4th Quartile Research Articles

ARTERIAL STIFFNESS ASSESSED BY SYSTEMIC VERSUS REGIONAL INDICES: DETERMINANTS AND DIAGNOSTIC AGREEMENT

Objective: Arterial stiffness is closely associated with aging and hypertension and may improve the stratification of cardiovascular risk in patients with hypertension. This study investigated the determinants and the diagnostic agreement of systemic (brachial-ankle pulse wave velocity [baPWV]) and regional (carotid distensibility coefficient [DC]) arterial stiffness indices. Design and method: Adults referred to a hypertension outpatient clinic were subjected to: (i) triplicate office blood pressure (BP) measurement using a validated professional oscillometric upper-arm cuff device Microlife WatchBP Office, (ii) baPWV measurements using an automated oscillometric device Microlife WatchBP Office Vascular, and (iii) DC and carotid intima-media thickness (cIMT) measurements with carotid ultrasound. Results: Data from 136 participants were analyzed (mean age 60±12 [SD] years, 71% males, body mass index 28±4 kg/m2, 83% hypertensives, 12% diabetics, 16% smokers, baPWV 14±2 m/sec, DC 24±9 10-3/kPa). There was a moderate negative association between baPWV and DC (r = -0.37, p<0.01). baPWV was positively correlated with age (r = 0.64, p<0.01), systolic office BP (r = 0.27, p<0.01) and cIMT (r = 0.29, p<0.01), while DC was inversely associated with age (r = -0.37, p<0.01), systolic office BP (r = -0.48, p<0.01), and cIMT (r = -0.29, p<0.01). In multivariable linear regression models (independent variables: age, sex, systolic office BP, cIMT, diabetes), age and systolic office BP appeared to be significant determinants of baPWV (beta = 0.12/0.05, respectively) and DC (beta = -0.32/-0.27, respectively). The agreement between the two methods in identifying individuals with increased arterial stiffness (1st quartile of DC distribution and 4th quartile of baPWV distribution) was fair (agreement 71%, kappa = 0.22, p<0.05). Conclusions: These results suggest that although these two methods for assessing arterial stiffness are correlated and determined by similar variables, their agreement in identifying individuals with increased arterial stiffness is fair, implying that they may provide complementary information.

Assessment of electronic health record (EHR) –based machine learning (ML) in predicting risk of brain metastasis among patients with early-stage non–small-cell lung cancer (eNSCLC).

2036 Background: Among patients (pts) with eNSCLC, development ofbrain metastasis (BM) is a poor prognostic sign, but routine surveillance for BM is not recommended post-therapy. EHR-based ML algorithms may identify pts who would benefit from active brain MRI surveillance and/or treatment intensification in the early-stage setting. Methods: ConcertAI Patient360 database, consisting of structured and curated EHR records from pts receiving care in ~900 US oncology clinics, was used to identify pts diagnosed with stage IB-IIIA NSCLC without prior evidence of BM between Jan 2010 – December 2021. Presence of BM was identified from human curation of patient documents. Gradient boosting (GB), random forest (RF), and logistic regression (LR) algorithms with 3-fold cross-validation were trained and compared to predict risk of BM at two landmarks: 18 and 24 months (mos) from initial diagnosis (index). Pts who did not develop BM and either died or were lost to follow-up prior to landmark times were removed. Feature importance was defined using Shapley Additive Explanation (SHAP)-derived marginal odds ratios (OR). Due to low prevalence of BM, AUPRC was used as performance metric. Pts in the 1st and 4th quartiles of predicted probabilities from GB model were flagged as low-risk vs. high-risk. Results: Among 7473 pts in 18 mos model, median age was 68.4 years (IQR 13.2), 50.5% were female, and 10.9% were black. Demographics were similar for 6863 pts in 24 mos model. 6.4% and 8.3% developed BM at 18 and 24 mos. Ability of GB, RF, and LR models to predict BM was similar with validation AUPRC of 0.109 at 18 mos and 0.137 at 24 mos. In the GB model, BM prevalence in high-risk vs. low-risk group was 10.3% vs. 3.1% at 18 mos and 13.4% vs. 4.4% at 24 mos. In both landmark models, N0 stage and surgery within 90 days after index diagnosis were protective against BM, while presence of EGFR targetable mutations, adenocarcinoma (AD) histology, higher platelets (PLT), and history of pneumonia were risk factors. A glucose-by-histology interaction was found: For pts with normal blood glucose (GLU), risk of BM was independent of histology, for pts with high GLU, AD conferred greater risk of BM. Conclusions: An EHR-based ML model identified risk factors for developing BM among pts with eNSCLC and may identify pts who would benefit from active brain MRI surveillance and treatment intensification. [Table: see text]

Impact of state health disparity on lung, breast, and prostate cancer incidence and mortality in the United States.

