International Journal of Cancer

Background: Rectal cancer (RC) is traditionally grouped within colorectal cancer (CRC), despite growing evidence of distinct epidemiologic features. However, global comparative assessments of lifetime risks of RC relative to CRC remain limited. We aimed to estimate lifetime risks of developing and dying from RC and CRC worldwide and to examine geographic, socioeconomic, and temporal variations in the proportional contribution of RC within CRC. Methods: Age-specific incidence and mortality estimates for RC and CRC across 185 countries were obtained from GLOBOCAN 2022, together with population and all-cause mortality data from the United Nations. Lifetime risks of incidence (LRI) and mortality (LRM) were calculated using the adjusted-for-multiple-primaries (AMP) method by sex, country, region, and Human Development Index (HDI). The RC-to-CRC lifetime risk ratio quantified the proportional contribution of RC. Temporal trends were assessed in 42 countries using Cancer Incidence in Five Continents Plus (CI5plus) data and average annual percent change (AAPC). Results: In 2022, the global lifetime risk of developing RC was 1.61% and dying from RC was 0.95%, accounting for approximately 35% of the corresponding CRC lifetime burden (4.61% and 2.68%). Absolute lifetime risks of both RC and CRC increased with HDI. In contrast, the proportional contribution of RC varied markedly, peaking at 41%-43% in Central and South-Eastern Asia but falling below 20% in the Caribbean and Central America, and showed a negative association with HDI. The LRI/LRM ratio increased with socioeconomic development. Temporal analyses showed increasing LRI trends in 17 of 42 countries for CRC versus 9 for RC, while declines occurred in 14 countries for RC and 11 for CRC. Conclusions: RC constitutes a substantial yet epidemiologically distinct component of the global CRC burden. Its proportional contribution varies across regions and does not parallel absolute risk patterns, supporting the need for subsite-specific surveillance and prevention strategies.

Introduction Pathogenic germline variants in the BRCA1 and BRCA2 genes confer a markedly increased risk of breast and ovarian cancer, for which effective preventive strategies are available. Although national and international guidelines recommend BRCA testing and cascade screening of relatives, implementation in Italy remains highly heterogeneous across regions. This study estimates the potential population health and cost impact of achieving full nationwide implementation of BRCA1/2 cascade screening in Italy and identifies key organisational barriers and priority actions for implementation. Methods We conducted a Health Impact Assessment integrating literature review, simulation modelling, and stakeholder consultation. A decision tree and Markov model compared the current heterogeneous implementation of BRCA screening in Italy with an ideal scenario reflecting full adherence to national guidelines, optimal cascade screening, and uptake of preventive strategies. Outcomes included breast and ovarian cancer incidence and mortality, healthcare costs over a lifetime horizon (80 years). Key barriers affecting organisational feasibility, acceptability, and patient well-being were assessed, and a set of priority action recommendations was developed. Results In the ideal scenario, 25,626 eligible cancer patients would undergo BRCA testing annually, identifying 4,254 mutation carriers and enabling cascade testing of 27,650 relatives, of whom 8,682 would be BRCA-positive. Under the current implementation, only 8,807 patients and 2,168 relatives are tested, identifying 948 carriers. Over 30 years, full implementation would prevent 821 cancer cases (- 27.9%) and 1,282 deaths (- 49.7%) compared with the current scenario. While initial expenditures increase due to expanded testing and preventive interventions, cumulative costs decrease over time, resulting in net savings of 5.8 million euros at 30 years and a saving per event avoided (- 2,779 euros). Major implementation barriers include fragmented governance, limited access to genetic counselling, heterogeneous laboratory practices, insufficient professional training, and weak referral pathways. Conclusion Full implementation of BRCA1/2 cascade screening in Italy would yield substantial population health benefits and long-term cost savings. Coordinated national governance, standardised pathways, investment in counselling and workforce capacity, and robust monitoring systems are essential to ensure equitable access and sustainable delivery of personalised cancer prevention. This study demonstrates the value of the HIA methodology for evaluating and guiding genomic prevention policies.

