Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas

Inhibition of iNOS as a Novel Effective Targeted Therapy Against Triple-Negative Breast Cancer

INTRODUCTION: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with no effective targeted therapy. Inducible nitric oxide synthase (iNOS) is associated with poor survival in patients with breast cancer by increasing tumor aggressiveness. This work aimed to investigate the potential of iNOS inhibitors as a targeted therapy for TNBC. We hypothesized that inhibition of endogenous iNOS would decrease TNBC aggressiveness by reducing tumor initiation and metastasis through modulation of epithelial-mesenchymal transition (EMT)-inducing factors. METHODS: iNOS protein levels were determined in 83 human TNBC tissues and correlated with clinical outcome. Proliferation, mammosphere-forming efficiency, migration, and EMT transcription factors were assessed in vitro after iNOS inhibition. Endogenous iNOS targeting was evaluated as a potential therapy in TNBC mouse models. RESULTS: High endogenous iNOS expression was associated with worse prognosis in patients with TNBC by gene expression as well as immunohistochemical analysis. Selective iNOS (1400 W) and pan-NOS (L-NMMA and L-NAME) inhibitors diminished cell proliferation, cancer stem cell self-renewal, and cell migration in vitro, together with inhibition of EMT transcription factors (Snail, Slug, Twist1, and Zeb1). Impairment of hypoxia-inducible factor 1α, endoplasmic reticulum stress (IRE1α/XBP1), and the crosstalk between activating transcription factor 3/activating transcription factor 4 and transforming growth factor β was observed. iNOS inhibition significantly reduced tumor growth, the number of lung metastases, tumor initiation, and self-renewal. CONCLUSIONS: Considering the effectiveness of L-NMMA in decreasing tumor growth and enhancing survival rate in TNBC, we propose a targeted therapeutic clinical trial by re-purposing the pan-NOS inhibitor L-NMMA, which has been extensively investigated for cardiogenic shock as an anti-cancer therapeutic

Characterizing cancer cells with cancer stem cell-like features in 293T human embryonic kidney cells

Abstract Background Since the first suggestion of prospectively identifiable cancer stem cells in solid tumors, efforts have been made to characterize reported cancer stem cell surrogates in existing cancer cell lines, and cell lines rich with these surrogates have been used to screen for cancer stem cell targeted agents. Although 293T cells were derived from human embryonic kidney, transplantation of these cells into the mammary fat pad yields aggressive tumors that self-renew as evidenced by serial xenograft passages through transplantation. Herein we fully characterize cancer stem cell-like features in 293T human embryonic kidney cells. Results 293T cells can be readily cultured and passaged as spheres in serum-free stem cell promoting culture conditions. Cells cultured in vitro as three-dimensional spheres (3D) were shown to contain higher ALDH1 and CD44+/CD24- population compared to monolayer cells. These cells were also resistant to radiation and upregulate stem cell survival signaling including β-catenin, Notch1 and Survivin in response to radiation. Moreover, 3D spheres generated from the 293T cells have increased expression of mesenchymal genes including vimentin, n-cadherin, zeb1, snail and slug as well as pro-metastatic genes RhoC, Tenascin C and MTA1. In addition, microRNAs implicated in self-renewal and metastases were markedly reduced in 3D spheres. Conclusions 293T cells exhibit a cancer stem cell-like phenotype when cultured as 3D spheres and represent an important research tool for studying the molecular and biological mechanisms of cancer stem cells and for testing and developing novel targets for cancer therapy. </jats:sec

Determinants of adult vaccination at inner-city health centers: A descriptive study

BACKGROUND: Pneumococcal polysaccharide vaccination rates among adults 65 years and older or less than 65 years with high risk medical conditions are still below Healthy People 2010 recommended levels of 90%. This study was designed to: 1) assess self-reported pneumococcal vaccination rates following health center level interventions to increase adult vaccination rates; and 2) determine factors associated with vaccination. METHODS: Tailored interventions to increase immunizations were implemented at two inner-city health centers. We surveyed 375 patients 50 years of age and older. Multivariate logistic regression examines the predictors of 1) self-reported pneumococcal vaccination and 2) combined self-reported influenza and pneumococcal vaccination. Both of these models were stratified by age group (50–64 years and 65 years and older). RESULTS: Pneumococcal vaccination rates were 45% by self-report, 55% by medical record review, 69% for patients 65 years old and older, 32% for patients 50–64 years; they did not differ by race. Receipt of the previous season's influenza vaccine was significantly related to pneumococcal vaccination among both younger and older patients. Receiving both the pneumococcal vaccine and the most recent influenza vaccine compared with receiving neither, among younger patients was related to unemployment, more frequent physician visits, and belief that those who do not receive the flu shot are more susceptible to the flu. For older patients, receipt of both vaccines was related to nonsmoking status, believing that friends/family think the patient should be vaccinated, seeing posters advertising flu shot clinics, and belief that those who do not receive the flu shot are more susceptible to the flu. CONCLUSION: Our findings suggest that improving overall pneumococcal vaccination rates among eligible adults, has the potential to eliminate racial disparities. Interventions delivering vaccination messages specific to older and younger adult groups may be the best strategy for improving adult vaccination rates

