Treatment Of Brain Tumors Research Articles

Multi-modal fusion deep transfer learning for accurate brain tumor classification using magnetic resonance imaging images

Early identification and treatment of brain tumors depend critically on accurate classification. Accurate brain tumor classification in medical imaging is essential for clinical decisions and individualized treatment plans. This paper introduces a novel method for classifying brain tumors called multimodal fusion deep transfer learning (MMFDTL) using original, contoured, and annotated magnetic resonance imaging (MRI) images to showcase its capabilities. The MMFDTL can capture complex tumor features frequently missed in analyzing individual modalities. The MMFDTL model employs three deep learning models for extracting features VGG16, Inception V3, and ResNet 50. The accuracy rate improves when combined with decision based multimodal fusion. It produces impressive outcomes of sensitivity 92.96%, specificity 98.54%, precision 93.60%, accuracy 98.80%, F1-score 93.26%, and kappa 91.86%. This research can improve medical imaging and brain tumor analysis through its multi modal fusion approach. It could give healthcare practitioners vital insights for personalized treatment plans and informed decision making.

Complex Treatment of A Rare Non-Germinomatous Germ Cell Optic-Chiasmal Brain Tumor In An Adolescent Child-A Clinical Case With Literature Review

Non-germ cell tumours (NGCTs) are rare intracranial neoplasms occurring in adolescents and young adults. A multidisciplinary team including a neurosurgeon, oncologist, radiologist, pathohistologist, ophthalmologist, pediatric oncohematologist, neurologist and endocrinologist is required for diagnosis and treatment. We present a rarely diagnosed optic-chiasmal non-germinomatous germ cell tumour (NGGCT) in a 16-year-old boy, accompanied by pituitary insufficiency (diabetes insipidus and central hypothyroidism) and severely impaired vision bilaterally. The immunohistochemistry (IHC) of the tumor biopsy, as well as the level of tumor markers (human chorionic gonadotropin and alpha-fetoprotein) in the serum and cerebrospinal fluid are significant factors for determining the diagnosis-cranial GCT or cranial NGCT. Because the tumor was inoperable, we performed 3 courses of neoadjuvant chemotherapy followed by definitive radiotherapy to a total tumor dose of 55 Gy. In such rare childhood brain tumors, complex treatment achieves long-term local tumor control, requiring long-term monitoring by an ophthalmologist and endocrinologist.

Molecular Modeling of Shockwave-Mediated Blood-Brain Barrier Opening for Targeted Drug Delivery.

Bubble-enhanced shock waves induce the transient opening of the blood-brain barrier (BBB) providing unique advantages for targeted drug delivery of brain tumor therapy, but little is known about the molecular details of this process. Based on our BBB model including 28 000 lipids and 280 tight junction proteins and coarse-grained dynamics simulations, we provided the molecular-level delivery mechanism of three typical drugs for the first time, including the lipophilic paclitaxel, hydrophilic gemcitabine, and siRNA encapsulated in liposome, across the BBB. The results show that the BBB is more difficult to be perforated by shock-induced jets than the human brain plasma membrane (PM), requiring higher shock wave speeds. For the pores formed, the BBB exhibits a greater ability to self-heal than PM. Hydrophobic paclitaxel can cross the BBB and be successfully absorbed, but the amount is only one-third of that of PM; however, the absorption of hydrophilic gemcitabine was almost negligible. Liposome-loaded siRNAs only stayed in the first layer of the BBB. The mechanism analysis shows that increasing the bubble size can promote drug absorption while reducing the risk of higher shock wave overpressure. An exponential function was proposed to describe the relation between bubble and overpressure, which can be extended to the experimental microbubble scale. The calculated overpressure is consistent with the experimental result. These molecular-scale details on shock-assisted BBB opening for targeted drug delivery would guide and assist experimental attempts to promote the application of this strategy in the clinical treatment of brain tumors.

