Glioblastoma Astrocytoma Research Articles

Mesenchymal Properties of Glioma Cell Lines.

Screening of cell surface markers of three glioma cell lines (astrocytoma 1321N1, glioblastoma T98g, and glioblastoma astrocytoma U373 MG) was performed. Glioma cells expressed common mesenchymal cell markers, although the expression levels varied between the cell lines. The expression of proneural markers and glioma cancer stem cell markers was very low and also varied. Induction of differentiation towards the mesodermal cell lineages showed effective adipogenic and osteogenic differentiation for only the U373 MG cell line, while the 1321N1 and T98g lines demonstrated weak adipogenic potential and failed to undergo osteogenic differentiation. The obtained results point to the intratumor phenotypical heterogeneity of cells in gliomas and to the differences between the three studied types of gliomas with regard to the content of cells with mesenchymal phenotype.

Implications of molecular classifications in glioma surgery.

The incorporation of molecular markers into neuro-oncology has transformed our understanding of adult diffuse gliomas. While surgical resection is the mainstay of treatment for many patients with gliomas, surgical management strategies warrant re-exploration in the context of characteristic molecular profiles. We reviewed the neurosurgical and neuro-oncological literature for studies investigating surgery in molecularly defined cohorts of adult diffuse gliomas. We discuss key molecular markers associated with the three subtypes of adult diffuse glioma: glioblastoma IDH-wildtype, astrocytoma IDH-mutant, and oligodendroglioma IDH-mutant and 1p/19q codeleted. We additionally discuss surgical strategies and extent of resection in these tumors, framing them in the context of key molecular alterations. Finally, we briefly discuss the practical utility of molecular markers in guiding surgical decision making. Molecular markers in gliomas are of growing relevance to surgical intervention. Advancements in preoperative and intraoperative molecular diagnostics will increase the utility of molecular biomarkers in informing surgical decision-making for patients with gliomas.

TMIC-19. EXCESSIVE LIPID PRODUCTION SHAPES GLIOMA TUMOR MICROENVIRONMENT

Abstract Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n=18) and IDH1 mutant (IDH1-mt) astrocytoma (n=12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature has lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.

Epidemiology and survival of primary intracranial malignant tumor patients with drop metastasis: a population-based analysis.

Drop metastasis significantly impacts the survival of patients with primary intracranial malignant tumors. Using the information of collaborative stage from the SEER database, we aim to analyze the epidemiology and prognosis of primary intracranial malignant tumor patients with drop metastasis. We analyzed the distribution of patients and the frequency according to the demography and clinical characteristics of patients with drop metastasis. We also analyzed the survival of these patients with drop metastasis. Multivariate Cox proportional hazards models were used to analyze possible prognostic indicators. A total of 56,839 cases with primary intracranial malignant tumors were ultimately included in this cohort study. A total of 792 cases were confirmed to have drop metastasis. The average rate of drop metastasis was 1.4%. Most of the patients with drop metastases were diagnosed before ten years old. The three most common primary intracranial malignant tumors with drop metastasis were glioblastoma, embryonal/primitive/medulloblastoma, and anaplastic astrocytoma. Embryonal/primitive/medulloblastoma had the highest drop metastasis rate, at 11.6%. Tumors located in the infratentorial space and ventricles had a higher rate of drop metastasis than tumors in other locations. The prognosis for patients with drop metastasis is poor. Routine complete treatment (surgery of the primary tumor plus chemoradiotherapy) can significantly improve overall survival. We conducted a population-based analysis of primary intracranial malignant tumor patients with drop metastasis. Our study can help clinicians acquire general information on the epidemiology and survival of primary intracranial malignant tumor patients with drop metastasis.

Excessive lipid production shapes glioma tumor microenvironment.

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.

Safety and Efficacy of Laser Interstitial Thermal Therapy as Upfront Therapy in Primary Glioblastoma and IDH-Mutant Astrocytoma: A Meta-Analysis.

