Publications by authors named "Timo Hakulinen"

118 Publications

Estimating multilevel regional variation in excess mortality of cancer patients using integrated nested Laplace approximation.

Stat Med 2019 02 17;38(5):778-791. Epub 2018 Oct 17.

Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.

Models of excess mortality with random effects were used to estimate regional variation in relative or net survival of cancer patients. Statistical inference for these models based on the Markov chain Monte Carlo (MCMC) methods is computationally intensive and, therefore, not feasible for routine analyses of cancer register data. This study assessed the performance of the integrated nested Laplace approximation (INLA) in monitoring regional variation in cancer survival. Poisson regression model of excess mortality including both spatially correlated and unstructured random effects was fitted to the data of patients diagnosed with ovarian and breast cancer in Finland during 1955-2014 with follow up from 1960 through 2014 by using the period approach with five-year calendar time windows. We estimated standard deviations associated with variation (i) between hospital districts and (ii) between municipalities within hospital districts. Posterior estimates based on the INLA approach were compared to those based on the MCMC simulation. The estimates of the variation parameters were similar between the two approaches. Variation within hospital districts dominated in the total variation between municipalities. In 2000-2014, the proportion of the average variation within hospital districts was 68% (95% posterior interval: 35%-93%) and 82% (60%-98%) out of the total variation in ovarian and breast cancer, respectively. In the estimation of regional variation, the INLA approach was accurate, fast, and easy to implement by using the R-INLA package.
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http://dx.doi.org/10.1002/sim.8010DOI Listing
February 2019

Comparing net survival estimators of cancer patients.

Stat Med 2016 May 28;35(11):1866-79. Epub 2015 Dec 28.

Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Unioninkatu 22, Helsinki, 00130, Finland.

The net survival of a patient diagnosed with a given disease is a quantity often interpreted as the hypothetical survival probability in the absence of causes of death other than the disease. In a relative survival framework, net survival summarises the excess mortality that patients experience compared with their relevant reference population. Based on follow-up data from the Finnish Cancer Registry, we derived simulation scenarios that describe survival of patients in eight cancer sites reflecting different excess mortality patterns in order to compare the performance of the classical Ederer II estimator and the new estimator proposed by Pohar Perme et al. At 5 years, the age-standardised Ederer II estimator performed equally well as the Pohar Perme estimator with the exception of melanoma in which the Pohar Perme estimator had a smaller mean squared error (MSE). At 10 and 15 years, the age-standardised Ederer II performed most often better than the Pohar Perme estimator. The unstandardised Ederer II estimator had the largest MSE at 5 years. However, its MSE was often superior to those of the other estimators at 10 and 15 years, especially in sparse data. Both the Pohar Perme and the age-standardised Ederer II estimator are valid for 5-year net survival of cancer patients. For longer-term net survival, our simulation results support the use of the age-standardised Ederer II estimator.
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http://dx.doi.org/10.1002/sim.6833DOI Listing
May 2016

Chernobyl cleanup workers from Estonia: cohort description and related epidemiological research.

J Radiol Prot 2015 Dec 29;35(4):R35-45. Epub 2015 Oct 29.

Department of Epidemiology and Biostatistics, National Institute for Health Development, Tallinn, Estonia.

The Estonian study of Chernobyl cleanup workers was one of the first investigations to evaluate the possible health consequences of working in the Chernobyl area (the 30 km exclusion zone and/or adjacent territories) after the 1986 reactor accident. The cohort consists of 4831 men who were dispatched in 1986-1991 for tasks involving decontamination, construction of buildings, transport, radiation measurement, guard duty or other activities. By 31 December 2012, the follow-up of the cohort yielded 102 158 person-years of observation. Exposure and health data were collected by postal questionnaires, biodosimetry evaluations, thyroid screenings, and record-linkages with cancer, causes of death and health insurance reimbursement registers and databases. These data cover socio-demographic factors, employment history, aspects of health behaviour, medical history, work and living conditions in the Chernobyl area, biomarkers of exposure, cancer and non-cancer disease occurrence and causes of death. Cancer incidence data were obtained for 1986-2008, mortality data for 1986-2011 and non-cancer morbidity data for 2004-2012. Although the cohort is relatively small, it has been extensively examined and benefited from comprehensive nationwide population and health registers. The major finding was an increased risk of suicide. Thyroid examinations did not reveal an association with thyroid nodular disease and radiation dose, but did indicate the importance of accounting for screening when making comparisons with unscreened populations. No risk of leukaemia was observed and risks higher than 2.5-fold could be excluded with 95% confidence. Biodosimetry included GPA analyses and chromosomal translocation analyses and indicated that the Estonian cleanup workers experienced a relatively low mean exposure of the order of 0.1 Gy. One value of the Estonian study is in the methodologic processes brought to bear in addressing possible health effects from the Chernobyl accident. Twenty-five years of research are summarised and opportunities for the future listed.
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http://dx.doi.org/10.1088/0952-4746/35/4/R35DOI Listing
December 2015

Sensitivity, effect and overdiagnosis in screening for cancers with detectable pre-invasive phase.

Int J Cancer 2015 Feb 7;136(4):928-35. Epub 2014 Jul 7.

Finnish Cancer Registry, Helsinki, Finland; School of Health Sciences, University of Tampere, Tampere, Finland.

