Somatic Versus Germline: A Case Series of Three Children With ATM-Mutated Medulloblastoma.

Somatic versus Germline-A Case Series of Three Children with ATM- mutated Medulloblastoma.

Maladaptive myelination promotes generalized epilepsy progression.

Activity-dependent myelination can fine-tune neural network dynamics. Conversely, aberrant neuronal activity, as occurs in disorders of recurrent seizures (epilepsy), could promote maladaptive myelination, contributing to pathogenesis. In this study, we tested the hypothesis that activity-dependent myelination resulting from absence seizures, which manifest as frequent behavioral arrests with generalized electroencephalography (EEG) spike-wave discharges, promote thalamocortical network hypersynchrony and contribute to epilepsy progression. We found increased oligodendrogenesis and myelination specifically within the seizure network in two models of generalized epilepsy with absence seizures (Wag/Rij rats and Scn8a+/mut mice), evident only after epilepsy onset. Aberrant myelination was prevented by pharmacological seizure inhibition in Wag/Rij rats. Blocking activity-dependent myelination decreased seizure burden over time and reduced ictal synchrony as assessed by EEG coherence. These findings indicate that activity-dependent myelination driven by absence seizures contributes to epilepsy progression; maladaptive myelination may be pathogenic in some forms of epilepsy and other neurological diseases.

Jagged Ends on Multinucleosomal Cell-Free DNA Serve as a Biomarker for Nuclease Activity and Systemic Lupus Erythematosus.

BACKGROUND: Jagged ends of plasma DNA are a recently recognized class of fragmentomic markers for cell-free DNA, reflecting the activity of nucleases. A number of recent studies have also highlighted the importance of jagged ends in the context of pregnancy and oncology. However, knowledge regarding the generation of jagged ends is incomplete. METHODS: Jaggedness of plasma DNA was analyzed based on Jag-seq, which utilized the differential methylation signals introduced by the DNA end-repair process. We investigated the jagged ends in plasma DNA using mouse models by deleting the deoxyribonuclease 1 (Dnase1), DNA fragmentation factor subunit beta (Dffb), or deoxyribonuclease 1 like 3 (Dnase1l3) gene. RESULTS: Aberrations in the profile of plasma DNA jagged ends correlated with the type of nuclease that had been genetically deleted, depending on nucleosomal structures. The deletion of Dnase1l3 led to a significant reduction of jaggedness for those plasma DNA molecules involving more than 1 nucleosome (e.g., size ranges 240-290 bp, 330-380 bp, and 420-470 bp). However, less significant effects of Dnase1 and Dffb deletions were observed regarding different sizes of DNA fragments. Interestingly, the aberration in plasma DNA jagged ends related to multinucleosomes was observed in human subjects with familial systemic lupus erythematosus with Dnase1l3 deficiency and human subjects with sporadic systemic lupus erythematosus. CONCLUSIONS: Detailed understanding of the relationship between nuclease and plasma DNA jaggedness has opened up avenues for biomarker development.

MRI Radiogenomics of Pediatric Medulloblastoma: A Multicenter Study.

Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (WNT) and non-sonic hedgehog (SHH) MB and then differentiates therapeutically relevant WNT from SHH. Further, a classifier that distinguishes high-risk group 3 from group 4 MB was developed. An independent, binary subgroup analysis was conducted to uncover radiomics features unique to infantile versus childhood SHH subgroups. The best-performing models from six candidate classifiers were selected, and performance was measured on holdout test sets. CIs were obtained by bootstrapping the test sets for 2000 random samples. Model accuracy score was compared with the no-information rate using the Wald test. Results The study cohort comprised 263 patients (mean age ± SD at diagnosis, 87 months ± 60; 166 boys). A two-stage classifier outperformed a single-stage multiclass classifier. The combined, sequential classifier achieved a microaveraged F1 score of 88% and a binary F1 score of 95% specifically for WNT. A group 3 versus group 4 classifier achieved an area under the receiver operating characteristic curve of 98%. Of the Image Biomarker Standardization Initiative features, texture and first-order intensity features were most contributory across the molecular subgroups. Conclusion An MRI-based machine learning decision path allowed identification of the four clinically relevant molecular pediatric medulloblastoma subgroups. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chaudhary and Bapuraj in this issue.

