Publications by authors named "Camelia-Maria Monoranu"

63 Publications

Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson's disease mice.

Brain Behav Immun 2022 Jan 12;101:194-210. Epub 2022 Jan 12.

Department of Neurology, University Hospital of Würzburg, Würzburg, Germany. Electronic address:

Background: Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson's disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model.

Methods: We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4/CD8, CD4/CD8, or CD4/CD8 (JHD) mice into the RAG-1 mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized.

Results: AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68-78) and surrounding the pathogenically relevant S129 (120-134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration.

Conclusions: Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.
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http://dx.doi.org/10.1016/j.bbi.2022.01.007DOI Listing
January 2022

Spontaneous regression of a congenital high-grade glioma-a case report.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab120. Epub 2021 Aug 25.

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

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http://dx.doi.org/10.1093/noajnl/vdab120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541705PMC
August 2021

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.

J Immunother Cancer 2021 10;9(10)

University Children's Hospital, University Medical Center Würzburg, Würzburg, Germany

Background: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells.

Methods: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM.

Results: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8 T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors.

Conclusions: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.
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http://dx.doi.org/10.1136/jitc-2021-003404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488729PMC
October 2021

Quantitative evidence of suppressed TMEM119 microglial immunohistochemistry in fatal morphine intoxications.

Int J Legal Med 2021 Nov 22;135(6):2315-2322. Epub 2021 Sep 22.

Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Butenfeld 34, 22529, Hamburg, Germany.

The aim of this pilot study was to investigate the diagnostic potential of TMEM119 as a useful microglia-specific marker in combination with immunostainings for phagocytic function and infiltrating capacity of monocytes in cases of lethal monosubstance intoxications by morphine (MOR), methamphetamine (METH), and of ethanol-associated death (ETH) respectively. Human brain tissue samples were obtained from forensic autopsies of cases with single substance abuse (MOR, n = 8; ETH, n = 10; METH, n = 9) and then compared to a cohort of cardiovascular fatalities as controls (n = 9). Brain tissue samples of cortex, white matter, and hippocampus were collected and stained immunohistochemically with antibodies against TMEM119, CD68KiM1P, and CCR2. We could document the lowest density of TMEM119-positive cells in MOR deaths with highly significant differences to the control densities in all three regions investigated. In ETH and METH deaths, the expression of TMEM119 was comparable to cell densities in controls. The results indicate that the immunoreaction in brain tissue is different in these groups depending on the drug type used for abuse.
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http://dx.doi.org/10.1007/s00414-021-02699-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523458PMC
November 2021

No Metagenomic Evidence of Causative Viral Pathogens in Postencephalitic Parkinsonism Following Encephalitis Lethargica.

Microorganisms 2021 Aug 12;9(8). Epub 2021 Aug 12.

Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.

Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP.
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http://dx.doi.org/10.3390/microorganisms9081716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398509PMC
August 2021

Myelin basic protein and neurofilament H in postmortem cerebrospinal fluid as surrogate markers of fatal traumatic brain injury.

Int J Legal Med 2021 Jul 24;135(4):1525-1535. Epub 2021 Apr 24.

Institute of Forensic Medicine, University of Wuerzburg, Versbacher Str. 3, 97078, Wuerzburg, Germany.

The aim of this study was to investigate if the biomarkers myelin basic protein (MBP) and neurofilament-H (NF-H) yielded informative value in forensic diagnostics when examining cadaveric cerebrospinal fluid (CSF) biochemically via an enzyme-linked immunosorbent assay (ELISA) and comparing the corresponding brain tissue in fatal traumatic brain injury (TBI) autopsy cases by immunocytochemistry versus immunohistochemistry. In 21 trauma and 19 control cases, CSF was collected semi-sterile after suboccipital puncture and brain specimens after preparation. The CSF MBP (p = 0.006) and NF-H (p = 0.0002) levels after TBI were significantly higher than those in cardiovascular controls. Immunohistochemical staining against MBP and against NF-H was performed on cortical and subcortical samples from also biochemically investigated cases (5 TBI cases/5 controls). Compared to the controls, the TBI cases showed a visually reduced staining reaction against MBP or repeatedly ruptured neurofilaments against NF-H. Immunocytochemical tests showed MBP-positive phagocytizing macrophages in CSF with a survival time of > 24 h. In addition, numerous TMEM119-positive microglia could be detected with different degrees of staining intensity in the CSF of trauma cases. As a result, we were able to document that elevated levels of MBP and NF-H in the CSF should be considered as useful neuroinjury biomarkers of traumatic brain injury.
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http://dx.doi.org/10.1007/s00414-021-02606-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205912PMC
July 2021

Peptide Receptor Radionuclide Therapy in Patients With Neurofibromatosis Type 2: Initial Experience.

