Recurrent High-grade Glioma Research Articles

An exploratory clinical trial on intra-lumbar injection of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.

2043 Background: No standard-of-care treatment was established for recurrent high-grade gliomas (rHGGs) yet. Intrathecal infusion of autologous chimeric antigen receptor-T (CAR-T) cells has displayed potent anti-tumor activity in one patient (Brown et al. N Engl J Med 2016). We evaluated the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of B7H3-specific allogeneic universal CAR-T (B7H3 UCAR-T) cells in patients with rHGGs. Methods: Eligible patients who had received standard treatment for newly-diagnosed high-grade gliomas but failed were treated with 2.5×107 B7H3 UCAR-T cells via intra-lumbar injection every month. Eligibility criteria included histologic and/or cytologic rHGGs, B7H3-positive antigen expression rate of >50% in tumor tissue and Karnofsky performance status (KPS) ≥ 40. The primary endpoint was treatment-related adverse events (TAEs); secondary endpoints include overall survival (OS) and objective response rate (ORR); exploratory endpoints were PK and PD characteristics of B7H3 UCAR-T cells. Results: In the 7 patients enrolled, 4 (57.1%) were female, 5 (71.4%) glioblastoma (WHO Grade IV) and 2 (28.6%) diffuse midline glioma (WHO Grade IV), and the mean age was 40.4 years. The most common reported TAEs were increased cerebrospinal fluid (CSF) IL-6 (7/7, 100%), headache (7/7, 100%), increased blood IL-6 (6/7, 86%) and fever (6/7, 86%). No adverse events of grade 3 or greater related to B7H3 UCAR-T cells were reported. All the adverse events recovered or relieved after treatment. No typical or severe systemic cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GvHD) were observed during the study period. Based on Immunotherapy Response Assessment in Neuro-Oncology (iRANO), 3 of 7 patients had response to therapy (42.9%; 95% CI: 15.8 to 75.0) and 7 of 7 patients were stable disease (100%; 95% CI: 64.6 to 100). As of cutoff date (January 30, 2023), two patients died. The median OS was not reached (95% CI: 12.9 to could not be estimated). The median follow-up for OS was 15.6 months (95% CI: 14.7 to 16.1). OS rate at 12 months was 85.7% (95% CI: 48.7 to 97.4). The CAR DNA copy numbers increased 1 day after each administration and persist at least 1 month in cerebrospinal fluid. IL-6 concentrations in CSF and peripheral blood increased after each administration while the change and concentration values in peripheral blood were much lower than those in CSF. Conclusions: In patients with rHGGs, B7H3 UCAR-T cells was not associated with any toxic effects of grade 3 or higher. B7H3 UCAR-T cells resulted in a significantly longer overall survival and a higher objective response rate than history data. B7H3 UCAR-T cells persist well in patients. Clinical trial information: ChiCTR2100047968 .

Phase 1/2, first-in-child study of sonodynamic therapy (SDT) using low intensity focused ultrasound and 5-aminolevulinic acid (ALA) for patients with diffuse intrinsic pontine glioma.

