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Immune-checkpoint inhibitor (ICI) therapy has been widely used to treat different human cancers, particularly advanced solid tumors. However, clinical studies have reported that ICI immunotherapy benefits only ∼15% of patients with colorectal cancer, specifically those with tumors characterized by microsatellite instability (MSI), a molecular marker of defective DNA mismatch repair (dMMR). For the majority of patients with colorectal cancer who carry proficient MMR (pMMR), ICIs have shown little clinical benefit. In this study, we examined the efficacy of sulindac to enhance the response of pMMR colorectal cancer to anti–PD-L1 immunotherapy. We utilized a CT26 syngeneic mouse tumor model to compare the inhibitory effects of PD-L1 antibody (Ab), sulindac, and their combination on pMMR colorectal cancer tumor growth. We found that mice treated with combination therapy showed a significant reduction in tumor volume, along with increased infiltration of CD8+ T lymphocytes in the tumor tissues. We also demonstrated that sulindac could downregulate PD-L1 by blocking NF-κB signaling, which in turn led to a decrease in exosomal PD-L1. Notably, PD-L1 Ab can be bound and consumed by exosomal PD-L1 in the blood circulation. Therefore, in combination therapy, sulindac downregulating PD-L1 leads to increased availability of PD-L1 Ab, which potentially improves the overall efficacy of anti–PD-L1 therapy. We also show that low-dose sulindac does not appear to have a systemic inhibitory effect on prostaglandin E2 (PGE2). In conclusion, our findings provide unique insights into the mechanism of action and efficacy for sulindac as an immunomodulatory agent in combination with anti–PD-L1 therapy for the treatment of pMMR colorectal cancer.

Third variable effect refers to the effect from a third variable that explains an observed relationship between an exposure and an outcome. Depending on whether there is causal relationship, typically, a third variable takes the format of a mediator or a confounder. A moderation effect is a special case of the third-variable effect, where the moderator and other variables have an interactive effect on the outcome. In this paper, we extend the R package 'mma' for moderation analysis so that third-variable effects can be reported at different levels of the moderator. The proposed moderation analysis use tree-structured models to automatically detect moderation effects and can handle both categorical and numerical moderators. We propose algorithms and graphical methods for making inference on moderation effects and illustrate the method under different scenarios of moderation effects. Finally, we apply the proposed method to explore the trend of racial disparities in the use of Oncotype DX recurrence tests among breast cancer patients. We found that the unexplained racial differences in using the tests have decreased from 2010 to 2015.

Background Vulvovaginal candidiasis (VVC) is a common infection affecting women worldwide. Reports of patterns/risk factors/trends for episodic/recurrent VVC (RVVC) are largely outdated. The purpose of this study was to obtain current patient perspectives of several aspects of VVC/RVVC. Methods Business cards containing on-line survey information were distributed to healthy volunteers and patients seeking standard, elective, or referral gynecologic care in university-affiliated Obstetrics/Gynecology clinics. The internet-based questionnaire was completed by 284 non-pregnant women (78% Caucasian, 14% African American, 8% Asian). Results The majority of the participants (78%) indicated a history of VVC with 34% defined as having RVVC. The most common signs/symptoms experienced were itching, burning and redness with similar ranking of symptoms among VVC and RVVC patients. Among risk factors, antibiotic use ranked highest followed by intercourse, humid weather and use of feminine hygiene products. A high number of respondents noted ‘no known cause’ (idiopathic episodes) that was surprisingly similar among women with a history of either VVC or RVVC. VVC/RVVC episodes reported were primarily physician-diagnosed (73%) with the remainder mostly reporting self-diagnosis and treating with over-the-counter (OTC) medications. Most physician-diagnosed attacks utilized a combination of pelvic examination and laboratory tests followed by prescribed antifungals. Physician-treated cases achieved a higher level of symptom relief (84%) compared to those who self-medicated (57%). The majority of women with RVVC (71%) required continual or long-term antifungal medication as maintenance therapy to control symptoms. Conclusions Current patient perspectives closely reflect historically documented estimates of VVC/RVVC prevalence and trends regarding symptomatology, disease management and post-treatment outcomes. Electronic supplementary material The online version of this article (10.1186/s12905-019-0748-8) contains supplementary material, which is available to authorized users.

Background The study aimed to examine racial/ethnic differences in chemotherapy utilization by breast cancer subtype. Methods Data on female non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic stage I-III breast cancer patients diagnosed in 2011 were obtained from a project to enhance population-based National Program of Cancer Registry data for Comparative Effectiveness Research. Hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) were used to classify subtypes: HR+/HER2-; HR+/HER2+; HR-/HER2-; and HR-/HER2 + . We used multivariable logistic regression models to examine the association of race/ethnicity with three outcomes: chemotherapy (yes, no), neo-adjuvant chemotherapy (yes, no), and delayed chemotherapy (yes, no). Covariates included patient demographics, tumor characteristics, Charlson Comorbidity Index, other cancer treatment, and participating states/areas. Results The study included 25,535 patients (72.1% NHW, 13.7% NHB, and 14.2% Hispanics). NHB with HR+/HER2- (adjusted odds ratio [aOR] 1.22, 95% CI 1.04–1.42) and Hispanics with HR-/HER2- (aOR 1.62, 95% CI 1.15–2.28) were more likely to receive chemotherapy than their NHW counterparts. Both NHB and Hispanics were more likely to receive delayed chemotherapy than NHW, and the pattern was consistent across each subtype. No racial/ethnic differences were found in the receipt of neo-adjuvant chemotherapy. Conclusions Compared to NHW with the same subtype, NHB with HR+/HER2- and Hispanics with HR-/HER2- have higher odds of using chemotherapy; however, they are more likely to receive delayed chemotherapy, regardless of subtype. Whether the increased chemotherapy use among NHB with HR+/HER2- indicates overtreatment needs further investigation. Interventions to improve the timely chemotherapy among NHB and Hispanics are warranted.