Barriers to Telemedicine Video Visits for Older Adults in Independent Living Facilities: Mixed Methods Cross-sectional Needs Assessment.

BACKGROUND: Despite the increasing availability of telemedicine video visits during the COVID-19 pandemic, older adults have greater challenges in getting care through telemedicine. OBJECTIVE: We aim to better understand the barriers to telemedicine in community-dwelling older adults to improve the access to and experience of virtual visits. METHODS: We conducted a mixed methods needs assessment of older adults at two independent living facilities (sites A and B) in Northern California between September 2020 and March 2021. Voluntary surveys were distributed. Semistructured interviews were then conducted with participants who provided contact information. Surveys ascertained participants' preferred devices as well as comfort level, support, and top barriers regarding telephonic and video visits. Qualitative analysis of transcribed interviews identified key themes. RESULTS: Survey respondents' (N=249) average age was 84.6 (SD 6.6) years, and 76.7% (n=191) of the participants were female. At site A, 88.9% (111/125) had a bachelor's degree or beyond, and 99.2% (124/125) listed English as their preferred language. At site B, 42.9% (51/119) had a bachelor's degree or beyond, and 13.4% (16/119) preferred English, while 73.1% (87/119) preferred Mandarin. Regarding video visits, 36.5% (91/249) of all participants felt comfortable connecting with their health care team through video visits. Regarding top barriers, participants at site A reported not knowing how to connect to the platform (30/125, 24%), not being familiar with the technology (28/125, 22.4%), and having difficulty hearing (19/125, 15.2%), whereas for site B, the top barriers were not being able to speak English well (65/119, 54.6%), lack of familiarity with technology and the internet (44/119, 36.9%), and lack of interest in seeing providers outside of the clinic (42/119, 35.3%). Three key themes emerged from the follow-up interviews (n=15): (1) the perceived limitations of video visits, (2) the overwhelming process of learning the technology for telemedicine, and (3) the desire for in-person or on-demand help with telemedicine. CONCLUSIONS: Substantial barriers exist for older adults in connecting with their health care team through telemedicine, particularly through video visits. The largest barriers include difficulty with technology or using the video visit platform, hearing difficulty, language barriers, and lack of desire to see providers virtually. Efforts to improve telemedicine access for older adults should take into account patient perspectives.

Predictors of rapidly progressive interstitial lung disease and mortality in patients with autoantibodies against melanoma differentiation-associated protein 5 dermatomyositis.

OBJECTIVE: Anti-melanoma differentiation-associated protein 5 (MDA5)-positive DM is associated with rapidly progressive interstitial lung disease (RP-ILD) and high mortality. This multicentre retrospective study aimed to identify predictors of mortality and RP-ILD. METHODS: Anti-MDA5-positive DM patients were identified from the Hong Kong Myositis Registry and the Clinical Data Analysis and Reporting System. Clinical characteristics were reviewed. Risk factors for mortality and RP-ILD were identified. RESULTS: Among the 116 recruited patients, 100 (86.2%) had ILD, 47 (40.5%) had RP-ILD and 44 (37.9%) patients died. Cox regression analysis revealed RP-ILD [hazard ratio (HR) 9.735 (95% CI 3.905, 24.272)], age >52 years [HR 4.750 (95% CI 1.692, 13.333)], ferritin level >2800 pmol/l [HR 3.042 (95% CI 1.323, 6.997)] and lactate dehydrogenase (LDH) >400 IU/l [HR 2.290 (95% CI 1.009, 5.198)] were independent predictors of mortality. With regard to RP-ILD, analyses showed that potential predictors at baseline included age >50 years [HR 2.640 (95% CI 1.277, 5.455)], LDH >300 IU/l [HR 3.189 (95% CI 1.469, 6.918)], fever [HR 1.903 (95% CI 0.956, 3.790)] and neutrophil:lymphocyte ratio >7.0 [HR 1.967 (95% CI 0.942, 4.107)]. We proposed a prediction model based on fever, LDH, age and white cell count (FLAW) to stratify the risk of development of RP-ILD. The probability of RP-ILD in a patient with a score of 4 was 100%. A small internal validation cohort showed the odds of RP-ILD with FLAW scores of 0, 1, 2 and 3 were 0%, 0%, 42.9% and 75%, respectively. CONCLUSIONS: Anti-MDA5-associated RP-ILD is significantly associated with poor survival rates. The FLAW model maybe useful to predict the development of RP-ILD.