Inhibitors of CK2 Kinase for the Treatment of Gliomas and Other Brain Tumors

Protein kinase CK2 has become a target of experimental antiglioma therapies as laboratory data are almost uniformly favorable and the number of synthetized CK2 inhibitors is rapidly growing. The evidence of their use for other brain tumors is on the increase as well. Great expectations are entrusted in naturally occurring compounds capable of inhibiting CK2 kinase. These compounds are extracted and purified by means of biochemistry methods and are amenable for innovative drug delivery systems as well. CK2 kinase inhibitors have been proven suitable for combined therapies with other investigational antiglioma agents and treatment modalities. However a greater share of efforts should be undertaken towards inhibiting functions relatively specific for glial tumors including infiltrative growth and invasiveness or maintenance of glioma initiating cells. Many of these function appear to converge on mTOR and JAK/STAT pathways which are being meticulously studied in this respect. Protein kinase CK2 holds therapeutic promise especially when combined with other agents aimed at molecular signatures of gliomas.

The role of hydrogels in the management of brain tumours: a narrative review.

Conventional therapeutic techniques for brain tumours have limitations and side effects, necessitating the need for alternative treatment options. MRI-monitored therapeutic hydrogel systems show potential as a non-surgical approach for brain tumour treatment. Hydrogels have unique physical and chemical properties that make them promising for brain tumour treatment, including the ability to encapsulate therapeutic agents, provide sustained and controlled drug release, and overcome the blood-brain barrier for better penetration. By combining hydrogel systems with MRI techniques, it is possible to develop therapeutic approaches that provide real-time monitoring and controlled release of therapeutic agents. Surgical resection remains important, but there is a growing need for alternative approaches that can complement or replace traditional methods. The objective of this comprehensive narrative review is to evaluate the potential of MRI-monitored therapeutic hydrogel systems in non-surgical brain tumour treatment.

787 Higher County-Level Socioeconomic Status Is Associated With Increased Meningioma Survival But Does Not Impact Likelihood of Surgical Treatment: A CBTRUS Analysis

INTRODUCTION: Prior literature suggests that individual socioeconomic status (SES) may influence access to treatment and outcomes for primary brain tumors. To date, no population-level studies have assessed the correlation between meningioma treatment and outcome with county-level SES. METHODS: Incidence data were extracted from the Central Brain Tumor Registry of the United States(CBTRUS), a combined dataset including the CDC’s National Program of Cancer Registries (NPCR) and NCI’s Surveillance, Epidemiology, and End Results Program data, for diagnosis years 2006-2019, and survival data were extracted from the NPCR survival analytic dataset from 2006-2018. SES quintiles were created using American Community Survey data. Logistic regression and Cox proportional hazards models were used to assess the relationship the odds of receiving treatment and overall survival and SES and the individual SES factors. RESULTS: There were 409,681 meningioma cases available from CBTRUS. Asian/Pacific-Islander non-Hispanic individuals (odds ratio [OR] = 1.28, p < 0.001) were more likely and Black non-Hispanic (BNH) individuals (OR = 0.90, p < 0.001) were less likely to receive surgery than White non-Hispanic (WNH) individuals. Female sex (OR = 1.31, p < 0.001), living in a metropolitan area (OR = 0.96, p < 0.001), and increased age at diagnosis (OR = 0.96, p < 0.001) were associated with decreased likelihood of surgery. There was no association between SES and likelihood to receive surgery. Overall median survival was 137 months and survival was higher in higher SES counties, which held true for both WNH and BNH. Age at diagnosis(hazard ratio [HR] = 1.01, p < 0.001), male sex (HR = 1.51, p < 0.001), BNH (HR = 1.31, p < 0.001), subtotal resection (HR = 1.38, p < 0.001), and malignant behavior(HR = 1.64, p < 0.001) were associated with increased hazard of death. CONCLUSIONS: In the US, county-level SES did not impact treatment patterns, but higher SES was associated with increased survival. These findings provide valuable insight into socioeconomic factors influencing treatment and outcomes in meningioma patients.