TPS10070 Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor with poor prognosis. Sonodynamic therapy (SDT) with ALA is a non-invasive strategy that sensitizes target tissues with a non-toxic chemical agent followed by exposure to low intensity MR-guided focused ultrasound (MRgFUS). Preclinical studies have shown that ALA is preferentially taken up by glioma cells and metabolized to protoporphyrin IX (PpIX). SDT activates protoporphyrin IX and induces tumor cell death via photodynamic effect (lipoperoxidation, apoptosis). Suheiro et al and Wu et al demonstrated that SDT killed tumors via apoptosis and lipoperoxidation in rodent glioma models with minimal damage to surrounding normal brain.1,2 ALA SDT was well-tolerated in an ongoing first-in-human trial in adults with recurrent high-grade gliomas and demonstrated biomarker evidence of the photodynamic effect3. Methods: A Phase 1/2, multicenter, open label study (NCT05123534) is enrolling patients at Children’s National Hospital. The study employs the Bayesian optimal interval (BOIN) algorithm to evaluate safety and tolerability of treatment with SDT in newly diagnosed DIPG subjects to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of MRgFUS energy in combination with ALA. The study will evaluate 3 ALA doses and 3 acoustic energy doses. ALA is administered IV six to nine hours prior to MRgFUS with the Exablate type-2 device. The first cohort, B1C1, evaluates the lowest drug-device dose combination and if no dose-limiting toxicity (DLT) is encountered after 3 patients, ascending dose-escalation will proceed to the second cohort, B2C1, treated with lowest dose of ALA with the second level of MRgFUS energy. Again, if no DLT is experienced, the next cohort will receive a higher dose combination. The initial patient in each cohort is treated in 2 sessions 21 to 28 days apart, each covering one-half of the pons. Subsequent patients are treated in 1 session to the whole pons. The primary objective is to evaluate the safety and tolerability of SDT in DIPG subjects. Secondary outcomes include preliminary efficacy assessments, pharmacokinetics of ALA and PpIX, mechanical performance of the Exablate Type-2 device, and radiographic evidence of tumor physiological changes associated with SDT. All patients at least 5 years of age with newly diagnosed, radiographically typical DIPG between 4-24 weeks after completion of standard radiotherapy are eligible for the trial. Patients with evidence of disease progression, diagnosis of porphyria, or prior or concurrent therapy with any other anticancer or investigational intervention will be excluded. Cohort 1 has been completed without DLT.

Re-irradiation for recurrent high-grade glioma: an analysis of prognostic factors for survival and predictors of radiation necrosis.

Recurrent high-grade glioma (rHGG) is a heterogeneous population, and the ideal patient selection for re-irradiation (re-RT) has yet to be established. This study aims to identify prognostic factors for rHGG patients treated with re-RT. We retrospectively reviewed consecutive adults with rHGG who underwent re-RT from 2009 to 2020 from our institutional database. The primary objective was overall survival (OS). Secondary endpoints included prognostic factors for early death (< 6months after re-RT) and predictors of radiation necrosis (RN). For the 79 patients identified, the median OS after re-RT was 9.9months (95% CI 8.3-11.6). On multivariate analyses, re-resection at progression (HR 0.56, p = 0.027), interval from primary treatment to first progression ≥ 16.3months (HR 0.61, p = 0.034), interval from primary treatment to re-RT ≥ 23.9months (HR 0.35, p < 0.001), and re-RT PTV volume < 112cc (HR 0.27, p < 0.001) were prognostic for improved OS. Patients who had unmethylated-MGMT tumours (OR 12.4, p = 0.034), ≥ 3 prior systemic treatment lines (OR 29.1, p = 0.022), interval to re-RT < 23.9months (OR 9.0, p = 0.039), and re-RT PTV volume ≥ 112cc (OR 17.8, p = 0.003) were more likely to die within 6months of re-RT. The cumulative incidence of RN was 11.4% (95% CI 4.3-18.5) at 12months. Concurrent bevacizumab use (HR < 0.001, p < 0.001) and cumulative equivalent dose in 2Gy fractions (EQD2, α/β = 2) < 99 Gy2 (HR < 0.001, p < 0.001) were independent protective factors against RN. Re-RT allowed for less corticosteroid dependency. Sixty-six percent of failures after re-RTwere in-field. We observe favorable OS rates following re-RT and identified prognostic factors, including methylation status, that can assist in patient selection and clinical trial design. Concurrent use of bevacizumab mitigated the risk of RN.

Bevacizumab is associated with cerebral microstructural alterations: a DTI study in high-grade glioma.

