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1.
J Neurooncol ; 145(1): 177-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522324

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

2.
Eur J Cancer ; 114: 27-35, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31022591

RESUMO

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brain tumour with fatal outcome. The Individualised Therapy For Relapsed Malignancies In Childhood (INFORM) registry study offers comprehensive molecular profiling of high-risk tumours to identify target alterations for potential precision therapy. We analysed molecular characteristics and clinical data after brainstem biopsy of all enrolled newly diagnosed DIPGs. PATIENTS AND METHODS: From -February 2015 to February 2018, 21 subsequent primary DIPG cases were enrolled in the nation-wide multicentre INFORM registry study after brainstem biopsy. Whole-genome, whole-exome sequencing and DNA methylation analysis were performed, and RNA-sequencing was added in case of sufficient material. Clinical data were obtained from standardised questionnaires and the INFORM clinical data bank. RESULTS: Tumour material obtained from brainstem biopsy was sufficient for DNA analysis in all cases and RNA analysis in 16 of 21 cases. In 16 of 21 cases (76%), potential targetable alterations were identified including highly relevant MET and NTRK1 fusions as well as an EZH2 alteration not previously described in DIPG. In 5 of 21 cases, molecular information was used for initiation of targeted treatment. The majority of patients (19/21) presented with neurological deficits at diagnosis. Newly arising or worsening of neurological deficits post-biopsy occurred in nine patients. Symptoms were reversible or improved notably in eight cases. CONCLUSION: In this multicentre study setting, brainstem biopsy of DIPG was feasible and yielded sufficient material for comprehensive molecular profiling. Relevant molecular targets were identified impacting clinical management in a substantial subset. Death or severe bleeding occurred in none of the cases. One of 20 patients experienced unilateral paraesthesia possibly related to biopsy.

3.
Mol Imaging Biol ; 21(6): 1182-1191, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30945122

RESUMO

PURPOSE: The enzyme O6-methylguanine-DNA methyltransferase (MGMT) is an important component of the DNA repair machinery. MGMT removes O6-methylguanine from the DNA by transferring the methyl group to a cysteine residue in its active site. Recently, we detected the single nucleotide polymorphism (SNP) rs12917 (C/T) in the MGMT sequence adjacent to the active site in Hodgkin lymphoma (HL) cell line KM-H2. We now investigated whether this SNP is also present in other HL cell lines and patient samples. Furthermore, we asked whether this SNP might have an impact on metabolic response in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET), and on overall treatment outcome based on follow-up intervals of at least 34 months. PROCEDURES: We determined the frequency of this MGMT polymorphism in 5 HL cell lines and in 29 pediatric HL (PHL) patients. The patient cohort included 17 female and 12 male patients aged between 4 and 18 years. After characterization of the sequence, we tested a possible association between rs12917 and age, gender, Ann Arbor stage, treatment group, metabolic response following two courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin) chemotherapy, radiotherapy indication, and relapse status. RESULTS: We detected the minor T allele in four of five HL cell lines. 11/29 patients carried the minor T allele whereas 18/29 patients showed homozygosity for the major C allele. Interestingly, we observed significantly better metabolic response in PHL patients carrying the rs12917 C allele resulting in a lower frequency of radiotherapy indication. CONCLUSION: MGMT polymorphism rs12917 seems to affect chemotherapy response in PHL. The prognostic value of this polymorphism should be investigated in a larger patient cohort.

4.
Oncologist ; 24(9): e921-e929, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30850560

RESUMO

BACKGROUND: Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce. PATIENTS AND METHODS: Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed. RESULTS: Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA-fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A], n = 4; posterior fossa ependymoma not further classifiable, n = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA, n = 1; PF-EPN-A, n = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively. CONCLUSION: Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified. IMPLICATIONS FOR PRACTICE: Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA-fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.

5.
Pediatr Blood Cancer ; 66(5): e27625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30693642

RESUMO

Noonan syndrome (NS) is an autosomal dominant disorder commonly caused by PTPN11 germline mutations. Patients are characterized by short stature, congenital heart defects, facial dysmorphism, and increased risk of malignancies including brain tumors. Commonly associated brain tumors are dysembryoplastic neuroepithelial tumor and low-grade glioma. We report two cases of anaplastic astrocytoma with PTPN11-related NS. We conducted a systematic search of medical databases looking for other reported cases of high-grade glioma associated with NS and identified 24 cases of brain tumors, all of which were low-grade glial or glioneuronal tumors except for one case of medulloblastoma.


