Search

Study Question: Is there an association between premature ovarian insufficiency (POI) and severe autoimmune diseases before and after POI diagnosis?, Summary Answer: Women with POI had at least one hospital-treated autoimmune disorder preceding POI diagnosis 2.6 times more often compared with matched female controls, and a 2- to 3-fold risk for these diseases for several years after POI diagnosis., What Is Known Already: It has been suggested that autoimmunity is an important factor in the pathogenesis of POI. Estimations of the prevalence of POI cases with autoimmune origin have ranged from 4% to 50%., Study Design, Size, Duration: This population-based registry study included 3972 women diagnosed with spontaneous POI between 1988 and 2017 and 15 708 female population controls and used both case-control and cohort analysis. Autoimmune disease diagnoses were evaluated from childhood until the end of the year 2017., Participants/materials, Setting, Methods: Women with POI were identified from the reimbursement registry of the Finnish Social Insurance Institution by their right to hormone replacement therapy (HRT). Four female population controls matched by age and municipality of residence were searched for each POI case to form a reference cohort. Women with a history of cancer or bilateral oophorectomy were excluded. Severe autoimmune disorder diagnoses for the years 1970-2017 were identified from the Hospital Discharge Registry. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using binary logistic regression for cases of having any, or one or more, specific autoimmune diseases preceding the index date (the date when reimbursement for HRT was granted for the POI) among women with POI as compared to controls. Standardized incidence ratios (SIR) with 95% CIs for getting diagnosed with an autoimmune disease after the index date in 3-year follow-up periods among women with POI (who did not have these diseases prior to the index date) were also calculated. The expected numbers of autoimmune disease cases were based on the incidence of first-onset severe autoimmune disease among the controls., Main Results and the Role of Chance: The prevalence of having at least one severe autoimmune disease in women with POI was 5.6% (n = 233), with an OR of 2.6 (95% CI 2.2, 3.1) when compared to population controls. Women with POI had an increased prevalence of several specific autoimmune diseases prior to the index date compared to controls: polyglandular autoimmune diseases (OR 25.8, 95% CI 9.0, 74.1), Addison's disease (OR 22.9, 95% CI 7.9, 66.1), vasculitis (OR 10.2, 95% 4.3, 24.5), systemic lupus erythematosus (OR 6.3 95% CI 4.2, 20.3), rheumatoid arthritis (OR 2.3, 95% CI 1.7, 3.2), sarcoidosis (OR 2.3, 95% CI 1.2, 4.5), inflammatory bowel diseases (OR 2.2, 95% CI 1.5, 3.3), and hyperthyroidism (OR 1.9, 95% CI 1.2, 3.1); whereas the prevalence of diabetes type 1 and ankylosing spondylitis did not differ between the women with POI and the reference cohort. The SIRs for being diagnosed for the first time with a severe autoimmune disease after POI diagnosis was 2.8 (95% CI 2.3, 3.4), during the first three years after POI diagnosis, decreasing gradually to 1.3 (1.1, 1.6) after 12 years., Limitations, Reasons for Caution: This study only included autoimmune disorders diagnosed in specialized health care; hence, the overall prevalence of autoimmune disorders in women with POI may be higher., Wider Implications of the Findings: Severe autoimmune diseases have a strong association with POI, suggesting that immunological mechanisms play a pivotal role in POI. Future studies should focus on specific autoimmune mechanisms behind POI, from both preventive and curative perspectives., Study Funding/competing Interest(s): This work was financially supported by Oulu University Hospital. S.M.S. received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. H.S. received grants from the Finnish Menopause Society, the Oulu Medical Research Foundation, the Finnish Research Foundation of Gynecology and Obstetrics, UniOGS graduate school, The Finnish Medical Society Duodecim, Orion Research Foundation, and the University of Oulu Scholarship Fund. M.-M.O. received a grant from the Sakari Alhopuro Foundation and the Finnish Diabetes Research Foundation. None of the funders had any involvement in the study design or its execution or reporting. The authors do not have any competing interests to report., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

