4572 Background: Metastatic urothelial carcinoma (mUC) has variable outcomes. Metastatic site count (MSC) correlates with prognosis; the genomic landscape underlying metastatic burden and survival is poorly characterized. We investigated associations among somatic alterations, metastatic patterns, and survival in a large clinical-genomic cohort. Methods: We analyzed 1,157 patients with metastatic bladder cancer by integrating genomic data from the AACR Project GENIE Cohort v18.0-public with clinical annotations and metastatic site information from the MSK-MET database. Associations between 428 genomic alterations and MSC were assessed using Mann-Whitney tests. Survival analyses (n=1,153; 364 events) used Kaplan-Meier estimation, log-rank tests, and Cox regression. Models were adjusted for age, MSC (stratified), and location (lymph, liver, lung). FDR correction was applied, and proportional hazards assumptions verified. Results: Median age was 68.7 years; median OS was 15.8 months. MSC stratification revealed survival differences: 0-1 sites (n=515, median OS not reached), 2-4 sites (n=415, median OS 62.8 months), and >=5 sites (n=223, median OS 13.1 months; log-rank p < 2.5 x 10 -19 ). Each increase in MSC category was associated with worse OS (FDR p < 0.001). MSC predicted 2-year survival with an AUC of 0.78 (95% CI: 0.75–0.82). Six alterations were significantly associated with lower MSC (FDR < 0.05): ERCC2 (n=122; d=0.50, FDR p=5.6 x 10 -6 ), STAG2 (n=128; d=0.40, FDR p=1.9 x 10 -4 ), FBXW7 (n=96; d=0.36, FDR p=7.1 x 10 -3 ), FGFR3 (n=291; d=0.17, FDR p=8.1 x 10 -3 ), TP53BP1 (n=35; d=0.59, FDR p=4.3 x 10 -2 ), and ARID2 (n=70; d=0.41, FDR p=4.6 x 10 -2 ). ERCC2 mutation frequency was 15.7% in 0-1 sites and 4.0% in >=5 sites. Conversely, CDKN2A/B deletions were enriched in patients with >=5 sites (28.3%/27.9%) compared with 0-1 sites (16.5%/15.9%; FDR p < 0.01). Five alterations were independently associated with OS in univariable analysis (FDR < 0.05): CDKN2B deletion (HR 1.81, 95% CI: 1.43–2.28, FDR p=1.7 x 10 -4 ), CDKN2A deletion (HR 1.79, 95% CI: 1.42–2.26, FDR p=1.7 x 10 -4 ), ERCC2 mutation (HR 0.39, 95% CI: 0.24–0.62, FDR p=1.1 x 10 -2 ), CREBBP mutation (HR 0.53, 95% CI: 0.37–0.75, FDR p=3.1 x 10 -2 ), and KDM6A mutation (HR 0.66, 95% CI: 0.52–0.84, FDR p=4.4 x 10 -2 . In multivariable analysis adjusting for age, MSC, and location, no genomic alterations retained independent significance, suggesting MSC mediates these prognostic effects. Penalized regression confirmed MSC as the dominant prognostic variable (HR 1.39 per site increase). Conclusions: DNA damage repair and chromatin modifier mutations are associated with oligometastatic phenotypes and favorable survival, whereas CDKN2A/B deletions correlate with polymetastatic disease. The attenuation of genomic effects after MSC adjustment suggests that metastatic burden is a key mediator. These findings support using genomic profiling to guide mUC prognosis.

