Glioblastoma Neurovascular Progenitor Orchestrates Tumor Cell Type Diversity.

Glioblastoma (GBM) is the deadliest form of primary brain tumor with limited treatment options. Recent studies have profiled GBM tumor heterogeneity, revealing numerous axes of variation that explain the molecular and spatial features of the tumor. Here, we seek to bridge descriptive characterization of GBM cell type heterogeneity with the functional role of individual populations within the tumor. Our lens leverages a gene program-centric meta-atlas of published transcriptomic studies to identify commonalities between diverse tumors and cell types in order to decipher the mechanisms that drive them. This approach led to the discovery of a tumor-derived stem cell population with mixed vascular and neural stem cell features, termed a neurovascular progenitor (NVP). Following in situ validation and molecular characterization of NVP cells in GBM patient samples, we characterized their function in vivo. Genetic depletion of NVP cells resulted in altered tumor cell composition, fewer cycling cells, and extended survival, underscoring their critical functional role. Clonal analysis of primary patient tumors in a human organoid tumor transplantation system demonstrated that the NVP has dual potency, generating both neuronal and vascular tumor cells. Although NVP cells comprise a small fraction of the tumor, these clonal analyses demonstrated that they strongly contribute to the total number of cycling cells in the tumor and generate a defined subset of the whole tumor. This study represents a paradigm by which cell type-specific interrogation of tumor populations can be used to study functional heterogeneity and therapeutically targetable vulnerabilities of GBM.

Meningeal solitary fibrous tumor cell states phenocopy cerebral vascular development and homeostasis.

BACKGROUND: Meningeal solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that are associated with local recurrence and hematogenous metastasis. The cell states and spatial transcriptomic architecture underlying the unique clinical behavior of meningeal SFTs are unknown. METHODS: Single-cell (n=4), spatial (n=8), and bulk RNA sequencing (n=22) was used to define the cell states and spatial transcriptomic architecture of meningeal SFTs across histological grades and in patient-matched pairs of primary/recurrent or intracranial/metastatic samples. Immunofluorescence, immunohistochemistry, and comparison of single-cell types to meningiomas, or to cerebral vascular development or homeostasis, were used for validation. RESULTS: Here we show meningeal SFTs are comprised of regionally distinct gene expression programs that resemble cerebral vascular development or homeostasis. Single-cell trajectory analysis and pseudotemporal ordering of single-cells suggest that meningeal SFT cell fate decisions are dynamic and interchangeable. Cell-cell communication analyses demonstrate receptor-ligand interactions throughout the meningeal SFT microenvironment, particularly between SFT cells, endothelia, and immature neurons. Direct comparison of single-cell transcriptomes from meningeal SFTs versus meningiomas shows that SFT cells are enriched in expression of endothelial markers while meningiomas cells are enriched in expression of mural cells markers. Meningeal SFT spatial transcriptomes show regionally distinct intratumor heterogeneity in cell states, gene expression programs, and cell-cell interactions across WHO histological grades and in patient-matched pairs of primary/recurrent or intracranial/metastatic samples. CONCLUSIONS: These results shed light on pathways underlying meningeal SFT biology in comparison to other central nervous system tumors and provide a framework for integrating single-cell, spatial, and bulk RNA sequencing data across human cancers and normal tissues.

Perivascular NOTCH3+ stem cells drive meningioma tumorigenesis and resistance to radiotherapy.

Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas and the cell types and signaling mechanisms that drive meningioma tumorigenesis and resistance to radiotherapy are incompletely understood. Here we report NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find that perivascular NOTCH3+ stem cells are conserved across meningiomas from humans, dogs, and mice. Integrating single-cell transcriptomics with lineage tracing and imaging approaches in genetically engineered mouse models and xenografts, we show NOTCH3 drives tumor initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. To translate these findings to patients, we show that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival.

Rural-Urban Differences in Overweight and Obesity, Physical Activity, and Food Security Among Children and Adolescents.