We examined the overall and site-specific cancer mortality disparities among first-generation - separately in adults (G1) and children (G1.5) at immigration - and second-generation (G2) immigrants and their countries of origin using population-based registries in Sweden, encompassing over 8.5 million individuals aged 20 and above residing in Sweden since 1990, with follow-up until December 31, 2023. Cox proportional hazard models were fitted, stratified by gender, to estimate hazard ratios and 95% confidence intervals compared to natives. Mortality rates for most cancers transitioned from lower in G1 towards the rate of natives in G2. However, elevated mortality rates were sustained across generations for liver cancer in males and stomach cancer in females. Among G2, mortality from lymphohematopoietic cancers in males, and lung and cervix uteri cancers in females were elevated - by 10%, 9%, and 17% respectively compared to natives. Country of origin analyses revealed substantial disparities. For instance, G2 females with Nordic parental origin had a 13% higher risk of death from lung cancer, while those with non-Western parental origin had a 54% lower risk as compared to natives. These findings suggest a generational and arrival-age dynamics of cancer mortality and highlight target groups for cancer prevention and control among immigrants., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: The impact of societal factors on the occurrence of head and neck cancers (HNCs) remains understudied, especially in the Nordic countries., Methods: To quantify the association between socio-economic status (SES) and the occurrence of HNCs, this cohort study uses data from the Nordic Occupational Cancer project that combine occupational and cancer registry data from 1961 to 2005 of 14.9 million individuals aged between 30 and 64 years. Occupational categories were combined into seven socio-economic categories. Standardized incidence ratio (SIR) analyses were conducted with the cancer incidence rates for the entire national study populations used as reference rates., Results: Altogether, 83 997 HNCs-72% in men and 28% in women-were recorded. Among men, a gradient of risk associated with SES was observed for cancers of the tongue, other oral cavity subsites, pharynx, oropharynx and larynx in groups with lower SES. Managers showed decreased SIRs of 0.50 to -0.90 also for cancers of the lip, tongue, other oral cavity subsites, oropharynx, nasopharynx, nose and larynx. In contrast, excess risks of tongue, other oral cavity subsites, pharyngeal, oropharyngeal and laryngeal cancers were observed among clerical (SIRs 1.05-1.16), skilled workers (1.04-1.14), unskilled workers (1.16-1.26) and economically inactive men (1.38-1.87). Among women, no risk gradient similar to that in men was revealed., Conclusions: The current study underscores the influence of SES on the incidence of HNCs and highlights the need for targeted interventions, including tobacco and alcohol control policies, and improved access to healthcare services, particularly for socio-economically disadvantaged populations., (© The Author(s) 2024; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Context: Incidence and causes of primary adrenal insufficiency (PAI) have not been comprehensively studied in children., Objective: Our objective was to describe the epidemiology and to assess causes of PAI in Finnish children., Methods: A population-based descriptive study of PAI in Finnish patients aged 0-20 years.Diagnoses referring to adrenal insufficiency in children born in 1996-2016 were collected from the Finnish National Care Register for Health Care. Patients with PAI were identified by studying patient records. Incidence rates were calculated in relation to person-years in the Finnish population of same age., Results: Of the 97 patients with PAI, 36% were female. The incidence of PAI was highest during the first year of life (in females 2.7 and in males 4.0/100 000 person-years). At 1-15 years of age, the incidence of PAI in females was 0.3/100 000 and in males 0.6/100 000 person-years. Cumulative incidence was 10/100 000 persons at age of 15 years and 13/100 000 at 20 years. Congenital adrenal hyperplasia was the cause in 57% of all patients and in 88% of patients diagnosed before age of 1 year. Other causes among the 97 patients included autoimmune disease (29%), adrenoleukodystrophy (6%), and other genetic causes (6%). From the age of 5 years, most of the new cases of PAI were due to autoimmune disease., Conclusion: After the first-year peak, the incidence of PAI is relatively constant through ages 1-15 years, and 1 out of 10 000 children are diagnosed with PAI before the age of 15 years., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Study Question: Are genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)?, Summary Answer: A wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI., What Is Known Already: POI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7-15% of POI cases., Study Design, Size, Duration: This population-based study included 5011 women diagnosed with POI in 1988-2017. The data were collected from various national registries and covers women with POI nationwide., Participants/materials, Setting, Methods: We identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported <2 years prior to the index date., Main Results and the Role of Chance: Of the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1-1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1-39.1). For autosomal single gene disorders, the OR was 16.5 (95% CI 6.2-43.7). Women with POI had a higher odds of having a GD/CM diagnosis in all categories. The OR for GD/CM diagnoses was highest among the youngest POI patients (10-14 years old, OR 24.1, 95% CI 15.1-38.2). The odds of having POI were higher the more GD or CM diagnoses a woman had., Limitations, Reasons for Caution: Some women with POI might not have sought help for their symptoms and therefore remain undiagnosed. Due to the register-based nature of our study, we did not have access to more specific genetic diagnoses than international classification of diseases offers., Wider Implications of the Findings: GD/CM diagnoses were strongly associated with POI, especially when POI was diagnosed at a young age. The risk of POI was highest in women with multiple GD/CM diagnoses. Early onset POI can be a sign of underlying genetic disorder or congenital anomaly, and this should serve as a reminder for clinicians to consider further examinations. To avoid unnecessary delay in the diagnosis of POI and starting relevant hormone replacement therapy treatment, clinicians should be aware of these associations., Study Funding/competing Interest(s): Oulu University Hospital financially supported this work. H.S. has received personal grants from the Finnish Menopause Society, Oulu Medical Research Foundation, and Finnish Research Foundation of Gynaecology and Obstetrics. S.S. has received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. None of the authors have any competing interests to declare., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Bladder cancer (BC) is the 10th most common type of cancer worldwide and the fourth most common type of cancer in Iran. Opium use is considered as one of the risk factors for BC. We aim to assess the association between various parameters of opium use, which in Iran is mainly ingested or smoked in various forms, and the risk of BC., Method: In this multi-centre case-referent study in Iran, 717 BC cases and 3477 referents were recruited to the study from May 2017 until July 2020. Detailed histories of opium use (duration, amount, frequency) and potential confounders were collected by trained interviewers. Multivariable unconditional logistic regression models were used to measure adjusted odds ratio (OR) and 95% confidence intervals (CI). The ORs were adjusted for age, gender, place of residence and pack-years of cigarette smoking., Results: Regular opium consumption was associated with an increased risk of BC (OR 3.5, 95% CI: 2.8, 4.3) compared with subjects who never used opium. Compared with continuous users, the risk decreased to one-third for those who stopped opium more than 10 years ago. The adjusted OR for those who used both crude opium (teriak) and opium juice was 7.4 (95% CI: 4.1, 13.3). There was a joint effect of opium and tobacco (OR for users of both opium and tobacco 7.7, 95% CI: 6.0, 9.7)., Conclusions: Regular opium use is associated with an approximately 4-fold risk for BC. The OR decreases along with the increasing time since stopping opium use., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Study Question: What is the incidence of premature ovarian insufficiency (POI), has the incidence of POI changed over time, and what is the risk of POI among relatives of POI women?, Summary Answer: The incidence of POI increased among females aged 15-19 years from 2007 onwards and decreased in older age groups, and among relatives of women with POI the risk of POI is significantly increased., What Is Known Already: So far, there has been no good quality, nationwide studies of the incidence of POI. Early menopause has been associated with the elevated risk of early menopause among relatives, but the knowledge of the familial risk of POI is scarce. Lower socioeconomic status has been associated with lower age at natural menopause., Study Design, Size, Duration: Population-based study with 5011 women diagnosed with POI in 1988-2017. The data were collected from national registries and covers POI subjects in entire Finland., Participants/materials, Setting, Methods: Women with hormone replacement therapy reimbursement for POI were identified from Social Insurance Institution (SII). We calculated POI incidence in different age groups and studied the changes in the incidence rate over time in 5-year segments. Four population-based controls were selected from the Digital and Population Data Services Agency (DVV) for each POI woman. Family members of the POI cases and controls were identified from the DVV and linked to SII reimbursement data to identify POI diagnoses among them. The familial risk of POI was estimated with a logistical regression model., Main Results and the Role of Chance: The incidence was highest in the 35-39 age group, ranging from 73.8/100 000 women-years in 1993-1997 to 39.9/100 000 women-years in 2013-2017. From 2007, the incidence among 15- to 19-year-olds rose from 7.0 to 10.0/100 000 women-years in 2015-2017. Cumulative incidence of POI for women under 40 years in 1988-2017 was 478/100 000 women. The relative risk of POI among relatives of women with POI was 4.6 (95% CI 3.3-6.5) compared to relatives of women without POI. POI women tended to have slightly lower socioeconomic status and level of education compared to controls., Limitations, Reasons for Caution: For some women with POI, diagnosis or reimbursement may be lacking. However, we presume that these women represent a minority due to the nature of the disease and the economic benefits of reimbursement. Some changes in the incidence of POI can reflect changes in clinical practice and changing treatments and reimbursement criteria., Wider Implications of the Findings: The risk of developing POI is significantly higher in women who have first-degree relatives diagnosed with POI. Raising awareness of the increased risk might lead to earlier diagnosis and initiation of hormonal replacement therapy, possibly preventing adverse effects of low oestrogen levels, such as osteoporosis., Study Funding/competing Interest(s): This work was financially supported by the Oulu University Hospital. H.S. received a grant from Finnish Menopause Society. S.M.S. received a grant from the Finnish Menopause Society, the Finnish Medical Foundation and the Juho Vainio Foundation. The authors do not have any competing interests to declare., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: The aim was to examine the hypothesis that antireflux surgery with fundoplication improves long-term survival compared with antireflux medication in patients with reflux oesophagitis or Barrett's oesophagus., Method: Individuals aged between 18 and 70 years with reflux oesophagitis or Barrett's oesophagus (intestinal metaplasia) documented from in-hospital and specialized outpatient care were selected from national patient registries in Denmark, Finland, Iceland, and Sweden from 1980 to 2014. The study investigated all-cause mortality and disease-specific mortality, comparing patients who had undergone open or laparoscopic antireflux surgery with fundoplication versus those using antireflux medication. Multivariable Cox regression analysis was used to estimate hazard ratios (HRs) with 95 per cent confidence intervals for all-cause mortality and disease-specific mortality, adjusted for sex, age, calendar period, country, and co-morbidity., Results: Some 240 226 patients with reflux oesophagitis or Barrett's oesophagus were included, of whom 33 904 (14.1 per cent) underwent antireflux surgery. The risk of all-cause mortality was lower after antireflux surgery than with use of medication (HR 0.61, 95 per cent c.i. 0.58 to 0.63), and lower after laparoscopic (HR 0.56, 0.52 to 0.60) than open (HR 0.80, 0.70 to 0.91) surgery. After antireflux surgery, mortality was decreased from cardiovascular disease (HR 0.58, 0.55 to 0.61), respiratory disease (HR 0.62, 0.57 to 0.66), laryngeal or pharyngeal cancer (HR 0.35, 0.19 to 0.65), and lung cancer (HR 0.67, 0.58 to 0.80), but not from oesophageal cancer (HR 1.05, 0.87 to 1.28), compared with medication, The decreased mortality rates generally remained over time., Conclusion: In patients with reflux oesophagitis or Barrett's oesophagus, antireflux surgery is associated with lower mortality from all causes, cardiovascular disease, respiratory disease, laryngeal or pharyngeal cancer, and lung cancer, but not from oesophageal cancer, compared with antireflux medication., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The age-adjusted incidence of cutaneous melanoma (CM) in the Nordic countries has increased during the last 60 years. Few prospective population-based studies have estimated the occupational variation in CM risk over time., Objectives: To determine occupational variation in CM risk., Methods: A historical prospective cohort study with a 45-year follow-up from 1961 to 2005 (Nordic Occupational Cancer Study, NOCCA) based on record linkages between census and cancer registry data for Nordic residents aged 30-64 years in Denmark, Finland, Iceland, Norway and Sweden. National occupational codes were converted to 53 occupational categories, and stratified into indoor, outdoor and mixed work, and into socioeconomic status. The standardized incidence ratios (SIRs) were estimated as observed number of CM cases divided by the expected number calculated from stratum-specific person-years and national CM incidence rates., Results: During a follow-up of 385 million person-years, 83 898 incident cases of CM were identified. In all countries combined, men with outdoor work had a low SIR of 0·79 [95% confidence interval (CI) 0·77-0·81] and men with indoor work had a high SIR of 1·09 (95% CI 1·07-1·11). Differences in women pointed in the same direction. High socioeconomic status was associated with an excess risk: SIR 1·34 (95% CI 1·28-1·40) in men and SIR 1·31 (95% CI 1·26-1·36) in women. Technical, transport, military and public safety workers with potential skin exposure to carcinogens had excess risks., Conclusions: Occupational variation in CM risk may be partly explained by host, socioeconomic and skin exposure factors. Differences in CM risk across socioeconomic groups attenuated slightly over time., (© 2020 British Association of Dermatologists.)

