Publications by authors named "Andreas von Deimling"

519 Publications

Local ablative treatment with surgery and/or radiotherapy in single-site and oligometastatic carcinoma of unknown primary.

Eur J Cancer 2021 Sep 11;157:179-189. Epub 2021 Sep 11.

Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany. Electronic address:

Background: Single-site carcinoma of unknown primary (CUP) is recognised as a distinct favourable subtype in the European Society of Medical Oncology (ESMO) classification. There is broad consensus that these patients are candidates for local ablative treatment strategies with surgery and/or radiotherapy, but data on their outcomes are scarce.

Patients And Methods: In this study, we have addressed the prospects of cure and prognostic factors in a retrospective cohort of 63 patients who were eligible for local treatment at our centre.

Results: Median event-free (EFS) and overall survival (OS) were 15.6 months and 52.5 months, respectively. Of 61 patients who received local treatment, 20 (32.8%) remained event-free over a median follow-up of 28 months. Baseline clinical parameters including affected organ, number, volume and histology of metastases had no significant impact on prognosis, whereas deleterious TP53 mutations and DNA copy number loss emerged as independent adverse risk factors with respect to EFS. Surgical treatment was associated with improved OS as compared to radiation-based therapy.

Conclusion: Our study advocates to pursue localised treatment with surgery and/or radiotherapy whenever feasible and implies that genetic parameters might additionally determine the clinical course of single-site CUP patients.
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http://dx.doi.org/10.1016/j.ejca.2021.08.019DOI Listing
September 2021

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.

Acta Neuropathol 2021 Aug 21. Epub 2021 Aug 21.

Paediatric and Adolescent Medicine, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
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http://dx.doi.org/10.1007/s00401-021-02354-8DOI Listing
August 2021

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Acta Neuropathol 2021 Aug 18. Epub 2021 Aug 18.

Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.
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http://dx.doi.org/10.1007/s00401-021-02358-4DOI Listing
August 2021

The pediatric precision oncology INFORM registry: clinical outcome and benefit for patients with very high-evidence targets.

Cancer Discov 2021 Aug 9. Epub 2021 Aug 9.

University Hospital Magdeburg.

INFORM is a prospective, multi-national registry gathering clinical and molecular data of relapsed, progressive or high-risk pediatric cancer patients. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a pre-defined 7-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, twenty patients received matched targeted treatment with a median PFS of 204 days (95% CI 99 - N.A.), compared with 117 days (95% CI 106 - 143; P=0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0094DOI Listing
August 2021

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors.

Acta Neuropathol 2021 Aug 5. Epub 2021 Aug 5.

Institute of Neuropathology, University of Giessen, Giessen, Germany.

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
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http://dx.doi.org/10.1007/s00401-021-02356-6DOI Listing
August 2021

Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature.

Mod Pathol 2021 Jul 26. Epub 2021 Jul 26.

Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISA) with MDM2 amplification as their molecular hallmark. Interestingly, undifferentiated pleomorphic sarcomas (UPS) of the heart have recently been suggested to represent the cardiac analog of ISA due to morphological overlap and high prevalence of MDM2 amplifications in both neoplasms. However, little is known about ISAs and cardiac UPS without MDM2 amplifications and molecular data supporting their common classification is sparse. Here, we report a series of 35 cases comprising 25 ISAs of the pulmonary artery, one ISA of the renal artery and 9 UPS of the left atrium. Tumors were analyzed utilizing the Illumina Infinium MethylationEPIC BeadChip array, enabling copy number profile generation and unsupervised DNA methylation analysis. DNA methylation patterns were investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis. Histologically, all ISAs and UPS of the left atrium resembled extra-cardiac UPS. All cases exhibited highly complex karyotypes with overlapping patterns between ISA and UPS. 29/35 cases showed mutually exclusive amplifications in the cell-cycle associated oncogenes MDM2 (25/35), MDM4 (2/35), and CDK6 (2/35). We further observed recurrent co-amplifications in PDGFRA (21/35), CDK4 (15/35), TERT (11/35), HDAC9 (9/35), and CCND1 (4/35). Sporadic co-amplifications occurred in MYC, MYCN, and MET (each 1/35). The tumor suppressor CDKN2A/B was frequently deleted (10/35). Interestingly, DNA methylation profiling (t-SNE) revealed an overlap of ISA and cardiac UPS. This "ISA" methylation signature was distinct from potential histologic and molecular mimics. In conclusion, our data reveal MDM4 and CDK6 amplifications in ISAs and UPS of the left atrium, lacking MDM2 amplification. We further report novel co-amplifications of various oncogenes, which may have therapeutic implications. Finally, the genetic and epigenetic concordance of ISAs and UPS of the left atrium further supports a shared pathogenesis and common classification.
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http://dx.doi.org/10.1038/s41379-021-00874-yDOI Listing
July 2021