Studies on cancer screening often evaluate the performance by indirect indicators. In case the screening detects pre-invasive lesions, they may be a mixture of benefit of sensitivity and effect as well as of harm of overdiagnosis. Here, we develop the formulae for the sensitivity, the effect and overdiagnosis in screening for pre-invasive lesions of cancer. Sensitivity is the ability of screening to identify a progressive lesion at the level of test (relevant for the laboratory), episode (relevant in the clinic) and programme (relevant at the population level). Effect is reduction of cancer incidence in those screened (efficacy) and in the target population (effectiveness). The sensitivity is estimated by interval cancers between two consecutive screens (incidence method) and the effect by interval cancers and cancers detected at the subsequent screen. Overdiagnosis is estimated as the detection rate of pre-invasive lesions minus the rate of invasive cancer prevented by screening in one screening round. All the indicators are corrected for nonattendance and selective attendance by disease risk. The population to be followed and the period of follow-up are defined for each indicator separately. Data on cervix cancer screening with Papnet® automation device are given as an example. Estimation of sensitivity and effect are consistent with the purpose of the screening to prevent invasive disease. We further define the purpose at the level of laboratory, clinical medicine and public health and derive six estimators corresponding to the specific purposes considered in our article.
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http://dx.doi.org/10.1002/ijc.29053DOI Listing
February 2015

Non-cancer morbidity among Estonian Chernobyl cleanup workers: a register-based cohort study.

BMJ Open 2014 May 14;4(5):e004516. Epub 2014 May 14.

Department of Epidemiology and Biostatistics, National Institute for Health Development, Tallinn, Estonia.

Objective: To examine non-cancer morbidity in the Estonian Chernobyl cleanup workers cohort compared with the population sample with special attention to radiation-related diseases and mental health disorders.

Design: Register-based cohort study.

Setting: Estonia.

Participants: An exposed cohort of 3680 men (cleanup workers) and an unexposed cohort of 7631 men (population sample) were followed from 2004 to 2012 through the Population Registry and Health Insurance Fund database.

Methods: Morbidity in the exposed cohort compared with the unexposed controls was estimated in terms of rate ratio (RR) with 95% CIs using Poisson regression models.

Results: Elevated morbidity in the exposed cohort was found for diseases of the nervous system, digestive system, musculoskeletal system, ischaemic heart disease and for external causes. The most salient excess risk was observed for thyroid diseases (RR=1.69; 95% CI 1.38 to 2.07), intentional self-harm (RR=1.47; 95% CI 1.04 to 2.09) and selected alcohol-related diagnoses (RR=1.25; 95% CI 1.12 to 1.39). No increase in morbidity for stress reactions, depression, headaches or sleep disorders was detected.

Conclusions: No obvious excess morbidity consistent with biological effects of radiation was seen in the exposed cohort, with the possible exception of benign thyroid diseases. Increased alcohol-induced morbidity may reflect alcohol abuse, and could underlie some of the higher morbidity rates. Mental disorders in the exposed cohort were probably under-reported. The future challenge will be to study mental and physical comorbidities in the Chernobyl cleanup workers cohort.
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http://dx.doi.org/10.1136/bmjopen-2013-004516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024594PMC
May 2014

Choosing the net survival method for cancer survival estimation.

Eur J Cancer 2015 Jun 29;51(9):1123-9. Epub 2013 Oct 29.

Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Pieni Roobertinkatu 9, FI-00130 Helsinki, Finland. Electronic address:

Background: A new net survival method has been introduced by Pohar Perme et al. (2012 [4]) and recommended to substitute the relative survival methods in current use for evaluating population-based cancer survival.

Methods: The new method is based on the use of continuous follow-up time, and is unbiased only under non-informative censoring of the observed survival. However, the population-based cancer survival is often evaluated based on annually or monthly tabulated follow-up intervals. An empirical investigation based on data from the Finnish Cancer Registry was made into the practical importance of the censoring and the level of data tabulation. A systematic comparison was made against the earlier recommended Ederer II method of relative survival using the two currently available computer programs (Pohar Perme (2013) [10] and Dickman et al. (2013) [11]).

Results: With exact or monthly tabulated data, the Pohar-Perme and the Ederer II methods give, on average, results that are at five years of follow-up less than 0.5% units and at 10 and 14 years 1-2% units apart from each other. The Pohar-Perme net survival estimator is prone to random variation and may result in biased estimates when exact follow-up times are not available or follow-up is incomplete. With annually tabulated follow-up times, estimates can deviate substantially from those based on more accurate observations, if the actuarial approach is not used.

Conclusion: At 5 years, both the methods perform well. In longer follow-up, the Pohar-Perme estimates should be interpreted with caution using error margins. The actuarial approach should be preferred, if data are annually tabulated.
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http://dx.doi.org/10.1016/j.ejca.2013.09.019DOI Listing
June 2015

Chernobyl fallout and cancer incidence in Finland.

Int J Cancer 2014 May;134(9):2253-63

Twenty-five years have passed since the Chernobyl accident, but its health consequences remain to be well established. Finland was one of the most heavily affected countries by the radioactive fallout outside the former Soviet Union. We analyzed the relation of the estimated external radiation exposure from the fallout to cancer incidence in Finland in 1988-2007. The study cohort comprised all ∼ 3.8 million Finns who had lived in the same dwelling for 12 months following the accident (May 1986-April 1987). Radiation exposure was estimated using data from an extensive mobile dose rate survey. Cancer incidence data were obtained for the cohort divided into four exposure categories (the lowest with the first-year committed dose <0.1 mSv and the highest ≥ 0.5 mSv) allowing for a latency of 5 years for leukemia and thyroid cancer, and 10 years for other cancers. Of the eight predefined cancer sites regarded as radiation-related from earlier studies, only colon cancer among women showed an association with exposure from fallout [excess rate ratio per increment in exposure category 0.06, 95% confidence interval (CI) 0.02-0.11]. No such effect was observed for men, or other cancer sites. Our analysis of a large cohort over two decades did not reveal an increase in cancer incidence following the Chernobyl accident, with the possible exception of colon cancer among women. The largely null findings are consistent with extrapolation from previous studies suggesting that the effect is likely to remain too small to be empirically detectable and of little public health impact.
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http://dx.doi.org/10.1002/ijc.28554DOI Listing
May 2014

Colorectal cancer survival in the USA and Europe: a CONCORD high-resolution study.

BMJ Open 2013 09 10;3(9):e003055. Epub 2013 Sep 10.

