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  • American Society of Clinical Oncology (ASCO)  (28)
  • 1
    Online Resource
    Online Resource
    High Frequency of Germline SUFU Mutations in Children With Desmoplastic/Nodular Medulloblastoma Younger Than 3 Years of Age
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 17 ( 2012-06-10), p. 2087-2093
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 17 ( 2012-06-10), p. 2087-2093
    Abstract: Germline mutations of the SUFU gene have been shown to be associated with genetic predisposition to medulloblastoma, mainly in families with multiple cases of medulloblastoma and/or in patients with symptoms similar to those of Gorlin syndrome. To evaluate the contribution of these mutations to the genesis of sporadic medulloblastomas, we screened a series of unselected patients with medulloblastoma for germline SUFU mutations. Patients and Methods A complete mutational analysis of the SUFU gene was performed on genomic DNA in all 131 consecutive patients treated for medulloblastoma in the pediatrics department of the Institut Gustave Roussy between 1972 and 2009 and for whom a blood sample was available. Results We identified eight germline mutations of the SUFU gene: one large genomic duplication and seven point mutations. Mutations were identified in three of three individuals with medulloblastoma with extensive nodularity, four of 20 with desmoplastic/nodular medulloblastomas, and one of 108 with other subtypes. All eight patients were younger than 3 years of age at diagnosis. The mutations were inherited from the healthy father in four of six patient cases in which the parents accepted genetic testing; de novo mutations accounted for the other two patient cases. Associated events were macrocrania in six patients, hypertelorism in three patients, and multiple basal cell carcinomas in the radiation field after age 18 years in one patient. Conclusion These data indicate that germline SUFU mutations were responsible for a high proportion of desmoplastic medulloblastoma in children younger than 3 years of age. Genetic testing should be offered to all children diagnosed with sonic hedgehog–driven medulloblastoma at a young age.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2011.38.7258
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Chromosome Instability Accounts for Reverse Metastatic Outcomes of Pediatric and Adult Synovial Sarcomas
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 5 ( 2013-02-10), p. 608-615
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 5 ( 2013-02-10), p. 608-615
    Abstract: Synovial sarcoma (SS) occurs in both children and adults, although metastatic events are much more common in adults. Whereas the importance of the t(X;18) translocation in SS oncogenesis is well established, the genetic basis of SS metastasis is still poorly understood. We recently reported expression (CINSARC; Complexity Index in Sarcoma) and Genomic Index prognostic signatures related to chromosome integrity in sarcomas and GI stromal tumors. Here we investigate whether these signatures can also predict outcomes in SS. Patients and Methods One hundred patients who had primary untreated SS tumors were selected for expression and genomic profiling in a training/validation approach. Results CINSARC and Genomic Index have strong independent and validated prognostic values (P 〈 .001). By comparing expression profiles of tumors with or without metastasis, 14 genes that are common to the CINSARC signature were identified, and the two top-ranked genes, KIF14 and CDCA2, were validated as prognostic markers in an independent cohort. Comparing genomic profiles of adult versus pediatric SS, we show that metastasis is associated with genome complexity in both situations and that the adult genome is more frequently rearranged. Accordingly, pediatric patients with an even genomic profile do not develop metastasis. Conclusion Metastasis development in SS is strongly associated with chromosome complexity, and CINSARC and Genomic Index are validated independent prognostic factors. The differences in metastasis frequency between adults and children are associated with genome instability, which is much more frequent in adults. Genomic Index is potentially the best overall biomarker and clearly the most clinically relevant, considering that genome profiling from formalin-fixed samples is already used in pathology.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2012.46.0147
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Online Resource
    Reply to S. Stegmaier et al
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 32 ( 2012-11-10), p. 4040-4041
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 32 ( 2012-11-10), p. 4040-4041
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2012.45.1112
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Emergence of New ALK Mutations at Relapse of Neuroblastoma
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 25 ( 2014-09-01), p. 2727-2734
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 25 ( 2014-09-01), p. 2727-2734
