Primary Central Nervous System Malignancies Research Articles

Molecular characterization and survival analysis of a cohort of glioblastoma, IDH-wildtype

Glioblastoma, IDH-wild type, the most common malignant primary central nervous system tumor, represents a formidable challenge in clinical management due to its poor prognosis and limited therapeutic responses. With an evolving understanding of its underlying biology, there is an urgent need to identify prognostic molecular groups that can be subject to targeted therapy. This study established a cohort of 124 sequential glioblastomas from a tertiary hospital and aimed to find correlations between molecular features and survival outcomes. Comprehensive molecular characterization of the cohort revealed prevalent alterations as previously described, such as TERT promoter mutations and involvement of the PI3K-Akt-mTOR, CK4/6-CDKN2A/B-RB1, and p14ARF-MDM2-MDM4-p53 pathways. MGMT promoter methylation is a significant predictor of improved overall survival, aligned with previous data. Conversely, age showed a marginal association with higher mortality. Multivariate analysis to account for the effect of MGMT promoter methylation and age showed that, in contrast to other published series, this cohort demonstrated improved survival for tumors harboring PTEN mutations, and that there was no observed difference for most other molecular alterations, including EGFR amplification, RB1 loss, or the coexistence of EGFR amplification and deletion/exon skipping (EGFRvIII). Despite limitations in sample size, this study contributes data to the molecular landscape of glioblastomas, prompting further investigations to examine these findings more closely in larger cohorts.

Abstract 1108: The impact of adjuvant radiotherapy (ART) and survival prediction by machine learning in intracranial hemangiopericytoma (HPC)

Abstract Background: Intracranial HPC is a rare brain tumor that accounts for less than 1% of all primary central nervous system malignancies. Surgery is the primary treatment, and while radiation may reduce the risk of local recurrence, its overall effectiveness remains uncertain. Therefore, it is crucial to develop reliable predictions for personalized care and improved management. In this study, we used machine learning (ML) techniques to predict the survival of patients with intracranial HPC. Methods: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2019). Patients with other malignancies or lack of pathological diagnosis were excluded. T-tests and chi-square tests compared variables, while Kaplan-Meier, log-rank tests, and Cox regression identified prognostic factors for overall survival (OS) and cancer-specific survival (CSS). Patient records were randomly divided into training (80 %) and validation (20 %) sets. Univariate Cox regression and least absolute shrinkage and selection operator were used to identify the significant factors linked to survival, which were used to establish a nomogram for predicting the 3- and 5-year OS and CSS. Results: Of the 367 included patients, 121 underwent surgery and 246 underwent surgery + ART. The median survival time was 54 months. Patients who underwent surgery had 5-year OS rates of 61% and 86% for CSS, while those treated with surgery + ART had 81% and 96% survival rates, respectively. The two treatment groups showed significant differences in the OS and CSS (p<0.022 and p<0.017, respectively). Age ≥ 50 years was a poor prognostic factor for OS, whereas ART, localized stage and regional stage were good prognostic factors. No significant factors were associated with CSS. To construct the OS Nomogram, three predictors, age, stage, and treatment method, were chosen. In the training and validation sets, the C-indices are 0.799 and 0.736, respectively. The receiver operating characteristic curves (AUCs) for the 3- and 5-year OS in the training set were 0.594 and 0.617, respectively, whereas those in the validation set were 0.56 and 0.59. For the CSS nomogram, two factors, age and stage, were utilized. The C-indices for the training and validation sets are 0.814 and 0.774, respectively. In the training set, the AUCs for 3- and 5-year CSS were 0.585 and 0.605, respectively, and 0.563 in the validation set. The most important risk factor was the distant stage, while the most important protective factor was age less than 50 years. Conclusion: This study shows that ART has a significant impact on the treatment of Intracranial HPC and provides better survival outcomes. ML has been used to create prediction models to support personalized patient care. These findings provide valuable insights into the management of this rare brain tumor and the potential of data-driven approaches to improve treatment and outcomes. Citation Format: Sakhr Alshwayyat, Anas Alaa Al-Khalili, Ayah Erjan, Haya Kamal, Tala Abdulsalam, Mustafa Alshwayyat. The impact of adjuvant radiotherapy (ART) and survival prediction by machine learning in intracranial hemangiopericytoma (HPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1108.