e18639 Background: Lung cancer is the second most common cancer and the leading cause of cancer deaths in both sex in the United States (US). Prostate cancer is the most common in men, while in women being breast cancer. America’s Health Rankings (AHR) is a comprehensive assessment of the nation's health on a state-by-state basis to determine state health rankings annually. We aimed to evaluate the association, which has not been investigated, between state-level health disparity as measured by AHR and lung, breast, and prostate cancer incidence and mortality in the US. Methods: We examined lung, breast and prostate cancer incidence and mortality data for 2015-2019 from the United States Cancer Statistics (USCS) database provided by the Centers for Disease Control and Prevention (CDC). Overall state health rankings were obtained from AHR and calculated by an equation using weighted measures in five different categories: 25% Behaviors, 22.5% Community & Environment, 12.5% Policy, 15% Clinical Care, and 25% Outcomes. We extracted 2015-2019 AHR data and further classified state health rankings into quartiles (1st [the healthiest] = rank 1 to 13; 4th [the least healthy] = rank 38 to 50). Associations of cancer incidence and mortality with overall state health rankings were analyzed by negative binomial regressions. Results: From 2015 to 2019, age-adjusted incidence rate per 100,000 population for lung, breast, and prostate cancer were 56.3, 128.0 and 109.8, respectively. Age-adjusted mortality rate per 100,000 population for lung, breast, and prostate cancer were 36.7, 19.9 and 18.9, respectively. Among 50 states we included for analysis, AHR indicated that Hawaii was the healthiest state (No.1) whereas Mississippi was the least healthy state (No. 50) for overall health rankings. States in the 4th quartile of health ranking were significantly associated with greater lung cancer incidence (Rate Ratio [RR]: 1.34 [95% CI, 1.18-1.52]) and mortality (1.50 [1.32-1.71]) than those in the 1st quartile. This was pronounced for age < 65 (Incidence [I]: 1.63 [1.36-1.96]; Mortality [M]: 1.93 [1.51-2.48]), Male (I: 1.48 [1.30-1.67]); M: 1.66 [1.47-1.87]), and Black (I: 1.43 [1.22-1.66]; M: 1.54 [1.32-1.79]). Black women living in states with worse health rankings had higher relative risks of breast cancer incidence (1.14 [1.03-1.26]) and mortality (1.27 [1.05-1.53]). There was no significant association between state health rankings and prostate cancer incidence and mortality in the US. Conclusions: There are significant differences in lung, breast, and prostate cancer incidence and mortality within the US. States with worse health rankings had higher cancer incidence and mortality, and varied by different demographics. Our findings suggests that advanced cancer screening and targeted public health interventions should be prioritized in areas with health disadvantages to improve cancer disparity.

Electronic health record (EHR)-based machine learning (ML) to predict disease recurrence after surgical resection of early-stage non-small cell lung cancer (eNSCLC).

6626 Background: Surgical resection (SR) is a guideline-recommended definitive therapy for patients (pts) with eNSCLC. However, 30–50% pts develop disease recurrence (DR) within the first 5 years (yrs) after surgery. ML applied to routinely collected EHR data could facilitate timely identification of pts at risk of DR who would benefit from enhanced surveillance or initial treatment (Tx) intensification. Methods: eNSCLC pts with stage IB-IIIA at the time of SR between Jan 2010 – February 2022 were identified from ConcertAI Patient360 oncology database comprising structured and curated records from US-based EHR. DR was defined as the human-curated earliest advanced/metastatic diagnosis date from SR. Gradient boosting (GB), random forest (RF), and logistic regression (LR) algorithms with 6-fold nested cross-validation were trained and compared to predict the risk of DR or death at 2 yrs from SR. Pts who did not experience DR and were lost to follow-up within 2 yrs from SR were removed. Feature importance was defined using Shapley Additive Explanation (SHAP)-derived odds ratios (OR). Due to low prevalence of DR at 2 yrs, AUPRC was used as performance metric. Pts in the 1st and 4th quartiles of predicted probabilities from XGB model were defined as low-risk vs. high-risk groups. Results: Among 3597 pts, median age was 68.3 yrs (IQR 12.5), 51.8% were female, and 8.6% were Black. 24.4% developed DR within 2 yrs. GB, RF, and LR models had similar ability to predict DR at 2 yrs with mean hold-out set AUPRC of 0.33. In GB model, DR prevalence at 2 yrs was 34% in the high-risk vs. 18% in the low-risk group in hold-out set. N0 stage, T stage < 3, receipt of adjuvant immune checkpoint inhibitor (ICI), and presence of EGFR mutations were protective against DR at 2 yrs, while history of anemia and congestive heart failure (CHF) were risk factors (Table). SHAP revealed a N stage-by-adjuvant therapy and a N stage-by-CHF interaction: benefit from adjuvant chemotherapy (CT) was limited to higher N stages, while adjuvant ICI was beneficial for all N stages. CHF was a risk factor for lower N stages but not for higher N stages. Conclusions: ML applied to structured and unstructuredEHRs identified predictors of risk of DR at 2 yrs after surgery in eNSCLC and may identify high-risk pts who would benefit from enhanced surveillance plans and Tx intensification in the eNSCLC setting. The model indicated favorable outcome from adjuvant targeted therapies in EGFR mutated pts. [Table: see text]

Comparison of lipid accumulation product and visceral adiposity index with traditional obesity indices in early-onset type 2 diabetes prediction: a cross-sectional study

