BACKGROUND:Despite effective screening technologies for smokers, lung cancer is often diagnosed late, especially among never-smokers who fall outside current screening guidelines. We developed 10-year risk prediction models for sex and smoking subgroups to support more precise identification of high-risk individuals in clinical settings. PATIENTS AND METHODS:Using the Singapore Chinese Health Study (n = 63,187; recruitment period: 1993-1998), we developed a robust Cox regression model to predict 10-year lung cancer risk. Essential predictors were identified from sociodemographic, smoking-related, environmental exposure, reproductive, and dietary factors using Elastic Net regularization with 10-fold cross-validation. External validation was conducted using the Singapore Multi-Ethnic Cohort (n = 12,944; recruitment period: 2004-2010). Sex- and smoking-specific risk models were developed using the same approach. RESULTS:The overall risk model demonstrated strong discrimination and calibration on external validation (C-index = 0.821; 95% CI, 0.738-0.895). Ranked by relative importance, key predictors included age, smoking exposure (pack-years, smoking status), body mass index, education, sex, environmental tobacco smoke exposure, and dietary factors (tea and fruit consumption). The ever-smoker risk model included age, body mass index, pack-years, education, and weekly fruit consumption (C-index = 0.734), while the never-smoker risk model included age, sex, environmental tobacco smoke exposure, personal cancer history, and allergic rhinitis (C-index = 0.702). Sex-specific risk models showed good discrimination (male C-index = 0.785; female C-index = 0.769), with the female risk model influenced by reproductive and medical history factors. CONCLUSION:These subgroup-specific risk models provide additional insights into lung cancer risk assessment beyond smoking history and, with further real-world evaluation, may support more tailored risk stratification in Singapore's clinical settings.

Importance:Screening by low-dose computed tomography can reduce lung cancer mortality among high-risk individuals, but many lung cancers occur among individuals with a smoking history who are not eligible for screening. Objective:To develop and validate the protein-based Integrative Analysis of Lung Cancer Risk and Etiology (INTEGRAL)-Risk model in individuals with a smoking history from the general population. Design, Setting, and Participants:Cohorts in the Lung Cancer Cohort Consortium recruited research participants in the US, Europe, Asia, and Australia between 1985 and 2009, who were followed up for lung cancer and other health outcomes until 2021. Fourteen case cohorts of 3695 participants with a smoking history within the Lung Cancer Cohort Consortium, including 2305 randomly sampled participants and 1390 patients diagnosed with lung cancer within 3 years after blood sample collection, were designed. Plasma or serum samples from each participant were assayed using the INTEGRAL protein panel in 2022. The INTEGRAL-Risk model was trained using 7 predefined case cohorts (training set; n = 1951) to estimate absolute risk of being diagnosed with lung cancer based on age, smoking history, and 13 proteins. The validity of the INTEGRAL-Risk model was assessed in 7 independent case cohorts (testing set; n = 1744) at 1, 2, and 3 years after blood collection. Exposure:Absolute risk estimates from the protein-based INTEGRAL-Risk model. Main Outcomes and Measures:The primary outcome was the validity of the INTEGRAL-Risk model in the testing set with respect to discrimination (area under the curve [AUC]) and calibration (ratio of expected-to-observed cases [E/O]). Results:A total of 3695 participants were included, with 1951 participants (including 807 with lung cancer) in the training set and 1744 participants (including 583 with lung cancer) in the testing set. In the combined 14 training and testing sets, after application of statistical weights, 323 570 participants were represented (185 016 [57%] female; median [IQR] age, 60 [51-67] years). In the independent testing set, discrimination of the INTEGRAL-Risk model was highest at 1 year of follow-up and exceeded that of the questionnaire-based PLCOm2012 (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) model (INTEGRAL-Risk AUC of 0.88 [95% CI, 0.85-0.91] vs PLCOm2012 AUC of 0.79 [95% CI, 0.75-0.83]; P value for difference <.001). Using a risk threshold to achieve the same specificity as US Preventive Services Task Force (USPSTF) 2021 criteria, the INTEGRAL-Risk model captured 85% of lung cancer cases compared with 63% by USPSTF 2021 and 70% by PLCOm2012. Discrimination of the INTEGRAL-Risk model decreased with longer prediction horizons, with a 2-year AUC of 0.84 (95% CI, 0.81-0.86) and 3-year AUC of 0.81 (95% CI, 0.79-0.83). The model was well calibrated (E/O over 3 years, 0.87 [95% CI, 0.69-1.14]). Conclusions and Relevance:Compared with questionnaire-based approaches, the protein-based INTEGRAL-Risk model improved short-term prediction of lung cancer in people with a smoking history. This model has potential to improve selection of high-risk individuals who are most likely to benefit from lung cancer screening.

