WHO Grade III-IV Research Articles

The TAC-GReD trial: The combination of talazoparib and carboplatin in DNA damage repair deficient recurrent high-grade glioma.

2047 Background: Recurrent high-grade glioma (rHGG) has a dismal prognosis with limited treatment options. Given that a high proportion of these gliomas harbor deficiencies in the DNA damage repair (DDRd) pathway, this genomic occurrence may confer synergistic lethality and sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, we hypothesize that DDRd rHGG may be sensitive to the combination of a PARP inhibitor, talazoparib, and carboplatin. Methods: This is a prospective phase II, single-arm open-label biomarker stratified single-institution trial conducted in Hong Kong (NCT04740190). Tumor tissue was sent for comprehensive next-generation sequencing (C-NGS) to screen for genomic aberrations associated with the DDRd pathway. Patients with rHGG (WHO grade III-IV) and at least one pathogenic mutation in the DDR pathway were deemed eligible. Patients were initially treated with whole-brain radiotherapy (2 Gy/1 Fr) on C1D1. Starting at dose level 0, talazoparib (0.75mg on Days 1-4) and carboplatin (AUC 1.5 on Day 1), were administered weekly for a total of 18 cycles, followed by maintenance talazoparib. The primary endpoint was the 6-month progression-free survival (PFS-6). Results: 61 patients were screened and 33 patients with DDRd rHGG were enrolled, 23 males, 10 females, and a median age of 55 years (range: 29-70 years). 73% (n=24) had a baseline ECOG PS of 0-1. Among the recruited patients, 12% (n=4) were classified as WHO grade III, while the remaining 88% (n=29) were WHO grade IV. Dose level escalation was achieved in 27% (n=9) of the cohort. The 6-PFS was 29% (95% CI 16.2-51.9%) and the median PFS was 3.5 months (95% CI: 2.4-6.3 months). The OS at 3 and 12 months were 90.4% (95% CI 80.7-100%) and 30% (95% CI 17-53%), respectively. The most common grade 3-4 toxicities were neutropenia (21.2%, n=7), thrombocytopenia (18.2%, n=6) and anemia (9.1%, n=3). One patient developed a grade 4 thromboembolic event. Dose level reduction was implemented in 54% (n=18) of patients and treatment was terminated in 6.1% (n=2) due to toxicity. Conclusions: Talazoparib and carboplatin in a DDRd-enriched rHGG is feasible and tolerable. Additional analysis including correlation of biomarkers with long-term outcomes is underway. Clinical trial information: NCT04740190 .

TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.

The impact of radiation therapy variables on pediatric high-grade glioma outcomes: A National Cancer Database analysis.

The purpose of this analysis is to report patterns of care for pediatric patients with high-grade glioma (pHGG) and evaluate the impact of radiotherapy (RT) variables on outcomes using the National Cancer Database (NCDB). Eligibility criteria included age<22 years, histologically diagnosed WHO grade III-IV gliomas treated with ≥50Gy and<76Gy RT between 2004 and 2013, and RT initiation within 90 days of diagnosis. RT variables including RT dose, RT timing, and RT modality were analyzed along with baseline demographic, tumor, and treatment variables to assess the impact on overall survival. A total of 498 pHGG patients were included. The median age was 15 years (range, 0-21), common diagnoses were astrocytoma (55%) and glioblastoma (30%), 73.5% underwent surgical resection and 90.2% received chemotherapy. The median RT dose was 59.4Gy (SD 2.9Gy) starting at a median of 4.4weeks from diagnosis (SD 2.5weeks). Fourteen patients were treated with proton therapy. Median follow-up was 19.6 months with 1- and 3-year overall survival of 78.4% and 40.4%, respectively. On multivariable analysis, female gender, older age, and RT delay of ≥6weeks were significantly associated with a lower rate of death; glioblastoma histology, no surgical resection/biopsy only, and earlier RT initiation<6weeks from diagnosis were associated with a higher rate of death. There was no relationship between RT dose or proton versus photon therapy and overall survival. Outcomes for pHGG are poor. There was no benefit to early RT timing when RT is initiated within 90 days of diagnosis or higher RT dose in this dataset.

