JNCI: Journal of the National Cancer Institute

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 [≥]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.

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 [≤] 6 or 7 (if 3 + 4 with T1c); and PSA [≤] 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.

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

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.

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.

ImportancePersistent racial and ethnic disparities in breast and prostate cancer mortality are well documented. Most prior studies emphasize between-group differences and rely on population averages or single composite measures of social disadvantage, which can obscure high-need communities within groups. How socio-behavioral determinants of health vary within groups across local gradients of cancer mortality remains incompletely characterized. A framework that combines race- and cancer-specific mortality with local, domain-level socio-behavioral profiles may help identify where burden is greatest and which specific barriers warrant prioritization. ObjectiveTo determine how socio-behavioral risk relates to breast and prostate cancer mortality within racial and ethnic groups and to characterize domain-specific behavioral profiles across low-, moderate- and high-mortality counties to inform targeted, equity-oriented cancer control strategies. DesignCross-sectional study of U.S. counties. Setting United States, county-level analysis. Participants3,141 U.S. counties, stratified within Non-Hispanic White, Non-Hispanic Black, and Hispanic populations. ExposuresCounty-level socio-behavioral determinants of health measured using a composite index comprising seven domains: community solidarity; education, health literacy, and digital connectivity; quality of care; housing and environmental risk; economic livelihoods; lifestyle behaviors; and touchpoints with care. Main outcomes and measuresRace/ethnicity-specific, age-adjusted breast and prostate cancer mortality rates (2018-2022) and county-level socio-behavioral risk scores. Counties were grouped into mortality tertiles within each race/ethnicity-by-cancer-stratum. ResultsAcross groups, higher socio-behavioral risk was associated with higher breast and prostate cancer mortality. For breast cancer, socio-behavioral risk increased monotonically across mortality tertiles for all groups, with the largest within-group increases among Hispanic and Non-Hispanic Black women. For prostate cancer, risk generally increased across mortality tertiles for all groups. Although Hispanic populations had lower population-average mortality, high-mortality Hispanic counties exhibited pronounced risk in lifestyle behaviors, economic livelihoods, and touchpoints with care. Domain patterns associated with high mortality varied by race, ethnicity, and cancer type, with touchpoints with care and economic livelihoods consistently prominent. Conclusions and relevanceWithin-group heterogeneity in socio-behavioral risk is substantial across U.S. counties. Linking population-specific, domain-level socio-behavioral profiles to cancer mortality may support more precise and equity-oriented cancer control strategies than reliance on group averages or composite indices. Key pointsO_ST_ABSQuestionC_ST_ABSWithin racial and ethnic groups, how do socio-behavioral determinants of health vary across US counties with low, moderate, and high breast and prostate cancer mortality? FindingsIn this cross-sectional study, higher county-level socio-behavioral risk was associated with higher breast and prostate cancer mortality across racial and ethnic groups. Race/ethnicity-specific, domain-level profiles revealed within-group heterogeneity, including persistently elevated risk among Non-Hispanic Black populations and pronounced domain-specific gaps in high-mortality Hispanic counties. MeaningLinking population-specific socio-behavioral profiles to local cancer mortality can guide more precise and equity-oriented prioritization of intervention domains and geographies than reliance on group averages or composite indices.

BackgroundTumor-associated macrophages (TAMs) display context-dependent functional polarization, but whether their prognostic impact is consistent across tumor types remains unclear. MethodsWe analyzed RNA-sequencing and clinical data from The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD; n=648), lung squamous carcinoma (LUSC; n=623), and melanoma (SKCM; n=466). Cox proportional hazards models adjusted for age and AJCC stage evaluated per-standard deviation (SD) expression of TAM markers (FOLR2, TREM2) and T-cell markers (CD8A, CXCL9). Cross-histology interaction terms tested divergence between LUAD and LUSC. ResultsIn melanoma, higher FOLR2 (HR 0.87), TREM2 (HR 0.83), CD8A (HR 0.69), and CXCL9 (HR 0.67) independently predicted improved survival. LUAD showed largely neutral macrophage effects. In contrast, LUSC demonstrated an adverse association for FOLR2 (HR 1.28). Interaction analysis confirmed significant divergence for FOLR2 and TREM2 between LUAD and LUSC. ConclusionsTAM-associated prognostic effects reverse by tumor histology, supporting tumor-context-dependent macrophage polarization and informing macrophage-targeted therapeutic strategies.

