Surveillance of patient outcomes with real-world data is essential to uncover regional disparities in clinical practice or quality of care. This study explored survival differences among glioblastoma patients in Norway and investigated the role of demographic and treatment factors. We analyzed real-world data from the Norwegian Cancer Registry on 1158 adults with histologically confirmed glioblastoma during 2019–2023. Surgical treatment rates per 100,000 inhabitants per region (South-East, West, Mid, North) were compared using adjusted Poisson models. Full treatment included surgical resection, radiotherapy (≥ 55 Gy for ≤ 70 years; ≥30 Gy for > 70 years), and temozolomide. Standardized survival was estimated with flexible parametric models, standardized for age, sex, year, and distances to treatment facilities. Patients from the North were older and lived further from treatment centers. For patients aged 18–70, treatment and survival did not significantly differ across regions; national median standardized survival was 14.4 months (95

Background Differentiating post-radiation MRI changes from progressive disease (PD) in glioblastoma (GBM) patients represents a major challenge. The clinical problem is two-sided; avoid termination of effective therapy in case of pseudoprogression (PsP) and continuation of ineffective therapy in case of PD. We retrospectively assessed the incidence, management, and prognostic impact of PsP and analyzed factors associated with PsP in a GBM patient cohort. Methods Consecutive GBM patients diagnosed in the South-Eastern Norway Health Region from 2015 to 2018 who had received RT and follow-up MRI were included. Tumor, patient, and treatment characteristics were analyzed in relationship to re-evaluated MRI examinations at 3 and 6 months post-radiation using Response Assessment in Neuro-Oncology criteria. Results A total of 284 patients were included in the study. PsP incidence 3 and 6 months post-radiation was 19.4% and 7.0%, respectively. In adjusted analyses, methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter and the absence of neurological deterioration were associated with PsP at both 3 (p < .001 and p = .029, respectively) and 6 months (p = .045 and p = .034, respectively) post-radiation. For patients retrospectively assessed as PD 3 months post-radiation, there was no survival benefit of treatment change (p = .838). Conclusions PsP incidence was similar to previous reports. In addition to the previously described correlation of methylated MGMT promoter with PsP, we also found that absence of neurological deterioration significantly correlated with PsP. Continuation of temozolomide courses did not seem to compromise survival for patients with PD at 3 months post-radiation; therefore, we recommend continuing adjuvant temozolomide courses in case of inconclusive MRI findings.

Abstract The 2021 WHO classification underscores the importance of molecular data integration in Central Nervous System (CNS) tumor diagnostics. However, currently used assays have disadvantages due to technical complexity, required equipment and reagent cost, as well as lengthy turnaround times. In response to these challenges, we introduce Rapid-CNS2 and MNP-Flex. Rapid-CNS2, an adaptive sampling-based nanopore sequencing workflow, offers real-time methylation classification and DNA copy-number information within a 30-minute window, suitable for intra-operative settings, followed by comprehensive molecular profiling within 24 h, covering the complete spectrum of diagnostically and therapeutically relevant information for the respective entity. We have prospectively validated Rapid-CNS2 in a multi-center setting on 223 samples. For even more widespread use of methylation-based CNS tumor classification, we developed MNP-Flex, a platform-agnostic methylation classifier encompassing 184 CNS tumor classes. MNP-flex achieved 92% accuracy across a global validation cohort of 78,000 samples spanning five different technologies. These innovations represent a significant advancement in CNS tumor diagnostics, making rapid, actionable molecular insights more widely and more rapidly available, which is crucial for personalized treatment strategies. Their integration streamlines the diagnostic process, broadening access to accurate molecular classification and promising improved patient outcomes in neurooncology on a global scale. MNP-Flex is available as a web-service https://mnp-flex.org and the Rapid-CNS2 workflow is available on Github.

Glioma resection is associated with prolonged survival, but neuro-oncological trials have frequently refrained from quantifying the extent of resection. The Response Assessment in Neuro-Oncology (RANO) resect group is an international, multidisciplinary group that aims to standardise research practice by delineating the oncological role of surgery in diffuse adult-type gliomas as defined per WHO 2021 classification. Favourable survival effects of more extensive resection unfold over months to decades depending on the molecular tumour profile. In tumours with a more aggressive natural history, supramaximal resection might correlate with additional survival benefit. Weighing the expected survival benefits of resection as dictated by molecular tumour profiles against clinical factors, including the introduction of neurological deficits, we propose an algorithm to estimate the oncological effects of surgery for newly diagnosed gliomas. The algorithm serves to select patients who might benefit most from extensive resection and to emphasise the relevance of quantifying the extent of resection in clinical trials.

