Cooperative Agreement Grant Research Articles

EXPLORATION OF FALL RISK OF PARTICIPANTS ACROSS EVIDENCE-BASED FALL PREVENTION PROGRAMS

Abstract The National Council on Aging houses the Administration for Community Living’s (ACL) national database on evidence-based, community-delivered fall prevention programs (EBFPP). Each year, cooperative agreement grants are awarded competitively to groups demonstrating readiness to deliver EBFPP in their communities. Participants in these programs completed a standardized pre-participation survey documenting demographic and self-reported fall risk factors that were entered into the national EBFPP database. Marymount University received permission to analyze the survey data entered into the ACL’s National Falls Prevention Database between July 2016 and June 2022. An exploratory analysis was conducted of 105,323 older adults who participated in one of eight ACL-approved EBFPP programs. EBFPPs vary in their targeted fall risk level, tailoring intervention components (health education, self-management training, physical exercise) and adjusting intensity and focus to match the risk level. It is unknown if people join the program that best fits their risk level. This study evaluates and compares participant demographic characteristics and fall risk across EBFPPs. We created an index to categorize risk levels, anchored in the CDC’s STEADI toolkit for fall risk, finding that 29% were high risk, 51% moderate risk, and 19% low risk. The factors used to establish risk level included 1) falling in the last 3 months, 2) referral from a healthcare professional, 3) fear of falling, 4) self-reported health (not excellent or very good), 5) depression, and 6) age 85 or older. Exploring participant characteristics by risk level and choice of EBFPP adds unique information to guide future EBFPP recruitment strategies.

Using an academic-community partnership model to deliver evidence-based falls prevention programs in a metropolitan setting: A community case study.

Prevention is an effective approach for mitigating the negative health outcomes associated with falls in older adults. The Administration for Community Living (ACL) has sponsored the implementation of evidence-based falls prevention programs (EBFPPs) across the United States through cooperative agreement grants to decrease the health and economic burden of falls. Marymount University received two of these grants to deliver three EBFPPs into the northern Virginia region. This community case study describes the development of a collaboration between a university and community-based organizations to adopt and implement multiple evidence-based programming in an area where none previously existed. Through an academic-community partnership, EBFPPs were introduced to and implemented by senior-focused organizations. Target adopters were senior and community centers, multi-purpose senior services organizations, recreational organizations, and residential facilities serving older adults. The three EBFPPs were (1) Stay Active and Independent for Life (SAIL), (2) a Matter of Balance (MOB) and (3) Otago Exercise Program (OEP). Key interdependent project elements included: (1) fostering ongoing community organization collaboration, (2) introducing programs in the community, (3) growing and sustaining delivery sites, (4) preparing trained program leaders, and (5) building community demand for the programs. From August 2016-June 2022, 5,857 older adults participated in one of the three EBFPPs. SAIL classes were offered at 33 sites and MOB workshops at 31 with over 70% of them occurring at community or senior centers. OEP was offered at 4 sites. Factors that influenced the implementation of these programs included having: key advocates at host organizations, programs embedded into site workflows, sufficient capacity and workforce, engaged invested partners, and flexibility in working with a complex set of agencies and systems with different administrative structures. By connecting academic faculty with various community members from multiple sectors, new initiatives can be successfully implemented. Results from this ACL-funded project indicate that using an academic-community partnership model to build relationships and capacity for ongoing delivery of health promotion programming for older adults is feasible and effective in delivering EBFPPs. In addition, academic-community partnerships can develop a strong network of invested partners to foster continued support of fall prevention activities.

FEASIBILITY OF FALLS PREVENTION PROGRAMS IMPLEMENTATION BASED ON ACADEMIC-COMMUNITY PARTNERSHIPS

Abstract The Northern Virginia (NoVa) region is diverse in age, race, ethnicity, economic status, health status, culture, and language. Based on state data, it is estimated that 28.7% of the 75,000 older adults in NoVa will experience at least one fall annually. Since 2014, the Administration for Community Living (ACL) has sponsored implementation of evidence-based fall prevention programs (EBFPPs). The aims of this study are to 1) describe the EBFPP participants and delivery sites and 2) report initial effectiveness. Marymount University (MU) received two cooperative agreement grants (2016, 2018) from the ACL to implement in NoVa three EBFPPs: 1) Stay Active and Independent for Life (SAIL), 2) A Matter of Balance (MOB), and 3) Otago Exercise Program (OEP). The Northern Virginia Falls Prevention Alliance was formed and a Regional Training Office was built. The data source is the ACL national falls database. From 2016–2022, over 5,000 older adults were reached, over 400 EBFPP leaders were trained, and programs were delivered at 60 sites. Data analysis indicates that falls decreased from 20% to 15%. Those participating in MOB showed the greatest decline in falls (from 34% to 14%). Fall injuries declined from 11% to 7% and ED visits decreased from 3% to 1%. Preliminary analysis indicates beneficial impact: this academic-community partnership has reached people at low risk of falling (SAIL), and had an impactful decline in falls for individuals at moderate to high risk (MOB). Future research will investigate program outcome differences based on other demographics and delivery models.

