Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program.

The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.

Pilot randomized controlled trial on early and late remote ischemic preconditioning prior to complex cardiac surgery in young infants.

BACKGROUND: Remote ischemic preconditioning involves providing a brief ischemia-reperfusion event to a tissue to create subsequent protection from a more severe ischemia-reperfusion event to a different tissue/organ. The few pediatric remote ischemic preconditioning studies in the literature show conflicting results. AIM: We conducted a pilot randomized controlled trial to determine the feasibility of conducting a larger trial and to gather provisional data on the effect of early and late remote ischemic preconditioning on outcomes of infants after surgery for congenital heart disease. METHODS: This single-center, double-blind randomized controlled trial of remote ischemic preconditioning vs control (sham-remote ischemic preconditioning) in young infants going for surgery for congenital heart disease at the Stollery Children's Hospital. Remote ischemic preconditioning was performed at 24-48 h preoperatively and immediately prior to cardiopulmonary bypass. Remote ischemic preconditioning stimulus was performed with blood pressure cuffs around the thighs. Primary outcomes were feasibility and peak blood lactate level on day 1 postoperatively. RESULTS: Fifty-two patients were randomized but seven patients became ineligible after randomization leaving 45 patients included in the study. In the included patients, 7 (15%) had protocol deviations (five infants did not have the preoperative intervention and two did not receive the intervention in the operating room). From a comfort point of view, only one subject in the control group and two in the Remote ischemic preconditioning group received sedation during the preoperative intervention. There were no study-related adverse events and no complications to the limbs subjected to preconditioning. There were no significant differences between the Remote ischemic preconditioning group and the control group in the highest blood lactate level on day 1 postoperatively (mean difference, 1.28; 95%CI, -0.22, 2.78; P-value = 0.093). CONCLUSION: In infants who underwent surgery for congenital heart disease, our pilot randomized controlled trial on early and late remote ischemic preconditioning proved to be feasible but did not find any significant difference in acute outcomes. A larger trial may be necessary.

Chronic Neuromotor Disability After Complex Cardiac Surgery in Early Life.

BACKGROUND AND OBJECTIVES: Little is known about chronic neuromotor disability (CND) including cerebral palsy and motor impairments after acquired brain injury in children surviving early complex cardiac surgery (CCS). We sought to determine the frequency and presentation of CND in this population while exploring potentially modifiable acute care predictors. METHODS: This prospective follow-up study included 549 children after CCS requiring cardiopulmonary bypass at ≤6 weeks of age. Groups included those with only 1 CCS, mostly biventricular CHD, and those with >1 CCS, predominantly single ventricle defects. At 4.5 years of age, 420 (94.6%) children received multidisciplinary assessment. Frequency of CND is given as percentage of assessed survivors. Predictors of CND were analyzed using multiple logistic regression analysis. RESULTS: CND occurred in 6% (95% confidence interval [CI] 3.7%-8.2%) of 4.5-year survivors; for 1 CCS, 4.2% (CI 2.3%-6.1%) and >1, 9.8% (CI 7%-12.6%). CND presentation showed: hemiparesis, 72%; spasticity, 80%; ambulation, 72%; intellectual disability, 44%; autism, 16%; epilepsy, 12%; permanent vision and hearing impairment, 12% and 8%, respectively. Overall, 32% of presumed causative events happened before first CCS. Independent odds ratio for CND are age (days) at first CCS, 1.08 (CI 1.04-1.12; P < .001); highest plasma lactate before first CCS (mmol/L), 1.13 (CI 1.03-1.23; P = 0.008); and >1 CCS, 3.57 (CI 1.48-8.9; P = .005). CONCLUSIONS: CND is not uncommon among CCS survivors. The frequency of associated disabilities characterized in this study informs pediatricians caring for this vulnerable population. Shortening the waiting period and reducing preoperative plasma lactate levels at first CCS may assist in reducing the frequency of CND.

Health-related quality of life in pediatric cardiac extracorporeal life support survivors.

OBJECTIVE: To assess the health-related quality of life of children who received cardiac extracorporeal life support. We hypothesized that extracorporeal life support survivors have lower health-related quality-of-life scores when compared with a healthy sample, with children with chronic conditions, and with children who had surgery for congenital heart disease and did not receive extracorporeal life support. DESIGN: Prospective cohort study. SETTING: Stollery Children's Hospital and Complex Pediatric Therapies Follow-up Program clinics. PATIENTS: Children less than or 5 years old with diagnosis of cardiac disease (congenital or acquired) who received extracorporeal life support at the Stollery Children's Hospital from 1999 to 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Health-related quality of life was assessed using the PedsQL 4.0 Generic Core Scales completed by the children's parents at the time of follow-up. Forty-seven cardiac extracorporeal life support survivors had their health-related quality of life assessed at a median age of 4 years. Compared with a healthy sample, children who received venoarterial extracorporeal life support have significantly lower PedsQL (64.9 vs 82.2; p < 0.0001). The PedsQL scores of children who received extracorporeal life support were also significantly lower than those of children with chronic health conditions (64.9 vs 73.1; p = 0.007). Compared with children with congenital heart disease who underwent cardiac surgery early in infancy and who did not receive extracorporeal life support, extracorporeal life support survivors had significantly lower PedsQL scores (64.9 vs 81.1; p < 0.0001). Multiple linear regression analysis found an independent association between both higher inotrope score in the first 24 hours of extracorporeal life support and longer hospital length of stay, with lower PedsQL scores. CONCLUSIONS: Pediatric cardiac extracorporeal life support survivors showed lower health-related quality of life than healthy children, children with chronic conditions, and children with congenital heart disease who did not receive extracorporeal life support.