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Free water elimination (FWE) in brain diffusion MRI has been shown to improve tissue specificity in human white matter characterization both in health and in disease. Relative to the classical diffusion tensor imaging (DTI) model, FWE is also expected to increase sensitivity to microstructural changes in longitudinal studies. However, it is not clear if these two models differ in their test-retest reproducibility. This study compares a bi-tensor model for FWE with DTI by extending a previous longitudinal-reproducibility 3T multisite study (10 sites, 7 different scanner models) of 50 healthy elderly participants (55–80 years old) scanned in two sessions at least one week apart. We computed the reproducibility of commonly used DTI metrics (FA: fractional anisotropy, MD: mean diffusivity, RD: radial diffusivity and AXD: axial diffusivity), derived either using a DTI model or a FWE model. The DTI metrics were evaluated over 48 white matter regions of the JHU-ICBM-DTI-81 white-matter labels atlas, and reproducibility errors were assessed. We found that relative to the DTI model, FWE significantly reduced reproducibility errors in most areas tested. In particular, for the FA and MD metrics there was an average reduction of approximately 1% in the reproducibility error. The reproducibility scores did not significantly differ across sites. This study shows that FWE improves sensitivity and is thus promising for clinical applications, with the potential to identify more subtle changes. The increased reproducibility allows for smaller sample size or shorter trials in studies evaluating biomarkers of disease progression or treatment effects.

W e describe two cases with central nervous system (CNS) metastases from anaplastic lymphoma kinase (ALK)positive non-small-cell lung cancer (NSCLC) that benefited from the ALK-inhibitor crizotinib. In both cases, crizotinib was dosed in serum and corresponding cerebrospinal fluid (CSF) through ultra-high performance liquid chromatography (Agilent Technologies, Santa Clara, CA). 1 CASE 1 A 58-year-old never-smoker with ALK-positive advanced NSCLC pretreated with chemotherapy developed asymptomatic CNS metastases consisting of a solitary brain lesion and cytologically confirmed meningeal carcinomatosis (Fig. 1A, B, C). At that time crizotinib was initiated, which resulted into complete CNS response (Fig. 1D, E, F). Serum and CSF were sampled 5 hours after a dose of crizotinib 250 mg, being measured at 587 ng/ml and 0.35 ng/ ml, respectively, for a CSF-to-serum ratio of 0.0006. CNS response lasted for a total of 5 months, after which the disease underwent both intra-and extra-cranial progression. Despite receiving whole-brain radiotherapy (WBRT), patient's clinical conditions worsened rapidly, and he died shortly thereafter.

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