Cancer Research UK Cancer Survival Group, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

Objectives: To assess the extent to which stage at diagnosis and adherence to treatment guidelines may explain the persistent differences in colorectal cancer survival between the USA and Europe.

Design: A high-resolution study using detailed clinical data on Dukes' stage, diagnostic procedures, treatment and follow-up, collected directly from medical records by trained abstractors under a single protocol, with standardised quality control and central statistical analysis.

Setting And Participants: 21 population-based registries in seven US states and nine European countries provided data for random samples comprising 12 523 adults (15-99 years) diagnosed with colorectal cancer during 1996-1998.

Outcome Measures: Logistic regression models were used to compare adherence to 'standard care' in the USA and Europe. Net survival and excess risk of death were estimated with flexible parametric models.

Results: The proportion of Dukes' A and B tumours was similar in the USA and Europe, while that of Dukes' C was more frequent in the USA (38% vs 21%) and of Dukes' D more frequent in Europe (22% vs 10%). Resection with curative intent was more frequent in the USA (85% vs 75%). Elderly patients (75-99 years) were 70-90% less likely to receive radiotherapy and chemotherapy. Age-standardised 5-year net survival was similar in the USA (58%) and Northern and Western Europe (54-56%) and lowest in Eastern Europe (42%). The mean excess hazard up to 5 years after diagnosis was highest in Eastern Europe, especially among elderly patients and those with Dukes' D tumours.

Conclusions: The wide differences in colorectal cancer survival between Europe and the USA in the late 1990s are probably attributable to earlier stage and more extensive use of surgery and adjuvant treatment in the USA. Elderly patients with colorectal cancer received surgery, chemotherapy or radiotherapy less often than younger patients, despite evidence that they could also have benefited.
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http://dx.doi.org/10.1136/bmjopen-2013-003055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773629PMC
September 2013

Fallout from the Chernobyl accident and overall cancer incidence in Finland.

Cancer Epidemiol 2013 Oct 22;37(5):585-92. Epub 2013 Jun 22.

Environmental Radiation Surveillance, Radiation and Nuclear Safety Authority, Laippatie 4, FI-00881 Helsinki, Finland.

Aim: We studied whether incidence of all cancer sites combined was associated with the radiation exposure due to fallout from the Chernobyl accident in Finland. An emphasis was on the first decade after the accident to assess the suggested "promotion effect".

Methods: The segment of Finnish population with a stable residence in the first post-Chernobyl year (2 million people) was studied. The analyses were based on a 250m × 250m grid squares covering all of Finland and all cancer cases except cancers of the breast, prostate and lung. Cancer incidence in four exposure areas (based on first-year dose due to external exposure <0.1 mSv, 0.1-1.3, 0.3-0.5, or ≥ 0.5 mSv) was compared before the Chernobyl accident (1981-1985) and after it (1988-2007) taking into account cancer incidence trends for a longer period prior to the accident (since 1966).

Results: There were no systematic differences in the cancer incidence in relation to radiation exposure in any calendar period, or any subgroup by sex or age at accident.

Conclusion: The current large and comprehensive cohort analysis of the relatively low levels of the Chernobyl fallout in Finland did not observe a cancer promotion effect.
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http://dx.doi.org/10.1016/j.canep.2013.05.006DOI Listing
October 2013

Site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers, 1986-2007.

Eur J Cancer 2013 Sep 15;49(13):2926-33. Epub 2013 May 15.

Department of Epidemiology and Biostatistics, National Institute for Health Development, Tallinn, Estonia.

Objective: To assess site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers, 1986-2007.

Methods: The Baltic cohort includes 17,040 men from Estonia, Latvia and Lithuania who participated in the environmental cleanup after the accident at the Chernobyl Nuclear Power Station in 1986-1991 and who were followed up for cancer incidence until the end of 2007. Cancer cases diagnosed in the cohort and in the male population of each country were identified from the respective national cancer registers. The proportional incidence ratio (PIR) with 95% confidence interval (CI) was used to estimate the site-specific cancer risk in the cohort. For comparison and as it was possible, the site-specific standardised incidence ratio (SIR) was calculated for the Estonian sub-cohort, which was not feasible for the other countries.

Results: Overall, 756 cancer cases were reported during 1986-2007. A higher proportion of thyroid cancers in relation to the male population was found (PIR=2.76; 95%CI 1.63-4.36), especially among those who started their mission shortly after the accident, in April-May 1986 (PIR=6.38; 95%CI 2.34-13.89). Also, an excess of oesophageal cancers was noted (PIR=1.52; 95% CI 1.06-2.11). No increased PIRs for leukaemia or radiation-related cancer sites combined were observed. PIRs and SIRs for the Estonian sub-cohort demonstrated the same site-specific cancer risk pattern.

Conclusion: Consistent evidence of an increase in radiation-related cancers in the Baltic cohort was not observed with the possible exception of thyroid cancer, where conclusions are hampered by known medical examination including thyroid screening among cleanup workers.
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http://dx.doi.org/10.1016/j.ejca.2013.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739289PMC
September 2013

Chernobyl cleanup workers from Estonia: follow-up for cancer incidence and mortality.

J Radiol Prot 2013 Jun 27;33(2):395-411. Epub 2013 Mar 27.

Department of Epidemiology and Biostatistics, National Institute for Health Development, Tallinn, Estonia.

