Tiit Mathiesen

We report findings from a Phase 1/2a clinical trial (EUCT No. 2024-514590-22-00, STOP-DCI), an interventional, randomized, double-blind, placebo-controlled, multiple ascending-dose, first-in-human trial to determine safety and evaluate clinical outcome for the MEK 1/2 inhibitor EDV2209 in patients with severe spontaneous subarachnoid hemorrhage (SAH). In Phase 1b ( N = 11), three cohorts received a single intracerebral ventricular (ICV) bolus (8.55 µg, 17–28.5 µg). In Phase 2a ( N = 16), two cohorts were given three ICV injections of 28.5 µg EDV2209 or placebo over 18 h, beginning within 8 h of SAH onset. The study found an equal distribution of adverse events between treatment and placebo with no treatment-associated safety concerns. Outcomes and mortality were as expected or better for patients with severe SAH in the patients treated with EDV2209. Pharmacokinetics were reproducibly stable in the CSF with no detectable levels of EDV2209 in plasma. Treatment with EDV2209 was considered safe and was interpreted to provide potential benefit for improving patient outcome following severe SAH. These results provide a rationale to continue with a Phase 2b / 3 study powered to determine efficacy as well as safety.

DNA methylation-based classification is increasingly a cornerstone of CNS tumor diagnostics. Recently,nanopore sequencing enables very rapid methylation profiling to support surgical decision making. Time-constrained sequencing yields sparse methylation profiles, necessitating specialized classifiers for accurate predictions. All publicly available sparse-profile classifiers rely on a single reference set of only 2,801 samples published in 2018 and its accompanying classification system. Here we present Sturgeon V2, trained on nearly 10,000 methylation profiles assembled from a range of public repositories and collaborations. To harmonize differences in tumor class labels, we developed an iterative semi-supervised relabeling strategy with a two-tiered concordance filter. We demonstrate that this filtering is essential for optimal performance. Compared to Sturgeon V1, we further redesigned the classifier architecture to provide more stable, and consistent confidence estimates while accumulating sequencing data and we introduce an updated class system including new classes, such as meningioma subtypes, PATZ-fusion neuroepithelial tumors and PLAG1/2-amplified embryonal tumors. In a retrospective intraoperative cohort of 94 pediatric cases, Sturgeon V2 was confidently correct in 85 cases (Sturgeon V1: 78) with one confident misclassification, and in simulated sequencing runs (n=1880) reduced the error rate among confident calls from 7.1% to 2.8%, outperforming publicly available alternatives. Sturgeon V2 is the first openly available, locally executable classifier for sparse methylation profiles trained beyond the 2018 reference era.

BACKGROUND AND OBJECTIVES: Simpson grading remains the most widely used clinical classification of extent of resection in meningioma surgery, yet its relevance in modern neurosurgical practice remains debated. The aim was to evaluate whether Simpson grading is associated with recurrence risk after gross total resection (GTR) of intracranial meningiomas within the context of tumor biology and anatomic location. METHODS: We analyzed 4074 patients undergoing GTR (Simpson grades 1-3) for primary intracranial meningioma, compiling data from 42 institutions worldwide. Cumulative incidence of recurrence was estimated using Aalen-Johansen methods. Multivariable inverse probability of censoring weighted logistic regression models were used to estimate adjusted recurrence risks at 5 and 10 years, adjusting for age, sex, World Health Organization (WHO) grade, Ki-67 proliferation index, and healthcare system setting. RESULTS: Higher Simpson grades were consistently associated with increased recurrence risk in WHO-1 and WHO-2. Among WHO-1, Simpson grade 2 had more than twice the recurrence odds compared with grade 1 at 5 years, whereas grade 3 showed even higher odds ratio of 3.47 (95% CI, 1.98-6.08). Similar patterns were observed in WHO-2 tumors. Interaction analyses suggested that differences between Simpson grades increase with higher Ki-67 proliferation indices. The prognostic significance of Simpson grade varied across anatomic locations, with clear associations observed for convexity and skull-base meningiomas, but limited relevance for parasagittal/falx meningiomas irrespective of WHO grade. CONCLUSION: Simpson grading remained strongly associated with recurrence after GTR. These findings suggest that the extent of dural and bony clearance remains clinically relevant; however, Simpson grading should be contextualized within tumor biology and anatomic constraints. Future recurrence models integrating molecular and surgical variables may refine prognostic frameworks rather than current standalone classification systems.