Third-Variable effect refers to the intervening effect from a third variable (called mediators or confounders) to the observed relationship between an exposure and an outcome. The general multiple third-variable effect analysis method (TVEA) allows consideration of multiple mediators/confounders (MC) simultaneously and the use of linear and non-linear predictive models for estimating MC effects. Previous studies have found that compared with non-Hispanic White population, Blacks and Hispanic Whites suffered disproportionally more with obesity and related chronic diseases. In this paper, we extend the general TVEA to deal with multivariate/multicategorical predictors and multivariate response variables. We designed algorithms and an R package for this extension and applied MMA on the NHANES data to identify MCs and quantify the indirect effect of each MC in explaining both racial and ethnic disparities in obesity and the body mass index (BMI) simultaneously. We considered a number of socio-demographic variables, individual factors, and environmental variables as potential MCs and found that some of the ethnic/racial differences in obesity and BMI were explained by the included variables.

Background: Studies on symptomatic osteoarthritis suggest that Black patients report worse pain and symptoms compared with White patients with osteoarthritis. In this study, we aimed to quantify the relationship among variables such as overall health and socioeconomic status that may contribute to disparities in patient-reported outcomes. Methods: A total of 223 patients were enrolled. A mediation analysis was used to evaluate cross-sectional associations between race and the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire, which was administered to patients prior to undergoing primary total knee arthroplasty. Results: Black patients had worse KOOS pain, symptoms, and activities of daily living subscale scores than White patients. In our cohort, Black patients were younger, more likely to be female, and more likely to report lower educational status. We identified age, sex, Charlson Comorbidity Index, and education as partial mediators of racial disparities in KOOS subscale scores. Insurance status, deformity, radiographic (Kellgren-Lawrence) grade, C-reactive protein level, marital status, body mass index, and income did not show mediating effects. We found that, if age and sex were equal in both cohorts, the racial disparity in KOOS symptom scores would be reduced by 20.7% and 9.1%, respectively (95% confidence intervals [CIs], −5.1% to 47% and −5.5% to 26.3%). For KOOS pain scores, age and education level explained 18.9% and 5.1% of the racial disparity (95% CIs, −0.6% to 37% and −10.8% to 22.9%). Finally, for KOOS activities of daily living scores, education level explained 3.2% of the disparity (95% CI, −19.4% to 26.6%). Conclusions: No single factor in our study completely explained the racial disparity in KOOS scores, but our findings did suggest that several factors can combine to mediate this disparity in outcome scores. Quantification of variables that mediate racial disparity can help to build models for risk adjustment, pinpoint vulnerable populations, and identify primary points of intervention. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Objectives Micro-invasive resin-infiltration has shown to inhibit lesion progression of proximal non-cavitated carious lesions, suggesting an alternative to early operative treatment. This split-mouth, randomized placebo-controlled clinical trial evaluated the effects of proximal lesion infiltration supplementary to standard-of-care management in high caries risk (HCR)-patients. Methods Forty-two HCR-subjects with two similar interproximal posterior lesions received professional HCR-regimen including repeated F-varnish applications. Two affected E2/D1-surfaces were randomized and concurrently treated by resin-infiltration or mock-infiltration (control). Individually standardized digital radiographs provided visual determination of lesion-size distribution at baseline and 2-year follow-up. Data were analyzed by logistic regression and McNemar’s test. Results Thirty-two lesion pairs (76%) were evaluated after 2 years. Categorical lesion depths were not different between groups (P > .5). Comparative pairwise assessment (image sets BL-2 yr) showed significantly more progression in control (7) versus infiltration (1) lesions (P = .035). Cumulative prevented fraction after two years was 97% for infiltrated lesions versus 74% for control lesions. Conclusions Two-year follow-up showed resin infiltration to be a highly efficacious (RRR: 86–89%) therapy. Long-term follow-up is needed to strengthen the evidence for efficacy of resin-infiltration as an adjunct to standard-of-care HCR-regimen including F-varnish. Clinical significance Showing 24% more stabilized lesions, the resin-infiltrated group performed significantly better than their controls, confirming successful early lesion management. Adjunct resin-infiltration provided an effective micro-invasive approach to inhibit short-term lesion progression.