Abstract 3331: Preclinical combination of ONC206 with radiotherapy and temozolomide in a GBM mouse orthotopic model

Abstract Glioblastoma multiforme (GBM) is the most common form of primary malignant brain tumor in adults. It is also the most aggressive and lethal. Standard of care therapy comprises maximal safe surgical resection followed by adjuvant alkylating agent temozolomide (TMZ) and radiotherapy (RT). There have only been five drugs and one device ever approved by the FDA for the treatment of GBM. The five-year survival rate for GBM patients has shown no notable improvement in the last three decades. We previously reported that the first-in-class imipridone small-molecule Dordaviprone (ONC201) decreases protein chaperone ClpX to unleash mitochondrial protease ClpP activity, integrated stress response and cell death. Preclinical combination of ONC201 (100 mg/kg weekly) with radiotherapy and Temozolomide in a GBM mouse orthotopic model results in reduced tumor burden and prolonged survival. The second generation imipridone ONC206 also activates integrated stress response and decreases ClpX in GBM cells but ONC206 is approximately 20 times more potent than its parent imipridone ONC201. ONC206 0.08 uM in combination with 12.5 uM TMZ and 2 Gy RT reduced the cell viability of GBM cells significantly compared to all single treatments and double treatments. During a short-term treatment of a GBM mouse orthotopic model, ONC206 (50 mg/kg weekly, half of ONC201 doses) synergizes with TMZ and RT to induce more tumor cell apoptosis and inhibits more tumor cell proliferation compared to other groups with single or double treatments. There are two ongoing clinical trials with ONC206: single weekly or multiple-day weekly dose regimens of single-agent, oral ONC206 in patients with recurrent, primary central nervous system (CNS) neoplasms (NCT04541082) and ONC206 alone or in combination with radiation therapy in treating patients with diffuse midline gliomas that is newly diagnosed or has come back (recurrent) or other recurrent primary malignant CNS tumors (NCT04732065). Future studies evaluating the role of immune function, mitochondrial metabolism, dopamine receptors, the ISR and TRAIL pathway in the synergistic effect would support further development of the triple combination regimen of ONC206, TMZ and radiation therapy for GBM clinical trial. Citation Format: Lanlan Zhou, Leiqing Zhang, Jun Zhang, Shengliang Zhang, Wafik S. El-Deiry. Preclinical combination of ONC206 with radiotherapy and temozolomide in a GBM mouse orthotopic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3331.

Anticoagulant prescribing patterns in patients with primary central nervous system malignancies and secondary metastases.

To evaluate the safety of direct oral anticoagulants (DOACs) versus low-molecular weight heparin (LMWH) in patients with central nervous system (CNS) malignancies and secondary metastases. All adult patients with CNS malignancies and secondary metastases who were treated with a DOAC or LMWH for any indication from 2018 to 2022 were included. The primary outcome was the incidence of any intracranial hemorrhage (ICH) after anticoagulation initiation. Secondary outcomes included non-ICH bleeding events and thromboembolic events. Tolerability was assessed by any changes in anticoagulant therapy during study period. 153 patients were included; 48 patients received enoxaparin and 105 received DOACs, of which apixaban was used most commonly. The population was predominantly White (74%) and male (59%) with a median age of 65. Data was censored for immortal time bias for outcomes evaluated beyond 3months. ICH occurred in 7.7% of the population, more frequently in the enoxaparin group (DOACs 4, 4% vs. enoxaparin 7, 16%, p = 0.037). Non-ICH bleeds were predominantly minor and more common in the DOAC group (DOACs 13, 13% vs. enoxaparin 1, 2%, p = 0.037). Thromboembolic events were not different between groups (DOACs 9. 9% vs, enoxaparin 2, 4%, p = 0.503). Anticoagulant switches occurred more in the enoxaparin group (DOACs 12, 12.4% vs. enoxaparin, 37.8%, p < 0.001), primarily due to patient or provider preference. Our data supports DOACs to be preferred over LMWH for the treatment of VTE or for stroke prevention with AF to prevent ICH in patients with brain tumors or metastases.

