Publications by authors named "Christine Haberler"

70 Publications

Histopathological patterns in atypical teratoid/rhabdoid tumors are related to molecular subgroup.

Brain Pathol 2021 May 3:e12967. Epub 2021 May 3.

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor that may not only contain rhabdoid tumor cells but also poorly differentiated small-round-blue cells as well as areas with mesenchymal or epithelial differentiation. Little is known on factors associated with histopathological diversity. Recent studies demonstrated three molecular subgroups of AT/RT, namely ATRT-TYR, ATRT-SHH, and ATRT-MYC. We thus aimed to investigate if morphological patterns might be related to molecular subgroup status. Hematoxylin-eosin stained sections of 114 AT/RT with known molecular subgroup status were digitalized and independently categorized by nine blinded observers into four morphological categories, that is, "rhabdoid," "small-round-blue," "epithelial," and "mesenchymal." The series comprised 48 ATRT-SHH, 40 ATRT-TYR, and 26 ATRT-MYC tumors. Inter-observer agreement was moderate but significant (Fleiss' kappa = 0.47; 95% C.I. 0.41-0.53; p < 0.001) and there was a highly significant overall association between morphological categories and molecular subgroups for each of the nine observers (p < 0.0001). Specifically, the category "epithelial" was found to be over-represented in ATRT-TYR (p < 0.000001) and the category "small-round-blue" to be over-represented in ATRT-SHH (p < 0.01). The majority of ATRT-MYC was categorized as "mesenchymal" or "rhabdoid," but this association was less compelling. The specificity of the category "epithelial" for ATRT-TYR was highest and accounted for 97% (range: 88-99%) whereas sensitivity was low [49% (range: 35%-63%)]. In line with these findings, cytokeratin-positivity was highly overrepresented in ATRT-TYR. In conclusion, morphological features of AT/RT might reflect molecular alterations and may also provide a first hint on molecular subgroup status, which will need to be confirmed by DNA methylation profiling.
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http://dx.doi.org/10.1111/bpa.12967DOI Listing
May 2021

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis.

J Pers Med 2021 Apr 12;11(4). Epub 2021 Apr 12.

Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.

Primary diffuse leptomeningeal melanomatosis (PDLMM) is an extremely rare and aggressive cancer type for which best treatment strategies remain to be elucidated. Herein, we present current and prospective diagnostic strategies and treatment management of PDLMM. Against the background of an extensive literature review of published PDLMM cases and currently employed therapeutic strategies, we present an illustrative case of a pediatric patient suffering from PDLMM. We report the first case of a pediatric patient with PDLMM who received combination treatment including trametinib and everolimus, followed by intravenous nivolumab and ipilimumab with concomitant intensive intraventricular chemotherapy, resulting in temporary significant clinical improvement and overall survival of 7 months. Following this clinical experience, we performed a comprehensive literature review, identifying 26 additional cases. By these means, we provide insight into current knowledge on clinical and molecular characteristics of PDLMM. Analysis of these cases revealed that the unspecific clinical presentation, such as unrecognized increased intracranial pressure (present in 67%), is a frequent reason for the delay in diagnosis. Mortality remains substantial despite diverse therapeutic approaches with a median overall survival of 4 months from diagnosis. On the molecular level, to date, the only oncogenic driver reported so far is mutation of ( = 3), underlining a close biological relation to malignant melanoma and neurocutaneous melanosis. We further show, for the first time, that this somatic mutation can be exploited for cerebrospinal fluid liquid biopsy detection, revealing a novel potential biomarker for diagnosis and monitoring of PDLMM. Last, we use a unique patient derived PDLMM cell model to provide first insights into in vitro drug sensitivities. In summary, we provide future diagnostic and therapeutic guidance for PDLMM and first insights into the use of liquid biopsy and in vitro models for this orphan cancer type.
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http://dx.doi.org/10.3390/jpm11040292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069125PMC
April 2021

Treatment of Embryonal Tumours with Multilayered Rosettes with Carboplatin/Etoposide Induction and High-dose Chemotherapy within the Prospective P-HIT Trial.

