International Agency for Research on Cancer

Importance Annual low-dose computed tomographic (LDCT) screening reduces lung cancer mortality, but harms could be reduced and cost-effectiveness improved by reusing the LDCT image in conjunction with deep learning or statistical models to identify low-risk individuals for biennial screening. Objective To identify low-risk individuals in the National Lung Screening Trial (NLST) and estimate, had they been assigned a biennial screening, how many lung cancers would have been delayed 1 year in diagnosis. Design, Setting, and Participants This diagnostic study included participants with a presumed nonmalignant lung nodule in the NLST between January 1, 2002, and December 31, 2004, with follow-up completed on December 31, 2009. Data were analyzed for this study from September 11, 2019, to March 15, 2022. Exposures An externally validated deep learning algorithm that predicts malignancy in current lung nodules using LDCT images (Lung Cancer Prediction Convolutional Neural Network [LCP-CNN]; Optellum Ltd) was recalibrated to predict 1-year lung cancer detection by LDCT for presumed nonmalignant nodules. Individuals with presumed nonmalignant lung nodules were hypothetically assigned annual vs biennial screening based on the recalibrated LCP-CNN model, Lung Cancer Risk Assessment Tool (LCRAT + CT [a statistical model combining individual risk factors and LDCT image features]), and the American College of Radiology recommendations for lung nodules, version 1.1 (Lung-RADS). Main Outcomes and Measures Primary outcomes included model prediction performance, the absolute risk of a 1-year delay in cancer diagnosis, and the proportion of people without lung cancer assigned a biennial screening interval vs the proportion of cancer diagnoses delayed. Results The study included 10 831 LDCT images from patients with presumed nonmalignant lung nodules (58.7% men; mean [SD] age, 61.9 [5.0] years), of whom 195 were diagnosed with lung cancer from the subsequent screen. The recalibrated LCP-CNN had substantially higher area under the curve (0.87) than LCRAT + CT (0.79) or Lung-RADS (0.69) to predict 1-year lung cancer risk ( P < .001). If 66% of screens with nodules were assigned to biennial screening, the absolute risk of a 1-year delay in cancer diagnosis would have been lower for recalibrated LCP-CNN (0.28%) than LCRAT + CT (0.60%; P = .001) or Lung-RADS (0.97%; P < .001). To delay only 10% of cancer diagnoses at 1 year, more people would have been safely assigned biennial screening under LCP-CNN than LCRAT + CT (66.4% vs 40.3%; P < .001). Conclusions and Relevance In this diagnostic study evaluating models of lung cancer risk, a recalibrated deep learning algorithm was most predictive of 1-year lung cancer risk and had least risk of 1-year delay in cancer diagnosis among people assigned biennial screening. Deep learning algorithms could prioritize people for workup of suspicious nodules and decrease screening intensity for people with low-risk nodules, which may be vital for implementation in health care systems.

Background: Helicobacter pylori infection is a major cause of non-cardia gastric cancer (NCGC), but uncertainty remains about the associations between sero-positivity to different H. pylori antigens and risk of NCGC and cardia gastric cancer (CGC) in different populations. Methods: A case-cohort study in China included ∼500 each of incident NCGC and CGC cases and ∼2000 subcohort participants. Sero-positivity to 12 H. pylori antigens was measured in baseline plasma samples using a multiplex assay. Hazard ratios (HRs) of NCGC and CGC for each marker were estimated using Cox regression. These were further meta-analysed with studies using same assay. Results: In the subcohort, sero-positivity for 12 H. pylori antigens varied from 11.4% (HpaA) to 70.8% (CagA). Overall, 10 antigens showed significant associations with risk of NCGC (adjusted HRs: 1.33 to 4.15), and four antigens with CGC (HRs: 1.50 to 2.34). After simultaneous adjustment for other antigens, positive associations remained significant for NCGC (CagA, HP1564, HP0305) and CGC (CagA, HP1564, HyuA). Compared with CagA sero-positive only individuals, those who were positive for all three antigens had an adjusted HR of 5.59 (95% CI 4.68-6.66) for NCGC and 2.17 (95% CI 1.54-3.05) for CGC. In the meta-analysis of NCGC, the pooled relative risk for CagA was 2.96 (95% CI 2.58-3.41) [Europeans: 5.32 (95% CI 4.05-6.99); Asians: 2.41 (95% CI 2.05-2.83); Pheterogeneity<0.0001]. Similar pronounced population differences were also evident for GroEL, HP1564, HcpC and HP0305. In meta-analyses of CGC, two antigens (CagA, HP1564) were significantly associated with a higher risk in Asians but not Europeans. Conclusions: Sero-positivity to several H. pylori antigens was significantly associated with an increased risk of NCGC and CGC, with varying effects between Asian and European populations.

