De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma.

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

Surgical Management of a Massive Frontal Bone Hemangioma: Case Report.

Intraosseous hemangiomas are rare, benign tumors that can arise from the calvarium. These lesions often invade the outer table of the skull, but typically spare the inner table and intracranial structures. En bloc surgical resection is the standard treatment for intraosseous hemangiomas. However, a piecemeal resection may be required to safely remove the tumor in cases involving the inner table to protect the underlying brain parenchyma and vascular structures. Proper reconstruction is critical to optimize the cosmetic outcome, and a staged procedure allowing implantation of a custom-made implant can be considered for large lesions involving the forehead. We present a case of a patient with a large frontal intraosseous hemangioma with intradural involvement to highlight the surgical nuances of resection and review the existing literature regarding optimal management of these patients.

Semi-Automated Computational Assessment of Cancer Organoid Viability Using Rapid Live-Cell Microscopy.

The creation of patient-derived cancer organoids represents a key advance in preclinical modeling and has recently been applied to a variety of human solid tumor types. However, conventional methods used to assess in vivo tumor tissue treatment response are poorly suited for the evaluation of cancer organoids because they are time-intensive and involve tissue destruction. To address this issue, we established a suite of 3-dimensional patient-derived glioma organoids, treated them with chemoradiotherapy, stained organoids with non-toxic cell dyes, and imaged them using a rapid laser scanning confocal microscopy method termed "Apex Imaging." We then developed and tested a fragmentation algorithm to quantify heterogeneity in the topography of the organoids as a potential surrogate marker of viability. This algorithm, SSDquant, provides a 3-dimensional visual representation of the organoid surface and a numerical measurement of the sum-squared distance (SSD) from the derived mass center of the organoid. We tested whether SSD scores correlate with traditional immunohistochemistry-derived cell viability markers (cellularity and cleaved caspase 3 expression) and observed statistically significant associations between them using linear regression analysis. Our work describes a quantitative, non-invasive approach for the serial measurement of patient-derived cancer organoid viability, thus opening new avenues for the application of these models to studies of cancer biology and therapy.

Implementation of IV Push Antibiotics for Outpatients During a National Fluid Shortage Following Hurricane Maria.

Background: Prior to the introduction of intravenous (IV) drip infusion, most IV drugs were delivered in a syringe bolus push. However, intravenous drip infusions subsequently became the standard of care. Puerto Rico is the largest supplier of IV fluid bags and in the aftermath of Hurricane Maria, there was a nationwide fluid bag shortage. This shortage required stewardship measures to maintain the operation of the self-administered outpatient parenteral antimicrobial therapy (OPAT) program at Parkland Health. Methods: Parkland pharmacists evaluated all self-administered antimicrobials for viability of administration as an IV syringe bolus push (IVP) instead of an IV-drip infusion. Medications deemed appropriate were transitioned to IVP. The hospital EMR was used to identify patients discharged to the OPAT clinic using all methods of parenteral drug delivery. Data was collected for patient demographics, patient satisfaction, and clinical outcomes. Finally cost of care was calculated for IVP and IV drip administration. Results: One-hundred and thirteen self-administered IVP and 102 self-administered IV drip treatment courses were identified during the study period. Individuals using IVP had a statistically significant decrease in hospital length of stay. Patient satisfaction was greater with IVP and IVP saved 504 liters of normal saline resulting in a savings of $43,652 over 6 months. The 30-day readmission rate and mortality were similar. Conclusion: The abrupt IV fluid shortage following a natural disaster led to implementation of a high value care model that improved efficiency, reduced costs, and did not affect safety or efficacy.

Establishment of patient-derived organoid models of lower-grade glioma.

