Patient-derived glioblastoma organoids reflect tumor heterogeneity and treatment sensitivity.

Background: Treatment resistance and tumor relapse are the primary causes of mortality in glioblastoma (GBM), with intratumoral heterogeneity playing a significant role. Patient-derived cancer organoids have emerged as a promising model capable of recapitulating tumor heterogeneity. Our objective was to develop patient-derived GBM organoids (PGO) to investigate treatment response and resistance. Methods: GBM samples were used to generate PGOs and analyzed using whole-exome sequencing (WES) and single-cell karyotype sequencing. PGOs were subjected to temozolomide (TMZ) to assess viability. Bulk RNA sequencing was performed before and after TMZ. Results: WES analysis on individual PGOs cultured for 3 time points (1-3 months) showed a high inter-organoid correlation and retention of genetic variants (range 92.3%-97.7%). Most variants were retained in the PGO compared to the tumor (range 58%-90%) and exhibited similar copy number variations. Single-cell karyotype sequencing demonstrated preservation of genetic heterogeneity. Single-cell multiplex immunofluorescence showed maintenance of cellular states. TMZ treatment of PGOs showed a differential response, which largely corresponded with MGMT promoter methylation. Differentially expressed genes before and after TMZ revealed an upregulation of the JNK kinase pathway. Notably, the combination treatment of a JNK kinase inhibitor and TMZ demonstrated a synergistic effect. Conclusions: Overall, these findings demonstrate the robustness of PGOs in retaining the genetic and phenotypic heterogeneity in culture and the application of measuring clinically relevant drug responses. These data show that PGOs have the potential to be further developed into avatars for personalized adaptive treatment selection and actionable drug target discovery and as a platform to study GBM biology.

The Next Step Toward Patient-Centeredness in Multidisciplinary Cancer Team Meetings: An Interview Study with Professionals.

BACKGROUND: Patient-centeredness is essential in complex oncological multidisciplinary team decision-making. Improvement seems to be needed, while there is a lack of knowledge about health care providers' needs for improvement. OBJECTIVE: To explore multidisciplinary team members' perspectives on the need to improve patient-centeredness in complex decision-making, and subsequently the strategies to enhance it. METHODS: This was a qualitative descriptive interview study. The participants were twenty-four professionals who attended multidisciplinary cancer team meetings weekly. The setting was five multidisciplinary teams (gastrointestinal, gynecological, urological, head and neck, and hematological cancer) in a Dutch academic hospital. Data were collected by semi-structured interviews and were analyzed with a combination of inductive and deductive content analysis. RESULTS: The participants voiced the need for additional information (patient-centered information, patients's needs and preferences, individualized medical information) during the multidisciplinary team meeting, to be more patient-centered in the decision-making conversation with the patient following the meeting, and for more information following the meeting to support patient-centeredness. The strategies, which mostly originated from the needs, were categorized as organization, decision-making, and communication. The most prominent strategies were those aimed at collecting and using patient-centered information, and to facilitate the decision-making conversation with the patient following the multidisciplinary team meeting. CONCLUSION: Our findings highlighted the need to improve patient-centeredness in oncological multidisciplinary teams and provided a comprehensive overview of strategies for improvement, supported by multidisciplinary team members. These strategies emphasize involvement of patients throughout the continuous process of decision-making for patients with cancer. These strategies may be implemented in other oncological multidisciplinary teams, taking in mind the local needs. Future research may help to prioritize the strategies and to determine and evaluate the effect on endpoints, like patient or professional satisfaction, shared decision-making, and on the decision that was made.

Microvascular Dysfunction Is Associated With Worse Cognitive Performance: The Maastricht Study.

Microvascular dysfunction may be associated with worse cognitive performance. Most previous studies did not adjust for important confounders, evaluated only individual measures of microvascular dysfunction, and showed inconsistent results. We evaluated the association between a comprehensive set of measures of microvascular dysfunction and cognitive performance in the population-based Maastricht Study. We used cross-sectional data including 3011 participants (age 59.5±8.2; 48.9% women; 26.5% type 2 diabetes mellitus [oversampled by design]). Measures of microvascular dysfunction included magnetic resonance imaging features of cerebral small vessel disease, plasma biomarkers of microvascular dysfunction, albuminuria, flicker light-induced retinal arteriolar and venular dilation response and heat-induced skin hyperemia. These measures were summarized into a microvascular dysfunction composite score. Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the sum of the scores on these 3 cognitive domains. The microvascular dysfunction score was associated with a worse cognitive function score (standardized ß, -0.087 [95% CI, -0.127 to -0.047]), independent of age, education level, sex, type 2 diabetes mellitus, smoking, alcohol use, hypertension, total/HDL (high-density lipoprotein) cholesterol ratio, triglycerides, lipid-modifying medication, prior cardiovascular disease, depression and plasma biomarkers of low-grade inflammation. The fully adjusted ß-coefficient of the association between the microvascular dysfunction score and the cognitive function score was equivalent to 2 (range, 1-3) years of aging for each SD higher microvascular dysfunction score. The microvascular dysfunction score was associated with worse memory and processing speed but not with worse executive function. The present study shows that microvascular dysfunction is associated with worse cognitive performance.