High-grade Glioma Patients Research Articles

Upregulated Immunogenic Cell-Death-Associated Gene Signature Predicts Reduced Responsiveness to Immune-Checkpoint-Blockade Therapy and Poor Prognosis in High-Grade Gliomas.

Background: Immunogenic cell death (ICD) has emerged as a potential mechanism mediating adaptive immune response and tumor immunity in anti-cancer treatment. However, the signature of ICD in high-grade gliomas (HGGs) remains largely unknown, and its relevance to immunotherapies is still undetermined. The purpose of this study is to identify ICD-associated genotypes in order to explore their relevance to tumor immunity, patient prognosis and therapeutic efficacy of immune checkpoint blockade (ICB) therapy in HGGs. Methods: Bulk RNA-seq data and clinical information on 169 and 297 patients were obtained from the Cancer Genome Atlas (TCGA) and China Glioma Genome Atlas (CGGA), respectively. The functional enrichment and characterization of ICD genotyping were detected, and the ICD prognostic signature prediction model was constructed using least absolute shrinkage and selection operator (LASSO) regression. The responsiveness to immunotherapy was predicted according to the scoring of the ICD prognostic signature. Results: The HGG patients with high ICD gene signature (C1) showed poor outcomes, increased activity of immune modulation and immune escape, high levels of immune-checkpoint markers, and HLA-related genes, which may explain their reduced response to ICB immunotherapy. A gene set of the ICD signature, composing FOXP3, IL6 LY96, MYD88 and PDIA3, showed an independent prognostic value in both the TCGA and the CGGA HGG cohort. Conclusions: Our in silico analyses identified the ICD gene signature in HGGs with potential implications for predicting the responsiveness to ICB immune therapy and patient outcomes.

CSIG-14. THE PDGFRA-REGULATING LNCRNA LINC02283 IS AMPLIFIED IN HIGH-GRADE GLIOMA AND FACILITATES GLIOMAGENESIS

Abstract Long non-coding RNAs (lncRNAs) regulate numerous physiological processes and the etiology of diseases including cancers. However, lncRNA-based therapies are limited because the mechanism of action of many lncRNAs and their interaction with binding partners is not completely understood. We have identified LINC02283, a novel oncogenic lncRNA, highly expressed in the PDGF Receptor A (PDGFRA)-mutation driven cohort of high-grade glioma (HGG) patients which accounts for ~8% of glioma cases. LINC02283 gene co-amplifies with the PDGFRA locus and is upregulated in HGG. LINC02283 expression and copy number variation were highly correlated to that of PDGFRA expression and amplification respectively, and high LINC02283 levels leads to worse survival in HGG patients. We found that LINC02283 transcription is essential for the survival of Glioma Stem cells (GSCs) with PDGFRA amplification mutation, and its inhibition significantly improves survival in orthotopic HGG xenograft models. Interestingly, overexpression of LINC02283 in GSCs with wild type (wt) - PDGFRA, enhance PDGFRA signaling, increases cell proliferation and worsens survival in orthotopic HGG xenograft models. Inhibition of PDGFRA signaling using AG1296, represses the high endogenous LINC02283 levels in PDGFRA-mutant GSCs, reduces LINC02283 induced signaling in PDGFRA-wt GSCs, and suppresses cell proliferation in both the cellular models of HGG. Moreover, LINC02283 co-localizes and interacts with the wild-type and mutant PDGFRA to enhance its signaling and that of its downstream targets Akt and Erk. In a feedback regulation, dysregulated PDGFRA signaling induces LINC02283 levels to enhance cell proliferation in GSC and GBM cellular models through activating its downstream, Akt and Erk signaling pathways, as their inhibition reduces the lncRNA induction and function. Thus, blocking the LINC02283-PDGFRA interaction could be a plausible therapeutic strategy in HGG. Altogether, our results provide strong evidence of lncRNAs as drivers of PDGF Receptor A activity and HGG progression and support the potential of lncRNAs as possible therapeutic targets.

