Prostate cancer incidence in men with prostate-specific antigen below 3 ng/mL: The Finnish Randomized Study of Screening for Prostate Cancer

Prostate-specific antigen (PSA)-based screening for prostate cancer (PCa) can reduce PCa mortality, but also involves overdetection of low-risk disease with potential adverse effects. We evaluated PCa incidence among men with PSA below 3 ng/mL and no PCa diagnosis at the first screening round of the Finnish Randomized Study of Screening for PCa. Follow-up started at the first screening attendance and ended at PCa diagnosis, emigration, death or the common closing date (December 2016), whichever came first. Cox regression analysis was used to estimate hazard ratios and their confidence intervals (CI). Among men with PSA <3 ng/mL, cumulative PCa incidence was 9.1% after 17.6 years median follow-up. Cumulative incidence was 3.6% among men with baseline PSA 0 to 0.99 ng/mL, 11.5% in those with PSA 1.0 to 1.99 ng/mL and 25.7% among men with PSA 2 to 2.99 ng/mL (hazard ratio 9.0, 95% CI: 7.9-10.2 for the latter). The differences by PSA level were most striking for low-risk disease based on Gleason score and EAU risk group. PSA values <1 ng/mL indicate a very low 20-year risk, while at PSA 2 to 2.99 ng/mL risks are materially higher, with 4- to 5-fold risk for aggressive disease. Using risk-stratification and appropriate rescreening intervals will reduce screening intensity and overdetection. Using cumulative incidence of clinically significant PCa (csPCa) as the criterion, rescreening intervals could range from approximately 3 years for men with initial PSA 2 to 2.99 ng/mL, 6 years for men with PSA 1 to 1.99 ng/mL to 10 years for men with PSA <1 ng/mL.     

Estimating the rate of overdiagnosis with prostate cancer screening: evidence from the Finnish component of the European Randomized Study of Screening for Prostate Cancer

Cancer Causes & Control - Screening for prostate cancer may have limited impact on decreasing prostate cancer-related mortality. A major disadvantage is overdiagnosis, whereby lesions are...     

Association of findings in flow-volume spirometry with high-resolution computed tomography signs in asbestos-exposed male workers

Introduction: Disorders of pulmonary tissue and pleura are visualized by findings in high‐resolution computed tomography (HRCT), and the impairment caused by these findings is assessed by pulmonary function tests. Our aim was to determine how some commonly used spirometric variables are related to certain HRCT signs, in order to find out which HRCT signs are associated with restrictive and which with obstructive ventilatory impairment. Methods: Altogether 590 asbestos‐exposed workers, 95% of whom were smokers or ex‐smokers, were studied with HRCT; 19 pathological signs were scored. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, forced expiratory flow at 50% of FVC (MEF50) and total lung capacity (TLC) were measured, and their relationship with HRCT signs was examined with bivariate correlations and multiple regression analysis. Results: FVC and TLC were negatively correlated with fibrosis score, parenchymal bands, extent of pleural thickenings and positively with widened retrosternal space. FEV1/FVC ratio was negatively correlated with emphysema types and widened retrosternal space and positively with parenchymal bands and subpleural nodules. Thickened bronchial walls did not separate between restrictive and obstructive ventilatory function. Conclusions: HRCT signs showed distinctive patterns in restrictive and obstructive ventilatory impairment. These results can be used to help to analyse the lung function of patients simultaneously exposed to asbestos and smoking, when this relationship requires elucidation. In addition, the results may be helpful in explaining some radiological findings.     

Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish section of the ERSPC

Background:

We derived estimates of overdiagnosis by polygenic risk groups and examined whether polygenic risk-stratified screening for prostate cancer reduces overdiagnosis.

Methods:

We calculated the polygenic risk score based on genotypes of 66 known prostate cancer loci for 4967 men from the Finnish section of the European Randomised Study of Screening for Prostate Cancer. We stratified the 72 072 men in the trial into those with polygenic risk below and above the median. Using a maximum likelihood method based on interval cancers, we estimated the mean sojourn time (MST) and episode sensitivity. For each polygenic risk group, we estimated the proportion of screen-detected cancers that are likely to be overdiagnosed from the difference between the observed and expected number of screen-detected cancers.

Results:

Of the prostate cancers, 74% occurred among men with polygenic risk above population median. The sensitivity was 0.55 (95% confidence interval (CI) 0.45–0.65) and MST 6.3 (95% CI 4.2–8.3) years. The overall overdiagnosis was 42% (95% CI 37–52) of the screen-detected cancers, with 58% (95% CI 54–65) in men with the lower and 37% (95% CI 31–47) in those with higher polygenic risk.

