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Ependymomas show poor correlation between World Health Organization grade and clinical outcome. A subgroup of supratentorial ependymomas are characterized by C11orf95-RELA fusions, presumed to be secondary to chromothripsis of chromosome 11, resulting in constitutive activation of the NF-κB signaling pathway and overexpression of cyclin D1, p65, and L1 cell adhesion molecule (L1CAM). These RELA-fused ependymomas are recognized as a separate, molecularly defined World Health Organization entity and might be associated with poor clinical outcome. In this study, we show that immunohistochemistry for NF-κB signaling components, such as L1CAM, p65, and cyclin D1, can help distinguish RELA-fused from non-RELA-fused supratentorial ependymomas. Furthermore, these three markers can reliably differentiate RELA-fused ependymomas from a variety of histologic mimics. Lastly, we report that RELA-fused ependymomas may be associated with different chromosomal copy number changes and molecular alterations compared to their non-RELA-fused counterparts, providing additional insight into the genetic pathogenesis of these tumors and potential targets for directed therapies.

Tumor recurrence is the leading cause of death among children with medulloblastoma, the most common type of malignant pediatric brain tumors. The mechanisms behind medulloblastoma recurrence are not fully understood. We previously showed that the transcription factor SOX9 promotes cisplatin treatment resistance in medulloblastoma. Here we show that SOX9 levels correlate with poor prognosis in Group 3 tumors. By studying paired primary-recurrent medulloblastoma samples and patient-derived xenograft (PDX) models we further identified rare SOX9-positive slow-cycling, therapy-resistant tumor cells that accumulate in relapses and in leptomenigeal metastases of Group 3 and Group 4 patients. By using an inducible Tet-OFF transgenic (GTML) mouse model for malignant MYCN-driven Group 3 tumors we identified rare SOX9-positive, quiescent brain tumor cells that are more resistant to cisplatin. Dox treatment normally cures GTML transgenic animals that developed aggressive medulloblastoma by turning MYCN off. However, when crossing the Tet-OFF GTML model with a Tet-ON rtTA-Sox9 model we can redirect MYCN expression to the Sox9 promoter ultimately driving brain tumor recurrence from rare SOX9-positive cells with 100% penetrance. In this novel animal model, recurrent tumors were actively disseminating from the hindbrain to the spinal cord and into the forebrain similar to distant relapses found in patients. By overexpressing SOX9 in human Group 3 tumor cells, MYC was directly inhibited and cell proliferation was decreased. PDX models of Group 3 tumors further showed increased levels of SOX9-positivity and less proliferative cells in metastatic compartments. Expression profiling revealed that recurrences were more inflammatory, metastatic, immune evasive and showed elevated MGMT methyltransferase levels which depleted recurrent cells and sensitized them for chemotherapy when using the MGMT inhibitor lomeguatrib. To summarize, our data clarify important and complex mechanisms by which latent medulloblastoma cells fail to respond to standard therapy and generate relapses.

Cutaneous mixed tumors, also known as chondroid syringomas, are benign adnexal neoplasms that share histomorphologic features with pleomorphic adenomas of the salivary gland. Recent work suggests that the similarity between these 2 tumor types extends to the molecular level because both harbor identical chromosomal rearrangements involving the PLAG1 gene. The resulting nuclear PLAG1 overexpression can be detected by immunohistochemistry and has become a useful diagnostic adjunct for both tumor types. In the skin, however, there are 2 morphologically distinct types of mixed tumor, which have been referred to as apocrine-type cutaneous mixed tumor (AMT) and eccrine-type cutaneous mixed tumor (EMT). Previous studies of PLAG1 expression in cutaneous mixed tumor did not distinguish between these types. Here, we evaluated PLAG1 expression by immunohistochemistry in a cohort of 25 cutaneous mixed tumors stratified by type. PLAG1 was overexpressed in the majority of AMT cases (14 of 16) but in none of the EMT cases (0 of 9). A second gene, HMGA2, known to be upregulated in a subset of salivary gland pleomorphic adenomas, was overexpressed in only 1 case of AMT (1 of 16) and in none of the cases of EMT (0 of 9). Our results indicate that apocrine- and eccrine-type mixed tumors are associated with different pathways of molecular pathogenesis and suggest that the emerging relationship between skin and salivary gland mixed tumors is likely limited to those of apocrine type.

BCOR is an epigenetic regulator and is genetically altered by mutation, deletion, or gene fusion in a range of cancers. "Central nervous system high-grade neuroepithelial tumor with BCOR alteration" is a recently described entity with characteristic internal tandem duplications within exon 15 of the BCOR gene (hereafter: CNS HGNET-BCOR ex15 ITD). In this case series of 3 patients, we report the clinicopathologic, molecular, and methylome features of gliomas with novel EP300-BCOR in-frame gene fusions, thus expanding the spectrum of BCOR alterations seen in CNS tumors. The gliomas in this series arise in children (ages 10-18), involve the supratentorial compartment, and have an infiltrative pattern of growth and a myxoid/microcystic background with frequent psammomatous calcifications and prominent chicken-wire vessels. All 3 cases had areas with low-grade morphology and 2 of them demonstrated histologic high-grade transformation. In contrast to CNS HGNET-BCOR ex15 ITD, they lack perivascular pseudorosettes. On a t-Distributed Stochastic Neighbor Embedding plot they cluster perfectly together, away from CNS HGNET-BCOR ex15ITD, consistent with a different entity. Gliomas with EP300-BCOR fusions and high-grade histology can demonstrate relatively rapid regrowth after debulking or subtotal resection.