BackgroundThe purpose of the study was to compare the efficacy of two novel obesity indices, lipid accumulation product (LAP) and visceral adiposity index (VAI), with traditional obesity indices in predicting early-onset type 2 diabetes (T2DM).MethodsIn this cross-sectional study, a total of 744 participants, including 605 patients newly diagnosed with T2DM and 139 non-diabetic control subjects, were enrolled from a tertiary care hospital in Tianjin, China. Participants with T2DM were divided into two groups based on their age at diagnosis, namely early-onset T2DM (age less than 40 years, n = 154) and late-onset T2DM (age 40 years or older, n = 451). The predictive power of each obesity index was evaluated using receiver operating characteristic (ROC) curve analysis. Furthermore, binary logistic regression analysis was conducted to examine the independent relationship between LAP and VAI with early-onset T2DM risk. The relationship between novel obesity indices and the age of T2DM onset was also evaluated through correlation and multiple linear regression analysis.ResultsIn males, LAP had the highest predictive power for early-onset T2DM with an area under the ROC curve (AUC) of 0.742 (95% CI 0.684–0.799, P < 0.001). In females, VAI had the highest AUC for early-onset T2DM with a value of 0.748 (95% CI 0.657–0.839, P < 0.001), which was superior to traditional indices. Patients in the 4th quartile of LAP and VAI had 2.257 (95% CI 1.116–4.563, P = 0.023) and 4.705 (95% CI 2.132–10.384, P < 0.001) times higher risk of T2DM before age 40, compared to those in the 1st quartile, respectively. A tenfold increase in LAP was associated with a decrease in T2DM onset age of 12.862 years in males (β = −12.862, P < 0.001) and 6.507 years in females (β = −6.507, P = 0.013). A similar decrease in T2DM onset age was observed for each tenfold increase in VAI in both male (β = −15.222, P < 0.001) and female (β = −12.511, P < 0.001) participants.ConclusionsIn young Chinese individuals, LAP and VAI are recommended over traditional obesity indices for improved prediction of early-onset T2DM risk.

Urinary tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and cognitive functioning in older adults: The National Health and Nutrition Examination Survey 2013-2014.

Tobacco contains carcinogens called tobacco-specific nitrosamines. Among the tobacco-specific nitrosamines, is nicotine-derived nitrosamine ketone (NNK) which produces the metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). We aimed to examine the association between urinary tobacco-specific NNAL and cognitive functioning among older adults. A total of 1673 older adults aged ≥60 years from the National Health and Nutrition Examination Survey 2013-2014 were included. Urinary tobacco-specific NNAL was analyzed in the laboratory. Cognitive functioning was measured using the Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest (CERAD-WL) immediate and delayed memory tests, the Animal Fluency test (AFT), and the Digit Symbol Substitution Test (DSST). Test-specific and global cognition z-scores were calculated based on means and standard deviations of the cognitive test scores. Multivariable linear regression models were constructed to examine the independent association between quartiles of urinary tobacco-specific NNAL and cognitive test-specific and global cognition z-scores controlling for age, sex, race/ethnicity, education level, depressive symptoms, body mass index, systolic blood pressure, urinary creatinine, hypertension, diabetes, alcohol use, and smoking status. About half of the participants (mean age 69.8 years) were female (52.1%), non-Hispanic White (48.3%), and completed some college and above (49.7%). Multivariable linear regression results showed that participants in the 4th quartile (highest quartile) of urinary NNAL, compared with those in the 1st quartile (lowest quartile), had lower DSST z-scores (β= -0.19; 95% CI: -0.34 - -0.04). Tobacco-specific NNAL was negatively associated with processing speed, sustained attention, and working memory in older adults.

Behavioral outcomes and exposure to perfluoroalkyl substances among children aged 6–13 years: The TEDDY child study

BackgroundAlthough some studies report that exposure to per- and polyfluoroalkyl substances (PFAS) during pregnancy and early life stages of a child could adversely impact neurodevelopment, literature shows mixed evidence. ObjectivesUsing an ecological framework for human development, we assessed the association of risk factors for environmental PFAS exposure and childhood PFAS concentrations with behavioral difficulties among school-age children exposed to PFAS from birth, while also controlling for the important influence of the parenting and familial environment. MethodsThe study participants included 331 school-age children (6–13 years) born in a PFAS-contaminated area in the Veneto Region (Italy). We study the associations between environmental risk factors of maternal PFAS exposure (residential time, consumption of tap water, residence in Red zone A or B), and breastfeeding duration with parent assessments of children's behavioral problems (using the Strengths and Difficulties Questionnaire [SDQ]), adjusting for socio-demographic, parenting and familial variables. The direct relationships between serum blood PFAS concentrations and SDQ scores was evaluated in a subset of children (n = 79), both with single PFAS and weighted quantile sum (WQS) regressions. ResultsPoisson regression models reported positive associations between high consumption of tap water and externalizing SDQ scores (Incidence Rate Ratio [IRR]: 1.18; 95% confidence interval [CI]: 1.04–1.32) and total difficulty scores (IRR: 1.14; 95% CI: 1.02–1.26). Childhood perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were associated with higher internalizing SDQ scores (4th vs. 1st quartile, PFOS IRR: 1.54, 95% CI: 1.06–2.25), externalizing scores (4th vs. 1st quartile, PFHxS IRR: 1.59, 95% CI: 1.09–2.32), and total difficulty scores (4th vs. 1st quartile, PFOS IRR: 1.37, 95% CI: 1.05–1.71; PFHxS IRR: 1.54, 95% CI: 1.09–1.90). The WQS regressions confirmed the associations reported by single-PFAS analyses. ConclusionsWe observed cross-sectional associations of tap water consumption and childhood PFOS, and PFHxS concentrations with greater behavioral difficulties.