Tumor suppressor p53 and its related proteins, p63 and p73, can be synthesized as multiple isoforms lacking part of the N- or C-terminal regions. Specifically, high expression of the ΔNp73α isoform is notoriously associated with various human malignancies characterized by poor prognosis. This isoform is also accumulated by oncogenic viruses, such as Epstein-Barr virus (EBV), as well as genus beta human papillomaviruses (HPV) that appear to be involved in carcinogenesis. To gain additional insight into ΔNp73α mechanisms, we have performed proteomics analyses using human keratinocytes transformed by the E6 and E7 proteins of the beta-HPV type 38 virus as an experimental model (38HK). We find that ΔNp73α associates with the E2F4/p130 repressor complex through a direct interaction with E2F4. This interaction is favored by the N-terminal truncation of p73 characteristic of ΔNp73 isoforms. Moreover, it is independent of the C-terminal splicing status, suggesting that it could represent a general feature of ΔNp73 isoforms (α, β, γ, δ, ε, ζ, θ, η, and η1). We show that the ΔNp73α-E2F4/p130 complex inhibits the expression of specific genes, including genes encoding for negative regulators of proliferation, both in 38HK and in HPV-negative cancer-derived cell lines. Such genes are not inhibited by E2F4/p130 in primary keratinocytes lacking ΔNp73α, indicating that the interaction with ΔNp73α rewires the E2F4 transcriptional program. In conclusion, we have identified and characterized a novel transcriptional regulatory complex with potential implications in oncogenesis. IMPORTANCE The TP53 gene is mutated in about 50% of human cancers. In contrast, the TP63 and TP73 genes are rarely mutated but rather expressed as ΔNp63 and ΔNp73 isoforms in a wide range of malignancies, where they act as p53 antagonists. Accumulation of ΔNp63 and ΔNp73, which is associated with chemoresistance, can result from infection by oncogenic viruses such as EBV or HPV. Our study focuses on the highly carcinogenic ΔNp73α isoform and uses a viral model of cellular transformation. We unveil a physical interaction between ΔNp73α and the E2F4/p130 complex involved in cell cycle control, which rewires the E2F4/p130 transcriptional program. Our work shows that ΔNp73 isoforms can establish interactions with proteins that do not bind to the TAp73α tumor suppressor. This situation is analogous to the gain-of-function interactions of p53 mutants supporting cellular proliferation.

The metabolomics literature suffers from ambiguity in the nomenclature for individual metabolites, which introduces a disconnect between publications and leads to misinterpretations. This Comment proposes recommendations for metabolite annotations to engage the scientific community and publishers to adopt a more consistent approach to metabolite nomenclature.

