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The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12 + endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation. Recent studies show that targeting CXCL12 can improve the effect of radiotherapy (RT) in preclinical models of glioblastoma (GBM). Here, the authors report the safety and preliminary efficacy of a phase I/II clinical trial investigating an L-RNA aptamer-based CXCL12 inhibitor (NOX-A12) in combination with RT in patients with newly-diagnosed GBM.

Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicentric phase 1/2 trial (NCT04121455), which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT promoter methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose, recommended phase 2 dose, NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life, median progression-free survival (PFS), 6-months PFS and overall survival (OS). For the expansion arm, six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTB high ) and delayed tumor regrowth as per mRANO. Median progression-free (PFS) and overall survival (OS) after RT + BEV + NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT + NOX-A12 ( p  = 0.009; p  = 0.021) in a post-hoc comparative analysis, with two patients exceeding 2-year OS. These findings establish proof-of-principle for dual inhibition of CXCL12 and VEGF in patients with newly-diagnosed GBM following RT. Recently, the dose escalation stage of the GLORIA trial investigating NOX-A12 (L-RNA aptamer-based CXCL12 inhibitor) in combination with radiotherapy in patients with glioblastoma was reported. Here, the authors report the preclinical rationale and an expansion arm of the GLORIA trial combining NOX-A12, radiotherapy and bevacizumab (anti-VEGF) in patients with newly diagnosed glioblastoma.

Glioblastomas (GBM) can recur in different ways. While local recurrence is most common, some GBM recur at distant sites or simultaneously at multiple sites. However, the consequences of different regrowth patterns for the clinical course and the factors that might influence regrowth patterns or different modalities of recurrence remain unclear. We wondered (1) whether a more accurate analysis of regrowth patterns helps to detect subgroups of GBM patients, (2) if evaluation of relapse patterns correlates with differences in survival, and (4) whether we can identify predictors for distinct regrowth patterns. Therefore, we retrospectively collected demographic data, as well as tumor‐ and patient‐characteristics, from 251 patients treated at two institutions and characterized their recurrence patterns by analyzing Magnetic Resonance Imaging data. We observed distinct differences in patients' overall and progression‐free survival with respect to multicentric and multifocal recurrences, further supporting the hypothesis that these recurrences develop differently. Several tumor relapse patterns were associated with patients' progression‐free and overall survival (e.g., unifocal local and multicentric recurrences; p < 0.05), even when other known prognostic factors were taken into account. TTFields were associated with prolonged progression‐free survival (mPFS 7.2 months vs. 4.8 months, p = 0.03). They were predictive of a higher frequency of non‐local recurrence patterns (OR 0.16, p = 0.02) and longer time to development of a local recurrence after subtotal tumor resection (mPFS 11.1 months vs. 5.2 months; p = 0.01). This can be interpreted as a sign of improved local control. Multiple glioblastoma relapse patterns were associated with patients' progression‐free and overall survival, even when other known prognostic factors were taken into account. Treatment with Tumor Treating Fields was associated with prolonged progression‐free survival and predictive for a higher frequency of non‐local recurrence patterns after subtotal tumor resection, most likely due to improved local control.

Introduction Prior research has identified temporal muscle thickness (TMT) as a prognostic marker in glioblastoma. Nonetheless, implementation in daily clinical practice is complicated due to the heterogeneity of previous studies. We performed a multicentric analysis aiming to validate recently proposed sex‐specific cutoff values using a homogeneous cohort of newly diagnosed MGMT promoter methylated glioblastoma patients; we included a balanced control cohort for comparison. Materials and Methods TMT was measured at baseline using the initial preoperative/postoperative magnetic resonance images (MRIs) and in disease course using the first MRI after radiotherapy. Patients were divided by sex and TMT into “at risk of sarcopenia” or “normal muscle status.” Kaplan–Meier and multivariable Cox regression analysis was used for survival correlation. Results In total, n = 126 patients were included (n = 66 treated with CCNU/temozolomide, n = 60 with single‐drug temozolomide). Patients with normal muscle mass at baseline had significantly prolonged survival (median overall survival: 44.2 months versus 16.7 months with CCNU/temozolomide, and 29.5 months versus 17.4 months with single‐drug temozolomide) compared to those at risk of sarcopenia. In a multivariable Cox regression analysis, normal muscle mass and an initial age at diagnosis of < 50 years emerged as significant prognostic markers. Longitudinally, survival was longest in patients with lack of TMT decline over the disease course. Discussion This analysis confirms TMT as an important prognostic marker in glioblastoma in two real‐life cohorts. However, in order to establish TMT assessment as a routine marker for patient selection and therapeutic measures, further validation in prospective controlled trials is necessary.

