BackgroundPerioperative immune checkpoint inhibition (ICI) has moved from investigational window studies to phase III supported strategies for resectable, locally advanced head and neck squamous cell carcinoma (HNSCC), with direct consequences for surgical timing, neck management, reconstruction and pathology workflows.MethodsWe performed a narrative review of phase III perioperative trials and key neoadjuvant studies in resectable HNSCC, focusing on outcomes and practical questions most relevant to surgeons and multidisciplinary teams (MDTs): pathway timing and attrition, operability, perioperative safety and feasibility of standardized response assessment.ResultsPhase III evidence supports two complementary perioperative approaches: (i) neoadjuvant PD-1 priming followed by surgery and risk−adapted postoperative radiotherapy/chemoradiotherapy with continued PD-1 blockade, improving event−free survival compared with standard care; and (ii) postoperative nivolumab added to adjuvant chemoradiotherapy in patients with pathological high−risk features, improving disease−free survival. Across neoadjuvant programs, short preoperative ICI exposure was generally feasible without compromising resectability but requires protected timelines to avoid delays to curative treatment. Key surgical considerations include management of the tumor−draining lymph nodes, anticipation of immune−related adverse events affecting wound healing and rehabilitation, and coordination of treatment with systemic therapy. Pathologic response, preferably reported as percent residual viable tumor separately in the primary tumor bed and nodal compartments, is currently the most widely used endpoint and a prerequisite for response−adapted de−escalation or escalation studies.ConclusionPerioperative ICI turns curative−intent HNSCC care into a tightly timed program. Successful implementation will depend on standardized pathology and radiology workflows, MDT−owned scheduling and prospective registries to define optimal sequencing and salvage after perioperative PD-1 exposure.

BACKGROUND/OBJECTIVES:Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, characterized by inevitable recurrence, extensive inter-and intratumoral heterogeneity, and resistance to current therapies. A defining feature of GBM is the dynamic interplay between malignant cells and a diverse tumor microenvironment (TME), which together drive disease progression, therapeutic adaptation, and relapse. Understanding these complex cellular ecosystems has therefore become a major focus of glioblastoma research. Recent advances in spatial omics technologies have transformed our ability to investigate GBM biology directly within intact tissue architectures. Over the past five years, an expanding array of spatial transcriptomic, proteomic, and multi-omic platforms has enabled high-dimensional characterization of cellular states, cell-cell interactions, and tissue niches while preserving spatial context. These approaches have generated unprecedented insights into tumor organization, cellular plasticity, immune landscapes, vascular niches, and treatment-induced ecosystem remodeling. METHODS:In this review, we provide an overview of spatial omics applications in glioblastoma research so far. RESULTS:We summarize the technologies employed, the types and numbers of patient samples analyzed, and the major biological and clinical insights generated. We compare the strengths and limitations of different spatial platforms, discuss key considerations for study design and data interpretation, and highlight emerging trends in multimodal and longitudinal analyses. CONCLUSIONS:By integrating both technological and biological perspectives, this review serves as a practical resource for researchers seeking to implement spatial omics approaches in glioblastoma studies and to advance precision neuro-oncology.