Assuntos
Neoplasias Encefálicas/patologia , Mutação em Linhagem Germinativa , Glioma/patologia , Síndrome de Noonan/complicações , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adolescente , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Criança , Feminino , Glioma/etiologia , Glioma/terapia , Humanos , Masculino , Gradação de Tumores
6.
Cancer Med ; 8(2): 527-542, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30652419

RESUMO

BACKGROUND: To evaluate optimal therapy and potential risk factors. METHODS: Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed. RESULTS: Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse. CONCLUSION: Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.

7.
Ann Palliat Med ; 8(2): 112-120, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30525761

RESUMO

BACKGROUND: In the last years, the structure of Pediatric Palliative Care in Germany has developed more and more. Since 2007, there is a legal claim for a specialized palliative care in German which also applies to children. Therefore, the need of an advance care planning for children is frequently discussed. In Germany, a written advance is judicially approved only when the person concerned is of full age, intentions to change this legal ground are going on. Nevertheless in many institutions involved in pediatric palliative care standard forms similar to an advance patient directive are used, especially since 2009 when a Do-Not-Resuscitate-Order (DNR-Order) equivalent for children was published on which many German pediatric medical societies had agreed. METHODS: To get an overview which DNR-Order equivalents are actually used in pediatric palliative care in Germany we sent a questionnaire with 10 items to 174 institutions that are involved in pediatric oncological palliative care between August 2012 and October 2013. RESULTS: Only 46.9% of replying institutions used the DNR-Order equivalent for children approved by many German pediatric societies. When asked for optimizing such an advance patient directive for minors it was mostly suggested to include always a protocol of the consenting talk, an individualized treatment algorithm of all therapeutic options (not only emergency measures) in the palliative setting, and a more detailed information about the patient's current palliative situation. CONCLUSIONS: All collected data were summarized within a suggestion for a new advance pediatric oncological care planning standard form for minors in Germany.


Assuntos
Criança Hospitalizada , Ordens quanto à Conduta (Ética Médica) , Adolescente , Criança , Pré-Escolar , Feminino , Alemanha , Humanos , Lactente , Masculino , Cuidados Paliativos , Pediatria , Inquéritos e Questionários , Adulto Jovem
8.
Acta Neuropathol Commun ; 6(1): 117, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30396367

RESUMO

Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail.Two hundred and fifteen patients younger than 18 years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (n = 140) and methylation (n = 80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG.Tumor classification based on gene expression (GE) data highlighted the similarity of K27M DMG independently of their location along the midline. T-distributed Stochastic Neighbor Embedding (tSNE) analysis of methylation profiling confirms the discrimination of DMG from other well defined supratentorial tumor subgroups. Patients with diffuse intrinsic pontine gliomas (DIPG) and thalamic DMG exhibited a similarly poor prognosis (11.1 and 10.8 months median overall survival, respectively). Interestingly, H3.1-K27M and H3.3-K27M primary tumor samples could be distinguished based both on their GE and DNA methylation profiles, suggesting that they might arise from a different precursor or from a different epigenetic reorganization.These differences in DNA methylation profiles were conserved in glioma stem-like cell culture models of DIPG which mimicked their corresponding primary tumor. ChIP-seq profiling of H3K27me3 in these models indicate that H3.3-K27M mutated DIPG stem cells exhibit higher levels of H3K27 trimethylation which are correlated with fewer genes expressed by RNAseq. When considering the global distribution of the H3K27me3 mark, we observed that intergenic regions were more trimethylated in the H3.3-K27M mutated cells compared to the H3.1-K27M mutated ones.H3 K27M-mutant DMG represent a homogenous group of neoplasms compared to other pediatric gliomas that could be further separated based on the type of histone H3 variant mutated and their respective epigenetic landscapes. As these characteristics drive different phenotypes, these findings may have important implication for the design of future trials in these specific types of neoplasms.