Radiomic signatures of posterior fossa ependymoma: Molecular subgroups and risk profiles.

BACKGROUND: The risk profile for posterior fossa ependymoma (EP) depends on surgical and molecular status [Group A (PFA) versus Group B (PFB)]. While subtotal tumor resection is known to confer worse prognosis, MRI-based EP risk-profiling is unexplored. We aimed to apply machine learning strategies to link MRI-based biomarkers of high-risk EP and also to distinguish PFA from PFB. METHODS: We extracted 1800 quantitative features from presurgical T2-weighted (T2-MRI) and gadolinium-enhanced T1-weighted (T1-MRI) imaging of 157 EP patients. We implemented nested cross-validation to identify features for risk score calculations and apply a Cox model for survival analysis. We conducted additional feature selection for PFA versus PFB and examined performance across three candidate classifiers. RESULTS: For all EP patients with GTR, we identified four T2-MRI-based features and stratified patients into high- and low-risk groups, with 5-year overall survival rates of 62% and 100%, respectively (P < .0001). Among presumed PFA patients with GTR, four T1-MRI and five T2-MRI features predicted divergence of high- and low-risk groups, with 5-year overall survival rates of 62.7% and 96.7%, respectively (P = .002). T1-MRI-based features showed the best performance distinguishing PFA from PFB with an AUC of 0.86. CONCLUSIONS: We present machine learning strategies to identify MRI phenotypes that distinguish PFA from PFB, as well as high- and low-risk PFA. We also describe quantitative image predictors of aggressive EP tumors that might assist risk-profiling after surgery. Future studies could examine translating radiomics as an adjunct to EP risk assessment when considering therapy strategies or trial candidacy.

Machine-Learning Approach to Differentiation of Benign and Malignant Peripheral Nerve Sheath Tumors: A Multicenter Study.

BACKGROUND: Clinicoradiologic differentiation between benign and malignant peripheral nerve sheath tumors (PNSTs) has important management implications. OBJECTIVE: To develop and evaluate machine-learning approaches to differentiate benign from malignant PNSTs. METHODS: We identified PNSTs treated at 3 institutions and extracted high-dimensional radiomics features from gadolinium-enhanced, T1-weighted magnetic resonance imaging (MRI) sequences. Training and test sets were selected randomly in a 70:30 ratio. A total of 900 image features were automatically extracted using the PyRadiomics package from Quantitative Imaging Feature Pipeline. Clinical data including age, sex, neurogenetic syndrome presence, spontaneous pain, and motor deficit were also incorporated. Features were selected using sparse regression analysis and retained features were further refined by gradient boost modeling to optimize the area under the curve (AUC) for diagnosis. We evaluated the performance of radiomics-based classifiers with and without clinical features and compared performance against human readers. RESULTS: A total of 95 malignant and 171 benign PNSTs were included. The final classifier model included 21 imaging and clinical features. Sensitivity, specificity, and AUC of 0.676, 0.882, and 0.845, respectively, were achieved on the test set. Using imaging and clinical features, human experts collectively achieved sensitivity, specificity, and AUC of 0.786, 0.431, and 0.624, respectively. The AUC of the classifier was statistically better than expert humans (P = .002). Expert humans were not statistically better than the no-information rate, whereas the classifier was (P = .001). CONCLUSION: Radiomics-based machine learning using routine MRI sequences and clinical features can aid in evaluation of PNSTs. Further improvement may be achieved by incorporating additional imaging sequences and clinical variables into future models.

