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author:("Pukkala, zero")
1.  Assessing the Effect of Treatment Duration on the Association between Anti-Diabetic Medication and Cancer Risk 
PLoS ONE  2014;9(11):e113162.
Most studies that have evaluated the association between anti-diabetic medication and cancer risk have suffered from methodological drawbacks. To avoid time-related biases, we evaluated the effect of treatment duration on the cancer risk among naive users of anti-diabetic medication as compared to non-users. In addition, we addressed the influence of common risk factors such as smoking and BMI. The study population comprised 23,394 participants of FINRISK surveys. Data on cancer and anti-diabetic medication were linked with the study cohorts. We applied Lexis tabulation to the data and analyzed split records by using Poisson regression. Changes in cancer incidence in relation to treatment duration were examined by modeling the rate ratio (RR). After a median follow-up of 9 years, 53 cancer cases among users of anti-diabetic medication and 1,028 among non-users were diagnosed. No significant difference in cancer risk between users and non-users was observed after adjustment. The RR for all medication regardless of its duration was 1.01 [95% CI 0.75–1.33], and 1.37 [0.94–1.94] for period of 1–4 years. The results were similar for metformin, sulfonylurea, and insulin. This study demonstrates that evaluation of the variation in cancer risk in relation to treatment duration is of particular importance for enhancing the accuracy of conclusions on the link between exposure to anti-diabetic medication and cancer risk.
doi:10.1371/journal.pone.0113162
PMCID: PMC4242520  PMID: 25419576
2.  Statin Use and Breast Cancer Survival: A Nationwide Cohort Study from Finland 
PLoS ONE  2014;9(10):e110231.
Recent studies have suggested that statins, an established drug group in the prevention of cardiovascular mortality, could delay or prevent breast cancer recurrence but the effect on disease-specific mortality remains unclear. We evaluated risk of breast cancer death among statin users in a population-based cohort of breast cancer patients. The study cohort included all newly diagnosed breast cancer patients in Finland during 1995–2003 (31,236 cases), identified from the Finnish Cancer Registry. Information on statin use before and after the diagnosis was obtained from a national prescription database. We used the Cox proportional hazards regression method to estimate mortality among statin users with statin use as time-dependent variable. A total of 4,151 participants had used statins. During the median follow-up of 3.25 years after the diagnosis (range 0.08–9.0 years) 6,011 participants died, of which 3,619 (60.2%) was due to breast cancer. After adjustment for age, tumor characteristics, and treatment selection, both post-diagnostic and pre-diagnostic statin use were associated with lowered risk of breast cancer death (HR 0.46, 95% CI 0.38–0.55 and HR 0.54, 95% CI 0.44–0.67, respectively). The risk decrease by post-diagnostic statin use was likely affected by healthy adherer bias; that is, the greater likelihood of dying cancer patients to discontinue statin use as the association was not clearly dose-dependent and observed already at low-dose/short-term use. The dose- and time-dependence of the survival benefit among pre-diagnostic statin users suggests a possible causal effect that should be evaluated further in a clinical trial testing statins’ effect on survival in breast cancer patients.
doi:10.1371/journal.pone.0110231
PMCID: PMC4203770  PMID: 25329299
3.  Stomach Cancer Risk After Treatment for Hodgkin Lymphoma 
Journal of Clinical Oncology  2013;31(27):3369-3377.
Purpose
Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear.
Patients and Methods
We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location.
Results
Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m2) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m2 (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m2; however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses.
Conclusion
Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly.
doi:10.1200/JCO.2013.50.6832
PMCID: PMC3770865  PMID: 23980092
4.  Radiation dose and subsequent risk for stomach cancer in long-term survivors of cervical cancer 
International journal of radiation oncology, biology, physics  2013;86(5):10.1016/j.ijrobp.2013.04.010.
Purpose
To assess the dose-response relationship for stomach cancer following radiotherapy for cervical cancer.
Methods and Materials
We conducted a nested, matched case-control study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943–1995, from five international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 gray [Gy], range 0.03–46.1 and following parallel opposed pelvic fields, 1.63 Gy, range 0.12–6.3).
Results
Over 90% of women received radiotherapy, mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was non-significantly increased (odds ratios [ORs] 1.27–2.28) for women receiving between 0.5–4.9 Gy to the stomach cancer site and significantly increased at doses ≥5 Gy (OR=4.20, 95% confidence interval, 1.41–13.4, Ptrend=0.047) compared to non-irradiated women. A highly significant radiation dose-response relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach (Ptrend=0.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach (Ptrend=0.23).
Conclusions
Our findings showed for the first time a significant linear dose-response relationship for risk of stomach cancer in long-term survivors of cervical cancer.
doi:10.1016/j.ijrobp.2013.04.010
PMCID: PMC3831516  PMID: 23707149
cervical cancer; stomach cancer; radiotherapy; case-control; second primary cancer
5.  Tetrachloroethylene Exposure and Bladder Cancer Risk: A Meta-Analysis of Dry-Cleaning-Worker Studies 
Environmental Health Perspectives  2014;122(7):661-666.