It has been suggested that the association between self-reported occupational noise exposure and vestibular schwannoma (VS), found in several studies, represents recall bias. Therefore, we aimed to study the relationship in a large case-control study using occupational noise measurements. We performed a case-control study using data from Sweden for 1,913 VS cases diagnosed in 1961-2009 and 9,566 age- and sex-matched population controls. We defined occupational history by linkage to national censuses from 1960, 1970, 1980, and 1990. We estimated occupational noise exposure for each case and control using a job-exposure matrix. There was no association between occupational noise exposure and VS. Among subjects assessed as ever exposed to occupational noise levels of ≥85 dB (214 cases and 1,142 controls), the odds ratio for VS per 5 years of exposure was 1.02 (95% confidence interval: 0.90, 1.17). Workers with noise levels of ≥85 dB for at least 15 years (5-year latency period), showed no increased risk of VS (odds ratio = 0.98, 95% confidence interval: 0.73, 1.31) compared with those who had never been exposed to noise levels of 75 dB or higher. In summary, our large study does not support an association between occupational noise exposure and VS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Human papillomavirus (HPV) vaccination of girls with very high (>90%) coverage has the potential to eradicate oncogenic HPVs, but such high coverage is hard to achieve. However, the herd effect (HE) depends both on the HPV type and the vaccination strategy., Methods: We randomized 33 Finnish communities into gender-neutral HPV16/18 vaccination, girls-only HPV16/18 vaccination, and hepatitis B virus vaccination arms. In 2007-2010, 11 662 of 20 513 of 40 852 of 39 420 resident boys/girls from 1992 to 1995 birth cohorts consented. In 2010-2014, cervicovaginal samples from vaccinated and unvaccinated girls at age 18.5 years were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68. Vaccine efficacy for vaccinated girls, HE for unvaccinated girls, and the protective effectiveness (PE) for all girls were estimated. We extended the community-randomized trial results about vaccination strategy with mathematical modeling to assess HPV eradication., Results: The HE and PE estimates in the 1995 birth cohort for HPV18/31/33 were significant in the gender-neutral arm and 150% and 40% stronger than in the girls-only arm. Concordantly, HPV18/31/33 eradication was already predicted in adolescents/young adults in 20 years with 75% coverage of gender-neutral vaccination. With the 75% coverage, eventual HPV16 eradication was also predicted, but only with the gender-neutral strategy., Conclusions: Gender-neutral vaccination is superior for eradication of oncogenic HPVs., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Bariatric surgery carries a risk of severe postoperative complications, sometimes leading to reinterventions or even death. The incidence and risk factors for reintervention and death within 90 days after bariatric surgery are unclear, and were examined in this study., Methods: This population-based cohort study included all patients who underwent bariatric surgery in one of the five Nordic countries between 1980 and 2012. Data on surgical and endoscopic procedures, diagnoses and mortality were retrieved from national high-quality and complete registries. Multivariable Cox regression analysis was used to calculate hazard ratios (HRs), adjusted for country, age, sex, co-morbidity, type of surgery and approach, year and hospital volume of bariatric surgery., Results: Of 49 977 patients, 1111 (2·2 per cent) had a reintervention and 95 (0·2 per cent) died within 90 days of bariatric surgery. Risk factors for the composite outcome reintervention/mortality were older age (HR 1·65, 95 per cent c.i. 1·36 to 2·01, for age at least 50 years versus less than 30 years) and co-morbidity (HR 2·66, 1·53 to 4·62, for Charlson co-morbidity index score 2 or more versus 0). The risk of reintervention/mortality was decreased for vertical banded gastroplasty compared with gastric bypass (HR 0·37, 0·28 to 0·48) and more recent surgery (HR 0·51, 0·39 to 0·67, for procedures undertaken in 2010 or later versus before 2000). Sex, surgical approach (laparoscopic versus open) and hospital volume did not influence risk of reintervention/mortality, but laparoscopic surgery was associated with a lower risk of 90-day mortality (HR 0·29, 0·16 to 0·53)., Conclusion: Reintervention and death were uncommon events within 90 days of bariatric surgery even in this unselected nationwide cohort from five countries. Older patients with co-morbidities have an increased relative risk of these outcomes., (© 2020 The Authors. British Journal of Surgery published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autoimmune endocrinopathy with severe and unpredictable course. The impact of APECED on mortality has not been determined., Objective: To assess overall and cause-specific mortality of patients with APECED., Design and Setting: A follow-up study of Finnish patients with APECED from 1971 to 2018. Causes and dates of death were collected from Finnish registries., Patients: Ninety-one patients with APECED., Main Outcome Measure: Overall and cause-specific standardized mortality ratios (SMRs) determined by comparing the observed numbers of death and those expected on the basis of respective population death rates in Finland., Results: The overall disease mortality was significantly increased (29 deaths, SMR 11; 95% confidence interval [CI] 7.2-16; P < 0.001). The relative risk (SMR) was highest in the youngest age groups but the absolute excess risk was similar (about 10 per 10 000 person-years) in all age categories. The highest SMRs were seen for endocrine and metabolic diseases (SMR 570; 95% CI, 270-1000; P < 0.001) and for oral and esophageal malignancies (SMR 170; 95% CI, 68-360; P < 0.001). Mortality was also increased for infections, diseases of digestive system, alcohol-related deaths, and for accidents. Due to the small number of cases we were unable to evaluate whether mortality was affected by disease severity., Conclusions: Patients with APECED have significantly increased mortality in all age groups. Highest SMRs are found for causes that are directly related to APECED but also for infections. Increased alcohol- and accident-related deaths may be influenced by psychosocial factors., (© Endocrine Society 2020.)

Background: Although stainless steel has been produced for more than a hundred years, exposure-related mortality data for production workers are limited., Aims: To describe cause-specific mortality in Finnish ferrochromium and stainless steel workers., Methods: We studied Finnish stainless steel production chain workers employed between 1967 and 2004, from chromite mining to cold rolling of stainless steel, divided into sub-cohorts by production units with specific exposure patterns. We obtained causes of death for the years 1971-2012 from Statistics Finland. We calculated standardized mortality ratios (SMRs) as ratios of observed and expected numbers of deaths based on population mortality rates of the same region., Results: Among 8088 workers studied, overall mortality was significantly decreased (SMR 0.77; 95% confidence interval [CI] 0.70-0.84), largely due to low mortality from diseases of the circulatory system (SMR 0.71; 95% CI 0.61-0.81). In chromite mine, stainless steel melting shop and metallurgical laboratory workers, the SMR for circulatory disease was below 0.4 (SMR 0.33; 95% CI 0.07-0.95, SMR 0.22; 95% CI 0.05-0.65 and SMR 0.16; 95% CI 0.00-0.90, respectively). Mortality from accidents (SMR 0.84; 95% CI 0.67-1.04) and suicides (SMR 0.72; 95% CI 0.56-0.91) was also lower than in the reference population., Conclusions: Working in the Finnish ferrochromium and stainless steel industry appears not to be associated with increased mortality., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine.)

