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.

Successful Treatment with Dabrafenib/Trametinib of a Malignantly Transformed and Metastasized BRAF V600E Mutant Pleiomorphic Xanthoastrocytoma: A Case Report and Review of the Literature.

Introduction: Pleiomorphic xanthoastrocytoma (PXA) is considered a low-grade glioma with a favorable prognosis following surgical resection. We present a case report of a BRAFV600E mutant malignantly transformed and disseminated PXA that was successfully treated with BRAF-/MEK-targeted therapy (dabrafenib/trametinib). Case Presentation: At the age of 16 years, our patient underwent an initial subtotal resection of a right occipital PXA. Six months later, a reintervention for an asymptomatic tumor recurrence was performed and complete resection was achieved. The patient has been followed up by MRI for 14 years without arguments for recurrence but was lost to follow-up thereafter. At 38 years of age, he presented with a symptomatic local recurrence with extra-cerebral soft tissue extension, for which a third surgical resection was performed. Anatomopathological examination reported a grade 3 anaplastic PXA (aPXA); molecular analysis detected a BRAFV600E mutation. Three months later, before the initiation of radiotherapy, a local tumor recurrence was diagnosed, for which he underwent a fourth surgical resection. Radiotherapy was performed following the surgical debulking. One month after completion of radiotherapy, disease progression was documented including multiple sites of extracranial metastases (skeletal, lung, cervical lymph node, and subcutaneous metastases). Systemic treatment with a combination of BRAF-/MEK-inhibitors (dabrafenib/trametinib) was initiated and resulted in a rapid and deep tumor response (partial response according to RECISTv1.1) and absence of BRAFV600E mutant ctDNA in plasma at 6 weeks after treatment initiation. A near-complete metabolic remission was documented on [18F]FDG-PET/CT 3 months after starting systemic therapy. Conclusion: We present a rare case of malignant transformation and systemic dissemination of a BRAFV600E mutant PXA, occurring 20 years after the initial diagnosis. This case highlights the importance of long-term follow-up of patients diagnosed with these rare central nervous system tumors that initially are considered benign and also illustrates that BRAF/MEK inhibition can be an effective therapy for BRAFV600E mutated PXA, underscoring the importance of performing molecular genetic profiling of these tumors.

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.

Computer-vision based analysis of the neurosurgical scene - A systematic review.

Introduction: With increasing use of robotic surgical adjuncts, artificial intelligence and augmented reality in neurosurgery, the automated analysis of digital images and videos acquired over various procedures becomes a subject of increased interest. While several computer vision (CV) methods have been developed and implemented for analyzing surgical scenes, few studies have been dedicated to neurosurgery. Research question: In this work, we present a systematic literature review focusing on CV methodologies specifically applied to the analysis of neurosurgical procedures based on intra-operative images and videos. Additionally, we provide recommendations for the future developments of CV models in neurosurgery. Material and methods: We conducted a systematic literature search in multiple databases until January 17, 2023, including Web of Science, PubMed, IEEE Xplore, Embase, and SpringerLink. Results: We identified 17 studies employing CV algorithms on neurosurgical videos/images. The most common applications of CV were tool and neuroanatomical structure detection or characterization, and to a lesser extent, surgical workflow analysis. Convolutional neural networks (CNN) were the most frequently utilized architecture for CV models (65%), demonstrating superior performances in tool detection and segmentation. In particular, mask recurrent-CNN manifested most robust performance outcomes across different modalities. Discussion and conclusion: Our systematic review demonstrates that CV models have been reported that can effectively detect and differentiate tools, surgical phases, neuroanatomical structures, as well as critical events in complex neurosurgical scenes with accuracies above 95%. Automated tool recognition contributes to objective characterization and assessment of surgical performance, with potential applications in neurosurgical training and intra-operative safety management.

Exploring technology acceptance of head-mounted device-based augmented reality surgical navigation in orthopaedic surgery.

BACKGROUND: This study used the Unified Theory of Acceptance and Use of Technology (UTAUT) to investigate the acceptance of HMD-based AR surgical navigation. METHODS: An experiment was conducted in which participants drilled 12 predefined holes using freehand drilling, proprioceptive control, and AR assistance. Technology acceptance was assessed through a survey and non-participant observations. RESULTS: Participants' intention to use AR correlated (p < 0.05) with social influence (Spearman's rho (rs) = 0.599), perceived performance improvement (rs = 0.592) and attitude towards AR (rs = 0.542). CONCLUSIONS: While most participants acknowledged the potential of AR, they also highlighted persistent barriers to adoption, such as issues related to user-friendliness, time efficiency and device discomfort. To overcome these challenges, future AR surgical navigation systems should focus on enhancing surgical performance while minimising disruptions to workflows and operating times. Engaging orthopaedic surgeons in the development process can facilitate the creation of tailored solutions and accelerate adoption.

