Malignant Brain Tumors Research Articles

Ghost cells: Wilder Penfield and the characterization of glia and glial pathology, 1924–1932

ABSTRACT Wilder Penfield is known for his contributions to the structure–function relationship of the brain and for the surgical treatment of focal epilepsy. Less well known are his contributions to the study of glial cells and his investigation of their role in human neuropathology. Penfield learned the gold and silver methods for staining neurons, glial cells, and their projections from Charles Sherrington and Pío del Río-Hortega. He and his colleague William Cone established a laboratory for the study of glial cells and human neuropathology using metallic stains, initially at the Presbyterian Hospital in New York City in 1925, and then at the Montreal Neurological Institute in 1928. Penfield, Cone, and their research fellows, building on the findings of Río-Hortega, confirmed the existence of oligodendrocytes and their relationship with myelin, and investigated the putative mesodermal origin of microglia. They discovered the reaction of oligodendrocytes to pathological stressors, and the phagocytic activity of microglia in human gliomas. In this article, we argue that Penfield’s studies of astrocytes, oligodendrocytes, and microglia, and their responses to craniocerebral trauma, epilepsy, malignant brain tumors, and other pathologies of the central nervous system inaugurated a new era in clinical neurocytology and neuropathology.

Prospects for the use of perampanel in the treatment of epilepsy in patients with malignant gliomas of the brain

Epilepsy occurs in 35-95% of patients with malignant cerebral gliomas of low malignancy and in 29-71% of patients with gliomas of high malignancy. Seizures can be both the first manifestation of malignant cerebral glioma and appear in the postoperative period and during chemoradiotherapy. This requires the use of antiepileptic drugs, which should control the seizure syndrome, provide control and secondary prevention of seizures, without reducing the response of anti-tumour therapy and the the patient QoL. The processes of epileptogenesis and oncogenesis are closely interrelated through common developmental mechanisms in which glutamate plays a key role. Hypersecretion of glutamate is accompanied by increased expression and activation of its receptors, which increases convulsive readiness. This is accompanied by increased level of brain neurotrophic growth factor, the number of synapses between peritumoral neurons and glioma cells, and increased expression of a number of growth factors, which contributes to tumourous proliferation. In this regard, special attention when treating epilepsy in patients with malignant cerebral gliomas is given to perampanel, a glutamate receptor blocker, a 3rd generation antiepileptic drug. The findings show that perampanel not only effectively controls seizures in patients with malignant cerebral gliomas, but also suppresses tumourous proliferation. Perampanel is able to dose-dependently enhance apoptosis and disrupt cell migration in malignant glioma cell lines. The findings have revealed synergistic effect of perampanel in combination with temozolamide. In conditions of chemoradiation therapy perampanel has a protective effect on healthy peritumoral tissues. Undesirable drug reactions during the use of perampanel are infrequent and insignificant. Additional studies are needed to further research the anticonvulsant and antitumour efficacy of perampanel to treat epilepsy in patients with malignant brain tumours.

The role of NPC2 gene in glioma was investigated based on bioinformatics analysis

Glioblastoma (GBM) is one of the most malignant primary brain tumors in adults. The NPC2 gene (Niemann–Pick type C intracellular cholesterol transporter 2) is a protein-coding gene with a lipid recognition domain. The NPC2 gene was found to be significantly increased in gliomas (LGG and GBM), and it is now thought to be a risk factor. COX analysis demonstrated that NPC2 was a significant risk factor for glioma. Functional enrichment analysis of genes that were differentially expressed between high and low expression groups revealed that genes were primarily enriched in the regulation of trans-synaptic signaling, Retrograde endocannabinoid signaling and other pathways. According to the findings of the immunoinfiltration investigation, the NPC2 gene and macrophage, DC, etc. have a strong positive association. In addition, patients with high NPC2 expression had higher levels of immune cell expression. Medication sensitivity research revealed that NPC2’s differential expression had some bearing on patients’ medication sensitivity. There was a strong correlation between the prognosis of glioma patients and the gene sets NUDT19 and NUME. In brief, the NPC2 gene was identified to be a possible biomarker of glioma, and preliminary analysis was done on the role of the NPC2 gene in immunological microenvironment of glioma.