This study examined cancer incidence (1986-2008) and mortality (1986-2011) among the Estonian Chernobyl cleanup workers in comparison with the Estonian male population. The cohort of 4810 men was followed through nationwide population, mortality and cancer registries. Cancer and death risks were measured by standardised incidence ratio (SIR) and standardised mortality ratio (SMR), respectively. Poisson regression was used to analyse the effects of year of arrival, duration of stay and time since return on cancer and death risks. The SIR for all cancers was 1.06 with 95% confidence interval 0.93-1.20 (232 cases). Elevated risks were found for cancers of the pharynx, the oesophagus and the joint category of alcohol-related sites. No clear evidence of an increased risk of thyroid cancer, leukaemia or radiation-related cancer sites combined was apparent. The SMR for all causes of death was 1.02 with 95% confidence interval 0.96-1.08 (1018 deaths). Excess mortality was observed for mouth and pharynx cancer, alcohol-related cancer sites together and suicide. Duration of stay rather than year of arrival was associated with increased mortality. Twenty-six years of follow-up of this cohort indicates no definite health effects attributable to radiation, but the elevated suicide risk has persisted.
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http://dx.doi.org/10.1088/0952-4746/33/2/395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720997PMC
June 2013

Order of HPV/Chlamydia infections and cervical high-grade precancer risk: a case-cohort study.

Int J Cancer 2013 Oct 17;133(7):1756-9. Epub 2013 Apr 17.

Institute for Statistical and Epidemiological Cancer Research, Finnish Cancer Registry, Helsinki, Finland.

Interactions of carcinogenic human papillomaviruses (most notably HPV types 16/18/31/33/45), and HPV6 or Chlamydia trachomatis are not well understood. We have used seroconversions to study effects the order of these infections has on the risk of high-grade cervical precancer. In a cohort of 94,349 Finnish women with paired sera from consecutive pregnancies within an average of 2.4 years, 490 were diagnosed with cervical CIN3/AIS. Serum antibodies to HPV6/16/18/31/33/45 and C. trachomatis were measured in paired sera of the cases and a subcohort of 2,796 women with a minimum of two pregnancies. HPV16-adjusted rate ratios (RR) and confidence intervals were estimated by stratified Cox model. Compared to dual seropositivity already at the first serum sampling, RRs related to HPV6 seropositivity before and after HPV31 seroconversion were 0.4 (95% CI 0.0, 4.4) and 10 (95% CI 1.8, 57). Furthermore, RR related to seroconversions of both HPV18/45 and C.trachomatis between the consecutive pregnancies was 28 (95% CI 4.3, 190). Virtually concomitant HPV18/45 and C.trachomatis infections are associated with very high CIN3 risk.
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http://dx.doi.org/10.1002/ijc.28173DOI Listing
October 2013

Impacts of a population-based prostate cancer screening programme on excess total mortality rates in men with prostate cancer: a randomized controlled trial.

J Med Screen 2013 Mar;20(1):33-38

Professor of Urology , Erasmus University Medical Centre , Rotterdam , the Netherlands.

Objectives To assess the effect of screening in terms of excess mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). Methods A total of 141,578 men aged 55-69 were randomized to systematic screening or usual care in ERSPC sections in Finland, Italy, the Netherlands and Sweden. The excess number of deaths was defined as the difference between the observed number of deaths in the prostate cancer (PC) patients and the expected number of deaths up to 31 December 2006. The expected number was derived from mortality of all study participants before a diagnosis with PC adjusted for study centre, study arm and study attendance. The excess mortality rates were compared between the two study arms. Results The PC incidence was 9.25 per 1000 person-years in the intervention arm and 5.49 per 1000 person-years in the control arm, relative risk (RR) 1.69 (95% confidence interval [CI] 1.62-1.76). The excess mortality among men with PC was 0.29 per 1000 person-years in the intervention arm and 0.37 per 1000 person-years in the control arm; the RR for excess mortality was 0.77 (95% CI 0.55-1.08). The absolute risk reduction in the excess mortality was 0.08 per 1000 person-years. The overall mortality was not significantly different between the intervention and the control arms of the study: RR 0.99 (95% CI 0.96-1.01). Conclusions Although the reduction in excess mortality was not statistically significant, the between-arm reduction in excess mortality rate was in line with the previously reported 20% reduction in the disease-specific mortality. This finding indicates that the reduction in PC mortality in the ERSPC trial cannot be due to a bias in cause of death adjudication.
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http://dx.doi.org/10.1258/jms.2013.012026DOI Listing
March 2013

Excess all-cause mortality in the evaluation of a screening trial to account for selective participation.

J Med Screen 2013 Mar 13;20(1):39-45. Epub 2013 May 13.

Department of Urology, Erasmus Medical Centre, Rotterdam, The Netherlands and Comprehensive Cancer Center the Netherlands (IKNL), Utrecht, The Netherlands.

Objective: In addition to disease-specific mortality, a randomized controlled cancer screening trial may be evaluated in terms of excess mortality, in which case no patient-specific information on causes of death is needed. We studied the effect of not accounting for attendance on the calculated excess mortality in a prostate cancer screening trial.

Methods: The numerator of the excess mortality rate related to prostate cancer diagnoses in each study arm equals the excess number of deaths observed in the cancer patients. The estimation of the expected number of deaths in the absence of the prostate cancer diagnoses has to account for the self-selection of those participating in the trial, particularly if the proportion of non-participants is substantial.

Setting: The European prostate cancer screening trial (ERSPC).

Results: In the screening arm, non-attendees had roughly twice the mortality rate of attendees. Approximately twice as many cancers were detected in the screening arm compared with the control arm, primarily in attendees. Unless attendance is properly accounted for, the expected mortality of prostate cancer patients in the screening arm is overestimated by 0.9-3.6 deaths per 1000 person-years.

Conclusions: Attendees have a lower all-cause mortality rate (are healthier) and a higher probability of a prostate cancer diagnosis than non-attendees and the men randomized to the control arm. If attendance is not accounted for, the excess mortality and the between-arm excess mortality rate ratio are underestimated and screening is considered more effective than it actually is. These effects may be sizeable, notably if non-attendance is common. Correcting for attendance status is important in the calculation of the excess mortality rate in prostate cancer patients that can be used in conjunction with a disease-specific mortality analysis in a randomized controlled cancer screening trial.
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http://dx.doi.org/10.1177/0969141312474443DOI Listing
March 2013

Impacts of a population-based prostate cancer screening programme on excess total mortality rates in men with prostate cancer: a randomized controlled trial.

