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Background: Tumor burden assessment is essential for radiation therapy (RT), treatment response evaluation, and clinical decision-making. However, manual tumor delineation remains laborious and challenging due to radiological complexity. The objective of this study was to investigate the feasibility of the HD-GLIO tool, an ensemble of pre-trained deep learning models based on the nnUNet-algorithm, for tumor segmentation, response prediction, and its potential for clinical deployment., Methods: We analyzed the predicted contrast-enhanced (CE) and non-enhancing (NE) HD-GLIO output in 49 multi-parametric MRI examinations from 23 grade-4 glioma patients. The volumes were retrospectively compared to corresponding manual delineations by 2 independent operators, before prospectively testing the feasibility of clinical deployment of HD-GLIO-output to a RT setting., Results: For CE, median Dice scores were 0.81 (95% CI 0.71-0.83) and 0.82 (95% CI 0.74-0.84) for operator-1 and operator-2, respectively. For NE, median Dice scores were 0.65 (95% CI 0.56-0,69) and 0.63 (95% CI 0.57-0.67), respectively. Comparing volume sizes, we found excellent intra-class correlation coefficients of 0.90 ( P < .001) and 0.95 ( P < .001), for CE, respectively, and 0.97 ( P < .001) and 0.90 ( P < .001), for NE, respectively. Moreover, there was a strong correlation between response assessment in Neuro-Oncology volumes and HD-GLIO-volumes ( P < .001, Spearman's R 2 = 0.83). Longitudinal growth relations between CE- and NE-volumes distinguished patients by clinical response: Pearson correlations of CE- and NE-volumes were 0.55 ( P = .04) for responders, 0.91 ( P > .01) for non-responders, and 0.80 ( P = .05) for intermediate/mixed responders., Conclusions: HD-GLIO was feasible for RT target delineation and MRI tumor volume assessment. CE/NE tumor-compartment growth correlation showed potential to predict clinical response to treatment., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Tenecteplase is a modified tissue plasminogen activator with pharmacological and practical advantages over alteplase-which is currently the only approved thrombolytic drug for ischaemic stroke. The NOR-TEST trial showed that 0·4 mg/kg tenecteplase had an efficacy and safety profile similar to that of a standard dose (0·9 mg/kg) of alteplase, albeit in a patient population with a high prevalence of minor stroke. The aim of NOR-TEST 2 was to establish the non-inferiority of tenecteplase 0·4 mg/kg to alteplase 0·9 mg/kg for patients with moderate or severe ischaemic stroke., Methods: This phase 3, randomised, open-label, blinded endpoint, non-inferiority trial was performed at 11 hospitals with stroke units in Norway. Patients with suspected acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or more who were eligible for thrombolysis and admitted within 4·5 h of symptom onset were consecutively included. Random assignment, done by a computer with a block size of 4 and with allocations placed into opaque envelopes to be opened consecutively, was 1:1 between intravenous tenecteplase (0·4 mg/kg) or standard dose alteplase (0·9 mg/kg). Doctors and nurses providing acute care were not masked to treatment, but primary outcome assessment at 3 months was masked. The primary outcome was favourable functional outcome defined as a modified Rankin Scale score of 0-1 at 3 months, assessed in the modified intention-to-treat analysis (excluding patients who did not qualify for thrombolysis after randomisation or who withdrew informed consent). The non-inferiority margin was 3%. This trial (NOR-TEST 2) is registered with EudraCT (number 2018-003090-95) and ClinicalTrials.gov (NCT03854500). The trial was stopped early for safety reasons and is designated part A for analysis. Part B is ongoing with a lower dose of tenecteplase (0·25 mg/kg)., Findings: Between Oct 28, 2019, and Sept 26, 2021, 216 patients were enrolled. Patient enrolment was stopped after a per-protocol safety review showed an imbalance in the rates of symptomatic intracranial haemorrhage between the treatment groups, which surpassed the prespecified criteria for stopping the trial. Of 204 patients entering the modified intention-to-treat analysis, 100 were randomly allocated tenecteplase and 104 were allocated alteplase. All patients were followed up within 14 days of the end of the 3-months' follow-up period. A favourable functional outcome was reported less frequently in patients receiving tenecteplase (31 [32%] of 96 patients) compared with alteplase (52 [51%] of 101 patients; unadjusted OR 0·45 [95% CI 0·25-0·80]; p=0·0064). Any intracranial haemorrhage was significantly more frequent with tenecteplase (21 [21%] of 