Tapio Luostarinen

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

Vitamin D inhibits the development and growth of prostate cancer cells. Epidemiologic results on serum vitamin D levels and prostate cancer risk have, however, been inconsistent. We conducted a longitudinal nested case‐control study on Nordic men (Norway, Finland and Sweden) using serum banks of 200,000 samples. We studied serum 25(OH)‐vitamin D levels of 622 prostate cancer cases and 1,451 matched controls and found that both low (≤19 nmol/l) and high (≥80 nmol/l) 25(OH)‐vitamin D serum concentrations are associated with higher prostate cancer risk. The normal average serum concentration of 25(OH)‐vitamin D (40–60 nmol/l) comprises the lowest risk of prostate cancer. The U‐shaped risk of prostate cancer might be due to similar 1,25‐dihydroxyvitamin D3 availability within the prostate: low vitamin D serum concentration apparently leads to a low tissue concentration and to weakened mitotic control of target cells, whereas a high vitamin D level might lead to vitamin D resistance through increased inactivation by enhanced expression of 24‐hydroxylase. It is recommended that vitamin D deficiency be supplemented, but too high vitamin D serum level might also enhance cancer development.

Chlamydia trachomatis infection as a risk factor for invasive cervical cancer

Cervical carcinoma is a sexually transmitted disease most strongly linked with human‐papillomavirus (HPV) infection. We conducted a prospective sero‐epidemiologic study to evaluate the role of Chlamydia trachomatis infection in the development of cervical carcinoma, with invasive cancer as an end point. A nested case‐control study within a cohort of 530000 Nordic women was performed. Linking data files of 3 Nordic serum banks and the cancer registries of Finland, Norway and Sweden identified 182 women with invasive cervical carcinoma diagnosed during a mean follow‐up of 5 years after serum sampling. The serum samples of the cases and matched cancer‐free controls were analyzed for IgG antibodies to C. trachomatis, C. pneumoniae (a control microbe) and HPV types 16, 18 and 33, as well as for serum cotinine (an indicator of tobacco smoking). Serum antibodies to C. trachomatis were associated with an increased risk for cervical squamous‐cell carcinoma (HPV‐ and smoking‐adjusted OR, 2.2; 95% CI, 1.3–3.5). The association remained also after adjustment for smoking both in HPV16‐seronegative and ‐seropositive cases (OR, 3.0; 95% CI, 1.8–5.1; OR, 2.3, 95% CI, 0.8–7.0 respectively). No such association was found for C. pneumoniae. Our prospective study provides sero‐epidemiologic evidence that infection with C. trachomatis confers an increased risk for subsequent development of invasive squamous‐cell carcinoma of the uterine cervix. Int. J. Cancer 85:35–39, 2000.

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

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

A population-based prospective study of Chlamydia trachomatis infection and cervical carcinoma

Persistent human papillomavirus (HPV) infection is an established cause of cervical cancer, but the role of other sexually transmitted agents, most notably Chlamydia trachomatis, has not been well defined. The women participating in the population‐based cervical cancer screening program in Västerbotten county of Northern Sweden were followed up for up to 26 years to identify 118 women who developed cervical cancer after having had a normal Pap smear (on average 5.6 years later; range 0.5 months–26 years). As controls, we selected another 118 women who were matched by birth cohort, time‐point of sampling of the baseline normal smear and who had a normal smear at the time when the corresponding case was diagnosed with cancer. The Pap smears and cervical cancer biopsies were analyzed by PCR for C. trachomatis DNA and for HPV DNA. At baseline, C. trachomatis DNA was present in 8% of cases but not among any one of the controls. The relative risk for cervical cancer associated with past C. trachomatis infection, adjusted for concomitant HPV DNA positivity, was 17.1 (95% CI 2.6–∞).The presence of C. trachomatis and of HPV were not interrelated. Whereas C. trachomatis was primarily found in specimens taken many years before cancer diagnosis, HPV DNA was associated with a short lag time before cancer diagnosis. Whereas most women who were HPV DNA‐positive in the prediagnostic smear were also positive for the same virus in the cervical cancer biopsy, none of the women were positive for C. trachomatis in both the prediagnostic smear and in the subsequent cervical cancer. In conclusion, a prior cervical C. trachomatis infection was associated with an increased risk for development of invasive cervical cancer.

