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Item A Review of Research on Disparities in the Care of Black and White Patients With Cancer in Detroit(Frontiers Media, 2021-07-07) Simon, Michael S.; Raychaudhuri, Sreejata; Hamel, Lauren M.; Penner, Louis A.; Schwartz, Kendra L.; Harper, Felicity W. K.; Thompson, Hayley S.; Booza, Jason C.; Cote, Michele; Schwartz, Ann G.; Eggly, Susan; Epidemiology, Richard M. Fairbanks School of Public HealthRacial disparities in cancer incidence and outcomes are well-documented in the US, with Black people having higher incidence rates and worse outcomes than White people. In this review, we present a summary of almost 30 years of research conducted by investigators at the Karmanos Cancer Institute's (KCI's) Population Studies and Disparities Research (PSDR) Program focusing on Black-White disparities in cancer incidence, care, and outcomes. The studies in the review focus on individuals diagnosed with cancer from the Detroit Metropolitan area, but also includes individuals included in national databases. Using an organizational framework of three generations of studies on racial disparities, this review describes racial disparities by primary cancer site, disparities associated with the presence or absence of comorbid medical conditions, disparities in treatment, and disparities in physician-patient communication, all of which contribute to poorer outcomes for Black cancer patients. While socio-demographic and clinical differences account for some of the noted disparities, further work is needed to unravel the influence of systemic effects of racism against Black people, which is argued to be the major contributor to disparate outcomes between Black and White patients with cancer. This review highlights evidence-based strategies that have the potential to help mitigate disparities, improve care for vulnerable populations, and build an equitable healthcare system. Lessons learned can also inform a more equitable response to other health conditions and crises.Item Analyzing Perceptions of Community-Engaged Health Research Partnerships Comprising Hispanic Groups and Academic Allies in Indiana(IUI Office of Community Engagement, 2022) Gil, Cindy; Armenta, Karla; Espada, Camila; Ontiveros-Salinas, Leonel; Maupome, Gerardo; Epidemiology, Richard M. Fairbanks School of Public HealthObjectives: To analyze perceptions about multiple community-engaged oral health research partnerships with various local Hispanic-serving institutions and community-based organizations occurring in Indiana from 2010 through 2020, via interviews with actors involved in those partnerships. Methods: We designed key informant interview questions based on a literature review to inform the approach at synthesizing perspectives from community partners and academic allies. Statements were categorized using thematic analysis and grounded theory. Lessons Learned: Forty percent of respondents stated that community-engaged research projects connect communities with educational information about dental care and low-cost resources. In terms of capacity building, about half of respondents felt these projects had a positive impact. Conclusions: Community partners defined positive impact as increasing access to dental care educational resources, helping to enhance communication networks through social media with community partners, and contributing to local Hispanic health education through TV, internet, and radio partnerships. The partnerships uniting Hispanic groups and academic allies appear to have helped set a foundation of trust to support current and future efforts in Indiana.Item Racial Differences in the Tumor Immune Landscape and Survival of Women with High-Grade Serous Ovarian Carcinoma(American Association for Cancer Research, 2022) Peres, Lauren C.; Colin-Leitzinger, Christelle; Sinha, Sweta; Marks, Jeffrey R.; Conejo-Garcia, Jose R.; Alberg, Anthony J.; Bandera, Elisa V.; Berchuck, Andrew; Bondy, Melissa L.; Christensen, Brock C.; Cote, Michele L.; Doherty, Jennifer Anne; Moorman, Patricia G.; Peters, Edward S.; Segura, Carlos Moran; Nguyen, Jonathan V.; Schwartz, Ann G.; Terry, Paul D.; Wilson, Christopher M.; Fridley, Brooke L.; Schildkraut, Joellen M.; Epidemiology, Richard M. Fairbanks School of Public HealthBackground: Tumor-infiltrating lymphocytes (TIL) confer a survival benefit among patients with ovarian cancer; however, little work has been conducted in racially diverse cohorts. Methods: The current study investigated racial differences in the tumor immune landscape and survival