BackgroundMetastasis significantly contributes to cancer-related mortality and therapeutic failure. Cancer cells acquire metastatic potential by losing epithelial characteristics and gaining mesenchymal properties through the epithelial-mesenchymal transition (EMT). Differential poly(A) site (PAS) usage, known as alternative polyadenylation (APA), generates mRNA isoforms differing in coding sequence, subcellular localization, stability, or translation efficiency. In cancer, 3'UTR shortening increases expression of proto-oncogenes by escaping miRNA-mediated repression. High expression of CPSF73, which cleaves mRNA precursors at PASs, is associated with unfavorable prognoses in cancer patients. However, the role of APA in regulating EMT remains poorly understood. MethodsIn this study, to investigate the role of APA in EMT, we employed JTE-607, a small-molecule inhibitor of CPSF73 activity, to examine the impact of catalytic inhibition of CPSF73 on proliferation and EMT in MDA-MB-231, MCF7, A549, and HepG2 cancer cells. To identify differential usage of PASs, global profiling of APA changes, and differential gene expression analysis were performed in MDA-MB-231 cells. Additionally, antisense oligonucleotides were used to block the use of a specific PAS whose APA change may be a driver of EMT reversal. ResultsOur findings showed that catalytic inhibition of CPSF73 not only attenuates cancer cell proliferation but also moves the cells away from the mesenchymal state across all four cell lines tested. Global profiling of APA changes following CPSF73 inhibition revealed widespread 3'UTR lengthening and suppression of intronic PASs in MDA-MB-231 cells. APA shifts were observed in key EMT-related genes, accompanied by decreased expression of corresponding proteins across all four cell lines. We used antisense morpholino oligonucleotides to block the proximal PAS of AKT2, shifting the balance of AKT2 mRNA isoforms toward the long isoform. This shift caused EMT reversal, marked by reduced AKT2 protein expression, changes in EMT-related markers, and impaired invasion by MDA-MB-231 cells. ConclusionTogether, these findings identify APA-mediated 3UTR lengthening, with functional consequences in EMT-related genes, as a coordinated mechanism leading to an attenuated EMT phenotype, highlighting a significant connection between APA and the EMT process. Interfering with these APA changes may offer a promising therapeutic strategy to suppress metastasis, with potential efficacy across multiple pathways. Statement of SignificanceOur findings highlight APA-mediated 3 UTR lengthening as a coordinated mechanism that promotes EMT reversal and support CPSF73 inhibition or APA-targeting strategies as potential therapeutic approaches to suppress metastasis across multiple pathways.

ObjectivesNon-communicable diseases (NCDs) account for almost 90% of deaths in Europe, yet comparative estimates of the productivity costs associated with premature NCD mortality across diseases and countries remain limited. This study estimates and compares productivity losses attributable to cardiovascular disease (CVD) and cancer mortality among working-age populations across Europe. Population-based data were used to estimate productivity costs for CVD and cancer deaths across 30 European countries. Sex- and age-specific mortality data for 2021 were obtained from the World Health Organization Mortality Database. Economic data, including wages, unemployment rates, and labour force participation rates, were sourced from Eurostat. Productivity losses were valued using a human capital approach incorporating an age-transition lifecycle simulation model that adjusts for lifetime wage trajectories and labour market dynamics. Costs were discounted at 3.5%. Total productivity losses from cancer and CVD mortality in working-age populations were estimated at {euro}195.7 billion, equivalent to 1.24% of European GDP. Cancer accounted for 62.5% ({euro}122.2 billion) of total productivity losses, while CVD accounted for 37.5% ({euro}73.5 billion). Total CVD-related productivity costs exceeded cancer-related costs in Central and Eastern Europe, whereas cancer productivity costs were higher in Western, Northern, and Southern Europe. Mean productivity costs per death were higher for CVD ({euro}219,848; 95% CI 165,241-270,247) than for cancer ({euro}217,744; 95% CI 166,554-273,144). A larger gender gap was observed for CVD mortality, with a male-to-female cost ratio of 2.5 compared with 1.6 for cancer. Productivity losses associated with premature cancer and CVD mortality represent a substantial economic burden across Europe, with pronounced variation by disease, region, and sex. These findings provide comparative, cross-country estimates of the human capital costs associated with major NCD causes of death.