BackgroundHuman papillomavirus (HPV) has substantially altered the epidemiology and prognosis of oropharyngeal squamous cell carcinomas (OPSCC), with an increasing incidence in younger patients and markedly improved survival outcomes. This shift presents an increasing clinical challenge: how to safely reduce treatment intensity, while maintaining cure and survival rates and minimizing therapy-related toxicity. Transoral robotic surgery (TORS) has emerged as a pivotal strategy in this context, with multiple clinical trials demonstrating promising outcomes. This review aims to summarize registered clinical trials evaluating TORS in OPSCC, identify existing gaps in the literature, and highlight directions for future research.MethodsA systematic search of ClinicalTrials.gov was conducted between May 2024 and January 2026 using the search terms “TORS” and “transoral robotic surgery.” The search included completed and analyzed studies, as well as completed but unanalyzed, ongoing or planned studies. Relevant publications were retrieved from databases including ClinicalTrials.gov, PubMed and The Cochrane Library. As this study was based on publicly available literature and trial registries, ethical committee approval was not required.ResultsA total of 51 clinical trials were identified. We retrieved a total of 23 publications and 3 abstracts. Across these studies, TORS demonstrated oncologic outcomes comparable to radiotherapy in early-stage OPSCC, with distinct but generally acceptable toxicity profiles. Several trials supported the feasibility of treatment de-escalation, including reduced-dose or omission of adjuvant radiotherapy in carefully selected HPV-positive patients, without compromising survival outcomes. Emerging evidence from biomarker-driven studies suggests that circulating cell-free HPV DNA (cfHPVDNA) may enable improved risk stratification and guide personalized de-intensification strategies. In addition, optimization studies indicate that advances in perioperative management and robotic technology may further improve functional outcomes, although high-quality evidence remains limited. Five key areas of research were identified, namely the optimization strategies, TORS as an alternative strategy, TORS for de-escalation, biomarker-driven de-escalation, and induction therapy.ConclusionTransoral robotic surgery demonstrates favorable oncological and functional outcomes, supporting its role as a de-intensification strategy in carefully selected patients with OPSCC. The integration of robust risk stratification methods, including biomarkers such as circulating cell-free HPV DNA (cfHPVDNA), holds promise for optimizing patient selection and tailoring treatment intensity. Continued advancements in robotic technology, along with the development of refined perioperative pain management strategies, may further enhance surgical precision and postoperative recovery.

Fluorine-18-labeled somatostatin receptor (SSTR) tracers are increasingly adopted as an alternative to generator-produced gallium-68 compounds for imaging neuroendocrine neoplasms (NENs). While [¹⁸F]AlF-NOTA-octreotide ([¹⁸F]AlF-OC) has shown comparable or even superior diagnostic performance in controlled clinical studies, real-world evidence remains limited, particularly for underrepresented NEN subtypes. This study evaluates the clinical implementation, biodistribution, and uptake characteristics of [¹⁸F]AlF-OC PET/CT in routine practice across the full NEN spectrum. In this retrospective single-center analysis, all patients referred for SSTR PET/CT between March 2023 and January 2024 were included. Relevant clinical and demographic data, along with procedural details, were collected. Lesions were segmented semi-automatically using MIM version 7.3.4 and quantitatively assessed. Uptake patterns were analyzed according to tumor grade, primary tumor origin, organ site and clinical indication. A total of 322 scans were performed in 288 patients (median age 64 years). The cohort included 93 Grade 1 (G1), 84 G2, 17 G3 NETs and 3 neuroendocrine carcinomas of gastroenteropancreatic (GEP) or unknown origin, alongside 15 phaeochromocytoma/paraganglioma (PPGL) cases and 40 lung NETs. In total, 4,677 lesions were evaluated. Mean injected activity was 208.5 ± 73.6 MBq with an average uptake time of 121 ± 14 min. G3 NETs demonstrated sufficient uptake (mean SUVmax 19.0), comparable to low-grade NETs. Uptake varied by primary origin, with the highest mean SUVmax values observed in gastric (53.3), sigmoidal (22.0), rectal (20.5), small intestinal (19.1) and pancreatic NETs (17.1). Lung NETs (17.0) also have comparable uptake. Strong tracer avidity was observed in lesions within the liver (19.8) and bone (12.1). Physiological distribution was consistent with known SSTR-expressing tissues. This large real-world series confirms that [¹⁸F]AlF-OC PET/CT is a robust and broadly applicable SSTR imaging modality across diverse NEN subtypes, including tumor groups traditionally underrepresented in prospective trials of SSTR tracers. The tracer demonstrates reliable uptake across grades and organ sites, supporting its routine clinical use as a practical, high-throughput alternative to ⁶⁸Ga-labeled SSAs.