Assuntos
Neoplasias Encefálicas/genética , Epigenômica , Glioma/genética , Histonas/genética , Mutação/genética , Transcriptoma/fisiologia , Adolescente , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Metilação de DNA/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Humanos , Lisina/genética , Masculino , Metionina/genética , Análise de Componente Principal , Células Tumorais Cultivadas
9.
Lancet Oncol ; 19(8): e419-e428, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30102236

RESUMO

Paediatric CNS tumours are the most common cause of childhood cancer-related morbidity and mortality, and improvements in their diagnosis and treatment are needed. New genetic and epigenetic information about paediatric CNS tumours is transforming the field dramatically. For most paediatric CNS tumour entities, subgroups with distinct biological characteristics have been identified, and these characteristics are increasingly used to facilitate accurate diagnoses and therapeutic recommendations. Future treatments will be further tailored to specific molecular subtypes of disease, specific tumour predisposition syndromes, and other biological criteria. Successful biomaterial collection is a key requirement for the application of contemporary methodologies for the validation of candidate prognostic factors, the discovery of new biomarkers, the establishment of appropriate preclinical research models for targeted agents, a quicker clinical implementation of precision medicine, and for other therapeutic uses (eg, for immunotherapies). However, deficits in organisational structures and interdisciplinary cooperation are impeding the collection of high-quality biomaterial from CNS tumours in most centres. Practical, legal, and ethical guidelines for consent, storage, material transfer, biobanking, data sharing, and funding should be established by research consortia and local institutions to allow optimal collection of primary and subsequent tumour tissue, body fluids, and normal tissue. Procedures for the collection and storage of biomaterials and related data should be implemented according to the individual and organisational structures of the local institutions.


Assuntos
Bancos de Espécimes Biológicos/normas , Biomarcadores Tumorais , Neoplasias do Sistema Nervoso Central , Oncologia/normas , Pesquisa Médica Translacional/métodos , Bancos de Espécimes Biológicos/ética , Bancos de Espécimes Biológicos/organização & administração , Criança , Feminino , Humanos , Masculino , Oncologia/organização & administração , Oncologia/tendências , Pesquisa Médica Translacional/organização & administração , Pesquisa Médica Translacional/normas
13.
Strahlenther Onkol ; 194(3): 215-224, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29022050

RESUMO

PURPOSE: As the efficacy of all pediatric high-grade glioma (HGG) treatments is similar and still disappointing, it is essential to also investigate the toxicity of available treatments. METHODS: Prospectively recorded hematologic and nonhematologic toxicities of children treated with radiochemotherapy in the HIT GBM-C/D and HIT-HGG-2007 trials were compared. Children aged 3-18 years with histologically proven HGG (WHO grade III and IV tumors) or unequivocal radiologic diagnosis of diffuse intrinsic pontine glioma (DIPG) were included in these trials. The HIT-HGG-2007 protocol comprised concomitant radiochemotherapy with temozolomide, while cisplatinum/etoposide (PE) and PE plus ifosfamide (PEI) in combination with weekly vincristine injections were applied during radiochemotherapy in the HIT GBM-C/D protocol. RESULTS: Regular blood counts and information about cellular nadirs were available from 304 patients (leukocytes) and 306 patients (thrombocytes), respectively. Grade 3-4 leukopenia was much more frequent in the HIT GBM-C/D cohort (n = 88, 52%) vs. HIT-HGG-2007 (n = 13, 10%; P <0.001). Grade 3-4 thrombopenia was also more likely in the HIT GBM-C/D cohort (n = 21, 12% vs. n = 3,2%; P <0.001). Grade 3-4 leukopenia appeared more often in children aged 3-7 years (n = 38/85, 45%) than in children aged 8-12 years (n = 39/120, 33%) and 13-18 years (24/100, 24%; P =0.034). In addition, sickness was more frequent in the HIT GBM-C/D cohort (grade 1-2: 44%, grade 3-4: 6% vs. grade 1-2: 28%, grade 3-4: 1%; P <0.001). CONCLUSION: Radiochemotherapy involving cisplatinum-based polychemotherapy is more toxic than radiotherapy in combination with temozolomide. Without evidence of differences in therapeutic efficacy, the treatment with lower toxicity, i. e., radiotherapy with temozolomide should be used.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/terapia , Quimiorradioterapia/efeitos adversos , Cisplatino/efeitos adversos , Dacarbazina/análogos & derivados , Glioma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/patologia , Quimiorradioterapia/métodos , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Estudos de Coortes , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Glioma/patologia , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Leucopenia/induzido quimicamente , Masculino , Gradação de Tumores , Estudos Prospectivos , Temozolomida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos
14.
Neuro Oncol ; 20(1): 123-131, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29016894