Background: Classic Kaposi sarcoma (cKS) is an inflammatory tumor caused by human herpesvirus 8 (HHV-8) commonly observed in elderly men of Mediterranean origin. We studied a Finnish family of 5 affected individuals in 2 generations. Except for atypical mycobacterial infection of the index case, the affected individuals did not have notable histories of infection., Methods: We performed genome and exome sequencing and mapped shared chromosomal regions to identify genetic predisposition in the family., Results: We identified 12 protein-coding candidate variants that segregated in the 3 affected cousins from whom we had samples. The affected mother of the index case was an obligatory carrier. Among the 12 candidates was a rare heterozygous substitution rs141331848 (c.1337C>T, p.Thr446Ile) in the DNA-binding domain of STAT4. The variant was not present in 242 Finnish control genomes or 180 additional regional controls. Activated T-helper cells from the HHV-8-negative variant carriers showed reduced interferon γ production, compared with age and sex matched wild-type individuals. We screened STAT4 in additional 18 familial KS cases and the variant site from 56 sporadic KS cases but detected no pathogenic mutations., Conclusions: Our data suggest that STAT4 is a potential cKS-predisposition gene, but further functional and genetic validation is needed., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background and Aim: Increased mortality has been reported in Crohn's disease (CD) but mostly not in ulcerative colitis (UC). We evaluated the overall and cause-specific mortality in a nationwide cohort of patients with inflammatory bowel disease (IBD) in Finland., Methods: A total of 21,964 patients with IBD (16,649 with UC and 5315 with CD) from the Special Reimbursement register were diagnosed 1987-1993 and 2000-2007 and followed up to the end of 2010 by collating these figures with the national computerized Cause-of-Death Register of Statistics Finland. In each cause-of-death category, the number of deaths reported was compared to that expected in general population, and expressed as a standardized mortality ratio (SMR)., Results: Overall mortality was increased among patients with CD (SMR 1.33, 95% confidence interval 1.21-1.46) and UC (1.10, 1.05-1.15). SMR was significantly increased for gastrointestinal causes in CD (6.53, 4.91-8.52) and UC (2.81, 2.32-3.34). Patients with UC were found also to have increased SMR from pulmonary (1.24, 1.02-1.46) and cardiovascular disease (1.14, 1.06-1.22) and cancers of the colon (1.90, 1.38-2.55), rectum (1.79, 1.14-2.69) and biliary tract (5.65, 3.54-8.54), whereas SMR from alcohol-related deaths was decreased (0.54, 0.39-0.71). Patients with CD had a significantly increased SMR for pulmonary diseases (2.01, 1.39-2.80), infections (4.27, 2.13-7.63) and cancers of the biliary tract (4.51, 1.23-11.5) and lymphoid and hematopoietic tissue (2.95, 1.85-4.45)., Conclusions: In this Finnish nationwide study increased overall mortality in both CD and UC was observed. The excess mortality of 14% in IBD is mainly due to deaths related to inflammation in the gut., (Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

This paper reviews the use of the Finnish Information System on Occupational Exposure (Finnish job-exposure matrix, FINJEM) in different applications in Finland and other countries. We describe and discuss studies on FINJEM and studies utilizing FINJEM in regard to the validity of exposure estimates, occupational epidemiology, hazard surveillance and prevention, the assessment of health risks and the burden of disease, the assessment of exposure trends and future hazards, and the construction of job-exposure matrices (JEMs) in countries other than Finland. FINJEM can be used as an exposure assessment tool in occupational epidemiology, particularly in large register-based studies. It also provides information for hazard surveillance at the national level. It is able to identify occupations with high average exposures to chemical agents and can therefore serve the priority setting of prevention. However, it has only limited use at the workplace level due to the variability of exposure between workplaces. The national estimates of exposure and their temporal trends may contribute to the assessment of both the recent and future burden of work-related health outcomes. FINJEM has also proved to be useful in the construction of other national JEMs, for example in the Nordic Occupational Cancer study in the Nordic countries. FINJEM is a quantitative JEM, which can serve many purposes and its comprehensive documentation also makes it potentially useful in countries other than Finland.

Increased incidence of skin cancers among airline cabin crew has been reported in several studies. We evaluated whether the difference in risk factor prevalence between Finnish airline cabin crew and the general population could explain the increased incidence of skin cancers among cabin crew, and the possible contribution of estimated occupational cosmic radiation exposure. A self-administered questionnaire survey on occupational, host, and ultraviolet radiation exposure factors was conducted among female cabin crew members and females presenting the general population. The impact of occupational cosmic radiation dose was estimated in a separate nested case-control analysis among the participating cabin crew (with 9 melanoma and 35 basal cell carcinoma cases). No considerable difference in the prevalence of risk factors of skin cancer was found between the cabin crew (N = 702) and the general population subjects (N = 1007) participating the study. The mean risk score based on all the conventional skin cancer risk factors was 1.43 for cabin crew and 1.44 for general population (P = 0.24). Among the cabin crew, the estimated cumulative cosmic radiation dose was not related to the increased skin cancer risk [adjusted odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.57-1.00]. The highest plausible risk of skin cancer for estimated cosmic radiation dose was estimated as 9% per 10 mSv. The skin cancer cases had higher host characteristics scores than the non-cases among cabin crew (adjusted OR = 1.43, 95% CI: 1.01-2.04). Our results indicate no difference between the female cabin crew and the general female population in the prevalence of factors generally associated with incidence of skin cancer. Exposure to cosmic radiation did not explain the excess of skin cancer among the studied cabin crew in this study.

Background: Trichloroethylene (TCE) is a widely used chlorinated solvent with demonstrated carcinogenicity in animal assays. Some epidemiologic studies have reported increased risk of cancer of the kidney, cervix, liver and biliary passages, non-Hodgkin lymphoma, and esophageal adenocarcinoma., Methods: We established a pooled cohort, including 5553 workers with individual documented exposure to TCE in Finland, Sweden, and Denmark. Study participants were monitored for the urinary TCE metabolite trichloroacetic acid from 1947 to 1989 and followed for cancer. Standardized incidence ratios (SIRs) were calculated based on cancer incidence rates in the three national populations. Cox proportionate hazard analyses were used for internal comparisons. Tests of statistical significance are two-sided., Results: Overall, 997 cases of cancer (n = 683 in men; n = 314 in women) were identified during 154 778 person-years of follow-up. We observed statistically significant elevated standardized incidence ratios for primary liver cancer (1.93; 95% confidence interval [CI] = 1.19 to 2.95) and cervical cancer (2.31; 95% CI = 1.32 to 3.75). The standardized incidence ratio for kidney cancer was 1.01 (95% CI = 0.70 to 1.42) based on 32 cases; we did not observe a statistically significant increased risk of non-Hodgkin's lymphoma (SIR = 1.26; 95% CI = 0.89 to 1.73) or esophageal adenocarcinoma (SIR = 1.84; 95% CI = 0.65 to 4.65). Tobacco- and alcohol-associated cancers were not statistically significantly increased., Conclusions: Our results suggest TCE exposure is possibly associated with an increased risk for liver cancer. The relationship between TCE exposure and risks of cancers of low incidence and those with confounding by lifestyle and other factors not known in our cohort require further study.

Background: Dermatitis herpetiformis (DH) is an extra-intestinal manifestation of coeliac disease and most patients adhere to a life-long gluten free diet (GFD). Increased mortality rates have been reported in coeliac disease but knowledge in DH is scanty., Objectives: To survey the mortality rate and causes of death in a large cohort of patients with DH., Material and Methods: Patients with DH (n = 476 consecutive patients) diagnosed from 1970 onwards at the Tampere University Hospital were analysed for causes of death during 1971-2010. A questionnaire survey on key aspects of health behaviour was performed in patients with DH and comparisons were made with the Finnish population., Results: The total number of deaths during 9079 person years followed up was 77 whereas 110 were expected. The standardized mortality rate (SMR) for all causes of death was significantly reduced, being 0·70 (95% CI 0·55-0·87), and similar in both sexes. The SMR was equal in the patients with DH with (0·73) and without (0·77) small bowel villous atrophy. The SMR was significantly reduced (0·38) for deaths due to cerebrovascular diseases. The SMR due to lymphoproliferative malignancies was significantly increased (6·86) in the first 5 years of follow-up but not thereafter. The questionnaire survey documented that 97·7% of the patients with DH adhered to a GFD. The patients reported significantly less hypercholesterolaemia and there were fewer current and past smokers compared with the age- and sex-matched control population., Conclusions: The present long-term follow-up study of DH documented significantly reduced all-cause and cerebrovascular disease mortality. Strict adherence to a GFD, less smoking and hypercholesterolaemia may play a role in the observed health benefit., (©The Authors BJD © 2012 British Association of Dermatologists.)

