Management Of High-grade Gliomas Research Articles

Hypofractionated Radiation Therapy Suppresses Radioresistance in U87 Human Glioma Cells by Inhibiting Yap1 and Hsp90 Proteins.

Radiotherapy plays a vital role in the management of high-grade gliomas. However, the radio resistance of glioma cells limits the effect of radiation and drives recurrence inside the irradiated tumor volume leading to poor outcomes for patients. High-grade glioma cell radioresistance significantly contributes to radiotherapy failure, highlighting the importance of identifying predictive biomarkers for radioresistance. An increasing body of evidence complies with the Yes Associated Protein 1 (Yap-1) and heat shock protein 90 (Hsp90) as biomarkers for radioresistance in glioma cells. A number of studies suggest the potential of radioresistance-associated factors as biomarkers and/ or novel therapeutic targets in glioma cells. Thus, it is essential for glioblastoma patients to identify robust druggable targets involved in radioresistance, optimizing irradiation protocol, and understanding their underlying molecular mechanisms. Therefore, in the present study, we hypothesized that hypofractionated Gamma Knife radiation therapy (HF-GKRT) could target Yap-1 and Hsp90 and downregulate the mechanism of radioresistance in high-grade glioma cells. For this purpose, expression levels of radioresistance markers Yap-1 and Hsp90 were evaluated after treatment with HF-GKRT, and this was compared with single fraction Gamma Knife radiation therapy (SF-GKRT) in U87MG primary human glioblastoma cell line model. This would help design a novel radiation therapy regimen for glioblastoma patients by reducing the risk of radioresistance.

Endovascular Applications for the Management of High-Grade Gliomas in the Modern Era.

High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood-brain barrier (BBB) penetration, hemodynamic complexities, and drug-tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care.

Repeated surgical resections for management of high-grade glioma and its impact on quality of life.

High-grade gliomas (HGG) are aggressive cancers, and their recurrence is inevitable, despite advances in treatment options. While repeated tumor resection has been shown to increase survival rate, its impact on quality of life is not clearly defined. To address this gap, we compared quality of life (QoL) changes in HGG patients who underwent first-time (FTR) versus repeat surgical resections (RSR) for management of recurrence. Forty-four adults with HGG who underwent tumor resection were included in this study and classified into either the FTR group (n = 23) or the RSR group (n = 21). All patients completed comprehensive neuropsychological evaluations that included the Functional Assessment of Cancer Therapy-General (FACT-G) and Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) scales, pre-operatively and at two weeks post-operatively. There was no difference between the FTR and RSR groups in any of the QoL indices (all p > .05), except for improved emotional well-being and worsened social well-being, suggesting minimal detrimental effects of repeat surgeries on QoL in comparison to first time surgery. These results suggest that repeated resection is a viable strategy in certain cases for management of HGG recurrence, with similar impact on QoL as observed in patients undergoing first time surgery. These encouraging outcomes provide useful insight to guide treatment strategies and patient and clinician decision making to optimize surgical and functional outcomes.

NCOG-41. REAL WORLD EXPERIENCE WITH TTFIELDS WITH EMPHASIS ON THERAPY COMPLIANCE

Abstract Tumor Treating Fields (TTF) therapy has emerged as a significant adjunctive component in the treatment of high-grade tumors following its validation in the EF-14 trial in 2017. The incorporation of TTF therapy, alongside cyclic temozolomide (TMZ) therapy, has demonstrated enhanced outcomes in terms of PFS and OS when the useage exceeds 18 hours per day (75% compliance rate). Post-hoc analysis of the EF-14 trial has demonstrated that compliance rates exceeding 90% are associated with an additional benefit. Given the cost-intensive nature and significant constraints associated with the therapy, our objective is to generate real-world data on compliance through a retrospective analysis at a high-throughput academic center. Between June 2015 and February 2022, a total of 115 patients were prescribed TTFields as pa rt of their treatment for high-grade glioma. Mean age was 50y and mean preoperative Karnofsky Index 80-90. The average duration of therapy was 8 months. The majority of patients (74%) initiated therapy concurrently with 1st-line treatment, while only 25% managed to start concomitant to the first cycle of temozolomide. 16.7% started TTFields in the 2nd-line and 9.3% in the 3rd-line setting. Thirteen patients discontinued TTFields treatment within the first 3 months and were consequently excluded from further compliance analysis. Across the study cohort, the median compliance rate was 72% (SD 22%), with an average of 41 days of breaks observed. Compliance was highest during the first 3 cycles, with rates of 79%, 73%, and 72%, respectively. Linear regression analysis did not identify any predictors of compliance, including age at surgery, timing of therapy, duration of therapy, gender, and preoperative Karnofsky Index. These findings highlight the importance of monitoring and promoting adherence to TTFields therapy to maximize its potential benefits in the management of high-grade gliomas. Further strategies are warranted to expedite the start of therapy and improve long-term compliance.

