In well-screened populations, most cervical cancers arise from small groups of women with inadequate screening. The present study aims to assess whether registry-based cancer risk assessment could be used to increase screening intensity among high-risk women. The National Cervical Screening Registry identified the 28,689 women residents in Sweden who had either no previous cervical screening or a screening history indicating high risk. We invited these women by SMS and/or physical letter to order a free human papillomavirus (HPV) self-sampling kit. The Swedish national HPV reference laboratory performed extended HPV genotyping and referred high-risk HPV-positive women to their regional gynecologist. A total of 3691/28,689 (12.9%) women ordered a self-sampling kit and 10.0% (2853/28,689) returned a sample for testing. Participation among women who had never attended screening was low, albeit improved. Up to 22.5% of women in other high-risk groups attended. High-risk HPV types were detected in 8.3% of samples. High-risk HPV-positive women (238/2853) were referred without further triaging and severe cervical precancer or cancer (HSIL+) in histopathology were detected in 36/158 (23%) of biopsied women. Repeat invitations gave modest additional participation. Nationwide contacting of women with high risk for cervical cancer with personal invitations to order HPV self-sampling kits resulted in high yield of detected CIN2+. Further efforts to improve risk-stratified screening strategies should be directed to improving (i) the precision of the risk-stratification algorithm, (ii) the convenience for the women to participate and, (iii) ensuring that screen-positive women are followed-up.

Pathological germline variants (PGVs) of RAD51D increase the risk of breast and ovarian cancer. In East Asia, c.270_271dup is the most frequently detected PGV of RAD51D; however, only a few cases have been reported in Japan. We report four cancer cases with a germline RAD51D c.270_271dup PGV. Three of them (lung cancer: 2, oral cancer: 1) were incidentally identified by whole genome sequencing in patients negative for the associated cancer histories, homologous recombination (HR) deficiency, or a second hit of RAD51D in the cancer DNA. For genetic counseling, we provided information on surveillance and cascade testing based on Western guidelines. The PGVs of moderate-risk HR-related genes are difficult to detect based on phenotype, especially in male-predominant pedigrees. The current spread of cancer genomic analysis will increase opportunities for incidental variant identification. The establishment of Japanese guidelines is expected to aid in the management of PGV carriers of moderate-risk genes.

UNASSIGNED: Breast density is associated with the risk of developing cancer and can be automatically estimated using deep learning models from digital mammograms. Our aim is to evaluate the capacity and reliability of such models to predict density from low-dose mammograms taken to enable risk estimates for younger women.
UNASSIGNED: We trained deep learning models on standard-dose and simulated low-dose mammograms. The models were then tested on a mammography dataset with paired standard- and low-dose images. The effect of different factors (including age, density, and dose ratio) on the differences between predictions on standard and low doses is analyzed. Methods to improve performance are assessed, and factors that reduce the model quality are demonstrated.
UNASSIGNED: We showed that, although many factors have no significant effect on the quality of low-dose density prediction, both density and breast area have an impact. The correlation between density predictions on low- and standard-dose images of breasts with the largest breast area is 0.985 (0.949 to 0.995), whereas that with the smallest is 0.882 (0.697 to 0.961). We also demonstrated that averaging across craniocaudal-mediolateral oblique (CC-MLO) images and across repeatedly trained models can improve predictive performance.
UNASSIGNED: Low-dose mammography can be used to produce density and risk estimates that are comparable to standard-dose images. Averaging across CC-MLO and model predictions should improve this performance. The model quality is reduced when making predictions on denser and smaller breasts.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked this relationship.
METHODS: This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancer-related data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods such as inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding factors.
RESULTS: GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known risk factors-including smoking, alcohol consumption, major depression, and body mass index (BMI)-these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer was (OR, 1.23; 95% CI: 1.14-1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03-1.36), for lung squamous cell carcinoma was (OR, 1.35; 95% CI: 1.19-1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI: 1.22-2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23-5.37). Mediation analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks.
CONCLUSIONS: This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer prevention strategies.

