Search

Artificial intelligence (AI) readers of mammograms compare favourably to individual radiologists in detecting breast cancer. However, AI readers cannot perform at the level of multi-reader systems used by screening programs in countries such as Australia, Sweden, and the UK. Therefore, implementation demands human-AI collaboration. Here, we use a large, high-quality retrospective mammography dataset from Victoria, Australia to conduct detailed simulations of five potential AI-integrated screening pathways, and examine human-AI interaction effects to explore automation bias. Operating an AI reader as a second reader or as a high confidence filter improves current screening outcomes by 1.9–2.5% in sensitivity and up to 0.6% in specificity, achieving 4.6–10.9% reduction in assessments and 48–80.7% reduction in human reads. Automation bias degrades performance in multi-reader settings but improves it for single-readers. This study provides insight into feasible approaches for AI-integrated screening pathways and prospective studies necessary prior to clinical adoption. Successful human-AI collaboration could greatly contribute to breast cancer mammographic screening. Here, the authors use a large-scale retrospective mammography dataset to simulate and compare five plausible AI-integrated screening pathways, finding optimal ways in which human-AI collaboration could be implemented in real-world settings. [ABSTRACT FROM AUTHOR]

Mammographic textures show promise as breast cancer risk predictors, distinct from mammographic density. Yet, there is a lack of comprehensive evidence to determine the relative strengths as risk predictor of textures and density and the reliability of texture-based measures. We searched the PubMed database for research published up to November 2023, which assessed breast cancer risk associations [odds ratios (OR)] with texture-based measures and percent mammographic density (PMD), and their discrimination [area under the receiver operating characteristics curve (AUC)], using same datasets. Of 11 publications, for textures, six found stronger associations (P < 0.05) with 11% to 508% increases on the log scale by study, and four found weaker associations (P < 0.05) with 14% to 100% decreases, compared with PMD. Risk associations remained significant when fitting textures and PMD together. Eleven of 17 publications found greater AUCs for textures than PMD (P < 0.05); increases were 0.04 to 0.25 by study. Discrimination from PMD and these textures jointly was significantly higher than from PMD alone (P < 0.05). Therefore, different textures could capture distinct breast cancer risk information, partially independent of mammographic density, suggesting their joint role in breast cancer risk prediction. Some textures could outperform mammographic density for predicting breast cancer risk. However, obtaining reliable texture-based measures necessitates addressing various issues. Collaboration of researchers from diverse fields could be beneficial for advancing this complex field. [ABSTRACT FROM AUTHOR]

Background: The prevalence of depression among people with chronic pain remains unclear due to the heterogeneity of study samples and definitions of depression. We aimed to identify sources of variation in the prevalence of depression among people with chronic pain and generate clinical prediction models to estimate the probability of depression among individuals with chronic pain. Methods: Participants were from the UK Biobank. The primary outcome was a "lifetime" history of depression. The model's performance was evaluated using discrimination (optimism-corrected C statistic) and calibration (calibration plot). Results: Analyses included 24,405 patients with chronic pain (mean age 64.1 years). Among participants with chronic widespread pain, the prevalence of having a "lifetime" history of depression was 45.7% and varied (25.0–66.7%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.66; good calibration on the calibration plot) included age, BMI, smoking status, physical activity, socioeconomic status, gender, history of asthma, history of heart failure, and history of peripheral artery disease. Among participants with chronic regional pain, the prevalence of having a "lifetime" history of depression was 30.2% and varied (21.4–70.6%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.65; good calibration on the calibration plot) included age, gender, nature of pain, smoking status, regular opioid use, history of asthma, pain location that bothers you most, and BMI. Conclusions: There was substantial variability in the prevalence of depression among patients with chronic pain. Clinically relevant factors were selected to develop prediction models. Clinicians can use these models to assess patients' treatment needs. These predictors are convenient to collect during daily practice, making it easy for busy clinicians to use them. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum). Methods: We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR. Results: Pks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01). Conclusion: Intratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause. [ABSTRACT FROM AUTHOR]

Background: Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus. Methods: We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants. Results: There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%). Conclusion: Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins. [ABSTRACT FROM AUTHOR]

Background: We examined associations between adherence to adaptations of the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and total, exposure-related and site-specific cancer risk. Methods: A total of 20,001 participants ages 40 to 69 years at enrollment into the Melbourne Collaborative Cohort Study in 1990 to 1994, who had diet, body size, and lifestyle reassessed in 2003 to 2007 ("baseline"), were followed-up through June 2021. We constructed diet and standardized lifestyle scores based on core WCRF/AICR recommendations on diet, alcohol intake, body size and physical activity, and additional scores incorporating weight change, sedentary behavior, and smoking. Associations with cancer risk were estimated using Cox regression, adjusting for confounders. Results: During follow-up (mean = 16 years), 4,710 incident cancers were diagnosed. For highest quintile ("most adherent") of the standardized lifestyle score, compared with lowest ("least adherent"), a HR of 0.82 [95% confidence interval (CI): 0.74-0.92] was observed for total cancer. This association was stronger with smoking included in the score (HR = 0.74; 95% CI: 0.67-0.81). A higher score was associated with lower breast and prostate cancer risk for the standardized score, and with lung, stomach, rectal, and pancreatic cancer risk when the score included smoking. Our analyses identified alcohol use, waist circumference and smoking as key drivers of associations with total cancer risk. Conclusions: Adherence to WCRF/AICR cancer prevention recommendations is associated with lower cancer risk. [ABSTRACT FROM AUTHOR]