100 patients) than with alteplase (seven [7%] of 104 patients; unadjusted OR 3·68 [95% CI 1·49-9·11]; p=0·0031). Mortality at 3 months was also significantly higher with tenecteplase (15 [16%] of 96 patients) than with alteplase (five [5%] of 101 patients; unadjusted OR 3·56 [95% CI 1·24-10·21]; p=0·013). Numerically more cases of symptomatic intracranial haemorrhage were reported with tenecteplase (six [6%] of 100 patients) than with alteplase (one [1%] of 104 patients; unadjusted OR 6·57 [95% CI 0·78-55·62]; p=0·061)., Interpretation: In this prematurely terminated study (terminated to fulfil the prespecified safety criteria), tenecteplase at a dose of 0·4 mg/kg yielded worse safety and functional outcomes compared with alteplase. Our study consequently could not show that 0·4 mg/kg tenecteplase is non-inferior to alteplase in moderate and severe ischaemic stroke. Future stroke trials should assess a lower dose of tenecteplase versus alteplase in patients with moderate or severe stroke., Funding: The Norwegian National Programme for Clinical Therapy Research., Competing Interests: Declaration of interests LT reports an unrestricted grant from Boehringer Ingelheim, but the company was not involved in the design or conduct of this trial. DMR reports honoraria from Boehringer Ingelheim for an educational event. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Glioblastoma (GBM) is an aggressive malignant brain tumor where median survival is approximately 15 months after best available multimodal treatment. Recurrence is inevitable, largely due to O 6 methylguanine DNA methyltransferase (MGMT) that renders the tumors resistant to temozolomide (TMZ). We hypothesized that pretreatment with bortezomib (BTZ) 48 hours prior to TMZ to deplete MGMT levels would be safe and tolerated by patients with recurrent GBM harboring unmethylated MGMT promoter. The secondary objective was to investigate whether 26S proteasome blockade may enhance differentiation of cytotoxic immune subsets to impact treatment responses measured by radiological criteria and clinical outcomes., Methods: Ten patients received intravenous BTZ 1.3 mg/m 2 on days 1, 4, and 7 during each 4th weekly TMZ-chemotherapy starting on day 3 and escalated from 150 mg/m 2 per oral 5 days/wk via 175 to 200 mg/m 2 in cycles 1, 2, and 3, respectively. Adverse events and quality of life were evaluated by CTCAE and EQ-5D-5L questionnaire, and immunological biomarkers evaluated by flow cytometry and Luminex enzyme-linked immunosorbent assay., Results: Sequential BTZ + TMZ therapy was safe and well tolerated. Pain and performance of daily activities had greatest impact on patients' self-reported quality of life and were inversely correlated with Karnofsky performance status. Patients segregated a priori into three groups, where group 1 displayed stable clinical symptoms and/or slower magnetic resonance imaging radiological progression, expanded CD4 + effector T-cells that attenuated cytotoxic T-lymphocyte associated protein-4 and PD-1 expression and secreted interferon γ and tumor necrosis factor α in situ and ex vivo upon stimulation with PMA/ionomycin. In contrast, rapidly progressing group 2 patients exhibited tolerised T-cell phenotypes characterized by fourfold to sixfold higher interleukin 4 (IL-4) and IL-10 Th-2 cytokines after BTZ + TMZ treatment, where group 3 patients exhibited intermediate clinical/radiological responses., Conclusion: Sequential BTZ + TMZ treatment is safe and promotes Th1-driven immunological responses in selected patients with improved clinical outcomes (Clinicaltrial.gov (NCT03643549))., (© 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

In this work we describe an integrated and automated workflow for a comprehensive and robust analysis of multimodal MR images from a cohort of more than hundred subjects. Image examinations are done three years apart and consist of 3D high-resolution anatomical images, low resolution tensor-valued DTI recordings and 4D resting state fMRI time series. The integrated analysis of the data requires robust tools for segmentation, registration and fiber tracking, which we combine in an automated manner. Our automated workflow is strongly desired due to the large number of subjects. Especially, we introduce the use of histogram segmentation to processed fMRI data to obtain functionally important seed and target regions for fiber tracking between them. This enables analysis of individually important resting state networks. We also discuss various approaches for the assessment of white matter integrity parameters along tracts, and in particular we introduce the use of functional data analysis (FDA) for this task., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)