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  • 1
    Keywords: CANCER ; SURVIVAL ; carcinoma ; Germany ; LUNG ; TOXICITY ; lung cancer ; LUNG-CANCER ; DISEASE ; TIME ; PATIENT ; primary ; QUALITY ; treatment ; STAGE ; DIFFERENCE ; CLINICAL-TRIALS ; RATES ; chemotherapy ; ELDERLY-PATIENTS ; PHASE-III ; MULTICENTER TRIAL ; PLUS VINORELBINE ; QUALITY-OF-LIFE ; SINGLE-AGENT GEMCITABINE
    Abstract: Purpose To evaluate whether cisplatin-based chemotherapy (gemcitabine, vinorelbine, and cisplatin [GVP]) prolongs overall survival in comparison to cisplatin-free chemotherapy (gemcitabine and vinorelbine [GV]) as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods Between September 1999 and June 2001, 300 patients with NSCLC stage 11113 with malignant pleural effusion or stage IV disease were randomly assigned to receive GV (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 every 3 weeks) or GVP (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days I and 8 + cisplatin 75 mg/m(2) on day 2 every 3 weeks). Primary end point of the study was overall survival. Results Two hundred eighty-seven patients (GV, 143 patients; GVP, 144 patients) were eligible for analysis. At the time of analysis, April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287 patients had died (73%). No statistically significant difference was observed for overall survival (P =.73; median survival, 35.9 versus 32.4 weeks; 1-year survival rate, 33.6% versus 27.5%) as well as for event-free survival (P =.35; median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred fourteen patients were assessable for best response. The overall response rates were 13.0% for GV versus 28.3% for GVP (P =.004; complete responders, 0% versus 3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP. No statistically significant difference in quality of life was observed. Conclusion In this phase III study, the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen, which was substantially better tolerated. (C) 2004 by American Society of Clinical Oncology
    Type of Publication: Journal article published
    PubMed ID: 15197195
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  • 2
    Keywords: measurement ; CANCER ; MODEL ; MODELS ; PROSTATE ; FOLLOW-UP ; SUPPORT ; POPULATION ; RISK ; RISKS ; METABOLISM ; PATIENT ; MARKER ; INDEX ; ASSOCIATION ; resistance ; PLASMA ; OBESITY ; prostate cancer ; PROSTATE-CANCER ; MARKERS ; cancer risk ; PARAMETERS ; UNITED-STATES ; GLUCOSE ; BODY ; SERUM LEVELS ; RELATIVE RISK ; leptin ; insulin ; MASS INDEX ; MASSES ; BODIES ; REGRESSION ; ASSOCIATIONS ; aging ; prospective studies ; 4.0 NG/ML ; BODY-SIZE ; fat distribution ; PHYSICAL-ACTIVITY ; PLASMA-GLUCOSE
    Abstract: Objectives. To examine the relationship of insulin, glucose, and anthropometry with the subsequent risk of prostate cancer. Methods. The relative risk of prostate cancer by insulin, glucose, and anthropometric measures was evaluated in 823 male participants (87 patients with prostate cancer in 10,737 person-years of follow-up) of the Baltimore Longitudinal Study of Aging who had at least one fasting plasma insulin measurement, which was prediagnostic for those with prostate cancer. Age-adjusted and multivariate-adjusted relative risks were estimated from Cox proportional hazards regression models. Results. Insulin concentrations were in the normal range (defined as less than 20 muU/mL) for 95.1% of participants. Fasting insulin and glucose levels were unrelated to prostate cancer risk in our overall analysis (P for trend = 0.56 and 0.45, respectively). The relative risk of prostate cancer for the second through fourth quartiles of the waist/hip ratio compared with the lowest quartile was 2.10, 1.96, and 2.06, respectively (P for trend = 0.32). Risk was unrelated to waist circumference and body mass index. Conclusions. The results of this study do not conclusively support positive associations of markers of insulin and glucose metabolism and obesity with prostate cancer. Additional larger prospective studies with repeated measure of these parameters are warranted to explore these associations further