Neuro Oncol 2021 Apr 28. Epub 2021 Apr 28.

Division of Oncology and Haematology, Department of Paediatrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.

Background: Embryonal tumours with multilayered rosettes (ETMR) are highly aggressive tumours occurring in early childhood. Published clinical data refer to retrospective, heterogeneously treated cohorts. Here, we describe the outcome of patients treated according to the prospective P-HIT trial and subsequent HIT2000-interim-registry.

Patients And Methods: Age-stratified treatment included carboplatin/etoposide-induction, tandem-high-dose chemotherapy ("CARBO/ETO+HDCT") and response-stratified radiotherapy. Patients with centrally reviewed neuropathological and molecularly confirmed diagnosis of ETMR recruited within the P-HIT trial (2001-2011; n=19), the HIT2000-interim-registry (2012-2014; n=12) and earlier HIT-trials (n=4) were selected for analysis.

Results: Age-adjusted incidence rate was 1.35 per 1 million children (aged 1-4 years) in the years 2012-2014. Median age at diagnosis for 35 patients was 2.9 years. Metastases at diagnosis were detected in 9 patients. One patient died due to postoperative complications. For 30 patients with non-brainstem tumour location, 5-year progression-free (PFS) and overall survival (OS) were 35% and 47% after treatment with CARBO/ETO+HDCT (n=17), compared to 0% and 8% with other treatments (n=13, p[OS]=0.011). All 4 patients with brainstem tumour died within 10 months after diagnosis. By multivariable analysis, supratentorial location: (HR[PFS]:0.07 [95%CI:0.01-0.38], p=0.003), localised disease (M0): (HR[OS] M0, no residual tumor:0.30 [95%CI:0.009-1.09], p=0.068; M0, residual tumor:0.18 [95%CI: 0.04-0.76], p=0.020) and CARBO/ETO+HDCT treatment (HR[OS]:0.16 [95%CI:0.05-054], p=0.003) were identified as independent prognostic factors. Of 9 survivors, 6 were treated with radiotherapy (craniospinal 4; local 2).

Conclusions: Our data indicate improved survival with intensified chemotherapy (CARBO/ETO+HDCT). However, despite intensive treatment, the outcome was poor. Thus, innovative therapies need to be evaluated urgently in an upfront setting.
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http://dx.doi.org/10.1093/neuonc/noab100DOI Listing
April 2021

Cross-species genomics reveals oncogenic dependencies in ZFTA/C11orf95 fusion-positive supratentorial ependymomas.

Cancer Discov 2021 Apr 20. Epub 2021 Apr 20.

Department of Neuropathology, Charite Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health.

Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histological features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0963DOI Listing
April 2021

Potential Importance of Early Focal Radiotherapy Following Gross Total Resection for Long-Term Survival in Children With Embryonal Tumors With Multilayered Rosettes.

Front Oncol 2020 17;10:584681. Epub 2020 Dec 17.

Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.

Embryonal tumor with multilayered rosettes (ETMR) is a rare, aggressive embryonal central nervous system tumor characterized by LIN28A expression and alterations in the locus. ETMRs predominantly occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on nine consecutive patients and review the role of initiation/timing of radiotherapy on survival. Between 2006 and 2018, nine patients were diagnosed with ETMR. Diagnosis was confirmed histopathologically, immunohistochemically and molecularly. Median age was 25 months (5-38). Location was supratentorial in five, pineal in three, and brainstem in one. Seven patients had a gross total resection, one a partial resection and one a biopsy at initial diagnosis. Chemotherapy augmented with intrathecal therapy started a median of 10 days (7-20) after surgery. Only two patients who after gross total resection received radiotherapy very early on (six weeks after diagnosis) are alive and in complete remission 56 and 50 months after diagnosis. All remaining patients for whom radiotherapy was deferred until the end of chemotherapy recurred, albeit none with leptomeningeal disease. A literature research identified 228 patients with ETMR. Including our patients only 26 (11%) of 237 patients survived >36 months with no evidence of disease at last follow-up. All but two long-term (>36 months) survivors received radiotherapy, ten of whom early on following gross total resection (GTR). GTR followed by early focal radiotherapy and intrathecal therapy to prevent leptomeningeal disease are potentially important to improve survival of ETMR in the absence of effective targeted therapies.
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http://dx.doi.org/10.3389/fonc.2020.584681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773839PMC
December 2020