OBJECTIVE: Lead (Pb) is a toxic heavy metal and pervasive environmental contaminant, and a class 2 A carcinogen according to the IARC classification, yet its link with cancer at several body sites remains uncertain. Here, we aimed at summarizing the scientific evidence regarding its association with cancer risk and mortality, focusing on studies that carried out Pb measurements in biological samples.
METHODS: We reviewed articles published in PubMed and EMBASE until January 2nd, 2024, that quantified the epidemiological association between Pb measured in blood, urine, nails, and other biological media, and cancer risk and mortality (overall and by cancer site/type).
RESULTS: We included 46 articles (out of 8022 screened) published in 1995-2023 and reporting on investigations conducted in fifteen countries. In terms of design, 20 were prospective, 24 were retrospective case-control studies, and 2 were cross-sectional. Pb levels were determined in blood in the majority of studies (n=28). The most consistent evidence was for the association of Pb with cancer of the gastrointestinal tract, particularly the oesophagus, stomach (RR ranging from 0.80 to 2.66), colon-rectum, and pancreas; and of the bladder and urinary tract (RR from 1.10 to 2.89). For other specific malignancies, the data were conflicting or too limited to draw reliable conclusions. Finally, increased Pb concentration in blood and urine was consistently associated with higher overall cancer incidence and mortality.
CONCLUSIONS: Lead is a widespread and highly persistent environmental pollutant associated with cancer at multiple body sites. Comprehensive primary prevention interventions aiming at reducing opportunities for Pb exposure need to be continuously promoted and implemented.

Due to rapid urbanization and industrial growth, groundwater globally is continuously deteriorating, posing significant health risks to humans. This study employed a comprehensive methodology to analyze groundwater in the Western Banat Plain (Serbia). Using Piper and Gibbs plots, hydrogeochemistry was assessed, while the entropy-weighted water quality index (EWQI) was used to evaluate groundwater quality. Pollution sources were identified using positive matrix factorization (PMF) accompanied by Pearson correlation and hierarchical cluster analysis, while Monte Carlo simulation assessed health risks associated with groundwater consumption. Results showed that groundwater, mainly Ca-Mg-HCO3 type, is mostly suitable for drinking. Geogenic pollution, agricultural activities, and sewage were major pollution sources. Consumption of contaminated groundwater poses serious non-carcinogenic and carcinogenic health risks. Additionally, arsenic from geogenic source was found to be the main health risks contributor, considering its worryingly elevated concentration, ranging up to 364 μg/L. These findings will be valuable for decision-makers and researchers in managing groundwater vulnerability. PRACTITIONER POINTS: Groundwater is severely contaminated with As in the northern part of the study area. The predominant hydrochemical type of groundwater in the area is Ca-Mg-HCO3. The PMF method apportioned three groundwater pollution sources. Monte Carlo identified rock dissolution as the primary health risk contributor. Health risks and mortality in the study area are positively correlated.

UNASSIGNED: With the increasing use of hormone replacement therapy (HRT), there is a need to understand its impact on the occurrence of female malignant tumors. This systematic review and meta-analysis aimed to assess the risk of ovarian cancer associated with HRT and its related risk factors.
UNASSIGNED: PUBMED, OVID, Embase, Cochrane, and Web of Science were searched from 1980 to April 2022 to identify studies on the risk of ovarian cancer and hormone replacement therapy. The random-effects model was used to estimate the pooled risk of HRT in ovarian cancer, both in cohort studies and case-control studies. Additionally, the analysis examined the outcomes associated with different types of estrogen plus progesterone regimens. Meta-regression and sensitive analysis were performed to evaluate the heterogeneity.
UNASSIGNED: 21 cohort studies (involving 15,313 cases and 4,564,785 participants) and 30 case-control studies (including 18,738 cases and 57,747 controls) were analyzed. The pooled risks of ovarian cancer for HRT users were 1.20 (95% confidence interval [CI] 1.01-1.44) from cohort studies and 1.13 (95%CI 1.04-1.22) from case-control studies. However, after restricting the study period to recent decades, the significant results indicating a higher risk disappeared in cohort studies conducted after 2010 and in case-control studies conducted after 2006. Furthermore, the continuous use of estrogen-progesterone replacement therapy (EPRT) was associated with a risk comparable to that of sequential use. Subgroup analysis showed that both estrogen replacement treatment (ERT) and EPRT had minor risks; The risk further increased with prolonged exposure time, particularly for durations exceeding 10 years. Additionally, serous ovarian cancer appeared to be more susceptible than other pathological types.
UNASSIGNED: The risk of ovarian cancer associated with HRT has been decreasing over time. However, ERT may increase this risk, particularly when used for an extended period. It is recommended that long-time users consider continuous EPRT as a safer alternative.
UNASSIGNED: www.crd.york.ac.uk/prospero/, identifier CRD42022321279.

