Publications by authors named "Monoranu C"

111 Publications

Primary brain amyloidoma, both a neoplastic and a neurodegenerative disease: a case report.

BMC Neurol 2019 Apr 10;19(1):59. Epub 2019 Apr 10.

Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstr. 19, 04103, Leipzig, Germany.

Background: Scattered extracellular deposits of amyloid within the brain parenchyma can be found in a heterogeneous group of diseases. Its condensed accumulation in the white matter without evidence for systemic amyloidosis is known as primary brain amyloidoma (PBA). Although originally considered as a tumor-like lesion by its space-occupying effect, this condition displays also common hallmarks of a neurodegenerative disorder.

Case Presentation: A 50-year-old woman presented with a mild cognitive decline and seizures with a right temporal, irregular and contrast-enhancing mass on magnetic resonance imaging. Suspecting a high-grade glioma, the firm tumor was subtotally resected. Neuropathological examination showed no glioma, but distinct features of a neurodegenerative disorder. The lesion was composed of amyloid AL λ aggregating within the brain parenchyma as well as the adjacent vessels, partially obstructing the vascular lumina. Immunostaining confirmed a distinct perivascular inflammatory reaction. After removal of the PBA, mnestic impairments improved considerably, the clinical course and MRI-results are stable in the 8-year follow-up.

Conclusion: Based on our histopathological findings, we propose to regard the clinicopathological entity of PBA as an overlap between a neoplastic and neurodegenerative disorder. Since the lesions are locally restricted, they might be amenable to surgery with the prospect of a definite cure.
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http://dx.doi.org/10.1186/s12883-019-1274-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458836PMC
April 2019

Post-mortem cerebrospinal fluid diagnostics: cytology and immunocytochemistry method suitable for routine use to interpret pathological processes in the central nervous system.

Int J Legal Med 2019 Jul 29;133(4):1141-1146. Epub 2019 Mar 29.

Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Josef-Schneider Str. 2, 97080, Wuerzburg, Germany.

Due to its protected anatomical location, cerebrospinal fluid (CSF) is a very stable fluid which undergoes comparatively little change in the early post-mortem phase. While many immunohistochemical markers already established for clinical diagnostic issues in tissue samples obtained by biopsy could meanwhile be translated also to post-mortem tissue, no systematic immunocytochemical investigations have generally been conducted on post-mortem body fluids and for CSF specifically, have not been established at all. CSF as the fluid directly surrounding the brain should also be examined to allow a more detailed characterization of processes in the central nervous system. Comparing traumatized tissue and CSF can complete forensic assessment and complement neuropathological evaluation.
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http://dx.doi.org/10.1007/s00414-019-02050-zDOI Listing
July 2019

The aggregation state of α-synuclein deposits in dermal nerve fibers of patients with Parkinson's disease resembles that in the brain.

Parkinsonism Relat Disord 2019 07 9;64:66-72. Epub 2019 Mar 9.

Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany.

Introduction: Phosphorylated α-synuclein (p-α-syn) can be detected in dermal nerve fibers of patients with Parkinson's disease (PD) and multiple system atrophy (MSA). Here we investigated whether p-α-syn in the cutaneous nerve fibers represents misfolded aggregated protein.

Methods: Using immunofluorescence with conformation specific antibodies and digestion with proteinase K (PK), we studied skin biopsies from a cohort of patients with early stage PD (Hoehn and Yahr I/II, n=27), MSA with predominant parkinsonism (MSA-P, n=8) and normal controls (n=21).

Results: We could show that α-synuclein (α-syn) found in the dermal nerve fibers in PD and MSA-P is not only phosphorylated but represents PK resistant and truncated aggregated protein. Comparison with a post mortem midbrain sample revealed a similar staining pattern of pathologic α-syn lesions in the PD brain.

Conclusion: Immunostaining of nerve fibers with different conformation specific antibodies and digestion with PK gave comparable results between midbrain and skin sections, showing that cutaneous nerve deposits of α-syn are structurally similar to Lewy pathology in the brain and are highly specific for synucleinopathy.
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http://dx.doi.org/10.1016/j.parkreldis.2019.03.003DOI Listing
July 2019

Impact of USP8 Gene Mutations on Protein Deregulation in Cushing Disease.

J Clin Endocrinol Metab 2019 07;104(7):2535-2546

Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany.

