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.

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 ...

Single-center retrospective study. The objective of this study was to evaluate the association of psoas muscle mass defined sarcopenia with perioperative outcomes in geriatric patients undergoing elective spine surgery. We included geriatric patients undergoing thoracolumbar spinal surgery. Total psoas surface area (TPA) was measured on preoperative axial computerized tomography or magnetic resonance imaging at the L3 vertebra and normalized to the L3 vertebral body area. Patients were divided into quartiles by normalized TPA, and the fourth quartile (Q4) was compared to quartiles 1–3 (Q1-3). Outcomes included perioperative transfusions, length of stay (LOS), delirium, pseudoarthrosis, readmission, discharge disposition, revision surgery, and mortality. Of the patients who met inclusion criteria (n = 196), the average age was 73.4 y, with 48 patients in Q4 and 148 patients in Q1-3. Q4 normalized TPA cut-off was <1.05. Differences in Q4 preoperative characteristics included significantly lower body mass index, baseline creatinine, and a greater proportion of females (Table 1). Q4 patients received significantly more postoperative red blood cell and platelet transfusions and had longer ICU LOS (P < .05; Table 2). There was no difference in intraoperative transfusion volumes, delirium, initiation of walking, discharge disposition, readmission, pseudoarthrosis, or revision surgery (Tables 2 and 3). Mortality during follow-up was higher in Q4 but was not statistically significant (P = .075). Preoperative TPA in geriatric patients undergoing elective spine surgery is associated with increased need for intensive care and postoperative blood transfusion. Preoperative normalized TPA is a convenient measurement and could be included in geriatric preoperative risk assessment algorithms.

Study Design: Retrospective case series study. Objectives: This study aims to compare preoperative indices, including the modified frailty index-11 (mFI-11), modified frailty index-5 (mFI-5), Oswestry Disability Index (ODI), and psoas muscle index (PMI), as they relate to outcomes in adult spinal deformity (ASD) surgery. Methods: We identified 235 patients who underwent thoracolumbar ASD surgery (≥4 levels). The mFI-11, mFI-5, ODI, and PMI were determined from preoperative visits and correlated to outcome measures, including perioperative transfusion, duration of anesthesia, hospital and ICU length of stay (LOS), discharge disposition, readmission, change in ODI at last follow-up, revision surgery, and mortality. Results: Our cohort had a mean age of 69.6 years and a male:female ratio of 1:2 with 177 undergoing an index surgery and 58 patients presenting after a failed multilevel fusion. The average number of levels fused was 9.3. The mFI-11 and mFI-5 were similar in predicting the need for intraoperative and postoperative transfusion. However, the mFI-11 was able to predict longer ICU and hospital LOS and mortality. The average preoperative ODI was 44.9% with an average decrease of 10.1% at the last follow-up. Preoperative ODI was the most significant predictor of postoperative change of ODI. Sarcopenia, defined as the lowest quartile of PMI values measured at L3 and L4, was not associated with any meaningful outcomes. Conclusion: The mFI-11 better correlated with outcomes, indicating its increased prognostic value compared to other preoperative indices in ASD surgery. Preoperative ODI remains a significant predictor of postoperative change in ODI when evaluating ASD patients.

Background: In vivo stable isotope tracing is useful for natively surveying glioma metabolism but can be difficult to implement. Stable isotope tracing is tractable using in vitro glioma models, but most models lack nutrient conditions and cell populations relevant to human gliomas. This limits our ability to study glioma metabolism in the presence of an intact tumor microenvironment (TME) and immune-metabolic crosstalk. Methods: We optimized an in vitro stable isotope tracing approach for human glioma explants and glioma stem-like cell (GSC) lines that integrates human plasma-like medium (HPLM). We performed ¹⁵ N ₂ -glutamine tracing in GSC monocultures and human IDH-wildtype glioblastoma explants and developed an analytical framework to evaluate microenvironment-dependent metabolic features that distinguish them. We also conducted spatial transcriptomics to assess transcriptional correlates to metabolic activities. Results: HPLM culture preserved glioma explant viability and stemness while unmasking metabolic and immune programs suppressed by conventional culture conditions. Stable isotope tracing in HPLM revealed TME-dependent and TME-independent features of tumor metabolism. Tissue explants recapitulated tumor cell-intrinsic metabolic activities, such as synthesis of immunomodulatory purines. Unlike GSC monocultures, tissue explants captured tumor cell- extrinsic activities associated with stromal cell metabolism, as exemplified by astrocytic GDP- mannose production in heterocellular explants. Finally, glioma explants displayed tumor subtype-specific metabolic reprogramming, including robust pyrimidine degradation in mesenchymal cells. Conclusions: We present a tractable approach to assess glioma metabolism in vitro under physiological nutrient levels and in the presence of an intact TME. This platform opens new avenues to interrogate glioma metabolism and its interplay with the immune microenvironment. Importance of the Study: Metabolic reprogramming is a hallmark of tumor biology, but in vitro studies of glioma metabolism often fail to replicate the nutrient complexity and cellular heterogeneity of the TME. We developed a method to perform stable isotope tracing in glioma explants grown in HPLM to analyze metabolism in a nutrient context that reflects in vivo conditions. By comparing metabolic activities between glioma cell monocultures and explanted tumor tissues, our approach captures features of tumor metabolism that are driven by the microenvironment. We show that HPLM not only sustains cell fitness and identity in tumor explants but also evokes distinct metabolic patterns and immune activation signatures repressed by standard culture conditions. Our approach offers a tractable and scalable way to study tumor cell intrinsic and microenvironmental metabolism in faithful tissue culture glioma models, complementing powerful yet low-throughput in vivo stable isotope tracing approaches. Key Points: HPLM supports culture of glioma explants and stimulates metabolic and immune transcriptional responses. Stable isotope tracing in glioma explants reveals contributions of tumor cells, stromal cells, and gene expression programs to tumor metabolism.

Background: In vivo stable isotope tracing is useful for natively surveying glioma metabolism but can be difficult to implement. Stable isotope tracing is tractable using in vitro glioma models, but most models lack nutrient conditions and cell populations relevant to human gliomas. This limits our ability to study glioma metabolism in the presence of an intact tumor microenvironment (TME) and immune-metabolic crosstalk. Methods: We optimized an in vitro stable isotope tracing approach for human glioma explants and glioma stem-like cell (GSC) lines that integrates human plasma-like medium (HPLM). We performed 15N2-glutamine tracing in GSC monocultures and human IDH-wildtype glioblastoma explants and developed an analytical framework to evaluate microenvironment-dependent metabolic features that distinguish them. We also conducted spatial transcriptomics to assess transcriptional correlates to metabolic activities. Results: Human plasma-like medium culture preserved glioma explant viability and stemness while unmasking metabolic and immune programs suppressed by conventional culture conditions. Stable isotope tracing in HPLM revealed TME-dependent and TME-independent features of tumor metabolism. Tissue explants recapitulated tumor cell-intrinsic metabolic activities, such as synthesis of immunomodulatory purines. Unlike GSC monocultures, tissue explants captured tumor cell-extrinsic activities associated with stromal cell metabolism, as exemplified by astrocytic guanosine diphosphate mannose production in heterocellular explants. Finally, glioma explants displayed tumor subtype-specific metabolic reprogramming, including robust pyrimidine degradation in mesenchymal cells. Conclusions: We present a tractable approach to assess glioma metabolism in vitro under physiologic nutrient levels and in the presence of an intact TME. This platform opens new avenues to interrogate glioma metabolism and its interplay with the immune microenvironment.