The authors conducted a nationwide cohort study to evaluate the association between postmenopausal hormone therapy and meningioma incidence in Finland. All women who had used hormone therapy at least for 6 months at the age of 50 years or older during 1994-2009 were included. Women who had used postmenopausal hormone therapy were identified from the medical reimbursement register of the Social Insurance Institution (131,480 estradiol users and 131,248 estradiol-progestin users), and meningioma cases were identified from the Finnish Cancer Registry. During the average 9 years of follow-up, 289 estradiol users and 196 estradiol-progestin users were diagnosed with meningioma. Ever use of estradiol-only therapy was associated with an increased risk of meningioma (standardized incidence ratio = 1.29, 95% confidence interval: 1.15, 1.44). Among women who had been using estradiol-only therapy for at least 3 years, the incidence of meningioma was 1.40-fold higher (95% confidence interval: 1.18, 1.64; P < 0.001) than in the background population. In contrast, this risk was not increased in users of combination therapy (standardized incidence ratio = 0.93, 95% confidence interval: 0.80, 1.06). There was no difference in risk between continuous and sequential use of hormone therapy. Estradiol-only therapy was accompanied with a slightly increased risk of meningioma.

Personality traits have been studied extensively as risk and prognostic factors for cancer; however, the association remains unclear. This prospective, population-based cohort study comprised 59,548 Swedish (1974-1999) and Finnish (1976-2004) participants who completed a questionnaire eliciting information for the Eysenck Personality Inventory and on health behavior at baseline. To analyze the association of personality traits extraversion and neuroticism with risk of cancer, the authors identified 4,631 cancer cases for a maximum 30 years of follow-up. To assess the association with cancer survival among the Finnish participants, they identified 2,733 cancer cases and, later, 1,548 deaths for a maximum 29 years of follow-up. Hazard ratios were estimated by treating the personality scales as continuous variables and are presented per one increase in score on each scale. In multivariate analyses, extraversion and neuroticism were not significantly associated with risk of cancers at all sites (extraversion: hazard ratio = 0.99, 95% confidence interval: 0.98, 1.01; neuroticism: hazard ratio = 1.00, 95% confidence interval: 0.99, 1.02). Results showed no significant association between these traits and the hazard ratio for death after cancers at all sites, and they do not support the hypothesis that extraversion and neuroticism are direct risk factors for cancer or survival after cancer.

The database of two population-based cancer registries (Philippine Cancer Society-Manila Cancer Registry and Department of Health-Rizal Cancer Registry) was used to generate age-standardized incidence rates of cancer during 1980-2002. Five-year relative survival rates were obtained for incident cases from 1993 to 2002 using a period analysis method. Overall incidence had increased in both males and females. Among males, lung cancer was the leading cancer and reached a peak in 1988-92. Colorectal and prostate cancers showed rising trends and became more common than liver cancer, with stable incidence over time. Stomach cancer incidence fell steeply. Among females, there was a steady increase in incidence of breast cancer. There was a slight decrease in the incidence of the second common cancer, cervical cancer, and colorectal cancer became equally common. Lung cancer incidence in females also reached a peak by 1998-2002 and then slightly decreased. Oral cavity cancer decreased strongly in the last period. In general, survival rates among Philippine residents were one-third lower than among Filipino-Americans and Whites in the USA especially in cancer sites wherein effective early detection methods may be available such as breast, cervix, colorectal and thyroid cancers. Survival was also lower in Philippine leukemia cases, a disease wherein effective treatment is proven in some types but is quite expensive. Lifestyle factors such as smoking, unhealthy diet, physical inactivity, and human papillomavirus and hepatitis B virus infections were associated with some incidence patterns. Late stage at diagnosis was largely responsible for low survival.

Background: The risk factors for Merkel cell carcinoma (MCC), a rare type of skin cancer, are poorly understood. Some evidence suggests that MCC is more common in individuals with abnormal immune function resulting from viral infection, autoimmune disease or organ trans- plantation., Methods: The national Renal Transplant Registry and the Finnish Cancer Registry data were searched for recipients of a renal transplant who were diagnosed with MCC. The MCC diagnoses were confirmed using immunohistochemistry., Results: Three cases of MCC were detected among 4200 individuals who underwent renal transplantation from 1967 to 2005 [expected number 0.05, standardized incidence ratio (SIR) 66, 95% CI 14-194, P <0.001]. The latency period between the transplant and detection of MCC ranged from 6 to 19 years. In all three cases, the cause of transplantation was an autoimmune disease. All three died from aggressive MCC with a survival time ranging from 0.5 to 2.1 years., Conclusions: The results indicate that the risk of MCC is greatly increased among subjects who have undergone renal transplantation. The course of the disease appears aggressive in this patient population. The physicians who treat recipients of a kidney transplant should be aware of the substantially increased risk of MCC.

Background: Our aim was to assess the mortality of fishermen and fishermen's wives in Finland, presuming that the mortality reflects their high consumption of contaminated fish., Methods: All Finnish fishermen, registered since 1980, were identified from the Professional Fishermen Register (N = 6410), and the fishermen's wives from the national population register (N = 4260). The cohorts were individually linked with cause-of-death data until 2005 at Statistics Finland. The follow-up started in the year after the first registration as a fisherman and at marriage (if later) for the wives. The standardized mortality ratios (SMRs) were calculated based on the national mortality rates. In addition, blood samples and food frequency questionnaire data were collected from a volunteer sample., Results: The average fish consumption and serum concentrations of fish-derived fatty acids and environmental contaminants were higher among the fishermen and their wives than among the general population from the same region. The fishermen and their wives had lower mortality from all causes (SMR 0.78, 95% confidence interval (CI) 0.73-0.82, and 0.84, 0.76-0.93, respectively), and ischaemic heart diseases (0.73, 0.65-0.81, and 0.65, 0.50-0.83) than the general population. Mortality from cerebrovascular diseases and malignant neoplasms was decreased among the fishermen (0.67, 0.52-0.85, and 0.90, 0.80-1.01), but not among the wives. In addition, the fishermen's mortality from water transport accidents was extremely high (8.31, 5.65-11.79)., Conclusions: The fishermen and their wives had lower mortality from many natural causes. The high intakes of environmental contaminants in fish were not seen as excess mortality.

Trends in incidence and mortality rates of prostate cancer were analyzed using data from the national cancer registries of Denmark, Finland, Iceland, Norway, and Sweden. Joinpoint regression models were used to quantify temporal trends for the period from 1980 to 2004. Incidence rates were increasing and similar in the Nordic countries during the 1980s. Around 1990, a more rapid incidence increase began in all Nordic countries except Denmark, where an increase was seen 5 years later. In 2001, incidence rates in Denmark were half of those seen in the other Nordic countries, but mortality rates varied only marginally among countries. Mean annual declines in prostate cancer mortality of 1.9% (95% CI = 0.4% to 3.3%) and 1.8% (95% CI = 0.5% to 3.0%) were observed from 1996 to 2004 in Finland and Norway, respectively. During the same period, mortality rates leveled off in Iceland and Sweden but continued to increase in Denmark. The rapid increase in incidence during the early 1990s coincided with the introduction of the prostate-specific antigen (PSA) test and conveys little information about the occurrence of potentially lethal disease. Mortality rates, however, have recently stabilized or declined in countries where PSA testing and curative treatment have been commonly practiced since the late 1980s. Although other explanatory factors may be in operation, these trends are consistent with a moderate effect of increased curative treatment of early diagnosed prostate cancer and improved treatment of more advanced disease.

Background: Given the extended survival of patients diagnosed with cervical cancer, the large number of these women treated with radiotherapy, and the presence in this population of established cancer risk factors such as human papillomavirus (HPV) infection and cigarette smoking, it is important to clarify long-term trends in second cancer risk., Methods: Using data from 104,760 one-year survivors of cervical cancer reported to 13 population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States, we calculated standardized incidence ratios (SIRs) for second cancers overall and cancers at particular sites among women with cervical cancer, including cervical cancer patients who were treated or not treated with radiation, over more than 40 years of follow-up. Cox regression models were used to assess the time-varying association of radiotherapy with risk of second cancers and to assess the interaction of radiation treatment with age at diagnosis. All statistical tests were two-sided., Results: Among 104,760 one-year survivors of cervical cancer, the risk of all second cancers taken together was increased to a statistically significant extent (n = 12,496; SIR = 1.30; 95% confidence interval [CI] = 1.28 to 1.33). Compared with the general population, in both radiotherapy (N = 52,613) and no-radiotherapy groups (N = 27,382), risks for HPV-related cancers (of the pharynx, genital sites, and rectum/anus) and smoking-related cancers (of the pharynx, trachea/bronchus/lung, pancreas, and urinary bladder) were elevated to a statistically significant extent. Cervical cancer patients treated with radiotherapy, but not those who did not receive radiotherapy, were at increased risk for all second cancers and cancers at heavily irradiated sites (colon, rectum/anus, urinary bladder, ovary, and genital sites) beyond 40 years of follow-up compared with women in the general population. The association of radiotherapy with second cancer risk was modified by age at cervical cancer diagnosis for rectum/anus, genital sites, and urinary bladder, with higher hazard ratios for second cancer at younger ages of cervical cancer. After adjustment for competing mortality, the 40-year cumulative risk of any second cancer was higher among women diagnosed with cervical cancer before age 50 (22.2%; 95% CI = 21.5% to 22.8%) than among women diagnosed after age 50 (16.4%; 95% CI = 16.1% to 16.9%)., Conclusion: Cervical cancer patients treated with radiotherapy are at increased risk of second cancers at sites in close proximity to the cervix beyond 40 years of follow-up.