Histopathologically confirmed radiation-induced damage of the brain – an in-depth analysis of radiation parameters and spatio-temporal occurrence

BackgroundRadiation-induced damage (RID) after radiotherapy (RT) of primary brain tumors and metastases can be challenging to clinico-radiographically distinguish from tumor progression. RID includes pseudoprogression and radiation necrosis; the latter being irreversible and often associated with severe symptoms. While histopathology constitutes the diagnostic gold standard, biopsy-controlled clinical studies investigating RID remain limited. Whether certain brain areas are potentially more vulnerable to RID remains an area of active investigation. Here, we analyze histopathologically confirmed cases of RID in relation to the temporal and spatial dose distribution.MethodsHistopathologically confirmed cases of RID after photon-based RT for primary or secondary central nervous system malignancies were included. Demographic, clinical, and dosimetric data were collected from patient records and treatment planning systems. We calculated the equivalent dose in 2 Gy fractions (EQD22) and the biologically effective dose (BED2) for normal brain tissue (α/β ratio of 2 Gy) and analyzed the spatial and temporal distribution using frequency maps.ResultsThirty-three patients were identified. High-grade glioma patients (n = 18) mostly received one normofractionated RT series (median cumulative EQD22 60 Gy) to a large planning target volume (PTV) (median 203.9 ccm) before diagnosis of RID. Despite the low EQD22 and BED2, three patients with an accelerated hyperfractionated RT developed RID. In contrast, brain metastases patients (n = 15; 16 RID lesions) were often treated with two or more RT courses and with radiosurgery or fractionated stereotactic RT, resulting in a higher cumulative EQD22 (median 162.4 Gy), to a small PTV (median 6.7 ccm). All (n = 34) RID lesions occurred within the PTV of at least one of the preceding RT courses. RID in the high-grade glioma group showed a frontotemporal distribution pattern, whereas, in metastatic patients, RID was observed throughout the brain with highest density in the parietal lobe. The cumulative EQD22 was significantly lower in RID lesions that involved the subventricular zone (SVZ) than in lesions without SVZ involvement (median 60 Gy vs. 141 Gy, p = 0.01).ConclusionsAccelerated hyperfractionated RT can lead to RID despite computationally low EQD22 and BED2 in high-grade glioma patients. The anatomical location of RID corresponded to the general tumor distribution of gliomas and metastases. The SVZ might be a particularly vulnerable area.

Tumor Models for Training of Fluorescence-Guided Brain Tumor Resection

BACKGROUND AND OBJECTIVES: Neurosurgical resection of brain tumors is a technically demanding task with a steep initial learning curve. Experience has been shown to improve surgical performance and increase the rates of resection. High-grade gliomas (HGG) are responsible for 65% of all primary malignant central nervous system tumors and are the commonest surgically treated brain tumor worldwide. There is increasing evidence that maximal safe surgical resection of HGG impacts on overall survival. The delineation of tumor tissue (and hence the extent of resection) is improved by the use of intraoperative tumor fluorescence, which is achieved by preoperative oral administration of 5-aminolevulinic acid. This however relies on the surgeon developing a skillset of operating under different light conditions for which specific training and experience are required. METHODS: We propose a novel, affordable, and highly adaptable model for recreating these surgical conditions and thus simulate fluorescence-guided HGG resection outside the operating theater for trainee neuro-oncological surgeons. We present a model incorporating plant-based polysaccharides, doped with protoporphyrin IX (PpIX), into cadaveric brains of animals. RESULTS: We show that the concentrations of polymer and PpIX can be titrated (using previously published data) to produce mechanical and fluorescence properties that model tumor tissue. We validate the simulation in a neurosurgical skills laboratory. Furthermore, we used a mini spectrometer with handheld probe to collect fluorescence signals and validate the spectroscopic signal from the PpIX. CONCLUSION: It is hoped that this model system will be useful in neurosurgical teaching and training courses and to neurosurgeons who want to try out new techniques or equipment in anatomy laboratories.

Management of Complications in Neuro-oncology Patients.