CTIM-13. LOCAL ADOPTIVE CELLULAR IMMUNOTHERAPY WITH CYTOKINE-INDUCED KILLER (CIK) CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH LONG-TERM FOLLOW-UP AND POTENTIAL FACTORS FOR SURVIVAL BENEFITS

Abstract BACKGROUND Immunotherapy is emerging as a promising approach for the treatment of high grade gliomas (HGGs). We reported the long-term follow-up of 6 HGG patients treated by local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor cavity following operation. Meanwhile, Gene expression profiles and immune microenvironments of tumors were further compared between the long-term and short -term survivors. METHODS Clinicopathological characteristics and outcomes of patients were reviewed and updated. Gene expression profiles, expressions of cytokines and infiltrations of immune cells in tumors were investigated by RNA sequencing, an electrochemiluminescence assay and immunohistochemistry staining, respectively RESULTS Fever and symptoms of encephaledema occurred in 5 patients after local administration of CIK cells, and could be efficiently relieved by mannitol and dexamethasone. Four patients died from progressive disease during follow-up, and their overall survival ranged from 6 to 26 months. Remarkably, 2 patients have survived more than 200 months without evidence of recurrence. Comparing with the tumors of the short-term survivors, 353 genes which were highly associated with tumor microenvironment immune were differentially expressed (false discovery rate (FDR) < 0.05 and log2 fold change (FC) ≥ 1) in the tumor of the long-term survivor. Higher expressions of cytokines, especially IL-8 and IL-10, were observed in the tumor of the long-term survivor, while the infiltrations of M2 polarized macrophages were significantly higher in the tumors of short-term survivors. CONCLUSION Long-term survival of HGG patients could achieve after local administration of CIK cells into tumor cavity postoperatively. High expressions of cytokines and low infiltrations of M2 polarized macrophages in the tumors potentially benefited the CIK cell therapy.

CTNI-17. A MULTI-INSTITUTIONAL RANDOMIZED CLINICAL TRIAL COMPARING ASSAY - GUIDED CHEMOTHERAPY WITH PHYSICIAN-CHOICE TREATMENT FOR RECURRENT HIGH-GRADE GLIOMA (NCT03632135)

Abstract The presence of therapy-resistant cancer stem cells (CSCs) in recurrent high-grade glioma (HGG) patients contributes to poor clinical outcomes. The ChemoID functional anti-cancer assay targets cancer stem cells along with the bulk of the tumor cells. This trial aims to determine if ChemoID assay-guided treatment improves survival rates for recurrent HGG patients compared to the empirically physician-selected treatment. Patients with grade-III/IV recurrent glioma who failed standard of care (SOC) therapy were randomized (1:1) between two intervention groups. They received one of fourteen mono or combination chemotherapies based on the ChemoID assay or physician choice. The study met the primary outcome in the first interim analysis of 50 patients as per protocol. The ChemoID group had an improved survival rate (vs physician-choice). Median OS (mOS) was 12.5 months in the ChemoID group (95% CI, 10.2-14.7) vs 9 months in the physician-choice (95% CI, 4.2-13.8; log-rank P = .010). Mortality risk was lower in the ChemoID group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression-free survival was 10.1 months in the ChemoID group vs 3.5 months in the physician choice (95% CI, 4.8-15.4 vs 1.9-5.1; log-rank < 0.001). Risk of progression was lower in the ChemoID group (HR = 0.25; 95% CI, 0.14-0.44; P < 0.001). The intention to treat (ITT) analysis of 78 patients showed substantially improved OS. The ChemoID group had a statistically significant longer median survival of 4.5 months. mOS was 12.0 months in the ChemoID group (95% CI, 10.8-13.2) vs 7.5 in the physician-choice group (95% CI, 3.5-11.5; log-rank P = .009). The ChemoID group had a decreased mortality risk (HR = 0.52; 95% CI, 0.24-0.81; P = .008). Compared with the physician-choice, the ChemoID group had a significantly longer OS in the ITT population. Our findings support that screening standard cytotoxic chemotherapies with a patient-specific anti-cancer assay improves survival outcomes in recurrent HGG patients.

