Relationship Between Posttraumatic Headache and Depression After Mild Traumatic Brain Injury.

OBJECTIVES: Mild traumatic brain injury (mTBI) can lead to psychiatric and somatic symptoms for some patients, including posttraumatic headache (PTH) and depression. This study attempted to further establish the relationship between PTH and depression following mTBI and investigate whether the presence of PTH immediately following injury can identify patients at risk for developing depressive symptoms up to 6 months later. METHODS: This study was a secondary analysis of data from Head Injury Serum Markers for Assessing Response to Trauma (HeadSMART), a prospective study of adult patients in the emergency department with head injury. Participants included 265 patients who met criteria for mTBI and completed the Rivermead Post-Concussion Symptoms Questionnaire, to identify PTH within 24 hours after injury, and the Patient Health Questionnaire-9, to assess depressive symptoms during follow-up. Measures were completed at the initial visit immediately after the injury in the emergency department and at 1-, 3-, and 6-month follow-up visits. RESULTS: Patients with acute PTH (aPTH) at time of injury were more likely to report PTH at 1, 3, and 6 months. They also had more severe depressive symptoms and a greater likelihood of clinically significant depression at all time points. CONCLUSIONS: Patients with aPTH within 24 hours after injury were more likely to report continued symptoms of PTH and clinically significant depression at 1, 3, and 6 months. These findings provide support for using the presence of aPTH in the emergency department following mTBI as an indicator for monitoring persistent PTH and depressive symptoms in the postacute recovery period.

Longitudinal Trajectories of Post-Concussive Symptoms Following Mild Traumatic Brain Injury.

BACKGROUND: Individuals recovering from mild traumatic brain injury (TBI) represent a heterogenous population that requires distinct treatment approaches. Identification of recovery trajectories improves our ability to understand the natural history of mild TBI recovery and develop targeted interventions. OBJECTIVE: To utilize group-based trajectory modeling (GBTM) to identify distinct patterns of symptom recovery following mild TBI in the first 6 months after mild TBI. METHODS: This study is comprised of 253 adults who presented to the emergency department with mild TBI and completed assessments for six-months post-injury. Patients were recruited for the prospective observational cohort study, HeadSMART. The primary outcome measure was the Rivermead Postconcussion Symptom Questionnaire. GBTM was used to identify longitudinal trajectories of recovery following mild TBI using Rivermead scores at baseline, one, three, and six months following diagnosis. RESULTS: Findings identified four distinct trajectories of symptom recovery follwing mild TBI including 9% of participants who were categorized with minimal acute symptoms that decreased over time, 45% with mild acute symptoms that decreased over time, 33% with relatively higher acute symptoms that decreased over time, and 13% with relatively higher acute symptoms that increased over time. CONCLUSIONS: GBTM identified four distinct trajectories of recovery following mild TBI and GBTM may be useful for research interventions that can alter recovery trajectories.

Prevalence and Correlates of Depressive Symptoms Within 6 Months After First-Time Mild Traumatic Brain Injury.

OBJECTIVE: Depressive symptoms are among the most common neuropsychiatric sequelae of mild traumatic brain injury (mTBI). Very few studies have compared correlates of depressive symptoms within the first 6 months of injury in cohorts experiencing their first TBI. The authors investigated whether the correlates of depressive symptoms (being female, older, lower education, having brain lesions, experiencing worse postconcussive symptoms, and incomplete functional recovery) that have been established in populations with moderate to severe TBI were the same for individuals with first-time mTBI within the first 6 months of recovery. METHODS: Two hundred seventeen individuals with first-time mTBI were divided into subgroups-new-onset depressive symptoms, recurrent depressive symptoms, prior depression history only, and never depressed-and compared on clinical and demographic variables and the presence of postconcussive symptoms and functional recovery at 3 and 6 months. RESULTS: New-onset depressive symptoms developed in 12% of the cohort, whereas 11% of the cohort had recurrent depressive symptoms. Both depressive symptoms groups were more likely to comprise women and persons of color and were at higher risk for clinically significant postconcussive symptoms and incomplete functional recovery for the first 6 months postinjury. CONCLUSIONS: Presence of depressive symptoms after first-time mTBI was associated with persistent postconcussive symptoms and incomplete functional recovery in the first 6 months. Adding to the existing literature, these findings identified correlates of depressive symptom development and poor outcomes after mTBI, thus providing further evidence that mTBI may produce persistent symptoms and functional limitations that warrant clinical attention.

