JNCI: Journal of the National Cancer Institute

BackgroundSubsequent primary malignancies following human papillomavirus (HPV)-related cancers represent an important survivorship concern. However, evidence remains limited regarding sociodemographic and clinical factors associated with registry-defined subsequent cancers among children, adolescents, and young adults in U.S. population-based cohorts. MethodsWe conducted a retrospective population-based analysis of 1,326 individuals diagnosed with HPV-related cancers using Surveillance, Epidemiology, and End Results (SEER) data. Registry-defined subsequent cancer was operationalized as the occurrence of additional primary HPV-related malignancies according to SEER multiple primary rules. Multivariable logistic regression models estimated associations with sex, age group, area-level socioeconomic status (Yost Index quintiles), persistent poverty census tract status, and primary cancer site. Sex-stratified analyses by cancer site were performed. ResultsRegistry-defined subsequent cancers were significantly associated with female sex and young adult age (20-29 years). Females had higher odds of subsequent cancer compared with males (OR = 1.06, 95% CI: 1.03-1.10), and individuals aged 20-29 years had higher odds than those aged 0-9 years (OR = 1.10, 95% CI: 1.05-1.16). Associations persisted after adjustment for socioeconomic indicators. No significant associations were observed with Yost Index quintiles or persistent poverty. Sex-stratified analyses showed higher odds of subsequent cancer for anal cancer among males and vulvar cancer among females relative to oropharyngeal cancer. ConclusionsSex and age are key determinants of registry-defined subsequent cancers following HPV-related malignancies, independent of area-level socioeconomic context. These findings support age- and sex-specific survivorship surveillance strategies across early life-course stages.

Background & AimsHepatocellular carcinoma (HCC) is the third top cause of cancer death globally, often arising on a background of cirrhosis. Here, we aimed to establish novel genetic drivers of HCC across ancestries at a population level through a large meta-analysis of all-cause HCC. Approach & ResultsWe included 15 cohorts comprising 17,329 HCC cases and 2,424,298 controls in this meta-analysis. We found 15 genome-wide significant (P < 5x10-8) germline loci, 6 novel in/near GCKR, MTTP, ADH5, MYC, MAP3K9, and GABPB2. MAP3K9, TERT, and GABPB2 variants act independently of cirrhosis on both co-localisation analysis and sensitivity analyses. There was significant ancestral heterogeneity in 6 loci including variants in the HLA locus that had divergent effects on HCC risk between East Asian and European ancestries. Fine-mapping identified 11 potentially causal coding variants, including p.Leu446Pro in GCKR and p.Asp418Glu in MEN1. MEN1, MYC, and TERT are all involved in the beta-catenin pathway transactivation complex. Transcriptome-wide analysis identified enrichment of germline-encoded DHRS1 in HCC. Regulome-wide analysis replicated the germline signal for EPHA2 and found a novel chromatin accessible region containing genes ZNF367 and HABP4. Finally, we demonstrated that population-level genetic architecture for HCC overlaps with steatotic and viral liver disease, and individuals with genetic risk for lower BMI have higher risk of HCC. ConclusionsGenetic risk for HCC is determined by germline susceptibility to beta-catenin pathway activation and cirrhosis. HCC is driven by both heterogenous and homogenous genetic factors across ancestries, which require further ancestral diversity in liver GWAS to fully dissect.