Although primary studies have reported the safety and efficacy of LITT as a primary treatment in glioma, they are limited by sample sizes and institutional variation in stereotactic parameters such as temperature and laser power. The current literature has yet to provide pooled statistics on outcomes solely for primary brain tumors according to the 2021 WHO Classification of Tumors of the Central Nervous System (WHO CNS5). In the present study, we identify recent articles on primary CNS neoplasms treated with LITT without prior intervention, focusing on relationships with molecular profile, PFS, and OS. This meta-analysis includes the extraction of data from primary sources across four databases using the Covidence systematic review manager. The pooled data suggest LITT may be a safe primary management option with tumor ablation rates of 94.8% and 84.6% in IDH-wildtype glioblastoma multiforme (GBM) and IDH-mutant astrocytoma, respectively. For IDH-wildtype GBM, the pooled PFS and OS were 5.0 and 9.0 months, respectively. Similar to rates reported in the prior literature, the neurologic and non-neurologic complication rates for IDH-wildtype GBM were 10.3% and 4.8%, respectively. The neurologic and non-neurologic complication rates were somewhat higher in the IDH-mutant astrocytoma cohort at 33% and 8.3%, likely due to a smaller cohort size.

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial

BackgroundZotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. MethodsEORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. ResultsThe MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. ConclusionsTG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.

The involvement of brain regions associated with lower KPS and shorter survival time predicts a poor prognosis in glioma.

Isocitrate dehydrogenase-wildtype glioblastoma (IDH-wildtype GBM) and IDH-mutant astrocytoma have distinct biological behaviors and clinical outcomes. The location of brain tumors is closely associated not only with clinical symptoms and prognosis but also with key molecular alterations such as IDH. Therefore, we hypothesize that the key brain regions influencing the prognosis of glioblastoma and astrocytoma are likely to differ. This study aims to (1) identify specific regions that are associated with the Karnofsky Performance Scale (KPS) or overall survival (OS) in IDH-wildtype GBM and IDH-mutant astrocytoma and (2) test whether the involvement of these regions could act as a prognostic indicator. A total of 111 patients with IDH-wildtype GBM and 78 patients with IDH-mutant astrocytoma from the Cancer Imaging Archive database were included in the study. Voxel-based lesion-symptom mapping (VLSM) was used to identify key brain areas for lower KPS and shorter OS. Next, we analyzed the structural and cognitive dysfunction associated with these regions. The survival analysis was carried out using Kaplan-Meier survival curves. Another 72 GBM patients and 48 astrocytoma patients from Harbin Medical University Cancer Hospital were used as a validation cohort. Tumors located in the insular cortex, parahippocampal gyrus, and middle and superior temporal gyrus of the left hemisphere tended to lead to lower KPS and shorter OS in IDH-wildtype GBM. The regions that were significantly correlated with lower KPS in IDH-mutant astrocytoma included the subcallosal cortex and cingulate gyrus. These regions were associated with diverse structural and cognitive impairments. The involvement of these regions was an independent predictor for shorter survival in both GBM and astrocytoma. This study identified the specific regions that were significantly associated with OS or KPS in glioma. The results may help neurosurgeons evaluate patient survival before surgery and understand the pathogenic mechanisms of glioma in depth.

5-Aminolevulinic acid fluorescence-guided endoscopic surgery for deep-seated intraparenchymal tumors

