Combination of dociparstat sodium (DSTAT), a CXCL12/CXCR4 inhibitor, with azacitidine for the treatment of hypomethylating agent refractory AML and MDS.

Leukemia stem cells utilize cell adhesion molecules like CXCR4/CXCL12 to home to bone marrow stromal niches where they are maintained in a dormant, protected state. Dociparstat sodium (DSTAT, CX-01) is a low anticoagulant heparin with multiple mechanisms of action, including inhibition of the CXCR4/CXCL12 axis, blocking HMGB1, and binding platelet factor 4 (PF-4). We conducted a pilot study adding DSTAT to azacitidine for patients with AML or MDS unresponsive to or relapsed after prior hypomethylating agent therapy, hypothesizing that DSTAT may improve response rates. Twenty patients were enrolled, with a median of 2 prior lines of therapy and 6 cycles of prior hypomethylating agents. Among fifteen patients evaluable for response, there was 1 complete remission, and 3 marrow complete remissions, for a response rate of 27 % among evaluable patients (20 % overall). Hematologic improvement was observed in 5 additional patients. The median overall survival for all enrolled patients was 205 days (95 % CI 119-302). While cytopenias and infections were common, these were not out of proportion to what would be expected in this population of patients undergoing treatment with azacitidine alone. In summary, this trial demonstrated the feasibility of combining DSTAT with azacitidine, with several responses observed, suggesting this combination warrants further study.

A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma.

PURPOSE: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. METHODS: This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety. RESULTS: From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1-12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase). CONCLUSIONS: Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.

Combination of the low anticoagulant heparin CX-01 with chemotherapy for the treatment of acute myeloid leukemia.

Relapses in acute myelogenous leukemia (AML) are a result of quiescent leukemic stem cells (LSCs) in marrow stromal niches, where they resist chemotherapy. LSCs employ CXCL12/CXCR4 to home toward protective marrow niches. Heparin disrupts CXCL12-mediated sequestration of cells in the marrow. CX-01 is a low-anticoagulant heparin derivative. In this pilot study, we combined CX-01 with chemotherapy for the treatment of AML. Induction consisted of cytarabine and idarubicin (7 + 3) with CX-01. Twelve patients were enrolled (median age, 56 years; 3 women). Three, 5, and 4 patients had good-, intermediate-, and poor-risk disease, respectively. Day 14 bone marrows were available on 11 patients and were aplastic in all without detectable leukemia. Eleven patients (92%) had morphologic complete remission after 1 induction (CR1). Eight patients were alive at a median follow-up of 24 months (4 patients in CR1). Three patients received an allogeneic stem cell transplant in CR1. Median disease-free survival was 14.8 months. Median overall survival was not attained at the maximum follow-up time of 29.4 months. No CX-01-associated serious adverse events occurred. Median day to an untransfused platelet count of at least 20 × 109/L was 21. CX-01 is well tolerated when combined with intensive therapy for AML and appears associated with enhanced count recovery and treatment efficacy.

Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth.

Neuroblastoma prognosis is dependent on both the differentiation state and stromal content of the tumor. Neuroblastoma tumor stroma is thought to suppress neuroblast growth via release of soluble differentiating factors. Here, we identified critical growth-limiting components of the differentiating stroma secretome and designed a potential therapeutic strategy based on their central mechanism of action. We demonstrated that expression of heparan sulfate proteoglycans (HSPGs), including TßRIII, GPC1, GPC3, SDC3, and SDC4, is low in neuroblasts and high in the Schwannian stroma. Evaluation of neuroblastoma patient microarray data revealed an association between TGFBR3, GPC1, and SDC3 expression and improved prognosis. Treatment of neuroblastoma cell lines with soluble HSPGs promoted neuroblast differentiation via FGFR1 and ERK phosphorylation, leading to upregulation of the transcription factor inhibitor of DNA binding 1 (ID1). HSPGs also enhanced FGF2-dependent differentiation, and the anticoagulant heparin had a similar effect, leading to decreased neuroblast proliferation. Dissection of individual sulfation sites identified 2-O, 3-O-desulfated heparin (ODSH) as a differentiating agent, and treatment of orthotopic xenograft models with ODSH suppressed tumor growth and metastasis without anticoagulation. These studies support heparan sulfate signaling intermediates as prognostic and therapeutic neuroblastoma biomarkers and demonstrate that tumor stroma biology can inform the design of targeted molecular therapeutics.