Distinctive traits of malignant tumours are abnormal angiogenesis and high pressure. Conventional magnetic resonance imaging (MRI) plays a critical role in radiological evaluation of patients and tumour grading, but challenges remain. Pressure and vasculature have a strong impact on the tissue rheology and therefore they can be quantified by Magnetic Resonance Elastography (MRE). We show that MRE allows to quantify non-invasively tumour grade using pressure and tumour vasculature through wave scattering. We believe that MRE could play a central role in tumour grading and diagnosis as well as in therapy planning and dosage, especially in multidrug treatments scenarios.

Abstract BACKGROUND Radiotherapy remains a cornerstone in glioblastoma (GBM) management. A continued and unmet need in neuro-oncology is efficient non-invasive methods to differentiate post-radiation magnetic resonance imaging (MRI) changes from progressive disease (PD) in GBM patients. The clinical challenge is two-sided; avoid termination of effective therapy in case of pseudoprogression (PsP) and continuation of ineffective therapy in case of PD. We retrospectively assessed incidence, management, prognostic impact, and associated factors with PsP in a real-world GBM patient cohort. MATERIAL AND METHODS Adult (≥18 years) GBM patients diagnosed in the South-Eastern Health Region of Norway from 2015 to 2018, had received radiotherapy, and follow-up MRIs were included. Patient, tumor, and treatment characteristics were analyzed in relationship to re-evaluated MRI examinations at three and six months post-radiation using response assessment in neuro-oncology criteria. RESULTS PsP incidences at three and six months post-radiation were 20% and 8%, respectively. In adjusted analyses, methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter and absence of neurological deterioration were associated with PsP at both three (p<0.001 and p=0.04, respectively) and six months (p=0.003 and p=0.04, respectively) post-radiation. Patients with PsP at MRI three months post-radiation had a median OS of 24.8 months compared to 11.4 months for patients with PD and 18.7 months in patients with stable disease (SD); the difference was significant only when comparing patients with PsP and PD (p<0.001). There was no survival benefit of treatment change for patients retrospectively evaluated as PD three months post-radiation (p=0.8). Median OS for patients in the PsP group was 31.8 months and thus longer than in the PD group (13.1 months) and the SD group (24.1 months). The difference was only significant when comparing patients with PsP and PD (p<0.001). CONCLUSION PsP incidence in this retrospective material was similar to previous reports. In addition to the previously described correlation of methylated MGMT promoter with PsP, we also found that the absence of neurological deterioration significantly correlated to PsP. Continuation of temozolomide courses did not compromise survival for patients with PD at three months post-radiation; therefore, we recommend continuing adjuvant temozolomide courses in case of inconclusive MRI findings. Funding: European Union's Horizon 2020 Programme European Research Council Grant 758657-ImPRESS.

Background:Biomechanical tissue properties of glioblastoma tumors are heterogeneous, but the molecular mechanisms involved and the biological implications are poorly understood. Here, we combine magnetic resonance elastography (MRE) measurement of tissue stiffness with RNA sequencing of tissue biopsies to explore the molecular characteristics of the stiffness signal. Methods:MRE was performed preoperatively in 13 patients with glioblastoma. Navigated biopsies were harvested during surgery and classified as "stiff" or "soft" according to MRE stiffness measurements (|G*|norm). Twenty-two biopsies from eight patients were analyzed by RNA sequencing. Results:The mean whole-tumor stiffness was lower than normal-appearing white matter. The surgeon's stiffness evaluation did not correlate with the MRE measurements, which suggests that these measures assess different physiological properties. Pathway analysis of the differentially expressed genes between "stiff" and "soft" biopsies showed that genes involved in extracellular matrix reorganization and cellular adhesion were overexpressed in "stiff" biopsies. Supervised dimensionality reduction identified a gene expression signal separating "stiff" and "soft" biopsies. Using the NIH Genomic Data Portal, 265 glioblastoma patients were divided into those with (n = 63) and without (n = 202) this gene expression signal. The median survival time of patients with tumors expressing the gene signal associated with "stiff" biopsies was 100 days shorter than that of patients not expressing it (360 versus 460 days, hazard ratio: 1.45, P < .05). Conclusion:MRE imaging of glioblastoma can provide noninvasive information on intratumoral heterogeneity. Regions of increased stiffness were associated with extracellular matrix reorganization. An expression signal associated with "stiff" biopsies correlated with shorter survival of glioblastoma patients.

