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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i115-i115
    Description: Abstract BACKGROUND Low-grade-glioma (LGG) is often a chronic disease requiring multiple treatment-interventions. The multi-state-model (MSM) analyzes almost unlimited disease-states that patients may undergo. PURPOSE We analyzed disease-state probability of German LGG-patients within the SIOP-LGG 2004 study. Starting-state was defined as “diagnosis” and final-state as “death” with in-between “disease-states”, i.e. surgery, chemotherapy or radiation. We then evaluated clinical risk factors associated with multiple interventions. RESULTS We identified 1587 patients and a total of 23 different states (median follow-up 6.2 years). For robust statistical calculation, we reduced the model to 10 states. Five years after diagnosis state probabilities of patients were as follows: 0.11 no therapy at all, 0.49 one and 0.10 two surgeries-only, 0.19 one, 0.04 two and 0.02 even three non-surgical interventions with or without prior surgery, 0.005 had developed a malignant tumor and 0.02 had deceased. Risk-group analysis revealed higher probability for multiple interventions for infants (0.40), tumor location in supratentorial midline (0.21) or cerebellum (0.20), astrocytic tumors (0.22) and degree of resection, i.e. partial resection (0.31) and biopsy-only (0.35) five years after diagnosis. Probabilities for patients with neurofibromatosis type-1 were most likely not to be treated at all (0.36) or to receive non-surgical therapy, if needed (0.45). Sex had no influence. CONCLUSION This is the first MSM analysis of a LGG clinical trial cohort reflecting natural history and transitions to multiple interventions. A substantial number of patients is at risk for successive treatments with associated neurotoxicity. This underscores the necessity that LGG-management attempts to save function.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Neurosurgery, 2018, Vol.65(CN_suppl_1 Suppl 1), pp.90-90
    Description: Abstract INTRODUCTION Diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumors with limited treatment options and dismal outcome. Brainstem biopsy to enable molecular characterization of the tumor is currently controversial due to unclear benefits. The INFORM...
    ISSN: 0148-396X
    E-ISSN: 15244040
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  • 3
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    In: Neuro-Oncology, 2014, Vol. 16(suppl3), pp.iii24-iii24
    Description: BACKGROUND: Although childhood malignancies have become curable in about 75% of cases due to empirically developed multi-modal therapeutic concepts applied in nation-wide collaborative trials, for children with a relapse, cure remains the exception. In the framework of the ICGC project PedBrain many new potentially druggable genetic lesions have been identified. However, it will not be feasible to conduct traditional phase I trials for all these new drugs in these overall rare entities. To still have our young patients participating in the recent advances in molecular targeted drug treatment, we initiated a novel innovative way of introducing these drugs in a clinical setting based on an individualized molecular rationale, a concept called INFORM (INdividualized therapy For Relapsed Malignancies in childhood). METHODS: Exome- and low-coverage whole-genome sequencing, RNA sequencing, gene expression profiling, DNA methylation profiling, bioinformatic prediction of drug targets and compound selection are carried out aiming at a turnaround time of 4 weeks or less after re-biopsy of the tumor. In the current feasibility phase, drug targets and prioritization are offered to the treating physician in the local hospital for individual treatment decisions. RESULTS: Ten patients were recruited to the INFORM-pilot study by now. For all but two, druggable targets have been identified. The first two patients with early follow-up MRIs after 6 weeks had stable disease (medulloblastoma) and 50% tumor volume reduction (myofibroblastc tumor), respectively. In an additional case with pontine glioma, molecular diagnostics significantly contributed to the establishment of an unambiguous diagnosis. CONCLUSIONS: This is the first population-based study using next-generation sequencing technologies to guide treatment decisions in a clinical setting. In addition to this advance in “next-generation” clinical oncology, INFORM will also reveal the largest comprehensive molecular datasets of relapsed tumors to date, and since primary tumor material from the same patient will also be analyzed whenever available, will likely identify key biological properties of relapsing malignancies and recurrent mechanisms of drug resistance across entities. SECONDARY CATEGORY: Pediatrics.