INTRODUCTION:Outcomes in unresected locally advanced NSCLC (LA-NSCLC) are poor despite improvement with immunotherapy after concurrent chemoradiation (cCRT). Although KRAS is the most common mutated oncogene in NSCLC, its impact on outcomes in LA-NSCLC treated with cCRT and durvalumab remains underexplored. METHODS:We conducted a multicenter retrospective analysis of patients with stage III nonsquamous NSCLC treated with definitive cCRT followed by durvalumab. Progression-free survival (PFS) and incidence of distant metastasis and locoregional recurrence were compared by KRAS status. Of patients who underwent next-generation sequencing, we assessed the impact of co-alterations on PFS. RESULTS:Among 208 consecutive patients, 117 had KRAS wild-type (WT) and 91 had KRAS-mutant disease. Median PFS was shorter for those with KRAS-mutant disease compared with those with KRAS WT (16 versus 28 mo, p = 0.024). KRAS mutations were associated with worse PFS on univariable and multivariable analyses. There was an increased incidence of distant metastasis for patients with KRAS-mutant disease compared with patients with KRAS WT disease (2 y, 44% versus 34%, p = 0.042), including increased brain metastasis incidence (p = 0.007). Among KRAS-mutant tumors, co-alterations with CDKN2A or STK11 were associated with worse PFS compared with KRAS WT, whereas KRAS mutations without CDKN2A or STK11 co-alterations were not. CONCLUSIONS:KRAS-mutant nonsquamous LA-NSCLC is associated with inferior outcomes, largely driven by increased distant and brain metastases. Tumors with concurrent CDKN2A or STK11 alterations had the poorest outcomes. These findings support the evaluation of KRAS inhibitors in this high-risk stage III population.

This cohort study assesses the association between use of palliative radiotherapy and inpatient radiation oncology consultation among patients with limited life expectancy.

Abstract Background: Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle loss that affects approximately 40-50% of patients with non-small cell lung cancer (NSCLC)Despite its clinical impact, reliable biomarkers for early detection and risk stratification remain poorly defined. Methods: In this prospective longitudinal study,we conducted an analysis of 27 patients with stage IV NSCLC from the SeroNet-CORALE cohort with at least two plasma samples collected between 2020-2023. Cachexia was defined according to international consensus criteria (weight loss >5% or >2% with BMI<20 kg/m2 over 6 months). We quantified 40 biomarkers using MesoScale Discovery platforms, including inflammatory cytokines, chemokines, metabolic hormones, angiogenic factors, and mitochondrial DNA. Firth penalized logistic regression models were used to evaluate associations between log2-transformed biomarker levels and cachexia status, with adjustment for age, sex, race, and treatment exposures. Results: We enrolled lung cancer patients (65% female, mean age 65±10 years) with predominantly adenocarcinoma histology (89 percent), and the proportion classified as cachectic was 22 percent at diagnosis and 20 percent and 19 percent at the subsequent timepoints. Cachectic patients showed consistently lower BMI (21.0±2.0 vs 27.0±7.0 at T1; 21.8±4.9 vs 25.2±4.9 at T2). At T1, cachexia was strongly associated with elevated GDF15 (OR: 4.29, 95% CI: 1.04-29.74, p=0.044) and IL-15 (OR: 43.83, 95% CI: 2.39->999, p=0.007), while IL-4 demonstrated protective effects (OR: 0.09, 95% CI: 0.00-0.66, p=0.013). By T2, the biomarker profile had shifted, with significant associations emerging for elevated mtDNA (OR: 2.13, 95% CI: 1.07-7.69, p=0.022) and reduced levels of IL-5 (OR: 0.17, p=0.011), IL12/IL23p40 (OR: 0.44, p=0.010), and MDC (OR: 0.26, p=0.006). Longitudinal analysis revealed that baseline inflammatory biomarkers were associated with future cachexia risk. Elevated MCP-1 at baseline showed a strong, though non-significant, trend toward association with increased odds of cachexia at the 6-month follow-up (OR: 3.72, 95% CI: 0.91-42.70, p=0.070). In contrast, higher levels of MDC (OR: 0.19, 95% CI: 0.02-0.77, p=0.016) and TARC (OR: 0.28, 95% CI: 0.04-0.96, p=0.041) at baseline were significantly associated with reduced odds of cachexia at the subsequent timepoint. Conclusion: This exploratory study reveals temporal variations in inflammatory profiles associated with cancer cachexia. While requiring validation in larger cohorts, the distinct biomarker patterns at different timepoints suggest cachexia biology may evolve from initial cytokine activation to later-stage mitochondrial and immune dysregulation. The association between baseline biomarkers and future cachexia development warrants cautious interpretation but may inform future research directions. Citation Format: Elham Kazemian, Carlos David Cruz-Hernandez, Karen L. Reckamp, Puneeth Iyengar, Neil A. Bhowmick, Jane C. Figueiredo, Kamya Sankar. Dynamic inflammatory biomarkers are associated with cancer cachexia in a prospective lung cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3928.