QLTI-05. HBA1C AND INSULIN COVERAGE FOR NEWLY DIAGNOSED HGG PATIENTS IN THE HOSPITAL

Abstract Corticosteroids are used in the management of patients with high-grade gliomas (HGG). Corticosteroids lead to elevated serum glucose levels, necessitating sliding-scale insulin. A hemoglobin A1c (HbA1c) reflects historical serum glucose levels but it’s unclear if it predicts corticosteroid-induced hyperglycemia. We retrospectively reviewed all newly diagnosed HGG patients who were admitted between Jan 2019 to July 2021 who had an HbA1c performed at the time of their diagnosis. HbA1c is classified into: normal (< 5.6%), elevated (5.7 – 6.4%) and diagnostic (> 6.5%). We identified 86 patients of whom 29 and 16 had elevated and diagnostic HbA1c, respectively. These patients were more likely to require sliding scale insulin at least twice during their hospitalization, 64% vs 13% of those with a normal HbA1c. Only 28% of patients had a history of diabetes. There was no correlation between elevated HbA1c and the likelihood of initiating post-operative therapy, surgical complications, or BMI results. When reviewing age, 39 patients were less than 65, of which 34% had at least an elevated HbA1c. Of those older than 65, 65% had at least an elevated HbA1c. Our analysis suggests there is a predictive value of HbA1c and the need for sliding-scale insulin while receiving corticosteroids in the HGG population, especially in the older population. We recommend screening all new HGG patients with an HbA1c at the time of diagnosis, regardless if they have a history of diabetes. We also recommend monitoring serum glucose less frequently with those who have a normal HbA1c. If the HbA1c is elevated or diagnostic, they should have monitored serum glucose levels with available sliding-scale insulin. If the patient is > 65 years of age, they should be considered a higher risk for having hyperglycemia and HbA1c should be reviewed. Further analysis is being conducted and will be reviewed at a later date.

CTNI-33. CSNO2012001 STUDY: A PHASE III TRIAL ON ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY WITH OR WITHOUT INTERFERON-ALPHA IN NEWLY DIAGNOSED HIGH-GRADE GLIOMAS

Abstract Purpose The therapeutic efficacy and toxicity of the combination of temozolomide (TMZ) with interferon-alpha (IFN-α) and TMZ alone were compared in newly diagnosed high-grade glioma (HGG) patients.Patients and Methods Following surgery, patients with newly diagnosed HGG (World Health Organization [WHO] grade 3 or 4)were eligible and randomized into two groups. All the patients were received standard radiotherapy concurrent with TMZ. After a 4-week break,patients in group A received standard TMZ (200mg/m2 for 5 days) combined with interferon-α (3mIU, subcutaneous, d1, d3, and d5) every 28 days. Patients in group B were received standard TMZ.Results A total of 199 HGG patients were enrolled, with a median follow-up time of 77.9 months. The median overall survival (OS) of patients in the TMZ+IFN group was significantly longer than that in the standard group, although the progression-free survival (PFS) of both groups was similar . In grade 3 gliomas, the median OS was 39.57 months in the TMZ+IFN group versus 29.40 months in TMZ alone. The median PFS was also longer in the TMZ+IFN group (24.33 months) than that in the TMZ group (14.13 months) . In grade 4 gliomas, the difference in PFS survival between TMZ+IFN and TMZ group showed no significant difference . However, the TMZ+IFN group had a longer OS than that of the TMZ alone group. TMZ+IFN also significantly improved the OS in O6-methylguanine-DNA methyltransferase (MGMT) unmethylation patients. The incidence of toxic effects such as neutropenia, thrombocytopenia, anemia, increased transaminase, skin reactions, fatigue, nausea, or vomiting, and skin reactions were similar in both groups. However, seizure and influenza-like symptoms were more common in the combination group but can be easily controllable.Conclusions Compared with the standard regimen, TMZ+IFN combination treatment could prolong the survival time of HGG patients, especially MGMT promoter unmethylated patients, and the toxicity remained tolerable.

EOLP-01. PALLIATIVE CARE REFERRAL ACROSS THE DISEASE TRAJECTORY IN HIGH-GRADE GLIOMA

Abstract BACKGROUND Patients with high-grade glioma (HGG), WHO grade 3 or 4, have substantial palliative care needs. As evidence suggests early palliative care consultation (PCC) yields improved quality of life in advanced cancer, our aim was to determine the occurrence, timing, and factors associated with PCC in HGG. METHODS Adults with HGG diagnosed between 8/3/2011 and 1/23/2020 were identified retrospectively from a large, academic, multi-center health system cancer registry. Patients were stratified by any prior PCC (yes/no), and timing of PCC by disease phase: (1) diagnosis (before radiation), (2) initial treatment (first-line chemotherapy/radiation), (3) second-line treatment (second-line to last chemotherapy), and (4) end-of-life (after last chemotherapy). Univariate analyses (e.g., Chi-square test) were conducted to compare PCC to non-PCC groups, based on data distribution. RESULTS Of 621 HGG patients, 134 (21.58%) received PCC, with 14 (10.45%) referred during phase 1; 35 (26.12%) in phase 2; 20 (14.93%) in phase 3; and 65 (48.51%) in phase 4 with a median of 74 days (IQR 15, 277) from initial PCC to death. The majority of referrals were inpatient (111 (82.84%)). The PCC group did not differ significantly from non-PCC in age, sex, language, race, or ethnicity, but did differ by marital status: single (263 (42.35%) vs 187 (38.4%)), divorced/separated (37 (27.61%) vs 107 (21.97%)), married/civil union (17 (12.69%) vs 154 (31.62%)); (Chi-square p < .01). Compared to non-PCC, more patients in the PCC group had glioblastoma histopathology (89.55% vs. 82.14%, p = .04). CONCLUSION A minority of HGG patients ever received PCC, which primarily occurred in the inpatient setting, and half of those referred for PCC received it during the end-of-life phase. Thus, only about one in 10 patients in the entire cohort potentially received the benefits of early PCC. Further studies should elucidate barriers and facilitators to early palliative care in HGG.