Short-chain fatty acids reverses gut microbiota dysbiosis-promoted progression of glioblastoma by up-regulating M1 polarization in the tumor microenvironment

Glioblastoma (GBM), known as the most malignant and common primary brain tumor of the central nervous system, has finite therapeutic options and a poor prognosis. Studies have shown that host intestinal microorganisms play a role in the immune regulation of parenteral tumors in a number of different ways, either directly or indirectly. However, the potential impact of gut microbiota on tumor microenvironment, particularly glioma immunological milieu, has not been clarified exactly. In this study, by using an orthotopic GBM model, we found gut microbiota dysbiosis caused by antibiotic cocktail treatment boosted the tumor process in vivo. An obvious change that followed gut microbiota dysbiosis was the enhanced percentage of M2-like macrophages in the TME, in parallel with a decrease in the levels of gut microbial metabolite, short-chain fatty acids (SCFAs) in the blood and tumor tissues. Oral supplementation with SCFAs can increase the proportion of M1-like macrophages in the TME, which improves the outcomes of glioma. In terms of mechanism, SCFAs-activated glycolysis in the tumor-associated macrophages may be responsible for the elevated M1 polarization in the TME. This study will enable us to better comprehend the “gut-brain” axis and be meaningful for the development of TAM-targeting immunotherapeutic strategies for GBM patients.

Symptom experience and symptom distress in patients with malignant brain tumor treated with proton therapy: A five-year follow-up study

Background and purposeSince patients with primary brain tumor are expected to become long-term survivors, the prevention of long-term treatment-induced side effects is particularly important. This study aimed to explore whether symptom experience and symptom distress change over five years in adults with primary brain tumors treated with proton therapy. An additional aim was to explore whether symptom experience and symptom distress correlate. Materials and methodsThe study had a longitudinal observational design. Adult (≥18 years) patients (n = 170) with primary brain tumors treated with proton therapy were followed over five years. Symptom experience and symptom distress were evaluated using the patient-reported Radiotherapy-Related Symptom Assessment Scale. Data from baseline, 1, 12, and 60 months were analyzed using non-parametric tests. ResultsOf the 170 patients, the levels of symptoms and symptom distress were low. Fatigue increased at 1 (p=0.005) and 12 months (p=0.025) and was the most frequent symptom from baseline to 60 months’ follow-up. Cognitive impairment increased at 12 (p=0.027) and 60 months (p<0.001) and was the most distressing symptom at 60 months’ follow-up. There were significant, moderate to strong, correlations at all time points between symptom experience and symptom distress of fatigue, insomnia, pain, dyspnea, cognitive impairment, worry, anxiety, nausea, sadness, constipation, and skin reactions. ConclusionSymptom experience and symptom distress changed in intensity over time with cognitive impairment as the most distressing symptom at 60 months. Future research should focus on identifying effective interventions aimed at alleviating these symptoms and reducing symptom distress for this vulnerable group of patients.

Unravelling the mosaic: Epigenetic diversity in glioblastoma.

Glioblastoma is the most common primary malignant brain tumour. Despite decades of intensive research in the disease, its prognosis remains poor, with an average survival of only 14 months after diagnosis. The remarkable level of intra- and interpatient heterogeneity is certainly contributing to the lack of progress in tackling this tumour. Epigenetic dysregulation plays an important role in glioblastoma biology and significantly contributes to intratumour heterogeneity. However, it is becoming increasingly clear that it also contributes to intertumour heterogeneity, which historically had mainly been linked to diverse genetic events occurring in different patients. In this review, we explore how DNA methylation, chromatin remodelling, microRNA (miRNA) dysregulation, and long noncoding RNA (lncRNA) alterations contribute to intertumour heterogeneity in glioblastoma, including its implications for advanced tumour stratification, which is the essential first step for developing more effective patient-specific therapeutic approaches.