ObjectiveTo examine how habitual ultraviolet (UV) exposure relates to cause-specific mortality and incidence, to quantify trade-offs between non-skin disease and skin cancer, and to explore potential circulating mediators. DesignA population-based prospective cohort study with epidemiological and proteomic mediation analyses. SettingUK Biobank, recruited from 22 assessment centres across England, Scotland, and Wales. Participants419 007 adults of White European ancestry with data on habitual UV exposure and follow-up for mortality and incident cardiovascular disease and cancer. A proteomic subcohort of 44 712 participants had plasma profiling. Main outcome measuresHabitual ultraviolet exposure was summarised using Sun-BEEM (Sun-Behavioural and Environmental Exposure Model), a multidimensional score integrating environmental and behavioural indicators, categorised as low, medium, or high. Primary outcomes were all-cause, cardiovascular, and cancer mortality and incidence, and associations with Sun-BEEM categories were estimated using multivariable Cox models. Two extensions were implemented: an epidemiological extension using parametric g-computation to estimate deaths under counterfactual low and high UV scenarios; and a biological extension using proteomic mediation analyses to identify circulating proteins potentially linking UV exposure to cardiovascular and cancer mortality. ResultsCompared with low Sun-BEEM, medium and high exposure were associated with lower all-cause mortality (hazard ratio 0.89, 95% confidence interval 0.87 to 0.91; and 0.84, 0.82 to 0.87), with similar inverse associations for cardiovascular and non-skin cancer mortality. Skin cancer mortality showed no clear dose-response relationship with UV exposure, although incident keratinocyte cancers increased across Sun-BEEM categories. Counterfactual modelling suggested that, if associations are causal, a uniformly high UV pattern would prevent many more cardiovascular and other cancer deaths than the additional melanoma and keratinocyte cancer deaths. Proteomic mediation analyses implicated UV-downregulated immunoregulatory, mucosal-barrier, and cardiorenal-neuroendocrine pathways. ConclusionsHigher habitual UV exposure, measured using a multidimensional score, was associated with lower cardiovascular and non-skin cancer mortality without clear increases in skin cancer mortality, supporting a more balanced view of sunlight and health. Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIPublic health advice in temperate countries mainly treats sunlight as a skin cancer hazard. C_LIO_LIFew studies have explicitly quantified the trade-off between the potential benefits of habitual ultraviolet exposure for major non-skin diseases and its harms for skin cancer. C_LIO_LIMechanistic research on how ultraviolet exposure affects health outcomes has focused largely on vitamin D, with only limited work on non-vitamin D pathways. C_LI What this study addsO_LIA multidimensional UV exposure score (Sun-BEEM), combining environmental and behavioural indicators, was associated with lower all-cause, cardiovascular, and non-skin cancer mortality, without clear increases in skin cancer mortality. C_LIO_LICounterfactual analyses suggested a net balance favouring cardiovascular and cancer mortality benefits over skin cancer harms; proteomics supported mainly non-vitamin D pathways. C_LI

BackgroundThere is growing evidence that individuals with different skin phototypes require tailored approaches to achieve optimal photoprotection. Individuals with darker skin phototypes are more prone to UVA1- and visible light-induced pigmentation, whereas lighter phototypes are more susceptible to shorter wavelengths such as UVB and UVA2. Thus, skin phototype is an important determinant of sunscreen efficacy. In the present study we have asked if ethnicity - independent of phototype - is another factor affecting sunscreen efficacy. Objectives(i) To determine the overall photoprotective effects of two sunscreen formulations against UVA1, visible light (VL), and combined visible light plus UVA1, and (ii) to compare the photoprotective efficacy of both products between Han Chinese and Caucasian participants. MethodsForty healthy volunteers (N=20 Han Chinese; N=20 Caucasian), matched for phototype, constitutive pigmentation, gender, and age, were exposed to VL, UVA1, and combined VL plus UVA1 to induce pigmentation responses following standardized irradiation protocols. Skin responses across treated and untreated sites were analysed using linear mixed-effects models. ResultsAcross all participants, both sunscreen formulations provided significant protection against VL, UVA1, and combined VL plus UVA1. Notably, photoprotective efficacy against UVA1-induced immediate (IPD) and persistent pigment darkening (PPD) differed significantly between ethnic groups, with one formulation showing stronger protection in Han Chinese. ConclusionThis study indicates that ethnicity could influence sunscreen efficacy. Thus, sunscreens should not only be tailored to different phototypes, but also consider ethnic background.

