Molecular umbrella conjugate for the ocular delivery of siRNA.

The synthesis, computer modeling, and biological activity of an octawalled molecular umbrella short interfacing RNA (siRNA) conjugate is described. This molecular umbrella-siRNA conjugate exhibited mRNA knockdown activity in vitro in the absence of a transfection reagent. Evaluation of this molecular umbrella conjugate in vivo, using the rat eye via intravitreal injection, resulted in sequence specific mRNA knockdown in the retina with no obvious signs of toxicity, as judged by ophthalmic examination.

Race, Affordability and Utilization of Supportive Care in Ovarian Cancer Patients.

OBJECTIVE: Lack of access to supportive care (SC) among cancer patients have been well documented. However, the role of affordability in this disparity among ovarian cancer (OC) patients remain poorly understood. METHODS: Patients with OC between 2008 and 2015 were identified from the SEER-Medicare dataset. Racial disparities in utilization of SC medications within the six months of OC diagnosis among patients with Medicare Part D coverage was examined. Multivariable log-binomial regression models were used to examine the associations of race, affordability and SC medications after adjusting for clinical covariates among all patients and separately among patients with advanced-stage disease. RESULTS: The study cohort included 3697 patients: 86% non-Hispanic White (NHW), 6% non-Hispanic Black (NHB), and 8% Hispanic. In adjusted models, NHB and Hispanic patients were less likely to receive antidepressants compared to NHW patients (NHB: aOR 0.46; 95% CI 0.33-0.63 and Hispanic: aOR 0.79; 95% CI 0.63-0.99). This association persisted for NHB patients with advanced-stage disease (aOR 0.42; 95% CI 0.28-0.62). Patients dual enrolled in Medicaid were more likely to receive antidepressants (overall: aOR 1.34; 95% CI 1.17-1.53 and advanced-stage: aOR 1.29; 95% CI 1.10-1.52). However, patients residing in areas with higher vs. lower proportions of lower educated adults (overall: aOR 0.82; 95% CI 0.70-0.97 and advanced-stage: aOR 0.82; 95% CI 0.68-0.99) were less likely to receive antidepressants. CONCLUSION: Black OC patients and those living in lower educated areas were less likely to receive antidepressants as SC. Given the importance of post-primary treatment quality of life for cancer patients, interventions are needed to enhance equitable access to SC.

Race, Socioeconomic Status, and Health-Care Access Disparities in Ovarian Cancer Treatment and Mortality: Systematic Review and Meta-Analysis.

BACKGROUND: Ovarian cancer remains a leading cause of death from gynecological malignancies. Race, socioeconomic status (SES), and access to health care are important predictors of quality treatment and survival. We provide a systematic review and meta-analysis on the role of these predictors on disparities in ovarian cancer treatment and mortality. METHODS: Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched PubMed, EMBASE, and Scopus for relevant articles published between January 2000 and March 2017. We selected studies published in the United States that evaluated the role of race, SES, or health-care access on disparities in ovarian cancer treatment or survival. Pooled relative risk (RR) and 95% confidence intervals (CIs) were calculated for each outcome using a random-effects model. RESULTS: A total of 41 studies met the inclusion criteria for systematic review. In meta-analysis, there was a 25% decrease (RR = 0.75, 95% CI = 0.66 to 0.84) in receipt of adherent ovarian cancer treatment and 18% increased risk (RR = 1.18, 95% CI = 1.11 to 1.26) of mortality for blacks compared to whites. Receipt of adherent ovarian cancer treatment was 15% lower (RR = 0.85, 95% CI = 0.77 to 0.94) in the lowest vs highest SES group and 30% lower (RR = 0.70, 95% CI = 0.58 to 0.85) among patients at lower vs higher hospital volumes. CONCLUSION: We found consistent and strong evidence for continued lack of quality ovarian cancer treatment and higher mortality among ovarian cancer patients who are black, are of low SES, and/or have poor access to care. Interventions focused on these groups targeting specific barriers to care are needed to reduce disparities in ovarian cancer treatment and mortality.

Identifying Smoking Status and Smoking Cessation Using a Data Linkage Between the Kentucky Cancer Registry and Health Claims Data.

PURPOSE: Linkage of cancer registry data with complementary data sources can be an informative way to expand what is known about patients and their treatment and improve delivery of care. The purpose of this study was to explore whether patient smoking status and smoking-cessation modalities data in the Kentucky Cancer Registry (KCR) could be augmented by linkage with health claims data. METHODS: The KCR conducted a data linkage with health claims data from Medicare, Medicaid, state employee insurance, Humana, and Anthem. Smoking status was defined as documentation of personal history of tobacco use (International Classification of Diseases, Ninth Revision [ICD-9] code V15.82) or tobacco use disorder (ICD-9 305.1) before and after a cancer diagnosis. Use of smoking-cessation treatments before and after the cancer diagnosis was defined as documentation of smoking-cessation counseling (Healthcare Common Procedure Coding System codes 99406, 99407, G0375, and G0376) or pharmacotherapy (eg, nicotine replacement therapy, bupropion, varenicline). RESULTS: From 2007 to 2011, among 23,703 patients in the KCR, we discerned a valid prediagnosis smoking status for 78%. KCR data only (72%), claims data only (6%), and a combination of both data sources (22%) were used to determine valid smoking status. Approximately 4% of patients with cancer identified as smokers (n = 11,968) and were provided smoking-cessation counseling, and 3% were prescribed pharmacotherapy for smoking cessation. CONCLUSION: Augmenting KCR data with medical claims data increased capture of smoking status and use of smoking-cessation modalities. Cancer registries interested in exploring smoking status to influence treatment and research activities could consider a similar approach, particularly if their registry does not capture smoking status for a majority of patients.

