Health-related quality of life and neurocognitive functioning in patients with recurrent glioblastoma treated with intracerebral immune checkpoint inhibition.

PURPOSE: After glioblastoma (GB) recurrence, prognosis is very cumbersome. Therefore, health-related quality of life (HRQoL) and neurocognitive functioning (NCF) have become important endpoints in clinical trials when evaluating novel treatments. We aimed to evaluate the HRQoL and NCF in patients with recurrent glioblastoma (rGB) treated with a combination of surgical intervention (reoperation or biopsy) and intracerebral immune checkpoint inhibition. METHODS: Patients who participated in the trial (N = 23), at a single-center university hospital were included. Data were collected using 3 patient-reported outcome measures (EORTC-QLQ-C30, EORTC-QLQ-BN20, and HADS) and computerized NCF testing. In the responder group, baseline values were compared to results at a 6-month follow-up. Additionally, exploratory analyses compared baseline HRQoL and NCF between responders and non-responders. RESULTS: There were five responders and 18 non-responders. When comparing the mean and individual baseline with follow-up results for the responders, we observed overall a stable to slight clinically relevant improvement of HRQoL in multiple subsets of the questionnaires while maintaining a stable NCF. One patient deteriorated on anxiety and depression symptoms from baseline to follow-up. CONCLUSIONS: In patients that responded to intracerebral immunotherapy in our institutional trial, HRQoL and NCF remained stable over time, suggesting that no detrimental effect on cognitive function or quality of life may be expected with this treatment approach. Furthermore, there seems to be an overall tendency for responders to score better on HRQoL and NCF than non-responders at baseline.

Modality redundancy for MRI-based glioblastoma segmentation.

PURPOSE: Automated glioblastoma segmentation from magnetic resonance imaging is generally performed on a four-modality input, including T1, contrast T1, T2 and FLAIR. We hypothesize that information redundancy is present within these image combinations, which can possibly reduce a model's performance. Moreover, for clinical applications, the risk of encountering missing data rises as the number of required input modalities increases. Therefore, this study aimed to explore the relevance and influence of the different modalities used for MRI-based glioblastoma segmentation. METHODS: After the training of multiple segmentation models based on nnU-Net and SwinUNETR architectures, differing only in their amount and combinations of input modalities, each model was evaluated with regard to segmentation accuracy and epistemic uncertainty. RESULTS: Results show that T1CE-based segmentation (for enhanced tumor and tumor core) and T1CE-FLAIR-based segmentation (for whole tumor and overall segmentation) can reach segmentation accuracies comparable to the full-input version. Notably, the highest segmentation accuracy for nnU-Net was found for a three-input configuration of T1CE-FLAIR-T1, suggesting the confounding effect of redundant input modalities. The SwinUNETR architecture appears to suffer less from this, where said three-input and the full-input model yielded statistically equal results. CONCLUSION: The T1CE-FLAIR-based model can therefore be considered as a minimal-input alternative to the full-input configuration. Addition of modalities beyond this does not statistically improve and can even deteriorate accuracy, but does lower the segmentation uncertainty.

Intracranial administration of anti-PD-1 and anti-CTLA-4 immune checkpoint-blocking monoclonal antibodies in patients with recurrent high-grade glioma.

BACKGROUND: Recurrent high-grade glioma (rHGG) lacks effective life-prolonging treatments and the efficacy of systemic PD-1 and CTLA-4 immune checkpoint inhibitors is limited. The multi-cohort Glitipni phase I trial investigates the safety and feasibility of intraoperative intracerebral (iCer) and postoperative intracavitary (iCav) nivolumab (NIVO) ± ipilimumab (IPI) treatment following maximal safe resection (MSR) in rHGG. MATERIALS AND METHODS: Patients received 10 mg IV NIVO within 24 h before surgery, followed by MSR, iCer 5 mg IPI and 10 mg NIVO, and Ommaya catheter placement in the resection cavity. Biweekly postoperative iCav administrations of 1-5-10 mg NIVO (cohort 4) or 10 mg NIVO plus 1-5-10 mg IPI (cohort 7) were combined with 10 mg IV NIVO for 11 cycles. RESULTS: 42 rHGG patients underwent MSR with iCer NIVO + IPI. 16 pts were treated in cohort 4 (postoperative iCav NIVO at escalating doses) while 28 patients were treated in cohort 7 (intra and postoperative iCav NIVO and escalating doses of IPI). The most common TRAE was fatigue; no grade 5 AE occurred. Dose-limiting toxicity was grade 3 neutrophilic pleocytosis (4 pts) receiving iCav NIVO plus 5 or 10 mg IPI. PFS and OS did not significantly differ between cohorts (median OS: 42 [95% CI 26-57] vs. 35 [29-40] weeks; 1-year OS rate: 37% vs. 29%). Baseline B7-H3 expression significantly correlated with worse survival. OS compared favorably to a historical pooled cohort (n = 469) of Belgian rHGG pts treated with anti-VEGF therapies (log-rank P = .015). CONCLUSION: Intraoperative iCer IPI + NIVO with postoperative iCav NIVO ± IPI up to biweekly doses of 1 mg IPI + 10 mg NIVO is feasible and safe, showing encouraging OS in rHGG patients. ClinicalTrials.gov registration: NCT03233152.

