BACKGROUND: This study tested the hypothesis that time of day of treatment with stereotactic radiosurgery (SRS) has an effect on local control (LC) and overall survival (OS) in a large cohort of patients with non-small cell lung cancer (NSCLC) brain metastases. METHODS: At Washington University in St. Louis, 437 patients with NSCLC were treated with SRS for NSCLC brain metastases. Receiver operating characteristics analysis was used to identify an optimal cut-point for OS relative to time of day. Kaplan-Meier logrank statistics, and Cox regression univariate and multivariate analysis were employed to isolate any independent effect of treatment time on OS and LC. Matched-pair analysis was performed to isolate any independent effect of time on OS and LC of day while controlling for confounding variables. RESULTS: Receiver operating characteristics analysis identified a cut-point of 11:41 AM as providing the highest predictive value for OS. On univariate analysis, late SRS was associated with decreased OS, as was age, Karnofsky performance status, risk-stratification schemes, extracranial disease status, and overall burden of brain metastases. On univariate analysis for LC, late SRS was associated with decreased LC, as was burden of brain metastases. On multivariate analysis, only Graded Prognostic Assessment remained predictive of OS, and total number of targets and total tumor volume remained predictive of LC. Matched-pair analysis demonstrated no significant effect of time of day on LC or OS. CONCLUSIONS: Although earlier treatment appears to be associated with improved LC and OS, treatment time fails to remain significant when accounting for confounding variables. Cancer 2013;119:3563-9. V C 2013 American Cancer Society.KEYWORDS: Gamma Knife; radiosurgery; chronobiology; non-small cell lung cancer; circadian rhythm; time of day; survival; local control; brain metastases. INTRODUCTIONThe brain is one of the most common sites of metastases, occurring in 20% to 50% of patients with lung cancer. Multiple treatment options exist for the management of brain metastases, including surgery, whole-brain radiation therapy (WBRT), stereotactic radiosurgery, or combinations thereof. One-year local control (LC) after radiosurgery ranges from 67% to 90%.1-4 Established factors predicting for improved LC after radiosurgery include smaller tumor size, nonradioresistant histology, and the addition of WBRT.5-7 Predictors of overall survival (OS) include Recursive Partitioning Analysis (RPA), Score Index for Radiosurgery (SIR), and the newer Graded Prognostic Assessment (GPA) indices, which account for the effects of age, performance status, extracranial disease status, and now number of brain metastases and histology.

Background Intraventricular hemorrhage (IVH) is the most frequent, severe neurological complication of prematurity and is associated with post-hemorrhagic hydrocephalus (PHH) in up to half of cases. PHH requires lifelong neurosurgical care and is associated with significant cognitive and psychomotor disability. Cerebrospinal fluid (CSF) biomarkers may provide both diagnostic information for PHH and novel insights into its pathophysiology. Objective To explore the diagnostic ability of candidate CSF biomarkers for PHH. Methods Concentrations of amyloid precursor protein (APP), soluble APPα, sAPPβ, NCAM-1, L1CAM, tau, phosphorylated tau, and total CSF protein (TP) were measured in lumbar CSF from neonates in six groups: (a) no known neurological disease (n=33); (b) IVH Grades I-II (n=13); (c) IVH Grades III-IV (n=12); (d) PHH (n=12); (e) ventricular enlargement without hydrocephalus (n=10); and (f) hypoxic ischemic encephalopathy (n=13). CSF protein levels were compared using analysis of variance, and logistic regression was performed to examine the predictive ability of each marker for PHH. Results Lumbar CSF levels of APP, sAPPα, L1CAM, and TP were selectively increased in PHH compared to all other conditions (all p<0.0001). The sensitivity, specificity, and odds ratios of candidate CSF biomarkers for PHH were determined for APP, sAPPα, and L1CAM; cutpoints of 699, 514, and 113 ng/ml yielded odds ratios for PHH of 80.0, 200.0, and 68.75, respectively. Conclusion Lumbar CSF APP, sAPPα, L1CAM, and TP were selectively increased in PHH. These proteins, and sAPPα in particular, hold promise as biomarkers of PHH and provide novel insight into PHH-associated neural injury and repair.