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  • 1
    Keywords: CANCER ; Germany ; LUNG ; lung cancer ; LUNG-CANCER ; SYSTEM ; CANCER MORTALITY ; COHORT ; cohort studies ; cohort study ; cohort-studies ; DEATH ; DISEASE ; DISEASES ; DNA adducts ; EPIDEMIOLOGY ; EXPOSURE ; HEPATOCELLULAR-CARCINOMA ; HISTORY ; incidence ; iron foundry ; larynx ; liver ; LONG-TERM ; missing death certificates ; MORTALITY ; mouth ; NEW-YORK ; occupation ; PHARYNX ; POPULATION ; PRIMARY LIVER-CANCER ; RISK ; RISKS ; SITE ; SITES ; WORKERS
    Abstract: Background Observations of an increased incidence of cancers of the upper aero-digestive tract (pharynx, esophagus, larynx, lung) among workers of local German foundries gave rise to concern about a potentially elevated occupational risk of those cancer sites. The purpose of the study was to examine whether occupational exposure in iron foundries increases the risk of cancer. Methods A historical cohort study of 17,708 male German production workers in 37 iron foundries who were first employed in 1950-1985 with a minimum employment period of 1 year was initiated. Employment and occupational histories were collected. Mortality was compared with that of the German general population during 1950-1993 using a new method for computing the SMR when not all causes of death are available (called SMR*). Results Mortality from all causes was elevated to SMR = 115.4 (95% confidence interval (CI) = 111.9-119.1), as was for total cancer (SMR* = 123.8, CI = 102.1-152.6), especially cancers of the lung (SMR* = 163.9, CI = 123.9-223.0) and liver (SMR* = 322.5, CI = 149.5-844.8), and diseases of the respiratory system (SMR* = 147.6, CI = 100.4-221.5). Non- significant elevations of mortality were also found for cancers of the mouth and pharynx (SMR* = 153.5, CI = 82.3-359.8) and larynx (SMR* = 173.1, CI = 85.5-550.5). Mortality from various causes of death was higher among workers with shorter exposure periods than among long-term employees. The elevated mortality persisted for years and decades after termination of employment. Conclusions The results provide further evidence for an increased risk of lung cancer and possibly other cancers of the upper aero-digestive tract among foundry workers. Special attention should be paid to the strongly increased mortality from liver cancer and the mortality pattern among employees having terminated work. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12594777
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VIVO ; LUNG-CANCER ; DNA adducts ; RISK ; GENE ; LINES ; ACTIVATION ; DNA ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; AIR ; CARCINOGENESIS ; CYP1A2 ; CYTO-TOXIC METABOLITES ; DIESEL EXHAUST ; DNA ADDUCT FORMATION ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; GENETIC POLYMORPHISMS ; HETEROCYCLIC AMINES ; HETEROLOGOUS EXPRESSION ; HUMAN CYTOSOLIC SULFOTRANSFERASES ; IONS ; metabolic activation ; NAT : SULT ; nitro-PAH ; P-32- postlabeling ; PHENOL SULFOTRANSFERASES ; POSTLABELING ANALYSIS
    Abstract: 3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust and ambient air pollution. 3-Aminobenzanthrone (3-ABA), 3- acetylaminobenzanthrone (3-Ac-ABA) and N-acetyl-N-hydroxy-3- aminobenzanthrone (N-Ac-N-OH-ABA) have been identified as 3-NBA metabolites. Recently we found that 3-NBA and its metabolites (3-ABA, 3-Ac-ABA and N-Ac-N-OH-ABA) form the same DNA adducts in vivo in rats. In order to investigate whether human cytochrome P450 (CYP) enzymes (i.e., CYPIA2), human N,O- acetyltransferases (NATs) and sulfotransferases (SULTs) contribute to the metabolic activation of 3-NBA and its metabolites we developed a panel of Chinese hamster V79MZ-hIA2 derived cell lines expressing human CYPIA2 in conjunction with human NATI, NAT2, SULTIAI or SULTIA2, respectively. Cells were treated with 0.01, 0.1 or I muM 3-NBA, or its metabolites (3- ABA, 3-Ac-ABA and N-Ac-N-OH-ABA). Using both enrichment versions of the P-32-postlabeling assay, nuclease P I digestion and butanol extraction, essentially 4 major and 2 minor DNA adducts were detected in the appropriate cell lines with all 4 compounds. The major ones were identical to those detected in rat tissue; the adducts lack an N-acetyl group. Human CYPIA2 was required for the metabolic activation of 3-ABA and 3-Ac-ABA (probably via N-oxidation) and enhanced the activity of 3-NBA (probably via nitroreduction). The lack of acetylated adducts suggests N-deacetylation of 3-Ac-ABA and N-Ac-N-OH-ABA. Thus, N-hydroxy-3-aminobenzanthrone (N-OH-ABA) appears to be a common intermediate for the formation of the electrophilic arylnitrenium ions capable of reacting with DNA. Human NAT I and NAT2 as well as human SULTIAI and SULTIA2 strongly contributed to the high genotoxicity of 3-NBA and its metabolites. Moreover, N,O-acetyltransfer reactions catalyzed by human NATs leading to the corresponding N-acetoxyester may be important in the bioactivation of N-Ac-N-OH-ABA. As human exposure to 3-NBA is likely to occur primarily via the respiratory tract, expression of CYPs, NATs and SULTs in respiratory tissues may contribute significantly and specifically to the metabolic activation of 3-NBA and its metabolites. Consequently, polymorphisms in these genes could be important determinants of lung cancer risk from 3-NBA
    Type of Publication: Journal article published
    PubMed ID: 12740904
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  • 3
    Keywords: CANCER ; PROTECTION ; MODEL ; DISEASE ; EPIDEMIOLOGY ; HISTORY ; RISK ; GENE ; GENES ; SAMPLE ; FAMILY ; RISK-FACTORS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; AGE ; BRCA1 ; case-only design ; family history ; gene carrier probability ; LINKAGE ANALYSIS ; mixture logistic model ; ovarian cancer ; OVARIAN-CANCER ; population and sibling controls ; WOMEN
    Abstract: Background The effect of environmental/lifestyle factors on breast cancer risk may be modified by genetic predisposition. Methods In a population-based case-control-family study performed in Germany including 706 cases by age 50 years, 1381 population, and 252 sister controls, we investigated main effects for environmental/lifestyle factors and genetic susceptibility and gene-environment interaction (G x E). Different surrogate measures for genetic predisposition using pedigree information were used: first-degree family history of breast or ovarian cancer; and gene carrier probability using a genetic model based on rare dominant genes. Possible G x E interaction was studied by (1) logistic regression using cases and population controls including an interaction term; (2) comparing results using sister controls and population controls; (3) case-only analysis with logistic regression and (4) a mixture logistic model. Results Familial predisposition showed the strongest main effect and the estimated gene carrier probability gave the best fit. High parity and longer duration of breastfeeding reduced breast cancer risk significantly, a history of abortions increased risk and age at menarche showed no significant effect. We found significant G x E interaction between parity and genetic susceptibility using different surrogate measures. In women most likely to have a high genetic susceptibility, high parity was less protective. Later age at menarche was protective in women with a positive family history. No evidence for G x E interaction was found for breastfeeding and abortion. Conclusions These findings corroborate results from other studies and provide further evidence that the magnitude of protection from parity is reduced in women most likely to have a genetic risk in spite of the limitations of using surrogate genetic measures
    Type of Publication: Journal article published
    PubMed ID: 12690006
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  • 4
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    Internist 44 (9), 1131-1139 
    Keywords: Germany ; THERAPY ; COMMON ; DIAGNOSIS ; DISEASE ; NEW-YORK ; POPULATION ; RISK ; TIME ; PATIENT ; NEPHRITIS ; INFECTION ; GRAFT ; renal ; STAGE ; IDENTIFICATION ; PROGRESSION ; EXPERIENCE ; RISK FACTOR ; RECURRENCE ; FREQUENT ; CLINICAL-FEATURES ; CLINICALLY-RELEVANT ; CYCLOPHOSPHAMIDE ; FAILURE ; glomerulonephritis ; HYPERTENSION ; INFECTIONS ; NATURAL-HISTORY ; NEPHROPATHY ; PREDICTORS ; PREVALENCE ; proteinuria ; RECURRENT ; renal insufficiency ; renoparenchymal hypertension ; RISK GROUP ; STAGE RENAL-FAILURE
