Functional diffusion mapping (fDM) is a cancer imaging technique that quantifies voxelwise changes in apparent diffusion coefficient (ADC). Previous studies have shown value of fDMs in bevacizumab therapy for recurrent glioblastoma multiforme (GBM). The aim of the present study was to implement explicit criteria for diffusion MRI quality control and independently evaluate fDM performance in a multicenter clinical trial (RTOG 0625/ACRIN 6677). A total of 123 patients were enrolled in the current multicenter trial and signed institutional review board-approved informed consent at their respective institutions. MRI was acquired prior to and 8 weeks following therapy. A 5-point QC scoring system was used to evaluate DWI quality. fDM performance was evaluated according to the correlation of these metrics with PFS and OS at the first follow-up time-point. Results showed ADC variability of 7.3% in NAWM and 10.5% in CSF. A total of 68% of patients had usable DWI data and 47% of patients had high quality DWI data when also excluding patients that progressed before the first follow-up. fDM performance was improved by using only the highest quality DWI. High pre-treatment contrast enhancing tumor volume was associated with shorter PFS and OS. A high volume fraction of increasing ADC after therapy was associated with shorter PFS, while a high volume fraction of decreasing ADC was associated with shorter OS. In summary, DWI in multicenter trials are currently of limited value due to image quality. Improvements in consistency of image quality in multicenter trials are necessary for further advancement of DWI biomarkers.

Alterations in the hedonic component of ingestive behaviors have been implicated as a possible risk factor in the pathophysiology of overweight and obese individuals. Neuroimaging evidence from individuals with increasing body mass index suggests structural, functional, and neurochemical alterations in the extended reward network and associated networks.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

Mediator is a general coactivator of RNA polymerase II (RNA pol II) bridging enhancer-bound transcriptional factors with RNA pol II. Mediator is organized in three distinct subcomplexes: head, middle, and tail modules. The head and middle modules interact with RNA pol II, and the tail module interacts with transcriptional activators. Deletion of one of the tail subunits SIN4 results in derepression of a subset of genes, including FLR1, by a largely unknown mechanism. Here we show that derepression of FLR1 transcription in sin4Δ cells occurs by enhanced recruitment of the mediator as well as Swi/Snf and SAGA complexes. The tail and head/middle modules of the mediator behave as separate complexes at the induced FLR1 promoter. While the tail module remains anchored to the promoter, the head/middle modules are also found in the coding region. The separation of the tail and head/middle modules in sin4Δ cells is also supported by the altered stoichiometry of the tail and head/middle modules at several tested promoters. Deletion of another subunit of the tail module MED2 in sin4Δ cells results in significantly decreased transcription of FLR1, pointing to the importance of the integrity of the separated tail module in derepression. All tested genes exhibited increased recruitment of the tail domain; however, only genes with increased occupancy of the head/middle modules also displayed increased transcription. The separated tail module thus represents a promiscuous transcriptional factor that binds to many different promoters and is necessary for derepression of FLR1 in sin4Δ cells.

Differentiating WHO grade I-III of meningioma by non-invasive imaging is challenging. This study investigated the potential of MR arterial spin labeling (ASL) to establish tumor grade in meningioma patients.

Despite the improved understanding of the molecular and genetic heterogeneity of glioblastoma, there is still an unmet need for better therapeutics, as treatment approaches have remained unchanged in recent years. Research into the role of the immune microenvironment has generated enthusiasm for testing immunotherapy (specifically, immune checkpoint inhibitors). However, to date, trials of immunotherapy in glioblastoma have not demonstrated a survival advantage. Combination approaches aimed at optimally inducing response to immune checkpoint inhibitors with radiotherapy are currently being investigated. Herein, the authors describe their experience of the potential benefit and clinical outcomes of using combination pembrolizumab (an immune checkpoint inhibitor) and laser interstitial thermal therapy in a case series of patients with recurrent IDH-wild-type glioblastoma.