Effect of a Novel High Phenolic Sorghum Bran (PI570481) on Lipid Accumulation in 3T3-L1 Cells

ObjectivesObesity is the leading public health problem and the main cause of many other metabolic and chronic complications. Sorghum is the fifth most important cereal crop in the world and certain varieties contain significantly greater amounts of biologically active phenolic compounds than other strains. PI570481 is a novel strain of high phenolic sorghum bran and show anti-cancer activities. The objective of this study is to explore a potential use of PI570481 with other phenolic sorghum bran extracts (SC84 and Sumac) and a sorghum grain (white sorghum) for the differentiation of preadipocytes and to investigate cellular and molecular responses in differentiated adipocytes to elucidate related mechanisms. Methods3T3-L1 preadipocytes were cultured with DMEM containing 10% FBS and differentiated using a differentiation cocktail containing 1 μM dexamethasone, 0.5 mM isobutylmethylxanthine, and 5 μg/mL insulin in 10% FBS/DMEM. Lipid accumulation was measured by Oil Red O (ORO) staining. Cellular reactive oxygen species (ROS) and glucose uptake were measured using DCFH-DA and 2-NBDG, respectively. Western blotting was performed to examine the expression of genes regulating adipogenesis, lipogenesis and cell signaling. ResultsSorghum extracts (PI570481, SC84, Sumac, white) did not cause cytotoxicity in both undifferentiated and differentiated 3T3-L1 cells. Sorghum bran extracts (PI570481, SC84, Sumac) reduced intracellular lipid accumulation and expression of adipogenic and lipogenic proteins in dose-dependent manner in differentiated 3T3-L1 cells. Regarding anti-adipogenic mechanism, sorghum bran extracts (PI570481, SC84, Sumac) represses ROS production and MAPK signaling pathways in differentiated 3T3-L1 cells. Sorghum bran extracts (PI570481, SC84, Sumac) also represses insulin signaling and glucose uptake in differentiated 3T3-L1 cells. ConclusionsThese data propose a potential use of a novel high phenolic sorghum bran as functional food. Funding SourcesMaryland Agricultural Experiment Station (MAES) and National Institute of Food and Agriculture (Project #: MD-NFSC-201,176) to S-HL Cooperative Agreement grant from USDA-ARS to S-HL.

Oxidative and Advanced Glycation End-Products Biomarkers and Their Association with the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC

Background: Type 1 diabetes confers a significant risk of cardiovascular disease (CVD), and new biomarkers of risk are needed for early detection. We have investigated the predictive value of oxidation products (OPs) and advanced glycation end-products (AGEs) for CVD events in the Diabetes Control and Complications Trial and the follow-up Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods: Using a case-control design, we measured plasma OPs including methionine sulfoxide [MetSO] and the AGE carboxyethyllysine [CEL] by LC/mass spectrometry in 459 participants (93 CVD cases and 366 controls) at three time points during DCCT, and at year 1-2 of EDIC. Cox proportional hazards models assessed the association between biomarkers as fixed or time-dependent covariates and the risk of subsequent CVD events. Prediction improvement was assessed using the C-statistic. Findings: Baseline CEL was associated with CVD (p=0·03, HR 1·15) when fully adjusted for age, HbA1c, BMI, HDL, LDL, sex, systolic and diastolic blood pressure, while MetSO at beginning of EDIC and as a time-dependent covariate, was strongly inversely associated with CVD outcomes (p < 0·001 and HR 0·58 and 0·61, respectively). MetSO also significantly increased the predictive c-statistic from 0·711 to 0·783 (p<0·001) when added to the other covariates. Interpretation: High levels of MetSO, a product of the free oxygen radical scavenger methionine, are associated with lower incidence of a primary CVD event during DCCT/EDIC· MetSO also significantly improved the predictive value over traditional risk factors, which may allow more timely institution of preventive therapies. Trial Registrations: NCT00360893, NCT00360815. Funding Statement: The DCCT/EDIC has been supported by cooperative agreement grants (1982-1993, 2012- 2017), and contracts (1982-2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease (current grant numbers U01 DK094176 and U01 DK094157), and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program (1993-2007), and Clinical Translational Science Center Program (2006-present), Bethesda, Maryland, USA. Declaration of Interests: None for JML and IB as noted below. PJB and Scott Howell have the following Declarations of interest: PJB is Chief Scientific Officer and Scott Howell is the Laboratory Director of PreventAGE Healthcare LLC (PHC), and PJB prepared and submitted the SBIR that funded the study in PHC’s name. PHCs goal is to develop precise biomarkers that can predict diabetic complications. Although no commercialization of the content of this manuscript has taken place, it is possible that this could occur in the future. Further detail on this relationship is contained in the enclosed ICJME form and in the “declaration of interests” section. Ethics Approval Statement: All appropriate written consents, permissions, and releases have been obtained from the participants by the DCCT/EDIC central overview committee.

Evaluating the Adoption of Laboratory Practice Guidelines.

To date, the College of American Pathologists (CAP) has developed 17 laboratory practice guidelines (LPGs) including updates. In 2013, the CAP was awarded a 5-year cooperative agreement grant from the United States Centers for Disease Control and Prevention to increase the effectiveness of LPGs. To assess the awareness and adoption of 2 CAP LPGs: immunohistochemical (IHC) assay validation and initial workup of acute leukemia. Baseline surveys for each LPG were conducted in 2010 and 2015, respectively. To measure the adoption of guideline recommendations and inform future updates, a follow-up study consisting of surveys, telephone interviews, and focus group sessions was conducted in laboratories that indicated they perform IHC testing. A follow-up study for the acute leukemia LPG is planned. For the IHC Validation LPG, a total of 1624 survey responses, 40 telephone interviews, and discussions with 5 focus group participants were analyzed. The response rate for the aforementioned 3 modalities was 46%, 13%, and 3%, respectively. All modalities indicated most respondents were aware of the LPG and had adopted most or all of its recommendations. Respondents expressed needs for continued communication, increased specificity, and more prescriptive recommendations when the guideline is updated. While data-driven development of evidence-based LPGs requires significant resources, active data collection to identify gaps and assess adoption contributes to improved laboratory testing practices in support of patient care. The CAP identified sustainable modalities to track metrics and developed multiple tools that should improve guideline development, adoption, and implementation. Of these modalities, written or electronic surveys were the most logistically feasible and had the highest response rate.