Background Food processing has been hypothesised to play a role in cancer development; however, data from large-scale epidemiological studies are scarce. This study investigated the association between dietary intake according to amount of food processing and risk of cancer at 25 anatomical sites using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods This study used data from the prospective EPIC cohort study, which recruited participants between March 18, 1991, and July 2, 2001, from 23 centres in ten European countries. Participant eligibility within each cohort was based on geographical or administrative boundaries. Participants were excluded if they had a cancer diagnosis before recruitment, had missing information for the NOVA food processing classification, or were within the top and bottom 1% for ratio of energy intake to energy requirement. Validated dietary questionnaires were used to obtain information on food and drink consumption. Participants with cancer were identified using cancer registries or during follow-up from a combination of sources, including cancer and pathology centres, health insurance records, and active follow-up of participants. We performed a substitution analysis to assess the effect of replacing 10% of processed foods and ultra-processed foods with 10% of minimally processed foods on cancer risk at 25 anatomical sites using Cox proportional hazard models. Findings 521 324 participants were recruited into EPIC, and 450 111 were included in this analysis (318 686 [70·8%] participants were female individuals and 131 425 [29·2%] were male individuals). In a multivariate model adjusted for sex, smoking, education, physical activity, height, and diabetes, a substitution of 10% of processed foods with an equal amount of minimally processed foods was associated with reduced risk of overall cancer (hazard ratio 0·96, 95% CI 0·95–0·97), head and neck cancers (0·80, 0·75–0·85), oesophageal squamous cell carcinoma (0·57, 0·51–0·64), colon cancer (0·88, 0·85–0·92), rectal cancer (0·90, 0·85–0·94), hepatocellular carcinoma (0·77, 0·68–0·87), and postmenopausal breast cancer (0·93, 0·90–0·97). The substitution of 10% of ultra-processed foods with 10% of minimally processed foods was associated with a reduced risk of head and neck cancers (0·80, 0·74–0·88), colon cancer (0·93, 0·89–0·97), and hepatocellular carcinoma (0·73, 0·62–0·86). Most of these associations remained significant when models were additionally adjusted for BMI, alcohol and dietary intake, and quality. Interpretation This study suggests that the replacement of processed and ultra-processed foods and drinks with an equal amount of minimally processed foods might reduce the risk of various cancer types.

Background: Colposcopy, currently included in WHO recommendations as an option to triage human papillomavirus (HPV)-positive women, remains as the reference standard to guide both biopsy for confirmation of cervical precancer and cancer and treatment approaches. We aim to evaluate the performance of colposcopy to detect cervical precancer and cancer for triage in HPV-positive women. Methods: This cross-sectional, multicentric screening study was conducted at 12 centres (including primary and secondary care centres, hospitals, laboratories, and universities) in Latin America (Argentina, Bolivia, Colombia, Costa Rica, Honduras, Mexico, Paraguay, Peru, and Uruguay). Eligible women were aged 30-64 years, sexually active, did not have a history of cervical cancer or treatment for cervical precancer or a hysterectomy, and were not planning to move outside of the study area. Women were screened with HPV DNA testing and cytology. HPV-positive women were referred to colposcopy using a standardised protocol, including biopsy collection of observed lesions, endocervical sampling for transformation zone (TZ) type 3, and treatment as needed. Women with initial normal colposcopy or no high-grade cervical lesions on histology (less than cervical intraepithelial neoplasia [CIN] grade 2) were recalled after 18 months for another HPV test to complete disease ascertainment; HPV-positive women were referred for a second colposcopy with biopsy and treatment as needed. Diagnostic accuracy of colposcopy was assessed by considering a positive test result when the colposcopic impression at the initial colposcopy was positive minor, positive major, or suspected cancer, and was considered negative otherwise. The main study outcome was histologically confirmed CIN3+ (defined as grade 3 or worse) detected at the initial visit or 18-month visit. Findings: Between Dec 12, 2012, and Dec 3, 2021, 42 502 women were recruited, and 5985 (14·1%) tested positive for HPV. 4499 participants with complete disease ascertainment and follow-up were included in the analysis, with a median age of 40·6 years (IQR 34·7-49·9). CIN3+ was detected in 669 (14·9%) of 4499 women at the initial visit or 18-month visit (3530 [78·5%] negative or CIN1, 300 [6·7%] CIN2, 616 [13·7%] CIN3, and 53 [1·2%] cancers). Sensitivity was 91·2% (95% CI 88·9-93·2) for CIN3+, whereas specificity was 50·1% (48·5-51·8) for less than CIN2 and 47·1% (45·5-48·7) for less than CIN3. Sensitivity for CIN3+ significantly decreased in older women (93·5% [95% CI 91·3-95·3] in those aged 30-49 years vs 77·6% [68·6-85·0] in those aged 50-65 years; p<0·0001), whereas specificity for less than CIN2 significantly increased (45·7% [43·8-47·6] vs 61·8% [58·7-64·8]; p<0·0001). Sensitivity for CIN3+ was also significantly lower in women with negative cytology than in those with abnormal cytology (p<0·0001). Interpretation: Colposcopy is accurate for CIN3+ detection in HPV-positive women. These results reflect ESTAMPA efforts in an 18-month follow-up strategy to maximise disease detection with an internationally validated clinical management protocol and regular training, including quality improvement practices. We showed that colposcopy can be optimised with proper standardisation to be used as triage in HPV-positive women. Funding: WHO; Pan American Health Organization; Union for International Cancer Control; National Cancer Institute (NCI); NCI Center for Global Health; National Agency for the Promotion of Research, Technological Development, and Innovation; NCI of Argentina and Colombia; Caja Costarricense de Seguro Social; National Council for Science and Technology of Paraguay; International Agency for Research on Cancer; and all local collaborative institutions.