Age differences in outcome after mild traumatic brain injury: results from the HeadSMART study.

This study longitudinally examined age differences across multiple outcome domains in individuals diagnosed with acute mild traumatic brain injury (mTBI). A sample of 447 adults meeting VA/DoD criteria for mTBI was dichotomized by age into older (≥65 years; n = 88) and younger (<65 years; n = 359) sub-groups. All participants presented to the emergency department within 24 hours of sustaining a head injury, and outcomes were assessed at 1-, 3-, and 6-month intervals. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), post-concussive symptoms (PCS) were ascertained with the Rivermead Post-Concussion Questionnaire (RPQ), and functional recovery from the Extended Glasgow Outcome Scale (GOSE). Mixed effects logistic regression models showed that the rate of change over time in odds of functional improvement and symptom alleviation did not significantly differ between age groups (p = 0.200-0.088). Contrary to expectation, older adults showed equivalent outcome trajectories to younger persons across time. This is a compelling finding when viewed in light of the majority opinion that older adults are at risk for significantly worse outcomes. Future work is needed to identify the protective factors inherent to sub-groups of older individuals such as this.

Loss of consciousness and altered mental state predicting depressive and post-concussive symptoms after mild traumatic brain injury.

Objective: Limited studies exist on the association between loss of consciousness (LOC) and altered mental state (AMS) and development of depressive and post-concussive symptoms within six months after mild traumatic brain injury (mTBI). We tested the hypothesis that presence of both LOC and AMS predict the highest risk of symptoms within the first six months post-mTBI compared to either variable alone, and that LOC alone is more strongly associated with these symptoms. Research design: We analyzed data from 407 subjects with mTBI from the Head injury Serum Markers for Assessing Response to Trauma (HeadSMART) cohort, a prospective cohort of patients post-TBI presenting to two urban emergency departments. Results: There were higher rates of depressive (44%) and post-concussive symptoms (54%) at 1 month post-injury, among participants with both LOC and AMS compared to other groups. AMS was associated with depressive symptoms at one and six months (OR = 1.59, p = .038; OR = 1.60; p = .060) and post-concussive symptoms at one month (OR = 1.56, p = .053). LOC was associated only with post-concussive symptoms at one month (OR = 1.55;p = .048). Among those without LOC, AMS was associated with depressive symptoms at one month (OR = 2.24; p = .028). Conclusions: AMS predicts post-mTBI depressive symptoms both in the acute and chronic mTBI phases whereas LOC is a more sensitive predictor of post-concussive symptoms in the acute mTBI period.

Clonal selection drives genetic divergence of metastatic medulloblastoma.

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

Influence of study population definition on the effect of age on outcomes after blunt head trauma.

OBJECTIVES: The purpose of this study was to assess whether study population definition influences the effect of age on outcomes after blunt head trauma. We hypothesized that examining 'all comers' receiving head computerized tomography after blunt head trauma, fewer older individuals would meet Veterans Administration and Department of Defense (VA/DoD) criteria for traumatic brain injury (TBI), and would, therefore, display better outcomes than younger cohorts. However, restricting to participants meeting VA/DoD criteria for TBI, we hypothesized that older individuals would have worse outcomes. METHODS: Data from a recently completed prospective cohort study were analysed with age dichotomized at 65 years. Logistic regression modelling, controlled for potential confounders including head trauma severity, was estimated to measure the effect of age on functional recovery, post-concussion symptoms (PCS), and depressive symptoms at 1-month post-TBI. RESULTS: Fewer older than younger individuals met VA/DoD criteria for TBI. Older individuals had better functional, PCS, and depressive outcomes at 1 month. Restricting to those meeting VA/DoD criteria for TBI, older individuals continued to have better functional and PCS outcomes but had outcomes comparable to younger on depressive symptoms. CONCLUSIONS: Contrary to our hypothesis, there was a tendency for older adults to have better outcomes than younger, independent of the diagnostic criteria applied.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.

BACKGROUND: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

Medulloblastoma subgroups remain stable across primary and metastatic compartments.

Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.

Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells.

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.

CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity.

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma.

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis.

BACKGROUND: Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. METHODS: We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. FINDINGS: We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037). INTERPRETATION: LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. FUNDING: Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.

Subgroup-specific alternative splicing in medulloblastoma.