RESUMO

Background: The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis. Methods: Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection. Results: We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival. Conclusion: These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Histonas/genética , Mutação/genética , Adolescente , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Criança , Feminino , Glioma/diagnóstico , Glioma/patologia , Humanos , Masculino , Gradação de Tumores , Prognóstico
15.
Oncotarget ; 8(38): 64564-64578, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28969094

RESUMO

In the past years, pediatric high-grade gliomas (HGG) have been the focus of several research articles and reviews, given the recent discoveries on the genetic and molecular levels pointing out a clinico-biological uniqueness of the pediatric population compared to their adult counterparts with HGG. On the other hand, there are only scarce data about HGG in very young children (below 3 years of age at diagnosis) due to their relatively low incidence. However, the few available data suggest further distinction of this very rare subgroup from older children and adults at several levels including their molecular and biological characteristics, their treatment management, as well as their outcome. This review summarizes and discusses the current available knowledge on the epidemiological, neuropathological, genetic and molecular data of this subpopulation. We discuss these findings and differences compared to older patients suffering from the same histologic disease. In addition, we highlight the particular clinical and neuro-radiological findings in this specific subgroup of patients as well as their current management approaches and treatment outcomes.

16.
Eur J Cancer ; 81: 1-8, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28586748

RESUMO

BACKGROUND: Temozolomide (TMZ) is widely used in high-grade glioma (HGG). There is a major concern of treatment-induced secondary haematological malignancies (SHMs). Due to the poor overall survival of HGG patients, the true incidence is yet elusive. Thus, the aim of this study was to determine the risk of SHMs following TMZ in paediatric HGG. METHODS: We analysed 487 patients from the HIT-HGG database of the German-speaking Society of Pediatric Oncology and Hematology with follow up beyond 1 year. RESULTS: The incidence of SHM was 7.7 ± 3.2% at 10 years. No SHM occurred in 194 patients after first-line TMZ therapy, but four out of 131 patients treated with TMZ for relapse following first-line multiagent chemotherapy experienced SHM (20% at 10 years; p = 0.041). SHMs occurred in two out of 162 patients who underwent multiagent chemotherapy without TMZ (4.1% at 10 years). Gender, patient age and acute haematological toxicity during treatment did not affect the incidence of SHMs. CONCLUSION: Data of our cohort do not indicate an increased risk of SHM following TMZ treatment when compared to previous chemotherapy regimen. However, if TMZ is administered as a second-line treatment following conventional chemotherapy regimen, the risk might be disproportionately increasing.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Neoplasias Hematológicas/induzido quimicamente , Adolescente , Áustria/epidemiologia , Criança , Pré-Escolar , Dacarbazina/efeitos adversos , Feminino , Seguimentos , Alemanha/epidemiologia , Neoplasias Hematológicas/epidemiologia , Humanos , Incidência , Lactente , Estimativa de Kaplan-Meier , Masculino , Suíça/epidemiologia , Temozolomida
17.
Oncotarget ; 8(16): 27300-27313, 2017 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-28460484

RESUMO

Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with a poor prognosis due to a lack of efficient therapeutic strategies. The ß-catenin/Wnt-signaling pathway was shown to hold promising potential as a treatment target in adult high-grade gliomas by abrogating tumor cell invasion and the acquisition of stem cell-like characteristics. Since pedHGG differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of ß-catenin/Wnt-signaling pathway-inhibition by the ß-catenin/CBP antagonist ICG-001 in pedHGG cell lines. In contrast to adult HGG, pedHGG cells displayed minimal detectable canonical Wnt-signaling activity. Nevertheless, low doses of ICG-001 inhibited cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, suggesting that ICG-001 affects pedHGG tumor cell characteristics independent of ß-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/ß-catenin-independent effect of ICG-001 on target gene transcription, revealing strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. Among these, high mRNA expression of cell cycle regulator JDP2 was found to confer a better prognosis for pedHGG patients. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients functioning to regulate cell phenotype and gene expression programs in absence of Wnt/ß-catenin signaling-activity.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proteína de Ligação a CREB/antagonistas & inibidores , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Glioma/metabolismo , Pirimidinonas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , Adolescente , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Autorrenovação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Embrião de Galinha , Criança , Pré-Escolar , Bases de Dados Genéticas , Modelos Animais de Doenças , Glioma/genética , Glioma/mortalidade , Glioma/patologia , Humanos , Estimativa de Kaplan-Meier , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Adulto Jovem
18.
Acta Neuropathol ; 134(3): 507-516, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28401334