    Type of Publication: Journal article published
    PubMed ID: 14972466
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  • 3
    Keywords: CANCER ; Germany ; human ; LUNG ; lung cancer ; LUNG-CANCER ; DISEASE ; EXPOSURE ; TISSUE ; MECHANISM ; DATABASE ; CONCURRENT ; CARCINOGEN ; METAANALYSIS ; data analysis ; development ; analysis ; silicosis
    Abstract: The alveolar fraction of quartz has been classified as a human carcinogen by the International Agency for Research on Cancer (IARC). Crystalline-silica-associated lung cancer concurrent with a proven silicosis or silicotuberculosis is an occupational disease (so-called BK 4112) in Germany. The mechanism of interaction between silicosis and the development of lung cancer, however, is still not known. Based on the Wismut database and tissue repository, the hypothesis was tested whether silicosis influences the distribution of the major histopathologic types of lung cancer. The degree of quartz exposure was included in the data analysis
    Type of Publication: Journal article published
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  • 4
    Keywords: CANCER ; COHORT ; POPULATION ; RISK ; GENE ; GENES ; ASSOCIATION ; POLYMORPHISMS ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; OVARIAN-CANCER ; EXCISION-REPAIR ; ONCOLOGY ; BRCA2 ; breast cancer risk ; NUCLEOTIDE ; ERCC4
    Abstract: BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
    Type of Publication: Journal article published
    PubMed ID: 19920816
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  • 5
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; GENE ; HYBRIDIZATION ; DNA ; INDEX ; tumour ; CONTRAST ; chromosome ; virus ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; cytogenetics ; LYMPHOMA ; MALIGNANCIES ; NUMBER ; leukemia ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; MORPHOLOGY ; ABNORMALITIES ; FLUORESCENCE ; IMBALANCES ; C-MYC ; INTERPHASE ; EPSTEIN-BARR-VIRUS ; B-CELL LYMPHOMA ; Bcl-2 ; chemoresistance ; F ; CHROMOSOMAL BREAKPOINTS ; Epstein-Barr virus ; FEATURES ; immunohistology ; molecular cytogenetics ; sporadic and endemic Burkitt's lymphoma ; TRANSLOCATIONS
    Abstract: The present study has compared immunohistological marker expression profiles and genomic imbalances in seven African endemic Burkitt's lymphomas (eBLs) with those in ten European B-cell lymphomas with MYC rearrangement as shown by fluorescence in situ hybridization (FISH) analysis. eBLs showed a typical histomorphology and a homogeneous immuno-profile: CD10+, CD38+, CD77+, bcl-2-, and IgM+. Epstein-Barr virus (EBV) DNA was present in all cases. On comparative genomic hybridization (CGH), only three out of six eBLs showed imbalances (median number of imbalances = 2), with gains on chromosome 17 in two eBLs. The European lymphomas were all highly proliferating, with a Ki-67 index of at least 90%, and included seven with morphology typical of sporadic Burkitt's lymphoma (sBL) and three immunoblastic diffuse large B-cell lymphomas with MYC rearrangement (MYC re+DLBCL). In contrast to eBL, the immuno-profiles of the European lymphomas were less homogeneous and inconsistent for CD10, CD38, CD77, IgM and bcl-2 expression. EBV DNA was not detected. In five of seven sBLs, CGH showed a higher number of imbalances (median = 6), with recurrent gains on chromosome 1q (3/7) and losses on 12q and 17p (2/7), whereas all three MYC re+DLBCLs had fewer imbalances (median = 4), with gains on 17q in two of three lymphomas. It is concluded that eBL has a homogeneous immunohistology and few secondary genomic aberrations, whereas MYC-rearranged and highly proliferating European B-cell lymphomas are a heterogeneous group that includes sBL and a subgroup of diffuse large B-cell lymphomas. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd
    Type of Publication: Journal article published
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  • 6