The US Food and Drug Administration Centers for Regulatory Science and Innovation: Current Activities and Future Promise to Accelerate Innovations.

The US Food and Drug Administration Centers for Regulatory Science and Innovation: Current Activities and Future Promise to Accelerate Innovations.

Emphasizing Public Health Within a Health Information Exchange: An Evaluation of the District of Columbia's Health Information Exchange Program.

Introduction:Clinovations Government Solutions (CGS) was contracted in 2013 to conduct a mixed-methods evaluation of the District of Columbia (D.C.) Health Information Exchange (HIE) program as part of their Cooperative Agreement Grant funded by the Office of the National Coordinator in 2010. The evaluation was to focus on the progress of the HIE, how many providers and hospitals were participating in the program, and what benefits were being realized through the use of the HIE. During the course of the evaluation, the CGS team found that the use of the HIE to support public health reporting was one of its core elements.Background:The D.C. HIE is one of 56 HIE that were funded out of the Cooperative Agreement program. The HIE program was managed by the District of Columbia Department of Health Care Finance (DHCF), which also manages the District of Columbia Medicaid Program. The program was initially designed to accomplish the following: developing state-level directories and enabling technical services for HIE within and across states; ensuring an effective model for governance and accountability; coordinating an integrated approach with Medicaid and public health; and developing or updating privacy and security requirements for HIE within and across state borders. As the evaluation progressed, the CGS team discovered that the relationship between the DHCF and the District of Columbia Department of Health (DOH) had become a cornerstone of the D.C. HIE program.Methods:The CGS team used a mixed-methods approach for the evaluation, including a review of documents developed by the DHCF in its HIE program, including its original application. We also conducted 10 key informant interviews and moderated two small-group discussions using a semistructured protocol; and we developed a survey that measured the use, satisfaction, and future sustainability of the HIE for over 200 providers within the District of Columbia.Findings:While the evaluation focused on the D.C. HIE program in its entirety, the results indicated the value of utilizing the HIE for public health reporting to enhance the surveillance activities of the DOH. Specifically, the DHCF and DOH collaboration resulted in using the HIE to electronically capture and report immunization data; and in requiring electronic lab reporting and results as part of the Meaningful Use Requirement—which can assist in detecting HIV/AIDS and providing better care for the district’s high population of individuals with HIV/AIDS. Electronic lab reporting and electronic prescribing within the HIE can assist the DOH and providers in identifying specific diseases, such as tuberculosis and viral hepatitis, before they affect a significant part of the population.Discussion:Given the severe health disparities in the district, the ability of the D.C. HIE program to collect public health information on affected populations will be instrumental in better understanding and identifying methods of supporting these populations through improved surveillance and identification of the appropriate treatments. The D.C. HIE program is uniquely positioned to support these populations due to the partnership of DHCF with the D.C. DOH.Conclusion and Next Steps:The District of Columbia has made significant strides in expanding its public health infrastructure and activities. Three key areas of growth were identified that have the potential to transform the District of Columbia’s public health approach: establishing sufficient feedback loops, collection of environmental data, integration, and interoperability.

Correction

HomeCirculation: Cardiovascular ImagingVol. 7, No. 2Correction Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection Originally published1 Mar 2014https://doi.org/10.1161/HCI.0000000000000003Circulation: Cardiovascular Imaging. 2014;7:415This article corrects the followingAdult Height and Prevalence of Coronary Artery CalciumA correction was needed to an article by Miedema et al, which published online December 11, 2013, and appeared in the January 2014 issue of this journal (Miedema MD, Petrone AB, Arnett DK, Dodson JA, Carr JJ, Pankow JS, Hunt SC, Province MA, Kraja A, Gaziano JM, Djousse L. Adult Height and Prevalence of Coronary Artery Calcium: The National Heart, Lung, and Blood Institute Family Heart Study. Circ Cardiovasc Imaging. 2014;7:).The Sources of Funding statement was revised and now appears as follows:The NHLBI Family Heart Study was supported by the NHLBI cooperative agreement grants U01 HL 67893, U01 HL67894, U01 HL67895, U01 HL67896, U01 HL67897, U01 HL67898, U01 HL67899, U01 HL67900, U01 HL67901, and U01 HL67902. Dr Dodson performed this work while on a T32 training grant from the National Institutes of Health/National Institute on Aging (T32 AG000158).This correction has been made to the current online version of the article, which is available at: http://circimaging.ahajournals.org/content/7/1/52.full Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesAdult Height and Prevalence of Coronary Artery CalciumMichael D. Miedema, et al. Circulation: Cardiovascular Imaging. 2014;7:52-57 March 2014Vol 7, Issue 2 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/HCI.0000000000000003 Originally publishedMarch 1, 2014 PDF download Advertisement

Evaluation Of Which Patients Get a Second Course Of 3+7 On Cooperative Group Trials For Newly Diagnosed Acute Myeloid Leukemia: A Report From SWOG

