Finnish Cancer Registry

The initial invasion of tumors requires a transition from a solid, jammed state to a fluid‐like, flocking, unjammed state that enables collective migration. Here, we show that de novo gene transcription is essential for the emergence of flocking in epithelial tissues and identify connexins (Cx) as key mediators of this transition. Using quiescent HaCaT keratinocytes, tumorigenic A431 epidermoid carcinoma cells, primary bronchial epithelial explants, and vocal fold carcinoma (VFC) cells, we find that flocking induction depends on transcriptional programs activated downstream of epidermal growth factor (EGF). EGF stimulation upregulates Cx26 and Cx31 and enhances gap‐junctional intercellular communication (GJIC), which is necessary—though not sufficient—to generate the large‐scale cell‐volume fluctuations and density heterogeneity that accompany unjamming. Sustained signaling through extracellular signal‐regulated kinase 1/2 (ERK1/2) and AKT serine/threonine kinase (AKT) downstream of the EGF receptor (EGFR) is required for connexin induction, linking mechanical state transitions to extracellular cues. Pharmacological inhibition and CRISPR‐Cas9 (clustered regularly interspaced short palindromic repeats–CRISPR associated protein 9) knockout of connexins block unjamming and collective motility. VFC cells display constitutively elevated connexins and persistent flocking that is highly sensitive to connexin inhibition. Consistently, high Cx26 expression correlates with reduced survival across carcinomas. These findings reveal a transcriptionally controlled, connexin‐dependent mechanism that enables tissue fluidization and collective invasion.

Mechanical forces of the tumor microenvironment change dynamically during key events of tumorigenesis such as invasion and metastasis. These changes in compressive forces often affect the breast cancer cell phenotype. However, it is lesser known how these dynamic mechanical forces in the tumor microenvironment affect the phenotypes of tumor infiltrated leukocytes (TIL) and their subsequent anticancer activities. Here we find, in primary patient-derived explant cultures (PDEC) containing resident TILs, that low compression promotes a change in the original identity of breast cancer cells from luminal to a more mesenchymal and undifferentiated state. These altered tumor cells induce an upregulation of immunosuppressive cytokines such as interleukin-10 (IL-10) and Transforming Growth Factor Beta (TGF-β), as well as polarization of macrophages towards pro-tumor M2(Gc)-type and depletion of CD8+ effector memory T-cells. These immunosuppressive events are mediated by tumor cell derived fibroblast growth factor 2 (FGF2) and prostaglandin E2 (PGE2). We also find that FGF2 rich areas in primary tumors show enrichment in M2-like-macrophages and diminished numbers of CD8 + T and B-cells. Our results suggest that low compressive forces in the tumor microenvironment induce local immunosuppression via FGF2 secretion arising from phenotypic plasticity of tumor cells.

BackgroundWithin Finland’s breast cancer screening program, all women aged 50–69 are invited to biennial screening. Current European guidelines recommend screening in ages 45–49 and 70–74 conditional upon, inter alia, demonstrated context-specific cost-effectiveness. This study aims to determine the cost-effectiveness of expanding the target population of biennial screening to ages 45 and/or 74, compared to the current national breast cancer screening strategy, in the Finnish setting.MethodsScreening strategies’ costs and quality-adjusted life years (QALY), aggregated over a lifetime horizon for the population simulated through a decision-analytic model, allow for comparison through incremental cost-effectiveness ratios. The model, using a Markov cohort simulation approach, was adapted to the cancer stage classification system used by the Finnish Cancer Registry (FCR) and calibrated to observed metrics in the Finnish female population. The analysis was conducted from a limited societal perspective, using a discount rate of 3% for costs and outcomes. Sensitivity analyses were performed to assess decision uncertainty, using an implicit willingness-to-pay (WTP) threshold range of €25 000–50 000 per incremental QALY.ResultsCompared to the current national screening strategy, both strategies with a starting age of 45 were cost-effective at the WTP-threshold of €50 000 per incremental QALY. Biennial screening in ages 45–69 was also cost-effective at €25 000 per QALY and demonstrated the highest probability of cost-effectiveness of all screening strategies over the whole WTP-threshold range of €25 000–50 000 per QALY. Biennial screening in ages 50–74 was dominated by all strategies over the threshold range.ConclusionsExpanding the national screening strategy target population age is likely to produce net health benefits to acceptable costs, insofar as women aged 45–49 are covered by the expansion. Only expanding the target population to age 74 is unlikely to be cost-effective, given a WTP-threshold range of €25 000–50 000 per incremental QALY.