This pilot study investigates structural alterations and their relationships with cognitive function in survivors of diffuse gliomas. Twenty-four survivors of diffuse gliomas (mean age 44.5 ± 11.5), from whom high-resolution T1-weighted images, neuropsychological tests, and self-report questionnaires were obtained, were analyzed. Patients were grouped by degree of cognitive impairment, and interregional correlations of cortical thickness were computed to generate morphometric correlation networks (MCNs). The results show that the cortical thickness of the right insula (R2 = 0.3025, p = 0.0054) was negatively associated with time since the last treatment, and the cortical thickness of the left superior temporal gyrus (R2 = 0.2839, p = 0.0107) was positively associated with cognitive performance. Multiple cortical regions in the default mode, salience, and language networks were identified as predominant nodes in the MCNs of survivors of diffuse gliomas. Compared to cognitively impaired patients, cognitively non-impaired patients tended to have higher network stability in network nodes removal analysis, especially when the fraction of removed nodes (among 66 nodes in total) exceeded 55%. These findings suggest that structural networks are altered in survivors of diffuse gliomas and that their cortical structures may also be adapting to support cognitive function during survivorship.

Degenerative cervical myelopathy (DCM) is a progressive condition characterized by degeneration of osseocartilaginous structures within the cervical spine resulting in compression of the spinal cord and presentation of clinical symptoms. Compared to healthy controls (HCs), studies have shown DCM patients experience structural and functional reorganization in the brain; however, sex-dependent cortical differences in DCM patients remains largely unexplored. In the present study, we investigate the role of sex differences on the structure of the cerebral cortex in DCM and determine how structural differences may relate to clinical measures of neurological function. T1-weighted structural MRI scans were acquired in 85 symptomatic and asymptomatic patients with DCM and 90 age-matched HCs. Modified Japanese Orthopedic Association (mJOA) scores were obtained for patients. A general linear model was used to determine vertex-level significant differences in gray matter volume (GMV) between the following groups (1) male HCs and female HCs, (2) male patients and female patients, (3) male patients and male HCs, and (4) female patients and female HCs. Within patients, males exhibited larger GMV in motor, language, and vision related brain regions compared to female DCM patients. Males demonstrated a significant positive correlation between GMV and mJOA score, in which patients with worsening neurological symptoms exhibited decreasing GMV primarily across somatosensory and motor related cortical regions. Females exhibited a similar association, albeit across a broader range of cortical areas including those involved in pain processing. In sensorimotor regions, female patients consistently showed smaller GMV compared with male patients, independent of mJOA score. Results from the current study suggest strong sex-related differences in cortical volume in patients with DCM, which may reflect hormonal influence or differing compensation mechanisms.

As treatments for diffuse gliomas have advanced, survival for patients with gliomas has also increased. However, there remains limited knowledge on the relationships between brain connectivity and the lasting changes to cognitive function that glioma survivors often experience long after completing treatment. This resting-state functional magnetic resonance imaging (rs-fMRI) study explored functional connectivity (FC) alterations associated with cognitive function in survivors of gliomas. In this pilot study, 22 patients (mean age 43.8 ± 11.9) with diffuse gliomas who completed treatment within the past 10 years were evaluated using rs-fMRI and neuropsychological measures. Novel rs-fMRI analysis methods were used to account for missing brain in the resection cavity. FC relationships were assessed between cognitively impaired and non-impaired glioma patients, along with self-reported cognitive impairment, non-work daily functioning, and time with surgery. In the cognitively non-impaired patients, FC was stronger in the medial prefrontal cortex, rostral prefrontal cortex, and intraparietal sulcus compared to the impaired survivors. When examining non-work daily functioning, a positive correlation with FC was observed between the accumbens and the intracalcarine cortices, while a negative correlation with FC was observed between the parietal operculum cortex and the cerebellum. Additionally, worse self-reported cognitive impairment and worse non-work daily functioning were associated with increased FC between regions involved in cognition and sensorimotor processing. These preliminary findings suggest that neural correlates for cognitive and daily functioning in glioma patients can be revealed using rs-fMRI. Resting-state network alterations may serve as a biomarker for patients' cognition and functioning.

Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction.

Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a Phase 2 clinical trial in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. We then performed deep, high-dimensional immune profiling of these patients to better understand how TLR agonists may influence the systemic immune responses induced by ATL-DC vaccination. Bulk RNAseq data demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant a TLR agonist together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased expression of PD-1 on CD4+ T-cells, decreases in CD38 and CD39 on CD8+ T cells and elevated proportion of monocytes after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLC induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population, which may represent an important blood biomarker for immunotherapy in this patient population.

Innovative clinical trial designs for glioblastoma (GBM) are needed to expedite drug discovery. Phase 0, window of opportunity, and adaptive designs have been proposed, but their advanced methodologies and underlying biostatistics are not widely known. This review summarizes phase 0, window of opportunity, and adaptive phase I-III clinical trial designs in GBM tailored to physicians.

Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.

VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM).

Although magnetic resonance imaging (MRI) and 18F-2-fluorodeoxyglucose-positron emission tomography (FDG-PET) are used for pre-surgical assessment of focal cortical dysplasia (FCD), they often disagree. This study aimed to identify factors that contribute to discrepancies in FCD imaging between MRI and FDG-PET.

Determining whether neurofilament light chain (NfL) elevations in patients who develop immune effector cell-associated neurotoxicity syndrome (ICANS) occur before or after infusion of cellular product is important to identify high-risk patients and inform whether neuroaxonal injury is latent or a consequence of treatment.

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing.

Glioblastoma (GBM) has high metabolic demands, which can lead to acidification of the tumor microenvironment. We hypothesize that a machine learning model built on temporal principal component analysis (PCA) of dynamic susceptibility contrast-enhanced (DSC) perfusion MRI can be used to estimate tumor acidity in GBM, as estimated by pH-sensitive amine chemical exchange saturation transfer echo-planar imaging (CEST-EPI). We analyzed 78 MRI scans in 32 treatment naïve and post-treatment GBM patients. All patients were imaged with DSC-MRI, and pH-weighting that was quantified from CEST-EPI estimation of the magnetization transfer ratio asymmetry (MTRasym) at 3 ppm. Enhancing tumor (ET), non-enhancing core (NC), and peritumoral T2 hyperintensity (namely, edema, ED) were used to extract principal components (PCs) and to build support vector machines regression (SVR) models to predict MTRasym values using PCs. Our predicted map correlated with MTRasym values with Spearman's r equal to 0.66, 0.47, 0.67, 0.71, in NC, ET, ED, and overall, respectively (p < 0.006). The results of this study demonstrates that PCA analysis of DSC imaging data can provide information about tumor pH in GBM patients, with the strongest association within the peritumoral regions.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural history, clinical, demographic and behavioral characteristics, search for new and evaluate candidate biomarkers, systematically test for contributions of infectious agents to symptoms, and conduct animal studies to understand underlying mechanisms for UCPPS. Study participants were enrolled in a one-year observational study and evaluated through a multisite, collaborative neuroimaging study to evaluate the association between UCPPS and brain structure and function. 3D T1-weighted structural images, resting-state fMRI, and high angular resolution diffusion MRI were acquired in five participating MAPP Network sites using 8 separate MRI hardware and software configurations. We describe the neuroimaging methods and procedures used to scan participants, the challenges encountered in obtaining data from multiple sites with different equipment/software, and our efforts to minimize site-to-site variation.

In the present study we investigated a combination of diffusion tensor imaging (DTI) and magnetic resonance spectroscopic (MRS) biomarkers in order to predict neurological impairment in patients with cervical spondylosis.