295 High Volume Centers Provide Superior Value of Care in the Surgical Treatment of Malignant Brain Tumor

INTRODUCTION: Improved outcomes in surgical patients have been associated with increasing volume of cases. This has led to the development of centers that facilitate care for a specific patient population. METHODS: The 2016-2020 National Inpatient Sample (NIS) was queried for patients undergoing resection of malignant brain tumors. Teaching hospitals with high case load (greater than two standrad deviations above the mean, or >140 cases) were categorized as high-volume centers (HVC). Value of care was computed by adding one point for each of the following variables: lower length of stay, lower total charges, discharge to home, and lack of major comorbidity or complication, as defined per DRG codes. RESULTS: A total of 118,390 patients underwent resection of malignant brain tumors in 3,009 hospitals. HVC criteria was met by 91 (3%) hospitals, which represented 20,230 (17.1%) of total cases. The Mid-Atlantic and South Atlantic regions had the highest percentage of cases (22.7% and 20.2%, respectively) and number of HVC (21 and 17, respectively). Value of care was higher at HVC (OR = 1.35 95%CI 1.31-1.39 p < 0.01). After controlling for baseline risk factors and high risk admissions, HVC was associated with decreased complications of intracranial hemorrhage, deep venous thrombosis, aspiration pneumonitis, acute kidney injury, and external ventricular drain requirement (p < 0.01 for all). HVC was also associated with decreased length of stay and increased rate of discharge to home (p < 0.01 for both). CONCLUSIONS: Patients undergoing craniotomy for malignant brain neoplasms have superior outcomes in HVC. Trends of centralization are likely a reflection of the benefits of multidisciplinary treatment for these patients. Improvement of access to care at these institutions may improve the efficiency of the delivery of care for these patients.

329 Same Day Discharge After Craniotomy for Brain Tumor Resection: Enhancing Patient Selection Through a Prognostic Scoring System

INTRODUCTION: Neurosurgery, among other surgical fields, is in the midst of a shift in patient management with enhanced recovery and same day discharge protocols slowly becoming more popular and feasible. While such protocols reduce risk of nosocomial complications and improve patient satisfaction, appropriate patient selection remains an area of debate. METHODS: Three arms of analysis were carried out. First, clinical data of SDD patients was prospectively collected between August 2021 and August 2022. In parallel, a retrospective analysis of patients who qualified for SDD but were excluded at surgeon clinical discretion over the same period was performed. Third, a comparative analysis of the pilot and follow-up studies was done from which a clinical scoring system for patient selection was derived. RESULTS: Over the length of the study, 31 of 334 patients were selected for SDD while 59 qualified by previously defined criteria but were not selected at the surgeon’s discretion. There was no difference in outcomes between the two groups nor any post-operative complications among the SDD group within 30 days of surgery. Preoperative clinical characteristics found to be significantly different between the two cohorts (Left sided lesion, extra-axial pathology, prior treatment of brain tumor, and tumor volume < 11.75 cm3) were included in a predictive scoring system for successful SDD. The system was found to significantly predict high or low likelihood for successful SDD when tested on the mixedprospective cohort. CONCLUSIONS: This study provides a straightforward clinical scoring system for appropriate selection of candidates for SDD after craniotomy for brain tumor resection. The application of this clinical tool aims to aid clinicians in appropriate admission course selection and builds on the growing literature surrounding same-day and outpatient cranial neurosurgery.

A Review of Brain Tumor Detection Techniques Using YOLOv8

Abstract: Brain tumors, whether benign or malignant, pose significant risks, especially in children and young adults, impacting both life expectancy and quality of life. This review addresses the critical importance of early detection and treatment of brain tumors. With a focus on artificial intelligence, particularly object detection using the YOLOv8 model, the paper explores the potential for accurate and efficient brain tumor detection from magnetic resonance images (MRI). The YOLOv8 model is known for its real-time performance, efficiency, and high accuracy, making it a promising tool in the field of medical image analysis. The paper presents a method for brain cancer detection and localization, discusses experimental results, reviews the state-of-theart literature, and outlines future research directions.[1-22]

Enhancing Brain Tumor Diagnosis: A Synergistic Approach with Support Vector Machines and Decision Trees for Improved Detection and Segmentation

Abstract: Brain tumor identification and segmentation are critical components of modern medical imaging, facilitating timely diagnoses and effective therapy planning. This paper introduces an innovative methodology that harmoniously integrates Support Vector Machines (SVM) and Decision Tree methods. SVM adeptly classifies brain images into tumor and nonneoplastic regions, harnessing its proficiency with complex datasets. Decision Tree methods complement this process, providing transparent segmentation that accurately delineates intricate tumor boundaries. The synergy between SVM and Decision Tree methods establishes a robust framework for brain tumor identification. This novel approach holds promise for enhanced diagnosis speed, particularly valuable in time-sensitive medical scenarios. Emphasizing potential advancements in patient care outcomes, the methodology enables tailored treatment plans with greater precision. Positioned at the core of brain image analysis, this novel methodology signifies a substantial step forward in healthcare practices, fostering personalized approaches to brain tumor diagnosis and treatment.