Serologically diagnosed infection with human papillomavirus type 16 and risk for subsequent development of cervical carcinoma: nested case-control study

Abstract Objective: To study human papillomavirus type 16 in the aetiology of cervical carcinoma. Design: Within a cohort of 18814 Finnish women followed for up to 23 years a nested case-control study was conducted based on serological diagnosis of past infection with human papillomavirus type 16. Subjects: 72 women (27 with invasive carcinoma and 45 with in situ carcinoma) and 143 matched controls were identified during the follow up. Main outcome measure: Relative risk of cervical carcinoma in presence of IgG antibodies to human papillomavirus type 16. Results: After adjustment for smoking and for antibodies to various other agents of sexually transmitted disease, such as herpes simplex virus type 2 and Chlamydia trachomatis, the only significant association was with infection with human papillomavirus type 16 (odds ratio 12.5; 95% confidence interval 2.7 to 57, 2P<0.001). Conclusion: This prospective study provides epidemiological evidence that infection with human papillomavirus type 16 confers an excess risk for subsequent development of cervical carcinoma. Key messages Key messages Human papillomavirus type 16 is the main micro-organism linked to the development of cervical cancer Prospective studies of infection with this virus and cervical cancer have not been reported because of ethical and clinical difficulties and because diagnosis of past infections with the virus has not been possible In this nested case-control study in over 18000 Finnish women who donated blood to a serum bank 25 years ago we were able to measure past infection with human papillomavirus type 16 with new serological tools The results show that infection with the virus confers an increased risk of developing cervical cancer

Survival of Cancer Patients in Finland 1955-1994

INTRODUCTION The study of survival of cancer patients is essential for monitoring the effectiveness of cancer control. The previous monograph describing cancer patient survival in Finland was published by the Finnish Cancer Registry in 1981 and covered patients diagnosed in 1953-1974. This new supplement assesses cancer patient survival up to the year 1995. MATERIAL AND METHODS The study includes over 560000 tumours registered at the Finnish Cancer Registry with a date of diagnosis between 1955 and 1994. Patients were followed up to the end of 1995. Trends in relative survival rates are studied over four 10-year diagnostic periods from 1955 to 1994. In addition, detailed results are presented for patients diagnosed during 1985-1994, including relative survival rates tabulated by stage, sex, and age. Additional sections describe differences in cancer patient survival according to social class and region of residence and a comparison of cancer patient survival in Finland to other European countries. RESULTS Patient survival improved over time for almost all anatomical sites. The main exception is in cancer of the cervix uteri, where patient survival has decreased slightly from 1965-1974 to 1985-1994 due to the selective prevention of less aggressive tumours through cytologic screening. Very few differences in patient survival are observed between males and females. A substantial improvement in survival can be seen for childhood cancers. CONCLUSION The increasing survival rates reflect improvements that have taken place in various areas of cancer control, from health education and early diagnosis to treatment and aftercare. This study provides valuable reference information for both clinicians and health administrators, as well as a baseline for more detailed studies of patient survival for individual anatomical sites.

Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study

Human papillomavirus has emerged as the leading infectious cause of cervical and other anogenital cancers. We have studied the relation between human papillomavirus infection and the subsequent risk of anal and perianal skin cancer. A case–cohort study within two large Nordic serum banks to which about 760 000 individuals had donated serum samples was performed. Subjects who developed anal and perianal skin cancer during follow up (median time of 10 years) were identified by registry linkage with the nationwide cancer registries in Finland and Norway. Twenty-eight cases and 1500 controls were analysed for the presence of IgG antibodies to HPV 16, 18, 33 or 73, and odds ratios of developing anal and perianal skin cancer were calculated. There was an increased risk of developing anal and perianal skin cancer among subjects seropositive for HPV 16 (OR=3.0; 95%CI=1.1–8.2) and HPV 18 (OR=4.4; 95%CI=1.1–17). The highest risks were seen for HPV 16 seropositive patients above the age of 45 years at serum sampling and for patients with a lag time of less than 10 years. This study provides prospective epidemiological evidence of an association between infection with HPV 16 and 18 and anal and perianal skin cancer.Human papillomavirus has emerged as the leading infectious cause of cervical and other anogenital cancers. We have studied the relation between human papillomavirus infection and the subsequent risk of anal and perianal skin cancer. A case–cohort study within two large Nordic serum banks to which about 760 000 individuals had donated serum samples was performed. Subjects who developed anal and perianal skin cancer during follow up (median time of 10 years) were identified by registry linkage with the nationwide cancer registries in Finland and Norway. Twenty-eight cases and 1500 controls were analysed for the presence of IgG antibodies to HPV 16, 18, 33 or 73, and odds ratios of developing anal and perianal skin cancer were calculated. There was an increased risk of developing anal and perianal skin cancer among subjects seropositive for HPV 16 (OR=3.0; 95%CI=1.1–8.2) and HPV 18 (OR=4.4; 95%CI=1.1–17). The highest risks were seen for HPV 16 seropositive patients above the age of 45 years at serum sampling and for patients with a lag time of less than 10 years. This study provides prospective epidemiological evidence of an association between infection with HPV 16 and 18 and anal and perianal skin cancer.