GLIOMA-08 INTRACRANIAL HIGH-GRADE GLIOMA MANAGEMENT IN COTE D’IVOIRE : ABOUT 19 COALIGATED CASES FROM MARCH 2019 TO JUNE 2021

Abstract INTRODUCTION Intracranial malignant gliomas are serious conditions that constitute a therapeutic challenge. In Côte d'Ivoire, since 2019, their care meets international standards with the advent of the National Center of Radiotherapy and Medical Oncology Alassane Ouattara and interdisciplinary consultation meetings. Our objective was to evaluate the morbidity and mortality of patients treated for high-grade gliomas in Côte d'Ivoire. MATERIALS AND METHODS We realized from March 2019 to June 2021, a retrospective cohort study on 19 patients with malignant intracranial glioma, without distinction of age and sex, whether alive or deceased. They were 12 male patients and 07 female patients. The parameters studied were, among others, the type and quality of complementary treatment, the evolution under treatment, and the time to onset of recurrence and death. RESULTS The time to consultation was early in 57.9% of cases. High ICP syndrome was the main reason for consultation at 51.6%, followed by neurological deficit. Surgery was performed on average in all patients within 30 days after imaging. The histological diagnosis of grade 4 glioma was pronounced in 16 patients. Postoperative radiotherapy was performed in 94.7% of cases, associated with concomitant then adjuvant chemotherapy with temozolomide in 84.2% of patients. During the treatment, two cases of local recurrence were notified. At the end of the cohort, the death rate was estimated at 73.7%, with a median survival of 11 months and extremes ranging from 06 months to 34 months. CONCLUSION Despite the availability and application of reference therapeutic processes, malignant glioma remains, due to many factors related to our context, a very pejorative prognosis. This study should continue with the inclusion of a larger number of patients in order to review the state of play of the management of high-grade gliomas in Côte d'Ivoire.

530P Ultra low bevacizumab (BEVULTRA-100) as a novel approach in symptomatic management of high grade glioma: Can minimal dose make a difference?

530P Ultra low bevacizumab (BEVULTRA-100) as a novel approach in symptomatic management of high grade glioma: Can minimal dose make a difference?

NEED OF THE HOUR TO USE MR PERFUSION TO DIFFERENTIATE BETWEEN RADIATION NECROSIS AND TUMOUR RECURRENCE IN KNOWN GLIOMA PATIENTS

Conventional MR imaging may be non-specific in diagnosing low-grade gliomas. Better modalities are used nowadays including MRS (spectroscopy), perfusion, and diffusion-weighted imaging (1).
 MR perfusion is better than CT perfusion in various aspects. MR perfusion does not expose the patient to ionizing radiation. CT perfusion, on the other hand, can be harmful if the patient receives repeated doses. However, CT perfusion may be more readily available in emergency settings and can be quicker to perform than MR perfusion, which requires a longer acquisition time. CT perfusion can also provide more precise measurements of blood flow in small vessels than MR perfusion. Ultimately, the choice between MR perfusion and CT perfusion depends on the specific clinical situation and the preferences of the medical team.
 Perfusion MRI studies have become an increasingly important tool in the management of high-grade gliomas as well. Perfusion MRI allows clinicians to assess the vascularity of these tumors, providing information on tumor grade, response to treatment, and prognosis. Perfusion imaging can be performed using various techniques, including dynamic susceptibility contrast (DSC) MRI and arterial spin labeling (ASL) MRI. DSC-MRI is the most commonly used technique, and it provides information on cerebral blood volume (CBV) and cerebral blood flow (CBF) in the tumor and surrounding tissue. ASL-MRI, on the other hand, measures blood flow by magnetically labeling arterial blood water protons and can provide information on tumor perfusion without the use of contrast agents. Overall, perfusion MRI studies have demonstrated significant potential for improving the diagnosis, management, and prognosis of high-grade gliomas. MR brain perfusion is a type of imaging technique that can be used to differentiate between radiation-related changes and tumor recurrence in patients who have undergone radiation therapy for brain tumors. (2).
 