Purpose: Recurrence risk estimates underpin meningioma research, including molecular classification and clinical trial benchmarking, yet are often based on retrospective or historical data. The aim of this study was to assess the variation of recurrence risk estimates across calendar periods, WHO classification editions, geographical settings, and healthcare systems.thetermine Methods: We analyzed 4,111 patients with primary WHO-1/-2 meningiomas from 31 centers in 15 countries (1990–2019). Recurrence was defined according to local radiological assessment. The 5- and 10-year recurrence risks were estimated using regression standardization with inverse probability of censoring weights, adjusting for key clinical, surgical, and histopathological variables. Results: Recurrence risk estimates varied across all domains examined. More recent calendar periods were associated with higher predicted recurrence risk, particularly for WHO-2 at 5 years (e.g., ≥ 2013 vs. ≤ 2007: RR 1.60, 95% CI 1.19–2.01). Differences were also observed across healthcare systems and geographical settings despite adjustment. In contrast, recurrence risk estimates were broadly comparable between WHO classification editions (2007 vs. 2016). Cohort-level visualization revealed substantial heterogeneity in follow-up duration, inclusion patterns, and recurrence detection. Conclusions: Recurrence risk estimates are not stable across time or settings and are influenced by several patterns, particularly data accrual patterns. Recurrence events are inherently “locked” to the historical context in which they were detected, which may have important implications for developing molecular classifiers using retrospective specimens and clinical trials relying on benchmark established in historical settings. We propose transparent visualization of observational cohort composition and individual-level event timing to improve interpretability and comparability.

Background: Persons with lived experiences are a valuable resource to ensure that support interventions are grounded in real-world needs and thereby become relevant, acceptable, and impactful. The aim of this study is 2-folded: (1) to design a supportive group-based intervention for caregivers of patients diagnosed with glioblastoma with user involvement and (2) to evaluate the user involvement process. Methods: An intervention development study using Patient and Public Involvement (PPI) engaged caregivers in the design of a supportive intervention for caregivers. The Workbook to Guide the Development of a Patient Engagement in Research Plan served as a guide for the PPI process and collaboration between a caregiver panel and the researcher team. The process was evaluated using a multi-methods approach, including quantitative and qualitative data. Results: A national panel of current- and bereaved caregivers (n = 10) was recruited from the Danish Brain Tumour Association. A multicomponent online intervention was developed during a 2-year PPI-process shaped by the panel members’ lived experiences. Participants evaluated engagement as highly meaningful, with an overall mean score of 94.9% (range 85.2%-100%). The qualitative findings supported the positive results, describing the process as well-structured, meaningful, and valuable for the participating caregivers. Conclusion: The study demonstrated successful engagement of neuro-oncology caregivers in a long-term, structured PPI process. Despite emotionally demanding life circumstances, including disease progression and bereavement, panel members consistently maintained their engagement in the panel. PPI was a resource-intensive process; however, the added value included enhancing relevance, strengthening population-targeted intervention design, and ensuring that lived experiences meaningfully shaped the supportive intervention.

Background: Intracranial meningiomas are associated with substantial psychological morbidity. We aimed to characterize patients’ subjective experience of their disease trajectories. Methods: We conducted an exploratory interview study. Ten adults with meningioma participated in semistructured interviews 6-36 months post-diagnosis. Data were analyzed using Braun and Clarke’s Reflexive Thematic Analysis. Results: Patients consistently framed meningioma as a recurrent threat, with 3 temporal anchors: diagnosis, surgery, and long-term postoperative surveillance. Threat encompassed identity, daily functioning, and bodily trust, with persistent uncertainty. Coping strategies included humor, social connectedness, and structured rehabilitation, whereas avoidance and internet searching often amplified distress. Clinical conversations could reframe the threat and restore a sense of safety. Conclusions: Intracranial meningioma is commonly experienced as a persistent, multifaceted threat. Care pathways should incorporate crisis-informed communication, expectation-setting regarding prognosis and surveillance, and distress triage using validated tools to align clinical care with lived experience and help prevent a smoldering crisis in patients and families.