Cooperative group protocols giving 3 days of anthracycline and 7 of cytarabine (3+7) to patients with newly-diagnosed AML typically call for a 2nd 3+7 in patients not in CR after course 1. However, it is unclear how often this practice is followed and, in particular, whether patients who receive a 2nd course differ from those who do not. If so, results following the second course might be confounded by selection bias, as would results of any “salvage” therapy given to patients taken off after course 1. MethodsOur database consisted of 595 patients aged 60 with de novo AML given 3+7+/- gemtuzumab ozogamicin (GO) on SWOG protocol S0106 (Blood 2013 121(24):4854-4860). 237 (40%) were not in CR after course 1, of whom 19 died on this course, leaving 218 who per protocol should have received a 2nd 3+7. Information is available on 216 of the 218. We compared patients who did and did not receive a 2nd course with respect to age, marrow blasts on “day 14” (the median when the first post treatment exam was performed), day 14 cellularity, day 14 infiltrate (blasts X cellularity), and change in blasts, cellularity and infiltrate vs. pre-treatment. Each of these covariates were regarded numerically and we also examined the categorical covariates pre-treatment performance status (PS, 0-1 vs. 2-3), cytogenetics (SWOG criteria), and whether treatment was at a SWOG member institution or a SWOG non-member institution (with intergroup patients registered through the CTSU excluded from associated analyses). We used multivariate analysis to identify covariates independently associated with receiving a 2nd 3+7 and area under receiver operating characteristic curves (AUC) to quantify how effective the multivariate models were at predicting who received a 2nd course (AUC 1.0 = perfect prediction, AUC 0.5 = “coin flip”). Results119 of the 216 patients (55%) not in CR after course 1 received course 2, and this proportion was the same for patients given or not given GO on course 1. 76% of the 97 patients who went off protocol received alternative chemotherapy, 6% received an allogeneic transplant, 7% received no further therapy, and in 10% information was lacking. Patients who received a second course had a higher day 14 blast % than off-protocol patients (p = 0.005, medians 28% vs. 15%), but did not differ in day 14 cellularity, infiltrate, or change in any of these parameters vs. pre-treatment. Off protocol and 2 course patients were similarly aged (medians 47 and 48). A 2nd 3+7 was given to 59% of patients with unfavorable cytogenetics and 57% of others. 58% of 186 patients with PS 0-1 received a 2nd course vs. 41% of 29 with PS 2-3 (p=0.11). 50% of the patients treated at SWOG member sites went off protocol vs. 32% at non-member sites (p=0.05). However, characteristics of patients who went off protocol were similar at member and non-member sites, with the exception that patients with unfavorable cytogenetics comprised a higher proportion of patients who got further therapy (on or off protocol) at member sites (p=0.03). Multivariate analysis indicated that being a SWOG member site was the only covariate that was independently associated with a patient receiving a 2nd course , with non-member patients being 6.1-fold more likely to do so (p=0.014). The AUC for the multivariate model was 0.70. ConclusionsThe AUC from the multivariate model suggests that our ability to identify patients who will receive a 2nd course of 3+7 rather than being removed from protocol is quite limited. Within this constraint, patients treated at SWOG member sites are more likely to be removed from protocol treatment. Whether this simply reflects the availability of more therapeutic options or a more systematic bias remains to be determined.ClinicalTrials.gov Identifier: NCT00085709 FundingThis work was supported in part by PHS Cooperative Agreement grants awarded by the National Cancer Institute, CA32102 and CA38926, and in part by Wyeth (Pfizer) Pharmaceuticals. Disclosures:No relevant conflicts of interest to declare.

Prediction Of CR On Reinduction In Patients With Newly Diagnosed Acute Myeloid Leukemia Given Intensive Induction Regimens: A Report From SWOG and Cleveland Clinic

3+7” (3 days of daunorubicin or idarubicin + 7 of cytarabine) is the most frequently used intensive induction regimen for newly diagnosed AML. While it is common practice to reinduce patients (pts) who do not achieve marrow ablation by day 14 with the same agents, it remains unclear whether any particular disease or treatment-related factors can predict for CR with such a strategy, or can identify pts who should more appropriately be considered to have primary refractory disease at day 14 and treated with different agents.This analysis was designed to address this question. MethodsWe analyzed 1505 pts given 3+7 on SWOG studies S8600 (n = 534), S9031 (n= 215), S9333 (n = 161), and S0106 (n = 595) and 235 treated at Cleveland Clinic from 2006-2010 of whom 54 were reinduced with anthracycline-based therapy. In the SWOG cohort, 49% of pts achieved CR on course 1. Of the 734 patients who were alive at day 28 but did not achieve CR on course 1, 336 (53%) had received a reinduction course of 3+7. We used multivariate logistic regression to identify covariates associated with achievement of CR to reinduction in these 336 pts. The area under receiver operating characteristic curves (AUC) were used to quantify the effectiveness of the multivariate models at predicting CR in reinduction (AUC 1.0 = perfect prediction, AUC 0.5 = “coin flip”). Numerical covariates examined were [median (range)]: age (51, 15-83), day the first post-induction marrow was examined (hereafter “day 14”, 15, 7-48), day 14 blasts % (20, 0-95), day 14 % cellularity (37, 1-85), and their product (infiltrate, 5, 0-74), change in % blasts from day 1 (-44, -96,50), change in cellularity from day 1 (-5, -99-80), change in infiltrate from day 1 (-2, 93-41), and days from start of course 1 to start of course 2 (21, 13-67). Categorical covariates examined were: pre-treatment performance status (PS, ECOG scale) and pre-treatment cytogenetics (SWOG criteria). Results40% of the 336 SWOG pts achieved CR to 3+7 reinduction, while 14% died during the first 28 days following reinduction, and 45% neither died during this time nor achieved CR (resistant). Age was associated with reinduction CR rate (median 47 for CR, 56 for no CR, p<0.001), as was day of reinduction (median 24 for CR, 20 for no CR, p=0.005), cytogenetics (CR rates 75% for favorable, 35% for intermediate, 18% for unfavorable, and 9% for unknown, p=0.04), and AML status (CR rate 42% for de novo and 16% for secondary AML). However, the AUC for age was 0.63, day of second induction was 0.59, cytogenetics was 0.60, and AML status was 0.53. Day 14 marrow blast % was similar in pts who did and did not achieve CR to reinduction (medians 20% and 22% respectively, p = 0.8). Similarly, day 14 cellularity, day 14 infiltrate, change in blast %, cellularity, infiltrate from pretreatment, and day when course 2 began were not associated with reinduction CR rate. On multivariate analysis, none of these covariates nor SWOG protocol was associated with second course CR rate, and the AUC for this multivariate model was only 0.70. There was no evidence that the effects of covariates differed in the different protocols. In the Cleveland Clinic cohort, 53% of pts achieved a CR on their reinduction or 3rd induction course, 11% died during the first 28 days of reinduction, and 33% were resistant. In this cohort, no covariates were associated with CR on reinduction or 3rd induction and AUC values were uniformly low and similar to the SWOG cohort. ConclusionIn AML pts treated with 3+7 regimens, our findings indicate that bone marrow parameters, specifically day 14 blasts %, marrow cellularity, and treatment-related changes do not predict for subsequent CR with a reinduction Perhaps too few patients not in CR after a first course of 3+7 receive reinduction with 3+7.ClinicalTrials.gov Identifier: NCT00085709 (others precede registry reporting) FundingThis work was supported by PHS Cooperative Agreement grants awarded by the National Cancer Institute, CA32102 and CA38926 Disclosures:No relevant conflicts of interest to declare.