P21.02.B THE EFFECT OF SOCIODEMOGRAPHIC FACTORS ON GLIOMA PROGNOSIS

Abstract BACKGROUND Sociodemographic factors are well known to contribute to health disparities for different cancer diagnoses, but they are not extensively studied for glioma patients. In this study socioeconomic status (SES), travel time to health care, cohabitation status, and region (northern Sweden compared to three regions in southern Sweden) were investigated in relation to prognosis for patients with glioma WHO grade I-IV. MATERIAL AND METHODS The Swedish National Quality Registry for Brain Tumors was used to identify 1276 patients with glioma WHO grade I-IV, diagnosed 2009-2013. The Swedish population-based database RISK North combines data from several health care and demographic registries through the unique personal identity number. The RISK North was used to study survival in relation to SES, cohabitation status (living alone vs living with another adult person), travel time to the closest regional hospital (i.e. the closest hospital with a neurosurgical unit), and region. Educational level was used as a proxy for SES. RESULTS In univariable survival analysis, patients with glioma WHO grade III-IV and high SES had a longer survival compared to patients with low SES (middle school (ref) HR:1, high school HR:0.67 CI[0.56-0.81], university/college HR:0.65 CI[0.53-0.79], p&amp;lt;0.0001). In the multivariable model for the same group, survival was longer for patients with higher SES (middle school (ref) HR:1, high school HR:0.81 CI[0.67-0.98], p=0.033; university/college HR:0.81 CI[0.66-1.00], p=0.048). For patients with glioma WHO grade I-IV, there were no significant differences in survival in relation to travel time, cohabitation status, or region in multivariable survival analysis. CONCLUSION Survival was significantly worse in patients with lower SES compared to higher SES for patients with glioma WHO grade III-IV. No significant differences were found in survival in relation to cohabitation status (between those living alone and those living with another adult person), travel time to regional hospital, or between the northern Sweden and three regions in southern Sweden.

NIMG-43. DIFFUSION BASIS SPECTRUM IMAGING DISTINGUISHES HIGH-GRADE GLIOMA TREATMENT EFFECT FROM TUMOR PROGRESSION

Abstract BACKGROUND Following standard-of-care chemoradiation therapy for high-grade glioma, it is often challenging to distinguish treatment changes from true tumor progression using conventional magnetic resonance imaging (MRI). Diffusion basis spectrum imaging (DBSI) uses a data-driven multiple-tensor modeling approach to disentangle specific histologic components and structural features present within individual imaging voxels, offering an opportunity to noninvasively differentiate treatment effect from tumor progression. This represents the first study of in vivo longitudinal DBSI for brain tumors in patients. METHODS Adult patients were prospectively recruited who met the criteria of known pathological diagnosis of high-grade glioma or glioblastoma (WHO grade III-IV) and undergoing or completing standard-of-care radiation therapy with concurrent chemotherapy. DBSI and conventional MRI data were acquired longitudinally beginning with a 4-week post-radiation therapy MRI until progression as defined by standard RANO criteria or biopsy. DBSI analyses were performed with isotropic diffusion profiles defined as restricted fraction (0 ≤ D ≤ 1.0 μm2/ms) and hindered fraction (1.0 &amp;lt; D ≤ 1.5 μm2/ms). RESULTS Eleven patients with contrast-enhancing high-grade gliomas were enrolled between June 2019 and March 2020, with final DBSI data obtained in November 2020. Of these, eight patients had tumor progression, two had treatment effect, and one had stable disease during the study period. Within the contrast-enhancing regions, the DBSI hindered fraction map demonstrated hypointensity for all cases of tumor progression, and hyperintensity for cases of treatment effect. DBSI-based biomarkers were present 0.7 to 12.0 months (median 2.4, IQR 2.8) before definitive diagnosis of treatment effect or tumor progression using conventional methods of MRI and/or biopsy. CONCLUSIONS DBSI hindered fraction can distinguish new contrast-enhancing lesions in the setting of high-grade glioma as treatment effect or tumor progression in advance of conventional MRI. Future work will incorporate machine learning algorithms to further improve DBSI-based predictions of tumor histopathology.

CLRM-06 PROSPECTIVE CLINICAL STUDY OF CONVENTIONALLY FRACTIONATED CONCURRENT CHEMORADIOTHERAPY AND HYPOFRACTIONATED CONCURRENT CHEMORADIOTHERAPY AFTER THE SURGERY OF HIGH-GRADE GLIOMAS

