Lessons from Exceptional Responders with High-Grade Brain Tumors Treated with Precision Targeted Therapies

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.

Introduction: High-grade gliomas comprise central nervous system (CNS) World Health Organization (WHO) Grade 3 and CNS WHO Grade 4 gliomas. Recurrence is seen in almost all patients who underwent treatment. Recurrent high-grade gliomas have poor prognosis. There are phase two trials that assessed the role of irinotecan and bevacizumab as combination regimen in recurrent High-grade gliomas and showed overall survival (OS) and progression-free survival (PFS) benefit. We did a retrospective analysis of our institutional experience on treating recurrent high-grade gliomas with combination of irinotecan and bevacizumab. Materials and Methods: This was a retrospective analysis including 58 patients treated at our center from January 1, 2010 to December 31, 2020. All patients were diagnosed case of CNS WHO Grade 3 and Grade 4 glioma, who received at least one modality of treatment. All patients received inj. Irinotecan 125 mg/m2 intravenous (IV) and inj. Bevacizumab 10 mg/kg IV, every 2 weekly. A base line radiological evaluation has been done with magnetic resonance imaging brain with contrast and repeated every 3 months. Patients have been assessed both for PFS and OS. Results: Median PFS was 6 months (95% confidence interval [CI] 4.395–7.605). Median OS was 8 months (95%CI 5.894–10.106). Six months PFS rate is 49% and 6 months OS is 58%. CNS WHO Grade 3 gliomas responded better to combination therapy as compared with CNS WHO Grade 4 gliomas. Conclusion: Combination of Bevacizumab and Irinotecan is well tolerated and improves OS and PFS in patients with recurrent high-grade gliomas. The effect of combination systemic therapy is more evident in CNS WHO Grade 3 gliomas as compared with glioblastoma multiforme.

Stereotactic radiosurgery (SRS) offers the precise, local delivery of radiation for the treatment of recurrent gliomas. We examined the comparative characteristics, treatments, and outcome in a population having with low– and high–grade gliomas. Between September 1991 and December 1995, 20 patients (13 males, 7 females) had SRS for low-grade [9 patients: World Health Organization (WHO) grade II] vs. high-grade (11 patients: 9 WHO grade IV and 2 WHO grade III) gliomas. The patients with low-grade gliomas were younger (mean age ± SE, 39.6 ± 5.4 years; range, 11.4–61.0 years) than those with high-grade gliomas (51.3 ± 13.9 years; range, 32.9–78.5 years) (P = 0.09). Tumor locations were similar in the two groups: lobar for 7 of 9 low-grade vs. 9 of 11 high-grade gliomas (P = NS) and diencephalic or cerebellar for the remainder. The initial surgical treatments were biopsy, subtotal resection, and total resection for three, three, and three patients with low-grade gliomas, vs. three, seven, and one patients with high-grade gliomas, respectively (P = NS). Except for three patients with low-grade gliomas, all patients had conventional postoperative fractionated external-beam radiotherapy. The doses were 5583 ± 342 vs. 5345 ± 261 cGy (P = NS) for low- vs. high-grade gliomas, respectively. Intervals from surgery and conventional radiation (if given) to progression and SRS tended to be longer for low-grade gliomas: 37.5 ± 9.5 vs. 30.6 ± 11.1 months (P = NS) for low- vs. high-grade gliomas, respectively. High-grade gliomas were larger. The diameters of the collimators that allowed enclosure of the enhancing tumor volume within the specified treatment isodoses were 22.4 ± 2.0 mm for low-grade vs. 29.8 ± 2.8 mm for high-grade gliomas (P = 0.02, ANOVA). SRS doses and isodose percentiles were similar, however, for the two groups: 1650 ± 191 cGy and 79 ± 4.0% vs. 1932 ± 182 cGy and75 ± 3.5% for low- vs. high-grade gliomas, respectively (P = NS, dose and isodose). All patients with high-grade gliomas were followed until death. The mean survival after SRS was 11.6 ± 1.5 months (42 ± 12 months after surgery). Five of nine patients with low-grade gliomas expired 31.6 ± 6.0 months after SRS (P < 0.001, Kaplan–Meier log rank) (74.0 ± 16.0 months after surgery). The four survivors have been followed for 8, 13, 35, and 38 months after SRS, respectively. Multivariate analysis shows that the category of histologic grade correlates significantly with survival after radiosurgery (P = 0.01). SRS may be an important therapeutic option for patients with recurrent gliomas, regardless of their grade.