Albumin-Based Microneedles for Spatiotemporal Delivery of Temozolomide and Niclosamide to Resistant Glioblastoma.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard therapy includes maximal surgical resection, radiotherapy, and adjuvant temozolomide (TMZ) administration. However, the rapid development of TMZ resistance and the impermeability of the blood-brain barrier (BBB) significantly hinder the therapeutic efficacy. Herein, we developed spatiotemporally controlled microneedle patches (BMNs) loaded with TMZ and niclosamide (NIC) to overcome GBM resistance. We found that hyaluronic acid (HA) increased the viscosity of bovine serum albumin (BSA) and evidenced that concentrations of BSA/HA exert an impact degradation rates exposure to high-temperature treatment, showing that the higher BSA/HA concentrations result in slower drug release. To optimize drug release rates and ensure synergistic antitumor effects, a 15% BSA/HA solution constituting the bottoms of BMNs was chosen to load TMZ, showing sustained drug release for over 28 days, guaranteeing long-term DNA damage in TMZ-resistant cells (U251-TR). Needle tips made from 10% BSA/HA solution loaded with NIC released the drug within 14 days, enhancing TMZ's efficacy by inhibiting the activity of O6-methylguanine-DNA methyltransferase (MGMT). BMNs exhibit superior mechanical properties, bypass the BBB, and gradually release the drug into the tumor periphery, thus significantly inhibiting tumor proliferation and expanding median survival in mice. The on-demand delivery of BMNs patches shows a strong translational potential for clinical applications, particularly in synergistic GBM treatment.

High Parathyroid Hormone Rather than Low Vitamin D Is Associated with Reduced Event-Free Survival in Childhood Cancer.

Vitamin D deficiency is linked to poor cancer outcomes but the impact of its consequence, elevated parathyroid hormone (PTH), remains understudied. PTH receptor activation influences cancer progression in vitro, yet the effect of elevated PTH on pediatric cancer survival is unexamined. This retrospective study examines associations between PTH, 25-OH vitamin D (25OHD), and event-free survival (EFS) and overall survival (OS) in patients with pediatric cancer. Laboratory data from 4,349 patients (0-18 years) at a tertiary pediatric cancer unit were analyzed for the highest PTH and lowest 25OHD levels at diagnosis and the following 5 years. Data on relapse, secondary malignancies, and mortality were stratified by PTH levels above/below the cohort median (47 pg/mL) and 25OHD levels ≤30 nmol/L. EFS and OS were analyzed and hazard ratios (HR) were calculated for the entire cohort and six cancer subgroups. PTH and 25OHD values were available for 1,286 patients (731 male). Higher PTH associated with inferior EFS in primary malignant brain tumors [HR, 1.80 (1.19-2.72)], embryonal malignancies [HR, 2.20 (1.1-4.43)], and lymphatic malignancies [HR 1.98 (1.05-3.72)]. Vitamin D deficiency associated with inferior EFS in embryonal malignancies [HR 2.41 (1.24-4.68)]. In a multivariate Cox model, only higher PTH remained significant for inferior EFS. Elevated PTH may indicate adverse outcomes in certain pediatric cancers. This study identifies elevated parathyroid hormone as a potential marker for poor outcomes in patients with pediatric cancer, emphasizing the need for adequate vitamin D and calcium management.

Trochlear nerve schwannoma with concomitant osimertinib-responsive stage IV lung adenocarcinoma: illustrative case.

The prognosis for cancer patients has been improved because of the development of molecularly targeted drugs. Treatment of intracranial tumors must be personalized while prioritizing the treatment of comorbid cancers. A 38-year-old man presented with bloody sputum, bilateral multiple nodules, and a mass in the lower lobe of his right lung. Bronchoscopy revealed stage IV lung adenocarcinoma with an epidermal growth factor receptor (EGFR) mutation. Screening head magnetic resonance imaging revealed a 38-mm-diameter mass in the left petroclival area. Because the patient was neurologically intact, the treatment of lung adenocarcinoma was prioritized, and the third-generation EGFR-tyrosine kinase inhibitor osimertinib was used. Although nodules in the lung began to shrink, the intracranial lesion expanded and caused hydrocephalus, necessitating a ventriculoperitoneal shunt. The tumor also caused diplopia, dysarthria, and gait abnormalities. A left anterior transpetrosal approach was used to remove the tumor derived from the trochlear nerve. The pathological examination revealed schwannoma. Neurological symptoms improved following surgery. Osimertinib was continued during the perioperative period. Osimertinib was effective for lung adenocarcinoma but not for trochlear nerve schwannoma, which required surgical intervention. It is necessary to tailor the treatment of benign brain tumors in patients with concurrent malignant cancers. https://thejns.org/doi/10.3171/CASE24144.