    Abstract: IgA nephropathy (IgAN) is the most common type of glomerulonephritis in the western world. In the majority of cases, it manifests in adolescence or early adulthood as recurrent macrohematuria, frequently triggered by infections, or persistent microhematuria as well as mild proteinuria, hypertension and/or renal insufficiency. In view of the later, it is not surprising that IgAN is often a chance finding. The majority of affected persons probably never come to medical attention, since in autopsies a prevalence of up to 1% of the population has been reported. About 20-30% of patients with a diagnosis of IgAN suffer from chronic, slowly progressive renal failure. Predictors include the degree of proteinuria and arterial hypertension as well as the established renal impairment at the time of diagnosis. Early identification of this risk group is of particular importance, since adequate therapy can stop or at least retard the progression of renal failure. When end stage renal failure has developed and a renal transplant is performed, about 25% of the patients will experience a clinically relevant recurrence of IgAN with progressive graft dysfunction
    Type of Publication: Journal article published
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  • 5
    Keywords: SURVIVAL ; tumor ; Germany ; INHIBITION ; MODEL ; MODELS ; DISEASE ; DISEASES ; incidence ; liver ; RISK ; SITE ; SITES ; GENE ; TUMORS ; STORAGE ; TIME ; PATIENT ; NITRIC-OXIDE SYNTHASE ; INJURIES ; DNA ; INFECTION ; RISK-FACTORS ; CARCINOGENESIS ; RAT ; RATS ; PROTEIN-KINASE ; treatment ; virus ; prevention ; STRESS ; risk factors ; metastases ; DAMAGE ; chemoprevention ; COLON CARCINOGENESIS ; copper toxicity ; curcumin ; ETHENO-DNA ADDUCTS ; HEREDITARY HEPATITIS ; LEC rats ; LIPID-PEROXIDATION ; MOUSE FIBROBLAST CELLS ; NIH 3T3 ; ORNITHINE DECARBOXYLASE ; OXIDATIVE STRESS
    Abstract: Long-Evans Cinnamon (LEC) rats, an inbred mutant strain which accumulates copper due to an aberrant copper-transporting ATPase gene, develop acute hepatitis, chronic liver injury and liver tumors as a result of copper-induced oxidative stress, lipid peroxidation and DNA damage. Curcumin, an antioxidant and anti-inflammatory agent, has shown anticancer properties in many rodent models. We investigated the modulating role of curcumin in liver and kidney carcinogenesis in LEC rats. Two groups of 4-week-old LEC rats (n = 60 each) were fed either a standard diet (control) or received 0.5% curcumin in the diet for life. In untreated LEC rats, the rate of acute liver failure, the incidence of liver tumors and of kidney tumors were 32, 100 and 10% respectively, which was not altered by curcumin treatment. However, curcumin reduced tumor incidence at other organ sites (15% versus 0%; P = 0.025) and suppressed formation of metastases (18% versus 0%; P = 0.01). Median survival time was decreased from 88.7 to 78.1 weeks in curcumin-treated rats (P = 0.002). The lack of chemoprevention of liver and kidney tumors in LEC rats by curcumin may be caused by enhanced toxicity and oxidative stress due to excess copper. We conclude that curcumin should be contra-indicated for patients suffering from inherited and acquired metal storage diseases that include patients with hepatitis C virus infection. (C) 2002 Elsevier Science B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12628510
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  • 6
    Keywords: CANCER ; FOLLOW-UP ; lung cancer ; LUNG-CANCER ; COHORT ; MORTALITY ; POPULATION ; RISK ; RISKS ; SITE ; SITES ; TIME ; SKIN ; IN-SITU ; MALIGNANCIES ; WOMEN ; smoking ; skin cancer ; bladder cancer ; BLADDER-CANCER ; SWEDEN ; cancer risk ; SQUAMOUS-CELL CARCINOMA ; CANCER RISKS ; COSMETOLOGISTS ; hair dyes ; hairdressers ; HEMATOPOIETIC NEOPLASMS ; NECK ; OCCUPATIONAL RISKS ; SAFETY ; SIR ; UNITED-STATES
    Abstract: More than a decade ago, an increased risk for bladder cancer among male hairdressers was established. Frequent changes of hair dye formulations together with their widespread use call for safety guarantees. We carried out a follow-up study of a cohort of 38,866 female and 6,824 male hairdressers from Sweden and analyzed all of their malignancies over a period of 39 years. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for 28 cancer sites were calculated using the economically active population as a reference. During the years 1960-1998 a total of 1,043 cancer cases were recorded in male hairdressers. Excess risks for cancers of the upper aerodigestive tract and lung and colorectal adenocarcinoma were observed. Additionally, male hairdressers working in 1960 had an increased risk for urinary bladder cancer, which was highest in the 1960s with an SIR of 2.56 (95% CI 1.36-4.39) and decreased with the follow-up time. A total of 2,858 cancers were recorded in female hairdressers. An increased risk was observed for cancers of the pancreas, lung and cervix and in situ cancer of the skin. The increased risk for in situ skin cancer specifically affected the scalp and neck, sites of contact for hair dyes, with an SIR of 2.43 (95% CI 1.14-4.44). The increase in lung cancer, the only site for which cancer was increased in either sex, may depend on confounding from smoking. Bladder cancer was not increased among hairdressers in the recent decades and is therefore not likely to be associated with modern hair dyes. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12672039
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  • 7
    Keywords: CANCER ; IN-VITRO ; tumor ; AGENTS ; Germany ; IN-VIVO ; INHIBITION ; screening ; SYSTEM ; SYSTEMS ; RISK ; ENZYMES ; DRUG ; NITRIC-OXIDE ; murine ; RISK-FACTORS ; CARCINOGENESIS ; INDUCTION ; KERATINOCYTES ; mechanisms ; culture ; IDENTIFICATION ; prevention ; risk factors ; MODULATION ; RISK FACTOR ; butyrate ; HEPATOMA ; fatty acids ; FATTY-ACIDS ; NF-kappa B ; ALCOHOL ; SODIUM-BUTYRATE ; curcumin ; ORNITHINE DECARBOXYLASE ; ANTIOXIDANT ; bioassay systems ; cancer chernoprevention ; CONSTITUENTS ; iNOS ; PEITC ; SULFORAPHANE ; SUPEROXIDE
    Abstract: Identification and use of effective cancer chemopreventive agents have become an important issue in public health-related research. For identification of potential cancer chemopreventive constituents we have set up a battery of cell- and enzyme-based in vitro marker systems relevant for prevention of carcinogenesis in vivo. These systems include modulation of drug metabolism (inhibition of Cyp1A activity, induction of NAD(P)H:quinone reductase (QR) activity in Hepalclc7 murine hepatoma cell culture), determination of radical scavenging (DPPH scavenging) and antioxidant effects (scavenging of superoxide anion-, hydroxyl- and peroxyl- radicals), anti-inflammatory mechanisms (inhibition of lipopolysaccharide (LPS)-mediated nitric oxide (NO) generation by inducible NO synthase (iNOS) in Raw 264.7 murine macrophages, cyclooxygenase-1 (Cox-1) inhibition), and anti- tumor promoting activities (inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity in 308 murine keratinocytes). We have tested a series of known chemopreventive substances belonging to several structural classes as reference compounds for the identification of novel chemopreventive agents or mechanisms. These include organosulfur compounds (phenethylisothiocyanate (PEITC), diallylsulfide, diallyldisulfide), terpenes (limonene, perillyl alcohol, oleanolic acid, 18-beta-glycyrrhetinic acid), short- chain fatty acids (sodium butyrate), indoles (indole-3- carbinol), isoflavonoids (quercetin, silymarin, genistein), catechins ((-)-epigallocatechin gallate (EGCG)), simple phenols (ellagic acid, resveratrol, piceatannol, curcumin), pharmaceutical agents (piroxicam, acetylsalicylic acid, tamoxifen), and vitamins/derivatives (ascorbic acid, Trolox). We confirmed known chemopreventive mechanisms of these compounds. Additionally, we could demonstrate the usefulness of our approach by identification of hitherto unknown mechanisms of selected agents. As an example, we detected anti- inflammatory properties of PEITC, based on NF-kappaB-mediated inhibition of NO production. Further, PEITC inhibited phorbol ester-induced superoxide anion radical production in granulocytes, and ODC induction in the 308 cell line. These mechanisms might contribute to the chemopreventive potential of PEITC. (C) 2002 Elsevier Science B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12628514
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  • 8
    Keywords: CANCER ; EXPRESSION ; carcinoma ; CELL ; Germany ; human ; LUNG ; lung cancer ; LUNG-CANCER ; EXPOSURE ; RISK ; GENE ; PROTEIN ; METABOLISM ; TISSUE ; PATIENT ; RISK-FACTORS ; FREQUENCY ; polymorphism ; SUSCEPTIBILITY ; PROMOTER ; OVARIAN-CANCER ; WOMEN ; MEN ; risk factors ; smoking ; PROSTATE-CANCER ; cancer risk ; RISK FACTOR ; CYP3A4 ; LINKAGE DISEQUILIBRIUM ; CANCER-PATIENTS ; CARCINOMAS ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; ADENOCARCINOMAS ; CARRIERS ; case-control studies ; CLINICAL PRESENTATION ; CYP3A,genetic polymorphism,lung cancer susceptibility,small cell lung cancer,LightCycler ; EXPRESSED HUMAN CYTOCHROME-P450S ; GENETIC VARIANT ; HUMAN LIVER-MICROSOMES ; PROSTATE TUMORS ; PROTEIN LEVELS ; squamous cell carcinoma ; TOBACCO