Background: In 2012, the International Agency for Research on Cancer classified tetrachloroethylene, used in the production of chemicals and the primary solvent used in dry cleaning, as “probably carcinogenic to humans” based on limited evidence of an increased risk of bladder cancer in dry cleaners.
Objectives: We assessed the epidemiological evidence for the association between tetrachloroethylene exposure and bladder cancer from published studies estimating occupational exposure to tetrachloroethylene or in workers in the dry-cleaning industry.
Methods: Random-effects meta-analyses were carried out separately for occupational exposure to tetrachloroethylene and employment as a dry cleaner. We qualitatively summarized exposure–response data because of the limited number of studies available.
Results: The meta-relative risk (mRR) among tetrachloroethylene-exposed workers was 1.08 (95% CI: 0.82, 1.42; three studies; 463 exposed cases). For employment as a dry cleaner, the overall mRR was 1.47 (95% CI: 1.16, 1.85; seven studies; 139 exposed cases), and for smoking-adjusted studies, the mRR was 1.50 (95% CI: 0.80, 2.84; 4 case–control studies).
Conclusions: Our meta-analysis demonstrates an increased risk of bladder cancer in dry cleaners, reported in both cohort and case–control studies, and some evidence for an exposure–response relationship. Although dry cleaners incur mixed exposures, tetrachloroethylene could be responsible for the excess risk of bladder cancer because it is the primary solvent used and it is the only chemical commonly used by dry cleaners that is currently identified as a potential bladder carcinogen. Relatively crude approaches in exposure assessment in the studies of “tetrachloroethylene-exposed workers” may have attenuated the relative risks.
Citation: Vlaanderen J, Straif K, Ruder A, Blair A, Hansen J, Lynge E, Charbotel B, Loomis D, Kauppinen T, Kyyronen P, Pukkala E, Weiderpass E, Guha N. 2014. Tetrachloroethylene exposure and bladder cancer risk: a meta-analysis of dry-cleaning-worker studies. Environ Health Perspect 122:661–666; http://dx.doi.org/10.1289/ehp.1307055
doi:10.1289/ehp.1307055
PMCID: PMC4080536  PMID: 24659585
6.  Risk of Leukemia Among Survivors of Testicular Cancer: A Population-based Study of 42,722 Patients 
Annals of epidemiology  2008;18(5):416-421.
Purpose
The aim of this study is to quantify excess absolute risk (EAR) and excess relative risk (ERR) of secondary leukemia among a large population-based group of testicular cancer survivors.
Methods
We identified 42,722 1-year survivors of testicular cancer within 14 population-based cancer registries in Europe and North America (1943–2002). Poisson regression analysis was used to model EAR (per 100,000 person-years [PY]) and ERR of secondary leukemia. Cumulative risks were calculated using a competing risk model.
Results
Secondary leukemia developed in 89 patients (EAR = 10.8 per 100,000 PY, 95% confidence interval [CI] = 7.6–14.6; ERR = 1.6, 95%CI = 1.0–2.2). Statistically significantly elevated risks were observed for acute myeloid leukemia (AML) (EAR = 7.2, 95%CI = 4.7–10.2) and acute lymphoblastic leukemia (EAR = 1.3, 95%CI = 0.4–2.8). In multivariate analyses, AML risk was higher among patients whose initial management included chemotherapy compared to those receiving radiotherapy alone (p = 0.1). Excess cumulative leukemia risk was approximately 0.23% by 30 years after testicular cancer diagnosis.
Conclusions
Although ERR of leukemia following testicular cancer is large, EAR and cumulative risk, which are better gauges of the population burden, are small.
doi:10.1016/j.annepidem.2008.01.003
PMCID: PMC4034178  PMID: 18433667
Testicular Neoplasms; Leukemia; Second Primary Neoplasms; Cohort Studies
7.  Cancer incidence and cause-specific mortality in patients with metal-on-metal hip replacements in Finland 
Acta Orthopaedica  2014;85(1):32-38.
Background and purpose
Metal-on-metal hip implants have been widely used, especially in the USA, Australia, England and Wales, and Finland. We assessed risk of death and updated data on the risk of cancer related to metal-on-metal hip replacements.
Patients and methods
A cohort of 10,728 metal-on-metal hip replacement patients and a reference cohort of 18,235 conventional total hip replacement patients were extracted from the Finnish Arthroplasty Register for the years 2001–2010. Data on incident cancer cases and causes of death until 2011 were obtained from the Finnish Cancer Registry and Statistics Finland. The relative risk of cancer and death were expressed as standardized incidence ratio (SIR) and standardized mortality ratio (SMR). SIR/SIR ratios and SMR/SMR ratios, and Poisson regression were used to compare the cancer risk and the risk of death between cohorts.
Results
The overall risk of cancer in the metal-on-metal cohort was not higher than that in the non-metal-on-metal cohort (RR = 0.91, 95% CI: 0.82–1.02). The risk of soft-tissue sarcoma and basalioma in the metal-on-metal cohort was higher than in the non-metal-on-metal cohort (SIR/SIR ratio = 2.6, CI: 1.02–6.4 for soft-tissue sarcoma; SIR/SIR ratio = 1.3, CI: 1.1–1.5 for basalioma). The overall risk of death in the metal-on-metal cohort was less than that in the non-metal-on-metal cohort (RR = 0.78, CI: 0.69–0.88).