Nonprogrammable Shunts for Communicating Hydrocephalus and Three-Dimensional Volumetry: A Retrospective Analysis.

OBJECTIVE: Although the use of different types of valves has been extensively studied in shunt surgery for communicating hydrocephalus (cHC), a consensus about the valve type remains absent. The objective of this study is to evaluate our results with the primary placement of nonprogrammable valves (NPVs) for this indication. METHODS: We retrospectively analyzed all first NPVs implanted between 2014 and 2020 for cHC. We studied the revision rate, clinical outcome described by modified Rankin Scale (mRS), and radiologic evolution using Evans Index (EI) and ventricular volumes three-dimensional semi-automatic segmentation (vv-3DSAS). RESULTS: Forty-one patients were shunted for posthemorrhagic (61%), posttraumatic (24.4%), and tumoral (14.6%) hydrocephalus. Mean age was 65 years (range, 25-89 years). Overall, 59 procedures were performed including 18 revision surgeries in 12 patients (29.3%). The underlying reasons for first shunt revision were valve type related (valve dysfunction, overdrainage, and underdrainage) and nonvalve type related (malpositioning, infection, and shunt migration). The shunt-related revision rate was 17.1%. Twenty-eight patients (68.3%) had an mRS score improvement of 1 or more points. We found a good correlation between ventricle volumes (VV) and EI and a significant reduction in VV measured by EI and vv-3DSAS was observed. However, the mRS improvement was not correlated with a reduction in ventricle volumes. CONCLUSIONS: Overall, our results in terms of shunt revisions as well as clinical and radiologic evolution are comparable to the literature for NPV. vv-3DSAS can be used and could be useful to detect small changes in VV in patients with cHC.

Overcoming the immune suppressive nature of glioblastoma by leveraging the surgical intervention - current status and future perspectives.

Despite relentless efforts to improve outcome, the prognosis of glioblastoma (GBM) remains poor. Standard therapy at first diagnosis consists of maximal safe surgical resection followed by radiochemotherapy, but treatment options at recurrence are scarce and have limited efficacy. Immunotherapy is a broad term that covers several treatment strategies, including immune checkpoint inhibition (ICI). The successes of systemically administered therapeutic monoclonal antibodies that block the Programmed death receptor or ligand (PD-(L)1) and Cytotoxic T-Lymphocyte associated protein (CTLA)-4 immune checkpoints in other cancer types could not be reproduced in glioblastoma. This is considered to be related to the intrinsic low immunogenicity and strong immunosuppressive tumor microenvironment of glioblastoma, in addition to the presence of a blood-glioma and blood-brain barrier that limits many systemically administered therapeutic agents from reaching their target. In this mini-review, we address the specific aspects of immune suppression in glioblastoma and discuss potential strategies that could help to overcome it. The potential advantages of incorporating surgical resection in clinical trials of immunotherapy for glioblastoma, including window-of-opportunity studies, are highlighted. Combination strategies that include surgical resection, as well as local administration of therapeutic agents in the brain are discussed as a potential strategy to achieve an effective immunological response against glioblastoma.

Low-Dose Bevacizumab for the Treatment of Focal Radiation Necrosis of the Brain (fRNB): A Single-Center Case Series.

Focal radiation necrosis of the brain (fRNB) is a late adverse event that can occur following the treatment of benign or malignant brain lesions with stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS). Recent studies have shown that the incidence of fRNB is higher in cancer patients who received immune checkpoint inhibitors. The use of bevacizumab (BEV), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), is an effective treatment for fRNB when given at a dose of 5-7.5 mg/kg every two weeks. In this single-center retrospective case series, we investigated the effectiveness of a low-dose regimen of BEV (400 mg loading dose followed by 100 mg every 4 weeks) in patients diagnosed with fRNB. A total of 13 patients were included in the study; twelve of them experienced improvement in their existing clinical symptoms, and all patients had a decrease in the volume of edema on MRI scans. No clinically significant treatment-related adverse effects were observed. Our preliminary findings suggest that this fixed low-dose regimen of BEV can be a well-tolerated and cost-effective alternative treatment option for patients diagnosed with fRNB, and it is deserving of further investigation.

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.

Pituitary carcinoma - case series and review of the literature.