INTRODUCTION: Childhood obesity has been associated with numerous poor health conditions, with geographic disparities demonstrated. Limited research has examined the association between rurality and food security, physical activity, and overweight or obesity among children. We examined rates of food security, physical inactivity, and overweight or obesity among rural and urban children and adolescents, and associations between rurality and these 3 outcomes. METHODS: We used cross-sectional data from a nationally representative sample of children and adolescents aged 10 to 17 years from the 2019-2020 National Survey of Children's Health (N = 23,199). We calculated frequencies, proportions, and unadjusted associations for each variable by using descriptive statistics and bivariate analyses. We used multivariable logistic regression models to examine the association between rurality and food security, physical activity, and overweight or obesity. RESULTS: After adjusting for sociodemographic factors, rural children and adolescents had higher odds than urban children and adolescents of being overweight or obese (adjusted odds ratio = 1.30; 95% CI, 1.11-1.52); associations between rurality and physical inactivity and food insecurity were not significant. CONCLUSION: The information from this study is timely for policy makers and community partners to make informed decisions on the allocation of healthy weight and obesity prevention programs for children and adolescents in rural settings. Our study provides information for public health programming and the designing of appropriate dietary and physical activity interventions needed to reduce disparities in obesity prevention among children and adolescents.

LIF signaling regulates outer radial glial to interneuron fate during human cortical development.

Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear. oRG cells express leukemia-inhibitory factor (LIF) receptors during neurogenesis, and consistent with a role in stem cell self-renewal, LIF perturbation impacts oRG proliferation in cortical tissue and organoids. Surprisingly, LIF treatment also increases the production of inhibitory interneurons (INs) in cortical cultures. Comparative transcriptomic analysis identifies that the enhanced IN population resembles INs produced in the caudal ganglionic eminence. To evaluate whether INs could arise from oRGs, we isolated primary oRG cells and cultured them with LIF. We observed the production of INs from oRG cells and an increase in IN abundance following LIF treatment. Our observations suggest that LIF signaling regulates the capacity of oRG cells to generate INs.

Meningeal solitary fibrous tumor cell states phenocopy cerebral vascular development and homeostasis.

Meningeal solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that are associated with hematogenous metastasis, and the cell states and spatial transcriptomic architecture of SFTs are unknown. Here we use single-cell and spatial RNA sequencing to show SFTs are comprised of regionally distinct gene expression programs that resemble cerebral vascular development and homeostasis. Our results shed light on pathways underlying SFT biology in comparison to other central nervous system tumors and provide a framework for integrating single-cell and spatial transcriptomic data from human cancers and normal tissues.

NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy.

Meningiomas are the most common primary intracranial tumors1-3. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental4,5. Resistance to radiotherapy is common in high-grade meningiomas6, and the cell types and signaling mechanisms driving meningioma tumorigenesis or resistance to radiotherapy are incompletely understood. Here we report NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find NOTCH3+ meningioma mural cells are conserved across meningiomas from humans, dogs, and mice. NOTCH3+ cells are restricted to the perivascular niche during meningeal development and homeostasis and in low-grade meningiomas but are expressed throughout high-grade meningiomas that are resistant to radiotherapy. Integrating single-cell transcriptomics with lineage tracing and imaging approaches across mouse genetic and xenograft models, we show NOTCH3 drives tumor initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. An antibody stabilizing the extracellular negative regulatory region of NOTCH37,8 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival in preclinical models. In summary, our results identify a conserved cell type and signaling mechanism that underlie meningioma tumorigenesis and resistance to radiotherapy, revealing a new therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.

The COVID-19 pandemic impact on independent and provider-based rural health clinics' operations and cancer prevention and screening provision in the United States.

INTRODUCTION: The COVID-19 pandemic has disrupted cancer care, but it is unknown how the pandemic has affected care in Medicare-certified rural health clinics (RHCs) where cancer prevention and screening services are critical for their communities. This study examined how the provision of these cancer services changed pre- and peri-pandemic overall and by RHC type (independent and provider-based). METHODS: We administered a cross-sectional survey to a stratified random sample of RHCs to assess clinic characteristics, pandemic stressors, and the provision of cancer prevention and control services among RHCs pre- and peri-pandemic. We used McNemar's test and Wilcoxon signed rank tests to assess differences in the provision of cancer prevention and screening services pre- and peri-pandemic by RHC type. RESULTS: Of the 153 responding RHCs (response rate of 8%), 93 (60.8%) were provider-based and 60 (39.2%) were independent. Both RHC types were similar in their experience of pandemic stressors, though a higher proportion of independent RHCs reported financial concerns and challenges obtaining personal protective equipment. Both types of RHCs provided fewer cancer prevention and screening services peri-pandemic-5.8 to 4.2 for provider-based and 5.3 to 3.5 for independent (P<.05 for both). Across lung, cervical, breast, and colorectal cancer-related services, the proportion of both RHC groups providing services dropped peri-pandemic. DISCUSSION: The pandemic's impact on independent and provider-based RHCs and their patients was considerable. Going forward, greater resources should be targeted to RHCs-particularly independent RHCs-to ensure their ability to initiate and sustain evidence-based prevention and screening services.