Background and ObjectiveRisk stratification in localized prostate cancer relies primarily on Grade group (GG). In GG2-4 disease, risk assignment depends on the proportions of pattern 3 and pattern 4. We hypothesized that total pattern 4 length on biopsy would better predict oncologic outcome than GG, percent pattern 4, and multivariable models ("nomograms") based on clinical variables. MethodsWe identified 2499 patients with GG2-4 prostate cancer on biopsy who underwent radical prostatectomy. Discrimination for predictors was calculated for adverse pathologic stage (seminal vesicle invasion or lymph node invasion) and biochemical recurrence (BCR). Key Findings and LimitationsTotal pattern 4 length for the case demonstrated the highest discrimination for adverse pathologic stage in comparison with GG (AUC 0.779 vs 0.658; p<0.0001), percent pattern 4 (0.719), and a model including prostate-specific antigen level, clinical stage, GG, PI-RADS score, and number of positive cores (0.762). Results were similar for BCR, with total pattern 4 length outperforming GG (C-index 0.716 vs 0.662), percent pattern 4 (0.695), and the clinical model (0.699). Neither mm of pattern 3 nor the clinical model added discrimination to total mm of pattern 4. Conclusions and Clinical ImplicationsTotal length of Gleason pattern 4 on biopsy best predicts oncologic outcome in GG2-4 prostate cancer. Other common clinicopathologic variables do not further aid discrimination. Further research is warranted to determine the optimal method for quantifying pattern 4 before incorporation into risk stratification algorithms. O_LIWhat does the study add?: Patients with Grade group 2-4 prostate cancer constitute both the largest group and the one in which treatment decision-making is most difficult. For such patients, total length of Gleason pattern 4 on biopsy predicted oncologic outcomes better than Grade group or multivariable models including the standard predictors of stage, grade, PSA, PI-RADS and number of positive cores. Neither mm of pattern 3 nor the standard predictors add discrimination once total length of pattern 4 is known. C_LIO_LIPatient Summary: Treatment decisions in prostate cancer are often determined by the ratio of pattern 4 to pattern 3 disease. We showed that, in GG2-4 disease, using the total amount of pattern 4 for the case better predicts risk and therefore provides a better basis for treatment decisions. C_LI Take Home MessageIn Grade group 2-4 prostate cancer, total Gleason pattern 4 length for the case is a stronger predictor of adverse pathologic stage and biochemical recurrence than Grade group and other standard clinical variables. Further research is warranted to determine the optimal method for quantifying pattern 4 before incorporation into risk stratification algorithms.

Cutaneous squamous cell carcinoma (SCC) can be time-consuming to treat with Mohs micrographic surgery (MMS) due to the need for intraoperative frozen section (FS) preparation. Two-photon fluorescence microscopy (TPFM) can generate H&E-equivalent images from fresh tissue specimens in a fraction of this time. To determine the accuracy of TPFM for the evaluation of squamous cell carcinoma in MMS margins compared to conventional FS Mohs slide preparation. TPFM was used to image 144 first stage MMS margins from patients being treated for SCC. A Mohs surgeon reviewed 44 training images and then evaluated 100 margins. After a delay, the same surgeon evaluated the corresponding FS slides. Pairs of TPFM and FS slides were reviewed by an expert dermatopathologist to form a consensus diagnosis. Agreement with consensus diagnosis as assessed by an independent dermatopathologist. 3 margins (3%) unequivocally disagreed with the consensus on TPFM and 2 margins (2%) disagreed on FS. The sensitivity and specificity of TPFM were 95.1% and 98.2%, respectively. This study demonstrates that slide-free histology can be interpreted equivalently to conventional Mohs slide processing by both MMS surgeons and dermatopathologists with minimal training.