Randomized, controlled trial of a multimodal intervention to improve cancer screening rates in a safety-net primary care practice.

BACKGROUND: Cancer screening rates are suboptimal for low-income patients. OBJECTIVE: To assess an intervention to increase cancer screening among patients in a safety-net primary care practice. DESIGN: Patients at an inner-city family practice who were overdue for cancer screening were randomized to intervention or usual care. Screening rates at 1 year were compared using the chi-square test, and multivariable analysis was performed to adjust for patient factors. SUBJECTS: All average-risk patients at an inner-city family practice overdue for mammography or colorectal cancer (CRC) screening. Patients' ages were 40 to 74 years (mean 53.9, SD 8.7) including 40.8 % African Americans, 4.2 % Latinos, 23.2 % with Medicaid and 10.9 % without any form of insurance. INTERVENTION: The 6-month intervention to promote cancer screening included letters, automated phone calls, prompts and a mailed Fecal Immunochemical Testing (FIT) Kit. MAIN MEASURES: Rates of cancer screening at 1 year. KEY RESULTS: Three hundred sixty-six patients overdue for screening were randomly assigned to intervention (n = 185) or usual care (n = 181). Primary analysis revealed significantly higher rates of cancer screening in intervention subjects: 29.7 % vs. 16.7 % for mammography (p = 0.034) and 37.7 % vs. 16.7 % for CRC screening (p = 0.0002). In the intervention group, 20 % of mammography screenings and 9.3 % of CRC screenings occurred at the early assessment, while the remainder occurred after repeated interventions. Within the CRC intervention group 44 % of screened patients used the mailed FIT kit. On multivariable analysis the CRC screening rates remained significantly higher in the intervention group, while the breast cancer screening rates were not statistically different. CONCLUSIONS: A multimodal intervention significantly increased CRC screening rates among patients in a safety-net primary care practice. These results suggest that relatively inexpensive letters and automated calls can be combined for a larger effect. Results also suggest that mailed screening kits may be a promising way to increase average-risk CRC screening.

Modulation of protein C activation by histones, platelet factor 4, and heparinoids: new insights into activated protein C formation.

OBJECTIVE: Histones are detrimental in late sepsis. Both activated protein C (aPC) and heparin can reverse their effect. Here, we investigated whether histones can modulate aPC generation in a manner similar to another positively charged molecule, platelet factor 4, and how heparinoids (unfractionated heparin or oxygen-desulfated unfractionated heparin with marked decrease anticoagulant activity) may modulate this effect. APPROACH AND RESULTS: We measured in vitro and in vivo effects of histones, platelet factor 4, and heparinoids on aPC formation, activated partial thromboplastin time, and murine survival. In vitro, histones and platelet factor 4 both affect thrombin/thrombomodulin aPC generation following a bell-shaped curve, with a peak of >5-fold enhancement. Heparinoids shift these curves rightward. Murine aPC generation studies after infusions of histones, platelet factor 4, and heparinoids supported the in vitro data. Importantly, although unfractionated heparin and 2-O, 3-O desulfated heparin both reversed the lethality of high-dose histone infusions, only mice treated with 2-O, 3-O desulfated heparin demonstrated corrected activated partial thromboplastin times and had significant levels of aPC. CONCLUSIONS: Our data provide a new contextual model of how histones affect aPC generation, and how heparinoid therapy may be beneficial in sepsis. These studies provide new insights into the complex interactions controlling aPC formation and suggest a novel therapeutic interventional strategy.