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated -Fusion Positive Pediatric High-Grade Glioma.

J Pers Med 2020 Dec 18;10(4). Epub 2020 Dec 18.

Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated -fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with -fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of -fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.
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http://dx.doi.org/10.3390/jpm10040290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766483PMC
December 2020

Infiltrative gliomas of the thalamus in children: the role of surgery in the era of H3 K27M mutant midline gliomas.

Acta Neurochir (Wien) 2020 Oct 22. Epub 2020 Oct 22.

Comprehensive Cancer Center-CCC CNS Unit, Medical University of Vienna, Vienna, Austria.

Background: The role of surgery in the management of pediatric non-pilocytic infiltrative thalamic gliomas needs to be revisited specifically with regard to molecularly defined subtypes.

Methods: A retrospective review of a consecutive series of children operated on a thalamic tumor between 1992 and May 2018 was performed. Neuroimaging data were reviewed for localization and extent of resection; pathology was re-reviewed according to the current WHO classification, including assessment of histone H3 K27 mutational status.

Results: Forty-nine patients with a thalamic tumor aged < 18 years at diagnosis were identified. Twenty-five patients (51%) had a non-pilocytic infiltrative glioma, of which the H3 K27M status was available in 22. Fourteen patients were diagnosed as diffuse midline glioma (DMG) H3 K27M mutant. There was no statistically significant difference in survival between patients harboring the H3 K27M mutation and wildtype. Resection ("any resection > 50%" vs "biopsy") and histological tumor grade ("°II" vs "°III+°IV") were statistically significant predictors of survival (univariate: p = 0.044 and p = 0.013, respectively). These results remained significant on multivariate analysis (HR 0.371/p = 0.048, HR 9.433/p = 0.035).

Conclusion: We advocate to still consider an attempt at maximal safe resection in the multidisciplinary treatment of unilateral thalamic non-pilocytic gliomas irrespective of their H3 K27-mutational status.
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http://dx.doi.org/10.1007/s00701-020-04589-yDOI Listing
October 2020

Single-Cell RNA-Seq Reveals Cellular Hierarchies and Impaired Developmental Trajectories in Pediatric Ependymoma.

Cancer Cell 2020 07;38(1):44-59.e9

Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

Ependymoma is a heterogeneous entity of central nervous system tumors with well-established molecular groups. Here, we apply single-cell RNA sequencing to analyze ependymomas across molecular groups and anatomic locations to investigate their intratumoral heterogeneity and developmental origins. Ependymomas are composed of a cellular hierarchy initiating from undifferentiated populations, which undergo impaired differentiation toward three lineages of neuronal-glial fate specification. While prognostically favorable groups of ependymoma predominantly harbor differentiated cells, aggressive groups are enriched for undifferentiated cell populations. The delineated transcriptomic signatures correlate with patient survival and define molecular dependencies for targeted treatment approaches. Taken together, our analyses reveal a developmental hierarchy underlying ependymomas relevant to biological and clinical behavior.
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http://dx.doi.org/10.1016/j.ccell.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479515PMC
July 2020

Laser ablation-ICP-TOFMS imaging of germ cell tumors of patients undergoing platinum-based chemotherapy.