The purpose of this article is to familiarize the reader with the spectrum of neurologic and medical complications relevant to the care of patients with neurologic cancer while highlighting best practices to prevent morbidity and mortality. Topics include tumor-related epilepsy, vasogenic edema, complications of corticosteroid use, disruption of the hypothalamic-pituitary axis, venous thromboembolism, and opportunistic infection. In 2021, a joint guideline from the Society for Neuro-Oncology and the European Association of Neuro-Oncology reaffirmed recommendations first established in 2000 that patients with newly diagnosed brain tumors should not be prescribed an antiseizure medication prophylactically. For those with tumor-related epilepsy, monotherapy with a non-enzyme-inducing anticonvulsant is the preferred initial treatment, and levetiracetam remains the preferred first choice. Surveys of physician practice continue to demonstrate excessive use of glucocorticoids in the management of patients with both primary and metastatic central nervous system malignancy. This is particularly concerning among patients who require checkpoint inhibitors as the efficacy of these agents is blunted by concomitant glucocorticoid use, resulting in a reduction in overall survival. Finally, direct oral anticoagulants have been shown to be safe in patients with brain tumors and are now favored as first-line treatment among those who require treatment for venous thromboembolism. Medical care for patients impacted by primary and secondary central nervous system malignancy is complex and requires a committed team-based approach that routinely calls upon the expertise of physicians across multiple fields. Neurologists have an important role to play and should be familiar with the spectrum of complications impacting these patients as well as the latest recommendations for management.

Spatial distribution of histological subtypes of Meningioma: A 14-Year longitudinal study in a developing country

BackgroundMeningiomas are extra-axial tumors that arise from meningothelial cells, accounting for about one-third of primary central nervous system malignancies. While they are often classified by location and histology, the role of the molecular profile in their development and progression is significant. The topographic distribution of meningiomas has not been extensively studied, and it is unclear whether specific histological subtypes have predilection sites. Therefore, this study analyzes the preferred locations of meningiomas according to different biological characteristics and their association with different gradings. MethodsThis is a retrospective chart review of patients in tertiary institutes over 14 years. The data were retrieved from medical and pathological record archives. An association between the biological nature of tumors and the location of meningiomas was analyzed. SPSS version 25 was used to analyze the data. ResultsOut of 272 patients, the predominant location for meningioma distribution was convexity (33.5%), followed by parafalcine (12.5%). WHO Grade I meningiomas were the most common, accounting for 84.2% of all meningiomas. The transitional histological subtype is the common variant (34.6%). The distribution of the histological subtype of meningioma in relation to tentorium was statistically significant. However, that was not the case with the skull base. ConclusionThe spatial distribution of meningiomas within the brain is not uniform. The most frequent locations for meningiomas were found to be convexity and parafalcine. Transitional and fibroblastic meningiomas were the predominant subtypes.

CTNI-60. TREATMENT OF RECURRENT GLIOBLASTOMA WITH APG-157 VIA EXPANDED ACCESS: PRELIMINARY RESULTS FROM SIX PATIENTS FROM A SINGLE-CENTER STUDY

Abstract INTRODUCTION Glioblastoma (GBM) is the most common primary central nervous system malignancy. There is poor long-term survival with a median survival of two years and little consensus on second line therapies after progression. APG-157 is a new class of botanical drugs developed under FDA’s Botanical Drugs Guidance. The purpose of this study is to assess the safety and effect of APG-157 on the six-month survival and quality of life (QoL) of patients with recurrent GBM. METHODS Approval was obtained from the Baylor Scott and White IRB (# 022-230, Approval number 58100462000) and under group expanded access protocol (IND 162339). Major inclusion criteria include histologically proven GBM and unequivocal tumor progression 12 weeks after completion of standard first-line therapy. APG-157 was administered either as monotherapy or in combination with temozolomide or tumor-treating fields. Adverse events were assessed at each study visit. Patient data were collected from study conception through April 25, 2023. RESULTS A total of 6 patients (3 male, 3 females) were treated (median age was 54). A median of 2 treatment cycles were administered. 2 Patients withdrew from the study voluntarily, 2 patients expired while on treatment, and 2 patients continued treatment at the time of data analysis. 47.4% (9/19) of the questionnaire time points were completed, however, we saw low QoL (EORTC-QLQ-C30 and EORTC-QLQ-BN20) with a mean global health status score of 4.5. No patient saw a significant increase in their symptoms and one patient reported a 6-point decrease in their neurological symptoms. One patient who was on monotherapy of APG-157 for two months showed stable disease by MRI evaluation. There were no reported adverse events from the study medication. CONCLUSION Future follow-up and a larger sample size are necessary to confirm the impact of APG-157 on six-month survival and QoL.