BackgroundGastric cancer is one of the most common malignancies worldwide and is associated with poor prognosis, placing a considerable burden on public health. Overall treatment outcomes remain unsatisfactory, and accurate lymph node staging is essential for optimizing therapeutic strategies and improving survival. This study aimed to compare the prognostic value of different lymph node staging systems in patients with gastric adenocarcinoma and to provide a more refined prognostic assessment tool for clinical practice. MethodsWe included 4,054 patients with gastric adenocarcinoma from the SEER database (2015-2019) and 383 patients from the First Affiliated Hospital of Hainan Medical University. All patients underwent gastrectomy with D2 lymphadenectomy. Clinicopathological variables included sex, age, race, tumor size, T stage, AJCC N stage (AJCC-N), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDs). Between-group comparisons were performed using the chi-square test. Optimal cut-off values were determined with X-tile software. Survival differences were evaluated by Kaplan-Meier curves. Receiver operating characteristic (ROC) curves were used to compare predictive performance. Cox regression models were applied to identify independent prognostic factors, which were then incorporated into a nomogram. Model performance was assessed using calibration curves and decision curve analysis (DCA). ResultsAJCC-N, LNR and LODDs were strongly and positively correlated in all three datasets (P < 0.001). ROC analysis showed that LODDs had slightly larger areas under the curve than LNR and AJCC-N for predicting 1-, 3- and 5-year survival. Multivariable Cox regression confirmed that LODDs, together with sex, age, race, T stage and tumor size, were independent risk factors for overall survival (P < 0.05). The nomogram constructed from these factors showed good agreement between predicted and observed outcomes on calibration curves, and DCA indicated meaningful clinical net benefit across a broad range of threshold probabilities. ConclusionBy integrating the numbers of positive and negative lymph nodes, LODDs more sensitively reflects changes in metastatic tumor burden and showed the best prognostic performance among the evaluated systems for gastric adenocarcinoma. The proposed nomogram may serve as a useful tool for individualized prognostic assessment.

While the prostate-specific antigen (PSA) test is a widely used prostate cancer screening tool, its application remains controversial. Opportunistic PSA testing generates complex data in which testing intensities, PSA levels, and prostate cancer diagnosis are interdependent. Conventional analyses rarely model these processes jointly. The objective of this study was to develop a population-based joint model to analyse PSA dynamics, retesting patterns, and prostate cancer risk. We used the Stockholm Prostate Cancer Diagnostics Register to identify 506,761 men with at least one PSA test between 2003 and 2020. We fitted a joint model linking three components: a linear mixed-effects submodel for PSA over age, and two proportional hazards submodels for time to next PSA test and time to prostate cancer diagnosis. PSA increased nonlinearly with age, with substantial between-person heterogeneity and increasing unexplained variation with increasing age. In the joint model, doubling of the total PSA values was associated with a hazard ratio (HR) of 2.01 (95% CI: 1.99-2.02; P < .001) for diagnosis and 1.163 (95% CI: 1.161-1.165; P < .001) for retesting. These hazard ratios were significantly stronger than estimates obtained when modelling these processes separately. As a limitation, the study is primarily limited by its observational nature and a lack of data on non-cancer factors that can elevate PSA, such as urinary tract infections or lower urinary tract symptoms. Furthermore, the model does not explicitly account for PSA trajectory changes after cancer onset. In conclusion, jointly modelling PSA dynamics and testing behaviour corrects for the informative observation bias inherent in opportunistic testing. This approach yields more accurate population estimates and personalised risk predictions compared to traditional isolated models. Our findings suggest that PSA dynamics may be clinically informative and that screening models should jointly incorporate testing history and PSA trajectories to improve precision.

