SummaryDiffusion tensor imaging (DTI) is a promising method for characterizing microstructural changes or differences with neuropathology and treatment. The diffusion tensor may be used to characterize the magnitude, anisotropy and orientation of the diffusion tensor. This paper reviews the biological mechanisms, acquisition and analysis methodology of DTI measurements. The relationships between DTI measures and white matter pathologic features (ischemia, myelination, axonal damage, inflammation, and edema) are summarized. Applications of DTI to tissue characterization in neurotherapeutic applications are reviewed. The interpretations of common DTI measures -mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (Dr) and axial diffusivity (Da) -are discussed. In particular, FA is highly sensitive to microstructural changes, but not very specific to the type of changes (e.g., radial or axial). In order to maximize the specificity, it is recommended that future studies use multiple diffusion tensor measures (e.g., MD and FA, or Da and Dr) to better characterize the tissue microstructure.

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The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC 0-' ) by approximately 4.6-fold and increased tacrolimus DN_AUC 0-' by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t ½ ) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t ½ of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. Conclusion: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or lifethreatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained.

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Context Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD), as well as other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal and anterior cingulate cortex (ACC), suggesting altered frontolimbic white matter connectivity in GAD. Objective To investigate structural connectivity between ventral prefrontal/ACC areas and the amygdala in GAD, and to assess associations with functional connectivity between those areas. Design Participants underwent diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) scans. Setting University magnetic resonance imaging facility. Participants Forty-nine GAD patients and 39 healthy volunteers, including a subset of 21 patients without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education. Main Outcome Measure Mean fractional anisotropy (FA) values in the left and right uncinate fasciculus, as measured by tract-based analysis for DTI data. Results Lower mean FA values in bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all subjects, higher FA values were associated with more negative functional coupling between the pregenual ACC and amygdala during the anticipation of aversion. Conclusions Decreased frontolimbic structural connectivity suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the ACC and amygdala in subjects with reduced structural integrity of the uncinate fasciculus.

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. .

Gemtuzumab ozogamicin (GO) 3 mg/m days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.

Background Biological measurements that distinguish individuals with autism from typically developing individuals and those with other developmental and neuropsychiatric disorders must demonstrate very high performance to have clinical value as potential imaging biomarkers. We hypothesized that further study of white matter microstructure (WMM) in the superior temporal gyrus (STG) and temporal stem (TS), two brain regions in the temporal lobe containing circuitry central to language, emotion and social cognition, would identify a useful combination of classification features and further understand autism neuropathology. Methods WMM measurements from the STG and TS were examined from thirty high-functioning males satisfying full criteria for idiopathic autism aged 8–26 years and 30 matched controls and a replication sample of 12 males with idiopathic autism and 7 matched controls that participated in a previous case-control diffusion tensor imaging (DTI) study. Language functioning, adaptive functioning and psychotropic medication usage were also examined. Results In the STG, we find reversed hemispheric asymmetry of two separable measures of directional diffusion coherence. Tensor skewness is greater on the right in autism and fractional anisotropy is decreased on the left. We also find increased diffusion parallel to white matter fibers bilaterally. In the right not left TS we find increased omnidirectional, parallel and perpendicular diffusion. These six multivariate measurements possess very high ability to discriminate individuals with autism from individuals without autism with 94% sensitivity, 90% specificity and 92% accuracy in our original and replication samples. We also report a near-significant association between the classifier and a quantitative trait index of autism and significant correlations between two classifier components and measures of language, IQ and adaptive functioning in autism.