    Abstract: In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigated the potential role of ALK mutations in neuroblastoma clonal evolution. Methods We analyzed ALK mutations in 54 paired diagnosis–relapse neuroblastoma samples using Sanger sequencing. When an ALK mutation was observed in one paired sample, a minor mutated component in the other sample was searched for by more than 100,000× deep sequencing of the relevant hotspot, with a sensitivity of 0.17%. Results All nine ALK-mutated cases at diagnosis demonstrated the same mutation at relapse, in one case in only one of several relapse nodules. In five additional cases, the mutation seemed to be relapse specific, four of which were investigated by deep sequencing. In two cases, no mutation evidence was observed at diagnosis. In one case, the mutation was present at a subclonal level (0.798%) at diagnosis, whereas in another case, two different mutations resulting in identical amino acid changes were detected, one only at diagnosis and the other only at relapse. Further evidence of clonal evolution of ALK-mutated cells was provided by establishment of a fully ALK-mutated cell line from a primary sample with an ALK-mutated cell population at subclonal level (6.6%). Conclusion In neuroblastoma, subclonal ALK mutations can be present at diagnosis with subsequent clonal expansion at relapse. Given the potential of ALK-targeted therapy, the significant spatiotemporal variation of ALK mutations is of utmost importance, highlighting the potential of deep sequencing for detection of subclonal mutations with a sensitivity 100-fold that of Sanger sequencing and the importance of serial samplings for therapeutic decisions.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2013.54.0674
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Online Resource
    Increased Risk of Systemic Relapses Associated With Bone Marrow Micrometastasis and Circulating Tumor Cells in Localized Ewing Tumor
    American Society of Clinical Oncology (ASCO) ; 2003
    In:  Journal of Clinical Oncology Vol. 21, No. 1 ( 2003-01-01), p. 85-91
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 21, No. 1 ( 2003-01-01), p. 85-91
    Abstract: Purpose: The presence of metastasis is a major prognostic factor in Ewing tumor (ET). The relapse pattern of patients with localized tumors has long indicated that cases with disseminated ET cells escape detection at diagnosis. ET cells are characterized by specific gene fusions that can be detected with high sensitivity and specificity by reverse transcriptase polymerase chain reaction (RT-PCR). Patients and Methods: RT-PCR targeting EWS-FLI-1 or EWS-ERG transcripts was used to search for occult tumor cells in peripheral blood (PB) and bone marrow (BM) at diagnosis in 172 patients with ET, and the prognostic significance of this parameter was assessed. Results: As we suggested previously in a smaller series of patients, RT-PCR positivity of the BM was correlated with a high risk of adverse outcome in the overall study population (P = .007). More interestingly, among patients with otherwise localized tumors, BM micrometastasis also predicted significantly poorer disease-free survival rates (P = .043). The presence of circulating tumor cells (CTC) was more frequently observed in patients with large tumors (P = .006). CTC were associated with a poor outcome among patients with clinically localized disease (P = .045). Patients with clinically localized disease and peripheral occult tumor cells as evidenced by BM and/or PB RT-PCR positivity had axial or proximal tumors and experienced relapses at a systemic rather than at a local level. Conclusion: Patients with localized ET and BM micrometastasis or CTC are comparable to patients with metastases in terms of the localization of the primary tumor, outcome, and relapse pattern.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2003.03.006
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2003
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Online Resource
    Development of prognostic molecular markers in pediatric rhabdomyosarcoma based on gene expression and copy number variations.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 9510-9510
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 9510-9510
    Abstract: 9510 Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and comprises two major histological subtypes: alveolar and embryonal. The majority of alveolar tumors harbor PAX/FOXO1 fusion genes. Current patient risk stratification, unlike other pediatric embryonal tumors, does not utilize any molecular data. Therefore, we aimed to improve the risk stratification of RMS patients through the use of molecular biological data. Methods: Two independent data sets of gene expression profiling for 124 and 101 RMS were used to derive prognostic gene signatures by meta-analysis. Genomic array CGH data for 109 RMS was also evaluated to develop a prognostic marker based on copy number variations (CNVs). The performance and usefulness of these derived metagenes and CNVs as well as a previously published metagene signature were evaluated using rigorous leave-one-out cross-validation analyses. Results: The new prognostic gene expression signature, MG15, and one previously published (MG34) (Davicioni. JCO. 2010) performed well with reproducible and significant effects (HR 3.2 [1.7-5.9] p 〈 0.001 and HR 2.5 [1.5-4.3] p 〈 0.001, respectively). However, they did not significantly add new prognostic information over the fusion gene status (PAX3/FOXO1, PAX7/FOXO1 and Negative). Similarly, a prognostic CNV marker, although showing HR 2.9 [1.5-5.6] p 〈 0.01, was also not improving models with fusion gene status. Within fusion negative RMS, the analysis identified prognostic markers based on either gene expression or CNVs and showed significant association with patients outcome (HR 6.3 [1.5-26.3] p ≤ 0.016 and HR 11.2 [2.5-50.7] p 〈 0.010, respectively). Moreover, these were able to identify distinct risk groups within the COG (Children's Oncology Group) risk categories, which is currently used to guide treatment. Conclusions: Molecular signatures derived using all RMS effectively stratify patients by their risk, but most of their prognostic information is contained in the PAX/FOXO1 fusion gene status which is simpler to assay. New markers developed within the fusion negative population seem improving current RMS risk classifier and should be tested in follow-up studies.