of age- and stage-matched non-Hispanic Black and non-Hispanic White women with high-grade serous ovarian carcinoma (HGSOC) enrolled in two population-based studies (n = 121 in each racial group). We measured TILs (CD3+), cytotoxic T cells (CD3+CD8+), regulatory T cells (CD3+FoxP3+), myeloid cells (CD11b+), and neutrophils (CD11b+CD15+) via multiplex immunofluorescence. Multivariable Cox proportional hazard regression was used to estimate the association between immune cell abundance and survival overall and by race. Results: Overall, higher levels of TILs, cytotoxic T cells, myeloid cells, and neutrophils were associated with better survival in the intratumoral and peritumoral region, irrespective of tissue compartment (tumor, stroma). Improved survival was noted for T-regulatory cells in the peritumoral region and in the stroma of the intratumoral region, but no association for intratumoral T-regulatory cells. Despite similar abundance of immune cells across racial groups, associations with survival among non-Hispanic White women were consistent with the overall findings, but among non-Hispanic Black women, most associations were attenuated and not statistically significant. Conclusions: Our results add to the existing evidence that a robust immune infiltrate confers a survival advantage among women with HGSOC; however, non-Hispanic Black women may not experience the same survival benefit as non-Hispanic White women with HGSOC. Impact: This study contributes to our understanding of the immunoepidemiology of HGSOC in diverse populations.Item Psychosocial factors associated with genetic testing status among African American women with ovarian cancer: Results from the African American Cancer Epidemiology Study(Wiley, 2022) McBride, Colleen M.; Pathak, Sarita; Johnson, Courtney E.; Alberg, Anthony J.; Bandera, Elisa V.; Barnholtz-Sloan, Jill S.; Bondy, Melissa L.; Cote, Michele L.; Moorman, Patricia G.; Peres, Lauren C.; Peters, Edward S.; Schwartz, Ann G.; Terry, Paul D.; Schildkraut, Joellen M.; Epidemiology, Richard M. Fairbanks School of Public HealthBackground: Racial disparities in the uptake of cancer genetic services are well documented among African American (AA) women. Understanding the multiple social and psychological factors that can influence the uptake of genetic testing among AA women is needed. Methods: Data came from 270 AA women diagnosed with ovarian cancer and participating in a population-based, case-control study of ovarian cancer who were asked about genetic testing. Logistic regression analyses tested the associations of predisposing, enabling, and need factors with reported genetic testing uptake. Results: One-third of the sample (35%) reported having had genetic testing. In the multivariable model, AA women with higher incomes had more than double the odds of being tested than those with the lowest income (odds ratio [OR] for $25,000-$74,999, 2.04; 95% confidence interval [CI], 1.06-3.99; OR for ≥$75,000, 2.32; 95% CI, 0.92-5.94). AA women who reported employment discrimination were significantly less likely to report genetic testing than those who did not report job discrimination (OR, 0.39; 95% CI, 0.14-0.95). Marital status, Medicaid versus other insurance, prayer frequency, and perceived social support were significantly associated with genetic testing uptake in bivariate analyses but were not significant contributors in multivariable analyses. Conclusions: Consistent with other studies of AA women, a minority of African American Cancer Epidemiology Study participants had undergone genetic testing. Having a lower income and experiencing job discrimination decreased the likelihood of testing. These results provide foundational evidence supporting the need for interventions to improve the uptake of genetic testing among AA women by reducing cost barriers and providing credible assurances that genetic results will be kept private and not affect social factors such as employability.Item Trends and racial disparities in aggressive end of life care for a national sample of women with ovarian cancer(Wiley, 2021) Mullins, Megan A.; Ruterbusch, Julie J.; Clarke, Philippa; Uppal, Shitanshu; Wallner, Lauren P.; Cote, Michele L.; Epidemiology, Richard M. Fairbanks School of Public HealthBackground: The clinical landscape has moved toward less aggressive end-of-life care for women with ovarian cancer. However, whether there has been a decline in the use of aggressive end-of-life services is unknown. The authors evaluated current national trends and racial disparities in end-of-life care