BackgroundThe FACE-Q Skin Cancer Module is a condition-specific patient-reported outcome measure for facial skin cancer. While its psychometric properties have been established, normative reference values that enable score interpretation in clinical practice and research are lacking. ObjectiveTo establish normative reference values for the FACE-Q Skin Cancer Module using preoperative patient data and to validate these values by comparison with a demographically matched cohort of healthy partners. MethodsTwo cohorts were analyzed: 287 patients with facial skin cancer (preoperative scores) and 82 healthy partners of skin cancer patients (same-age population without facial skin cancer). Both cohorts completed the Appearance (9 items) and Psychosocial Distress (8 items) scales. Patients additionally completed the Cancer Worry scale (10 items) and Sun Protection scale (5 items). Scores were transformed to a 0-100 scale. Normative values were expressed as percentiles overall and stratified by sex and age group. Group comparisons used independent t-tests, Mann-Whitney U tests, and Cohens d. Internal consistency was assessed with Cronbachs alpha. ResultsPatient and partner cohorts were well matched for age (68.6{+/-}11.9 vs 68.4{+/-}13.0, p=0.902) and sex (46.7% vs 41.5% female, p=0.476). Surprisingly, preoperative facial appearance scores were virtually identical between patients and partners (55.6{+/-}14.0 vs 56.6{+/-}13.6, p=0.590, d=-0.08), as were psychosocial distress scores (14.3{+/-}12.0 vs 14.4{+/-}13.3, p=0.942, d=-0.01). This equivalence held across age groups. A significant sex interaction was identified: female patients scored lower on appearance than female partners (54.3 vs 59.9, p=0.048, d=-0.40), whereas no difference existed among males (56.9 vs 53.1, p=0.168). Internal consistency was excellent in both cohorts (Cronbachs 0.82-0.93). Patients reported marginally higher sun protection behaviors than partners (38.0 vs 33.6, p=0.050). ConclusionsPreoperative FACE-Q Skin Cancer scores in patients are equivalent to those of demographically matched healthy individuals, confirming that these scores serve as valid normative references. The established percentile norms enable clinicians and researchers to interpret individual patient scores in context. The sex-specific difference in appearance scores warrants further investigation.

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 [&ge;]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.

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.

Early-onset colorectal cancer (EOCRC) is rising most rapidly among Hispanic/Latino (H/L) populations, yet the prognostic relevance of WNT pathway alterations under contemporary therapies remains unclear. We conducted a multi-cohort analysis integrating somatic genomics with clinical and treatment annotations (including bevacizumab exposure) from public CRC datasets, stratifying by age of onset and ancestry (H/L vs. non-Hispanic White [NHW]). WNT alterations, dominated by APC, were ubiquitous, but their distribution and outcome associations were context dependent. Across several strata, bevacizumab exposure was associated with lower observed mutation frequencies in select WNT genes (notably RNF43, AXIN1/2, TCF7L2, AMER1), consistent with biological interplay or treatment-related selection. Prognostically, WNT alterations predicted improved overall survival in H/L EOCRC and in NHW late-onset CRC (LOCRC), but worse survival in NHW EOCRC. These findings nominate WNT pathway context as a candidate biomarker for disparity-aware risk stratification in EOCRC and motivate mechanistic studies of anti-angiogenic WNT interactions. Prospective, multi-institutional validation incorporating treatment timing, tumor microenvironment, and social context is warranted to translate these signals into equitable precision oncology.

PurposeTumor comprehensive genomic profiling (CGP) has revolutionized cancer care and identifies patients for biomarker-specific therapy. In metastatic hormone-sensitive prostate cancer (mHSPC), CGP is not currently prognostic and no DNA-based genomic classification exists that accounts for combinations of alterations. We developed a DNA-based CGP classification that is prognostic for overall survival (OS) and could inform treatment. MethodsRetrospective cross-sectional study using multivariable models to develop a clinico-genomic prognostic risk classification in U.S. Veterans diagnosed with synchronous mHSPC. Primary outcome was overall survival (OS) from time of metastatic diagnosis. Results7201 Veterans with metastatic prostate cancer who underwent CGP were identified. There were 2484 Veterans (median [IQR] age 72 [67-77] years) with synchronous mHSPC and tissue CGP, which were divided into training and testing datasets. 16 genes associated with survival were identified and favorable, intermediate, and unfavorable genomic prognostication groups were created based upon mortality risk to generate the STRATOS-P classification. In a multivariable model, classification into intermediate and unfavorable groups was associated with increased mortality relative to the favorable group (aHR 1.54 [95% CI 1.33-1.78]; aHR 2.37 [95% CI 1.97-2.485], respectively), demonstrating an average AUC of 0.83. In an external validation cohort of non-Veterans, intermediate and unfavorable classifications were associated with increased mortality (aHR 2.45 [95% CI 1.87-3.21]; aHR 4.37 [95% CI 3.06-6.22], respectively) with an AUC of 0.79. The intermediate and unfavorable genomic prognostication groups were also associated with increased mortality across multiple disease states including synchronous and metachronous diagnoses, castration-resistance, and analyte type. ConclusionsIn metastatic prostate cancer, tumor DNA genomic alterations are prognostic for OS. The STRATOS-P classification is a validated prognostic tool that has the potential to guide decision-making in mHSPC.