PURPOSETo observe and evaluate the efficacy and safety of conventional fractionated concurrent chemoradiotherapy and hypofractionated concurrent chemoradiotherapy for adjuvant treatment of newly treated high-grade glioma. METHODFor newly treated patients with high-grade gliomas with WHO grade III-IV, all patients started concurrent chemoradiotherapy within 1 month after surgery, and received concurrent temozolomide 75 mg/m2 during radiotherapy until the end of radiotherapy. Sequential temozolomide chemotherapy at 200 mg/m2 for at least 6 cycles. All patients were randomly divided into groups, one group was given conventional fractional irradiation, 60Gy/30f in high-risk areas, 46Gy/23f in low-risk areas, and the other group was given low-fractionated irradiation, 53Gy/15f in high-risk areas, and 53Gy/15f in low-risk areas 43Gy/15f. The overall survival (OS), progression-free survival (PFS), radiation-induced cerebral edema and radiation-induced brain necrosis were evaluated. RESULTAs of December 31, 2022, a total of 60 patients were enrolled, including 30 in the conventional fractionation treatment group and 30 in the hypofractionated treatment group. At present, 58 patients survived and 2 died, 2 in the conventional fractionation group, one due to tumor recurrence and one due to cardiac accident; 7 patients recurred, including 4 in the conventional fractionation group and 3 in the low fractionation group. Radiation cerebral edema occurred in 9 cases, 6 cases in the hypofractionated group and 3 cases in the conventional fractionation group, all of which were completely relieved after dehydration with mannitol, which did not affect the progress of radiotherapy. No radiation necrosis occurred during follow-up. CONCLUSIONCompared with the standard stupp regimen, using 53Gy/15f in the high-risk area and 43Gy/15f in the low-risk area as an adjuvant therapy with concurrent temozolomide and sequential temozolomide, there was no increased risk of disease recurrence, no increased risk of death, and no increased risk of death.

3D-CRT versus RapidArc in Deep Tempero-Parietal High Grade Gliomas: Do We Really Need Higher Technology?

Purpose:The aim of this study was to dosimetrically compare single arc RapidArc with conventional 3D-CRT plans for tempero-parietal high grade gliomas with respect to PTV coverage and doses perceived by surrounding critical organs at risk. Methods:Thirty patients with the pathological diagnosis of high grade gliomas (WHO grade III-IV) were selected to be enrolled in our study. Patients were referred to our center (center of Clinical Oncology and Radiotherapy, Cairo University) during the period March 2020 till June 2021 for post-operative irradiation using 3D-CRT technique. For all patients, the dose prescribed to the planning target volume (PTV) was 60 Gy in 30 fractions. A RA plan was performed for each patient and dosimetrically was compared to the 3D-CRT plan. Results:The PTV coverage in terms of V95% was significantly superior in the RA plans with values of 98.4 ± 1.7 compared to 94.4 ± 2.6 for the 3D-CRT plans (p-value of 0.004). The doses risk structures ( eyes, optic nerves and cochleae) was lower with the RA plans as contrasted to the 3D-CRT plan with an exception for the intraocular lens which received higher doses in the RA plan with a statistically significant p-value of 0.001 and 0.002 for the Ipsilateral and contralateral lens, respectively. The average number of MUs ± SD was 358.6± 44.4 for the RA plans versus 247.6 ± 16.1 for 3D-CRT plans (p-value 0.001). The Dmean of healthy brain tissue was nearly equal for both plans (p-value of 0.071). Conclusion:The plans achieved by RA showed superior dose conformity, PTV coverage, more homogeneous dose distribution when contrasted to 3D-CRT plans. With the exception of both intraocular lenses, the RA plans showed better OAR sparing and utilized a higher number of MUs compared to the 3D-CRT.

Spatial organization of heterogeneous immunotherapy target antigen expression in high-grade glioma

High-grade (WHO grades III-IV) glioma remains one of the most lethal human cancers. Adoptive transfer of tumor-targeting chimeric antigen receptor (CAR)-redirected T cells for high-grade glioma has revealed promising indications of anti-tumor activity, but objective clinical responses remain elusive for most patients. A significant challenge to effective immunotherapy is the highly heterogeneous structure of these tumors, including large variations in the magnitudes and distributions of target antigen expression, observed both within individual tumors and between patients. To obtain a more detailed understanding of immunotherapy target antigens within patient tumors, we immunochemically mapped at single cell resolution three clinically-relevant targets, IL13Rα2, HER2 and EGFR, on tumor samples drawn from a 43-patient cohort. We observed that within individual tumor samples, expression of these antigens was neither random nor uniform, but rather that they mapped into local neighborhoods – phenotypically similar cells within regions of cellular tumor – reflecting not well understood properties of tumor cells and their milieu. Notably, tumor cell neighborhoods of high antigen expression were not arranged independently within regions. For example, in cellular tumor regions, neighborhoods of high IL13Rα2 and HER2 expression appeared to be reciprocal to those of EGFR, while in areas of pseudopalisading necrosis, expression of IL13Rα2 and HER2, but not EGFR, appeared to reflect the radial organization of tumor cells around hypoxic cores. Other structural features affecting expression of immunotherapy target antigens remain to be elucidated. This structured but heterogeneous organization of antigen expression in high grade glioma is highly permissive for antigen escape, and combinatorial antigen targeting is a commonly suggested potential mitigating strategy. Deeper understanding of antigen expression within and between patient tumors will enhance optimization of combination immunotherapies, the most immediate clinical application of the observations presented here being the importance of including (wild-type) EGFR as a target antigen.