QLTI-03. AN INNOVATIVE APPROACH TO ACCESSIBLE INFORMATION FOR BRAIN TUMOUR PATIENTS AND THEIR LOVED ONES

Abstract Patient information for cancer patients is acknowledged for its vital contribution to informed consent and a positive patient experience. It forms a measure to which UK oncology centres are held to account in the national cancer patient experience survey. It could be argued that this has driven the production of such information rather than it being designed to best meet the need of the neuro-oncology patient. With this in mind a YouTube channel was set up after consulting current High Grade Glioma patients on their preferred medium. Patients wanted short clips in a conversational style explaining aspects of their treatment and the pathway. They wanted it to be available in a medium that they were familiar with either s a podcast or YouTube shorts. The CNS team requested patients choose the name of the channel and began making short videos with patients and professionals on subjects suggested by patients. In twelve weeks, we have produced 23 videos, which have had 2282 views and 105 hours of watch time. The average person watches for two hours and forty-six minutes. It is possible to extrapolate from this that people are engaging with the content. The availability of information in this form has reduced the length of conversations and emails with the CNS’s pre-operatively. Patients have reported a greater sense of comfort from hearing other patient’s stories. The authors acknowledge there is not enough data available yet to formerly support this. In conclusion patient information should be designed to meet the needs of the patient not the guidance. It needs to be accessible to patients who have neurological impairments including changes in vision and concentration and provided in a medium that is current, visual and easily accessible.

CTNI-54. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA

Abstract BACKGROUND The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients. METHODS Eligible patients had recurrent HGG with (1) RB+, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of ribociclib (400mg QD) plus everolimus (2.5mg QD) and underwent tumor resection at 2, 8 or 24 hours following the last dose. Six dose-escalation cohorts (n = 3 each) reached a dose-level of ribociclib (600mg QD) plus everolimus (70mg QW). Tumor tissue, CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration > 5-fold biochemical IC50) and a PD ‘trigger’ ( >30% decrease in both pRB and pS6) in Gd-nonenhancing tissue were set to qualify patients for expansion. RESULTS 24 patients with WHO Grade III (n = 2) and Grade IV (n = 22) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM whereas no unbound everolimus concentrations were detected. Across all dose-levels, 57% (13/23) and 43% (10/23) of tumors demonstrated RB and S6 phosphorylation decrease, respectively. CONCLUSION In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor. Everolimus exhibits limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.

CTNI-48. TRIAL UPDATE -RESULTS OF A PHASE I WINDOW OF OPPORTUNITY TRIAL EVALUATING A FIRST-IN-CLASS CD29 INHIBITOR, OS2966, IN RECURRENT HIGH-GRADE GLIOMA

Abstract BACKGROUND OS2966 is a first-in-class, humanized, and deimmunized anti-CD29 (β1integrin) monoclonal antibody. CD29 is a mechanosignaling receptor prominently upregulated in glioblastoma. Preclinical studies in mice and non-human primates have demonstrated safety and encouraging efficacy. A phase I clinical trial was therefore initiated to evaluate the safety and feasibility of delivering OS2966 directly to the site of disease via convection-enhanced delivery (CED) in recurrent high-grade glioma patients. METHODS This study employs a 2-part design: In part 1, patients undergo stereotactic tumor biopsy followed by placement of a CED catheter(s) for delivery of OS2966 to the bulk contrast-enhancing tumor. Subsequently, in part 2, patients undergo a clinically-indicated tumor resection followed by placement of CED catheter(s) and delivery of OS2966 to the surrounding tumor-infiltrated brain. Co-convection of gadolinium enables real-time monitoring of therapeutic delivery. A concentration-based accelerated titration design is utilized for dose escalation. Given availability of pre and post-infusion samples, pharmacodynamic data will be analyzed to explore mechanism of action of OS2966. RESULTS Four patients have completed treatment in both study parts. No dose-limiting toxicity or adverse events related to treatment with OS2966 or CED catheter placement have been reported at the first 3 dose levels (ie, doses up to 0.6 mg/mL). For the four patients treated an average of 4.2 mL and 3.2 mL were infused in study parts 1 and 2 respectively. The Vd/Vi ratio ranged from 0.6 to 1.6 in part 1, and from 2.0 to 4.3 in Study Part 2. Analysis of tissue samples collected during the trial has demonstrated decreased VEGF expression post-treatment, with preinfusion samples showing > 50% VEGF expression and post-infusion samples showing 10% expression. Additional pharmacodynamic analysis via tissue-level biomarkers is ongoing and will be presented. CONCLUSION Initial data demonstrate the safety and feasibility of direct intracranial delivery of OS2966.