Despite significant advances in molecular genetic approaches, fluorescence in situ hybridization (FISH) remains the gold standard for the diagnostic evaluation of genomic aberrations in patients with chronic lymphocytic leukemia (CLL). Efforts to improve the diagnostic utility of molecular cytogenetic testing have led to the expansion of the traditional 4-probe CLL FISH panel. Not only do these efforts increase the cost of testing, they remain hindered by the inherent limitations of FISH studies - namely the inability to evaluate genomic changes outside of the targeted loci. While array-based profiling and next generation sequencing (NGS) have critically expanded our understanding of the molecular pathogenesis of CLL, these methodologies are not routinely used by diagnostic laboratories to evaluate copy number changes or the mutational profile of this disease. Mitogenic stimulation of CLL specimens with CpG-oligonucleotide (CpG-ODN) has been identified as a reliable and reproducible means of obtaining a karyotype, facilitating a low-resolution genome-wide analysis. Across a cohort of 1255 CpG-ODN-stimulated CLL specimens, we describe the clinical utility associated with the combinatorial use of FISH and karyotyping. Our testing algorithm achieves a higher diagnostic yield (∼10%) through the detection of complex karyotypes, well-characterized chromosomal aberrations not covered by the traditional CLL FISH panel and through the detection of concurrent secondary malignancies. Moreover, the single cell nature of this approach permits the evaluation of emerging new clinical concepts including clonal dynamics and clonal evolution. This approach can be broadly applied by diagnostic laboratories to improve the utility of traditional and molecular cytogenetic studies of CLL. Am. J. Hematol. 91:978-983, 2016. © 2016 Wiley Periodicals, Inc.

Astroblastomas are rare primary brain tumors, diagnosed based on histologic features. Not currently assigned a WHO grade, they typically display indolent behavior, with occasional variants taking a more aggressive course. We characterized the immunohistochemical characteristics, copy number (high-resolution array comparative genomic hybridization, OncoCopy) and mutational profile (targeted next-generation exome sequencing, OncoPanel) of a cohort of seven biopsies from four patients to identify recurrent genomic events that may help distinguish astroblastomas from other more common high-grade gliomas. We found that tumor histology was variable across patients and between primary and recurrent tumor samples. No common molecular features were identified among the four tumors. Mutations commonly observed in astrocytic tumors ( IDH1/2 , TP53 , ATRX , and PTEN ) or ependymoma were not identified. However one case with rapid clinical progression displayed mutations more commonly associated with GBM ( NF1 N1054H/K63 *, PIK3CA R38H and ERG A403T ). Conversely, another case, originally classified as glioblastoma with nine-year survival before recurrence, lacked a GBM mutational profile. Other mutations frequently seen in lower grade gliomas ( BCOR, BCORL1, ERBB3, MYB, ATM ) were also present in several tumors. Copy number changes were variable across tumors. Our findings indicate that astroblastomas have variable growth patterns and morphologic features, posing significant challenges to accurate classification in the absence of diagnostically specific copy number alterations and molecular features. Their histopathologic overlap with glioblastoma will likely confound the observation of long-term GBM "survivors". Further genomic profiling is needed to determine whether these tumors represent a distinct entity and to guide management strategies.

Tumor recurrence is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. Recurrence occurs when subpopulations of cancer cells evade standard therapy by acquiring features of immune escape, metastatic spread, and treatment resistance. The transcription factor SOX9 correlated with treatment resistance and dissemination in aggressive Group 3 medulloblastoma. By studying paired primary-recurrent medulloblastoma samples and patient-derived xenograft models, we identified rare SOX9-positive slow-cycling, therapy-resistant tumor cells that accumulate in relapses and in metastases. In an inducible transgenic Group 3 tumor model, doxycycline treatment kills all tumor cells by turning MYC off. However, when MYC expression was redirected to the SOX9 promoter, recurrences from rare, dormant SOX9-positive cells developed with 100% penetrance. Expression profiling revealed that recurrences were more inflammatory, metastatic, and showed elevated MGMT methyltransferase levels which depleted recurrent cells when selectively inhibited. Our model explains how recurrences develop from SOX9-induced quiescence in MYC-driven brain cancer.

The clinical behavior of meningiomas often belies their histopathologic grade. Increasing data suggest that molecular features augment classic World Health Organization (WHO) classification in predicting recurrent risk. We investigated the influence of histopathology, chromosome copy number, and treatment on meningioma outcome to construct a simple, scalable, molecularly integrated classifier. METHODS: We analyzed 684 meningiomas with genome-wide chromosomal copy-number profiling for clinical features, pre-/post-operative tumor volume, histopathology, and recurrence. We devised a point-based molecularly-integrated classification system (IC 1-3), incorporating mitotic count and nine common molecular alterations consistently associated with risk of recurrence across four independent statistical tests. We used brier curves, time-dependent area-under-the-curve, and average precision to assess model performance. We added treatment variables, including primary or recurrent status, tumor size, and extent of resection, to the Integrated class to formulate a nomogram of recurrence risk at 5 years. RESULTS: The Integrated Class significantly associated with recurrence in a multivariate model (IC Class 2 vs 1: HR 3.60, 95% CI 2.19-5.91; Class 3 vs 1: HR 5.15, 95% CI 3.28-8.09) and outperformed WHO grade in predicting recurrence (by integrated brier score, 0.093 vs 0.178, internally and independently validated). WHO Grade I and IC-1 exhibited 86% concordance, 31.5% between Grade II and IC-2, and 64% between Grade III and IC-3. WHO grade I meningiomas with IC 2-3 fared significantly worse than WHO grade II-III meningiomas with IC-1 designation. Each additional molecular feature incrementally strengthens the classifier, allowing for application of single-arm FISH or combinatorial genome-wide signatures based on available resources. Intriguingly, receipt of adjuvant radiation in newly diagnosed WHO Grade II-III or IC 2-3 meningiomas was associated with greater propensity for recurrence, after controlling for extent of resection. CONCLUSION: We present a scalable, molecularly-integrated classification for meningioma that better predicts recurrence compared to classic histopathologic grades to aid in clinical management.

