Feasibility of deep learning-based tumor segmentation for target delineation and response assessment in grade-4 glioma using multi-parametric MRI.

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 R2 = 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.

Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial.

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.

Study protocol of the Bergen brain-gut-microbiota-axis study: A prospective case-report characterization and dietary intervention study to evaluate the effects of microbiota alterations on cognition and anatomical and functional brain connectivity in patients with irritable bowel syndrome.

INTRODUCTION: Irritable bowel syndrome (IBS) is a common clinical label for medically unexplained gastrointestinal (GI) symptoms, recently described as a disturbance of the brain-gut-microbiota (BGM) axis. To gain a better understanding of the mechanisms underlying the poorly understood etiology of IBS, we have designed a multifaceted study that aim to stratify the complex interaction and dysfunction between the brain, the gut, and the microbiota in patients with IBS. METHODS: Deep phenotyping data from patients with IBS (n = 100) and healthy age- (between 18 and 65) and gender-matched controls (n = 40) will be collected between May 2019 and December 2021. Psychometric tests, questionnaires, human biological tissue/samples (blood, faeces, saliva, and GI biopsies from antrum, duodenum, and sigmoid colon), assessment of gastric accommodation and emptying using transabdominal ultrasound, vagal activity, and functional and structural magnetic resonance imaging (MRI) of the brain, are included in the investigation of each participant. A subgroup of 60 patients with IBS-D will be further included in a 12-week low FODMAP dietary intervention-study to determine short and long-term effects of diet on GI symptoms, microbiota composition and functions, molecular GI signatures, cognitive, emotional and social functions, and structural and functional brain signatures. Deep machine learning, prediction tools, and big data analyses will be used for multivariate analyses allowing disease stratification and diagnostic biomarker detection. DISCUSSION: To our knowledge, this is the first study to employ unsupervised machine learning techniques and incorporate systems-based interactions between the central and the peripheral components of the brain-gut-microbiota axis at the levels of the multiomics, microbiota profiles, and brain connectome of a cohort of 100 patients with IBS and matched controls; study long-term safety and efficacy of the low-FODMAP diet on changes in nutritional status, gut microbiota composition, and metabolites; and to investigate changes in the brain and gut connectome after 12 weeks strict low-FODMAP-diet in patients with IBS. However, there are also limitations to the study. As a restrictive diet, the low-FODMAP diet carries risks of nutritional inadequacy and may foster disordered eating patterns. Strict FODMAP restriction induces a potentially unfavourable gut microbiota, although the health effects are unknown. TRIAL REGISTRATION NUMBER: NCT04296552 (ClinicalTrials.gov).

Sequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B study.

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 O6 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/m2 on days 1, 4, and 7 during each 4th weekly TMZ-chemotherapy starting on day 3 and escalated from 150 mg/m2 per oral 5 days/wk via 175 to 200 mg/m2 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)).

Fractional anisotropy shows differential reduction in frontal-subcortical fiber bundles-A longitudinal MRI study of 76 middle-aged and older adults.

Motivated by the frontal- and white matter (WM) retrogenesis hypotheses and the assumptions that fronto-striatal circuits are especially vulnerable in normal aging, the goal of the present study was to identify fiber bundles connecting subcortical nuclei and frontal areas and obtain site-specific information about age related fractional anisotropy (FA) changes. Multimodal magnetic resonance image acquisitions [3D T1-weighted and diffusion weighted imaging (DWI)] were obtained from healthy older adults (N = 76, range 49-80 years at inclusion) at two time points, 3 years apart. A subset of the participants (N = 24) was included at a third time-point. In addition to the frontal-subcortical fibers, the anterior callosal fiber (ACF) and the corticospinal tract (CST) was investigated by its mean FA together with tract parameterization analysis. Our results demonstrated fronto-striatal structural connectivity decline (reduced FA) in normal aging with substantial inter-individual differences. The tract parameterization analysis showed that the along tract FA profiles were characterized by piece-wise differential changes along their extension rather than being uniformly affected. To the best of our knowledge, this is the first longitudinal study detecting age-related changes in frontal-subcortical WM connections in normal aging.

Interactive visual analysis of heterogeneous cohort-study data.