Purpose Fluorine-18-labeled somatostatin receptor (SSTR) tracers are increasingly adopted as an alternative to generator-produced gallium-68 compounds for imaging neuroendocrine neoplasms (NENs). While [& sup1;F-8]AlF-NOTA-octreotide ([& sup1;F-8]AlF-OC) has shown comparable or even superior diagnostic performance in controlled clinical studies, real-world evidence remains limited, particularly for underrepresented NEN subtypes. This study evaluates the clinical implementation, biodistribution, and uptake characteristics of [& sup1;F-8]AlF-OC PET/CT in routine practice across the full NEN spectrum. Materials and methods In this retrospective single-center analysis, all patients referred for SSTR PET/CT between March 2023 and January 2024 were included. Relevant clinical and demographic data, along with procedural details, were collected. Lesions were segmented semi-automatically using MIM version 7.3.4 and quantitatively assessed. Uptake patterns were analyzed according to tumor grade, primary tumor origin, organ site and clinical indication. Results A total of 322 scans were performed in 288 patients (median age 64 years). The cohort included 93 Grade 1 (G1), 84 G2, 17 G3 NETs and 3 neuroendocrine carcinomas of gastroenteropancreatic (GEP) or unknown origin, alongside 15 phaeochromocytoma/paraganglioma (PPGL) cases and 40 lung NETs. In total, 4,677 lesions were evaluated. Mean injected activity was 208.5 +/- 73.6 MBq with an average uptake time of 121 +/- 14 min. G3 NETs demonstrated sufficient uptake (mean SUVmax 19.0), comparable to low-grade NETs. Uptake varied by primary origin, with the highest mean SUVmax values observed in gastric (53.3), sigmoidal (22.0), rectal (20.5), small intestinal (19.1) and pancreatic NETs (17.1). Lung NETs (17.0) also have comparable uptake. Strong tracer avidity was observed in lesions within the liver (19.8) and bone (12.1). Physiological distribution was consistent with known SSTR-expressing tissues. Conclusion This large real-world series confirms that [& sup1;F-8]AlF-OC PET/CT is a robust and broadly applicable SSTR imaging modality across diverse NEN subtypes, including tumor groups traditionally underrepresented in prospective trials of SSTR tracers. The tracer demonstrates reliable uptake across grades and organ sites, supporting its routine clinical use as a practical, high-throughput alternative to Ga-6(8)-labeled SSAs.

BackgroundPatients with glioblastoma experience a substantial symptom burden that negatively affects functioning in daily life. Symptoms frequently co-occur and may form symptom clusters, yet the robustness, generalizability, and temporal stability of these clusters remain insufficiently studied. This is particularly relevant given the dynamic disease course and treatment-related effects in glioblastoma.MethodsWe used data from the CODAGLIO 2.0 database, comprising adult patients with newly diagnosed or recurrent glioblastoma from seven randomized controlled trials not included in previous clustering studies. Symptoms were assessed using 18 symptom scales from EORTC QLQ-C30 and QLQ-BN20 questionnaires at baseline and 3-month follow-up. Symptom prevalence and multi-symptom co-occurrence were described. Symptom clusters were identified using Spearman correlations, partial correlations, and hierarchical cluster analysis and compared with previously reported clusters. Cluster stability over time was evaluated using cophenetic correlation, tanglegrams, entanglement, and adjusted Rand index scores.ResultsAmong 1,795 patients with baseline HRQoL data, 1678 patients (94%) reported multi-symptom co-occurrence at baseline and 1045 patients (96%) at follow-up. Fatigue, communication deficits, motor dysfunction, drowsiness, insomnia, and visual disorder were most prevalent. Four clinically meaningful symptom clusters were identified: pain–headache, motor dysfunction–weakness of the legs, fatigue–drowsiness, and a seizure-related cluster. These clusters largely aligned with previously reported findings and showed moderate stability over time (cophenetic correlation 0.84; adjusted Rand index 0.41), with greatest variability observed in seizure-related symptoms.ConclusionSymptom clusters in glioblastoma are robust yet dynamic. Incorporating cluster-based and longitudinal symptom assessment may enhance symptom monitoring and support more personalized supportive care strategies.