Mediation analysis allows the examination of effects of a third variable in the pathway between an exposure and an outcome. The general multiple mediation analysis method, proposed by Yu et al, improves traditional methods (eg, estimation of natural and controlled direct effects) to enable consideration of multiple mediators/confounders simultaneously and the use of linear and nonlinear predictive models for estimating mediation/confounding effects. In this paper, we extend the method for time-to-event outcomes and apply the method to explore the racial disparity in breast cancer survivals. Breast cancer is the most common cancer and the second leading cause of cancer death among women of all races. Despite improvement of survival rates of breast cancer in the US, a significant difference between white and black women remains. Previous studies have found that more advanced and aggressive tumors and less than optimal treatment may explain the lower survival rates for black women as compared to white women. Due to limitations of current analytic methods and the lack of comprehensive data sets, researchers have not been able to differentiate the relative effect each factor contributes to the overall racial disparity. We use the CDC-funded Patterns of Care study to examine the determinants of racial disparities in breast cancer survival using a novel multiple mediation analysis. Using the proposed method, we applied the Cox hazard model and multiple additive regression trees as predictive models and found that all racial disparity in survival among Louisiana breast cancer patients were explained by factors included in the study.

Objective: The purpose of this study was to determine if changes in dental development are associated with Attention Deficit Hyperactivity Disorder (ADHD) or ADHD medications. Study Design: This retrospective chart review evaluated the dental age of 128 patients between 6 and 16 years of age using the Demirjian method from the following two groups a) children with ADHD b) unaffected children. The ADHD group was further stratified into four groups according to the medication type. The impact of ADHD on dental age difference (the difference between dental age and chronologic age) was analyzed using T-test and the association between medication type and dental age difference was analyzed through one way ANOVA. Results: The mean difference between estimated dental age and chronologic age (dental age difference) for all subjects was 0.80 years. There was no significant dental age difference in subjects with ADHD and the control group (0.78±1.28vs. 0.84 ±1.09 years respectively; P=0.75) and there was no significant difference in dental age difference and type of medication (P=0.84). Conclusion: No significant difference was found between children with ADHD and unaffected children with respect to dental age difference. No significant differences were found in dental age difference in the four medication groups.

Objectives To investigate the race-specific second primary bladder cancer (SPBC) risk following prostatic irradiation. Methods Louisiana residents who were diagnosed with localized prostate cancer (PCa) in 1996–2013 and received surgery or radiation were included. Patients were followed until SPBC diagnosis, death, or Dec. 2018. The exposure variable was type of treatment (radiation only vs. surgery only). The outcome was time from PCa diagnosis to SPBC diagnosis, stratified by race. Fine and Gray’s competing risk model was applied with death as a competing event and adjustment of sociodemographic and tumor characteristics. We used 5 years and 10 years as lag time in the analyses. Results A total of 26,277 PCa patients with a median follow-up of 10.7 years were analyzed, including 18,598 white and 7679 black patients. About 42.9 % of whites and 45.7 % of blacks received radiation. SPBC counted for 1.84 % in the radiation group and 0.90 % in the surgery group among white patients and for 0.91 % and 0.58 %, respectively, among black patients. The adjusted subdistribution hazard ratio of SPBC was 1.80 (95 % CI: 1.30–2.48) for radiation recipients compared to surgery recipients among white patients; 1.93 (95 % CI: 1.36–2.74) if restricted to external beam radiation therapy (EBRT). The SPBC risk was not significantly different between irradiated and surgically treated among blacks. Conclusions The SPBC risk is almost two-fold among white irradiated PCa patients compared to their counterparts treated surgically. Our findings highlight the need for enhanced surveillance for white PCa survivors receiving radiotherapy, especially those received EBRT.

To evaluate the cariogenic properties of almond milk beverages, 6 almond milks, along with soy and whole bovine milk, were analyzed for their abilities to support Streptococcus mutans biofilm formation and acid production, and their capacity to buffer changes in pH. Biofilm formation by S. mutans was analyzed using an in vitro 96-well plate model and measured by crystal violet staining. Acid production by S. mutans was evaluated by a colorimetric L-lactate assay and pH measurement of bacterial cultures. Buffering capacity was assessed by a pH titration assay. Soy milk supported the most biofilm growth, while the least was observed with unsweetened almond milk (both p < 0.001). Among almond milks, sucrose-sweetened milk led to the highest level of biofilm formation (p < 0.001), while the least was observed with unsweetened milk (p < 0.05). Sucrose-sweetened almond milk yielded the lowest pH (4.56 ± 0.66), followed by soy milk and bovine milk; the highest pH was with unsweetened almond milk (6.48 ± 0.5). When analyzed by pH titration, the unsweetened almond milk displayed the weakest buffering capacity while bovine milk showed the highest (p < 0.001). These results suggest that the almond milk beverages, except those that are sweetened with sucrose, possess limited cariogenic properties, while soy milk exhibits the most cariogenic potential. As milk alternatives become increasingly popular, dentists must counsel their patients that almond milks, especially sucrose-sweetened varieties, have cariogenic potential. For patients who are lactose-intolerant or suffer from milk allergy, almond milks may be a better alternative than soy-based products.

