Citations

Abstract Diffuse gliomas are aggressive brain tumors that lack effective therapies. Despite advances in the molecular characterization of gliomas, targeted treatments have failed to improve patient outcomes to date. Here, we employed a functional genomics approach to rapidly identify therapeutic vulnerabilities and provide a strategy to individualize patient treatment. Our process combined comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3-dimensional ex vivo models (mcancers) for drug screening to assess response to therapeutic agents targeting specific molecular alterations. A total of 32 cases, including 5 oligodendrogliomas (1 primary and 4 recurrent), 5 astrocytomas (1 primary and 4 recurrent), and 22 glioblastomas (5 primary and 17 recurrent), were included in the study. Immunohistochemistry and integrated genomics confirmed that mcancers maintain key molecular alterations, including mutations, chromosomal rearrangements and focal amplifications, cellularity, and heterogeneity, faithfully recapitulating the original tumor. A total of 119 single drugs and 183 combinations were tested, including a panel of 26-brain penetrant targeted agents (18 single drugs and 8 combinations) that was curated to target common glioma oncogenic pathways and was tested across all cases. A strong correlation was observed between therapeutic vulnerabilities of glioma mcancers to targeted agents (EGFR, MET, PDGFR, HDAC inhibitors, etc.) and clinical experience. Single agent activity of panel compounds in the ex vivo setting was generally poor, with only 35% mCancers exhibiting > 70% growth inhibition at Cmax. In contrast, combination strategies, especially ones including epigenetic drugs, were significantly more effective (affecting 22 out of 32 mCancers), underscoring the molecular complexity of gliomas and the need for clinical trials testing combination treatments. Our data identified a number of novel combination treatments with significant efficacy across glioma subtypes and molecular profiles, suggesting that our functional genomics pipeline can guide treatment selection and inform clinical trial enrollment for gliomas.

Abstract BACKGROUND Despite advances in cancer biology, surgery and its extent of resection remains the most important prognostic modulator in gliomas, with the distinction between infiltrated and non-infiltrated tissues being an issue at the penumbra. Isocitrate dehydrogenase (IDH) mutation is unique to IDH-mutant glioma cells and can be used as a potential surrogate for tumor infiltration. Here we evaluate desorption electrospray ionization-mass spectrometry (DESI-MS) as a near real-time method for detecting infiltration at the margin of IDH-mutant gliomas. METHODS We conducted a prospective study in which DESI-MS analysis was performed on freshly obtained tissue biopsies to detect the presence of 2-Hydroxyglutarate (2HG), with subsequent review of each sample by a board-certified neuropathologist. RESULTS A total of 247 biopsies from a 49-patient study were previously collected and analyzed at Indiana University. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%, respectively. Subsequent improvement of the method, including the measurement of 2HG relative to an internal control (Glutamate, Glu), allowed for detection of IDH-mutant infiltration at surgical margins. We have collected 183 biopsies (116 core and 67 margin) from 23 patients. Preliminary results of IDH mutation assessments of core biopsies indicate 93% sensitivity, 100% specificity, and 98% accuracy and margin biopsies indicate 88% sensitivity, 100% specificity, and 94% accuracy. Tumor infiltration at the margin of the surgical resection by detection of IDH-mut infiltration was detected in 88% of margin biopsies from IDH mutant tumors (30 of 34 biopsies). CONCLUSION We present a novel method to allow intraoperative evaluation of IDH mutation presence in glioma margin biopsies. Our method and its ongoing validation identified tumor infiltration beyond surgical margins and serves as a foundation for molecularly guided surgery in IDH-mut gliomas via DESI-MS.

Abstract Glioblastoma (GBM) is the most aggressive adult brain tumor with no effective therapy. Despite advances on its molecular characterization, targeted therapeutics remain out of reach. This lack-of-progress is largely attributed to molecular and spatial heterogeneity and absence of clinically applicable models to guide patient care. Moreover, as standard surgical resection is aimed at contrast-enhancing (CE) tumor, the molecular landscape and treatment response of the remaining non-contrast enhancing (nCE) component is largely unknown despite its active role in tumor progression and local recurrence. Here, we aimed to identify the functional impact of tumor heterogeneity and to explore therapeutic vulnerabilities of both CE and nCE components. Four tumor regions (two CE and two nCE) from each of five GBM patients were collected under neuronavigation. The resulting tissue was subjected to generation of 3D tumor models (a brain tumor initiating-enriched cell line and a spheroid-based mcancer model) with comparable success in both CE and nCE samples. A panel of 25 brain penetrant drugs (alone and in combination) targeting GBM drivers (i.e. RTK/Ras/PI3K, RB/cell cycle, p53/apoptosis, DNA damage repair, transcription addiction) was developed and used to test for therapeutic vulnerabilities. From each tumor region, 4.5 ± 3.7 (average ± SD) different targeting strategies were identified exhibiting at least 70% growth inhibition at Cmax. Drug response heterogeneity was relatively rare, varied among cases, and was independent of tumor enhancement status. To our knowledge, this is the first study to systemically assess treatment response from both CE and nCE patient-derived GBM models. Ongoing studies include comprehensive genome and transcriptome profiling and pathway analysis from these different tumor regions. We postulate that interrogation of molecular landscapes and vulnerability profiles of both CE and nCE tumor regions, will enable us to personalize and prioritize effective targeted interventions for GBM treatment.