α,β-Unsaturated carbonyl compounds in cigarette smoke, such as acrolein and acrylamide, are considered as possible causative factors for chronic obstructive pulmonary disease (COPD) in people who smoke cigarettes. A major route of metabolism of these compounds is reaction with glutathione to form adducts that are further metabolized and excreted in the urine as mercapturic acids, which serve as useful dosimeters of exposure. In this study, we analyzed urine samples from the Singapore Chinese Health Study, a prospective epidemiology study of 63,257 men and women 45-74 years old with Chinese origin who were permanent residents or citizens of Singapore when they were enrolled in 1993-1998. A case-control study with 100 incident cases of COPD and 100 matched controls, all of whom were current cigarette smokers, was conducted within this cohort. Urine samples of the study subjects were collected during follow-up I (2000-2005) and the COPD cases were identified in follow-up II interviews (2006-2010). Urinary mercapturic acids of acrolein (3-hydroxypropyl mercapturic acid, 3-HPMA, 1), acrylamide (2-carbamoylethyl mercapturic acid, 2-CaEMA, 2), acrylonitrile (2-cyanoethyl mercapturic acid, 2-CyEMA, 3), crotonaldehyde (3-hydroxy-1-methylpropyl mercapturic acid, HMPMA-1, 4), methacrolein (3-hydroxy-2-methylpropyl mercapturic acid, HMPMA-2, 5), and methyl vinyl ketone (3-hydroxy-3-methylpropyl mercapturic acid, HMPMA-3, 6) were quantified using a LC-MS/MS method. Urinary levels of 2-CaEMA, the mercapturic acid of acrylamide, were significantly higher in cases (geometric mean 361.0 pmol/mg creatinine) than in controls (293.7 pmol/mg creatinine) and the increasing level of 2-CaEMA in tertiles was significantly associated with increased odds of developing COPD (both P <0.05), after adjustment for cigarettes per day and years of cigarette smoking. For the mercapturic acid of acrylonitrile, a weak trend of increasing 2-CyEMA with the COPD status was observed (p trend = 0.033), while none of the other mercapturic acids were significantly related to the risk of COPD. These results indicate that acrylamide in cigarette smoke should be given strong consideration as a cause of COPD in people who smoke.

Abstract Purpose To quantify survival differences between colorectal cancer (CRC) patients with healthier and those with less healthy pre-diagnosis lifestyles using restricted mean survival time (RMST) at 5 and 10 years, and to assess which lifestyle components contribute to these differences. Methods Incident CRC cases (n = 2124) were identified from the Singapore Chinese Health Study, a prospective cohort of 63 257 adults enrolled in 1993-1998. Cancer status and cause of death were obtained via linkage with the National Disease Registry through 31 December 2015. A pre-diagnosis lifestyle score (0-7) incorporated BMI and smoking, sleep duration, diet, and weekly physical activity at baseline. RMST differences comparing less healthy (scores 0-3) versus healthier (4-7) lifestyles were estimated at 5- and 10-years post-diagnosis, adjusted for CRC stage (early, late) and age at diagnosis, sex, education attainment, and the interval between lifestyle assessment and diagnosis. Results Over a median follow-up of 4.8 years (IQR 1.2-11.8) from CRC diagnosis, 1557 deaths occurred, including 1103 CRC-specific deaths. Late-stage diagnosis was associated with shorter survival than early stage by 1.53 years (95% CI 1.35 to 1.72) at 5 years and 3.33 years (2.93 to 3.72) at 10 years. The median interval between lifestyle assessment and diagnosis was 12.2 years (IQR 6.9 to 16.7). RMST for all-cause deaths was significantly improved by a healthier lifestyle but results for CRC-specific deaths were mixed. For all-cause mortality, adjusted RMST differences (less healthy - healthier) were −0.15 (95% CI −0.32 to 0.01) at 5 years and −0.37 (−0.71 to −0.02) at 10 years. CRC-specific mortality: At 5 years, the adjusted RMST difference (less healthy − healthier) was −0.15 years (−0.32 to 0.02), and at 10 years it was −0.34 years (−0.71 to 0.03). Among patients diagnosed at age ≤70 years, healthier pre-diagnosis lifestyles were associated with modestly longer survival, with a 10-year CRC-specific RMST gain of 0.58 years (0.03 to 1.13), while other estimates were borderline or not significant. Lifestyle components associated with improved CRC-specific survival included diet (lower vs higher AHEI category: 5-year RMST difference −0.20 (−0.38 to −0.02); 10-year −0.46 (−0.84 to −0.08)) and weekly physical activity (no vs yes: 5-year −0.19 (−0.37 to −0.02); 10-year −0.42 (−0.78 to −0.06)). Similar results were obtained for all-cause death. Smoking and sleep duration were not significantly associated with survival. Conclusions A healthier pre-diagnosis lifestyle was associated with improved long-term survival in CRC patients. Short-term differences were modest after accounting for CRC stage at diagnosis, underscoring the importance of early detection. Having maintained healthy behaviors before diagnosis may favorably influence long-term outcomes among CRC patients. Citation Format: Peh Joo Ho, Aizhen Jin, Jian-Min Yuan, Woon-Puay Koh, Adeline L. H. Seow. Healthier pre-diagnosis lifestyle and long-term survival in patients after diagnosis of colorectal cancer: Evidence from the Singapore Chinese Health Study [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 5050.