Intraocular Lymphoma and Metastatic Tumors of the Retina

Intraocular lymphomas (IOLs) are a rare, heterogeneous group of malignancies often misdiagnosed and underrecognized. These tumors are often non-Hodgkin's and B-cell type when they occur. Primary IOLs are classified into two groups: primary uveal lymphomas (PULs) and primary vitreoretinal lymphomas (PVRLs). PULs are small cells, low-to-moderately aggressive, relatively benign, and rarely associated with central nervous system (CNS) involvement. PVRLs often diffuse large B-cells, are highly aggressive, and are related to malignant primary CNS lymphoma. Secondary IOLs that metastasize to intraocular structures other than the CNS constitute the last group of IOLs. Secondary IOLs typically metastasize to the choroid and have a poor prognosis due to associated systemic disease. All IOLs are challenging to diagnose, leading to treatment delays. Metastatic tumors are the most common intraocular malignancies. However, metastases mainly occur in the choroid. Retinal metastases are much rarer. Primary tumor sites are the most common skin, gastrointestinal tract, lung, and breast cancers. A biopsy is helpful to confirm the diagnosis and may help locate the primary tumor. Radiotherapy is the most common treatment modality. A multidisciplinary approach is essential in treatment management. Despite successful treatment of retinal metastases, patients have a poor prognosis for survival of primary tumors. This review aims to increase awareness and share diagnostic clues and treatment strategies in these critical and insidious malignancies in light of current literature. IOLs and metastatic tumors of the retina will be evaluated separately under the headings.

Prognostic value of indoleamine 2, 3-dioxygenase-1 expression in glial tumors.

<p>Gliomas are the most common primary malignant central nervous system tumors in adults, exhibiting a poor prognosis. Indoleamine 2, 3-dioxygenase-1 (IDO-1) has important functions in cancer immunotherapy due to its role in escaping cancer cells from the immune system. In this study we purposed to evaluate the correlation between IDO-1 expression and clinicopathological parameters in gliomas, and whether IDO-1 can be a prognostic marker.</p>. <p>n=75 patients in total, n=25 patients with low grade glial tumors (LGG, grade 1-2), n=25 patients with high grade glial tumors (HGG, grade 3-4), and n=25 persons with normal brain tissue as control group were included in this study. IDO-1 expression was categorized by using immunohistochemical staining in biopsy specimens as high (H) and low (L) groups among the patients with gliomas. We used a 95% percent confidence interval and p &lt;0.05 to analyze the association between the degree of IDO-1 expression, clinicopathological characteristics, and survival rates in glioma patients.&nbsp;</p>. <p>In HGG, IDO-1 levels were higher than in control brain tissue and LGG (p&lt; 0.001). The mean overall survival (OS) was longer in the L-IDO-1 group (64.53 &plusmn; 3.34) in months (95% CI: 57.969-71.098) compared to the H-IDO-1 group (43.74 &plusmn; 4.36) in months, (95% CI: 35.218-52.330) (p&lt; 0.05).</p>. <p>IDO-1 expression is an in&shy;de&shy;pendent prognostic biomarker to predict&nbsp;<br>OS and progression in HGG. IDO-1 can be&nbsp;evaluated as an alternative instrument for precision medicine in the treatment of gliomas.</p>.

Brain Tumor Classification using Transfer Learning

Brain tumors are one of the more severe medical conditions that can affect both children and adults. Brain tumors make up between 85 and 90 percent of all primary Central Nervous System (CNS) malignancies. Each year, brain tumors are found in about 11,700 persons. The 5-year survival rate is around 34% for males and 36% for female patients with malignant brain or CNS tumors. Brain tumors can be classified as benign, malignant, pituitary, and other forms. Appropriate treatment, meticulous planning, and exact diagnostics must be used to prolong patient lives. The most reliable way for detecting brain cancer is Magnetic Resonance Imaging (MRI). The images are examined by the radiologist. As brain tumors are complex the MRI serve as guide to diagnose the seriousness of the disease. Since the placement and size of the brain tumor seems incredibly abnormal for persons affected by the disease it becomes difficult to properly comprehend the nature of the tumor. For MRI analysis, a qualified neurosurgeon is also necessary. Compiling the results of an MRI can be extremely difficult and time-consuming because there are typically not enough qualified medical professionals and individuals who are knowledgeable about malignancy in poor countries. Thus, this issue can be resolved by an automated cloud-based solution. In the proposed model, The Convolutional Neural Networks (CNN) is used for the classification of the brain tumor dataset with an accuracy of 99%.