e15575 Background: High resolution single nucleotide polymorphism (SNP) chromosomal microarrays (CMA) detect copy number changes and copy neutral-loss of heterozygosity (CN-LOH) across the entire genome, currently providing the best assessment for these types of genomic variants. Chromosomal microarrays are first tier tests utilized in the postnatal detection of microdeletions, microduplications and uniparental disomy/regions of homozygosity in constitutional disorders involving congenital abnormalities, developmental delay and intellectual disability. Methods: In the oncology setting, aberrations detected may be diagnostic, prognostic, and therapeutic. Because CMA assesses the entire genome and can readily detect aberrations as small as a single exon to as large as a whole chromosome, this is an important clinical tool to bridge the gap between low resolution of metaphase chromosome analysis and PCR-based short read sequencing-based assays. Results: No single genomic technique (metaphase chromosome analysis, FISH, CMA or Next Generation Sequencing, including large targeted gene panels) has the ability to detect all relevant information. Therefore, CMA should be considered an important clinical tool for solid and liquid tumors. Across a wide variety of solid tumors, whole genome assessment (including oncogene amplification, tumor suppressor loss, and copy number burden) leads not only to possible therapy targets but also to opportunities for participation in active clinical trials. Recently, the Cancer Genomics Consortium has published evidenced-based reviews on the clinical utility of CMA for copy number and CN-LOH assessment in a variety of hematologic malignancies, and similar papers in solid tumors are in review. Recognizing the growing evidence for CMA, the American Medical Association (AMA) CPT editorial board recently created a new Tier 1 test for cytogenomic arrays in neoplasia, and Centers for Medicare and Medicaid Services (CMS) approved crosswalking the price of the new code to the well-established constitutional cytogenomic array CPT code. Conclusions: For this presentation, examples of diagnostic, prognostic, and therapeutic utility and inclusion in clinical trials across many hematologic and solid tumor neoplasms will be presented to demonstrate the efficacy, cost effectiveness and sensitivity of whole genome assessment of copy number and copy neutral loss of heterozygosity

BACKGROUND: Advances in genomic profiling, together with a better understanding of cancer genetic drivers have generated opportunities for precision medicine trials in newly diagnosed glioblastoma (GBM). ALLELE is a consortium to create independent infrastructure for prospective genomics and functional diagnostics to support biomarker-driven trials in GBM. METHODS: Multi-center prospective study of molecular profiling in newly diagnosed GBM. Clinical (CLIA) tumor/normal whole exome sequencing (WES) and genome-wide copy number array (CNA) were performed. Primary objective: to evaluate the feasibility of genotyping tumors with a turnaround time allowing prospective data use in prospective trials. Secondary objectives included developing infrastructure for novel functional biomarker assays and investigating the clinical yield of tumor/normal WES and CNA in GBM. RESULTS: As of 5/1/18, 65 patients with GBM enrolled among 7 sites. Median age was 59. WES and CMA were completed in 60 patients, with a median time between tissue submission and reporting of 22 days (range 15–35). 33 patients were enrolled in INSIGhT, a randomized platform adaptive trial comparing standard of care versus adjuvant CC-115, neratinib or abemaciclib in MGMT unmethylated newly diagnosed GBM (NCT02977780). In each arm, pre-defined biomarkers (EGFR, PI3K and CDK) will be evaluated for their ability to predict outcome. Potentially actionable findings were identified in 30 patients, and included EGFR amplification, mutations of BRAF, FGFR1, IDH1/2 or FGFR3 or MET fusion. Four tumors were reclassified based on genomics. Functional biomarker assays were developed for real-time evaluation of pharmacodynamic responses in ex vivo models. Updated results of exploratory biomarker analyses will be presented at the conference. CONCLUSIONS: Real-time WES, copy number arrays and functional diagnostics are feasible in newly diagnosed glioblastoma, and can support a variety of biomarker-driven trials. Genomic analyses conducted in a prospective manner can inform subsequent clinical trial analysis aiming at matching outcome with tumor genotyping.

Tumor recurrence is the main cause of death among children with medulloblastoma, the most frequent type of malignant pediatric brain tumors. The medulloblastoma subgroup Group 3 has the poorest survival of all four subgroups, and is associated with a high rate of tumor recurrence in children. Mechanisms behind medulloblastoma recurrence are not yet well understood. We found that the transcription factor SOX9 marks quiescent brain tumor stem cells and is suppressed by MYC overexpression in aggressive Group 3 tumors. By using our inducible Tet-OFF transgenic (GTML) mouse model for malignant MYCN-driven Group 3 tumors and human Group 3 MYC-driven patient-derived xenograft (PDX) models we identified rare SOX9-positive, slow-cycling brain tumor cells that are more resistant to standard chemotherapy. Dox treatment normally cures GTML transgenic animals that developed aggressive medulloblastoma by turning MYCN off. However, when crossing the Tet-OFF GTML model with a Tet-ON rtTA-Sox9 model we can redirect MYCN expression to the control of the Sox9 promoter - ultimately driving brain tumor recurrence from rare SOX9-positive cells with 100% penetrance. These recurrent tumors were actively disseminating from the hindbrain into the forebrain. Expression profiling shows that recurring tumors have increased levels of SOX9, are more inflammatory and have elevated levels of MGMT methyltransferase, compared to the primary tumors. Overexpressing SOX9 into Group 3 MB cells directly inhibited MYC, and decreased cell proliferation while promoting metastasis. Paired primary and recurrent human Group 3 and Group 4 tumor biopsies also showed significantly higher levels of SOX9 at recurrence. PDX models of Group 3 tumors further showed increased levels of SOX9 positivity in metastatic compartments. Our data unveils complex mechanisms by which dormant medulloblastoma cells fail to respond to standard therapy and generate tumor relapses.