Background Epidemiological studies assessing the influence of vegetarian diets on breast cancer (BC) risk have produced inconsistent results. Few studies have assessed how the incremental decrease in animal foods and the quality of plant foods are linked with BC. Objectives Disentangle the influence of plant-based diet quality on BC risk between postmenopausal females. Methods Total of 65,574 participants from the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l’Education Nationale) cohort were followed from 1993–2014. Incident BC cases were confirmed through pathological reports and classified into subtypes. Cumulative average scores for healthful (hPDI) and unhealthful (uPDI) plant-based diet indices were developed using self-reported dietary intakes at baseline (1993) and follow-up (2005) and divided into quintiles. Cox proportional hazards models were used to estimate adjusted HR and 95% CI. Results During a mean follow-up of 21 y, 3968 incident postmenopausal BC cases were identified. There was a nonlinear association between adherence to hPDI and BC risk (Pnonlinear < 0.01). Compared to participants with low adherence to hPDI, those with high adherence had a lower BC risk [HRQ3 compared with Q1 (95% CI): 0.79 (0.71, 0.87) and HRQ4 compared with Q1 (95% CI): 0.78 (0.70, 0.86)]. In contrast, higher adherence to unhealthful was associated with a linear increase in BC risk [Pnonlinear = 0.18; HRQ5 compared with Q1 (95% CI): 1.20 (1.08, 1.33); Ptrend < 0.01]. Associations were similar according to BC subtypes (Pheterogeneity > 0.05 for all). Conclusions Long-term adherence to healthful plant foods with some intake of unhealthy plant and animal foods may reduce BC risk with an optimal risk reduction in the moderate intake range. Adherence to an unhealthful plant-based diet may increase BC risk. These results emphasize the importance of the quality of plant foods for cancer prevention. This trial was registered at clinicaltrials.gov (NCT03285230).

