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Timo Hakulinen

Publications and source records attributed to Timo Hakulinen.

At least 37 records · Page 2Linked to original sources
PubMed2004

High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study.

Androgens stimulate prostate cancer in vitro and in vivo. However, evidence from epidemiologic studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent. We investigated the association of serum levels of testosterone, the principal androgen in circulation, and sex hormone-binding globulin (SHBG) with risk in a case-control study nested in cohorts in Finland, Norway and Sweden of 708 men who were diagnosed with prostate cancer after blood collection and among 2,242 men who were not. In conditional logistic regression analyses, modest but significant decreases in risk were seen for increasing levels of total testosterone down to odds ratio for top vs. bottom quintile of 0.80 (95% CI = 0.59-1.06; p(trend) = 0.05); for SHBG, the corresponding odds ratio was 0.76 (95% CI = 0.57-1.01; p(trend) = 0.07). For free testosterone, calculated from total testosterone and SHBG, a bell-shaped risk pattern was seen with a decrease in odds ratio for top vs. bottom quintile of 0.82 (95% CI = 0.60-1.14; p(trend) = 0.44). No support was found for the hypothesis that high levels of circulating androgens within a physiologic range stimulate development and growth of prostate cancer.

Adult↗
PubMed2004

Regression models for relative survival.

Four approaches to estimating a regression model for relative survival using the method of maximum likelihood are described and compared. The underlying model is an additive hazards model where the total hazard is written as the sum of the known baseline hazard and the excess hazard associated with a diagnosis of cancer. The excess hazards are assumed to be constant within pre-specified bands of follow-up. The likelihood can be maximized directly or in the framework of generalized linear models. Minor differences exist due to, for example, the way the data are presented (individual, aggregated or grouped), and in some assumptions (e.g. distributional assumptions). The four approaches are applied to two real data sets and produce very similar estimates even when the assumption of proportional excess hazards is violated. The choice of approach to use in practice can, therefore, be guided by ease of use and availability of software. We recommend using a generalized linear model with a Poisson error structure based on collapsed data using exact survival times. The model can be estimated in any software package that estimates GLMs with user-defined link functions (including SAS, Stata, S-plus, and R) and utilizes the theory of generalized linear models for assessing goodness-of-fit and studying regression diagnostics.

Adolescent↗
PubMed2004

Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries.

Vitamin D inhibits the development and growth of prostate cancer cells. Epidemiologic results on serum vitamin D levels and prostate cancer risk have, however, been inconsistent. We conducted a longitudinal nested case-control study on Nordic men (Norway, Finland and Sweden) using serum banks of 200,000 samples. We studied serum 25(OH)-vitamin D levels of 622 prostate cancer cases and 1,451 matched controls and found that both low (</=19 nmol/l) and high (>/=80 nmol/l) 25(OH)-vitamin D serum concentrations are associated with higher prostate cancer risk. The normal average serum concentration of 25(OH)-vitamin D (40-60 nmol/l) comprises the lowest risk of prostate cancer. The U-shaped risk of prostate cancer might be due to similar 1,25-dihydroxyvitamin D(3) availability within the prostate: low vitamin D serum concentration apparently leads to a low tissue concentration and to weakened mitotic control of target cells, whereas a high vitamin D level might lead to vitamin D resistance through increased inactivation by enhanced expression of 24-hydroxylase. It is recommended that vitamin D deficiency be supplemented, but too high vitamin D serum level might also enhance cancer development.

Adult↗
PubMed2004

An alternative approach to age adjustment of cancer survival rates.

The measures of cancer prognosis most commonly reported by cancer registries are 5- or 10-year absolute or relative survival rates. Because cancer survival rates often vary by the age of cancer patients, and because the age structure of cancer patients often varies between populations, age adjustment is crucial for comparative analyses of cancer survival rates. However, traditional age adjustment often breaks down for long-term survival rates, particularly for sparse data, and it may provide inconsistent results for relative survival rates, even if age adjustment is made to the study population's own age distribution. In this manuscript, we propose an alternative approach to age adjustment of both absolute and relative survival rates to overcome both the practical and conceptual problems inherent in traditional age adjustment. We outline the computational realisation of this approach, and we give an empirical illustration of its application using data from the nationwide Finnish Cancer Registry.

Adolescent↗
PubMed2004

Blood biochemistry and the risk of cancer.