Effects of Age on White Matter Microstructure in Children With Neurofibromatosis Type 1.

Children with neurofibromatosis type 1 (NF1) often report cognitive challenges, though the etiology of such remains an area of active investigation. With the advent of treatments that may affect white matter microstructure, understanding the effects of age on white matter aberrancies in NF1 becomes crucial in determining the timing of such therapeutic interventions. A cross-sectional study was performed with diffusion tensor imaging from 18 NF1 children and 26 age-matched controls. Fractional anisotropy was determined by region of interest analyses for both groups over the corpus callosum, cingulate, and bilateral frontal and temporal white matter regions. Two-way analyses of variance were done with both ages combined and age-stratified into early childhood, middle childhood, and adolescence. Significant differences in fractional anisotropy between NF1 and controls were seen in the corpus callosum and frontal white matter regions when ages were combined. When stratified by age, we found that this difference was largely driven by the early childhood (1-5.9 years) and middle childhood (6-11.9 years) age groups, whereas no significant differences were appreciable in the adolescence age group (12-18 years). This study demonstrates age-related effects on white matter microstructure disorganization in NF1, suggesting that the appropriate timing of therapeutic intervention may be in early childhood.

MRI-based radiomics for prognosis of pediatric diffuse intrinsic pontine glioma: an international study.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors. Presently, MRI is the mainstay of disease diagnosis and surveillance. We identify clinically significant computational features from MRI and create a prognostic machine learning model. METHODS: We isolated tumor volumes of T1-post-contrast (T1) and T2-weighted (T2) MRIs from 177 treatment-naïve DIPG patients from an international cohort for model training and testing. The Quantitative Image Feature Pipeline and PyRadiomics was used for feature extraction. Ten-fold cross-validation of least absolute shrinkage and selection operator Cox regression selected optimal features to predict overall survival in the training dataset and tested in the independent testing dataset. We analyzed model performance using clinical variables (age at diagnosis and sex) only, radiomics only, and radiomics plus clinical variables. RESULTS: All selected features were intensity and texture-based on the wavelet-filtered images (3 T1 gray-level co-occurrence matrix (GLCM) texture features, T2 GLCM texture feature, and T2 first-order mean). This multivariable Cox model demonstrated a concordance of 0.68 (95% CI: 0.61-0.74) in the training dataset, significantly outperforming the clinical-only model (C = 0.57 [95% CI: 0.49-0.64]). Adding clinical features to radiomics slightly improved performance (C = 0.70 [95% CI: 0.64-0.77]). The combined radiomics and clinical model was validated in the independent testing dataset (C = 0.59 [95% CI: 0.51-0.67], Noether's test P = .02). CONCLUSIONS: In this international study, we demonstrate the use of radiomic signatures to create a machine learning model for DIPG prognostication. Standardized, quantitative approaches that objectively measure DIPG changes, including computational MRI evaluation, could offer new approaches to assessing tumor phenotype and serve a future role for optimizing clinical trial eligibility and tumor surveillance.

Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction.

Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.

Cerebral volume and diffusion MRI changes in children with sensorineural hearing loss.