SURG-24. QUANTITATIVE ANALYSIS OF TUMOR CELL DENSITY AND PROTOPORPHYRIN IX FLOURESCENCE IN GLIOMA PATIENTS USING PAIRED STIMULATED RAMAN HISTOLOGY AND TWO-PHOTON EXCITATION FLUORESCENCE MICROSCOPY

Abstract Fluorescence guidance is widely utilized to improve the precision of cancer surgery. 5-aminolevulinic acid, the most widely used fluorophore in glioma surgery, is thought to cause selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumor cells by exploiting pathologic alterations in heme biosynthetic pathways. PpIX-induced fluorescence is highly specific for densely tumor-infiltrated tissue but less effective for visualizing the tumor periphery. To improve clinical detection of PpIX, we developed a microscope to perform paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF) and validated it in 175 fresh, unprocessed core tumor specimens from 75 high-grade glioma patients and three central nervous system lymphoma patients across three institutions. Surprisingly, intracellular PpIX accumulation was observed primarily in cells with histiocytic, rather than neoplastic morphology, and the number of cells concentrating PpIX within the cytoplasm was associated with the abundance of CD163 positive cells (p< 0.02). There was no correlation between the degree of tumor cellularity and the concentration of PpIX across all imaged specimens (R=-0.21). Our findings encourage reconsideration of the existing theory of 5-ALA-induced tumor cell fluorescence in gliomas and demonstrate how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of human gliomas.

CTNI-05. MOLECULAR ANALYSIS OF THE PHASE I D-TERMINED TRIAL ON CONCURRENT AND ADJUVANT TEMOZOLOMIDE WITH MINOCYCLINE IN NEWLY DIAGNOSED HIGH-GRADE GLIOMA

Abstract BACKGROUND Minocycline blocks microglial TNF signaling and downstream NF-κB activation, which reduces the mesenchymal phenotype in preclinical models of GBM. Primary analysis of the D-TERMINED trial identified a maximal tolerated dose (MTD) of oral minocycline at 150 mg BID in combination with temozolomide and radiation. In the overall population, the secondary objective of improved PFS was not met. Here, response is further stratified by biomarkers delineating mesenchymal subtype (OLIG2, CD44), microglial activation (IBA-1), and NF-κB signaling (P-p65). METHODS Patients with newly diagnosed high-grade glioma received continuous oral minocycline during concurrent chemoradiation and adjuvant temozolomide. Twenty patients were included in the MTD efficacy population. Within this cohort, immunohistochemistry for OLIG2, CD44, IBA-1, and P-p65 was performed on nineteen patient tumor samples. For each biomarker, the mean percent positivity or number/HPF was compared between patients who exceeded or did not exceed expected PFS. Spearman correlation coefficients were also generated for pairwise comparison of these biomarkers. RESULTS In patients with high PFS, 12.7% of tumor cells were positive for OLIG-2, 36.5% for CD44, and 23.9% for P-p65, with 41.7 cells/HPF positive for IBA-1. Comparatively, in patients with low PFS, 9.4% of tumor cells were positive for OLIG-2 (p = 0.59), 34.1% for CD44 (p = 0.77), and 22.3% for P-p65 (p = 0.85), with 31.1 cells/HPF positive for IBA-1 per HPF (p = 0.38). The only biomarkers demonstrating significant relationship were P-p65 and IBA-1, with a rank correlation of 0.637 (p = 0.007). CONCLUSIONS Exploratory analysis of D-TERMINED concludes that OLIG-2, CD44, IBA-1, and P-p65 are not predictive of improved PFS within high-grade glioma patients treated with SOC and minocycline. Concurrent use of minocycline with chemoradiation is therefore not indicated in these or unselected populations. Significant correlation is seen between IBA-1 and P-p65, biomarkers of microglial activation and NF-κB signaling. SPONSORSHIP: Funding provided by the Musella Foundation and NIH grant P30CA042014.