Aim The usefulness of 5-aminolevulinic acid (5-ALA) fluorescence-assisted surgery for maximum resection of malignant gliomas has been established. However, its usefulness when combined with endoscopic surgery for deep-seated tumors has not been well established. In this study, whether 5-ALA photodynamic diagnosis (PDD) is feasible and useful for endoscopic surgery was investigated. Methods A specially designed endoscope for PDD that delivers white light or blue light (375–440 nm) as excitation light was used. The fluorescence emitted by the tumor was evaluated in the cavity during resection or at the tip of the sheath during biopsy. The intensity of fluorescence was classified into three categories: strong, vague, and negative. Results A total of 30 intraparenchymal tumors were observed with a neuroendoscope and 5-ALA PDD; 16 patients underwent resection, and 14 underwent biopsy. Overall, 67% (20/30) of tumors showed positive fluorescence of protoporphyrin IX. High-grade gliomas (HGGs) including glioblastoma (GBM) and anaplastic astrocytoma (AA) showed strong fluorescence in 47% (7/15), vague fluorescence in 33% (5/15), and negative fluorescence in 20% (3/15) of cases. Low-grade gliomas (LGGs) showed vague fluorescence in 33% (1/3) and negative fluorescence in 67% (2/3). Diffuse large B-cell lymphoma (DLBCL) showed vague fluorescence in 38% (3/8) and negative fluorescence in 63% (5/8). Metastatic tumors showed strong fluorescence in 25% (1/4) and vague fluorescence in 75% (3/4). In the comparison of fluorescence evaluation, a significant difference was observed only in the comparison between HGGs and DLBCL (p = 0.049). Conclusion These results suggest that 5-ALA PDD-assisted endoscopic surgery is feasible and useful for deep-seated intraparenchymal tumors.

CTNI-34. ZOTIRACICLIB (TG02) FOR NEWLY DIAGNOSED GLIOBLASTOMA IN THE ELDERLY OR FOR RECURRENT GLIOBLASTOMA: FINAL RESULTS OF THE EORTC 1608 STEAM TRIAL

Abstract BACKGROUND Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor that is supposed to suppress tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. METHODS EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients with IDH1R132H-non-mutant newly diagnosed glioblastoma or anaplastic astrocytoma, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), based on O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 in IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months. Secondary objectives included efficacy, quality of life, and safety. Expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. RESULTS The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B) in elderly patients. Two dose-limiting toxicities were observed at 150 mg, one in group A (grade 3 seizure) and one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders, and hepatotoxicity. Progression-free survival at 6 months in group C was 6.7%. CDK9 and its indirect targets, c-MYC and MCL-1, were confirmed to be expressed and their expression was correlated, supporting a regulatory role for CDK-9. The protein levels of CDK-9 and MCL-1 correlated with overall survival. CONCLUSION TG02 exhibits overlapping toxicity with alkylating agents and low clinical activity as a single agent. Larger randomized trials are required to explore activity in combination with RT or TMZ. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.

CTNI-43. A PHASE 1/2 STUDY OF LOW DOSE FRACTIONATED RADIATION THERAPY AS A CHEMOPOTENTIATOR OF SALVAGE TEMOZOLOMIDE FOR HIGH-GRADE GLIOMA

Abstract Cell-survival curves demonstrate low-dose radiation hypersensitivity, with steepest cell kill at 0.3-0.5 Gy/fx. This phase 1/2 study assessed the safety/efficacy of low-dose fractionated radiotherapy (LDFRT) as a chemopotentiator of TMZ in recurrent glioblastoma or anaplastic astrocytoma (AA) patients. Patients with recurrent glioblastoma/AA following standard-of-care therapy, > 12 months from prior RT and >2 months from prior TMZ were eligible for 0.5 Gy RT twice daily x10 fractions with concurrent TMZ (150-200 mg/m2), both delivered in 5 days of a 28-day cycle up to 6 cycles, followed by 6 cycles of adjuvant TMZ. In phase 1, hematologic toxicity was assessed 1 month after initiating therapy. Brain MRIs were obtained every 2 months, or monthly when concerned for progression (defined by RANO criteria). Pseudoprogression consisted of MRI changes irrespective of clinical deterioration/steroid use that stabilized/reversed without oncologic intervention. The primary endpoint, 1-year overall survival (OS), would be considered for future investigation with a lower bound of 80% CI > 28%, chosen from historical data. Secondary endpoints included rates of pseudoprogression and hematologic toxicity. 31 patients were enrolled/analyzed. Grade 3-4 acute hematologic toxicity was observed in 8(27%) patients. Median follow-up was 9.5(range:0.1-66.3) months. Median OS was 9.6(95%CI 7.0-15.4) months. 1-year OS was 34.5%(95%CI 20.9%-57.0%; lower bound of 80%CI = 24.8%). 77% of patients experienced pseudoprogression, with a median time from start of LDFRT of 1.9(95%CI 1.7-4.4) months and median duration of 3.6(95%CI 1.6-Not estimable) months. Patients with pseudoprogression had improved OS vs. those without (N = 6; median 10.6 vs 3.9 months, HR = .12[95%CI .03-.40];P < .01). LDFRT for recurrent glioblastoma/AA was safe. High pseudoprogression rates were observed at low RT doses, with improved OS amongst patients with pseudoprogression. LDFRT with TMZ may elicit low-dose RT hypersensitivity in patients with glioblastoma/AA. Further study is needed to optimally apply this radiobiological property to improve clinical outcomes.

