Komotar, Ricardo J.

Abstract Glioblastoma (GBM) remains the most common and lethal adult malignant primary brain cancer with few treatment options. A significant issue hindering GBM therapeutic development is intratumor heterogeneity. GBM tumors contain neoplastic cells within a spectrum of different transcriptional states. Identifying effective therapeutics requires a platform that predicts the differential sensitivity and resistance of these states to various treatments. Here, we developed a novel framework, ISOSCELES ( I nferred cell S ensitivity O perating on the integration of S ingle- C ell E xpression and L 1000 E xpression S ignatures), to quantify the cellular drug sensitivity and resistance landscape. Using single-cell RNA sequencing of newly diagnosed and recurrent GBM tumors, we identified compounds from the LINCS L1000 database with transcriptional response signatures selectively discordant with distinct GBM cell states. We validated the significance of these findings in vitro, ex vivo, and in vivo , and identified a novel combination of an OLIG2 inhibitor and Depatux-M for GBM. Our studies suggest that ISOSCELES identifies cell states sensitive and resistant to targeted therapies in GBM and that it can be applied to identify new synergistic combinations. Highlights Integration of GBM single-cell RNA sequencing data with L1000-derived drug response signatures facilitates clustering of tumor cells and small molecules on cell-drug connectivity. Cell-drug connectivity predicts the identities of drug-sensitive and resistant cell states. In silico perturbation analysis using cell-drug connectivity predicts drug-induced changes in the cell-drug connectivity landscape in vivo. In silico perturbation analysis to predict drug-induced changes in the tumor cell-drug connectivity landscape predicts drug combinations that synergize in vivo to extend survival.

BACKGROUND AND OBJECTIVES: Bilateral/butterfly glioblastoma (bGBM) has a poor prognosis. Resection of these tumors is limited due to severe comorbidities that arise from surgical procedures. Laser interstitial thermal therapy (LITT) offers a minimally invasive cytoreductive therapy for deep-seated tumors such as bGBM. The objective of this study was to evaluate the safety of bilateral LITT in patients with bGBM. METHODS: Medical records of all consecutive patients diagnosed with bGBM by a single surgeon at a single institution from January 2014 to August 2022 were reviewed. Clinical, safety, and radiographic volumetric data were obtained. In addition, an exploratory analysis of survival was performed. RESULTS: A total of 25 patients were included; 14 underwent biopsy only, and 11 underwent biopsy + LITT (7 underwent bilateral and 4 underwent unilateral LITT). No (0%) intraoperative or postoperative complications were recorded in the treatment group. Tumor volume negatively correlated with extent of treatment (r 2 = 0.44, P = .027). The median progression-free survival was 2.8 months in the biopsy-only group and 5.5 months in the biopsy + LITT group ( P = .026). The median overall survival was 4.3 months in the biopsy-only group and 10.3 months in the biopsy + LITT group ( P = .035). CONCLUSION: Bilateral LITT for bGBM can be safely performed and shows early improvement of the progression-free survival and long-term survival outcomes of these patients.

AbstractBackgroundWearable technology is growing in popularity as a result of its ability to interface with normal human movement and function.MethodsUsing proprietary hardware and software, neuronavigation images were captured and transferred wirelessly via a password‐encrypted network to the head‐up display. The operating surgeon wore a loupe‐mounted wearable head‐up display during image‐guided parieto‐occipital ventriculoperitoneal shunt placement in two patients.ResultsThe shunt placement was completed successfully without complications. The tip of the catheter ended well within the ventricles away from the ventricular wall. The wearable device allowed for continuous monitoring of neuronavigation images in the right upper corner of the surgeon's visual field without the need for the surgeon to turn his head to view the monitors.ConclusionsThe adaptable nature of this proposed system permits the display of video data to the operating surgeon without diverting attention away from the operative task. This technology has the potential to enhance image‐guided procedures.