Characteristics, Patterns of Care and Predictive Geriatric Factors in Elderly Patients Treated for High-Grade IDH-Mutant Gliomas: A French POLA Network Study.

Describe the characteristics, patterns of care, and predictive geriatric factors of elderly patients with IDHm high-grade glioma (HGG) included in the French POLA network. The characteristics of elderly (≥70 years) patients IDHm HGG were compared to those of younger patients IDHm HGG (<70 years) and of elderly patients IDHwt HGG. Geriatric features were collected. Out of 1433 HGG patients included, 119 (8.3%) were ≥70 years. Among them, 39 presented with IDHm HGG. The main characteristics of elderly IDHm HGG were different from those of elderly IDHwt HGG but similar to those of younger IDHm HGG. In contrast, their therapeutic management was different from those of younger IDHm HGG with less frequent gross total resection and radiotherapy. The median progression-free survival (PFS) and overall survival (OS) were longer for elderly patients IDHm HGG (29.3 months and 62.1 months) than elderly patients IDHwt HGG (8.3 months and 13.3 months) but shorter than those of younger patients IDHm HGG (69.1 months and not reached). Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, body mass index, and autonomy. Geriatric factors associated with PFS and OS were mobility, neuropsychological disorders, and body mass index, and autonomy. the outcome of IDHm HGG in elderly patients is better than that of IDHwt HGG. Geriatric assessment may be particularly important to optimally manage these patients.

Perfusion MR prior to radiotherapy is a strong predictor of survival in high-grade gliomas after proton and carbon ion radiotherapy

To assess the survival predictability of perfusion magnetic resonance imaging (MRI) by the normalized cerebral blood volume (nCBV) prior to particle beam radiotherapy (PBRT) in high-grade glioma (HGG) patients underwent particle therapy. The study retrieved dynamic susceptibility contrast MRI acquired prior to PBRT between 6/2015 and 3/2019 in 45 patients with HGG. Maximum nCBV (nCBVmax) within or adjacent to surgical/tumor bed was measured using 'hot-spot' method. The predictive values of nCBVmax for progression-free survival (PFS) and overall survival (OS) were assessed in univariate Kaplan-Meier curve and multivariate Cox proportional hazards (CPH) models. Nomograms based on CPH results were constructed to individualize the predicted probability of OS and PFS. The Kaplan-Meier curves and all CPH models based on nCBVmax as continuous variable (nCBVmax-C), group by cut-off derived from median value and Youden-index method showed that nCBVmax prior to radiotherapy was a strong predictor for both PFS and OS in HGG patients who underwent PBRT. Nomograms built on CPH models showed similar excellent performance in both discrimination and calibration. Perfusion imaging prior to PBRT is a strong predictor of survival in HGG. Novel perfusion MR-based nomogram with prospective validation could potentially be formally used in future clinical practice to individualize survival probability.

434P Outcome of high grade glioma patients: A single institution experience

High Grade Glioma include all grade III/IV primary brain tumors of Astrocytic, oligodendroglial and mixed cellular lineage and are associated with poor prognosis. The standard of care for high grade glioma is concomitant chemoradiation and Temozolomide with median survival of 12-15 months in glioblastoma and 2-5 years with newly diagnosed anaplastic gliomas. Prognosis is poor with the median survival of 3-9 months at first recurrence which drops to few weeks for more than 90% of the patients at second or subsequent recurrence.

5-Aminolevulinic acid-enhanced fluorescence-guided treatment of high-grade glioma using angled endoscopic blue light visualization: technical case series with preliminary follow-up.