OBJECTIVES:Tumour treating fields (TTF) improve survival in newly diagnosed glioblastoma (GBM) in randomized trials, but real-world impact in Belgium remains unclear due to limited access and lack of reimbursement. This study evaluates progression-free survival (PFS) and overall survival (OS) in Belgian patients with newly diagnosed GBM treated with TTF alongside standard therapy. METHODS:We conducted a retrospective single-centre cohort study at UZ Leuven including patients with histologically confirmed newly diagnosed GBM treated with TTF between April 2019 and July 2026. TTF was initiated during adjuvant temozolomide. Clinical, molecular and treatment data were extracted from institutional records. Primary outcomes were PFS and OS from diagnosis. Kaplan-Meier survival analyses were performed, including subgroup analyses by MGMT status, device adherence (>75%), and extent of resection. RESULTS:Twenty-eight patients were analysed (median age 52 years; 71% male). MGMT promoter methylation was present in 29% and gross total resection was achieved in 50%. Adherence exceeded 75% in 96%. Median PFS was 6.8 months and median OS 24.6 months, comparing favourably with EF-14 outcomes. ECOG status predicted survival (p = 0.04). Survival was not associated with MGMT status or adherence. Gross total resection showed a clinically meaningful association with improved OS (30.7 vs 8.2 months; p = 0.07). Treatment was well tolerated. CONCLUSION:In this real-world Belgian cohort, TTF with standard therapy yielded survival outcomes consistent with or exceeding pivotal trials. While clinical benefit appears evident, implementation remains challenged by financial costs. Further prospective Belgian studies are needed to assess cost-effectiveness and quality-of-life impact.

Background Central nervous system (CNS) metastases represent a complication in solid tumors and often harbour unique genomic alterations diverging from those in primary tumor tissue or plasma; however, direct sampling of CNS lesions carries procedural risks, limiting its molecular profiling. The main aim of the present analysis was to assess the feasibility of Cerebrospinal Fluid (CSF) ctDNA profiling and to descriptively compare genomic alterations detected in matched tumor tissue, plasma, and CSF samples, including in patients with leptomeningeal metastases (LM). Patients and methods BrainStorm (NCT04109131) is a prospective, international, multicenter study enrolling patients at high risk of developing CNS metastases from different solid tumors. In the present analysis, we evaluated matched samples of tumor tissue, plasma, and CSF ctDNA from patients who developed CNS metastases. Tumor tissue was profiled using the OncoDEEP® 638-gene NGS panel, while matched plasma and CSF ctDNA were sequenced with OncoFOLLOW® tumor-informed panel (plus 50 hotspot genes). Descriptive statistics and Jaccard index-based concordance analyses were performed to compare mutational profiles across compartments. Results CSF ctDNA was detectable in 21 out of the 25 evaluable CSF samples (84%) and in 10 out of 11 patients with LM (91%). Overall concordance among genomic alterations in samples was 52% between tissue and plasma, 45% between tissue and CSF, and 75% between plasma and CSF. In the subset of 11 patients with LM, concordance was 39% (tissue-plasma), 42% (tissue-CSF) and 91% (plasma-CSF). Overall, seven alterations were identified exclusively in CSF (or CSF and tissue) but not in plasma, including variants in TP53, PIK3CA, and ERBB2. Conclusions These preliminary findings indicate that CSF ctDNA can provide a sensitive, compartment-specific molecular portrait of CNS disease, complementing plasma-based analyses, and supporting its integration as a minimally invasive tool to capture the evolving genomic landscape of CNS metastases. Clinical trial registration number NCT04109131

BACKGROUND:The CATNON trial investigated the benefit of the addition of concurrent or adjuvant temozolomide to radiotherapy in individuals with anaplastic astrocytoma. We report the long-term follow-up of the study focusing on the individuals with isocitrate dehydrogenase (IDH) mutated (IDHmt) tumours. METHODS:This randomised, open-label, phase 3 study in 137 institutions across Australia, Europe, and North America included participants aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Participants were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. The eighth amendment of the study protocol (June 27, 2011) incorporated analysis of IDH mutational status into the study. We report the intention-to-treat analysis and the exploratory analysis within the population of participants with astrocytoma with an IDH mutation. As the safety data have been published previously, no safety data are reported. This trial is registered with ClinicalTrials.gov, NCT00626990, and is completed. FINDINGS:Between Dec 4, 2007, and Sept 11, 2015, 1407 participants were registered and 751 participants were randomly allocated, 444 of whom were diagnosed with an IDHmt tumour. After a median follow-up for overall survival of 10·9 years (IQR 9·5-12·7), in the intention-to-treat population, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (hazard ratio [HR] 0·65 [95% CI 0·54-0·77]), but concurrent did not compared with no concurrent temozolomide (HR 0·91 [0·76-1·08]). In univariable analysis of the participants with an IDHmt tumour, concurrent temozolomide had no statistically significant effect on overall survival (median 9·7 years [8·2-12·5] vs 7·2 years [6·2-9·4]; HR 0·81 [0·63-1·04]), but median overall survival was 12·5 years (95% CI 9·4-15·0) with adjuvant temozolomide compared with 6·0 years (5·1-7·2) with no adjuvant temozolomide (HR 0·54 [0·42-0·69]). No benefit of temozolomide, neither concurrent nor adjuvant, was observed in participants with IDH wild-type tumours. Methylation-based subtyping and several DNA alterations (eg, amplification of PDGFRA and CDK4, homozygous deletion of CDKN2A, and total copy number variation) were associated with worse outcome, none of which was predictive for benefit to temozolomide. INTERPRETATION:Long-term follow-up confirms that radiotherapy followed by 12 cycles of adjuvant temozolomide without concurrent temozolomide during radiotherapy improves survival for individuals with aggressive IDHmt astrocytoma. FUNDING:MSD.