Evaluating postgraduate public health and biomedical training program outcomes: : lost opportunities and renewed interest.

To identify recent studies in the scientific literature that evaluated structured postgraduate public health and biomedical training programs and reported career outcomes among individual trainees, a comprehensive search of several databases was conducted to identify published studies in English between January 1995 and January 2012. Studies of interest included those that evaluated career outcomes for trainees completing full-time public health or biomedical training programs of at least 12 months duration, with structured training offered on-site. Of the over 600 articles identified, only 13 met the inclusion criteria. Six studies evaluated US federal agency programs and six were of university-based programs. Seven programs were solely or predominantly of physicians, with only one consisting mainly of PhDs. Most studies used a cohort or cross-sectional design. The studies were mainly descriptive, with only four containing statistical data. Type of employment was the most common outcome measure (n = 12) and number of scientific publications (n = 6) was second. The lack of outcomes evaluation data from postgraduate public health and biomedical training programs in the published literature is a lost opportunity for understanding the career paths of trainees and the potential impact of training programs. Suggestions for increasing interest in conducting and reporting evaluation studies of these structured postgraduate training programs are provided.

Examining the Relationship between Choice, Therapeutic Alliance and Outcomes in Mental Health Services.

BACKGROUND: Self-determination within mental health services is increasingly recognized as an ethical imperative, but we still know little about the impact of choice on outcomes among people with severe mental illnesses. This study examines whether choice predicts outcomes and whether this relationship is mediated by therapeutic alliance. METHOD: The study sample of 396 participants completed a survey measuring choice, therapeutic alliance, recovery, quality of life and functioning. Multivariate analyses examined choice as a predictor of outcomes, and Sobel tests assessed alliance as a mediator. RESULTS: Choice variables predicted recovery, quality of life and perceived outcomes. Sobel tests indicated that the relationship between choice and outcome variables was mediated by therapeutic alliance. IMPLICATIONS: The study demonstrates that providing more choice and opportunities for collaboration within services does improve consumer outcomes. The results also show that collaboration is dependent on the quality of the relationship between the provider and consumer.

Assessing the value of team science: a study comparing center- and investigator-initiated grants.

BACKGROUND: Large cross-disciplinary scientific teams are becoming increasingly prominent in the conduct of research. PURPOSE: This paper reports on a quasi-experimental longitudinal study conducted to compare bibliometric indicators of scientific collaboration, productivity, and impact of center-based transdisciplinary team science initiatives and traditional investigator-initiated grants in the same field. METHODS: All grants began between 1994 and 2004 and up to 10 years of publication data were collected for each grant. Publication information was compiled and analyzed during the spring and summer of 2010. RESULTS: Following an initial lag period, the transdisciplinary research center grants had higher overall publication rates than the investigator-initiated R01 (NIH Research Project Grant Program) grants. There were relatively uniform publication rates across the research center grants compared to dramatically dispersed publication rates among the R01 grants. On average, publications produced by the research center grants had greater numbers of coauthors but similar journal impact factors compared with publications produced by the R01 grants. CONCLUSIONS: The lag in productivity among the transdisciplinary center grants was offset by their overall higher publication rates and average number of coauthors per publication, relative to investigator-initiated grants, over the 10-year comparison period. The findings suggest that transdisciplinary center grants create benefits for both scientific productivity and collaboration.

U.S. primary care physicians' lung cancer screening beliefs and recommendations.