Two geophysical expeditions (LOMROG II and III) were carried out in 2009 and 2012 to acquire seismic data in the western Amundsen Basin in the Arctic Ocean, a basin formed by ultraslow seafloor spreading at the Gakkel Ridge. Previous studies show alternating magmatic and amagmatic segments at the ridge but it is unclear if such segmentation persisted throughout the entire opening history of the basin. The seismic refraction data were used to develop P -wave velocity models down to the uppermost mantle using forward modelling of traveltimes. The coincident seismic reflection data were used to constrain the geometry of the sedimentary layers and for characterizing the acoustic basement. 2-D gravity modelling was used to determine the Moho depth in areas when data quality was insufficient to resolve a Moho reflection. The models distinguish three different basement types: oceanic crust with layers 2 and 3, oceanic crust that is lacking a layer 3 and exhumed and serpentinized mantle. The maximum observed crustal thickness is 6 km. Areas with thin crust (<3 km) may be underlain by partially serpentinized mantle. Where exhumed mantle is observed, a serpentinization front separates highly serpentinized mantle at the top from partially serpentinized mantle below. The presence of oceanic crust off-axis of the presently amagmatic sector of the Gakkel Ridge indicates that there is both a spatial and temporal variation of crustal accretion processes at the ridge. [ABSTRACT FROM AUTHOR]

Background: Naloxone distribution and overdose education are key preventive strategies to reduce opioid overdose deaths. This paper describes the development and evaluation of The Lookout Project (TLP), a 501(c)(3) organization led by college students and based in Ann Arbor, Michigan. This research aimed to examine the outreach of TLP with hopes of creating a reproducible mail-based kit distribution program for college student-run organizations to replicate., Methods: TLP used a targeted social media advertising campaign to ask participants 7 multiple-choice questions concerning their demographics, previous incarcerations, experiences with intranasal naloxone (IN), and if they had watched the optional informational video in the opioid overdose response kit (OORK) order form., Results: TLP's team distributed over 900 OORKs from August 3, 2020, to January 4, 2022, first by word of mouth and then through social media advertising that began on February 13, 2021. Of the 657 respondents who agreed to participate in research, the majority identified as white (76.0%, n = 400), did not identify with any specified ethnicity group (60.2%, n = 318), were female (60.8%, n = 356), were between the ages of 18 and 22 (35.4%, n = 209), had not been previously incarcerated (95.6%, n = 564), and did watch the hyperlinked video detailing how to respond to an overdose (74.7%, n = 438). Additionally, several kit recipients (2.8%, n = 19) responded to a follow-up survey. Of those, 7 people reported using the IN provided by TLP to reverse an overdose (36.8%, n = 7)., Conclusion: TLP, a nonprofit organization founded by college students, shows potential for informing other student-run organizations about naloxone distribution programs using social media advertising., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Shelby A. Shaughnessy and Victoria Garrow were co-directors and volunteers for The Lookout Project. Katherine C. Hankes was a volunteer and is now the current President of The Lookout Project at the University of Michigan, since registering the 501(c)(3) organization as a student organization.

Background: Breast cancer (BC) incidence is increasing in women under age 40 years, underscoring the need for research on BC risk factors for younger women., Methods: We used data from an international family cohort (n=26,348) to examine whether recreational physical activity (RPA) during adolescence and early adulthood are associated with BC risk before age 40. The cohort includes 2,502 women diagnosed with BC before age 40, including 2,408 diagnosed before study enrollment (68% within 5 years of enrollment). Women reported their average hours-per-week of moderate and strenuous RPA during adolescence (12-17 years) and early adulthood (25-34 years), which were converted to total age-adjusted metabolic equivalents-per-week and categorized into quartiles. We conducted attained age analyses until age 40 (follow-up time began at age 18) using Cox proportional hazards regression models adjusted for study center, race and ethnicity, and education., Results: Being in the highest versus lowest quartile of RPA during adolescence and early adulthood were respectively associated with 12% [HR (95% CI): 0.88 (0.78, 0.98)] and 16% [HR (95% CI): 0.84 (0.74, 0.95) lower BC risks before age 40. Being in the highest quartile of RPA during both adolescence and early adulthood (Pearson correlation=0.52) versus neither timepoint was associated with a 22% lower risk [HR (95% CI): 0.78 (0.68, 0.89)]., Conclusions: Findings suggest that RPA during adolescence and early adulthood may lower BC risk before age 40., Impact: Policies promoting physical activity during adolescence and early adulthood may be important for reducing the growing burden of breast cancer in younger women.