The gas phase of tobacco smoke has been implicated as a major cause of cancer and chronic obstructive pulmonary disease. Furan, a component of the gas phase, is highly toxic and carcinogenic in rodents; however, its toxicity in humans has not been well investigated. Furan's toxicity results from cytochrome P450 2E1-catalyzed oxidation to cis-2-butene-1,4-dial (BDA). The structure of furan metabolites demonstrates that BDA reacts with glutathione (GSH) to form a reactive GSH conjugate, 2-(S-glutathionyl)succinaldehyde (GSH-BDA), which reacts with protein lysine groups as well as other cellular nucleophiles. In this report, GSH-BDA-glycerolphosphorylethanolamine (GSH-BDA-GPE), GSH-BDA-ethanolamine, and GSH-BDA-glutamic acid are identified as human hepatocellular metabolites of furan. To determine if the downstream mercapturic acid metabolites are present in human urine, stable isotopically labeled forms of the expected metabolites were used as internal standards in an established liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. This approach indicated that N-acetyl-S-(1-(2-hydroxyethyl)-1H-pyrrol-3-yl)cysteine sulfoxide (NAC-BDA-ethanolamine sulfoxide) was detected in human urine. A sensitive LC-MS/MS assay for this metabolite was developed and applied to urine samples from a variety of smoke-exposed individuals as well as nonsmokers. Its levels were 2.5-5 times higher in people who smoke than in nonsmokers. They were not elevated in exclusive e-cigarette or cannabis users. Two case-control studies were performed to determine whether NAC-BDA-lysine metabolites or NAC-BDA-ethanolamine sulfoxide were associated with smoking-related diseases. In the first study, there was no association between any of the furan metabolites and liver cancer. In the second study, there was a suggestive association between NAC-BDA-ethanolamine sulfoxide and the risk of smoking-related respiratory disease symptoms. However, the overall trend was not significant. Therefore, there was no clear link between this furan metabolite and the risk of smoking-related respiratory disease symptoms.

Supplementary Table 3 describes Characteristics of Study Participants according to Quartiles of Plant-Based Diet Indices, the Singapore Chinese Health Study, 1993 to 2015

Supplementary Table 2 provides the Spearman Correlation Coefficients Between the Three PDI Scores in the Singapore Chinese Health Study, 1993 to 2015