Interpretation
The overall risk of cancer or risk of death because of cancer is not increased after metal-on-metal hip replacement. The well-patient effect and selection bias contribute substantially to the findings concerning mortality. Arthrocobaltism does not increase mortality in patients with metal-on-metal hip implants in the short term. However, metal-on-metal hip implants should not be considered safe until data with longer follow-up time are available.
doi:10.3109/17453674.2013.878830
PMCID: PMC3940989  PMID: 24397743
8.  Cancer incidence among Finnish ferrochromium and stainless steel production workers in 1967–2011: a cohort study 
BMJ Open  2013;3(11):e003819.
Objectives
The aim of the study was to assess the risk of cancer among workers employed in the Finnish ferrochromium and stainless steel industry since the beginning of production in 1967.
Methods
The study cohort was made up of all persons employed by the Finnish stainless steel production chain from chromite mining to cold rolling of stainless steel during the period 1967–2004, and it was divided into subcohorts by production units with specific exposure patterns of the subcohorts assessed in previous studies. Follow-up for cancer through the files of the Finnish Cancer Registry was performed using the personal identity code as key. Standardised incidence ratios (SIRs) were calculated as the ratios of observed numbers of cancer cases and numbers expected on the basis of incidence rates in the population of the same region.
Results
The overall cancer incidence was at the expected level. The lung cancer risk was decreased in the whole cohort (SIR 0.79; 95% CI 0.65 to 1.08). The incidence of prostate cancer was significantly increased (1.31; 1.05 to 1.61) and that for kidney cancer was significantly decreased (0.38; 0.14 to 0.82). None of the department-specific SIRs for lung cancer were significantly different from 1.0. No cancers of the nose and nasal sinuses were observed among workers in the ferrochromium smelter or the stainless steel melting shop.
Conclusions
It is not likely that the occupational exposures in the Finnish ferrochromium and stainless steel industry would have increased the risk of cancer.
doi:10.1136/bmjopen-2013-003819
PMCID: PMC3840348  PMID: 24253032
Chromium; Nickel; Cancer; Epidemiology; Stainless Steel
9.  Long-Term Non-Cancer Mortality in Pediatric and Young Adult Cancer Survivors in Finland 
Pediatric blood & cancer  2011;58(3):421-427.
BACKGROUND
Excess late mortality has been reported among pediatric cancer survivors, but there is a need to further establish risk profiles for non-cancer death and to examine cause-specific mortality among survivors of young adult cancers.
PROCEDURES
In a nationwide record linkage study in Finland, we identified 9,245 five-year cancer survivors diagnosed before age 35 and treated between 1966 -1999, and followed them for mortality endpoints from 1971 through 2008. Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated to compare the observed number of deaths with those expected in the general Finnish population. Primary endpoints included death from cardiovascular and respiratory diseases; death from malignant diseases was excluded.
RESULTS
Non-malignant disease mortality in the cohort was 90% higher [SMR=1.9, 95%CI 1.7-2.2] than expected, with SMRs for circulatory and respiratory disease similarly elevated [SMR=1.9, 95%CI 1.5-2.3 and SMR=2.3, 95% CI 1.3-3.8, respectively]. Important differences were noted amongst patient subgroups, with risk greatest for survivors of central nervous system (CNS) cancer, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). The SMR’s for circulatory disease were 6.6 (95% CI 4.8-8.9) for HL and 4.8 (95% CI 2.6-8.1) for NHL for the entire population; but these risks remained elevated for survivors diagnosed between 15-34 years of age.
CONCLUSIONS
Previous studies have shown that there is an elevated risk of non cancer mortality in childhood cancer survivors; this is one of the first studies that show an increase in cardiovascular and respiratory mortality in long term survivors of adolescent and young adult cancers.
doi:10.1002/pbc.23296
PMCID: PMC3237747  PMID: 21910209
cancer; mortality; pediatrics; adolescent; survival; cardiovascular diseases
10.  Circulating estrogens and progesterone during primiparous pregnancies and risk of maternal breast cancer 
Pregnancy reduces maternal risk of breast cancer in the long-term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases, 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women, who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (±6 months) and date of sampling (±3 months) were selected. Estradiol, estrone, and progesterone in first-trimester serum were measured by High Performance Liquid Chromatography Tandem Mass Spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population, there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), pinteraction 0.004. Risk estimates for estrone mirrored those for estradiol, but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40.
doi:10.1002/ijc.26070
PMCID: PMC3189290  PMID: 21413009
breast cancer; pregnancy; estrogens; progesterone; nested case-control study
11.  Nationwide Registry-Based Analysis of Cancer Clustering Detects Strong Familial Occurrence of Kaposi Sarcoma 
PLoS ONE  2013;8(1):e55209.