    Abstract: CYP3A isozymes are involved in tobacco carcinogen- and steroid-metabolism, and are expressed in human lung tissue showing interindividual variation in expression and activity. The CYP3A4* 1 B allele has been associated with a two-fold higher promoter activity and with high-grade prostate cancers. The very frequent intron 3 polymorphism in the CYP3A5 gene (CYP3A5*3) results in decreased CYP3A5 protein levels. A case-control study was conducted in 801 Caucasian lung cancer patients that included 330 adenocarcinomas, 260 squamous cell carcinomas, 171 small cell lung cancers (SCLC) and 432 Caucasian hospital-based controls. CYP3A-genotyping was performed by capillary polymerase chain reaction followed by fluorescence-based melting curve analysis. A significantly increased SCLC risk for CYP3A4* 1B allele carriers [odds ratio (OR) 2.25, 95% confidence interval (CI) 1.11-4.55, P = 0.02] was found. After dividing cases and controls by gender, an increased lung cancer risk for CYP3A4* 1B carriers (OR 3.04, 95% CI 0.94-9.90, P= 0.06) for women but not for men (OR 1.00, 95% CI 0.56-1.81) was revealed. Heavier smoking men (greater than or equal to 20 pack-years) with the CYP3A4* 1 B allele had a significant OR for lung cancer of 3.42 (95% CI 1.65-7.14, P= 0.001) compared to * 1A/1* 1A carriers with lower tobacco exposure (〈 20 pack-years). For women, the respective OR was 8.00 (95% CI 2.12-30.30, P = 0.005). Genotype frequencies were generally in Hardy-Weinberg equilibrium, except for CYP3A5 where a greater than expected number of CYP3A5* 1 homozygotes was observed among cases (P = 0.006). In addition, we observed linkage disequilibrium of CYP3A4 and CYP3A5 (P 〈 0.00001), but a nonsignificantly increased lung cancer risk was only found for homozygous CYP3A5* 1 allele carriers (OR 5.24,95% CI 0.85-102.28, P = 0.14) but not for heterozygotes. To confirm our observation that the CYP3A4* 1B allele increases SCLC risk and modifies the smoking-related lung cancer risk in a gender-specific manner, further studies, including CYP3A haplotype analysis, will be necessary. Pharmacogenetics 13:607-618 (C) 2003 Lippincott Williams Wilkins
    Type of Publication: Journal article published
    PubMed ID: 14515059
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  • 9
    Keywords: CANCER ; tumor ; carcinoma ; Germany ; LONG-TERM ; NEW-YORK ; RISK ; transcription ; TRANSCRIPTION FACTOR ; CARCINOGENESIS ; hormone ; NEOPLASIA ; WOMEN ; cervical cancer ; cervical intraepithelial neoplasia ; HPV ; HUMAN KERATINOCYTES ; ORAL-CONTRACEPTIVES ; intraepithelial neoplasia ; cervical carcinoma ; DEPENDENT TRANSFORMATION ; ESTROGEN METABOLISM ; GLUCOCORTICOID RESPONSE ELEMENTS ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; LONG CONTROL REGIONS ; SQUAMOUS-CELL CARCINOMAS ; VIRAL GENE-EXPRESSION
    Abstract: Available data demonstrate an increase in the transcription of high-risk papillomaviruses by the 16alpha-hydroxylation of estrogens, which is in line with the epidemiologic data showing an increased cervical carcinogenesis risk for long-term contraceptive-using, HPV-infected women. No evidence exists for an increase in HPV-negative contraceptive users. (C) 2002 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12516087
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  • 10
    Keywords: CANCER ; BLOOD ; DISEASE ; RISK ; GENE ; PROTEIN ; SAMPLES ; PATIENT ; DNA ; FAMILY ; FREQUENCY ; BREAST ; BREAST-CANCER ; family history ; OVARIAN-CANCER ; WOMEN ; MUTATION ; MUTATIONS ; PREVALENCE ; BRCA1/2 ; BRCA2 MUTATIONS ; early-onset breast cancer ; German population ; germline mutations ; POPULATION-BASED SAMPLE
    Abstract: This study was undertaken to investigate the prevalence of BRCA1 and BRCA2 germline mutations in 91 German patients unselected for family history, who were diagnosed with breast cancer before the age of 41 years. Clinical information and blood samples were obtained from all patients. A comprehensive BRCA1 and BRCA2 mutational analysis was performed using the protein truncation assay and single-strand conformational polymorphism analysis followed by DNA sequencing of variant signals detected by these assays. Five different deleterious germline mutations including four frameshift mutations and one missense mutation were identified, three in BRCA1 (3.3%) and two mutations (2.2%) in BRCA2. Both BRCA2 mutations are novel and might be specific for the German population. An additional BRCA1 missense mutation previously described and classified as an unknown variant was found. This mutation was also detected in two breast cancer patients of family P 328 and not in 140 healthy controls suggesting that it is disease associated. In addition, one common polymorphism and five novel intronic sequence variants with unknown significance were found. Our findings show that mutations in BRCA1 and BRCA2 may contribute similarly to early-onset breast cancer in Germany. Given current constraints on health-care resources, these results support the notion that BRCA1 and BRCA2 mutation screening may have the strongest impact on health-care when targeted to high- risk populations
    Type of Publication: Journal article published
    PubMed ID: 12774040
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  • 11
    Keywords: GROWTH ; tumor ; Germany ; MORTALITY ; NEW-YORK ; RISK ; PROTEIN ; PATIENT ; TUMOR-NECROSIS-FACTOR ; INTERVENTION ; treatment ; PLASMA ; DECREASE ; AGE ; MUSCLE ; AMINO-ACIDS ; OXIDATIVE STRESS ; ANTIOXIDANT ; aging-related wasting ; ALPHA-LIPOIC ACID ; antioxidants and aging ; cysteine ; ELDERLY HUMANS ; INJURIOUS FALLS ; MUSCLE PROTEIN-SYNTHESIS ; muscular aging ; P70 S6 KINASE ; PLASMA REDOX STATE ; RAT SKELETAL-MUSCLE ; RESISTANCE EXERCISE ; role in aging ; tumor necrosis factor in aging
    Abstract: Aging-related loss of muscle function is a predictor of mortality and a surrogate parameter of the aging process. Its consequences include a high risk for falls, hip fractures, and loss of autonomy. Aging is associated with changes in the oxidant/antioxidant balance including a decrease in plasma thiol (cysteine) concentration. To assess the importance of cysteine, we determined in a double-blind study the effects of N-acetylcysteine on the functional capacity of frail geriatric patients and their response to physical exercise. The subjects on placebo showed only a relatively weak response, and 31% showed even a decrease in more than one parameter during the observation period. Low plasma arginine levels were correlated with a weak overall performance before exercise and a poor response to exercise. N-Acetyl-cysteine strongly enhanced the increase in knee extensor strength and significantly increased the sum of all strength parameters if adjusted for baseline arginine level as a confounding parameter. N-acetylcysteine had no significant effect on growth hormone and IGF-1 levels but caused a significant decrease in plasma TNF-alpha. These findings may provide a basis for therapeutic intervention and suggest that the loss of function involves limitations in cysteine and one or more other amino acids which may compromise muscular protein synthesis
    Type of Publication: Journal article published
    PubMed ID: 12601528
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  • 12
    Keywords: RISK ; MELANOMA ; DATABASE ; MUTATIONS ; CANCER RISKS ; AUSTRALIA ; INCIDENCE RATES ; SPOUSES
    Type of Publication: Journal article published
    PubMed ID: 12873883
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  • 13
    Keywords: CANCER ; FOLLOW-UP ; DISEASE ; RISK ; SAMPLE ; TIME ; RISK-FACTORS ; AGE ; WOMEN ; risk factors ; SWEDEN ; RISK FACTOR ; SIR ; ASBESTOS ; time trends ; TRENDS ; mesothelioma
    Abstract: Epidemiologic data on peritoneal mesothelioma are scarce but exposure to asbestos is an identified risk factor. To characterize the disease, time trends, age-incidence relationships, and occupational risk factors for peritoneal mesothelioma were studied based on the Swedish Family-Database covering years 1961 to 1998. Peritoneal mesothelioma is a rare disease and only 96 male and 113 female cases were recorded during the 38-year period, Age-standardized incidence of the disease has increased for men until 1985 and leveled off thereafter. The incidence in women has been equally high but it has continued to increase toward the end of the follow-up period. The incidence was maximal at an age around 80 years for both genders. No female occupational or socioeconomic group was at risk. For men, 29% of the cases had typical asbestos related jobs with a SIR of 1.70. Bricklayers and plumbers had the highest risk of 7.22 and 5.12 respectively Within limits of the sample,. size, no evidence was noted for risk from environmental exposures to asbestos because the risk of farmers and that of urban residents were not different