A longitudinal study based on a serum sample bank was carried out in Finland to find out the association between biochemical substances and the subsequent risk of cancer. The objective was to evaluate the consistency between means of individually estimated levels of these compounds and levels based on pooling. Levels of alpha-tocopherol, beta-carotene, retinol, retinol-binding protein, and ceruloplasmin were estimated by primary site and sex and partly by age and morphology. The concentrations in pooled samples were consistently lower than the averages of the individual samples. On the basis of individual samples, all the five biochemical compounds had a rather consistent protective effect on the risk of cancers at most primary sites. This protective effect disappeared in the pool analyses, and more than half of exposure contrasts showed an opposite sign. For ceruloplasmin, the effect of pooling was smaller but not negligible. The results of this study emphasize the demand to standardize the collecting, handling, and analysing of samples in serum banks. They are, furthermore, consistent with the hypothesis that pooling of biochemical samples affects the levels of the substances and may affect the conclusions of epidemiological studies on causes of diseases.

Biomarkers, Tumor↗
PubMed2004

Class I and II HLA genes are associated with susceptibility and age at onset in Finnish families with type 1 diabetes.

OBJECTIVES: We explored the properties of the long-term survivor model (LTS) in the genetic association studies and studied allelic and haplotypic associations between the age at onset and partially latent susceptibility of type 1 diabetes (T1DM) and Human Leucocyte Antigen (HLA) A, B and DR loci. METHODS: The authors applied the long-term survivor model (LTS) for sibships collected in a population-based registry during a calendar time period. The method uses sibs that could not become probands and includes the proband's age at onset during the recruitment period. Association between the candidate gene and the partially latent susceptibility is modeled with logistic regression and the age at onset with a two-parameter gamma distribution, where a scale parameter depends on the candidate genotypes. We also performed a simulation study of nuclear families to compare the power of the likelihood ratio tests of the genetic association based on the LTS model with those obtained using family-based association method (FBAT) and bias of the case-pseudo control design. In addition, we analysed allele and haplotype associations between HLA A, B and DR loci (IDDM1) with T1DM, using population-based ascertainment of 705 sibships with complete HLA information. RESULTS: A simulation study showed that the estimates of the genetic association using an ascertainment-corrected LTS model are virtually unbiased and that the relative risk estimates obtained from case-pseudo control design (TDT) are negatively biased. In the analysis of the Finnish T1DM families we found that only B62 (p < 0.05) is positively significantly associated with susceptibility after adjusting for the haplotype effects. Five alleles were significantly associated with age at onset (B8 and DR3, p < 0.01; A2, B60 and DR6, p < 0.05). No significant three-locus haplotype associations with the susceptibility were found, but A3B18DR4 (p < 0.001) haplotype was associated with older age at onset than average. CONCLUSIONS: Estimates of genetic relative risk obtained from the case-pseudo control design are negatively biased and the prospective LTS model is an appropriate choice, when there are non-susceptible subjects in the population with variable age at onset. Based on the analysis of T1DM, we conclude that there are gene(s) in the HLA region that are associated with susceptibility and/or age at onset of T1DM, and this should be taken into account in future studies.

Age Factors↗
PubMed2004

Testicular cancer incidence in eight northern European countries: secular and recent trends.

OBJECTIVE: Striking geographic variation and marked increasing secular trends characterize the incidence of testicular cancer. However, it is not known whether these patterns have attenuated in recent years and whether they are similar for seminomas and nonseminomas, the two main histologic groups of testicular cancer. METHOD: Cancer registry data, including 27,030 testicular cancer cases, were obtained from Denmark, Estonia, Finland, Latvia, Lithuania, Norway, Poland, and Sweden. Between 57 (Denmark) and 9 (Poland) years of registration were covered. Country-specific temporal trends were estimated, with focus on the last decade and seminomas and nonseminomas. Data from the Nordic countries were further analyzed using an age-period-cohort approach. RESULTS: Age-standardized incidence rates increased annually by 2.6% to 4.9% during the study period, with marginal differences between seminomas and nonseminomas. In the last decade, the increasing trend attenuated only in Denmark (annual change, -0.3%; 95% confidence interval, -1.5 to 0.9). In 1995, the highest and the lowest age-standardized incidence rates (per 10(5)) were 15.2 in Denmark and 2.1 in Lithuania. Incidence rates (i.e., for all cancers and for seminomas and nonseminomas, separately) depended chiefly on birth cohort rather than on calendar period of diagnosis (although both birth cohort and period determined the Danish incidence rates). CONCLUSIONS: Testicular cancer incidence is still increasing, with the exception of Denmark, and a large geographic difference exists. The increasing trend is mainly a birth cohort phenomenon also in recent cohorts. Temporal trends for seminomas and nonseminomas are similar, which suggests that they share important causal factors.