PURPOSE: Sensorineural hearing loss (SNHL) is the most prevalent congenital sensory deficit in children. Information regarding underlying brain microstructure could offer insight into neural development in deaf children and potentially guide therapies that optimize language development. We sought to quantitatively evaluate MRI-based cerebral volume and gray matter microstructure children with SNHL. METHODS & MATERIALS: We conducted a retrospective study of children with SNHL who obtained brain MRI at 3 T. The study cohort comprised 63 children with congenital SNHL without known focal brain lesion or structural abnormality (33 males; mean age 5.3 years; age range 1 to 11.8 years) and 64 age-matched controls without neurological, developmental, or MRI-based brain macrostructure abnormality. An atlas-based analysis was used to extract quantitative volume and median diffusivity (ADC) in the following brain regions: cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem, and cerebral white matter. SNHL patients were further stratified by severity scores and hearing loss etiology. RESULTS: Children with SNHL showed higher median ADC of the cortex (p = .019), thalamus (p < .001), caudate (p = .005), and brainstem (p = .003) and smaller brainstem volumes (p = .007) compared to controls. Patients with profound bilateral SNHL did not show any significant differences compared to patients with milder bilateral SNHL, but both cohorts independently had smaller brainstem volumes compared to controls. Children with unilateral SNHL showed greater amygdala volumes compared to controls (p = .021), but no differences were found comparing unilateral SNHL to bilateral SNHL. Based on etiology for SNHL, patients with Pendrin mutations showed higher ADC values in the brainstem (p = .029, respectively); patients with Connexin 26 showed higher ADC values in both the thalamus (p < .001) and brainstem (p < .001) compared to controls. CONCLUSION: SNHL patients showed significant differences in diffusion and volume in brain subregions, with region-specific findings for patients with Connexin 26 and Pendrin mutations. Future longitudinal studies could examine macro- and microstructure changes in children with SNHL over development and potential predictive role for MRI after interventions including cochlear implant outcome.

Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging.

Importance: Epidemiological studies indicate a link between obsessive-compulsive disorder and infections, particularly streptococcal pharyngitis. Pediatric acute-onset neuropsychiatric syndrome (PANS) manifests suddenly with obsessions, compulsions, and other behavioral disturbances, often after an infectious trigger. The current working model suggests a unifying inflammatory process involving the central nervous system, particularly the basal ganglia. Objective: To investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects microstructural abnormalities across the brain regions of children with PANS. Design, Setting, and Participants: Case-control study performed at a single-center, multidisciplinary clinic in the United States focusing on the evaluation and treatment of children with PANS. Sixty consecutive patients who underwent 3 Tesla (T) magnetic resonance imaging (MRI) before immunomodulation from September 3, 2012, to March 30, 2018, were retrospectively reviewed for study inclusion. Six patients were excluded by blinded investigators because of imaging or motion artifacts, 3 patients for major pathologies, and 17 patients for suboptimal atlas image registration. In total, 34 patients with PANS before initiation of treatment were compared with 64 pediatric control participants. Main Outcomes and Measures: Using atlas-based MRI analysis, regional brain volume, diffusion, and cerebral blood flow were measured in the cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, and brainstem. An age and sex-controlled multivariable analysis of covariance was used to compare patients with control participants. Results: This study compared 34 patients with PANS (median age, 154 months; age range, 55-251 months; 17 girls and 17 boys) and 64 pediatric control participants (median age, 139 months; age range, 48-213 months); 41 girls and 23 boys). Multivariable analysis demonstrated a statistically significant difference in MRI parameters between patients with PANS and control participants (F21,74 = 6.91; P < .001; partial η2 = 0.662). All assessed brain regions had statistically significantly increased median diffusivity compared with 64 control participants. Specifically, the deep gray matter (eg, the thalamus, basal ganglia, and amygdala) demonstrated the most profound increases in diffusivity consistent with the cardinal clinical symptoms of obsessions, compulsions, emotional dysregulation, and sleep disturbances. No statistically significant differences were found regarding volume and cerebral blood flow. Conclusions and Relevance: This study identifies cerebral microstructural differences in children with PANS in multiple brain structures, including the deep gray matter structures (eg, the thalamus, basal ganglia, and amygdala). Further study of MRI is warranted in prospective, clinical trials as a potential quantitative method for assessing patients under evaluation for PANS.

Electrical and synaptic integration of glioma into neural circuits.

High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.

Circulating miR-99b-5p as a novel predictor of erosion progression on high-resolution peripheral quantitative computed tomography in early rheumatoid arthritis: A prospective cohort study.