    Keywords: CANCER ; carcinoma ; CELL ; Germany ; LUNG ; PATHWAYS ; EXPOSURE ; RISK ; TISSUE ; radiation ; CIGARETTE-SMOKING ; SIGNAL-TRANSDUCTION ; adenocarcinoma ; squamous cell carcinoma ; PREVALENCE ; LUNG-CARCINOMA ; MATRIX ; radon ; INCREASE ; LEVEL ; lung carcinoma ; HISTOLOGY ; RADIATION EXPOSURE ; HEDGEHOG ; DAUGHTERS ; silicosis ; uranium mining
    Abstract: BACKGROUND. In East Germany, uranium mining was undertaken on a large scale from 1946 to 1990. Poor working conditions led to a high level of exposure to ionizing radiation and quartz dust. This analysis evaluates the histopathology of lung carcinoma ill uranium miners in relation to radon exposure and silicosis. METHODS. A database developed for autopsy cases ascertained in a pathological tissue repository, of German uranium miners was used to estimate odds ratios for developing lung carcinoma by major cell type with regard to radon exposure and silicosis. Silicosis information was extracted from autopsy protocols. Working level months (WLM) were calculated with a job-exposure matrix to assess lifetime radon exposure. Risk estimates were based oil 3414 male miners who died from small cell lung carcinoma (SCLC, n = 1446), squamous cell carcinoma (SqCC, n = 1006), or adenocarcinoma (AC, n = 962) between 1957 and 1990. RESULTS. SCLC and SqCC seem more likely to be associated with high radon exposure than AC. Mean Cumulative radon exposure was 868 (SD 631) WLM in SCLC, 871 (SD 652) WLM in SqCC, and 743 (SD 598) WLM in AC. Silicosis prevalence was 26% in SCLC 38% in SqCC, and 30% in AC. In silicotics, AC and SqCC had a relatively higher frequency at the expense of SCLC. SCLC occurred earlier than AC and SqCC. CONCLUSION. High radon exposure was associated with a higher relative frequency of SCLC and SqCC than AC. Silicosis tended to increase the appearance of SqCC and AC
    Type of Publication: Journal article published
    PubMed ID: 16411224
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  • 7
    Keywords: PEPTIDE ; CANCER ; CELLS ; BLOOD ; CELL ; CLINICAL-TRIAL ; COMBINATION ; NEW-YORK ; DISTINCT ; SAMPLE ; SAMPLES ; RESPONSES ; BASE ; CD8(+) T-CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; ASSOCIATION ; TRIAL ; TRIALS ; IDENTIFICATION ; ASSAY ; NUMBER ; CLINICAL-TRIALS ; COUNTRIES ; MELANOMA ; LYMPHOCYTES ; VARIABILITY ; PEPTIDES ; NETHERLANDS ; CD8(+) ; ELISPOT ; IMMUNOTHERAPY ; T-LYMPHOCYTES ; T lymphocyte ; sensitivity ; PERIPHERAL-BLOOD ; PROJECT ; INTERFERON-GAMMA ; tetramer ; T lymphocytes ; GUIDELINES ; HETEROGENEITY ; CANCER VACCINES ; ONCOLOGY ; monitoring ; INCREASE ; analysis ; methods ; ASSAYS ; PHASE ; technique ; USA ; RECOMMENDATIONS ; STANDARDIZATION ; VARIABLES ; immunology ; INCREASES ; clinical trial ; CELL RESPONSES ; IMPORTANT DETERMINANT ; CD4+T-CELL IMMUNITY ; CYTOKINE FLOW-CYTOMETRY ; GAMMA ELISPOT ASSAYS ; Interlaboratory testing
    Abstract: The interpretation of the results obtained from immunomonitoring of clinical trials is a difficult task due to the variety of methods and protocols available to detect vaccine-specific T-cell responses. This heterogeneity as well as the lack of standards has led to significant scepticism towards published results. In February 2005, a working group was therefore founded under the aegis of the Association for Immunotherapy of Cancer ("CIMT") in order to compare techniques and protocols applied for the enumeration of antigen-specific T-cell responses. Here we present the results from two consecutive phases of an international inter-laboratory testing project referred to as the "CIMT monitoring panel". A total of 13 centers from six European countries participated in the study in which pre-tested PBMC samples, synthetic peptides and PE-conjugated HLA-tetramers were prepared centrally and distributed to participants. All were asked to determine the number of antigen-specific T-cells in each sample using tetramer staining and one functional assay. The results of the first testing round revealed that the total number of cells analyzed was the most important determinant for the sensitive detection of antigen-specific CD8(+) T-cells by tetramer staining. Analysis by ELISPOT was influenced by a combination