Importance Screening by low-dose computed tomography can reduce lung cancer mortality among high-risk individuals, but many lung cancers occur among individuals with a smoking history who are not eligible for screening. Objective To develop and validate the protein-based Integrative Analysis of Lung Cancer Risk and Etiology (INTEGRAL)–Risk model in individuals with a smoking history from the general population. Design, Setting, and Participants Cohorts in the Lung Cancer Cohort Consortium recruited research participants in the US, Europe, Asia, and Australia between 1985 and 2009, who were followed up for lung cancer and other health outcomes until 2021. Fourteen case cohorts of 3695 participants with a smoking history within the Lung Cancer Cohort Consortium, including 2305 randomly sampled participants and 1390 patients diagnosed with lung cancer within 3 years after blood sample collection, were designed. Plasma or serum samples from each participant were assayed using the INTEGRAL protein panel in 2022. The INTEGRAL-Risk model was trained using 7 predefined case cohorts (training set; n = 1951) to estimate absolute risk of being diagnosed with lung cancer based on age, smoking history, and 13 proteins. The validity of the INTEGRAL-Risk model was assessed in 7 independent case cohorts (testing set; n = 1744) at 1, 2, and 3 years after blood collection. Exposure Absolute risk estimates from the protein-based INTEGRAL-Risk model. Main Outcomes and Measures The primary outcome was the validity of the INTEGRAL-Risk model in the testing set with respect to discrimination (area under the curve [AUC]) and calibration (ratio of expected-to-observed cases [E/O]). Results A total of 3695 participants were included, with 1951 participants (including 807 with lung cancer) in the training set and 1744 participants (including 583 with lung cancer) in the testing set. In the combined 14 training and testing sets, after application of statistical weights, 323 570 participants were represented (185 016 [57%] female; median [IQR] age, 60 [51-67] years). In the independent testing set, discrimination of the INTEGRAL-Risk model was highest at 1 year of follow-up and exceeded that of the questionnaire-based PLCOm2012 (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) model (INTEGRAL-Risk AUC of 0.88 [95% CI, 0.85-0.91] vs PLCOm2012 AUC of 0.79 [95% CI, 0.75-0.83]; P value for difference <.001). Using a risk threshold to achieve the same specificity as US Preventive Services Task Force (USPSTF) 2021 criteria, the INTEGRAL-Risk model captured 85% of lung cancer cases compared with 63% by USPSTF 2021 and 70% by PLCOm2012. Discrimination of the INTEGRAL-Risk model decreased with longer prediction horizons, with a 2-year AUC of 0.84 (95% CI, 0.81-0.86) and 3-year AUC of 0.81 (95% CI, 0.79-0.83). The model was well calibrated (E/O over 3 years, 0.87 [95% CI, 0.69-1.14]). Conclusions and Relevance Compared with questionnaire-based approaches, the protein-based INTEGRAL-Risk model improved short-term prediction of lung cancer in people with a smoking history. This model has potential to improve selection of high-risk individuals who are most likely to benefit from lung cancer screening.

Cis-regulatory elements (CREs) are central to dynamic gene regulation in hepatocytes, yet most functional annotations derive from in vitro models that poorly capture physiological regulation. We systematically profiled 109,386 human liver-derived CREs using massively parallel reporter assays in hepatocytes under matched in vitro and in vivo conditions. In vivo-active functional CREs (fCREs) were enriched for H3K27ac and chromatin accessibility and were regulated by diverse transcription factors in the human liver. We further demonstrate that gut microbiota-derived signals modulate fCRE activity and target gene expression in vivo, in part via the KEAP1/NFE2L2 antioxidant pathway. Specific microbial metabolites directly altered the activity of selected fCREs, and genetic variation within fCREs modified their responsiveness to microbial signals. Together, these findings reveal microbiota-dependent regulation of hepatic CREs and highlight condition-specific gene regulatory mechanisms in vivo.

Abstract Background Tuberculosis (TB) continues to be a leading cause of morbidity and mortality worldwide. Although numerous genome-wide association studies (GWAS) have explored TB susceptibility across various ethnic groups, multi-population replication of findings has been very limited, particularly outside the HLA region, and a significant portion of TB heritability remains unexplained. Methods We conducted GWAS in the Singapore Chinese and Vietnamese, followed by a comprehensive meta-analysis incorporating 4 independent East Asian datasets (N = 11,841 cases; N = 197,373 controls). The transferability of any identified association was assessed using summary statistics from independent European populations. Potential candidate genes were prioritized using gene-based association testing and integrative bioinformatic database mining, followed by functional validation through assessment of Mycobacterium marinum (M.marinum) infection burden in CRISPR-Cas9-edited zebrafish embryos. Results We identified a novel susceptibility locus for pulmonary TB (PTB) at 22q12.2 in East Asians [rs6006426, OR (95%Cl) = 1.097(1.066, 1.130), P meta =3.31 × 10− 10]. The association was further validated in Europeans [OR (95%Cl) = 1.101(1.002, 1.211), P = 0.046] and was strengthened in the combined meta-analysis including a total of 12,736 PTB cases and 673,864 controls [OR (95%Cl) = 1.098 (1.068, 1.129); P meta =4.33 × 10− 11]. Gene-based association test identified Oncostatin M (OSM) to be significantly associated with PTB (ZSTAT = 5.013; P = 2.68 × 10− 7; P adj =0.005). The lead SNP rs6006426 affected Splicing factor 3a subunit 1 (SF3A1) expression in various immune cells (P from 0.003 to 6.17 × 10− 18) and OSM expression in monocytes post lipopolysaccharide stimulation (P = 5.57 × 10− 4) as reported in the eQTL Catalogue. CRISPR-Cas9 edited zebrafish embryos with osm depletion resulted in decreased burden of M.marinum in infected embryos (P = 0.047). Conclusions Our findings offer novel insights into the genetic factors underlying TB and reveals new avenues for understanding its etiology.