    Type of Publication: Journal article published
    PubMed ID: 12708149
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  • 14
    Keywords: FOLLOW-UP ; LUNG-CANCER ; CANCER MORTALITY ; DISEASE ; RISK ; RISKS ; WORKERS ; TIME ; PATIENT ; RISK-FACTORS ; AGE ; MEN ; risk factors ; RATES ; SWEDEN ; DATABASE ; SIR ; INCIDENCE RATES ; FAMILY-CANCER DATABASE ; ASBESTOS ; ASBESTOS EXPOSURE ; EUROPE ; MALIGNANT MESOTHELIOMA ; REFINERY/PETROCHEMICAL PLANT COHORTS
    Abstract: Epidemiologic data on pleural mesothelioma are scarce on regional and occupational time trends, which would monitor the effects of changes in exposure to asbestos. We aim to characterize time trends, regional, socioeconomic, and occupational risk factors for pleural mesothelioma in Sweden in the years from 1961 to 1998. The Swedish Family-Cancer Database was used to identify patients with pleural mesothelioma. Age- standardized incidence rates and standardized incidence ratio (SIR) were calculated for the population in the Database. A total of 1298 male and 233 female pleural mesotheliomas were retrieved. Age-standardized incidence of the disease was highest, and the trend increased in residents of large industrial and shipbuilding cities. In the last follow-up period, the male rate exceeded the female rate about 10-fold. Among male socioeconomic groups, manual workers showed the highest and ever-increasing SIR. No female socioeconomic group was at risk. For men, plumbers and seamen had the highest risk of 4.56 and 2.83, respectively, but the risks appeared to be decreasing for plumbers, whereas no clear trend was noted for seamen, probably because of indirect expose in ships. Farmers showed an SIR of 0.28, indicating that the population at large was at four times higher risk than farmers. The SIRs of many academic/college-educated groups were two to six times higher than those of farmers, suggesting indirect exposure to asbestos in these groups
    Type of Publication: Journal article published
    PubMed ID: 12708150
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  • 15
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    International Journal of Cancer 105 (5), 692-700 
    Keywords: CANCER ; LUNG-CANCER ; RISK ; SITES ; TIME ; SKIN ; lifestyle ; WOMEN ; risk factors ; MELANOMA ; DATABASE ; GASTRIC-CANCER ; HELICOBACTER-PYLORI ; ATTRIBUTABLE RISKS ; CARCINOID-TUMORS ; causes of cancer ; ENDOMETRIAL CANCER ; environmental risks ; EPSTEIN-BARR-VIRUS ; LIFE-STYLE ; sociol factors ; SWEDISH POPULATION
    Abstract: It is well known that certain cancers have shown clustering in socioeconomic groups, but limited data are available on recent results and time trends in such clustering. We determined standardized incidence ratios (SIR) for cancer, adjusted for age, period, region, parity and age at first childbirth among men and women in 6 socioeconomic groups based on the Swedish Family-Cancer Database. Persons had to be identified with the same socioeconomic status in the census of years 1960 and 1970, or of years 1960, 1970 and 1980; the comparison group was all people according to the same censuses. Cancers were followed from years 1970 to 1998 or from 1980 to 1998. Both increased and decreased SIRs were found, and a consistent pattern emerged, although the overall SIRs for cancer did not differ much, the lowest being for farmers (0.8S) and the highest for professional men (1.07) and women (1.11). At individual sites, manual workers were at risk of tobacco-, alcohol- and occupation- and human papilloma virus-related cancers and at a decreased risk at most other cancers. Manual workers and farmers showed an excess of stomach cancer; professionals had an excess of melanoma and squamous cell skin cancer. Male and female SIRs correlated highly for manual and blue-collar workers and for professionals. The overall population- attributable fraction for selected sites was 16.7% for men and 10.9% for women and it was highest, over 50%, for lung cancer in both genders
    Type of Publication: Journal article published
    PubMed ID: 12740920
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  • 16
    Keywords: CANCER ; human ; RISK ; SWEDEN ; POPULATIONS ; SPOUSES ; LANGUAGE
    Type of Publication: Journal article published
    PubMed ID: 12673273
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  • 17
    Keywords: CANCER ; carcinoma ; SYSTEM ; HEPATOCELLULAR-CARCINOMA ; incidence ; liver ; POPULATION ; RISK ; RISKS ; GENE ; GENES ; FAMILY ; primary ; tumour ; MEMBER ; MEMBERS ; ASSOCIATION ; CANDIDATE GENE ; SUSCEPTIBILITY ; AGE ; ovarian cancer ; OVARIAN-CANCER ; CERVICAL-CANCER ; bladder cancer ; BLADDER-CANCER ; SWEDEN ; DATABASE ; SIR ; familial risk ; CARRIERS ; FAMILY-CANCER DATABASE ; bile duct ; BILE-DUCTS ; CHOLECYSTECTOMY ; GALLBLADDER-CANCER ; RELATIVES ; VIRAL-HEPATITIS
    Abstract: Background and aims: Familial risks in liver and biliary cancers have been assessed in small case control studies, usually based on reported, but not medically verified, cancers in family members. Thus the degree of familial clustering for these cancers remains to be established. Methods: The nationwide Swedish Family-Cancer Database was used, covering 10.2 million individuals for the years 1961-1998 from the Swedish Cancer Registry. Liver and biliary tract cancers were identified from 1121 offspring between the ages of 0 and 66 years and 17 131 parents. Standardised incidence ratios (SIRs) and 95% confidence intervals (Cls) were calculated for cancers in family members. Results: All cancers in the liver and biliary system showed a familial SIR of 1.65 (95% Cl 1.05- 2.46). This was mainly explained by a high risk for familial gall bladder cancer (SIR 5.21 (95% Cl 2.07-10.80)) and for familial primary liver cancer with hepatocellular carcinoma histology (SIR 4.69 (95% Cl 1.48-11.04)). For gall bladder and hepatocellular cancer, maternal transmission appeared to be favoured. Gall bladder cancer was associated with pancreatic cancer (SIR 2.39 (95% Cl 1.23-4.18)). Primary liver cancer was associated with cervical, urinary bladder, and endocrine gland tumours. Cancer in extrahepatic bile ducts was associated with ovarian cancer and that in ampulla of Vater with thyroid cancer; however, these associations may have been fortuitous. Conclusions: This study has provided the first data on familial clustering of liver and gall bladder cancers, based on medically confirmed records. The risks were so high that heritable factors were likely to contribute, possibly modified by environmental factors. The demonstration of candidate genes would help to further characterise the familial risks
    Type of Publication: Journal article published
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  • 18
    Keywords: CANCER ; neoplasms ; THERAPY ; DISEASE ; incidence ; RISK ; RISKS ; SITE ; SITES ; PATIENT ; primary ; SKIN ; LYMPHOMA ; MALIGNANCIES ; skin cancer ; MELANOMA ; SWEDEN ; DATABASE ; SQUAMOUS-CELL CARCINOMA ; SIR ; PRIMARY CANCERS ; FAMILY-CANCER DATABASE ; 2ND PRIMARY NEOPLASMS ; CANCER-THERAPY ; immunological factors ; immunosuppression ; LONG-TERM SURVIVORS ; MULTIPLE PRIMARY CANCERS ; non-hodgkin's lymphoma ; second cancer ; therapeutic effects
    Abstract: Successes in cancer therapy have led to increasing numbers of cancer survivors, who are at risk of developing second primary cancers. Therapy- or disease-induced suppression of the immune function may predispose cancer patients to a second malignancy. An excess of squamous cell skin cancers (SCC) and non-Hodgkin's lymphomas has been found in immunosuppressed patients. We used the nationwide Swedish Family-Cancer Database on 10.2 million individuals to calculate the risk of second primary skin cancers and non-Hodgkin's lymphomas following a previous malignancy. A total of 4301 second skin cancers and 1672 non- Hodgkin's lymphomas were identified. Standardised incidence ratios (SIR)s and 95% Confidence Intervals (CIs) were calculated and compared. Among 14 different sites for male or female first primary malignancies, 11 of these sites were followed by an increased risk of skin cancer (SIRs for males for risk of skin cancer as a second primary cancer: 14.1 for SCC; 9.7 for melanoma; 6.1 for leukaemia as the first site; SIRs for females for risk of skin cancer: 14.6 for SCC; 6.8 for larynx; 6.2 for upper aerodigestive tract (UADT) as the first site). The risk of non-Hodgkin's lymphoma was increased after 10 of 14 different male neoplasms and 12 of 17 different female neoplasms. (SIRs for males for risk of non-Hodgkin's lymphoma as a second primary cancer: 6.4 for non-Hodgkin's lymphoma; 3.2 for leukaemias; 3.1 for multiple myeloma as the first site; SIRs for females for risk of non-Hodgkin's lymphoma as a second primary cancer: 12.5 for leukaemias; 7.0 for Hodgkin's disease; 3.6 for UADT as the first site). The high, and after certain sites, very high risks of second skin cancer and non-Hodgkin's lymphoma suggest that immune suppression may be a contributory mechanism. (C) 2002 Elsevier Science Ltd. All rights reserved