BackgroundNo randomized clinical trial comparing the most established new modalities of treatment for patients with localized prostate cancer has been published, and there is scarce comparative effectiveness research assessing Patient-Reported Outcome Measures (PROMs). Objectiveto compare the impact of active surveillance, robot-assisted radical prostatectomy (RARP), Intensity-modulated radiotherapy (IMRT), and real-time brachytherapy on patients, through PROMs, from pre-treatment to five years after diagnosis of localized prostate cancer. MethodsProspective observational study (ClinicalTrials.gov, NCT05523856) of 566 male patients diagnosed in 2014 to 2021 with clinically localized prostate cancer (50-75 years old; stage cT1 or cT2, N0/Nx and M0/Mx; Gleason [&le;] 6 or 7 (if 3 + 4 with T1c); and PSA [&le;] 10 ng/ml) and followed until 2019-2026. The Expanded Prostate Cancer Index Composite (EPIC-26) measures urinary incontinence, urinary irritative/obstructive symptoms, sexual, bowel and hormonal domains. EPIC-26 was centrally administered via telephone interviews before treatment and then annually after treatment. Generalized estimating equation (GEE) models were constructed with overlap propensity score-based weights and adjusted by age and clinical tumor stage. ResultsWeighted results of adjusted GEE models showed significant declines for sexual health during the 5yr in all treatment groups (ranging from -19.8 to -27.6), but this worsening appeared earlier in those of active treatment (RARP, IMRT and brachytherapy) than in active surveillance. The RARP group presented the greatest deterioration in urinary incontinence (-28.5 vs -11.7 in active surveillance), while the greatest impairment in bowel symptoms was observed in both radiotherapy groups (around -3 vs +0.3 in active surveillance). ConclusionOur findings provide detailed novel evidence, measured over 5 yr, on the long-term impact of disease and treatment on patients with localized prostate cancer. While all treatment groups showed large sexual deterioration overtime, important differences in urinary incontinence (highest after RARP) and bowel symptoms (after IMRT and brachytherapy) persisted. These findings can inform patients during shared decision-making on the alignment between localized prostate cancer treatment choices and their priorities.

BackgroundCutaneous melanoma incidence is rising globally, yet epidemiological data from the high ultraviolet (UV) environment in the United Arab Emirates (UAE), with its diverse expatriate population, remain scarce. This study aims to characterize the epidemiological and histopathological features of cutaneous melanoma in a large, multi-ethnic cohort in the UAE. MethodsThis cross-sectional study analyzed histopathologically confirmed cases of cutaneous melanoma diagnosed at a tertiary referral center in the UAE from January 2017 to January 2025. Patient demographics, tumor location, histologic subtype, Clark level, and Breslow thickness were extracted and analyzed. Descriptive statistics, group comparisons, and multivariable logistic regression were performed using IBM SPSS version 29.0 to identify predictors of thick melanoma (Breslow thickness >1.0 mm). ResultsA total of 597 patients met the inclusion criteria (50.8% male; mean age 47.4{+/-}12.3 years). Individuals of European ancestry constituted 73.4% of cases. Superficial spreading melanoma was the predominant subtype (58.5%), and 46.9% of tumors were thin ([&le;]1.0 mm). Males presented with significantly thicker tumors than females (Breslow thickness of 0.72{+/-}1.32 vs. 0.50{+/-}0.58 mm; p < 0.01) and exhibited distinct anatomical distributions predominant to the back and torso as compared to females with leg and foot predominance. Multivariable analysis identified nodular melanoma (OR 18.40; 95% CI [7.08, 47.86]; p < 0.001) and increasing Clark level (OR 18.50; 95% CI [8.44, 40.58]; p < 0.001) as strong independent predictors of thick melanoma. ConclusionMelanoma in the UAE disproportionately affects fair-skinned expatriates and frequently presents with sex-specific clinical patterns. These findings highlight the need for targeted public awareness initiatives to reduce melanoma morbidity and mortality in the region.