Many cancer predisposition syndromes are rare or have incomplete penetrance, and traditional epidemiological tools are not well suited for their detection. Here we have used an approach that employs the entire population based data in the Finnish Cancer Registry (FCR) for analyzing familial aggregation of all types of cancer, in order to find evidence for previously unrecognized cancer susceptibility conditions. We performed a systematic clustering of 878,593 patients in FCR based on family name at birth, municipality of birth, and tumor type, diagnosed between years 1952 and 2011. We also estimated the familial occurrence of the tumor types using cluster score that reflects the proportion of patients belonging to the most significant clusters compared to all patients in Finland. The clustering effort identified 25,910 birth name-municipality based clusters representing 183 different tumor types characterized by topography and morphology. We produced information about familial occurrence of hundreds of tumor types, and many of the tumor types with high cluster score represented known cancer syndromes. Unexpectedly, Kaposi sarcoma (KS) also produced a very high score (cluster score 1.91, p-value <0.0001). We verified from population records that many of the KS patients forming the clusters were indeed close relatives, and identified one family with five affected individuals in two generations and several families with two first degree relatives. Our approach is unique in enabling systematic examination of a national epidemiological database to derive evidence of aberrant familial aggregation of all tumor types, both common and rare. It allowed effortless identification of families displaying features of both known as well as potentially novel cancer predisposition conditions, including striking familial aggregation of KS. Further work with high-throughput methods should elucidate the molecular basis of the potentially novel predisposition conditions found in this study.
doi:10.1371/journal.pone.0055209
PMCID: PMC3554690  PMID: 23365693
12.  Determinants of Maternal Sex Steroids During the First Half of Pregnancy 
Obstetrics and gynecology  2011;118(5):1029-1036.
Objective
To examine the associations of maternal and child characteristics with early pregnancy maternal concentrations of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone and estradiol.
Methods
We analyzed these hormones among 1,343 women with singleton pregnancies who donated serum samples to the Finnish Maternity Cohort from 1986 to 2006 during the first half of pregnancy (median, 11 weeks). The associations of maternal and child characteristics with hormone concentrations were investigated by correlation and multivariable regression.
Results
Women above age 30 had lower androgen and estradiol but higher progesterone concentrations than women below that age. Multiparous women had 14% lower testosterone, 11% lower androstenedione and 17-hydroxyprogesterone, 9% lower progesterone, and 16% lower estradiol concentrations compared to nulliparous women (all P<.05). Smoking mothers had 11%, 18%, and 8% higher testosterone, androstenedione, and 17-hydroxyprogesterone levels, respectively, but 10% lower progesterone compared to non-smoking women (all P<.05). Estradiol concentrations were 9% higher (P<0.05) among women with a female fetus compared to those with a male fetus.
Conclusions
Parity, smoking, and to a lesser extent maternal age and child gender are associated with sex steroid levels during the first half of a singleton pregnancy. The effects of smoking on the maternal hormonal environment and the possible long-term deleterious consequences on the fetus deserve further evaluation.
doi:10.1097/AOG.0b013e3182342b7f
PMCID: PMC3207141  PMID: 22015870
13.  Occupational exposure to wood dust and formaldehyde and risk of nasal, nasopharyngeal, and lung cancer among Finnish men 
Controversy exists over whether or not occupational inhalation exposure to wood dust and/or formaldehyde increases risk for respiratory cancers. The objective of this study was to examine the risk of nasal, nasopharyngeal, and lung cancer in relation to occupational exposure to wood dust and formaldehyde among Finnish men. The cohort of all Finnish men born between the years 1906 and 1945 and in employment during 1970 was followed up through the Finnish Cancer Registry for cases of cancers of the nose (n = 292), nasopharynx (n = 149), and lung (n = 30,137) during the period 1971–1995. The subjects’ occupations, as recorded in the population census in 1970, were converted to estimates of exposure to wood dust, formaldehyde, asbestos, and silica dust through the Finnish job-exposure matrix. Cumulative exposure (CE) was calculated based on the prevalence, average level, and estimated duration of exposure. The relative risk (RR) estimates for the CE categories of wood dust and formaldehyde were defined by Poisson regression, with adjustments made for smoking, socioeconomic status, and exposure to asbestos and/or silica dust. Men exposed to wood dust had a significant excess risk of nasal cancer overall (RR, 1.59; 95% confidence interval [CI], 1.06–2.38), and specifically nasal squamous cell carcinoma (RR, 1.98; 95% CI, 1.19–3.31). Workers exposed to formaldehyde had an RR of 1.18 (95% CI, 1.12–1.25) for lung cancer. There was no indication that CE to wood dust or formaldehyde would increase the risk of nasopharyngeal cancer. Occupational exposure to wood dust appeared to increase the risk of nasal cancer but not of nasopharyngeal or lung cancer. The slight excess risk of lung cancer observed for exposure to formaldehyde may be the result of residual confounding from smoking. In summary, this study provides further evidence that exposure to wood dust in a variety of occupations may increase the risk of nasal cancer.
doi:10.2147/CMAR.S30684
PMCID: PMC3421471  PMID: 22904644
job-exposure matrix; inhalation exposure; cumulative exposure; cancer risk
14.  Circulating insulin-like growth factor-1 in pregnancy and maternal risk of breast cancer 
Background
Elevated serum concentrations of insulin-like growth factor (IGF)-1 have been associated with increased risk of breast cancer. Previously, we reported a similar association in samples obtained during pregnancy. The current study was conducted to further characterize the association of IGF-1 during pregnancy with maternal breast cancer risk.