Development of Randomized Trials in Adults with Medulloblastoma-The Example of EORTC 1634-BTG/NOA-23.

Cancers (Basel) 2021 Jul 9;13(14). Epub 2021 Jul 9.

Erasmus Medical Center Cancer Institute, Department of Neuro-Oncology, 3015 GD Rotterdam, The Netherlands.

Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (Odomzo, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.
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http://dx.doi.org/10.3390/cancers13143451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303185PMC
July 2021

Fibroblast Activation Protein specific PET/CT imaging in fibrotic interstitial lung diseases and lung cancer: a translational exploratory study.

J Nucl Med 2021 Jul 16. Epub 2021 Jul 16.

University Hospital Heidelberg, Germany.

Interstitial lung diseases (ILD) comprise over 200 parenchymal lung disorders. Among them, fibrosing ILDs, especially idiopathic pulmonary fibrosis (IPF) in particular are associated with a poor prognosis, while some others ILDs like sarcoidosis have a much better prognosis. A high proportion of ILD manifests as fibrotic ILD (fILD). Lung cancer (LC) is a frequent complication of fILD. Activated fibroblasts are crucial for fibrotic processes in fILD. The aim of this exploratory study was to evaluate the imaging properties of static and dynamic FAPI-PET/CT in various types of fILD and to confirm FAP expression of fILD lesions by FAP immunohistochemistry of human fILD biopsy samples and of lung sections of genetically engineered (Nedd4-2 -/- ) mice with an idiopathic pulmonary fibrosis (IPF) -like lung disease. PET-Scans of 15 patients with fILD and suspected LC were acquired 10, 60 and 180 minutes after the administration of 150-250 MBq of a Ga labelled FAPI tracer (FAPI-46). In three patients, dynamic scans over 40 mins were performed instead of imaging after 10 minutes. Standardized uptake values (SUV and SUVmean) of fibrotic lesions and LC were measured and CT-density-corrected. Target-to-background ratios (TBR) were calculated. PET imaging was correlated with CT-based fibrosis scores. Time-activity curves derived from dynamic imaging were analyzed. FAP immunohistochemistry of 4 human fILD biopsy samples and of fibrotic lungs of Nedd4-2-/- mice was carried out. FILD lesions as well as LC showed markedly elevated FAPI-uptake (density corrected SUV / mean values 60 minutes post injection: 11,12 +/- 6,71 and 4,29 +/- 1,61 for fILD lesions and 16,69 +/- 9,35 and 6,44 +/- 3,29 for LC) and high TBR (TBR of density corrected SUV/SUVmean values 60 minutes post injection: 2,30 +/- 1,47 and 1,67 +/- 0,79 for fILD and 3,90 +/- 2,36 and 2,37 +/- 1,14 for LC). SUV and SUVmean values decreased over time with stable TBR of fILD and increasing TBR in LC on trend. Dynamic imaging showed differing time activity curves of fILD and LC. FAPI uptake showed a positive correlation with the CT-based fibrosis index (FIBI). Immunohistochemistry of human biopsy samples and lungs of Nedd4-2-/- mice showed a patchy expression of FAP in fibrotic lesions, preferentially in the transition zone to healthy lung parenchyma. FAPI-PET/CT imaging is a promising new imaging modality for fILD and LC. Its potential clinical value for monitoring and therapy evaluation of fILD should be investigated in future studies.
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http://dx.doi.org/10.2967/jnumed.121.261925DOI Listing
July 2021

Intrathecal activation of CD8 memory T cells in IgG4-related disease of the brain parenchyma.

EMBO Mol Med 2021 Aug 13;13(8):e13953. Epub 2021 Jul 13.