TIPS-12 PHASE I CLINICAL STUDY OF TG02 CAPSULE IN THE TREATMENT OF RECURRENT HIGH-GRADE GLIOMAS WITH FAILED TMZ TREATMENT

Abstract BACKGROUND This study(NCT 03904628) is a dose-escalation, open-label phase I study which enrolled high grade glioma patients who failed with temozolomide(TMZ) treatment. The study purpose is to investigate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of an multi-kinase inhibitor (TG02 capsule, with primary inhibitory effects on cyclin-dependent kinases), as a new therapy for patients with recurrent high-grade glioma patients. METHODS The key inclusion criteria were 18-75 years old, glioblastoma or anaplastic astrocytoma confirmed by histology; when disease progression after receiving temozolomide; according to RANO criteria had evaluable lesions; ECOG performance status of 0-2. Eligible patients were enrolled sequentially into different dose groups and received TG02 capsule every 4 weeks .The dose was increased in a traditional 3 + 3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose(MTD). Second endpoints were pharmacokinetic characteristics and preliminary efficacy. RESULTS Between May 2019 and November 2021, twelve patients were enrolled. No DLT was occurred and MTD was not defined in study. The plasma concentration of TG02 reached the maximum at 2 h after administration, and the elimination half-life was about 7 h. Eleven patients(91.7%) had one or more treatment-related adverse events (TRAEs) assessed using CTCAE 5.0. Most frequent TRAEs were vomiting (91.7%), diarrhea (75.0%), and 50% of the patients had grade 3 or 4 AEs. There were no treatment-related deaths. The median progression-free survival (PFS) was 1.77 months (95%CI:0.82 ~ 4.24). The median OS was 9.63 months (95%CI:2.66 ~ NE). CONCLUSION TG02 capsule is safe and tolerable in patients with recurrent high-grade gliomas. Switching to using TG02 capsule showed some patients had intracranial tumor reduction who failed to treat with TMZ. TG02 can be further explored with combined therapy in the treatment of gliomas.

Vascular differences between IDH-wildtype glioblastoma and astrocytoma IDH-mutant grade 4 at imaging and transcriptomic levels.

Global agreement in central nervous system (CNS) tumor classification is essential for predicting patient prognosis and determining the correct course of treatment, as well as for stratifying patients for clinical trials at international level. The last update by the World Health Organization of CNS tumor classification and grading in 2021 considered, for the first time, IDH-wildtype glioblastoma and astrocytoma IDH-mutant grade 4 as different tumors. Mutations in the genes isocitrate dehydrogenase (IDH) 1 and 2 occur early and, importantly, contribute to gliomagenesis. IDH mutation produces a metabolic reprogramming of tumor cells, thus affecting the processes of hypoxia and vascularity, resulting in a clear advantage for those patients who present with IDH-mutated astrocytomas. Despite the clinical relevance of IDH mutation, current protocols do not include full sequencing for every patient. Alternative biomarkers could be useful and complementary to obtain a more reliable classification. In this sense, magnetic resonance imaging (MRI)-perfusion biomarkers, such as relative cerebral blood volume and flow, could be useful from the moment of presurgery, without incurring additional financial costs or requiring extra effort. The main purpose of this work is to analyze the vascular and hemodynamic differences between IDH-wildtype glioblastoma and IDH-mutant astrocytoma. To achieve this, we evaluate and validate the association between dynamic susceptibility contrast-MRI perfusion biomarkers and IDH mutation status. In addition, to gain a deeper understanding of the vascular differences in astrocytomas depending on the IDH mutation, we analyze the transcriptomic bases of the vascular differences.