Profiles of poor and good spellers in German noun capitalization

This study investigated how fourth graders with different proficiency levels (1st and 4th quartile, 192 and 195 pupils respectively) produce and detect German noun capitalization in relation to two factors, lexical-semantic characteristics of the noun and the structure of the noun phrase (NP). The first factor includes concrete and abstract nouns, and nominalized verbs and adjectives, the second factor the syntactic context of the NP (with or without determiner and/or adjective, including bare noun). The two proficiency groups showed different patterns in the production and detection of capitalization in relation to these two factors after three years of instruction in noun capitalization. The low-proficiency group performed on chance level only for concrete nouns in the context with precedent determiner, the context highlighted at school. The high-proficiency group seemed to make use systematically of the expanded NP in order to recognize and capitalize the noun but still had difficulties with most bare nouns. The paper discusses the type of information low- and high-achieving pupils seem to use in noun capitalization and detection.

Causal structure search and modeling of precision dairy farm data for automated prediction of ketosis risk, and the effect of potential interventions

Causal search techniques enable inference from observational data, such as that produced in Precision Livestock Farming. The Peter-Clark algorithm was used to produce four causal models, for the risk of ketosis in individual cows. The data set covered 1542 Holstein-Friesian cows on a commercial dairy farm in Slovakia, over a period of 18 months and had 483 variables, split into four samples for four-way cross validation. The cow data was sorted into quartiles by predicted postpartum blood ketone value. The observed incidences of ketosis by quartile were 3.14%, 6.35%, 6.77%, 15.1%. To test the effect of intervention on the reduction of ketosis cases on the farm, we predicted the expected effect of 20% lower dry matter in the total mixed ration over the 6 months pre-partum. Predicted reductions in incidence of ketosis for the highest risk (4th) quartile were -4.96%, -7.4%, -11.21%, and -11.07% of animals in the herd, respectively for the four models. The different predictions were due to the different causal structures estimated from the four data samples by the Peter-Clark causal model search algorithm. To accurately predict the effect of intervention for automatic optimization of herd performance it is necessary to determine the correct causal structure of the model. Collinearity of inputs due to e.g. grouping by pens, reduced the conditional independence of their effects, and therefore the ability of the Peter-Clark algorithm to determine the correct causal structure. To reduce the collinearity of variables, we recommend causal search on datasets from multiple farms or multiple years.

Predictive value of elevated neutrophil gelatinase-associated lipocalin (NGAL) levels for assessment of in hospital adverse outcomes among myocardial infarction patients

Abstract Funding Acknowledgements Type of funding sources: None. Background Inflammatory biomarkers are known to rise and have significant predictive value for adverse outcomes in patients with acute coronary ischemia .Neutrophil gelatinase-associated lipocalin (NGAL), a glycoprotein stored in mature neutrophil granules, is significantly increased in patients with myocardial infarction compared with patients with stable coronary artery disease and healthy subjects. To date, very few studies have assessed the prognostic value of NGAL in this setting. Purpose We investigated the prognostic utility of elevated NGAL levels on clinical outcomes among ST elevation myocardial infarction patients (STEMI) treated with primary coronary intervention (PCI). Methods Blood samples for plasma NGAL were drawn immediately after admission. High NGAL was defined as values within the 4th quartile (&amp;gt;75percentile). Patients were assessed for major in-hospital adverse clinical events (MACE). These included reduced left ventricular ejection fraction, clinical heart failure findings and 30-day mortality. Multivariable logistic regression was used to evaluate the association between NGAL group and MACE. Receiver operating characteristic curve (AUC) was used to evaluate the discrimination ability of NGAL compared with other inflammatory biomarkers including white blood cell count(WBC), peak troponin level, peak C-reactive protein(CRP) and neutrophil/lymphocyte ratio(NLR) for the prediction of MACE. Results A total of 273 patients were included (mean age 66 ± 14 years, 81% males). Patients with high NGAL were at increased risk for MACE (62% vs. 19%; OR 6.88, 95%CI 3.77-12.54, p&amp;lt;0.001, Figure 1). After propensity score matching, 55 pairs of comparable patients were identified. Following matching, the incidence of MACE was significantly higher in patients with high vs. low NGAL levels (69% vs. 6%, p=0.002; figure 1). In the multivariable logistic regression high NGAL level was independently associated with MACE (OR 9.25, 95%CI 4.33-19.76, P&amp;lt;0.001). The discrimination ability of NGAL to identify MACE (AUC 0.823) was significantly better (figure 2; p&amp;lt;0.001) than that of CRP (AUC 0.627), troponin (AUC 0.588), WBC (AUC 0.583) and NLR (AUC 0.601). Conclusions Among STEMI patients undergoing primary PCI, high NGAL levels are associated with adverse outcomes, independent of traditional inflammatory markers.

Weight-adjusted waist index is not superior to conventional anthropometric indices for predicting type 2 diabetes: a secondary analysis of a retrospective cohort study.

Weight-adjusted waist index (WWI) is a new anthropometric indicator to assess adiposity. Current knowledge regarding its association with type 2 diabetes mellitus (T2DM) is limited. This present study aims to evaluate the association of WWI with the risk of T2DM in the Japanese population, and to compare its predictive ability with body mass index (BMI) and waist circumference (WC). This was a secondary analysis of a retrospective cohort study involving 15,464 participants. Participants were divided into quartiles based on baseline WWI levels. Cox regression model, Kaplan-Meier curve, and smooth curve fitting were used to explore the relationship between WWI and T2DM. The discriminative ability of obesity indices in predicting T2DM was compared by the receiver operating characteristic (ROC) curve. After a mean follow-up of 6.05 years, 373 participants were diagnosed with T2DM. In fully adjusted models, the risk of incident T2DM was 1.96 times higher for each 1-unit increment in WWI levels (95% CI: 1.61-2.39, P < 0.001). Smooth curve fitting analysis showed a linear positive association between baseline WWI and new-onset T2DM. Subgroup analysis showed consistent results which subjects in the 4th WWI quartile had the highest risk of developing T2DM in different age, gender, and BMI groups. WWI did not exhibit better predictive ability compared with BMI and WC in the results of ROC curve. WWI, a new metabolic index, can be used to predict new-onset T2DM in the Japanese population. However, its predictive capability was not superior to conventional anthropometric indices.