DKTK Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4-restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and pathophysiological mechanisms of IgG4-RD remain elusive. There are very few cases of IgG4-RD with isolated central nervous system manifestation. By leveraging single-cell sequencing of the cerebrospinal fluid (CSF) of a patient with an inflammatory intracranial pseudotumor, we provide novel insights into the immunopathophysiology of IgG4-RD. Our data illustrate an IgG4-RD-associated polyclonal T-cell response in the CSF and an oligoclonal T-cell response in the parenchymal lesions, the latter being the result of a multifaceted cell-cell interaction between immune cell subsets and pathogenic B cells. We demonstrate that CD8 T effector memory cells might drive and sustain autoimmunity via macrophage migration inhibitory factor (MIF)-CD74 signaling to immature B cells and CC-chemokine ligand 5 (CCL5)-mediated recruitment of cytotoxic CD4 T cells. These findings highlight the central role of T cells in sustaining IgG4-RD and open novel avenues for targeted therapies.
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http://dx.doi.org/10.15252/emmm.202113953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350898PMC
August 2021

Molecular diagnostics in drug-resistant focal epilepsy define new disease entities.

Brain Pathol 2021 Jul;31(4):e12963

Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.

Structural brain lesions, including the broad range of malformations of cortical development (MCD) and glioneuronal tumors, are among the most common causes of drug-resistant focal epilepsy. Epilepsy surgery can provide a curative treatment option in respective patients. The currently available pre-surgical multi-modal diagnostic armamentarium includes high- and ultra-high resolution magnetic resonance imaging (MRI) and intracerebral EEG to identify a focal structural brain lesion as epilepsy underlying etiology. However, specificity and accuracy in diagnosing the type of lesion have proven to be limited. Moreover, the diagnostic process does not stop with the decision for surgery. The neuropathological diagnosis remains the gold standard for disease classification and patient stratification, but is particularly complex with high inter-observer variability. Here, the identification of lesion-specific mosaic variants together with epigenetic profiling of lesional brain tissue became new tools to more reliably identify disease entities. In this review, we will discuss how the paradigm shifts from histopathology toward an integrated diagnostic approach in cancer and the more recent development of the DNA methylation-based brain tumor classifier have started to influence epilepsy diagnostics. Some examples will be highlighted showing how the diagnosis and our mechanistic understanding of difficult to classify structural brain lesions associated with focal epilepsy has improved with molecular genetic data being considered in decision making.
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http://dx.doi.org/10.1111/bpa.12963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412082PMC
July 2021

The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.

Neuro Oncol 2021 08;23(8):1231-1251

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

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.
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http://dx.doi.org/10.1093/neuonc/noab106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328013PMC
August 2021

Myxoid pleomorphic liposarcoma-a clinicopathologic, immunohistochemical, molecular genetic and epigenetic study of 12 cases, suggesting a possible relationship with conventional pleomorphic liposarcoma.

Mod Pathol 2021 Jun 24. Epub 2021 Jun 24.

Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.

Myxoid pleomorphic liposarcoma is a recently defined subtype of liposarcoma, which preferentially involves the mediastinum of young patients and shows mixed histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma. While myxoid pleomorphic liposarcoma is known to lack the EWSR1/FUS-DDIT3 fusions characteristic of the former, additional genetic data are limited. To further understand this tumor type, we extensively examined a series of myxoid pleomorphic liposarcomas by fluorescence in situ hybridization (FISH), shallow whole genome sequencing (sWGS) and genome-wide DNA methylation profiling. The 12 tumors occurred in 6 females and 6 males, ranging from 17 to 58 years of age (mean 33 years, median 35 years), and were located in the mediastinum (n = 5), back, neck, cheek and leg, including thigh. Histologically, all cases consisted of relatively, bland, abundantly myxoid areas with a prominent capillary vasculature, admixed with much more cellular and less myxoid foci containing markedly pleomorphic spindled cells, numerous pleomorphic lipoblasts and elevated mitotic activity. Using sWGS, myxoid pleomorphic liposarcomas were found to have complex chromosomal alterations, including recurrent large chromosomal gains involving chromosomes 1, 6-8, 18-21 and losses involving chromosomes 13, 16 and 17. Losses in chromosome 13, in particular loss in 13q14 (including RB1, RCTB2, DLEU1, and ITM2B genes), were observed in 4 out of 8 cases analyzed. Additional FISH analyses confirmed the presence of a monoallelic RB1 deletion in 8/12 cases. Moreover, nuclear Rb expression was deficient in all studied cases. None showed DDIT3 gene rearrangement or MDM2 gene amplification. Using genome-wide DNA methylation profiling, myxoid pleomorphic liposarcomas and conventional pleomorphic liposarcomas formed a common methylation cluster, which segregated from conventional myxoid liposarcomas. While the morphologic, genetic and epigenetic characteristics of myxoid pleomorphic liposarcoma suggest a link with conventional pleomorphic liposarcoma, its distinctive clinical features support continued separate classification for the time being.
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http://dx.doi.org/10.1038/s41379-021-00862-2DOI Listing
June 2021