Context: Cushing disease (CD) is a rare disorder with severe sequels and incompletely understood pathogenesis. The underlying corticotroph adenomas harbor frequently somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene. These mutations render USP8 hyperactive and prevent client proteins from degradation.

Objective: To investigate the impact of USP8 mutations on proteins deregulated in CD.

Design: One hundred eight pituitary adenomas (75 corticotroph [58 USP8 wild type (WT) and 17 USP8 mutated], 14 somatotroph, and 19 nonfunctioning) were investigated by immunohistochemistry. All evaluated proteins [USP8, arginine vasopressin receptor 1b and 2, corticotropin-releasing hormone receptor, cAMP response element-binding protein (CREB), p27/kip1, cyclin E, heat shock protein 90 (HSP90), orphan nuclear receptor 4, epidermal growth factor receptor, histone deacetylase 2, glucocorticoid receptor, cyclin-dependent kinase 5 and Abelson murine leukemia viral oncogene homolog 1 enzyme substrate 1] were known to be deregulated in CD. Furthermore, AtT20 cells were transfected with USP8 to investigate the expression of possible downstream proteins by immunoblot.

Results: Whereas most of the investigated proteins were not differentially expressed, the cell-cycle inhibitor p27 was significantly reduced in USP8 mutated corticotroph adenoma (H-score 2.0 ± 1.0 vs 1.1 ± 1.1 in WT adenomas; P = 0.004). In contrast, the chaperone HSP90 was expressed higher (0.5 ± 0.4 vs 0.2 ± 0.4; P = 0.29), and the phosphorylation of the transcription factor CREB was increased in USP8 mutated adenomas (1.30.5 ± 0.40.9 vs 0.70.5 ± 0.40.7; P = 0.014). Accordingly, AtT20 cells transfected with the USP8 P720R mutant had higher phosphorylated CREB (pCREB) levels than WT transfected cells (1.3 ± 0.14 vs 1 ± 0.23; P = 0.13).

Conclusions: We could demonstrate that USP8 mutations are associated with deregulation of p27/kip1, HSP90, and pCREB. These findings suggest that these proteins are direct or indirect clients of USP8 and could therefore be potential targets for therapeutic approaches in patients with CD.
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http://dx.doi.org/10.1210/jc.2018-02564DOI Listing
July 2019

Human Brain Endothelial CXCR2 is Inflammation-Inducible and Mediates CXCL5- and CXCL8-Triggered Paraendothelial Barrier Breakdown.

Int J Mol Sci 2019 01 30;20(3). Epub 2019 Jan 30.

Department of Neurology, University of Würzburg, 97080 Würzburg, Germany.

Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood-brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood-brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood-brain barrier stabilization.
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http://dx.doi.org/10.3390/ijms20030602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387364PMC
January 2019

Cognate Nonlytic Interactions between CD8 T Cells and Breast Cancer Cells Induce Cancer Stem Cell-like Properties.

Cancer Res 2019 04 28;79(7):1507-1519. Epub 2019 Jan 28.

Department of Obstetrics and Gynecology, Würzburg University Hospital, University of Würzburg, Würzburg, Germany.

Targeting of tumor immune escape mechanisms holds enormous therapeutic potential. Still, most patients progress under immune checkpoint blockade and some even become hyperprogressors. To investigate how cancer cells respond to activated but ineffective T cells, we challenged peptide-loaded MCF-7 breast cancer cells with antigen-specific CD8 T cells in which lytic granules had been destroyed by pretreatment with Concanamycin A. Gene expression analysis after coculture revealed simultaneous induction of PD-L1, IDO1, CEACAM1, and further immunoregulatory checkpoints in breast cancer cells. Strikingly, we further observed gene signatures characteristic for dedifferentiation and acquisition of pluripotency markers including Yamanaka factors. Cognate interaction with nonlytic CD8 T cells also increased the proportion of stem cell-like cancer cells in a cell-to-cell contact- or (at least) proximity-dependent manner in various cell lines and in primary breast cancer cell cultures; this induction of stem cell-like properties was confirmed by enhanced tumor-forming capacity in immunodeficient mice. Resulting tumors were characterized by enhanced cell density, higher proliferation rates, and increased propensity for lymphoid metastasis. These findings describe a widely underappreciated pathway for immune escape, namely immune-mediated dedifferentiation of breast cancer cells, which is associated with profound changes in gene expression and cellular behavior. As the enhanced malignant potential of cancer cells after nonlytic cognate interactions with CD8 T cells enables increased tumor growth and metastasis in BALB/c mice, the described mechanism may provide a possible explanation for the clinical phenomenon of hyperprogression in response to unsuccessful immunotherapy. SIGNIFICANCE: This study shows that ineffective immune responses not only fail to clear a malignancy, but can also activate pathways in cancer cells that promote stemness and tumor-seeding capacity.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0387DOI Listing
April 2019

Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients.