Metallomics 2020 08;12(8):1246-1252

Institute of Analytical Chemistry, University of Vienna, Waehringer Strasse 38, 1090 Vienna, Austria.

A low dispersion laser ablation setup in combination with inductively coupled plasma-time-of-flight mass spectrometry (LA-ICP-TOFMS) was applied to clinical samples of patients undergoing platinum-based chemotherapy. The platinum accumulation together with the distribution of elements with biological key functions (Mg, P, S, Ca, Fe, Cu and Zn) was studied in central nervous system germ cell tumor (CNS GCT) tissue, which is an aggressive tumor type located in the brain. Heterogeneous elemental distribution patterns were obtained with a pixel size of 10 μm and were correlated to histological analysis of serial sections using hematoxylin eosin staining. Highest platinum accumulation correlated with areas of necrosis, which exhibited high levels of magnesium, sulphur and calcium. Small traces of gadolinium were found in the tumor sections, which is a result of prior magnetic resonance imaging. Iron accumulated in regions, which were dense in blood vessels, whereas areas with fibrosis scar showed the lowest levels of all detected elements. This LA-ICP-TOFMS study demonstrates that the chemotherapeutic drug cisplatin accumulated in the germ cell tumor located in the brain, which is also reflected by the therapy response of the patients.
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http://dx.doi.org/10.1039/d0mt00080aDOI Listing
August 2020

Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort.

J Clin Oncol 2020 06 24;38(18):2028-2040. Epub 2020 Apr 24.

Department of Neuropathology, Institute for Pathology, Hannover Medical School, Hannover, Germany.

Purpose: The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy.

Patients And Methods: From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia.

Results: Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, iSHH-II, 83%; = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], 74 [CSI]; = .012).

Conclusion: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.
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http://dx.doi.org/10.1200/JCO.19.03057DOI Listing
June 2020

cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading.

Brain Pathol 2020 07 19;30(4):844-856. Epub 2020 Apr 19.

Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany.

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.
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http://dx.doi.org/10.1111/bpa.12832DOI Listing
July 2020

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Cancer Discov 2020 Jul 1;10(7):942-963. Epub 2020 Apr 1.

Department of Neuropathology, University Hospital Hamburg-Eppendorf, and Research Institute Children's Cancer Center, Hamburg, Germany.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ( = 31), ( = 21), ( = 9), and ( = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of , or gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1030DOI Listing
July 2020

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities.

Front Oncol 2019 10;9:1436. Epub 2020 Jan 10.

Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czechia.

Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort ( = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.
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http://dx.doi.org/10.3389/fonc.2019.01436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965319PMC
January 2020

Ectopic Cushing's syndrome in a patient with inferior petrosal sinus sampling indicating pituitary-dependent ACTH secretion.

Clin Case Rep 2020 Jan 14;8(1):104-107. Epub 2019 Dec 14.

Department of Internal Medicine III Division of Endocrinology and Metabolism Medical University Vienna Vienna Austria.

In an unclear case of Cushing's syndrome, IPSS identifies the origin of ACTH secretion, and together with MRI enables the localization of an ectopic corticotroph adenoma in the parasellar or cavernous sinuses region.
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http://dx.doi.org/10.1002/ccr3.2586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982514PMC
January 2020

The molecular landscape of ETMR at diagnosis and relapse.

Nature 2019 12 4;576(7786):274-280. Epub 2019 Dec 4.

Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.
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http://dx.doi.org/10.1038/s41586-019-1815-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908757PMC
December 2019

EANO-EURACAN clinical practice guideline for diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma.

Lancet Oncol 2019 12;20(12):e715-e728

Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.