Alteration Of Cytogenetic Risk Stratification In New Diagnosis Of Leukemia By FISH Testing – Retrospective Review Of The SWOG Experience

▪ BackgroundFluorescence in situ hybridization (FISH) is an invaluable tool for complementing conventional karyotype analysis in the diagnosis of leukemia. FISH panels are often requested by clinicians, along with karyotype analysis, for molecular determination of clinically actionable abnormalities. For most cooperative group clinical trials, unlike karyotype analysis, FISH has not been required to determine eligibility or risk stratification. Yet no previous studies have shown how often FISH results might alter the cytogenetic risk category determined by karyotype analysis. Furthermore, FISH panels which may include 5∼10 probe sets are costly while karyotype analysis for new diagnosis of myeloid leukemia is routine and highly informative. Therefore we aim to determine the frequency of cytogenetic risk alteration by FISH testing to serve as an evidence base for future study design and best clinical practice. Patients and MethodsOur study set includes all leukemia patients enrolled in SWOG leukemia studies from 2002 to 2012 with both cytogenetic and FISH results available at the time of initial diagnosis (n=248), representing 12% of total patients enrolled in these studies. There are 169 patients with acute myeloid leukemia (AML), 22 of whom had acute promyelocytic leukemia (APL); 45 with chronic myeloid leukemia (CML-CP); and 34 with acute lymphocytic leukemia (ALL). The age range was 19-87 (median 51) years. Patients received various therapies based on the study protocols. All cytogenetic and FISH results were submitted from SWOG-approved laboratories and were reviewed by the SWOG Cytogenetics Committee. Risk categorization was based on combined SWOG and MRC criteria. ResultsThere was great variation in the number and the type of FISH probes used for the workup of new diagnosis of leukemia (range 1-12 per patient). The most frequent FISH findings with added value were cryptic translocations, including amplification and/or rearrangement of MYC (mean overall survival 8.2 months without remission) and rearrangement of MLL. In the submitted studies, there were no misses for subtle chromosome abnormalities by karyotype analysis, including the inv(16), although FISH clarified deletion 16q instead of inv(16) occasionally. FISH and karyotype analyses were consistent for large chromosome abnormalities such as deletions of 5q and 7q, t(8;21), and trisomy 8. Of all 248 patients, 47 (19.0%) had favorable cytogenetics, 133 (53.6%) intermediate, 64 (25.8%) unfavorable, and 4 (1.6%) unknown. Of the 147 non-APL AML patients, 23 (15.6%) had favorable cytogenetics, 79 (53.7%) intermediate [72 (49.0%) after FISH], and 64 (43.5%) unfavorable [71 (48.3%) after FISH]. Overall, eight patients (3.2%) demonstrated alterations in risk categorization after FISH analysis: 7 from intermediate to unfavorable among AML patients, and 1 from favorable to intermediate among ALL patients. Of the 45 CML patients, karyotyping adequately identified all t(9;22), and 3 patients demonstrated additional secondary abnormalities. FISH identified 5 patients with submicroscopic deletions on the derivative 9 (which was once considered a higher-risk feature but appears to have been overcome by therapy with tyrosine kinase inhibitors). Of the 34 ALL patients, 16 (47.1%) had unfavorable cytogenetics; 12 (35.3%) intermediate; and the remaining 2 showed favorable hyperdiploidy, one of which was reclassified as intermediate due to detection of structural rearrangements by FISH. ConclusionThe frequency of cytogenetic risk alteration by FISH after karyotyping analysis for new diagnosis of leukemia was low, supporting current clinical trial designs that do not require extensive FISH panel testing for protocol eligibility. However, FISH clearly adds value in detecting cases with cryptic rearrangements, which can contribute to altered risk stratification. It may be helpful to ascertain subtle rearrangements by FISH, such as inv(3), inv(16), t(6;9), MLL (11q23) rearrangement, and MYC (8q24) amplification and rearrangement.This work was supported by PHS Cooperative Agreement grants awarded by the National Cancer Institute, CA32102 and CA38926. Disclosures:No relevant conflicts of interest to declare.