Impact of the Affordable Care Act on Colorectal Cancer Screening, Incidence, and Survival in Kentucky.

BACKGROUND: Kentucky ranks first in the US in cancer incidence and mortality. Compounded by high poverty levels and a high rate of medically uninsured, cancer rates are even worse in Appalachian Kentucky. Being one of the first states to adopt the Affordable Care Act (ACA) Medicaid expansion, insurance coverage markedly increased for Kentucky residents. The purpose of our study was to determine the impact of Medicaid expansion on colorectal cancer (CRC) screening, diagnosis, and survival in Kentucky. STUDY DESIGN: The Kentucky Cabinet for Health and Family Services and the Kentucky Cancer Registry were queried for individuals (≥20 years old) undergoing CRC screening (per US Preventative Services Task Force) or diagnosed with primary invasive CRC from January 1, 2011 to December 31, 2016. Colorectal cancer screening rates, incidence, and survival were compared before (2011 to 2013) and after (2014 to 2016) ACA implementation. RESULTS: Colorectal cancer screening was performed in 930,176 individuals, and 11,441 new CRCs were diagnosed from 2011 to 2016. Screening for CRC increased substantially for Medicaid patients after ACA implementation (+230%, p < 0.001), with a higher increase in screening among the Appalachian (+44%) compared with the non-Appalachian (+22%, p < 0.01) population. The incidence of CRC increased after ACA implementation in individuals with Medicaid coverage (+6.7%, p < 0.001). Additionally, the proportion of early stage CRC (stage I/II) increased by 9.3% for Appalachians (p = 0.09), while there was little change for non-Appalachians (-1.5%, p = 0.60). Colorectal cancer survival was improved after ACA implementation (hazard ratio 0.73, p < 0.01), particularly in the Appalachian population with Medicaid coverage. CONCLUSIONS: Implementation of Medicaid expansion led to a significant increase in CRC screening, CRC diagnoses, and overall survival in CRC patients with Medicaid, with an even more profound impact in the Appalachian population.

Population-Based Assessment of HPV Genotype-Specific Cervical Cancer Survival: CDC Cancer Registry Sentinel Surveillance System.

Background: Human papillomavirus (HPV) genotype influences the development of invasive cervical cancer (ICC); however, there is uncertainty regarding the association of HPV genotype with survival among ICC patients. Methods: Follow-up data were collected from 693 previously selected and HPV-typed ICC cases that were part of the Centers for Disease Control and Prevention Cancer Registry Surveillance System. Cases were diagnosed between 1994 and 2005. The Kaplan-Meier method was used to estimate five-year all-cause survival. A multivariable Cox proportional hazards model was used to estimate the effect of HPV genotype on survival after adjusting for demographic, tumor, and treatment characteristics. Results: Five-year all-cause survival rates varied by HPV status (HPV 16: 66.9%, HPV 18: 65.7%, HPV 31/33/45/52/58: 70.8%, other oncogenic HPV genotypes: 79.0%, nononcogenic HPV: 69.3%, HPV-negative: 54.0%). Following multivariable adjustment, no statistically significant survival differences were found for ICC patients with HPV 16-positive tumors compared with women with tumors positive for HPV 18, other oncogenic HPV types, or HPV-negative tumors. Women with detectable HPV 31/33/33/45/52/58 had a statistically significant 40% reduced hazard of death at five years (95% confidence interval [CI] = 0.38 to 0.95), and women who tested positive for nononcogenic HPV genotypes had a statistically significant 57% reduced hazard of death at five years (95% CI = 0.19 to 0.96) compared with women with HPV 16 tumors. Few statistically significant differences in HPV positivity, tumor characteristics, treatment, or survival were found by race/ethnicity. Conclusions: HPV genotype statistically significantly influenced five-year survival rates among women with ICC; however, screening and HPV vaccination remain the most important factors to improve patient prognosis and prevent future cases.

Computational design and experimental characterization of peptides intended for pH-dependent membrane insertion and pore formation.

There are many opportunities to use macromolecules, such as peptides and oligonucleotides, for intracellular applications. Despite this, general methods for delivering these molecules to the cytosol in a safe and efficient manner are not available. Efforts to develop a variety of intracellular drug delivery systems such as viral vectors, lipoplexes, nanoparticles, and amphiphilic peptides have been made, but various challenges such as delivery efficiency, toxicity, and controllability remain. A central challenge is the ability to selectively perturb, not destroy, the membrane to facilitate cargo introduction. Herein, we describe our efforts to design and characterize peptides that form pores inside membranes at acidic pH, so-called pH-switchable pore formation (PSPF) peptides, as a potential means for facilitating cargo translocation through membranes. Consistent with pore formation, these peptides exhibit low-pH-triggered selective release of ATP and miRNA, but not hemoglobin, from red blood cells. Consistent with these observations, biophysical studies (tryptophan fluorescence, circular dichroism, size-exclusion chromatography, analytical ultracentrifugation, and attenuated total reflectance Fourier transformed infrared spectroscopy) show that decreased pH destabilizes the PSPF peptides in aqueous systems while promoting their membrane insertion. Together, these results suggest that reduced pH drives insertion of PSPF peptides into membranes, leading to target-specific escape through a proposed pore formation mechanism.