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  • 1
    facet.materialart.
    Unknown
    German Medical Science GMS Publishing House; Düsseldorf
    In:  PTCOG 48; Meeting of the Particle Therapy Co-Operative Group; 20090928-20091003; Heidelberg; DOC09ptcog150 /20090924/
    Publication Date: 2009-09-25
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Keywords: COMBINATION ; INDEX ; TRANSFORMATION ; doxorubicin ; CYCLOPHOSPHAMIDE ; B-CELL LYMPHOMA ; LOW-GRADE LYMPHOMA ; rituximab ; VINCRISTINE ; EZH2 MUTATIONS
    Abstract: BACKGROUND: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. METHODS: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7.7 years (IQR 5.5-9.3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6.7 years (IQR 5.7-7.6). FINDINGS: We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38.29% (95% CI 25.31-57.95) versus 77.21% (95% CI 69.21-86.14) for the low-risk group (hazard ratio [HR] 4.14, 95% CI 2.47-6.93; p〈0.0001; bootstrap-corrected HR 2.02), and outperformed a prognostic model of only gene mutations (HR 3.76, 95% CI 2.10-6.74; p〈0.0001; bootstrap-corrected HR 1.57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0.80 (95% CI 0.71-0.89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25.00% (95% CI 12.50-49.99) versus 68.24% (58.84-79.15) in the low-risk group (HR 3.58, 95% CI 2.00-6.42; p〈0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0.79 (95% CI 0.69-0.89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2.18, 95% CI 1.21-3.92), and FLIPI combined with ECOG performance status (HR 2.03, 95% CI 1.12-3.67). INTERPRETATION: Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. FUNDING: Deutsche Krebshilfe, Terry Fox Research Institute.
    Type of Publication: Journal article published
    PubMed ID: 26256760
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  • 3
    Abstract: Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf-/- mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposon-mediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations DeltaNTrp63 and DeltaNTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy.
    Type of Publication: Journal article published
    PubMed ID: 28265066
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  • 4
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    Unknown
    German Medical Science GMS Publishing House; Düsseldorf
    In:  PTCOG 48; Meeting of the Particle Therapy Co-Operative Group; 20090928-20091003; Heidelberg; DOC09ptcog052 /20090924/
    Publication Date: 2009-09-25
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 5
    Publication Date: 2018-05-25
    Description: In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton’s tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of patients with DLBCL. Here, we used lymphoma cells isolated from patients with DLBCL to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC upregulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in xenografts and cell lines derived from patients with DLBCL independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients.
    Keywords: Lymphoid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 6
    Publication Date: 2018-10-10
    Description: We recently reported that NF-B–mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the α subunit of casein kinase II (CK2α) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the -secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR–CK2α–p65 complex to induce NF-B activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-B p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-B responsive elements and IL-6 promoter. Furthermore, the transcription of NF-B target genes was not inhibited by a -secretase inhibitor, suggesting that Psen1 regulates NF-B activation in a manner independent of -secretase activity. Mechanistically, Psen1 associated with the BCR–CK2α complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-α–induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR–CK2α–p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR–CK2α–p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 7
    Publication Date: 2018-10-10
    Description: Bmi1 is a polycomb group protein and regulator that stabilizes the ubiquitination complex PRC1 in the nucleus with no evidently direct link to the NF-B pathway. In this study, we report a novel function of Bmi1: its regulation of IBα ubiquitination in the cytoplasm. A deficiency of Bmi1 inhibited NF-B–mediated gene expression in vitro and a NF-B–mediated mouse model of arthritis in vivo. Mechanistic analysis showed that Bmi1 associated with the SCF ubiquitination complex via its N terminus and with phosphorylation by an IKKα/β-dependent pathway, leading to the ubiquitination of IBα. These effects on NF-B–related inflammation suggest Bmi1 in the SCF complex is a potential therapeutic target for various diseases and disorders, including autoimmune diseases.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 8
    Publication Date: 2018-03-09
    Description: Approximately 7 years has passed since Japan’s 2011 Fukushima Daiichi Nuclear Power Station accident, triggered by the Great East Japan Earthquake and the subsequent huge tsunami. This was the world’s worst nuclear accident since Ukraine’s 1986 Chernobyl accident. The radiation exposure attributable to the accident is limited to a lifetime effective dose of ~30 mSv. 1 In Fukushima, as at Chernobyl and other nuclear disasters, radiological measures for individuals—whole-body counter (WBC) testing, personal dosimetry and thyroid examination testing—have been implemented, with different ‘nudge’ design in testing measures. 2 For WBC testing, adults are voluntarily tested (opt-in; ‘not get tested’ is the default selection and ‘get tested’ is a choice). In contrast, thyroid ultrasound examination, offered in every school, is designed for children to participate as the default (opt-out; ‘get tested’ is the default selection and ‘not get tested’ is an option). Further, personal dosimetry, administered by local authorities, was...
    Keywords: Epidemiology
    Print ISSN: 0143-005X
    Electronic ISSN: 1470-2738
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 9
    ISSN: 1437-7772
    Keywords: Key words Radiotherapy ; Non-small cell lung cancer ; Early stage lung cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background. Surgery has been regarded as the standard treatment for patients with non-small cell lung cancer in the early stage, while radiotherapy has become an effective alternative for medically inoperable patients and those who refuse surgery. Methods. We reviewed the records of 31 patients with stage I–II non-small cell lung cancer treated by radiotherapy between 1980 and 1997. There were 15 patients in stage I and 16 in stage II. The variables analyzed for influence on cause-specific survival and loco-regional control were: age, performance status, clinical stage, tumor size, tumor site, radiation field, radiation dose, and combination with chemotherapy. Results. The overall and cause-specific 1-, 2-, 3-, and 5-years survival rates were 71% and 77%; 63% and 73%; 34% and 48%; and 17% and 32%, respectively. Five-year survival rate for patients with peripheral tumor in the lung was 72%, with 70% loco-regional control, while the 5-year survival rate of patients whose tumor originated in the central region was 20%, with 25% loco-regional control. These differences had marginal significance on univariate analysis (P = 0.07), but only tumor site (central vs peripheral ) showed marginal significant influence on cause-specific survival (P = 0.08) and loco-regional control (P = 0.07) on multivariate analysis. There were no fatal complications, including radiation-induced myelopathy. Conclusion. The present series showed satisfactory results with definitive radiotherapy for patients with medically inoperable stage I–II non-small cell lung cancer, with results similar to those in recent reports of radiotherapy. The only significant variable was that patients with peripheral tumors had a better prognosis than patients with central tumors.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1435-1536
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Type of Medium: Electronic Resource
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