Abstract 3015: Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore

Abstract Background: Chronic inflammation plays a significant role in hepatocellular carcinoma (HCC). With rising incidence and poor prognosis of HCC, identifying relatively less invasive biomarkers, especially inflammatory ones, may improve the assessment and stratification of HCC risk. The objective of our studies was to assess if CD8+ T cell cytokines in pre-diagnostic serum are associated with risk of HCC development. Methods: We conducted two parallel case-control studies of HCC nested within the Shanghai Cohort Study (SCS) and the Singapore Chinese Health Study (SCHS), two prospective cohorts of 81,000 individuals with 25+ years of follow-up. The serum concentrations of five CD8+ T cell cytokines ─ soluble CD137 (sCD137), soluble Fas (sFas), perforin, macrophage inflammatory protein 1-beta (MIP-1β), and tumor necrosis factor alpha (TNF-α) ─ were determined using Luminex bead-based immunoassay on 315 HCC cases and 315 individually matched controls in the SCS, and on 197 HCC case-control pairs in the SCHS. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for HCC with elevated levels of cytokines with adjustment for body mass index, alcohol drinking, cigarette smoking, seropositivity of hepatitis surface antigen (HBsAg), and history of diabetes. Results: sCD137 levels were statistically significantly higher in HCC cases than controls in both cohorts. Compared with the 1st quartile (Q1) of sCD137, multivariable-adjusted ORs (95% CI) of HCC for the 4th quartile (Q4) were 3.8 (1.7-8.3) in the SCS and 3.5 (1.4 -8.5) in the SCHS (both Ptrend’s &amp;lt; 0.001). Among HBsAg-negative individuals, ORs (95% CIs) for Q2, Q3, &amp; Q4 of sCD137 were 2.7 (1.5-4.9), 2.7 (1.4-5.0), and 4.5 (2.4-8.5), respectively, compared with Q1 (Ptrend &amp;lt; 0.001) in both SCS and SCHS combined. The corresponding ORs (95% CIs) among HBsAg- positive individuals were 21.0 (9.3-47.6), 34.1 (13.8-84.2), and 56.7 (23.3-137.9), respectively, with a P=0.095 for multiplicative interaction. The sCD137-HCC risk association remained constant over different time periods from blood draw to HCC diagnosis: ORs (95% CIs) for Q4 vs. Q1 were 4.7 (1.2-17.5) for &amp;lt;5 years, 3.7 (1.3-10.6) for 5-10 years, and 3.94 (1.6-9.5) for more than 10 years between blood collection and cancer diagnosis. sFas was positively associated with HCC risk in the SCHS but not in the SCS. There was no statistically significant association for perforin, MIP-1β, or TNF-α with HCC risk in either cohort. Conclusion: These novel and validated findings demonstrated that serum sCD137 levels were significantly elevated many years prior to HCC diagnosis, and had a potential synergistic effect with chronic viral infection on the HCC risk. sCD137 may be developed as a immune monitoring biomarker for risk stratification and assessment, which can lead to early diagnosis and improve prognosis of HCC patients. Citation Format: Claire E. Thomas, Jennifer J. Adibi, Allison L. Kuipers, Brenda Diergaarde, Hung N. Luu, Aizhen Jin, Woon-Puay Koh, Yu-Tang Gao, Jennifer Adams-Haduch, Renwei Wang, Anna Lokshin, Jaideep Behari, Jian-Min Yuan. Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3015.

Abstract 4216: Interactions of greenness with air pollution in relation to postmenopausal breast cancer risk in UK Biobank