ATM gene is implicated in the development of breast cancer in the heterozygous state, and Ataxia-telangiectasia (A-T) in a homozygous or compound heterozygous state. Ataxia-telangiectasia (A-T) is a rare cerebellar ataxia syndrome presenting with progressive neurologic impairment, telangiectasia, and an increased risk of leukemia and lymphoma. Although the role of ATM, separately, in association with A-T and breast cancer is well documented, there is a limited number of studies investigating ATM variants when segregating with both phenotypes in the same family. Here, using joint analysis and whole genome sequencing, we investigated ATM c.1564_1565del in a family with one homozygous member presenting with A-T (OMIM # 208900) and three heterozygous members, of whom one had breast cancer (OMIM #114480). To our knowledge, this is the first study of ATM c.1564_1565del segregation with both A-T and breast cancer phenotypes within the same kindred. This study highlights the need for a comprehensive genomic approach in the appropriate cancer risk management of heterozygote carriers of ATM in families with A-T.

The study assessed the health risks associated with heavy metal ingestion and explored the use of honey bee products as a bio-indicator for heavy metal pollution. All honey bee products tested showed heavy metals, but some honey samples had concentrations exceeding permissible limits for Cd, Pb, Ni, and Cr. The mean concentrations of heavy metals (mg/kg) in the honey, propolis, bee wax, and bee pollen were Fe (1.32) > Zn (1.31) > Pb (0.46) > Ni (0.18) > Cr (0.16) > Cu (0.14) > Co (0.12) > Mn (0.05) > Cd (0.03), Fe (8) > Zn (1.13) > Mn (0.59) > Pb (0.13) > Ni (0.07) > Cu (0.06) > Co (0.05) > Cr (0.03) > Cd (0.02), Fe (1.31) > Pb (0.41) > Ni (0.407) > Zn(0.25) > Mn (0.12) > Co(0.10) > Cu (0.07) > Cr (0.05) > Cd (0.002), and Fe (2.2) > Zn (0.75) > Ni (0.25) > Pb (0.16) > Cu (0.05) > Mn (0.045) > Co (0.04) > Cr (0.01) > Cd(0.002), respectively. Similarly, the mean concentration of heavy metals (mg/kg) in the soil, flowers and pine pollen was Fe (539.08) > Zn (89.53) > Mn (66.91) > Ni (58.5) > Co (19.2) > Cr (11.42) > Pb (6.58) > Cu (5.71) > Cd (0.19), Fe (3.12) > Zn (0.95) > Mn (0.72) > Ni (0.29) > Cu (0.16) > Cr (0.14) > Pb (0.059) > Co (0.057) > Cd (0.003) and Fe (2.59) > Zn (1.75) > Mn (0.43) > Pb (0.34) > Co (0.1) > Cr (0.07) > Cu (0.06) > Cd (0.039) > Ni (0.03), respectively. The atomic absorption spectrophotometry procedure was validated through a recovery study and achieved accuracy through the limit of detection (LOD) and limit of quantification (LOQ). The mean Bio concentration factor (BCF) indicated that the transfer from soil to honey was higher than from soil to flower. The metal pollution index (MPI) of the selected indicators was in descending order: soil > honey > flowers > propolis > pine pollen > beeswax > bee pollen. The hazard quotient (HQ) and hazard index (HI) were below one, showing no chronic health risk. The carcinogenic risk (CR) of Cd, Cr, and Ni in honey for children, male and female adults for the consumers exceeds the acceptable level, making Cd, Cr, and Ni the most concerning heavy metals in honey. The study suggests that regular monitoring of heavy metal pollution is essential.

Breast cancer (BC) risks imparted by CHEK2 c.1100delC (\"1100delC\") germline pathogenic/likely pathogenic variant (GPV) are 20-30%, compared to CHEK2 c.470T>C (\"I157T\") GPV with <20%, leading to different breast screening recommendations through MRI. We compared cancer risk management (CRM) across these two GPVs. Study participants were adult females with an 1100delC or I157T GPV drawn from the Inherited Cancer Registry (ICARE) across the United States. Cancer history, clinical characteristics, and CRM were compared using chi-squared tests, t-tests, and logistic regression. Of 150 CHEK2 carriers, 40.7% had BC, with a mean age of 50. Comparing 1100delC and I157T GPVs, there were no differences in rates of (1) breast MRI among those with (65.2% versus 55.6% of 23 and 9; p = 0.612) and without (44.0% versus 44.8% of 50 and 29; p = 0.943) BC; (2) risk-reducing mastectomy among those with (50% versus 38.9% of 46 and 15; p = 0.501) and without (13.8% versus 6.5% of 58 and 31; p = 0.296) BC; and (3) risk-reducing salpingo-oophorectomy among those with (24.2% versus 22.2% of 45 and 18; p = 0.852) and without (17.5% versus 16.7% of 57 and 30; p = 0.918) BC. The results suggest over-screening with breast MRI among CHEK2 I157T GPV carriers and possible overuse of risk-reducing surgeries among CHEK2 carriers.