Early Unplanned Reoperation After Glioma Craniotomy: Incidence, Predictor and Process Improvement.

ObjectiveTo evaluate the rate of, reasons for, and predictors of unplanned reoperation after craniotomy for glioma in a single-institution consecutive series.MethodsPatients who underwent glioma resection at our hospital from 2015 to 2021 were included (n=1563). Multivariate logistic regression was used to examine the predictors of early unplanned cranial reoperation. The predictors that were screened included patient age, sex, tumor properties, blood loss, blood pressure and antiplatelets drugs usage.ResultsA total of 3.6% (56/1563) of the patients underwent an early unplanned reoperation after craniotomy for glioma. The reasons for early unplanned reoperation were brain edema (48.2%), cerebral infarction (33.9%) and hemorrhage (17.9%). The predictors of early unplanned reoperation were WHO grade III-IV, peritumoral edema ≥1 cm, subtotal resection, arterial/venous involvement and elevation in blood pressure ≥50 mmHg.ConclusionsGlioma properties and blood pressure management are decisive predictors of early unplanned reoperation for glioma resection. The authors provide a nuanced discussion regarding early unplanned reoperations and perioperative process improvement as a quality indicator for glioma patient populations.

Phase 2 trial of newly diagnosed high-grade glioma treated with concurrent radiation therapy, temozolomide, and BMX-001.

TPS2069 Background: High-grade gliomas (WHO grade III-IV) patients experience marked morbidity and mortality. While the standard of care for newly diagnosed high-grade glioma patients is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. As shown in preclinical evaluations, BMX-001, when used with radiation, can protect normal, healthy tissues and augment cell kill in malignant cancer cells, notably, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase 1 study of newly diagnosed high-grade glioma patients and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase 2 study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints are objective cognitive performance, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are patient-reported outcomes of health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase 2 study has enrolled 147 of 160 high-grade glioma patients at nine sites in US. Clinical trial information: NCT02655601.

The first experience of application of remote radiotherapy in combination with hyperthermia and electrotherapy (oncothermia) in the treatment of patients with primary gliomas of the brain of a high degree of malignancy

High-grade brain gliomas are characterized by a rapid clinical course and a 2-year survival rate of 8-12%. Despite the improvement of methods of surgery, radiotherapy( RT), and systemic drug therapy, it is still not possible to significantly increase the overall and relapse-free survival in patients with this neuro-oncological pathology, and the combination of RT and CT with hyperthermic electrotherapy (oncothermy) (OT) looks like a promising method that helps to increase the effectiveness of special treatment.&#x0D; At the same time, oncothermia does not cause brain edema and does not worsen the quality of life of neuro-oncological patients. At the same time, a possible alternative to further progress in improving the results of treatment of primary brain gliomas (WHO Grade III-IV) is not only to optimize the radiotherapy program, but also to combine standard methods of radical treatment with hyperthermic electrotherapy.&#x0D; This article presents preliminary immediate results of treatment of 20 patients who received special treatment in the RSCRR with an assessment of the toxicity and safety of its implementation and with an assessment of the likely resumption of continued tumor growth 1.5 and 3 months after the end of treatment. In General, the data obtained indicate the safety of the developed method of special treatment of this category of neuro-oncological patients,&#x0D; which confirms the results obtained in 28.09.2019 patent for an invention. However, for final conclusions, further clinical studies are required on a larger group of patients with longer follow-up periods, followed by a thorough analysis of the results.