Imaging Genomics of Glioma Revisited: Analytic Methods to Understand Spatial and Temporal Heterogeneity.

An improved understanding of the cellular and molecular biologic processes responsible for brain tumor development, growth, and resistance to therapy is fundamental to improving clinical outcomes. Imaging genomics is the study of the relationships between microscopic, genetic, and molecular biologic features and macroscopic imaging features. Imaging genomics is beginning to shift clinical paradigms for diagnosing and treating brain tumors. This article provides an overview of imaging genomics in gliomas, in which imaging data including hallmarks such as IDH-mutation, MGMT methylation, and EGFR-mutation status can provide critical insights into the pretreatment and posttreatment stages. This article will accomplish the following: 1) review the methods used in imaging genomics, including visual analysis, quantitative analysis, and radiomics analysis; 2) recommend suitable analytic methods for imaging genomics according to biologic characteristics; 3) discuss the clinical applicability of imaging genomics; and 4) introduce subregional tumor habitat analysis with the goal of guiding future radiogenetics research endeavors toward translation into critically needed clinical applications.

Abstract 5703: Development of RVL-101, a CDK4/6-selective, small molecule inhibitor with superior CNS penetration and combinability potential for the effective treatment of primary and metastatic brain tumors

Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle that are frequently dysregulated in cancer, leading to unchecked cell growth. CDK4/6 inhibitors have emerged as a promising class of anticancer agents that selectively target this pathway. The primary mode of action of CDK4/6 inhibitors relies on the disruption of retinoblastoma (Rb) protein phosphorylation, which thereby blocks cell cycle progression from G1 to S phase and reduces proliferation of cancer cells by a cytostatic mechanism. However, despite their efficacy, approved and clinical-stage CDK4/6 inhibitors have modest penetration of unbound drug into the brain, limiting their utility in the treatment of brain metastases and primary brain tumors. Additionally, despite the potential benefits of CDK4/6 inhibitors as combination therapies with cytotoxic agents, adjunctive treatment options remain underexplored due to the poor safety profiles of existing therapies. RVL-101 is a preclinical, investigational drug with a novel pharmacophore that has a low nanomolar activity against CDK4, is CDK2,6,7,9-sparing, and maintains >500-fold selectivity over CDK1. To maximize the potential of RVL-101 as a preferred combination partner, this novel agent has been engineered to have exquisite kinome- and safety-panel selectivity with no measured CYP inhibition or induction liabilities. RVL-101 is differentiated from approved and clinical stage CDK4/6 inhibitors having both high partitioning into the brain (Kp) and high free-brain (Kpu,u = 0.7) levels resulting in equal levels of unbound drug in all relevant compartments at steady state. Like other CDK4/6 agents, RVL-101 is broadly efficacious in vivo in ER+/HER2- xenograft models at well-tolerated doses. However, RVL-101 has also demonstrated robust activity in HR-/HER2+ xenograft models as a single-agent and has uniquely shown improved tumor inhibition effect in combination with approved HER2 cytotoxic therapeutics tucatinib and fam-trastuzumab-deruxtecan. RVL-101 was also tested in a GBM model as a monotherapy and in conjunction with the cytotoxic agent temozolomide (TMZ). Remarkably, QD dosing of the cytostatic agent, RVL-101, after pulsatile pretreatment with TMZ led to dramatic synergistic efficacy compared to either agent alone, leading to 100% survival of all animals on the dual therapy arm for more than 3 weeks post discontinuation of dosing. RVL-101 offers the combination of substantial therapeutic benefit and consistent free-drug levels in plasma and CNS that could lead to safe and effective treatment for a broader patient population. Citation Format: John E. Campbell, Bo-Sheng Pan, Michael Bower, Peter Bertinato, Nisha Perez, Victoria Gras Andreu, Neha Rana, Sophia Tabchouri, Ankit Gupta, Jonah Kallenbach. Development of RVL-101, a CDK4/6-selective, small molecule inhibitor with superior CNS penetration and combinability potential for the effective treatment of primary and metastatic brain tumors [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 5703.