Conclusion:

Targeting screening to men at higher polygenic risk could reduce the proportion of cancers overdiagnosed.     

Family history in the Finnish Prostate Cancer Screening Trial

Family history (FH) is one of the few known risk factors for prostate cancer (PC). There is also new evidence about mortality reduction in screening of PC with prostate‐specific antigen (PSA). Therefore, we conducted a prospective study in the Finnish Prostate Cancer Screening Trial to evaluate the impact of FH on outcomes of PC screening. Of the 80,144 men enrolled, 31,866 men were randomized to the screening arm and were invited for screening with PSA test (cut‐off 4 ng/ml) every 4 years. At the time of each invitation, FH of PC (FH) was assessed through a questionnaire. The analysis covered a follow‐up of 12 years from randomization for all men with data on FH. Of the 23,702 (74.3%) invited men attending screening, 22,756 (96.0%) provided information of their FH. Altogether 1,723 (7.3%) men reported at least one first‐degree relative diagnosed with PC and of them 235 (13.6%) were diagnosed with PC. Men with a first‐degree FH had increased risk for PC (risk ratio (RR) 1.31, p < 0.001) and the risk was especially elevated for interval cancer (RR 1.65, 95% CI 1.27–2.15). Risk for low‐grade (Gleason 2–6) tumors was increased (RR 1.46, 95% CI 1.15–1.69), but it was decreased for Gleason 8–10 tumors (RR 0.48, 95% CI 0.25–0.95). PSA test performance (sensitivity and specificity) was slightly inferior for FH positives. No difference in PC mortality was observed in terms of FH. Our findings provide no support for selective PSA screening targeting men with FH of PC.     

Glucose status and depressive symptoms: a cohort study of elderly people in northwest Finland

Objective: To assess the association between depressive symptoms and impaired glucose metabolism in the elderly population in arctic latitudes.

Design: A population-based study. Setting. Community.

Subjects: The study population consisted of 1,830 subjects born between the years 1915 and 1958 in the northernmost part of Finland, the Muonio-Enontekiö district, who participated in a health survey during 1974–1984. In 2014, a health questionnaire was sent to 1,037 subjects, and 757 participants (73%) answered it. Those (n?=?629) living in the Muonio-Enontekiö district undergone a clinical examination in 2014 and 2015 including blood collections.

Main outcome measures: Depressive symptoms defined by the Beck Depression Inventory II (BDI II) with a cut-off point of 14. Different diabetic states based on WHO’s classification criteria defined by fasting plasma glucose and ADA’s criteria by glycosylated haemoglobin (HbA1c) values.

Results: According to logistic regression analysis, depressive symptoms (BDI-II ≥ 14) were associated statistically significantly with previously known type 2 diabetes, the odds ratio (OR) being 4.33 (95% CI 1.53–14.14). Regarding prediabetic fasting glucose/HbA1c values, the corresponding OR was 2.94 (95% CI 1.17–8.94). The prevalence of depressive symptoms (BDI-II ≥ 14) was 7.1%, (men 9.7% and women 5.4%) and 13.7% (men 9.9% and women 17.0%) in subjects living in Muonio-Enontekiö district and in those who had moved away from there, respectively.

Conclusions: The association of depressive symptoms between prediabetes and diabetes seems to be present also in the northernmost latitudes of the world.     

Clonal Analysis of Regulatory T Cell Defect in Patients with Autoimmune Polyendocrine Syndrome Type 1 Suggests Intrathymic Impairment

Mutations in the autoimmune regulator gene disrupt thymic T cell development and negative selection, leading to the recessively inherited polyendocrine autoimmune disease autoimmune polyendocrine syndrome type 1 (APS‐1). The patients also have a functional defect in the FOXP3⁺ regulatory T cell population, but its origin is unclear. Here, we have used T cell receptor sequencing to analyse the clonal relationship of major CD4⁺ T cell subsets in three patients and three healthy controls. The naive regulatory T cells showed little overlap with helper T cell subsets, supporting divergence in the thymus. The activated/memory regulatory T cell subset displayed more sharing with helper T cells, but was mainly recruited from the naive regulatory T cell population. These clonal patterns were very similar in both patients and controls. However, naive regulatory T cells isolated from the patients had a significantly longer T cell receptor complementarity‐determining region 3 than any other population, suggesting failure of thymic selection. These data indicate that the peripheral differentiation of regulatory T cells in APS‐1 patients is not different from that in healthy controls. Rather, the patients' naive regulatory T cells may have an intrinsic defect imprinted already in the thymus.