Abstract BACKGROUND Age, molecular features, extent of resection, and adjuvant treatment are well established prognostic factors for patients with glioblastoma. Neurological Assessment in Neuro-Oncology (NANO) Scale was designed as a tool to provide an objective clinician-reported outcome of neurologic and complements the radiological evaluation of the Response Assessment in Neuro-Oncology (RANO) criteria. Despite the generally detrimental prognosis associated with severe new neurological deficits after surgery, a comprehensive understanding of the impact of pre- and postoperative neurological status remains limited. This study explores the potential of the NANO scale to predict survival when applied immediately before and after surgery. METHODS This retrospective study examined adult patients in South-Eastern Norway who underwent resection for IDH wildtype glioblastoma between January 2020 and December 2021. We used Kaplan Meier curve calculate median overall survival and chi-square and log rank test were used to compare groups. RESULTS The study included 187 patients, with a median overall survival was 14.9 months. Patients with a preoperative NANO-score of 0-2 had a median survival of 17.4 months, compared to 11.3 months for patients scoring 3 or more points (p< 0.001). Neither Postoperative NANO scores nor changes in NANO scores in pre- to postoperative score were found to be significant predictors for survival. CONCLUSIONS This study indicates that a low preoperative NANO were predictive for a longer median survival, whereas postoperative NANO scores didn’t show the same impact. Surprisingly, an increase in the postoperative NANO score, indicating new, or worsening of the neurological deficits, didn′t correlate with a shorter median survival.

Glioblastoma is the most common form of primary brain cancer in adults, and the disease has a serious prognosis. Although great progress has been made in molecular characteristics, no major breakthroughs in treatment have been achieved for many years. In this article we present a clinical review of current diagnostics and treatment, as well as the challenges and opportunities inherent in developing improved and more personalised treatment.

Glioblastoma is the most common form of primary brain cancer in adults, and the disease has a serious prognosis. Although great progress has been made in molecular characteristics, no major breakthroughs in treatment have been achieved for many years. In this article we present a clinical review of current diagnostics and treatment, as well as the challenges and opportunities inherent in developing improved and more personalised treatment.

Background: Brain metastases (BM) are common in cancer patients and are associated with high morbidity and mortality. Surgery is an option, but the optimal selection of patients for surgery is challenging and controversial. Current prognostication tools are not ideal for preoperative prognostication. By using a reference population (derivation data set) and two external populations (validation data set) of patients who underwent surgery for BM, we aimed to create and validate a preoperative prognostic index. Methods: The derivation data set consists of 590 patients who underwent surgery for BM (2011–2018) at Oslo University Hospital. We identified variables associated with survival and created a preoperative prognostic index with four prognostic groups, which was validated on patients who underwent surgery for BM at Karolinska University Hospital and St. Olavs University Hospital during the same time period. To reduce over-fitting, we adjusted the index in accordance with our findings. Results: 438 patients were included in the validation data set. The preoperative prognostic index correctly divided patients into four true prognostic groups. The two prognostic groups with the poorest survival outcomes overlapped, and these were merged to create the adjusted preoperative prognostic index. Conclusion: We created a prognostic index for patients with BM that predicts overall survival preoperatively. This index might be valuable in supporting informed choice when considering surgery for BM.

