Recurrent Low-grade Gliomas Research Articles

Identification of Novel Prognostic Signature of Recurrent Low-Grade Glioma

The prognosis of patients with recurrent low-grade glioma (rLGG) varies greatly. Some patients can survive more than 10 years after recurrence, while other patients have less than 1 year of survival. In order to identify the related risk factors affecting the prognosis of rLGG patients, we performed a series of bioinformatics analyses on RNA-sequencing data of rLGG based on the CGGA database, and finally constructed a 12-genes prognostic signature, dividing all the rLGG patients into high- and low-risk subgroups. The result showed an excellent predictive effect in both the training cohort and the validation cohort using LASSO-COX regression. Moreover, multivariate COX analysis identified 4 independent prognostic factors of rLGG, and among them, ZCWPW1 is identified as a high-value protective factor. In all, this prognostic model displayed robust predictive capability for the overall survival (OS) of rLGG patients, providing a new monitoring method for rLGG, and the 4 independent prognostic factors, especially ZCWPW1, can be potential targets for rLGG, bringing new possibilities for the treatment of rLGG patients.

LMIC-02. FREQUENCY OF NTRK FUSIONS IN PEDIATRIC LOW GRADE GLIOMAS. DATA FROM A SINGLE CENTER IN MONTERREY, MEXICO

Abstract BACKGROUND Neurotrophic tyrosine receptor kinases (NTRK 1-3)fusions have been identified in a range of pediatric cancer. Among children with cancer NTRK fusions can be detected in less than 1% of cases. Low grade gliomas (LGG) are the most pediatric brain tumors and the frequency of NTRK fusions reported is between 0.4 -4.3%. NTRK2 fusions are the most commonly reported in pediatric brain tumors. METHOD We describe the characteristics of patients analysed. Due to limited access to Next Generation Sequencing (NGS) only patients with recurrent, progressive, metastatic or midline location LGG were tested during 2021-2022. Positivity to Pan-Trk immunohistochemistry was needed to proceed to confirmation with NGS. 10 patients with LGG were included. Median age of patients at baseline was 4.7 (range,1-12) years. 10/10 showed positivity to Pan-Trk stain and NTRK fusions were detected in 6/10 patients, 3/6 had NTRK1 fusions, 2/6 NTRK2 fusion and 1 with NTRK3 fusion.. All 4 patients without NTRK fusions are off therapy (more than 1 year survellaince) and 2/4 were treated with surgery only. All patients with NTRK fusions are still on treatment due to progressive disease, 4/6 patients have required 2 or more surgeries and 5/6 patients have needed 2 or more chemotherapy regimens. CONCLUSION This small cohort of patients represents a highly selected population with LGG and the frequency of NTRK fusions resulted significantly higher than expected (6 out of 10 patients tested). This finding could reflect a clinical or prognostic significance, it will be important to analyze a larger cohort of patients that share these same clinical characteristics to determine its real value as a prognostic marker in these heavily treated patients. There is well known molecular alterations that predict outcome in patients with LGG. NTRK targeted therapy already exists with proven efficacy although access may limits its use.

The safety and efficacy of bevacizumab in treatment of recurrent low-grade glioma: a systematic review and meta-analysis.

Central nervous system (CNS) tumors are among the most common malignancies in various age ranges. Low-grade glioma (LGG) can account for nearly 30% of pediatric CNS malignancies. Progression or recurrence after the first-line treatments is common among these patients. Therefore, more treatments are required. Bevacizumab as an anti-VEGF antibody has come into the spotlight recently and is especially used in relapse or recurrence settings. This review aims to study the safety and efficacy of bevacizumab for patients with recurrent LGG. This study was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Scopus, Web of Science, and Embase were comprehensively searched using the relevant key terms until 24th August 2023 to retrieve the studies that investigated clinical outcomes of bevacizumab in patients with recurrent LGG. All statistical analysis was performed by STATA v.17. A total of 1306 papers were gathered, out of which 13 were incorporated in the meta-analysis. The pooled incidence rate of treatment according to the RANO scale was 70% (95% CI = 43-98%) for objective response rate, 26% (95% CI = 58-96%) for partial response, 21% (95% CI = 15-28%) for minor response, 14% (95% CI = 3-24%) for complete response, 48% (95% CI = 37-59%) for stable disease, and 8% (95% CI = 4-11%) for progressive disease. Furthermore, according to progressive survival after treatment, it was 4% (95% CI = -1 to 9%) for 6-month PFS, 41% (95% CI = 32-50%) for 2-year PFS, and 29% (95% CI = 22-35%) for 3-year PFS. According to the RANO scale and PFS, clinicians should be aware that Bevacizumab could be a favorable alternative therapy for recurrent LGG. Furthermore, bevacizumab exhibits minimal toxicity and high tolerability in recurrent LGG.