Potential for boron neutron capture therapy (BNCT) with ASCT2-targeted boron agents.

233 Background: Boron Neutron Capture Therapy (BNCT) is a cutting-edge particle irradiation technique that utilizes the nuclear reaction triggered by the irradiation of non-radioactive boron-10 with thermal neutrons, selectively annihilating tumor cells that have incorporated boron. In the clinical arena, Boronophenylalanine (BPA), a phenylalanine compound targeting amino acid receptors, has been the cornerstone of BNCT. While BNCT has been effective against malignant gliomas, its dependency on BPA uptake has illuminated the existence of inherent resistance within specific cells, tissues, and cancer types. This study pivots towards the Alanine-serine-cysteine transporter 2 (ASCT2)—a transporter distinct from LAT1—investigating its potential as a gateway for the development of innovative boron carriers, with the aim of expanding the clinical applicability and effectiveness of BNCT. Methods: This research embarked on in vitro investigations to evaluate boron accumulation in F98 and C6 rat glioma cells, and 9L rat gliosarcoma, following 24 hours of exposure to BPA and GluB-2 (10 μg B/ml each). Complementary in vivo studies involved the intravenous administration of these compounds to an F98 rat brain tumor model, with the subsequent measurement of boron distribution at 2.5, 6, and 24 hours post-administration. The efficacy of these treatments was then ascertained through neutron irradiation experiments, gauging therapeutic outcomes via the survival periods of the subjects. Results: In vitro findings highlighted that GluB-2 facilitated a significantly higher intracellular boron concentration compared to BPA in F98 cells (p=0.02, Student's t-test). In vivo results indicated that the apex of boron biodistribution in tumors was achieved at 2.5 hours post-BPA treatment and at 6 hours post-GluB-2 treatment, with GluB-2 securing a superior maximum intratumor boron concentration. Survival analysis revealed a mean survival of 28.0±2.5 days for the neutron alone group, 37.7±5.0 days for the group receiving BPA IV + BNCT at 2.5 hours, 55.1±19.9 days for the group treated with GluB-2 IV + BNCT at 6 hours, and 25.3±1.4 days for the untreated group. Remarkably, the group treated with GluB-2 demonstrated significantly prolonged survival compared to the BPA-treated group (p&lt;0.001, log-rank test). Conclusions: Combining BNCT with GluB-2 showed superior efficacy over BPA. Further research is needed to optimize boron concentration timing and ASCT2 expression levels, yet GluB-2 presents a promising advancement in BNCT, potentially transforming malignant brain tumor treatment.

An investigator-initiated trial to evaluate safety and tolerability of YSCH-01 in patients with recurrent glioblastoma.

TPS33 Background: Glioblastoma (GBM), accounting for 55% of primary malignant brain tumors, is characterized by its highly aggressive nature, poor prognosis, and high recurrence rate. Surgical resection is the primary treatment, yet recurrence is common, and survival rates remain dismal. Recurrent GBM lacks established interventions and standardized therapies. YSCH-01 is an oncolytic adenovirus, developed based on cancer-targeting gene-viro-therapy strategy (1), that has been incorporated with an interferon-like immune anticancer gene (L-IFN). Our preclinical studies have demonstrated significant tumor inhibition by YSCH-01 in both cell-line derived xenograft and patient-derived xenograft models (2). This investigator-initiated trial aims to evaluate the safety and efficacy of YSCH-01 in subjects with recurrent GBM. Methods: Six subjects with recurrent GBM are planned to be enrolled, receiving intracranial injections of YSCH-01 via Ommaya reservoir at a dosage of 5.0×1010 VP, once every 3 weeks for a total of 5 administrations, with a dose-limiting toxicity (DLT) assessment period of 3 weeks. Ommaya reservoir implantation will precede drug administration by one day. Inclusion criteria specify pathology-confirmed recurrent GBM, age 18-75 years, expected survival ≥ 12 weeks, and Karnofsky Performance Status (KPS) score ≥ 50 points, with at least one enhanced lesion of ≥ 1 cm diameter. Safety will be evaluated based on DLT and adverse events (AEs) assessed using CTCAE 5.0. Efficacy will be assessed every 5 weeks using Response Assessment in Neuro-Oncology (RANO) criteria, with overall survival follow-up at 12 weeks for two years. Two of the planned six cases have been enrolled, completing the DLT period without DLTs. The trial is registered with Clinical Trial Registry under NCT05914935. Clinical trial information: NCT05914935 .