BackgroundThe tumor immune microenvironment likely plays a central role in progression of thyroid cancer. As for most other solid tumors, it is unknown if immune dysregulation contributes to earlier, subclinical stages of thyroid tumor development, or whether thyroid tumor heterogeneity might involve differential expression of pro-inflammatory mediators. MethodsThe time course of tumor-associated inflammation was studied in Tg-CreERT2;Braf CA/+ mice representing a model of BRAFV600E-driven papillary thyroid carcinoma (PTC). Tumor growth was estimated by histological examination and magnetic resonance imaging. Cytokine expression was monitored by quantitative RT-PCR, RNAScope and Western blot analyses. ResultsBased on spontaneous BrafCA activation due to leaky Cre activity in a minority of targeted cells tumors developed within a preserved thyroid tissue architecture to multifocal papillary thyroid carcinoma (PTC) over a period of 12 months. Tumorigenesis was accompanied by a gradually increased mRNA and protein expression of interleukin-1beta (IL-1{beta}), interleukin-6 and tumor necrosis factor-alpha (TNF-) starting already before Braf mutant cells commenced neoplastic growth. RNAScope revealed that both follicular cells and stromal cells expressed Il1b whereas Il6 and Tnfa transcripts were mostly confined to neoplastic epithelia. Early cytokine expression was associated with oncogene-induced senescence, whereas during tumor development (3-6 months) and in advanced tumor stages (at 12 months) the cytokine expression pattern differed among glands and tumor foci of the same gland accompanied by a highly variable locoregional lymphocytic infiltration. Oral treatment of mutant mice for 1 month with PLX4720, a vemurafenib prodrug, partially reduced cytokine expression along with inhibited tumor growth and redifferentiation of thyroid function. The magnitude of reduced cytokine expression differed much between glands and among mice of both sexes. ConclusionsThese findings indicate that oncogenic BRAFV600E targeted to the thyroid both stimulates endogenous production of IL-1{beta}, IL-6 and TNF- and recruits inflammatory cells to foci of early tumor development. PTCs of different clonal origin are distinguished by differential expression of pro-inflammatory cytokines. The anti-inflammatory effect of mutant Braf kinase inhibition varies presumably related to heterogeneous tumor development, which evolves from stochastic BrafCA activation suggesting there are clonally different probabilities of acquiring drug resistance among Braf mutant thyroid follicular cells.

BackgroundHomozygous biallelic inactivation of CDKN1B is thought to be rare in cancer. Herein we evaluate the prevalence of intratumoral (subclonal) complete p27 protein loss (IPPL) in primary prostate cancer. Experimental DesignWe used immunohistochemistry (IHC) for p27 in a large cohort of whole tissue sections from radical prostatectomy (n=412) and metastases from self-identified African American (AA) and European American (EA) individuals. IPPL was evaluated alongside CDKN1B mRNA in-situ hybridization and next generation sequencing of laser captured cancer regions. Cox proportional hazards analyses assessed the association of IPPL with biochemical recurrence and development of metastases after radical prostatectomy. ResultsIPPL was detected in 18.1% of AA versus 12.2% of EA cases and was tightly correlated with CDKN1B mRNA loss and biallelic genomic loss. IPPL was associated with [≥]pT3 pathologic stage and pN1 disease, however these associations were only significant among AA participants. IPPL was further associated in both univariate and multivariate analyses with the development of biochemical recurrence and metastasis after primary treatment, specifically in AA individuals. The prevalence of p27 genomic alterations in metastatic disease is higher than that of primary prostate cancer in publicly available datasets as well as our analysis of autopsy cases via IHC, indicating that complete p27 loss may be selected for in metastatic disease. ConclusionsSubclonal biallelic loss of CDKN1B resulting in complete p27 protein loss is one of the most commonly occurring biallelic tumor suppressor genomic alterations in primary prostate cancer, and could contribute to worse prostate cancer outcomes, specifically in AA males.

ObjectiveTo evaluate risk of early-onset dementia (EOD) after diagnosis of cancer among Medicaid beneficiaries. DesignLongitudinal observational study of Medicaid enrollment, inpatient, and outpatient claims data from 26 states and Washington, DC, 2001-2019. MethodsBeneficiaries aged 18-64 with [≥]6 months of enrollment were matched 1:1 on cancer status (lung, colon, breast, prostate) by age, sex, race, year and state. We estimated the weighted cumulative incidence functions of EOD at 1, 2, and 5 years after cancer diagnosis using the Aalen-Johansen estimator to account for the competing risk of death and cluster stratified analyses to account for matching. We calculated the corresponding risk differences (RD) and 95% confidence intervals (CI) using the 2.5th and 97.5th percentile of point estimates from 500 bootstrap resamples. ResultsThe 5-year risk of EOD was 4.7% (95%CI: 4.5,5.0) and 4.7% (95%CI: 4.4, 4.9) among those with and without lung cancer, respectively (RD:0.08; 95%CI: -0.27,0.42). The 5-year risk of EOD was 4.1% (95%CI: 3.8, 4.4) and 3.9% (95%CI:3.7,4.3) among those with and without colon cancer, respectively, (RD 0.18; 95%CI: -0.25,0.55). The 5-year risk of EOD was 3.0% (95%CI: 2.8,3.1) and 2.9% (95%CI: 2.7,3.0) among those with and without breast cancer, respectively, (RD 0.10; 95%CI: -0.14,0.43). The 5-year risk of EOD was 4.6% (95%CI: 4.3,4.9) and 5.3% (95%CI: 4.9,5.7) among those with and without prostate cancer, respectively; those with prostate cancer had a lower EOD risk (RD -0.66; 95%CI: -1.2,-0.16). ConclusionsEOD incidence peaked at 4-5% among beneficiaries with and without cancer. Diagnosis of lung, colon, breast and prostate cancers were not strongly associated with EOD within 5 years. Additional work is needed to identify risk factors for EOD.