For recurrent high-grade glioma, especially glioblastoma, no standard of care treatment exists. Due to the prolongation of progression-free survival and a cortiocosteroid-sparing effect, bevacizumab is often used in this condition. Despite initial clinical responses, there is growing evidence that bevacizumab may potentiate microstructural alterations which may cause cognitive decline, mostly affecting learning and memory. To investigate bevacizumab-associated microstructural damage of defined regions of interest (ROIs) in the white matter, diffusion tensor imaging (DTI) was performed in 10 patients with a case history or third-party report for neurological dysfunction concerning cognitive performance. Serial DTI data before and under bevacizumab were collected and longitudinal changes of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were assessed in mesiotemporal (hippocampal), frontal, and occipital regions. The longitudinal DTI data under bevacizumab compared to DTI prior to bevacizumab demonstrated a significant decrease in FA and increase in AD and RD both in mesiotemporal (hippocampal) regions and in frontal regions, whereas occipital regions showed no significant alterations in DTI metrics. The regionally impaired microstructure in mesiotemporal (hippocampal) regions and in frontal regions is in line with the fact that neurocognitive impairment in learning and memory is mostly related to hippocampal integrity and attentional control in frontal regions. Further studies could investigate the potential of DTI to assess bevacizumab-associated microstructural damages in vulnerable brain regions.

PO-1144 Radiosurgery and Regorafenib in recurrent high-grade gliomas: is it feasible?

PO-1144 Radiosurgery and Regorafenib in recurrent high-grade gliomas: is it feasible?

Outcome of Second Line Treatment of Recurrent High- Grade Glioma by re-Irradiation or Bevacizumab-based Chemotherapy: A Cross Sectional Study.

Currently, there is no standard of treatment for the management of the recurrent high-grade glioma. Re-resection, re-irradiation, and chemotherapy are among main treatment options without any proven efficacy. To compare the outcome of second line treatment of recurrent high-grade glioma by re-irradiation or bevacizumab-based chemotherapy. Retrospectively, patients with the recurrent high-grade glioma treated by re-irradiation (ReRT group) (34 patients) or bevacizumab-based chemotherapy (Bev group) (40 patients) as the first-file after the first recurrence were compared in term of first-line progression free survival (PFS), second-line PFS, and overall survival (OS). Both groups were similar in term of gender (p=0.859), age (=0.071), type of first-line treatment (p=0.227), and performance status (p=0.150). With a median follow-up of 31 months (m), mortality rate was 41.2% and 70% in the ReRT and Bev groups, respectively. In the Bev and ReRT groups, median OS was 27 m (95% confidence interval (CI) 20-33.9 m) vs. 132 m (95% CI 52.9-211 m) (p<0.0001), median first-line PFS was 11 m (95% CI 7.14-28.7 m) vs. 37 m (95% CI 8.42-65.75 m) (p<0.0001), and median second-line PFS was 7 m (95% CI 3.9-10 m) vs. 9 m (95% CI 5.5-12.4 m) (p=0.564), respectively. The PFS is similar after the second line treatment of recurrent primary central nervous system malignancies either by re-irradiation or bevacizumab-based chemotherapy.

PO-1137 Reirradiation versus systemic therapy for recurrent high-grade glioma: A systematic review

PO-1137 Reirradiation versus systemic therapy for recurrent high-grade glioma: A systematic review

Variables associated with cortical motor mapping thresholds: A retrospective data review with a unique case of interlimb motor facilitation.