Key Points Question What is the increase in the colorectal cancer incidence rate from 49 to 50 years of age when large segments of the population begin average-risk screening? Findings This cross-sectional analysis of colorectal cancer incidence rates in 1-year age increments (30-60 years) from 2000 to 2015 in the Surveillance, Epidemiology, and End Results 18 registries found an incidence rate increase of 46.1% from 49 to 50 years of age. A total of 92.9% of the cases of colorectal cancer diagnosed at 50 years of age were invasive (beyond in situ stage). Meaning Steep incidence increases from 49 to 50 years of age are consistent with preexisting colorectal cancers diagnosed via screening uptake, supporting the presence of a large undetected preclinical case burden in patients younger than 50 years that is not reflected in observed Surveillance, Epidemiology, and End Results incidence rates., Importance Early-onset colorectal cancer incidence rates among patients aged 45 to 49 years have been considered much lower compared with the rates among patients aged 50 to 54 years, prompting debate about earlier screening benefits at 45 years. However, the observed incidence rates in the Surveillance, Epidemiology, and End Results (SEER) registries may underestimate colorectal cancer case burdens in those younger than 50 years compared with those older than 50 years because average-risk screening is generally not performed to detect preclinical cases of colorectal cancer. Finding steep incidence increases of invasive stage (beyond in situ) cases of colorectal cancer from age 49 to 50 years would be consistent with high rates of preexisting, undetected cancers in younger patients ultimately receiving a diagnosis of colorectal cancer after undergoing screening at 50 years. Objective To assess the preclinical burden of colorectal cancer by analyzing its incidence in 1-year age increments, focusing on the transition between ages 49 and 50 years. Design, Setting, and Participants Data from the SEER 18 registries, representing 28% of the US population, were used to conduct a cross-sectional study of colorectal cancer incidence rates from January 1, 2000, to December 31, 2015, in 1-year age increments (ages 30-60 years) stratified by US region (South, West, Northeast, and Midwest), sex, race, disease stage, and tumor location. Statistical analysis was conducted from November 1, 2018, to December 15, 2019. Main Outcomes and Measures Incidence rates of colorectal cancer. Results A total of 170 434 cases of colorectal cancer were analyzed among 165 160 patients (92 247 men [55.9%]; mean [SD] age, 51.6 [6.7] years). Steep increases in the incidence of colorectal cancer in the SEER 18 registries were found from 49 to 50 years of age (46.1% increase: 34.9 [95% CI, 34.1-35.8] to 51.0 [95% CI, 50.0-52.1] per 100 000 population). Steep rate increases from 49 to 50 years of age were also seen in all US regions, men and women, white and black populations, and in colon and rectal cancers. The rate ratio incidence increase in the SEER 18 registries from 49 to 50 years of age (1.46 [95% CI, 1.43-1.51]) was significantly higher than earlier 1-year age transitions. Steep rate increases in the SEER 18 registries were found from 49 to 50 years of age in localized-stage (75.9% increase: 11.2 [95% CI, 10.7-11.7] to 19.7 [95% CI, 19.0-20.3] per 100 000) and regional-stage (30.3% increase: 13.2 [95% CI, 12.7-13.8] to 17.2 [95% CI, 16.7-17.8] per 100 000) colorectal cancers. A total of 8799 of the 9474 cases (92.9%) of colorectal cancer in the SEER 18 registries from 2000 to 2015 that were diagnosed among individuals aged 50 years were invasive. Conclusions and Relevance Steep incidence increases between 49 and 50 years of age are consistent with previously undetected colorectal cancers diagnosed via screening uptake at 50 years. These cancers are not reflected in observed rates of colorectal cancer in the SEER registries among individuals younger than 50 years. Hence, using observed incidence rates from 45 to 49 years of age alone to assess potential outcomes of earlier screening may underestimate cancer prevention benefits., This cross-sectional study uses data from the Surveillance, Epidemiology, and End Results registries to assess the preclinical burden of colorectal cancer by analyzing its incidence in 1-year age increments, focusing on the transition between 49 and 50 years of age.

Introduction Quitting smoking has been proven to benefit smokers with diabetes. However, among older patients with diabetes, the evidence regarding an association between smoking status and the risk of type 2 diabetes mellitus-related emergency department (ED) visits has not been well investigated. Methods A retrospective cohort study was performed by using the Louisiana State University Health Care Services Division electronic health records from 2009 to 2011. Patients aged 65 years or older with type 2 diabetes and smoking status recorded at least twice in 2010 were selected. Selected patients with diabetes were classified into nonsmokers, former smokers, continuing smokers, and relapsed smokers. Cox proportional hazards regression models were used to estimate the adjusted hazard ratio (aHR) of 1-year type 2 diabetes-related ED visits for each group compared with nonsmokers. Results There were 174 (8.2%) continuing smokers and 77 (3.6%) relapsed smokers in 2,114 patients with diabetes who were studied. Rates of type 2 diabetes-related ED visits were highest in relapsed smokers (28.6%). Compared with nonsmokers, relapsed smokers had a significantly higher risk of type 2 diabetes-related ED visits (aHR = 1.62; 95% confidence interval [CI], 1.04-2.50). After stratifying by sex, a significantly increased risk of type 2 diabetes-related ED visits was shown only in male relapsed smokers (aHR = 2.05; 95% CI, 1.13-3.71) and female continuing smokers (aHR = 1.65; 95% CI, 1.10-2.47) compared with nonsmokers. Conclusion Older men with diabetes who were relapsed smokers had a higher risk of type 2 diabetes-related ED visits. Future research and clinical practice should focus on these patients and create more effective interventions for smoking cessation and diabetes management.