Background: Previous studies on calcium intake and lung cancer risk reported inconsistent associations, possibly due to differences in intake amounts and contributing sources of calcium and smoking prevalence. Objective: We investigated associations of lung cancer risk with intakes of calcium from foods and/or supplements and major calcium-rich foods in 12 studies. Methods: Data from 12 prospective cohort studies conducted in the US, Europe, and Asia were pooled and harmonized. We applied Dietary Reference Intake to categorize calcium intake based on the recommendations and quintile distribution to categorize calcium-rich food intakes. We ran multivariable Cox regression by each cohort and pooled risk estimates to compute overall hazard ratios (HR) (95% confidence intervals [CI]). Results: Among 1,624,244 adult men and women, 21,513 incident lung cancer cases were ascertained during a mean follow-up of 9.9 years. Overall, dietary calcium intake was not significantly associated with lung cancer risk; the HRs (95% CI) were 1.08 (0.98-1.18) for higher (>1,500 [men] or >1,800 [women] mg/d) and1.01 (0.95-1.07) for lower intake (≤500 [men] or ≤600 [women] mg/d) comparing with recommended intake (800-1,200 mg/d). Milk and soy food intake was positively or inversely associated with lung cancer risk (HR [95% CI]=1.07 [1.02-1.12] and 0.92 [0.84-1.00]), respectively. The positive association with milk intake was significant only in European and US studies (P-interaction for region=0.04). No significant association was observed for calcium supplements. Conclusions: In this largest prospective investigation, overall, calcium intake was not associated with risk of lung cancer, but milk intake was associated with a higher risk. Our findings underscore the importance of considering food sources of calcium in studies of calcium intake.

Background: Regulating meal timing may have efficacy for improving metabolic health for preventing or managing chronic disease. However, the reliability of measuring meal timing with commonly used dietary assessment tools needs characterization prior to investigating meal timing and health outcomes in epidemiologic studies. Objective: To evaluate the reliability of estimating meal timing parameters including overnight fasting duration, midpoint of overnight fasting time, number of daily eating episodes, period with largest percentage of daily caloric intake, and late last eating episode (>9pm) from repeated 24-hour dietary recalls (24HR). Design: Intraclass correlation coefficients, Light's kappa estimates and 95% confidence intervals (CIs) were calculated from repeated 24HR administered in three epidemiologic studies: United States-based IDATA study (n=996, six 24HR collected over 12-months), German EPIC-Potsdam Validation Study (n=134, twelve 24HR collected over 12-months) and EPIC-Potsdam BMBF-II Study (n=725, four 24HR collected over 36-months). Results: Measurement reliability of overnight fasting duration based on a single 24HR was "poor" in all studies (ICC range 0.27, 95% CI 0.23, 0.32 to 0.46, 95% CI 0.43, 0.50). Reliability was "moderate" with three 24HR (ICC range: 0.53, 95% CI 0.47, 0.58 in IDATA, 0.62, 95% CI 0.52, 0.69 in the EPIC-Potsdam Validation Study, and 0.72, 95% CI 0.70-0.75 in the EPIC-Potsdam BMBF-II Study). Results were similar for midpoint of overnight fasting time and number of eating episodes. Reliability of measuring late eating was "fair" in IDATA (Light's Kappa 0.30, 95% CI 0.21, 0.39) and "slight" in the EPIC-Potsdam Validation study and the EPIC-Potsdam BMBF-II study (Light's Kappa 0.19, 95% CI 0.15, 0.25 and 0.09, 95% CI 0.06, 0.12, respectively). Reliability estimates differed by sex, body mass index, and weekday and season of 24HR administration in some studies. Conclusions: Our result show that at least three 24HR over a 1-3-year period are required for reliable estimates of meal timing variables.

Background: Thyroid cancer incidence in France has increased rapidly in recent decades. Most of this increase has been attributed to overdiagnosis, the major consequence of which is overtreatment. We aimed to estimate the cost of thyroid cancer management in France and the corresponding cost proportion attributable to the treatment of overdiagnosed cases. Methods: Multiple data sources were integrated: the mean cost per thyroid cancer patient was estimated by using the Echantillon Généraliste des Bénéficiaires dataset; thyroid cancer cases attributable to overdiagnosis were estimated for 21 departments using data from the French network of cancer registries and extrapolated to the whole country; medical records from six departments were used to refine the diagnosis/care pathway RESULTS: Between 2011-2015, 33,911 women and 10,846 men in France were estimated to be diagnosed with thyroid cancer, with mean cost per capita of € 6248. Among those treated, 8114-14,925 women and 1465-3626 men were due to overdiagnosis. The total cost of thyroid cancer patient management was € 203·5 million (€ 154·3 million for women and € 49·3 million for men), of which between € 59·9 million (or 29·4% of the total cost) and € 115·9 million (or 56·9% of the total cost) attributable to treatment of overdiagnosed cases. Conclusions: The management of thyroid cancer represents not only a relevant clinical and public health problem in France, but also a potentially important economic burden. Overdiagnosis and corresponding associated treatments play an important role on the total costs of thyroid cancer management.