Onco Targets Ther 2018 4;11:8673-8684. Epub 2018 Dec 4.

Department of Neurosurgery, Tumorbiology Laboratory, University of Würzburg, Würzburg, Germany,

Background: ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM.

Patients And Methods: ATF5 mRNA was extracted from frozen samples of patients' GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry.

Results: ATF5 mRNA was overexpressed in LGA (sevenfold, <0.001) and GBM (tenfold, <0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients' age (=0.339, =0.028) and inversely with Ki67-staining (=-0.421, =0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan-Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (,12 months, median survival 18 vs 13 months, =0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, =0.024). This advantage vanished after 24 months (=0.084).

Conclusion: ATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors.
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http://dx.doi.org/10.2147/OTT.S176549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287669PMC
December 2018

Astrocyte- and Microglia-Specific Mitochondrial DNA Deletions Levels in Sporadic Alzheimer's Disease.

J Alzheimers Dis 2019 ;67(1):149-157

Institute of Pathology, Department of Neuropathology, University of Wuerzburg, Germany.

Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage with an age-dependent accumulation. In a previous study, we analyzed mtDNA levels in diverse neuronal cell types in order to unravel the impact of oxidative stress in brains of AD patients. The aim of this study was to identify possible correlations between mtDNA deletion levels of selected astrocytes and microglia from three brain regions with different vulnerability to AD pathology and different stages of disease compared to controls. Our results reflect a higher vulnerability of hippocampal astrocytes and microglia to oxidative stress compared to other brain regions, such as cerebellum and brainstem.
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http://dx.doi.org/10.3233/JAD-180661DOI Listing
March 2020

Hyper--glycosylated SAMD14 and neurabin-I as driver autoantigens of primary central nervous system lymphoma.

Blood 2018 12 24;132(26):2744-2753. Epub 2018 Sep 24.

José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.

To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper--glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.
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http://dx.doi.org/10.1182/blood-2018-03-836932DOI Listing
December 2018

Correction to: DNA methylation-based reclassification of olfactory neuroblastoma.

Acta Neuropathol 2018 09;136(3):505

In the original publication, the second name of the twentieth author was incorrect. It should read as 'Miguel Sáinz-Jaspeado'. The original publication of the article has been updated to reflect the change. This correction was authored by Ulrich Schüller on behalf of all authors of the original publication.
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http://dx.doi.org/10.1007/s00401-018-1887-yDOI Listing
September 2018

High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with T depletion.

Cancer Immunol Immunother 2018 Oct 27;67(10):1545-1558. Epub 2018 Jul 27.

Department of Pediatric Oncology, University Children's Hospital Würzburg, Josef-Schneider-Strasse 2, 97080, Würzburg, Germany.

High-grade gliomas (HGG) exert systemic immunosuppression, which is of particular importance as immunotherapeutic strategies such as therapeutic vaccines are increasingly used to treat HGGs. In a first cohort of 61 HGG patients we evaluated a panel of 30 hematological and 34 plasma biomarkers. Then, we investigated in a second cohort of 11 relapsed HGG patients receiving immunomodulation with metronomic cyclophosphamide upfront to a DC-based vaccine whether immune abnormalities persisted and whether they hampered induction of IFNγ T-cell responses. HGG patients from the first cohort showed increased numbers of leukocytes, neutrophils and MDSCs and in parallel reduced numbers of CD4/CD8 T-cells, plasmacytoid and conventional DC2s. MDSCs and T-cell alterations were more profound in WHO IV° glioma patients. Moreover, levels of MDSCs and epidermal growth factor were negatively associated with survival. Serum levels of IL-2, IL-4, IL-5 and IL-10 were altered in HGG patients, however, without any impact on clinical outcome. In the immunotherapy cohort, 6-month overall survival was 100%. Metronomic cyclophosphamide led to > 40% reduction of regulatory T cells (T). In parallel to T-depletion, MDSCs and DC subsets became indistinguishable from healthy controls, whereas T-lymphopenia persisted. Despite low T-cells, IFNγ-responses could be induced in 9/10 analyzed cases. Importantly, frequency of CD8VLA-4 T-cells with CNS-homing properties, but not of CD4 VLA-4 T-cells, increased during vaccination. Our study identifies several features of systemic immunosuppression in HGGs. Metronomic cyclophosphamide in combination with an active immunization alleviates the latter and the combined treatment allows induction of a high rate of anti-glioma immune responses.
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http://dx.doi.org/10.1007/s00262-018-2214-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182405PMC
October 2018

Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features.

