Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.

End-of-Life Care for Patients With Metastatic Renal Cell Carcinoma in the Era of Oral Anticancer Therapy.

PURPOSE: New therapies including oral anticancer agents (OAAs) have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). However, little is known about the quality of end-of-life (EOL) care and systemic therapy use at EOL in patients receiving OAAs or with mRCC. METHODS: We retrospectively analyzed EOL care for decedents with mRCC in two parallel cohorts: (1) patients (RCC diagnosed 2004-2015) from the University of North Carolina's Cancer Information and Population Health Resource (CIPHR) and (2) patients (diagnosed 2007-2015) from SEER-Medicare. We assessed hospice use in the last 30 days of life and existing measures of poor-quality EOL care: systemic therapy, hospital admission, intensive care unit admission, and > 1 ED visit in the last 30 days of life; hospice initiation in the last 3 days of life; and in-hospital death. Associations between OAA use, patient and provider characteristics, and EOL care were examined using multivariable logistic regression. RESULTS: We identified 410 decedents in the CIPHR cohort (53.4% received OAA) and 1,508 in SEER-Medicare (43.5% received OAA). Prior OAA use was associated with increased systemic therapy in the last 30 days of life in both cohorts (CIPHR: 26.5% v 11.0%; P < .001; SEER-Medicare: 23.4% v 11.7%; P < .001), increased in-hospital death in CIPHR, and increased hospice in the last 30 days in SEER-Medicare. Older patients were less likely to receive systemic therapy or be admitted in the last 30 days or die in hospital. CONCLUSION: Patients with mRCC who received OAAs and younger patients experienced more aggressive EOL care, suggesting opportunities to optimize high-quality EOL care in these groups.

Healthcare Utilization for Medicaid-Insured Children with Medical Complexity: Differences by Sociodemographic Characteristics.

OBJECTIVE: To compare differences in healthcare utilization and costs for Medicaid-insured children with medical complexity (CMC) by race/ethnicity and rurality. METHODS: Retrospective cohort of North Carolina (NC) Medicaid claims for children 3-20 years old with 3 years continuous Medicaid coverage (10/1/2015-9/30/2018). Exposures were medical complexity, race/ethnicity, and rurality. Three medical complexity levels were: without chronic disease, non-complex chronic disease, and complex chronic disease; the latter were defined as CMC. Race/ethnicity was self-reported in claims; we defined rurality by home residence ZIP codes. Utilization and costs were summarized for 1 year (10/1/2018-9/30/2019) by complexity level classification and categorized as acute care (hospitalization, emergency [ED]), outpatient care (primary, specialty, allied health), and pharmacy. Per-complexity group utilization rates (per 1000 person-years) by race/ethnicity and rurality were compared using adjusted rate ratios (ARR). RESULTS: Among 859,166 Medicaid-insured children, 118,210 (13.8%) were CMC. Among CMC, 36% were categorized as Black non-Hispanic, 42.7% White non-Hispanic, 14.3% Hispanic, and 35% rural. Compared to White non-Hispanic CMC, Black non-Hispanic CMC had higher hospitalization (ARR = 1.12; confidence interval, CI 1.08-1.17) and ED visit (ARR = 1.17; CI 1.16-1.19) rates; Hispanic CMC had lower ED visit (ARR = 0.77; CI 0.75-0.78) and hospitalization rates (ARR = 0.79; CI 0.73-0.84). Black non-Hispanic and Hispanic CMC had lower outpatient visit rates than White non-Hispanic CMC. Rural CMC had higher ED (ARR = 1.13; CI 1.11-1.15) and lower primary care utilization rates (ARR = 0.87; CI 0.86-0.88) than urban CMC. DISCUSSION: Healthcare utilization varied by race/ethnicity and rurality for Medicaid-insured CMC. Further studies should investigate mechanisms for these variations and expand higher value, equitable care delivery for CMC.

Oral Anticancer Agent (OAA) Adherence and Survival in Elderly Patients With Metastatic Renal Cell Carcinoma (mRCC).