J Med Screen 2013 Mar;20(1):33-8

Erasmus University MedicalCentre, Rotterdam, the Netherlands.

Objectives: To assess the effect of screening in terms of excess mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC).

Methods: A total of 141,578 men aged 55–69 were randomized to systematic screening or usual care in ERSPC sections in Finland, Italy, the Netherlands and Sweden. The excess number of deaths was defined as the difference between the observed number of deaths in the prostate cancer (PC)patients and the expected number of deaths up to 31 December 2006. The expected number was derived from mortality of all study participants before a diagnosis with PC adjusted for study centre,study arm and study attendance. The excess mortality rates were compared between the two study arms.

Results: The PC incidence was 9.25 per 1000 person-years in the intervention arm and 5.49 per 1000 person-years in the control arm, relative risk (RR) 1.69 (95% confidence interval [CI]1.62–1.76). The excess mortality among men with PC was 0.29 per 1000 person-years in the intervention arm and 0.37 per 1000 person-years in the control arm; the RR for excess mortality was 0.77 (95% CI 0.55–1.08). The absolute risk reduction in the excess mortality was 0.08 per 1000 person-years. The overall mortality was not significantly different between the intervention and the control arms of the study: RR 0.99 (95% CI 0.96–1.01).

Conclusions: Although the reduction in excess mortality was not statistically significant, the between arm reduction in excess mortality rate was in line with the previously reported 20% reduction in the disease-specific mortality. This finding indicates that the reduction in PC mortality in the ERSPC trial cannot be due to a bias in cause of death adjudication.
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http://dx.doi.org/10.1177/0969141313476632DOI Listing
March 2013

Coffee consumption and risk of gastric and pancreatic cancer--a prospective cohort study.

Int J Cancer 2013 Apr 1;132(7):1651-9. Epub 2012 Sep 1.

Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Only few prospective studies have examined the association between coffee consumption and risk of gastric and pancreatic cancer. This study is designed to evaluate this relationship among Finns, whose coffee consumption is the highest in the world. A total of 60,041 Finnish men and women who were 26-74 years of age and without history of any cancer at baseline were included in the present analyses. Coffee consumption and other study parameters were determined at baseline using standardized measurements. Participants were prospectively followed up for onset of gastric and/or pancreatic cancer, emigration, death or until June 30, 2006. During a mean follow-up period of 18 years, 299 cases of gastric cancer and 235 cases of pancreatic cancer were found. There was a nonsignificant inverse association between coffee consumption and risk of gastric cancer among men but not in the women. The multivariate-adjusted hazard ratio of stomach and pancreatic cancer incidence for ≥ 10 cups of coffee per day compared with nondrinkers were 0.75 (95% CI, 0.40-1.41) (P for trend = 0.19) and 0.82 (95% CI, 0.38-1.76) (P for trend = 0.95) for the combined population of men and women, respectively. We did not find a significant association between coffee consumption and the risk of gastric and/or pancreatic cancers.
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http://dx.doi.org/10.1002/ijc.27773DOI Listing
April 2013

Breast cancer survival in the US and Europe: a CONCORD high-resolution study.

Int J Cancer 2013 Mar 18;132(5):1170-81. Epub 2012 Sep 18.

Cancer Research UK Cancer Survival Group, Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.

Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study (CONCORD) found wide international differences in age-standardized survival. The aim of this study is to explain these survival differences. Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were collected for about 20,000 women diagnosed with breast cancer aged 15-99 years during 1996-98 in 7 US states and 12 European countries. Age-standardized net survival and the excess hazard of death up to 5 years after diagnosis were estimated by jurisdiction (registry, country, European region), age and stage with flexible parametric models. Breast cancers were generally less advanced in the US than in Europe. Stage also varied less between US states than between European jurisdictions. Early, node-negative tumors were more frequent in the US (39%) than in Europe (32%), while locally advanced tumors were twice as frequent in Europe (8%), and metastatic tumors of similar frequency (5-6%). Net survival in Northern, Western and Southern Europe (81-84%) was similar to that in the US (84%), but lower in Eastern Europe (69%). For the first 3 years after diagnosis the mean excess hazard was higher in Eastern Europe than elsewhere: the difference was most marked for women aged 70-99 years, and mainly confined to women with locally advanced or metastatic tumors. Differences in breast cancer survival between Europe and the US in the late 1990s were mainly explained by lower survival in Eastern Europe, where low healthcare expenditure may have constrained the quality of treatment.
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http://dx.doi.org/10.1002/ijc.27725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706735PMC
March 2013

Survival of Sami cancer patients.

Int J Circumpolar Health 2012 Jul 2;71:18959. Epub 2012 Jul 2.

Hjelt Institute, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Objectives: The incidence of cancer among the indigenous Sami people of Northern Finland is lower than among the Finnish general population. The survival of Sami cancer patients is not known, and therefore it is the object of this study.

Study Design: The cohort consisted of 2,091 Sami and 4,161 non-Sami who lived on 31 December 1978 in the two Sami municipalities of Inari and Utsjoki, which are located in Northern Finland and are 300-500 km away from the nearest central hospital. The survival experience of Sami and non-Sami cancer patients diagnosed in this cohort during 1979-2009 was compared with that of the Finnish patients outside the cohort.

Methods: The Sami and non-Sami cancer patients were matched to other Finnish cancer patients for gender, age and year of diagnosis and for the site of cancer. An additional matching was done for the stage at diagnosis. Cancer-specific survival analyses were made using the Kaplan-Meier method and Cox regression modelling.

Results: There were 204 Sami and 391 non-Sami cancer cases in the cohort, 20,181 matched controls without matching with stage, and 7,874 stage-matched controls. In the cancer-specific analysis without stage variable, the hazard ratio for Sami was 1.05 (95% confidence interval 0.85-1.30) and for non-Sami 1.02 (0.86-1.20), indicating no difference between the survival of those groups and other patients in Finland. Likewise, when the same was done by also matching the stage, there was no difference in cancer survival.