Intraoperative neuromonitoring (IONM) is crucial to preserve eloquent neurological functions during brain tumor resections. We observed a rare interlimb cortical motor facilitation phenomenon in a patient with recurrent high-grade glioma undergoing craniotomy for tumor resection; the patient's upper arm motor evoked potentials (MEPs) increased in amplitude significantly (up to 44.52 times larger, p < 0.001) following stimulation of the ipsilateral posterior tibial nerve at 2.79 Hz. With the facilitation effect, the cortical MEP stimulation threshold was reduced by 6 mA to maintain appropriate continuous motor monitoring. It likely has the benefit of reducing the occurrence of stimulation-induced seizures and other adverse events associated with excessive stimulation. We conducted a retrospective data review including 120 patients who underwent brain tumor resection with IONM at our center from 2018 to 2022. A broad range of variables collected pre-and intraoperatively were reviewed. The review aimed to determine: (1) whether we overlooked this facilitation phenomenon in the past, (2) whether this unique finding is related to any specific demographic information, clinical presentation, stimulation parameter (s) or anesthesia management, and (3) whether it is necessary to develop new techniques (such as facilitation methods) to reduce cortical stimulation intensity during intraoperative functional mapping. There is no evidence suggesting that clinical presentation, stimulation configuration, or intraoperative anesthesia management of the patient with the facilitation effect were significantly different from our general patient cohort. Even though we did not identify the same facilitation effect in any of these patients, we were able to determine that stimulation thresholds for motor mapping are significantly associated with the location of stimulation (p = 0.003) and the burst suppression ratio (BSR) (p < 0.001). Stimulation-induced seizures, although infrequent (4.05%), could occur unexpectedly even when the BSR was 70%. We postulated that functional reorganization and neuronal hyperexcitability induced by glioma progression and repeated surgeries were probable underlying mechanisms of the interlimb facilitation phenomenon. Our retrospective review also provided a practical guide to cortical motor mapping in brain tumor patients under general anesthesia. We also underscored the need for developing new techniques to reduce the stimulation intensity and, hence, seizure occurrence.

Abstract 3404: Single nuclei RNAseq analysis of recurrent high-grade glioma tumors from patients in the phase 0/1 ‘trigger’ trial of ribociclib plus everolimus

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. Furthermore, single nuclei RNA sequencing (snRNAseq) provides further insight on the transcriptomic and cell state change in all patients enrolled in the Phase 0 trial. 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 &amp;gt; 5-fold biochemical IC50) and a PD ‘trigger’ (&amp;gt;30% decrease in both pRB and pS6) in Gd-nonenhancing tissue were set to qualify patients for expansion. Single nuclei cell analysis was performed on 21 fresh frozen surgical tumor samples to capture transcriptional and cell state changes. 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. snRNAseq analysis revealed significant downregulation of mTOR signaling only in endothelial cells at higher dose levels of everolimus. Amongst the tumor cells, the neural progenitor-like cell state was decreased whereas oligodendrocyte progenitor-like cell state was increased compared to standard-of-care cohort, suggesting a possible inhibition of CDK4-driven neural progenitor-like cell state. Conclusion: In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor. Everolimus exhibits limited penetration into human glioma tissue. Phase 0 surgical tumor tissue is shown to be great resource for identifying pharmacodynamic treatment effect at the single nuclei level. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients. Citation Format: Nader Sanai, An-Chi Tien, Kevin Johnson, Jun Jiang, Yu-Wei Chang, Chelsea Montgomery, Anita DeSantis, Yoko Fujita, Seongho Kim, Jing Li, Roel Verhaak, Shwetal Mehta. Single nuclei RNAseq analysis of recurrent high-grade glioma tumors from patients in the phase 0/1 ‘trigger’ trial of ribociclib plus everolimus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3404.

Recurrent high grade glioma surgery with carmustine wafers implantation: a long-term nationwide retrospective study.

Widespread use of carmustine wafers (CW) to treat high-grade gliomas (HGG) has been limited by uncertainties about its efficacy. To assess the outcome of patients after recurrent HGG surgery with CW implantation and, search for associated factors. We processed the French medico-administrative national database between 2008 and 2019 to retrieve ad hoc cases. Survival methods were implemented. 559 patients who had CW implantation after recurrent HGG resection at 41 different institutions between 2008 and 2019 were identified. 35.6% were female and, median age at HGG resection with CW implantation was 58.1years, IQR [50-65.4]. 520 patients (93%) had died at data collection with a median age at death of 59.7years, IQR [51.6-67.1]. Median overall survival (OS) was 1.1years, 95%CI[0.97-1.2], id est 13.2months. Median age at death was 59.7years, IQR [51.6-67.1]. OS at 1, 2 and 5years was 52.1%, 95%CI[48.1-56.4], 24.6%, 95%CI[21.3-28.5] & 8%, 95%CI[5.9-10.7] respectively. In the adjusted regression, bevacizumab given before CW implantation, (HR = 1.98, 95%CI[1.49-2.63], p < 0.001), a longer delay between the first and the second HGG surgery (HR = 1, 95%CI[1-1], p < 0.001), RT given before and after CW implantation (HR = 0.59, 95%CI[0.39-0.87], p = 0.009) and TMZ given before and after CW implantation (HR = 0.81, 95%CI[0.66-0.98], p = 0.034) remained significantly associated with a longer survival. OS of patients with recurrent HGG that underwent surgery with CW implantation is better in case of prolonged delay between the two resections and, for the patients who had RT and TMZ before and after CW implantation.