 Tumor resection followed by chemoradiation remains the current criterion standard treatment for high-grade gliomas. Radiation therapy can cause changes in the brain that may appear similar to tumor recurrence on conventional MRI scans. However, MR brain perfusion can detect differences in blood flow patterns between tumor tissue and normal brain tissue, which can help to differentiate between radiation-related changes/necrosis and tumor recurrence (3).
 Every institute should start using MR perfusion studies to differentiate these. This will eventually help in patient correct diagnosis and reduction in morbidity and mortality.
 Key-words:
 Gliomas, MR Perfusion, CT Perfusion, Tumour Recurrence, Radiation Necrosis.
 
 Conflict of Interest: All authors declare no conflict of interest.
 
 Funding Role: None to declare.
 
 Author Contributions: All authors contributed equally to the drafting of study.
 
 Ethical Statement: Written as per the ethical guidelines of hospital board.
 

Integrative analyses reveal biological function and prognostic role of m7G methylation regulators in high-grade glioma.

Based on 29 m7G regulators, glioma patients were categorized into three groups using data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets. Distinct characteristics were observed in immune cell infiltration, functional enrichment, and clinical prognosis for every glioma subtype. Analyzing the differentially expressed genes (DEGs) confirmed the distinction among the three m7G clusters. A predictive tool for overall survival (OS) in high-grade glioma patients was developed and confirmed, consisting of 13 m7G regulators forming a prognostic signature. Elevated m7G levels were found to be associated with increased tumor mutation burden and immune activation, indicating a tumor microenvironment characterized by inflammation and a lower overall survival rate. In contrast, reduced m7G scores were linked to a deficiency in immune infiltration, a low burden of mutations, and a non-inflamed phenotype, suggesting a more positive clinical outlook. Additionally, the m7G risk scores were found to impact chemotherapy sensitivity. The m7G predictive pattern shows potential as a marker for the overall survival of patients with high-grade glioma. By significantly improving our comprehension of the functional role of m7G regulators in the advancement of glioma and their impact on clinical results, this study offers valuable perspectives for precision therapy in the management of high-grade glioma.

Preoperative stereotactic radiosurgery in the management of brain metastases and gliomas.

Stereotactic radiosurgery (SRS) is the delivery of a high dose ionizing radiation in a highly conformal manner, which allows for significant sparing of nearby healthy tissues. It is typically delivered in 1-5 sessions and has demonstrated safety and efficacy across multiple intracranial neoplasms and functional disorders. In the setting of brain metastases, postoperative and definitive SRS has demonstrated favorable rates of tumor control and improved cognitive preservation compared to conventional whole brain radiation therapy. However, the risk of local failure and treatment-related complications (e.g. radiation necrosis) markedly increases with larger postoperative treatment volumes. Additionally, the risk of leptomeningeal disease is significantly higher in patients treated with postoperative SRS. In the setting of high grade glioma, preclinical reports have suggested that preoperative SRS may enhance anti-tumor immunity as compared to postoperative radiotherapy. In addition to potentially permitting smaller target volumes, tissue analysis may permit characterization of DNA repair pathways and tumor microenvironment changes in response to SRS, which may be used to further tailor therapy and identify novel therapeutic targets. Building on the work from preoperative SRS for brain metastases and preclinical work for high grade gliomas, further exploration of this treatment paradigm in the latter is warranted. Presently, there are prospective early phase clinical trials underway investigating the role of preoperative SRS in the management of high grade gliomas. In the forthcoming sections, we review the biologic rationale for preoperative SRS, as well as pertinent preclinical and clinical data, including ongoing and planned prospective clinical trials.