Metastatic pancreatic ductal adenocarcinoma (PDAC) remains deadly, with minimal improvement in prognosis over the past 20 years despite expansion of our chemotherapeutic arsenal. The complex tumor microenvironment (TME) of PDAC in the advanced stage, which often accompany clinical diagnosis, likely contributes to the limited efficacy of current standard of care chemotherapy. Informed by mechanistic preclinical studies, we evaluated the impact of inhibition of Hedgehog (Hh) signaling to prime PDAC TME and leverage anti-tumor efficacy of Gemcitabine plus nab-Paclitaxel (GnP) together with anti-CTLA-4 immune check point inhibitor (ICI, zalifrelimab). Hh inhibition using NLM-001 (an oral small molecule inhibitor of Smo) aimed to polarize the PDAC TME, including cancer associated fibroblasts (CAFs) and intratumoral immune profile, and to foster an immunosuppressive milieu that engages ICI. In this Phase 1b/2, open label, single arm study, patients with metastatic PDAC received standard GnP every 28-day cycles. In addition, NLM-001 was given at 800 mg daily on days -4 to -1 and days 10 to 13 of the GnP cycles 1 to 3, 6 to 8, 11 to 13 onwards (3 cycles on, followed by 2 rest cycles). Anti CTLA-4 inhibitor, zalifrelimab, was administered at 1mg/kg on day 15 of cycle 1 and every 6 weeks thereafter. The primary end point was to assess efficacy by objective response rate (ORR) as per RECIST v1.1. Treatment was overall well tolerated in the 28 patients enrolled. Most frequent grade 3-4 adverse events (AEs) were neutropenia (46.4%), asthenia (21.4%), and neurotoxicity (14.3%). No patient discontinued treatment due to toxicity. ORR was 50% [95% CI, 29.1-70.9] and disease control rate was 95.5% [95% CI, 86.8 - 100.0]. Median progression-free survival (PFS) was 7.3 months 95.5% [95% CI, 5.564 - 9.041] and median overall survival (OS) was 11.5 months [95% CI, 10.23 -12.73]; 1-year PFS was 18.2% [95% CI, 2.1 - 34.3] and 1-year OS was 50% [95% CI, 29.0 - 710]. Patients who achieved ctDNA clearance at cycle 4 had a significant better PFS (10.7 vs 6.0 months; p<0.0001). Paired biopsies immunolabeling and spatial transcriptomic analyses showed polarization of the TME, with increased CD4+ and CD8+ T cells infiltration, down trending Tregs, and decreased SMA/FAP ratio. Hedgehog inhibitor NLM-001 in combination with gemcitabine/nab-paclitaxel and zalifrelimab was safe and well tolerated and showed encouraging objective responses in the first line treatment of advanced PDAC. Clinical Trial RegistrationEudraCT: 2020-004932-52; NCT04827953.

IntroductionMortality and smoking rates vary over time across the US. The Cancer Intervention and Surveillance Modeling Network--Lung Working Group (CISNET-LWG) has developed a smoking history generator to describe the effects smoking on health. This work further refines these parameters and quantifies effects on life expectancy MethodsData from the National Health Interview Survey (NHIS) and the Tobacco Use Supplement to the Current Population Survey (TUS-CPS) were used to estimate smoking history parameters for each state. The age-period-cohort was used in most cases, but an age-cohort mode was used for cessation probabilities. Population mortality data were used to estimate mortality rates for all causes, lung cancer, and non-lung cancer. These were partitioned by smoking status. ResultsCalifornia and Kentucky are states with more or less aggressive tobacco control. The difference between population cohort life expectancy and life expectancy of never smoker was greater for males than for females, and it was greater in Kentucky than California because of higher smoking rates. These differences decreased with time. Similar result are shown for each state. ConclusionsVariation in smoking parameters and mortality trends vary considerably among states. These show variation in exposure to tobacco smoking and their effects on life expectancy. The Southeast region tends to have greater differences from never smokers because of higher smoking rates. However, there are also other factors affecting mortality rates.