Introduction Olfactory impairment is common in glioblastoma and has been associated with unfavorable overall survival. However, prior studies were limited by imbalances in key prognostic factors and the absence of longitudinal olfactory assessments to evaluate treatment-related neurotoxicity. The aim of the study is to determine whether olfactory function serves as an independent prognostic marker for survival, neurocognitive outcomes, and quality of life in glioblastoma. Methods Prospective, multicenter cohort study enrolling 64 glioblastoma patients and 64 matched healthy controls. Patients are stratified by extent of resection, O6-Methylguanine-DNA Methyltransferase promoter methylation, radiographic involvement of olfactory regions, baseline olfactory status, age, and Karnofsky performance status. Olfactory function is assessed serially using Sniffin’ Sticks (identification and threshold tests) from diagnosis through treatment. Coronal T2- and T1-weighted MRI scans are reviewed independently by two blinded neuroradiologists to detect olfactory region involvement. Neurocognitive testing, psychosocial screening, and quality of life assessments are conducted at defined intervals. Next-generation sequencing from tumor tissue is employed to explore molecular underpinnings of hyposmia. Blood samples are collected in every study visit for potential parallel translational studies. Perspective This is the first longitudinal study evaluating olfactory function as a prognostic biomarker in glioblastoma. Findings may inform risk stratification, guide neuroprotective strategies, and improve survivorship care. Trial registration ClinicalTrials.gov, NCT06954636, date of registration 04-16-2025 (retrospectively registered); https://clinicaltrials.gov/study/NCT06954636?cond=glioblastoma&intr=olfactory&rank=1 .

An imbalanced T-cell homeostasis plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Co-stimulatory and co-inhibitory molecules regulate T-cell differentiation, survival, and cytokine production. B- and T-lymphocyte attenuator (BTLA) is a co-inhibitory molecule which negatively regulates T-cell activation. The aim of this study was to investigate BTLA expression on regulatory and effector CD4+ T-cells in SLE patients with and without lupus nephritis (LN) during active and inactive disease. Therefore, peripheral blood of forty-one SLE patients and twenty-one healthy controls (HC) was phenotypically analyzed. Next, ex vivo stimulated T-cells were analyzed for the expression of BTLA on Th1-, Th2-, and Th17-effector cells by flow cytometry. Renal involvement was defined as biopsy-proven LN. Disease activity was assessed by SLE disease activity index (SLEDAI). Percentages of peripheral unstimulated BTLA+ CD4+ T-cells were significantly decreased in SLE patients with active disease. However, ex vivo stimulated Th1, Th2, and Th17 effector T-cells, expressed increased percentages of BTLA expression in active disease. In contrast, the BTLA expression on CD4+CD25++CD127− regulatory T-cells was not significantly different. BTLA seems to be an important co-inhibitory molecule in the T-cell homeostasis of patients with systemic lupus erythematosus and crucial for disease activity.