BACKGROUND: No high-quality study to date has shown that screening reduces lung cancer mortality, and expert groups do not recommend screening for asymptomatic individuals. Nevertheless, lung cancer screening tests are available in the U.S., and primary care physicians (PCPs) may have a role in recommending them to patients. PURPOSE: This study describes U.S. PCPs' beliefs about and recommendations for lung cancer screening and examines characteristics of PCPs who recommend screening. METHODS: A nationally representative survey of practicing PCPs was conducted in 2006-2007. Mailed questionnaires were used to assess PCPs' beliefs about lung cancer screening guidelines and the effectiveness of screening tests and to determine whether PCPs would recommend screening for asymptomatic patients. Data were analyzed in 2009. RESULTS: Nine hundred sixty-two PCPs completed the survey (absolute response rate=70.6%; cooperation rate=76.8%). One quarter said that major guidelines support lung cancer screening. Two thirds said that low-radiation dose spiral computed tomography (LDCT) screening is very or somewhat effective in reducing lung cancer mortality in current smokers; LDCT was perceived as more effective than chest x-ray or sputum cytology. Responding to vignettes describing asymptomatic patients of varying smoking exposure, 67% of PCPs recommended lung cancer screening for at least one of the vignettes. Most PCPs recommending screening said they would use chest x-ray; up to 26% would use LDCT. In adjusted analyses, PCPs' beliefs and practice style were strongly associated with their lung cancer screening recommendations. CONCLUSIONS: Many PCPs' lung cancer screening beliefs and recommendations are inconsistent with current evidence and guidelines. Provider education regarding the evidence base and guideline content of lung cancer screening is indicated.

Mapping U.S. government tobacco control leadership: networked for success?

INTRODUCTION: In order to better understand how tobacco control efforts are coordinated across agencies of the Department of Health and Human Services (DHHS), we assessed tobacco control-related communication between tobacco control leaders across DHHS. METHODS: Cross-sectional surveys were collected from individuals representing 11 DHHS agencies, and social network analyses were used to assess linkages and map agencies' tobacco control communication. RESULTS: Individuals within the Office of the Secretary and Centers for Disease Control and Prevention (CDC) were most central to the network, and those of highest rank were most likely to be central to the network (F = 4.03, p = .024). The Centers for Medicare and Medicaid Services, Food and Drug Administration, Health Resources and Services Administration, and Substance Abuse and Mental Health Services Administration had no or almost no contact with other agencies. There was considerable between-agency contact variability, and the CDC was the most central agency. DISCUSSION: Tobacco control communication across DHHS agencies was present but extremely variable. This inconsistency may compromise the ability of the DHHS to address tobacco use, a critical public health problem, in a coordinated and efficient fashion. In light of the new leadership at DHHS, this analysis describes a systems approach that can be reimplemented as a means of understanding and improving communication and collaboration to improve public health.

Adolescent attributes and young adult smoking cessation behavior.

This study collected data five times between 1983 and 2002 from 400 participants who originally came from upstate New York. These participants completed structured interviews as did their mothers three times. LISREL analysis generally supported the hypothesized model. The results indicated that having parents who smoked and having low educational aspirations and expectations were associated with being unconventional, which, in turn, was related to having low emotional control and reporting more internalizing behaviors. Internalizing behaviors were directly associated with a lower likelihood of smoking cessation, as was parental smoking. Research and clinical implications are discussed and the limitations noted.

Surveillance indicators for potential reduced exposure products (PREPs): developing survey items to measure awareness.

BACKGROUND: Over the past decade, tobacco companies have introduced cigarettes and smokeless tobacco products (known as Potential Reduced Exposure Products, PREPs) with purportedly lower levels of some toxins than conventional cigarettes and smokeless products. It is essential that public health agencies monitor awareness, interest, use, and perceptions of these products so that their impact on population health can be detected at the earliest stages. METHODS: This paper reviews and critiques existing strategies for measuring awareness of PREPs from 16 published and unpublished studies. From these measures, we developed new surveillance items and subjected them to two rounds of cognitive testing, a common and accepted method for evaluating questionnaire wording. RESULTS: Our review suggests that high levels of awareness of PREPs reported in some studies are likely to be inaccurate. Two likely sources of inaccuracy in awareness measures were identified: 1) the tendency of respondents to misclassify "no additive" and "natural" cigarettes as PREPs and 2) the tendency of respondents to mistakenly report awareness as a result of confusion between PREPs brands and similarly named familiar products, for example, Eclipse chewing gum and Accord automobiles. CONCLUSION: After evaluating new measures with cognitive interviews, we conclude that as of winter 2006, awareness of reduced exposure products among U.S. smokers was likely to be between 1% and 8%, with the higher estimates for some products occurring in test markets. Recommended measurement strategies for future surveys are presented.