Characterization and clinical implications of different malignant transformation patterns in diffuse low-grade gliomas.

Malignant transformation (MT) of low-grade gliomas (LGGs) to a higher-grade variant seems inevitable, yet it remains unclear which LGG patients will progress to grade 3 or even directly to grade 4 after receiving a long course of treatment. To elucidate this, we conducted a retrospective cohort study based on 229 adults with recurrent LGG. Our study aimed to disclose the characteristics of different MT patterns and to build predictive models for patients with LGG. Patients were allocated into group 2-2 (n = 81, 35.4%), group 2-3 (n = 91, 39.7%), and group 2-4 (n = 57, 24.9%), based on their MT patterns. Patients who underwent MT showed lower Karnofsky performance scale (KPS) scores, larger tumor sizes, smaller extents of resection (EOR), higher Ki-67 indices, lower rates of 1p/19q codeletion, but higher rates of subventricular involvement, radiotherapy, chemotherapy, astrocytoma, and post-progression enhancement (PPE) compared with those in group 2-2 (p < 0.01). On multivariate logistic regression, 1p/19q codeletion, Ki-67 index, radiotherapy, EOR, and KPS score were independently associated with MT (p < 0.05). Survival analyses demonstrated that patients in group 2-2 had the longest survival, followed by group 2-3 and then group 2-4 (p < 0.0001). Based on these independent parameters, we constructed a nomogram model that exhibited superior potential (sensitivity: 0.864, specificity: 0.814, and accuracy: 0.843) compared with PPE in early prediction of MT. Combining the factors of 1p/19q codeletion, Ki-67 index, radiotherapy, EOR, and KPS score that were presented at initial diagnosis could precisely forecast the subsequent MT patterns of patients with LGG.

BIOL-20. BIOPROCESSING OF SURGICAL PEDIATRIC BRAIN TUMOR SPECIMENS FOR GENOME-GUIDED PERSONALIZED DRUG TESTING

Abstract Novel treatment approaches are urgently needed for pediatric central nervous system (CNS) tumors as they are the leading cause of cancer-related deaths in children. A lack of research materials impedes progress towards developing such therapies. Although various brain cancer biobanks exist, these rarely store viable patient-derived tissue and cells for live cell analyses, including cell fate assays and testing for drug sensitivities. We propose that a biorepository of viable cell dissociates and tissue broadly representing CNS tumor entities overcomes these limitations. From a combination of molecular diagnoses and histopathologic assessment of over 90 samples collected, we generated a biorepository of roughly 35 distinct entities of pediatric CNS tumors in our Stanford neuro-bioprocessing cohort. Based on the Central Brain Tumor Registry of the United States, the proportion of subtypes represented in our cohort match that of the general population with exceptions. We established a standardized bioprocessing pipeline that can be used as a template for tissue collection and model development in the broader disease context and for multiple downstream applications. Our emphasis on cryostorage of viable cells and tissue facilitates ad hoc live cell analyses. In addition to gaining a better understanding of tumor pathophysiology, we attempted a rapid bed-to-bench-to-bedside approach using comparative RNA expression profile analyses in an individual patient’s pilocytic astrocytoma. Novel drug targets were identified by analyzing RNA transcripts that are highly expressed (outliers) compared with a compendium of 12,747 brain and non-brain tumor samples. We validated outliers as drug targets using acute cell isolates, and identified a novel target in recurrent low-grade glioma. These studies illustrate that biobanking of viable patient-derived material enables developing personalized therapies with the goal of improving patient outcomes. As demonstrated here, patient-derived acute cell isolates facilitate identifying drug vulnerability, creating an opportunity for more personalized treatment of patients with CNS tumors.