IntroductionBuilding on our previously published methodology for claims-based pathway mapping, we extended the analysis by incorporating disease staging. The aim of this study was to develop and evaluate quality indicators (QIs) in patients with non-small cell lung cancer (NSCLC). MethodsThis retrospective, longitudinal cohort study spanned 2017-2023, with follow-up data extending to September 2025. Data were obtained from the National Cancer Registry (NCR), the National Registry of Reimbursed Health Services (NRRHS), which is organized through seven health insurance funds providing nationwide coverage. The index date was defined as the date of the first biopsy (BX) followed by a histopathological examination (HP), along with the ICD-10 code C34. Incident patients aged [&ge;]18 years were included if no prior malignancy was reported, and the presence of PET/CT or CT examination was mandatory in the final verified cohort. The presence of multidisciplinary team (MDT) discussion, time to treatment, availability of care in a Complex Oncology Center (COC), and completeness of predictive biomarker testing were considered key QIs. ResultsWe analyzed the care pathways of 15,886 patients with NSCLC; 3,380 (21.3%) were not treated, and 1,837 (11.6%) were excluded due to the absence of (PET) CT prior to biopsy (BX). The final verified cohort included 10,669 patients with a median age of 69 years (interquartile range, 64-74). The incident stage distribution comprised of stage I/II (27.6%), stage III/IV (67.9%), and 4.5% unknown. Multidisciplinary team (MDT) review was reported in 53.9% of patients, with a median time to MDT discussion of 37 days. Surgery (SX) was performed in 81.0% of stage I and 68.4% of stage II patients. Fewer than 50% of patients initiated treatment within 8 weeks, regardless of disease stage. Centralization of care in COCs and implementation of MDT review showed a positive temporal trend, although disparities across disease stages and regions persisted. PD-L1 testing was documented in 70.0% of stage IV and 65.2% of stage III patients. ConclusionsAdministrative claims data linked with the NCR enabled stage-stratified monitoring of NSCLC care pathways and the identification of actionable QIs, which were implemented as a national tool for continuous quality evaluation of cancer care in the Czech Republic. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIPatient pathway monitoring and quality indicators (QIs) for lung cancer care -- including timeliness of treatment, multidisciplinary team discussion (MDT), and centralization in specialized centers (COCs) -- have been established in several European countries. C_LIO_LIPopulation-level data integrating administrative claims with cancer registry staging data to evaluate QIs across disease stages remain limited. C_LI What this study addsO_LIStage-stratified analysis of 10,669 NSCLC patients revealed that fewer than 50% initiated treatment within 8 weeks, with a declining trend over time despite improvements in MDT utilization and care centralization in COCs. C_LIO_LIPD-L1 testing rates in stages III-IV increased over 2021-2023 but showed substantial regional variability, highlighting opportunities for improving equity of access to biomarker-guided therapy. C_LI How this study might affect research, practice or policyO_LIThe methodology has been implemented as a national tool for continuous quality evaluation of cancer care in the Czech Republic, with PD-L1 testing completeness proposed as an additional OI alongside MDT discussion, time to treatment, and COC centralization. C_LI

PurposeCirculating tumor DNA (ctDNA) analyses are informative as an early indicator of immunotherapy response in advanced non-small cell lung cancer (NSCLC); however, the clinical value of ctDNA molecular response requires further validation. Patients and MethodsAs part of a prospective clinical protocol (NCT05995821), we conducted targeted error-correction sequencing of ctDNA (n=328) and matched WBC DNA (n=109) from 109 patients with metastatic NSCLC who received anti-PD-(L)1 either as monotherapy or in combination. Following cellular origin resolution of 2,818 variants, landmark molecular response (mR) was defined as undetectable ctDNA within 3-9 weeks of treatment initiation. ResultsPre-treatment ctDNA burden, but not blood tumor mutation burden, predicted survival. Implementing a tumor-naive WBC DNA-informed approach increased the number of evaluable cases without compromising the overall accuracy of landmark ctDNA molecular responses. A direct comparison of single-timepoint on-therapy ctDNA assessment with ctDNA dynamics from baseline to the 3-9-week interval, along with an analysis of heterogeneity in molecular response within the 3-9-week window, showed that undetectable ctDNA at the landmark timepoint can effectively predict survival outcomes. A significant enrichment in landmark ctDNA mR was noted among patients with progression-free survival (PFS) [&ge;]6 months with immunotherapy (p=2.5e-05) and chemo-immunotherapy (p=0.02). Patients in the landmark mR group had longer progression-free (p=1.6e-06) and overall survival (p=2.5e-05) than those with molecular progression. ConclusionsLandmark ctDNA molecular response provides a real-time, accurate approach for monitoring immunotherapy clinical outcomes. Although not currently validated for regulatory use, these findings demonstrate the potential utility of ctDNA as an early endpoint in clinical trials. Translational RelevanceEmploying circulating tumor DNA (ctDNA) dynamics as an early indicator of immunotherapy response requires a roadmap for the next-generation sequencing approach, definition of molecular response and establishment of its clinical sensitivity. In this study, we introduce the concept of a landmark ctDNA molecular response, determined 3-9 weeks after initiation of immunotherapy, that maximizes the number of evaluable patients without sacrificing the specificity of the approach. Notably, when evaluating heterogeneity in ctDNA detection within the landmark 3-9-week window and assessing the impact of landmark interval dynamics on survival, we found that a single ctDNA assessment performed similarly to multiple ctDNA measurements within the landmark window (most notably, regardless of whether the timepoints were concordant or discordant). Our findings demonstrate that a single assessment of early on-therapy landmark ctDNA molecular response, can identify patients at risk of disease progression and enable future intervention and therapy optimization.