    Type of Publication: Journal article published
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  • 19
    Keywords: CANCER ; NEW-YORK ; RISK ; SKIN ; ASSOCIATION ; BREAST-CANCER ; IN-SITU ; RATES ; MELANOMA ; SWEDEN ; DATABASE ; SQUAMOUS-CELL CARCINOMA ; NATIONWIDE ; CUTANEOUS MELANOMA ; OCULAR MELANOMA ; FAMILY-CANCER DATABASE ; 2ND PRIMARY CANCERS ; MALIGNANT- MELANOMA
    Type of Publication: Journal article published
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  • 20
    Keywords: CANCER ; tumor ; carcinoma ; neoplasms ; FOLLOW-UP ; RISK ; RISKS ; SITE ; SITES ; TISSUE ; TUMORS ; primary ; RISK-FACTORS ; SKIN ; treatment ; ASSOCIATION ; BREAST-CANCER ; PATTERNS ; WOMEN ; leukemia ; SWEDEN ; DATABASE ; HEREDITARY ; SIR ; familial risk ; SMALL-INTESTINE ; BRCA2 MUTATIONS ; germline mutations ; double primaries ; endometrioid tumor ; FAMILY-CANCER DATABASE ; FIRST- DEGREE RELATIVES ; heritable effects ; HODGKINS- DISEASE ; multiple primaries ; NONPOLYPOSIS COLORECTAL-CANCER ; second carcinoma ; synchronous carcinoma
    Abstract: BACKGROUND. Population-based data on subsequent neoplasms after women are diagnosed with endometrial and ovarian carcinomas are limited, particularly regarding specific histologic tumor types. METHODS. The nationwide Swedish Family-Cancer Database of 10.2 million individuals, which includes 19,128 invasive endometrial carcinomas and 19,440 ovarian carcinomas, was used to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) for second primary carcinomas. SIRs were calculated for specific follow-up periods. Data on histopathologic types also were used. RESULTS. An excess of subsequent malignancies after women were diagnosed with endometrial carcinoma was noted at 11 sites. The highest SIRs were recorded for synchronous or metasynchronous ovarian carcinomas (SIR, 55.77; 95% CI, 48.82-63.43) and carcinomas of the small intestines (SIR, 14.71; 95% Cl, 4.64-34.59). Primary ovarian carcinoma was followed by an increased risk of developing endometrial carcinoma, and the risks of developing many other malignancies also were increased after women were diagnosed with endometrial carcinoma, including intestinal malignancies, renal cell carcinoma, bladder carcinoma, squamous cell skin carcinoma, connective tissue malignancies, and leukemia. When ovarian endometrioid histology was diagnosed synchronously with primary endometrial carcinoma, the SIR was 140; when endometrial carcinoma was the subsequent neoplasm, the SIR was 87. A small familial component was found in the cooccurrence of endometrial carcinoma and ovarian carcinoma. CONCLUSIONS. The current data show a strong clustering of endometrial carcinomas and ovarian carcinomas, particularly involving tumors of endometrioid morphology. The patterns of second neoplasms also suggest that hereditary nonpolyposis colorectal. carcinoma may contribute to the association between endometrial and ovarian malignancies. Increased risks for connective tissue tumors and leukemia may signal a response to treatment, and an increased risk for squamous cell skin carcinoma may signal a depressed immune function. (C) 2003 American Cancer Society
    Type of Publication: Journal article published
    PubMed ID: 12733142
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  • 21
    Keywords: CANCER ; LUNG-CANCER ; MORTALITY ; RISK ; SWEDEN ; DATABASE ; GASTRIC-CANCER ; HELICOBACTER-PYLORI ; ATTRIBUTABLE RISKS ; ENDOMETRIAL CANCER ; time trends ; education ; INCIDENCE TRENDS ; SOCIOECONOMIC GROUPS
    Type of Publication: Journal article published
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  • 22
    Keywords: CANCER ; Germany ; human ; incidence ; POPULATION ; RISK ; RISKS ; SITE ; SITES ; IMPACT ; cancer prevention ; prevention ; HEALTH ; lifestyle ; WOMEN ; MEN ; SWEDEN ; cancer risk ; DATABASE ; SIR ; TOBACCO ; ALCOHOL ; FAMILY-CANCER DATABASE ; BRITAIN ; INEQUALITIES ; LONE MOTHERS ; MIDDLE-AGED WOMEN ; NESTED CASE-CONTROL ; NORWEGIAN WOMEN BORN
    Abstract: Limited data are available on the possible changes in cancer risk brought about by widowhood and divorce, an increasing segment of the population. We calculated standardized incidence ratios (SIRs) for cancer among 47,000 widows/widowers and 60,000 divorced people, based on the Swedish Family-Cancer Database. Persons had to be identified with the same civil status in the census of years 1960 and 1970; the comparison group was married people according to the same censuses. Cancers were followed from years 1971 to 1998. Both increased and decreased SIRs were found, and a consistent pattern emerged. The effects on the divorced were always stronger than those in widows/widowers, irrespective of the direction of the effect. Every significant SIR for a cancer site in widows/widowers was accompanied by a more deviant and significant SIR in the divorced. SIRs between divorced men and women (r = 0.83, P 〈 0.0001) and between widows and divorcees correlated (r = 0.70, P 〈 0.0001). The overall cancer risk for the divorced was 0.92-0.94, and it was a balance between increased risks at tobacco-, alcohol-, and human papilloma virus-related sites, and decreased risks at most other sites. The data suggest that the changes in lifestyle on the loss of a spouse impact on the incidence of almost every type of cancer. The effects were so large that a failure to consider marital status in epidemiological studies may be a source to bias. Understanding these lifestyle changes may provide new insight in cancer prevention
    Type of Publication: Journal article published
    PubMed ID: 14504201
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  • 23
    Keywords: CANCER ; Germany ; EPIDEMIOLOGY ; incidence ; RISK ; RISKS ; GENE ; GENES ; SUSCEPTIBILITY ; SUSCEPTIBILITY GENES ; BREAST ; breast cancer ; BREAST-CANCER ; IDENTIFICATION ; prevention ; DESIGN ; DIFFERENCE ; AGE ; BRCA1 ; WOMEN ; SWEDEN ; DATABASE ; REGION ; MUTATIONS ; MORPHOLOGY ; SIR ; familial risk ; NATIONWIDE ; FAMILY-CANCER DATABASE ; RELATIVES ; familial risk,half sisters,risk factors,sibling risk ; INTERPRETING FAMILY ; SUSCEPTIBILITY GENE
    Abstract: Purpose. The familial risk of female breast cancer is somewhat less than 2.0 when a first-degree relative is diagnosed with breast cancer, but it is not known to what extent heritable or environmental factors explain the familial clustering. Such data would be valuable for prevention and gene identification strategies.Experimental design. We used the nation-wide Swedish Family-Cancer Database on 10.2 million individuals and 190,000 mothers' and 26,000 daughters' breast cancers to calculate familial standardised incidence ratios (SIRs), for all invasive breast cancers in daughters, who were 0-66 years old. Over 5500 familial breast cancers were recorded.Results. The familial SIR for all invasive breast cancer was 1.71 by breast cancer in the mother only, 1.95 by breast cancer in a sister only, and 2.75 by breast cancer in both a mother and sister. The SIRs did not change when adjustments were done for period, age at first birth, parity, socio-economic status and region. Age difference between sisters showed a small variation in risk for breast cancer but the highest SIR was found for those whose age difference was from 6 to 10 years. Half sisters showed an excess of familial risks exactly half of full sisters, the SIR being 1.44.Conclusions. These data suggest that familial aggregation of breast cancer is mainly due to heritable causes. Because the known susceptibility genes only explain about a quarter of the familial aggregation, the remaining majority offers a challenge to new genomic approaches
    Type of Publication: Journal article published
    PubMed ID: 14672399
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  • 24
    Keywords: RISK ; SURGERY ; TIME ; PATIENT ; INDEX ; colon ; CONSTRUCTION ; CHOLECYSTECTOMY ; COMPLICATIONS ; ANASTOMOSIS ; ANAL ANASTOMOSIS ; HOSPITALIZATION ; ileoanal pouch ; ileostomy ; INFLAMMATORY BOWEL-DISEASE ; laparoscopically assisted proctocolectomy ; LOOP ILEOSTOMY ; RANDOMIZED PROSPECTIVE TRIAL ; RESTORATIVE PROCTOCOLECTOMY ; ULCERATIVE-COLITIS