Conclusion: Long distances to medical care or Sami ethnicity have no influence on the cancer patient survival in Northern Finland.
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http://dx.doi.org/10.3402/ijch.v71i0.18959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417662PMC
July 2012

Prospective study of human papillomavirus seropositivity and risk of nonmelanoma skin cancer.

Am J Epidemiol 2012 Apr 14;175(7):685-95. Epub 2012 Mar 14.

Department of Medical Microbiology, Skåne University Hospital, Malmö, Sweden.

Cutaneous human papillomaviruses (HPVs) have been associated with squamous cell carcinoma (SCC) in case-control studies, but there are limited data from prospective studies assessing whether virus exposure predicts risk of future cancer development. Two major biobanks, the Southern Sweden Microbiology Biobank (1971-2003) and the Janus Biobank (1973-2003) in Norway, containing samples from 850,000 donors, were searched for incident skin cancer for up to 30 years using registry linkages. Altogether, 2,623 donors with samples taken before diagnosis of SCC or basal cell carcinoma (BCC) of the skin were identified. Prediagnostic samples and samples from 2,623 matched controls were tested for antibodies against 33 types of HPV. Baseline seropositivity to HPV types in genus β species 2 was associated with SCC risk (odds ratio = 1.3, 95% confidence interval: 1.1, 1.7); this was also the case for samples taken more than 18 years before diagnosis (odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). Type-specific persistent seropositivity entailed elevated point estimates for SCC risk for 29 HPV types and decreased point estimates for only 3 types. After multiple hypothesis adjustment, HPV 76 was significantly associated with SCC risk and HPV 9 with BCC risk. In summary, seropositivity for certain HPV types was associated with an increased risk for future development of SCC and BCC.
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http://dx.doi.org/10.1093/aje/kwr373DOI Listing
April 2012

Has equity in relative survival improved over time in Finland - a methodological exercise.

Acta Oncol 2011 Nov 3;50(8):1235-43. Epub 2011 Aug 3.

Institute of Biostatistics and Medical Informatics, University of Ljubljana, Slovenia.

Background: Population-based relative survival is widely used as a method of monitoring the success of cancer control. This success may not be relevant only for an entire country but also regional developments over time are of interest. It would not only be important that the relative survival improved but also that the differences between regions decreased over time.

Methods: In this paper the authors show how relative survival methods can be used to study such differences. In addition to standard methods, some more recently introduced approaches are used, most notably a method for checking the goodness of fit of the relative survival model. This gives confidence in the obtained results and provides additional insight when assumptions are not met.

Results: An analysis of cancers of the colon and ovary by cancer control region in Finland in 1953-2003 shows an overall improvement in relative survival, accompanied in colon cancer also by a decrease of differences in relative survival between the regions. Thus, the desired course was observed in colon cancer but not in cancer of the ovary.

Conclusions: These results, applied to further sites, should lead to investigation of differences in cancer control policies between regions.
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http://dx.doi.org/10.3109/0284186X.2011.599814DOI Listing
November 2011

Choosing the relative survival method for cancer survival estimation.

Eur J Cancer 2011 Sep 4;47(14):2202-10. Epub 2011 May 4.

Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Pieni Roobertinkatu 9, FI-00130 Helsinki, Finland.

Background: The methods on how to calculate cumulative relative survival have been ambiguous and have given differences in empirical results.

Methods: The gold standard for the cumulative relative survival ratio is the weighted average of age-specific cumulative relative survival ratios, with weights proportional to numbers of patients at diagnosis. Mathematics and representative empirical materials from the population-based Finnish Cancer Registry were studied for the different relative survival methods and compared with the gold standard.

Results: The theoretical and empirical results show a good agreement between the method suggested in 1959 by Ederer and Heise (the so-called Ederer II method) and the gold standard. This result is in part due the fact that as follow-up time increases the conditional (annual) relative survival ratios become increasingly more independent of age. Moreover, the dependence between the excess mortality due to cancer and the baseline general mortality does not introduce an important enough selection in practice to cause a notable bias.

Conclusion: The use of the method by Ederer and Heise, multiplication of the annual relative survival ratios, instead of direct standardisation, should be considered in future applications. This would be particularly important for the long-term follow-up when age-specific relative survival is not available in the oldest age categories.
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http://dx.doi.org/10.1016/j.ejca.2011.03.011DOI Listing
September 2011

Coverage and performance of colorectal cancer screening with the faecal occult blood test in Finland.

J Med Screen 2011 ;18(1):18-23

Finnish Cancer Registry, Pieni Roobertinkatu 9, FIN-00130 Helsinki, Finland.

Introduction: Mortality from colorectal cancer has been shown to decrease by repeated screening using faecal occult blood (FOB) testing in randomized screening trials. This report presents coverage and performance of organized screening among the general population in Finland.

Methods: In 2004-2007, people aged 60-69 years were randomized into biennial screening and control arms. The screening test was a guaiac-based FOB test (Hemoccult) with dietary restriction and three test cards for six consecutive samples. Test positives were referred for full colonoscopy. The programme was launched in 2004 and subsequently it expanded over regions and age-cohorts.

Results: In 2007, the programme covered one-third of the target population and 74,592 people had been invited for screening, of them 26,866 for the second round. Uptakes for the first and second rounds, respectively, were 62% and 68% in men and 77% and 80% in women. The proportion of test positives increased from 2.4% to 2.9% from the first to the second round and the positive predictive value for cancers decreased from 7.5% to 4.3%.