Etoricoxib-Cannabidiol Combo: Potential Role in Glioblastoma Treatment and Development of PLGA-Based Nanoparticles.

Glioblastoma (GBM) is the most frequently occurring primary malignant central nervous system tumor, with a poor prognosis and median survival below two years. Administration of a combination of non-steroidal anti-inflammatory drugs and natural compounds that exhibit a curative or prophylactic effect in cancer is a new approach to GBM treatment. This study aimed to investigate the synergistic antitumor activity of etoricoxib (ETO) and cannabidiol (CBD) in a GBM cell line model, and to develop poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) for these two substances. The activity of ETO+CBD was determined using the MTT test, cell-cycle distribution assay, and apoptosis analysis using two GBM cell lines, namely, T98G and U-138 MG. The PLGA-based NPs were developed using the emulsification and solvent evaporation method. Their physicochemical properties, such as shape, size, entrapment efficiency (EE%), in vitro drug release, and quality attributes, were determined using scanning electron microscopy, diffraction light scattering, high-performance liquid chromatography, infrared spectroscopy, and differential scanning calorimetry. The combination of ETO and CBD reduced the viability of cells in a dose-dependent manner and induced apoptosis in both tested GBM cell lines. The developed method allowed for the preparation of ETO+CBD-NPs with a spherical shape, mean particle size (MPS) below 400 nm, zeta potential (ZP) values from -11 to -17.4 mV, polydispersity index (PDI) values in the range from 0.029 to 0.256, and sufficient EE% of both drugs (78.43% for CBD, 10.94% for ETO). The combination of ETO and CBD is a promising adjuvant therapeutic in the treatment of GBM, and the prepared ETO+CBD-NPs exhibit a high potential for further pharmaceutical formulation development.

The use of bevacizumab in primary malignant tumors of the central nervous system: A single-center experience.

Primary central nervous system tumors rank 8 among other cancers in patients over 40 years of age. Glioblastoma is the most common primary central nervous system malignancy, accounting for 48 percent of the cases. The present study evaluates the effect of bevacizumab on the disease course in patients who received bevacizumab therapy due to primary central nervous system tumors in our clinic. The study was designed as a retrospective study. The records of patients treated between January 2000 and August 2021 were reviewed and patients who received bevacizumab therapy due to primary central nervous system tumor were included in the study to evaluate the effect of the therapy on disease course among the subgroups of patients. The study included 70 patients. Of these patients, 40 were male (57.1%) and 30 (42.9%) were female. The median duration of follow-up was 28 months (8-209 months). The median age of the patients was 47 years. The median duration of exposure to bevacizumab was 5 months (1-33 months). Forty-nine patients (71.4%) were histologically diagnosed with glioblastoma multiforme. The median progression-free survival (PFS) was 5 months (95% confidence interval 4-6). The median overall survival (OS) was 8 months (95% confidence interval 6.97-9.02). No statistically significant difference in OS or PFS was observed in any patient subgroup. The therapy was discontinued only in 2 patients (2.9%) due to side effects (1 patient with pulmonary embolism and 1 patient with intracranial hemorrhage). The present study found that the use of bevacizumab is safe in terms of side effects. No statistically significant difference in OS or PFS was observed in any patient subgroup. There is a need for studies on a larger number of patients to find out which patient subgroup benefit the most from bevacizumab therapy.

Comparison of the outcomes following bevacizumab and/or temozolamide/radiosurgery treatment in patients with glioblastoma.

Glioblastoma multiforme (GBM) is the most frequent and malignant primary central nervous system tumor in adults. The gold-standard management of GBM includes post-operative radiotherapy (RT) with concurrent and secondary temozolomide (TMZ) treatment. The present meta-analysis study examined the efficacy of the early administration of bevacizumab prior to standard RT plus TMZ in managing patients with GBM and unfavorable prognostic factors. Between 1983 and 2020, the present study looked for comparative articles involving standard RT plus TMZ and RT/TMZ combined with bevacizumab treatment in patients with GBM. The primary outcomes involved in this study include progression-free survival and overall survival. The present study suggested that bevacizumab administration plus standard RT/TMZ (BEV group) treatment was associated with increased survival of patients with GBM compared with those treated with standard RT/TMZ (CG/Control group) treatment only.