among women with ovarian cancer using the Surveillance, Epidemiology, and End Results-Medicare-linked data set. Methods: In total, 7756 Medicare beneficiaries aged >66 years with ovarian cancer who died between 2007 and 2016 were identified. The authors examined trends and racial disparities in late hospice or no hospice use, >1 emergency department (ED) visit, intensive care unit admission, >1 hospitalization, terminal hospitalization, chemotherapy, and invasive and/or life-extending procedures using multivariable logistic regression. Results: The median hospice length of stay did not change over time; however, women were increasingly admitted to the intensive care unit and had multiple ED visits in the last month of life (P < .001). Not enrolling in hospice at the end of life and terminal hospitalizations decreased over time (P < .001). Non-White women were more likely to receive aggressive end-of-life care, particularly for hospital-related utilization and life-extending procedures, whereas non-Hispanic Black women were more likely to have >1 ED visit (odds ratio, 2.04; 95% CI, 1.57-2.64) or life-extending procedures (odds ratio, 1.89; 95% CI, 1.45-2.48) compared with non-Hispanic White women. Conclusions: Despite clinical guidelines and increasing emphasis on reducing aggressive end-of-life care, the use of aggressive end-of-life care for women with ovarian cancer persists, and care is most aggressive for non-White women.Item Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response(American Association for Cancer Research, 2023) Carreras-Torres, Robert; Kim, Andre E.; Lin, Yi; Díez-Obrero, Virginia; Bien, Stephanie A.; Qu, Conghui; Wang, Jun; Dimou, Niki; Aglago, Elom K.; Albanes, Demetrius; Arndt, Volker; Baurley, James W.; Berndt, Sonja I.; Bézieau, Stéphane; Bishop, D. Timothy; Bouras, Emmanouil; Brenner, Hermann; Budiarto, Arif; Campbell, Peter T.; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Chen, Xuechen; Conti, David V.; Dampier, Christopher H.; Devall, Matthew A. M.; Drew, David A.; Figueiredo, Jane C.; Gallinger, Steven; Giles, Graham G.; Gruber, Stephen B.; Gsur, Andrea; Gunter, Marc J.; Harrison, Tabitha A.; Hidaka, Akihisa; Hoffmeister, Michael; Huyghe, Jeroen R.; Jenkins, Mark A.; Jordahl, Kristina M.; Kawaguchi, Eric; Keku, Temitope O.; Kundaje, Anshul; Le Marchand, Loic; Lewinger, Juan Pablo; Li, Li; Mahesworo, Bharuno; Morrison, John L.; Murphy, Neil; Nan, Hongmei; Nassir, Rami; Newcomb, Polly A.; Obón-Santacana, Mireia; Ogino, Shuji; Ose, Jennifer; Pai, Rish K.; Palmer, Julie R.; Papadimitriou, Nikos; Pardamean, Bens; Peoples, Anita R.; Pharoah, Paul D. P.; Platz, Elizabeth A.; Rennert, Gad; Ruiz-Narvaez, Edward; Sakoda, Lori C.; Scacheri, Peter C.; Schmit, Stephanie L.; Schoen, Robert E.; Shcherbina, Anna; Slattery, Martha L.; Stern, Mariana C.; Su, Yu-Ru; Tangen, Catherine M.; Thomas, Duncan C.; Tian, Yu; Tsilidis, Konstantinos K.; Ulrich, Cornelia M.; van Duijnhoven, Fränzel J. B.; Van Guelpen, Bethany; Visvanathan, Kala; Vodicka, Pavel; Wawan Cenggoro, Tjeng; Weinstein, Stephanie J.; White, Emily; Wolk, Alicja; Woods, Michael O.; Hsu, Li; Peters, Ulrike; Moreno, Victor; Gauderman, W. James; Epidemiology, Richard M. Fairbanks School of Public HealthBackground: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. Impact: These findings can guide potential prevention treatments.Item A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO(Springer Nature, 2021) Blackford, Amanda L.; Childs, Erica J.; Porter, Nancy; Petersen, Gloria M.; Rabe, Kari G.; Gallinger, Steven; Borgida, Ayelet; Syngal, Sapna; Cote, Michele L.; Schwartz, Ann G.; Goggins, Michael G.; Hruban, Ralph H.; Parmigiani, Giovanni; Klein, Alison P.; Epidemiology, Richard M. Fairbanks School of Public HealthIntroduction: Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO) and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility. Methods: We expanded the existing framework for PANCPRO and BRCAPRO to jointly model risk of pancreatic, breast, and ovarian cancer and validated this new model, BRCAPANCPRO on three data sets each reflecting the common target populations. Results: BRCAPANCPRO outperformed the prior BRCAPRO and PANCPRO models and yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUCs 0.79, 95% CI: 0.73-0.84 and 0.70, 95% CI: 0.60-0.80) in families seen in high-risk clinics and pancreatic cancer family registries, respectively. In addition, BRCAPANCPRO was reasonably well calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.81 [0.69, 0.94]). Discussion: The BRCAPANCPRO model provides