OBJECTIVES: To compare micro RNA (miRNA) expression: (a) between healthy individuals and early rheumatoid arthritis (ERA) patients with and without erosion on high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline; and (b) to explore whether these miRNAs could inform a signature predictive of erosion progression despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). METHODS: The second metacarpophalangeal head (MCP2) was scanned by HR-pQCT at baseline and 1 year in 117 ERA patients. We performed global profiling of 377 miRNAs in 10 ERA patients with and without erosion on HR-pQCT at baseline and six healthy controls. Validation of the miRNAs of interest were conducted using TaqMan® quantitative real-time polymerase chain reaction in the validation ERA cohort (n = 117) at baseline. Correlation between the candidate miRNAs and erosion progression over 1 year were also assessed. RESULTS: In the 377 screened miRNAs, 94 (60.6%) miRNAs were upregulated in patients with erosions, with 13 (8.4%) upregulated more than 2-fold. Sixty-one (39.4%) miRNAs were downregulated in patients with erosions, with 6 (3.9%) downregulated more than 2-fold. Expression of miR-143-3p, miR-145-5p and miR-99b-5p were significantly higher in the plasma of ERA patients with erosions compared with those without erosions. Logistic regression analysis revealed that the baseline expression of miR-99b-5p was an independent predictor of erosion progression at month 12 (Exp [B] = 4.257, 95% CI 1.178-15.386, P = 0.027). CONCLUSIONS: Differential expressions of circulating miR-143-3p, miR-145-5p and miR-99b-5p in the plasma of ERA patients may characterize a severe form of the disease. MiR-99b-5p, in particular, may serve as a possible predictor for erosion progression.

Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment.

Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment. VIDEO ABSTRACT.

Effect of Treat-to-target Strategies Aiming at Remission of Arterial Stiffness in Early Rheumatoid Arthritis: A Randomized Controlled Study.

OBJECTIVE: To determine the efficacy of 2 tight control treatment strategies aiming at Simplified Disease Activity Score (SDAI) remission (SDAI ≤ 3.3) compared to 28-joint count Disease Activity Score (DAS28) remission (DAS28 < 2.6) in the prevention of arterial stiffness in patients with early rheumatoid arthritis (RA). METHODS: This was an open-label study in which 120 patients with early RA were randomized to receive 1 year of tight control treatment. Group 1 (n = 60) aimed to achieve SDAI ≤ 3.3 and Group 2 (n = 60), DAS28 < 2.6. Pulse wave velocity (PWV) and augmentation index (AIx) were measured at baseline and 12 months. A posthoc analysis was also performed to ascertain whether achieving sustained remission could prevent progression in arterial stiffness. RESULTS: The proportions of patients receiving methotrexate monotherapy were significantly lower in Group 1 throughout the study period. At 12 months, the proportions of patients achieving DAS28 and SDAI remission, and the change in PWV and AIx, were comparable between the 2 groups. In view of the lack of differences between the 2 groups, a posthoc analysis was performed at Month 12, including all 110 patients with PWV, to elucidate the independent predictors associated with the change in PWV. Multivariate analysis revealed that achieving sustained DAS28 remission at months 6, 9, and 12 and a shorter disease duration were independent explanatory variables associated with less progression of PWV. CONCLUSION: With limited access to biologic disease-modifying antirheumatic drugs, treatment efforts toward DAS28 and SDAI remission had similar effects in preventing the progression of arterial stiffness at 1 year. However, achieving sustained DAS28 remission was associated with a significantly greater improvement in PWV. [Clinical Trial registration: Clinicaltrial.gov NCT01768923.].

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma.

High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG). An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway. However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.

Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy.

Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although there is currently limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBsAg-positive patients receiving novel treatments, especially the Bruton tyrosine kinase inhibitors and the phosphatidylinositol 3-kinase inhibitors, which are B-cell receptor signaling modulators and reduce proliferation of malignant B-cells. Further studies are needed to clarify the risk of HBV reactivation with these agents and the best prophylactic strategy in the era of targeted therapy for hematological malignancies.