Adolescent↗
PubMed2003

Are patients diagnosed with breast cancer before age 50 years ever cured?

PURPOSE: Breast cancer diagnosed before the age of 50 years has become a common disease in many developed countries. Although average remaining life expectancy in the affected age groups is usually several decades, data regarding survival perspectives beyond 10 to 20 years after diagnosis are sparse. The aim of this study was to assess long-term survival in a large population-based sample of patients diagnosed with breast cancer before age 50 years. PATIENTS AND METHODS: Relative survival within up to 40 years after diagnosis was assessed for cohorts of women diagnosed with breast cancer before age 50 years and notified to the nationwide Finnish Cancer Registry within various time intervals since 1953. In addition, up-to-date estimates of 40-year relative survival were obtained by exclusively looking at the survival experience of breast cancer patients in recent years (1993 to 1999) using period analysis, a new method of survival analysis. RESULTS: Prognosis of patients diagnosed with breast cancer before age 50 years has considerably improved during the past decades. According to the latest estimates from period analysis, cumulative 40-year relative survival is now approximately 43% for all cancers combined, 57% for localized cancers, and 24% for cancers with regional tumor spread. Nevertheless, patients diagnosed with breast cancer before age 50 years continue to have increased mortality throughout at least four decades after diagnosis. This applies even if breast cancer is diagnosed in a localized stage and in the absence of a second primary breast cancer. CONCLUSION: Despite major improvement in prognosis over time, breast cancer occurring among patients who are younger than 50 years remains a chronic disease that affects prognosis for decades.

Adult↗
PubMed2003

Prediction of cancer incidence in the Nordic countries: empirical comparison of different approaches.

Prediction of the future number of cancer cases is of great interest to society. The classical approach is to use the age-period-cohort model for making cancer incidence predictions. We made an empirical comparison of different versions of this model, using data from cancer registries in the Nordic countries for the period 1958-1997. We have applied 15 different methods to 20 sites for each sex in Denmark, Finland, Norway and Sweden. Median absolute value of the relative difference between observed and predicted numbers of cases for these 160 combinations of site, sex and country was calculated. The medians varied between 10.4 per cent and 15.3 per cent in predictions 10 years ahead, and between 15.1 per cent and 32.0 per cent for 20 year predictions. We have four main conclusions: (i) projecting current trends worked better than assuming that future rates are equal to present rates; (ii) the method based on the multiplicative APC model often overestimated the number of cancer cases due to its exponential growth over time, but using a power function to level off this growth improved the predictions; (iii) projecting only half of the trend after the first 10 years also gave better long-term predictions; (iv) methods that emphasize trends in the last decade seem to perform better than those that include earlier time trends.

Cohort Studies↗
PubMed2003

Stage at diagnosis is a key explanation of differences in breast cancer survival across Europe.

We used multiple regression models to assess the influence of disease stage at diagnosis on the 5-year relative survival of 4,478 patients diagnosed with breast cancer in 1990-1992. The cases were representative samples from 17 population-based cancer registries in 6 European countries (Estonia, France, Italy, Netherlands, Spain and UK) that were combined into 9 regional groups based on similar survival. Five-year relative survival was 79% overall, varying from 98% for early, node-negative (T1N0M0) tumours; 87% for large, node-negative (T2-3N0M0) tumours; 76% for node-positive (T1-3N+M0) tumours and 55% for locally advanced (T4NxM0) tumours to 18% for metastatic (M1) tumours and 69% for tumours of unspecified stage. There was considerable variation across Europe in relative survival within each disease stage, but this was least marked for early node-negative tumours. Overall 5-year relative survival was highest in the French group of Bas-Rhin, Côte d'Or, Hérault and Isère (86%), and lowest in Estonia (66%). These geographic groups were characterised by the highest and lowest percentages of women with early stage disease (T1N0M0: 39% and 9%, respectively). The French, Dutch and Italian groups had the highest percentage of operated cases. The number of axillary nodes examined, a factor influencing nodal status, was highest in Italy and Spain. After adjusting for TNM stage and the number of nodes examined, survival differences were greatly reduced, indicating that for these women, diagnosed with breast cancer in Europe during 1990-1992, the survival differences were mainly due to differences in stage at diagnosis. However, in 3 regional groups, the relative risks of death remained high even after these adjustments, suggesting less than optimal treatment. Screening for breast cancer did not seem to affect the survival patterns once stage had been taken into account.