Availability of hospital-based cancer services before and after rural hospital closure, 2008-2017.

INTRODUCTION: Rural populations have less access to cancer care services and experience higher cancer mortality rates than their urban counterparts, which may be exacerbated by hospital closures. Our objective was to examine the impact of hospital closures on access to cancer-relevant hospital services across hospital service areas (HSAs). METHODS: We used American Hospital Association survey data from 2008 to 2017 to examine the change in access to cancer-related screening and treatment services across rural HSAs that sustained hospitals over time, experienced any closures, or had all hospitals close. We performed a longitudinal analysis to assess the association between hospital closure occurrence and maintenance or loss of cancer-related service lines accounting for hospital and HSA-level characteristics. Maps were also developed to display changes in the availability of services across HSAs. RESULTS: Of the 2,014 rural HSAs, 3.8% experienced at least 1 hospital closure during the study period, most occurring in the South. Among HSAs that experienced hospital closure, the loss of surgery services lines was most common, while hospital closures did not affect the availability of overall oncology and radiation services. Screening services either were stable (mammography) or increased (endoscopy) in areas with no closures. DISCUSSION: Rural areas persistently experience less access to cancer treatment services, which has been exacerbated by hospital closures. Lack of Medicaid expansion in many Southern states and other policy impacts on hospital financial viability may play a role in this. Future research should explore the impact of closures on cancer treatment receipt and outcomes.

The Problem Of The Color Line: Spatial Access To Hospital Services For Minoritized Racial And Ethnic Groups.

Examining how spatial access to health care varies across geography is key to documenting structural inequalities in the United States. In this article and the accompanying StoryMap, our team identified ZIP Code Tabulation Areas (ZCTAs) with the largest share of minoritized racial and ethnic populations and measured distances to the nearest hospital offering emergency services, trauma care, obstetrics, outpatient surgery, intensive care, and cardiac care. In rural areas, ZCTAs with high Black or American Indian/Alaska Native representation were significantly farther from services than ZCTAs with high White representation. The opposite was true for urban ZCTAs, with high White ZCTAs being farther from most services. These patterns likely result from a combination of housing policies that restrict housing opportunities and federal health policies that are based on service provision rather than community need. The findings also illustrate the difficulty of using a single metric-distance-to investigate access to care on a national scale.

Trends in Cancer Treatment Service Availability Across Critical Access Hospitals and Prospective Payment System Hospitals.

BACKGROUND: Rural residents experience worse cancer prognosis and access to cancer care providers than their urban counterparts. Critical access hospitals (CAHs) represent over half of all rural community hospitals. However, research on cancer services provided within CAHs is limited. OBJECTIVE: The objective of this study was to investigate trends in cancer services availability in urban and rural Prospective Payment System (PPS) hospitals and CAHs. DESIGN: Retrospective, time-series analysis using data from 2008 to 2017 American Hospital Association Annual Surveys. Multivariable logistic regressions were used to examine differential trends in cancer services between urban PPS, rural PPS, and CAHs, overall and among small (<25 beds) hospitals. SUBJECTS: All US acute care and cancer hospitals (4752 in 2008 to 4722 in 2017). MEASURES: Primary outcomes include whether a hospital provided comprehensive oncology services, chemotherapy, and radiation therapy each year. RESULTS: In 2008, CAHs were less likely to provide all cancer services, especially chemotherapy (30.4%) and radiation therapy (2.9%), compared with urban (64.4% and 43.8%, respectively) and rural PPS hospitals (42.0% and 23.3%, respectively). During 2008-2017, compared with similarly sized PPS hospitals, CAHs were more likely to provide oncology services and chemotherapy, but with decreasing trends. Radiation therapy availability between small PPS hospitals and CAHs did not differ. CONCLUSIONS: Compared with all PPS hospitals, CAHs offered fewer cancer treatment services and experienced a decline in service capability over time. These differences in chemotherapy services were mainly driven by hospital size, as small urban and rural PPS hospitals had lower rates of chemotherapy than CAHs. Still, the lower rates of radiotherapy in CAHs highlight disproportionate challenges facing CAHs for some specialty services.