The effectiveness of gamma knife radiosurgery for the management of residual high-grade gliomas: A single institutional study

High-grade gliomas (HGGs) are presently managed via surgical resection, external beam radiation therapy (EBRT), and chemotherapy. Although Gamma Knife radiosurgery (GKRS) is currently used to manage HGGs, it has not been considered standard care. This paper aims to compare the contribution of GKRS to clinical outcomes in patients in which gross total resection (GTR) cannot be achieved. We retrospectively reviewed the data of 99 patients with HGG (World Health Organization (WHO) grade III and IV) from two groups: group 1 consisted of 68 patients for which only EBRT was administered, and group 2 consisted of 31 patients for which EBRT and GKRS were administered. Patient demographic data, the extent of resection, IDH mutation, radiation dosage, progression-free survival (PFS), overall survival (OS), and follow-up time were recorded and compared across groups. The grade III/IV tumor ratio was 10/58 and 10/21 in groups 1 and 2, respectively. In group 2, PFS and OS were higher than in group 1 (P = 0.030 and 0.021). The mean follow–up time was 15.02 ± 11.8 (3–52) and 18.9 ± 98.6 (7–43) months in groups 1 and 2, respectively. In addition to the standard management of HGGs in patients without GTR, boost GKRS during the early postoperative period is beneficial for increasing PFS and OS.

Combined treatment modality in pediatric infratentorial midline high‐grade glioma can lead to long‐term survival: A case study and review of literature

AbstractCentral nervous system high‐grade glioma (HGG) occurring in an infratentorial midline location is not commonly found in the pediatric population. Though pediatric HGGs appear similar to their adult counterparts histopathologically, they differ in molecular, genetic, and clinical characteristics. Evidence for the management of HGG is sparse in the literature. Surgery in the form of maximum safe resection is the backbone of management and has been variably supplemented with external beam radiotherapy and cytotoxic chemotherapy. The outcome, though largely dismal, has some positive surprises too. As shown in the presented case, the combined modality of management in a 5‐year‐old female child has resulted in a disease‐free survival of 3.5 years.

Contribution of spectroscopic magnetic resonance imaging to target volume delineation in Gamma Knife Radiosurgery: Myth or reality?

Brain malignancies are still associated with poor prognosis despite multimodal radiosurgical therapeutic approach using Gamma Knife (GK), CyberKnife (CK), and linear accelerator-based technologies [1]. These advances have significantly improved the treatment outcome. However, the surgical and radiosurgical concept is still “image-guided”, and the success is closely related to precise tumor volume definition. The gross tumor volume (GTV) is defined as the visible contrast- enhancing lesion on magnetic resonance (MR) images with high three-dimensional spatial accuracy. Target delineation requires always both T2-weighted and volumetric T1-weighted sequences. T2-weighted fluid attenuated inversion recovery (FLAIR) sequences analyze the lesions surrounding brain tissues [2,3]. Objective assessment of apparently healthy tissue surrounding brain tumors seems to be a considerable factor interfering not only with the radiosurgical procedure, but also with the recurrence rate and overall survival. Several studies identified infiltrative spectroscopic pattern of the perilesional edema in more than 96% of high-grade gliomas cases and in 11,5% of patients with brain metastasis [4]. Moreover, some autopsy series of brain metastases confirmed infiltrative growth in radiologically healthy surrounding tissues in more than 60% of cases. This unseen malignant component is responsible of 80 % of “early recurrence” which should be considered as natural evolution of the main tumor [5]. In the management of high grade gliomas, the radiosurgeons are faced either to carcinologic incomplete procedures or to overestimated target irradiation with unbalanced benefit/risk action mostly related to radiation-induced brain necrosis [6]. The delineation of clinical target volume (CTV) which is defined as the volume of tissue that contains the GTV and any microscopic tumor or paths of spread, became a standard for any radio-surgical planning. Since a decade, the magnetic resonance spectroscopy (MRS) was standardized in the target volume assessment. The aim is to establish a metabolic lesional cartography. It had been reported that choline/ N- acetylaspartate (NAA) multivoxel MR spectroscopy index higher that 2,5 is in favor of malignancy in glioma with sensitivity of 90 % and specificity of 85 % [7]. However, NAA/Creatine (Cr) and Choline/Cr ratios are more relevant in the analysis of perilesional edema in brain metastasis cases. The introduction of MRS metabolic cartography concept, the use of relevant metabolite and adapted metabolites ratio estimation contributed to precision in radiosurgery. However, MRS is not used for target delineation for Gamma Knife radiosurgical treatment because of its incompatibility with the Leksell Gamma Knife planning software. Recently, we described the development of the first software allowing the integration of metabolic cartography based on multivoxel spectroscopic MRI in the radiosurgical planning for Leksell Gamma Knife Radiosurgery. The few existing meta-analysis could not lead to gold standard volume delineation techniques despite objective advance in imaging assessment [8,9]. Prospective studies using multimodal imaging data will help to overcome this insufficiency for target delineation in radiosurgery

Narrative review of palliative hypofractionated radiotherapy for high grade glioma.