Objectives: The objective of this study was to evaluate the performance and effectiveness of a register of employees exposed to carcinogens (the ASA Register) which has been in operation in Finland since 1979, and to study cancer risks among the notified workers., Methods: The impact of ASA at workplaces was studied by questionnaires mailed to 1448 work departments, which were notified to ASA in 1996, and to 1033 departments, which departed ASA in 1991-1996. The mailing was responded by 69% of departments. The cancer incidence of 35,138 workers notified to ASA in 1979-1988 was followed up through the files of the Finnish Cancer Register for the period 1980-2003., Results: Changes eliminating or substantially reducing exposure to carcinogens were reported by 73% of departments notified to ASA in 1996. The ASA notification process had directly prompted measures to reduce exposure (8% of cases) or contributed to them (24% of cases). Estimations based on responses of the workplaces suggested that the ASA registration had decreased exposure of 600 workers year(-1) (out of approximately 15,000 notified workers, which is <1% of the employed in Finland), preventing thereby an unknown number of occupational cancers. Other benefits of ASA included the saving of the treatment costs of prevented cancers, the prevention of other health outcomes of carcinogens, improved safety behaviour of exposed workers and avoidance of human suffering among cancer patients and their families. The labour safety authorities had better possibilities to direct their activities against carcinogen exposure. These benefits should be considered against the annual costs, mainly due to 7-8 person-years of work required by tasks related to ASA. The results of the cancer incidence study among notified workers were based on a relatively short follow-up (on average 19 years). The incidence of mesothelioma was significantly increased in the ASA cohort, probably due to exposure to asbestos., Conclusions: These results suggest that a national exposure register may stimulate preventive measures at workplaces. Partially based on the results of the present study the Finnish Ministry of Social Affairs and Health continues ASA registration.

Background: Although modern treatments for testicular cancer are associated with increased survival, the long-term health effects of these treatments are unclear. We conducted a population-based study to quantify the long-term risks of mortality from noncancer causes among men with testicular cancer., Methods: We identified 38,907 one-year survivors of testicular cancer within 14 population-based cancer registries in North America and Europe (from 1943 through 2002). We used data from these registries to calculate standardized mortality ratios (SMRs) for noncancer deaths and to evaluate associations between histology, age at testicular cancer diagnosis, calendar year of diagnosis, and initial treatment and the risk of noncancer mortality. All statistical tests were two-sided., Results: A total of 2942 deaths from all noncancer causes were reported after a median follow-up of 10 years, exceeding the expected number of deaths from all noncancer causes in the general population by 6% (SMR = 1.06, 95% confidence interval [CI] = 1.02 to 1.10); the noncancer standardized mortality ratios did not differ statistically significantly between patients diagnosed before and after 1975, when cisplatin-based chemotherapy came into widespread use. Compared with the general population, testicular cancer survivors had higher mortality from infections (SMR = 1.28, 95% CI = 1.12 to 1.47) and from digestive diseases (SMR = 1.44, 95% CI = 1.26 to 1.64). Mortality from all circulatory diseases was statistically significantly elevated in men diagnosed with testicular cancer before age 35 years (1.23, 95% CI = 1.09 to 1.39) but not in men diagnosed at older ages (SMR = 0.94; 95% CI = 0.89 to 1.00). Men treated with chemotherapy (with or without radiotherapy) in 1975 or later had higher mortality from all noncancer causes (SMR = 1.34, 95% CI = 1.15 to 1.55), all circulatory diseases (SMR = 1.58, 95% CI = 1.25 to 2.01), all infections (SMR = 2.48, 95% CI = 1.70 to 3.50), and all respiratory diseases (SMR = 2.53, 95% CI = 1.26 to 4.53). Testicular cancer patients who were younger than 35 years at diagnosis and were treated with radiotherapy alone in 1975 or later had higher mortality from all circulatory diseases (SMR = 1.70, 95% CI = 1.21 to 2.31) compared with the general population., Conclusion: Men who have survived for at least 1 year after being diagnosed with testicular cancer have a slightly higher risk of dying from noncancer causes, including infections, digestive diseases, and circulatory diseases, than the general population. Men treated with chemotherapy in 1975 or later may be at particularly high risk.

After identifying an association between maternal Epstein-Barr virus (EBV) reactivation and acute lymphoblastic leukemia (ALL), the authors analyzed a nested case-control study within Finnish and Icelandic maternity cohorts with 7 million years of follow-up to confirm EBV's role in ALL. Offspring of 550,000 mothers were followed up to age 15 years during 1975-1997 by national cancer registries to identify leukemia cases. Mothers of cases and three quarters of matched mothers of controls were identified by national population registers. First-trimester sera from mothers of 304 ALL cases and 39 non-ALL cases and from 943 mothers of controls were analyzed for antibodies to viral capsid antigen, early antigen, and EBV transactivator protein ZEBRA. Relative risk, estimated as odds ratio (95% confidence interval), was adjusted for birth order and sibship size. Combining early antigen and/or ZEBRA immunoglobulin G antibodies with the presence of viral capsid antigen immunoglobulin M antibodies did not increase the estimate for ALL risk for viral capsid antigen immunoglobulin M alone (odds ratio = 1.9, 95% confidence interval: 1.2, 3.0). Both ZEBRA immunoglobulin G antibodies and viral capsid antigen immunoglobulin M antibodies were associated with an increased risk of non-ALL in the offspring (odds ratio = 4.5, 95% confidence interval: 1.3, 16; odds ratio = 5.6, 95% confidence interval: 1.1, 29, respectively), suggesting EBV reactivation in the mothers of non-ALL cases. EBV reactivation may be associated with a proportion of childhood leukemia.

Few studies have examined long-term suicide risk among breast cancer survivors, and there are no data for women in the United States. We quantified suicide risk through 2002 among 723,810 1-year breast cancer survivors diagnosed between January 1, 1953, and December 31, 2001, and reported to 16 population-based cancer registries in the United States and Scandinavia. Among breast cancer survivors, we calculated standardized mortality ratios (SMRs) and excess absolute risks (EARs) compared with the general population, and the probability of suicide. We used Poisson regression likelihood ratio tests to assess heterogeneity in SMRs; all statistical tests were two-sided, with a .05 cutoff for statistical significance. In total 836 breast cancer patients committed suicide (SMR = 1.37, 95% confidence interval [CI] = 1.28 to 1.47; EAR = 4.1 per 100,000 person-years). Although SMRs ranged from 1.25 to 1.53 among registries, with 245 deaths among the sample of US women (SMR = 1.49, 95% CI = 1.32 to 1.70), differences among registries were not statistically significant (P for heterogeneity = .19). Risk was elevated throughout follow-up, including for 25 or more years after diagnosis (SMR = 1.35, 95% CI = 0.82 to 2.12), and was highest among black women (SMR = 2.88, 95% CI = 1.44 to 5.17) (P for heterogeneity = .06). Risk increased with increasing stage of breast cancer (P for heterogeneity = .08) and remained elevated among women diagnosed between 1990 and 2001 (SMR = 1.36, 95% CI = 1.18 to 1.57). The cumulative probability of suicide was 0.20% 30 years after breast cancer diagnosis.