ERK1/2 Phosphorylation Predicts Survival in Recurrent Glioblastoma Following Intracerebral and Adjuvant PD-1/CTLA-4 Immunotherapy: A REMARK-guided Analysis.

PURPOSE: Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in patients with recurrent glioblastoma receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts. EXPERIMENTAL DESIGN: In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and OS. Patients received intravenous nivolumab, followed by maximal safe resection and an intracerebral injection of either ipilimumab alone or combined with nivolumab. Biweekly adjuvant nivolumab was then administered up to five times (NCT03233152). Using REporting recommendations for tumor MARKER prognostic studies (REMARK) criteria, we conducted independent analyses for p-ERK quantification and statistical evaluations. Additional comparative analysis included prior cohorts, totaling 65 patients. Cox proportional hazards models and meta-analysis were employed to assess p-ERK as a predictive biomarker after immunotherapy. RESULTS: Lower median p-ERK+ cell density was observed compared with prior studies, likely due to variable tissue processing across cohorts. Nonetheless, high p-ERK was associated with prolonged OS, particularly in isocitrate dehydrogenase wild-type glioblastomas (P = 0.036). Median OS for high and low p-ERK patients were 55.6 and 30 weeks, respectively. Multivariable analysis reinforced p-ERK's significance in survival prediction (P = 0.011). Upon p-ERK normalization across cohorts (n = 65), meta-analysis supported the survival benefit of elevated tumor p-ERK levels (P = 0.0424). CONCLUSIONS: This study strengthens the role of p-ERK as a predictive biomarker for OS in patients with glioblastoma on immune checkpoint blockade. Future research should focus on further validation in prospective trials and the standardization of preanalytical variables influencing p-ERK quantification.

Neuro-oncological augmented reality planning for intracranial tumor resection.

Background: Before 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. Methods: We 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. Results: During 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%. Conclusion: By 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.

GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide.

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.

Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial.

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.

The Added Value of High Dose Spinal Cord Stimulation in Patients with Failed Back Surgery Syndrome after Conversion from Standard Spinal Cord Stimulation.

Patients with Failed Back Surgery Syndrome (FBSS) report a considerably lower health- related quality of life (HRQoL), compared to the general population. Spinal cord stimulation (SCS) is an effective treatment to offer pain relief in those patients. Despite initial treatment success of SCS, its effect sometimes wears off over time. This study investigates the added value of high dose SCS (HD-SCS) in patients with unsatisfactory conventional SCS, from a quality of life perspective. Seventy-eight FBSS patients who were treated with conventional SCS that failed to provide pain relief, were recruited in 15 centers. HRQoL was assessed before converting to HD-SCS (baseline) and three times after converting to HD-SCS using the EuroQol-5D-3L. Quality adjusted life years (QALY) were calculated and compared with conventional SCS. An overall significant increase over time was seen in utility values of the EQ5D-3L, as the mean value at baseline 0.283 (±0.21) increased to 0.452 (±0.29) at 12 months of HD-SCS. This average increase in utility coincides with an average increase of 0.153 (±0.24) QALY's in comparison to continued conventional SCS. Besides the potential of HD-SCS to salvage patients with failed responses to conventional SCS, this treatment seems to be a more efficient treatment than conventional SCS.