BACKGROUND:We assessed the clinical relevance of age and sex as risk factors for health-related quality of life (HRQoL) in patients with adult-type diffuse glioma. MATERIALS AND METHODS:The CODAGLIO 2.0 database contains 16 randomized trials from 5369 patients with glioma. Patients' HRQoL was assessed using EORTC QLQ-C30 and QLQ-BN20 questionnaires. In 8 HRQoL scales, we compared mean HRQoL at baseline with the general population and evaluated factors associated with HRQoL over time using linear mixed models (LMMs). We used the anchor-based minimally important difference to interpret clinically relevant changes. RESULTS:We included 4301 patients with baseline HRQoL followed up to 3 months. Compared to the general population, patients with glioma at baseline had statistically and clinically relevant worse HRQoL, which was still evident after stratifying by age and sex groups. In LMMs, compared to patients aged ≤60 years, those >60 years had statistically significant associations with worse physical functioning: -2.40 (95% confidence interval [CI] -4.14 to -0.71), better social: 4.88 (2.68-7.30) and role: 3.79 (1.39-6.16) functioning, and less fatigue: -3.43 (-5.44 to -1.33) and pain: -4.56 (-6.18 to -2.93). Compared to men, women had statistically significant associations with worse physical and social functioning and more fatigue and pain. Associations between age, sex, and HRQoL were not clinically relevant. Performance status had clinically relevant associations in 5/8 scales. CONCLUSION:Patients with glioma have clinically relevant worse HRQoL compared to the general population. There are statistically but not clinically significant associations between age, sex, and certain HRQoL scales.

Lists of differentially expressed genes in RNA-seq analyses of bulk biopsies

Background:Thymomas are thymic epithelial tumors (TETs) and the most common tumors of the anterior mediastinum. In the natural course of this malignancy, there is no tendency towards extrathoracic metastasis. This report describes an extremely rare case of splenic metastatic disease from a thymoma. Additionally, the patient developed Good's syndrome, a thymoma-associated immunological disorder which makes the patient vulnerable for opportunistic infections. This syndrome is generally treated with intravenous immunoglobulins. Case Description:The patient is an asymptomatic 73-year-old man of Caucasian origin without significant past medical history. He was diagnosed with an anterior mediastinal mass on computed tomography (CT) of the chest in the work-up of his newly diagnosed prostate carcinoma, which turned out to be a thymoma after surgical resection. During follow-up the patient developed a splenic lesion which was difficult to characterize. After laparoscopic splenectomy the diagnosis of metastatic thymoma was confirmed. Additionally, the patient developed Good's syndrome. Unfortunately, the patient died of associated infectious complications after thorough intensive care treatment. Conclusions:Metastatic splenic disease from a thymoma, further complicated by development of Good's syndrome is extremely rare and hitherto never described before. To anticipate possible infectious complications in patients with newly diagnosed thymoma, we advise to routinely check immunoglobulin levels in these patients.