Methods
A case-control study was nested within the Finnish Maternity Cohort. The study was limited to primiparous women less than 40 years of age, who donated blood samples during early (median, 12 weeks) pregnancy and delivered a single child at term. Seven hundred and nineteen women with invasive breast cancer were eligible. Two controls (n = 1,434) were matched to each case on age and date at blood donation. Serum IGF-1 concentration was measured using an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI).
Results
No significant associations were observed between serum IGF-1 concentrations and breast cancer risk in both the overall analysis (OR 1.08 (95% CI 0.80–1.47) and in analyses stratified by histological subtype, lag-time to cancer diagnosis, age at pregnancy or age at diagnosis.
Conclusion
There was no association between IGF-1 and maternal breast cancer risk during early pregnancy in this large nested case-control study.
Impact
Serum IGF-1 concentrations during early pregnancy may not be related to maternal risk of breast cancer.
doi:10.1158/1055-9965.EPI-11-0441
PMCID: PMC3153607  PMID: 21680537
insulin-like growth factor-1 (IGF-1); pregnancy; breast cancer; nested case-control study
15.  HIGH CONSTANT INCIDENCE RATES OF SECOND PRIMARY CANCERS OF THE HEAD AND NECK: A POOLED ANALYSIS OF 13 CANCER REGISTRIES 
Scanty data are available on the incidence (i.e., the absolute risk) of second cancers of the head and neck (HN) and its pattern with age. We investigated this issue using data from a multicentric study of 13 population-based cancer registries from Europe, Canada, Australia and Singapore for the years 1943-2000. A total of 99,257 patients had a first primary HN cancer (15,985 tongue, 22,378 mouth, 20,758 pharyngeal, and 40,190 laryngeal cancer), contributing to 489,855 person-years of follow-up. 1294 of the patients (1.3%) were diagnosed with second HN cancers (342 tongue, 345 mouth, 418 pharynx, and 189 larynx). Male incidence rates of first HN cancer steeply increased from 0.68/100,000 at age 30-34 to 46.2/100,000 at age 70-74, and leveled off at higher age; female incidence increased from 0.50/100,000 at age 30-34 to 16.5/100,000 at age 80-84. However, age-specific incidence of second HN cancers after a first HN cancer in men was around 200-300/100,000 between age 40-44 and age 70-74, and tended to decline at subsequent ages (150/100,000 at age 80-84); in women, incidence of second HN cancers was around 200-300/100,000 between age 45-49 and 80-84. The patterns of age-specific incidence were consistent for different subsites of second HN cancer and sexes; moreover, they were similar for age-specific incidence of first primary HN cancer in patients who subsequently developed a second HN cancer. The incidence of second HN cancers does not increase with age, but remains constant, or if anything, decreases with advancing age.
Impact statement
While the incidence of first primary cancers of the head and neck increases with advancing age that of second primary cancers is stable between age 40 and 70 and, if anything, declines thereafter.
doi:10.1002/ijc.25652
PMCID: PMC3037425  PMID: 20824702
second neoplasms; head and neck cancer; incidence; age
16.  Circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer 
Background
Sex steroid hormones have been proposed to play a role in the development of non-epithelial ovarian cancers (NEOC) but so far no direct epidemiological data are available.
Methods
A case-control study was nested within the Finnish Maternity Cohort, the world’s largest bio-repository of serum specimens from pregnant women. Study subjects were selected among women who donated a blood sample during a singleton pregnancy that led to the birth of their last child preceding diagnosis of NEOC. Case subjects were 41 women with sex-cord stromal tumors (SCST) and 21 with germ cell tumors (GCT). Three controls, matching the index case for age, parity at the index pregnancy, and date at blood donation were selected (n=171). Odds ratios (OR) and 95% confidence intervals (CI) associated with concentrations of testosterone, androstenedione, 17-OH-progesterone, progesterone, estradiol and sex hormone binding globulin (SHBG) were estimated through conditional logistic regression.
Results
For SCST, doubling of testosterone, androstenedione and 17-OH-progesterone concentrations were associated with about 2-fold higher risk of SCST [ORs and 95% CI of 2.16 (1.25–3.74), 2.16 (1.20–3.87), and 2.62 (1.27–5.38), respectively]. These associations remained largely unchanged after excluding women within 2, 4 or 6 years lag-time between blood donation and cancer diagnosis. Sex steroid hormones concentrations were not related to maternal risk of GCT.
Conclusions
This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST.