The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. The guideline is based on the 2016 WHO classification of tumours of the CNS and on scientific developments published since 1980. It aims to provide direction for diagnostic and management decisions, and for limiting unnecessary treatments and cost. In view of the scarcity of data in adults with medulloblastoma, we base our recommendations on adult data when possible, but also include recommendations derived from paediatric data if justified. Our recommendations are a resource for professionals involved in the management of post-pubertal and adult patients with medulloblastoma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
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http://dx.doi.org/10.1016/S1470-2045(19)30669-2DOI Listing
December 2019

Transcriptional profiling of medulloblastoma with extensive nodularity (MBEN) reveals two clinically relevant tumor subsets with VSNL1 as potent prognostic marker.

Acta Neuropathol 2020 03 28;139(3):583-596. Epub 2019 Nov 28.

Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients' clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: "TCL1 MBEN" and "TCL2 MBEN" which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable "TCL1 MBEN" subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable "TCL2 MBEN" subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. "TCL2 MBEN" also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.
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http://dx.doi.org/10.1007/s00401-019-02102-zDOI Listing
March 2020

High impact of miRNA-4521 on FOXM1 expression in medulloblastoma.

Cell Death Dis 2019 09 20;10(10):696. Epub 2019 Sep 20.

Department of Pediatrics and Adolescent Medicine, Molecular Neuro-Oncology, Medical University of Vienna, Vienna, Austria.

Medulloblastoma, an embryonal tumor of the cerebellum/fourth ventricle, is one of the most frequent malignant brain tumors in children. Although genetic variants are increasingly used in treatment stratification, survival of high-risk patients, characterized by leptomeningeal dissemination, TP53 mutation or MYC amplification, is still poor. FOXM1, a proliferation-specific oncogenic transcription factor, is deregulated in various solid tumors, including medulloblastoma, and triggers cellular proliferation, migration and genomic instability. In tissue samples obtained from medulloblastoma patients, the significant upregulation of FOXM1 was associated with a loss of its putative regulating microRNA, miR-4521. To understand the underlying mechanism, we investigated the effect of miR-4521 on the expression of the transcription factor FOXM1 in medulloblastoma cell lines. Transfection of this microRNA reduced proliferation and invasion of several medulloblastoma cell lines and induced programmed cell death through activation of caspase 3/7. Further, downstream targets of FOXM1 such as PLK1 and cyclin B1 were significantly reduced thus affecting the cell cycle progression in medulloblastoma cell lines. In conclusion, a restoration of miRNA-4521 may selectively suppress the pathophysiological effect of aberrant FOXM1 expression and serve as a targeted approach for medulloblastoma therapy.
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http://dx.doi.org/10.1038/s41419-019-1926-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754377PMC
September 2019

WHO grade has no prognostic value in the pediatric high-grade glioma included in the HERBY trial.

Neuro Oncol 2020 01;22(1):116-127

Joint Research Unit 8203, Gustave Roussy Institute and University of Paris Saclay, Villejuif, France.

Background: The World Health Organization (WHO) adult glioma grading system is questionable in pediatric high-grade gliomas (pHGGs), which are biologically distinct from adult HGGs. We took advantage of the neuropathological review data obtained during one of the largest prospective randomized pHGG trials, namely HERBY (NCT01390948), to address this issue in children with newly diagnosed non-brainstem HGG.

Methods: HGG diagnosis was confirmed by pre-randomization, real-time central pathology review using WHO 2007 criteria, followed by a consensus review blinded to clinical factors and outcomes. We evaluated association between WHO 2007 grade and other clinical/radiological/biological characteristics and the prognostic value of WHO 2007 grade, midline location, and selected biomarkers (Ki-67 index/Olig2/CD34/EGFR/p53/H3F3A K27M mutation) on overall survival.

Results: Real-time central neuropathological review was feasible in a multicenter study, with a mean time of 2.4 days, and led to the rejection of HGG diagnosis in 20 of 163 cases (12.3%). The different grading criteria and resulting WHO grade were not significantly associated with overall survival in the entire population (n = 118) or in midline and non-midline subgroups. H3F3A K27M mutation was significantly associated with poor outcome. No significant prognostic value was observed for grade, even after regrading H3F3A K27M-mutated midline glioma as grade IV (WHO 2016). Midline location and a high Ki-67 index (≥20%) were associated with poor outcome (P = 0.004 and P = 0.04, respectively). A 10% increase in Ki-67 index was associated with a hazard ratio of 1.53 (95% CI: 1.27-1.83; P < 0.0001).