PURPOSE: To examine (1) the trend and associated factors of Oncotype DX (ODX) use among hormone receptor-positive (HR+) breast cancer (BC) patients in 2004–2015; (2) the trend of reported chemotherapy by Recurrence Score (RS); and (3) the survival differences associated with ODX use. METHODS: ODX data from Genomic Health Inc. were linked with 17 SEER registries data. HR + BC cases with lymph node negative (N0) or 1–3 positive LNs (N1) from 2004–2015 were analyzed. The Cochrane-Armitage trend test, logistic regression, Kaplan–Meier survival curve, and stratified Cox model were performed. Survival analysis was restricted to HR+/HER2− patients from 2010 to 2014, matched on propensity score. RESULTS: ODX use increased substantially from 2004 to 2015 (N0: 2.0% to 42.7%; N1: 0.3% to 27.9%). Non-Hispanic black and Medicaid insured patients had lower odds of receiving ODX. N0 patients with moderately differentiated or 2.1–5.0 cm tumor and N1 patients with well-differentiated or < 2.0 cm tumor had higher odds of using ODX. The reported chemotherapy use decreased significantly with low and intermediate RS, and increased for high RS among N0 patients. ODX use was associated with better breast cancer-specific survival [hazard ratio (95% CI) N0 1.96 (1.60–2.41), N1 1.90 (1.42–2.54)] and overall survival [N0 2.06 (1.83–2.31), N1 1.72 (1.42–2.09)], especially in the first 36 months. CONCLUSION: ODX use has increased significantly since 2004, nonetheless disparities remain, especially for racial/ethnic minorities and Medicaid insured patients. Administering chemotherapy based on ODX results has been improved among N0 patients. Patients receiving ODX had better survival than those not.

BACKGROUND Facial cellulitis of odontogenic origin (FCOO) can lead to systemic complications in children. Research on factors leading to improvement of outcomes is limited. AIM The aim of this study was to investigate patient characteristics, treatment modalities (antibiotics and route of administration), length of stay in the hospital, time till definitive treatment, and factors related to early treatment of FCOO. DESIGN A retrospective review was performed to identify children presenting to the emergency department of a paediatric hospital with FCOO over a 5-year period. Data were extracted from records of included patients. RESULTS Sixty-four records were included for analysis with mean age of 8.19 ± 4.5 years. Significantly more patients received clindamycin (79.7%) than penicillin-based antibiotic (18.8%) with P

Triple Negative Breast Cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer, which is more frequently diagnosed in African American (AA) women than in European American (EA) women. The purpose of this study is to investigate the role of social determinants in racial disparities in TNBC. Data on Louisiana TNBC patients diagnosed in 2010–2012 were collected and geocoded to census tract of residence at diagnosis by the Louisiana Tumor Registry. Using multilevel statistical models, we analyzed the role of neighborhood concentrated disadvantage index (CDI), a robust measure of physical and social environment, in racial disparities in TNBC incidence, stage at diagnosis, and stage-specific survival for the study population. Controlling for age, we found that AA women had a 2.21 times the incidence of TNBC incidence compared to EA women. Interestingly, the incidence of TNBC was independent of neighborhood CDI and adjusting for neighborhood environment did not impact the observed racial disparity. AA women were more likely to be diagnosed at later stages and CDI was associated with more advanced stages of TNBC at diagnosis. CDI was also significantly associated with poorer stage-specific survival. Overall, our results suggest that neighborhood disadvantage contributes to racial disparities in stage at diagnosis and survival among TNBC patients, but not to disparities in incidence of the disease. Further research is needed to determine the mechanisms through which social determinants affect the promotion and progression of this disease and guide efforts to improve overall survival.

Health disparities research increasingly relies on a social determinants of health approach, which focuses on identifying modifiable social and environmental factors that adversely affect health outcomes to create health disparities. We have used a multilevel framework that leverages cancer registry and US census data to examine the role of neighborhood social determinants in cancer incidence and survival in Louisiana. Multilevel studies of cases of colorectal, liver, and breast cancer reveal that differential exposure to unfavorable social and physical environments do contribute to racial disparities in cancer. In particular, we have observed that concentrated disadvantage, a robust measure of neighborhood environment, was positively associated with the incidence of colorectal cancer and hepatocellular carcinoma but not triple-negative breast cancer. Citation Format: Richard Scribner, Denise Danos, Claudia Leonardi, Tekeda Ferguson, Qingzhao Yu, Neal Simonsen, Xiao-Cheng Wu. Exploring social determinants of cancer outcomes using multilevel spatial analysis [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA08.