We evaluated acute toxicity and disease control in 42 patients receiving thoracic radiotherapy with concurrent KRAS G12C inhibitors. Toxicity included 13 grade 2 events (31%) and one grade 3 pneumonitis. There were no significant differences in toxicity between patients who held versus continued inhibitors during radiotherapy. The estimated cumulative incidence of local failure at 6 months was 5%.

OBJECTIVES:Head and neck cancer (HNC) remains a major global cause of cancer morbidity and mortality, with disproportionately poor outcomes in low- and middle-income countries. Substantial cross-national disparities suggest an important role for health system strengthening. We evaluated associations between national health system characteristics and global HNC outcomes. METHODS:We conducted a cross-sectional ecological analysis of 185 countries using sex-stratified, age-standardized incidence and mortality estimates from the International Agency for Research on Cancer (IARC) GLOBOCAN 2022 database. The primary outcome was the composite mortality-to-incidence ratio (MIR) for aggregated HNCs, including cancers of the lip and oral cavity, oropharynx, larynx, nasopharynx, hypopharynx, and salivary gland. Eleven national health system indicators capturing health financing, workforce density, service availability, socioeconomic development, and gender equity were evaluated. Univariable linear regressions identified candidate variables using Bonferroni correction (p < 0.0045), followed by multivariable modeling with assessment for multicollinearity using variance inflation factors. RESULTS:All 11 health system indicators were significantly associated with HNC MIR on univariable analysis (p < 0.001 for all). In multivariable analysis of 123 countries with complete data, higher Universal Health Coverage (UHC) service coverage index and higher gross domestic product (GDP) per capita were independently associated with lower (improved) HNC MIR (model R2 = 0.70). Findings were consistent in sex-stratified analyses. CONCLUSIONS:Across countries, progress toward universal health coverage and greater national economic capacity was independently associated with improved HNC outcomes. These findings may help to inform efforts at the level of health systems to improve HNC outcomes worldwide. LEVEL OF EVIDENCE:N/A.

ABSTRACT Background Unintentional weight loss (UWL) is the primary diagnostic parameter for cancer cachexia in the clinic. Prompt identification of UWL can lead to earlier diagnoses and interventions for cancer. This study investigates the frequency and timing of UWL documentation and diagnoses in a cohort of cancer patients with measured UWL and sought to understand how recognition of UWL is related to stage of disease at cancer diagnosis. Methods A retrospective cohort of adult gastrointestinal and non‐small cell lung cancer patients with measured UWL was evaluated. Body weight histories were manually reviewed for UWL. Patients with intentional weight loss, weight loss related to fluid status or weight loss with unclear intention were excluded. Records were assessed for the use of UWL‐related International Classification of Diseases codes and documentation of UWL. ULW was considered missed if it was not documented or diagnosed by a healthcare provider. Associations between weight loss over time, documentation and/or diagnosis of UWL and stage of disease at cancer diagnosis were investigated through repeated measures mixed models and univariate and multivariate tests. Results In total, 374 patients (24%) met the definition of UWL with an average weight loss of 8.6% ± 0.3%. UWL was missed in 161 (43%) patients with cancer cachexia. The odds of undetected UWL were greater in patients < 65 years old, with NSCLC, with obesity and who were White. In the 213 patients with recognized UWL, the documentation of UWL occurred approximately 7 months after their initial weight loss. The magnitude of weight loss was associated with cancer stage at cancer diagnosis (p < 0.0001). Patients who experienced ≥ 7.5% UWL pre‐cancer diagnosis had a median cancer stage of 3 whereas patients who experienced < 7.5% UWL had a median cancer stage of 2 at cancer diagnosis (p < 0.0001). Relative to patients with ≥ 7.5% weight loss, the < 7.5% weight loss group had 73.7% more patients with Stage 1 disease (p < 0.0001) and 32.5% fewer patients with Stage 4 disease (p = 0.0006) resulting in median cancer stage increasing from Stages 2 to 3. Conclusions UWL was missed in 43% of cancer cachexia patients despite 8.6% ± 0.3% body weight loss prior to cancer diagnosis. When recognized, documentation of UWL did not occur until 7 months after weight loss initiation. A greater magnitude of UWL was associated with more advanced disease at cancer diagnosis. Recognition and timely diagnosis of UWL will increase the percentage of patients with curable, early‐stage disease.