Spindle Cell Sarcoma of the Uterine Corpus With Adipose Metaplasia: Expanding the Morphologic Spectrum of Neoplasms With MEIS1-NCOA2 Gene Fusion.

Int J Gynecol Pathol 2021 Jun 23. Epub 2021 Jun 23.

Departments of General Pathology (F.K.F.K., C.K.) Neuropathology (A.V.D.), Institute of Pathology, Heidelberg University Hospital Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK) (A.V.D.), Heidelberg Dermatopathologie Bodensee (T.M.) Institute of Pathology, Medizin Campus Bodensee (F.K.), Friedrichshafen MVZ für Histologie, Zytologie und molekulare Diagnostik Trier GmbH, Trier, Germany (D.S.) Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK (W.G.M.C.).

We report a spindle cell sarcoma arising in the uterine corpus of a 26-yr-old patient. The patient underwent a simple hysterectomy and the uterine corpus contained a 9 cm tumor showing nodular and "finger-like" myometrial invasion. Histologically, the tumor was composed of a monomorphic population of atypical spindle cells which contained widespread foci of cytologically benign adipocytes. Immunohistochemistry revealed diffuse strong positivity for CD10, CD56, and CD99 and diffuse weak positive staining with ER and WT1 while smooth muscle markers, S100, TLE1, and cyclin D1 were negative. Total RNA sequencing identified an in-frame fusion between exon 6 of MEIS1 and exon 12 of NCOA2. Copy number analysis revealed few aberrations with no deletions or amplifications identified. No adjuvant therapy was given and the patient is disease-free 9 yr after initial diagnosis. This case represents the second report of a uterine sarcoma harboring a MEIS1-NCOA2/1 gene fusion and expands the morphologic spectrum of recently reported spindle cell sarcomas arising in the genitourinary tract harboring MEIS1-NCOA2/1 gene fusions. This is the first reported case of such tumors with an adipocytic component.
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http://dx.doi.org/10.1097/PGP.0000000000000803DOI Listing
June 2021

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel-Lindau disease-related tumours.

Neuropathol Appl Neurobiol 2021 Jun 5. Epub 2021 Jun 5.

Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Aims: Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours.

Methods: Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis.

Results: VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL-disease-related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test).

Conclusion: Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs.
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http://dx.doi.org/10.1111/nan.12741DOI Listing
June 2021

Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study.

Neuro Oncol 2021 Sep;23(9):1597-1611

Department of Neurooncology, Russian Scientific Center of Radiology, Moscow, Russia.

Background: Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies.

Methods: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed.

Results: DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively.

Conclusion: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.
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http://dx.doi.org/10.1093/neuonc/noab136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408859PMC
September 2021

Deep Neural Network for Differentiation of Brain Tumor Tissue Displayed by Confocal Laser Endomicroscopy.

Front Oncol 2021 11;11:668273. Epub 2021 May 11.

Department of Neurosurgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Background: Reliable on site classification of resected tumor specimens remains a challenge. Implementation of high-resolution confocal laser endoscopic techniques (CLEs) during fluorescence-guided brain tumor surgery is a new tool for intraoperative tumor tissue visualization. To overcome observer dependent errors, we aimed to predict tumor type by applying a deep learning model to image data obtained by CLE.

Methods: Human brain tumor specimens from 25 patients with brain metastasis, glioblastoma, and meningioma were evaluated within this study. In addition to routine histopathological analysis, tissue samples were stained with fluorescein and analyzed with CLE. We trained two convolutional neural networks and built a predictive level for the outputs.