Nasal endoscopy score thresholds to trigger consideration of chronic rhinosinusitis treatment escalation and implications for disease control

Background: In the absence of direct evidence supporting how to use nasal endoscopy findings to judge chronic rhinosinusitis (CRS) disease control, experts' practice patterns could provide guidance. Methodology: Participants consisted of a diverse group of twenty-nine rhinologists. Participants were presented with every possible combination of bilateral nasal endoscopy findings represented by the modified Lund-Kennedy (MLK; range: 0–12) endoscopic scoring system and Nasal Polyp Score (NPS; range: 0–8). Reflecting the practical consequence of CRS disease control assessment, participants were asked whether they would consider CRS treatment escalation based on each scenario in the absence of any CRS symptoms, and how strongly they considered escalating therapy. The same scenarios were then presented in the context of 1 burdensome CRS symptom and participants again were asked whether they would consider treatment escalation. Results: The median threshold total MLK score for considering treatment escalation was ≥4 and 75.9% of participants’ MLK thresholds were within 1 point of 4. The median threshold total NPS for considering treatment escalation was ≥3 and 62.5% of participants’ NPS thresholds were within 1 point of 3. Endoscopy score thresholds decreased in the presence of 1 burdensome symptom and generally increased when requiring stronger affirmation for considering CRS treatment escalation. Conclusion: Reflecting the practice patterns of a diverse group of rhinologists, MLK score ≥4 or NPS ≥3 may serve as thresholds for considering CRS treatment escalation. Alternatively, MLK score <4 or NPS <3 may serve as endoscopic goals of CRS treatment. These results provide guidance for using nasal endoscopy findings as a criterion of CRS disease control

A Renewable Tissue Resource of Phenotypically Stable, Biologically and Ethnically Diverse, Patient-Derived Human Breast Cancer Xenograft Models

Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~21% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2−, one ER+PR+HER2− and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis

Abstract A91: Developing novel treatment strategies for triple-negative breast cancer metastasis

Abstract Despite the significant advances in breast cancer biology, there has been limited progress in the treatment of advanced breast cancer, with little change in the overall survival for women with metastatic breast cancer over the last several decades. There were approximately 180,000 new cases of breast cancer diagnosed in the United States in 2007. About 15% of these, accounting for 25,000 to 30,000 cases each year, are “triple-negative breast cancer” (TNBC) in that the tumors do not express the estrogen receptor (ER), progesterone receptor (PR), or HER-2/neu. Unlike therapies targeted against steroid hormone receptors or HER2, there is no Food and Drug Administration (FDA) approved targeted drugs for the treatment of TNBC, and hence these cancers are associated with the worst prognosis with patients ultimately succumbing to metastatic disease. Systemic therapies are effective initially in controlling and reversing tumor growth; however, residual cancers will invariably re-grow despite this initial response causing recurrence or metastasis at distant sites. The identification of new therapeutic targets against TNBC is crucial to improving the outcome of this subtype. Our goal is to eliminate TNBC metastasis by developing novel therapies capable of attacking and destroying the “lethal seeds” driving these cancers and metastases, the “tumor initiating cells” (TICs) or “cancer stem cells” (CSCs). Hypothesis: Targeting cancer stem cells will eliminate metastasis, ultimately improving survival in TNBC. Data from paired clinical human breast cancer biopsies showed that standard therapy every three weeks kills dividing daughter cells but not tumor-initiating cells (TICs), so that tumor tissue obtained after therapy is enriched for “tumor-initiating” or “cancer stem” cells. Using patient-derived tumorgraft models, we further discovered that despite complete eradication of primary TNBC tumors by multiple cycles of standard chemotherapy, metastases in distant sites ultimately developed, causing death. We analyzed the gene expression of CSC isolated from patient biopsies to identify therapeutic targets regulating CSCs. Based on the signaling pathways identified through this microarray analysis, we treated mice with small molecule inhibitors of STAT3 or the Notch signaling pathway and showed remarkable reduction of CSCs in primary tumors. We expect that the addition of CSC-targeted therapy to standard chemotherapy will eliminate metastasis. Single agent targeted therapy may only reduce metastatic burden, suggesting a cocktail of targeted-therapies will be required to eradicate metastasis, in which case, we would combine multiple therapies that target CSCs. Citation Format: Melissa D. Landis, Lacey A. Burey, Jenny C. Chang. Developing novel treatment strategies for triple-negative breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A91.</jats:p