Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspective, we provide an overview of immune interventions performed to date in glioblastoma patients and re-evaluate their performance. We argue that shortcomings of current immune therapies in glioblastoma are related to three major determinants of resistance, namely: low immunogenicity; immune privilege of the central nervous system; and immunosuppressive micro-environment. In this perspective, we propose strategies that are guided by exact shortcomings to sensitize glioblastoma prior to treatment with therapies that enhance numbers and/or activation state of CD8 T cells.

WHO grade II-III gliomas are rare primary brain tumors occurring at a median age of about 35-55 years. Median survival is longer in WHO grade II-III glioma compared with WHO grade IV glioblastoma as survival times of up to 10 years and longer can be observed. Maximal safe resection and adjuvant therapies including chemotherapy and radiotherapy are the mainstay of treatment. Clinical trials in WHO grade II-III tumors are challenging due to the rarity and the long follow up times. The 2016 WHO Classification of Central Nervous Tumours introduced a new diagnostic framework relying on molecular characteristics, providing the definition of prognostically more homogenous subgroups compared to the histopathological analysis. Most available evidence on the adjuvant treatment of WHO II-III gliomas was generated in the pre-molecular era, challenging the interpretation of study results. The present review therefore summarizes the available data from prospective trials on systemic treatment options in WHO grade II-III glioma, considering molecular markers, recently published results and future outlooks in the field.

Background and Purpose—We assessed whether the effects of surgical decompression for space-occupying hemispheric infarction, observed at 1 year, are sustained at 3 years. Methods—Patients with space-occupying hemispheric infarction, who were enrolled in the Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial within 4 days after stroke onset, were followed up at 3 years. Outcome measures included functional outcome (modified Rankin Scale), death, quality of life, and place of residence. Poor functional outcome was defined as modified Rankin Scale >3. Results—Of 64 included patients, 32 were randomized to decompressive surgery and 32 to best medical treatment. Just as at 1 year, surgery had no effect on the risk of poor functional outcome at 3 years (absolute risk reduction, 1%; 95% confidence interval, −21 to 22), but it reduced case fatality (absolute risk reduction, 37%; 95% confidence interval, 14–60). Sixteen surgically treated patients and 8 controls lived at home (absolute risk reduction, 27%; 95% confidence interval, 4–50). Quality of life improved between 1 and 3 years in patients treated with surgery. Conclusions—In patients with space-occupying hemispheric infarction, the effects of decompressive surgery on case fatality and functional outcome observed at 1 year are sustained at 3 years. Clinical Trial Registration—URL: http://www.controlled-trials.com. Unique identifier: ISRCTN94237756.

Background and Purpose—: Animal studies suggest that cooling improves outcome after ischemic stroke. We assessed the feasibility and safety of surface cooling to different target temperatures in awake patients with acute ischemic stroke. Methods—: A multicenter, randomized, open, phase II, clinical trial, comparing standard treatment with surface cooling to 34.0°C, 34.5°C, or 35.0°C in awake patients with acute ischemic stroke and an National Institutes of Health Stroke Scale score of ≥6, initiated within 4.5 hours after symptom onset and maintained for 24 hours. The primary outcome was feasibility, defined as the proportion of patients who had successfully completed the assigned treatment. Safety was a secondary outcome. Results—: Inclusion was terminated after 22 patients because of slow recruitment. Five patients were randomized to 34.0°C, 6 to 34.5°C, 5 to 35.0°C (cooling was initiated in 4), and 6 to standard care. No (0%), 1 (17%), and 3 (75%) patients, respectively, completed the assigned treatment ( P =0.03). No (0%), 2 (33%), and 4 (100%) patients reached the target temperature ( P =0.01). Pneumonia occurred in 8 cooled patients but not in controls (absolute risk increase, 53%; 95% confidence interval, 28–79%; P =0.002). Conclusions—: In awake patients with acute ischemic stroke, surface cooling is feasible to 35.0°C, but not to 34.5°C and 34.0°C. Cooling is associated with an increased risk of pneumonia. Clinical Trial Registration—: URL: http://www.trialregister.nl . Unique identifier: NTR2616.

The standard of care for adult patients with gliomas, glioneuronal, and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a major part of the standard treatment; however, the predictive significance of most of the targets for treatment in systemic cancer is less well-established in central nervous system tumors. In 2023 the European Association for NeuroOncology (EANO) Guideline Committee presented evidence-based recommendations for rational testing of molecular targets for targeted treatments. From all targets reviewed, only testing for BRAF V600E mutations was of proven clinical benefit; despite regulatory approvals for tumor agnostic treatment of NTRK gene fusions and high tumor mutational burden (TMB) for patients with adult brain tumors, the evidence of clinical benefit for adult patients was still limited. This guideline has a modular structure, allowing regular updating of individual sections and adding new ones. The present version (Update 1) presents a review of the rationale of testing for PTEN, H3F3A, MTAP, RET and IDH, and presents an update of the text on TMB high and mismatch repair deficiency. It also presents an overview of the therapeutic yield of routine next-generation sequencing for mutations and fusion detection. The Supplemental File II accompanying this version contains an in-depth review of all targets, whereas, in the main manuscript, the final recommendations of the revised and new targets are presented. Updates will be made on a regular basis.