CTIM-23. A PHASE 1 TRIAL OF D2C7-IT IN COMBINATION WITH ATEZOLIZUMAB IN RECURRENT WHO GRADE IV MALIGNANT GLIOMA (MG)

Abstract BACKGROUND D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR-wt and mutant-specific (EGFRvIII) monoclonal antibody fragment and a genetically engineered form of the pseudomonas exotoxin. When injected directly into the tumor mass by convection enhanced delivery (CED), in addition to direct tumor cell killing, immunotoxins induce secondary immune responses by the activation of CD4+ and CD8+ T-cells. We completed a phase 1 dose escalation study of D2C7-IT injected by CED into recurrent WHO grade III-IV MG and identified the phase 2 dose (6,920 ng/mL). Three patients remain in partial response more than 58, 38, and 32 months after a single D2C7-IT intratumoral infusion. As optimal induction of anti-tumor immune responses by immunotoxins is impeded by potent MG-mediated immunosuppression, we are assessing the toxicity of the combination of D2C7-IT with atezolizumab in patients with recurrent WHO grade IV MG. METHODS Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade IV MG; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS &amp;gt;70%. Patient receives an intratumoral infusion of D2C7-IT and initiates two weeks later atezolizumab at 1200mg, followed by atezolizumab every 3 weeks for up to 2 years. Two cohorts of 3 patients are initially accrued to assess the toxicity of the combination. Assuming accrual continues after the initial two cohorts of 3 patients, an additional 12 patients will be accrued to the study. RESULT The first enrolled patient experienced a grade 3 DLT (grade III ALT elevation) after the first infusion of atezolizumab, but showed a more extensive immunotherapeutic effect by imaging than observed with patients on the D2C7-IT monotherapy trial. Enrollment is ongoing. CONCLUSION D2C7-IT monotherapy has shown prolonged survival and disease control in some patients. We are now evaluating the combination of D2C7-IT with checkpoint inhibition.

Association between supratentorial pediatric high-grade gliomas involved with the subventricular zone and decreased survival: a multi-institutional retrospective study.

The subventricular zone (SVZ), housed in the lateral walls of the lateral ventricles, is the largest neurogenic niche in the brain. In adults, high-grade gliomas in contact or involved with the SVZ are associated with decreased survival. Whether this association holds true in the pediatric population remains unexplored. To address this gap in knowledge, the authors conducted this retrospective study in a pediatric population with high-grade gliomas treated at three comprehensive centers in the United States. The authors retrospectively identified 63 patients, age ≤ 21 years, with supratentorial WHO grade III-IV gliomas treated at three academic centers. Basic demographic and clinical data regarding presenting signs and symptoms and common treatment variables were obtained. Preoperative MRI studies were evaluated to assess SVZ contact by tumor and to quantify tumor volume. Sixty-three patients, including 34 males (54%), had a median age of 12.3 years (IQR 6.50-16.2) and a median tumor volume of 39.4 ml (IQR 19.4-65.8). Tumors contacting the SVZ (SVZ+) were noted in 34 patients (54%) and overall were larger than those not in contact with the SVZ (SVZ-; 51.1 vs 27.3, p = 0.002). The SVZ+ tumors were also associated with decreased survival. However, age, tumor volume, tumor grade, and treatment with chemotherapy and/or radiation were not associated with survival in the 63 patients. In the univariable analysis, near-total resection, gross-total resection, and seizure presentation were associated with increased survival (HR = 0.23, 95% CI 0.06-0.88, p = 0.03; HR = 0.26, 95% CI 0.09-0.74, p = 0.01; and HR = 0.46, 95% CI 0.22-0.97, p = 0.04, respectively). In a multivariable stepwise Cox regression analysis, only SVZ+ tumors remained significantly associated with decreased survival (HR = 1.94, 95% CI 1.03-3.64, p = 0.04). High-grade glioma contact with the SVZ neural stem cell niche was associated with a significant decrease in survival in the pediatric population, as it is in the adult population. This result suggests that tumor contact with the SVZ is a general negative prognosticator in high-grade glioma independent of age group and invites biological investigations to understand the SVZ's role in glioma pathobiology.

BMX-HGG: Phase II trial of newly diagnosed high-grade glioma treated with concurrent radiation therapy, temozolomide, and BMX-001.

TPS2577 Background: Patients diagnosed with malignant high-grade gliomas (WHO grade III-IV) experience significant morbidity and mortality associated with these cancers. While the mainstay of therapy for patients with newly diagnosed high-grade glioma is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain very poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. Early preclinical studies demonstrated BMX-001’s ability to act as a radioprotectant to healthy tissue such as a central nervous white matter and as a radiosensitizer to cancer cells, in particular, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase I study of newly diagnosed high-grade glioma patients, and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase II study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints include cognitive performance as assessed by standardized cognitive testing, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase II study has enrolled 64 of 160 high-grade glioma patients at six sites with future sites planned to be implemented. Clinical trial information: NCT02655601 .