The Addition Of Gemtuzumab Ozogamicin (GO) To Induction Chemotherapy Reduces Relapse and Improves Survival In Patients Without Adverse Risk Karyotype: Results Of An Individual Patient Meta-Analysis Of The Five Randomised Trials

IntroductionGemtuzumab ozogamicin (GO, Mylotarg) in AML treatment remains controversial: some studies report significant survival benefits either overall or in patient subgroups, but one study showed no, with an excess of early mortality in the GO arm. The five trials so far reported had the common aim of augmenting standard induction chemotherapy which lends itself to a meta-analysis, to determine whether the totality of the evidence demonstrates any benefit for GO, and/or in which specific subgroups of patients. We therefore performed an individual patient data (IPD) meta-analysis of these trials. An IPD meta-analysis has considerable advantages over a published data meta-analysis. Analyses can take into account updated data, unpublished trials, and also look at stratified analyses to identify subgroups of patients. Methods and MaterialsThe 5 trials combining GO with the first course of standard induction chemotherapy were identified, the SWOG-0106 study (ClinicalTrials.gov Identifier: NCT00085709), the ALFA-0701 trial, the UK MRC/NCRI AML15 & 16 trials, and the GOELAMS AML2006IR trial. The last of these is so far unpublished. Updated datasets were requested from all trialists. A total of 3339 patients, ranging in age from 0 to 84 were recruited. Information was requested on age, sex, de Novo/Secondary disease, performance status, cytogenetics, FLT-3 ITD, NPM1 status, survival, relapse, remission, and stem cell transplant. Outcomes were assessed using standard meta-analytic techniques, where patients within the same trial were compared and then summary statistics combined to obtain overall estimates. Heterogeneity between trials, and interactions between treatment and baseline covariates were explored using standard heterogeneity and trend statistics. ResultsThe addition of GO did not change remission rate (OR 0.91, 95% CI 0.77-1.07, p=0.3). However, there was a suggestion of slightly greater early mortality (30-day mortality HR 1.28 (0.97-1.70) p=0.08. Overall survival was improved (HR 0.89 (0.82-0.97) p=0.01), due to a significant reduction is relapse (HR 0.80 (0.72-0.89) p=0.00006), leading to significantly improved survival from remission (HR 0.84 (0.76-0.94). p=0.001). In all cases there was no significant heterogeneity between trials, although there was a suggestion that the excess early mortality was greater in patients given higher dose of GO. In analyses stratified by baseline covariates, there was no evidence of significant interaction between either age or FLT-3 ITD status and the effect of GO on survival (p=0.9 for trend by age, p=0.9 for heterogeneity by ITD mutation status). However, there was a highly significant interaction between cytogenetic risk group, as defined by each cooperative group, and treatment (p=0.003 for trend, p=0.006 for heterogeneity). There was highly significant benefit for patients with favourable (HR 0.50 (0.33-0.77) p=0.001) and intermediate (HR 0.85 (0.76-0.96) p=0.007) risk patients, but no evidence of benefit for patients with adverse risk cytogenetics (HR 1.04 (0.86-1.25) p=0.7). ConclusionsThe combined evidence from 5 randomised trials of GO given with course 1 of induction chemotherapy shows a significant benefit in survival which more than outweighs any possible increase in early mortality. However, the benefit appears to be restricted to patients who have favourable or intermediate risk cytogenetics, with the greatest benefit in patients with a core binding factor leukaemia, although survival is still highly significantly improved in intermediate risk patients. On the basis of this IPD meta-analysis, adding GO to induction improves survival in the majority of patients with AML with no restriction by age of FLT3 ITD mutation status.On behalf of the GO trialists collaborative group.The SWOG-0106 Study was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926 and in part by Pfizer Pharmaceuticals. Disclosures:Off Label Use: Gemtuzumab Ozogamicin in AML.

Innovations in Diabetes Care From One of America's Most Wired Communities: Effects of an Electronic Emergency Department/Admission Alert System in Cincinnati, Ohio

Managing costs and improving care associated with type 1 and type 2 diabetes has proven to be as difficult as managing the disease itself. Diabetes care is costly, complications are common, and prevalence is growing. In addition, the need for improved coordination and management of care is hindered by barriers in the monitoring and tracking of diabetes care across multiple clinical settings.1–7 To better manage patients and improve care, many hospitals and primary care practices have adopted electronic health records (EHRs), many with clinical decision support (CDS) functionality that facilitates closer monitoring of A1C, LDL cholesterol, blood pressure, and eye and foot exams.8 The use of EHRs with CDS has been associated with improved outcomes for patients with diabetes; decreased use of outpatient, specialist, and inpatient services; and reduced overall costs, particularly when integrated into quality improvement (QI) activities.9,10 However, a sizeable proportion of primary care providers (PCPs) and emergency departments (EDs) do not have or adequately leverage EHRs, and many communities are just beginning to develop the health information exchange (HIE) infrastructure necessary to share meaningful clinical information across care settings.6,11 Without EHRs and more advanced HIE infrastructure, providers often lack the resources to capture QI data and communicate clinical patient information across care settings. The alternatives—phone, mail, or fax communication—can lead to inefficiencies, opportunities for error, and misplacement of records.12 In September 2010, the Greater Cincinnati Beacon Collaboration (GCBC), a group of six organizations in Cincinnati, Ohio, representing different stakeholders in the health care system, was awarded a Beacon Community cooperative agreement grant from the Office of the National Coordinator for Health Information Technology (IT). The purpose of the Beacon Community program is to develop and test health information technology and QI innovations to improve health outcomes …

SWOG S0533: A pilot trial of cisplatin (C)/etoposide (E)/radiotherapy (RT) followed by consolidation docetaxel (D) and bevacizumab (B) (NSC-704865) in three cohorts of patients (pts) with inoperable locally advanced stage III non-small cell lung cancer (NSCLC).