Conclusion: Our findings suggest that WHO grade III versus IV has no prognostic value in pediatric HGG.
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http://dx.doi.org/10.1093/neuonc/noz142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954414PMC
January 2020

TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAF/TERT promoter double-mutated glioma.

Acta Neuropathol Commun 2019 08 7;7(1):128. Epub 2019 Aug 7.

Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, Spitalgasse 23, BT86/E 01, 1090, Vienna, Austria.

The BRAF gene and the TERT promoter are among the most frequently altered genomic loci in low-grade (LGG) and high-grade-glioma (HGG), respectively. The coexistence of BRAF and TERT promoter aberrations characterizes a subset of aggressive glioma. Therefore, we investigated interactions between those alterations in malignant glioma. We analyzed co-occurrence of BRAF and TERT promoter mutations in our clinical data (n = 8) in addition to published datasets (n = 103) and established a BRAF-positive glioma cell panel (n = 9) for in vitro analyses. We investigated altered gene expression, signaling events and TERT promoter activity upon BRAF- and E-twenty-six (ETS)-factor inhibition by qRT-PCR, chromatin immunoprecipitation (ChIP), Western blots and luciferase reporter assays. TERT promoter mutations were significantly enriched in BRAF-mutated HGG as compared to BRAF-mutated LGG. In vitro, BRAF/TERT promoter double-mutant glioma cells showed exceptional sensitivity towards BRAF-targeting agents. Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAF-only cells. Various ETS-factors were broadly expressed, however, only ETS1 expression and phosphorylation were consistently downregulated following BRAF-inhibition. Knock-down experiments and ChIP corroborated the notion of a functional role for ETS1 and, accordingly, all double-mutant tumor cells were highly sensitive towards the ETS-factor inhibitor YK-4-279. In conclusion, our data suggest that concomitant BRAF and TERT promoter mutations synergistically support cancer cell proliferation and immortalization. ETS1 links these two driver alterations functionally and may represent a promising therapeutic target in this aggressive glioma subgroup.
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http://dx.doi.org/10.1186/s40478-019-0775-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685154PMC
August 2019

Resolving medulloblastoma cellular architecture by single-cell genomics.

Nature 2019 08 24;572(7767):74-79. Epub 2019 Jul 24.

Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Research Discovery Institute, La Jolla, CA, USA.

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
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http://dx.doi.org/10.1038/s41586-019-1434-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754173PMC
August 2019

An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma.

Cell 2019 08 18;178(4):835-849.e21. Epub 2019 Jul 18.

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, 1090, Austria.

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.
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http://dx.doi.org/10.1016/j.cell.2019.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703186PMC
August 2019

Predisposition of Wingless Subgroup Medulloblastoma for Primary Tumor Hemorrhage.

Neurosurgery 2020 04;86(4):478-484

Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Background: Primary intratumoral hemorrhage as a presenting sign is rare in children with medulloblastomas but may result in severe complications. Given the distinct properties of molecular medulloblastoma subgroups, the impact on neurosurgical practice has still to be defined.

Objective: To investigate both clinical and radiological presentation of intratumoral hemorrhage in medulloblastoma patients in the context of molecular subgroups.

Methods: Data of all consecutive medulloblastoma patients treated at our institution between 1993 and 2018 (n = 104) were retrospectively reviewed in respect of clinical and radiological presentation as well as molecular subgroups. For cases with available tumor tissue (n = 86), subgroups were assigned by either 450 K methylation array or immunohistochemistry and CTNNB1 sequencing. Available imaging at diagnosis (n = 62) was reviewed by an experienced neuroradiologist.