Impact
Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC.
doi:10.1158/1055-9965.EPI-10-0857
PMCID: PMC3082204  PMID: 21177423
testosterone; androstenedione; 17-OH-progesterone; progesterone; estradiol; pregnancy; non-epithelial ovarian cancer; nested case-control study
17.  Cervical cancer screening in primary health care setting in Sudan: a comparative study of visual inspection with acetic acid and Pap smear 
Objective
To determine the feasibility of visual inspection with the use of acetic acid (VIA) as a screening method for cervical cancer, an alternative to the Pap smear used in primary health care setting in Sudan, and to compare sensitivity, specificity, positive and negative predictive values, and histological diagnosis of positive cases of both tests.
Methods
A cross-sectional study of 934 asymptomatic women living in Khartoum, Sudan, was conducted during 2009–2010. A semi-structured questionnaire containing socio-economic and reproductive variables was used to collect data from each participant. Methods of screening used were VIA and conventional Pap smear, followed by colposcopy and biopsy for confirmation of the positive results of both screening tests.
Results
The tests identified altogether 119 (12.7%) positive women. VIA detected significantly more positive women than Pap smear (7.6% versus 5.1%; P = 0.004), with an overlap between the two screening tests in 19% of positive results. There was no significant difference between VIA and Pap smear findings and sociodemographic and reproductive factors among screened women. Use of colposcopy and biopsy for positive women confirmed that 88/119 (73.9%) were positive for cervical intraepithelial neoplasia. VIA had higher sensitivity than Pap smear (74.2% versus 72.9%; P = 0.05) respectively. Out of 88 confirmed positive cases, 22 (25.0%) cases were invasive cervical cancer in stage 1, of which 19 versus three were detected by VIA and Pap smear respectively (P = 0.001). VIA had higher sensitivity and lower specificity than Pap smear (60.2% versus 47.7%) and (41.9% versus 83.8%) respectively. The combination of VIA/Pap has better sensitivity and specificity than each independent test (82.6% and 92.2%).
Conclusion
The findings of this study showed that VIA has higher sensitivity and lower specificity compared to Pap smear, but a combination of both tests has greater sensitivity and specificity than each test independently. It indicates that VIA is useful for screening of cervical cancer in the primary health care setting in Sudan, but positive results need to be confirmed by colposcopy and biopsy.
doi:10.2147/IJWH.S28406
PMCID: PMC3302762  PMID: 22423181
cervical; cancer; screening; VIA; Pap smear; colposcopy; sensitivity; specificity; predictive value; primary health care setting
18.  Survival of Sami cancer patients 
International Journal of Circumpolar Health  2012;71:10.3402/ijch.v71i0.18959.
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.
doi:10.3402/ijch.v71i0.18959
PMCID: PMC3417662  PMID: 22765936
Sami; cancer; cancer survival; arctic population
19.  Predictors of cervical cancer being at an advanced stage at diagnosis in Sudan 
Background
Cervical cancer is the second most common cancer among women in Sudan, with more than two-thirds of all women with invasive cervical cancer being diagnosed at an advanced stage (stages III and IV). The lack of a screening program for cervical cancer in Sudan may contribute to the late presentation of this cancer, but other factors potentially associated with advanced stages of cervical cancer at diagnosis are unknown. The purpose of this research was to investigate the relationship between age, marital status, ethnicity, health insurance coverage, residence in an urban vs a rural setting, and stage (at diagnosis) of cervical cancer in Sudan.
Methods
This was a cross sectional study of 197 women diagnosed with different stages of cervical cancer. Data was obtained from the cancer registry unit at the Radiation and Isotopes Centre in Khartoum for all women diagnosed with cervical cancer in 2007.
Results
There was an association between older age and advanced stage (at diagnosis) of cervical cancer (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.01–1.05). Being of African ethnicity was associated with 76% increased odds (OR: 1.76, 95% CI: 1.01–3.05), living in a rural area was associated with 13% increased odds (OR: 1.13, 95% CI: 1.78–5.50), and being uninsured was associated with an almost eight-fold increase in odds (OR: 7.7, 95% CI: 3.76–15.38). Marital status and education level were not associated with an advanced stage of cervical cancer at diagnosis.
Conclusion
Women with cervical cancer who are elderly, not covered by health insurance, of African ethnicity, and living in a rural area are more likely to be diagnosed at an advanced stage of cervical cancer in Sudan. These women should be targeted for cervical cancer screening and a health education program, and encouraged to have health insurance.
doi:10.2147/IJWH.S21063
PMCID: PMC3225468  PMID: 22140326
predictors; cervical cancer; diagnosis; advanced; health insurance; Sudan
20.  Cervical cancer risk factors and feasibility of visual inspection with acetic acid screening in Sudan 
Objectives:
To assess the risk factors of cervical cancer and the feasibility and acceptability of a visual inspection with acetic acid (VIA) screening method in a primary health center in Khartoum, Sudan.
Methods:
A cross-sectional prospective pilot study of 100 asymptomatic women living in Khartoum State in Sudan was carried out from December 2008 to January 2009. The study was performed at the screening center in Khartoum. Six nurses and two physicians were trained by a gynecologic oncologist. The patients underwent a complete gynecological examination and filled in a questionnaire on risk factors and feasibility and acceptability. They were screened for cervical cancer by application of 3%–5% VIA. Women with a positive test were referred for colposcopy and treatment.