Clin Nucl Med 2021 06;46(6):e312-e316

Department of Neurosurgery.

Purpose: Neurofibromatosis type 2 (NF2) is a genetic disorder that is associated with multiple tumors of the nervous system, and approximately one half of patients present with meningiomas. For patients with multifocal disease, somatostatin receptor-targeted peptide receptor radionuclide therapy (PRRT) might be a suitable systemic treatment option.

Patients And Methods: Between March 2015 and August 2017, 11 NF2 patients (7 females and 4 males; mean age, 39 ± 12 years) with multifocal, progressive meningiomas underwent a median of 4 cycles of PRRT (range, 2-6 cycles). Acute and chronic adverse events were recorded according to National Institutes of Health's Common Toxicity Criteria (CTC) version 5.0. Follow-up MRIs (every 3 to 6 months), using the Response Assessment in Neuro-Oncology response criteria for meningiomas, were used to assess treatment responses.

Results: Peptide receptor radionuclide therapy was well tolerated in all patients without any relevant acute adverse effects. Transient hematologic toxicity (CTC grade 3) was observed in 2 subjects. Somatostatin receptor-directed radiopeptide therapy resulted in radiological disease stabilization in 6 of 11 patients. Median progression-free survival was 12 months (range, 1-55 months), and overall survival was 37 months (range, 5-61 months).

Conclusions: Based on our retrospective pilot data, PRRT is feasible and well-tolerated in NF2 patients. It might offer a suitable treatment option in subjects with multiple, recurrent, or treatment-refractory meningiomas.
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http://dx.doi.org/10.1097/RLU.0000000000003627DOI Listing
June 2021

The genetic landscape of choroid plexus tumors in children and adults.

Neuro Oncol 2021 04;23(4):650-660

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

Background: Choroid plexus tumors (CPTs) are intraventricular brain tumors predominantly arising in children but also affecting adults. In most cases, driver mutations have not been identified, although there are reports of frequent chromosome-wide copy-number alterations and TP53 mutations, especially in choroid plexus carcinomas (CPCs).

Methods: DNA methylation profiling and RNA-sequencing was performed in a series of 47 CPTs. Samples comprised 35 choroid plexus papillomas (CPPs), 6 atypical choroid plexus papillomas (aCPPs) and 6 CPCs plus three recurrences thereof. Targeted TP53 and TERT promotor sequencing was performed in all samples. Whole exome sequencing (WES) and linked-read whole genome sequencing (WGS) was performed in 25 and 4 samples, respectively.

Results: Tumors comprised the molecular subgroups "pediatric A" (N=11), "pediatric B" (N=12) and "adult" (N=27). Copy-number alterations mainly represented whole-chromosomal alterations with subgroup-specific enrichments (gains of Chr1, 2 and 21q in "pediatric B" and gains of Chr5 and 9 and loss of Chr21q in "adult"). RNA sequencing yielded a novel CCDC47-PRKCA fusion transcript in one adult choroid plexus papilloma patient with aggressive clinical course; an underlying Chr17 inversion was demonstrated by linked-read WGS. WES and targeted sequencing showed TP53 mutations in 7/47 CPTs (15%), five of which were children. On the contrary, TERT promoter mutations were encountered in 7/28 adult patients (25%) and associated with shorter progression-free survival (log-rank test, p=0.015).

Conclusion: Pediatric CPTs lack recurrent driver alterations except for TP53, whereas CPTs in adults show TERT promoter mutations or a novel CCDC47-PRKCA gene fusion, being associated with a more unfavorable clinical course.
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http://dx.doi.org/10.1093/neuonc/noaa267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041331PMC
April 2021

TMEM119 as a specific marker of microglia reaction in traumatic brain injury in postmortem examination.