Results: Multiple CLE images were obtained from each specimen with a total number of 13,972 fluorescein based images. Test accuracy of 90.9% was achieved after applying a two-class prediction for glioblastomas and brain metastases with an area under the curve (AUC) value of 0.92. For three class predictions, our model achieved a ratio of correct predicted label of 85.8% in the test set, which was confirmed with five-fold cross validation, without definition of confidence. Applying a confidence rate of 0.999 increased the prediction accuracy to 98.6% when images with substantial artifacts were excluded before the analysis. 36.3% of total images met the output criteria.

Conclusions: We trained a residual network model that allows automated, on site analysis of resected tumor specimens based on CLE image datasets. Further studies are required to assess the clinical benefit CLE can have.
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http://dx.doi.org/10.3389/fonc.2021.668273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147727PMC
May 2021

DNA methylation-based profiling of bone and soft tissue tumours: a validation study of the 'DKFZ Sarcoma Classifier'.

J Pathol Clin Res 2021 Jul 5;7(4):350-360. Epub 2021 May 5.

Research Department of Pathology, University College London, UCL Cancer Institute, London, UK.

Diagnosing bone and soft tissue neoplasms remains challenging because of the large number of subtypes, many of which lack diagnostic biomarkers. DNA methylation profiles have proven to be a reliable basis for the classification of brain tumours and, following this success, a DNA methylation-based sarcoma classification tool from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg has been developed. In this study, we assessed the performance of their classifier on DNA methylation profiles of an independent data set of 986 bone and soft tissue tumours and controls. We found that the 'DKFZ Sarcoma Classifier' was able to produce a diagnostic prediction for 55% of the 986 samples, with 83% of these predictions concordant with the histological diagnosis. On limiting the validation to the 820 cases with histological diagnoses for which the DKFZ Classifier was trained, 61% of cases received a prediction, and the histological diagnosis was concordant with the predicted methylation class in 88% of these cases, findings comparable to those reported in the DKFZ Classifier paper. The classifier performed best when diagnosing mesenchymal chondrosarcomas (CHSs, 88% sensitivity), chordomas (85% sensitivity), and fibrous dysplasia (83% sensitivity). Amongst the subtypes least often classified correctly were clear cell CHSs (14% sensitivity), malignant peripheral nerve sheath tumours (27% sensitivity), and pleomorphic liposarcomas (29% sensitivity). The classifier predictions resulted in revision of the histological diagnosis in six of our cases. We observed that, although a higher tumour purity resulted in a greater likelihood of a prediction being made, it did not correlate with classifier accuracy. Our results show that the DKFZ Classifier represents a powerful research tool for exploring the pathogenesis of sarcoma; with refinement, it has the potential to be a valuable diagnostic tool.
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http://dx.doi.org/10.1002/cjp2.215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185366PMC
July 2021

Ga-FAPI-PET/CT improves diagnostic staging and radiotherapy planning of adenoid cystic carcinomas - Imaging analysis and histological validation.

Radiother Oncol 2021 07 1;160:192-201. Epub 2021 May 1.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.

Background: Adenoid cystic carcinomas (ACCs) are rare epithelial tumors mostly situated in the head and neck region and characterized by infiltrative growth. The tumor stroma of ACCs includes cancer-associated fibroblasts (CAFs) expressing Fibroblast Activation Protein (FAP), a new target for positron emission tomography (PET) imaging. Here we describe the value of PET/ computed tomography (PET/CT) imaging using Ga-labelled FAP-Inhibitors (Ga-FAPI-PET/CT) and their clinical potential for staging and radiotherapy planning in 12 ACC patients (7 primary, 5 recurrent).

Patients And Methods: Patients underwent contrast enhanced staging CT (ceCT) and magnetic resonance imaging (ceMRI) before Ga-FAPI - PET/CT. PET-scans were acquired 10, 60 and 180 minutes after administration of 150-250 MBq of Ga-labelled FAPI tracers. SUV and SUV values of ACCs and healthy organs were obtained using a 60% of maximum iso-contour. FAP and alpha smooth muscle actin (α-SMA) immunohistochemistry was performed in 13 cases (3 with and 10 without Ga FAPI-PET/CT). Staging and radiotherapy planning based on Ga-FAPI-PET/CT versus ceCT/MRI alone were compared.