Background: Epidemiological studies have found that menopausal hormone therapy (MHT) use is associated with an increased ovarian cancer risk. However, whether different MHT types confer the same level of risk is unclear. We estimated the associations between different MHT types and the risk of ovarian cancer in a prospective cohort. Methods: The study population included 75,606 postmenopausal women from the E3N cohort. Exposure to MHT was identified from self-reports in biennial questionnaires between 1992 and 2004 and from drug claim data matched to the cohort between 2004 and 2014. Hazard ratios (HR) and 95% confidence intervals (CI) of ovarian cancer were estimated using multivariable Cox proportional hazards models with MHT as a time-varying exposure. Tests of statistical significance were 2-sided. Results: Over an average 15.3 years follow-up, 416 ovarian cancers were diagnosed. HRs of ovarian cancer associated with ever use of estrogens combined with progesterone or dydrogesterone and ever use of estrogens combined with other progestagen were equal to 1.28 (95%CI 1.04 to 1.57) and 0.81 (0.65 to 1.00), respectively (p-homogeneity = 0.003), compared with never use. The HR for unopposed estrogen use was 1.09 (0.82 to 1.46). We found no trend according to duration of use or time since last use except for estrogens combined with progesterone/dydrogesterone which showed decreasing risk with increasing time since last use. Conclusion: Different MHT types may impact ovarian cancer risk differentially. The possibility that MHT containing progestagens other than progesterone or dydrogesterone may confer some protection should be evaluated in other epidemiological studies.

Background: The commonality of risk factors between cancer and cardiovascular disease suggests that primordial prevention (preventing the onset of risk factors) is a relevant strategy for cancer prevention. Objectives: This study sought to examine the association between baseline and change in the cardiovascular health (CVH) score and incident cancer. Methods: Using serial examinations of the GAZEL (GAZ et ELECTRICITE de France) study in France, we examined the associations between the American Heart Association's Life's Simple 7 CVH score (range: 0-to 14 [poor, intermediate, and ideal level of smoking, physical activity, body mass index, diet, blood pressure, diabetes status, or lipids]) in 1989/1990, their change over 7 years, and incident cancer and cardiac events up to 2015. Results: The study population included 13,933 participants (mean age: 45.3 ± 3.4 years, 24% women). After a median follow-up of 24.8 years (Q1-Q3: 19.4-24.9 years), 2,010 participants had an incident cancer and 899 a cardiac event. The risk of cancer (any site) decreased by 9% (HR: 0.91; 95% CI: 0.88-0.93) per 1-point increase in the CVH score in 1989/1990 compared with a 20% (HR: 0.80; 95% CI: 0.77-0.83) risk reduction for cardiac events. The risk of cancer decreased by 5% (HR: 0.95; 95% CI: 0.92-0.99) per unit of change in the CVH score between 1989/1990 and 1996/1997 compared with a 7% risk reduction for cardiac events (HR: 0.93; 95% CI: 0.88-0.98). These associations remained after omitting the smoking metric from the CVH score. Conclusions: Primordial prevention is a relevant strategy for the prevention of cancer in the population.