Results: Within the entire cohort, 4 patients (4%) presented with massive spontaneous hemorrhage. Although no patient died as a direct consequence of hemorrhage, all suffered from serious sequelae. Moreover, 3 additional patients displayed radiological evidence of significant hemorrhage. Interestingly, all 7 cases belonged to the wingless (WNT) subgroup (n = 13), resulting in intratumoral hemorrhage in 54% (7/13) of pediatric WNT medulloblastomas. In contrast, significant hemorrhage was absent in all other molecular subgroups.

Conclusion: Our results suggest that a substantial proportion of pediatric WNT medulloblastomas display significant intratumoral hemorrhage at the time of diagnosis. Consequently, the presence of significant hemorrhage in fourth ventricle childhood tumors is suggestive of WNT medulloblastoma and should lead to a less aggressive attempt for total resection in this prognostically favorable tumor type.
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http://dx.doi.org/10.1093/neuros/nyz148DOI Listing
April 2020

Management of choroid plexus tumors-an institutional experience.

Acta Neurochir (Wien) 2019 04 19;161(4):745-754. Epub 2019 Feb 19.

Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: Choroid plexus tumors are rare entities. Resection is the mainstay of treatment in grade I and grade II tumors and adjuvant treatment is usually reserved for the less frequent choroid plexus carcinoma (CPC). Outcome is not only related to their histological grade but also dependent on their size, location, and presence of often multifactorial disturbances of cerebrospinal fluid (CSF) circulation.

Methods: Retrospective analysis of 36 consecutive patients operated on a choroid plexus tumor at our institution in a mixed pediatric and adult population between 1991 and 2016.

Results: Twenty-one CPP, 11 atypical choroid plexus papillomas (aCPP), and four CPC were encountered in 17 children and 19 adults. Regardless of histological grading, gross-total resection (GTR) could be achieved in 91.7% of patients. Tumor recurrence (25.0%) was significantly associated with histological grading (p = 0.004), subtotal resection (p = 0.002), and intraoperatively evident zones of tumor infiltration (p = 0.001). Adjuvant therapy was performed in 19.4% of patients, mainly diagnosed with CPC. The 5-year overall survival rate was 95.2% for CPP and 100.0% for both aCPP and CPC. Survival was related to the extent of resection (p = 0.001), tumor progression (p = 0.04), and the presence of leptomeningeal metastases (p = 0.002). Even after resection, either ventricular or subdural shunting was required in 25.0% of patients.

Conclusions: We could confirm that GTR is crucial for treatment of choroid plexus tumors. Parenchymal tumor infiltration as detected intraoperatively was associated with the extent of resection and not limited to CPC. CSF disturbances mandating treatment may persist after resection.
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http://dx.doi.org/10.1007/s00701-019-03832-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431303PMC
April 2019

Immunological analysis of phase II glioblastoma dendritic cell vaccine (Audencel) trial: immune system characteristics influence outcome and Audencel up-regulates Th1-related immunovariables.

Acta Neuropathol Commun 2018 12 5;6(1):135. Epub 2018 Dec 5.

Activartis Biotech GmbH, Wilhelminenstraße 91/IIf, 1160, Vienna, Austria.