Mediation effect refers to the effect conveyed by a third variable, the mediator, to an observed relationship between an exposure and a response variable of interest. Mediation analysis is used widely in fields such as social science, prevention study, behavior research, and epidemiology. For example, it has been well established that low socioeconomic status is associated with poor health status. To reduce this health disparity, investigators would need to quantify the effects, called mediation effects, from different risk factors that intervene in the relationship between the socioeconomic status and health outcomes, so that efficient interventions can be carried out. The general multiple mediation analysis method, proposed by Yu et al., improved traditional methods (e.g., estimation of natural and controlled direct effects) to enable consideration of multiple mediators simultaneously and the use of linear and nonlinear predictive models for estimating mediation effects. A big data set includes a large number of variables. Within big data mediation analysis, the number of potential mediators is big. For example, in explaining the racial disparity in breast cancer survival, there are a lot of risk factors that need to be considered such as individual behaviors, environmental factors, social-economic status, treatment effects, diagnosis characters, and even gene expression variables. In this study, we propose to use a regularized mediation analysis method that identifies significant mediators and estimates their indirect effects simultaneously. Breast cancer is the most common cancer and the second leading cause of cancer death among women of all races. Despite the improvement of survival rates of breast cancer in the U.S., a significant difference between white and black women remains. Due to limitations of current analytic methods and the lack of comprehensive data sets, researchers have not been able to differentiate the relative effect that each factor contributes to the overall racial disparity. We use the CDC-funded Patterns of Care study and Enhancing Cancer Registry Data for Comparative Effectiveness Research study to examine the determinants of racial disparities in breast cancer survival using the propose regularized multiple mediation analysis. Using the proposed method, we identified important factors that explain the racial disparity in breast cancer survival, which includes the cancer stage-related variables (stage, tumor size, lymph nodes involvement, extension, and tumor size), molecular subtype, treatment methods such as surgery and hormonal therapy, and tumor grade. Age also contributed to the racial differences, but in an opposite direction. Black patients are more likely to be diagnosed at a younger age, which is related with better survival outcomes. Overall, we found that all racial disparity in survival among Louisiana breast cancer patients was explained by factors included in the study. Citation Format: Qingzhao Yu, Lu Zhang, Meichin Hsieh, Xiaocheng Wu, Richard A Scribner, Bin Li. Regularized multiple mediation analysis for big data set—With an application to explore racial disparity in breast cancer survival [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C020.

PURPOSE: To investigate the impact of chemotherapy relative dose intensity (RDI) on cause-specific and overall survival for stage I–III breast cancer: estrogen receptor or progesterone receptor positive, human epidermal-growth factor receptor negative (ER+/PR+ and HER2−) vs. triple-negative (TNBC) and to identify the optimal RDI cut-off points in these two patient populations. METHODS: Data were collected by the Louisiana Tumor Registry for two CDC-funded projects. Women diagnosed with stage I–III ER+/PR+, HER2− breast cancer, or TNBC in 2011 with complete information on RDI were included. Five RDI cut-off points (95, 90, 85, 80, and 75%) were evaluated on cause-specific and overall survival, adjusting for multiple demographic variables, tumor characteristics, comorbidity, use of granulocyte-growth factor/cytokines, chemotherapy delay, chemotherapy regimens, and use of hormone therapy. Cox proportional hazards models and Kaplan–Meier survival curves were estimated and adjusted by stabilized inverse probability treatment weighting (IPTW) of propensity score. RESULTS: Of 494 ER+/PR+, HER2− patients and 180 TNBC patients, RDI < 85% accounted for 30.4 and 27.8%, respectively. Among ER+/PR+, HER2− patients, 85% was the only cut-off point at which the low RDI was significantly associated with worse overall survival (HR = 1.93; 95% CI 1.09–3.40). Among TNBC patients, 75% was the cut-off point at which the high RDI was associated with better cause-specific (HR = 2.64; 95% CI 1.09, 6.38) and overall survival (HR = 2.39; 95% CI 1.04–5.51). CONCLUSIONS: Higher RDI of chemotherapy is associated with better survival for ER+/PR+, HER2− patients and TNBC patients. To optimize survival benefits, RDI should be maintained ≥ 85% in ER+/PR+, HER2− patients, and ≥ 75% in TNBC patients.

Research shows aconsistent racial disparity in obesity between white and black adults in the United States. Accounting for the disparity is a challenge given the variety of the contributing factors, the nature of the association, and the multilevel relationships among the factors. We used the multivariable mediation analysis (MMA) method to explore the racial disparity in obesity considering not only the individual behavior but also geospatially derived environmental risk factors. Results from generalized linear models (GLM) were compared with those from multiple additive regression trees (MART) which allow for hierarchical data structure, and fitting of nonlinear and complex interactive relationships. As results, both individual and geographically defined factors contributed to the racial disparity in obesity. MART performed better than GLM models in that MART explained a larger proportion of the racial disparity in obesity. However, there remained disparities that cannot be explained by factors collected in this study.

