Patient Knowledge and Expectations About Return of Genomic Results in a Biomarker-Driven Master Protocol Trial (SWOG S1400GEN).

PURPOSE: Biomarker-driven master protocols represent a new paradigm in oncology clinical trials, but their complex designs and wide-ranging genomic results returned can be difficult to communicate to participants. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung Cancer Master Protocol (Lung-MAP). METHODS: Eligible participants with previously treated advanced non-small-cell lung cancer were recruited from patients enrolled in Lung-MAP. Participants completed a 38-item telephone survey ≤ 30 days from Lung-MAP consent. The survey assessed understanding about the benefits and risks of Lung-MAP participation and knowledge of the potential uses of somatic testing results returned. Descriptive statistics and odds ratios for associations between demographic factors and correct responses to survey items were assessed. RESULTS: From August 1, 2017, to June 30, 2019, we recruited 207 participants with a median age of 67, 57.3% male, and 94.2% White. Most participants "strongly/somewhat agreed" with statements that they "received enough information to understand" Lung-MAP benefits (82.6%) and risks (69.5%). In items asking about potential uses of Lung-MAP genomic results, 87.0% correctly indicated that the results help to select cancer treatment, but < 20% correctly indicated that the results are not used to confirm cancer diagnosis, would not reveal risk of developing diseases besides cancer, and would not indicate if family members had increased cancer risk. There were no associations between sociodemographic factors and proportions providing correct responses. CONCLUSION: In a large National Clinical Trials Network biomarker-driven master protocol, most participants demonstrated incorrect knowledge and expectations about the uses of genomic results provided in the study despite most indicating that they had enough information to understand benefits and risks.

Effective stakeholder engagement: design and implementation of a clinical trial (SWOG S1415CD) to improve cancer care.

BACKGROUND: The Fred Hutchinson Cancer Research Center has engaged an External Stakeholder Advisory Group (ESAG) in the planning and implementation of the TrACER Study (S1415CD), a five-year pragmatic clinical trial assessing the effectiveness of a guideline-based colony stimulating factor standing order intervention. The trial is being conducted by SWOG through the National Cancer Institute Community Oncology Research Program in 45 clinics. The ESAG includes ten patient partners, two payers, two pharmacists, two guideline experts, four providers and one medical ethicist. This manuscript describes the ESAG's role and impact on the trial. METHODS: During early trial development, the research team assembled the ESAG to inform plans for each phase of the trial. ESAG members provide feedback and engage in problem solving to improve trial implementation. Each year, members participate in one in-person meeting, web conferences and targeted email discussion. Additionally, they complete a survey that assesses their satisfaction with communication and collaboration. The research team collected and reviewed stakeholder input from 2014 to 2018 for impact on the trial. RESULTS: The ESAG has informed trial design, implementation and dissemination planning. The group advised the trial's endpoints, regimen list and development of cohort and usual care arms. Based on ESAG input, the research team enhanced patient surveys and added pharmacy-related questions to the component application to assess order entry systems. ESAG patient partners collaborated with the research team to develop a patient brochure and study summary for clinic staff. In addition to identifying recruitment strategies and patient-oriented platforms for publicly sharing results, ESAG members participated as co-authors on this manuscript and a conference poster presentation highlighting stakeholder influence on the trial. The annual satisfaction survey results suggest that ESAG members were satisfied with the methods, frequency and target areas of their engagement in the trial during project years 1-3. CONCLUSIONS: Diverse stakeholder engagement has been essential in optimizing the design, implementation and planned dissemination of the TrACER Study. The lessons described in the manuscript may assist others to effectively partner with stakeholders on clinical research.

Brief communication: Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin.

BACKGROUND: Preoperative low-molecular-weight heparin (LMWH) is often used when warfarin therapy is interrupted for surgery. OBJECTIVE: To determine the preoperative anticoagulant activity of LMWH following a standardized "bridging" regimen. DESIGN: Prospective cohort study. SETTING: Single university hospital. PATIENTS: Consecutive patients who had warfarin therapy interrupted before an invasive procedure. INTERVENTION: Enoxaparin, 1 mg/kg of body weight, twice daily. The last dose was administered the evening before surgery. MEASUREMENTS: Blood anti-factor Xa heparin levels measured shortly before surgery. RESULTS: Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels. LIMITATIONS: The small sample size limits accurate estimates of the frequency of the clinical outcomes. A single regimen of LMWH was evaluated. CONCLUSIONS: Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.

Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1.

Branching of ureteric bud-derived epithelial tubes is a key morphogenetic process that shapes development of the kidney. Glial cell line-derived neurotrophic factor (GDNF) initiates ureteric bud formation and promotes subsequent branching morphogenesis. Exactly how GDNF coordinates branching morphogenesis is unclear. Here we show that the absence of the receptor tyrosine kinase antagonist Sprouty1 (Spry1) results in irregular branching morphogenesis characterized by both increased number and size of ureteric bud tips. Deletion of Spry1 specifically in the epithelium is associated with increased epithelial Wnt11 expression as well as increased mesenchymal Gdnf expression. We propose that Spry1 regulates a Gdnf/Ret/Wnt11-positive feedback loop that coordinates mesenchymal-epithelial dialogue during branching morphogenesis. Genetic experiments indicate that the positive (GDNF) and inhibitory (Sprouty1) signals have to be finely balanced throughout renal development to prevent hypoplasia or cystic hyperplasia. Epithelial cysts develop in Spry1-deficient kidneys that share several molecular characteristics with those observed in human disease, suggesting that Spry1 null mice may be useful animal models for cystic hyperplasia.

Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction.

Intercellular signaling molecules and their receptors, whose expression must be tightly regulated in time and space, coordinate organogenesis. Regulators of intracellular signaling pathways provide an additional level of control. Here we report that loss of the receptor tyrosine kinase (RTK) antagonist, Sprouty1 (Spry1), causes defects in kidney development in mice. Spry1(-/-) embryos have supernumerary ureteric buds, resulting in the development of multiple ureters and multiplex kidneys. These defects are due to increased sensitivity of the Wolffian duct to GDNF/RET signaling, and reducing Gdnf gene dosage correspondingly rescues the Spry1 null phenotype. We conclude that the function of Spry1 is to modulate GDNF/RET signaling in the Wolffian duct, ensuring that kidney induction is restricted to a single site. These results demonstrate the importance of negative feedback regulation of RTK signaling during kidney induction and suggest that failures in feedback control may underlie some human congenital kidney malformations.