Although pituitary adenomas (PAs) account for 15% of intracranial tumors, pituitary carcinomas (PCs) are a rare entity. Most commonly, PCs evolve from aggressive PAs invading the surrounding structures and eventually leading to metastatic lesions. Due to the low incidence, the diagnosis and treatment remains challenging. We report a case series of five patients with pituitary carcinoma (PC) treated in our center. At first diagnosis 3 patients had an ACTH-producing adenoma, 1 a prolactinoma and 1 a double secreting adenoma (GH and prolactin). The mean time interval from initial diagnosis to diagnosis of PC was 10.7 years (range 5-20 years). All patients underwent multiple surgical resections and radiotherapy. Four patients were treated with temozolomide for metastatic disease. One patient with concomitant radiochemotherapy for local recurrence. Temozolomide led to a stable disease in 2 patients. One patient had a progressive disease after 9 cycles of temozolomide. In absence of standard treatment, immunotherapy was initiated, resulting in a stable disease. We report five cases of PCs. Three patients obtained a stable disease after tailored multidisciplinary treatment. Additionally, one patient was treated with immunotherapy, opening a new treatment option in PCs. Overall, PCs are rare intracranial neoplasms occurring several years after the initial diagnosis of aggressive PAs. Currently, the absence of predictive factors for an aggressive clinical course, provokes a challenging management.

Randomized Trial Comparing Burr Hole Craniostomy, Minicraniotomy, and Twist Drill Craniostomy for Treatment of Chronic Subdural Hematoma.

BACKGROUND: The mainstay of treatment for symptomatic or large chronic subdural hematoma (CSDH) is surgery, but controversy still exists regarding the best surgical technique. Three different techniques are commonly used: burr hole craniostomy (BHC), minicraniotomy (MC), and twist drill craniostomy (TDC). OBJECTIVE: To determine which surgical technique for drainage of CSDH offers best results. METHODS: We set up a multicenter prospective randomized trial (Comparison of Chronic Subdural Hematoma Treatment [COMPACT] trial) comparing BHC, MC, and TDC for the surgical treatment of CSDH. The primary end point was reoperation rate, and secondary end points included complication rates and clinical outcome. Patients were considered to have good outcome when they did not undergo reoperation, suffered no surgical or medical complication, and had no related mortality. Clinical outcome was also evaluated by evolution of the Markwalder score and the modified Rankin score. RESULTS: Two-hundred forty-five patients were included in the final analysis: 79 BHC, 84 MC, and 82 TDC. Mean duration of surgery was shorter for TDC than for BHC and MC ( P < .001). Reoperation rate was 7.6% for BHC, 13.1% for MC, and 19.5% for TDC ( P = .07). This trend toward better results for BHC was not statistically significant in logistic regression analysis. The proportion of patients with good outcome was 78.5% for BHC group, 76.2% for MC, and 69.5% for TDC ( P = .4). Evolution of the Markwalder score and modified Rankin score were not significantly different between treatment groups. CONCLUSION: All 3 techniques are effective at treating patients with CSDH with eventual 6-month outcome being similar. Although not reaching statistical significance in our study, BHC offers the lowest recurrence rate combined with manageable complication rate.

The effect of augmented reality on the accuracy and learning curve of external ventricular drain placement.

OBJECTIVE: The traditional freehand technique for external ventricular drain (EVD) placement is most frequently used, but remains the primary risk factor for inaccurate drain placement. As this procedure could benefit from image guidance, the authors set forth to demonstrate the impact of augmented-reality (AR) assistance on the accuracy and learning curve of EVD placement compared with the freehand technique. METHODS: Sixteen medical students performed a total of 128 EVD placements on a custom-made phantom head, both before and after receiving a standardized training session. They were guided by either the freehand technique or by AR, which provided an anatomical overlay and tailored guidance for EVD placement through inside-out infrared tracking. The outcome was quantified by the metric accuracy of EVD placement as well as by its clinical quality. RESULTS: The mean target error was significantly impacted by either AR (p = 0.003) or training (p = 0.02) in a direct comparison with the untrained freehand performance. Both untrained (11.9 ± 4.5 mm) and trained (12.2 ± 4.7 mm) AR performances were significantly better than the untrained freehand performance (19.9 ± 4.2 mm), which improved after training (13.5 ± 4.7 mm). The quality of EVD placement as assessed by the modified Kakarla scale (mKS) was significantly impacted by AR guidance (p = 0.005) but not by training (p = 0.07). Both untrained and trained AR performances (59.4% mKS grade 1 for both) were significantly better than the untrained freehand performance (25.0% mKS grade 1). Spatial aptitude testing revealed a correlation between perceptual ability and untrained AR-guided performance (r = 0.63). CONCLUSIONS: Compared with the freehand technique, AR guidance for EVD placement yielded a higher outcome accuracy and quality for procedure novices. With AR, untrained individuals performed as well as trained individuals, which indicates that AR guidance not only improved performance but also positively impacted the learning curve. Future efforts will focus on the translation and evaluation of AR for EVD placement in the clinical setting.