Purpose We present the case of a 24-year-old male with CNS granulomatosis due to an immunodeficiency syndrome which was identified as deficiency of adenosine deaminase 2 (DADA2) as a cause of brainstem infarction. Methods Case report and detailed description of the clinical course of diagnosis and treatment. Case The patient’s medical history consisted of an unknown immunodeficiency syndrome. Based on former findings, common variable immunodeficiency (CVID) was diagnosed. The patient suffered from three consecutive brainstem strokes of unknown etiology within 3 years. An MRI scan detected gadolinium-enhancing, granulomatous-suspect lesions in the interpeduncular cistern, temporal lobe, and tegmentum. Laboratory analysis was compatible with CVID, with leukopenia and immunoglobulin deficiency. Because granulomatous CNS inflammation was suspected, the patient received methylprednisolone immunosuppressive therapy, which led to partially regressive MRI lesions. However, in contrast to imaging, the patient showed a progressive cerebellar syndrome, indicating plasma exchange therapy and immunoglobulin treatment, which led to rapid symptom amelioration. After a relapse and a further stroke, expanded analysis confirmed DADA2 (and not CVID) as the inflammatory cause for recurrent stroke. After starting the therapy with immunoglobulins and adalimumab, no further strokes occurred. Conclusion We present the case of a young adult with diagnosis of DADA2 as a cause for recurrent strokes due to vasculitis. This stroke etiology is rare but should be considered as a cause of recurrent stroke of unknown origin in young patients to avoid a disabling disease course by disease-specific treatment options.

PurposeIn the EF-14 trial for newly diagnosed glioblastoma (ndGBM) patients addition of Tumour Treating Fields (TTFields) to temozolomide treatment resulted in a significantly improved overall survival (OS). In the NOA-09/CeTeG trial, combination of lomustine and temozolomide was superior to temozolomide monotherapy in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylated (MGMTm) ndGBM. We evaluated combination of these two treatment modalities in patients with MGMTm ndGBM. There have been so far no data on the combination of these two efficient regimens.MethodsThis bicentric retrospective analysis investigated 16 patients. Parameters evaluated included safety outcome as measured by Common Toxicity Criteria for Adverse Events (CTCAE), clinical outcomes, and compliance to treatment.ResultsHematologic adverse events CTCAE ≥ 3 were observed in seven, hepatotoxic adverse events of CTCAE ≥ 3 in four patients. Mild to moderate skin toxicity was detected in six patients. At data cutoff, patients demonstrated a median progression-free survival (PFS) of 20 months. The usage rate of TTFields showed a high median adherence (83%) to the therapy.ConclusionsThis analysis provides first indication that the combination of TTFields/lomustine/temozolomide is safe and feasible. The observed survival outcomes might suggest potential beneficial effects.

Purpose When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse. Methods We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic target of rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted. Results The investigation included 41 patients, of whom 32 had isocitrate dehydrogenase ( IDH ) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p  = 0.0057; mOS: 13.0 versus 4.3 months, p  = 0.0357). Conclusion These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider the prevalence and persistence of actionable molecular alterations in patient tissue.

Background: Patients with primary brain tumors face profound disease- and treatment-related immunosuppression, placing them at high risk for severe infections. Their capacity to mount protective immune responses to vaccination, particularly to repeated antigen exposures such as COVID-19 boosters, remains critically under-defined, leading to uncertainty in clinical practice. Methods: In this prospective cohort study, we analyzed humoral responses to seasonal COVID-19 (mRNA-based) and influenza vaccination in 17 patients with primary brain tumors (recruited from an initial cohort of 37) who received a booster shot, and 19 healthy controls. Serum samples were collected before (T1) and 30 ± 2 days after (T2) vaccination to quantify SARS-CoV-2 anti-Spike (S) IgG and anti-Influenza IgG titers. Results: Despite ongoing chemotherapy in 47% of patients, baseline anti-S antibody titers were comparable between groups. Following the booster, median anti-S titers increased significantly and to a similar magnitude in both patients (from 5030 to 18,500 BAU/mL; IQR: 13,885–24,420) and controls (from 4429 to 20,200 BAU/mL; IQR: 11,075–26,680; p = 0.6137, Mann–Whitney U test). Only two heavily pre-treated patients showed no booster response. All participants showed sero-positivity to Anti-Influenza IgG at baseline. For the primary brain tumor cohort, a significant increase for anti-Influenza IgG at T2 was observed (p = 0.0002). Mean antibody titers did not differ between both cohorts. Conclusions: Our findings provide evidence that patients with primary brain tumors can mount robust recall immunity to mRNA vaccines, addressing clinical uncertainty about booster efficacy in this population. These data provide a strong rationale for prioritizing booster vaccinations in this vulnerable population and argue for the inclusion of these patients in future pivotal vaccine trials.