The Intersection of Rural Residence and Minority Race/Ethnicity in Cancer Disparities in the United States.

One in every twenty-five persons in America is a racial/ethnic minority who lives in a rural area. Our objective was to summarize how racism and, subsequently, the social determinants of health disproportionately affect rural racial/ethnic minority populations, provide a review of the cancer disparities experienced by rural racial/ethnic minority groups, and recommend policy, research, and intervention approaches to reduce these disparities. We found that rural Black and American Indian/Alaska Native populations experience greater poverty and lack of access to care, which expose them to greater risk of developing cancer and experiencing poorer cancer outcomes in treatment and ultimately survival. There is a critical need for additional research to understand the disparities experienced by all rural racial/ethnic minority populations. We propose that policies aim to increase access to care and healthcare resources for these communities. Further, that observational and interventional research should more effectively address the intersections of rurality and race/ethnicity through reduced structural and interpersonal biases in cancer care, increased data access, more research on newer cancer screening and treatment modalities, and continued intervention and implementation research to understand how evidence-based practices can most effectively reduce disparities among these populations.

Reciprocal Interaction between Vascular Filopodia and Neural Stem Cells Shapes Neurogenesis in the Ventral Telencephalon.

Angiogenesis and neurogenesis are tightly coupled during embryonic brain development. However, little is known about how these two processes interact. We show that nascent blood vessels actively contact dividing neural stem cells by endothelial filopodia in the ventricular zone (VZ) of the murine ventral telencephalon; this association is conserved in the human ventral VZ. Using mouse mutants with altered vascular filopodia density, we show that this interaction leads to prolonged cell cycle of apical neural progenitors (ANPs) and favors early neuronal differentiation. Interestingly, pharmacological experiments reveal that ANPs induce vascular filopodia formation by upregulating vascular endothelial growth factor (VEGF)-A in a cell-cycle-dependent manner. This mutual relationship between vascular filopodia and ANPs works as a self-regulatory system that senses ANP proliferation rates and rapidly adjusts neuronal production levels. Our findings indicate a function of vascular filopodia in fine-tuning neural stem cell behavior, which is the basis for proper brain development.

Rural-Urban Mortality Disparities: Variations Across Causes of Death and Race/Ethnicity, 2013-2017.

Objectives. To examine rural-urban disparities in overall mortality and leading causes of death across Hispanic (any race) and non-Hispanic White, Black, American Indian/Alaska Native (AI/AN), and Asian/Pacific Islander populations.Methods. We performed a retrospective analysis of age-adjusted death rates for all-cause mortality and 5 leading causes of death (cardiovascular, cancer, unintentional injuries, chronic lower respiratory disease, and stroke) by rural versus urban county of residence in the United States and race/ethnicity for the period 2013 to 2017.Results. Rural populations, across all racial/ethnic groups, had higher all-cause mortality rates than did their urban counterparts. Comparisons within causes of death documented rural disparities for all conditions except cancer and stroke among Hispanic individuals; Hispanic rural residents had death rates similar to or lower than urban residents. Rural Black populations experienced the highest mortality for cardiovascular disease, cancer, and stroke. Unintentional injury and chronic lower respiratory disease mortality were highest in rural AI/AN and rural non-Hispanic White populations, respectively.Conclusions. Investigating rural-urban disparities without also considering race/ethnicity leaves minority health disparities unexamined and thus unaddressed. Further research is needed to clarify local factors associated with these disparities and to test appropriate interventions.

Racial and Geographic Disparities in Endocrine Therapy Adherence Among Younger Breast Cancer Survivors.