A phase I dose-escalation study of SYHA1813, a VEGFR and CSF1R inhibitor, in patients with recurrent High-Grade Gliomas or Advanced Solid Tumors

SYHA1813 is a potent multikinase inhibitor that targets vascular endothelial growth factor receptors (VEGFRs)/colony-stimulating factor 1 receptor (CSF1R). This study aimed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of escalating doses of SYHA1813 in patients with recurrent high-grade gliomas (HGGs) or advanced solid tumors. This study adopted a combination of accelerated titration and a 3 + 3 design for dose escalation, with a starting dose of 5 mg once daily. The dose escalation continued at successive dose levels until the maximum tolerated dose (MTD) was determined. A total of 14 patients were enrolled and treated, including 13 with WHO grade III or IV gliomas and 1 with colorectal cancer. Two patients experienced dose-limiting toxicities (grade 4 hypertension and grade 3 mucositis oral) at 30 mg SYHA1813. The MTD was defined as 15 mg once daily. Hypertension (n = 6, 42.9%) was the most frequent treatment-related adverse event. Among evaluable patients (n = 10), 2 (20%) patients achieved partial response, and 7 (70%) had stable disease. The exposure increased with increasing doses within the studied dose range of 5 to 30 mg. Biomarker assessments demonstrated significant reductions in the levels of soluble VEGFR2 (P = .0023) and increases in the levels of VEGFA (P = .0092) and placental growth factor (P = .0484). The toxicities of SYHA1813 were manageable, and encouraging antitumor efficacy was observed in patients with recurrent malignant glioma. This study is registered with the Chinese Clinical Trial Registry (www.chictr.org.cn/index.aspx; identifier ChiCTR2100045380).

Association between objective neurocognitive functioning and neurocognitive complaints in recurrent high-grade glioma: Longitudinal evidence of cognitive awareness from EORTC brain tumour trials

BackgroundPatients’ reduced awareness of neurocognitive functioning (NCF) may negatively affect the reliability of patient-reported outcomes (PROs) and clinical decision-making. This study evaluated cognitive awareness, defined as the association between NCF and neurocognitive complaints, over the disease course of patients with recurrent high-grade glioma (HGG). MethodsWe assessed NCF using the EORTC core clinical trial battery and neurocognitive complaints using the Medical Outcome Study questionnaire. Patients were categorised as impaired or intact, based on their neurocognitive performance. Spearman’s rank correlations were calculated between NCF and neurocognitive complaints at baseline and each 12 weeks, until 36. The association between changes in NCF and neurocognitive complaints scores between these follow-up assessments was determined using Pearson’s correlation. ResultsA total of 546 patients were included. Neurocognitively impaired patients (n = 437) had more neurocognitive complaints (range: 10.51 [p < 0.001] to 13.34 [p = 0.001]) than intact patients (n = 109) at baseline, at 12 and 24 weeks. In intact patients, NCF and neurocognitive complaints were correlated for only one domain at baseline (0.202, p = 0.036), while in impaired patients correlations were more frequently found in various domains and time points (range: 0.164 [p = 0.001] to 0.334 [p = 0.011]). Over the disease course, NCF and neurocognitive complaints were correlated for only one domain at baseline (0.357, p = 0.014) in intact patients while in impaired patients they were correlated for more domains and time points (range: 0.222 [p < 0.001] to 0.366 [p < 0.001]). ConclusionNeurocognitively impaired patients with recurrent HGG are aware of their neurocognitive limitations at study entry and during follow-up, which should be considered in clinical decision-making and when interpreting PRO results.