ZIKV infection differentially affects the transcriptional profiles in HTR8 and U251 cells

The mechanism by which Zika virus (ZIKV) causes severe birth defects in pregnant women remains unclear. Cell tropisms in placenta and brain play a crucial role in ZIKV pathogenesis, leading to congenital Zika syndrome (CZS). To identify the host factors involved in ZIKV infection, we compared the transcriptional profiles of ZIKV-infected human first-trimester placental trophoblast cells HTR8/SVneo and a human glioblastoma astrocytoma cell line U251. Our results demonstrated that ZIKV exhibited lower rates of mRNA replication and protein expression in HTR8 than in U251 cells, while showing a higher release of infectious viral particles. However, a greater number of differentially expressed genes (DEGs) were found in ZIKV-infected U251 cells than in ZIKV-infected HTR8 cells. Several of these DEGs were enriched in distinct biological processes related to the characteristics of each cell type that may contribute to foetal damage. Both cell types exhibited activation of common interferons, inflammatory cytokines, and chemokine production upon ZIKV infection. Moreover, the neutralization of tumour necrosis factor-alpha (TNF-α) promoted ZIKV infection in both trophoblasts and glioblastoma astrocytoma cells. Overall, we identified multiple DEGs associated with ZIKV pathogenesis.

Clinico-epidemiological Profile of Primary Brain Tumours in North-Eastern Region of India:A Retrospective Single Institution Study

Background: Brain tumours are mixed group of neoplasms originating from the intracranial tissues. The two basic types of brain tumours are primary and metastatic tumours. Very little is known about the epidemiology of primary brain tumours in the North-Eastern region of India. We carried out a 5-year retrospective study on the epidemiology of the primary brain tumour treated in our hospital.Aim: To study the clinico-epidemiological patterns of brain tumour in a tertiary care center in North-Eastern region of India. Materials and Methods: A retrospective epidemiological approach has been used. The records of patients registered in our hospital from 2017-2022 diagnosed as primary brain tumours have been selected. Data regarding age,sex,site of the tumour, histology, geographical distribution and treatment delivered have been collected. Results: Out of a total of 100 patients studied, males (68%) outnumbered females (32%) with a male:female ratio of 2.1:1. Frequency of brain tumours was found to be higher in the age group 31-40 years i.e. 23% compared to age groups 21-30 years and 41-50 years which were 18% and 15% respectively. Mean age was 38.23 years with ages ranging from 4 to 73 years. The most common presenting symptom was headache (53%), followed by vomiting (28%).The most common anatomical site was found to be cerebrum (81%), followed by ventricular and periventricular regions (6%). Supratentorial tumours (91%) were predominant over infratentorial tumours (9%). Histologically, the most common variety was found to be Glioblastoma Multiforme(30%) followed by Grade II Astrocytoma (15%) and GradeIII Astrocytoma (15%). Patients were mostly seen to be belonging to Lower Assam region (46%) . Among all the patients in the study, surgery was done for 90% of patients while 10% did not undergo surgery. 61% of the patients took radiotherapy and chemotherapy, 22% took radiotherapy alone, 7% defaulted treatment(drop outs) and 10% didn’t turn up for treatment. All patients received a radiation dose of 54-60 Gy. A total of 41 patients took adjuvant chemotherapy with Temozolomide. Conclusion: Glioblastoma Multiforme and Astrocytoma are the most common brain tumours in our study. Multimodality management including surgery, radiotherapy and chemotherapy is the cornerstone in the management of brain tumours.