BackgroundCurrent British Society of Gastroenterology (BSG) guidelines misclassify metachronous lesion risk after polypectomy in approximately 40% of patients. Building on evidence that immune exclusion drives progression of adenomas to colorectal cancer, this study examined immune profiles in screen-detected adenomas as a predictive biomarker for metachronous lesion risk. MethodsPatients undergoing polypectomy within the Scottish Bowel Screening Programme, with surveillance colonoscopy between 6 months and 6 years were included. Chromogenic immunohistochemistry (IHC; n=2642), 6-plex multiplex immunofluorescence (mIF; n=334), and spatially resolved 6000-plex single cell transcriptomics (n=7) were applied to adenoma microarrays. Cell density and location were measured using QuPath. Hierarchical then K-means clustering was used to define immune cell density-based clusters, which were compared to future lesion events using Kaplan-Meier curves and the log rank test. ResultsAfter adjustment for age, sex, site, size and dysplasia, adenoma CD3+ T cell density was significantly associated with future colorectal neoplasia (HR 1.43, 95% CI 1.19-1.71, p<0.001). Using mIF three immune cell density clusters were identified; 1) high T cell density, low macrophage density, 2) low T cell density, low macrophage density, and 3) high T cell, macrophage and SMA density, with significant differences in future lesion risk (Cluster 1: 22%, Cluster 2: 41%, Cluster 3: 36%, p=0.032). Bulk RNAseq and spatial transcriptomic analysis revealed significant variation in T cell and macrophage co-location and gene expression profiles between clusters. ConclusionAdenoma immune contexture emerges as a determinant of future metachronous lesion risk, offering a novel biomarker to refine surveillance and reduce disease burden. SummaryWhat is already known on this topic: O_LIPost-polypectomy surveillance is currently recommended to patients with high-risk pathological features to detect metachronous lesions and cancer. However current guidelines misclassify risk in a proportion of patients, leading to unnecessary surveillance for some, whilst falsely reassuring others. C_LI What this study adds: O_LIAnalysis of this large post-polypectomy surveillance cohort reveals that adaptive immune responses within removed index adenomas predicts low risk of metachronous lesions, while an immune excluded phenotype signals higher risk, independent of pathological characteristics, and patient risk factors. C_LI How this study might affect research, practice or policy: O_LIDefining immune cell spatial distributions and interactions that drive future adenoma and cancer risk will enable more precise risk stratification for surveillance, informing surveillance guidelines and shaping targeted colorectal cancer prevention strategies. C_LI

BackgroundDigestive system cancer is a leading cause of mortality worldwide. This study aimed to identify changes in digestive system cancer mortality in Peru (2001-2020) by age and sex, and to predict trends through 2030. MethodsDeath records for digestive system cancers (anus, colon, esophagus, stomach, liver and intrahepatic bile ducts, small intestine, pancreas, rectum, biliary tract, and gallbladder) in Peru were analyzed from the World Health Organization mortality database for 2001-2020. Crude mortality rates (CMR) and age-standardized mortality rates (ASMR) per 100,000 inhabitants were calculated by sex, as well as sex ratios and the difference in ASMR between the study period endpoints. Trends were evaluated using Joinpoint regression, and projections to 2030 were performed using the Age-Period-Cohort model with the Nordpred package in R. ResultsOn average during the period, a digestive system cancer CMR and ASMR of 23.47 and 27.32, respectively, were identified; stomach cancer presented the highest mortality in the study period. During this time, colon cancer surpassed liver cancer as the second leading cause of mortality, with a 65.0% increase in ASMR, representing the largest increase variation between 2001-2020. Conversely, esophageal cancer showed the greatest reduction, with a 25.8% decrease. Regarding projections, we found that between 2021 and 2025, compared to 2020, an increase in ASMR would occur in both sexes only for biliary tract cancer; and this increase is projected to affect six of the ten cancer types during the 2026-2030 period for both sexes. ConclusionMortality patterns were heterogeneous, with marked increases observed from 2016 to 2020. Projections suggest a subtle reduction in the 2021-2025 period followed by a resurgence between 2026 and 2030, particularly for colon, stomach, small intestine, pancreas, rectum, and biliary tract cancers. Strengthening prevention and early detection strategies is crucial.