Acta Neuropathol 2018 08 15;136(2):239-253. Epub 2018 May 15.

Clinical Cooperation Unit Neuropathology, German Cancer Consortium, German Cancer Research Center, 69120, Heidelberg, Germany.

Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p < 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively-laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT.
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http://dx.doi.org/10.1007/s00401-018-1865-4DOI Listing
August 2018

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

Lancet Oncol 2018 06 9;19(6):785-798. Epub 2018 May 9.

Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.

Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.

Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MB), SHH (MB), group 3 (MB), and group 4 (MB). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.

Findings: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MB subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MB subgroup). Patients with germline APC mutations developed MB and accounted for most (five [71%] of seven) cases of MB that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MB. Germline TP53 mutations presented only in childhood patients in the MB subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MB, MB, and MB molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.

Interpretation: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MB and MB because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.

Funding: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.
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http://dx.doi.org/10.1016/S1470-2045(18)30242-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984248PMC
June 2018

DNA methylation-based reclassification of olfactory neuroblastoma.

Acta Neuropathol 2018 08 5;136(2):255-271. Epub 2018 May 5.

Institute of Pathology, Julius-Maximilians-University, Würzburg, Germany.

Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.
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http://dx.doi.org/10.1007/s00401-018-1854-7DOI Listing
August 2018

Chronophin regulates active vitamin B6 levels and transcriptomic features of glioblastoma cell lines cultured under non-adherent, serum-free conditions.

BMC Cancer 2018 May 3;18(1):524. Epub 2018 May 3.

Department of Neuropathology, Regensburg University Hospital, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.

Background: The phosphatase chronophin (CIN/PDXP) has been shown to be an important regulator of glioma cell migration and invasion. It has two known substrates: p-Ser3-cofilin, the phosphorylated form of the actin binding protein cofilin, and pyridoxal 5'-phosphate, the active form of vitamin B6. Phosphoregulation of cofilin, among other functions, plays an important role in cell migration, whereas active vitamin B6 is a cofactor for more than one hundred enzymatic reactions. The role of CIN has yet only been examined in glioblastoma cell line models derived under serum culture conditions.

Results: We found that CIN is highly expressed in cells cultured under non-adherent, serum-free conditions that are thought to better mimic the in vivo situation. Furthermore, the substrates of CIN, p-Ser3-cofilin and active vitamin B6, were significantly reduced as compared to cell lines cultured in serum-containing medium. To further examine its molecular role we stably knocked down the CIN protein with two different shRNA hairpins in the glioblastoma cell lines NCH421k and NCH644. Both cell lines did not show any significant alterations in proliferation but expression of differentiation markers (such as GFAP or TUBB3) was increased in the knockdown cell lines. In addition, colony formation was significantly impaired in NCH644. Of note, in both cell lines CIN knockdown increased active vitamin B6 levels with vitamin B6 being known to be important for S-adenosylmethionine biosynthesis. Nevertheless, global histone and DNA methylation remained unaltered as was chemoresistance towards temozolomide. To further elucidate the role of phosphocofilin in glioblastoma cells we applied inhibitors for ROCK1/2 and LIMK1/2 to our model. LIMK- and ROCK-inhibitor treatment alone was not toxic for glioblastoma cells. However, it had profound, but antagonistic effects in NCH421k and NCH644 under chemotherapy.

Conclusion: In non-adherent glioblastoma cell lines cultured in serum-free medium, chronophin knockdown induces phenotypic changes, e.g. in colony formation and transcription, but these are highly dependent on the cellular background. The same is true for phenotypes observed after treatment with inhibitors for kinases regulating cofilin phosphorylation (ROCKs and LIMKs). Targeting the cofilin phosphorylation pathway might therefore not be a straightforward therapeutic option in glioblastoma.
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http://dx.doi.org/10.1186/s12885-018-4440-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934884PMC
May 2018

Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations.