Medical cohort studies enable the study of medical hypotheses with many samples. Often, these studies acquire a large amount of heterogeneous data from many subjects. Usually, researchers study a specific data subset to confirm or reject specific hypotheses. A new approach enables the interactive visual exploration and analysis of such data, helping to generate and validate hypotheses. A data-cube-based model handles partially overlapping data subsets during the interactive visualization. This model enables seamless integration of the heterogeneous data and the linking of spatial and nonspatial views of the data. Researchers implemented this model in a prototype application and used it to analyze data acquired in a cohort study on cognitive aging. Case studies employed the prototype to study aspects of brain connectivity, demonstrating the model's potential and flexibility.

Salient measures of inhibition and switching are associated with frontal lobe gray matter volume in healthy middle-aged and older adults.

OBJECTIVE: To investigate brain-behavior relationships between morphometric brain measures and salient executive function (EF) measures of inhibition and switching. METHOD: One hundred participants (49-80 years) performed the Color Word Interference Test from the Delis-Kaplan Executive Function System (D-KEFS). Salient measures of EF components of inhibition and switching, of which the effect of more fundamental skills were regressed out, were analyzed using linear models and a conditional inference trees analysis taking intercorrelations between predictor variables (brain volumes, age, gender, and education) into account. RESULTS: The conditional inference trees analysis demonstrated a primary role of the middle frontal gyrus (MFG) in explaining variations in the salient EF measure of switching and combined inhibition/switching. Age predicted measures of inhibition. CONCLUSION: The study highlights the importance of considering fundamental cognitive skills and the use of a statistical method taking possible complex relationships between predictor variables into account when interpreting standard EF test results. Further studies should include MRI measures representing neural networks that may relate to CWIT performance, and longitudinal studies are required to investigate any causal relationships.

General fluid-type intelligence is related to indices of white matter structure in middle-aged and old adults.

General fluid-type intelligence (gF) reflects abstract reasoning and problem solving abilities, and is an important predictor for lifetime trajectories of cognition, and physical and mental health. Structural and functional neuroimaging studies have demonstrated the role of parieto-frontal gray matter, but the white matter (WM) underpinnings of gF and the contribution of individual gF components to gF-WM relationship still need to be explored. The aim of this study was to characterize, in a sample of 100 healthy middle-aged and old subjects (mean=63.8 years), the relationship between gF and indices of WM structure obtained from diffusion tensor magnetic resonance imaging (DT-MRI) (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD)). gF was estimated by principal component analysis including measures of episodic memory, reasoning, and processing speed. Tract-based spatial statistics and permutation-based inference statistics were used to test the association between gF and WM indices, while controlling for the effect of age and sex. We hypothesized a positive relationship between gF and WM structure. Based on previous studies, we further hypothesized that this relationship was heavily influenced by the processing speed component of gF. We found a robust relationship between gF and DT-MRI measures of FA, RD and MD in all major WM tracts. Higher gF score was related to higher degree of WM integrity, in middle-aged as well as old individuals. Thus, the distributed relationship between gF and indices of WM microstructure is consistent with the notion that gF reflects efficient signaling between cortical areas. Furthermore, analysis of relationships between WM measures and gF components revealed an association with information processing speed and reasoning ability, but not with episodic memory. Thus, although all subcomponents loaded high on gF factor, the speed-related components were most strongly associated with DT-MRI-derived measures. These results suggest that DT-MRI can be used to parse gF.

Episodic memory of APOE ε4 carriers is correlated with fractional anisotropy, but not cortical thickness, in the medial temporal lobe.

The ε4 allele of apolipoprotein E (apoE, protein; APOE, gene) is the most important genetic risk factor for the development of Alzheimer's disease (AD). Cortical structures in the medial temporal lobe (MTL) are important for memory function and are affected early in AD. Both gray matter (GM) and white matter (WM) structures in the MTL have been reported to display AD related changes in healthy APOE ε4 carriers, but the effects are relatively small and somewhat deviating. Still, there is a lack of studies directly linking structural measures with performance on psychometric tests in ε4+ individuals. We hypothesized that intact WM integrity in the MTL facilitates episodic memory, and predicted a higher correlation between WM integrity and memory performance in APOE ε4 carriers due to a possible limiting effect of WM microstructure. In the present study of 92 healthy (MMSE>27) participants we acquired T1 3D and DTI images from a 1.5T MRI scanner, and tested the participants with California Verbal Learning Test II (CVLT-II). The study had two main aims: 1) to relate verbal memory performance to entorhinal WM (EWM) integrity in APOE ε4 carriers and non-carriers, and 2) to investigate APOE ε4 effects on EWM and EC thickness. We observed a strong, positive correlation between FA in the EWM and memory performance, which was driven solely by APOE ε4 carriers. These effects were significant while controlling for age, sex, EWM volume and EC thickness. Although EC thickness was significantly reduced in ε4 carriers, we did not find a relationship between EC thickness and memory performance. Thus, increased susceptibility of the WM structures underpinning the entorhinal-hippocampal network, offers a plausible explanation for the earlier onset of cognitive decline previously reported in APOE ε4 carriers.