The brain operates through networks of interconnected regions, which can be disrupted by glial tumors and their treatment. This study investigates associations between this altered functional network topology and cognition in gliomas. We studied 50 adult glioma survivors (>1-year posttherapy) and 50 healthy controls. Participants underwent cognitive assessments across six domains and an 8-min resting-state functional MRI. Based on the BOLD signal, partial correlations were computed among 78 brain regions. From their absolute values, whole-brain and nodal graph metrics were derived and normalized to random graphs. Group differences in whole-brain and nodal graph metrics were assessed with Mann-Whitney U tests and mixed-design analyses of variance, respectively. Metrics exhibiting significant intergroup differences were correlated with cognitive scores, with p bonf < 0.050 indicating significance. Among controls, 8 of 78 nodes were identified as hubs. Patients exhibited significantly higher whole-brain clustering, correlating with intelligence (r(98) = -0.409, p bonf < 0.001) and executive functioning (r(98) = 0.300, p bonf = 0.014). Lower centrality, higher nodal clustering, and assortativity were also observed in patients, particularly in hubs, correlating with language and executive functioning, respectively (all r(98) > 0.300, p bonf < 0.050). Glioma patients commonly experience cognitive deficits alongside posttreatment alterations in functional network topology. Alterations in clustering, assortativity, and centrality may specifically act as compensatory mechanisms, significantly influencing cognitive functioning.

Supplementary Figure 3: Characteristics of RTK1 tumors in comparison to RTK2 and MES. A Distribution of MGMT promotor methylation in main glioblastoma methylation subgroups. Classifier assignment is based on the v12.5 version (n = 295). Mutational profiles in B RTK1 tumors (n = 89), C RTK2 tumors (n = 140) and D MES tumors (n = 66).

Supplementary Table 1: Representativeness of study participants.

Lisavanbulin is a prodrug of the microtubule-targeting agent avanbulin. Both avanbulin and lisavanbulin have demonstrated significant antitumor activity in several preclinical tumor models including glioblastoma. Previous human studies demonstrated that 48-h infusions of intravenous lisavanbulin were well tolerated with preliminary activity in recurrent glioblastoma. The current phase 1/2a study evaluates the safety and tolerability of once-daily oral lisavanbulin in patients with solid tumors or recurrent glioblastoma or high-grade glioma. Lisavanbulin is associated with profound, durable responses in a subset of patients with recurrent refractory grade 4 astrocytoma or glioblastoma. We present here the clinical and translational results from this trial, including a description of a response-predictive molecular signature that warrants further exploration in these tumor types of significant unmet need. The study is registered at ClinicalTrials.gov (NCT02490800).

Glioblastoma remains a highly malignant, inevitably recurring brain tumor with dismal prognosis. Tumor progression is influenced by cellular interactions between the tumor and its microenvironment, yet quantitative data on these interactions, particularly under standard of care therapy, remains sparse. We utilized spatial, single-cell, multiome profiling to map therapy-induced changes in the architecture of >700 paired glioblastoma samples derived from 101 patients at diagnosis and recurrence. This approach categorized patients into groups reflecting specific evolutionary responses to therapy, with implications for prognosis and treatment. Favourable outcomes were linked to shifts towards enriched perivascular, oligodendrocyte-progenitor-like niches with deep tissue infiltration of activated immune cells, whereas poor outcomes correlated with shifts towards an immunosuppressive mesenchymal environment with poor immune infiltration. Finally, while mutations in EGFR/PTEN, or MGMT-promoter methylation influenced tumor evolution, we also identified a defined subset of patients that were more responsive to lomustine after early recurrence. Our findings offer a framework to stratify patient treatment based on tumor and microenvironmental evolution. Maxime Vanmechelen, Pouya Nazari, Jan Beckervordersandforth, Daphne Leunissen, Basiel Cole, Brecht Decraene, Yanti De Visser, Gautam Shankar, Maikel Verduin, Daniele Pantano, Carmen Bravo Gonzalez-Blas, Chiara Caprioli, Sien Bevers, Tom Moors, Jayesh Telang, Ivey Sebasstian, Julie Messiaen, Yannick Van Herck, Emma Geens, Danielle Eekers, Annelies Claeys, Marleen Derweduwe, Axel Zur Hausen, Francesca Bosisio, Frank Weyns, Thomas Daenekindt, Peter Van Eyken, Mieke Govers, Ferdinand Mennens, Koos Hovinga, Steven De Vleeschouwer, Paul Clement, Martijn Broen, Marc Vooijs, Raf Sciot, Asier Antoranz, Jon Pey, Ernst-Jan Speel, Ann Hoeben, Frederik De Smet. Characterization of therapeutic effects in glioblastoma through integrated spatial single-cell multiome profiling of longitudinal samples: Unveiling clinically relevant subtypes of pathological changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6362.