OBJECTIVES: African American (AA) women with breast cancer (BrCA) have higher mortality than any other race. Differential mortality has been attributed to nonadherence to endocrine therapy (ET). ET can lower the risk of dying by one third; yet 50% to 75% of all women are nonadherent to ET. Despite the wealth of research examining adherence to ET, understanding which groups of women at risk for poor adherence is not well established. The aim of this investigation was to describe ET adherence by race and geographic location among a cohort of younger BrCA survivors. MATERIALS AND METHODS: Cancer registry records were linked to administrative data from Medicaid and a private insurance plan in South Carolina. Inclusion criteria included: European American (EA) or AA race, 3 years of continuous enrollment in the insurance plan after diagnosis, and BrCA diagnosis between 2002 and 2010. Adherence was measured by computing a medication possession ratio (MPR) based upon refill service dates and the number of pills dispensed. Adjusted least squared means were calculated by racial and geographic group using analysis of covariance methods. RESULTS: The average MPR for EA women was significantly higher at 96% compared with 92% for AA women (P<0.01). After adjustment for years on hormone therapy, age, and number of pharmacies utilized, rural AA women had an average MPR of 90% compared with 95% for EA women (P<0.01). CONCLUSIONS: AA women residing in rural areas demonstrate significantly lower adherence compared with their EA counterparts. Interventions are needed to improve adherence that may ameliorate AA mortality disparities.

Outer Radial Glia-like Cancer Stem Cells Contribute to Heterogeneity of Glioblastoma.

Glioblastoma is a devastating form of brain cancer. To identify aspects of tumor heterogeneity that may illuminate drivers of tumor invasion, we created a glioblastoma tumor cell atlas with single-cell transcriptomics of cancer cells mapped onto a reference framework of the developing and adult human brain. We find that multiple GSC subtypes exist within a single tumor. Within these GSCs, we identify an invasive cell population similar to outer radial glia (oRG), a fetal cell type that expands the stem cell niche in normal human cortex. Using live time-lapse imaging of primary resected tumors, we discover that tumor-derived oRG-like cells undergo characteristic mitotic somal translocation behavior previously only observed in human development, suggesting a reactivation of developmental programs. In addition, we show that PTPRZ1 mediates both mitotic somal translocation and glioblastoma tumor invasion. These data suggest that the presence of heterogeneous GSCs may underlie glioblastoma's rapid progression and invasion.

Assessing Change in Physician Practice Organization Profile in South Carolina: A Longitudinal Study.

BACKGROUND: Physician practice organization is shifting away from solo, independent practices toward direct employment, but trends for rural-urban differences are often analyzed by dichotomizing rurality. The purpose of this analysis was to examine trends in practice organization across 3 levels of rurality over a 21-year period in South Carolina. METHODS: Physician license renewal forms were used to ascertain type of practice organization where physicians worked in South Carolina between 1995 and 2015. Physicians were divided into 4 categories: physicians in independent solo practices, physicians in independent group practices, employed physicians, and other. Historical trends in type of practice organization were evaluated for each level of rurality (metropolitan, micropolitan, and small adjacent/remote rural) using the National Cancer Institute's Joinpoint regression models. RESULTS: There was a continual increase in physician renewals indicating employment, with an average annual increase of 5.9%. Micropolitan rural counties demonstrated the greatest average increase in license renewals for employed physicians (average annual increase = 7.4%; P < .05). The ratio of license renewals per 100,000 population for physicians in independent solo practices declined significantly over time. Micropolitan and small adjacent/remote rural counties saw an increase in the annual decline for this type of practice organization in 2007. CONCLUSIONS: A shift toward physician employment was observed at all levels of rurality. Rural counties exhibited a more pronounced transition between the types of practice organization compared to metropolitan counties. Research is needed to address the implications of these changes for rural providers and patients.

Geographic disparities in residential proximity to colorectal and cervical cancer care providers.