    Abstract: Background: Apart from an obviously better cosmetic situation, there is controversy on the actual benefit of laparoscopic and laparoscopically assisted techniques in restorative proctocolectomy. The need for a protective ileostomy remains unclear. Methods: Fifty-nine consecutive patients with ulcerative colitis and familial polyposis were included in this prospective cohort study. The colon was mobilized laparoscopically with a four-trocar technique, facilitating vascular dissection, rectal resection, and ileoanal pouch construction to be done through a Pfannenstiel incision. A protective ileostomy was constructed only in patients where the operation was difficult or where the anastomosis was under tension. Intra- and postoperative data were recorded; statistical analyses were performed by exact logistic regression. Results: Laparoscopic mobilisation was successful in 54 patients (91.2%). Two patients had to be primarily converted because of exceeding the set time limit; 3 other patients had to have an additional median laparotomy. These 5 patients all had an increased body mass index (BMI), which was a statistically significant risk factor for failure of the laparoscopic technique. 18.6% of patients developed major complications (n = 11). Nine patients required secondary ileostomies; all of them either were under high dose immunosuppressants (n = 5) or had an increased BMI (average 28.42 kg/m(2)). Failure of the laparoscopic technique was associated with major complications. Conclusion: Laparoscopically assisted restorative proctocolectomy is technically feasible; an increased BMI is a relevant risk factor for failure. The minimally invasive approach probably does not reduce the need for a protective ileostomy in selected patients. The selection criteria for the addition or omission of a protective ileostomy in minimally invasive restorative proctocolectomy remain to be clearly defined
    Type of Publication: Journal article published
    PubMed ID: 12616394
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  • 25
    Keywords: OPTIMIZATION ; SPECTRA ; radiotherapy ; evaluation ; MODEL ; THERAPY ; SYSTEM ; SYSTEMS ; VOLUME ; RISK ; radiation ; TIME ; PATIENT ; BASE ; treatment ; TARGET ; RADIATION-THERAPY ; adaptive triangulation ; clustering techniques ; multi-criteria optimization ; representative pareto solutions
    Abstract: Radiation therapy planning is often a tightrope walk between dangerous insufficient dose in the target volume and life threatening overdosing of organs at risk. Finding ideal balances between these inherently contradictory goals challenges dosimetrists and physicians in their daily practice. Todays inverse planning systems calculate treatment plans based on a single evaluation function that measures the quality of a radiation treatment plan. Unfortunately, such a one dimensional approach cannot satisfactorily map the different backgrounds of physicians and the patient dependent necessities. So, too often a time consuming iterative optimization process between evaluation of the dose distribution and redefinition of the evaluation function is needed. In this paper we propose a generic multi-criteria approach based on Pareto's solution concept. For each entity of interest - target volume or organ at risk - a structure dependent evaluation function is defined measuring deviations from ideal doses that are calculated from statistical functions. A reasonable bunch of clinically meaningful Pareto optimal solutions are stored in a data base, which can be interactively searched by physicians. The system guarantees dynamic planning as well as the discussion of tradeoffs between different entities. Mathematically, we model the inverse problem as a multi-criteria linear programming problem. Because of the large scale nature of the problem it is not possible to solve the problem in a 3D-setting without adaptive reduction by, appropriate approximation schemes. Our approach is twofold: First, the discretization of the continuous problem results from an adaptive hierarchical clustering process which is used for a local refinement of constraints during the optimization procedure. Second, the set of Pareto optimal solutions is approximated by an adaptive grid of representatives that are found by a hybrid process of calculating extreme compromises and interpolation methods
    Type of Publication: Journal article published
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  • 26
    Keywords: CANCER ; LUNG-CANCER ; NEW-YORK ; RISK ; GENE ; PROTEINS ; radiation ; DNA ; SKIN ; FREQUENCY ; polymorphism ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; DNA-REPAIR ; REPAIR ; MELANOMA ; SWEDEN ; cancer risk ; genotyping ; DIMER ; DNA repair ; 6-4 PHOTOPRODUCTS ; CYCLOBUTANE PYRIMIDINE DIMERS ; EXCISION-REPAIR ; photoproducts and breast cancer ; SKIN IN-SITU ; XERODERMA-PIGMENTOSUM ; XPG
    Abstract: In this study we determined the effect of single nucleotide polymorphisms in the XPG gene on DNA repair and breast cancer susceptibility. Ninety individuals, with previously studied DNA repair rate at 24 hr of 2 types of UV-specific cyclobutane pyrimidines dimers (CPDs) in skin were genotyped for XPG polymorphism at codon 1104 (exon I S G〉C; Asp〉His). The repair rate of TT=C dimer was similar in both wild-type GG homozygotes and GC heterozygotes, whereas, for TT=T, dimer repair was non- significantly (Student's t-test, p = 0.34) lower in GC heterozygotes than wild-type GG homozygotes. Genotyping of 220 breast cancer cases and 308 controls for the same single nucleotide polymorphism in exon 15 of the XPG gene exhibited marginally significant increased frequency of the variant allele (chi(2) 3.84, p = 0.05; OR 1.33, 95% Cl 1.0-1.8) in cases (C-allele 0.29) compared to controls (C-allele 0.24). Combined heterozygote and variant homozygote genotype frequency was also higher in cases than controls (chi(2) 4.79, p = 0.03; OR 1.50, 95% CI 1.04-2.16). (C) 2002 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12494477
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  • 27
    Keywords: CANCER ; IRRADIATION ; radiotherapy ; tumor ; carcinoma ; THERAPY ; RISK ; CONFORMAL RADIOTHERAPY ; EXPERIENCE ; head and neck ; IMRT ; ACCELERATED FRACTIONATION ; ADENOID CYSTIC CARCINOMA ; intensity modulated radiation therapy ; inverse treatment planning ; NASOPHARYNGEAL CARCINOMA ; PAROTID-GLAND ; SALIVARY-GLAND CARCINOMA
    Abstract: Purpose/Objective: The aim of this analysis is to evaluate the feasibility of inverse treatment planning and intensity modulated radiation therapy (IMRT) for head and neck cancer in daily clinical routine. A step and shoot IMRT approach was developed which allows the treatment of large target volumes without the need to use a split beam technique. By using the INIRT approach better protection of different organs at risk in the head and neck region may be achieved and an escalation of the dose in the tumor should be possible. We evaluated the feasibility of the treatment technique and the patient tolerance to the treatment. First clinical results are reported. Materials and Methods: Between 1999 and 2002, 48 patients with a carcinoma of the head and neck region were treated with curative intention. All patients were treated in a patient-specific Scotch-Cast mask. Patients who required treatment of the lymph node levels I-VI, were additionally positioned by a vacuum pillow in order to immobilize the upper part of the thorax. For inverse treatment planning, the software module KonRad was used which was integrated into the VIRTUOS planning system. Each treatment plan was verified using quantitative film dosimetry in a head and neck phantom. The step and shoot IMRT technique with a multileaf collimator integrated in a Primus (Siemens(R)) accelerator was used for treatment. For all target volumes the whole target including the lymph nodes were covered completely by the INIRT treatment. Results: The mean total dose for the target volumes of macroscopic disease ranged between 63.0 and 64.1 Gy. The mean total dose of microscopic disease ranged between 55.2 and 60.1 Gy. The mean percentage of planning target volume receiving 〈 90% of the prescribed dose ranged between 3.0 and 11.5%. For the treatment, the median number of beams was seven (range: five to nine). The time to deliver the treatment ranged between 9 and 18 min. The results of the verification revealed a mean deviation between measured and calculated absolute doses for the 48 patients of 0.1 +/- 1.4%. Including the phantom verification the IMRT treatment of the patients could be started approximately after five working days. The treatment was well tolerated by all patients. The 2-year actuarial overall survival was 92% and the 2-year actuarial local control rate was 93%. According to the Radiation Therapy Oncology Group (RTOG), no higher acute toxicity than Grade 3 was seen. Observation of the late effects revealed only one transient Grade 4 toxicity of the bone and only four patients had a xerostomia higher than Grade 1. Conclusion: The use of an inversely-planned and intensity-modulated step and shoot approach is feasible in clinical routine for head and neck tumors. Treatment could be applied as planned and no increased toxicity was found. Compared to other IMRT approaches for the head and neck region the used technique allows the treatment of the primary tumor and the lymph nodes level I-VI with only one intensity modulated treatment volume. The presented technique avoids to match conventional radiotherapy fields and INIRT fields, and therefore, reduce the risk of overdosage or underdosage at the matching line. Compared to conventional treatment techniques INIRT shows advantages in tumor dose and dose at the organs at risk. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12742271