High grade gliomas (HGG) include World Health Organization (WHO) grade III anaplastic astrocytoma (AA) and WHO grade IV glioblastoma (GBM). As genomic alterations are prognostic, even WHO grade II, IDH-wildtype gliomas may be considered as HGG. Current management of HGG include best supportive care (BSC), surgery, radiation therapy (RT), chemotherapy, and a combination. Elderly patients (defined here as age ≥65) with GBM have significantly worse survival compared to younger patients. Similarly, patients with poor performance status [defined as Karnofsky performance status (KPS) <60 or ECOG performance status (PS) >2], regardless of age have worse outcomes. The standard of care for treatment of HGG involves surgery and chemoradiation. However, the optimal treatment in terms of efficacy, safety and maintaining quality of life (QoL), remains a matter of debate in the elderly and/or poor performing patients due to their worse prognosis. Less aggressive interventions are usually reserved for these patients despite surgery providing a survival and neurologic benefit. Improved survival has been noted in elderly patients treated with RT in comparison with those receiving best supportive care (BSC) alone, with similar survival for patients undergoing standard RT (60 Gy/30 fractions) and hypofractionated RT (25-40 Gy in 5-15 daily fractions). An alkylating agent, temozolomide (TMZ), represents a safe and effective option in select patients with promoter methylation of O6-methylguanine-DNA-methyltransferase (MGMT) gene. A recent phase III randomized trial for GBM patients (age ≥65 years, ECOG PS 0-2) demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS) with hypofractionated RT (40 Gy/15 fractions) with concurrent and adjuvant TMZ vs. RT alone, without adversely impacting either QoL or functional status. Despite chemoradiation becoming the recommended treatment in GBM patients who are elderly but fit, several questions remain unanswered. This includes the survival impact of chemoradiation in patients with severe comorbidities or with ECOG PS >2 or a combination of poor prognostic features such as male gender, poor neurocognition, biopsy only and lack of MGMT methylation. Personalized management of patients with HGG is warranted in the modern era as we attempt to balance the benefit of efficacious treatment with potential toxicity while appreciating the many nuances associated with multiple prognostic factors on anticipated survival. Here, we aim to review the palliative management options available for HGG patients with an emphasis on the role of RT.

HGG-11. HIGH-GRADE GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS HIGHLIGHT HISTOMOLECULAR DIFFERENCES WITH THEIR ADULT AND PAEDIATRIC COUNTERPARTS

BACKGROUNDConsidering that paediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs).METHODSWe performed a multicentric retrospective study of 112 AYAs from adult and paediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyse their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25-years, histopathological HGG diagnosis, available clinical data, pre-operative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next generation sequencing, whole exome sequencing and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 WHO classification.RESULTSBased on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of paediatric-subtypes (Histone H3-mutants, 40%) but also adult-subtypes (IDH-mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH-mutant and 1p/19q co-deleted and the relative high frequency of “rare adult IDH mutations” (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, the non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance.CONCLUSIONSHGGs in AYAs could benefit from a more personalized neuro-oncological management, driven by molecular subtyping rather than age group. Collaborative efforts are needed from paediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.

Standard awake surgery versus hypnosis aided awake surgery for the management of high grade gliomas: A non-randomized cohort comparison controlled trial

Hypnosis could extend the time of Intraoperative Neuropsychological Testing and Brain Mapping in Awake Surgery. A clinical validation for the Hypnosis aided AS (HAs) is still ongoing and further evidences are required. The objective of the present study is to compare two homogeneous cohorts of patients undergoing AS, the first with the aid of the hypnosis and the second according to a standard AS (SAs) protocols. The clinical, radiological and surgical data of two comparable procedures cohorts were retrospectively examined for the present study. All surgeries in Group A were performed with a HAs protocol. Procedures belonging to Group B were performed with a SAs protocol. Endpoints: to compare 1. Incidence of complications in the immediate postoperative period, 2. Clinical and neurological status in the immediate postoperative period and 30 days after surgery, 3. Duration of surgical interventions, 4. Extent of Resection (EOR). The final cohort is composed of 15 procedures; 6 belonging to Group A and 9 to Group B. The different methods outline statistically comparable results from the clinical (Neurological outcomes) both in the postoperative period and one month after surgery and from the surgical point of view (comparable EOR). The incidence of complications is comparable either. The duration of the procedures was significantly longer in HAs group. Hypnosis is a promising approach to increasing the duration of intraoperative “testability” of patients at the price of a longer operative time. A specific professional is needed to induce hypnosis in the difficult intraoperative setting.