BACKGROUND: Persistent rural-urban disparities for colorectal and cervical cancers raise concerns regarding access to treatment providers. To the authors knowledge, little is known regarding rural-urban differences in residential proximity to cancer specialists. METHODS: Using the 2018 Physician Compare data concerning physician practice locations and the 2012 to 2016 American Community Survey, the current study estimated the driving distance from each residential zip code tabulation area (ZCTA) centroid to the nearest cancer provider of the following medical specialties involved in treating patients with colorectal and cervical cancer: medical oncology, radiation oncology, surgical oncology, general surgery, gynecological oncology, and colorectal surgery. Using population-weighted multivariable logistic regression, the authors analyzed the associations between ZCTA-level characteristics and driving distances >60 miles to each type of specialist. ZCTA-level residential rurality was defined using rural-urban commuting area codes. RESULTS: Nearly 1 in 5 rural Americans lives >60 miles from a medical oncologist. Rural-urban differences in travel distances to the nearest cancer care provider(s) increased substantially for cancer surgeons; greater than one-half of rural residents were required to travel 60 miles to reach a gynecological oncologist, compared with 8 miles for their urban counterparts. Individuals residing within ZCTAs with a higher poverty rate, those of American Indian/Alaska Native ethnicity, and/or were located in the South and West regions were more likely than their counterparts to be >60 miles away from any of the aforementioned providers. CONCLUSIONS: The substantial travel distances required for rural, low-income residents to reach a cancer specialist should prompt a policy action to increase access to specialized cancer care for millions of rural residents.

Rural-Urban Differences in Access to Thoracic Surgery in the United States, 2010 to 2014.

BACKGROUND: Because of recent lung cancer screening recommendations and corresponding insurance coverage, it is expected that more early stage cases will be identified that require thoracic surgery. However, these services may not be equally available in all regions. Our objective is to describe the availability of thoracic surgeons by examining geographic variation, rural-urban differences, and temporal changes before and after screening recommendation and insurance coverage policy changes. METHODS: We examined the U.S. thoracic surgery workforce using the 2010 and 2014 Area Health Resource Files. We calculated the density of thoracic surgeons per 100,000 persons for each year at the state and county level. We performed descriptive statistics and developed maps highlighting changes over time and geographic regions. RESULTS: Despite an overall increase in thoracic surgeons from 2010 to 2014, we observed declining density nationwide (1.5% change) and in sparsely populated states. The difference in thoracic surgeon density widened slightly between 2010 from 0.80 per 100,000 compared with 0.84 per 100,000 in 2014 in all rural counties compared with urban counties (P < .001 for both years). The difference in thoracic surgeon density was most pronounced between small adjacent rural and urban counties (0.95 and 0.96 per 100,000 for 2010 and 2014, respectively; P < .001 for both years). The Northeast held a disproportionate share of the thoracic surgery workforce. CONCLUSIONS: Limited access to thoracic surgeons in rural areas is a concern, given an older and retiring surgical workforce, the higher burden of lung cancer in rural areas, and recent policy changes for screening reimbursement.

Rural-Urban Differences in Costs of End-of-Life Care for the Last 6 Months of Life Among Patients with Breast, Lung, or Colorectal Cancer.

PURPOSE: The purpose of this study was to examine rural-urban differences in utilization and expenditures in the last 6 months of life for patients with breast, lung, or colorectal cancer. METHODS: The study used a 5% sample of the 2013 Medicare Research Identifiable Files to study utilization and expenditures for beneficiaries with breast, lung, or colorectal cancer during the last 6 months before death (n = 6,214). End of life expenditures were calculated as the sum of total Medicare expenditures for inpatient, outpatient, physician, home health, hospice, and skilled nursing facility costs during the last 6 months of life. FINDINGS: For each type of cancer, total Medicare expenditures in the last 6 months of life were lower for rural decedents compared to their urban counterparts. During the last 6 months of life, median Medicare expenditures were lower for rural decedents for breast cancer ($21,839 vs $25,698), lung cancer ($22,814 vs $27,635), and colorectal cancer ($24,156 vs $28,035; all differences significant at P < .05). In adjusted models, care for rural decedents was less costly than urban decedents for breast, lung, and colorectal cancer, respectively. CONCLUSIONS: Our findings indicate that Medicare expenditures are lower for rural beneficiaries with each type of cancer than urban beneficiaries, even after adjusting for age, gender, race, dual eligibility, region, chronic conditions, and type of service utilization. The findings from this study can be useful for policymakers in developing programs and resource allocation decisions that impact rural beneficiaries.