Exploratory phase I study of HF1K16 for the treatment of patients with refractory/recurrent advanced glioma.

TPS32 Background: Glioblastoma (GBM) is the most common primary and aggressive malignant brain tumor in adults. Almost all patients with glioblastoma eventually have disease relapse and the median overall survival (OS) remains at only 30 weeks for those recurrent GBM patients. However, very few therapies had been approved over the past two decades, emphasizing the need for novel treatments. It is now wildly acknowledged that the immune microenvironment in brain offers adequate opportunities to implement immunotherapy for the treatment. Since most recurrent tumors had previously been exposed to the genotoxic stress of irradiation and/or chemotherapy, it is predicted to resulted in a higher mutational load and more immunogenic. However, The limited success of T cell immunomodulatory approach for advanced glioma has prompted a deeper understanding of the brain tumor and the immune microenvironment. GBM tumors are well-appreciated to be a immunosuppressive and a hallmark of GBM immunosuppression is the appearance of circulating myeloid-derived suppressor cells (MDSCs) at higher levels. Our preliminary data suggests that HF1K16, a liposome ATRA (all trans retinoic acid) suspension, is capable of relieving immune suppression induced by MDSCs. Further, we recently completed a phase I dose escalation study which showed that HF1K16 is safe, well-tolerated with preliminary efficacy in brain tumor. Thus, we hypothesized that HF1K16 may reverse GBM-associated immune suppression and leading to an increase in TILs and improved survival. Methods: This is an advanced glioma-specific expansion arm for adult patients with prior confirmed brain tumor and failed standard treatment. We plan to enroll 20~30 evaluable patients. Key eligibility criteria include candidates age ≥ 18 years, Karnofsky performance status ≥ 60 with and at least one measurable lesion. The primary endpoint is determination of overall response rate (ORR), duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) according to RANO criteria. Secondary endpoints include longitudinal assessment of the peripheral immune response by changes in MDSC and T cell subsets and numbers. HF1K16 infusions were administered in 21-day cycles (q.o.d days 1-14). Prior to and during treatment, peripheral blood mononuclear cells were collected and analyzed with flow cytometry to monitor the changes in myeloid cell phenotype and T cell composition. The recruitment of patients is anticipated completed in 2024. Clinical trial information: NCT05388487 .

Cell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone.

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially because of subventricular zone contact. Despite this, cross-talk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. In addition, GBM brain tumor-initiating cells (BTICs) increase expression of cathepsin B (CTSB) upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal that both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Last, we show LV-proximal CTSB up-regulation in patients, showing the relevance of this cross-talk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.

Potential of GSPT1 as a novel target for glioblastoma therapy.

Glioblastoma is the most common malignant brain tumor in adults, the survival rate of which has not significantly improved over the past three decades. Therefore, there is an urgent need to develop novel treatment modalities. We previously reported that G1 to S phase transition 1 (GSPT1) depletion induces delayed cell cycle in primary astrocytes. Herein, we examined the potential of GSPT1 as a novel target for glioblastoma therapy. CC-885, a cereblon modulator that degrades GSPT1 by bridging GSPT1 to the CRL4 E3 ubiquitin ligase complex, was administered to nude mice with transplanted brain tumors of U87 glioblastoma cells. The survival period was significantly longer in CC-885 treated mice than in control mice. Furthermore, we generated GSPT1-knockout (KO) U87 cells and GSPT1-KO U87 cells with stable overexpression of FLAG-tagged GSPT1 (Rescued GSPT1-KO). Mice with transplanted GSPT1-KO U87 cells and Rescued GSPT1-KO U87 cells showed significantly longer and similar survival periods, respectively, as those with wild-type (WT) U87 cells. GSPT1-KO U87 cells showed enhanced apoptosis, detected by cleaved PARP1, compared to WT U87 cells. Brain tumors with transplantation of GSPT1-KO U87 cells also showed enhanced apoptosis compared to those with transplantation of WT and Rescued GSPT1-KO U87 cells. GSPT1 expression was confirmed in patients with glioblastoma. However, the clinical study using 87 glioblastoma samples showed that GSPT1 mRNA levels were not associated with overall survival. Taken together, we propose that GSPT1 is an essential protein for glioblastoma growth, but not its malignant characteristics, and that GSPT1 is a potential target for developing glioblastoma therapeutics.