Adenocarcinoma↗
PubMed2003

Maternal herpesvirus infections and risk of acute lymphoblastic leukemia in the offspring.

A critical role for infection in the etiology of childhood leukemia has repeatedly been suggested. The authors undertook a case-control study nested within national maternity cohorts with altogether 7 million years of follow-up to assess the relative role of three maternal herpesvirus infections in childhood acute lymphoblastic leukemia (ALL). Offspring of 550,000 mothers in Finland and Iceland formed the joint study cohort that was followed up for cancer in the offspring before age 15 years during 1975-1997 through national cancer registries. For each index mother-case pair, three or four matched control mother-control pairs were identified from national population registers. First-trimester sera were retrieved from mothers of 342 ALL and 61 other leukemia cases and from 1,216 control mothers and were tested for antibodies to cytomegalovirus, Epstein-Barr virus (EBV), and human herpesvirus 6. Serum EBV DNA was also analyzed. Conditional logistic regression-based estimates of relative risk (odds ratio) adjusted for birth order and sibship size, and population attributable fractions, were calculated. Only EBV immunoglobulin M positivity in EBV-immunoglobulin-G-positive mothers was associated with a highly significant increased risk of ALL in the offspring (adjusted odds ratio = 2.9, 95% confidence interval: 1.5, 5.8). Results indicate that reactivation of maternal EBV infection is probably associated with childhood ALL.

Adult↗
PubMed2003

On crude and age-adjusted relative survival rates.

Relative survival rates, such as 5- or 10-year relative survival rates, which quantify "net survival" of cancer patients, are the most commonly reported measures of cancer outcome by cancer registries. Because relative survival rates vary with age for many forms of cancer, and because the age distribution of cancer patients varies between different populations or within one population over time, age adjustment of relative survival rates is often employed in international comparisons or in time series analyses of cancer patient survival. In this article, we show that derivation of crude and of age-adjusted relative survival rates in the traditional way is conceptually inconsistent, and that this inconsistency has important practical implications. We show ways to overcome this inconsistency in the derivation and interpretation of crude and age-adjusted relative survival rates.

Adolescent↗
PubMed2003

Pleural mesothelioma incidence in Europe: evidence of some deceleration in the increasing trends.

OBJECTIVE: To summarize the geographical and temporal variations in incidence of pleural mesothelioma in Europe, using the extensive data available from European general cancer registries, and consider these in light of recent trends in asbestos extraction, use and import in European countries. MATERIAL AND METHODS: The data were extracted from the European Cancer Incidence and Mortality database (EUROCIM). The inclusion criteria was acceptance in Volume VII of Cancer Incidence in Five Continents. Truncated age-standardized rates per 100,000 for the ages 40-74 were used to summarise recent geographical variations. Standardized rate ratios and 95% confidence intervals for the periods 1986-1990 and 1991-1995 were compared to assess geographical variations in risk. To investigate changes in the magnitude of most recent trends, regression models fitted to the latest available 10-year period (1988-1997) were compared with trends in the previous decade. Fitted rates in younger (40-64) and older adults (65-74) in the most recent period were also compared. RESULTS: There was a great deal of geographical variation in the risk of mesothelioma, annual rates ranging from around 8 per 100,000 in Scotland, England and The Netherlands, to lower than 1 per 100,000 in Spain (0.96), Estonia (0.85), Poland (0.85) and Yugoslavia, Vojvodina (0.56) among men. The rank of the rates for women was similar to that observed for men, although rates were considerably lower. Between 1978 and 1987, rates in men significantly increased in all countries (excepting Denmark). In the following 10 years, there was a deceleration in trend, and a significant increase was detectable only in England and France. In addition, the magnitude of recent trends in younger men was generally lower than those estimated for older men, in both national and regional cancer registry settings. CONCLUSIONS: While mesothelioma incidence rates are still rising in Europe, a deceleration has started in some countries. A decrease may begin in the next few years in certain European populations considering the deceleration of observed trends in mesothelioma and asbestos exposure, as well as the recent ban on its use.