5-Aminolevulinic acid (5-ALA)-enhanced fluorescence-guided resection of high-grade glioma (HGG) using microscopic blue light visualization offers the ability to improve extent of resection (EOR); however, few descriptions of HGG resection performed using endoscopic blue light visualization are currently available. In this report, the authors sought to describe their surgical experience and patient outcomes of 5-ALA-enhanced fluorescence-guided resection of HGG using primary or adjunctive endoscopic blue light visualization. The authors performed a retrospective review of prospectively collected data from 30 consecutive patients who underwent 5-ALA-enhanced fluorescence-guided biopsy or resection of newly diagnosed HGG was performed. Patient demographic data, tumor characteristics, surgical technique, EOR, tumor fluorescence patterns, and progression-free survival were recorded. In total, 30 newly diagnosed HGG patients were included for analysis. The endoscope was utilized for direct 5-ALA-guided port-based biopsy (n = 9), microscopic to endoscopic (M2E; n = 18) resection, or exoscopic to endoscopic (E2E; n = 3) resection. All endoscopic biopsies of fluorescent tissue were diagnostic. 5-ALA-enhanced tumor fluorescence was visible in all glioblastoma cases, but only in 50% of anaplastic astrocytoma cases and no anaplastic oligodendroglioma cases. Gross-total resection (GTR) was achieved in 10 patients in whom complete resection was considered safe, with 11 patients undergoing subtotal resection. In all cases, endoscopic fluorescence was more avid than microscopic fluorescence. The endoscope offered the ability to diagnose and resect additional tumor not visualized by the microscope in 83.3% (n = 10/12) of glioblastoma cases, driven by angled lenses and increased fluorescence facilitated by light source delivery within the cavity. Mean volumetric EOR was 90.7% in all resection patients and 98.8% in patients undergoing planned GTR. No complications were attributable to 5-ALA or blue light endoscopy. The blue light endoscope is a viable primary or adjunctive visualization platform for optimization of 5-ALA-enhanced HGG fluorescence. Implementation of the blue light endoscope to guide resection of HGG glioma is feasible and ergonomically favorable, with a potential advantage of enabling increased detection of tumor fluorescence in deep surgical cavities compared to the microscope.

Simultaneous Integrated Boost Technique for Pediatric High-Grade Gliomas: A Single-Institution Experience

<h3>Purpose/Objective(s)</h3> The prognosis for pediatric patients with high grade glioma (HGG) remains dismal despite aggressive multidisciplinary treatment, and there is marked variability regarding the optimal radiation approach. We report outcomes from a retrospective review of pediatric patients with HGG treated using a simultaneous integrated boost (SIB) technique at a single institution. <h3>Materials/Methods</h3> The medical records of patients ages 0–22y with biopsy-proven non-DIPG localized HGG treated with radiotherapy (RT) from January 2006 to May 2021 were retrospectively reviewed on an IRB approved protocol. Endpoints were Kaplan-Meier estimates of overall survival (OS) and progression free survival (PFS), and patterns of failure. <h3>Results</h3> There were 32 patients in the cohort; 24 patients had glioblastoma without further molecular characterization, 2 had H3 K27M mutant diffuse midline gliomas, 2 had G34R mutant glioma, 2 had glioblastoma with IDH1 mutation, 1 had high-grade astrocytoma, and 1 had high-grade glial neoplasm. Median age at diagnosis was 14.9 (1.9–21.5) years. Prior to RT, 6 patients obtained both spinal MRIs and lumbar punctures, 5 obtained spinal MRIs, and 1 had a lumbar puncture; none had evidence of distant metastases. All patients were treated with intensity modulated radiotherapy (IMRT) using SIB with two dose levels. The most common (n=25) dose to the high dose volume was 60 Gy (range, 40–60 Gy); the most common (n=24) dose to the low dose volume was 50 Gy (range, 30–55 Gy). Treatment was most commonly (n=26) delivered in 30 fractions (range, 15-33). One patient did not complete planned RT due to tumor hemorrhage. Median follow up for all patients was 17 (0–164.4) months. For patients who completed planned RT, median PFS was 20.1 (1–140) months from RT start. Median OS was 25.9 months with one- and two-year survival rates of 80% and 56%, respectively. Of 19 patients with known recurrence, 8 recurred locally, 7 recurred in the distant brain, and 4 developed leptomeningeal dissemination. Three patients were alive at 10 years after initial diagnosis; none of these patients were known to have tumors with IDH mutations. <h3>Conclusion</h3> This study explores outcomes in a cohort of pediatric HGG patients treated with SIB technique, with encouraging initial results. Future efforts will be necessary to identify additional molecular and treatment factors that impact outcome.