Circulating enterolactone and prostate cancer risk: A Nordic nested case‐control study

Enterolactone, a phytoestrogen belonging to the class of lignans, is produced by the intestinal microflora from precursors in plant foods and has been implicated in protection against cancer. We study the effect of enterolactone on the risk of a subsequent diagnosis of prostate cancer. We conducted a longitudinal, nested case‐control study by linkage of 3 biobanks to the cancer registries in Finland, Norway and Sweden, respectively. Enterolactone concentrations were measured by time‐resolved fluoroimmunoassay in serum from 794 men who had a diagnosis of prostate cancer at a mean follow‐up time of 14.2 years after blood collection and among 2,550 control men matched within each cohort for age (±2 years), date of blood collection (±2 months) and county. The median enterolactone concentrations did not differ between case and control subjects in the full study group (8.4 nmol/L [25th–75th percentile = 4.5–15.0] vs. 8.5 nmol/L [25th–75th percentile = 4.3–15.9]), nor in the national groups. Odds ratios of prostate cancer risk estimated by conditional logistic regression for increasing concentrations of enterolactone in quartiles in the full study group were 1.00 (referent), 1.21 (95% confidence interval [CI] = 0.96–1.52), 1.16 (95% CI = 0.91–1.47) and 1.08 (95% CI = 0.83–1.39). The OR estimate for the highest vs. the lowest quartile of enterolactone in separate analyses of the Norwegian, Finnish and Swedish cohort was 1.21 (95% CI = 0.91–1.60), 1.02 (95% CI = 0.59–1.76) and 0.87 (95% CI = 0.45–1.67), respectively. No support for the hypothesis that high circulating enterolactone is protective against prostate cancer was found.

Self-sample HPV Tests As an Intervention for Nonattendees of Cervical Cancer Screening in Finland: a Randomized Trial

Background: Attendance in screening is an important determinant of cervical cancer. Previous experience on high-risk human papillomavirus (hrHPV) DNA testing on patient-obtained samples suggests a good effect among nonattendees of screening. We assessed the effects of self-sampling on attendance in the Finnish screening program. Methods: Nonattendees after the primary invitation in one municipality (Espoo) were randomized to receive either a self-sampling kit (2,397 women) or an extra invitation (6,302 women). One fourth (1,315 women) of reminder letter arm nonattendees also received a self-sampling kit as a third intervention. Main outcomes were increases in screening attendance and coverage. Results: The adjusted relative risk for participation by self-sampling as a second intervention in comparison to a reminder letter arm was 1.21 (95% CI: 1.13–1.30). Total attendance increased from 65% to 76% by self-sampling and from 65% to 74% with a reminder letter. Combining the interventions (reminder letter and then self-sampling) increased total attendance from 63% to 78%. One fifth of the participants in all three groups increased screening coverage (previous Pap smear ≥5 years ago or never). Self-obtained samples were more often HPV positive than provider-obtained ones (participants after primary invitation and reminder letter), 12% to 13% versus 7%. Conclusions: Self-sampling is a feasible option in enhancing the attendance at organized screening, particularly as an addition to a reminder letter. Impact: If self-sampling is used as a third intervention after two written invitations, the overall attendance in Finland could most likely reach the desired 80% to 85%. Cancer Epidemiol Biomarkers Prev; 20(9); 1960–9. ©2011 AACR.

Nordic biological specimen banks as basis for studies of cancer causes and control - More than 2 million sample donors, 25 million person years and 100 000 prospective cancers

The Nordic countries have a long tradition of large-scale biobanking and comprehensive, population-based health data registries linkable on unique personal identifiers, enabling follow-up studies spanning many decades. Joint Nordic biobank-based studies provide unique opportunities for longitudinal molecular epidemiological research. The purpose of the present paper is to describe the possibilities for such joint studies, by describing some of the major Nordic biobank cohorts with a standardised calculation of the cancer incidence in these cohorts. Altogether two million donors have since 1966 donated more than four million biological samples, stored at −20°C to −135°C, to 17 biobank cohorts in Finland, Iceland, Norway and Sweden. As a result of joint database handling principles, the accuracy of personal identifiers and completeness of follow-up for vital status in all participating biobanks was improved. Thereafter, the cancer incidence was determined using follow-up through the national cancer registries. Biobanks based on random samples of population typically showed slightly lower cancer incidence rates than the general population, presumably due to better participation rates among health-conscious subjects. On the other hand, biobanks including samples for viral screening or clinical testing showed 1.5 to 2.1 fold increased incidence of cancer. This excess was very high immediately after sampling, but for some cancer sites remained elevated for years after clinical sampling. So far, more than 100 000 malignant neoplasms have occurred after sample donation, and the annual increase of the cancer cases in these cohorts is about 10 000. The estimates on the population-representativity of the biobanks will assist in interpretation of generalizability of results of future studies based on these samples, and the systematic tabulations of numbers of cancer cases will serve in study power estimations. The present paper summarizes optimal study designs of biobank-based studies of cancer.