Context: Increasing incidence and improved prognosis of thyroid cancer have led to concern about the development of second primary cancers, especially after radioiodine treatment. Thyroid cancer can also arise as a second primary neoplasm after other cancers., Objective: The objective of the study was to assess the risk of second primary cancer after thyroid cancer and vice versa., Design: This was a multinational record linkage study., Setting: The study was conducted at 13 population-based cancer registries in Europe, Canada, Australia, and Singapore., Patients or Other Participants: A cohort of 39,002 people (356,035 person-yr of follow-up) with primary thyroid cancer were followed up for SPN for up to 25 yr, and 1,990 cases of thyroid cancer were diagnosed after another primary cancer., Main Outcome Measures: To assess any possible excess of second primary neoplasms after thyroid cancer, the observed numbers of neoplasms were compared with expected numbers derived from age-, sex-, and calendar period-specific cancer incidence rates from each of the cancer registries, yielding standardized incidence ratios (SIRs). The SIR of second primary thyroid cancer after various types of cancer was also calculated., Results: During the observation period, there were 2821 second primary cancers (all sites combined) after initial diagnosis of thyroid cancer, SIR of 1.31 (95% confidence interval 1.26-1.36) with significantly elevated risks for many specific cancers. Significantly elevated risks of second primary thyroid cancer were also seen after many types of cancer., Conclusion: Pooled data from 13 cancer registries show a 30% increased risk of second primary cancer after thyroid cancer and increased risks of thyroid cancer after various primary cancers. Although bias (detection, surveillance, misclassification) and chance may contribute to some of these observations, it seems likely that shared risk factors and treatment effects are implicated in many. When following up patients who have been treated for primary thyroid cancer, clinicians should maintain a high index of suspicion for second primary cancers.

Studies of pancreatic cancer in the setting of second primary malignant neoplasms can provide etiologic clues. An international multicenter study was carried out using data from 13 cancer registries with a registration period up to year 2000. Cancer patients were followed up from the initial cancer diagnosis, and the occurrence of second primary malignant neoplasms was compared with expected values derived from local rates, adjusting for age, sex, and period of diagnosis. Results from individual registries were pooled by use of a fixed-effects model. People were at higher risk of developing pancreatic cancer within 10 years of a diagnosis of cancers of the pharynx, stomach, gallbladder, larynx, lung, cervix, corpus uteri, bladder, and eye and 10 years or later following a diagnosis of cancers of the stomach, colon, gallbladder, breast, cervix, placenta, corpus uteri, ovary, testis, bladder, kidney, and eye, as well as Hodgkin's and non-Hodgkin's lymphomas. Pancreatic cancer was connected with smoking-related cancers, confirming the etiologic role of tobacco. The associations with uterine and ovarian cancers suggest that reproductive factors might be implicated in pancreatic carcinogenesis. The elevated pancreatic cancer risk in young patients observed among several types of cancer implies a role of genetic factors. Radiotherapy is also suggested as a risk factor.

Knowledge is limited on mortality of grand multiparous women (> or =5 deliveries), whose hormonal, metabolic, and social conditions differ from the average. The authors studied overall and cause-specific mortality in 1974-2001 among 87,922 grand multiparous women including 3,678 grand grand multiparous women (> or =10 deliveries) in Finland. Standardized mortality ratios were defined as ratios of observed to expected numbers of deaths, both derived from national cause-of-death files. During follow-up, 18,870 grand multiparous women and 625 grand grand multiparous women died (standardized mortality ratios (SMRs) = 0.95 and 1.01, respectively). Decreased mortality among grand multiparous women was found for cancers of the breast (SMR = 0.64, 95% confidence interval (CI): 0.59, 0.69), corpus uteri (SMR = 0.68, 95% CI: 0.56, 0.80), ovary (SMR = 0.68, 95% CI: 0.60, 0.75), bladder (SMR = 0.59, 95% CI: 0.41, 0.82), and respiratory tract (SMR = 0.80, 95% CI: 0.72, 0.88). The only malignant tumor associated with elevated mortality was kidney cancer (SMR = 1.38, 95% CI: 1.21, 1.56). The standardized mortality ratio was also low for dementia (SMR = 0.78, 95% CI: 0.72, 0.84), respiratory diseases (SMR = 0.80, 95% CI: 0.75, 0.85), and accidents and violent causes (SMR = 0.79, 95% CI: 0.73, 0.84). Mortality from diabetes mellitus (SMR = 1.42, 95% CI: 1.29, 1.55) and ischemic heart disease (SMR = 1.10, 95% CI: 1.08, 1.13) was increased. According to this study, overall mortality among grand multiparous women is not elevated. Low mortality from cancers is offset by higher mortality from cardiovascular conditions and diabetes mellitus.

Treatments for Hodgkin lymphoma are associated with large relative risks of acute myeloid leukemia (AML), but there are few estimates of the excess absolute risk (EAR), a useful measure of disease burden. One-year Hodgkin lymphoma survivors (N = 35,511) were identified within 14 population-based cancer registries in Nordic countries and North America from January 1, 1970, through December 31, 2001. We used Poisson regression analysis to model the EAR of AML, per 10,000 person-years. A total of 217 Hodgkin lymphoma survivors were diagnosed with AML (10.8 expected; unadjusted EAR = 6.2; 95% confidence interval = 5.4 to 7.1). Excess absolute risk for AML was highest during the first 10 years after Hodgkin lymphoma diagnosis but remained elevated thereafter. In subsequent analyses, adjusted for time since Hodgkin lymphoma diagnosis and presented for the 5-9 year interval, the EAR was statistically significantly (P < .001) larger in patients diagnosed with Hodgkin lymphoma at age 35 years and older than in those diagnosed before 35 years of age. The EAR of AML declined statistically significantly after 1984 (7.0 to 4.2 and 16.4 to 9.9 in the < 35 and > or = 35 age groups, respectively), which may be associated with modifications in chemotherapy.

Background: Many women develop breast cancer after treatment for Hodgkin lymphoma (HL) at a young age. We estimated this future risk, taking into account age and calendar year of HL diagnosis, HL treatment information, population breast cancer incidence rates, and competing causes of death., Methods: Relative risks of breast cancer for categories defined by radiation dose to the chest (0, 20- < 40 Gy, or > or = 40 Gy) and use of alkylating agents (yes or no) were estimated from a case-control study conducted within an international population-based cohort of 3817 female 1-year survivors of HL diagnosed at age 30 years or younger from January 1, 1965, through December 31, 1994. To compute cumulative absolute risks of breast cancer, we used modified standardized incidence ratios to relate cohort breast cancer risks to those in the general population, enabling application of population-based breast cancer rates, and we allowed for competing risks by using population-based mortality rates in female HL survivors., Results: Cumulative absolute risks of breast cancer increased with age at end of follow-up, time since HL diagnosis, and radiation dose. For an HL survivor who was treated at age 25 years with a chest radiation dose of at least 40 Gy without alkylating agents, estimated cumulative absolute risks of breast cancer by age 35, 45, and 55 years were 1.4% (95% confidence interval [CI] = 0.9% to 2.1%), 11.1% (95% CI = 7.4% to 16.3%), and 29.0% (95% CI = 20.2% to 40.1%), respectively. Cumulative absolute risks were lower in women treated with alkylating agents., Conclusions: Breast cancer projections varied considerably by type of HL therapy, time since HL diagnosis, and age at end of follow-up. These estimates are applicable to HL survivors treated with regimens of the past and can be used to counsel such patients and plan management and preventive strategies. Projections should be used with caution, however, in patients treated with more recent approaches, including limited-field radiotherapy and/or ovary-sparing chemotherapy.

A case-control study was nested within two maternity cohorts with a total of 7 million years of follow-up for assessment of the role of bacterial infections in childhood leukemia. Offspring of 550,000 mothers in Finland and Iceland were combined to form a joint cohort that was followed for cancer up to 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 population registers. First-trimester serum samples were retrieved from mothers of 341 acute lymphoblastic leukemia cases and 61 other leukemia cases and from 1,212 control mothers. Sera were tested for antibodies to the genus Chlamydia, Helicobacter pylori, and Mycoplasma pneumoniae. Odds ratios and 95% confidence intervals, adjusted for sibship size, were calculated as estimates of relative risk. M. pneumoniae immunoglobulin M appeared to be associated with increased risk (odds ratio (OR) = 1.6), but the association lost statistical significance when the specificity of the immunoglobulin M was considered (OR = 1.5, 95% confidence interval: 0.9, 2.4). In Iceland, H. pylori immunoglobulin G was associated with increased risk of childhood leukemia in offspring (OR = 2.8, 95% confidence interval: 1.1, 6.9). Since H. pylori immunoglobulin G indicates chronic carriage of the microorganism, early colonization of the offspring probably differs between Iceland and Finland, two affluent countries.