OBJECTIVE: To examine real-world adherence to oral anticancer agents (OAAs) and its association with outcomes among Medicare beneficiaries with metastatic renal cell carcinoma (mRCC). METHODS: SEER-Medicare retrospective cohort study of patients with metastatic renal cell carcinoma (mRCC) who received an OAA between 2007 and 2015. We examined A) adherence and B) overall and disease-specific 2-year survival landmarked at 3 months after OAA initiation. Adherence was assessed by calculating the proportion of days covered (PDC) within 3 months of OAA initiation, with adherent use being defined as PDC > 80%. RESULTS: A total of 905 patients met study criteria, of whom 445 patients (49.2%) were categorized as adherent to initial OAA treatment. Adjusting for clinical and demographic factors revealed decreased odds of adherence associated with living within an impoverished neighborhood (OR 0.49, CI 0.0.33 - 0.74) and out-of-pocket costs > $200 (OR 0.68, CI 0.47-.98). Adherence was associated with improved 2-year survival in univariate analysis (logrank test, P = .01) and a non-significant trend toward an association with decreased all-cause (HR 0.87, CI 0.72 - 1.05) and RCC-specific survival (HR 0.84, CI 0.69 - 1.03) in multivariable analysis. CONCLUSION: Local poverty levels and high out-of-pocket costs are associated with poor initial adherence to OAA therapy in Medicare beneficiaries with mRCC, which in turn, suggests a trend toward poor overall and disease-specific survival. Efforts to improve outcomes in the broader mRCC population should incorporate OAA adherence and economic factors.

Association between cognitive impairment and oral anticancer agent use in older patients with metastatic renal cell carcinoma.

BACKGROUND: Kidney cancer is the fastest-growing cancer diagnosis in the developed world. About 16% of new cases are stage IV, which has a low five-year survival rate. Many patients with metastatic renal cell carcinoma (mRCC) are older and may have mild cognitive impairment or dementia (MCI/D). Given prior reports of patients with dementia initiating less cancer therapy and the importance of oral anticancer agents (OAAs) in mRCC treatment, we investigated the prevalence of preexisting MCI/D in patients with mRCC and their OAA use. METHODS: SEER-Medicare patients were analyzed who were ≥65 years, diagnosed with mRCC between 2007 and 2015, and had Medicare part D coverage. Patterns and predictors of (a) OAA utilization within the 12 months following mRCC diagnosis and (b) adherence (percent of days covered [PDC] ≥ 80%) during the first 90 days following treatment initiation were assessed. RESULTS: Of the 2792 eligible patients, 268 had preexisting MCI/D, and 907 initiated OAA treatment within 12 months of mRCC diagnosis. Patients with preexisting MCI/D were less likely to begin an OAA than those without MCI/D (fully-adjusted HR 0.53, 95% CI 0.38-0.76). Among OAA initiators, a preexisting MCI/D diagnosis did not alter the likelihood that a person would be adherent (adjusted RR 0.84, 95% CI 0.55-1.28). CONCLUSIONS: Patients with preexisting MCI/D were half as likely to start an OAA during the year following mRCC diagnosis than patients without comorbid MCI/D. The 90-day adherence of OAA initiators was not significantly different between those with and without preexisting MCI/D. In light of this, clinicians should assess mRCC patients for cognitive impairment and take steps to optimize OAA utilization by those with MCI/D.

Patient- And Provider-Level Predictors of Survival Among Patients With Metastatic Renal Cell Carcinoma Initiating Oral Anticancer Agents.