BackgroundWe previously reported that >5% of the population carries pathogenic or likely pathogenic variants (P/LPVs) in key cancer susceptibility genes. However, gene-specific cancer prevalence, spectrum, burden, lifetime risk, comorbidity, and the risk associated with autosomal recessive (AR) genes among carriers remain incompletely defined. MethodsWe analyzed 72 cancer susceptibility genes in the All of Us dataset (N=633,547), including 287,076 participants with both genomic and electronic health record data. Cancer diagnoses were identified using SNOMED codes and grouped into 35 categories. Associations between P/LPVs and overall and site-specific cancer risk were evaluated using regression models adjusted for age, sex, race, and ethnicity. ResultsAmong genes with [&ge;]10 unique carriers, cancer prevalence was highest for MEN1 (80%), followed by TP53 (57.7%), MLH1 (48.4%), and MSH2 (47.2%). Carriers of P/LPVs in BRCA1, BRCA2, MLH1, APC, NF1, PTEN, and PALB2 had significantly earlier cancer diagnosis compared to non-carriers. Cancer prevalence was markedly higher in BRCA1 and BRCA2 carriers who are also mono-allelic MUTYH carriers (75% and 45.5%, respectively) compared with BRCA1 and BRCA2 alone (43.2% and 36.5%). Adjusted survival analysis showed increased cancer risk for MLH1 (OR=6.08), PTEN (OR=5.80), and MSH2 (OR=5.19). Novel associations included MITF with anal/perianal and prostate cancer; BLM with ovarian and soft tissue/sarcoma; WRN with gynecologic cancer (NOS); and FH with hematologic malignancy. ConclusionsThis population-based analysis defines gene-specific cancer prevalence, spectrum, and risk, including contributions from AR variants, in the U.S. population. These findings support more precise genetic testing, screening, and risk stratification for individuals carrying inherited P/LPVs.

IntroductionBRCA1/2 alterations are increasingly recognized as biologically and clinically relevant features in prostate cancer, yet the prognostic and therapeutic significance of zygosity status remains uncertain. Understanding differences between monoallelic and biallelic inactivation may refine risk stratification and guide therapeutic decision-making. Materials and MethodsA retrospective, desk-based observational analysis was performed using publicly accessible datasets from TCGA-PRAD (primary disease) and SU2C/PCF (metastatic disease). BRCA1/2 status was categorized as wild-type, monoallelic, or biallelic based on mutation, copy-number, and loss-of-heterozygosity profiles. Overall survival was evaluated using Kaplan-Meier estimates and Cox models. Systemic therapy outcomes were assessed by treatment class, incorporating exploratory interaction tests. ResultsIn TCGA-PRAD (n=300), OS did not significantly differ by zygosity (global log-rank p=0.45), with median OS of 80.0 months (wild-type), 78.0 months (monoallelic), and 55.0 months (biallelic). In SU2C/PCF (n=200), zygosity stratified outcomes significantly (global log-rank p=0.04): median OS was 22.0 months (wild-type), 14.0 months (monoallelic), and 16.0 months (biallelic). Treatment analyses showed ARSI exposure improved OS in wild-type disease (HR 0.60; 95% CI 0.38-0.95), while interaction testing suggested potential heterogeneity without statistical confirmation (interaction p=0.092). PARP inhibitor exposure showed directionally favorable HRs in wild-type and monoallelic groups but no significant interaction (interaction p=0.757). No therapy class demonstrated consistent effect modification by zygosity. ConclusionBRCA1/2 zygosity shows prognostic relevance in metastatic prostate cancer but not clearly in primary disease. While zygosity did not consistently modify systemic therapy associations in this dataset, findings support zygosity-aware reporting as a practical tool for molecular stratification and future research design.

BackgroundHistologic descriptors such as lymphovascular invasion (LVI), visceral pleural invasion (VPI), spread through air spaces (STAS), and grading system have each been associated with adverse outcomes in lung adenocarcinoma (LUAD). However, with the exception of VPI, these features are not formally incorporated into the TNM staging system. We evaluated the prognostic value and incremental contribution of these histologic descriptors within the framework of the 9th edition TNM staging system. MethodsIn total, 1,745 individuals diagnosed with stage I-III invasive non-mucinous lung adenocarcinoma (NM-LUAD) were included in this study, comprising 1139 French-Canadian patients who underwent surgical resection at IUCPQ-Universite Laval (discovery cohort) and 606 patients from the National Cancer Center Hospital in Tokyo, Japan (validation cohort). The objective of this study was to assess the prognostic contribution of histologic descriptors, including STAS, and LVI, as complements to conventional 9th edition TNM staging. ResultsGrade 3 tumors, LVI, and STAS were identified in 880 (50.4%), 809 (46.4%), and 775 (44.4%) of 1745 cases, respectively. Histologic grade and LVI demonstrated the strongest associations, particularly in early-stage disease, while STAS exhibited a stage-dependent effect, being more impactful in stages II-III. VPI showed less consistent prognostic value. Incorporating these histologic descriptors into TNM staging improved prognostic model performance, with the largest gains driven by histologic grade and LVI, while STAS provided additional, complementary prognostic refinement. ConclusionThese findings demonstrate that key histologic descriptors--including grading system, LVI, and STAS--represent robust and reproducible prognostic parameters. Importantly, these descriptors provide complementary, stage-dependent information that may enhance risk stratification and inform refinement of future TNM staging frameworks, including the forthcoming 10th edition.