Abstract 4031: P-selectin as an emerging target for the treatment of primary and secondary brain tumors

Abstract Glioblastoma (GB) is an aggressive type of brain cancer with a high mortality rate. It is a highly angiogenic tumor exhibiting an extremely invasive nature. As such, its brain microenvironment plays a crucial role in its progression. Microglia are the brain resident immune cells that have been shown to facilitate GB cell invasion and immune suppression. The mechanism by which GB cells alter microglia behavior is yet to be fully understood. One proposed mechanism involves adhesion molecules such as the Selectins family of proteins which are expressed on the surface of endothelial and immune cells and are involved in immune modulation and cancer immunity. We have previously shown that one member of the Selectin family, P-Selectin (SELP), is expressed by GB cells. Here, we investigated the functional role of SELP in GB-microglia interactions. First, we found that microglia cells facilitate the expression and secretion of SELP by GB cells, and that GB cells facilitate the expression of P-Selectin ligand-1 (PSGL-1) by Glioma-associated microglia/macrophages (GAMs). We then showed that SELP mediates GAMs-enhanced GB invasion and proliferation in our unique 3D-bioprinted ex vitro models and has a role in GAMs activation state. These findings were validated in vivo, showing that inhibition or downregulation of SELP leads to reduced tumor growth, increased overall survival, and improved immune response. Single-cell RNA-seq analysis of the tumors revealed an increase in pro-inflammatory GAMs signature, reduction in cancer cell tumorigenesis potential, and improved T cell activation. Thus, combining SELP inhibition with other immune checkpoint inhibitors, such as anti-PD-1, may have a synergistic effect by harnessing both the innate and the adaptive immune systems against the tumor. Furthermore, we found SELP/PSGL-1 axis to be involved in the progression of brain metastasis originating from melanoma, and breast, and lung cancer. Thus, we have begun an investigator-initiated clinical trial, testing the efficacy of the anti-SELP antibody, Crizanlizumab, alone or in combination with anti-PD-1 antibody, Nivolumab, for GB and melanoma brain metastasis patients (NCT05909618). Crizanlizumab, approved by the FDA and EMA for sickle cell pain crisis (VOC, Vaso-Occlusive Crisis) of sickle-cell anemia patients, was proven to be safe for human use, and efficient in inhibiting SELP function. As such, it has the potential to reduce tumor burden and improve patient outcomes. This work can improve our understanding of GAMs function, which may pave the way for new and effective treatments for primary and secondary brain tumors. Citation Format: Eilam Yeini, Ronnie Frommer-Shapira, Alisa Talianski, Paula Ofek, Sabina Pozzi, Nitzan Albeck, Dikla Ben-Shushan, Galia Tiram, Sapir Golan, Ron Kleiner, Ron Sheinin, Shlomit Reich-Zeliger, Rachel Grossman, Zvi Ram, Henry Brem, Thomas M. Hyde, Prerna Magod, Dinorah Friedmann-Morvinski, Asaf Madi, Ronit Satchi-Fainaro. P-selectin as an emerging target for the treatment of primary and secondary brain tumors [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 4031.

A study on the treatment of brain tumors with BNCT using several moderators with different thicknesses

Boron neutron capture therapy (BNCT) is an effective binary radiation therapy that depends on nuclear capture reactions. In recent years, BNCT can be performed without a reactor owing to the development of accelerator-based neutron sources. A new BNCT irradiation facility is proposed, which is based on a 15 mA 2.5 MeV proton accelerator with a 100 μm thickness natural lithium target as a neutron converter. A great quantity of studies has shown that neutron beams with different spectra have unique therapeutic effects on tumors. An appropriate neutron beam for BNCT is obtained by Beam Shaping Assembly (BSA) and the moderator plays a main role in determining the BSA outlet beam spectrum. To figure out the dose distribution in phantom with various kinds of neutron spectrum modes during BNCT, a series of cases are calculated by MCNPX code. The results give a database for treatment of brain tumors with BNCT by using different moderators.