BackgroundMulticancer early detection tests could be used for cancer screening, but may lead to harms, including false positive results and overdiagnosis of indolent tumours that would not have become clinically evident during that persons lifetime. We assessed the potential for these screening harms in the context of future population-based screening with a multicancer early detection test. MethodsWe used a microsimulation model to assess potential population-level impacts of screening at ages 50-75 years with a multicancer early detection test in Canada. We assumed high test specificity (97-99.1%) and test sensitivity increasing with cancer stage. The model includes latent indolent cancers that would not be diagnosed within that persons lifetime but can be overdiagnosed through screen-detection. We calculated the yearly and cumulative lifetime probabilities of screening overdiagnosis and false positive test results, assuming a range of preclinical screen-detectable periods (2-5 years). ResultsAn estimated 2.1-6.0% of all yearly screen-detected cancers with a multicancer screening test were predicted to be overdiagnoses across scenarios. The proportion of overdiagnosis varied by site, and strongly increased with age, going from 1% at age 50 to over 10% of screen-detected cancers by age 75. The test positive predictive value ranged from 15.9%-77.6%, meaning that there could be 0.3-5.3 false positives with no underlying cancer for every true cancer case detected by the test. ConclusionPopulation-level multicancer screening with a multicancer early detection test would likely not lead to substantial screen-related overdiagnosis. Healthcare systems should consider how screening false positives may increase their diagnostic service caseload.

PurposeProgastrin, aberrantly expressed in colorectal cancer (CRC), is an established trophic factor for tumour epithelial cells. Whether it also promotes CRC progression by reprogramming stromal fibroblasts remains unclear. We investigated progastrin-induced colonic fibroblast activation and its functional consequences on CRC cell migration. MethodsFibroblast activation was assessed in the colonic mucosa of hGAS mice and in the human normal colonic fibroblast line CCD18Co exposed to synthetic progastrin. The impact of tumour-derived progastrin on epithelial cell motility was analysed using HCT116 cells expressing a control shRNA (shLuc) or a progastrin-targeting shRNA (shPG) in transwell migration assays performed with or without fibroblasts. Candidate paracrine mediators were evaluated by RT-qPCR, ELISA and neutralization experiments, and signalling was interrogated using the PI3K inhibitor LY294002. ResultsColonic fibroblasts from hGAS mice displayed stromal FAP and SMA expression, indicating fibroblast activation in vivo. In CCD18Co cells, progastrin increased FAP and SMA protein levels. Fibroblasts enhanced HCT116 cell migration. This effect was stronger when tumour cells expressed progastrin or when fibroblasts were preconditioned by progastrin-producing HCT116 cells. Progastrin induced CXCL12/SDF-1 and CXCL8/IL-8 expression and secretion by fibroblasts, and neutralization of either chemokine abrogated the additional migratory effect conferred by progastrin-activated fibroblasts. Progastrin triggered sustained Akt phosphorylation in fibroblasts, while PI3K inhibition suppressed CXCL12 and CXCL8 secretion and abolished fibroblast-dependent tumour cell migration. ConclusionThese data identify a stromal dimension of progastrin signalling in CRC and support a model in which tumour-derived progastrin activates colonic fibroblasts and elicits a PI3K/Akt-dependent paracrine programme that enhances CRC cell migration.

ObjectiveTo quantify the gap between pregnancy desire and pregnancy attempts among young women with and without a history of breast cancer (BC), and to identify factors associated with this gap. DesignCross-sectional cohort study. SettingThe FEERIC study, conducted in France. PopulationWomen aged 18-43 years without or with prior BC filling inclusion forms of a collaborative study. MethodsPregnancy desire was assessed by self-report ("Do you currently desire a pregnancy?"). Attempt was defined as engaging in unprotected intercourse with the intention to conceive. The pregnancy desire-attempt gap was defined as expressing a desire for pregnancy without actively trying to conceive. Logistic regression was used to evaluate associated demographic, clinical, and treatment-related factors. Main outcome measuresPrevalence of the pregnancy desire-attempt gap and predictors of this gap among BC survivors. ResultsOf 4,351 participants (517 with BC and 3,834 controls), 735 (16.9%) reported a pregnancy desire with 54% attempting conception and 46% who did not. The desire-attempt gap was significantly more frequent in women with a history of BC (OR=1.62, 95%CI[1.15-2.30]). Among BC survivors, younger age (<30years), nulliparity, being single, and ongoing endocrine therapy were independently associated with the gap, whereas prior chemotherapy or trastuzumab were not. ConclusionsNearly half of women declaring desiring pregnancy do not initiate pregnancy attempts, with a larger gap among BC survivors. These findings highlight the need to explore both medical barriers and psychosocial determinants underlying this gap and underscore the importance of refining the language used in reproductive research. FundingThis study was supported by "SHS INCa" grant no.2016-124 and is part of a research project on young women funded by Monoprix*.