Persistent postconcussion syndrome (PPCS) after mild traumatic brain injury (mTBI) is a significant public health and military problem for which there is limited treatment evidence. The aim of this study was to determine whether forty 150 kPa hyperbaric oxygen therapies (HBOTs) can improve symptoms and cognitive function in subjects with the PPCS of mTBI, using a randomized controlled crossover design with 2-month follow-up. Sixty-three civilian and military subjects with mTBI/PPCS were randomized to either 40 HBOTs at 150 kPa/60 minutes, once daily, 5 days per week in 8 weeks or an equivalent no-treatment control period. The Control Group was then crossed over to HBOT. Subjects underwent symptom, neuropsychological, and psychological testing, before and after treatment or control with retesting 2 months after the 40th HBOT. Fifty subjects completed the protocol with primary outcome testing. HBOT subjects experienced significant improvements in Neurobehavioral Symptom Inventory, Memory Index, Automated Neuropsychological Assessment Metrics, Hamilton Depression Scale, Hamilton Anxiety Scale, Post-Traumatic Stress Disorder Checklist, Pittsburgh Sleep Quality Index, and Quality Of Life after Brain Injury compared to the Control Group. After crossing over to HBOT the Control Group experienced near-identical significant improvements. Further improvements were experienced by both groups during the 2-month follow-up period. These data indicate that 40 HBOTs at 150 kPa/60 minutes demonstrated statistically significant improvements in postconcussion and Post-Traumatic Stress Disorder symptoms, memory, cognitive functions, depression, anxiety, sleep, and quality of life in civilian and military subjects with mTBI/PPCS compared to controls. Improvements persisted at least 2 months after the 40th HBOT. The study was registered on ClinicalTrials.gov (NCT02089594) on March 18, 2014 and with the U.S. Food and Drug Administration under Investigational New Drug #113823. The Institutional Review Boards of the United States Army Medical Research and Materiel Command Office of Research Protections Human Research Protection Office and the Louisiana State University School of Medicine (approval No. 7381) approved the study on May 13, 2014 and December 20, 2013, respectively.

Purpose: Radiation therapy has been found associated with increased risk of secondary bladder cancer diagnosis among prostate cancer patients. It is unknown whether this association varies by race. This study aimed to investigate whether the association between radiation and secondary bladder cancer differs for white vs. black prostate cancer patients. Methods: Data on white or black men who were diagnosed with primary localized prostate cancer in Louisiana between 2004 and 2013 and received radiation only or surgery only were obtained from Louisiana Tumor Registry. We excluded those who developed secondary bladder cancer within 180 days of the prostate cancer diagnosis or had follow-up less than 180 days or with unknown tumor size or Gleason score. Every patient was followed up until the end of 2016. The exposure variable was treatment (radiation only vs. surgery only). The outcome variable was the diagnosis of secondary bladder cancer and the time from prostate cancer diagnosis to secondary bladder cancer diagnosis or to loss to or end of follow-up. Covariates included age at diagnosis, marital status, insurance, census tract level poverty, tumor size, and Gleason score group. The competing risk survival analysis was applied. Death during follow-up was considered as competing event. Analysis was stratified by race. Results: Of 10,861 white and 5,117 black prostate cancer patients, 52.7% and 56.8% received only radiation respectively. Regardless of race, patients who only received surgery were younger, more likely to be married, privately insured, live in low poverty census tract, and have smaller or lower grade tumor (P Conclusions: Radiation is associated with increased risk of secondary bladder cancer among white prostate cancer patients, but not among black patients. Early screening of secondary bladder cancer need to be emphasized among white prostate cancer patients who received radiation therapy. Citation Format: Lu Zhang, Mei-Chin Hsieh, Qingzhao Yu, Xiao-Cheng Wu. Racial difference in the risk of secondary bladder cancer following radiation therapy among prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4204.

Background Adherence to self-management recommendations is critical for patients with chronic disease. Compared to nonsmokers, smokers with conditions such as diabetes, HIV, and heart disease are less likely to adhere to provider recommendations. Regarding lung disease, asthma and COPD can be caused and/or exacerbated by smoking, however little is known on the relationship between adherence and smoking status in these patients. The purpose of this study was to characterize the relationship between smoking status and adherence to multiple measures of self-care- including medication taking, medication filling, appointment keeping, yearly vaccinations, carrying medical supplies, and healthcare utilization- in patients with asthma and/or COPD. In addition to smoking status, we also included an examination of these measures by race/ethnicity, gender, and diagnosis. Methods This study employed a cross-sectional design on a convenience sample of n = 84 patients (40–64 years old) with a diagnosis of asthma and/or COPD. The study was conducted between November 2015 and February 2016 in the waiting rooms of the outpatient pulmonary clinics at the University Medical Center of New Orleans. Patients completed surveys while awaiting their clinic appointments. Smoking status, gender, race, and diagnosis were explored as predictors of adherence using descriptive statistics, chi square, and regression analyses. Results Compared to nonsmokers, smokers were less adherent to medication filling (p

Introduction This study aimed to determine the feasibility of using electronic health record (EHR) data from a federally qualified health center (FQHC) to assess the association between street connectivity, a measure of walkability for the local environment, and BMI obtained from EHRs. Methods The study included patients who visited Daughters of Charity clinics in 2012–2013. A total of 31,297 patients were eligible, of which 28,307 were geocoded. BMI and sociodemographic information were compiled into a de-identified database. The street connectivity measure was intersection density, calculated as the number of three-way or greater intersections per unit area. Multilevel analyses of BMI, measured on 17,946 patients who were aged ≥20 years, not pregnant, had complete sociodemographic information, and a BMI value that was not considered an outlier, were conducted using random intercept models. Results Overall, on average, patients were aged 44.1 years, had a BMI of 30.2, and were mainly non-Hispanic black (59.4%). An inverse association between BMI and intersection density was observed in multilevel models controlling for age, gender, race, and marital status. Tests for multiple interactions were conducted and a significant interaction between race and intersection density indicated the decrease in BMI was strongest for non-Hispanic whites (decreased by 2) compared with blacks or Hispanics (decreased by 0.6) ( p =0.0121). Conclusions EHRs were successfully used to assess the relationship between street connectivity and BMI in a multilevel framework. Increasing street connectivity levels measured as intersection density were inversely associated with directly measured BMI obtained from EHRs, demonstrating the feasibility of the approach.