INTRODUCTION:In ADRIATIC, consolidation durvalumab significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with limited-stage SCLC without progression after concurrent chemoradiotherapy (cCRT). Exploratory analyses were conducted in prespecified subgroups per protocol-permitted cCRT components, prophylactic cranial irradiation (PCI) receipt, and time from end of cCRT to randomization. METHODS:Prior cCRT comprised cisplatin-etoposide or carboplatin-etoposide with thoracic radiotherapy (60-66 Gy once daily over 6 weeks or 45 Gy twice daily over 3 weeks), with or without PCI. Patients received durvalumab (n = 264) or placebo (n = 266) for up to 24 months. Multivariable Cox proportional hazards models compared treatment effect across subgroups. RESULTS:OS hazard ratios (HRs) generally favored durvalumab versus placebo across subgroups, including cisplatin-etoposide (HR = 0.82 [95% confidence interval {CI}: 0.61-1.10]) and carboplatin-etoposide (HR = 0.56 [95% CI: 0.35-0.89]) chemotherapy, once-daily (HR = 0.72 [95% CI: 0.55-0.96]) and twice-daily (HR = 0.68 [95% CI: 0.40-1.14]) radiotherapy, PCI-yes (HR = 0.75 [95% CI: 0.52-1.07]) and PCI-no (HR = 0.71 [95% CI: 0.51-0.99]), as well as time from cCRT completion to randomization subgroups. PFS also favored durvalumab across subgroups. OS and PFS HRs were consistent in multivariable analyses, with no significant interactions between treatment and subgroup pairs or time from cCRT completion to randomization (all p > 0.05). Safety profiles were generally consistent across subgroups. CONCLUSION:Consolidation durvalumab demonstrated consistent benefit versus placebo irrespective of prior cCRT components, PCI use, and time from cCRT completion to randomization, supporting its role as the new standard-of-care treatment in limited-stage SCLC. TRIAL REGISTRATION:ClinicalTrials.gov: NCT03703297 (ADRIATIC).

Background: Cancer-associated cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and/or adipose tissue loss and affects approximately 40% of patients with non-small cell lung cancer (NSCLC). However, reliable circulating biomarkers for early detection and risk stratification remain undefined. Based on prior observations linking elevated circulating mitochondrial DNA (mtDNA) to cachexia, we hypothesized that mtDNA and inflammatory protein levels in plasma could predict cachexia onset and trajectories. Methods: We evaluated 27 patients with stage IV NSCLC enrolled in the SeroNet-CORALE cohort with plasma samples collected between 2020 and 2023. Forty biomarkers were quantified at two timepoints (T1 and T2) using a multiplexed MesoScale Discovery platform. Associations between log2-transformed biomarker levels and cachexia status were assessed using Firth's penalized logistic regression. Results: Among 27 patients (65% female; mean age 65 ± 10 years; 89% adenocarcinoma histology), cachectic patients exhibited lower body mass index at both time points (T1: 21.0 ± 2.0 vs. 27.0 ± 7.0; T2: 21.8 ± 4.9 vs. 25.2 ± 4.9). At T1, cachexia was strongly associated with elevated GDF15 (OR 4.29; 95% CI 1.04-29.74; p = 0.044) and IL-15 (OR 43.83; 95% CI 2.39->999; p = 0.007), whereas IL-4 had a protective association (OR 0.09; 95% CI 0.00-0.66; p = 0.013). At T2, cachexia was associated with higher mtDNA levels (OR 2.13; 95% CI 1.07-7.69; p = 0.022) and lower levels of IL-15, IL12/IL23p40, and MDC. Conclusions: Distinct inflammatory and mitochondrial biomarkers tracked cachexia evolution in advanced NSCLC, with early GDF-15/IL-15 elevations and later increases in circulating mtDNA. Larger longitudinal studies are warranted to validate these findings and define their clinical relevance.

The management of unresectable stage III non-small cell lung cancer (NSCLC) continues to evolve with the integration of immunotherapy and targeted agents into treatment paradigms. The PACIFIC trial established consolidation durvalumab following concurrent chemoradiotherapy (CRT) as the standard of care in many settings. However, emerging evidence challenges the one-size-fits-all approach, particularly for molecularly defined subsets and specific patient populations. This debate article examines the evolving landscape of non-surgical stage III NSCLC management, presenting evidence-based arguments for refining treatment strategies based on molecular biomarkers, novel immunotherapy combinations, and alternative sequencing approaches.