7018 Background: Bevacizumab combined with chemotherapy has improved survival in the treatment of advanced NSCLC. This pilot trial was conducted to determine if bevacizumab could be incorporated into the standard chemotherapy/RT for locally advanced NSCLC. Methods: Pts with unresectable stage III NSCLC, PS 0-1, and adequate organ function were eligible. Pts were accrued in two strata, low and high risk (squamous histology, hemoptysis, tumor with cavitation or near a major vessel). Pts were treated with C 50mg/m2 (d 1 and 8), E 50mg/m2 (d 1-5) for 2 cycles concurrent with RT (64.8 Gy at 1.8 Gy/fx for 36 fxs) followed by consolidation D 75mg/m2 and B 15 mg/kg for 3 cycles (Cohort 1). If safety was established then accrual would continue to Cohort 2 (B, d 15, 36, 57) and then Cohort 3 (B d 1, 22, 43). Results: 29 pts (17 Low, 12 High) were registered, all to Cohort 1. 26 pts (stage IIIB 19 pts, squamous 4 pt, adenosquamous 1 pt) were evaluable. 25 completed chemo/RT. Grade 3/4 toxicities during chemo/RT included: neutropenia 10 pts, thrombocytopenia 2, anemia 2, febrile neutropenia 3, esophagitis 2, pneumonitis 1. 21 were assessed for safety with D/B consolidation. The major adverse events during D/B consolidation were pneumonitis (Gr 3 - 2 pt) and 2 episodes of fatal hemoptysis in the high risk group resulting in closure of this stratum. The low risk stratum subsequently closed because of poor accrual. Median overall survival was 23 mos for low risk pts and 17 mos for the high risk stratum. Conclusions: In this trial, bevacizumab could not be successfully integrated into chemo-radiation for stage III NSCLC, particularly in pts considered at high risk for hemoptysis. The trial suffered from several temporary closures as mandated by CTEP when new bevacizumab-related toxicities were reported, contributing to slow accrual. In lower risk pts the data are insufficient to determine safety or efficacy. Supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102 and CA38926.

Strategies to increase efficiency in protocol development.

e16508 Background: In 2010, the NCI’s Operational Efficiency Working Group recommended changes aimed at compressing the timeline for cancer clinical trial activation. SWOG implemented multiple changes prior to and since that report, intended to increase protocol development efficiency. Two protocol development interventions were piloted; weekly meetings of SWOG leadership and the study team, or SWOG Activation Team (“SWAT”), which began in 2007, and intensive RaPID Protocol Development Meetings, beginning in 2010. Methods: The highest priority developing trial was selected for SWAT, with only one trial using this mechanism at a time. RaPID trials were chosen based on trial complexity and urgency. We reviewed all protocol development milestones across SWOG protocols activated between 2007 and 2011. Results of the review were compared and contrasted for 1) the two piloted interventions 2) pre- and post-OEWG implementation and 3) time from trial activation to first patient entered. Results: Time to activation results are outlined in the table. Within SWAT, the median time to activation was 400 days, 190 days sooner that all trials developed in the same time period. RaPID trials median time to activation was 225 days, 365 days sooner than others developed in the same timeframe. Regardless of intervention type, median time from concept submission to trial activation was 724 days pre-OEWG and 286 days post-OEWG. The median time from trial activation to first patient accrued was 106 days pre-OEWG implementation and 75 days post-OEWG. Conclusions: While barriers to timely trial activation still exist, SWOG programs aimed at enhancing the efficiency of protocol development, in partnership with the implemented OEWG recommendations, have been successful. SWOG has developed effective and timely protocol develop strategies among diverse, and geographically dispersed, study teams with only modest increases in effort and cost. Supported in part by PHS Cooperative Agreement grant awarded by the National Cancer Institute, DHHS: CA032102. [Table: see text]

Older patient participation in SWOG lung cancer trials: Comparative analysis from 1993 to 2008.

7570 Background: In 1999, SWOG published a study demonstrating the underrepresentation of patients 65 years and older on clinical trials (Hutchins NEJM). A second report published in 2006 demonstrated increasing proportions of patients &gt; 65 years (31% 1997-2000; 38% 2001-2003) being enrolled into SWOG trials (Unger JCO). Older patient enrollment was still disproportionately low compared to the US cancer population. The current analysis focuses on patients with lung cancer from 1993-2008. Methods: The proportions of enrollment onto SWOG lung cancer treatment trials by age (65-69, 70-79, ≥80 years) and gender were computed for 4-year time intervals between 1993 and 2008; corresponding rates in the US were derived from US Census and National Cancer Institute SEER data. Proportions in the SWOG trials were compared to the SEER proportions using a 1-sample binomial test of proportions. Time trends within SWOG were evaluated using linear regression. Results: The proportion of patients 65-69 was significantly higher than the US population between 1993 and 2004, but was not significantly different after 2004. Proportions of patients on SWOG trials 70-79 years old and ≥ 80 were significantly smaller than the US population. Females were underrepresented from 1993-2004. Between 2005 and 2008 female enrollment was not significantly different from the US population. Conclusions: Currently, the proportion of patients 65-69 years of age and of female gender enrolled in SWOG trials is representative of the general lung cancer population. Although some progress has been made in increasing trial participation of patients &gt; 70, enrollment remains disproportionately low. The disparity is most evident in patients &gt; 80. Continued efforts are needed to increase older patient participation in lung cancer trials. Supported in part by PHS Cooperative Agreement grants awarded by the National Cancer Institute: DHHS, CA32102 and CA38926. [Table: see text]

Randomized Controlled Trial Demonstrates that Exposure to Mercury from Dental Amalgam Does Not Adversely Affect Neurological Development in Children