PURPOSE: In an era of rapid expansion of FDA approvals for oral anticancer agents (OAAs), it is important to understand the factors associated with survival among real-world populations, which include groups not well-represented in pivotal clinical trials of OAAs, such as the elderly, racial minorities, and medically complex patients. Our objective was to evaluate patient- and provider-level characteristics' associations with mortality among a multi-payer cohort of metastatic renal cell carcinoma (mRCC) patients who initiated OAAs. METHODS: This retrospective cohort study was conducted using data from the North Carolina state cancer registry linked to multi-payer claims data for the years 2004 to 2015. Provider data were obtained from North Carolina Health Professions Data System and the National Plan & Provider Enumeration System. Included patients were individuals with mRCC who initiated an OAA and survived ≥90 days after beginning treatment. We estimated hazard ratios (HR) and corresponding 95% confidence limits (CL) using Cox hazard models for associations between patient demographics, patient clinical characteristics, provider-level factors, and 2-year all-cause mortality. RESULTS: The cohort included 207 patients with mRCC who received OAAs. In multivariable models, clinical variables such as frailty (HR: 1.36, 95% CL: 1.11-1.67) and de novo metastatic diagnosis (HR: 2.63, 95%CL: 1.67-4.16) were associated with higher all-cause mortality. Additionally, patients solely on Medicare had higher adjusted all-cause mortality compared with patients with any private insurance (HR: 2.35, 95% CL: 1.32-4.18). No provider-level covariates investigated were associated with all-cause mortality. CONCLUSIONS: Within a real-world population of mRCC patients taking OAAs, survival differed based on patient characteristics. In an era of rapid expansion of FDA approvals for OAAs, these real-world data underscore the continued importance of access to high-quality care, particularly for medically complex patients with limited resources.

Single-cell analysis of cultured bone marrow stromal cells reveals high similarity to fibroblasts in situ.

Within the heterogenous pool of bone marrow stromal cells, mesenchymal stromal cells (MSCs) are of particular interest because of their hematopoiesis-supporting capacities, contribution to disease progression, therapy resistance, and leukemic initiation. Cultured bone marrow-derived stromal cells (cBMSCs) are used for in vitro modeling of hematopoiesis-stroma interactions, validation of disease mechanisms, and screening for therapeutic targets. Here, we place cBMSCs (mouse and human) in a bone marrow tissue context by systematically comparing the transcriptome of plastic-adherent cells on a single-cell level with in vivo counterparts. Cultured BMSCs encompass a rather homogenous cell population, independent of the isolation method used and, although still possessing hematopoiesis-supporting capacity, are distinct from freshly isolated MSCs and more akin to in vivo fibroblast populations. Informed by combined cell trajectories and pathway analyses, we illustrate that TGFb inhibition in vitro can preserve a more "MSC"-like phenotype.

Patient, provider, and hospital factors associated with oral anti-neoplastic agent initiation and adherence in older patients with metastatic renal cell carcinoma.

INTRODUCTION: Oral anti-neoplastic agents (OAAs) for metastatic renal cell carcinoma (mRCC) are associated with increased cancer-specific survival. However, racial disparities in survival persist and older adults have the lowest rates of cancer-specific survival. Research from other cancers demonstrates specialty access is associated with high-quality cancer care, but older adults receive cancer treatment less often than younger adults. We therefore examined whether patient, provider, and hospital characteristics were associated with OAA initiation, adherence, and cancer-specific survival after initiation and whether race, ethnicity, and/or age was associated with an increased likelihood of seeing a medical oncologist for diagnosis of mRCC. PATIENTS AND METHODS: We used Surveillance, Epidemiology, and End Results (SEER)Medicare data to identify patients ≥65 years of age who were diagnosed with mRCC from 2007 to 2015 and enrolled in Medicare Part D. Insurance claims were used to identify receipt of OAAs within twelve months of metastatic diagnosis, calculate proportion of days covered, and to identify the primary cancer provider and hospital. We examined provider and hospital characteristics associated with OAA initiation, adherence, and all-cause mortality after OAA initiation. RESULTS: We identified 2792 patients who met inclusion criteria. Increased OAA initiation was associated with access to a medical oncologist. Patients were less likely to begin OAA treatment if their primary oncologic provider was a urologist (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.49-0.77). Provider/hospital characteristics were not associated with differences in OAA adherence or mortality. Patients who started sorafenib (odds ratio [OR] 0.50; 95% CI 0.29-0.86), were older (aged >81 OR 0.56; 95% CI 0.34-0.92), and those living in high poverty ZIP codes (OR 0.48; 95% CI 0.29-0.80) were less likely to adhere to OAA treatment. Furthermore, provider characteristics did not account for differences in mortality once an OAA was initiated. Last, only age > 81 years was statistically and clinically associated with a decreased relative risk of seeing a medical oncologist (risk ratio [RR] 0.87; CI 0.82-0.92). CONCLUSION: Provider/hospital factors, specifically, being seen by a medical oncologist for mRCC diagnosis, are associated with OAA initiation. Older patients were less likely to see a medical oncologist; however, race and/or ethnicity was not associated with differences in seeing a medical oncologist. Patient factors are more critical to OAA adherence and mortality after OAA initiation than provider/hospital factors.