Identification of Rocaglate Acyl Sulfamides as Selective Inhibitors of Glioblastoma Stem Cells.

Glioblastoma (GBM) is the most aggressive and frequently occurring type of malignant brain tumor in adults. The initiation, progression, and recurrence of malignant tumors are known to be driven by a small subpopulation of cells known as tumor-initiating cells or cancer stem cells (CSCs). GBM CSCs play a pivotal role in orchestrating drug resistance and tumor relapse. As a prospective avenue for GBM intervention, the targeted suppression of GBM CSCs holds considerable promise. In this study, we found that rocaglates, compounds which are known to inhibit translation via targeting of the DEAD-box helicase eIF4A, exert a robust, dose-dependent cytotoxic impact on GBM CSCs with minimal killing of nonstem GBM cells. Subsequent optimization identified novel rocaglate derivatives (rocaglate acyl sulfamides or Roc ASFs) that selectively inhibit GBM CSCs with nanomolar EC50 values. Furthermore, comparative evaluation of a lead CSC-optimized Roc ASF across diverse mechanistic and target profiling assays revealed suppressed translation inhibition relative to that of other CSC-selective rocaglates, with enhanced targeting of the DEAD-box helicase DDX3X, a recently identified secondary target of rocaglates. Overall, these findings suggest a promising therapeutic strategy for targeting GBM CSCs.

Immunotherapy for children with malignant brain tumors

The incidence of high-grade malignant gliomas (MG) ranges from 35 to 46% of all central nervous system tumors. Despite combined therapy including surgery, radiation treatment and chemotherapy, overall five-year survival does not exceed 10%. The advent of novel immunotherapeutic strategies has promoted a renewed hopes for the treatment of MG. The aim of the present study was to improve the survival rates of glioma patients. Our study included 5 pediatric patients at the median age of 7.6 years (2-16). Three pts had anaplastic astrocytoma (AA) (1st relapse, 1 pt; 2nd relapse, in 2 pts), One patient was diagnosed with glioblastoma multiforme (GBM) (3rd recurrence), and 1 child had diffuse brainstem glioma (BSG). The median time to the first relapse was 12 months (4 to 16), the second relapse occurred at a median of 5 months (1 to 8). The protocol of immunotherapy included combined administration of autologous dendritic cell-based vaccine (DV) and repeated intrathecal/intraventricular injections of donor allogeneic immunocompetent cells (alloIC) for at least 2 years. Two of 3 pts with AA experienced a progression-free interval of 67 and 71 months. One patient with 3rd GBM relapse is alive without any treatment for 13.3 years after starting the immunotherapy. The median time of follow-up was 67 months, with the 2-year overall survival rate of 58%. Two pts died from the disease progression within 6 and 7 months from the beginning of immunotherapy. Over the period of treatment, the patients received a median of 20 alloIC injections (8 to 60), and 18 DV administrations (8 to 44). No serious side-effects were observed. Immunotherapy could be an promising option for treating patients with high-grade malignant gliomas refractory to conventional therapy and, therefore, deserves further investigations.

Cannabis and Craniotomy for Glioblastoma: Impact on Complications and Health Care Utilization

Despite advances in treatment of glioblastomas (GBMs), the median survival remains 14-16 months. In the United States, 52.5 million people ≥12 years of age used cannabis in 2021. We aim to elucidate differences in complications after craniotomy for resection of GBM between users and nonusers of cannabis. Merative MarketScan Research Data (2008-2019) (includes >265 million patients) were used to extract adults (≥18 years of age) with GBM diagnosis (International Classification of Diseases-9 code 191.x and International Classification of Diseases-10 code C71.x) who had a craniotomy (Current Procedure Terminology code 61510) from inpatient admission data. The inverse probability treatment weighted analysis balanced the groups of cannabis abuse disorder (CAD) and no CAD in terms of age, gender, insurance coverage, comorbidities, and prior 12-month opioid dependence. Individuals with CAD were younger (median, 37 vs. 51 years; P < 0.0001). There was a lower percentage of women (19% vs. 45%; P < 0.0001). In the CAD group, opioid abuse pattern for ≥12 months was higher (16% vs. 5%; P=0.001) and the rate of complications was higher (32% vs. 15%; P= 0.001) during index hospital stay. At 6 months postdischarge, neurologic complications were higher among the CAD group (27% vs. 8%; P < 0.001). At 1 year postdischarge, patients with CAD sought feweroutpatient services (P= 0.012). More neurologic complications were seen in the CAD group (31% vs. 12%; P< 0.001). This retrospective population-based study sounds a higher rate of neurologic complications among patients using cannabis who also had a newly diagnosed GBM. This suggests the lack of a protective effect from use of cannabis in patients with primary malignant brain tumors.