High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Clinical Characteristics and Prognostic Analysis of Glioma in Human Immunodeficiency Virus-Infected Patients.

Evidence strongly indicates that a small fraction of cells within a tumor known as cancer stem cells (CSCs) drive tumorigenesis in solid neoplasms, including gliomas. CSCs are hypothesized not only to initiate new tumors but also to mediate recurrence by resistance to standard anticancer therapies. The CSC population has been enriched from brain and other tumors using the stem cell surface antigen CD133. CD133+ glioma cells are highly tumorigenic in animal models. For the first time, researchers at the German Cancer Research Center in Heidelberg, Germany recently showed that CD133 expression in primary tumor specimens correlates with survival and outcome measures in patients with gliomas (Clin Cancer Res 14:123–129, 2008). This group analyzed CD133 expression by immunohistochemistry in a series of surgical pathological specimens from 95 gliomas of various grades. CD133 expression and the topographical arrangement of CD133+ cells into clusters significantly increased with higher tumor grade. In 18 of 24 Grade II specimens, CD133 was either not detected or, when detected, was present in less than 1% of tumor cells. In contrast, CD133 was present in greater than 5% of tumor cells in 45 of 47 glioblastomas multiforme and present in 10 to 50% of these cells in 21 of those tumors. A high percentage of CD133+ tumor cells and the presence of clusters correlated with decreased progression-free and overall survival, independent of tumor grade, extent of surgical resection, or age. Moreover, tumor recurrence and progression from lower to higher grade were predicted by an increasing proportion of CD133+ cells within the initial specimen. CD133 was colocalized in a subset of nestin+ cells, indicating that CD133 expression may identify an increasingly tumorigenic subpopulation of CSCs. Further, CD133 was coexpressed with epidermal growth factor receptor vIII mutant, when present, proving that CD133+ cells derived from the tumor. This is one of a handful of recently published reports suggesting that a subset of cells within human gliomas express known neural stem cell markers (CD133, Sox2, Musashi-1, and others) and that such expression correlates with clinical outcomes. The CSC hypothesis dictates that targeting and eradicating these tumorigenic cells may significantly improve glioma treatment. Homing in on CSCs by these antigens may be confounded by their expression in normal neural stem cells, but work such as this may ultimately lead to better treatments and outcomes for patients.FIGURE: Differential expression of CD133 in gliomas of various grades correlates with clinical outcome. A, CD133 was not detectable in some World Health Organization (WHO) Grade II gliomas, whereas expression was detected in relatively few cells in other tumors of the same grade (B, arrows). C, WHO Grade III anaplastic astrocytoma with an increased percentage of CD133+ cells. D, WHO Grade IV glioblastoma multiforme with CD133+ cells arranged in clusters (arrowheads). E, Recurrence and malignant progression correlated with increased CD133 expression in WHO Grade II and III gliomas. F, Kaplan-Meier curves depict progression to glioblastoma multiforme and overall survival (G) in relation to higher CD133 expression in WHO Grade II gliomas. From Clin Cancer Res (14:123–129, 2008).BRIAN M. HOWARD, MD JOHN A. BOOCKVAR, MD STEM CELL RESEARCH

Navigated transcranial magnetic stimulation (nTMS) is a well-established preoperative mapping tool for motor-eloquent glioma surgery. Machine learning (ML) and nTMS may improve clinical outcome prediction and histological correlation. This was a retrospective cohort study of patients who underwent surgery for motor-eloquent gliomas between 2018 and 2022. Ten healthy subjects were included. Preoperative nTMS-derived variables were collected: resting motor threshold (RMT), interhemispheric RMT ratio (iRMTr)-abnormal if above 10%-and cortical excitability score-number of abnormal iRMTrs. World Health Organization (WHO) grade and molecular profile were collected to characterize each tumor. ML models were fitted to the data after statistical feature selection to predict tumor grade. A total of 177 patients were recruited: WHO grade 2-32 patients, WHO grade 3-65 patients, and WHO grade 4-80 patients. For the upper limb, abnormal iRMTr were identified in 22.7% of WHO grade 2, 62.5% of WHO grade 3, and 75.4% of WHO grade 4 patients. For the lower limb, iRMTr was abnormal in 23.1% of WHO grade 2, 67.6% of WHO grade 3%, and 63.6% of WHO grade 4 patients. Cortical excitability score ( P = .04) was statistically significantly related with WHO grading. Using these variables as predictors, the ML model had an accuracy of 0.57 to predict WHO grade 4 lesions. In subgroup analysis of high-grade gliomas vs low-grade gliomas, the accuracy for high-grade gliomas prediction increased to 0.83. The inclusion of molecular data into the model-IDH mutation and 1p19q codeletion status-increases the accuracy of the model in predicting tumor grading (0.95 and 0.74, respectively). ML algorithms based on nTMS-derived interhemispheric excitability assessment provide accurate predictions of HGGs affecting the motor pathway. Their accuracy is further increased when molecular data are fitted onto the model paving the way for a joint preoperative approach with radiogenomics.