Acta Neuropathol 2018 08 21;136(2):273-291. Epub 2018 Mar 21.

Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
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http://dx.doi.org/10.1007/s00401-018-1837-8DOI Listing
August 2018

DNA methylation-based classification of central nervous system tumours.

Nature 2018 03 14;555(7697):469-474. Epub 2018 Mar 14.

Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
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http://dx.doi.org/10.1038/nature26000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093218PMC
March 2018

CXCR4: A new player in vestibular schwannoma pathogenesis.

Oncotarget 2018 Feb 10;9(11):9940-9950. Epub 2018 Jan 10.

Department of Neurosurgery, University Hospital Würzburg, 97080 Würzburg, Germany.

Background: CXCR4 is a chemokine receptor that recruits blood stem cells and increases tumor cell growth and invasiveness. We examined CXCR4 expression in vestibular schwannomas (VS) from patients with and without neurofibromatosis type 2 (NF2) and correlated the levels with the patients' clinical characteristics. The aim was to determine whether CXCR4 can be used as a prognostic marker and as a target for systemic therapy.

Results: Overall, CXCR4 mRNA levels were 4.6-fold higher in VS versus control; the levels were 4.9-fold higher in NF2 patients and 4.2-fold higher in sporadic VS patients. IHC and WB showed heterogeneous protein expression, and CXCR4 was expressed mainly in S100-positive Schwann cells. There was no correlation between the CXCR4 protein levels and tumor extension. However, there was a trend towards correlation between higher expression levels and greater hearing loss.

Materials And Methods: CXCR4 mRNA and protein levels were determined in VS samples ( = 60); of these, 30 samples were from patients with NF2. Healthy nerves from autopsies served as controls. CXCR4 mRNA levels were measured by PCR, and protein levels were measured by immunohistochemistry (IHC) and Western blotting (WB). Tumor extension and hearing loss were categorized according to the Hannover Classification as clinical parameters.

Conclusions: CXCR4 mRNA was overexpressed in VS relative to healthy vestibular nerves, and there was a trend towards higher CXCR4 expression levels being correlated with greater functional impairment. Thus, CXCR4 may be a prognostic marker of VS, and CXCR4 inhibition has potential as a systemic approach for the treatment of VS.
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http://dx.doi.org/10.18632/oncotarget.24119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839412PMC
February 2018

Neurochemical markers as potential indicators of postmortem tissue quality.

Handb Clin Neurol 2018 ;150:119-127

Center for Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany. Electronic address:

Premortem, postmortem, and storage conditions are parameters that can influence the quality and interpretation of data from studies of postmortem tissue. While many neurochemicals in the brain are relatively stable for several hours after death if stored at 4°C, the postmortem delay nevertheless becomes an important variable when examining the disease state because neurochemical levels may change with extended postmortem delay. Moreover, in the postmortem brain, neurochemical levels may also play a key role in determining the diagnosis. This is particularly true for some neurodegenerative disorders where many of the clinical features of the disease are not exclusive to one illness. It is therefore imperative to employ brain tissue of the highest quality from both nondiseased (control) and diseased brain tissue to ascertain the specific molecular and genetic mechanisms particular to the disease pathogenesis. Consequently, it would be very useful if specific markers could be employed to demonstrate and determine the quality of postmortem brain tissue that is suitable for such studies. In this chapter, the following neurochemical markers are critically reviewed as potential candidates to assess the quality of postmortem brain tissue: tryptophan levels, glutathione levels (and glutathione metabolic enzymes), enzymatic activities (glutamate decarboxylase, phosphofructokinase-1), epigenetic enzymes (acetyltransferase, methyltransferase), and tissue pH. In conclusion, the neurochemical tryptophan appears to be the most suitable candidate for assessing the integrity and quality of postmortem brain tissue. However, to optimize the quality of the samples, neuropathologic diagnostic characterization must also be employed in the interpretation and understanding of the data generated. It would also be judicious to consider as many premortem and postmortem conditions as possible as they can also affect the genetic and molecular integrity of the brain tissue.
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http://dx.doi.org/10.1016/B978-0-444-63639-3.00009-8DOI Listing
August 2018

Differential Alterations in Metabolism and Proteolysis-Related Proteins in Human Parkinson's Disease Substantia Nigra.