QOLP-16. DISTRESSED (D TYPE) PERSONALITY, PREOPERATIVE PSYCHOLOGICAL DISTRESS, COGNITIVE FUNCTIONING, QUALITY OF LIFE, AND TREATMENT OUTCOMES OF GLIOMA PATIENTS: PROSPECTIVE STUDY

Abstract BACKGROUND This study aimed to evaluate impact of distressed (D type) personality on preoperative psychological distress, cognitive functioning and quality of life (QoL) as well as short-term and long-term treatment outcomes of glioma patients. METHOD One-hundred and seventy patients (93 men, mean age=51.1±14.5 years) participated in the study. Fifty-four (31.8%) patients were diagnosed with low grade (WHO grade I-II), and 116 (68.2%) with high grade (WHO grade III-IV) tumors. Psychological assessment was performed 2–3 days before surgery using a set of self-report questionnaires (NCCN Distress thermometer, EORTC-QLQ-C30, EORTCQLQ-BN20, HADS, DS-14) and a short battery of neuropsychological tests. Functional status at the discharge was assessed using the GOS. Follow-up period was 40 months. RESULTS Thirty-nine (22.9%) of patients met criteria for D type personality. D-type patients relative to non D-type patients reported significantly worse QoL, higher number tumor related symptoms, greater depression and anxiety symptoms, and demonstrated slowing of psychomotor speed in neuropsychological tests. However, no personality related differences were observed in level of functioning at time of discharge as well as long-term patients’ survival. Path analysis using SEM revealed non-direct impact of D-type personality traits on patients QoL (Chi-square value=16.73, df=13, p=0.212). The model indicated statistically significant indirect effects of D-type Negative Affectivity on QoL (IPC -0.285, 95% CI [-0.386; -0.178], p=0.003) and tumor related symptoms (IPC 0.196, 95% CI [0.117; 0.296], p=0.002) mediated via depression and anxiety. Social Inhibition was also indirectly associated with QoL (IPC -0.047, 95% CI [-0.120; -0.002], p=0.035) and symptoms (IPC 0.033, 95% CI [0.002; 0.097], p=0.032) through depression and anxiety. CONCLUSION D-type personality contributes to impairment of QoL and higher number of reported symptoms in glioma patients via increased susceptibility for depression and anxiety.

Introducing Fluorescence Guided Surgery into Neuro-Oncology Practice and Getting It Right First Time

Abstract Introduction Fluorescence Guided Surgery (FGS) using 5-ALA is recommended for patients undergoing resection of suspected high grade glioma and this type of surgery is increasingly being used in more units throughout the UK. We report on our experience of introducing 5-ALA guided surgery for suspected HGG in a regional neurosciences unit. Methods Consecutive series of the first 24 patients in our unit to receive 5-ALA guided surgery for suspected HGG from June 2017 to October 2018. Data was prospectively collected. Results 5-ALA fluorescence guided surgery was used for a range of histologically confirmed WHO grade III-IV gliomas. All but 1 tumour (GBM) fluoresced with 5-ALA, with strong fluorescence in recurrent GBM and anaplastic foci of grade 3 tumours. EOR varied according to the eloquence of the lesion with 70% of cases achieving gross total resection. 40% of cases used awake mapping or intraoperative neurophysiology. 5 patients (20.8%) had temporary neurological deficits which resolved in all cases. Individual surgeon learning curves resulted in 2 styles of practice- complete FGS with fluorescence used throughout the case, and intermittent use of fluorescence as an adjunct often at the end of debulking under white light. Conclusions Adopting 5-ALA use comes with specific challenges in terms of service organisation, learning curves and complication avoidance. Our experience is that it is useful both to improve EOR and as an adjunct to identify tumour tissue in eloquent region tumours with monitoring of function. This is possible through a day admission pathway in line with GIRFT.

P14.65 Anaplastic pleomorphic xanthoastrocytoma: literature review&amp; case report