Diagnosis and Classification of Brain Tumors from MRI Images Using the SVM Algorithm

Background: A brain tumor is one of the most common and fatal neurological diseases that may require surgery. The correct diagnosis of the location and size of the tumor can be a diagnostic aid program for medical robots during surgery, and it also helps doctors formulate a suitable treatment plan for the patient. Objectives: To develop an algorithm based on support vector machine (SVM) for the detection and classification of tumors into benign and malignant types on MRI images. Methods: In this retrospective study, 160 MRI images were obtained from the KAGGLE website. The studied subjects included two groups: Benign tumors and malignant tumors. At first, preprocessing and noise removal were done by comparing four filters: Butterworth, wavelet, ideal, and median. Finally, the SVM algorithm was used to classify brain tumors into benign and malignant. Results: The performance evaluation of the filters showed that the median and wavelet filters had the best performance in removing noise from MRI images. Then, the discrete wavelet transform (DWT) extracted the required features from MRI images and was used as the input of the SVM algorithm. The accuracy, precision and specificity of the proposed algorithm in diagnosing benign and malignant brain tumors were 95%, 88% and 91%. Conclusions: The findings of recent studies show that this algorithm can be used to improve the accurate diagnosis of brain tumors and their types. Combining morphological features can also be a diagnostic tool to increase accuracy in robotic surgeries.

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.

AB032. The effect of high-dose dexamethasone on systemic immune-inflammation index (SII) in patients with brain tumor, a retrospective study in tertiary hospital in Indonesia.

Inflammation plays an important role in proliferation, migration, and invasion of tumor cells; therefore, many research has been done to investigate inflammation parameters including systemic immune-inflammatory index (SII). Dexamethasone, a strong anti-inflammatory, is still widely used as the main treatment in vasogenic edema. High-dose administration (16 mg/day) is recommended in patients with brain tumors with increased intracranial pressure. We performed this retrospective study to determine SII profile, dexamethasone use, and the effect of high-dose dexamethasone on SII in patients with brain tumors. We performed a retrospective study on patients with brain tumors in 2022-2023 period who were treated with intravenous high-dose dexamethasone. Patient demographics, clinical characteristics of the brain tumor, concurrent infection, as well as dexamethasone dose and duration were recorded. Platelet, neutrophil, and lymphocyte count obtained prior to dexamethasone administration, and on the fifth to seventh day were also collected. SII was calculated by the following formula: neutrophil × platelet counts/lymphocyte. Data were then analyzed using Microsoft Excel 2019 and SPSS 29.0.2.0. We enrolled 56 patients with brain tumors, age 47±13.5 years, 78.6% were female, 69.6% had malignant brain tumors (brain metastases and high-grade primary brain tumors) and 26.8% had concurrent infection. High-dose dexamethasone was administered with average dose of 16.8±3.3 mg/day for average duration of 4.8±1.8 days. SII was significantly higher in malignant compared to benign brain tumors both in prior and after dexamethasone administration (P=0.02, P=0.01). SII was significantly higher in metastasis brain tumor compared to primary brain tumor (P=0.005). High-dose dexamethasone significantly increased SII and decreased lymphocyte count (P=0.006, P=0.04). SII was found higher in malignant brain tumor and brain metastasis. High-dose dexamethasone was administered with average dose of 16.81±3.37 mg/day for average duration of 4.78±1.84 days. SII was found to be higher after high-dose dexamethasone, due to a decrease of lymphocyte counts in peripheral blood.