Background: The global burden of lung cancer (LC) is increasing. Quantitative projections of the future LC burden in different world regions could help optimize the allocation of resources and provide a benchmark for evaluating LC prevention and control interventions. Objective: We aimed to predict the future incidence of LC in 40 countries by 2035, with an emphasis on country- and sex-specific disparities. Methods: Data on LC incidence from 1978 to 2012 were extracted from 126 cancer registries of 40 countries in Cancer Incidence in Five Continents Volumes V-XI and used for the projection. Age-standardized incidence rates (ASRs) per 100,000 person-years and the number of incident cases were predicted through 2035, using the NORDPRED age-period-cohort model. Results: Global ASRs of the 40 studied countries were predicted to decrease by 23% (8.2/35.8) among males, from 35.8 per 100,000 person-years in 2010 to 27.6 in 2035, and increase by 2% (0.3/16.8) among females, from 16.8 in 2010 to 17.1 in 2035. The ASRs of LC among females are projected to continue increasing dramatically in most countries by 2035, with peaks after the 2020s in most European, Eastern Asian, and Oceanian countries, whereas the ASRs among males will continue to decline in almost all countries. The ASRs among females are predicted to almost reach those among males in Ireland, Norway, the United Kingdom, the Netherlands, Canada, the United States, and New Zealand in 2025 and in Slovenia in 2035 and even surpass those among males in Denmark in 2020 and in Brazil and Colombia in 2025. In 2035, the highest ASRs are projected to occur among males in Belarus (49.3) and among females in Denmark (36.8). The number of new cases in 40 countries is predicted to increase by 65.32% (858,000/1,314,000), from 1.31 million in 2010 to 2.17 million in 2035. China will have the largest number of new cases. Conclusions: LC incidence is expected to continue to increase through 2035 in most countries, making LC a major public health challenge worldwide. The ongoing transition in the epidemiology of LC highlights the need for resource redistribution and improved LC control measures to reduce future LC burden worldwide.

Background Diet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods This analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons. Results Consumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintileQ5−Q1=0.77, 95% CI = 0.64; 0.92, ptrend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk. Conclusion Our results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer.

Objective: In low- and middle-income countries (LMICs), advanced-stage diagnosis of breast cancer (BC) is common, and this contributes to poor survival. Understanding the determinants of the stage at diagnosis will aid in designing interventions to downstage disease and improve survival from BC in LMICs. Methods: Within the South African Breast Cancers and HIV Outcomes (SABCHO) cohort, we examined factors affecting the stage at diagnosis of histologically confirmed invasive breast cancer at five tertiary hospitals in South Africa (SA). The stage was assessed clinically. To examine the associations of the modifiable health system, socio-economic/household and non-modifiable individual factors, hierarchical multivariable logistic regression with odds of late-stage at diagnosis (stage III-IV), was used. Results: The majority (59%) of the included 3497 women were diagnosed with late-stage BC disease. The effect of health system-level factors on late-stage BC diagnosis was consistent and significant even when adjusted for both socio-economic- and individual-level factors. Women diagnosed in a tertiary hospital that predominantly serves a rural population were 3 times (OR = 2.89 (95% CI: 1.40-5.97) as likely to be associated with late-stage BC diagnosis when compared to those diagnosed at a hospital that predominantly serves an urban population. Taking more than 3 months from identifying the BC problem to the first health system entry (OR = 1.66 (95% CI: 1.38-2.00)), and having luminal B (OR = 1.49 (95% CI: 1.19-1.87)) or HER2-enriched (OR = 1.64 (95% CI: 1.16-2.32)) molecular subtype as compared to luminal A, were associated with a late-stage diagnosis. Whilst having a higher socio-economic level (a wealth index of 5) reduced the probability of late-stage BC at diagnosis, (OR = 0.64 (95% CI: 0.47-0.85)). Conclusion: Advanced-stage diagnosis of BC among women in SA who access health services through the public health system was associated with both modifiable health system-level factors and non-modifiable individual-level factors. These may be considered as elements in interventions to reduce the time to diagnosis of breast cancer in women.