Surgical resection of brain metastases improves symptoms and survival in selected patients. The benefit of gross total resection is disputed, as most patients are believed to succumb from their non-CNS tumor burden. We investigated the association between overall survival and residual tumor after surgery for single brain metastases. We reviewed adults who underwent surgery for a single brain metastasis at a regional referral center (2011–2018). Gross total resection was defined as no visible residual tumor on cerebral MRI 12–48 h postoperatively. We included 373 patients. The most common primary tumors were lung cancer (36%) and melanoma (24%). We identified gross total resection in 238 patients (64%). Median overall survival was 11.0 months, 8.0 (6.2–9.8) months for patients with subtotal resection and 13.0 (9.7–16.3) months for patients with gross total resection. In a multivariate regression analysis including preoperative prognostic factors, gross total resection was associated with longer overall survival (HR: 0.66, p = 0.003). Postoperative radiotherapy administered within 6 weeks did not significantly alter the hazard ratio estimates for grade of resection. Our study suggests improved survival with gross total resection compared to subtotal resection. The importance of extent of resection in surgery for brain metastases should not be discarded.

Abstract INTRODUCTION The median survival for patients with glioblastoma is less than one year, and survival beyond five years is rare. Radiotherapy combined with chemotherapy has improved survival since its introduction in 2005. No new treatment modalities have been widely adopted after this, but treatment development has focused on achieving maximal resection and the introduction of coordinated clinical care pathways. We hypothesize that these changes in approach have resulted in an improved survival in surgically treated patients. METHODS Retrospective analysis of a prospectively collected database in the adult population (2.4 million habitants) of South-Eastern Norway. Patients were divided in three periods; radiotherapy- (2003-2005), temozolomide- (2006-2012), and resection focused-period (2013-2019). Patients were also stratified according to age and grade of resection. Relative survival, Cox hazard-ratio, 3- and 5- year survival were calculated. RESULTS We identified 1663 surgically treated glioblastoma patients eligible for the study. The median overall survival was 11.4 months. Complete resection of contrast-enhanced tumor (CRCET) was achieved in 387 (23.2%) patients. The frequency of CRCET increased during the observation time (32 - 116 - 239), but there was no increase in reoperation rates (13%). Significant improvement between the last period and the first two periods was observed (12.3 vs. 10.5 months, p < 0.006), with a significant increase in 3- and 5- year survival probability between the first two groups (p = 0.01). No difference was found in median survival in CRCET among periods. Patients with CRCET demonstrated significantly longer median survival than patients with non-CRCET (16.1 vs. 10.8 months; p < 0.001). Incidence in the elder group increased from 2.6 to 13.2 per 100,000 habitants, and median survival doubled when CRT was achieved. CONCLUSIONS There is an increase in median survival, 3- and 5- year survival probability when comparing time-periods. We suggest this survival benefit is related to improved CRCET rates.

Glioblastoma is the most common form of brain cancer in adults and is invariably fatal despite extensive treatment with surgery, radio- and chemotherapy. Research on glioblastoma and other cancers is often based on studies of cells in cultures (commercial or patient-derived). However, the impact of cell culturing on the glioblastoma proteome is not yet studied in detail. To investigate this, comprehensive proteome analyses were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to compare glioblastoma tissue from three patients with cultured cells derived from these tissues. A 200 cm micro-pillar array column (µPAC) was used for separating peptides, applying a 5-hour LC solvent gradient. For sample preparation, we compared filter aided sample preparation (FASP), fractionation with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and fractionation with off-line high-pH reversed-phase LC (48 fractions concatenated in 8 vials) using nano-LC columns. Fractionation provided higher total protein coverages compared to FASP in combination with µPAC. However, FASP + µPAC was arguably more attractive when considering running times and simplicity. FASP in combination with µPAC also provided similar output compared to fractionation in combination with commonly used columns (15 cm, 2.6 µm C18), exemplifying the resolving power of the pillar array format. Using FASP in combination with µPAC, a total of 8469 proteins were quantified across all samples. Among these were proteins specific to either cell culture samples or tissue biopsies. Overall enrichment of transcription factors and other nucleic acid binding factors was observed in the cell culture samples, while proteins related to the vasculature, extracellular matrix, immune response, and proteases were lost upon culturing. Proteins detected in both tissue biopsies and cultured cells from each patient showed a significant correlation of expression levels, indicating that patient-derived cell cultures retain some specific characteristics of the parent tumor.