Automated approaches for analysis of multimodal MRI acquisitions in a study of cognitive aging.

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.

Cortico-striatal connectivity and cognition in normal aging: a combined DTI and resting state fMRI study.

Resting state fMRI studies have found that cognitive decline in aging is associated with alterations in functional connectivity of distributed neural systems in the brain. While functional connections have been shown to rely on the underlying structural connectivity, direct structural connections have been studied in only a few distributed cortical systems so far. It is well known that subcortical nuclei have structural connections to the entire cortex. We hypothesized that structural subcortico-cortical connections may provide integral routes for communication between cortical resting state networks, and that changes in the integrity of these connections have a role in cognitive aging. We combined anatomical MRI, diffusion tensor MRI, and resting state fMRI in 100 healthy elderly to identify fiber bundles connecting cortical resting state networks to subcortical nuclei. In identified tracts, white matter fiber bundle integrity measures were compared to composite cognitive measures on executive function, processing speed, and memory performance. The integrity (FA values) in selected fiber bundles correlated strongly with cognitive measures on executive function and processing speed. Correlation was most pronounced between executive function and fiber bundles connecting the putamen to the dorsal attention network (r=0.73, p<0.001). Our findings show that unique cortico-subcortical fiber bundles can be identified for a range of cortical resting state networks, and indicate that these connections play an important role in cortical resting state network communication and cognition.

Transfemoral endovascular treatment of proximal common carotid artery lesions: a single-center experience on 153 lesions.

PURPOSE: To assess primary success and safety of percutaneous transluminal angioplasty (PTA) and/or stenting of ostial/proximal common carotid artery lesions (pCCA) and to compare its 30-day stroke/mortality level with the literature data for surgical options. METHODS: A total of 147 patients (153 stenoses, 6 recurrent) (71 female; 121 left) with significant diameter stenosis (>70% in symptomatic, n = 46; >85% in asymptomatic, n = 101 patients) of pCCA treated between 1994 and 2006 were retrospectively reviewed. With the exception of one, all procedures were performed using a transfemoral approach. A stent was implanted in 108 (70.5%) of cases. Stents were not available in the early years of our experience, but gradually became a routine practice. Embolic protection devices were used in 16 cases. Follow-up included neurological examination, carotid duplex scan, and office/telephone interview. RESULTS: Primary technical success was 98.7% (151/153 stenoses). There were no deaths. Periprocedural (<48 hours) neurological complications included 3/153 (2.0%) ipsilateral major strokes and 4/153 (2.6%) TIAs (including one contralateral TIA). There were 8/153 (5.2%) access site hematomas, 1/153 (0.7%) bradycardia, and 1/153 (0.7%) acute left ventricular failure with respiratory distress. Follow-up was achieved in 115/147 patients (78.2%) undergoing 120 procedures for a mean of 24.7 months and revealed one additional contralateral TIA and one additional minor stroke in an asymptomatic patient. In patients with follow-up, the 30-day procedural death/all-stroke rate was 3/120 (2.5%) The cumulative primary patency rate in the 115 patients with follow-up was 97.9% +/- 2.1% at 1 year, 82.0% +/- 7.1% at 4-years, and 73.5% +/- 12.7% at 7 years. The cumulative secondary patency rate was 100% at 1 year, 88.0% +/- 7.0% at 4 years, and 88.0% +/- 11% at 7 years. Log-rank test showed no statistical difference (P = .82) in primary cumulative patency between PTA alone (n = 34) or PTA/stent (n = 86). CONCLUSION: Transfemoral PTA/stenting appears to be appropriate treatment option for ostial/proximal common carotid artery significant stenoses. This study should also draw attention to the lack of data on natural history or effect of best medical treatment alone for these lesions, making evidence-based decision currently impossible for treatment of symptomatic or asymptomatic ostial and proximal common carotid artery significant stenoses.