BackgroundPeople with HIV (PWH) experience higher cancer-specific mortality and may have worse surgical outcomes than people without HIV (PWoH), though the limited prior evidence largely predates the treat-all antiretroviral therapy (ART) era. We examined postoperative outcomes among PWH and PWoH enrolled in Medicaid in 26 states and Washington, D.C. from 2001-2021. MethodsWe identified the first inpatient/outpatient surgery for anal, bladder, breast, colorectal, female genitourinary, gastroesophageal, head and neck, kidney, liver, lung, ovarian, or pancreatic cancer among adults with continuous enrollment for at least 6 months pre- and 3 months post-surgery. Outcomes included length of stay (LOS), 7- and 30-day readmissions (overall and unplanned), emergency department (ED) use, surgical site infection (SSI), and mortality (30-day, 90-day, 1-year, 5-year). Linear, logistic, and Cox proportional hazards models were adjusted for demographics, comorbidities, cancer type, surgical setting and risk, metastasis, and preoperative treatment (radiation/chemotherapy). ResultsAmong 198,535 beneficiaries undergoing cancer surgery, 4,199 (2.1%) were PWH. PWH were more likely to have inpatient procedures (72.6% vs. 56.4%). Compared to PWoH, PWH had more utilization with longer LOS (7.0 vs. 4.3 days; adjusted mean difference [aMD] = 0.79, 95% CI = 0.60-0.99), extended hospital stays (13.8 vs. 7.4 days; aMD=2.76, 95% CI= 2.42-3.10), and more ED visits (0.82 vs. 0.55 per 90 days; aMD = 0.19, 95% CI = 0.15-0.23). There were no significant differences in readmission, SSI, or 30-day mortality. PWH had higher 90-day mortality (3.2% vs. 1.8%; adjusted odds ratio [aOR] = 1.31, 95% CI = 1.08-1.57), though this was attenuated in the treat-all ART era (2012 - 2021). Results were similar for inpatient surgeries and most common cancer types. PWH had an elevated hazard of 1-year and 5-year mortality post-surgery with an adjusted hazard ratio [aHR] of 1.31 (95% CI = 1.17-1.46) and 1.22 (95% CI= 1.14-1.31), respectively, especially for colorectal cancer (1-year aHR= 1.53, 95% CI=1.24-1.88; 5-year aHR=1.32, 95% CI= 1.14-1.52). ConclusionsPWH had higher post-cancer surgery utilization but similar short-term complications, which supports current guidelines to provide standard cancer care for PWH. More work is needed to elucidate the factors contributing to higher long-term mortality among PWH.

Excess body weight has been associated with increased cancer risk, but the role of weight change across adulthood remains unclear. We examined body weight trajectories from ages 17 to 60 and their associations with site-specific cancer incidence. Data were based on the ODDS study, a pooled, nationwide cohort study in Sweden, with data on weight spanning 1911 to 2020, and cancer follow-up through 2023. Weight trajectories were estimated with linear mixed effects models in individuals with at least three weight measurements. Cox regressions estimated hazard ratios for associations between weight trajectories and established and potentially obesity-related cancers. Fifth versus first quintile of weight change was associated with many cancers, most strongly with esophageal adenocarcinoma in men (HR 2.25; 95% CI 1.66-3.04), liver cancer in men (HR 2.67; 95% CI 2.15-3.33), endometrial cancer in women (HR 3.78; 95% CI 3.09-4.61), and pituitary tumors in both sexes (men: HR 3.13 [95% CI 2.13-4.61]; women: HR 2.13 [95% CI 1.41-3.22]). Associations varied by sex and age. Heavier weight at age 17 years and earlier obesity onset were also associated with higher cancer incidence. These findings highlight the importance of a life-course approach to weight management and support sex- and age-targeted cancer prevention strategies.