BACKGROUND: Management of degenerative disease of the spine has evolved to favor minimally invasive techniques, including nonrobotic-assisted and robotic-assisted minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). Value-based spending is being increasingly implemented to control rising costs in the US healthcare system. With an aging population, it is fundamental to understand which procedure(s) may be most cost-effective. OBJECTIVE: To compare robotic and nonrobotic MIS-TLIF through a cost-utility analysis. METHODS: We considered direct medical costs related to surgical intervention and to the hospital stay, as well as 1-yr utilities. We estimated costs by assessing all cases involving adults undergoing robotic surgery at a single institution and an equal number of patients undergoing nonrobotic surgery, matched by demographic and clinical characteristics. We adopted a willingness to pay of $50 000/quality-adjusted life year (QALY). Uncertainty was addressed by deterministic and probabilistic sensitivity analyses. RESULTS: Costs were estimated based on a total of 76 patients, including 38 undergoing robot-assisted and 38 matched patients undergoing nonrobot MIS-TLIF. Using point estimates, robotic surgery was projected to cost $21 546.80 and to be associated with 0.68 QALY, and nonrobotic surgery was projected to cost $22 398.98 and to be associated with 0.67 QALY. Robotic surgery was found to be more cost-effective strategy, with cost-effectiveness being sensitive operating room/materials and room costs. Probabilistic sensitivity analysis identified robotic surgery as cost-effective in 63% of simulations. CONCLUSION: Our results suggest that at a willingness to pay of $50 000/QALY, robotic-assisted MIS-TLIF was cost-effective in 63% of simulations. Cost-effectiveness depends on operating room and room (admission) costs, with potentially different results under distinct neurosurgical practices.

Abstract BACKGROUND Intraoperative detection of residual tumor and isocitrate dehydrogenase (IDH) mutations can assist in maximizing surgical resection beyond contrast enhancing margins and guide intraoperative surgical decision making for glioma patients. We aimed to evaluate the use of desorption electrospray ionization-mass spectrometry (DESI-MS) for intraoperative assessment of IDH mutations and estimation of tumor cell percentage (TCP). METHODS This is a prospective study using intraoperative DESI-MS analysis of freshly obtained tissue samples to evaluate IDH mutations via 2-hydroxyglutarate (2-HG) intensity and TCP via measurement of N-acetylaspartic acid (NAA) intensity and characteristic lipid profiles. These IDH mutation and TCP estimates were subsequently validated by a senior neuropathologist. RESULTS A total of 247 biopsies from a 49-patient study were previously collected and analyzed at Indiana University. Assessment of TCP in 203 margin and core biopsies based on NAA intensity yielded sensitivity, specificity, and accuracy values of 91, 76, and 83%, whereas TCP assessment based on characteristic lipid profiles yielded 76, 85, and 81%, respectively. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%. Further validation of the methodology is being performed in an ongoing collaboration with Mayo Clinic-Jacksonville, where we have collected 178 biopsies from 24 patients. Preliminary results of IDH mutation assessments indicate 100% sensitivity, specificity, and accuracy. DISCUSSION/CONCLUSION We present a novel system to allow intraoperative evaluation of IDH status and to guide surgical resection by TCP measurement from tissue biopsies. Prospectively, we propose to modify our DESI-MS system by placing a surgical material (e.g. cottonoid) along the surgical margin and transferring material from the blot to a microscope slide prior to DESI-MS analysis. This will allow the retention of the spatial distribution of diagnostic molecules while analyzing a wall of the surgical cavity without the need for biopsy.