Clinical activity of pan-RAF inhibitor tovorafenib in the registrational pediatric low-grade glioma arm of the phase 2 FIREFLY-1 (PNOC026) study.

10004 Background: Pediatric low-grade gliomas (LGGs) are the most common brain tumors of childhood. Genomic alterations of BRAF ( KIAA1549-BRAF fusions, 50–60% and BRAF V600E mutations, 5–15%) are the most frequent oncogenic drivers in pLGGs. Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II pan-RAF inhibitor. Tovorafenib has demonstrated clinically meaningful responses in 24/35 patients (2 CR, 7 PR and 15 SD) in the pediatric phase 1B PNOC014 (NCT03429803) trial in patients with RAF-altered cancers (Wright, SNO 2022). Methods: FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the efficacy and safety of tovorafenib monotherapy in patients with BRAF-altered cancers. Registrational arm 1 of FIREFLY-1 includes patients 6 months–25 years of age with recurrent or progressive LGG previously treated with ≥1 prior line of systemic therapy. Tovorafenib 420 mg/m2 (not to exceed 600 mg) is administered weekly, in 28-day cycles, (tablet or liquid suspension formulation) until progression. The primary endpoint of arm 1 is ORR, as defined by Response Assessment in Neuro-Oncology (RANO) criteria and determined by blinded independent review. Results: As of September 28, 2022, arm 1 had enrolled 77 patients and is fully accrued. All patients had ≥6 months of follow-up. Median age at enrollment was 8 years (range 2–21). Patients were pretreated with a median of 3 prior lines of systemic therapy (range: 1–9); 60% had received prior MAPK pathway-targeted agents. The most common tumor site was optic pathway (51%). Sixty-four patients harbored a BRAF fusion/rearrangement (83%) in their tumors, and 13 (17%) had a BRAF V600E mutation. Median duration of tovorafenib treatment is 8.4 months (range 0.7–16.8), with 59 patients (77%) remaining on treatment at the time of data cutoff. Per independent assessment in 69 RANO-evaluable patients, ORR was 64%, [3 CR, 41 PR (10 unconfirmed) and 19 SD] with a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations, including those previously treated with MAPK inhibitors. The most common treatment-related adverse events (TRAEs) of any grade were hair color changes (75%), increased creatine phosphokinase (64%), anemia (46%), fatigue (42%) and maculopapular rash (42%). Tovorafenib dose modifications occurred in 16 (21%) and discontinuations in 2 (3%) patients due to TRAEs. Updates from a longer follow-up on the 77 patients in arm 1 will be presented at the meeting. Conclusions: Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children and young adults with recurrent/progressive BRAF-altered pLGG. LOGGIC/FIREFLY-2 (NCT05566795), a global, phase 3 trial is evaluating once-weekly tovorafenib monotherapy in newly-diagnosed patients with pLGG harboring a known activating RAF alteration. Clinical trial information: NCT04775485 .

Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of d-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1–97.6) and 91.1% (95% CrI, 72.0–97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of ‘proneural’ and ‘stemness’ gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.

Recurrent insular low-grade gliomas: factors guiding the decision to reoperate.