Advances in systemic therapy have improved outcomes for metastatic non-small cell lung cancer (NSCLC), yet resistance and progression remain nearly universal. Local therapies such as radiotherapy, surgery, and image-guided ablation can extend disease control in selected patients, but existing classifications-including dynamic models of oligometastatic disease-assign a single state per patient and do not capture lesion-level heterogeneity. We introduce the concept of metastatic trajectories-the spatiotemporal dynamics of response and progression across lesions, organs, and patients-as a framework to characterize intrapatient heterogeneity and inform adaptive treatment strategies. Dimensions of metastatic trajectories include the magnitude and homogeneity of response, mechanisms of resistance, organotropism, and the pattern, site, extent, and pace of progression. This framework shifts the focus from overall disease states to individual lesion behavior over time, enabling reactive strategies based on observed trajectories and anticipatory strategies based on predicted ones. We review the biological foundations of intrapatient heterogeneity-including genomic diversification, nongenetic plasticity, and tumor-microenvironmental adaptation-that drive divergent lesion evolution and treatment response. Emerging biomarkers such as circulating tumor DNA and radiomic signatures, together with integrative genomic and functional imaging approaches, may allow tracking and prediction of trajectory evolution. Standardized reporting parameters are proposed to ensure consistent documentation and facilitate validation across studies. Integrating trajectory-based assessment into clinical practice could refine patient selection for local and systemic therapy, enable biology-informed adaptation of treatment timing and intensity, and provide a foundation for next-generation clinical trials aimed at precision management of metastatic NSCLC.

INTRODUCTION:In this systematic review and associated guidelines, the American Radium SocietyTM (ARS) thoracic and gastrointestinal oncology expert panels worked together to thoroughly evaluate current literature and provide treatment recommendations for best outcomes for resectable esophagus or gastroesophageal junction adenocarcinoma. To represent a diverse group representing all key specialties, thoracic and gastrointestinal radiation and medical oncologists, gastroenterologists, and thoracic surgeons were included in development of these consensus guidelines. METHODS:Using the Population, Intervention, Comparator, Outcome, Timing and Study Design framework, the evidence was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included randomized Phase II and III trials and retrospective subset analyses of randomized controlled trials published between January 1, 2019 and July 7, 2025 in the Ovid Medline database. These references were assessed via ARS Appropriate Use Criteria (AUC) methodology. RAND-UCLA consensus methodology was used to rate the appropriateness of various treatments. RESULTS:For patients with adenocarcinoma of the esophagus or gastroesophageal junction, the standard treatment approach has been trimodality therapy including chemotherapy, radiation, and surgery which is associated with significant long-term toxicity. Recent randomized controlled trials have compared perioperative chemotherapy to trimodality therapy affording the omission of radiotherapy for suitable patients and a resulting reduction in associated treatment-related toxicities. Recommendations for adjuvant and neoadjuvant therapies are provided, including chemotherapy, immunotherapy, targeted therapy and radiation therapy, and active surveillance after chemoradiation is also detailed. CONCLUSIONS:The updated 2026 ARS AUC for Operable Esophageal and Gastroesophageal Junction Adenocarcinoma is presented in this manuscript.

BACKGROUND:Early radiation therapy (RT) reduces the rate of skeletal-related events (SRE), which can affect patients' functionality and quality of life (QoL). We aimed to determine predictors of SRE and the effect of early RT on individual QoL dimensions. METHODS:We conducted a secondary analysis of a multicenter, randomized phase II trial (ClinicalTrials.gov identifier: NCT03523351) assessing early RT to asymptomatic, high-risk bone metastases. A competing risks analysis evaluated patient-level factors associated with SRE. Linear mixed models evaluated dimensions of the EuroQol 5-Dimension 5-Level (EQ-5D-5L) QoL assessment (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) over time by study arm. RESULTS:Overall, 78 patients with 122 bone metastases were enrolled; 71 (91%) patients were evaluable for the primary endpoint of SRE (35 patients in the early RT arm vs 36 in the control arm). A total of 15 SREs occurred among 11 unique patients during the 1-year follow-up period. Receipt of early RT was statistically significantly correlated with a lower risk of SRE (hazard ratio, 0.09; 95% CI, 0.01-0.66; P=.018). In the linear mixed model predicting self-care, the interaction between time and study arm was statistically significant (P=.022). At 6 months, the control arm had a decline in self-care, whereas patients in the RT arm experienced an improvement. Anxiety/depression was worse at 3 months in the RT arm, but this was not statistically significant (P=.120). CONCLUSIONS:Rates of SRE were high among patients with bone metastases, and these findings underscore the importance of early RT in their prevention. Patient-reported QoL suggests preservation of self-care with early RT, and that survival beyond 6 months may be needed to observe a benefit. Further research regarding patient selection and the impact of SRE on QoL and functionality are needed, and a phase III randomized trial (NRG CC014; NCT06745024) is in progress. CLINICALTRIALS:gov identifier: NCT03523351.