BACKGROUND:Stomach cancer presents complex etiologic heterogeneity. Ethanol in alcoholic beverages and its metabolite acetaldehyde are carcinogens causally linked to several cancers, but their role in gastric carcinogenesis has not been established. We analyzed harmonized, individual-level prospective data to examine associations between alcohol intake and risk of stomach cancer and its subtypes. METHODS:2,009,951 participants in 20 cohorts (mean follow-up=9-29 years) within the Pooling Project of Prospective Studies of Diet and Cancer (n = 8,357 incident invasive gastric adenocarcinomas) were included. We used Cox regression to assess associations between alcohol intake and risk of stomach cancer overall and by anatomical and histological subtype and population subgroup, adjusting for confounders. RESULTS:Evidence for an association between alcohol intake and overall stomach cancer risk was weak (hazard ratio, HR, for ≥30 v 0.1-<5 g/day: 1.06 [95% confidence interval, CI, 0.96 to 1.16], P between-studies heterogeneity=0.43). Positive associations with stomach cancer risk were observed in never smokers (HR, for ≥30 v 0.1-<5 g/day: 1.20 [95% CI, 1.02 to 1.42]; P interaction=0.02) and for Asian studies (HR, 1.21 [95% CI, 1.02 to 1.42]; P interaction=0.01). Modest increased risks were observed for non-cardia cancers such as those of the fundus, body and greater curvature, but not distally located non-cardia cancers. HRs did not differ materially between diffuse- and intestinal-type cancers (P heterogeneity>0.05). CONCLUSION:There was little evidence of an overall association between alcohol intake and stomach cancer risk, although modest positive associations were observed among never smokers and in Asian cohorts.

BACKGROUND AND AIMS:PNPLA3 variants are associated with increased hepatocellular carcinoma (HCC) risk. We examined the association between a combination of the PNPLA3 I148M genotype and clinical risk factors with HCC risk using data from a large, ongoing, population-based, prospective cohort study, the Singapore Chinese Health Study. APPROACH AND RESULTS:This study included 24,979 participants (54.2% female). The primary outcome was incident HCC. Fine-Grey models were used to examine the association between a combination of the PNPLA3 I148M genotype and clinical risk factors and risk of HCC. After a median follow-up of 19.8 years, we identified 214 HCC incident cases. Males who were homozygous carriers for PNPLA3 I148M (adjusted hazard ratio [aHR] = 9.23, 95% confidence interval [CI]: 4.81-17.70) had a nine-fold risk of HCC, while heterozygous male carriers (aHR 4.83, CI: 2.63-8.89) had a five-fold risk of HCC, compared to non-carrier females. Homozygous carriers who were overweight (aHR = 2.92, 95% CI: 1.74-4.89) had a three-fold risk of HCC compared to non-carriers who were not overweight. Participants with diabetes and who were homozygous carriers (aHR 2.83, 95% CI: 1.21-6.61) had an approximately three-fold risk of HCC compared to non-carriers without diabetes. CONCLUSION:The frequency of rs738409-G alleles was associated with a dose-dependent increase in HCC risk and was independent of other clinical risk factors. Among participants who were male, overweight, and those with diabetes, the risk of HCC was further elevated among those with rs738409-G alleles. These data may be helpful for the development of future risk stratification strategies.