Aims The PHOX2B gene regulates neuronal maturation in the brain stem nuclei associated with cardiorespiratory function and in the autonomic sympathetic and enteric nervous system. PHOX2B expression is a reliable immunomarker for peripheral neuroblastic tumours; however, no systematic evaluation of central nervous system (CNS) embryonal tumours was included in the studies. We encountered two cases in which the differential diagnosis included neuroblastoma and CNS embryonal tumour, and we hypothesised that PHOX2B immunostain would be helpful in establishing the diagnosis. Methods and results PHOX2B immunostain was performed on 29 paediatric cases, with adequate controls: one retroperitoneal embryonal tumour in a child with retinoblastoma (index 1), one posterior fossa embryonal tumour in a child with a neuroblastoma (index 2), seven medulloblastomas, four atypical teratoid/rhabdoid tumours (ATRT), four retinoblastomas, six pineoblastomas, four embryonal tumours with multilayered rosettes (ETMR) and two CNS embryonal tumours, not elsewhere classified. Cell lineage immunomarkers (GFAP, OLIG2, synaptophysin, NeuN, CRX, PGP 9.5), immunosurrogates for molecular alterations (beta-catenin, INI1, Lin-28), array CGH and OncoPanel were performed as needed. Medulloblastomas, ATRTs, ETMRs, retinoblastomas and CNS embryonal tumours not elsewhere classified were essentially negative for PHOX2B. Two of six pineoblastomas had significant PHOX2B expression, while the rest were negative. Index 1 was negative for PHOX2B and PGP 9.5 and positive for CRX, consistent with retinoblastoma. Index 2 had diffuse PHOX2B expression, MYCN amplification and no copy number changes of medulloblastoma, in keeping with neuroblastoma. Conclusion PHOX2B antibody is helpful in distinguishing between peripheral neuroblastic and CNS embryonal tumours, which are immunonegative, with the caveat that a subset of pineoblastomas has significant expression.

Purpose: Chromosomal microarray (CMA) is recommended as the first tier test in evaluation of individuals with neurodevelopmental disability and congenital anomalies. CMA may not detect balanced cytogenomic abnormalities or uniparental disomy (UPD), and deletion/duplications and regions of homozygosity may require additional testing to clarify the mechanism and inform accurate counseling. We conducted an evidence review to synthesize data regarding the benefit of additional testing after CMA to inform a genetic diagnosis. Methods: The review was guided by key questions related to the detection of genomic events that may require additional testing. A PubMed search for original research articles, systematic reviews, and meta-analyses were evaluated from articles published between January 1, 1983 and March 31, 2017. Based on the key questions, articles were retrieved and data extracted in parallel with comparison of results and discussion to resolve discrepancies. Variables assessed included study design and outcomes. Results: A narrative synthesis was created for each question to describe the occurrence of, and clinical significance of, additional diagnostic findings from subsequent testing performed after CMA. Conclusion: These findings may be used to assist the laboratory and clinician when making recommendations about additional testing after CMA, as it impacts clinical care, counseling, and diagnosis.

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

A highly aggressive subgroup of the pediatric brain tumor medulloblastoma is characterized by overexpression of the proto-oncogene c-Myc, which encodes a transcription factor that normally maintains neural progenitor cells in an undifferentiated, proliferating state during embryonic development. Myc-driven medulloblastomas typically show a large-cell anaplastic (LCA) histological pattern, in which tumor cells display large, round nuclei with prominent nucleoli. This subgroup of medulloblastoma is therapeutically challenging because it is associated with a high rate of metastatic dissemination, which is a powerful predictor of short patient survival times. Genetically engineered mouse models have revealed important insights into the pathogenesis of medulloblastoma and served as preclinical testing platforms for new therapies. Here we report a new mouse model of Myc-driven medulloblastoma, in which tumors arise in situ after retroviral transfer and expression of Myc in Nestin-expressing neural progenitor cells in the cerebella of newborn mice. Tumor induction required concomitant loss of Tp53 or overexpression of the antiapoptotic protein Bcl-2. Like Myc-driven medulloblastomas in humans, the tumors induced in mice by Myc + Bcl-2 and Myc - Tp53 showed LCA cytoarchitecture and a high rate of metastatic dissemination to the spine. The fact that Myc - Tp53 tumors arose only in Tp53(-/-) mice, coupled with the inefficient germline transmission of the Tp53-null allele, made retroviral transfer of Myc + Bcl-2 a more practical method for generating LCA medulloblastomas. The high rate of spinal metastasis (87% of brain tumor-bearing mice) will be an asset for testing new therapies that target the most lethal aspect of medulloblastoma.

Background Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. Methods We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry-based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. Results OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. Conclusions Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma.

Background Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling. Objective This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation. Methods Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture. Results We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition. Conclusions Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome., Graphical abstract

Molecular taxonomy augments traditional histopathology in defining tumor subclasses and improves clinical risk stratification. We investigated the molecular signatures of over 2,000 central nervous system (CNS) tumors using a clinical multiplexed next-generation sequencing assay, to investigate cardinal mutations, copy number alterations, and rearrangements. These included over 1000 gliomas, 170 meningiomas, 150 pituitary adenomas, 25 vestibular schwannomas, and other less common pathologies. Machine learning clustering analysis partitioned CNS tumors into four robust categories, with critical contribution from the extent of copy number alterations within tumors. An unbiased decision tree constructed based on the entropic contribution of the molecular features in our dataset recapitulated the known histological subtypes among gliomas and suggests a rank order of significance in molecular signatures. We further correlated the genomic data with clinical annotation and survival outcomes to provide prognostic guidance in the interpretation of molecular signatures. Lastly, we described the role of targetable oncogenic pathways in specific cancers to postulate potential therapeutic venues in CNS tumors. This analysis of a large series of CNS tumors from a clinical setting confirms previously identified molecular subclasses for diverse tumors, describe the incidence of genomic alterations in specific tumors, and present potential novel signatures that emerge with large-scale profiling of tumors.