Results: We observed elevated tracer uptake in all ACCs. Immunohistochemistry showed FAP-expressing CAFs in the tumor. Compared to conventional staging, Ga-FAPI-PET/CT led to upstaging in 2/12 patients and to detection of additional metastases in 3 patients, thus in total 42% of patients had their staging altered. Moreover, Ga-FAPI PET improved the accuracy of target volume delineation for radiotherapy, as compared to CT and MRI.

Conclusion: Ga-FAPI-PET/CT is a promising imaging modality for ACC, increasing the accuracy of staging exams and radiotherapy planning volumes, as compared conventional to CT and MRI.
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http://dx.doi.org/10.1016/j.radonc.2021.04.016DOI Listing
July 2021

Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma.

Neuro Oncol 2021 Sep;23(9):1547-1559

Pathology Department, Erasmus MC, Rotterdam, the Netherlands.

Background: Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients.

Methods: The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization.

Results: Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication.

Conclusion: Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.
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http://dx.doi.org/10.1093/neuonc/noab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408862PMC
September 2021

DNA Methylation Profiling Discriminates between Malignant Pleural Mesothelioma and Neoplastic or Reactive Histologic Mimics.

J Mol Diagn 2021 07 20;23(7):834-846. Epub 2021 Apr 20.

Department of Neuropathology, Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

The diagnosis of malignant pleural mesothelioma (MPM) is challenging because of its potential overlap with other neoplasms or even with reactive conditions. DNA methylation analysis is effective in diagnosing tumors. In the present study, this approach was tested for use in MPM diagnosis. The DNA methylation patterns of a discovery cohort and an independent-validation cohort of MPMs were compared to those of 202 cases representing malignant and benign diagnostic mimics (angiosarcoma, desmoid-type fibromatosis, epithelioid sarcoma, leiomyosarcoma, lung adenocarcinoma, lung squamous cell carcinoma, melanoma, nodular fasciitis, reactive mesothelial hyperplasia, sclerosing fibrous pleuritis, solitary fibrous tumor, and synovial sarcoma). By both unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis, MPM samples in the discovery cohort exhibited a DNA methylation profile different from those of other neoplastic and reactive mimics. These results were confirmed in the independent validation cohort and by in silico analysis of the MPM-The Cancer Genome Atlas data set. Copy number variation profiles were also inferred to identify molecular hallmarks of MPM, including CDKN2A and NF2 deletions. Methylation profiling was effective in the diagnosis of MPM, although caution is advised in samples with low tumor cell content.
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http://dx.doi.org/10.1016/j.jmoldx.2021.04.002DOI Listing
July 2021

Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas.

Cancer Discov 2021 Sep 20;11(9):2230-2247. Epub 2021 Apr 20.

Department of Neuropathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Molecular groups of supratentorial ependymomas comprise tumors with or -involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histologic features containing alternative translocations that shared as a partner gene. Somatic overexpression of -associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation , and cross-species comparative analyses identified as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors. SIGNIFICANCE: fusions are a hallmark feature of supratentorial ependymoma. We find that ZFTA acts as a partner for alternative transcriptional activators in oncogenic fusions of supratentorial tumors with various histologic characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by fusion-positive tumors, such as GLI2..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0963DOI Listing
September 2021

Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1.

Acta Neuropathol 2021 07 19;142(1):179-189. Epub 2021 Apr 19.

Division of Neuropathology, Institute of Pathology, Basel University Hospital, Basel, Switzerland.

Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53, RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.
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http://dx.doi.org/10.1007/s00401-021-02302-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217054PMC
July 2021

Clinicopathologic and molecular analysis of embryonal rhabdomyosarcoma of the genitourinary tract: evidence for a distinct DICER1-associated subgroup.

Mod Pathol 2021 08 12;34(8):1558-1569. Epub 2021 Apr 12.