Supplementary Table 1 describes the Criteria for Scoring Each Component of Dietary Pattern Indices in the Singapore Chinese Health Study, 1993 to 2015

A low carbohydrate diet (LCD) reflects a dietary pattern characterized by reduced carbohydrate intake and higher consumption of protein and fat. Evidence on the role of LCD and risk of breast cancer is inconclusive. We, therefore, prospectively examined the association between LCD scores and breast cancer risk in the Singapore Chinese Health Study (SCHS). We used data of 34,028 female participants in the SCHS, a prospective cohort study with subjects recruited in Singapore during 1993–1998 period. LCD scores were derived from the semi-quantitative food frequency questionnaire at baseline. Breast cancer cases were identified through record linkage with the Singapore cancer registry. Cox proportional hazard regression method was used to calculate hazard ratios (HRs) and 95

Purpose:Antibodies to Epstein-Barr virus (EBV) proteins can predict nasopharyngeal carcinoma (NPC) risk. We previously defined a prototype EBNA1 protein panel and multiplex immunoblot assay that distinguishes NPC risk several years pre-diagnosis. Assay throughput and specificity are critical to effectively implement a population-level screening program. Here, we developed a strip test assay - EBNA1 SeroStrip-HT - with an objective to increase throughput and maximize specificity. Experimental Design:EBNA1 full-length (FL) and glycine-alanine repeat deletion mutants (dGAr) were purified from insect and mammalian cells to screen serum IgA/IgG from prospective cohorts in Singapore and Shanghai, China, with known time intervals to NPC diagnosis. Twenty pre-diagnostic sera within 4 years to diagnosis were compared to 96 healthy controls using a nested case-control study design. Results:IgA to mammalian-derived EBNA1 dGAr achieved 85.0% sensitivity and 94.8% specificity (AUC, 0.939) for NPC status. IgA to insect-derived EBNA1 dGAr showed the same sensitivity (85.0%) and similar specificity (93.8%) (AUC, 0.941). IgA to insect-derived EBNA1 FL had a higher 90% sensitivity, but lower 91.7% specificity (AUC, 0.940). Combining EBNA1 FL and dGAr results showed that subjects positive for both proteins had a 243.67 odds ratio for NPC incidence compared to double-negative scores. Conclusion:This study demonstrated the efficacy of EBNA1 SeroStrip-HT for NPC risk assessment and stratification in high- and intermediate-risk populations, yielding high accuracy and a 12-fold increased throughput over the prototype. The insect system was appropriate for large-scale production of purified EBNA1. Larger, geographically diverse cohorts are warranted to confirm these results, especially in low-incidence populations.

The gas phase of tobacco smoke has been implicated as a major cause of cancer and chronic obstructive pulmonary disease. Furan, a component of the gas phase, is highly toxic and carcinogenic in rodents; however, its toxicity in humans has not been well investigated. Furan's toxicity results from cytochrome P450 2E1-catalyzed oxidation to cis-2-butene-1,4-dial (BDA). The structure of furan metabolites demonstrates that BDA reacts with glutathione (GSH) to form a reactive GSH conjugate, 2-(S-glutathionyl)succinaldehyde (GSH-BDA), which reacts with protein lysine groups as well as other cellular nucleophiles. In this report, GSH-BDA-glycerolphosphorylethanolamine (GSH-BDA-GPE), GSH-BDA-ethanolamine, and GSH-BDA-glutamic acid are identified as human hepatocellular metabolites of furan. To determine if the downstream mercapturic acid metabolites are present in human urine, stable isotopically labeled forms of the expected metabolites were used as internal standards in an established liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. This approach indicated that N-acetyl-S-(1-(2-hydroxyethyl)-1H-pyrrol-3-yl)cysteine sulfoxide (NAC-BDA-ethanolamine sulfoxide) was detected in human urine. A sensitive LC-MS/MS assay for this metabolite was developed and applied to urine samples from a variety of smoke-exposed individuals as well as nonsmokers. Its levels were 2.5-5 times higher in people who smoke than in nonsmokers. They were not elevated in exclusive e-cigarette or cannabis users. Two case-control studies were performed to determine whether NAC-BDA-lysine metabolites or NAC-BDA-ethanolamine sulfoxide were associated with smoking-related diseases. In the first study, there was no association between any of the furan metabolites and liver cancer. In the second study, there was a suggestive association between NAC-BDA-ethanolamine sulfoxide and the risk of smoking-related respiratory disease symptoms. However, the overall trend was not significant. Therefore, there was no clear link between this furan metabolite and the risk of smoking-related respiratory disease symptoms.