Nuts are nutrient-rich foods that contain many bioactive compounds that are beneficial for cardiovascular health. Higher consumption of nuts has been associated with a reduced risk of several cardiovascular diseases (CVD) in prospective cohort studies, including a 19% and 25% lower risk of CVD incidence and mortality, respectively, and a 24% and 27% lower risk of coronary heart disease incidence and mortality, respectively. An 18% lower risk of stroke mortality, a 15% lower risk of atrial fibrillation, and a 19% lower risk of total mortality have also been observed. The role of nuts in stroke incidence, stroke subtypes, peripheral arterial disease and heart failure has been less consistent. This narrative review summarizes recommendations for nuts by clinical practice guidelines and governmental organizations, epidemiological evidence for nuts and CVD outcomes, nut-containing dietary patterns, potential mechanisms of nuts and CVD risk reduction, and future research directions, such as the use of biomarkers to help better assess nut intake. Although there are still some uncertainties around nuts and CVD prevention which require further research, as summarized in this review, there is a substantial amount of evidence that supports that consuming nuts will have a positive impact on primary and secondary prevention of CVD.

The carcinogenicity of opium consumption was recently evaluated by a Working Group convened by the International Agency for Research on Cancer (IARC). We supplement the recent IARC evaluation by conducting an extended systematic review as well as a quantitative meta-analytic assessment of the role of opium consumption and risk for selected cancers, evaluating in detail various aspects of study quality on meta-analytic findings. We searched the published literature to identify all relevant studies on opium consumption and risk of selected cancers in humans through 31 October, 2022. Meta-relative risks (mRRs) and associated 95% confidence intervals (CIs) were estimated using random-effects models for studies of cancer of the urinary bladder, larynx, lung, oesophagus, pancreas, and stomach. Heterogeneity among studies was assessed using the I2 statistic. We assessed study quality and conducted sensitivity analyses to evaluate the impact of potential reverse causation, protopathic bias, selection bias, information bias, and confounding. In total, 2 prospective cohort studies and 33 case–control studies were included. The overall pooled mRR estimated for ‘ever or regular’ versus ‘never’ use of opium ranged from 1.50 (95% CI 1.13–1.99, I2 = 0%, 6 studies) for oesophageal cancer to 7.97 (95% CI 4.79–13.3, I2 = 62%, 7 studies) for laryngeal cancer. Analyses of cumulative opium exposure suggested greater risk of cancer associated with higher opium consumption. Findings were robust in sensitivity analyses excluding studies prone to potential methodological sources of biases and confounding. Findings support an adverse association between opium consumption and cancers of the urinary bladder, larynx, lung, oesophagus, pancreas and stomach.

Background: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive. Methods: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method. Results: Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HRQ5vs.Q1:0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HRQ5vs.Q1:0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HRQ5vs.Q1:1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HRQ5vs.Q1:1.11, 95%CI:0.94, 1.31), heme (HRQ5vs.Q1:0.95; 95%CI:0.84, 1.07) or non-heme iron (HRQ5vs.Q1:1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99). Conclusions: Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources.

Introduction Recently, accurate machine learning and deep learning approaches have been dedicated to the investigation of breast cancer invasive disease events (IDEs), such as recurrence, contralateral and second cancers. However, such approaches are poorly interpretable. Methods Thus, we designed an Explainable Artificial Intelligence (XAI) framework to investigate IDEs within a cohort of 486 breast cancer patients enrolled at IRCCS Istituto Tumori “Giovanni Paolo II” in Bari, Italy. Using Shapley values, we determined the IDE driving features according to two periods, often adopted in clinical practice, of 5 and 10 years from the first tumor diagnosis. Results Age, tumor diameter, surgery type, and multiplicity are predominant within the 5-year frame, while therapy-related features, including hormone, chemotherapy schemes and lymphovascular invasion, dominate the 10-year IDE prediction. Estrogen Receptor (ER), proliferation marker Ki67 and metastatic lymph nodes affect both frames. Discussion Thus, our framework aims at shortening the distance between AI and clinical practice