improved risk assessment over our previous risk models, particularly for pedigrees with a co-occurrence of pancreatic cancer and breast and/or ovarian cancer.Item Disparities in Adjuvant Treatment of High-Grade Endometrial Cancer in the Medicare Population(Elsevier, 2022) Corey, Logan; Cote, Michele L.; Ruterbusch, Julie J.; Winer, Ira; Epidemiology, Richard M. Fairbanks School of Public HealthBackground: Black women experience worse survival effects with high-grade endometrial cancer. Differences in adjuvant treatment have been proposed to be major contributors to this disparity. However, little is known about the differences in type or timing of adjuvant treatment as it relates to race and ethnicity in the Medicare population. Objective: This study aimed to examine patterns of adjuvant therapy and survival for non-Hispanic Black women vs non-Hispanic White women and Hispanic women who have undergone surgery for high-grade endometrial cancer in the Medicare population. Study design: We used the Medicare-linked Surveillance, Epidemiology, and End Results database to identify women who underwent surgery as a primary treatment for uterine grade 3 endometrioid adenocarcinoma, carcinosarcoma, clear-cell carcinoma, or serous carcinoma between the years 2000 and 2015. Women who did not identify as White or Black race or Hispanic ethnicity were excluded. Multinomial logistic regression was used to estimate odds ratios and 95% confidence intervals for receiving a treatment delay or not receiving adjuvant treatment (compared with those who received adjuvant treatment within 12 weeks) adjusted for clinical and demographic characteristics. Overall survival was stratified by race and ethnicity, route of surgery, operative complications, and type and timing of adjuvant therapy, which were analyzed using the Kaplan-Meier method. Cox proportional-hazards regression was used to estimate the hazard ratio of death by race and ethnicity adjusted for known predictors and surgical outcomes and adjuvant therapy patterns. Results: A total of 12,201 women met the study inclusion criteria. Non-Hispanic Black patients had a significantly worse 5-year overall survival than Hispanic and non-Hispanic White patients (30.9 months vs 51.0 months vs 53.6 months, respectively). Approximately 632 of 7282 patients (8.6%) who received adjuvant treatment experienced a treatment delay. Delay in treatment of ≥12 weeks was significantly different by race and ethnicity (P=.034), with 12% of Hispanic, 9% of non-Hispanic Black, and 8% of non-Hispanic White women experiencing a delay. After adjustment for the number of complications, age, histology (endometrioid vs nonendometroid), International Federation of Gynecology and Obstetrics stage, marital status, comorbidity count, surgical approach, lymph node dissection, and urban-rural code, Hispanic women had a 71% increased risk of treatment delay (odds ratio, 1.71; 95% confidence interval, 1.23-2.38) for all stages of disease. In the same model, non-Hispanic Black race was independently predictive of decreased use of adjuvant treatment for the International Federation of Gynecology and Obstetrics stage II and higher (odds ratio, 1.32; 95% confidence interval, 1.04-1.68). Non-Hispanic Black race, number of perioperative complications, and nonendometrioid histology were predictive of worse survival in univariate models. Treatment delay was not independently predictive of worse 1- or 5-year survival at any stage. Conclusion: Non-Hispanic Black race was predictive of worse 5-year survival across all stages and was associated with omission of adjuvant treatment in International Federation of Gynecology and Obstetrics stage II or higher high-grade endometrial cancer. In unadjusted analyses, patients who experience treatment omission or delay experienced poorer overall survival, but these factors were not independently associated in multivariate analyses. This study suggests that race and ethnicity are independently associated with the type and timing of adjuvant treatment in patients with high-grade endometrial cancer. Further efforts to identify specific causes of barriers to care and timely treatment are imperative.Item Trends in hospice referral timing and location among individuals dying of ovarian cancer: persistence of missed opportunities(BMJ, 2023-07-03) Mullins, Megan A.; Ruterbusch, Julie J.; Cote, Michele L.; Uppal, Shitanshu; Wallner, Lauren P.; Epidemiology, Richard M. Fairbanks School of Public HealthObjective: To evaluate trends, racial disparities, and opportunities to improve the