Consumer awareness and attitudes related to new potential reduced-exposure tobacco product brands.

INTRODUCTION: In recent years, there has been a proliferation of potential reduced-exposure tobacco products (PREPs) marketed that claim to be less harmful or less addictive, compared with conventional cigarettes. Tobacco control scientists have raised concerns about the potential adverse impact of marketing of these products for smoking prevention and cessation efforts. Although these products have not been widely used among smokers, there are few data available on consumers' awareness and attitudes toward these products. METHODS: Data were obtained from the 2003 and 2005 Health Information National Trends Survey, a nationally representative telephone survey of adults 18 years and older regarding health communication and associated beliefs and behaviors. Our study population consisted of 6,369 respondents in 2003 and 5,586 respondents in 2005, of whom 19% were current smokers and 28% were former smokers. RESULTS: In 2005, 45% of respondents had heard of at least one PREP product, while only 4.8% had actually tried one. Awareness and use were substantially higher among current smokers (55.6% and 12.7%). Awareness was highest for Marlboro Ultra Smooth (MUS) (30.2%), Eclipse (18.2%), Quest (7.8%), and Ariva (5.4%), while less than 2% for any other product. Of respondents who had tried a PREP, 50% cited harm reduction or assistance in quitting as a reason for trying the product and 30% believed that the product was less harmful than their usual brand. In the combined 2003 and 2005 dataset, 54.4% of current smokers stated that they would be "very" or "somewhat" interested in trying a cigarette advertised as less harmful, while only 3.2% of former smokers and 1.1% of never-smokers were interested. Among current smokers, interest was higher in females and non-Hispanic Whites, and among daily smokers, those who smoked 20 or more cigarettes per day and those who were not considering quitting. Smokers interested in PREPs were substantially more likely to rate their perceived lung cancer risk as high (40.3% vs. 8.3%) and to worry frequently about developing lung cancer (19.7% vs. 4%). DISCUSSION: These results suggest that there is a substantial level of interest among current smokers in cigarettes marketed with claims of reduced exposure or harm. Of particular concern is that "health conscious" smokers and heavy smokers not planning to quit may be especially vulnerable to PREP marketing messages and view such products as an alternative to smoking cessation.

Monitoring the tobacco use epidemic I. Overview: Optimizing measurement to facilitate change.

OBJECTIVE: This Overview paper (I of V) summarizes research work to date on monitoring the tobacco use epidemic, discusses the recommendations made at the November, 2002 National Tobacco Monitoring, Research and Evaluation Workshop sponsored by the U.S. National Cancer Institute (NCI), Centers for Disease Control and Prevention (CDC), the American Legacy Foundation, and the Robert Wood Johnson Foundation on the topic of tobacco surveillance and evaluation, and discusses the current state of affairs. METHODS: A conceptual model based on the classical infectious diseases framework/paradigm focusing on the Agent, Host, Vector and Environment is used to integrate the work presented in the four other papers that appear in this supplemental issue of Preventive Medicine. RESULTS: The Agent paper (II) describes surveillance on tobacco products and biomarkers; the Host paper (III) describes surveillance on the smoker/user, or potential smoker/user; the Vector paper (IV) describes monitoring of industry activity; and the Environment paper (V) describes several key strategies for monitoring influential environmental factors. Overall, some improvements to the nation's surveillance system have been made in recent years. However, additional steps are needed to optimize measurement of tobacco use and factors influencing use in the United States. CONCLUSIONS: Tobacco monitoring efforts play a vital role in combating the epidemic of addiction and disease produced by various tobacco products. The knowledge and experience gained by the tobacco use prevention and control community through this commitment to linkages of data collected in the domains of Vector and Environment, in addition to Agent and Host, could inform monitoring of a wide range of other public health issues as well, including diet and nutrition, physical activity, overweight and obesity, and substance abuse.