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.9510
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN -Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 31 ( 2020-11-01), p. 3685-3697
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 31 ( 2020-11-01), p. 3685-3697
    Abstract: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome. PATIENTS AND METHODS Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children’s Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group. RESULTS Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD] , 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients 〈 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in 〈 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In 〈 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038). CONCLUSION Genomic aberrations of resectable non– MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients 〈 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those 〉 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.18.02132
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 8
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    Online Resource
    Loss of STAG2 expression and prognosis in Ewing sarcoma family of tumors.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 10024-10024
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 10024-10024
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.10024
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 9
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    Impact of EWS-ETS Fusion Type on Disease Progression in Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumor: Prospective Results From the Cooperative Euro-E.W.I.N.G. 99 Trial
    American Society of Clinical Oncology (ASCO) ; 2010
    In:  Journal of Clinical Oncology Vol. 28, No. 12 ( 2010-04-20), p. 1982-1988
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 12 ( 2010-04-20), p. 1982-1988
    Abstract: EWS-ETS fusion genes are the driving force in Ewing's sarcoma pathogenesis. Because of the variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. Since previous retrospective studies suggested prognostic differences among patients expressing different EWS-FLI1 fusion types, the impact of fusion RNA architecture on disease progression and relapse was studied prospectively within the Euro-E.W.I.N.G. 99 clinical trial. Patients and Methods Among 1,957 patients who registered before January 1, 2007, 703 primary tumors were accessible for the molecular biology study. Fusion type was assessed by polymerase chain reaction on frozen (n = 578) or paraffin-embedded materials (n = 125). The primary end point was the time to disease progression or relapse. Results After exclusion of noninformative patients, 565 patients were entered into the prognostic factor analysis comparing type 1 (n = 296), type 2 (n = 133), nontype 1/nontype 2 EWS-FLI1 (n = 91) and EWS-ERG fusions (n = 45). Median follow-up time was 4.5 years. The distribution of sex, age, tumor volume, tumor site, disease extension, or histologic response did not differ between the four fusion type groups. We did not observe any significant prognostic value of the fusion type on the risk of progression or relapse. The only slight difference was that the risk of progression or relapse associated with nontype 1/nontype 2 EWS-FLI1 fusions was 1.38 (95% CI, 0.96 to 2.0) times higher than risk associated with other fusion types, but it was not significant (P = .10). Conclusion In contrast to retrospective studies, the prospective evaluation did not confirm a prognostic benefit for type 1 EWS-FLI1 fusions.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2009.23.3585
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2010
    detail.hit.zdb_id: 2005181-5
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  • 10
    Online Resource
    Online Resource
    PAX3/FOXO1 Fusion Gene Status Is the Key Prognostic Molecular Marker in Rhabdomyosarcoma and Significantly Improves Current Risk Stratification
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 14 ( 2012-05-10), p. 1670-1677
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 14 ( 2012-05-10), p. 1670-1677
    Abstract: To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data. Patients and Methods Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated. Results We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme. Conclusion Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2011.38.5591
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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