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 gliomagenesis, 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.
Meningioma prognostication and treatment continues to evolve with an increasing understanding of tumor biology. In this study, the authors aimed to test conventional predictors of meningioma recurrence, histopathology variables for which there exists some controversy (brain invasion), as well as a novel molecular-based location paradigm.This is a retrospective study of a consecutive series of patients with WHO grade I-III meningioma resected at The University of Texas Southwestern Medical Center between 1994 and 2015. Time to meningioma recurrence (i.e., recurrence-free survival [RFS]) was the primary endpoint measured. Kaplan-Meier curves were constructed and compared using log-rank tests. Cox univariate and multivariate analyses were performed to identify predictors of RFS.A total of 703 consecutive patients with meningioma underwent resection at The University of Texas Southwestern Medical Center between the years 1994 and 2015. A total of 158 patients were excluded for insufficient follow-up (< 3 months). The median age of the cohort was 55 years (range 16-88 years) and 69.5% (n = 379) were female. The median follow-up was 48 months (range 3-289 months). There was not a significantly increased risk of recurrence in patients with evidence of brain invasion, in patients with otherwise WHO grade I meningioma (Cox univariate HR 0.92, 95% CI 0.44-1.91, p = 0.82, power 4.4%). Adjuvant radiosurgery to subtotally resected WHO grade I meningiomas did not prolong the time to recurrence (n = 52, Cox univariate HR 0.21, 95% CI 0.03-1.61, p = 0.13, power 71.6%). Location (midline skull base, lateral skull base, and paravenous) was significantly associated with RFS (p < 0.01, log-rank test). In patients with high-grade meningiomas (WHO grade II or III), location was predictive of RFS (p = 0.03, log-rank test), with paravenous meningiomas exhibiting the highest rates of recurrence. Location was not significant on multivariate analysis.The data suggest that brain invasion does not increase the risk of recurrence in otherwise WHO grade I meningioma. Adjuvant radiosurgery to subtotally resected WHO grade I meningiomas did not prolong the time to recurrence. Location categorized by distinct molecular signatures did not predict RFS in a multivariate model. Larger studies are needed to confirm these findings.
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.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.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.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.
Blastomycosis infection is caused by the inhalation of the spores of the dimorphic Blastomyces sp.fungus. While more commonly a self-limited infection of the lungs, extrapulmonary manifestations arise from hematogenous or contiguous spread. Disseminated infection most often includes skin lesions and osteomyelitis; however, central nervous system (CNS) involvement is infrequently reported in the literature. Herein, we present a case of a retropharyngeal blastomycosis abscess leading to cervical spine osteonecrosis with retropulsion, deformity, and a spinal epidural abscess, and we discuss the relevant literature. The patient was successfully treated with cervical traction, followed by a combined anterior-posterior cervical approach, including abscess drainage, corpectomies, and instrumented fixation. Postoperatively, the patient completed 12 months of voriconazole and had near resolution of preoperative symptoms. Expediting neurosurgical intervention, such as the utilization of decompression, the clearance of infectious burden, and the correction of alignment, is critical for preventing downstream complications. Retropharyngeal blastomycosis abscesses are rare, and we report one of the rare instances of dissemination to and the degeneration of the cervical spine.
Despite advances in the treatment paradigm for patients with metastatic melanoma, melanoma brain metastasis (MBM) continues to represent a significant treatment challenge. The study of MBM is limited, in part, by shortcomings in existing preclinical models. Surgically eXplanted Organoids (SXOs) are ex vivo, three-dimensional cultures prepared from primary tissue samples with minimal processing that recapitulate genotypic and phenotypic features of parent tumors without an artificial extracellular scaffold. MBM SXOs were created by a novel protocol incorporating techniques for establishing glioma and cutaneous melanoma organoids. A BRAFV600K-mutant and BRAF-wildtype MBM sample were collected directly from the operating room. Organoids were cultured in an optimized culture medium without an artificial extracellular scaffold. Concurrently, matched patient-derived cell lines were created. Organoid growth was observed within 3–4 weeks, and MBM SXOs retained histological features of the parent tissue, including pleomorphic epithelioid cells with abundant cytoplasm, large nuclei, focal melanin accumulation, and strong SOX10 positivity. After sufficient growth, organoids could be manually parcellated to increase the number of replicates. Matched SXOs and cell lines demonstrated sensitivity to BRAF and MEK inhibitors. Further study using SXOs may improve the translational relevance of preclinical studies and enable the study of the metastatic melanoma tumor microenvironment.
Study Design Single-center retrospective study. Objective 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. Methods 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. Results 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). Conclusion 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.
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.
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