OBJECTIVE High-grade spinal glioma (HGSG) is a rare but aggressive tumor that occurs in both adults and children. Histone H3 K27M mutation correlates with poor prognosis in children with diffuse midline glioma. However, the role of H3 K27M mutation in the prognosis of adults with HGSG remains unclear owing to the rarity of this mutation, conflicting reports, and the absence of multicenter studies on this topic. METHODS The authors studied a cohort of 30 adult patients with diffuse HGSG who underwent histological confirmation of diagnosis, surgical intervention, and treatment between January 2000 and July 2020 at six tertiary academic centers. The primary outcome was the effect of H3 K27M mutation status on progression-free survival (PFS) and overall survival (OS). RESULTS Thirty patients (18 males and 12 females) with a median (range) age of 50.5 (19–76) years were included in the analysis. Eighteen patients had H3 K27M mutation–positive tumors, and 12 had H3 K27M mutation–negative tumors. The median (interquartile range) PFS was 3 (10) months, and the median (interquartile range) OS was 9 (23) months. The factors associated with increased survival were treatment with concurrent chemotherapy/radiation (p = 0.006 for PFS, and p ≤ 0.001 for OS) and American Spinal Injury Association grade C or better at presentation (p = 0.043 for PFS, and p < 0.001 for OS). There were no significant differences in outcomes based on tumor location, extent of resection, sex, or H3 K27M mutation status. Analysis restricted to HGSG containing necrosis and/or microvascular proliferation (WHO grade IV histological features) revealed increased OS for patients with H3 K27M mutation–positive tumors (p = 0.017). CONCLUSIONS Although H3 K27M mutant–positive HGSG was associated with poor outcomes in adult patients, the outcomes of patients with H3 K27M mutant–positive HGSG were somewhat more favorable compared with those of their H3 K27M mutant–negative HGSG counterparts. Further preclinical animal studies and larger clinical studies are needed to further understand the age-dependent effects of H3 K27M mutation.

Abstract Background En bloc spondylectomy is the gold standard for surgical resection of sacral chordomas (CHO), but the effect of extent of resection on recurrence and survival in patients with CHO of the cervical spine remains elusive. Methods MEDLINE, Embase, Scopus, and Cochrane were systematically reviewed. Patients with cervical CHO treated at three tertiary-care academic institutions were reviewed for inclusion. We performed an individual participant data meta-analysis to assess the overall survival (OS) and progression free survival (PFS) after en bloc-gross total resection (GTR) and intralesional-GTR compared to subtotal resection (STR). We then performed an intention-to-treat analysis including all patients with attempted en bloc resection in the en bloc group, regardless of the surgical margins. Results There was a total of 13 series including 161 patients with cervical CHO, including our current series of 22 patients. GTR (en bloc-GTR + intralesional-GTR) was associated with a significant decrease in the risk of local progression (pooled hazard ratio (PHR) = 0.22; 95% CI = 0.08–0.59; p = 0.003) and risk of death (PHR = 0.31; 95%; CI:0.12–0.83; p = 0.020). A meta-regression analyses determined that intralesional-GTR improved PFS (PHR = 0.35; 95%CI = 0.16–0.76; p = 0.009) as well as OS (PHR = 0.25; 95%CI = 0.08–0.79; p = 0.019) when compared to STR. En bloc-GTR was associated with a significant reduction in the risk of local progression (PHR = 0.06; 95%CI = 0.01–0.77; p = 0.030), but not a decreased OS (PHR = 0.50; 95% CI = 0.19–1.27; p = 0.145). Our intention-to-treat analyses revealed a near significant improvement in OS for the en bloc group (PHR: 0.15; 95%CI:0.02–1.22; p = 0.054), and nearly identical improvement in PFS. Radiation data was not available for the studies included in the meta-analysis. Conclusion This is the first and only meta-analysis of patients with cervical CHO. We found that both en bloc-GTR and intralesional-GTR resulted in improved local tumor control when compared to STR.

Background: During awake craniotomy, securing the patient’s airway might be necessary electively or emergently. The objective of this study was to compare the feasibility of airway management using a laryngeal mask airway (LMA) and 4 alternative airway management techniques in an awake craniotomy simulation. Methods: After completing a questionnaire, 9 anesthesia providers attempted airway management in a cadaver positioned to simulate awake craniotomy conditions. Following the simulation, participants rated and ranked the devices in their order of preference. Results: Only 3 approaches resulted in the successful securement of an airway device for 100% of participants: LMA (median; interquartile range time to secure the airway 6 s, 5 to 10 s), fiberoptic bronchoscopy through an LMA (41 s; 23 to 51 s), and video laryngoscopy (49 s; 43 to 127 s). In contrast, the oral and nasal fiberoptic approaches demonstrated only 44.4% (154.5 s; 134.25 to 182 s) and 55.6% (75 s; 50 to 117 s) success rates, respectively. The LMA was the fastest and most reliable primary method to secure the airway (P=0.001). After the simulation, 100% of participants reported that an LMA would be their first choice for emergency airway management, followed by fiberoptic intubation through the LMA (7 of 9 participants) if the LMA failed to properly seat. Conclusions: We demonstrated that an LMA was the fastest and most reliable primary method to secure an airway in a laterally positioned cadaver with 3-pin skull fixation. Fiberoptic and video laryngoscope airway equipment should be readily available during awake craniotomy procedures, and an attempt to visualize the vocal cords through the LMA should be attempted before removing it for alternative techniques.