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  • 28
    Keywords: CANCER ; Germany ; FOLLOW-UP ; LUNG-CANCER ; COHORT ; RISK ; MECHANISM ; mechanisms ; ASSOCIATION ; FREQUENCY ; ACID ; ACIDS ; WOMEN ; fatty acids ; FATTY-ACIDS ; DIETARY ; PREVALENCE ; OXIDATIVE STRESS ; ANTIOXIDANT ; European Prospective Investigation into Cancer and Nutrition ; nutrition ; QUESTIONNAIRE ; questionnaires ; SMOKERS ; antioxidants ; FOOD ; DIETARY-INTAKE ; WEST-GERMANY ; asthma ; antioxidants,diet,EPIC,fatty acids,hay fever ; ATOPY ; BETA-CAROTENE ; EAST-GERMANY ; EPIC-GERMANY ; FOOD FREQUENCY QUESTIONNAIRE ; FREQUENCY QUESTIONNAIRE ; NUTRIENTS ; VITAMIN-E
    Abstract: Background: The objective of the investigation was to explore in a prospective study the associations between dietary intake of fatty acids, antioxidants and hay fever manifestation in adulthood.Methods: Three hundred and thirty-four hay fever cases with adult onset of clinical symptoms from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort were identified during follow-up and matched with 1336 controls. Dietary intake data were obtained by means of validated food frequency questionnaires. The influence of dietary fatty acid and vitamin intake on hay fever risk was estimated by means of unconditional logistic regression.Results: High intake of oleic acid was positively associated with hay fever [odds ratio (OR): 2.86, 95% confidence intervals (95% CI): 1.22-6.70], whereas high intake of eicosapentaenoic acid was inversely related to hay fever (OR: 0.45, 95% CI: 0.22-0.93). Furthermore, high beta-carotene intake increased the risk of hay fever (OR: 1.69, 95% CI: 1.09-2.63) while increasing intake of vitamin E was a protective factor (OR: 0.38, 95% CI: 0.17-0.85). In grouped analyses, the effects of beta-carotene and vitamin E were mainly observed among women and ex-/current-smokers; in these subgroups, linoleic acid increased the risk of hay fever.Conclusions: In conclusion, the present results provide further evidence that dietary factors might affect the risk of clinical manifestation of hay fever. However, the effects in smokers and women may suggest different biological mechanisms for the investigated nutrients, which need further research
    Type of Publication: Journal article published
    PubMed ID: 14616103
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  • 29
    Keywords: CANCER ; GROWTH ; FOLLOW-UP ; RISK ; INDEX ; colon ; BREAST ; WOMEN ; OBESITY ; DATABASE ; COLON-CANCER ; GLUCOSE ; DEATH RATES ; INSULIN RESPONSES
    Abstract: Mounting evidence suggests that high circulating levels of insulin might be associated with increased colorectal cancer risk. The glycemic effects of diets high in refined starch may increase colorectal cancer risk by affecting insulin and/or insulin-like growth factor-I levels. We examined the association between dietary intake and colorectal cancer risk in a cohort of 49 124 women participating in a randomized, controlled trial of screening for breast cancer in Canada. Linkages to Canadian mortality and cancer databases yielded data on mortality and cancer incidence up to December 31, 2000. During an average 16.5 years of follow-up, we observed 616 incident cases of colorectal cancer (436 colon cancers, 180 rectal cancers). gate ratios for colorectal cancer for the highest versus the lowest quintile level were 1.05 (95% confidence interval [CI] = 0.73 to 1.53; P-trend = .94) for glycemic load, 1.01 (95% CI = 0.68 to 1.51; P-trend = .66) for total carbohydrates, and 1.03 (95% CI = 0.73 to 1.44; P-trend = .71) for total sugar. Our data do not support the hypothesis that diets high in glycemic load, carbohydrates, or sugar increase colorectal cancer risk
    Type of Publication: Journal article published
    PubMed ID: 12813175
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  • 30
    Keywords: CANCER ; MODEL ; FOLLOW-UP ; cohort studies ; MORTALITY ; RISK ; TUMORS ; tumour ; BREAST ; breast cancer ; BREAST-CANCER ; ovarian cancer ; OVARIAN-CANCER ; WOMEN ; smoking ; TOBACCO ; ALCOHOL ; HISTOLOGIC TYPE ; COFFEE ; menopause ; NORWEGIAN MEN ; ovarian neoplasms
    Abstract: Few cohort studies have examined the association between cigarette smoking and ovarian cancer risk, either overall, or by histological subtype. In relation to the latter, it has been suggested that mucinous ovarian tumours may be aetiologically unrelated to the other types of epithelial tumours and that their respective associations with cigarette smoking may differ. We examined the association between smoking and ovarian cancer risk using data from participants in a randomised controlled trial of screening for breast cancer involving 89,835 women aged 40-59 years at recruitment. Cox proportional hazards models were used to estimate rate ratios (RR) and 95% confidence intervals (CI). During an average of 16.5 years of follow-up, we observed 454 incident cases of ovarian cancer (184 serous, 67 endometrioid, 32 mucinous, 171 other or unknown). We found that women who had smoked for several decades had an approximately two-fold increased risk of epithelial ovarian cancer. Relative to never-smokers, women who had smoked for 40 years or more were at the highest risk (RR = 2.50, 95% CI = 1.37-4.56). The association with non-mucinous tumours was similar to that observed overall. For mucinous tumours, a two-fold increased risk was observed with smoking of shorter duration, although the number of mucinous turnours in our data-set was small. Long-term cigarette smoking may be associated with an increased risk of epithelial ovarian turnours. (C) 2003 Elsevier Science Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 12736118
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  • 31
    Keywords: tumor ; AGENTS ; INHIBITION ; DISEASE ; RISK ; PROTEIN ; PROTEINS ; DRUG ; MESSENGER-RNA EXPRESSION ; RISK-FACTORS ; mechanisms ; treatment ; antibodies ; risk factors ; NON-HODGKINS-LYMPHOMA ; 4 SUBSTRATE-ANALOGS ; A-CHAIN IMMUNOTOXIN ; antitumor agents ; CELLS IN-VITRO ; Chinese herbal medicines ; CYTOKINE-STIMULATING ACTIVITIES ; high molecular natural compounds ; LYCIUM-BARBARUM L ; MOUSE PERITONEAL- MACROPHAGES ; MULTIPLE PHARMACOLOGICAL PROPERTIES ; RIBOSOME-INACTIVATING PROTEIN
    Abstract: High molecular compound from Chinese herbal medicines, including ribosome-inactivating proteins and polysaccharides from both fungi and high plants have been tested for the treatment of malignant diseases. Polysaccharides possessing immunostimulating activities can be used as adjuvants in tumor treatment. The fungi containing such polysaccharides are usually edible mushrooms or tonics in Traditional Chinese Medicine. Parts from high plants such as Radix Astragali and Fructus Lycii containing polysaccharides are mainly used as tonic in Traditional Chinese Medicine. Ribosome-inactivating proteins are a group of proteins exerting cytotoxic activities via inhibition of protein synthesis. Some of the ribosome- inactivating proteins have been used as the cytotoxic part in conjugates with monoclonal antibodies as tumor-targeting drugs. The cytotoxic and antineoplastic mechanisms of the high molecular compounds are rather different from those of the low molecular compounds described in part I
    Type of Publication: Journal article published
    PubMed ID: 12677520
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  • 32
    Keywords: CANCER ; PROTECTION ; BLOOD ; carcinoma ; evaluation ; human ; ALGORITHM ; RISK ; GENE ; INFECTION ; CARCINOGENESIS ; ANTIGEN ; BINDING ; ASSOCIATION ; LESIONS ; WOMEN ; cervical cancer ; HPV ; HPV16 ; VACCINE ; HLA class I ; EPITOPES ; intraepithelial neoplasia ; cervical carcinoma ; HLA ; PERIPHERAL-BLOOD ; E6 prototype ; E6 variant