The Nordic countries benefited from declines in cervical cancer incidence rates due to the implementation of screening programmes. However, it is unclear whether all social groups have equally benefited from these preventive services. We provide an assessment of the temporal trends in cervical cancer incidence by socioeconomic position (SEP) in Denmark, Norway, Finland and Sweden, using data from the Nordic Occupational Cancer Study. Truncated age-standardized incidence rates and 95% confidence intervals (CI) of cervical cancer per 100,000 person-years were computed for women aged 50-69 by SEP and country within the period 1961-2005. We used Poisson regression models to compute relative risks (RRs) and 95% CIs of cervical cancer across SEP, pooling data for the three most recent 5-year periods (except for Denmark 1991-1995 and Norway 1991-2003). Throughout the study period, declines in the rates of cervical cancer were observed among all SEP groups. Lower SEP rates, which started from higher values, declined faster than those for higher SEP. At the conclusion of the study period, we still observed a social gradient, with higher rates seen in lower SEP women. Farmers had the lowest risk in all four countries. The RRs for lowest versus highest SEP ranged from 1.33 (95% CI 1.05-1.69) in Sweden to 1.76 (95% CI 1.13-2.85) in Denmark, with a pooled RR of 1.41 (95% CI 1.22-1.64). Lower SEP women still face the highest risks, indicating a need for continued efforts to provide equitable access to preventive services.

Despite the implementation of the WHO Framework Convention on Tobacco Control (FCTC) program in Iran, the regulation of second-hand smoke (SHS) exposure-an often-overlooked hazard-, still requires improvement. We employed a multi-center case-control study to investigate the association between exposure to secondhand smoke (SHS) from various tobacco products (cigarettes, water-pipes, pipes, and chopogh), opium use, and the risk of lung cancer. We included 627 lung cancer cases and 3477 controls. Exposure to SHS tobacco and SHS opium was collected through a questionnaire. We used mixed-model logistic regressions to estimate odds ratios (ORs) and 95% confidence intervals (CI). Among the overall population exposed to second-hand tobacco smoke (SHTS), the odds ratio (OR) compared to those never exposed was 1.35 (95% CI: 1.08-1.71). Never smokers who were ever exposed to second-hand tobacco smoke (SHTS) had 1.69-fold risk of lung cancer compared to those who were never exposed (95% CI: 1.13-2.52). Exposure to SHTS between 2-3 per day (OR = 2.27, 95% CI: 1.13-4.53) and more than three hours per day (OR = 2.29, 95% CI: 1.20-4.37) can increase the risk of lung cancer compared with the no exposure group (P-trend <0.01). We did not observe any association between exposure to second-hand opium smoke (SHOS) and the risk of lung cancer, either in the overall population or among never-smokers. Our study estimates the impact of second-hand tobacco smoke (SHTS) on lung cancer risk in both the overall population and never-smokers. Additional studies are required to evaluate the association between exposure to second-hand smoke from opium and other type of tobacco, including water-pipe and the risk of lung cancer.

Numerous studies have reported lower overall cancer mortality rates among immigrants compared to native populations. However, limited information exists regarding cancer mortality among immigrants based on specific birth countries and cancer types. We used population-based registries and followed 10 million individuals aged 20 years or older in Sweden between 1992 and 2016. The Cox proportional hazard model was used to explore the disparities in cancer mortality by country of birth and cancer type, stratified by gender. Age-standardized mortality rates were also computed using the world standard population. Hazard ratio (HR) of all-site cancer was slightly lower among immigrants (males: HRm = 0.97: 95% confidence interval: 0.95, 0.98; females: HRf = 0.93: 0.91, 0.94) than Swedish-born population. However, the immigrants showed higher mortality for infection-related cancers, including liver (HRf = 1.10: 1.01, 1.19; HRm = 1.10: 1.02, 1.17), stomach (HRf = 1.39: 1.31, 1.49; HRm = 1.33: 1.26, 1.41) cancers, and tobacco-related cancers, including lung (HRm = 1.44: 1.40, 1.49), and laryngeal cancers (HRm = 1.47: 1.24, 1.75). The HR of mesothelioma was also significantly higher in immigrants (HRf = 1.44: 1.10, 1.90). Mortality from lung cancer was specifically higher in men from Nordic (HRm = 1.41: 1.27, 1.55) and non-Nordic Europe (HRm = 1.49: 1.43, 1.55) countries and lower in Asian (HRm = 0.78: 0.66, 0.93) and South American men (HRm = 0.70: 0.57, 0.87). In conclusion, there are large variations in cancer mortality by country of birth, and cancer type and require regular surveillance. Our detailed analyses lead to some novel findings such as excess mortality rate of mesothelioma and laryngeal cancers in Immigrants in Sweden. A targeted cancer prevention program among immigrants in Sweden is needed.