Tumor recurrence is the leading cause of death among children with medulloblastoma, the most frequent type of malignant pediatric brain tumor. The mechanisms behind medulloblastoma recurrence are not fully understood. We found that the transcription factor SOX9 marks quiescent brain tumor stem cells and is suppressed by MYC overexpression in aggressive Group 3 tumors. By using an inducible Tet-OFF transgenic (GTML) mouse model for malignant MYCN-driven Group 3 tumors and human Group 3 MYC-driven PDX models we identified rare SOX9+, slow-cycling brain tumor cells that are more resistant to standard chemotherapy. Dox treatment normally cures GTML transgenic animals that developed aggressive medulloblastoma by turning MYCN off. However, when crossing the Tet-OFF GTML model with a Tet-ON rtTA-Sox9 model we can redirect MYCN expression to the SOX9 promoter ultimately driving brain tumor recurrence from rare SOX9+ cells with 100% penetrance. These recurrent tumors were actively disseminating from the hindbrain to the spinal cord and into the forebrain. Expression profiling comparing primary to recurrent tumors shows that recurring tumors maintain their molecular subgroup but have severely defective DNA repair system and present an increased inflammatory immune response. By overexpressing SOX9 into human Group 3 MB cells MYC was directly inhibited and decreased cell proliferation while promoting migration and metastasis. Paired primary and recurrent human Group 3 and Group 4 tumor biopsies further showed significantly higher levels of SOX9 at recurrence. Finally, PDX models of Group 3 tumors showed increased levels of SOX9 positivity in metastatic compartments. To summarize, our data clarify important and complex mechanisms by which dormant medulloblastoma cells fail to respond to standard therapy and generate relapses.

Medulloblastoma is the most common malignant paediatric brain tumour and is associated with high morbidity and mortality. Medulloblastomas are currently classified into four distinct molecular subgroups (WNT, SHH, Group 3 and Group 4) with different prognosis and responses to therapy. The Polycomb group protein BMI1 sustains self-renewal of neural stem cells and promotes proliferation of neural progenitors during development and in adult tissue homeostasis. Upregulation of BMI1 has been described in a plethora of cancers, including medulloblastoma, and it correlates with clinical stage and poor prognosis. BMI1 is overexpressed across all medulloblastoma subgroups but it is highest in Group 4 where it sustains tumour growth. Insertional mutagenesis of the T2Onc2 transposon by Sleeping Beauty transposase in glutamatergic progenitors overexpressing BMI1 leads to medulloblastoma formation, while neither Bmi1 over-expression nor T2Onc2 transposition alone drives tumorigenesis. These medulloblastomas show frequent inactivating insertions in the chromatin remodelling factor Chd7 (Chromodomain helicase DNA binding factor 7), suggesting that upregulation of BMI1 together with CHD7 loss of function can cooperate to initiate MB tumorigenesis. A BMI1High;CHD7Low molecular signature is associated with poor prognosis in human medulloblastoma and single copy loss and inactivating mutations of CHD7 are found in medulloblastoma Group 4. Silencing of CHD7 in primary patient-derived Group 4 medulloblastoma cells results in increased proliferation and upregulation of markers characteristic of undifferentiated and highly proliferative progenitors. Notably, we demonstrate that the proliferative phenotype driven by CHD7 knockdown is dependent on BMI1. Finally we show a molecular convergence on ERK signalling mediated by CHD7 and dependent on BMI1 expression. These results shed further light on the role of BMI1 and CHD7 in medulloblastoma pathogenesis and raise the possibility that pharmacological targeting of BMI1 or ERK may be particularly indicated in a subgroup of medulloblastoma with low expression level of CHD7.

Anaplastic Lymphoma Kinase (ALK) expression, rearrangements, and single nucleotide variants have been reported in several brain tumor types, but the significance and function of each aberration in adults and children have not been clearly established. To determine the degree to which ALK represents a relevant therapeutic target in gliomas, we first examined ALK expression using immunohistochemistry (IHC) in a panel of 148 adult GBM and 49 pediatric GBM/high grade gliomas. We identified high ALK expression was most frequent in pediatric gliomas (32%, 16/49, IHC score 2+ or 3+). Copy arrays/sequencing and FISH for the ALK locus revealed high level ALK amplification in 31% of ALK-expressing cases (5/16) but was a rare event in gliomas overall. Whole-genome sequencing and RNA sequencing identified novel and recurrent PPP1CB-ALK fusions in 43% of ALK-expressing pediatric GBM (7/16), suggesting IHC may be an efficient means of screening for ALK aberrations as in the identification of EML4-ALK lung cancer. All ALK- amplified cases harbored PPP1CB-ALK fusion but 2 PPP1CB-ALK cases were copy neutral. The phosphatase PPP1CB was fused in-frame to ALK at exon 20 with preservation of the ALK kinase domain and predicted to activate via the same mechanism as other ALK rearranged cancers. ALK fusion proteins promoted cell proliferation and constitutive kinase activity and upregulated STAT and AKT signaling pathways. However, expression of novel ALK missense mutations in NSCs did not promote proliferation. Administration of ALK inhibitor Crizotinib reduced tumor growth in a PDX GBM from a patient with a novel ALK fusion. This work validates amplification and rearrangement of ALK as a highly recurrent driver event and therapeutic target in GBM, particularly in young children where it may be the sole driver event.