Audencel is a dendritic cell (DC)-based cellular cancer immunotherapy against glioblastoma multiforme (GBM). It is characterized by loading of DCs with autologous whole tumor lysate and in vitro maturation via "danger signals". The recent phase II "GBM-Vax" trial showed no clinical efficacy for Audencel as assessed with progression-free and overall survival in all patients. Here we present immunological research accompanying the trial with a focus on immune system factors related to outcome and Audencel's effect on the immune system. Methodologically, peripheral blood samples (from apheresis before Audencel or venipuncture during Audencel) were subjected to functional characterization via enzyme-linked immunospot (ELISPOT) assays connected with cytokine bead assays (CBAs) as well as phenotypical characterization via flow cytometry and mRNA quantification. GBM tissue samples (from surgery) were subjected to T cell receptor sequencing and immunohistochemistry. As results we found: Patients with favorable pre-existing anti-tumor characteristics lived longer under Audencel than Audencel patients without them. Pre-vaccination blood CD8+ T cell count and ELISPOT Granzyme B production capacity in vitro upon tumor antigen exposure were significantly correlated with overall survival. Despite Audencel's general failure to induce a significant clinical response, it nevertheless seemed to have an effect on the immune system. For instance, Audencel led to a significant up-regulation of the Th1-related immunovariables ELISPOT IFNγ, the transcription factor T-bet in the blood and ELISPOT IL-2 in a dose-dependent manner upon vaccination. Post-vaccination levels of ELISPOT IFNγ and CD8+ cells in the blood were indicative of a significantly better survival. In summary, Audencel failed to reach an improvement of survival in the recent phase II clinical trial. No clinical efficacy was registered. Our concomitant immunological work presented here indicates that outcome under Audencel was influenced by the state of the immune system. On the other hand, Audencel also seemed to have stimulated the immune system. Overall, these immunological considerations suggest that DC immunotherapy against glioblastoma should be studied further - with the goal of translating an apparent immunological response into a clinical response. Future research should concentrate on investigating augmentation of immune reactions through combination therapies or on developing meaningful biomarkers.
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http://dx.doi.org/10.1186/s40478-018-0621-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280511PMC
December 2018

Pattern of myogenesis and vascular repair in early and advanced lesions of juvenile dermatomyositis.

Neuromuscul Disord 2018 12 19;28(12):973-985. Epub 2018 Sep 19.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Regenerative processes that counteract perifascicular muscle atrophy and capillary loss in juvenile dermatomyositis (JDM) are not well characterized. We aimed to analyze the pattern of myo-regeneration in relation to vascular damage and repair in muscle specimens from JDM patients. Myogenic regulatory factors that are sequentially expressed during myogenesis were studied by immunohistochemistry. Capillary density, numbers of CD34 endothelial progenitor cells within the endomysium and molecules implicated in angiogenesis were evaluated by double-immunofluorescence techniques. Myogenic regulatory factors were significantly up-regulated in JDM muscle exhibiting a different pattern in early and advanced lesions. In early lesions Pax7 satellite cells and both MyoD and Myogenin myogenic cells were moderately increased. In lesions with advanced perifascicular atrophy Pax7 satellite cells were numerous, but absence of MyoD in the context of increased Myogenin expression suggested a dysregulation of the myogenic regenerative pathway. The overall capillary density in JDM was decreased, but regions of capillary loss in advanced lesions alternated with focal increase of hyperplastic endothelial cells in early lesions. Up-regulation of endoglin in hyperplastic endothelial cells in conjunction with overexpression of TGF-β1 and VEGF suggested activation of neovascularization. Conversely, CD34 endothelial progenitor cells were not increased arguing against relevant contribution to vascular repair. Our results demonstrate substantial induction of myogenesis in JDM. While the early phase of myogenesis appears to be associated with endothelial cell activation, an altered expression of MRFs in perifascicular regions with capillary depletion suggests an impairment of myogenic differentiation that may contribute to perifascicular muscle fiber atrophy in JDM.
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http://dx.doi.org/10.1016/j.nmd.2018.09.002DOI Listing
December 2018

Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features.

Brain Pathol 2019 03 11;29(2):205-216. Epub 2018 Nov 11.

Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.
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http://dx.doi.org/10.1111/bpa.12659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379249PMC
March 2019

Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial.

Cancer Cell 2018 05;33(5):829-842.e5

Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK. Electronic address:

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8 tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term "HGG" in the pediatric population.
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http://dx.doi.org/10.1016/j.ccell.2018.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956280PMC
May 2018