Reoperation has been established as an effective therapeutic strategy in recurrent diffuse low-grade gliomas (LGGs). Insular gliomas represent a specific surgical challenge because of the surrounding vascular and functional structures. The aim of this study was to investigate the main clinicoradiological factors guiding the decision to reoperate on recurrent insular LGGs (ILGGs). In this retrospective consecutive series, the authors screened all patients operated on for an ILGG in their institution who further presented with a tumor regrowth without the development of contrast enhancement. They compared patients who were subsequently offered a reoperation under awake mapping at recurrence or who underwent reoperation after adjuvant treatment had reduced the volume of the initial tumor recurrence (with a proven pathological diagnosis of LGG after the second surgery) to patients who were not selected for a reoperation. The first group (reoperated group; n = 20) included all recurrent ILGG patients who underwent second resection, and the second group (nonreoperated group; n = 60) included patients who did not undergo reoperation but underwent adjuvant oncological treatment. Factors significantly associated with reoperation were extent of resection (EOR) at first surgery (91.9% vs 89.7%, p = 0.014), residual tumor volume (9.5 ± 7.1 mL [range 0-30 mL] vs 6.3 ± 7.3 mL [range 0-30 mL], p = 0.02) at first surgery and left temporopolar infiltration at the time of tumor recurrence (Liebermeister statistical analysis, 4293 voxels survived false discovery rate correction with p < 0.05; maximal z-statistic = 6.50). Infiltration of the anterior perforated substance at tumor recurrence was significantly anticorrelated to reoperation (179 voxels survived false discovery rate correction with p < 0.05; minimal z-statistic = -4.33). The mean EOR was 83.7% at reoperation with a 90% survival rate at last follow-up (9.3 ± 3.8 years), low postsurgical morbidity (Karnofsky Performance Status score ≥ 80 in 95% of patients), a high rate of postoperative professional resumption (95%), and seizure control in 57.1% of patients. In selected patients with recurrent ILGG without radiographic evidence of malignant transformation, reoperation with intraoperative awake mapping is associated with favorable oncological outcomes and a low postsurgical morbidity. A greater EOR and a lower residual tumor volume at first surgery were significantly associated with reoperation. Patients who benefited from a second surgery typically had a recurrent pattern within cortical areas (such as the temporopolar region), while other patients typically presented with a deeper infiltrative pattern within the anterior perforated substance and the surrounding white matter pathways. Such original findings may be helpful to select the optimal indications of reoperation in recurrent ILGG.

LTBK-04. LATE BREAKING ABSTRACT: MEK162 (binimetinib) in children with progressive or recurrent low-grade glioma: a multi-institutional phase II and target validation study

BACKGROUNDRAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (pLGG). MEK162 (binimetinib) is an orally bioavailable MEK1/2 inhibitor with superior brain penetration in a preclinical model. The primary objective of this multi-institutional phase II and target validation study was to assess stratum-specific efficacy of binimetinib in progressive pLGG.METHODSEligible children aged 1-18 years with previously treated radiographically progressive pLGG were enrolled and treated with binimetinib, starting dose 32mg/m2/dose twice daily. Stratum 1 included patients with pLGG with documented BRAF fusion; stratum 2, neurofibromatosis 1 (NF1)-associated pLGG; stratum 3, sporadic pLGG without documented BRAF fusion; and stratum 4, patients undergoing planned tumor biopsy who began binimetinib preoperatively. Partial and minor responses (PR and MR) were defined as ≥50% and ≥25% decrease in maximal two-dimensional measurements.RESULTSOf 86 patients enrolled, 85 were evaluable for response. Of these, 48 (56%) showed a radiographic response (30 PR and 18 MR) in the first year of treatment. Response rate for stratum 1 (n=28) was 50% (12 PR and 2 MR); 12 (43%) had stable disease (SD) and 2 (7%) progressive disease (PD). Stratum 2 (n=21) response rate was 43% (5 PR, 4 MR), with 12 (57%) SD and no PD. Stratum 3 (n=29) response rate was 69% (10 PR, 10 MR), 4 (14%) SD and 5 (17%) PD. Stratum 4 (n=7) include 3 PR, 2 MR, 2 SD. Nineteen (22%) discontinued treatment for toxicity (most commonly dermatologic), and an additional 42 (49%) required dose reduction. Median dose at the time of PR/MR was 28mg/m2; responses were seen at doses as low 16mg/m2.CONCLUSIONBinimetinib is highly effective in the treatment of both NF1-associated and sporadic pLGG, with or without documented BRAF fusion. Modified dosing strategies to improve tolerability may be considered in future trials.