    Keywords: Pediatrics ; Drug Resistance ; Magnetic Resonance Imaging ; Population Studies ; Oncology ; Tumors ; Children ; Clinical Trials ; Brain Tumors ; Gene Expression ; Malignancy ; RNA ; DNA Methylation ; Medulloblastoma ; Glioma ; Bioinformatics ; Drugs ; Hospitals ; Neurology & Neuropathology;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 5
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i182-i182
    Description: Precise diagnosis and robust detection of actionable alterations is required for individualized treatments. The Pediatric Targeted Therapy (PTT) 2.0 program aims at improvement of diagnostic accuracy and detection of targetable alterations by extended molecular diagnostics. The impact of these analyses on clinical management is being evaluated. Pediatric patients with relapsed or progressive tumors after treatment according to standard protocols are included, independent of the histological diagnosis. Formalin fixed paraffin embedded material and a blood sample for germline correction are requested. The methods employed are DNA methylation array, customized targeted gene panel sequencing (130 genes), RNA and Sanger sequencing in selected cases, and immunohistochemistry (IHC) of selected markers. A questionnaire-based follow-up is used to determine the clinical impact of the analysis. We have included n=111 cases from 22.02.2017.-31.12.2017, analysis was completed for n=83 cases (75%) at the time of abstract submission. The most common entities were brain tumors (n=56/83, 67%). DNA methylation array alone allowed diagnostic classification in n=45/83 cases (54.2%) and n=34/56 brain tumor cases (60,7%), respectively. Actionable targets as detected by copy number calculation, gene panel sequencing, RNA sequencing and IHC were found in n=47/83 cases (56.6%). Pathogenic germline alterations with clinical relevance were identified in n=7/83 cases (8.4%) and were confirmed by Sanger sequencing. Follow-up analyses are ongoing. In conclusion, combination of next-generation diagnostics such as methylation arrays and targeted sequencing in addition to selected IHC markers added robust information concerning diagnosis and targetable alterations. The impact on clinical decision-making and on outcome is currently being evaluated.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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    In: Neuro-Oncology, 2016, Vol. 18(suppl3), pp.iii110-iii110
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 8
    In: Neuro-Oncology, 2017, Vol. 19(12), pp.1607-1617
    Description: BackgroundEmbryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive embryonal brain tumor that solely occurs in infants and young children and has only recently been recognized as a separate brain tumor entity in the World Health Organization classification for CNS tumors. Patients have a very dismal prognosis with a median survival of 12 months upon diagnosis despite aggressive treatment. The aim of this study was to develop novel treatment regimens in a preclinical drug screen in order to inform potentially more active clinical trial protocols. MethodsWe have carried out an in vitro and in vivo drug screen using the ETMR cell line BT183 and its xenograft model. Furthermore, we have generated the first patient-derived xenograft (PDX) model for ETMR and evaluated our top drug candidates in an in vitro drug screen using this model. ResultsBT183 cells are very sensitive to the topoisomerase inhibitors topotecan and doxorubicin, to the epigenetic agents decitabine and panobinostat, to actinomycin D, and to targeted drugs such as the polo-like kinase 1 (PLK1) inhibitor volasertib, the aurora kinase A inhibitor alisertib, and the mammalian target of rapamycin (mTOR) inhibitor MLN0128. In xenograft mice, monotherapy with topotecan, volasertib, and actinomycin D led to a temporary response in tumor growth and a significant increase in survival. Finally, using multi-agent treatment regimens of topotecan or doxorubicin combined with methotrexate and vincristine, the response in tumor growth and survival was further increased compared with mice receiving single treatments. ConclusionsWe have identified several promising candidates for combination therapies in future clinical trials for ETMR patients.
    Keywords: Actinomycin D ; Brain Tumor ; Etmr ; Topotecan ; Volasertib
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 9
  • 10
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i155-i155
    Description: Identification of multiple distinct subtypes of pediatric brain tumors raises the need for more and better preclinical models reflecting these subtypes. Orthotopic patient-derived xenograft (PDX) models generated by injection of human tumor cells into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Extensive molecular characterization of PDX and matching primary tumor/blood are needed to see how well the PDX represents the original disease, to learn about targetable oncogenic drivers in each model, and to establish or confirm predictive biomarkers. In an ongoing world-wide effort we have generated and fully characterized thus far 130 PDX models reflecting 22 distinct molecular subtypes of pediatric brain tumors. PDX models always retain their molecular subtype as assessed by DNA methylation analysis and in the vast majority of cases also the mutations and copy number alterations when compared to their primary tumors. Most aggressive tumors, such as those having MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines are included. All models and corresponding molecular data will become available for the community for preclinical research. Our repertoire of PDX models and corresponding molecular characterizations allow researchers to find the right models for their specific scientific questions. It provides an unprecedented resource to study tumor biology and paves the way for improving treatment strategies for children with malignant brain tumors.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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