Background: microRNA-9 is a key regulator of neuronal development aberrantly expressed in brain malignancies, including medulloblastoma. The mechanisms by which microRNA-9 contributes to medulloblastoma pathogenesis remain unclear, and factors that regulate this process have not been delineated. Methods: Expression and methylation status of microRNA-9 in medulloblastoma cell lines and primary samples were analysed. The association of microRNA-9 expression with medulloblastoma patients' clinical outcome was assessed, and the impact of microRNA-9 restoration was functionally validated in medulloblastoma cells. Results: microRNA-9 expression is repressed in a large subset of MB samples compared with normal fetal cerebellum. Low microRNA-9 expression correlates significantly with the diagnosis of unfavourable histopathological variants and with poor clinical outcome. microRNA-9 silencing occurs via cancer-specific CpG island hypermethylation. HES1 was identified as a direct target of microRNA-9 in medulloblastoma, and restoration of microRNA-9 was shown to trigger cell cycle arrest, to inhibit clonal growth and to promote medulloblastoma cell differentiation. Conclusions: microRNA-9 is a methylation-silenced tumour suppressor that could be a potential candidate predictive marker for poor prognosis of medulloblastoma. Loss of microRNA-9 may confer a proliferative advantage to tumour cells, and it could possibly contribute to disease pathogenesis. Thus, re-expression of microRNA-9 may constitute a novel epigenetic regulation strategy against medulloblastoma.

While medulloblastoma, a pediatric tumor of the cerebellum, is characterized by aberrations in developmental pathways, the majority of genetic determinants remain unknown. An unbiased Sleeping Beauty transposon screen revealed MyoD as a putative medulloblastoma tumor suppressor. This was unexpected, as MyoD is a muscle differentiation factor and not previously known to be expressed in cerebellum or medulloblastoma. In response to deletion of one allele of MyoD, two other Sonic hedgehog-driven mouse medulloblastoma models showed accelerated tumor formation and death, confirming MyoD as a tumor suppressor in these models. In normal cerebellum, MyoD was expressed in the proliferating granule neuron progenitors that are thought to be precursors to medulloblastoma. Similar to some other tumor suppressors that are induced in cancer, MyoD was expressed in proliferating medulloblastoma cells in three mouse models and in human medulloblastoma cases. This suggests that although expression of MyoD in a proliferating tumor is insufficient to prevent tumor progression, its expression in the cerebellum hinders medulloblastoma genesis. Cancer Res; 73(22); 6828–37. ©2013 AACR.

Background Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established. Methods Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints. Results Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas. Conclusion The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.

Aberrant expression of microRNAs has been implicated in many cancers. We recently demonstrated differential expression of several microRNAs in medulloblastoma. In this study, the regulation and function of microRNA 218 (miR-218), which is significantly underexpressed in medulloblastoma, was evaluated. Re-expression of miR-218 resulted in a significant decrease in medulloblastoma cell growth, cell colony formation, cell migration, invasion, and tumor sphere size. We used C17.2 neural stem cells as a model to show that increased miR-218 expression results in increased cell differentiation and also decreased malignant transformation when transfected with the oncogene REST. These results suggest that miR-218 acts as a tumor suppressor in medulloblastoma. MicroRNAs function by down-regulating translation of target mRNAs. Targets are determined by imperfect base pairing of the microRNA to the 3′-UTR of the mRNA. To comprehensively identify actual miR-218 targets, medulloblastoma cells overexpressing miR-218 and control cells were subjected to high throughput sequencing of RNA isolated by cross-linking immunoprecipitation, a technique that identifies the mRNAs bound to the RNA-induced silencing complex component protein Argonaute 2. High throughput sequencing of mRNAs identified 618 genes as targets of miR-218 and included both previously validated targets and many targets not predicted computationally. Additional work further confirmed CDK6, RICTOR, and CTSB (cathepsin B) as targets of miR-218 and examined the functional role of one of these targets, CDK6, in medulloblastoma. Background: MicroRNAs are differentially expressed in medulloblastoma. Results: MicroRNA 218 expression is decreased in medulloblastoma. Re-expression of miR-218 suppresses the malignant cell phenotype in medulloblastoma cells. Unbiased HITS-CLIP analysis identified multiple oncogenic genes as miR-218 targets. Conclusion: miR-218 inhibits medulloblastoma tumor cell phenotype by targeting multiple oncogenes. Significance: miR-218-regulated pathways are important in medulloblastoma pathogenesis.

BACKGROUND. Comprehensive genomic profiling of a patient's cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprise-wide, unselected cancer patient population has yet to be reported. METHODS. We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested. RESULTS. Our cohort consists of cancer patients unrestricted by disease site or stage. Across all consented patients, half had sufficient and available (>20% tumor) material for profiling; once specimens were received in the laboratory for pathology review, 73% were scored as adequate for genomic testing. When sufficient DNA was obtained, OncoPanel yielded a result in 96% of cases. 73% of patients harbored an actionable or informative alteration; only 19% of these represented a current standard of care for therapeutic stratification. The findings recapitulate those of previous studies of common cancers but also identify alterations, including in AXL and EGFR, associated with response to targeted therapies. In rare cancers, potentially actionable alterations suggest the utility of a "cancer-agnostic" approach in genomic profiling. Retrospective analyses uncovered contextual genomic features that may inform therapeutic response and examples where diagnoses revised by genomic profiling markedly changed clinical management. CONCLUSIONS. Broad sequencing-based testing deployed across an unselected cancer cohort is feasible. Genomic results may alter management in diverse scenarios; however, additional barriers must be overcome to enable precision cancer medicine on a large scale. FUNDING. This work was supported by DFCI, BWH, and the National Cancer Institute (5R33CA155554 and 5K23CA157631).