Purpose: The Ki-67 proliferation index (Ki-67 PI) has been associated with meningioma recurrence, yet its clinical utility remains debated. Whether Ki-67 PI provides prognostic information across subgroups defined by both WHO grade and extent of resection remains to be investigated. Methods: We analyzed 5,050 patients with intracranial meningiomas from the international PERNS cohort (42 centers, diagnosed between 1989–2019) who underwent surgical resection without postoperative radiotherapy. Ki-67 PI prognostic accuracy was assessed up to 10 years postoperatively by using ROC analyses and estimating its association with the risk of recurrence. Results: Results demonstrated that the prognostic value of Ki-67 PI differed by subgroups defined by WHO grade and Simpson grade. For patients with the same Simpson grade (1–3), the predictive accuracy of Ki-67 PI for 10-year recurrence risk was stronger in WHO-2 than in WHO-1. Within WHO-1 and WHO-2 meningiomas, the predictive accuracy of Ki-67 PI increased with higher Simpson grade (1–3). However, no predictive value was observed in Simpson grade 4 resections regardless of WHO grade. Conclusion: These findings highlight that Ki-67 PI should be interpreted in the context of both WHO grade and extent of resection, and, if done so, may offer potential value to refine individualized surveillance strategies in meningioma patients with gross total resection in the initial 10-year postoperative timeframe. Findings cannot be extrapolated beyond 10 years, which may be particularly relevant for WHO-1 tumors with low Ki-67 PI and Simpson grade 1 resection.

Background: Caregivers to a person diagnosed with a glioblastoma often face significant responsibilities, balancing the demands of care with the complexities of the disease and treatment trajectory, while also coping with concerns and uncertainty of the future. Caregivers report unmet needs of information and support throughout the patient’s disease and treatment trajectory, and they may benefit from targeted supportive care interventions. Objective: The aim of this study is to develop, test, and evaluate the feasibility of a supportive group intervention among caregivers to patients diagnosed with a glioblastoma. Methods: The study consists of 3 phases with ongoing patient and public involvement (PPI). In the first phase, a systematic review will be carried out exploring the outcome of supportive group interventions for caregivers to patients diagnosed with a primary brain tumor. In the second phase, the design and development of the intervention will be conducted in cooperation with a panel of caregivers using PPI process. The third phase will include the feasibility and evaluation of the intervention. The study will be guided by the British Medical Research Council’s framework for developing complex interventions. The feasibility of the intervention will be tested in reference to relevant parameters. Quantitative data in terms of questionnaires will be analyzed using descriptive statistics, and qualitative evaluation interviews will be analyzed using thematic analysis. Results: A national panel of caregivers (N=10) has been established, and the final design of the intervention is currently developed through an ongoing PPI process. A total of 3 hospitals in Denmark have committed to participating in the recruitment for the feasibility study. Recruitment began in April 2025, and the SUGRI (Supportive Group Intervention for caregivers to patients diagnosed with a glioblastoma) intervention will undergo a feasibility assessment in a multicenter study starting in August 2025, with the final evaluation planned for April 2026. Conclusions: This study is expected to provide necessary insights to guide caregiver initiatives, ultimately improving support for caregivers within the neuro-oncology field. A supportive group intervention offered to the caregivers has the potential to address specific caregiver needs and strengthen their supportive network. Providing caregivers with support may enhance their perceived support, strengthen family functioning, and provide them with strategies to manage caregiving challenges, ultimately benefiting both caregivers and patients. Trial Registration: ClinicalTrials.gov NCT06869577; https://clinicaltrials.gov/study/NCT06869577 International Registered Report Identifier (IRRID): PRR1-10.2196/81948