Factors affecting administration of palliative care in primary central nervous system tumors: An NCDB analysis.

e24146 Background: Primary central nervous system (CNS) tumors are a diverse group of neoplasms that can vary greatly in terms of their cellular origin, histological features, clinical behavior, and prognosis. Many diagnoses leave patients with a poor prognosis and an impaired quality of life. Palliative care (PC) has long been used as a means to improve quality of life and symptoms associated with debilitating malignancies; however, its use in CNS tumors is not well characterized. Yet, the plethora of life-altering symptoms such as gait impairment, cognitive decline, motor deficits, and seizures provide a need for further multidisciplinary approaches to integrating PC with primary CNS tumor diagnoses. We aim to assess factors that influence the receipt of PC in the current data on central nervous system tumor patients and assess differences in overall survival. Methods: This study retrospectively evaluated the use of PC in patients with single primary malignant central nervous system tumors (gliomas, neuroepitheliomatous neoplasms, and meningiomas) diagnosed and recorded in the National Cancer Database (NCDB) between 2004 and 2020. Patients were identified by ICD-O-3 coding and patients with other malignancies were excluded. Multivariable logistic regression was performed to evaluate associations between patient characteristics and the use of PC, and Kaplan-Meier curves with log-rank analysis were used to determine survival for each group. Results: After excluding patients without information on utilization of PC, a total of 9295 patients with primary CNS tumors were considered in the final analysis. Overall, 1.31% received palliative care. From patients receiving palliative care, 81.1-93.4% received non-curative treatment with surgery, radiation, chemotherapy, or a combination of one or more of these modalities with additional pain management. Odds of receiving palliative care were decreased in black patients, patients who received non-palliative surgical treatment, patients with a primary tumor site at the optic chiasm, patients with unilateral tumors, and patients with private, medicaid, other government, or unknown insurance status. Odds of receiving palliative care were increased with increased Charlson-Deyo Score, in patients receiving non-palliative systemic or radiation treatment, and patients with a primary site at the spinal dura. Utilization of PC was associated with a decreased 1-year and 5-year overall survival. Conclusions: PC use in CNS tumors was influenced by tumor location, treatment type, insurance status, patient race, and comorbidity index. This study demonstrates the areas in which use of PC utilization is still lacking across a diverse set of CNS tumors and patients. Further exploration is needed into the integration of palliative care broadly across these malignancies as it still remains low despite the abundance of quality-of-life altering symptoms.

PIK3CB as a potential target to regulate chemosensitivity in glioblastoma.

e14051 Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy but exhibits universally poor outcomes in part due to chemoresistance. Temozolomide (TMZ) can significantly improve overall survival, but resistance mechanisms limit its consistent efficacy. The phosphoinositide 3 kinase (PI3K) pathway is involved in multiple TMZ resistance mechanisms and is highly druggable; however, pan-inhibition of its four grossly homologous but functionally distinct catalytic subunits (PIK3CA/B/D/G encode p110α/β/δ/γ, respectively) was unsuccessful clinically. Therefore, by understanding how the individual PI3K subunits regulate TMZ sensitivity, a more selective treatment strategy can be developed to combat chemoresistance. Methods: Differential expression of PI3K subunit genes was assessed using RNA sequencing (RNAseq) results obtained from public databases (e.g., DepMap, The Cancer Tissue Genome Atlas) for GBM cell lines and patient tumors expressing high or low O6-methylguanine-DNA-methyltransferase (MGMT), a DNA repair enzyme highly implicated in TMZ resistance. PI3K protein levels were assessed using immunohistochemistry of gliomas available at The Human Protein Atlas (THPA). PI3K gene expression was correlated with PI3K pathway activation, quantified as protein kinase B phosphorylation (pAKT). PI3K mRNAs and pAKT were then correlated with the half maximal inhibitory concentrations (IC50s) of TMZ in GBM cell lines to evaluate for a relationship between PI3K gene expression, PI3K pathway activity, and TMZ sensitivity. Finally, hazard ratios were used to compare PI3K gene expression in patient tumors with survival and response to chemotherapy to determine if expression was predictive of prognosis and/or chemosensitivity. Results: PIK3CB was the only PI3K gene enriched in both GBM cell lines and tumors, demonstrating significantly higher expression than all other PI3K genes in GBM (P &lt; 0.0001), independent of MGMT levels. PIK3CB expression remained the highest even after controlling for GBM risk factors such as tumor recurrence, isocitrate dehydrogenase (IDH) mutations, molecular subtypes, or patient gender/age differences. Levels of the p110β protein were also significantly higher than those of other PI3K catalytic subunits (P &lt; 0.001). PIK3CB expression was positively correlated with pAKT levels (P &lt; 0.05), but only in cell lines and tumors with low MGMT activity. Both PIK3CB expression and pAKT levels correlated positively with TMZ IC50s (P &lt; 0.05) in MGMT-deficient GBMs, suggesting an inverse relationship between PIK3CB and TMZ sensitivity. Finally, better prognosis and significant survival benefit with chemotherapy were both associated with lower levels of PIK3CB in MGMT-deficient patients. Conclusions: PIK3CB may selectively regulate chemoresistance in GBM, suggesting a role for p110β selective inhibition to improve chemosensitivity.

