSIONS

Sema3C signaling drives canonical Wnt signaling, providing an escape mechanism for cancer cells despite Wnt ligand-receptor interruption. Sema3C-β-catenin signaling promotes GSC self-renewal and tumor progression. Upstream Wnt pathway inhibition alone is insufficient to control tumors. Our data provide a therapeutic strategy of dual blockade of Wnt and Sema3C pathways to provide clinically significant tumor control.
DDRE-16. DRUG REPURPOSING SCREEN REVEALS GLIOBLASTOMA CELL LINE SUSCEPTIBILITY TO STATINS
Authors: Harwood Dylan , Michaelsen Signe , Mundt Filip , Kristensen Bjarne
Published: November 2021

BACKGROUND

The standard therapy for glioblastoma patients is tumor resection followed by radiotherapy and temozolomide chemotherapy. Although glioblastoma has been extensively molecularly profiled along with other cancers, this knowledge has not yet been translated into improved survival outcomes. We used a bioinformatics approach to identify potential novel therapeutic strategies for glioblastoma. OBJECTIVES: Comprehensive online datasets which have assessed up to 1376 cancer cell lines in multiple ways were interrogated to identify potential drug candidates for glioblastoma.

METHODS

Datasets included were from the cancer cell line encyclopedia (mRNA expression), the Achilles project (cell viability following Crispr-Cas9 knockout) and PRISM (drug treatment). A t-test comparing cell viability of glioblastoma cell lines versus other cancers was used to identify potential drug candidates, followed by the use of multiple statistical tools to investigate potential mechanism of action and status of biomarkers.

RESULTS

Fluvastatin and pitavastatin produced the most significant effects in glioblastoma cell lines. The anti-cancer properties of statins have previously been attributed to the inhibition of HMG-Coa reductase. Here, we found their effects correlated with erastin, an enhancer of ferroptosis and with gene knockout of UBIAD1, which participates in non-mitochondrial ubiquinone synthesis. These effects were both found in glioblastoma cells and other cancers with a mesenchymal-like phenotype.

CONCLUSION

Statins appeared to be especially effective against glioblastoma lines and the effect could be linked to ferroptosis and inhibition of UBIAD1. In vitro validation of this finding is ongoing.
DDRE-17. TARGETING GLIOBLASTOMA’S GALACTOSE SCAVENGING PATHWAY
Authors: Sharpe Martyn , Baskin Alexandra , Baskin Brianna , Baskin David , Raghavan Sudhir
Published: November 2021

BACKGROUND

We have recently shown that GBM use D-galactose (Gal) as a substrate, in vitro and in vivo. Gal is imported via Glut3 and/or Glut14 and metabolized through the Leloir pathway. We investigated 4-deoxy-4-fluorogalactose (4DFG) as the lead compound in a family of galactose-based antimetabolites. 4DFG is a potent chemotherapeutic in monotherapy and can bolster existing therapies.

METHODS

We examined the alteration of glioma metabolism in vitro and in vivo induced by 4DFG. 1H/13C-NMR and optical probes were used to interrogate the effects of 4DFG on glycolysis and mitochondrial respiration in primary glioma cell cultures. Labeled lectins were used to assay for the disruption of glycan synthesis induced by 4DFG. An intracranial model of primary GBM was used to assess efficacy and toxicity in vivo.

RESULTS

NMR reveals that at physiological concentrations of glucose, low concentrations of 4DFG (5 μM) is able to inhibit glycolytic and mitochondrial flux by approximately 12%, p< 0.05. Analysis using lectins shows a collapse in general glycan synthesis, but most especially in the incorporation of both Gal and GalNAc sugars. In nude mice with intracranial primary GBM, six treatments of 4DFG increased survival from 23 to 50 days, p< 0.002.

DISCUSSION

The ability of GBM to scavenge galactose allows us to target the Glut3/14 import and Leloir metabolic pathway using galactose-based anti-metabolites. Our first-generation compound is highly effective as a monotherapy, inhibiting glucose metabolism and glycan synthesis.
DDRE-26. INHIBITION OF PRMT5 SENSITIZES GLIOBLASTOMA MODELS TO TRAMETINIB TREATMENT
Authors: Banasavadi Yesh , Namagiri Sriya , Otani yoshihiro , Thammegowda Shilpa , Sur Hannah , Rivas Sarah , Bryant Jean-Paul , Chowdhury Ashis , Lewis Cole , Shimizu Toshihiko , Walbridge Stuart , Lee Tae Jin , Maric Dragan , Yoo Ji Young , Heiss John , Kaur Balveen
Published: November 2021

With limited effective therapeutic strategies, the prognosis for glioblastoma (GBM) is very poor. Our previous study shows that the expression of Protein Arginine Methyltransferase 5 (PRMT5) is upregulated in GBM; its inhibition promotes apoptosis and senescence in differentiated and stem-like tumor cells, respectively. MEK inhibitors, including trametinib, are currently under investigation for GBM therapy. In this study, we tested whether inhibition of PRMT5 can enhance the anti-GBM efficacy of trametinib. Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, ELISA, and western blot analysis were conducted. In vivo, PRMT5-intact and -depleted GBMNS were intracranially implanted in NSG mice and treated with trametinib by daily oral gavage, and tumor progression and mice survival rate were analyzed by MRI and Kaplan-Meier survival curve, respectively. Depletion of PRMT5 increased the cytotoxic effect of trametinib in GBMNS. Trametinib treatment increased the activity of ERBB3 and AKT; With PRMT5 knockdown, the activity of both AKT and ERBB3 decreased significantly. But, inhibition of ERBB3 alone failed to block the trametinib-induced AKT activity suggesting that even though PRMT5 regulates the activity of both ERBB3 and AKT, the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib treated GBMNS is because of AKT inhibition alone. In vivo, PRMT5-depletion extended the survival of the tumor-bearing mice that further increased in combination with trametinib treatment. Interestingly, trametinib treatment alone had no survival benefit.
DDRE-28. IDENTIFICATION OF SYNERGISTIC DRUG COMBINATIONS FOR THE THERAPY OF IDHmut GLIOMA
Authors: Warta Rolf , Stammler Florian , Unterberg Andreas , Herold-Mende Christel
Published: November 2021

OBJECTIVE

Isocitrate Dehydrogenase (IDH) mutation in glioma results in a multitude of biological differences with consequences for survival and therapy response. Therefore, IDH mutated (IDHmut) and wildtype (IDHwt) tumors are regarded as separate entities with the need for adjusted therapy like the combination of procarbazine, CCNU and vincristine (PCV). However, as vincristine has often severe side effects like neuropathy new effective therapy options are required. Therefore, we searched for combinations of FDA-approved drugs which effectively inhibit the growth of IDHmut cells in vitro.

METHODS

We tested different drug combinations of a drug library consisting of 146 FDA-approved drugs on two established IDHmut GSC lines. Based on a previous single agent drug screen, six drugs were selected (Idarubicin, Ixazumib, Ponatinib, Neratinib, Romidepsin) to be combined with all 146 drugs of the library. Cell viability was assessed by the CellTiterGlo 3D assay (Promega) in 96 well plates, while Caspase-Glo 3/7 3D assay was used to measure induction of apoptosis.

RESULTS

Out of 1460 drug combinations tested altogether 21 synergistic drug combinations could be identified and validated. The combination with the highest blood-brain-barrier permeability score was further investigated. Finally, drug-concentrations elucidating the highest synergistic effect on proliferation was further studied in a 8-point dose-response matrix followed by validation in additional four IDHmut GSC lines.

CONCLUSION

This work can lay the foundation for future improvements of the therapy of patients suffering from LGGs.