BACKGROUND: Historically, creating patient-derived models of lower-grade glioma (LGG) has been challenging, contributing to few experimental platforms that support laboratory-based investigations of this disease. Although organoid modeling approaches have recently been employed to create in vitro models of high-grade glioma (HGG), it is unknown whether this approach can be successfully applied to LGG. METHODS: In this study, we developed an optimized protocol for the establishment of organoids from LGG primary tissue samples by utilizing physiologic (5%) oxygenation conditions and employed it to produce the first known suite of these models. To assess their fidelity, we surveyed key biological features of patient-derived organoids using metabolic, genomic, histologic, and lineage marker gene expression assays. RESULTS: Organoid models were created with a success rate of 91% (n = 20/22) from primary tumor samples across glioma histological subtypes and tumor grades (WHO Grades 1-4), and a success rate of 87% (13/15) for WHO Grade 1-3 tumors. Patient-derived organoids recapitulated stemness, proliferative, and tumor-stromal composition profiles of their respective parental tumor specimens. Cytoarchitectural, mutational, and metabolic traits of parental tumors were also conserved. Importantly, LGG organoids were maintained in vitro for weeks to months and reanimated after biobanking without loss of integrity. CONCLUSIONS: We report an efficient method for producing faithful in vitro models of LGG. New experimental platforms generated through this approach are well positioned to support preclinical studies of this disease, particularly those related to tumor immunology, tumor-stroma interactions, identification of novel drug targets, and personalized assessments of treatment response profiles.

Large Animal Models of Glioma: Current Status and Future Prospects.

Enhanced understanding of the molecular features of glioma has led to an expansion of murine glioma models and successful preclinical studies. However, clinical trials continue to have a high cost, extended production time, and low proportion of success. Studies in large-animal models of various cancer types have emerged to bridge the translational gap between in vitro and in vivo animal studies and human clinical trials. The anatomy and physiology of large animals are of more direct relevance to human disease, allowing for more rigorous testing of treatments such as surgical resection and adjuvant therapy in glioma. The recent generation of multiple porcine glioma models supports their use in high-throughput preclinical studies. The demonstration of spontaneous glioblastoma formation in canines further provides a unique avenue for the study of de novo glioma. The aim of this review was to outline the current status of large animal models of glioma and their value as a transitional step between rodent models and human clinical trials.

Primary peripheral T-cell central nervous system lymphoma.

BACKGROUND: Primary peripheral T-cell central nervous system lymphoma (PCNSL) is a rare, aggressive tumor that arises in the craniospinal axis and has an increased risk in individuals who are immunocompromised. This lesion often mimics other benign and malignant processes on radiographic imaging, leading to misdiagnosis and delays in treatment. We present a case of a patient with a history of Sjögren's syndrome and progressive neurologic symptoms who underwent craniotomy for diagnosis. CASE DESCRIPTION: A 61-year-old woman with a history of Sjögren's syndrome, progressive aphasia, left facial droop, and right-sided paresthesias for 4 months presented for evaluation and management. An enhancing, infiltrative lesion in the left frontal lobe with underlying vasogenic edema was appreciated and suggestive of a primary or metastatic neoplasm. The patient underwent an open biopsy for further evaluation of the lesion. Extensive histopathologic evaluation revealed a diagnosis of T-cell PCNSL. The patient was started on induction methotrexate and temozolomide followed by consolidative radiotherapy. CONCLUSION: Autoimmune conditions are a risk factor for T-cell PCNSL development. T-cell PCNSL has radiographic and gross histologic features that are consistent with a broad differential, including gliomas and inflammatory processes. Prompt diagnosis and extensive histopathological evaluation is essential to ensure appropriate treatment.

Distance traveled to glioblastoma treatment: A measure of the impact of socioeconomic status on survival.

BACKGROUND: Previous studies have shown improved post-surgical outcomes in patients who travel farther for glioblastoma treatment. This study investigates socioeconomic and facility factors that may influence this relationship. METHODS: Overall survival was calculated and compared by distance to treatment facility using univariate and multivariate survival models. The analysis was stratified by facility type, income quartile and insurance status and the association re-evaluated. Kaplan-Meier survival curves were created to analyze the relationship between overall survival and distance group. RESULTS: Individuals who traveled less than 5 miles to treatment had the shortest overall survival (11.8 months), while those who traveled greater than 50 miles had the longest survival (12.9 months). Stratification by income quartile failed to demonstrate an association between distance traveled and survival for those making less than $63,000 (adjusted hazard ratio range: 0.94-1.01). There was no association between survival and distance traveled for patients treated at a community cancer center, comprehensive community cancer center or an integrated network cancer program (adjusted hazard ratio range: 0.86-1.04). CONCLUSION: Financial strain, rather than distance traveled to treatment, may be associated with glioblastoma survival.

Correction: A Quantitative Analysis of Social Media to Determine Trends in Brain Tumor Care and Treatment.

[This corrects the article DOI: 10.7759/cureus.11530.].

Economic implications of the modern treatment paradigm of glioblastoma: an analysis of global cost estimates and their utility for cost assessment.