Exploring the Functional Roles of Telomere Maintenance 2 in the Tumorigenesis of Glioblastoma Multiforme and Drug Responsiveness to Temozolomide.

Glioblastoma multiforme (GBM) is a grade IV human glioma. It is the most malignant primary central nervous system tumor in adults, accounting for around 15% of intracranial neoplasms and 40-50% of all primary malignant brain tumors. However, the median survival time of GBM patients is still less than 15 months, even after treatment with surgical resection, concurrent chemoradiotherapy, and adjuvant chemotherapy with temozolomide (TMZ). Telomere maintenance 2 (TELO2) mRNA is highly expressed in high-grade glioma patients, and its expression correlates with shorter survival outcomes. Hence, it is urgent to address the functional role of TELO2 in the tumorigenesis and TMZ treatment of GBM. In this study, we knocked down TELO2 mRNA in GBM8401 cells, a grade IV GBM, compared with TELO2 mRNA overexpression in human embryonic glial SVG p12 cells and normal human astrocyte (NHA) cells. We first analyzed the effect of TELO2 on the Elsevier pathway and Hallmark gene sets in GBM8401, SVG p12, and NHA via an mRNA array analysis. Later, we further examined and analyzed the relationship between TELO2 and fibroblast growth factor receptor 3, cell cycle progression, epithelial-mesenchymal transient (EMT), reactive oxygen species (ROS), apoptosis, and telomerase activity. Our data showed that TELO2 is involved in several functions of GBM cells, including cell cycle progression, EMT, ROS, apoptosis, and telomerase activity. Finally, we examined the crosstalk between TELO2 and the responsiveness of TMZ or curcumin mediated through the TELO2-TTI1-TTI2 complex, the p53-dependent complex, the mitochondrial-related complex, and signaling pathways in GBM8401 cells. In summary, our work provides new insight that TELO2 might modulate target proteins mediated through the complex of phosphatidylinositol 3-kinase-related kinases in its involvement in cell cycle progression, EMT, and drug response in GBM patients.

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

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

A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death.

Glioblastoma (GBM) is the most prevalent and aggressive primary central nervous system (CNS) malignancy. YM155 is a highly potent broad-spectrum anti-cancer drug that was derived from a phenotypic screen for functional inhibitors of survivin expression, but for which the relevant biomolecular target remains unknown. Presumably as a result of its lack of cell-type selectivity, YM155 has suffered from tolerability issues in the clinic. Based on its structural similarity to the GBM-selective prodrug RIPGBM, here, we report the design, synthesis, and characterization of a prodrug form of YM155, termed aYM155. aYM155 displays potent cell killing activity against a broad panel of patient-derived GBM cancer stem-like cells (IC50 = 0.7-10 nM), as well as EGFR-amplified and EGFR variant III-expressing (EGFRvIII) cell lines (IC50 = 3.8-36 nM), and becomes activated in a cell-type-dependent manner. Mass spectrometry-based analysis indicates that enhanced cell-type selectivity results from relative rates of prodrug activation in transformed versus non-transformed cell types. The prodrug strategy also facilitates transport into the brain (brain-to-plasma ratio, aYM155 = 0.56; YM155 = BLQ). In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2). In an orthotopic intracranial GBM xenograft model, aYM155 prodrug significantly inhibits brain tumor growth in vivo, which correlates with cell-type selective survivin-based pharmacodynamic effects.