Nasal administration of a temozolomide-loaded thermoresponsive nanoemulsion reduces tumor growth in a preclinical glioblastoma model.

Glioblastoma (GB) is the worst and most common primary brain tumor. Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, at least 50% of TMZ treated patients do not respond to TMZ and the development of chemoresistance is a major problem. Here, we designed a lipid nanoemulsion containing a thermoresponsive polymer (poloxamer 407) aiming to improve TMZ release into the brain via nasal delivery. Increasing amounts of poloxamer 407 were added to preformed nanoemulsions (250nm-range) obtained by spontaneous emulsification. The influence of the polymer concentration (from 2.5% to 12.5%) and temperature on viscosity was clearly evidenced. Such effect was also noticed on the mucoadhesiveness of formulations, as well as TMZ release rate and retention/permeation through nasal porcine mucosa using Franz-type diffusion cells. From these results, a formulation containing 10% of poloxamer (NTMZ-P10) was selected for further experiments by nasal route. A significantly higher TMZ amount was observed in the brain of rats from NTMZ-P10 in comparison with controls. Finally, our results show that formulation reduced significantly tumor growth by three-fold: 103.88±43.67mm3 (for NTMZ-P10) and 303.28±95.27mm3 (control). Overall, these results suggest the potential of the thermoresponsive formulation, administered by the non-invasive nasal route, as a future effective glioblastoma treatment.

Acetazolamide versus placebo for cerebral oedema requiring dexamethasone in recurrent and/or progressive high-grade glioma: phase II randomised placebo-controlled double-blind study

ObjectivesSymptoms of raised intracranial pressure (ICP) in recurrent high-grade glioma (HGG) generally require corticosteroid treatment, often causing toxicity with variable effects on ICP symptoms. Acetazolamide reduces ICP when used in...

The efficacy and adverse effects of anlotinib in the treatment of high-grade glioma: A retrospective analysis.

Anlotinib, a novel multi-kinase inhibitor, was found to improve progression-free survival (PFS) in brain metastases. This paper retrospectively analyzed 26 newly diagnosed or recurrent high-grade gliomas from 2017 to 2022, and the patients received oral anlotinib during concurrent postoperative chemoradiotherapy or after recurrence. Efficacy was evaluated according to the Response Assessment in Neuro-Oncology (RANO) criteria, and the main study endpoints were PFS at 6 months and overall survival (OS) at 1 year. After the follow-up, until May 2022, 13 patients survived and 13 patients died, with a median follow-up time of 25.6 months. The disease control rate (DCR) was 96.2% (25/26), and the overall response rate (ORR) rate was 73.1% (19/26). The median PFS after oral anlotinib was 8.9 months (0.8-15.1), and the PFS at 6 months was 72.5%. The median OS after oral anlotinib was 12 months (1.6-24.4), and the OS at 12 months was 42.6%. Anlotinib-related toxicities were observed in 11 patients, mostly grades 1-2. In the multivariate analysis, patients with Karnofsky Performance Scale (KPS) above 80 had a highermedian PFS of 9.9months (p = 0.02), and their sex, age, IDH mutation, MGMTmethylation, and whether anlotinib was combined with chemoradiotherapy or maintenance treatment had no effect on PFS. We found that anlotinib combined with chemoradiotherapy in treating high-grade central nervous system (CNS) tumors can prolong PFS and OS and that it was safe.

Late-line treatment with bevacizumab alone or in combination with chemotherapy in recurrent high-grade gliomas.