Accurate cancer stage at diagnosis is essential not only for assessing quality of care and associated prognosis but also for monitoring trends in cancer stages and for assessing effectiveness of early detection interventions. Because the cancer stage is associated with many factors that are not under control of cancer registries, it is infeasible to completely record stages in all cases from registry database. It is necessary to reduce the bias in stage analysis induced by unknown stage cases through statistical adjustment. In this paper, we propose a new adaptive robust method that estimates the distribution of unknown stage cases using both essential and nonessential predictors of cancer stage. Multiple additive regression trees were used to assess the association of explanatory variables (including patient demographics, tumor characteristics, and treatment) with unknown stage. The 2004-2009 incidence data on invasive lung cancer from 38 population-based cancer registries that met NAACCR’s high data quality criteria were used to estimate the population stage distribution of lung cancer over the years. Multiple artificial incomplete datasets with unknown stages and predictors were created from the complete datasets, with varying missing data mechanism and different proportions of missingness. The simulated datasets were used to test the efficiency of the proposed method in estimating population stage distribution. In general, the proposed method is more efficient in terms of estimation accuracy and time consumption, compared with the traditional methods such as multiple imputation method and weighting method.

Mediation refers to the effect transmitted by mediators that intervenes in the relationship between an exposure and a response variable. Mediation analysis has been broadly studied in many fields. However, it remains a challenge for researchers to differentiate individual effect from multiple mediators. This paper proposes general definitions of mediation effects that are consistent for all different types (categorical or continuous) of response, exposure, or mediation variables. With these definitions, multiple mediators can be considered simultaneously, and the indirect effects carried by individual mediators can be separated from the total effect. Moreover, the derived mediation analysis can be performed with general predictive models. For linear predictive models with continuous mediators, we show that the proposed method is equivalent to the conventional coefficients product method. We also establish the relationship between the proposed definitions of direct or indirect effect and the natural direct or indirect effect for binary exposure variables. The proposed method is demonstrated by both simulations and a real example examining racial disparities in three-year survival rates for female breast cancer patients in Louisiana.

154 Background: Identification of distinct molecular subtypes has expanded the treatment options for breast cancer, however, chemotherapy remains the common and effective treatment for each subtype. The objective is to compare the frequency and predictors of insufficient chemotherapy use among two subtypes of stage I-III breast cancer patients: luminal A and triple negative breast cancer (TNBC). Methods: We analyzed data from a CDC funded project - Enhancing Cancer Registry Data for Comparative Effectiveness Research (CER) collected by Louisiana Tumor Registry. Women aged < = 70 years, diagnosed in 2011 with stage I-III luminal A or TNBC breast cancer, tumor size > 1cm, were included (N = 1,189). Insufficient chemotherapy (i.e. no chemotherapy use, nonstandard regimen use, and low relative dose intensity (RDI < 85%)) was evaluated respectively. Potential predictors included age, race, insurance, marital status, census tract-poverty, AJCC stage, grade, tumor size, lymph node status, and Charlson comorbidity. Stepwise model selection with p-value for entry at 0.2 and for stay at 0.25 was used to select the most relevant predictors. Results: The frequencies of no chemotherapy use were significantly different (p < .0001) between luminal A (42%, N = 913) and TNBC patients (9%, N = 241). Older age, white race, no insurance, lower stage or grade, and without lymph node involvement were related with no chemotherapy for luminal A patients; older age, not married, and high poverty for TNBC. There were 36% of luminal A and 40% of TNBC patients receiving nonstandard regimen (p = 0.27). Predictors of nonstandard regimen use were increased age, insurance, stage, and grade for luminal A and high poverty level and stage for TNBC. Reduced RDI occurred in 9% luminal A and 10% TNBC patients (p = 0.61). Small cases precluded the prediction model for low RDI. Conclusions: Luminal A patients are less likely to receive chemotherapy than TNBC patients. Low social economic status factors are associated with no chemotherapy use and nonstandard regimens use, especially for TNBC patients.

Many previous studies have suggested a link between alcohol outlets and assaultive violence. In this paper, we evaluate the impact of the “1992 Civil Unrest” in Los Angeles (which followed the “Rodney King incident”), in which many alcohol outlets were damaged leading to a decrease in alcohol outlet density, on crime. We leverage the natural experiment created by the closure of alcohol outlets in certain areas and not others to explore the effects of alcohol availability on assault crimes at the census tract level. We develop a hierarchical model that controls for important covariates (such as race and socio-economic status) and accounts for unexplained spatial and temporal variability. While our model is somewhat complex, its hierarchical Bayesian analysis is accessible via the WinBUGS software. Our results show that, keeping other effects fixed, the reduction in alcohol availability within a census tract was associated with a drop in the assaultive violence rate at the census tract level. Comparing several dual candidate changepoint models using the Deviance Information Criterion, the drop in assaultive violence rate is best seen as having occurred one year after the reduction in alcohol availability, with the effect lasting roughly five years. We also create maps of the fitted assault rates in Los Angeles, as well as spatial residual maps that suggest various spatially-varying covariates are still missing from our model.