Social determinants of health and US cancer screening interventions: A systematic review.

There remains a need to synthesize linkages between social determinants of health (SDOH) and cancer screening to reduce persistent inequities contributing to the US cancer burden. The authors conducted a systematic review of US-based breast, cervical, colorectal, and lung cancer screening intervention studies to summarize how SDOH have been considered in interventions and relationships between SDOH and screening. Five databases were searched for peer-reviewed research articles published in English between 2010 and 2021. The Covidence software platform was used to screen articles and extract data using a standardized template. Data items included study and intervention characteristics, SDOH intervention components and measures, and screening outcomes. The findings were summarized using descriptive statistics and narratives. The review included 144 studies among diverse population groups. SDOH interventions increased screening rates overall by a median of 8.4 percentage points (interquartile interval, 1.8-18.8 percentage points). The objective of most interventions was to increase community demand (90.3%) and access (84.0%) to screening. SDOH interventions related to health care access and quality were most prevalent (227 unique intervention components). Other SDOH, including educational, social/community, environmental, and economic factors, were less common (90, 52, 21, and zero intervention components, respectively). Studies that included analyses of health policy, access to care, and lower costs yielded the largest proportions of favorable associations with screening outcomes. SDOH were predominantly measured at the individual level. This review describes how SDOH have been considered in the design and evaluation of cancer screening interventions and effect sizes for SDOH interventions. Findings may guide future intervention and implementation research aiming to reduce US screening inequities.

Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1.

Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify nongenetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.

Barriers, facilitators, and priority needs related to cancer prevention, control, and research in rural, persistent poverty areas.

PURPOSE: The purpose of this study was to identify the barriers, facilitators, and priority needs related to cancer prevention, control, and research in persistent poverty areas. METHODS: We conducted three focus groups with 17 providers and staff of primary care clinics serving persistent poverty areas throughout the state of Arkansas. RESULTS: We identified multiple barriers, facilitators, and priority needs related to cancer prevention and control at primary care clinics serving persistent poverty areas. Barriers included transportation, medical costs, limited providers and service availability, and patient fear/discomfort with cancer topics. Facilitators identified were cancer navigators and community health events/services, and priority needs included patient education, comprehensive workflows, improved communication, and integration of cancer navigators into healthcare teams. Barriers to cancer-related research were lack of provider/staff time, patient uncertainty/skepticism, patient health literacy, and provider skepticism/concerns regarding patient burden. Research facilitators included better informing providers/staff about research studies and leveraging navigators as a bridge between clinic and patients. CONCLUSION: Our results inform opportunities to adapt and implement evidence-based interventions to improve cancer prevention, control, and research in persistent poverty areas. To improve cancer prevention and control, we recommend locally-informed strategies to mitigate patient barriers, improved patient education efforts, standardized patient navigation workflows, improved integration of cancer navigators into care teams, and leveraging community health events. Dedicated staff time for research, coordination of research and clinical activities, and educating providers/staff about research studies could improve cancer-related research activities in persistent poverty areas.

Sampling coverage of the Arkansas all-payer claims database by County's persistent poverty designation.

OBJECTIVES: To evaluate the quality of Arkansas All-Payer Claims Database (APCD) for disparity research in persistent poverty areas by determining (1) its representativeness of Arkansas population, (2) variation by county, and (3) differences in coverage between persistent poverty and other counties. DATA SOURCES: Cross-sectional study using 2019 Arkansas APCD member enrollment data and county-level data from various agencies. DATA COLLECTION/EXTRACTION METHODS: An alias identifier linked persons across insurance plans. County FIPS codes were used to extract county-level variables. STUDY DESIGN: Cohort 1 included individuals with ≥1 day of medical coverage in 2019. Cohort 2 included individuals with medical coverage in June, 2019. Cohort 3 included individuals with continuous medical coverage in 2019. Sampling proportions of a county's population in the three cohorts were compared between persistent poverty and other counties. Inverse-variance weighted linear regression was used to identify county-level socioeconomic and demographic characteristics associated with inclusion in each cohort. PRINCIPAL FINDINGS: In 2019, 73.6% of Arkansans had medical coverage for ≥1 day (Cohort 1), 66.3% had coverage in June (Cohort 2), and 58.8% had continuous coverage (Cohort 3) in APCD. Sampling proportions varied by county (median[range]: Cohort 1, 78% [58%-95%]; Cohort 2, 71% [51%-88%]; and Cohort 3, 64% [44%-80%]), and were higher among persistent poverty counties than others for all three cohorts (mean [SD], persistent poverty vs. other: Cohort 1: 80.9% [6.4%] vs. 77.1% [6.3%], p = 0.04; Cohort 2: 74.0% [6.4%] vs. 70.1% [6.2%], p = 0.03; Cohort 3: 66.4% [6.1%] vs. 62.7% [6.0%], p = 0.03). In the 2019 APCD, larger counties and those with higher proportions of females or persons 65+ years had higher coverage, whereas counties with higher per capita household income, median home value, or disproportionately more persons of other races (non-White and non-Black) had lower coverage (p < 0.05 for all three cohorts). CONCLUSIONS: The Arkansas APCD had good coverage of Arkansas population. Coverage was higher in persistent poverty counties than others.