Conclusions: By 2007, organized colorectal cancer screening covered one-third of the target population in Finland. Implementation of screening measured with response rate was successful and met the criteria for a public health programme, but performance in terms of positive predictive value needs monitoring.
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http://dx.doi.org/10.1258/jms.2010.010036DOI Listing
August 2011

Disease-specific mortality may underestimate the total effect of prostate cancer screening.

J Med Screen 2010 ;17(4):204-10

Erasmus University Medical Centre, Rotterdam, The Netherlands.

Objectives: To study the difference between the disease-specific and excess mortality rate in the European Randomized Study of Screening for Prostate Cancer section Rotterdam.

Methods: A total of 42,376 men were randomized to systematic screening or usual care. The excess number of deaths was defined as the difference between the observed number of deaths in the prostate cancer (PC) patients and the expected number of deaths up to 31 December 2006. The expected number was derived from mortality of all study participants before a possible diagnosis with PC. The disease-specific mortality rate was based on the number of men who died from PC. The excess mortality rate based on the arm-specific excess number of deaths and the disease-specific mortality rate were compared between the two study arms.

Results: The overall mortality rate was not significantly different between the intervention and the control arms of the study: RR 1.02 (95% CI 0.98-1.07). The disease-specific mortality rate was 0.42 men per 1000 person-years in the intervention and 0.48 men per 1000 person-years in the control arm: RR 0.86 (95% CI 0.64-1.17). The excess mortality rate was 0.40 per 1000 person-years in the intervention arm and 0.61 men per 1000 person-years in the control arm, and the RR for excess mortality was 0.66 (95% CI 0.39-1.13).

Conclusions: In contrast to the disease-specific mortality rates an increased difference in the excess mortality rates was observed between the two arms. This observation may be due to a systematic underestimation of the disease-specific deaths, and/or an additional disease-related mortality that is measured by an excess mortality analysis but not by a disease-specific mortality.
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http://dx.doi.org/10.1258/jms.2010.010074DOI Listing
May 2011

Dietary intervention in infancy and later signs of beta-cell autoimmunity.

N Engl J Med 2010 Nov;363(20):1900-8

Hospital for Children and Adolescents, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

Background: Early exposure to complex dietary proteins may increase the risk of beta-cell autoimmunity and type 1 diabetes in children with genetic susceptibility. We tested the hypothesis that supplementing breast milk with highly hydrolyzed milk formula would decrease the cumulative incidence of diabetes-associated autoantibodies in such children.

Methods: In this double-blind, randomized trial, we assigned 230 infants with HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes to receive either a casein hydrolysate formula or a conventional, cow's-milk-based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma-associated 2 molecule (IA-2), and zinc transporter 8 were analyzed with the use of radiobinding assays, and islet-cell antibodies were analyzed with the use of immunofluorescence, during a median observation period of 10 years (mean, 7.5). The children were monitored for incident type 1 diabetes until they were 10 years of age.

Results: The unadjusted hazard ratio for positivity for one or more autoantibodies in the casein hydrolysate group, as compared with the control group, was 0.54 (95% confidence interval [CI], 0.29 to 0.95), and the hazard ratio adjusted for an observed difference in the duration of exposure to the study formula was 0.51 (95% CI, 0.28 to 0.91). The unadjusted hazard ratio for positivity for two or more autoantibodies was 0.52 (95% CI, 0.21 to 1.17), and the adjusted hazard ratio was 0.47 (95% CI, 0.19 to 1.07). The rate of reported adverse events was similar in the two groups.

Conclusions: Dietary intervention during infancy appears to have a long-lasting effect on markers of beta-cell autoimmunity--markers that may reflect an autoimmune process leading to type 1 diabetes. (ClinicalTrials.gov number, NCT00570102.).
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http://dx.doi.org/10.1056/NEJMoa1004809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242902PMC
November 2010

Cure fraction model with random effects for regional variation in cancer survival.

Stat Med 2010 Nov;29(27):2781-93

Finnish Cancer Registry, Pieni Roobertinkatu 9, 00130 Helsinki, Finland.

Assessing regional differences in the survival of cancer patients is important but difficult when separate regions are small or sparsely populated. In this paper, we apply a mixture cure fraction model with random effects to cause-specific survival data of female breast cancer patients collected by the population-based Finnish Cancer Registry. Two sets of random effects were used to capture the regional variation in the cure fraction and in the survival of the non-cured patients, respectively. This hierarchical model was implemented in a Bayesian framework using a Metropolis-within-Gibbs algorithm. To avoid poor mixing of the Markov chain, when the variance of either set of random effects was close to zero, posterior simulations were based on a parameter-expanded model with tailor-made proposal distributions in Metropolis steps. The random effects allowed the fitting of the cure fraction model to the sparse regional data and the estimation of the regional variation in 10-year cause-specific breast cancer survival with a parsimonious number of parameters. Before 1986, the capital of Finland clearly stood out from the rest, but since then all the 21 hospital districts have achieved approximately the same level of survival.
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http://dx.doi.org/10.1002/sim.4046DOI Listing
November 2010

Future lung cancer incidence in Poland and Finland based on forecasts on hypothetical changes in smoking habits.

Acta Oncol 2011 Jan 16;50(1):81-7. Epub 2010 Jun 16.

Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 5 Roentgen St, 02-781, Warsaw, Poland.

Objective: the aim is to estimate the future lung cancer incidence in Poland and Finland based on forecasts on hypothetical changes in smoking habits.

Material And Methods: data on population, lung cancer and smoking prevalence come from known sources. The simulation model utilized for forecasting was based on smoothing the smoking habit - specific risk ratios estimated for males and females in Europe.

Results: depending on the analyzed scenario in 2030 in Poland mortality rates among men would range from 8 to 125/10(5) and among women from 7 to 47/10(5); in Finland among men 5 to 60/10(5) and among women 4 to 22/10(5).

Conclusions: the results obtained clearly indicate that cutting down on the number of smokers translates directly into a considerable reduction of the lung cancer incidence rate.
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http://dx.doi.org/10.3109/0284186X.2010.488247DOI Listing
January 2011

Trends in the overall survival of cancer patients diagnosed 1964-2003 in the Nordic countries followed up to the end of 2006: the importance of case-mix.