of cell number and a resting phase after thawing of peripheral blood mononuclear cells. Therefore, the experiments were repeated in a second phase but now the participants were asked to change their protocols according to the new guidelines distilled from the results of the first phase. The recommendations improved the number of antigen-specific T-cell responses that were detected and decreased the variability between the laboratories. We conclude that a two-step approach in inter-laboratory testing allows the identification of distinct variables that influence the sensitivity of different T-cell assays and to formally show that a defined correction to the protocols successfully increases the sensitivity and reduces the inter-center variability. Such "two-step" inter-laboratory projects could define rational bases for accepted international guidelines and thereby lead to the harmonization of the techniques used for immune monitoring
    Type of Publication: Journal article published
    PubMed ID: 17721783
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  • 8
    Keywords: CANCER ; GROWTH ; GROWTH-FACTOR ; SUPPORT ; COHORT ; cohort study ; POPULATION ; RISK ; GENE ; ASSOCIATION ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; BRCA1 ; MUTATION ; cancer risk ; GENOTYPES ; BETA ; TGF-BETA-1 ; BRCA2 ; VARIANT ; secretion ; TGF-BETA ; risk modifiers ; GENOTYPE ; USA ; CANCER-RISK ; GENERAL-POPULATION ; CONSORTIUM ; Hereditary cancer ; TRANSFORMING-GROWTH-FACTOR-BETA-1 GENE
    Abstract: Background The transforming growth factor beta-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-beta, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population. Methods To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers. Results We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92-1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81-1.04) in BRCA2 mutation carriers. Conclusions These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers
    Type of Publication: Journal article published
    PubMed ID: 18523885
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  • 9
    Keywords: CANCER ; carcinoma ; CELL ; Germany ; LUNG ; lung cancer ; LUNG-CANCER ; DISEASE ; EXPOSURE ; MORTALITY ; MECHANISM ; mechanisms ; SKIN ; ASSOCIATION ; DISTRIBUTIONS ; PATTERNS ; HEALTH ; smoking ; DATABASE ; STEM-CELLS ; SQUAMOUS-CELL CARCINOMA ; adenocarcinoma ; squamous cell carcinoma ; non-small cell lung cancer ; HETEROGENEITY ; CYTOKERATIN EXPRESSION ; LUNG-DISEASE ; MATRIX ; CELL CARCINOMA ; arsenic ; development ; HISTOLOGY ; USA ; PHOSPHATASE ; SQUAMOUS-CELL ; silicosis ; uranium mining ; PROPORTION ; CELL-LUNG-CANCER ; COPPER SMELTER ; HISTOLOGIC TYPES ; SMELTER WORKERS
    Abstract: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. These results indicate a cell type characteristic effect of arsenic in the development of lung cancer
    Type of Publication: Journal article published
    PubMed ID: 19020892
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  • 10
    Keywords: CANCER ; MODELS ; POPULATION ; RISK ; VARIANTS ; BREAST ; BREAST-CANCER ; OVARIAN-CANCER ; PHENOTYPE ; PREVALENCE ; ESTROGEN-RECEPTOR ; GENETIC SUSCEPTIBILITY ; LOCI ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; Risk prediction
    Abstract: ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumor. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumor, to assess the associations of twelve loci with breast cancer tumor characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for eleven loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, SNP rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele HR for ER-positive=1.35, 95%CI:1.17-1.56 vs HR=0.91, 95%CI:0.85-0.98 for ER-negative, P-heterogeneity=6.5e-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS: The associations of the twelve SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumor subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.
    Type of Publication: Journal article published
    PubMed ID: 22053997
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