RESUMO

Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes 'pedGBM_MYCN' (enriched for MYCN amplification), 'pedGBM_RTK1' (enriched for PDGFRA amplification) and 'pedGBM_RTK2' (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show a significantly longer survival time (median OS 44 months), pedGBM_MYCN display extremely poor outcomes (median OS 14 months), and pedGBM_RTK1 tumors harbor an intermediate prognosis. In addition, the various molecular subtypes of H3-/IDH-wt pedGBM were clearly distinguishable from their adult counterparts, underlining their biological distinctiveness. In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Histonas/genética , Isocitrato Desidrogenase/genética , Mutação , Adolescente , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Criança , Pré-Escolar , Metilação de DNA , Análise Mutacional de DNA , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Histonas/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Prognóstico , Regiões Promotoras Genéticas
19.
Eur J Cancer ; 73: 38-47, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28161497

RESUMO

BACKGROUND: Overall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor. The purpose of this study is to analyse benefit and toxicity of re-irradiation at first progression. METHODS: At first progression, 31 children with DIPG, aged 2-16 years, underwent re-irradiation (dose 19.8-30.0 Gy) alone (n = 16) or combined with systemic therapy (n = 15). At initial presentation, all patients had typical symptoms and characteristic MRI features of DIPG, or biopsy-proven high-grade glioma. An interval of ≥3 months after upfront radiotherapy was required before re-irradiation. Thirty-nine patients fulfilling the same criteria receiving radiotherapy at diagnosis, followed by best supportive care (n = 20) or systemic therapy (n = 19) at progression but no re-irradiation, were eligible for a matched-cohort analysis. RESULTS: Median OS for patients undergoing re-irradiation was 13.7 months. For a similar median progression-free survival after upfront radiotherapy (8.2 versus 7.7 months; P = .58), a significant benefit in median OS (13.7 versus 10.3 months; P = .04) was observed in favour of patients undergoing re-irradiation. Survival benefit of re-irradiation increased with a longer interval between end-of-radiotherapy and first progression (3-6 months: 4.0 versus 2.7; P < .01; 6-12 months: 6.4 versus 3.3; P = .04). Clinical improvement with re-irradiation was observed in 24/31 (77%) patients. No grade 4-5 toxicity was recorded. On multivariable analysis, interval to progression (corrected hazard ratio = .27-.54; P < .01) and re-irradiation (corrected hazard ratio = .18-.22; P < .01) remained prognostic for survival. A risk score (RS), comprising 5 categories, was developed to predict survival from first progression (ROC: .79). Median survival ranges from 1.0 month (RS-1) to 6.7 months (RS-5). CONCLUSIONS: The majority of patients with DIPG, responding to upfront radiotherapy, do benefit of re-irradiation with acceptable tolerability.


Assuntos
Neoplasias do Tronco Encefálico/radioterapia , Glioma/radioterapia , Reirradiação/estatística & dados numéricos , Adolescente , Neoplasias do Tronco Encefálico/mortalidade , Criança , Pré-Escolar , Progressão da Doença , Feminino , Glioma/mortalidade , Humanos , Imagem por Ressonância Magnética , Masculino , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
20.
Am J Med Genet A ; 173(4): 1017-1037, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28168833

RESUMO

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.


Assuntos
Predisposição Genética para Doença , Neoplasias Hematológicas/diagnóstico , Mutação , Proteínas de Neoplasias/genética , Neoplasias/diagnóstico , Adolescente , Criança , Grupos Focais/métodos , Expressão Gênica , Aconselhamento Genético/ética , Testes Genéticos/métodos , Genética Médica/história , Genética Médica/instrumentação , Genética Médica/métodos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , História do Século XXI , Humanos , Neoplasias/genética , Neoplasias/patologia , Sociedades Médicas/história , Síndrome
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