BACKGROUND:Low-dose CT (LDCT) imaging screening reduces lung cancer mortality, the leading cause of cancer deaths globally. Segmentation-free deep learning (DL) models such as Sybil can improve screening efficiency but require extensive validation and possible improvement. RESEARCH QUESTION:Can the integration of DL based on LDCT scans and clinical data improve lung cancer risk prediction? STUDY DESIGN AND METHODS:Retrospective cohort data from 4 different screening programs, 1 used for model training and 3 used for external validation. Data were collected between 2002 and 2021. The median follow-up period was 7 years. All participants had a history of either current or former smoking, with at least 10 pack-years of smoking or who smoked over 20 years. The area under the receiver operating characteristic curve (AUC) was calculated for lung cancer risk within 1 to 6 years, stratified by pulmonary nodule presence and size. Key clinical and epidemiologic factors were evaluated for their added predictive value. RESULTS:This analysis used 52,482 LDCT scan series from 22,469 participants. Sybil's AUC ranged from 0.93 in year 1 and reduced to 0.79 in year 6 in the independent cohorts. The predictive performance was suboptimal in the absence of documented nodules (AUC, 0.64) and for small nodules (AUC, 0.61) in year 6. Our new model, Sybil-Epi, trained with baseline scans, achieved higher predictive performance (AUC, 0.83; 95% CI, 0.81-0.85) compared with Sybil (AUC, 0.80; 95% CI, 0.78-0.82) in year 6. The difference is most notable when nodules are absent. Sybil-Epi's AUC was 0.76 (95% CI, 0.70-0.82) and Sybil's AUC was 0.64 (95% CI, 0.57-0.70). INTERPRETATION:Our results show that Sybil performs better for short-term lung cancer risk, but the predictive accuracy was suboptimal when nodules were absent. Our integrated Sybil-Epi model with DL and clinical and epidemiologic factors significantly improved model predictive performance.

Abstract Background: Obesity and metabolic dysfunction are established risk factors for liver cancer and other malignancies. They may enhance the progression of liver disease to advanced stages such as liver cirrhosis and liver failure. Bariatric surgery greatly reduces body weight, but data on the association between bariatric surgery and liver cancer and other advanced stage diseases are sparse. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are two major types of bariatric surgery that have different impacts on weight loss. We evaluated if there was any difference between the two bariatric surgical procedures in risk of developing liver cancer and other advanced stage diseases. Methods: In a cohort study of adults with obesity who underwent RYGB or SG between 2009-2022 from 8 U.S. hospital sites, patients were followed from surgery to first liver-related event, death, or last contact with the healthcare system. The primary outcome was time to first liver-related event defined as liver cancer, decompensated cirrhosis, liver transplant, or liver failure as a composite outcome. Risk associations for individual liver endpoints were also explored. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age, sex, comorbidity score, BMI, race, smoking, dyslipidemia, hypertension, type 2 diabetes, and medications for obesity and diabetes at baseline. The overall Cox model did not hold for assumptions. We conducted two separate analyses before and after the cutoff point of 3 years. Results: The cohort included 29,573 patients (14,256 RYGB; 15,317 SG) with average follow-up of 7.7 years and total 59,121 person-years for RYGB and 49,211 for SG. At baseline, the mean (SD) age and BMI were 43.4 (11.5) years and 46.7 (7.4) for RYGB, respectively. The corresponding figures for SG were 42.1 (11.8) years and 46.2 (7.7). The composite outcome was identified for 30 individuals in RYGB and 14 in SG. The incidence rates (per 100,000 person-years) of the composite liver outcomes were 51 in RYGB and 29 in SG. Overall, the difference between the two rates was statistically not significant. In analysis by time interval after bariatric surgery (<3 and 3+ years), patients with RYGB had an adjusted HR of 16.1 (95% CI 5.33-48.9) of composite liver outcomes compared with those with SG during <3 years. There was no significant association during 3+ years. Conclusions: In this large real-world cohort, RYGB was associated with a higher risk of liver-related outcomes compared to SG during the first 3-years after surgery. The early divergence in liver outcomes may reflect different short-term metabolic or inflammatory effects of bariatric procedures, which are biologically relevant to liver disease progression and hepatocarcinogenesis. This emphasizes the clinical relevance of early post-operative monitoring. Our findings support the need for additional long-term analysis of outcomes. Citation Format: Sindhu Karnam, Jaideep Behari, Kathryn Demanelis, Renwei Wang, Jian-Min Yuan. Early postoperative liver outcomes differ by bariatric surgery procedure in multi-site cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB388.