ObjectiveAround 70% of vaginal cancers and 40–50% of vulvar cancers are attributable to human papillomavirus (HPV). Globally the burden of these diseases is estimated to grow due to the increasing HPV prevalence and rapidly aging global population. We aimed to examine if HPV screening for cervical cancer has an additional beneficial effect in preventing vaginal and vulvar cancers. To assess this, we used long-term follow-up data from the Finnish randomized HPV screening trial. MethodsBetween 2003 and 2008, over 236,000 women were individually randomized (1:1) to primary HPV or cytology screening in Southern Finland. We followed this cohort up to the year 2020. To compare the study arms, we calculated site-specific and pooled incidence rate ratios (IRRs) and mortality rate ratios (MRRs) for vaginal and vulvar cancers using Poisson regression. ResultsDuring 3,5 million person-years of follow-up, the IRR for vaginal cancer in the HPV arm compared to the cytology arm was 0.40 (95% CI 0.17–0.88) and the corresponding MRR was 0.74 (95% 0.21–2.24). The corresponding IRR for vulvar cancer was 0.73 (95% 0.50–1.08) and the MRR was 0.64 (95% 0.23–1.62). The pooled IRR was 0.67 (95% 0.47 ̶ 0.95) and MRR 0.67 (95% 0.31 ̶ 1.37). ConclusionWe found lower incidence of vaginal cancers with HPV screening compared to cytology screening. To validate our results, we recommend analyzing data on vaginal and vulvar cancers also from other HPV screening studies.

The Cohort Study of Mobile Phone Use and Health (COSMOS) has repeatedly collected self-reported and operator-recorded data on mobile phone use. Assessing health effects using self-reported information is prone to measurement error, but operator data were available prospectively for only part of the study population and did not cover past mobile phone use. To optimize the available data and reduce bias, we evaluated different statistical approaches for constructing mobile phone exposure histories within COSMOS. We evaluated and compared the performance of 4 regression calibration (RC) methods (simple, direct, inverse, and generalized additive model for location, shape, and scale), complete-case analysis, and multiple imputation in a simulation study with a binary health outcome. We used self-reported and operator-recorded mobile phone call data collected at baseline (2007-2012) from participants in Denmark, Finland, the Netherlands, Sweden, and the United Kingdom. Parameter estimates obtained using simple, direct, and inverse RC methods were associated with less bias and lower mean squared error than those obtained with complete-case analysis or multiple imputation. We showed that RC methods resulted in more accurate estimation of the relationship between mobile phone use and health outcomes by combining self-reported data with objective operator-recorded data available for a subset of participants.

Survivors of childhood cancer may face difficulties at school. We investigated whether childhood cancer affects attainment of upper secondary education, in a register-based cohort study from Denmark, Finland, and Sweden, where we limit bias from selection and participation. From the national cancer registers, we identified all long-term survivors of childhood cancer diagnosed aged 0-14 years in 1971-2005 (n = 7629), compared them to matched population comparisons (n = 35,411) and siblings (n = 6114), using odds ratios (OR) and 95% confidence intervals (CI). Overall, 6127 survivors (80%) had attained upper secondary education by age 25, compared to 84% among comparison groups. Elevated OR for not attaining this level were mainly confined to survivors of central nervous system (CNS) tumours (ORSurv_PopComp2.05, 95%CI: 1.83-2.29). Other risk groups were survivors who had spent more time in hospital around cancer diagnosis and those who had hospital contacts in early adulthood, particularly psychiatric. Survivors of all cancer types were less likely to have attained upper secondary education without delay. Although survivors of childhood cancer experienced delays in their education, many had caught up by age 25. Except for survivors of CNS tumours, survivors attained upper secondary education to almost the same extent as their peers.