Bevacizumab's use in recurrent high-grade glioma is controversial. This study evaluates outcomes in recurrent high-grade glioma patients receiving bevacizumab alone or combined with chemotherapy as a late-line treatment. We retrospectively analyzed patients treated with bevacizumab alone or combined with chemotherapy for high-grade gliomas who showed tumor progression after multiple treatment attempts. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier curves. Predictors of PFS according to prognostic variables were assessed with regression analysis. Between 2010 and 2022, 31 consecutive patients received bevacizumab alone or combined with chemotherapy as a late-line treatment for recurrent high-grade gliomas. Of these patients, 14 (45.2%) were responders according to RANO criteria, and 17 (54.8%) showed progressive or stable disease. OS at 3, 6, and 12months was 80.3%, 62.1%, and 43.5. PFS was 48.4%, 34.3%, and 21.8%, respectively. In the multivariate survival analysis, the only factor independently associated with PFS was smaller 2D tumor size in post-contrast T1-weighted MRI at bevacizumab initiation (p = 0.02). Median time-to-progression was 3months (95%CI: 1-4) in the unmethylated MGMT promoter group and 6 (95%CI: 1-11) in the methylated MGMT promoter group. This difference was not statistically significant (p = 0.37). Bevacizumab alone or in combination with chemotherapy could be beneficial as a late-line therapy in a subset of patients with recurrent high-grade glioma. Small 2D tumor size in post-contrast T1 weighted MRI at bevacizumab initiation was independently associated with prolonged time to progression.

Concurrent immunotherapy and re-irradiation utilizing stereotactic body radiotherapy for recurrent high-grade gliomas.

Clinical trials evaluating immune checkpoint inhibition (ICI) in recurrent high-grade gliomas (rHGG) report 7%-20% 6-month progression-free survival (PFS), while re-irradiation demonstrates 28%-39% 6-month PFS. We evaluate outcomes of patients treated with ICI and concurrent re-irradiation utilizing stereotactic body radiotherapy/fractionated stereotactic radiosurgery (SBRT) compared to ICI monotherapy. Patients ≥18-years-old with rHGG (WHO grade III and IV) receiving ICI + SBRT or ICI monotherapy between January 1, 2016 and January 1, 2019 were included. Adverse events, 6-month PFS and overall survival (OS) were assessed. Log-rank tests were used to evaluate PFS and OS. Histogram analyses of apparent diffusion coefficient maps and dynamic contrast-enhanced magnetic resonance perfusion metrics were performed. Twenty-one patients with rHGG (ICI + SBRT: 16; ICI: 5) were included. The ICI + SBRT and ICI groups received a mean 7.25 and 6.2 ICI cycles, respectively. There were five grade 1, one grade 2 and no grade 3-5 AEs in the ICI + SBRT group, and four grade 1 and no grade 2-5 AEs in the ICI group. Median PFS was 2.85 and 1month for the ICI + SBRT and ICI groups; median OS was 7 and 6months among ICI + SBRT and ICI groups, respectively. There were significant differences in pre and posttreatment tumor volume in the cohort (12.35 vs. 20.51; p= .03), but not between treatment groups. In this heavily pretreated cohort, ICI with re-irradiation utilizing SBRT was well tolerated. Prospective studies are warranted to evaluate potential therapeutic benefits to re-irradiation with ICI + SBRT in rHGG.

MR Intensity Normalization Methods Impact Sequence Specific Radiomics Prognostic Model Performance in Primary and Recurrent High-Grade Glioma.