Evaluation of mild cognitive impairment and dementia in patients with metastatic renal cell carcinoma.

BACKGROUND: Dementia and cancer are both more common in adults as they age. As new cancer treatments become more popular, it is important to consider how these treatments might affect older patients. This study evaluates metastatic renal cell carcinoma (mRCC) as a risk factor for older adults developing mild cognitive impairment or dementia (MCI/D) and the impact of mRCC-directed therapies on the development of MCI/D. METHODS: We identified patients diagnosed with mRCC in a Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset from 2007 to 2015 and matched them to non-cancer controls. Exclusion criteria included age < 65 years at mRCC diagnosis and diagnosis of MCI/D within the year preceding mRCC diagnosis. The main outcome was time to incident MCI/D within one year of mRCC diagnosis for cases or cohort entry for non-cancer controls. Cox proportional hazards models were used to measure associations between mRCC and incident MCI/D as well as associations of oral anticancer agent (OAA) use with MCI/D development within the mRCC group. RESULTS: Patients with mRCC (n = 2533) were matched to non-cancer controls (n = 7027). mRCC (hazard ratio [HR] 8.52, p < .001), being older (HR 1.05 per 1-year age increase, p < .001), and identifying as Black (HR 1.92, p = .047) were predictive of developing MCI/D. In addition, neither those initiating treatment with OAAs nor those who underwent nephrectomy were more likely to develop MCI/D. CONCLUSIONS: Patients with mRCC were more likely to develop MCI/D than those without mRCC. The medical and surgical therapies evaluated were not associated with increased incidence of MCI/D. The increased incidence of MCI/D in older adults with mRCC may be the result of the pathology itself or risk factors common to the two disease processes.

Provider- and patient-level predictors of oral anticancer agent initiation and adherence in patients with metastatic renal cell carcinoma.

BACKGROUND: Improving oral anticancer agent (OAA) initiation and adherence is the important quality-of-care issues, particularly since one fourth of anticancer agents being developed will be administered orally. Our objective was to identify provider- and patient-level characteristics associated with OAA initiation and adherence among individuals with metastatic renal cell carcinoma (mRCC). METHODS: We used state cancer registry data linked to multi-payer claims data to identify patients with mRCC diagnosed in 2004-2015. Provider data were obtained from North Carolina Health Professions Data System and the National Plan & Provider Enumeration System. We estimated risk ratios (RRs) and corresponding 95% confidence limits (CLs) using modified Poisson regression to evaluate factors associated with OAA initiation and adherence. RESULTS: Among the 207 (out of 687) patients who initiated an OAA following mRCC diagnosis and survived 90 days, median proportion of days covered was 0.91. Patients with a modal provider specializing in hematology/medical oncology were much more likely to initiate OAAs than those seen by other specialties. Additionally, patients with a female provider were more likely to initiate OAAs than those with a male provider. Compared to patients treated by providers practicing in both urban and rural areas, patients with providers practicing solely in urban areas were more likely to initiate OAAs, after controlling for patient-level factors (RR = 1.37; 95% CL: 1.09-1.73). Medicare patients were less likely to be adherent than those with private insurance (RR = 0.61; 95% CL: 0.42-0.87). CONCLUSIONS: Our results suggest that provider- and patient-level factors influence OAA initiation in patients with mRCC but only insurance type was associated with adherence.

Patterns and Predictors of Oral Anticancer Agent Use in Diverse Patients With Metastatic Renal Cell Carcinoma.