Institute of Pathology, Department of General Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Embryonal rhabdomyosarcoma (ERMS) of the uterus has recently been shown to frequently harbor DICER1 mutations. Interestingly, only rare cases of extrauterine DICER1-associated ERMS, mostly located in the genitourinary tract, have been reported to date. Our goal was to study clinicopathologic and molecular profiles of DICER1-mutant (DICER1-mut) and DICER1-wild type (DICER1-wt) ERMS in a cohort of genitourinary tumors. We collected a cohort of 17 ERMS including nine uterine (four uterine corpus and five cervix), one vaginal, and seven urinary tract tumors. DNA sequencing revealed mutations of DICER1 in 9/9 uterine ERMS. All other ERMS of our cohort were DICER1-wt. The median age at diagnosis of patients with DICER1-mut and DICER1-wt ERMS was 36 years and 5 years, respectively. Limited follow-up data (available for 15/17 patients) suggested that DICER1-mut ERMS might show a less aggressive clinical course than DICER1-wt ERMS. Histological features only observed in DICER1-mut ERMS were cartilaginous nodules (6/9 DICER1-mut ERMS), in one case accompanied by foci of ossification. Recurrent mutations identified in both DICER1-mut and DICER1-wt ERMS affected KRAS, NRAS, and TP53. Copy number analysis revealed similar structural variations with frequent gains on chromosomes 2, 3, and 8, independent of DICER1 mutation status. Unsupervised hierarchical clustering of array-based whole-genome DNA methylation data of our study cohort together with an extended methylation data set including different RMS subtypes from genitourinary and extra-genitourinary locations (n = 102), revealed a distinct cluster for DICER1-mut ERMS. Such tumors clearly segregated from the clusters of DICER1-wt ERMS, alveolar RMS, and MYOD1-mutant spindle cell and sclerosing RMS. Only one tumor, previously diagnosed as ERMS arising in the maxilla of a 6-year-old boy clustered with DICER1-mut ERMS of the uterus. Subsequent sequencing analysis identified two DICER1 mutations in the latter case. Our results suggest that DICER1-mut ERMS might qualify as a distinct subtype in future classifications of RMS.
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http://dx.doi.org/10.1038/s41379-021-00804-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295035PMC
August 2021

A vaccine targeting mutant IDH1 in newly diagnosed glioma.

Nature 2021 Apr 24;592(7854):463-468. Epub 2021 Mar 24.

Neurology Clinic, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany.

Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H) tumours in syngeneic MHC-humanized mice. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H) astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG and CXCL13 T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
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http://dx.doi.org/10.1038/s41586-021-03363-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046668PMC
April 2021

Diagnostic biomarkers from proteomic characterization of cerebrospinal fluid in patients with brain malignancies.

J Neurochem 2021 Jul 9;158(2):522-538. Epub 2021 Apr 9.

Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Recent technological advances in molecular diagnostics through liquid biopsies hold the promise to repetitively monitor tumor evolution and treatment response of brain malignancies without the need of invasive surgical tissue accrual. Here, we implemented a mass spectrometry-based protein analysis pipeline which identified hundreds of proteins in 251 cerebrospinal fluid (CSF) samples from patients with four types of brain malignancies (glioblastoma, lymphoma, brain metastasis, and leptomeningeal disease [LMD]) and from healthy individuals with a focus on glioblastoma in a retrospective and confirmatory prospective observational study. CSF proteome deregulation via disruption of the blood brain barrier appeared to be largely conserved across brain tumor entities. CSF analysis of glioblastoma patients identified two proteomic clusters that correlated with tumor size and patient survival. By integrating CSF data with proteomic analyses of matching glioblastoma tumor tissue and primary glioblastoma cells, we identified potential CSF biomarkers for glioblastoma, in particular chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). Key findings were validated in a prospective cohort consisting of 35 glioma patients. Finally, in LMD patients who frequently undergo repeated CSF work-up, we explored our proteomic pipeline as a mean to profile consecutive CSF samples. Therefore, proteomic analysis of CSF in brain malignancies has the potential to reveal biomarkers for diagnosis and therapy monitoring.
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http://dx.doi.org/10.1111/jnc.15350DOI Listing
July 2021

The age of adult pilocytic astrocytoma cells.

Oncogene 2021 Apr 17;40(16):2830-2841. Epub 2021 Mar 17.

Group Genome Instability in Tumors, DKFZ, Heidelberg, Germany.