Neurotox Res 2018 04 7;33(3):560-568. Epub 2017 Dec 7.

Eve Topf Center, Faculty of Medicine, Technion-Israel Institute of Technology, P.O.B. 9697, 31096, Haifa, Israel.

Parkinson's disease is the most common neurodegenerative disorder after Alzheimer's disease, with the majority of cases being sporadic or "idiopathic". The aetiology of the sporadic form is still unknown, but there is a broad consensus that Parkinson's disease involves multiple pathways. In previous human post-mortem studies investigating substantia nigra of parkinsonian subjects, gene expression alterations in various metabolic pathways including protein folding, trafficking, aggregation, ubiquitination and oxidative stress were found. These studies revealed transcriptomic dysregulation of various genes, amongst others Skp1A and PSMC4 (part of ubiquitin-proteasome system), HSC70 (belonging to the chaperone family) and ALDH1A1 (an enzyme involved in the catabolism of dopamine). To investigate whether these alterations are manifested at the protein level, we performed immunohistochemical analysis in the substantia nigra of Parkinson's disease and compared them to Alzheimer's disease and non-neurological post-mortem controls. We were able to confirm cell-specific reductions in the protein content of ALHD1A1 and Skp1A in the dopaminergic neurons of the substantia nigra of Parkinsonian patients compared to Alzheimer's and control subjects. Furthermore, we observed particular distribution for HSC70 and PSMC4 in the cytoplasm and accumulation within Lewy body in the dopaminergic neurons of the substantia nigra in Parkinson patients. These findings, together with previous evidence, suggest a malfunction of the ubiquitin-proteasome and possible autophagy systems as major players in protein misfolding and aggregation in Parkinson's disease. Nevertheless, this needs further proof, possibly with trajectory time line.
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http://dx.doi.org/10.1007/s12640-017-9843-5DOI Listing
April 2018

Lesions Mimicking Small Vestibular Schwannomas.

J Neurol Surg B Skull Base 2017 Dec 19;78(6):447-453. Epub 2017 Jul 19.

Department of Neuropathology, University of Würzburg, Würzburg, Germany.

 Most tumors of the internal auditory canal and cerebellopontine angle (CPA) are vestibular schwannomas (VSs). Preoperative diagnosis is based on typical clinical symptoms and radiological findings. In rare cases, histopathology can, however, show different results.  This is a retrospective chart and database review.  The study was conducted at a tertiary skull base referral center at a university hospital.  A total of 207 consecutive cases of VS surgery via the middle cranial fossa approach performed between December 2005 and January 2015 were reviewed.  The main outcome measures were definitive histologic findings in 198 specimens, analysis of preoperative magnetic resonance imaging (MRI) and computed tomography.  Histopathology revealed three meningiomas and two cases of lipochoristomas. Clinical presentation was typical for VS in all five cases. In preoperative MRI, all tumors were suspected to be VSs. Retrospective analysis of the preoperative imaging did not lead to a modification of the diagnosis. Intraoperative findings showed increased adherence of the tumor to the adjacent tissue in two of the five cases.  CPA lesions other than VSs are unusual but have to be taken into account. In very small tumors, imaging still remains difficult.
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http://dx.doi.org/10.1055/s-0037-1604160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680035PMC
December 2017

Expression of D-Amino Acid Oxidase (/) and D-Amino Acid Oxidase Activator () during Development and Aging in the Human Post-mortem Brain.

Front Neuroanat 2017 6;11:31. Epub 2017 Apr 6.

Molecular and Neurobiochemistry Laboratory, Centre for Child and Adolescent Psychiatry Research, Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of ZurichZurich, Switzerland.

