Glioblastomas are the most common primary brain tumour in adults. While the prognosis for patients is poor, gene expression profiling has detected signatures that can sub-classify GBMs relative to histopathology and clinical variables. One category of GBM defined by a gene expression signature is termed ProNeural (PN), and has substantially longer patient survival relative to other gene expression-based subtypes of GBMs. Age of onset is a major predictor of the length of patient survival where younger patients survive longer than older patients. The reason for this survival advantage has not been clear.

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.

Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach.

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.

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.

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.

The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA). In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS) of an affected dog. This revealed a 6-8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10-11) that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10-19). In a pooled analysis of both studies (73 cases and 186 controls), the LINE-1 insertion was associated with a ~20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99-49.86, P-value 1.3 x 10-27). Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function.

The development of automatic methods for segmenting anatomy from medical images is an important goal for many medical and healthcare research areas. Datasets that can be used to train and test computer algorithms, however, are often small due to the difficulties in obtaining experts to segment enough examples. Citizen science provides a potential solution to this problem but the feasibility of using the public to identify and segment anatomy in a medical image has not been investigated. Our study therefore aimed to explore the feasibility, in terms of performance and motivation, of using citizens for such purposes. Public involvement was woven into the study design and evaluation. Twenty-nine citizens were recruited and, after brief training, asked to segment the spine from a dataset of 150 magnetic resonance images. Participants segmented as many images as they could within three one-hour sessions. Their accuracy was evaluated by comparing them, as individuals and as a combined consensus, to the segmentations of three experts. Questionnaires and a focus group were used to determine the citizens' motivation for taking part and their experience of the study. Citizen segmentation accuracy, in terms of agreement with the expert consensus segmentation, varied considerably between individual citizens. The citizen consensus, however, was close to the expert consensus, indicating that when pooled, citizens may be able to replace or supplement experts for generating large image datasets. Personal interest and a desire to help were the two most common reasons for taking part in the study.

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.

Patients with gliomas, isocitrate dehydrogenase 1 (IDH1) mutation status have been studied as a prognostic indicator. Recent advances in machine learning (ML) have demonstrated promise in utilizing radiomic features to study disease processes in the brain. We investigate whether ML analysis of multiparametric radiomic features from preoperative Magnetic Resonance Imaging (MRI) can predict IDH1 mutation status in patients with glioma. This retrospective study included patients with glioma with known IDH1 status and preoperative MRI. Radiomic features were extracted from Fluid-Attenuated Inversion Recovery (FLAIR) and Diffused Weighted Imaging (DWI). The dataset was split into training, validation, and testing sets by stratified sampling. Synthetic Minority Oversampling Technique (SMOTE) was applied to the training sets. eXtreme Gradient Boosting (XGBoost) classifiers were trained, and the hyperparameters were tuned. Receiver operating characteristic curve (ROC), accuracy, and f1-scores were collected. A total of 100 patients (age: 55 ± 15, M/F 60/40); with IDH1 mutant (n = 22) and IDH1 wildtype (n = 78) were included. The best performance was seen with a DWI-trained XGBoost model, which achieved ROC with Area Under the Curve (AUC) of 0.97, accuracy of 0.90, and f1-score of 0.75 on the test set. The FLAIR-trained XGBoost model achieved ROC with AUC of 0.95, accuracy of 0.90, f1-score of 0.75 on the test set. A model that was trained on combined FLAIR-DWI radiomic features did not provide incremental accuracy. The results show that a XGBoost classifier using multiparametric radiomic features derived from preoperative MRI can predict IDH1 mutation status with > 90% accuracy.

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.

Machine learning algorithms could be used as the basis for clinical decision-making aids to enhance clinical practice.

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.

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.

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.

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.

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.

Temozolomide (TMZ) is an oral DNA-alkylating agent used for treating patients with glioblastoma. However, therapeutic benefits of TMZ can be compromised by the expression of O6-methylguanine methyltransferase (MGMT) in tumor tissue. Here we used MGMT-expressing glioblastoma stem cells (GSC) lines as a model for investigating the molecular mechanism underlying TMZ resistance, while aiming to explore a new treatment strategy designed to possibly overcome resistance to the clinically relevant dose of TMZ (35 μM).

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.

There is considerable interest in defining the metabolic abnormalities of IDH mutant tumors to exploit for therapy. While most studies have attempted to discern function by using cell lines transduced with exogenous IDH mutant enzyme, in this study, we perform unbiased metabolomics to discover metabolic differences between a cohort of patient-derived IDH1 mutant and IDH wildtype gliomaspheres.