Purpose: Glioma is a rare and debilitating brain cancer with one of the lowest cancer survival rates. Genome-wide association studies have identified 34 genetic susceptibility regions. We sought to discover novel susceptibility regions using approaches which test groups of contiguous genetic markers simultaneously., Patients and Methods: We analyzed data from three independent glioma studies of European ancestry, GliomaScan (1,316 cases/1,293 controls), AGOG (560 cases/2,237 controls), and GICC (4,000 cases/2,411 controls), using the machine-learning algorithm DEPTH and a region-based regression method based on the generalized Berk-Jones (GBJ) statistic, to assess the association of glioma with genomic regions by glioma type and sex. Summary statistics from the UCSF/Mayo Clinic study were used for independent validation. We conducted a meta-analysis using GliomaScan, AGOG, GICC and UCSF/Mayo., Results: We identified 11 novel candidate genomic regions for glioma risk common to multiple studies. Two of the 11 regions, 16p13.3 containing RBFOX1 and 1p36.21 containing PRDM2, were significantly associated with female and male glioma risk respectively, based on results of the meta-analysis. Both regions have been previously linked to glioma tumor progression. Three of the 11 regions contain neurotransmitter receptor genes (7q31.33 GRM8, 5q35.2 DRD1, 15q13.3 CHRNA7)., Conclusions: Our region-based approach identified 11 genomic regions that suggest association with glioma risk of which two regions, 16p13.3 and 1p36.21, warrant further investigation as genetic susceptibility regions for female and male risk respectively. Our analyses suggest that genetic susceptibility to glioma may differ by sex and highlights the possibility that synapse-related genes play a role in glioma susceptibility.

Purpose: It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers., Methods: Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression., Results: Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and >10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively)., Conclusion: Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual.

Background: Elevated mammographic density (MD) for a woman's age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD)., Methods: ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35-85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest., Results: Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (β: - 0.05, 95% confidence interval (CI): - 0.07, - 0.03) and √DA (β: - 0.08, 95% CI: - 0.12, - 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (β:0.06, 95% CI:0.03, 0.10) and √DA (β:0.06, 95% CI:0.02, 0.10), and lower √NDA (β: - 0.06, 95% CI: - 0.11, - 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD., Conclusions: Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk., (© 2024. The Author(s).)

Background: Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels., Methods: Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures., Results: In biallelic MUTYH cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6%±29.6%) were not significantly different to those observed in CRCs (76.2%±20.5%, p-value =0.37), but were significantly higher compared with non-hereditary adenomas (7.6%±7.0%, p-value =3.4×10 -4 ). Similarly, in biallelic NTHL1 cases, SBS30 signature proportions in adenomas (74.5%±9.4%) were similar to those in CRCs (78.8%±2.4%) but significantly higher compared with non-hereditary adenomas (2.8%±3.6%, p-value =5.1×10 -7 ). Additionally, a compound heterozygote with the c.1187G>A p.(Gly396Asp) pathogenic variant and the c.533G>C p.(Gly178Ala) variant of unknown significance (VUS) in MUTYH demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic., Conclusions: SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions observed in CRCs from biallelic MUTYH and biallelic NTHL1 cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention., Competing Interests: Robert C. Grant received a scholarship from Pfizer and provided consulting or advisory roles for Astrazeneca, Tempus, Eisai, Incyte, Knight Therapeutics, Guardant Health, and Ipsen. All other authors have no relevant financial or non-financial interests to disclose.

Background: Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus., Methods: We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants., Results: There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%)., Conclusion: Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins., Impact: Early-life factors, shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognized as a critical window of vulnerability to breast carcinogens., (©2023 American Association for Cancer Research.)

Background: We examined associations between adherence to adaptations of the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and total, exposure-related and site-specific cancer risk., Methods: A total of 20,001 participants ages 40 to 69 years at enrollment into the Melbourne Collaborative Cohort Study in 1990 to 1994, who had diet, body size, and lifestyle reassessed in 2003 to 2007 ("baseline"), were followed-up through June 2021. We constructed diet and standardized lifestyle scores based on core WCRF/AICR recommendations on diet, alcohol intake, body size and physical activity, and additional scores incorporating weight change, sedentary behavior, and smoking. Associations with cancer risk were estimated using Cox regression, adjusting for confounders., Results: During follow-up (mean = 16 years), 4,710 incident cancers were diagnosed. For highest quintile ("most adherent") of the standardized lifestyle score, compared with lowest ("least adherent"), a HR of 0.82 [95% confidence interval (CI): 0.74-0.92] was observed for total cancer. This association was stronger with smoking included in the score (HR = 0.74; 95% CI: 0.67-0.81). A higher score was associated with lower breast and prostate cancer risk for the standardized score, and with lung, stomach, rectal, and pancreatic cancer risk when the score included smoking. Our analyses identified alcohol use, waist circumference and smoking as key drivers of associations with total cancer risk., Conclusions: Adherence to WCRF/AICR cancer prevention recommendations is associated with lower cancer risk., Impact: With <0.2% of our sample fully adherent to the recommendations, the study emphasizes the vast potential for preventing cancer through modulation of lifestyle habits., (©2023 American Association for Cancer Research.)