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.

Augmented Reality-Assisted Neurosurgical Drain Placement (ARANED): Technical Note.

BACKGROUND: Many surgical procedures, such as placement of intracranial drains, are currently being performed blindly, relying on anatomical landmarks. As a result, accuracy results still have room for improvement. Neuronavigation could address this issue, but its application in an urgent setting is often impractical. Augmented reality (AR) provided through a head-worn device has the potential to tackle this problem, but its implementation should meet physicians' needs. METHODS: The Surgical Augmented Reality Assistance (SARA) project aims to develop an AR solution that is suitable for preoperative planning, intraoperative visualisation and navigational support in an everyday clinical setting, using a Microsoft HoloLens. RESULTS: Proprietary hardware and software adaptations and dedicated navigation algorithms are applied to the Microsoft HoloLens to optimise it specifically for neurosurgical navigation. This includes a pipeline with an additional set of advanced, semi-automated algorithms responsible for image processing, hologram-to-patient registration and intraoperative tracking using infrared depth-sensing. A smooth and efficient workflow while maintaining high accuracy is prioritised. The AR solution provides a fully integrated and completely mobile navigation setup. Initial preclinical and clinical validation tests applying the solution to intracranial drain placement are described. CONCLUSION: AR has the potential to vastly increase accuracy of everyday procedures that are frequently performed without image guidance, but could still benefit from navigational support, such as intracranial drain placements. Technical development should go hand in hand with preclinical and clinical validation in order to demonstrate improvements in accuracy and clinical outcomes.

Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization.

Glioblastomas are aggressive primary brain cancers that recur as therapy-resistant tumors. Myeloid cells control glioblastoma malignancy, but their dynamics during disease progression remain poorly understood. Here, we employed single-cell RNA sequencing and CITE-seq to map the glioblastoma immune landscape in mouse tumors and in patients with newly diagnosed disease or recurrence. This revealed a large and diverse myeloid compartment, with dendritic cell and macrophage populations that were conserved across species and dynamic across disease stages. Tumor-associated macrophages (TAMs) consisted of microglia- or monocyte-derived populations, with both exhibiting additional heterogeneity, including subsets with conserved lipid and hypoxic signatures. Microglia- and monocyte-derived TAMs were self-renewing populations that competed for space and could be depleted via CSF1R blockade. Microglia-derived TAMs were predominant in newly diagnosed tumors, but were outnumbered by monocyte-derived TAMs following recurrence, especially in hypoxic tumor environments. Our results unravel the glioblastoma myeloid landscape and provide a framework for future therapeutic interventions.

CSF and Blood Neurofilament Levels in Athletes Participating in Physical Contact Sports: A Systematic Review.

OBJECTIVE: To evaluate whether participating in physical contact sports is associated with a release of neurofilaments and whether such release is related to future clinical neurologic and/or psychiatric impairment. METHODS: We performed a systematic review of the PubMed, MEDLINE, and Cochrane Library databases using a combination of the search terms neurofilament(s)/intermediate filament and sport(s)/athletes. Original studies, written in English, reporting on neurofilaments in CSF and/or serum/plasma of contact sport athletes were included. This review was conducted following the Preferred Reporting Items for Systematic Review and Analyses guidelines. RESULTS: Eighteen studies in 8 different contact sports (i.e., boxing, American football, ice hockey, soccer, mixed martial arts, lacrosse, rugby, and wrestling) matched our criteria. Elevated light chain neurofilament (NfL) levels were described in 13/18 cohorts. Most compelling evidence was present in boxing and American football, where exposure-related increases were appreciable at the intraindividual level (up to 4.1- and 2.0-fold, respectively) in well-defined groups. Differences in exposure severity (including previous cumulative effects), sampling/measurement time points (with regard to expected peak values), and definitions of the baseline setting are considered as main contributors to the variability in findings. No studies were encountered that have investigated the relationship with the targeted clinical end points; therefore no NfL cutoffs exist that are associated with a poor outcome. CONCLUSION: NfL release can be seen, as a potential marker of neuronal brain damage, in participants of physical contact sports, particularly boxing and American football. The exact significance regarding the risk for future clinical impairment remains to be elucidated.

Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx).

BACKGROUND: No treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death ligand 1 blocking monoclonal antibody avelumab may result in synergistic activity against rGB. METHODS: Adult patients with rGB following prior surgery, radiation therapy and temozolomide chemotherapy were stratified according to their baseline use of corticosteroids. Patients with a daily dose of ≤8 mg of methylprednisolone (or equivalent) initiated treatment with axitinib (5 mg oral two times per day) plus avelumab (10 mg/kg intravenous every 2 weeks) (Cohort-1). Patients with a higher baseline corticosteroid dose initiated axitinib monotherapy; avelumab was added after 6 weeks of therapy if the corticosteroid dose could be tapered to ≤8 mg of methylprednisolone (Cohort-2). Progression-free survival at 6 months (6-m-PFS%), per immunotherapy response assessment for neuro-oncology criteria, served as the primary endpoint. RESULTS: Between June 2017 and August 2018, 54 patients (27 per cohort) were enrolled and initiated study treatment (median age: 55 years; 63% male; 91% Eastern Cooperative Oncology Group Performance Status 0-1). Seventeen (63%) patients treated in Cohort-2 received at least one dose of avelumab. The 6-m-PFS% was 22.2% (95% CI 6.5% to 37.9%) and 18.5% (95% CI 3.8% to 33.2%) in Cohort-1 and Cohort-2, respectively; median overall survival was 26.6 weeks (95% CI 20.8 to 32.4) in Cohort-1 and 18.0 weeks (95% CI 12.5 to 23.5) in Cohort-2. The best objective response rate was 33.3% and 22.2% in Cohort-1 and Cohort-2, respectively, with a median duration of response of 17.9 and 19.0 weeks. The most frequent treatment-related adverse events were dysphonia (67%), lymphopenia (50%), arterial hypertension and diarrhea (both 48%). There were no grade 5 adverse events. CONCLUSION: The combination of avelumab plus axitinib has an acceptable toxicity profile but did not meet the prespecified threshold for activity justifying further investigation of this treatment in an unselected population of patients with rGB.

Durable Complete Response of a Recurrent Mesencephalic Glioblastoma Treated with Trametinib and Low-Dose Dabrafenib in a Patient with Neurofibromatosis Type 1.

Patients with neurofibromatosis type 1 (NF1) have an increased lifetime risk for the development of nervous system tumors, including high-grade gliomas (glioblastoma). NF1 is associated with the loss of expression of neurofibromin 1 (NF1 gene product). This hyperactivates the mitogen-activated protein kinase pathway, leading to cellular proliferation and survival. MEK-inhibitor monotherapy is a promising treatment strategy in this setting, but is associated with distinct adverse events, most prominently cutaneous toxicity. We report the case of a young NF1 patient with a recurrent, heavily pretreated mesencephalic glioblastoma who was treated with the MEK-inhibitor trametinib (2 mg once daily). A partial response was documented, but unfortunately, he developed dose-limiting cutaneous toxicity (rash, paronychia). Based on interim results of a phase 2 trial in advanced BRAF V600 wild-type melanoma indicating that a low dose of the BRAF-inhibitor dabrafenib is able to counter trametinib-related cutaneous toxicity, dabrafenib 50 mg twice daily was added. The cutaneous adverse events gradually recovered after addition of dabrafenib to trametinib. The patient eventually achieved a durable complete response, has excellent tolerance of his treatment and remains fully active.

Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies.

Cancer immunotherapy by immune checkpoint blockade has proven its great potential by saving the lives of a proportion of late stage patients with immunogenic tumor types. However, even in these sensitive tumor types, the majority of patients do not sufficiently respond to the therapy. Furthermore, other tumor types, including glioblastoma, remain largely refractory. The glioblastoma immune microenvironment is recognized as highly immunosuppressive, posing a major hurdle for inducing immune-mediated destruction of cancer cells. Scattered information is available about the presence and activity of immunosuppressive or immunostimulatory cell types in glioblastoma tumors, including tumor-associated macrophages, tumor-infiltrating dendritic cells and regulatory T cells. These cell types are heterogeneous at the level of ontogeny, spatial distribution and functionality within the tumor immune compartment, providing insight in the complex cellular and molecular interplay that determines the immune refractory state in glioblastoma. This knowledge may also yield next generation molecular targets for therapeutic intervention.