To prospectively evaluate whether diffusion-tensor magnetic resonance (MR) imaging depicts differences in World Health Organization (WHO) grade II and III glial brain tumors on the basis of tumor architecture and peritumoral tract invasion. The study protocol was approved by the local ethics committee, and written informed consent was obtained. Diffusion-tensor MR imaging was performed in 23 patients (15 men, eight women; mean age, 47 years) with histologically confirmed brain gliomas. Eleven of the 23 tumors were low-grade gliomas (WHO grade II) and 12 were anaplastic gliomas (WHO grade III). Regions of interest were placed in the tumor center, tumor border, normal-appearing white matter (NAWM) adjacent to the tumor, and NAWM of the contralateral hemisphere. fractional anisotropy (FA) ratios were calculated for regions of interest in relation to the NAWM of the contralateral hemisphere. Pairwise comparisons were performed by using the Mann-Whitney U test. Median FA ratios for grade II versus grade III gliomas were 0.406 versus 0.405, respectively, for tumor center, 0.733 versus 0.449, respectively, for tumor border, and 0.962 versus 0.943, respectively, for NAWM adjacent to the tumor. Differences in FA ratio between low-grade and high-grade tumors were significant in the tumor border only (P = .01). Differences in FA ratio were not significant between low-grade and high-grade gliomas in the tumor center or in the NAWM adjacent to the tumor. The periphery of low-grade gliomas contains a considerable amount of preserved fiber tracts. In high-grade gliomas, however, most of these tracts are disarranged. Low FA ratios in the tumor center are consistent with a high degree of disorganization of myelinated fiber tracts in the center of both low-grade and high-grade gliomas.

Objective To investigate the clinical characteristics and treatment regimens of high-grade gliomas in the elderly patients. Methods A retrospective study including 32 elderly patients with high-grade gliomas was conducted. Those patients were consecutively admitted to Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences from April 2012 to August 2017 and enrolled into this study. Clinical characteristics, Karnofsky performance status (KPS), comorbidities (Charlson comorbidity index), tumor pathology classification, treatment regimen and overall patient survival were analyzed. All patients underwent tumor resection or biopsy, followed by concurrent chemoradiotherapy, chemotherapy, or targeted therapy. The Kaplan-Meier method was used to explore the effects of surgical methods, comorbidities and KPS on the overall survival of patients. Results The patients enrolled into this study included 21 males and 11 females. Their age ranged from 65 to 79 years old with an average of 71.9±6.9 years old. Among them, there were 22 (68.7%) cases with glioblastoma [World Health Organization (WHO) grade Ⅳ] and 10 (31.3%) cases with WHO grade Ⅲ gliomas. The median KPS score was 78.1 (range: 40-90). The range of assessment results based on Charlson comorbidity index was 4 to 8 with a median of 5.7. Of the 32 patients, 21 patients (65.6%) underwent resection and 11 (34.4%) underwent biopsy. Seven patients underwent standard Stupp regimen after operation, 9 patients received temozolomide adjuvant chemotherapy without radiotherapy, 1 patient received targeted therapy, and 11 patients received no further treatment. Four cases were lost to follow-up. The median survival time of 32 patients was 15.8 months(range: 1.2-73.3 months). Survival analysis showed that surgical methods, preoperative KPS, and Charlson comorbidity index were not factors influencing overall survival of patients (all P>0.05). Conclusions Elderly patients with high-grade gliomas are generally in poor health conditions and have multiple comorbidities. Despite having undergone comprehensive treatment, including surgery, radiotherapy and chemotherapy, survival of those patients still seems to be relatively short. Therefore, when deciding treatment regimen, a relatively favorable treatment plan should be selected according to the specific conditions of the patient. Key words: Glioma; Aged; Disease attributes; Treatment; High grade glioma