Outcomes of presumed malignant glioma treated without pathological confirmation: a retrospective, single-center analysis.

Tissue diagnosis is essential in the usual management of high-grade glioma. In rare circumstances, due to patient preference, performance status, comorbidities, or tumor location, biopsy is not feasible. Sometimes a biopsy is nondiagnostic. Many neuro-oncology clinics have patients like this, but these patients' outcomes and responses to treatment are not known. We retrospectively reviewed records from adult patients diagnosed with presumed high-grade glioma of the brain without definitive pathology, diagnosed between 2004 and 2016. We recorded several clinical variables including date of first diagnostic imaging and date of death. We identified 61 patients and subclassified them to brainstem glioma (n = 32), supratentorial presumed glioblastoma (n = 24), presumed thalamic diffuse midline glioma (n = 2), gliomatosis cerebri (n = 2), and cerebellar glioma (n = 1). Most brainstem glioma patients had no biopsy because of tumor location. Supratentorial presumed glioblastoma patients had no biopsy predominantly because of comorbidities. Median survival, from first diagnostic imaging, was 3.2 months (95% CI: 2.9 to 6.3 months) in the supratentorial glioblastoma group and 18.5 months (95% CI: 13.0 to 44.1 months) in the brainstem group. Treatment with radiation or chemotherapy did not alter the median survival of the supratentorial glioblastoma group (hazard ratio 1.41, uncorrected P = .5). Patients with imaging diagnoses of high-grade glioma have similar, if not worse, survival than those with pathological confirmation. Based on these uncontrolled data, it is unclear how effective radiation or chemotherapy is in this population.

A phase I trial of surgical resection with Gliadel Wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with malignant glioma

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.

High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs). We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification. Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of "rare adult IDH mutations" (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance. HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.

Fluorescein-guided resection of gliomas

Standard of care in the management of high-grade gliomas includes gross total resection (GTR) followed by treatment with radiation and temozolomide. GTR remains one of the few independent prognostic factors for improved survival in this disease. Sodium fluorescein is an organic fluorophore that has been studied as a surgical adjunct to improve the likelihood of achieving GTR in gliomas. Though sodium fluorescein does not selectively accumulate in glioma cells, it allows for real-time identification of regions of blood brain barrier breakdown, corresponding to the contrast-enhancing cores of high-grade gliomas. In addition to its high predictive value for identifying pathologic tissue, use of fluorescein has been shown to improve rates of GTR. In stereotactic needle biopsies, it helps reduce procedure time by rapidly confirming the presence of diagnostic tissue. Furthermore, in non-enhancing, low-grade gliomas, it labels focal regions of vascular dysregulation that have been correlated with high-grade features. Fluorescein has also been shown to be significantly less expensive than other contemporary surgical adjuncts such as intraoperative ultrasound, intraoperative MRI, and the recently FDA approved fluorophore, 5-aminolevulinic acid (5-ALA). Here, we review the current literature on the effectiveness of fluorescein as a surgical tool in the resection of gliomas.

Biological intratumoral therapy for the high-grade glioma part II: vector- and cell-based therapies and radioimmunotherapy.

Management of high-grade gliomas (HGGs) remains a complex challenge with an overall poor prognosis despite aggressive multimodal treatment. New translational research has focused on maximizing tumor cell eradication through improved tumor cell targeting while minimizing collateral systemic side effects. In particular, biological intratumoral therapies have been the focus of novel translational research efforts due to their inherent potential to be both dynamically adaptive and target specific. This two part review will provide an overview of biological intratumoral therapies that have been evaluated in human clinical trials in HGGs, and summarize key advances and remaining challenges in the development of these therapies as a potential new paradigm in the management of HGGs. Part II discusses vector-based therapies, cell-based therapies and radioimmunotherapy.