Comparison of ASL and DSC perfusion methods in the evaluation of response to treatment in patients with a history of treatment for malignant brain tumor

ObjectivePerfusion MRI is of great benefit in the post-treatment evaluation of brain tumors. Interestingly, dynamic susceptibility contrast-enhanced (DSC) perfusion has taken its place in routine examination for this purpose. The use of arterial spin labeling (ASL), a perfusion technique that does not require exogenous contrast material injection, has gained popularity in recent years. The aim of the study was to compare two different perfusion techniques, ASL and DSC, using qualitative and quantitative measurements and to investigate the diagnostic effectiveness of both. The fact that the number of patients is higher than in studies conducted with 3D pseudo-continious ASL (pCASL), the study group is heterogeneous as it consists of patients with both metastases and glial tumors, the use of 3D Turbo Gradient Spin Echo (TGSE), and the inclusion of visual (qualitative) assessment make our study unique.MethodsNinety patients, who were treated for malignant brain tumor, were enrolled in the retrospective study. DSC Cerebral Blood Volume (CBV), Cerebral Blood Flow (CBF) and ASL CBF maps of each case were obtained. In qualitative analysis, the lesions of the cases were visually classified as treatment-related changes (TRC) and relapse/residual mass (RRT). In the quantitative analysis, three regions of interest (ROI) measurements were taken from each case. The average of these measurements was compared with the ROI taken from the contralateral white matter and normalized values (n) were obtained. These normalized values were compared across events.ResultsUncorrected DSC normalized CBV (nCBV), DSC normalized CBF (nCBF) and ASL nCBF values of RRT cases were higher than those of TRC cases (p < 0.001). DSC nCBV values were correlated with DSC nCBF (r: 0.94, p < 0.001) and correlated with ASL nCBF (r: 0.75, p < 0.001). Similarly, ASL nCBF was positively correlated with DSC nCBF (r: 0.79 p < 0.01). When the ROC curve parameters were evaluated, the cut-off values were determined as 1.211 for DSC nCBV (AUC: 0.95, 93% sensitivity, 82% specificity), 0.896 for DSC nCBF (AUC; 0.95, 93% sensitivity, 82% specificity), and 0.829 for ASL nCBF (AUC: 0.84, 78% sensitivity, 75% specificity). For qualitative evaluation (visual evaluation), inter-observer agreement was found to be good for ASL CBF (0.714), good for DSC CBF (0.790), and excellent for DSC CBV (0.822). Intra-observer agreement was also evaluated. For the first observer, good agreement was found in ASL CBF (0.626, 70% sensitive, 93% specific), in DSC CBF (0.713, 76% sensitive, 95% specific), and in DSC CBV (0.755, 87% sensitive - 88% specific). In the second observer, moderate agreement was found in ASL CBF (0.584, 61% sensitive, 97% specific) and DSC CBF (0.649, 65% sensitive, 100% specific), and excellent agreement in DSC CBV (0.800, 89% sensitive, 90% specific).ConclusionIt was observed that uncorrected DSC nCBV, DSC nCBF and ASL nCBF values were well correlated with each other. In qualitative evaluation, inter-observer and intra-observer agreement was higher in DSC CBV than DSC CBF and ASL CBF. In addition, DSC CBV is found more sensitive, ASL CBF and DSC CBF are found more specific for both observers. From a diagnostic perspective, all three parameters DSC CBV, DSC CBF and ASL CBF can be used, but it was observed that the highest rate belonged to DSC CBV.

Abstract 458: Nanoparticle-mediated delivery of miR-590-3p decreases recurrent GBM tumor growth by inhibits multiple oncogenic nodes