Hypofractionated stereotactic radiotherapy combined with topotecan in recurrent malignant glioma

Accurately distinguishing the different molecular subtypes of 2021 World Health Organization (WHO) grade 4 Central Nervous System (CNS) gliomas is highly relevant for prognostic stratification and personalized treatment. To develop and validate a machine learning (ML) model using multiparametric MRI for the preoperative differentiation of astrocytoma, CNS WHO grade 4, and glioblastoma (GBM), isocitrate dehydrogenase-wild-type (IDH-wt) (WHO 2021) (Task 1:grade 4 vs. GBM); and to stratify astrocytoma, CNS WHO grade 4, by distinguish astrocytoma, IDH-mutant (IDH-mut), CNS WHO grade 4 from astrocytoma, IDH-wild-type (IDH-wt), CNS WHO grade 4 (Task 2:IDH-mut grade 4 vs. IDH-wt grade 4). Additionally, to evaluate the model's prognostic value. We retrospectively analyzed 320 glioma patients from three hospitals (training/testing, 7:3 ratio) and 99 patients from ‌The Cancer Genome Atlas (TCGA) database for external validation‌. Radiomic features were extracted from tumor and edema on contrast-enhanced T1-weighted imaging (CE-T1WI) and T2 fluid-attenuated inversion recovery (T2-FLAIR). Extreme gradient boosting (XGBoost) was utilized for constructing the ML, clinical, and combined models. Model performance was evaluated with receiver operating characteristic (ROC) curves, decision curves, and calibration curves. Stability was evaluated using six additional classifiers. Kaplan-Meier (KM) survival analysis and the log-rank test assessed the model's prognostic value. In Task 1 and Task 2, the combined model (AUC = 0.907, 0.852 and 0.830 for Task 1; AUC = 0.899, 0.895 and 0.792 for Task 2) and the optimal ML model (AUC = 0.902, 0.854 and 0.832 for Task 1; AUC = 0.904, 0.899 and 0.783 for Task 2) significantly outperformed the clinical model (AUC = 0.671, 0.656, and 0.543 for Task 1; AUC = 0.619, 0.605 and 0.400 for Task 2) in both the training, testing and validation sets. Survival analysis showed the combined model performed similarly to molecular subtype in both tasks (p = 0.964 and p = 0.746). The multiparametric MRI ML model effectively distinguished astrocytoma, CNS WHO grade 4 from GBM, IDH-wt (WHO 2021) and differentiated astrocytoma, IDH-mut from astrocytoma, IDH-wt, CNS WHO grade 4. Additionally, the model provided reliable survival stratification for glioma patients across different molecular subtypes.

Gliomas are the most frequent primary brain tumors. In a minority of cases, the differentiation between astrocytomas and oligodendrogliomas based on morphologic characteristics alone can be difficult; though it is important, as patients with oligodendrogliomas follow a more favorable clinical course. Here we report on the immunohistochemical expression pattern of the oligodendrocytic marker Nogo-A in 113 central nervous system tumors including 28 oligodendrogliomas [15, World Health Organization (WHO) grade II; 13, grade WHO III], 50 astrocytomas [10, grade WHO II; 11, grade WHO III; 29 glioblastoma multiforme (GBM)], 11 ependymomas WHO grade II, 7 central neurocytomas, 2 dysembryoplastic neuroepithelial tumors (DNTs), 5 clear cell meningiomas, and 10 metastases to the brain. The oligodendrocytic marker Nogo-A was found to be strongly expressed in 71% of oligodendrogliomas, but in 0% of ependymomas WHO grade II, astrocytomas WHO grade II or III, DNTs, central neurocytomas, or clear cell meningiomas. In GBM, a subgroup of tumors (24%) showed strong expression of Nogo-A coincidently with Ki67 positivity but glial fibrillary acidic protein-negativity. However, neither in oligodendrogliomas nor GBM was a correlation between the loss of 1p19q and the extent of Nogo-A expression observed. Our findings indicate that Nogo-A is strongly expressed in the majority of oligodendrogliomas and might be a helpful marker to distinguish oligodendrogliomas from astrocytomas WHO grades II and III as well as ependymomas. They also support the hypothesis that GBM may be a heterogeneous group of tumors derived from different progenitor cells.