The study subjects were 507 children (228 females and 279 males) from the Casa Pia school system in Lisbon, Portugal; the same cohort of children used in a previous study. The children were 8 to 12 years old at the time of enrollment in the study, which began in January of 1997. To be included in the study, a child must have had at baseline at least one carious lesion in a permanent tooth, no previous exposure to amalgam treatments, urinary mercury level less than 10 mg/L, blood lead level less than 15 mg/dL, IQ greater than or equal to 67 as obtained with the Comprehensive Test of Nonverbal Intelligence, and no interfering health condition. Study subjects were randomly assigned to receive dental treatment with either amalgam or resin-based composite for posterior restorations (and composite for all anterior restorations). By the end of year 1, the participants had a mean of 8.3 surfaces restored with amalgam, and the mean number of surfaces restored varied between 7.7 and 10.7 during the 7 years of follow-up. The primary outcome measures for the study were the presence of neurological hard signs (NHSs), such as tremor, and the presence and severity of neurological soft signs (NSSs), such as synkinesias. NHSs were scored as present or absent. Tremor was reported separately from other NHSs because of its relationship to mercury toxicity. Observation of NSSs did not begin until follow-up year 2, so there were no baseline data for NSSs. NSSs were evaluated using the examination described by Peters et al, and each item was scored from 0 (absent) to 3 (maximum deviation). Over the 7-year duration of the study, there were slight differences in the percentages of subjects exhibiting any NHSs (including tremor, which was reported separately) between the 2 treatment groups, but the directions of the differences were not consistent from year to year, and the differences were not statistically significant in any year. No statistically significant difference in NSSs--either percentage of subjects exhibiting NSSs or NSS severity scores--was observed between the 2 groups in any year. The results of this study demonstrate that exposure to mercury from dental amalgam does not adversely affect neurological development in children.

Abstract PL04-04: Vitamin E and selenium for prostate cancer prevention: The SELECT experience

Abstract The Selenium and Vitamin E Cancer Prevention Trial (SELECT) tested its namesake agents in the prevention of prostate cancer, a continuing major health threat, especially for African American men, in the United States, including Puerto Rico, and Canada. Designed as a large, simple trial conforming as closely as possible with community standards of care, SELECT was a phase III randomized, placebo-controlled trial of selenium (200 g/day from L-selenomethionine) and/or vitamin E (400 IU/day of all rac -tocopheryl acetate) in men at least 55 years of age (non-African American) or at least 50 years of age (African American) with a serum prostate-specific antigen (PSA) ≤ 4 ng/mL and a digital rectal examination (DRE) not suspicious for prostate cancer. The planned intervention duration was a minimum of 7 years, maximum of 12 years. The strongest evidence supporting the SELECT hypothesis came from secondary clinical results indicating that prostate cancer risk was reduced by vitamin E in the Alpha-Tocopherol, Beta-Carotene (ATBC) Study (designed to prevent lung cancer) and by selenium in the Nutritional Prevention of Cancer (NPC) trial (designed to prevent skin cancer); this evidence was supported by epidemiologic and preclinical data. 35,533 men were randomly assigned at a faster-than-expected accrual rate to the four, well-balanced study arms (selenium, vitamin E, selenium plus vitamin E, placebo) between 2001 and 2004. As a result of a planned interim analysis (at 7 years) and by recommendation of the Data and Safety Monitoring Committee, the interventions were discontinued because of convincing evidence of no benefit from either study agent (p &amp;lt; 0.0001) and no possibility of a benefit to the planned degree with additional follow-up. With a median overall follow-up of 5.46 years (range, 4.17 to 7.33 years), the primary analysis showed the following prostate cancer results (versus placebo, n=416): vitamin E hazard ratio (HR) = 1.13 (n=473; 99% confidence interval [CI], 0.95 - 1.35), selenium HR = 1.04 (n=432; 99% CI, 0.87 – 1.24), combination HR = 1.05 (n=437; 99% CI, 0.88 – 1.25). No significant differences were seen in any prespecified cancer endpoints including lung, colorectal, and overall cancer. A nonsignificant increased risk of prostate cancer occurred in the vitamin E arm (p=0.06; relative risk [RR]=1.13; 99% CI, 0.95 – 1.35), and the selenium arm showed a nonsignificant increased risk of Type 2 diabetes mellitus (p=0.16; RR=1.07; 99% CI, 0.94–1.22); neither of these increases appeared in the combination arm. Selenium, vitamin E, and their combination did not reduce the risk of prostate cancer in SELECT. One important lesson learned from the SELECT experience, building on lessons learned from the earlier ATBC and NPC experiences, is that we should step back and do more small, lead-up preclinical and early-phase clinical studies that increase our understanding of cancer biology and agent effects before moving ahead with large clinical trials of natural or other potential preventive agents. Epidemiologic and secondary clinical data are great pathfinders, but the heaviest supportive evidence for definitive trials may come mainly from more extensive preliminary research, including mechanistic studies that can validate the biologic plausibility of the clinical, risk reduction hypothesis. Another important lesson SELECT has provided for any large prevention trial is built-in opportunity for translational research. The SELECT design comprised sub-studies of molecular and standard epidemiology, diet and nutrition, and other important correlative endpoints that informed the collection of data and biospecimens in the trial and resulted in an invaluable repository for future research. Support for this work was received from Public Health Service Cooperative Agreement grant CA37429 (National Cancer Institute, National Institutes of Health, Department of Health and Human Services) and from the National Center for Complementary and Alternative Medicine (National Institutes of Health). Citation Information: Cancer Prev Res 2010;3(1 Suppl):PL04-04.

The Conceptual Development of DSM-V

The Conceptual Development of DSM-V