Abstract Glioblastoma (GBM) is the most lethal and aggressive form of brain cancer. Despite aggressive therapy consisting of surgery followed by radio/chemotherapy GBM recurs in almost all patients and, currently, there are no proven therapies to treat recurrent GBM (rGBM). Recent developments in nanomedicine provide new and promising opportunities to develop new targeted therapeutics to treat brain tumors. We have recently developed PBAE nanoparticle formulations optimized for in vivo miRNA delivery to brain tumor stem cells, or GSCs. Carefully selecting one miRNA to target several mRNAs dysregulated within a pathway can allow the targeting of multiple nodes using a single agent, mimicking combinatorial therapies. To test this hypothesis, we performed bioinformatic analysis of RNA sequencing from GSCs and clinical rGBM specimens combined with gene set enrichment analysis (GSEA) and identified TGFBR2 signaling as a targetable pathway in rGBM. We show that SMAD2 signaling, a downstream effector of TGFBR2, is enriched in rGBM and that patients with elevated TGFBR2 transcripts respond poorly to current standard of care. Utilizing patient-derived xenograft lines from rGBM, we show that blocking TGFBR2 signaling using siRNAs or ITD1, a selective TGFBR2 inhibitor, decreases the stem cell capacity, cell viability and re-sensitizes clinical rGBM cells to temozolomide (TMZ) in-vitro. In vivo, we show that ITD1 is modestly effective in subcutaneous and ineffective in orthotopic rGBM models. Not surprisingly, these tumors exhibited classical growth patterns associated with acquisition of resistance. To overcome this obstacle, we performed a miRNA-based network analysis in rGBM and identified miR-590-3p as a putative tumor suppressor that targets SMAD2 signaling at multiple nodes in rGBM. In-vitro, transgenic miR-590-3p robustly decreased the expression of 37 putative oncogenes simultaneously concurrent with decreasing stem cell capacity, cell viability and re-sensitizing rGBM PDX cells to TMZ. In vivo delivery of miR-590-3p to established PDX-derived rGBM orthotopic tumors using novel PBAE nanocarriers robustly decreased tumor sizes and increased tumor necrosis. These results show that the promiscuous nature of miRNAs, in combination with cutting-edge nucleic acid delivery vehicles, can be leveraged as advanced targeted therapeutics for rGBM bypasses the resistance that is developed to standard of care and available small molecules. Citation Format: Hernando Lopez-Bertoni, Sophie Sall, Harmon Khela, Jack Korleski, Katherine Luly, Maya Johnson, Bachchu Lal, Amanda Johnson, Stephany Tzeng, Jordan Green, John Laterra. Nanoparticle-mediated delivery of miR-590-3p decreases recurrent GBM tumor growth by inhibits multiple oncogenic nodes [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 458.

Abstract 2632: A new paradigm for brain tumors treatment: Guadecitabine as a fundamental player to improve tumor immune response

Abstract Background:Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor refractory to standard treatments and to immunotherapy with immune-checkpoint inhibitors (ICI) (PMID: 35626018). Interestingly, melanoma brain metastases (MM-BM), sharing the same niche as GBM, often respond to current ICI immunotherapies (PMID: 36521332). The role of epigenetic modifications in regulating GBM cellular proliferation, invasion, and prognosis, as well as their impact on the cross-talk between GBM and immune cells in the tumor milieu, has become evident (PMID: 34361090). Consequently, manipulating the epigenome has emerged as a therapeutic opportunity in GBM. Methods:Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were conducted to study the differences in constitutive expression profiles between GBM and MM-BM cells compared to extracranial MM cells. Additionally, the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine on different tumor cells were investigated. The prognostic relevance of DHA-modulated genes was assessed through Cox analysis in a TCGA GBM patients' cohort. Results:The most notable differences between constitutive GBM and MM-BM cells lie in the enrichment of biological processes associated with tumor growth, invasion, and extravasation, as well as the inhibition of MHC class II antigen processing/presentation in GBM cells. Guadecitabine treatment appeared to shrink these differences, shifting the phenotype of GBM cells towards the more immunogenic MM-BM profile. This was achieved through promoter hypomethylation and subsequent up-regulation of genes mainly associated with the activation, proliferation, and migration of T and B cells, along with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% exhibited significant prognostic relevance. Moreover, a substantial set of immune-related upstream regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and/or MM cells: DHA-activated URs enriched biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and Type I/II/III IFN-mediated signaling. DHA-inhibited URs were associated with metabolic and proliferative pathways. Conclusions:Epigenetic remodeling of GBM by DHA represents a promising strategy to enhance the efficacy of cancer immunotherapy, supporting the rationale for developing new combinatorial approaches for the treatment of brain malignancies. Citation Format: Maria Fortunata Lofiego, Francesca Piazzini, Francesca Pia Caruso, Francesco Marzani, Laura Solmonese, Emma Bello, Fabrizio Celesti, Maria Claudia Costa, Teresa Maria Noviello, Roberta Mortarini, Andrea Anichini, Michele Ceccarelli, Sandra Coral, Anna Maria Di Giacomo, Michele Maio, Alessia Covre. A new paradigm for brain tumors treatment: Guadecitabine as a fundamental player to improve tumor immune response [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 2632.