BACKGROUND: Understanding how mechanical properties relate to functional changes in glioblastomas may help explain variation between patients. PURPOSE: To map differences in biomechanical and functional properties between tumor and healthy tissue, to study their spatial distribution, and to assess any relationship between biomechanical and functional properties. STUDY TYPE: Prospective. SUBJECTS: Nine patients with glioblastoma, 17 healthy subjects FIELD STRENGTH/SEQUENCE: 3T, MRE, DSC, DTI, ASL ASSESSMENT: Stiffness and viscosity measurements G' and G'', cerebral blood flow (CBF), apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in patients' contrast-enhancing tumor, necrosis, edema, and gray and white matter, and in gray and white matter for healthy subjects. STATISTICAL TESTS: Voxel-wise regression analysis using a linear and a random forest model for CBF as a function of ADC, FA, G' and G''. Model performance was evaluated by root-mean-square error with a leave-one-patient-out cross-validation strategy. A paired Wilcoxon signed-rank test was used for comparisons of different regions and models. A significance level of P<0.05 was assumed for all tests. RESULTS: Median G' and G'' in contrast-enhancing tumor were 15 % and 39 % lower than in normal-appearing white matter (cNAWM), respectively (P<0.01). FA was 53 % lower in tumor compared to cNAWM (P<0.01). ADC and CBF were 50 % and 2.9 times higher in tumor than in cNAWM, respectively (P<0.01). For both models, prediction of CBF was improved by adding MRE measurements to the model, compared to a baseline model with ADC and FA as predictors (P<0.05). DATA CONCLUSION: Tumors differed from healthy tissue with regard to G' and G'', CBF, ADC and FA, with heterogeneity both between patients and within tumors. Measurements approached values in normal-appearing tissue when moving outward from the tumor core, but abnormal tissue properties were still present in regions of normal-appearing tissue. The inclusion of MRE measurements in statistical models helped predict perfusion, with stiffer tissue associated with lower perfusion values.

Abstract Tumor heterogeneity is one of the hallmarks of glioblastoma multiforme (GBM). Morphology within a given GBM tumor can be extremely variable where some regions of the tumor have a soft, gel-like structure while other areas are dense and fibrous. Abnormal mechanical stress and tissue stiffening caused by cancer proliferation are believed to affect vascularity by compressing structurally weak blood vessels and restricting the supply of nutrients and oxygen to the tissue. These effects contribute to a hypoxic microenvironment that promotes disease progression and chemoresistance. The genetic and molecular mechanisms that govern tissue stiffness within GBM tumors, however, are largely unknown. Magnetic Resonance Elastography (MRE) is an emerging technique for quantifying tissue stiffness non-invasively. We have evaluated 10 GBM patients by MRE imaging obtained prior to surgical resection. During surgery, 2–7 stereotactically navigated biopsies were collected from locations within the tumor with varying degrees of measured stiffness. Biopsies were processed to extract RNA, proteins, polar metabolites and lipids. Biomolecules were analyzed on relevant -omics platforms (RNA sequencing, MS-proteomics and lipidomics, NMR of polar metabolites). Differential expression and gene set enrichment analysis of patient paired biopsies indicate an overall increase in macrophage infiltration and extracellular matrix re-organization associated with increased tumor stiffness. Among the most highly upregulated genes in stiff tumor tissue were lymphatic endothelial hyaluronic acid receptor 1 (LYVE-1) and macrophage receptor with collagenous structure (MARCO), both of which have been associated with immune cell infiltration and tissue stiffness. Our preliminary findings offer novel insights into tumor morphology in GBM that can be inferred from imaging prior to surgery. This can be used to identify tumor regions with high risk of progression and infiltration, thereby informing and guiding surgical strategy and may ultimately lead to novel treatment strategies.