Results:
Sixteen percent of screened women were tested positive. Statistically significant associations were observed between being positive with VIA test and the following variables: uterine cervix laceration (odds ratio [OR] 18.6; 95% confidence interval [CI]: 4.64–74.8), assisted vaginal delivery (OR 13.2; 95% CI: 2.95–54.9), parity (OR 5.78; 95% CI: 1.41–23.7), female genital mutilation (OR 4.78; 95% CI: 1.13–20.1), and episiotomy (OR 5.25; 95% CI: 1.15–23.8). All these associations remained statistically significant after adjusting for age, educational level, employment, and potential confounding factors such as smoking, number of sexual partners, and use of contraceptive method. Furthermore, the VIA screening method was found to be feasible and acceptable to participants.
Conclusion:
This pilot study showed that women who have uterine cervix laceration, assisted vaginal delivery, female genital mutilation, or episiotomy are at an increased risk of cervical cancer. It also showed that VIA is a feasible and acceptable cervical cancer screening method in a primary health care setting.
doi:10.2147/IJWH.S14189
PMCID: PMC3089429  PMID: 21573147
cervical cancer; screening; visual inspection; acetic acid; feasibility
21.  Risk of Cancer Among Children of Cancer Patients - A Nationwide Study in Finland 
Cancer treatments have the potential to cause germline mutations that might increase the risk of cancer in the offspring of former cancer patients. This risk was evaluated in a population-based study of early onset cancer patients in Finland.
Using nationwide registry data, 26,331 children of pediatric and early onset cancer patients (diagnosed under age 35 between 1953 and 2004) were compared to 58,155 children of siblings. Cancer occurrence among the children was determined by linkage with the cancer registry, and standardized incidence ratios (SIRs) were calculated comparing the observed number of cancers with that expected, based on rates in the general population of Finland.
Among the 9877 children born after their parent’s diagnosis, cancer risk was increased (SIR 1.67; 95% CI 1.29–2.12). However, after removing those with hereditary cancer syndromes, this increase disappeared (SIR 1.03; 95% CI 0.74–1.40). The overall risk of cancer among the offspring of siblings (SIR 1.07; 95% CI 0.94–1.21) was the same as among the offspring of the patients with non-hereditary cancer. Risk of cancer in offspring born prior to their parents cancer diagnosis was elevated (SIR 1.37, 95% CI 1.20–1.54), but removing hereditary syndromes resulted in a diminished and non-significant association (SIR 1.08, 95% CI 0.93–1.25).
This study shows that offspring of cancer patients are not at an increased risk of cancer except when the patient has a cancer-predisposing syndrome. These findings are directly relevant to counseling cancer survivors with regard to family planning.
doi:10.1002/ijc.24856
PMCID: PMC2801768  PMID: 19728329
Offspring; cancer survivors; genetic effects
22.  Exposure to benzene at work and the risk of leukemia: a systematic review and meta-analysis 
Environmental Health  2010;9:31.
Background
A substantial number of epidemiologic studies have provided estimates of the relation between exposure to benzene at work and the risk of leukemia, but the results have been heterogeneous. To bridge this gap in knowledge, we synthesized the existing epidemiologic evidence on the relation between occupational exposure to benzene and the risk of leukemia, including all types combined and the four main subgroups acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).
Methods
A systematic literature review was carried out using two databases 'Medline' and 'Embase' from 1950 through to July 2009. We selected articles which provided information that can be used to estimate the relation between benzene exposure and cancer risk (effect size).
Results
In total 15 studies were identified in the search, providing 16 effect estimates for the main analysis. The summary effect size for any leukemia from the fixed-effects model was 1.40 (95% CI, 1.23-1.57), but the study-specific estimates were strongly heterogeneous (I2 = 56.5%, Q stat = 34.47, p = 0.003). The random-effects model yielded a summary- effect size estimate of 1.72 (95% CI, 1.37-2.17). Effect estimates from 9 studies were based on cumulative exposures. In these studies the risk of leukemia increased with a dose-response pattern with a summary-effect estimate of 1.64 (95% CI, 1.13-2.39) for low (< 40 ppm-years), 1.90 (95% CI, 1.26-2.89) for medium (40-99.9 ppm-years), and 2.62 (95% CI, 1.57-4.39) for high exposure category (> 100 ppm-years). In a meta-regression, the trend was statistically significant (P = 0.015). Use of cumulative exposure eliminated heterogeneity. The risk of AML also increased from low (1.94, 95% CI, 0.95-3.95), medium (2.32, 95% CI, 0.91-5.94) to high exposure category (3.20, 95% CI, 1.09-9.45), but the trend was not statistically significant.
