Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse.

BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS: This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. RESULTS: Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). CONCLUSIONS: TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.

Quantitative Susceptibility Mapping of Time-Dependent Susceptibility Changes in Multiple Sclerosis Lesions.

BACKGROUND AND PURPOSE: MR imaging studies have demonstrated that magnetic susceptibility in multiple sclerosis lesions is dependent on lesion age. The objective of this study was to use quantitative susceptibility mapping to determine whether lesions with a hyperintense rim, indicative of iron-laden inflammatory cells (rim+), follow a unique time-dependent trajectory of susceptibility change compared with those without (rim-). MATERIALS AND METHODS: We studied patients with MS with at least 1 new gadolinium-enhancing lesion and at least 3 longitudinal quantitative susceptibility mapping scans obtained between 1.1 and 6.1 years. Lesions were classified as rim+ if a hyperintense rim appeared on quantitative susceptibility mapping at any time. A multilevel growth curve model compared longitudinal susceptibility among rim+ and rim- lesions. RESULTS: Thirty-two new gadolinium-enhancing lesions from 19 patients with MS were included, and 16 lesions (50%) were identified as rim+. Quantitative susceptibility mapping rim+ lesions were larger than rim- lesions with gadolinium enhancement (P < .001). Among all lesions, susceptibility increased sharply after enhancement to a peak between 1 and 2 years followed by a decrease. The overall susceptibility curve height for rim- lesions was 4.27 parts per billion lower than that for rim+ lesions (P = .01). Rim- lesions demonstrated a higher linear slope relative to rim+ lesions (P = .023) but faster cubic decay relative to rim+ lesions (P = .005). Rim- lesions started decaying approximately 2 years earlier compared with rim+ lesions. CONCLUSIONS: There was a marked difference in the susceptibility temporal trajectory between rim+ and rim- lesions during the first 6 years of lesion formation. Most rim+ lesions retain iron for years after the initial lesion appearance.

CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5-year data from CIPRA HT-001.

SETTING: Port-au-Prince, Haiti. OBJECTIVE: To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals. DESIGN: Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was <200 cells/mm(3). The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up. RESULTS: A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm(3), 95% confidence interval [CI] 477-515 vs. 373 cells/mm(3), 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis. CONCLUSION: Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm(3) can result in long-term immune dysfunction and persistent increased risk for TB.