Intraoperative computed tomography perfusion navigation for maximal resection of high grade gliomas: a prospective non-randomized trial

Background: The main purpose of surgery for glioblastoma is to ensure the maximally possible cytoreduction. Computed tomography perfusion imaging has non-invasive tools for assessment of tumor blood flow and allows for visualization of the tumor borders and its most malignant zones.
 Aim: To evaluate the efficacy of intraoperative computed tomography perfusion navigation (ICTPN) during surgery for high grade gliomas.
 Materials and methods: This prospective non-randomized study included 142 patients (76 men and 66 women) with morphologically verified diagnosis of glioblastoma or diffuse astrocytoma grade 4 (World Health Organization 2021 criteria), who had surgery from 2016 to 2022. The ICTPN-based procedures were performed in 94 patients, with 55 with gross total and 39 with subtotal tumor resection. The control group included 48 patients with non-ICTPN-based surgical procedures. All patients were treated with standard adjuvant chemoradiation therapy. The efficacy of surgery was assessed every 3 months. The study endpoint was any tumor progression. The duration of the follow-up was 15 months. Baseline and contrast-enhanced preoperative imaging and postoperative follow-up assessments were performed with a 3T magnetic resonance imaging scanner (General Electric Discovery W750). ICTPN was done with a 32 slice computed tomography scanner (Toshiba Aquilion LB).
 Results: In the totally resected ICTPN group, the mean duration of the relapse-free period was 13.05 months; the relapse-free survival at 6 and 12 months was 92 and 55%, respectively (p 0.001). These results were significantly better than those in the subtotally resected ICTPN patients (8.98 months, 66 and 9%, respectively; log rank test for Kaplan-Meier curves, p 0.001) and in non-ICTPN patients (5.81 months, 23 and 0%, respectively, log rank test, p 0.001).
 Conclusion: ICTPN enables a more objective assessment of the tumor borders and the extent of its resection, as well as relapse-free survival benefits for the patients.

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial.

2054 Background: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor, including CDK-9, that inhibits tumor growth down-stream via depletion of survival proteins such as MCL-1 and MYC. MCL-1 and MYC are frequently overexpressed in glioblastoma. Methods: The EORTC 1608 (NCT03224104) (STEAM) phase 1b trial had a three parallel group (A,B,C) open-label, non-randomized, multicenter design. Groups A and B explored the maximum tolerated dose (MTD) of zotiraciclib in elderly patients (more than 65 years) with IDH1R132H-non-mutant newly diagnosed glioblastoma or anaplastic astrocytoma, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), based on O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of zotiraciclib in IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months. Secondary objectives included efficacy, quality of life, and safety. Results: The MTD was 150 mg in combination with radiotherapy alone (group A, n=12) or temozolomide alone (group B, n=9) in elderly patients. Two dose-limiting toxicities were observed at 150 mg, one in group A (grade 3 seizure) and one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastro-intestinal disorders, and hepatotoxicity. Progression-free survival at 6 months in group C (n=50) was 6.7%. Conclusions: Zotiraciclib exhibits overlapping toxicity with alkylating agents and low clinical activity as a single agent. Larger randomized trials may be required to explore activity in combination with radiotherapy or temozolomide. Clinical trial information: NCT03224104 .

HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells.