IMG-01. Quantitative Direct Sodium (23Na) MRI in Pediatric Gliomas

BACKGROUND: The treatment of pediatric gliomas is typically assessed with proton (1H) MRI, which can have limitations. 23Na MRI has been shown in adult brain tumors to measure intra-tumoral total sodium concentration as a correlate of tumor proliferation. 23Na MRI sodium studies in pediatric patients are lacking. PURPOSE: (1) To compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) Compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging. MATERIALS AND METHODS: TSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas [diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)] on sodium MRI images co-registered with proton MRI. In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed for tissue conspicuity using voxel-based parametric maps. RESULTS: Twenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9 – 23.3 years) were scanned with 23Na MRI. Uninvolved tissues demonstrated a range of TSC values similar to published adult values. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (P<0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (P<0.002 for LGG, and P<0.02 for HGG). The dual echo 23Na MRI suppresses the sodium signal within both CSF and necrotic foci, resulting in improved conspicuity of both non-neoplastic and neoplastic, compared to serial TSC imaging. CONCLUSION: Quantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging. Future studies are needed to determine the value of 23Na MRI in delineating therapeutic responses in pediatric gliomas.

FIREFLY-1 (PNOC 026): A phase 2 study to evaluate the safety and efficacy of tovorafenib (DAY101) in pediatric patients with RAF-altered recurrent or progressive low-grade glioma or advanced solid tumors.

TPS10062 Background: RAF gene fusions ( BRAF and RAF1) and BRAF V600E mutations are oncogenic drivers found on a mutually exclusive basis in most pediatric low-grade gliomas (LGGs). In addition, RAF fusions ( BRAF and RAF1) have also been identified in other pediatric solid tumors. Tovorafenib (DAY101) is an investigational, oral, highly selective, CNS-penetrant, small molecule, type II pan-RAF inhibitor. In contrast to type I BRAF inhibitors, tovorafenib does not induce RAS-dependent paradoxical activation of the MAPK pathway. In the phase 1 PNOC014 study in pediatric patients with recurrent/progressive LGG, tovorafenib was well tolerated and 7/8 patients with tumor harboring RAF fusions had meaningful clinical benefit. Recently, a child with a novel SNX8-BRAF fusion spindle cell sarcoma demonstrated a rapid and deep response when treated with tovorafenib. Methods: FIREFLY-1 (NCT04775485) is an open-label, multicenter, phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy in pediatric patients with RAF-altered recurrent or progressive LGG or advanced solid tumors. The initial design included only patients with LGG (arm 1). Two new arms have now been added; arm 2 will allow tovorafenib treatment for patients with LGG harboring an activating RAF alteration after completion of enrollment to arm 1 and prior to tovorafenib regulatory approval; arm 3 will enroll patients with advanced solid tumors harboring an activating RAF fusion. Eligible patients are 6 months to 25 years of age, who have received ≥1 prior line of systemic therapy with documented radiographic progression, have evaluable and/or measurable disease by appropriate criteria, a Karnofsky or Lansky performance score of at least 50, and adequate organ function. Patients are excluded if their tumor has other driver mutations, they have neurofibromatosis type 1, central serous retinopathy, retinal vein occlusion, clinically significant active cardiovascular disease, or are currently being treated with a strong CYP2C8 inhibitor or inducer other than those allowed per protocol. Approximately 140 patients in total will be enrolled including 60 in arm 1, 60 in arm 2 and 20 in arm 3. Tovorafenib will be administered at 420 mg/m2 (not to exceed 600 mg) weekly (days 1, 8, 15 and 22) for 26, 28-day cycles (in the absence of disease progression or unacceptable toxicity). They may then continue tovorafenib or enter a drug holiday period. The primary endpoint is overall response rate, as defined by the RANO criteria (arm 1) or RECIST v1.1 (arm 3) and as determined by an independent radiology review committee. Secondary endpoints (arms 1 and 3) include safety and tolerability, pharmacokinetics, duration of response, time to response and progression-free survival. Tovorafenib is available in tablet or liquid suspension formulations. Clinical trial information: NCT04775485.

Recurrence- and Malignant Progression-Associated Biomarkers in Low-Grade Gliomas and Their Roles in Immunotherapy.