Cigarette smoking and health-related quality of life in Medicare beneficiaries.

This study examined associations between cigarette smoking, cancer, and self-reported physical (SF-36 Physical Component Summary Score, [PCS]) and mental health (SF-36 Mental Component Summary Score, [MCS]) among 123,567 Medicare beneficiaries enrolled in managed care plans. As expected for a sample of older individuals, the SF-36 PCS mean (42.6) was lower than the U.S. general population mean of 50. The SF-36 MCS mean (51.7) for the sample was higher than the general population mean. In addition, least squares means revealed significantly poorer health for current smokers and those who recently quit, regardless of their cancer status. Although statistically significant, the differences between current smokers and never smokers were small among those with or without cancer. Encouraging smokers to quit and providing abstinence support to persons who have recently quit may help reduce health-related impacts of cigarette use.

Gender differences among hardcore smokers: an analysis of the tobacco use supplement of the current population survey.

BACKGROUND: Despite significant declines in smoking rates in the United States, a substantial percentage of adults continue to smoke. Improved understanding of current smokers and their contact with sources of cessation support future tobacco control efforts. Recent evidence suggests that hardcore smokers, established smokers without a history of quit attempts, have less contact with cessation support. Although gender is among the major factors that influence smoking cessation, no research is available on gender differences among hardcore smokers. METHODS: Demographic, environmental, and smoking-related characteristics of female hardcore smokers and male hardcore smokers and other female smokers were examined. Data from 17,777 smokers from the 2003 Current Population Survey Tobacco Use Supplement were analyzed. RESULTS: Compared with female hardcore smokers, male hardcore smokers were more likely to have contact with smoking restrictions at work (OR = 1.69) and at home (OR = 1.45). Compared with female hardcore smokers, female other smokers were more likely to have seen a healthcare provider during the past year who advised them to quit smoking (OR = 1.39) and more likely to have smoking restrictions at work (OR = 1.25) and at home (OR = 2.32)). Measures of nicotine dependence suggested that female hardcore smokers were less dependent than male hardcore smokers but more dependent than other female smokers. CONCLUSIONS: The sociodemographic and healthcare access variations in tobacco use identified in our analyses have significant public health implications and underscore the vital need for clinical and scientific advances in tobacco use prevention and control efforts.

Measuring collaboration and transdisciplinary integration in team science.

PURPOSE: As the science of team science evolves, the development of measures that assess important processes related to working in transdisciplinary teams is critical. Therefore, the purpose of this paper is to present the psychometric properties of scales measuring collaborative processes and transdisciplinary integration. METHODS: Two hundred-sixteen researchers and research staff participating in the Transdisciplinary Tobacco Use Research Centers (TTURC) Initiative completed the TTURC researcher survey. Confirmatory-factor analyses were used to verify the hypothesized factor structures. Descriptive data pertinent to these scales and their associations with other constructs were included to further examine the properties of the scales. RESULTS: Overall, the hypothesized-factor structures, with some minor modifications, were validated. A total of four scales were developed, three to assess collaborative processes (satisfaction with the collaboration, impact of collaboration, trust and respect) and one to assess transdisciplinary integration. All scales were found to have adequate internal consistency (i.e., Cronbach alpha's were all >0.70); were correlated with intermediate markers of collaborations (e.g., the collaboration and transdisciplinary-integration scales were positively associated with the perception of a center's making good progress in creating new methods, new science and models, and new interventions); and showed some ability to detect group differences. CONCLUSIONS: This paper provides valid tools that can be utilized to examine the underlying processes of team science--an important step toward advancing the science of team science.