BackgroundHelicobacter pylori infection accounts for 98% of gastric cancer (GC) cases in Japan. Since 2013, the nationwide expansion of H. pylori eradication therapy to chronic gastritis patients has created a unique opportunity to evaluate its population-level impact on GC primary prevention. However, short-term reductions in GC deaths are difficult to interpret given the long natural history of gastric carcinogenesis. This study aimed to assess the early impact of population-level eradication on GC deaths. MethodsWe applied a two-layer analytic framework consisting of a counterfactual analysis comparing observed GC deaths during 2013-2021 with expected GC deaths had eradication uptake remained at pre-2013 levels. This was combined with a structured, time-dependent, multilayer state-transition model to estimate GC deaths prevented by eradication using GC incidence integrated with age-dependent H. pylori prevalence. ResultsObserved GC deaths declined from 48,632 in 2013 to 41,624 in 2021, whereas counterfactual GC deaths declined more modestly, from 49,794 to 45,654. The divergence between observed and counterfactual GC deaths widened steadily from 1,162 in 2013 to 4,030 in 2021. Model-based estimates indicated that eradication prevented 1,427 GC deaths during 2013-2021, with annual GC deaths prevented increasing from 17 in 2015 to 417 in 2021, particularly among adults aged 50-79. ConclusionsThis study demonstrates that H. pylori eradication has already contributed to a 10.4% reduction in GC deaths in Japan by 2021, with annual expansion of primary prevention effects. This framework supports evidence-based evaluation of short-term reductions in GC deaths attributable to H. pylori eradication in high-prevalence settings.

BackgroundEndoscopic resection is the standard treatment for rectal neuroendocrine tumors (r-NETs) [&le;]10 mm, yet the optimal technique remains controversial. Modified endoscopic mucosal resection (m-EMR) has emerged as a potential alternative compared to endoscopic submucosal dissection (ESD), but existing evidence is largely retrospective and the results of recent randomized controlled trials (RCTs) are inconclusive. AimsTo compare the efficacy and safety of m-EMR versus ESD for r-NETs [&le;]10 mm. MethodsWe systematically searched CENTRAL, PubMed, Embase, and WanFang from January 1st, 1970 to December 23, 2025 for RCTs comparing m-EMR with ESD in r-NETs [&le;]10 mm. The GRADE framework assessed evidence certainty, while trial sequential analysis (TSA) controlled random errors and evaluated conclusion validity. ResultsSix RCTs involving 440 patients were analyzed. No significant difference between m-EMR and ESD was found in histologic complete resection (RR = 1.00, 95% CI 0.97-1.03; I2 = 0%), en bloc resection rates (P = 0.75) and procedure-related complications (P = 0.94). And m-EMR was associated with a significantly shorter procedure time (P<0.00001) and lower hospitalization cost (P<0.00001). The evidence was of moderate certainty; TSA confirmed its reliability, and both cumulative and sensitivity analyses supported the robustness. ConclusionsModerate-certainty evidence indicates m-EMR achieves oncologic outcomes comparable to ESD while offering clear advantages in procedural efficiency and cost for r-NETs [&le;]10 mm, supporting m-EMR possibly as a preferred endoscopic strategy in clinical practice.

BackgroundPlatelet count and C-reactive protein (CRP) are blood tests commonly used in primary care as part of diagnostic work up for symptomatic patients. Abnormal results of these tests can indicate an undetected cancer; however, it is not known whether the association between an abnormal test result and cancer risk varies by patient ethnicity. MethodsThis cohort study used routinely collected primary and secondary health care records in England with linkage to national cancer registry data. Included patients had a record of ethnicity, no prior malignancy, a platelet count or CRP record between 1st January 2010 and 31st December 2017, and were aged 40 years or over at the time of that test. Ethnicity was categorised as White, Asian, Black, Other, and Mixed. Multi-level logistic regression models estimated cancer incidence within one-year of testing, adjusted for age, sex, comorbidities, BMI, deprivation, and year of test. ResultsAmong 4,948,342 patients with a platelet record and 811,559 with a CRP record, one-year cancer incidence was highest among White patients and lowest among Asian patients. Following a normal platelet count, cancer incidence was 1.3% (95% CI 1.3-1.3%) for White patients and 0.63% (0.60-0.66%) for Asian patients; following thrombocytosis, incidence increased to 4.1% (4.0-4.2%) and 1.8% (1.5-2.0%), respectively. After a normal CRP result, cancer incidence was 1.5% (1.4-1.5%) for White patients and 0.79% (0.71-0.88%) for Asian patients, rising to 3.6% (3.5-3.7%) and 1.9% (1.7-2.2%) for a high CRP result, respectively. No significant interactions were found between ethnicity, blood test result, and overall cancer diagnosis, and similar diagnostic odds ratios (dOR) were observed across all ethnic groups. However, for colorectal cancer, Black patients with abnormal results showed higher diagnostic odds ratios (dOR) compared with White patients, relative to a normal result. The dOR for thrombocytosis was 11.1 (7.8-15.6) for Black patients versus 5.7 (5.4-6.0) for White patients (interaction p-value <0.001), and for raised CRP was 4.1 (2.6-6.6) for Black patients versus 2.5 (2.3-2.7) for White patients (interaction p-value=0.043). ConclusionThis large primary care study underscores the need for ethnically diverse cohorts when evaluating diagnostic tests to avoid widening healthcare inequalities.