Cancer cachexia is a wasting syndrome that remodels the anatomy of the patient. How this remodeling unfolds across tissues, whether it defines distinct disease states, and how these states relate to underlying biology remain unknown. We used longitudinal computed tomography imaging from 4,516 patients to quantify evolution of muscle, adipose, and organs during cachexia. Across two independent institutional cohorts, unsupervised analysis identified three reproducible anatomical subtypes of cachexia, including an inflammatory Type A marked by progressive hepatosplenic enlargement and inferior survival, a Type B dominated by visceral organ atrophy, and a mild Type C. These anatomical subtypes were associated with distinct serological signatures and reflected in molecular phenotypes in tumors and non-cancerous liver tissue, establishing cachexia as discrete anatomical disease states that link whole-body remodeling to systemic and tissue-level biology. This anatomy-first framework for cachexia classification provides a foundation for future patient stratification and development of subtype-specific anti-cachexia therapies.

Hematological malignancies are a major contributor to cancer morbidity and mortality in North Africa, yet regional epidemiologic data remain limited. The region’s distinct demographic, sociocultural, and healthcare characteristics underscore the need for contemporary, country-specific estimates. This study characterizes the current burden of leukemia, non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and multiple myeloma (MM) across six North African nations and projects their future burden to 2050. We extracted incidence and mortality estimates for hematological malignancies from GLOBOCAN 2022 for Algeria, Egypt, Libya, Mauritania, Morocco, and Tunisia. Age-standardized incidence (ASIR) and mortality rates (ASMR) were calculated using the Segi-Doll world standard population. Projections to 2050 were generated by applying 2022 ASIRs and ASMRs to UN World Population Prospects demographic forecasts, assuming stable rates over time. Analyses were stratified by cancer type and sex. In 2022, hematological malignancies accounted for 9% of all cancer incidence (31,876 cases) and 10% of cancer deaths (18,241 deaths) in North Africa. Leukemia and NHL comprised nearly four-fifths of incidence and mortality. Men experienced consistently higher ASIRs and ASMRs than women across all countries. By 2050, cases and deaths are projected to nearly double to 61,144 and 40,004, respectively, driven predominantly by population growth and ageing. MM exhibited the fastest relative growth, particularly in Libya and Mauritania. Hematological malignancies represent a substantial and rising public health burden in North Africa. Strengthening cancer registries, diagnostics, workforce capacity, and equitable access to essential and advanced therapies is critical to mitigate the projected increase and to support regionally tailored cancer control strategies.

Member states of the South Asian Association for Regional Cooperation (SAARC), home to over 2 billion people, carry a disproportionate cancer burden shaped by stark heterogeneity in risk, access, and outcomes. Beyond large proportions of people living in poverty in the context of frail infrastructure, inequities are compounded by intersecting identities, including gender, caste, religion, language, geography, and sexual or gender minority status. Commonly, women face delayed diagnosis amid low human papillomavirus vaccination and screening; rural communities confront distance and cost; Dalit, indigenous, and refugee groups experience structural exclusion; and language discordance and cultural beliefs impede timely care. Financial toxicity is pervasive, pushing households into poverty despite emerging insurance schemes. Drawing on targeted literature from SAARC countries, we argue for an intersectionality-informed agenda: strengthen registries and national cancer control programmes with disaggregated data; expand equitable financing and workforce deployment; embed cultural competence and bias mitigation in clinical training; and prioritise research that models intersecting risks. Implementing context-appropriate strategies will be essential for achieving equitable cancer control across the region.