Abstract Purpose: The evidence of the association between natural vegetation, or greenness, and breast cancer (BCa) remains inconsistent, with some studies reporting possible interactions with air pollution. We previously found a positive association of particulate matter with diameters than are 10 micrometers or smaller (PM10) with BCa risk among postmenopausal women in the UK Biobank. In this study, we investigated the associations of greenness with postmenopausal BCa risk, as well as whether association of PM10 with BCa differ by the level of greenness. Methods: This study included 155,235 postmenopausal women (6,146 with BCa) from UK Biobank, a population-based prospective cohort. Cancer diagnoses were ascertained through the linkage to the UK National Health Service Central Registers. Greenness measures (Greenspace percentage [GP], Natural environment percentage [NEP], and the Normalized Difference Vegetation Index [NDVI]) were available at baseline assessment (2006 -2010). GP and NEP coverage were calculated at 300 m and 1000 m, respectively, around participant residence locations, while the mean NDVI was calculated within a 500 m residential buffer of each UK Biobank participant. Annual averages for PM10 were available from 2007 and 2010. Information on BCa risk factors was collected at baseline. We used Cox proportional hazards regression to evaluate associations between greenness (continuous as well as quartiles) and BCa risk, while adjusting for BCa risk factors. Next, we examined associations for year-specific and cumulative average PM10 exposure measures (per 5 µg/m3) within each stratum of greenness measure. Interactions between PM10 and greenness measures were assessed by including an interaction term in the main models. Results: BCa risk increased by 29% per one unit increase in NDVI (Hazard ratio [HR]=1.29, 95% CI 1.03, 1.61). Compared to women in the lowest NDVI quartile, women with higher levels of NDVI had higher risk of BCa (HR=1.10, 95% CI 1.01, 1.21 for 2nd quartile, HR=1.10, 95% CI 1.00, 1.20 for 3rd quartile, and HR=1.13, 95% CI 1.04, 1.24 for 4th quartile, p-trend=0.012). No significant associations were found for any other greenness measure in relation to BCa risk. We found a significant interaction between NDVI and cumulative average PM10 exposure (p&amp;lt;0.0001). The association of PM10 cumulative average with BCa risk was stronger at lower levels of NDVI (HR per 5 µg/m3=1.12, 95% CI 1.07, 1.17 for 1st quartile) compared to higher levels of NDVI (HR=1.04, 95% CI 1.02, 1.07 for 4th quartile). We found no interactions with other greenness measures. Conclusions: We found a positive association of NDVI with BCa risk and an interaction between cumulative average PM10 and NDVI, with stronger positive association of cumulative average PM10 exposure with postmenopausal BCa risk at lower compared to higher levels of greenness. Citation Format: Carmen Smotherman, Brian Sprague, Susmita Datta, Dejana Braithwaite, Huaizhen Qin, Lusine Yaghjyan. Interactions of greenness with air pollution in relation to postmenopausal breast cancer risk in UK Biobank. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4216.

Abstract 743: Association between physical activity and lipid profile among breast cancer survivors

Abstract Backgrounds/Aims: Unfavorable lipid profiles may be associated with prognosis among breast cancer survivors. We aimed to examine the association between physical activity levels and subclasses of lipoprotein among breast cancer survivors. Methods: We included a total of 378 women diagnosed with primary breast cancer and survived for ≥6 months since the surgery. Physical activity levels were presented as the metabolic equivalent of task (MET) hours/week from a structured questionnaire. High-throughput proton nuclear magnetic resonance (NMR) metabolomics platform was used to quantify plasma levels of specific lipid biomarkers and particle sizes. The multivariable adjusted least-square means (LS-means) and 95% confidence intervals (CIs) of lipid profile markers across physical activity (quartile) were estimated by using generalized linear models. Results: We observed inverse associations of physical activity levels with circulating levels of total triglycerides (TG), TG in very low-density lipoprotein (VLDL), and TG in high-density lipoprotein (HDL) among breast cancer survivors. LS-means (95% CIs) for 1st and 4th quartiles of physical activity were 1.07 (0.99-1.17) and 0.96 (0.88-1.04; p for trend=0.048) for total TG (nmol/L), 0.68 (0.62-0.74) and 0.60 (0.54-0.66; p for trend=0.045) for TG in VLDL (nmol/L), and 0.14 (0.13-0.15) and 0.12 (0.11-0.13; p for trend=0.045) for TG in HDL (nmol/L). These associations were limited to breast cancer survivors with stage II or III. We also found a smaller VLDL size with high physical activity among those with stage II or III. Among participants with a BMI of ≥25 kg/m2, we found that high physical activity was associated with decreased levels of TG in VLDL and small VLDL size; according to subsequent quartiles of physical activity, LS-means (95% CIs) were 0.73 (0.62-0.87), 0.88 (0.72-1.08), 0.74 (0.61-0.89), and 0.56 (0.44-0.71) for TG in VLDL (nmol/L), respectively (p for trend=0.047); and 38.67 (38.34-39.00), 38.75 (38.36-39.15), 38.65 (38.28-39.01), and 37.98 (37.52-38.45) for VLDL size (nm), respectively (p for trend=0.024). Conclusions: We found that high physical activity was associated with lower circulating levels of subclasses of TG and smaller VLDL size among breast cancer survivors with stage II or III or those with a BMI of ≥25 kg/m2. Further prospective or randomized controlled studies are warranted to confirm the significance of physical activity associated with favorable lipid profiles among breast cancer survivors. Funding Information: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT, MSIT) (No. 2014R1A2A2A01007794, 2019R1F1A1061017, and 2021R1F1A1062476) and K-BIO KIURI Center program (NRF2020M3H1A107330413). Citation Format: Hyun Jeong Cho, Minji Kang, Zisun Kim, Hyun Jo Youn, Jihyoung Cho, Jun Won Min, Yoo Seok Kim, Jung Eun Lee. Association between physical activity and lipid profile among breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 743.