Acta Oncol 2010 Jun;49(5):713-24

Department of Cancer Prevention and Documentation, Danish Cancer Society, Strandboulevarden 49, Copenhagen, Denmark.

Aim: Overall survival after cancer is frequently used when assessing the health care service performance as a whole. While used by the public, politicians, and the media, it is often discarded by clinicians and epidemiologists due to the heterogeneous mix of different cancers, risk factors and treatment modalities. We studied the trend in the Nordic 5-year relative survival and excess mortality for all cancers combined to see if the impact of case-mix and variations between countries in diagnostic methods such as breast screening and PSA testing could explain the lower survival in Denmark.

Material And Methods: From the NORDCAN database 1964-2003, we defined two cohorts of cancer patients, one excluding non-melanoma skin cancer and another also excluding breast and prostate cancer. We estimated age-standardised incidence and mortality rates, 5-year relative survival, and excess mortality rates for varying follow-up periods, and age-specific 5-year relative survival by country, sex and 5-year diagnostic period.

Results: Prostate cancer is the main driver of the incidence increase in men, as do breast cancer in women, whereas cancer mortality in all Nordic countries is declining. The 5-year relative survival ratios are increasing in each Nordic population, but less so in Denmark. Country differences in survival stem mainly from follow-up periods immediately after diagnosis. Adjusting for the case-mix of diagnoses diminished differences a little while exclusion of breast and prostate cancer reduced the gap between countries in survival and excess mortality more considerably, yet post-adjustment, Danish patients still fare worse during the first three months after diagnosis.

Conclusion: Adjustment for case-mix and exclusion of sites where diagnostic procedures change the pattern of incidence is important when comparing overall cancer survival across countries, but the correction only explains part of the observed differences in survival. Other factors such as stage at presentation, co-morbidity, tobacco and alcohol consumption are likely contributors.
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http://dx.doi.org/10.3109/0284186X.2010.484426DOI Listing
June 2010

Trends in the survival of patients diagnosed with malignant neoplasms of lymphoid, haematopoietic, and related tissue in the Nordic countries 1964-2003 followed up to the end of 2006.

Acta Oncol 2010 Jun;49(5):694-712

Department of Cancer Prevention and Documentation, Danish Cancer Society, Strandboulevarden 49, Copenhagen, Denmark.

Background: Hodgkin lymphoma, Non-Hodgkin lymphoma, multiple myeloma, and acute and other leukaemias constitute about 7% of the overall cancer incidence and 8% of cancer mortality in the Nordic countries. The aim of this study is to describe and interpret the trends in relative survival and excess mortality in the five Nordic populations among these patients.

Material And Methods: Using the NORDCAN database 1964-2003, we estimated age-standardised incidence and mortality rates, 5-year relative survival, and excess mortality rates for varying follow-up periods, and age-specific 5-year relative survival by country, sex, and 5-year diagnostic period.

Results: Taking into account classification and registration problems in the earlier periods, the patterns of incidence, mortality, and survival are fairly similar between the countries within each cancer form studied. High 5-year relative survival ratios of over 80% were seen in the most recent period 1999-2003 for Hodgkin lymphoma, between 50 and 60% for Non-Hodgkin lymphoma, 38-49% for acute leukaemia and 60-73% for other leukaemia. The variations were between 28 and 41% for multiple myeloma. Danish patients diagnosed with these malignancies tend to fare slightly worse than their Nordic neighbours, with excess mortality rates marginally higher one to three months after diagnosis.

Conclusion: Although the recent trends and absolute levels of incidence, mortality and survival for the lympho-haematopoietic malignancies are similar, the consistently lower survival of Danish patients--irrespective of type of malignancy--points to an impact of co-morbidity related lifestyle factors, which may negatively affect the chemotherapy and radiation offered as standard treatments for these diseases.
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http://dx.doi.org/10.3109/02841861003631495DOI Listing
June 2010

Trends in the survival of patients diagnosed with malignant melanoma of the skin in the Nordic countries 1964-2003 followed up to the end of 2006.

Acta Oncol 2010 Jun;49(5):665-72

Icelandic Cancer Registry, Icelandic Cancer Society, Reykjavik, Iceland.

Unlabelled: A previous Nordic study showed a marked and steady increase in the age-adjusted 5-year relative survival of skin melanoma patients diagnosed during the period 1958 through 1987. Males had considerably poorer survival than females.

Material And Methods: Using the NORDCAN database, we studied relative survival and excess mortality of patients diagnosed with melanoma of the skin in the Nordic countries 1964-2003 followed up to the end of 2006. These were contrasted with concomitant trends in incidence and mortality.

Results: The overall incidence of melanoma almost quadrupled, but there was considerable variation in the trends in the five countries. Mortality was low but doubled during the study period. Survival ratios increased steadily to between 80% and 90% for patients diagnosed in 1999-2003. Swedish patients had consistently higher survival, whereas Danish patients had the highest excess death rates the first three months after diagnosis up until 1990, but thereafter, rates reached a similar low level to that observed in the other Nordic countries. The survival of Nordic women is still higher than that of men, but the difference has diminished, while the mortality rates among men are becoming increasingly higher relative to those for women among individuals 50 years and older. In younger individuals, mortality rates are similar in the two sexes, and declining.

Conclusions: Nordic patient survival following melanoma diagnosis is generally high and has been steadily increasing in the last decades. Differences in incidence between the five countries are more pronounced than the differences in survival. The strong upward trends in incidence and survival may mainly be the result of extensive changes in sunbathing habits or other UV exposure and, more recently, of an increasing awareness by the medical community and the public concerning early detection of melanoma of the skin.
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http://dx.doi.org/10.3109/02841861003702528DOI Listing
June 2010
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