BackgroundColorectal cancer (CRC) is a molecularly heterogeneous disease shaped by both genetic and epigenetic alterations. Approximately 15% of CRCs display widespread CpG island hypermethylation, known as the CpG Island Methylator Phenotype (CIMP). CIMP-high (CIMP-H) tumours frequently exhibit MLH1 promoter hypermethylation, leading to mismatch repair deficiency (MMRd) and microsatellite instability (MSI). However, DNA methylation patterns associated with MSI, independent of CIMP and MLH1 silencing, and the influence of clinical variables such as anatomical location and patient age on the CRC methylome remain poorly characterised. MethodsWe performed epigenome-wide DNA methylation profiling of 259 primary CRC tissue samples using the Illumina EPICv2 array, comparing differential methylation between MSI and microsatellite stable (MSS) CRC, adjusting for tumour purity, MLH1 promoter methylation, CIMP status, and anatomical location, to account for known confounders. We further evaluated the independent effects of anatomical location and patient age on global methylation patterns. ResultsEpigenome-wide differential methylation between MSS and MSI CRC was dominated by MLH1 promoter hypermethylation. After adjusting for MLH1 hypermethylation and CIMP status, we identified a distinct set of 656 CpG sites associated with MMRd independent of MLH1 silencing. These included hypermethylation at LRP6, GSK3{beta}, and CDK12, implicating altered WNT signalling and transcriptional regulation pathways. Comparison of MSI subgroups revealed the co-occurrence of MLH1 hypermethylation with promoter hypermethylation at TXNRD1. Anatomical location showed a strong independent effect on methylation patterns, while we observed only modest effects of patient age on the CRC methylome after adjustment for confounders. ConclusionsWe identified a distinct methylation profile distinguishing MSS and MSI CRC, including MLH1-independent markers of MMRd, as well as novel differentially methylated loci within MSI subgroups. We further showed that anatomical location has a strong independent impact on the CRC methylome. Together, these findings refine the molecular characterisation of CRC and highlight potential epigenetic markers that could inform patient stratification and precision oncology.

Prostate cancer overdiagnosis is detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patients lifetime. It is a major concern to policymakers due to its impact on quality of life. We used long-term followup data from the CAP randomised trial of a one-off screen, and English male competing mortality rates (2021-23), to estimate the impact of age on excess prostate cancer incidence within 15 years ( overdiagnosis) using competing risks methods. In total, 2249 (1.19%) of 189,386 men invited for a PSA test in CAP had cancer detected at the one-off screen. Prostate cancer cumulative incidence at 15 years was 7.08% (95%CI 6.95 to 7.21%) in those invited to screening, compared with 6.94% (95%CI 6.82 to 7.06%) in the control arm; an absolute excess incidence difference of 0.14% (95%CI -0.04% to 0.37%). Excess net incidence to 15 years was 0.14/1.19 = 11.7% (95%CI 0.0% to 26.7%) of cases detected at a single prevalent screen. Accounting for competing mortality, English men diagnosed aged 50 years were projected to have a 16% chance the cancer would not have been detected within 15 years, rising to 32% aged 70 years and 58% aged 80 years. Thus, prostate cancer overdiagnosis rises substantially with age due to competing mortality, and is relatively low for younger men. Accordingly, opportunistic testing policies should be re-examined in settings where they have led to high rates of screening in older men.

PurposeGermline deletions affecting the Y-chromosomal gr/gr region were reported in 2005 as associated with susceptibility to testicular germ cell tumor (TGCT), a highly heritable tumor type that is the most common cancer type affecting adult men under the age of 45. Attempts to replicate this association have been equivocal, primarily due to limited power. MethodsHere, we compare and validate two computational approaches to gr/gr deletion calling in high-, low- and ultra-low-coverage whole genome sequencing data, applying these to two datasets from UK Biobank and the TECAC consortium. We generate dataset-specific effect size estimates for the gr/gr deletion-TGCT association using Firths bias-reduced logistic regression across a total of 198,306 men of European-like ancestry (2231 with and 196,075 without TGCT). ResultsUpon random-effects meta-analysis of estimated effect sizes in the two datasets, we found no significant association between gr/gr deletion status and TGCT risk (combined odds ratio=1.24, 95% CI=0.74-2.07, p=0.42), nor upon stratification of seminoma and non-seminoma/mixed histological subtypes. ConclusionOur analysis suggests gr/gr deletion status alone is likely not predictive of TGCT risk in population-scale analyses of European-like individuals; however, the importance of other proposed determinants of gr/gr deletion impact, including Y-haplogroups and semen phenotype, remains unexplored at scale.