Conclusions
Our study provides consistent evidence that exposure to benzene at work increases the risk of leukemia with a dose-response pattern. There was some evidence of an increased risk of AML and CLL. The meta-analysis indicated a lack of association between benzene exposure and the risk of CML.
doi:10.1186/1476-069X-9-31
PMCID: PMC2903550  PMID: 20584305
23.  Effect of long-term storage on hormone measurements in samples from pregnant women: The experience of the Finnish Maternity Cohort 
Validity of biobank studies on hormone associated cancers depend on the extent the sample preservation is affecting the hormone measurements. We investigated the effect of long-term storage (up to 22 years) on immunoassay measurements of three groups of hormones and associated proteins: sex-steroids [estradiol, progesterone, testosterone, dihydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG)], pregnancy-specific hormones [human chorionic gonadotropin (hCG), placental growth hormone (pGH), alpha-fetoprotein (AFP)], and insulin-like growth factor (IGF) family hormones exploiting the world largest serum bank, the Finnish Maternity Cohort (FMC). Hormones of interest were analyzed in a random sample of 154 Finnish women in the median age (29.5 years, range 25 to 34 years) of their first pregnancy with serum samples drawn during the first trimester. All hormone measurements were performed using commercial enzyme-linked- or radio-immunoassays. Storage time did not correlate with serum levels of testosterone, DHEAS, hCG, pGH and total IGFBP-1. It had a weak or moderate negative correlation with serum levels of progesterone (Spearman’s ranked correlation coefficient (rs)=− 0.36), IGF-I (rs=−0.23) and IGF binding protein (BP)-3 (rs=−0.38), and weak positive correlation with estradiol (rs=0.23), SHBG (rs=0.16), AFP (rs=0.20) and non-phosphorylated IGF binding protein (BP)-1 (rs=0.27). The variation of all hormone levels studied followed the kinetics reported for early pregnancy. Bench-lag time (the time between sample collection and freezing for storage) did not materially affect the serum hormone levels. In conclusion, the stored FMC serum samples can be used to study hormone-disease associations, but close matching for storage time and gestational day are necessary design components of all related biobank studies.
doi:10.1080/02841860701592400
PMCID: PMC2886582  PMID: 17891670
24.  A retrospective comparative study of mortality and causes of death among patients with metal-on-metal and metal-on-polyethylene total hip prostheses in primary osteoarthritis after a long-term follow-up 
Background
All patients with total hip arthroplasty (THA), especially those with metal-on-metal (MM) THA, are exposed to metallic particles and ions, which may cause total or site-specific mortality. We analyzed the causes of total and site-specific mortality among a cohort of patients with MM and with metal-on-polyethylene (MP) THA after a long follow-up time.
Methods
Standardized mortality ratios (SMR) of total and site-specific causes of death were calculated for 579 patients with MM (McKee-Farrar) and 1585 patients with MP (Brunswik, Lubinus) THA for primary osteoarthritis.
Results
Mean follow-up time was 17.9 years for patients with MM and 16.7 years for patients with MP. Overall SMR was 0.95 for the MM cohort and 0.90 for the MP cohort, as compared to the normal population. Both cohorts showed significantly decreased mortality for the first decade postoperatively, equal mortality over the next 10 years, and significantly increased mortality after 20 years. Patients with MM THA had higher cancer mortality (SMR 1.01) than those with MP THA (SMR 0.66) during the first 20 years postoperatively, but not thereafter.
Conclusion
Both MM and MP prostheses are safe based on total and site-specific mortality of recipients during the first 20 postoperative years in comparison with the general population.
doi:10.1186/1471-2474-11-78
PMCID: PMC2874765  PMID: 20416065
25.  Second Cancers After Squamous Cell Carcinoma and Adenocarcinoma of the Cervix 
Journal of Clinical Oncology  2008;27(6):967-973.
Purpose
Although cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) are both caused by human papillomavirus (HPV) infection, they differ in cofactors such as cigarette smoking. We assessed whether these cofactor differences translate into differences in second cancer risk.
Patients and Methods
We assessed second cancer risk among 85,109 cervical SCC and 10,280 AC survivors reported to population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States. Risks compared to the general population were assessed using standardized incidence ratios (SIR).
Results
Overall cancer risk was significantly increased among both cervical SCC survivors (n = 10,559 second cancers; SIR, 1.31; 95% CI, 1.29 to 1.34) and AC survivors (n = 920 second cancers; SIR, 1.29; 95% CI, 1.22 to 1.38). Risks of HPV-related and radiation-related cancers were increased to a similar extent among cervical SCC and AC survivors. Although significantly increased in both groups when compared with the general population, risk of smoking-related cancers was significantly higher among cervical SCC than AC survivors (P = .015; SIR for cervical SCC = 2.07 v AC = 1.78). This difference was limited to lung cancer (SIR for cervical SCC = 2.69 v AC = 2.18; P = .026). The increased lung cancer risk among cervical AC survivors was observed for both lung SCC and lung AC. SIRs for second cancers of the colon, soft tissue, melanoma, and non-Hodgkin's lymphoma were significantly higher among cervical AC than SCC survivors.
Conclusion
The second cancer profiles among cervical SCC and AC survivors mirror the similarities and differences in cofactors for these two histologies. Because smoking is not a cofactor for cervical AC, the increased lung cancer risk suggests a role for additional factors.
doi:10.1200/JCO.2008.18.4549
PMCID: PMC2738433  PMID: 19114696

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