A Randomized Trial of Comparative Dosimetric Study of Radiotherapy in High Grade Gliomas Based on the Guidelines of 2019-NRG and EORTC Target Delineation

<h3>Purpose/Objective(s)</h3> Postoperative radiotherapy is important for high-grade glioma (WHO Grade 3-4), but the optimal way for contouring the target area for radiotherapy is still unclear. The purpose of this randomized trial was to compare the dosimetric differences in radiation treatment plans (TPS) generated based on the European Organization for Research and Treatment of Cancer (EORTC) and NRG consensus (NRG-2019) guidelines to provide evidence for optimal target delineation for high-grade glioma. <h3>Materials/Methods</h3> Patients with diagnosis of high-grade glioma were randomly assigned (1:1) to receive postoperative radiotherapy based on either EORTC guideline or NRG-2019 guideline. We report the result of dosimetric comparison first. In 13 high grade glioma patients, both EORTC and NRG-2019 radiation treatment plans were generated for dosimetric comparison. For EORTC group, the prescription dose was 95% PTV 60 Gy in 30 fractions. The gross tumor volume (GTV) including resection cavity and residual tumor encompassed the T1-weighted images (T1WI) and T2 FLAIR contrast-enhancing lesion. For NRG-2019group, GTV involved the T1-weighted images (T1WI) and T2 FLAIR contrast-enhancing foci and peritumoral edema on the preoperative CT or MRI. The prescription dose of PTV1 was 46 Gy in 23 fractions. The areas were then diminished to contain merely the contrast enhancing foci with a 2.5 cm margin as CTV2, and PTV2 was equal the CTV2 plus 0.3 cm margin for additional prescription dose was 14 Gy in 7 fractions. It should be noted that CTV1 and CTV2 were trimmed according to the anatomical barriers, falx, ventricles, etc. This trial is registered with chictr.org.cn, number ChiCTR2100046667. <h3>Results</h3> The median volume for PTV of EORTC plans, PTV1 of NRG-2019 plans, PTV2 of NRG-2019 plans were 336.6 cm³ (range 161.1-511.5 cm³), 365.3 cm³ (range 123.4-535.0 cm³), and 263.2 cm³ (range 116.8-497.7 cm³), respectively. Both treatment plans were found to have similar efficiency and evaluated as acceptable for patient treatment. Both treatment plans showed well conformal index and homogeneity index and were not statistically significantly different. There was no significant difference in the volume percent of brain irradiated to 30 Gy, 46 Gy, and 60 Gy according to different target delineations (P = 0.397, P = 0.590 and P = 0.739, respectively). These two plans also showed no significant differences in the doses to the brainstem, optic chiasm, optic nerve, lens, eyes, pituitary, and temporal lobes (P = 0.858, P = 0.858, 0.701, P = 0.794, P = 0.701, P = 0.427, P = 0.489, P = 0.898, P = 0.626, P = 0.942 and P = 0.161, respectively). <h3>Conclusion</h3> Compared with EORTC guidelines for postoperative radiotherapy for high-grade glioma, the NRG-2019 target area delineation guidelines were able to include peritumor edema in the CTV without increasing the radiation dose to organs at risk (OARs). This study further provides a foundation for the application of the NRG-2019 consensus in radiotherapy for patients with high-grade gliomas.

Health-Related Quality of Life in Patients With High-Grade Glioma: A Systematic Review

Abstract AIMS Several studies have evaluated health-related quality of life (HRQoL) through patient-reported outcomes (PROs) in high-grade glioma (HGG) patients. No systematic review has summarised this increasingly important research area. METHOD Seven electronic databases were systematically searched. Primary research articles evaluating HRQoL in HGG patients through PRO assessment were included. Global, physical, mental, and social health were summarised descriptively. Risk of bias (RoB) of included studies was assessed using The Joanna Briggs Institute Critical Appraisal tool or Newcastle Ottawa Scale. Quality of study reporting was assessed using a modified ISOQOL checklist. RESULTS Twenty-six studies were included (4,451 patients): cross-sectional (n=14), longitudinal (n=12). RoB and quality of reporting were satisfactory. Ten PRO measurement instruments were identified, of which EORTC-QLQ-C30 (n=15) was utilised most frequently. Fatigue significantly impacted both physical and global health. HRQoL improved after surgery but recurrence, fatigue, and difficulties with activities of daily living were associated with worsening HRQoL. HGG patients had higher anxiety and depression scores than the general population, negatively impacting overall HRQoL. Social health was superior for patients with good supportive networks, but a majority do not return to full-time employment post-diagnosis. Long-term survivors reported improvements in their physical, social and emotional functioning over time. CONCLUSION With HGG life expectancy less than 12 months post-diagnosis, HRQoL is of paramount importance to patients. PRO assessment of HRQoL can be used to evaluate self-reported functioning and well-being in both routine practice and clinical trial settings and provide opportunities for timely intervention.

CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers

Abstract AIMS CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their caregivers. METHOD CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance. RESULTS 36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Role Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires. CONCLUSION Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers’ daily lives.