PURPOSE: Availability of targeted oral anticancer agents (OAAs) has transformed care for patients with metastatic renal cell carcinoma (mRCC). Our objective was to identify patterns and predictors of OAA use within 12 months after mRCC was detected to understand real-world adoption of OAAs. METHODS: We used a novel, North Carolina cancer registry-linked multipayer claims data resource to examine patterns of use of five oral therapies among patients with mRCC diagnosed in 2006-2015, with claims through 2016. Patients were required to have 12 months of continuous enrollment before metastatic index date. Log-Poisson models estimated unadjusted and adjusted risk ratios (RRs) for associations between patient characteristics and OAA use. In sensitivity analyses, we used a competing risk framework to estimate adjusted risk differences in OAA use. RESULTS: Our population-based study of 713 patients demonstrated low (37%) OAA use during the first year after metastatic index date among both publicly and privately insured patients, with shifting patterns of use consistent with regulatory approvals over time. Compared with patients age 18-49 years, patients age 70-74 years were half likely to use OAAs (95% confidence limit [CL], 0.34 to 0.78) and patients age 80+ years were 71% less likely to use OAAs (95% CL, 0.17 to 0.50). Patients with two comorbidities (RR, 0.73; 95% CL, 0.55 to 0.98) and those with 3+ comorbidities (RR, 0.68; 95% CL, 0.50 to 0.91) were less likely to receive OAA than those without comorbidities. Patients with higher frailty also had lower OAA utilization (RR, 0.67; 95% CL, 0.52 to 0.85). CONCLUSION: These findings suggest a need to better understand the system-level and provider-level drivers of OAA underuse, as well as OAA adherence and associated survival.

Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) that leads to progressive bone marrow (BM) fibrosis. Although the cellular mutations involved in the pathogenesis of PMF have been extensively investigated, the sequential events that drive stromal activation and fibrosis by hematopoietic-stromal cross-talk remain elusive. Using an unbiased approach and validation in patients with MPN, we determined that the differential spatial expression of the chemokine CXCL4/platelet factor-4 marks the progression of fibrosis. We show that the absence of hematopoietic CXCL4 ameliorates the MPN phenotype, reduces stromal cell activation and BM fibrosis, and decreases the activation of profibrotic pathways in megakaryocytes, inflammation in fibrosis-driving cells, and JAK/STAT activation in both megakaryocytes and stromal cells in 3 murine PMF models. Our data indicate that higher CXCL4 expression in MPN has profibrotic effects and is a mediator of the characteristic inflammation. Therefore, targeting CXCL4 might be a promising strategy to reduce inflammation in PMF.

A mechanistic study of the effect of doxorubicin/adriamycin on the estrogen response in a breast cancer model.

OBJECTIVE: Estrogen treatment limits the cytotoxic effects of chemotherapy in estrogen receptor-positive (ER+) breast cancer cell lines, suggesting that estrogen pathway signaling may confer chemotherapeutic resistance. This study investigates the molecular responses of ER+ breast cancer cell lines to the chemotherapeutic agent, doxorubicin, in the presence or absence of estrogen. METHODS: ER+ MCF-7 and T47-D cells were cultured in hormone-starved or estrogen-containing media with or without doxorubicin at concentrations mimicking the low concentrations seen in plasma and tumor microenvironments in humans following typical bolus administration. Protein levels, phosphorylations, and interactions of estrogen-signaling molecules were assessed following these treatments, as well the effects of ER signaling inhibitors on cell proliferation. RESULTS: Surprisingly, estrogen and doxorubicin co-treatment markedly induced pro-growth alterations compared to doxorubicin alone and modestly enhanced estrogen alone-induced changes. Several inhibitors suppressed cell proliferation in the presence of doxorubicin and estrogen. CONCLUSIONS: These findings demonstrate that molecular changes caused by doxorubicin in ER+ breast cancer cells can be reversed by estrogen, providing molecular evidence for the poorer responses of ER+ tumors to doxorubicin in the presence of physiologic estrogen levels. Our results also suggest that the addition of drugs targeting the ER, EGFR, the SFKs, MEK, PI3K, and/or the MMP proteins to a conventional chemotherapy regimen may improve chemosensitivity.