Background: Although second primary cancers are a leading cause of death among men with testicular cancer, few studies have quantified risks among long-term survivors., Methods: Within 14 population-based tumor registries in Europe and North America (1943-2001), we identified 40,576 1-year survivors of testicular cancer and ascertained data on any new incident solid tumors among these patients. We used Poisson regression analysis to model relative risks (RRs) and excess absolute risks (EARs) of second solid cancers. All statistical tests were two-sided., Results: A total of 2,285 second solid cancers were reported in the cohort. The relative risk and EAR decreased with increasing age at testicular cancer diagnosis (P < .001); the EAR increased with attained age (P < .001) but the excess RR decreased. Among 10-year survivors diagnosed with testicular cancer at age 35 years, the risk of developing a second solid tumor was increased (RR = 1.9, 95% confidence interval [CI] = 1.8 to 2.1). Risk remained statistically significantly elevated for 35 years (RR = 1.7, 95% CI = 1.5 to 2.0; P < .001). We observed statistically significantly elevated risks, for the first time, for cancers of the pleura (malignant mesothelioma; RR = 3.4, 95% CI = 1.7 to 5.9) and esophagus (RR = 1.7, 95% CI = 1.0 to 2.6). Cancers of the lung (RR = 1.5, 95% CI = 1.2 to 1.7), colon (RR = 2.0, 95% CI = 1.7 to 2.5), bladder (RR = 2.7, 95% CI = 2.2 to 3.1), pancreas (RR = 3.6, 95% CI = 2.8 to 4.6), and stomach (RR = 4.0, 95% CI = 3.2 to 4.8) accounted for almost 60% of the total excess. Overall patterns were similar for seminoma and nonseminoma patients, with lower risks observed for nonseminoma patients treated after 1975. Statistically significantly increased risks of solid cancers were observed among patients treated with radiotherapy alone (RR = 2.0, 95% CI = 1.9 to 2.2), chemotherapy alone (RR = 1.8, 95% CI = 1.3 to 2.5), and both (RR = 2.9, 95% CI = 1.9 to 4.2). For patients diagnosed with seminomas or nonseminomatous tumors at age 35 years, cumulative risks of solid cancer 40 years later (i.e., to age 75 years) were 36% and 31%, respectively, compared with 23% for the general population., Conclusions: Testicular cancer survivors are at statistically significantly increased risk of solid tumors for at least 35 years after treatment. Young patients may experience high levels of risk as they reach older ages. The statistically significantly increased risk of malignant mesothelioma in testicular cancer survivors has, to our knowledge, not been observed previously in a cohort of patients treated with radiotherapy.

Few studies have suggested that elevated blood pressure might be associated with increased risk of lung cancer and that this association might vary according to smoking status. The aim of this study was to assess the effect of blood pressure and its possible interaction with smoking on lung cancer incidence in hypertensive patients. Lung cancer incidence was determined for 7,908 men enrolled in the hypertension register of the North Karelia Project between 1972 and 1988 by record linkage to the nationwide Finnish Cancer Registry. In a Cox regression model, both systolic and diastolic blood pressures were significant predictors of lung cancer, with a 10% increase in risk per 10-mmHg increment in blood pressure. In smokers, the age-adjusted hazard ratio associated with a 10-mmHg increment in diastolic blood pressure was 1.17 (95% confidence interval: 1.05, 1.29), and in nonsmokers it was 0.98 (95% confidence interval: 0.80, 1.16). For systolic blood pressure, these hazard ratios were 1.11 (95% confidence interval: 1.05, 1.17) for smokers and 1.04 (95% confidence interval: 0.95, 1.14) for nonsmokers. These findings suggest that high blood pressure levels are associated with increased risk of lung cancer in smoking, hypertensive men.

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.

There is concern about the health effects of exposure to cosmic radiation during air travel. To study the potential health effects of this and occupational exposures, the authors investigated mortality patterns among more than 44,000 airline cabin crew members in Europe. A cohort study was performed in eight European countries, yielding approximately 655,000 person-years of follow-up. Observed numbers of deaths were compared with expected numbers based on national mortality rates. Among female cabin crew, overall mortality (standardized mortality ratio (SMR) = 0.80, 95% confidence interval (CI): 0.73, 0.88) and all-cancer mortality (SMR = 0.78, 95% CI: 0.66, 0.95) were slightly reduced, while breast cancer mortality was slightly but nonsignificantly increased (SMR = 1.11, 95% CI: 0.82, 1.48). In contrast, overall mortality (SMR = 1.09, 95% CI: 1.00, 1.18) and mortality from skin cancer (for malignant melanoma, SMR = 1.93, 95% CI: 0.70, 4.44) among male cabin crew were somewhat increased. The authors noted excess mortality from aircraft accidents and from acquired immunodeficiency syndrome in males. Among airline cabin crew in Europe, there was no increase in mortality that could be attributed to cosmic radiation or other occupational exposures to any substantial extent. The risk of skin cancer among male crew members requires further attention.

Background: Human serum paraoxonase eliminates carcinogenic lipid-soluble radicals. Because expression of the main human paraoxonase gene PON1 varies widely in humans, certain PON1 polymorphisms might be associated with increased risks of cancer. We sought new functional mutations in PON1 and determined whether known or new PON1 mutations were associated with the risk for prostate cancer in a prospective, random, population-based sample of Finnish men and in a case-control study., Methods: Serum paraoxonase activity was measured in 835 healthy men in the Kuopio Ischaemic Heart Disease Risk Factor Study. PON1 mutations were identified by hierarchical phenotype-targeted sequencing in DNAs from the 100 men with the lowest paraoxonase activity in this cohort, and 1595 men in the cohort were genotyped for PON1 mutations by restriction fragment length polymorphism. Multivariable analysis was used to investigate the association of known and new PON1 mutations with incident prostate cancer in 1569 cancer-free men in the cohort followed for 9-14 years. In a case-control study of Finnish men, the association of prostate cancer with the PON1 mutation identified in the cohort study was investigated in 69 case patients with familial prostate cancer and 69 unmatched healthy control subjects., Results: We identified a new single-nucleotide PON1 polymorphism associated with decreased serum paraoxonase activity that caused an isoleucine-->valine change at codon 102 in exon 4 (I102V). Of the 1569 men cancer-free at baseline, 56 (3.6%) were carriers of the I102V mutation. After adjusting for age and cholesterol-lowering medications, the relative risk for developing prostate cancer during follow-up was 6.3 (95% confidence interval [CI] = 2.1 to 19.2) among 102V allele carriers compared with noncarriers. Other PON1 alleles were not statistically significantly associated with prostate cancer. In the case-control study, patients with familial prostate cancer were more likely to be carriers of the PON1 I102V mutation than control subjects (odds ratio = 4.3, 95% CI = 0.9 to 21.5)., Conclusion: The PON1 102V allele appears to be associated with an increased risk for prostate cancer.

Background: Both hereditary and environmental factors are implicated in the aetiology of cutaneous neoplasms. Studies of twins make it possible to estimate the contribution of inherited genes to the development of disease., Objective: To assess the importance of hereditary and environmental factors (including physical environment and lifestyles) in malignant melanoma and malignant nonmelanoma of the skin., Methods: The Finnish Twin Cohort, comprising 25 882 adult like-sexed twins with established zygosity, was linked with the Finnish Cancer Registry to identify malignant skin cancers in a prospective follow-up from 1976 to 1997. Standardized incidence ratios were computed based on national rates., Results: Sixty twins were diagnosed with melanoma and 49 twins with nonmelanoma during the follow-up. The risks of these cancers did not differ from the risk in the population at large. There was only one pair where both twins had a malignant skin cancer (dizygotic male twins both with squamous cell carcinoma)., Conclusions: The near-total lack of concordance for skin cancer in twin pairs suggests that environmental and not hereditary effects are most important in the causation of malignant skin cancers in a white population with low levels of sun exposure.

Background: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use., Methods: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided., Results: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment., Conclusions: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.