Background:Emerging evidence suggests that cognitive dysfunction may result from damage to the brain's functional network. This study explores the dose-dependent susceptibility of functional hubs to radiotherapy (RT) and associations with cognitive outcomes. Methods:Attention, language, memory, motor, and executive functioning were assessed ≥1-year post-radiotherapy in 39 WHO grade 2 or 3 glioma patients with lesions predominantly located in the left frontal lobe and 50 matched healthy controls. Using resting-state functional imaging, weighted functional graphs were constructed for each participant, identifying hubs through graph measures. Linear regression models and Spearman's rho correlations assessed associations between mean RT dose per region and cognitive domains. Results:Higher RT doses to the left fusiform and inferior temporal gyri were linked to memory impairment (r(37) ≥ -0.565, P FDR ≤ 0.026), while poorer language outcomes were associated with higher doses to the left pars opercularis, rostral middle frontal gyrus, and caudate (r(37) ≥ -0.510, P FDR ≤ .040). Attention deficits were linked to higher doses to the left posterior cingulate, precentral, supramarginal, and postcentral gyrus ((37) ≥ -0.499, P FDR ≤ .040), with the left postcentral gyrus also associated with executive dysfunction (r(37) = -0.526, P FDR = .029). Significant correlations between RT dose and cognitive outcomes were more frequent in hubs than in non-hubs (50% vs. 12%, P = .005) and exclusively found in left-sided regions. Conclusions:RT seems to adversely affect left-sided functional hubs in a dose-dependent manner in glioma patients, which may contribute to cognitive dysfunction. Protecting these regions from the dose may potentially mitigate cognitive side effects in glioma patients. However, since most lesions were located in the left hemisphere and baseline testing was unavailable, a potential effect of tumor location cannot be entirely ruled out.

PURPOSE:Cognitive sequelae are a concern in glioma patients postradiation therapy. As there is uncertainty regarding which brain regions to spare during radiation therapy to preserve cognition, we explored structural brain network hubs as potential organs at risk. METHODS AND MATERIALS:We conducted a cross-sectional study, involving 39 irradiated adult WHO grade 2 and 3 gliomas along with 50 healthy controls. Cognitive domains (language, memory, attention, motor-, and executive functioning) were assessed ≥1 year postradiation therapy. Using multishell diffusion-weighted imaging, weighted structural graphs were constructed, and graph measures calculated to define hubs. The association between mean radiation therapy (RT) dose in each region and nodal strength and cognitive domains were tested with a linear regression model and Spearman's rho correlations, respectively. RESULTS:Lower nodal strength was significantly associated with increasing RT dose in 9 brain regions, significantly (McNemar test, P < .01) impacting hubs more often than nonhubs (58% vs 7%). Executive performance (r(37) ≥ -.474, PFDR ≤ .045) and attention (r(37) ≥ -.471, PFDR ≤ .045) were significantly correlated with RT doses to the left pre- and postcentral gyrus and right posterior cingulate cortex, whereas poorer language outcomes were observed in patients receiving higher doses to the left insula, superior frontal, and precentral gyrus (r(37) ≥ -.460, PFDR ≤ .045). These correlations were more prevalent in hubs than nonhubs (P = .33), and higher than those between memory and left (r(37) = -.359) and right (r(37) = .059) hippocampal dose. CONCLUSIONS:Higher RT doses to specific brain regions, particularly left-sided hubs, were associated with reduced nodal strength (ie, lower network centrality) and poorer cognitive performance. Although baseline cognitive testing is unavailable and cognitive functioning is influenced by multiple factors, this study highlights the potential value of network- or hub-sparing RT dose planning. Future longitudinal studies are needed to validate these findings before clinical implementation.