Revolutionizing brain interventions: the multifaceted potential of histotripsy.

Histotripsy, a non-thermal ultrasound technique, holds significant promise in various applications within the realm of brain interventions. While its use for treating brain tumors is somewhat limited, focused ultrasound technology has been extensively investigated for a wide range of purposes within the brain, including disrupting the blood-brain barrier, supporting immunotherapy, addressing conditions like essential tremor, Parkinson's disease, Alzheimer's disease, epilepsy, and neuropathic pain. Research findings indicate that histotripsy can reduce tumor cells with fewer pulses, minimizing the risk of bleeding and cellular injury. The use of MRI sequences such as T2 and T2* enhances the evaluation of the effects of histotripsy treatment, facilitating non-invasive assessment of treated areas. Furthermore, histotripsy displays promise in creating precise brain lesions with minimal edema and inflammation, particularly in porcine models, suggesting considerable progress in the treatment of brain lesions. Moreover, studies confirm its feasibility, safety, and effectiveness in treating intracerebral hemorrhage by safely liquefying clots without causing significant harm to surrounding brain tissue., opening exciting possibilities for clinical applications. The development of transcranial MR-guided focused ultrasound systems based on histotripsy represents a significant breakthrough in overcoming the limitations associated with thermal ablation techniques. Histotripsy's ability to efficiently liquefy clots, minimize skull heating, and target shallow lesions near the skull establishes it as a promising alternative for various brain treatments. In conclusion, histotripsy offers diverse potential in the field of brain interventions, encompassing applications ranging from tumor treatment to the management of intracerebral hemorrhage. While challenges such as accurate monitoring and differentiation of treatment effects persist, ongoing research efforts and technological advancements continue to expand the role of histotripsy in both neurology and neurosurgery.

How Microbubble-Enhanced Shock Waves Promote the Delivery of Lipid-siRNA across Neuronal Plasma Membrane: A Computational Study.

In this computational study, we examine the potential of microbubble-enhanced shock waves to improve the delivery of lipid-siRNA nanoparticles across neuronal plasma membranes with the ultimate aim of enhancing brain tumor treatment. We critically evaluate several variables related to experiments, including the bubble size, the shock speed and action time, and the amount of siRNA encapsulated in the liposome. Our findings reveal that microbubble-enhanced shock waves are essential for the high delivery of small lipid vesicles (under 30 nm diameter); its corresponding variables significantly impact drug penetration and absorption rates and influence the overall efficacy of the drug delivery system. Long-time recovery simulations further provide valuable insights into the self-healing ability of the plasma membrane following shock wave exposure and the subsequent absorption dynamics of siRNA. This work provides the dynamic process of siRNA released from lipid vesicles with shock wave and nanobubbles, thereby serving as a molecular mechanism support for developing tunable delivery systems for RNA-based therapy in brain tumors.

Multigrade brain tumor classification in MRI images using Fine tuned efficientnet

Medical imaging plays a vital role in detecting and treating brain tumors. Malignant or non-malignant brain tissue’s abnormal growth causes long-term brain damage. It is crucial to detect and properly categorize the kind of brain tumor. Specialists normally use MRI to create high-contrast grayscale brain images to segment them. Convolutional neural networks (CNN) driven by deep learning (DL) have transformed computer-assisted testing systems by producing good results in a wide range of medical imaging analytics applications, including tumor diagnosis in the brain. The paper introduces a lightweight fine-tuned Convolutional Neural Network EfficientNet ’ECNN’ to detect brain tumors. In this study, we provide a transfer learning-based measurement strategy for grouping cerebrum growths in three distinct datasets with different classifications, such as meningioma, glioma, and pituitary growth, using fine-tuned EfficientNets. The findings of this research rely on Efficient Nets to classify brain tumors in three different types of datasets utilizing a fine-tuned transfer learning mechanism. With EfficientNetV2S as the system’s foundation, our proposed way of fine-tunned pre-trained EfficientNetV2S model outperformed for all datasets over state of the art methods. The effectiveness of the suggested model has been assessed using performance metrics, and outcomes were compared to those produced using state-of-the-art approaches. The average test accuracy, recall, precision, and sensitivity score are 98.48%, 98%, 98.5%, and 98.71%, respectively.