Medulloblastoma comprises four distinct molecular variants: WNT, SHH, Group 3, and Group 4. We analyzed alternative splicing usage in 14 normal cerebellar samples and 103 medulloblastomas of known subgroup. Medulloblastoma samples have a statistically significant increase in alternative splicing as compared to normal fetal cerebella (2.3-times; P < 6.47E-8). Splicing patterns are distinct and specific between molecular subgroups. Unsupervised hierarchical clustering of alternative splicing events accurately assigns medulloblastomas to their correct subgroup. Subgroup-specific splicing and alternative promoter usage was most prevalent in Group 3 (19.4%) and SHH (16.2%) medulloblastomas, while observed less frequently in WNT (3.2%), and Group 4 (9.3%) tumors. Functional annotation of alternatively spliced genes reveals overrepresentation of genes important for neuronal development. Alternative splicing events in medulloblastoma may be regulated in part by the correlative expression of antisense transcripts, suggesting a possible mechanism affecting subgroup-specific alternative splicing. Our results identify additional candidate markers for medulloblastoma subgroup affiliation, further support the existence of distinct subgroups of the disease, and demonstrate an additional level of transcriptional heterogeneity between medulloblastoma subgroups.

A Prognostic Model for Predicting One-Month Outcomes among Emergency Department Patients with Mild Traumatic Brain Injury and a Presenting Glasgow Coma Scale of Fifteen.

The lack of well-performing prognostic models for early prognostication of outcomes remains a major barrier to improving the clinical care of patients with mild traumatic brain injury (mTBI). We aimed to derive a prognostic model for predicting incomplete recovery at 1-month in emergency department (ED) patients with mTBI and a presenting Glasgow Coma Scale (GCS) score of 15 who were enrolled in the HeadSMART (Head Injury Serum Markers for Assessing Response to Trauma) study. The derivation cohort included 355 participants with complete baseline (day-of-injury) and follow-up data. The primary outcome measure was the Glasgow Outcome Scale Extended (GOSE) at 1-month and incomplete recovery was defined as a GOSE <8. At 1-month post-injury, incomplete recovery was present in 58% (n = 205) of participants. The final multi-variable logistic regression model included six variables: age in years (odds ratio [OR] = 0.98; 95% confidence interval [CI]: 0.97-1.00), positive head CT (OR = 4.42; 95% CI: 2.21-9.33), history of depression (OR = 2.59; 95% CI: 1.47-4.69), and self-report of moderate or severe headache (OR = 2.49; 95% CI: 1.49-4.18), difficulty concentrating (OR = 3.17; 95% CI: 1.53-7.04), and photophobia (OR = 4.17; 95% CI: 2.08-8.92) on the day-of-injury. The model was validated internally using bootstrap resampling (1000 resamples), which revealed a mean over-optimism value of 0.01 and an optimism-corrected area under the curve (AUC) of 0.79 (95% CI: 0.75-0.85). A prognostic model for predicting incomplete recovery among ED patients with mTBI and a presenting GCS of 15 using easily obtainable clinical and demographic variables has acceptable discriminative accuracy. External validation of this model is warranted.

Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas.

Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both cell lines and primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr(705)) occurs in a dose- and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2) were not inhibited by sorafenib in these cells. Both D-type cyclins (D1, D2, and D3) and E-type cyclin were down-regulated by sorafenib. Also, expression of the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by sorafenib. Finally, sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data show that sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas. These findings provide a rationale for treatment of pediatric medulloblastomas with sorafenib.

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

Poor sleep is linked to impeded recovery from traumatic brain injury.

Study Objectives: While disruptions in sleep are common after mild traumatic brain injury (TBI), the longitudinal relationships between sleep problems and global functioning after injury are poorly understood. Here, we prospectively investigate risk for functional impairment during the first 6 months of TBI recovery based on sleep onset insomnia symptoms and short sleep. Methods: Patients presenting to the Emergency Department (ED) at Johns Hopkins Hospital within 24 hours of head injury and evaluated for TBI were eligible for our study. Demographic and injury-related information were collected in the ED. Patients then completed in-person surveys and phone interviews to provide follow-up data on global functioning, sleep, and depressive symptoms at 1, 3, and 6 months post-injury. A total of 238 patients provided sufficient data for analysis, and hypotheses were tested using mixed effects modeling. Results: Sleep quality and global functioning improved over the 6 months of TBI recovery, but patients were at increased risk for functional impairment when sleeping poorly (odds ratio [OR] = 7.69, p < .001). Sleep onset insomnia symptoms and short sleep both independently corresponded to poor global functioning. Functional impairment was highest among those with both insomnia and short sleep (43%-79%) compared to good sleepers (15%-25%) and those with short sleep (29%-33%) or insomnia alone (33%-64%). A bidirectional relationship between sleep quality and functioning was observed. Conclusions: Functionally impaired patients diagnosed predominantly with mild TBI exhibit high rates of insomnia and short sleep, which may impede TBI recovery. Monitoring sleep after head injury may identify patients with poor prognoses and allow for early intervention to improve functional outcomes.