Int J Legal Med 2020 Nov 27;134(6):2167-2176. Epub 2020 Jul 27.

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

The aim of the present study was a refined analysis of neuroinflammation including TMEM119 as a useful microglia-specific marker in forensic assessments of traumatic causes of death, e.g., traumatic brain injury (TBI). Human brain tissue samples were obtained from autopsies and divided into cases with lethal TBI (n = 25) and subdivided into three groups according to their trauma survival time and compared with an age-, gender-, and postmortem interval-matched cohort of sudden cardiovascular fatalities as controls (n = 23). Brain tissue samples next to cortex contusions and surrounding white matter as well as samples of the ipsilateral uninjured brain stem and cerebellum were collected and stained immunohistochemically with antibodies against TMEM119, CD206, and CCR2. We could document the highest number of TMEM119-positive cells in acute TBI death with highly significant differences to the control numbers. CCR2-positive monocytes showed a significantly higher cell count in the cortex samples of TBI cases than in the controls with an increasing number of immunopositive cells over time. The number of CD206-positive M2 microglial cells increased survival time-dependent. After 3 days of survival, the cell number increased significantly in all four regions investigated compared with controls. In sum, we validate a specific and robustly expressed as well as fast reacting microglia marker, TMEM119, which distinguishes microglia from resident and infiltrating macrophages and thus offers a great potential for the estimation of the minimum survival time after TBI.
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http://dx.doi.org/10.1007/s00414-020-02384-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578160PMC
November 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

Complete radiological response following subtotal resection in three glioblastoma patients under treatment with Tumor Treating Fields.

Oncol Lett 2020 Jan 19;19(1):557-561. Epub 2019 Nov 19.

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

Glioblastoma multiforme (GBM) treatment consists of surgery, radiotherapy and chemotherapy with Temozolomide (TMZ). After subtotal resection (STR), residual tumors rarely undergo spontaneous regression. Overall survival (OS) and progression-free survival (PFS) are reduced when compared with gross total resection. There is evidence that adding Tumor Treating Fields (TTFields) to standard management may lead to a significant increase in PFS and OS. In 2015 and 2016, STR was performed in 27 patients with GBM. Of these, four subsequently received TTFields therapy in addition to chemotherapy. The present study presents a series of three patients with GBM (44-54 years; isocitrate dehydrogenase wild-type, methylated O6-methylguanine-DNA methyltransferase promoter) that were treated with radiochemotherapy and TTFields after STR. Therapy with TTFields started concomitantly to TMZ following radiotherapy and was maintained for 14, 24 and 37 months. TTFields were used as monotherapy in one case, as TMZ treatment had to be stopped due to toxicity for 1 month. In all patients, TTFields therapy was well tolerated at high compliance levels, resulting in complete response (CR) after 4, 5 and 7 months, respectively. Two patients remain tumor-free at 16 and 40 months after STR. One patient exhibited multifocal recurrence 11 months after the beginning of TTFields treatment but remains alive, presenting a mild neurological decline 24 months after starting TTFields. All three presented patients gave written informed consent for their data to be published. In conclusion, the current report detailed three patients with GBM who underwent STR and were subsequently treated with TMZ and TTFields. TTFields treatment was tolerated well and was applied accurately and with high compliance by these patients, which may have contributed to the complete response. Four of the 27 patients treated with STR received additional TTFields treatment. Three of these 4 showed a CR, while a CR was observed only 2 of the remaining 23 patients without TTFields. The current series supports the effects in clinical practice, as demonstrated in recent clinical trials. The results also demonstrated that adjuvant TTFields therapy can structurally affect residual tumors after STR.
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http://dx.doi.org/10.3892/ol.2019.11110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924031PMC
January 2020

Molecular characterization of histopathological ependymoma variants.

Acta Neuropathol 2020 02 2;139(2):305-318. Epub 2019 Nov 2.