In the brain, D-amino acid oxidase (DAO/DAAO) mainly oxidizes D-serine, a co-agonist of the -methyl-D-aspartate (NMDA) receptors. Thus, DAO can regulate the function of NMDA receptors via D-serine breakdown. Furthermore, DAO activator (DAOA)/G72 has been reported as both DAOA and repressor. The co-expression of DAO and DAOA genes and proteins in the human brain is not yet elucidated. The aim of this study was to understand the regional and age span distribution of DAO and DAOA (mRNA and protein) in a concomitant manner. We determined DAO and DAOA mRNA and protein expression across six brain regions in normal human post-mortem brain samples (16 weeks of gestation to 91 years) using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. We found higher expression of mRNA in the cerebellum, whereas lower expression of DAO protein in the cerebellum compared to the other brain regions studied, which suggests post-transcriptional regulation. We detected DAOA protein but not mRNA in all brain regions studied, suggesting a tightly regulated expression. To understand this regulation at the transcriptional level, we analyzed DNA methylation levels at and CpG sites in the cerebellum and frontal cortex of control human post-mortem brain obtained from Gene Expression Omnibus datasets. Indeed, and CpG sites in the cerebellum were significantly more methylated than those in the frontal cortex. While investigating lifespan effects, we found that mRNA levels were positively correlated with age <2 years in the cerebellum and amygdala. We also detected a significant positive correlation (controlled for age) between DAO and DAOA protein in all of the brain regions studied except for the frontal cortex. In summary, DAO and DAOA expression in the human brain are both age and brain region dependent.
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http://dx.doi.org/10.3389/fnana.2017.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382383PMC
April 2017

Cerebral amyloidoma is characterized by B-cell clonality and a stable clinical course.

Brain Pathol 2018 03 13;28(2):234-239. Epub 2017 Mar 13.

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

Amyloidomas are rare amyloid-containing lesions, which may also occur in the central nervous system. Etiology, pathogenesis and clinical course are poorly understood. To gain more insight into the biology of cerebral amyloidoma, they aimed to characterize its histopathological, molecular and clinical features in a retrospective series of seven patients. FFPE tissue specimens were examined using immunohistochemistry, chromogenic in situ hybridization (CISH) for light chains kappa and lambda as well as an IgH gene clonality analysis. Follow-up information was gathered by reviewing patient records and imaging results. Median age of the three males and four females was 50 years (range: 35-53 years). All cerebral amyloidomas were located supratentorially and were classified as lambda light chain amyloidosis (AL-λ; n = 6) and kappa light chain amyloidosis (AL-κ; n = 1) on immunohistochemistry and CISH. B-cell clonality was confirmed by IgH gene clonality assay in all cases examined. After a median follow-up of 21 months, all patients were alive and showed stable disease. No progression to systemic disease was observed. In conclusion, their data suggest that cerebral amyloidoma is a local disease characterized by B-cell clonality and associated with a stable clinical course.
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http://dx.doi.org/10.1111/bpa.12493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028616PMC
March 2018

Targeting coagulation factor XII as a novel therapeutic option in brain trauma.

Ann Neurol 2016 06 28;79(6):970-82. Epub 2016 Apr 28.

Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.

Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.

Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.

Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.

Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. Ann Neurol 2016;79:970-982.
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http://dx.doi.org/10.1002/ana.24655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074329PMC
June 2016

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors.

Acta Neuropathol 2016 06 26;131(6):847-63. Epub 2016 Feb 26.

Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.
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http://dx.doi.org/10.1007/s00401-016-1549-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039033PMC
June 2016

New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

Cell 2016 Feb;164(5):1060-1072

Department of Radiological, Oncological and Anatomic-Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy.

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.
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http://dx.doi.org/10.1016/j.cell.2016.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5139621PMC
February 2016

(68)Ga-Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression in Glioblastoma.

Theranostics 2016 25;6(3):428-34. Epub 2016 Jan 25.

1. Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany; 2. Comprehensive Cancer Center Mainfranken, Würzburg, Germany; 7. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, USA.

Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand (68)Ga-Pentixafor. 15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent (68)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUVmax, SUVmean). Tumor-to-background ratios (TBR) were calculated for both PET probes. (68)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples. (68)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUVmean and SUVmax of 3.0±1.5 and 3.9±2.0 respectively. Respective values for (18)F-FET were 4.4±2.0 (SUVmean) and 5.3±2.3 (SUVmax). TBR for SUVmean and SUVmax were higher for (68)Ga-Pentixafor than for (18)F-FET (SUVmean 154.0±90.7 vs. 4.1±1.3; SUVmax 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high (68)Ga-Pentixafor uptake; regions of the same tumor without apparent (68)Ga-Pentixafor uptake showed no or low receptor expression. In this pilot study, (68)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, (68)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy.
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http://dx.doi.org/10.7150/thno.13986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737728PMC
November 2016

MB3W1 is an orthotopic xenograft model for anaplastic medulloblastoma displaying cancer stem cell- and Group 3-properties.

BMC Cancer 2016 Feb 17;16:115. Epub 2016 Feb 17.

University Children's Hospital, Pediatric Oncology, Hematology and Stem Cell Transplantation, University of Würzburg, Würzburg, Germany.