ObjectivesTo estimate current, and 5- and 10-year projected, number of cases of cancer per year in transgender and gender diverse (TGD) people in England, overall and by tumour type, accounting for uptake of gender affirming care (GAC). DesignPopulation-based epidemiological modelling study using an age-stratified Monte Carlo simulations approach and the NORDPRED method for predictions. SettingModels estimating cancer case numbers for TGD people in England based on publicly available 2023 cancer surveillance data and survey-based 2025 GAC access, and predicted at 5 and 10 years hence. ParticipantsTGD people aged 15 years and above. Main outcome measuresPrimary cancer cases per year overall, by gender, age group, tumour type, and current and planned GAC. ResultsThe estimated TGD population size in England is 441547 (95% uncertainty interval (UI) 429207- 452890). Total cases per year of cancer in TGD people is expected to be 966 (95% UI 882-1069) excluding non-melanoma skin. Most cases are expected to occur in people aged 60-64. The top 5 expected cancers in TGD people are breast (19%, n = 187, 95% UI 149-241), colorectal (12%, n = 117, 95% UI 106-129), lung (11%, n = 108, 95% UI 96-122), melanoma (7.1%, n = 69, 95% UI 64-74) and urinary (6.2%, n = 60, 95% UI 54-67). Total cases of cancer in TGD people are estimated to be 1740 (95% UI 1584-1934) in 5 years and 2258 (95% UI 2066-2507) in 10 years (excluding non-melanoma skin). If TGD people were able to access their planned level of GAC, this would reduce these figures to 1555 (95% CI 1386-1766) and 2012 (95% CI 1797-2282) respectively. ConclusionsThis study provides prediction of cancer cases in TGD people in England, supporting the planning of service provision and training. This is vital, as with increasing disclosure, and long wait times for GAC, cancer cases in TGD people are predicted to increase. Summary BoxesO_ST_ABSWhat is already known on this topicC_ST_ABSThe annual number of cases of cancer in transgender and gender diverse (TGD) people in England is currently unknown as gender incongruence is not collected as part of the National Cancer Registration and Analysis Service. Some gender-affirming care (GAC) interventions are known to modulate cancer risk. Use of testosterone and chest reconstruction for transmasculine people is known to reduce their incidence of breast cancer compared to cisgender women. Use of oestradiol alongside medical or surgical androgen suppression has been shown to reduce the incidence of prostate cancer in transfeminine people while increasing their risk of breast cancer, compared to cisgender men. What this study addsThis study found that there are likely to be approximately 966 cases of cancer (excluding non-melanoma skin) in TGD people per year in the UK. Though total annual cases of cancer in TGD people are expected to be 2258 in 10 years, improved access to gender-affirming care could reduce total cases to 2012 (a 11% reduction). These figures provide additional justification for funding to improve access to GAC via the National Health Service (NHS), as well as for training on the oncological needs of this population.

Introduction The link between Human Papillomavirus (HPV) and cancer is well-established. In Singapore, bivalent HPV vaccines are subsidised for females, but not males. Economic analysis of HPV vaccination has generally assessed the costs to the health system, but this may not be as relevant to individual decision-making as potential lost income. We estimated the impact of bivalent HPV 16/18 vaccination on sick leave, unemployment, and premature mortality as a function of age and sex to understand the broader impact of HPV-related cancers. Methods We developed a population-level economic model to estimate lifetime income losses by diagnosis age, sex and cancer type. We applied sex- and cancer-specific Cox regressions to the Singapore Cancer Registry for annual predicted survival from 1992 to 2022. These were combined with census and employment data to estimate HPV-associated income losses in Singapore. Attributable fractions and vaccine effectiveness data for HPV 16/18 from the literature were used to estimate the effectiveness of bivalent HPV vaccination. Structural sensitivity analysis examined the role of 80% population coverage conferring herd immunity. Results The registry contained 17,294 individuals with an HPV-associated cancer diagnosis. Lost income was greatest for cervical cancer due to its high prevalence, however the losses per diagnosis were highest for oropharyngeal cancer. Bivalent HPV vaccination led to income benefits of $SGD1,397 [$895 to $1,838] in girls and -$62 [-$76 to -$48] in boys. A gender-neutral HPV vaccination of 80% of 15-year-old Singaporeans, conferring herd immunity, would have lifetime income protective benefits of $24.4m [$14.2m, $33.7m] per cohort, a five-fold return on investment. Conclusions In addition to avoiding healthcare costs and lost quality of life, parents should consider vaccination as a means of avoiding potential income losses. A national policy of gender-neutral HPV vaccination could deliver substantial income protection due to both individual vaccine protection and herd immunity.