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

According to the WHO classification, ependymal tumors are classified as subependymomas, myxopapillary ependymomas, classic ependymomas, anaplastic ependymomas, and RELA-fusion-positive ependymomas (RELA-EPN). Among classic ependymomas, the WHO defines rare histological variants, i.e., the clear cell, papillary, and tanycytic ependymoma. In parallel, global DNA methylation patterns distinguish nine molecular groups, some of which tightly overlap with histopathological subgroups. However, the match of the aforementioned histological variants to DNA methylation classes remains unclear. We analyzed histomorphology, clinical parameters, and global DNA methylation of tumors with the initial histological diagnoses of tanycytic (n = 12), clear cell (n = 14), or papillary ependymoma (n = 19). Forty percent of these tumors did not match to the epigenetic profile of ependymomas, using a previously published DNA methylation-based classifier for brain tumors. Instead, they were classified as low-grade glioma (n = 3), plexus tumor (n = 2), CNS high-grade neuroepithelial tumor with MN1 alteration (n = 2), papillary tumor of the pineal region (n = 2), neurocytoma (n = 1), or did not match to any known brain tumor methylation class (n = 8). Overall, integrated diagnosis had to be changed in 35.6% of cases as compared to the initial diagnosis. Among the tumors molecularly classified as ependymoma (27/45 cases), tanycytic ependymomas were mostly located in the spine (5/7 cases) and matched to spinal or myxopapillary ependymoma. 6/8 clear cell ependymomas were found supratentorially and fell into the methylation class of RELA-EPN. Papillary ependymomas with a positive ependymoma match (12/19 cases) showed either a "papillary" (n = 5), a "trabecular" (n = 1), or a "pseudo-papillary" (n = 6) growth pattern. The papillary growth pattern was strongly associated with the methylation class B of posterior fossa ependymoma (PFB, 5/5 cases) and tumors displayed DNA methylation sites that were significantly different when compared to PFB ependymomas without papillary growth. Tumors with pseudo-papillary histology matched to the methylation class of myxopapillary ependymoma (4/6 cases), whereas the trabecular case was anatomically and molecularly a spinal ependymoma. Our results show that the diagnosis of histological ependymoma variants is challenging and epigenetic profiles may improve diagnostic accuracy of these cases. Whereas clear cell and papillary ependymomas display correlations between localization, histology, and methylation, tanycytic ependymoma does not represent a molecularly distinct subgroup.
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http://dx.doi.org/10.1007/s00401-019-02090-0DOI Listing
February 2020

Clinical Utility of Different Approaches for Detection of Late Pseudoprogression in Glioblastoma With O-(2-[18F]Fluoroethyl)-L-Tyrosine PET.

Clin Nucl Med 2019 Sep;44(9):695-701

Departments of Nuclear Medicine.

Purpose: PET/CT using O-(2-[F]fluoroethyl)-L-tyrosine (F-FET) has proven valuable in differentiating tumor recurrence and progression from therapy-induced changes. This study aimed to investigate the diagnostic performance of several analytic approaches in the setting of suspected late pseudoprogression (PsP) in glioblastoma multiforme (GBM).

Methods: Retrospective analysis of tumor recurrence was performed in 36 patients with histopathologically confirmed GBM and suspicion of recurrence/disease progression more than 12 weeks from cessation of irradiation based on MRI and Response Assessment in Neuro-Oncology working group criteria. For differentiation of late PsP from true tumor recurrence, images were analyzed semiquantitatively employing tumor-to-brain ratios using 5 different approaches for tumor and normal brain reference region definition, respectively. Histopathology and/or clinical and imaging follow-up served as reference. Respective areas under the receiver operating characteristic curve were compared.

Results: F-FET PET was able to reliably differentiate PsP from true tumor progression with areas under the receiver operating characteristic curve ranging from 0.80 to 0.88 (all P < 0.01). Irrespective of the approach chosen, the classification differences between the applied methods were not significant (all P > 0.05), albeit approaches focusing on voxels with the highest uptake tended to perform superior.

Conclusions: Irrespective of the analytical approach, F-FET PET is a robust tool for detection of late PsP with only minor differences between different analytical approaches. However, methodological standardization and harmonization are needed to ensure comparability between different centers.
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http://dx.doi.org/10.1097/RLU.0000000000002652DOI Listing
September 2019

α-Synuclein in Parkinson's disease: causal or bystander?