Despite a generally better prognosis than high-grade glioma (HGG), recurrence and malignant progression are the main causes for the poor prognosis and difficulties in the treatment of low-grade glioma (LGG). It is of great importance to learn about the risk factors and underlying mechanisms of LGG recurrence and progression. In this study, the transcriptome characteristics of four groups, namely, normal brain tissue and recurrent LGG (rLGG), normal brain tissue and secondary glioblastoma (sGBM), primary LGG (pLGG) and rLGG, and pLGG and sGBM, were compared using Chinese Glioma Genome Atlas (CGGA) and Genotype-Tissue Expression Project (GTEx) databases. In this study, 296 downregulated and 396 upregulated differentially expressed genes (DEGs) with high consensus were screened out. Univariate Cox regression analysis of data from The Cancer Genome Atlas (TCGA) yielded 86 prognostically relevant DEGs; a prognostic prediction model based on five key genes (HOXA1, KIF18A, FAM133A, HGF, and MN1) was established using the least absolute shrinkage and selection operator (LASSO) regression dimensionality reduction and multivariate Cox regression analysis. LGG was divided into high- and low-risk groups using this prediction model. Gene Set Enrichment Analysis (GSEA) revealed that signaling pathway differences in the high- and low-risk groups were mainly seen in tumor immune regulation and DNA damage-related cell cycle checkpoints. Furthermore, the infiltration of immune cells in the high- and low-risk groups was analyzed, which indicated a stronger infiltration of immune cells in the high-risk group than that in the low-risk group, suggesting that an immune microenvironment more conducive to tumor growth emerged due to the interaction between tumor and immune cells. The tumor mutational burden and tumor methylation burden in the high- and low-risk groups were also analyzed, which indicated higher gene mutation burden and lower DNA methylation level in the high-risk group, suggesting that with the accumulation of genomic mutations and epigenetic changes, tumor cells continued to evolve and led to the progression of LGG to HGG. Finally, the value of potential therapeutic targets for the five key genes was analyzed, and findings demonstrated that KIF18A was the gene most likely to be a potential therapeutic target. In conclusion, the prediction model based on these five key genes can better identify the high- and low-risk groups of LGG and lay a solid foundation for evaluating the risk of LGG recurrence and malignant progression.

Quantitative Sodium (23Na) MRI in Pediatric Gliomas: Initial Experience.

Background: 23Na MRI correlates with tumor proliferation, and studies in pediatric patients are lacking. The purpose of the study: (1) to compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging. Methods: TSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas (diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)). In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed. Results: Twenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9–23.3 years) were scanned with 23Na MRI. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (p < 0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (p < 0.002 for LGG, and p < 0.02 for HGG). The dual echo 23Na MRI suppressed the sodium signal within both CSF and necrotic foci. Conclusion: Quantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging.

The role of irinotecan-bevacizumab as rescue regimen in children with low-grade gliomas: a retrospective nationwide study in 72 patients.

At least half of children with low-grade glioma (LGG) treated with first line chemotherapy experience a relapse/progression and may therefore need a second-line chemotherapy. Irinotecan-bevacizumab has been recommended in this setting in France after encouraging results of pilot studies. We performed a retrospective analysis to define the efficacy, toxicity and predictors for response to the combination on a larger cohort. We reviewed the files from children < 19 years of age with progressive or refractory LGG treated between 2009 and 2016 in 7 French centers with this combination. 72 patients (median age 7.8 years [range 1-19]) received a median of 16 courses (range 3-30). The median duration of treatment was 9 months (range 1.4-16.2). 96% of patients experienced at least disease stabilization. The 6-month and 2-year progression-free survivals (PFS) were 91.7% [IC 95% 85.5-98.3] and 38.2% [IC 95% 28.2-51.8] respectively. No progression occurred after treatment in 18 patients with a median follow-up of 35.6 months (range 7.6-75.9 months). Younger patients had a worse PFS (p = 0.005). Prior chemoresistance, NF1 status, duration of treatment, histopathology or radiologic response did not predict response. The most frequent toxicities related to bevacizumab included grades 1-2 proteinuria in 21, epistaxis in 10, fatigue in 12 and hypertension in 8 while gastro-intestinal toxicity was the most frequent side effect related to irinotecan. Bevacizumab-irinotecan has the potential of disease control clinically and radiographically in children with recurrent LGG whatever their previous characteristics; in many cases however these responses are not sustained, especially in younger children.