1596 Background: Global disparities in access to cancer diagnostics and care drive substantial variation in cancer outcomes worldwide. Identifying actionable health system factors at the country level is critical to improving survival and closing global equity gaps. We applied explainable machine learning methods to explore the interrelations among these interrelated factors. Methods: We developed and validated a machine learning model using data from 185 countries, obtained from GLOBOCAN 2022, WHO, and the World Bank. Mortality-to-incidence ratios (MIRs) were predicted using repeated leave-one-country-out cross-validation. SHapley Additive exPlanations (SHAP) analysis decomposed each prediction into country-specific health system-feature attributions, revealing the principal drivers of cancer outcomes. Results: The model achieved robust performance (R²=0.852; RMSE=0.057; Pearson r=0.923, p<0.001). Globally, GDP per capita, radiotherapy center density, and the universal health coverage (UHC) index were the top contributors to MIRs. SHAP analysis revealed significant heterogeneity, identifying distinct priority drivers for each country. For example, radiotherapy infrastructure was most impactful in Turkey, UHC in Brazil and Ghana, and GDP per capita in Malaysia and China. Higher health spending as a percent of GDP was often paradoxically associated with higher MIR, underscoring the need not only for sufficient funding but also for strategic allocation. We developed a web tool that provides policymakers with country-specific SHAP estimates. Conclusions: Explainable machine learning translates global associations into actionable, country-specific insights. Access to radiotherapy, workforce development, and UHC expansion are consistently associated with improved cancer survival. These findings support resource prioritization in national cancer control planning and inform hypothesis generation for future causal studies. National-level analyses guide targeted investment in infrastructure and health coverage, potentially accelerating progress toward reducing global disparities in cancer mortality.

Cachexia is a wasting syndrome involving adipose, muscle, and body weight loss in cancer patients. Tumor loss-of-function mutations in STK11/LKB1, a regulator of AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are linked to weight loss in non-small cell lung cancer (NSCLC) patients. This study examines the role of the integrated stress response (ISR) cytokine growth differentiation factor 15 (GDF15) in regulating cachexia using patient-derived and engineered STK11/LKB1-mutant NSCLC lines. Tumor cell-derived serum GDF15 levels are elevated in mice bearing these tumors. Treatment with a GDF15-neutralizing antibody or silencing GDF15 from tumor cells prevents adipose/muscle loss, strength decline, and weight reduction, identifying tumors cells as the GDF15 source. Restoring wild-type STK11/LKB1 in NSCLC lines with endogenous STK11/LKB1 loss reverses the ISR and reduces GDF15 expression rescuing the cachexia phenotype. Collectively, these findings implicate tumor-derived GDF15 as a key mediator and therapeutic target in STK11/LKB1-mutant NSCLC-associated cachexia.

PURPOSE:We hypothesized that, in patients at high risk for radiation esophagitis (RE), giving sucralfate prophylactically would reduce the need for opioid pain medication. METHODS AND MATERIALS:Patients were enrolled from January 2023 to April 2025 at a single tertiary care center. Patients were randomized to receive 1 g twice a day within the first 5 fractions of radiation therapy (RT), with frequency increased during RT at the clinician's discretion, or standard supportive care. The proportion of patients who took any opioids over the previous 24 hours at the end of the treatment course was compared between groups using logistic regression with the stratification variables and concurrent chemotherapy status as covariates. RESULTS:The trial was closed early due to lack of differences between arms, with 117 patients randomized (n = 56 in the experimental arm). Rates of opioid use were 30% in both groups (absolute adjusted decrease in the prophylactic sucralfate arm -0.4%; 95% CI, -14% to 13%, P > .9). Rates of grade 2 to 3 RE were nonsignificantly lower in the prophylactic sucralfate arm (59% vs 69%, absolute adjusted risk decrease 11%; 95% CI, -7.2% to 28%; P = .2). In patients receiving very high esophageal dose (V60 Gy ≥15%), all controls (n = 4) experienced grade 2 to 3 RE compared with only half of those in the experimental arm (6 of 12) (Fisher's exact test P = .2). CONCLUSIONS:We did not find evidence to support early use of sucralfate in patients at high risk of RE. Limited medical options for the management of RE warrant the continued need to explore further avenues to combat this painful condition.