Abstract Pleomorphic xanthoastrocytoma (PXA) is a rare glial brain tumor. 9% to 30% cases have anaplastic features which determine poor prognosis. Anaplastic features may be found either in primary tumor or in recurrent PXA in any time frame. According to WHO 2016 Brain Tumor Classification, anaplastic pleomorphic xanthoastrocytoma (aPXA) was reclassified as grade III tumor (previously grade II). Characteristic features for aPXA are mitotic index of 5% or higher and worse 5-year survival rates in comparison with PXA: 57.1% and 90.4%, respectively. About 6% cases have TP53 gene mutation. About 60–78% tumors are BRAF-mutated, which is a potential target for therapy. Currently there are ongoing clinical trials to determine efficacy of BRAF and MEK inhibitors in pediatric patients with high-grade glioma with BRAF mutation. There is a number of publications showing positive outcome of targeted therapy both in children and adults. Treatment protocol for aPXA has not been defined. Case report Patient N. 14-y.o. female. MRI showed tumor of left occipital lobe. 02.03.2016 stereotactic biopsy was performed. Histological examination revealed diffuse astrocytic glioma WHO grade III-IV. Radiation therapy was performed, after which patient’s condition abruptly deteriorated with back pain, patient became almost unable to walk, however control MRI showed no signs of spinal dissemination. 01.12.2016 surgery to remove left occipital lobe tumor was performed. 07.12.2016 MRI showed contrast enhancing lesions throughout entire length of the spinal cord. Histological examination revealed aPXA gr. III, Ki-67 up to 8%. From December to June 2017 patient received 6 cycles of chemotherapy with temozolomide. Molecular testing discovered BRAF V600 mutation in exon 15. Chemotherapy regimen was thereby changed to vemurafenib 1920 mg/day from July 2017. After a month of treatment patient developed cutaneous toxicity and the dose was lowered to 960 mg/day. Patient’s condition improved: back pain syndrome regressed, lower extremity muscle strength increased, patient became able to walk. MRI 03.12.2017 revealed an increase of contrast enhancing lesion and T2-FLAIR hyperintense signal area in left occipital lobe, no progression in spinal cord. Methionine PET/CT was performed, the findings were evaluated as a combination of radiation necrosis and glioma growth. In view of MRI and PET/CT findings, amount of time passed after radiation therapy, we decided to include bevacizumab 400 mg every 2 weeks in the regimen. Since January 2018 patient is receiving vemurafenib 960 mg/day and bevacizumab 400 mg every 2 weeks. There is a marked positive dynamic in clinical findings and imaging data (MRI and PET/CT). We report the patient with aPXA and prolonged response to targeted therapy. The presence of the BRAF V600E mutation was possibility of treatment which led to successful results.

P04.02 Postponing the medical treatment is possible in selected cases of diffuse low-grade glioma with foci of WHO grade III-IV after total or subtotal resection

Abstract BACKGROUND Diffuse low-grade gliomas (DLGG) are defined by a continuous growth and an unavoidable malignant transformation. Foci of malignant transformation may be found within DLGG samples obtained from surgical resections. As the medical management is classically based on the higher tumor grade, an immediate adjuvant treatment is usually proposed (radiotherapy [RT] with Temozolomide or PCV), whatever the extent of resection. Yet, early RT has no impact on overall survival compared with late RT, and is associated with cognitive toxicity. An alternative approach consists in postponing the medical treatment in selected patients. MATERIAL AND METHODS We conducted a monocentric retrospective analysis of a consecutive series of patients managed with this conservative approach. Inclusion criteria were: DLGG (WHO 2016 grade II) with at least one focus of malignant transformation (grade III-IV); no previous chemotherapy or RT; no less than a subtotal resection of the FLAIR tumor volume; no intention of treating with immediate adjuvant therapy; at least two years of postoperative follow-up. The time interval to the next medical treatment (chemotherapy and/or radiotherapy) was assessed, as well as the functional and survival results. RESULTS Forty-five DLGG patients, of median age 36.5 years, were included in the analysis (median time interval from diagnosis: 7.3 months). The histo-molecular diagnosis was diffuse astrocytoma, IDH mutant in 46.7% of cases, astrocytoma, IDH wild-type in 13.3% and oligodendroglioma, IDH mutant and 1p/19q codeleted in 40.0%. Ten tumors presented with grade IV foci. The quality of resection was subtotal (FLAIR tumor residue ≤15 cm3) in 73.3%, total (no FLAIR tumor residue) in 24.4% and supratotal in 2.2%. After surgery, patients were managed with regular clinical and radiological follow-up. With a median postoperative follow-up of 6.3 years, 75.5% of patients received a subsequent medical treatment, after a median time interval of 3.7 years. The first treatment after surgery consisted of repeated surgery in 11 patients, Temozolomide in 28 patients, RT in one patient. At the time of analysis, 19 patients (42.2%) had been treated with RT, after a median time interval of 9.5 years. Nine patients (20.0%) had died (median overall survival not reached, 5-years and 7-years survival rates: 95.2% and 67.0%). Most surviving patients were still active professionally (69.4%), with a median Karnofsky performance status of 90, and no or rare seizures. CONCLUSION In this series, total or subtotal resection of DLGG with a least one focus of grade III-IV glioma radically changed the natural history of these tumors and allowed delaying the following medical treatment by several years. This strategy is feasible in selected patients and should be considered on a case-by-case basis in patients with foci of malignant transformation following total or subtotal resection.

Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.

e13526 Background: Recurrence of high-grade glioma (HGG) (WHO grade III-IV) is a nearly universal phenomenon and necessitates the development of new therapeutic modalities. Two possible immunotherapeutic modalities are checkpoint blockade with agents such as nivolumab, a blocking antibody against the inhibitory checkpoint programmed cell death-1 (PD-1), and dendritic cell (DC) vaccination. We have shown in phase 1 and 2 trials that DC vaccination against the glioblastoma (GBM)-associated antigen human cytomegalovirus pp65-lysosomal-associated membrane protein (CMVpp65) is safe and possesses potential benefit. We hypothesized that nivolumab-induced immune checkpoint blockade could enhance efficacy of DC vaccination. Therefore, we undertook a phase 1 study to evaluate safety of nivolumab in combination with CMVpp65 mRNA pulsed DC vaccination in subjects with first or second recurrence of resectable HGG. Methods: We performed a phase 1, single-center, randomized study of nivolumab alone versus nivolumab + DC vaccination prior to planned surgical resection for both groups. We administered nivolumab 3 mg/kg IV q2weeks for 8 weeks followed by surgery and planned continuation of nivolumab. For the group receiving nivolumab + DC vaccination, we administered 3 vaccines before surgical resection with both groups receiving 5 planned post-resection DC vaccines. Primary endpoint was safety assessment using NCI-CTCAE 4.03. Results: We enrolled 6 subjects (4: GBM, 1: anaplastic astrocytoma, 1: anaplastic oligodendroglioma) with 3 receiving nivolumab alone and 3 receiving nivolumab + DC vaccination. Age range was 45-63 years subjects. We documented similar adverse events in both groups with most common grade 1-2 toxicities being fatigue (2 subjects, nivolumab alone) and thrombocytopenia (2 subjects, nivolumab + DC vaccine). Grade 4 toxicities included wound infection (2 subjects, nivolumab + DC vaccine) and meningitis (1 subject, nivolumab + DC vaccine). While we designed the study to enroll 66 subjects, we terminated the study early in light of CheckMate 143 phase III data showing nivolumab did not improve overall survival in recurrent GBM. Conclusions: Safety of nivolumab + DC vaccination in recurrent HGG is similar to nivolumab alone. Continued evaluation of new therapeutics including immunotherapy is underway for this patient population. Clinical trial information: NCT02529072.

Relaxation-compensated amide proton transfer (APT) MRI signal intensity is associated with survival and progression in high-grade glioma patients.

The purpose of this study was to investigate the association of relaxation-compensated chemical exchange saturation transfer (CEST) MRI with overall survival (OS) and progression-free survival (PFS) in newly diagnosed high-grade glioma (HGG) patients. Twenty-six patients with newly diagnosed high-grade glioma (WHO grades III-IV) were included in this prospective IRB-approved study. CEST MRI was performed on a 7.0-T whole-body scanner. Association of patient OS/PFS with relaxation-compensated CEST MRI (amide proton transfer (APT), relayed nuclear Overhauser effect (rNOE)/NOE, downfield-rNOE-suppressed APT (dns-APT)) and diffusion-weighted imaging (apparent diffusion coefficient) were assessed using the univariate Cox proportional hazards regression model. Hazard ratios (HRs) and corresponding 95% confidence intervals were calculated. Furthermore, OS/PFS association with clinical parameters (age, gender, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status, and therapy: biopsy + radio-chemotherapy vs. debulking surgery + radio-chemotherapy) were tested accordingly. Relaxation-compensated APT MRI was significantly correlated with patient OS (HR = 3.15, p = 0.02) and PFS (HR = 1.83, p = 0.009). The strongest association with PFS was found for the dns-APT metric (HR = 2.61, p = 0.002). These results still stand for the relaxation-compensated APT contrasts in a homogenous subcohort of n = 22 glioblastoma patients with isocitrate dehydrogenase (IDH) wild-type status. Among the tested clinical parameters, patient age (HR = 1.1, p = 0.001) and therapy (HR = 3.68, p = 0.026) were significant for OS; age additionally for PFS (HR = 1.04, p = 0.048). Relaxation-compensated APT MRI signal intensity is associated with overall survival and progression-free survival in newly diagnosed, previously untreated glioma patients and may, therefore, help to customize treatment and response monitoring in the future. • Amide proton transfer (APT) MRI signal intensity is associated with overall survival and progression in glioma patients. • Relaxation compensation enhances the information value of APT MRI in tumors. • Chemical exchange saturation transfer (CEST) MRI may serve as a non-invasive biomarker to predict prognosis and customize treatment.