Prenatal arsenic exposure, arsenic metabolism and neurocognitive development of 2-year-old children in low-arsenic areas

BackgroundThere is limited evidence on the effects of arsenic species and metabolic capacity on child neurodevelopment, particularly at low levels. Further, little is known about the critical window of exposure. ObjectiveTo estimate the associations of arsenic exposure and arsenic metabolism in different pregnancy periods with neurodevelopment of two-year-old children. MethodsConcentrations of arsenobetaine (AsB), arsenite, arsenate, monomethyl arsenic acid (MMA), and dimethyl arsenic acid (DMA) in urine samples collected in three trimesters from 1006 mothers were measured using HPLC − ICPMS. Inorganic arsenic (iAs) was calculated as the sum of arsenite and arsenate. Total arsenic (tAs) was calculated as the sum of iAs, MMA and DMA. Child neurodevelopment was assessed with the Bayley Scales of Infant Development. ResultsThe geometric mean (GM) of SG-adjusted tAs in the first, second, third trimester was 16.37, 12.94, 13.04 μg/L, respectively. The mental development index (MDI) score was inversely associated with iAs and tAs. Compared to the 1st quartile, the MDI score decreased 0.43 (95%CI: −4.22, 3.36) for the 2nd, 6.50 (95%CI: −11.73, −1.27) for the 3rd, 5.42 (95%CI: −10.74, −0.10) for the 4th quartiles of iAs, and decreased 4.03 (95%CI: −7.90, −0.15) in the 4th quartile of tAs. In trimester-specific models, negative associations of DMA [−1.94 (95%CI: −3.18, −0.71)] and tAs [−1.61 (95%CI: −3.02, −0.20)] with the psychomotor development index (PDI) were only observed in 1st trimester. ConclusionsOur study found inverse associations between prenatal arsenic exposure, especially in early pregnancy, and neurodevelopment of children at two years old, even at low exposure levels.

Growth Differentiation Factor 15: A Prognostic Marker in Patients with Acute Chest Pain without Acute Myocardial Infarction.

Acute chest pain is associated with an increased risk of death and cardiovascular events even when acute myocardial infarction (AMI) has been excluded. Growth differentiation factor-15 (GDF-15) is a strong prognostic marker in patients with acute chest pain and AMI, but the prognostic value in patients without AMI is uncertain. This study sought to investigate the ability of GDF-15 to predict long-term prognosis in patients presenting with acute chest pain without AMI. In total, 1320 patients admitted with acute chest pain without AMI were followed for a median of 1523 days (range: 4 to 2208 days). The primary end point was all-cause mortality. Secondary end points included cardiovascular (CV) death, future AMI, heart failure hospitalization, and new-onset atrial fibrillation (AF). Higher concentrations of GDF-15 were associated with increased risk of death from all causes (median concentration in non-survivors vs survivors: 2124 pg/mL vs 852 pg/mL, P < 0.001), and all secondary end points. By multivariable Cox regression, GDF-15 concentration ≥4th quartile (compared to <4th quartile) remained an independent predictor of all-cause death (adjusted hazard ratio (HR): 2.75; 95% CI, 1.69-4.45, P < 0.001), CV death (adjusted HR: 3.74; 95% CI, 1.31-10.63, P = 0.013), and heart failure hospitalization (adjusted HR: 2.60; 95% CI, 1.11-6.06, P = 0.027). Adding GDF-15 to a model consisting of established risk factors and high-sensitivity cardiac troponin T (hs-cTnT) led to a significant increase in C-statistics for prediction of all-cause mortality. Higher concentrations of GDF-15 were associated with increased risk of mortality from all causes and risk of future CV events.

The state of cancer research in fragile and conflict-affected settings in the Middle East and North Africa Region: A bibliometric analysis.

Cancer represents a disproportionate burden in LMICs, especially conflict-affected countries in the MENA region. Research output on cancer fails to match the growing burden in the region. This bibliometric study aims to examine the status and trends of cancer research in fragile and conflict-affected settings in the MENA region from 2000 to 2021, while also incorporating economic and demographic indicators as additional factors of analysis. The Web of Science databases were searched for publications related to cancer research in Iraq, Lebanon, Libya, Palestine, Syria, and Yemen from January 1, 2000, to December 31, 2021. The retrieved publications were screened based on preset eligibility criteria and the final list was analyzed using the Bibliometrix Package in R to generate the annual scientific production and citations, journals, institutions, authors, collaborations, keywords, and title co-occurrence. Each country's annual scientific production was analyzed against its annual GDP per capita. A total of 4,280 documents met the inclusion criteria in this research. The annual number of publications revealed a significant increase over the past 20 years. These publications were mostly published in international journals that had impact factors rated in the 3rd or 4th quartiles. The overall contribution of researchers from Fragile and Conflict-Affected Settings (FCS) to cancer research was 6.5% of the MENA cancer research productivity, despite comprising around 23% of the total MENA region's population. Lebanon had the highest publication productivity at the country level, followed by Iraq and Syria. GDP per capita was not significantly correlated with cancer research across the countries under investigation. At the institutional level, the American University of Beirut was the most prolific institution and had the highest number of collaborations and the widest range of cooperative partners. Most first authors were male researchers. There is an interest in cancer expression, prevalence, diagnosis, and management in terms of commonly researched topics. This study underscores the need for a concerted effort to improve cancer research outcomes in FCS, which can be achieved through targeted research, increased investment in research infrastructure and capacity-building initiatives, and greater regional and global collaboration.

Cerebral Hemodynamics Underlying Artery-to-Artery Embolism in Symptomatic Intracranial Atherosclerotic Disease.