Physical activity among cancer survivors: do neighborhood walkability and metropolitan size play a role?

PURPOSE: To examine associations between walkability, metropolitan size, and physical activity (PA) among cancer survivors and explore if the association between walkability and PA would vary across United States metropolitan sizes. METHODS: This study used data from the 2020 National Health Interview Survey to examine independent associations of walkability and metropolitan size with engaging in moderate-to-vigorous PA (MVPA) and to explore the effect modification of metropolitan size using log-binomial regression. The dependent variable was dichotomized as < vs. ≥ 150 min/week of MVPA. The predictors were perceived walkability, a total score comprising eight neighborhood attributes, and metropolitan size. Covariates included sociodemographic and health characteristics, geographic region, cancer type, and time since cancer diagnosis. RESULTS: Engaging in 150 + min/wk of MVPA significantly increased among cancer survivors (n = 3,405) who perceived their neighborhoods as more walkable (prevalence ratio:1.04; p = 0.004). Engaging in 150 + min/wk of MVPA significantly increased among cancer survivors living in medium and small metropolitan areas vs. those living in large central metropolitan areas (prevalence ratio:1.12; p = 0.044). Perceived walkability levels were similar among cancer survivors in nonmetropolitan areas vs. those living in large central metropolitan areas. Association between walkability and PA did not significantly vary across metropolitan sizes. CONCLUSIONS: Perceived neighborhood walkability is positively associated with MVPA among cancer survivors, regardless of metropolitan size. IMPLICATIONS FOR CANCER SURVIVORS: Findings highlight the importance of investing in the built environment to increase walkability among this population and translating lessons from medium and small metropolitan areas to other metropolitan areas to address the rural-urban disparity in PA among cancer survivors.

Microengineered tumor models: insights & opportunities from a physical sciences-oncology perspective.

Prevailing evidence has established the fundamental role of microenvironmental conditions in tumorigenesis. However, the ability to identify, interrupt, and translate the underlying cellular and molecular mechanisms into meaningful therapies remains limited, due in part to a lack of organotypic culture systems that accurately recapitulate tumor physiology. Integration of tissue engineering with microfabrication technologies has the potential to address this challenge and mimic tumor heterogeneity with pathological fidelity. Specifically, this approach allows recapitulating global changes of tissue-level phenomena, while also controlling microscale variability of various conditions including spatiotemporal presentation of soluble signals, biochemical and physical characteristics of the extracellular matrix, and cellular composition. Such platforms have continued to elucidate the role of the microenvironment in cancer pathogenesis and significantly improve drug discovery and screening, particularly for therapies that target tumor-enabling stromal components. This review discusses some of the landmark efforts in the field of micro-tumor engineering with a particular emphasis on deregulated tissue organization and mass transport phenomena in the tumor microenvironment.

"It was kind of a nightmare, it really was:" financial toxicity among rural women cancer survivors.

PURPOSE: The purpose of this study was to examine how rural women cancer survivors experience and manage financial toxicity. METHODS: A qualitative descriptive design was used to explore experiences of financial toxicity among rural women who received cancer treatment. We conducted qualitative interviews with 36 socioeconomically diverse rural women cancer survivors. RESULTS: Participants were categorized into three groups: (1) survivors who struggled to afford basic living expenses but did not take on medical debt; (2) survivors who took on medical debt but were able to meet their basic needs; and (3) survivors who reported no financial toxicity. The groups differed by financial and job security and insurance type. We describe each group and, for the first two groups, the strategies they used to manage financial toxicity. CONCLUSIONS: Financial toxicity related to cancer treatment is experienced differently by rural women cancer survivors depending on financial and job security and insurance type. Financial assistance and navigation programs should be tailored to support rural patients experiencing different forms of financial toxicity. IMPLICATIONS FOR CANCER SURVIVORS: Rural cancer survivors with financial security and private insurance may benefit from policies aimed at limiting patient cost-sharing and financial navigation to help patients understand and maximize their insurance benefits. Rural cancer survivors who are financially and/or job insecure and have public insurance may benefit from financial navigation services tailored to rural patients that can assist with living expenses and social needs.

A National Map of NCI-Designated Cancer Center Catchment Areas on the 50th Anniversary of the Cancer Centers Program.