J Neural Transm (Vienna) 2019 07 25;126(7):815-840. Epub 2019 Jun 25.

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

Parkinson's disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying LB generation and its causal trigger molecules are not yet fully understood. α-Synuclein (α-syn) is a major component of LB and SNCA gene missense mutations or duplications/triplications are causal for rare hereditary forms of PD. As typical sporadic PD is associated with LB pathology, a factor of major importance is the study of the α-syn protein and its pathology. α-Syn pathology is, however, also evident in multiple system atrophy (MSA) and Lewy body disease (LBD), making it non-specific for PD. In addition, there is an overlap of these α-synucleinopathies with other protein-misfolding diseases. It has been proven that α-syn, phosphorylated tau protein (pτ), amyloid beta (Aβ) and other proteins show synergistic effects in the underlying pathogenic mechanisms. Multiple cell death mechanisms can induce pathological protein-cascades, but this can also be a reverse process. This holds true for the early phases of the disease process and especially for the progression of PD. In conclusion, while rare SNCA gene mutations are causal for a minority of familial PD patients, in sporadic PD (where common SNCA polymorphisms are the most consistent genetic risk factor across populations worldwide, accounting for 95% of PD patients) α-syn pathology is an important feature. Conversely, with regard to the etiopathogenesis of α-synucleinopathies PD, MSA and LBD, α-syn is rather a bystander contributing to multiple neurodegenerative processes, which overlap in their composition and individual strength. Therapeutic developments aiming to impact on α-syn pathology should take this fact into consideration.
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http://dx.doi.org/10.1007/s00702-019-02025-9DOI Listing
July 2019

Driver mutations in USP8 wild-type Cushing's disease.

Neuro Oncol 2019 10;21(10):1273-1283

Department of Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg (UKW), Würzburg, Germany.

Background: Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.

Methods: Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.

Results: Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion.

Conclusions: USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.
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http://dx.doi.org/10.1093/neuonc/noz109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784271PMC
October 2019

Melanin and Neuromelanin Fluorescence Studies Focusing on Parkinson's Disease and Its Inherent Risk for Melanoma.

Cells 2019 06 15;8(6). Epub 2019 Jun 15.

Institute of Pathology, Department of Neuropathology, University of Wuerzburg, Comprehensive Cancer Center (CCC) Mainfranken Wuerzburg, 97080 Wuerzburg, Germany.

Parkinson's disease is associated with an increased risk of melanoma (and vice versa). Several hypotheses underline this link, such as pathways affecting both melanin and neuromelanin. For the first time, the fluorescence of melanin and neuromelanin is selectively accessible using a new method of nonlinear spectroscopy, based on a stepwise two-photon excitation. Cutaneous pigmentation and postmortem neuromelanin of Parkinson patients were characterized by fluorescence spectra and compared with controls. Spectral differences could not be documented, implying that there is neither a Parkinson fingerprint in cutaneous melanin spectra nor a melanin-associated fingerprint indicating an increased melanoma risk. Our measurements suggest that Parkinson's disease occurs without a configuration change of neuromelanin. However, Parkinson patients displayed the same dermatofluorescence spectroscopic fingerprint of a local malignant transformation as controls. This is the first comparative retrospective fluorescence analysis of cutaneous melanin and postmortem neuromelanin based on nonlinear spectroscopy in patients with Parkinson's disease and controls, and this method is a very suitable diagnostic tool for melanoma screening and early detection in Parkinson patients. Our results suggest a non-pigmentary pathway as the main link between Parkinson's disease and melanoma, and they do not rule out the melanocortin-1-receptor gene as an additional bridge between both diseases.
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http://dx.doi.org/10.3390/cells8060592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627191PMC
June 2019

Tumor growth under rhGM-CSF application in an orthotopic rodent glioma model.

Oncol Lett 2019 Jun 21;17(6):4843-4850. Epub 2019 Mar 21.

Department of Neurosurgery, Julius Maximilians University, Wuerzburg, D-97080 Wuerzburg, Germany.