Adult pilocytic astrocytomas (PAs) have been regarded as indistinguishable from pediatric PAs in terms of genome-wide expression and methylation patterns. It has been unclear whether adult PAs arise early in life and remain asymptomatic until adulthood, or whether they develop during adulthood. We sought to determine the age and origin of adult human PAs using two types of "marks" in the genomic DNA. First, we analyzed the DNA methylation patterns of adult and pediatric PAs to distinguish between PAs of different anatomic locations (n = 257 PA and control brain tissues). Second, we measured the concentration of nuclear bomb test-derived C in genomic DNA (n = 14 cases), which indicates the time point of the formation of human cell populations. Our data suggest that adult and pediatric PAs developing in the infratentorial brain are closely related and potentially develop from precursor cells early in life, whereas supratentorial PAs might show age and location-specific differences.
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http://dx.doi.org/10.1038/s41388-021-01738-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062266PMC
April 2021

Telomerase reverse transcriptase promoter mutation- and O-methylguanine DNA methyltransferase promoter methylation-mediated sensitivity to temozolomide in isocitrate dehydrogenase-wild-type glioblastoma: is there a link?

Eur J Cancer 2021 Apr 22;147:84-94. Epub 2021 Feb 22.

Institute of Neuropathology, Heinrich Heine University, Medical Faculty, Düsseldorf, Germany; German Cancer Consortium, Partner Site Essen/Düsseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Aim Of The Study: Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wild-type glioblastoma is essentially limited to patients with O-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumours. Recent studies suggested that telomerase reverse transcriptase (TERT) promoter hotspot mutations may have an impact on the prognostic role of the MGMT status in patients with glioblastoma.

Methods: MGMT promoter methylation and TERT promoter mutation status were retrospectively assessed in a prospective cohort of patients with IDH-wild-type glioblastoma of the German Glioma Network (GGN) (n = 298) and an independent retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n = 302).

Results: In the GGN cohort, but not in the Düsseldorf/Zurich cohort, TERT promoter mutation was moderately associated with inferior outcomes in patients with MGMT promoter-unmethylated tumours (hazard ratio 1.74; 95% confidence interval: 1.07-2.82; p = 0.026). TERT promoter mutations were not associated with better outcomes in patients with MGMT promoter-methylated tumours in either cohort. The two different TERT promoter hotspot mutations (C228T and C250T) were not linked to distinct outcomes.

Conclusions: Analysis of two independent cohorts of patients with glioblastoma did not confirm previous data, suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in patients with IDH-wild-type glioblastoma.
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http://dx.doi.org/10.1016/j.ejca.2021.01.014DOI Listing
April 2021

Integrated molecular analysis of adult sonic hedgehog (SHH)-activated medulloblastomas reveals two clinically relevant tumor subsets with VEGFA as potent prognostic indicator.

Neuro Oncol 2021 Sep;23(9):1576-1585

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.

Background: Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology. Approximately 70% of adult MB disclose a sonic hedgehog (SHH) molecular signature in contrast to about 30% in pediatric cohorts. In addition, adult SHH-MB (aSHH-MB) are clinically heterogeneous but there is consensus neither on their optimal treatment nor on risk stratification. Thus, the identification of clinically relevant molecular subsets of aSHH-MB and identification of potential treatment targets remains inconclusive.

Methods: We analyzed 96 samples of institutionally diagnosed aSHH-MB through genome-wide DNA methylation profiling, targeted DNA sequencing, and RNA sequencing to identify molecular subcategories of these tumors and assess their prognostic significance.

Results: We defined two aSHH-MB numerically comparable epigenetic subsets with clinical and molecular variability. The subset "aSHH-MBI" (46%/48%) was associated with PTCH1/SMO (54%/46%) mutations, "neuronal" transcriptional signatures, and favorable outcomes after combined radio-chemotherapy (5-year PFS = 80% and OS = 92%). The clinically unfavorable "aSHH-MBII" subset (50%/52%; 5-year PFS = 24% and OS = 45%) disclosed GLI2 amplifications (8%), loss of 10q (22%), and gene expression signatures associated with angiogenesis and embryonal development. aSHH-MBII tumors revealed strong and ubiquitous expression of VEGFA both at transcript and protein levels that was correlated with unfavorable outcome.

Conclusions: (1) The histologically uniform aSHH-MB cohort exhibits clear molecular heterogeneity separating these tumors into two molecular subsets (aSHH-MBI and aSHH-MBII), which are associated with different cytogenetics, mutational landscapes, gene expression signatures, and clinical course. (2) VEGFA appears to be a promising biomarker to predict clinical course, which needs further prospective validation as its potential role in the pathogenesis of this subset.
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http://dx.doi.org/10.1093/neuonc/noab031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408884PMC
September 2021
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