Death Receptor 6 as a Prognostic Marker in Low-grade Glioma.

Low-grade gliomas (LGG) are heterogenous tumours, causing variable survivals in patients. Identifying molecular markers for a more accurate prognosis is, therefore, important. Since death receptor 6 (DR6) is up-regulated in gliomas and shows an aberrant signalling network, we tested its suitability as a prognostic marker. DR6 was investigated in patient samples via PCR and western blot. Clinical data were analysed and compared to The Cancer Genome Atlas (TCGA) 'brain lower grade glioma' dataset. DR6 was found to be enhanced in LGG and its expression increased in recurrent LGG. The receptor showed a protective effect in primary LGG with a significantly elongated progression-free survival that was confirmed in the TCGA study. This effect was reversed in relapsed LGG in which cases with high DR6 expression reveal a shorter overall survival. DR6 is an interesting candidate for further studies regarding its effect as a prognostic marker, playing an opposing role in primary and relapsed LGG.

Recurrent Low-Grade Gliomas: Does Reoperation Affect Neurocognitive Functioning?

Reoperations in patients with recurrent low-grade gliomas (RLGG) were proposed to control tumor residual and delay the risk of malignant transformation over time. To investigate neurocognitive outcomes in patients with RLGG who underwent a second surgery with awake monitoring. In this retrospective study, patients who underwent a second awake surgery for RLGG were included. Patients had presurgical and 3-mo postsurgical neuropsychological assessments. Data were converted into Z-scores and combined by the cognitive domain. Number of patients with cognitive deficits (Z-score <-1.65), variations of Z-scores, and extent of resection (EOR) were analyzed. Sixty-two patients were included (mean age: 41.2 ± 10.0 yr). None had permanent neurological deficits postoperatively. Eight patients (12.9%) had a cognitive deficit preoperatively. Four additional patients (6.5%) had a cognitive deficit 3 mo after reoperation. Among other patients, 13 (21.0%) had a mild decline without cognitive deficits while 29 (46.8%) had no change of their performances and 8 (12.9%) improved. Overall, 94.2% of the patients returned to work. There were no correlations between EOR and Z-scores. Total/subtotal resections were achieved in 91.9% of the patients (mean residual: 3.1 cm3). Fifty-eight patients (93.5%) were still alive after an overall follow-up of 8.3 yr. Reoperation with awake monitoring in patients with RLGG was compatible with an early recovery of neuropsychological abilities. Four patients (6.5%) presented a new cognitive deficit at 3 mo postoperatively. Total/subtotal resections were achieved in most patients. Based on these favorable outcomes, reoperation should be considered in a more systematic way.

CTIM-24. RANDOMIZED TRIAL OF NEOADJUVANT VACCINATION WITH TUMOR-CELL LYSATE INDUCES T CELL RESPONSE IN LOW-GRADE GLIOMAS

Abstract BACKGROUND The prognosis of WHO grade II low-grade gliomas (LGG) is varied with potential for long survival.Given their relatively intact immune system and slow growth rate, vaccines are an attractive treatment strategy for LGG in an attempt to defer more toxic treatments. The goals of this pilot study were to evaluate safety and immunological effects of vaccination with GBM6-AD, an allogeneic glioblastoma stem cell line lysate, with poly-ICLC in LGG. METHODS Eligible patients were ≥ 18 years old, ≥ 70 KPS, with recurrent LGG or imaging consistent with LGG, and amenable to resection. Patients were randomized to vaccine prior to surgery (Arm 1) or not (Arm 2) and all received adjuvant vaccine. Co-primary outcomes were safety and immune response in the tumor, with exploratory outcomes of survival and immunologic effects in peripheral blood. RESULTS A total of 17 eligible patients were evaluable – nine into Arm 1 and eight into Arm 2. Median age was 33 years, with median time from initial diagnosis of 4.7 years (0 – 20). Two patients (11.8%) previously received radiotherapy and seven (41.2%) prior systemic therapy. No dose limiting toxicities or grade 3 AEs were observed. Neoadjuvant vaccination induced up regulation of type-1 cytokines and chemokines in peripheral blood, and CD8+ T cell clones that reacted to the vaccine were also detected in the tumor. Median follow-up time from first post-operative vaccine was 20.8 months with median PFS of 11.0 months and time to change in therapy of 23.7 months. Of the six patients to receive additional treatment, three had second surgery only one confirming malignant progression to anaplastic oligodendroglioma. CONCLUSION Treatment was well-tolerated with no regimen-limiting toxicity. GBM6-AD plus poly-ICLC induced effector CD8+ T cell response in peripheral blood and enables some vaccine-reactive CD8+ T cells to migrate into the TME. Further investigation is warranted.