BackgroundThe dynamic associations of lifestyle factors with fatigue and work ability in colorectal cancer (CRC) from pre-diagnosis, over rehabilitation until convalescence in the first year after rehabilitation are largely unexplored. MethodsN = 682 CRC patients were recruited for the MIRANDA cohort study in 4 German rehabilitation clinics. The five-component Healthy Lifestyle Score (HLS; smoking, alcohol, diet, physical activity, BMI) was assessed pre-diagnosis, during rehabilitation (which was up to 12 months after surgery), and 12 months after rehabilitation. Fatigue and the ability to work were assessed during rehabilitation and in 3-month-intervals thereafter. ResultsThe HLS was rather stable over time, whereas fatigue and ability to work improved in the first 3 months after rehabilitation and remained stable thereafter. Higher HLS points, either assessed prior diagnosis or during rehabilitation, were associated with lower fatigue and better ability to work during in-patient rehabilitation. Compliance with the smoking criterion was the most important factor. Compliance with the physical activity criterion during rehabilitation was also associated with fatigue and ability to work during rehabilitation. In longitudinal analysis adjusted for fatigue and ability to work at rehabilitation, pre-diagnosis adherence to the alcohol consumption criterion was associated with favorable changes of fatigue and ability to work from rehabilitation to 3- and 12-month follow-up. However, the total HLS and other life-style factors were not associated with the outcomes in longitudinal analysis. ConclusionsAddressing lifestyle factors during rehabilitation is an important cornerstone in fatigue management and can improve the ability to work of CRC patients.

Background&AimsPatients with microsatellite-instable (MSI) colorectal cancer (CRC) benefit from immune checkpoint therapy. For patients with microsatellite-stable (MSS) non-MSI tumors targeting alternative immune checkpoints, such as the Poliovirus receptor (PVR/CD155), may extend response to checkpoint inhibitors and thereby improve outcomes. The drugable transcription factor REVERB (NR1D1) is a master repressor of macrophage function. We hypothesized that regulation of PVR allows elimination of tumor cells by macrophage-directed precision therapy. MethodsHuman CRC cell lines (MSS+: HT29, SW480; MSI+: HCT116), patient-derived organoids (MSS+ PDOs) and tissues were assessed by PCR, Western blot, immunohistochemistry and flow cytometry. 3D co-cultures of CRC cells with macrophages derived from THP1 monocytic leukemia cells or peripheral blood of healthy donors were analysed by microscopy and viability assays. Functional perturbation of PVR and REVERB was achieved by CRISPR/Cas9-sgRNA gene modification, synthetic ligands or blocking antibodies (Abs). ResultsREVERB bound a cognate DNA-element in the -1 kb human PVR gene promoter, and its agonist (SR9009) super-repressed, whereas its antagonist (SR8278) de-repressed transcription of PVR mRNA in macrophages. Macrophages with CRISPR-modified REVERB were unresponsive to ligand, devoid of PVR protein, showed more phagocytosis, tumor cell efferocytosis and expression of genes related to host immunity (PDL1, TLR4 e.a.) than clones with the wild-type receptor. Macrophages lowered the viability of tumor cells, potentiated by PVR blocking Ab or PVR knock-out in tumor cells. Consistently, REVERB antagonist augmented tumor cell death in co-cultures with macrophages and PVR blocking Ab. ConclusionCo-addressing the checkpoint axis REVERB-PVR may represent a novel intervention strategy for patients with MSS+ CRC.

BackgroundTimely cancer diagnosis in children and adolescents is critical to improving outcomes, yet substantial variation in diagnostic intervals persists across cancer types and care settings. We aimed to quantify time to diagnosis and assess variations by patient, demographic, and system-level factors. MethodsWe conducted a retrospective population-based study of children and adolescents aged 0-19 years diagnosed with one of 12 common cancers between 2010 and 2022 in Quebec, Canada. The diagnostic interval was defined as the time from first cancer-related healthcare encounter to diagnosis. We calculated medians and interquartile ranges (IQR) overall and by cancer type and used multivariable quantile regression to identify factors associated with time to diagnosis at the 25th, 50th, and 75th percentiles. ResultsAmong 2,927 individuals with cancer, diagnostic intervals varied by cancer type and age. Median intervals were longest for carcinomas (100 days; IQR 33-192) and shortest for leukemias (8 days; IQR 3-44). Compared with children living in Montreal, living in regional areas and other large urban centres was associated with longer 50th and 75th percentiles of time to diagnosis for hepatic and central nervous system (CNS) tumours. Diagnostic intervals were shorter in the post-pandemic period (2020-2022) across several cancer sites, with CNS tumours showing reductions across all quantiles. InterpretationDiagnostic timeliness differed by cancer type, age, and rurality, but not by sex, material, or social deprivation. The shorter diagnostic intervals observed in the post-pandemic period suggest that pandemic-related changes in care pathways may have expedited diagnosis for some cancers.