BackgroundGlyphosate-based herbicides are among the most widely used agricultural chemicals globally. Concerns regarding their carcinogenic potential, particularly in relation to non-Hodgkins lymphoma (NHL), persist despite multiple prior systematic reviews and meta-analyses. However, these reviews have demonstrated important methodological limitations and inconsistent analytic decisions, limiting confidence in their conclusions. ObjectiveTo conduct a rigorous, up-to-date systematic review and meta-analysis of observational studies examining the association between glyphosate-based herbicide exposure and risk of NHL and its subtypes, while addressing methodological and analytic shortcomings of prior syntheses. MethodsWe searched MEDLINE (1970-February 26, 2026) and EMBASE (inception-February 26, 2026), supplemented by reference list review. Eligible studies included cohort, case-control, and pooled analyses reporting effect estimates (or sufficient data) for glyphosate exposure and NHL incidence. Two reviewers independently assessed risk of bias using the Newcastle-Ottawa Scale (for primary studies) and structured criteria for pooled analyses. Random- and fixed-effects meta-analyses were conducted using inverse-variance methods. Heterogeneity was evaluated using Cochrans Q and I{superscript 2} statistics. Publication bias was assessed using standard and contour-enhanced funnel plots. Sensitivity analyses addressed overlapping cohorts, hazard ratio inclusion, exposure definitions, and model overfitting (events-per-variable considerations). Certainty of evidence was graded using GRADE. ResultsSeventeen publications were identified, representing 20 unique study populations; after accounting for overlap, 10 primary datasets were included in quantitative synthesis. Five studies were assessed as low risk of bias, four as moderate risk, and one as high risk. For ever exposure, the random-effects model across all eligible datasets yielded an odds ratio (OR) of 1.11 (95% CI: 0.98-1.27), with moderate heterogeneity (I{superscript 2}{approx}53%). In sensitivity analyses excluding hazard ratio-only studies and overlapping cohorts, pooled ORs ranged from 1.19 to 1.23, with estimates approaching or reaching statistical significance depending on modeling assumptions. For the highest exposure categories, the random-effects model demonstrated a statistically significant association (OR{approx}1.38; 95% CI: 1.00-1.90), with moderate heterogeneity (I{superscript 2}{approx}61%). Sensitivity analyses excluding selected pooled cohort estimates strengthened the association (OR{approx}1.47; 95% CI: 1.04-2.06). Analyses incorporating alternative cumulative exposure metrics yielded similar significant associations (OR{approx}1.33-1.45) with low or absent residual heterogeneity. Subtype analyses suggested elevated risks particularly for diffuse large B-cell lymphoma and follicular lymphoma in certain datasets. Publication bias assessments revealed evidence of small-study effects in some models, though contour-enhanced analyses suggested that not all asymmetry was attributable to selective publication. Overall certainty of evidence was graded as moderate for highest exposure analyses and low-to-moderate for ever-exposure analyses due to residual heterogeneity and observational design limitations. ConclusionsThis updated synthesis indicates that while associations with ever exposure to glyphosate are modest and sensitive to analytic decisions, higher levels of exposure are consistently associated with increased odds of NHL. Findings are robust across multiple sensitivity analyses addressing overlapping data, exposure classification, and model overfitting. These results support a dose-related association between glyphosate-based herbicide exposure and NHL risk and underscore the need for continued surveillance, improved exposure characterization, and prospective cohort analyses with minimized loss to follow-up and transparent analytic reporting.