BACKGROUND: In 1971, the National Cancer Act created a process to recognize the leadership, facilities, and research efforts at cancer centers throughout the United States. Toward this goal, each NCI-designated cancer center defines and describes a catchment area to which they tailor specific scientific and community engagement activities. METHODS: The geographically defined catchment areas of 63 NCI-designated comprehensive and clinical cancer centers are collated and presented visually. In addition, the NCI-designated cancer center catchment areas are geographically linked with publicly available data sources to aggregate sociodemographic and epidemiologic characteristics across the NCI Cancer Centers Program. RESULTS: The national map portrays the size, shape, and locations for 63 catchment areas of the 71 NCI-designated cancer centers. The findings illustrate the geographic extent of the NCI Cancer Centers Program during the 50th anniversary of the National Cancer Act. CONCLUSIONS: NCI-designated cancer centers occupy a prominent role in the cancer control ecosystem and continue to perform research to address the burden of cancer among their local communities. The strength of the NCI Cancer Centers Program is partly defined by the scope, quality, and impact of community outreach and engagement activities in the catchment areas. IMPACT: The collation and geographic presentation of the distinct, but complementary, NCI-designated cancer center catchment areas are intended to support future research and community outreach activities among NCI-designated cancer centers. See related commentary by Vadaparampil and Tiro, p. 952.

Cancer metabolism gets physical.

Patient-derived culture models enable assessment of drug sensitivity and can connect personalized genomics with therapeutic options. However, their clinical translation is constrained by limited fidelity. We outline how the physical microenvironment regulates cell metabolism and describe how engineered culture systems could enhance the predictive power for precision medicine.

3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways.

Oxygen status and tissue dimensionality are critical determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression analysis of tumor cells cultured in 2D versus 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro-inflammatory pathways are critical regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathologically relevant tissue culture models to study the complex physical and chemical processes by which the cancer microenvironment mediates new vessel formation.

In vitro models of tumor vessels and matrix: engineering approaches to investigate transport limitations and drug delivery in cancer.

Tumor-stroma interactions have emerged as critical determinants of drug efficacy. However, the underlying biological and physicochemical mechanisms by which the microenvironment regulates therapeutic response remain unclear, due in part to a lack of physiologically relevant in vitro platforms to accurately interrogate tissue-level phenomena. Tissue-engineered tumor models are beginning to address this shortcoming. By allowing selective incorporation of microenvironmental complexity, these platforms afford unique access to tumor-associated signaling and transport dynamics. This review will focus on engineering approaches to study drug delivery as a function of tumor-associated changes of the vasculature and extracellular matrix (ECM). First, we review current biological understanding of these components and discuss their impact on transport processes. Then, we evaluate existing microfluidic, tissue engineering, and materials science strategies to recapitulate vascular and ECM characteristics of tumors, and finish by outlining challenges and future directions of the field that may ultimately improve anti-cancer therapies.

Physicochemical regulation of endothelial sprouting in a 3D microfluidic angiogenesis model.

Both physiological and pathological tissue remodeling (e.g., during wound healing and cancer, respectively) require new blood vessel formation via angiogenesis, but the underlying microenvironmental mechanisms remain poorly defined due in part to the lack of biologically relevant in vitro models. Here, we present a biomaterials-based microfluidic 3D platform for analysis of endothelial sprouting in response to morphogen gradients. This system consists of three lithographically defined channels embedded in type I collagen hydrogels. A central channel is coated with endothelial cells, and two parallel side channels serve as a source and a sink for the steady-state generation of biochemical gradients. Gradients of vascular endothelial growth factor (VEGF) promoted sprouting, whereby endothelial cell responsiveness was markedly dependent on cell density and vessel geometry regardless of treatment conditions. These results point toward mechanical and/or autocrine mechanisms that may overwhelm pro-angiogenic paracrine signaling under certain conditions. To date, neither geometrical effects nor cell density have been considered critical determinants of angiogenesis in health and disease. This biomimetic vessel platform demonstrated utility for delineating hitherto underappreciated contributors of angiogenesis, and future studies may enable important new mechanistic insights that will inform anti-angiogenic cancer therapy.

Formation of microvascular networks in vitro.

This protocol describes how to form a 3D cell culture with explicit, endothelialized microvessels. The approach leads to fully enclosed, perfusable vessels in a bioremodelable hydrogel (type I collagen). The protocol uses microfabrication to enable user-defined geometries of the vascular network and microfluidic perfusion to control mass transfer and hemodynamic forces. These microvascular networks (µVNs) allow for multiweek cultures of endothelial cells or cocultures with parenchymal or tissue cells in the extra-lumen space. The platform enables real-time fluorescence imaging of living engineered tissues, in situ confocal fluorescence of fixed cultures and transmission electron microscopy (TEM) imaging of histological sections. This protocol enables studies of basic vascular and blood biology, provides a model for diseases such as tumor angiogenesis or thrombosis and serves as a starting point for constructing prevascularized tissues for regenerative medicine. After one-time microfabrication steps, the system can be assembled in less than 1 d and experiments can run for weeks.