Abstract Background Clear identification of tumor subtype is the main predictor of patient outcome and ultimately what is considered an adequate level of surgical risk. At brain tumor resection, imaging modalities and intraoperative histology often give an ambigious diagnosis, complicating intraoperative surgical decision-making. Here, we report a nanopore DNA methylation analysis (NDMA) sequencing approach combined with machine learning for classification of tumor entities that could be used intraoperatively. Methods We analyzed 50 biopsies obtained from biobanked tissue (43, prospective) or sampled at surgery (7, intraoperative) from 20 female and 30 male patients with a median age of 8 years. DNA was extracted using spin columns, quantified on a Qubit fluorometer and assessed for purity using NanoDrop spectrophotometer. DNA was then barcoded with the Rapid Barcoding kit from Oxford Nanopore technologies and loaded onto a MinION flow cell. Sequencing was performed for 3 hours (intraoperative) and 24 hours (prospective). Raw reads were basecalled using the Guppy algorithm, then fed into a snakemake workflow (nanoDx pipeline). This generated a report showing the copy number profile, genome-wide methylation status and subclassification of the tumor according to the Heidelberg reference cohort. Results Twelve different tumor classes were discovered within our cohort spanning from WHO Grade I to Grade IV. The results generated by NDMA were concordant with standard neuropathological diagnosis in 43 out of 50 cases (86%). Of the discordant cases, six were due to the biological complexity of the tumor and one case was misclassified by the pipeline. NDMA enabled correct subclassification of 6/7 intraop cases within a mean of 129 minutes. Conclusion NDMA can accurately subclassify tumor entities intraoperatively and guide surgical procedures when preoperative imaging and frozen section evaluation are unclear.

Background Surgical resection of brain metastases (BM) improves overall survival (OS) in selected patients. Selecting those patients likely to benefit from surgery is challenging. The Graded Prognostic Assessment (GPA) and the diagnosis-specific Graded Prognostic Assessment (ds-GPA) were developed to predict survival in patients with BM, but not specifically to guide patient selection for surgery. Our aim was to evaluate the feasibility of preoperative GPA/ds-GPA scores and assess variables associated with OS. Methods We retrospectively reviewed first-time surgical resection of BM from solid tumors at a Norwegian regional referral center from 2011 to 2018. Results Of 590 patients, 51% were female and median age was 63 years. Median OS was 10.3 months and 74 patients (13%) died within three months after surgery. Preoperatively tumor origin was unknown in 20% of patients. A GPA score could be calculated for 92% of the patients preoperatively, but could not correctly predict survival. A ds-GPA score could be calculated for 46% of patients. Multivariable regression analysis revealed shorter OS in patients with higher age, worse functioning status, colorectal primary cancer compared to lung cancer, presence of extracranial metastases, and more than four BM. Patients with preoperative progressive extracranial disease or synchronous BM had shorter OS compared to patients with stable extracranial disease. Conclusion Ds-GPA could be calculated in less than half of patients preoperatively and GPA poorly identified patients which had minimal benefit of surgery. Including status of extracranial disease improve prognostication and therefore selection to surgery for brain metastases.

Purpose: Relative cerebral blood volume (rCBV) from dynamic susceptibility contrast (DSC)-MRI is a valuable biomarker in patients with glioblastoma for assessing treatment response and predicting overall survival. DSC-MRI based on echo planar images (EPI) may possess severe geometric distortions from magnetic field inhomogeneities up to the order of centimeters. The aim of this study is to assess how much two readily available EPI-based geometric distortion correction methods, FSL TOPUP and EPIC, affect rCBV values from DSC-MRI in patients with confirmed glioblastoma. Method: We used a combined single-shot 2D gradient-echo (T2*), spin-echo (T2) EPI sequence to estimate both T2* and T2-weighted rCBV from the same contrast agent injection. Effects of distortion correction on the positive phase-encoded T2- and T2*-images were assessed in healthy anatomical brain regions in terms of Wilcoxon signed rank tests on median rCBV change and on Dice coefficients, as well as in tumor lesions in terms of Wilcoxon signed rank tests on median rCBV change. Results: Our results show that following distortion correction, both gradient-echo and spin-echo rCBV increased in cortical areas of the frontal, temporal and occipital lobe, including the posterior orbital gyri in the frontal lobe and middle frontal gyri (p < 0.0008). Similar, improved Dice coefficients were observed for gradient-echo EPI in temporal, occipital and frontal lobe. Only spin-echo rCBV in enhancing lesion increased with correction (p = 0.0002). Conclusion: Our study sheds light on the importance of performing geometric distortion correction on EPI-based MRI data before assessing functional information such as rCBV values. Our findings may indicate that uncorrected rCBV values can be underestimated from positive phase-encoding EPI and that geometric distortion correction is warranted when comparing EPI-based data to conventional MRI.