Background: Medulloblastoma is the most common malignant brain tumor in children and can be divided in different molecular subgroups. Patients whose tumor is classified as a Group 3 tumor have a dismal prognosis. However only very few tumor models are available for this subgroup.

Methods: We established a robust orthotopic xenograft model with a cell line derived from the malignant pleural effusions of a child suffering from a Group 3 medulloblastoma.

Results: Besides classical characteristics of this tumor subgroup, the cells display cancer stem cell characteristics including neurosphere formation, multilineage differentiation, CD133/CD15 expression, high ALDH-activity and high tumorigenicity in immunocompromised mice with xenografts exactly recapitulating the original tumor architecture.

Conclusions: This model using unmanipulated, human medulloblastoma cells will enable translational research, specifically focused on Group 3 medulloblastoma.
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http://dx.doi.org/10.1186/s12885-016-2170-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756501PMC
February 2016

Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups.

Neuro Oncol 2016 06 28;18(6):790-6. Epub 2016 Jan 28.

Institute of Neuropathology, University Hospital Münster, Münster, Germany (C.T., V.R., A.J., W.P., M.H.); Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany (M.S.); Core Facility Genomics of the Medical Faculty Münster, Münster, Germany (A.W.); Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (S.H., U.K.); Department of Neuropathology, Institute for Pathology and Neuropathology, University of Tübingen, Tübingen, Germany (R.B.); Faculty of Medicine, Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany (K.K.); Department of Neuropathology, Klinikum Bremen-Mitte, Bremen, Germany (M.B.); Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany (M.M.); Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany (T.P.); Department of Neuropathology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany (J.F.); Department of Neuropathology, Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken (CCCM), Würzburg, Germany (C.M.M.); Department of Neuropathology, Sainte-Anne Hospital, Paris, France (P.V.); 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary (P.H.); Department of Hematopathology, Molecular Diagnostic Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.O.); Children's Brain Tumour Research Centre, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, UK (R.G.G.); Department of Pediatric Hematology Oncology and Blood and Marrow Transplantation, Cleveland Clinic Children's Hospital, Cleveland, Ohio (J.E.W.); Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany (A.K., A.v.D., D.C.); Clinical Cooperation Unit Neuropathology, German Research Center (DKFZ), Heidelberg, Germany (A.K., A.v.D., D.C.); German Cancer Consortium (DKTK), German Cancer Research Ce

Background: Choroid plexus tumors are intraventricular neoplasms derived from the choroid plexus epithelium. A better knowledge of molecular factors involved in choroid plexus tumor biology may aid in identifying patients at risk for recurrence.

Methods: Methylation profiles were examined in 29 choroid plexus papillomas (CPPs, WHO grade I), 32 atypical choroid plexus papillomas (aCPPs, WHO grade II), and 31 choroid plexus carcinomas (CPCs, WHO grade III) by Illumina Infinium HumanMethylation450 Bead Chip Array.

Results: Unsupervised hierarchical clustering identified 3 subgroups: methylation cluster 1 (pediatric CPP and aCPP of mainly supratentorial location), methylation cluster 2 (adult CPP and aCPP of mainly infratentorial location), and methylation cluster 3 (pediatric CPP, aCPP, and CPC of supratentorial location). In methylation cluster 3, progression-free survival (PFS) accounted for a mean of 72 months (CI, 55-89 mo), whereas only 1 of 42 tumors of methylation clusters 1 and 2 progressed (P< .001). On stratification of outcome data according to WHO grade, all CPCs clustered within cluster 3 and were associated with shorter overall survival (mean, 105 mo [CI, 81-128 mo]) and PFS (mean, 55 mo [CI, 36-73 mo]). The aCPP of methylation cluster 3 also progressed frequently (mean, 69 mo [CI, 44-93 mo]), whereas no tumor progression was observed in aCPP of methylation clusters 1 and 2 (P< .05). Only 1 of 29 CPPs recurred.

Conclusions: Methylation profiling of choroid plexus tumors reveals 3 distinct subgroups (ie, pediatric low-risk choroid plexus tumors [cluster 1], adult low-risk choroid plexus tumors [cluster 2], and pediatric high-risk choroid plexus tumors [cluster 3]) and may provide useful prognostic information in addition to histopathology.
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http://dx.doi.org/10.1093/neuonc/nov322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864264PMC
June 2016
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