INTRODUCTION: Glioblastoma is the most common primary brain tumor in adults. Standard of care includes maximal surgical resection of the tumor followed by concurrent chemotherapy and radiation. The treatment of glioblastoma must account for an increased disease severity and treatment intensity compared to other cancers which place a significant cost burden on the patient and health system. Cost assessments of glioblastoma treatment have been sparse in comparison to other solid cancer subtypes. This study evaluates all currently available cost literature with an emphasis on the modern treatment paradigm to properly assess the economic implications of this disease. METHODS: A critical review of 21 studies from 13 different countries measuring direct costs related to glioblastoma management was performed. Evaluated data included itemized costs, total costs of treatment regimens from diagnosis until death, the cost of second-line care after recurrence, and the incremental costs and cost-effectiveness of emerging therapies. RESULTS: The average cost of a craniotomy was $10,042 across studies. Imaging for the duration of glioblastoma care had a mean cost of $2,788 ± 3,719. Studies examined different combinations of treatment modalities. Utilization of the modern treatment paradigm led to survival of 16.3 months across studies and had a mean cost of $62,602. Surgery for the recurrent disease had an average cost of $27,442 ± 18,992. LIMITATIONS AND CONCLUSIONS: Direct cost estimates for glioblastoma varied substantially between institutions and countries and often failed to uniformly describe direct cost estimates associated with care for glioblastoma. The limitations of these studies make a true economic assessment of standards of care, costs of recurrence, and incremental costs associated with adjunctive therapy uncertain.

Patient-Derived Cancer Organoids for Precision Oncology Treatment.

The emergence of three-dimensional human organoids has opened the door for the development of patient-derived cancer organoid (PDO) models, which closely recapitulate parental tumor tissue. The mainstays of preclinical cancer modeling include in vitro cell lines and patient-derived xenografts, but these models lack the cellular heterogeneity seen in human tumors. Moreover, xenograft establishment is resource and time intensive, rendering these models difficult to use to inform clinical trials and decisions. PDOs, however, can be created efficiently and retain tumor-specific properties such as cellular heterogeneity, cell-cell and cell-stroma interactions, the tumor microenvironment, and therapeutic responsiveness. PDO models and drug-screening protocols have been described for several solid tumors and, more recently, for gliomas. Since PDOs can be developed in clinically relevant time frames and share many characteristics of parent tumors, they may enhance the ability to provide precision oncologic care for patients. This review explores the current literature on cancer organoids, highlighting the history of PDO development, organoid models of glioma, and potential clinical applications of PDOs.

Contemporary Mouse Models in Glioma Research.

Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models.

A Quantitative Analysis of Social Media to Determine Trends in Brain Tumor Care and Treatment.

Background Approximately 80,000 primary brain tumors are diagnosed annually. Social media provides a source of information and support for patients diagnosed with brain tumors; however, use of this forum for dissemination of information about brain tumors has not been evaluated. The objective of this study was to evaluate social media utilization and content related to brain tumors with an emphasis on patients' trends in usage. Methods Social media platforms were systematically evaluated using two search methods: systematic manual inquiry and a keyword-based social media tracker. The search terms included brain tumor, glioblastoma, glioma, and glioblastoma multiforme. Social media content (which includes Facebook pages and groups, YouTube videos, and Twitter or Instagram accounts) and posts were assessed for activity (as quantified by views of posts) and analyzed using a categorization framework. Results The manual and keyword searches identified 946 sources of social media content, with a total count of 7,184,846 points of engagement. Social media platforms had significant variations in content type. YouTube was the largest social media platform for sharing content related to brain tumors overall, with an emphasis on surgical videos and documented patient experiences. Facebook accounted for the majority of patient-to-patient support, and Twitter was the most common platform for scientific dissemination. Overall social media content was mostly focused on treatment overviews and patient experience. When evaluated by search term, most social media posts by the "brain tumor" community shared illness narratives, and searches specific to "glioma" and "glioblastoma" demonstrated a higher proportion of educational and treatment posts. Conclusions This study presents novel observations of the characteristics of social media utilization for the online brain tumor community. A robust patient community exists online, with an emphasis on sharing personal narratives, treatment information, patient-to-patient support, treatment options, and fundraising events. This study provides a window to the role of social media utilization by patients, their families, and health professionals. These findings demonstrate the different roles of Facebook, YouTube, and Twitter in the rapidly changing era of social media and its relationship with neurosurgery and neuro-oncology.