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BackgroundBefore starting surgery for the resection of an intracranial tumor, its outlines are typically marked on the skin of the patient. This allows for the planning of the optimal skin incision, craniotomy, and angle of approach. Conventionally, the surgeon determines tumor borders using neuronavigation with a tracked pointer. However, interpretation errors can lead to important deviations, especially for deep-seated tumors, potentially resulting in a suboptimal approach with incomplete exposure. Augmented reality (AR) allows displaying of the tumor and critical structures directly on the patient, which can simplify and improve surgical preparation.MethodsWe developed an AR-based workflow for intracranial tumor resection planning deployed on the Microsoft HoloLens II, which exploits the built-in infrared-camera for tracking the patient. We initially performed a phantom study to assess the accuracy of the registration and tracking. Following this, we evaluated the AR-based planning step in a prospective clinical study for patients undergoing resection of a brain tumor. This planning step was performed by 12 surgeons and trainees with varying degrees of experience. After patient registration, tumor outlines were marked on the patient's skin by different investigators, consecutively using a conventional neuronavigation system and an AR-based system. Their performance in both registration and delineation was measured in terms of accuracy and duration and compared.ResultsDuring phantom testing, registration errors remained below 2.0 mm and 2.0° for both AR-based navigation and conventional neuronavigation, with no significant difference between both systems. In the prospective clinical trial, 20 patients underwent tumor resection planning. Registration accuracy was independent of user experience for both AR-based navigation and the commercial neuronavigation system. AR-guided tumor delineation was deemed superior in 65% of cases, equally good in 30% of cases, and inferior in 5% of cases when compared to the conventional navigation system. The overall planning time (AR = 119 ± 44 s, conventional = 187 ± 56 s) was significantly reduced through the adoption of the AR workflow (p < 0.001), with an average time reduction of 39%.ConclusionBy providing a more intuitive visualization of relevant data to the surgeon, AR navigation provides an accurate method for tumor resection planning that is quicker and more intuitive than conventional neuronavigation. Further research should focus on intraoperative implementations.

Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma. This response is, however, blunted in recurring glioblastoma from the same patient. Further, we describe that disrupting cellular fatty acid homeostasis in favor of accumulation of saturated fatty acids such as palmitate synergizes with temozolomide treatment. Pharmacological inhibition of SCD and/or FADS2 allows palmitate accumulation and thus greatly augments temozolomide efficacy. This effect was independent of common GBM prognostic factors and was effective against cancer cells from recurring glioblastoma. In summary, we provide evidence that intracellular accumulation of saturated fatty acids in conjunction with temozolomide based chemotherapy induces death in glioblastoma cells derived from patients.

Background Patients with recurrent glioblastoma (rGB) have a poor prognosis with a median overall survival (OS) of 30–39 weeks in prospective clinical trials. Intravenous administration of programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4 inhibitors has low activity in patients with rGB. In this phase I clinical trial, intracerebral (IC) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with intravenous administration of NIVO was investigated.Methods Within 24 hours following the intravenous administration of a fixed dose (10 mg) of NIVO, patients underwent a maximal safe resection, followed by injection of IPI (10 mg; cohort-1), or IPI (5 mg) plus NIVO (10 mg; cohort-2) in the brain tissue lining the resection cavity. Intravenous administration of NIVO (10 mg) was repeated every 2 weeks (max. five administrations). Next generation sequencing and RNA gene expression profiling was performed on resected tumor tissue.Results Twenty-seven patients were enrolled (cohort-1: n=3; cohort-2: n=24). All patients underwent maximal safe resection and planned IC administrations and preoperative NIVO. Thirteen patients (cohort-1: n=3; cohort-2: n=10) received all five postoperative intravenous doses of NIVO. In cohort-2, 14 patients received a median of 3 (range 1–4) intravenous doses. Subacute postoperative neurological deterioration (n=2) was reversible on steroid treatment; no other central nervous system toxicity was observed. Immune-related adverse events were infrequent and mild. GB recurrence was diagnosed in 26 patients (median progression-free survival (PFS) is 11.7 weeks (range 2–152)); 21 patients have died due to progression. Median OS is 38 weeks (95% CI: 27 to 49) with a 6-month, 1-year, and 2-year OS-rate of, respectively, 74.1% (95% CI: 57 to 90), 40.7% (95% CI: 22 to 59), and 27% (95% CI: 9 to 44). OS compares favorable against a historical cohort (descriptive Log-Rank p>0.003). No significant difference was found with respect to PFS (descriptive Log-Rank test p>0.05). A higher tumor mRNA expression level of B7-H3 was associated with a significantly worse survival (multivariate Cox logistic regression, p>0.029).Conclusion IC administration of NIVO and IPI following maximal safe resection of rGB was feasible, safe, and associated with encouraging OS.Trial registration NCT03233152.