NIMG-33. VOLUMETRIC TUMOR MEASUREMENTS ARE SUPERIOR TO 2D BIDIRECTIONAL MEASUREMENTS IN THE EVALUATION OF IDH INHIBITION IN DIFFUSE GLIOMAS: EVIDENCE FROM A PROSPECTIVE PHASE I TRIAL OF IVOSIDENIB

Abstract Since IDH mutant (mIDH) low-grade gliomas (LGGs) progress slowly and patients have a relatively long survival, testing of new therapies in clinical trials based solely on survival can take more than 20 years. Guidance on therapeutic evaluation using LGG RANO criteria recommends serial bidirectional (2D) measurements on a single slice; however, questions remain as to the best approach for evaluating LGGs in clinical trials including use of volumetric (3D) measurements, which would theoretically allow for more accurate measurements of irregular shaped lesions and allow readers to better assess areas of change within these tumors. A total of 21 (out of 24) non-enhancing, recurrent mIDH LGGs with imaging pre- and post-treatment enrolled in a phase I, multicenter, open-label study to assess the safety and tolerability of oral ivosidenib (NCT02073994) were included in this exploratory ad hoc analysis. 2D bidirectional and 3D volumetric measurements were centrally evaluated by one of 3 radiologists at an imaging CRO using a paired read and forced adjudication paradigm. The effects of 2D vs. 3D measurements on progression-free survival (PFS), growth rate measurement variability, and reader concordance and adjudication rates were then quantified. 3D volumetric measurements had significantly longer estimates of PFS (P=0.0181), more stable (P=0.0063) and considerably lower measures of tumor growth rate (P=0.0037), the highest inter-reader agreement (weighted Kappa=0.7057), and significantly lower reader discordance rates (P=0.0002) with comparable recommended LGG RANO 2D approaches. In summary, 3D volumetric measurements are better for determining response assessment in LGGs due to longer PFS and more stable measures of tumor growth rates (i.e. less “yo-yo-ing” of measurements over time causing fewer erroneous calls of progression and more accurate growth rates), highest inter-reader agreement, and lowest reader discordance rates. Future studies will focus on validating this in a larger cohort and determining whether these measurements better reflect clinical benefit.

The Clinical Significance and Transcription Regulation of a DNA Damage Repair Gene, SMC4, in Low-Grade Glioma via Integrated Bioinformatic Analysis.

Glioma is the most common type of malignant tumor in the central nervous system with an unfavorable prognosis and limited treatment. In this study, we are devoted to addressing the prognostic value of DNA damage repair-related genes in low-grade glioma (LGG). We plotted the landscape of DNA damage repair (DDR)-related genes and identified SMC4 as an independent prognostic marker with integrated bioinformatics analysis, which is overexpressed in different histologic subtypes of glioma. We observed that SMC4 expression is elevated in recurrent LGG patients or those with advanced histologic staging. SMC4 depletion inhibits proliferation and induces increased replication damage in LGG cells. Lastly, we predicted and validated the transcription modulation of SMC4 by a transcription factor, MYB, at the -976bp~ -837bp of the SMC4 promoter region in LGG cells. Together, our study identified SMC4 as a potential prognostic biomarker for LGG patients, which functions to promote cell proliferation by repairing replication damage and the expression of SMC4 could be transcriptionally regulated by MYB.

Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas.

Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications. We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes. Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM. TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.