Artery-to-artery embolism (AAE) is a common stroke mechanism in intracranial atherosclerotic disease (ICAD), associated with a considerable risk of recurrent stroke. We aimed to investigate cerebral hemodynamic features associated with AAE in symptomatic ICAD. Patients with anterior-circulation, symptomatic ICAD confirmed in CT angiography (CTA) were recruited. We classified probable stroke mechanisms as isolated parent artery atherosclerosis occluding penetrating artery, AAE, hypoperfusion, and mixed mechanisms, largely based on infarct topography. CTA-based computational fluid dynamics (CFD) models were built to simulate blood flow across culprit ICAD lesions. Translesional pressure ratio (PR = Pressurepost-stenotic/Pressurepre-stenotic) and wall shear stress ratio (WSSR = WSSstenotic-throat/WSSpre-stenotic) were calculated, to reflect the relative, translesional changes of the two hemodynamic metrics. Low PR (PR ≤ median) and high WSSR (WSSR ≥ 4th quartile) respectively indicated large translesional pressure and elevated WSS upon the lesion. Among 99 symptomatic ICAD patients, 44 had AAE as a probable stroke mechanism, 13 with AAE alone and 31 with coexisting hypoperfusion. High WSSR was independently associated with AAE (adjusted OR = 3.90; P = 0.022) in multivariate logistic regression. There was significant WSSR-PR interaction on the presence of AAE (P for interaction = 0.013): high WSSR was more likely to associate with AAE in those with low PR (P = 0.075), but not in those with normal PR (P = 0.959). Excessively elevated WSS in ICAD might increase the risk of AAE. Such association was more prominent in those with large translesional pressure gradient. Hypoperfusion, commonly coexisting with AAE, might be a therapeutic indicator for secondary stroke prevention in symptomatic ICAD with AAE.

Impact of ramucirumab pharmacokinetics in combination with docetaxel on the efficacy and survival in patients with advanced non-small cell lung cancer

ObjectivesRamucirumab, an anti-vascular endothelial growth factor receptor-2 antibody, has been approved for the treatment of non-small cell lung cancer (NSCLC); however, its pharmacokinetic properties in clinical practice are unknown. We aimed to measure ramucirumab concentrations and conduct a retrospective pharmacokinetic analysis using real-world data. Materials and MethodsPatients with stage III–IV and recurrent NSCLC who received ramucirumab plus docetaxel were evaluated in this study. After the first administration, the ramucirumab trough concentration (Ctrough) was measured using liquid chromatography-mass spectrometry. Patient characteristics, adverse events, tumor response, and survival time were retrospectively extracted from medical records from August 2, 2016 to July 16, 2021. ResultsA total of 131 patients were examined to assess serum ramucirumab concentrations. Ctrough ranged from below the lower limit of quantification (BLQ) to 48.8 µg/mL (BLQ ≤ 1st quartile (Q1) ≤ 7.34, 7.34 < 2nd quartile (Q2) ≤ 14.7, 14.7 < 3rd quartile (Q3) ≤ 21.9 and 21.9 < 4th quartile (Q4) ≤ 48.8 µg/mL). The overall response rate was significantly higher in Q2–4 than that in Q1 (p = 0.011). The median progression-free survival was marginally longer, and overall survival was significantly longer in Q2–4 (p = 0.009). The Glasgow prognostic score (GPS) in Q1 was significantly higher than in Q2–4 (p = 0.034) and associated with Ctrough (p = 0.002). ConclusionPatients with higher ramucirumab exposure had a high ORR and prolonged survival time, whereas patients with lower ramucirumab exposure were characterized by a high GPS and poor prognosis. Cachexia may reduce the exposure level of ramucirumab in certain patients, reducing the clinical benefits of ramucirumab treatment.

First Responder CPR and Survival Differences in Texas Minority and Lower Socioeconomic Status Neighborhoods

Introduction First responder (FR) cardiopulmonary resuscitation (CPR) is an important component of out-of-hospital cardiac arrest (OHCA) care. However, little is known about FR CPR disparities. Methods We linked the 2014–2021 Texas Cardiac Arrest Registry to Enhance Survival (TX-CARES) database to census tract data. We included non-traumatic OHCAs that were not witnessed by 9-1-1 responders and did not receive bystander CPR. We defined census tracts as having >50% of a race/ethnicity: White, Black, or Hispanic/Latino. We also stratified patients into quartiles based on socioeconomic status (SES): household income, high school graduation, and unemployment. We also combined race/ethnicity and income to create a total of five mixed strata, comparing lower income and minority census tracts to high income White census tracts. We created mixed model logistic regression models, adjusting for confounders and modeling census tract as a random intercept. Using the models, we compared FR CPR rates for census race/ethnicity (Black and Hispanic/Latino compared to White), and SES quartiles (2nd, 3rd, and 4th quartiles compared to 1st quartiles). Secondarily, we evaluated the association between FR CPR and survival for all strata. Results We included 21,966 OHCAs, and 57.4% had FR CPR. Evaluating the association between census tract characteristic and FR CPR, majority Black (aOR 0.30, 95% CI 0.22–0.41) had a lower bystander CPR rate when compared to majority White. The lowest income quartile had a lower rate of bystander CPR (aOR 0.80, 95% CI 0.65–0.98). The worst unemployment quartile was also associated with a lower rate of FR CPR (aOR 0.75, 95% CI 0.61–0.92). Combining race/ethnicity and income, middle income majority Black (30.0%; aOR 0.27, 95% CI 0.17–0.46) and low income >80% Black (31.8%; aOR 0.27, 95% CI 0.10–0.68) had lower rates of FR CPR in comparison to high income majority White. There were no associations between Hispanic or lower high school graduation and lower rates of FR CPR. We found no association between FR CPR and survival for all three strata. Conclusion While we identified disparities in FR CPR in low SES and majority Black census tracts, we identified no association between FR CPR and survival in Texas.