The brain's cells are dependent on their own biosynthesis of cholesterol as the blood-brain barrier prevents uptake from the circulation. In normal glial cells, regulation of cholesterol synthesis depends on cell density and is turned off when density exceeds a certain level. Gliomas maintain high levels of cholesterol synthesis genes to support abnormal growth. Upregulation of cholesterol synthesis genes is associated with decreased survival in patients with glioblastoma (GBM). Therefore, gliomas are potentially sensitive to cholesterol synthesis inhibition. DSP-0390, an investigational small molecule, inhibits EBP, an enzyme in one of the last, crucial steps of cholesterol biosynthesis. By inhibiting cholesterol synthesis, cytotoxicity can be induced selectively against hyperproliferative GBM cells. DSP-0390 has shown significant antitumor activity in orthotopic xenograft models of human GBM (data on file).DSP-0390 will be evaluated in a phase 1 study in patients with recurrent, high-grade glioma (NCT05023551). Key eligibility criteria: age &amp;gt;18 years; Karnofsky Performance Status score &amp;gt;70%; adequate renal, hepatic, and hematologic function. Patients must not have multifocal disease, leptomeningeal metastasis or extracranial metastasis, abnormal electrocardiograms, or significant cardiovascular disease. In Dose Escalation, 21-30 patients with World Health Organization (WHO) grade III or IV malignant glioma who progressed after &amp;gt;1 prior therapy will be enrolled. Dose level enrollment will be guided by a Bayesian Logistic Regression Model until identification of the maximum tolerated dose or recommended dose for expansion. Dose Expansion for clinical activity will enroll approximately 20-40 patients with WHO grade IV GBM who progressed after primary therapy and have measurable disease. Patients will receive oral DSP-0390 once daily. Study endpoints include safety (treatment-emergent adverse events [AEs], serious AEs, and dose-limiting toxicities), efficacy (6-month progression-free survival [PFS], objective response, PFS, duration of response, and 12-month overall survival), pharmacokinetics (PK), and pharmacodynamic biomarkers. This study is currently recruiting in the United States and Japan.

TPS2077 Background: The brain’s cells are fully dependent on their own de novo biosynthesis of cholesterol as the blood-brain barrier prevents its uptake from the circulation. In normal glial cells, proper regulation of cholesterol synthesis depends on its cell density and is turned off when the cell density exceeds a certain level. On the other hand, gliomas maintain high levels of cholesterol synthesis to support abnormal growth under any condition. Upregulation of cholesterol synthesis genes is associated with decreased survival in patients with glioblastoma (GBM). Therefore, gliomas are potentially sensitive to cholesterol synthesis inhibition. DSP-0390, an investigational small molecule, is an inhibitor of EBP, an enzyme in one of the last and crucial steps of cholesterol biosynthesis. By inhibiting de novo cholesterol synthesis, cytotoxicity can be induced more selectively against hyperproliferative GBM cells. DSP-0390 has shown significant antitumor activity in orthotopic xenograft models of human GBM (data on file). Methods: DSP-0390 will be evaluated in a phase 1 study in patients with recurrent, high-grade glioma (NCT05023551). Key eligibility criteria: age ≥18 years; Karnofsky Performance Status score ≥70%; and adequate renal, hepatic, and hematologic function. Patients must not have multifocal disease, leptomeningeal metastasis or extracranial metastasis, abnormal electrocardiograms, or significant cardiovascular disease. In Dose Escalation, 21–30 patients with World Health Organization (WHO) grade III or IV malignant glioma who progressed after ≥1 prior therapy will be enrolled. Dose level enrollment will be guided by a Bayesian Logistic Regression Model until identification of the maximum tolerated dose or recommended dose for expansion. Dose Expansion for clinical activity will enroll approximately 20–40 patients with WHO grade IV GBM who progressed after primary therapy and have measurable disease. Patients will receive oral DSP-0390 once daily. Study endpoints include safety (treatment-emergent adverse events [AEs], serious AEs, and dose-limiting toxicities), efficacy (6-month progression-free survival [PFS], objective response, PFS, duration of response, and 12-month overall survival), pharmacokinetics (PK), and pharmacodynamic biomarkers. This study is currently recruiting in the United States and Japan. Clinical trial information: NCT05023551.

64-Year-Old Woman With Aphasia and Troponin Elevation