Wilms tumor 1 expression in malignant gliomas and correlation of +KTS isoforms with p53 status.

OBJECT: The WT1 gene is overexpressed in many types of human cancer. It has been demonstrated that Wilms tumor 1 (WT1) promotes tumor cell proliferation and survival in some cell lines by inhibiting p53-mediated apoptosis; however, this relationship has not been investigated in gliomas. The goal in this study was to characterize the expression pattern of WT1 in human gliomas and to determine if a correlation exists between WT1 expression and p53 status. METHODS: The authors screened nine malignant glioma cell lines, 50 glioblastoma multiforme (GBM) samples, and 16 lower-grade glial tumors for WT1 expression. RESULTS: Five of nine cell lines, 44 of 50 GBM samples, and 13 of 16 lower-grade gliomas expressed WT1 mRNA on reverse transcriptase polymerase chain reaction (PCR) analysis. Expression of WT1 was not detected in normal astrocytes. Two WT1 isoforms, +/+ and -/+, were expressed in the majority of these samples. Real-time PCR analysis of the GBM cell lines revealed that the level of WT1 mRNA ranged from 6.33 to 214.70 ng per ng 18S ribosomal RNA. The authors screened the GBM samples for p53 mutation by using PCR and single-stranded conformational polymorphism analysis, and they demonstrated an association between WT1 expression and p53 status. Tumors that contained wild-type p53 were significantly more likely to express WT1 than tumors that contained mutant p53. CONCLUSIONS: The presence of WT1 in glioma cell lines and the majority of primary tumor samples and its absence in normal astrocytes support the suggestion that WT1 expression is important in glioma biology.

Derivation of a Three Biomarker Panel to Improve Diagnosis in Patients with Mild Traumatic Brain Injury.

BACKGROUND: Nearly 5 million emergency department (ED) visits for head injury occur each year in the United States, of which <10% of patients show abnormal computed tomography (CT) findings. CT negative patients frequently suffer protracted somatic, behavioral, and neurocognitive dysfunction. Our goal was to evaluate biomarkers to identify mild TBI (mTBI) in patients with suspected head injury. METHODS: An observational ED study of head-injured and control patients was conducted at Johns Hopkins University (HeadSMART). Head CT was obtained (ACEP criteria) in patients with Glasgow Coma Scale scores of 13-15 and aged 18-80. Three candidate biomarker proteins, neurogranin (NRGN), neuron-specific enolase (NSE), and metallothionein 3 (MT3), were evaluated by immunoassay (samples <24 h from injury). American Congress of Rehabilitation Medicine (ACRM) criteria were used for diagnosis of mTBI patients for model building. Univariate analysis, logistic regression, and random forest (RF) algorithms were used for data analysis in R. Overall, 662 patients were studied. Statistical models were built using 328 healthy controls and 179 mTBI patients. RESULTS: Median time from injury was 5.9 h (IQR, 4.0; range 0.8-24 h). mTBI patients had elevated NSE, but decreased MT3 versus controls (p < 0.01 for each). NRGN was also elevated but within 2-6 h after injury. In the derivation set, the best model to distinguish mTBI from healthy controls used three markers, age, and sex as covariates (C-statistic = 0.91, sensitivity 98%, specificity 72%). Panel test accuracy was validated with the 155 remaining ACRM+ mTBI patients. Applying the RF model to the ACRM+ mTBI validation set resulted in 78% correctly classified as mTBI (119/153). CT positive and CT negative validation subsets were 91% and 75% correctly classified. In samples taken <2 h from injury, 100% (10/10) samples classified correctly, indicating that hyperacute testing is possible with these biomarker assays. The model accuracy varied from 72-100% overall, and had greater accuracy with increasing severity, as shown by comparing CT+ with CT- (91% versus 75%), and Injury Severity Score ≥16 versus <16 (88% versus 72%, respectively). Objective blood tests, detecting NRGN, NSE, and MT3, can be used to identify mTBI, irrespective of neuroimaging findings.