Asbestos↗
PubMed2003

Serum antibody response to the heat shock protein 60 of Chlamydia trachomatis in women with developing cervical cancer.

OBJECTIVE: The purpose of this study was to determine whether serum antibody response to the three versions of chlamydial heat shock protein 60 is associated with an increased risk for cervical cancer. STUDY DESIGN: Women with cervical carcinoma were identified by linking the data files of three Nordic serum banks with cancer registries. Overall, 178 women with invasive cervical carcinoma were identified. For each case, the earliest prediagnostic serum sample was chosen, and three matched control subjects who were free of cancer at the time of the case diagnosis were selected randomly. Serum antibodies to the chlamydial heat shock protein 60 were measured by enzyme-linked immunosorbent assay and correlated with the risk of the subsequent development of cervical cancer. RESULTS: Antibodies to chlamydial heat shock protein 60-1 were associated with cervical squamous cell carcinoma among cases with long lag time (>3.5 years; odds ratio, 2.4; 95% CI, 1.1-5.1). Antibodies to chlamydial heat shock protein 60-2 or chlamydial heat shock protein 60-3 were not associated with cervical cancer risk. CONCLUSIONS: The finding that chlamydial heat shock protein 60-1 antibodies are associated with an increased cervical cancer risk suggests that persistent Chlamydia trachomatis infection may contribute to cervical neoplasia.

Antibodies↗
PubMed2003

Serum fatty acids and breast cancer incidence.

Fatty acid composition of the diet may be essential to the development of breast cancer. We studied the ability of several fatty acids of serum total lipids to predict breast cancer incidence in a case-control study nested within a longitudinal population study. The proportions of fatty acids in serum total lipids were determined from stored serum samples collected at baseline for 127 incident breast cancer cases and 242 matched controls. Women with a higher proportion of total polyunsaturated fatty acids (PUFAs) in serum had a reduced risk of breast cancer. The odds ratio (OR) between the highest and lowest tertiles of serum PUFA was 0.31 (95% confidence interval, CI = 0.12-0.77). This association was mainly due to n-6 PUFAs and especially to linoleic acid. The ORs were 0.35 (CI = 0.14-0.84) and 0.29 (CI = 0.12-0.73), respectively. Of the monounsaturated fatty acids (MUFAs), higher trans-11-18:1 levels were related to an increased breast cancer risk (OR = 3.69, CI = 1.35-10.06). The association was stronger in postmenopausal than in premenopausal women. The present study suggests that higher serum proportions of the n-6 PUFA linoleic acid and lower proportions of the MUFA trans-11-18:1 fatty acid predict a reduced incidence of breast cancer.

Adult↗
PubMed2003

Hereditary minisatellite mutations among the offspring of Estonian Chernobyl cleanup workers.

A single accidental event such as the fallout released from the Chernobyl reactor in 1986 can expose millions of people to non-natural environmental radiation. Ionizing radiation increases the frequency of germline mutations in experimental studies, but the genetic effects of radiation in humans remain largely undefined. To evaluate the hereditary effects of low radiation doses, we compared the minisatellite mutation rates of 155 children born to Estonian Chernobyl cleanup workers after the accident with those of their siblings born prior to it. All together, 94 de novo paternal minisatellite mutations were found at eight tested loci (52 and 42 mutants among children born after and before the accident, respectively). The minisatellite mutation rate was nonsignificantly increased among children born after the accident (0.042 compared to 0.036, OR 1.33, 95% CI 0.80-2.20). Furthermore, there was some indication of an increased mutation rate among offspring born after the accident to workers who had received doses of 20 cSv or above compared with their siblings born before the accident (OR 3.0, 95% CI 0.97-9.30). The mutation rate was not associated with the father's age (OR 1.04, 95% CI 0.94-1.15) or the sex of the child (OR 0.95, 95% CI 0.50-1.79). Our results are consistent with both no effect of radiation on minisatellite mutations and a slight increase at dose levels exceeding 20 cSv.

Adult↗