(1) Background: Zika virus (ZIKV), an arbo-flavivirus, is transmitted via Aeges aegyptii mosquitoes Following its major outbreaks in 2013, 2014 and 2016, WHO declared it a Public Health Emergency of International Concern. Symptoms of ZIKV infection include acute fever, conjunctivitis, headache, muscle & joint pain and malaise. Cases of its transmission also have been reported via perinatal, sexual and transfusion transmission. ZIKV pathologies include meningo-encephalitis and myelitis in the central nervous system (CNS) and Guillain-Barré syndrome and acute transient polyneuritis in the peripheral nervous system (PNS). Drugs like azithromycin have been tested as inhibitors of ZIKV infection but no vaccines or treatments are currently available. Astrocytes are the most abundant cells in the CNS and among the first cells in CNS infected by ZIKV; (2) Methods: We previously used SOMAScan proteomics to study ZIKV-infected astrocytic cells. Here, we use mass spectrometric analyses to further explain dysregulations in the cellular expression profile of glioblastoma astrocytoma U251 cells. We also knocked down (KD) some of the U251 cellular proteins using siRNAs and observed the impact on ZIKV replication and infectivity; (3) Results & Conclusions: The top ZIKV dysregulated cellular networks were antimicrobial response, cell death, and energy production while top dysregulated functions were antigen presentation, viral replication and cytopathic impact. Th1 and interferon signaling pathways were among the top dysregulated canonical pathways. siRNA-mediated KD of HLA-A, IGFBP5, PSMA2 and HSPA5 increased ZIKV titers and protein synthesis, indicating they are ZIKV restriction factors. ZIKV infection also restored HLA-A expression in HLA-A KD cells by 48 h post-infection, suggesting interactions between this gene product and ZIKV.

Biocompatibility of a Ti-Rich Medium-Entropy Alloy with Glioblastoma Astrocytoma Cells

Titanium and titanium alloys are widely used in medical devices and implants; thus, the biocompatibility of these metals is of great importance. In this study, glioblastoma astrocytoma cellular responses to Ti65-Zr18-Nb16-Mo1 (Ti65M, metastable medium-entropy alloy), Ti-13Nb-7Sn-4Mo (TNSM, titanium alloy), and commercially pure titanium (CP-Ti) were studied. Several physical parameters (crystal phase structure, surface roughness and hardness) of the titanium alloys were measured, and the correlation with the cellular viability was investigated. Finally, the relative protein expression in cellular proliferation pathways was measured and compared with mRNA expression assessed with quantitative real-time reverse transcription polymerase chain reaction assay (qRT-PCR).

Carbon-ion radiotherapy boost with standard dose proton radiation for incomplete-resected high-grade glioma: a phase 1 study

To investigate the maximal tolerated dose (MTD) of a carbon-ion radiotherapy (CIRT) boost prior to standard dose proton radiotherapy (PRT) for newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA) patients with residual lesion after resection. In total, 18 patients with high-grade glioma (HGG) (16 with GBM and 2 with AA) were enrolled in a prospective 3×3 design phase 1 trial. We investigated four dose-levels of CIRT boost [9 (starting level), 12, 15, and 18 Gy relative biological effectiveness (RBE)] delivered in three equal fractions prior to the standard dose PRT (60 Gy RBE in 30 fractions). Concurrent temozolomide (TMZ) was not provided during the CIRT boost but was initiated on the first day of PRT. Acute and late toxicities were scored based on the Common Terminology Criteria for Adverse Events (CTCAE, v 4.03). Dose-limiting toxicities (DLTs) were defined as radiation-induced severe toxicities (≥ grade 3). With a median follow-up of 17.9 months, no severe (≥ grade 3) acute or late toxicities were observed in patients treated with the first three dose levels (CIRT boost doses of 9, 12, 15 Gy RBE). Severe late toxicity (grade 3 radiation necrosis) was observed in the first patient treated with the 18 Gy RBE CIRT boost level. Therefore, this trial was terminated and the MTD of the induction CIRT boost was determined at 15 Gy RBE in 3 fractions. At the time of this analysis, both patients with AA were alive without disease progression. The progression-free survival (PFS) and overall survival (OS) for GBM at 12 months were 50.6% and 78.6%, respectively. Particle beam radiotherapy consisting of a CIRT boost of 15 Gy RBE (in 3 fractions) following standard dose PRT (60 Gy RBE in 30 fractions), and used in conjunction with TMZ, is safe and potentially effective for patients with HGG.