    Abstract: Persistent infection with human papillomavirus (HPV), particularly HPV16, represents the prime risk factor in cervical carcinogenesis. HPV variants (e.g., within the E6 gene) together with immunogenetic factors of the host may be responsible either for effective viral clearance, or alternatively, for viral persistence. Peripheral blood from 27 HPV16 positive Swedish women with cervical carcinoma, who had previously been tested for HPV16 E6 variants, was used for human leukocyte antigen (HLA) class 1 typing. Women with HLA- B*44, HLA-B*51, or HLA-B*57 who were infected with the HPV16 E6 variant L83V had an approximately four- to fivefold increased risk for cancer compared with controls (odds ratio [OR] = 3.5, 95 % CI = 1.1-11.1, OR = 4.2, 95% CI = 1.19-14.69, or OR = 4.67, 95176 CI = 1.2-18.6, respectively). Epitope predictive algorithm with SYFPEITHI revealed that the variant at amino acid 83 affects the binding affinity in association with HLA- B*44. Interestingly, the HLA-B*15 allele seems protective because it was absent in HPV16 positive cancer. It is concluded that specific HLA class I alleles, combined with certain HPV16 E6 variants, may be crucial for immune surveillance in cervical carcinogenesis. The evaluation of associations of HLA alleles with HPV variants may be helpful in defining prognostic markers and in designing vaccines capable of mediating immune protection against HPV infection
    Type of Publication: Journal article published
    PubMed ID: 12691704
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  • 33
    Keywords: CANCER ; EXPRESSION ; carcinoma ; CELL ; Germany ; LUNG ; COMMON ; lung cancer ; LUNG-CANCER ; EXPOSURE ; RISK ; GENE ; GENES ; HYBRIDIZATION ; DNA ; MECHANISM ; primary ; RISK-FACTORS ; mechanisms ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; NO ; AMPLIFICATION ; AGE ; DNA-REPAIR ; REPAIR ; CIGARETTE-SMOKING ; risk factors ; smoking ; PCR ; cancer risk ; DAMAGE ; RISK FACTOR ; REGION ; CARCINOGENS ; adenocarcinoma ; case-control studies ; squamous cell carcinoma ; INDIVIDUALS ; CANCER-RESEARCH ; SMOKERS ; NUCLEOTIDE EXCISION-REPAIR ; CELL CARCINOMA ; case control study ; case-control study ; REGRESSION ; OCCUPATIONAL-EXPOSURE ; CARCINOGEN ; HEAVY ; LUNG ADENOCARCINOMA ; PIGMENTOSUM GROUP-A
    Abstract: Polymorphisms of genes coding for DNA repair can affect lung cancer risk. A common single nucleotide (-4) G-to-A polymorphism was identified previously in the 5' untranslated region of the XPA gene. In a case-control study in European Caucasians, the influence of this polymorphism on primary lung cancer risk overall and according to histologic subtypes was investigated. Four hundred sixty-three lung cancer cases (including 204 adenocarcinoma and 212 squamous cell carcinoma) and 460 tumor-free hospital controls were investigated using PCR amplification and melting point analysis of sequence-specific hybridization probes. Odds ratios (OR) were calculated by multiple logistic regression analysis adjusting for age, gender, smoking habits, and occupational exposure and showed a slightly enhanced risk for all lung cancer cases as well as for squamous cell carcinoma and adenocarcinoma cases. Gene-environment interactions were analyzed with respect to smoking and occupational exposure. A nearly 3-fold increased risk for adenocarcinoma associated with the XPA AA genotype was observed for occupationally exposed individuals (OR, 2.95; 95% confidence interval, 1.42-6.14) and for heavy smokers (OR, 2.52; 95% confidence interval, 1.17-5.42). No genotype-dependent increase in OR was found for nonexposed individuals or those smoking 〈20 pack-years. The significant effect of the XPA polymorphism in heavy smokers and occupationally exposed individuals suggests an important gene-environment interaction for the XPA gene. The underlying mechanisms as to why AA homozygotes are predisposed to lung adenocarcinoma and which specific carcinogens are involved remains to be determined
    Type of Publication: Journal article published
    PubMed ID: 15598786
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    Keywords: CANCER ; EXPRESSION ; tumor ; COMMON ; RISK ; CDNA ; GENE ; HYBRIDIZATION ; microarray ; SAMPLE ; SAMPLES ; TUMORS ; DNA ; CELL-LINES ; chromosome ; ELEMENT ; STAGE ; PROGRESSION ; AMPLIFICATION ; chromosome 2 ; COPY NUMBER ; COPY-NUMBER ; PATTERNS ; microarrays ; SINGLE-COPY ; ELEMENTS ; NUMBER ; REQUIRES ; EFFICIENT ; REGION ; PHENOTYPE ; FREQUENT ; RECURRENT ; gene amplification ; IMBALANCES ; CDNA MICROARRAYS ; GENOMIC HYBRIDIZATION ; COPY NUMBER CHANGES ; MYCN ; CDNA MICROARRAY ; neuroblastoma ; N-MYC ; CHROMOSOMES ; AMPLIFICATIONS ; TUMORIGENESIS ; 17Q GAIN
    Abstract: Background: Recurrent non-random genomic alterations are the hallmarks of cancer and the characterization of these imbalances is critical to our understanding of tumorigenesis and cancer progression. Results: We performed array-comparative genomic hybridization (A-CGH) on cDNA microarrays containing 42,000 elements in neuroblastoma ( NB). We found that only two chromosomes (2p and 12q) had gene amplifications and all were in the MYCN amplified samples. There were 6 independent non-contiguous amplicons (10.4 - 69.4 Mb) on chromosome 2, and the largest contiguous region was 1.7 Mb bounded by NAG and an EST ( clone: 757451); the smallest region was 27 Kb including an EST ( clone: 241343), NCYM, and MYCN. Using a probabilistic approach to identify single copy number changes, we systemically investigated the genomic alterations occurring in Stage 1 and Stage 4 NBs with and without MYCN amplification ( stage 1-, 4-, and 4+). We have not found genomic alterations universally present in all (100%) three subgroups of NBs. However we identified both common and unique patterns of genomic imbalance in NB including gain of 7q32, 17q21, 17q23-24 and loss of 3p21 were common to all three categories. Finally we confirm that the most frequent specific changes in Stage 4+ tumors were the loss of 1p36 with gain of 2p24-25 and they had fewer genomic alterations compared to either stage 1 or 4-, indicating that for this subgroup of poor risk NB requires a smaller number of genomic changes are required to develop the malignant phenotype. Conclusions: cDNA A-CGH analysis is an efficient method for the detection and characterization of amplicons. Furthermore we were able to detect single copy number changes using our probabilistic approach and identified genomic alterations specific to stage and MYCN amplification
    Type of Publication: Journal article published
    PubMed ID: 15380028
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    Keywords: ENERGIES ; CANCER ; Germany ; human ; MODEL ; MODELS ; FOLLOW-UP ; COHORT ; EPIDEMIOLOGY ; RISK ; RISK-FACTORS ; ASSOCIATION ; BREAST ; breast cancer ; BREAST-CANCER ; TRIAL ; hormone ; HEALTH ; ENERGY ; AGE ; WOMEN ; HORMONE REPLACEMENT THERAPY ; OBESITY ; risk factors ; COUNTRIES ; cancer risk ; RISK FACTOR ; EPIC ; EPIC study ; European Prospective Investigation into Cancer and Nutrition ; nutrition ; POSTMENOPAUSAL WOMEN ; MASS INDEX ; PH ; WEIGHT ; body weight ; fat distribution ; HEIGHT ; ADIPOSITY ; breast neoplasm ; HORMONE-REPLACEMENT THERAPY ; METAANALYSIS
    Abstract: The evidence for anthropometric factors influencing breast cancer risk is accumulating, but uncertainties remain concerning the role of fat distribution and potential effect modifiers. We used data from 73,542 premenopausal and 103,344 postmenopausal women from 9 European countries, taking part in the EPIC study. RRs from Cox regression models were calculated, using measured height, weight, BMI and waist and hip circumferences; categorized by cohort wide quintiles; and expressed as continuous variables, adjusted for study center, age and other risk factors. During 4.7 years of follow-up, 1,879 incident invasive breast cancers were identified. In postmenopausal women, current HRT modified the body size-breast cancer association. Among nonusers, weight, BMI and hip circumference were positively associated with breast cancer risk (all P-trend less than or equal to 0.002); obese women (BMI 〉 30) had a 31% excess risk compared to women with BMI 〈 25. Among HRT users, body measures were inversely but nonsignificantly associated with breast cancer. Excess breast cancer risk with HRT was particularly evident among lean women. Pooled RRs per height increment of 5 cm were 1.05 (95% CI 1.00-1.16) in premenopausal and 1.10 (95% CI 1.05-1.16) in postmenopausal women. Among premenopausal women, hip circumference was the only other measure significantly related to breast cancer (P-trend = 0.03), after accounting for BMI. In postmenopausal women not taking exogenous hormones, general obesity is a significant predictor of breast cancer, while abdominal fat assessed as waist-hip ratio or waist circumference was not related to excess risk when adjusted for BMI. Among premenopausal women, weight and BMI showed nonsignificant inverse associations with breast cancer. (C) 2004 Wiley-Liss, Inc