The tumor microenvironment is a critical modulator of carcinogenesis; however, in many tumor types, the influence of the stroma during preneoplastic stages is unknown. Here we explored the relationship between pre-tumor cells and their surrounding stroma in malignant progression of the cerebellar tumor medulloblastoma (MB). We show that activation of the vascular regulatory signalling axis mediated by Norrin (an atypical Wnt)/Frizzled4 (Fzd4) inhibits MB initiation in the Ptch+/− mouse model. Loss of Norrin/Fzd4-mediated signalling in endothelial cells, either genetically or by short-term blockade, increases the frequency of pre-tumor lesions and creates a tumor-permissive microenvironment at the earliest, preneoplastic stages of MB. This pro-tumor stroma, characterized by angiogenic remodelling, is associated with an accelerated transition from preneoplasia to malignancy. These data expose a stromal component that regulates the earliest stages of tumorigenesis in the cerebellum, and a novel role for the Norrin/Fzd4 axis as an endogenous anti-tumor signal in the preneoplastic niche. DOI: http://dx.doi.org/10.7554/eLife.16764.001

To evaluate professional practices relative to episiotomies in the Provence Alpes Côte d'Azur (PACA) region by analysing their incidence in maternity hospitals, by type and by sector of activity. Following this, to analyse maternal and obstetric characteristics associated with episiotomies and the occurrence of perineal tears in Marseille's university hospitals (CHU).Data were extracted from the database for the period from 1st January 2012 to 31 December 2014. The sample included 41 maternity hospitals: 13 private and 28 public. Twenty of the maternity hospitals were level 1, 15 were level 2, and 2 were level 3 (Nice and AP-HM).In the PACA region, 176,573 patients gave birth by vaginal delivery. The incidence of episiotomy over the 3 years was 21.6% (0.50% - 76.13%) with a statistically significant reduction in the incidence between 2012 and 2014 (P0.001). There was a significant difference by sector (P0.001) and level (P0.001) of maternity hospitals. In the Marseille CHU, 21.6% of women had an episiotomy (66.4% in primiparas - 33.6% in multiparous) and 43% had perineal tears (62.3% in primiparas - 37.7% in multiparous). After multivariate analysis, gender, weight of the newborn, presentation, gestational age, and mode of delivery were shown to be factors significantly associated with occurrence of episiotomy and occurrence of perineal tear (P0.001).A significant decrease in the incidence of episiotomy was observed in the PACA region from 2012 to 2014, associated with a wide variation in rates depending on the maternity hospitals, their types and their sectors.

Accurate and consistent variant classification is required for Precision Medicine. But clinical variant classification remains in its infancy. While recent guidelines put forth jointly by the American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) for the classification of Mendelian variants has advanced the field, the degree of subjectivity allowed by these guidelines can still lead to inconsistent classification across clinical molecular genetic laboratories. In addition, there are currently no such guidelines for somatic cancer variants, only published institutional practices. Additional variant classification guidelines, including disease- or gene-specific criteria, along with inter-laboratory data sharing is critical for accurate and consistent variant interpretation.

Resistance to the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance., University of Texas M.D. Anderson Cancer Center (Support Grant CA016672), National Science Foundation (U.S.) (DMR-1310266), Harvard University. Materials Research Science and Engineering Center (DMR-1420570), National Natural Science Foundation (China) (81372496)

Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27-) and dismal (K4-/K27-) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation (EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease.

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Very little is known about aggressive forms of this disease, such as metastatic or recurrent MBs. In order to identify pathways involved in aggressive MB pathophysiology, we performed unbiased, whole genome microarrays on MB tumors at both the human and murine levels. Primary human MBs were compared, transcriptomically, to their patient-matched recurrent or metastatic tumors. Expression profiling was also performed on murine tumors from two spontaneously developing MB mouse models (Ptch+/- and Smo/Smo) that present with differing clinical severities. At both the human and murine levels we identified transforming growth factor-beta (TGF-β) as a potential contributor to MB progression/metastasis. Smad3, a major downstream component of the TGF-β pathway, was also evaluated using immunohistochemistry in malignant human tissues and was shown to correlate with MB metastasis and survival. Similarly, Smad3 expression during development identified a subset of cerebellar neuronal precursors as putative cells of origin for the Smad3-positive MBs. To our knowledge, this is the first study that links TGF-β to MB pathogenesis. Our research suggests that canonical activation of this pathway leads to better prognosis for patients.

Medulloblastomas are malignant brain tumors that arise in the cerebellum in children and disseminate via the cerebrospinal fluid to the leptomeningeal spaces of the brain and spinal cord. Challenged by the poor prognosis for patients with metastatic dissemination, pediatric oncologists have developed aggressive treatment protocols, combining surgery, craniospinal radiation, and high-dose chemotherapy, that often cause disabling neurotoxic effects in long-term survivors. Insights into the genetic control of medulloblastoma dissemination have come from transposon insertion mutagenesis studies. Mobilizing the Sleeping Beauty transposon in cerebellar neural progenitor cells caused widespread dissemination of typically nonmetastatic medulloblastomas in Patched+/− mice, in which Shh signaling is hyperactive. Candidate metastasis genes were identified by sequencing the insertion sites and then mapping these sequences back to the mouse genome. To determine whether genes located at transposon insertion sites directly caused medulloblastomas to disseminate, we overexpressed candidate genes in Nestin+ neural progenitors in the cerebella of mice by retroviral transfer in combination with Shh. We show here that ectopic expression of Eras, Lhx1, Ccrk, and Akt shifted the in vivo growth characteristics of Shh-induced medulloblastomas from a localized pattern to a disseminated pattern in which tumor cells seeded the leptomeningeal spaces of the brain and spinal cord. Cancer Res; 72(19); 4944–53. ©2012 AACR.

Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 that catalyzes the trimethylation of histone H3 on Lys 27, and represses gene transcription. EZH2 enhances cancer-cell proliferation and regulates stem cell maintenance and differentiation. Here, we demonstrate that EZH2 is highly expressed in medulloblastoma, a highly malignant brain tumor of childhood, and this altered expression is correlated with genomic gain of chromosome 7 in a subset of medulloblastoma. Inhibition of EZH2 by RNAi suppresses medulloblastoma tumor cell growth. We show that 3-deazaneplanocin A, a chemical inhibitor of EZH2, can suppress medulloblastoma cell growth partially by inducing apoptosis. Suppression of EZH2 expression diminishes the ability of tumor cells to form spheres in culture and strongly represses the ability of known oncogenes to transform neural stem cells. These findings establish a role of EZH2 in medulloblastoma and identify EZH2 as a potential therapeutic target especially in high-risk tumors.

Medulloblastoma prognosis tends to be poor, despite aggressive therapy, but defining molecular subgroups may identify patients who could benefit from targeted therapies. This study used human gene array and associated clinical data to identify a new molecular subgroup of medulloblastoma characterized by coactivation of the Sonic hedgehog (SHH) and CXCR4 pathways. SHH–CXCR4 tumors were more common in the youngest patients where they were associated with desmoplastic histology. In contrast to tumors activating SHH but not CXCR4, coactivated tumors exhibited greater expression of Math1 and cyclin D1. Treatment with the CXCR4 antagonist AMD3100 inhibited cyclin D1 expression and maximal tumor growth in vivo. Mechanistic investigations revealed that SHH activation stimulated CXCR4 cell surface localization and effector signaling activity, whereas SHH absence caused CXCR4 to assume an intracellular localization. Taken together, our findings define a new medulloblastoma subgroup characterized by a functional interaction between the SHH and CXCR4 pathways, and they provide a rationale to clinically evaluate combined inhibition of SHH and CXCR4 for medulloblastoma treatment. Cancer Res; 72(1); 122–32. ©2011 AACR.

Resume L’annonce du diagnostic du caractere psychogene d’une manifestation d’allure neurologique « neuroforme » est un moment delicat de la consultation neurologique, et qui conditionne fortement la qualite de la prise en charge qui doit suivre, et le pronostic global. L’attitude medicale doit rester bienveillante et adaptee a la situation clinique, en particulier au mecanisme psychologique suppose. Cet article presente une methode generale de presentation du diagnostic, qui ne pretend pas a l’exhaustivite, mais peut fournir une base de reflexion au clinicien place dans cette situation.

Medulloblastoma (MB), an aggressive embryonal tumor of the cerebellum, is the most common malignant pediatric brain tumor and a major cause of pediatric morbidity and mortality. Recent advances in ...

2003Background: Multi-dimensional genomic analyses may improve outcome in glioblastoma (GB) but are not widely available as routine clinical care. ALLELE is an ABC2-funded consortium to generate pr...

International audience; OBJECTIVE: This study compared anxiety and depression in patients presenting with psychogenic non-epileptic seizures (PNES) with those suffering from psychogenic movement disorders (PMD) to assess the link between these psychiatric pathologies and neurological symptoms. METHODS: This clinically descriptive, prospective study involved consecutive patients who fulfilled the clinical and video-EEG criteria for PNES and PMD, and who were recruited over an 18-month period. Semi-structured (according to DSM-IV criteria) psychiatric interviews and self-evaluation using the Beck Depression Inventory and Spielberger State-Trait Anxiety Inventory were carried out. Clinical follow-up was conducted 8-12 months after the first evaluation. RESULTS: A total of 17 patients were recruited: nine presented with PNES; and eight had PMD. Both patient groups had similar demographic and clinical data as well as depression and personality disorders. Although not statistically significant, there was a trend towards an increased prevalence of a familial medical history of epilepsy and a higher incidence of anxiety disorders among patients with PNES. CONCLUSION: The data from this prospective study underscore the clinical and psychiatric similarity between PNES and PMD patients. Further studies involving a larger number of subjects should confirm, from a statistical point of view, the differences suggested in the present investigation and, in particular, the greater incidence of anxiety disorders in PNES patients and the presence of an epileptic parent as a risk factor for PNES.

Brain tumors are the most common childhood solid malignancy and the leading cause of cancer-related death in children. Medulloblastoma, ependymoma, supratentorial primitive neuroectodermal tumors, and pilocytic astrocytoma are the most prevalent types, all of which are clinically, histologically, and genetically heterogeneous. Despite an incomplete molecular understanding of these tumors, we have made significant headway in the past 5 years in identifying and classifying important genetic alterations and pathways central to the disease process. This review summarizes our current state of knowledge, emphasizes recent seminal findings in the field, and proposes future research efforts needed to further characterize the genetic basis of pediatric brain tumors.

Les reunions de concertation pluridisciplinaires (RCP) soins de support-soins palliatifs s’integrent aux RCP de specialite d’organe du 3C du CHU de Grenoble. C’est en partie a travers elles que la coordination des soins de support definie par la circulaire du 22 fevrier 2005 relative a l’organisation des soins en cancerologie est actee et mise en place autour des patients. Elles permettent l’apport de competences de recours et leur coordination. L’experience presentee souligne la diversite des questions abordees (douleurs rebelles, souffrance psychologique, prise en charge sociale, projet therapeutique…) ainsi que les aspects organisationnels de ces RCP avec les modalites de selection des patients, la tracabilite de l’activite, les modalites de suivi des avis. La forte participation medicale et paramedicale rappelle le role formateur de ces RCP aupres des professionnels, mais aussi leur fonction de soutien et de regulation par la parole echangee et la reprise des projets therapeutiques.