Backgroundfollowing a first cutaneous squamous cell carcinoma (CSCC), one-third of patients develop new primaries, escalating their risk of metastasis and poor outcomes. However, current follow-up strategies are not risk-stratified, representing a critical gap in patient management. Objectiveto develop and validate a prognostic model to quantify individualized absolute risk of a first metachronous CSCC after an index tumor, accurately accounting for the high competing risk of mortality in this typically elderly population. Methodswe conducted a nationwide, population-based cohort study of 11,737 patients with a first histologically confirmed CSCC (Netherlands Cancer Registry, 2007-2008) with up to 10 years of follow-up. Data on subsequent tumors was retrieved via linkage to the Automated National Pathological Anatomy Archive (Palga). A Fine-Gray competing-risk model was developed using routinely available clinical and pathological predictors (age, sex, hematologic malignancy, basal cell carcinoma (BCC) and actinic keratosis (AK) history, presence of synchronous CSCC, primary tumor location, and differentiation). Model performance was assessed 10-fold cross-validation, quantifying discrimination (time-dependent C-index) and calibration. Resultsduring follow-up, 3,288 (28%) developed a first metachronous CSCC. The model identified key predictors: markers of cumulative UV-exposure (included AK history, [&ge;]5 prior BCCs), and immunosuppression (chronic lymphocytic leukaemia/small lymphocytic leukaemia). Male sex, presence of synchronous CSCC at baseline were also associated with higher risk. While discrimination was modest (cross-validated 5-year C-index: 0.64), the model demonstrated excellent calibration. Conclusionsthis competing-risk model provides individualized, well-calibrated absolute risk estimates for a first metachronous CSCC. Based on routinely available clinical features, it offers insight into how established predictors shape risk in this high-susceptibility population. External validation and the identification of novel predictors are necessary to further refine the model and support personalized dermatologic care.

This study aimed to evaluate the prognostic value of quantitative analysis of {superscript 1}F-FDG positron emission tomography (PET)/computed tomography (CT) metabolic parameters in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy (NACT). A retrospective analysis was conducted on the clinical and imaging data of 44 patients with pathologically confirmed PDAC who received NACT. All patients completed standard chemotherapy regimens and underwent {superscript 1}F-FDG PET/CT examinations within 2 weeks before and after chemotherapy. Multiple metabolic parameters of lesions were extracted, their percentage changes were calculated, and the optimal cut-off values for each parameter were determined. Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were applied to explore the prognostic value of the metabolic parameters, and the prognostic stratification performance of PET Response Criteria in Solid Tumors (PERCIST) 1.0 was compared with that of Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. PERCIST 1.0 demonstrated significantly superior prognostic stratification compared with RECIST 1.1. A peak standardized uptake value corrected for lean body mass (SULpeak2) > 3.07 and a percentage change in SULpeak between pre- and post-treatment scans ({Delta}SULpeak%) [&le;] 37.66% were identified as independent risk factors for poor prognosis. Furthermore, SUL-related parameters exhibited markedly better predictive efficacy than traditional metabolic parameters such as the standardized uptake value and metabolic tumor volume. Quantitative analysis of {superscript 1}F-FDG PET/CT metabolic parameters can effectively predict prognosis in PDAC after NACT, and PERCIST 1.0 is a more optimal criterion for efficacy and prognostic assessment. A post-NACT SULpeak > 3.07 and {Delta}SULpeak% [&le;] 37.66% were core independent indicators for predicting poor prognosis in these patients.