timing and location of hospice referral for women dying of ovarian cancer. Methods: This retrospective claims analysis included 4258 Medicare beneficiaries over age 66 diagnosed with ovarian cancer who survived at least 6 months after diagnosis, died between 2007 and 2016, and enrolled in a hospice. We examined trends in timing and clinical location (outpatient, inpatient hospital, nursing/long-term care, other) of hospice referrals and associations with patient race and ethnicity using multivariable multinomial logistic regression. Results: In this sample, 56% of hospice enrollees were referred to a hospice within a month of death, and referral timing did not vary by patient race. Referrals were most commonly inpatient hospital (1731 (41%) inpatient, 703 (17%) outpatient, 299 (7%) nursing/long-term care, 1525 (36%) other), with a median of 6 inpatient days prior to hospice enrollment. Only 17% of hospice referrals were made in an outpatient clinic, but participants had a median of 1.7 outpatient visits per month in the 6 months prior to hospice referral. Referral location varied by patient race, with non-Hispanic black people experiencing the most inpatient referrals (60%). Hospice referral timing and location trends did not change between 2007 and 2016. Compared with individuals referred to a hospice in an outpatient setting, individuals referred from an inpatient hospital setting had more than six times the odds of a referral in the last 3 days of life (OR=6.5, 95% CI 4.4 to 9.8) versus a referral more than 90 days before death. Conclusion: Timeliness of hospice referral is not improving over time despite opportunities for earlier referral across multiple clinical settings. Future work delineating how to capitalize on these opportunities is essential for improving the timeliness of hospice care.Item MMP-3 mediates copper oxide nanoparticle-induced pulmonary inflammation and fibrosis(Springer Nature, 2024-07-19) Zhang, Yuanbao; Zhang, Zhenyu; Mo, Yiqun; Zhang, Yue; Yuan, Jiali; Zhang, Qunwei; Epidemiology, Richard M. Fairbanks School of Public HealthBackground: The increasing production and usage of copper oxide nanoparticles (Nano-CuO) raise human health concerns. Previous studies have demonstrated that exposure to Nano-CuO could induce lung inflammation, injury, and fibrosis. However, the potential underlying mechanisms are still unclear. Here, we proposed that matrix metalloproteinase-3 (MMP-3) might play an important role in Nano-CuO-induced lung inflammation, injury, and fibrosis. Results: Exposure of mice to Nano-CuO caused acute lung inflammation and injury in a dose-dependent manner, which was reflected by increased total cell number, neutrophil count, macrophage count, lactate dehydrogenase (LDH) activity, and CXCL1/KC level in bronchoalveolar lavage fluid (BALF) obtained on day 3 post-exposure. The time-response study showed that Nano-CuO-induced acute lung inflammation and injury appeared as early as day 1 after exposure, peaked on day 3, and ameliorated over time. However, even on day 42 post-exposure, the LDH activity and macrophage count were still higher than those in the control group, suggesting that Nano-CuO caused chronic lung inflammation. The Nano-CuO-induced pulmonary inflammation was further confirmed by H&E staining of lung sections. Trichrome staining showed that Nano-CuO exposure caused pulmonary fibrosis from day 14 to day 42 post-exposure with an increasing tendency over time. Increased hydroxyproline content and expression levels of fibrosis-associated proteins in mouse lungs were also observed. In addition, Nano-CuO exposure induced MMP-3 overexpression and increased MMP-3 secretion in mouse lungs. Knocking down MMP-3 in mouse lungs significantly attenuated Nano-CuO-induced acute and chronic lung inflammation and fibrosis. Moreover, Nano-CuO exposure caused sustained production of cleaved osteopontin (OPN) in mouse lungs, which was also significantly decreased by knocking down MMP-3. Conclusions: Our results demonstrated that short-term Nano-CuO exposure caused acute lung inflammation and injury, while long-term exposure induced chronic pulmonary inflammation and fibrosis. Knocking down MMP-3 significantly ameliorated Nano-CuO-induced pulmonary inflammation, injury, and fibrosis, and also attenuated Nano-CuO-induced cleaved OPN level. Our study suggests that MMP-3 may play important roles in Nano-CuO-induced pulmonary inflammation and fibrosis via cleavage of OPN and may provide a further understanding of the mechanisms underlying Nano-CuO-induced pulmonary toxicity.