This study investigates the impact of different intensity normalization (IN) methods on the overall survival (OS) radiomics models' performance of MR sequences in primary (pHGG) and recurrent high-grade glioma (rHGG). MR scans acquired before radiotherapy were retrieved from two independent cohorts (rHGG C1: 197, pHGG C2: 141) from multiple scanners (15, 14). The sequences are T1 weighted (w), contrast-enhanced T1w (T1wce), T2w, and T2w-FLAIR. Sequence-specific significant features (SF) associated with OS, extracted from the tumour volume, were derived after applying 15 different IN methods. Survival analyses were conducted using Cox proportional hazard (CPH) and Poisson regression (POI) models. A ranking score was assigned based on the 10-fold cross-validated (CV) concordance index (C-I), mean square error (MSE), and the Akaike information criterion (AICs), to evaluate the methods' performance. Scatter plots of the 10-CV C-I and MSE against the AIC showed an impact on the survival predictions between the IN methods and MR sequences (C1/C2 C-I range: 0.62-0.71/0.61-0.72, MSE range: 0.20-0.42/0.13-0.22). White stripe showed stable results for T1wce (C1/C2 C-I: 0.71/0.65, MSE: 0.21/0.14). Combat (0.68/0.62, 0.22/0.15) and histogram matching (HM, 0.67/0.64, 0.22/0.15) showed consistent prediction results for T2w models. They were also the top-performing methods for T1w in C2 (Combat: 0.67, 0.13; HM: 0.67, 0.13); however, only HM achieved high predictions in C1 (0.66, 0.22). After eliminating IN impacted SF using Spearman's rank-order correlation coefficient, a mean decrease in the C-I and MSE of 0.05 and 0.03 was observed in all four sequences. The IN method impacted the predictive power of survival models; thus, performance is sequence-dependent.

How I treat recurrent pediatric high-grade glioma (pHGG): a Europe-wide survey study

PurposeAs there is no standard of care treatment for recurrent/progressing pediatric high-grade gliomas (pHGG), we aimed to gain an overview of different treatment strategies.MethodsIn a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on therapeutic options in four case scenarios (children/adolescents with recurrent/progressing HGG).Results139 clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further oncological treatment in three out of four cases and chose palliative care in one case with marked symptoms. Depending on the case, 8–92% would initiate a re-resection (preferably hemispheric pHGG), combined with molecular diagnostics. Throughout all case scenarios, 55–77% recommended (re-)irradiation, preferably local radiotherapy > 20 Gy. Most respondents would participate in clinical trials and use targeted therapy (79–99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitor, 64–88%; EGFR overexpression: anti-EGFR treatment, 46%; CDKN2A deletion: CDK inhibitor, 18%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31–72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20–69% proposed immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6–18%), HDAC inhibitors (4–15%), tumor-treating fields (1–26%), and intraventricular chemotherapy (4–24%).ConclusionIn each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressing HGG.

Diagnostic Accuracy of Arterial Spin-Labeling, Dynamic Contrast-Enhanced, and DSC Perfusion Imaging in the Diagnosis of Recurrent High-Grade Gliomas: A Prospective Study.

For patients with high-grade gliomas, the appearance of a new, enhancing lesion after surgery and chemoradiation represents a diagnostic dilemma. We hypothesized that MR perfusion without and with contrast can differentiate tumor recurrence from radiation necrosis. In this prospective study, we performed 3 MR perfusion methods: arterial spin-labeling, DSC, and dynamic contrast enhancement. For each lesion, we measured CBF from arterial spin-labeling, uncorrected relative CBV, and leakage-corrected relative CBV from DSC imaging. The volume transfer constant and plasma volume were obtained from dynamic contrast-enhanced imaging without and with T1 mapping using modified Look-Locker inversion recovery (MOLLI). The diagnosis of tumor recurrence or radiation necrosis was determined by either histopathology for patients who underwent re-resection or radiologic follow-up for patients who did not have re-resection. There were 26 patients with 32 lesions, 19 lesions with tumor recurrence and 13 lesions with radiation necrosis. Compared with radiation necrosis, lesions with tumor recurrence had higher CBF (P = .033), leakage-corrected relative CBV (P = .048), and plasma volume using MOLLI T1 mapping (P = .012). For differentiating tumor recurrence from radiation necrosis, the areas under the curve were 0.81 for CBF, 0.80 for plasma volume using MOLLI T1 mapping, and 0.71 for leakage-corrected relative CBV. A correlation was found between CBF and leakage-corrected relative CBV (r s = 0.54), volume transfer constant, and plasma volume (0.50 < r s< 0.77) but not with uncorrected relative CBV (r s = 0.20, P = .29). In the differentiation of tumor recurrence from radiation necrosis in a newly enhancing lesion, the diagnostic value of arterial spin-labeling-derived CBF is similar to that of DSC and dynamic contrast-enhancement-derived blood volume.