Regulation of the host immune response serves a pivotal role in the persistence and progression of malignant glioma. To date, cytotoxic cluster of differentiation (CD)-8+ T and natural killer cells are considered the main cellular components of host tumor control. The influence of macrophages in an orthotropic C6 tumor implantation model was investigated and the aim of the present study was to characterize the effects of systemic macrophage-activation on glioma growth by using the granulocyte macrophage colony stimulating factor (rhGM-CSF). A total of 20 male Sprague-Dawley rats were orthotopically implanted with C6 glioma spheroids and treated subcutaneously with 10 µg/kg rhGM-CSF every other day; 9 animals served as controls. Serial magnetic resonance imaging was performed on days 7, 14, 21, 28, 32 and 42 post-implantation to monitor tumor volume. Histological work-up included hematoxylin and eosin, CD68/ED-1 macrophage, CD8 T-cell and Ki-67 MIB1 proliferation staining in gliomas and spleen. Experimental C6-gliomas developed in 15/20 (75%) animals. In rhGM-CSF treated rats, tumors developed significantly later and reached a smaller size (median, 134 mm) compared with the controls (median, 262 mm). On day 14, solid tumors presented in 11/17 (65%) rhGM-CSF-treated animals; in control animals tumor growth was detected in 3/9 animals on day 7 and in all animals on day 14. The mean survival time was 35 days in the rhGM-CSF group and significantly longer when compared with the control group (24 days). Immunohistochemistry exhibited significantly more macrophages in tumors, particularly in the perivascular zone of the rhGM-CSF group when compared with untreated animals; intratumoral CD8+ counts were equal in both groups. A systemic stimulation of macrophages by rhGM-CSF resulted in significantly reduced and delayed tumor growth in the rodent C6 glioma model. The present data suggested a significant role of macrophages in host control of experimental gliomas on the innate immune response. Until now, the role of macrophages may have been underestimated in host glioma control.
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http://dx.doi.org/10.3892/ol.2019.10179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507467PMC
June 2019

Prognostic Value of O-(2-[F]Fluoroethyl)-L-Tyrosine PET/CT in Newly Diagnosed WHO 2016 Grade II and III Glioma.

Mol Imaging Biol 2019 12;21(6):1174-1181

Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080, Wurzburg, Germany.

Purpose: The use of [F]fluoroethyl)-L-tyrosine ([F]FET) positron emission tomography/computed tomography (PET/CT) has proven valuable in brain tumor management. This study aimed to investigate the prognostic value of radiotracer uptake in newly diagnosed grade II or III gliomas according to the current 2016 World Health Organization (WHO) classification.

Procedures: A total of 35 treatment-naive patients (mean age, 48 ± 17 years) with histologically proven WHO grade II or III gliomas as defined by the current 2016 WHO classification were included. Static PET/CT imaging was performed 20 min after intravenous [F]FET injection. Images were assessed visually and semi-quantitatively using regions of interest for both tumor (SUVmax, SUVmean) and background (BKGmean) to calculate tumor-to-background (TBR) ratios. The association among histological results, molecular markers (including isocitrate dehydrogenase enzyme and methylguanine-DNA methyltransferase status), clinical features (age), and PET findings was tested and compared with outcome (progression-free [PFS] and overall survival [OS]).

Results: Fourteen patients presented with grade II (diffuse astrocytoma n = 10, oligodendroglioma n = 4) and 21 patients with grade III glioma (anaplastic astrocytoma n = 15, anaplastic oligodendroglioma n = 6). Twenty-seven out of the 35 patients were PET-positive (grade II n = 8/14, grade III n = 19/21), with grade III tumors exhibiting significantly higher amino acid uptake (TBR and TBR; p = 0.03 and p = 0.02, respectively). PET-negative lesions demonstrated significantly prolonged PFS (p = 0.003) as compared to PET-positive gliomas. PET-positive disease had a complementary value in prognostication in addition to patient age, glioma grade, and molecular markers.

Conclusions: Amino acid uptake as assessed by [F]FET-PET/CT imaging is useful as non-invasive read-out for tumor biology and prognosis in newly diagnosed, treatment-naive gliomas according to the 2016 WHO classification.
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http://dx.doi.org/10.1007/s11307-019-01357-yDOI Listing
December 2019

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

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

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

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

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

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
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