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.

Combining Quantitative Susceptibility Mapping with Automatic Zero Reference (QSM0) and Myelin Water Fraction Imaging to Quantify Iron-Related Myelin Damage in Chronic Active MS Lesions.

BACKGROUND AND PURPOSE: A hyperintense rim on susceptibility in chronic MS lesions is consistent with iron deposition, and the purpose of this study was to quantify iron-related myelin damage within these lesions as compared with those without rim. MATERIALS AND METHODS: Forty-six patients had 2 longitudinal quantitative susceptibility mapping with automatic zero reference scans with a mean interval of 28.9 ± 11.4 months. Myelin water fraction mapping by using fast acquisition with spiral trajectory and T2 prep was obtained at the second time point to measure myelin damage. Mixed-effects models were used to assess lesion quantitative susceptibility mapping and myelin water fraction values. RESULTS: Quantitative susceptibility mapping scans were on average 6.8 parts per billion higher in 116 rim-positive lesions compared with 441 rim-negative lesions (P < .001). All rim-positive lesions retained a hyperintense rim over time, with increasing quantitative susceptibility mapping values of both the rim and core regions (P < .001). Quantitative susceptibility mapping scans and myelin water fraction in rim-positive lesions decreased from rim to core, which is consistent with rim iron deposition. Whole lesion myelin water fractions for rim-positive and rim-negative lesions were 0.055 ± 0.07 and 0.066 ± 0.04, respectively. In the mixed-effects model, rim-positive lesions had on average 0.01 lower myelin water fraction compared with rim-negative lesions (P < .001). The volume of the rim at the initial quantitative susceptibility mapping scan was negatively associated with follow-up myelin water fraction (P < .01). CONCLUSIONS: Quantitative susceptibility mapping rim-positive lesions maintained a hyperintense rim, increased in susceptibility, and had more myelin damage compared with rim-negative lesions. Our results are consistent with the identification of chronic active MS lesions and may provide a target for therapeutic interventions to reduce myelin damage.

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.

Cost-effectiveness of CT angiography and perfusion imaging for delayed cerebral ischemia and vasospasm in aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia and vasospasm are significant complications following SAH leading to cerebral infarction, functional disability, and death. In recent years, CTA and CTP have been used to increase the detection of delayed cerebral ischemia and vasospasm. Our aim was to perform comparative-effectiveness and cost-effectiveness analyses evaluating CTA and CTP for delayed cerebral ischemia and vasospasm in aneurysmal SAH from a health care payer perspective. MATERIALS AND METHODS: We developed a decision model comparing CTA and CTP with transcranial Doppler sonography for detection of vasospasm and delayed cerebral ischemia in SAH. The clinical pathways were based on the "Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association" (2012). Outcome health states represented mortality and morbidity according to functional outcomes. Input probabilities of symptoms and serial test results from CTA and CTP, transcranial Doppler ultrasound, and digital subtraction angiography were directly derived from an SAH cohort by using a multinomial logistic regression model. Expected benefits, measured as quality-adjusted life years, and costs, measured in 2012 US dollars, were calculated for each imaging strategy. Univariable, multivariable, and probabilistic sensitivity analyses were performed to determine the independent and combined effect of input parameter uncertainty. RESULTS: The transcranial Doppler ultrasound strategy yielded 13.62 quality-adjusted life years at a cost of $154,719. The CTA and CTP strategy generated 13.89 quality-adjusted life years at a cost of $147,097, resulting in a gain of 0.27 quality-adjusted life years and cost savings of $7622 over the transcranial Doppler ultrasound strategy. Univariable and multivariable sensitivity analyses indicated that results were robust to plausible input parameter uncertainty. Probabilistic sensitivity analysis results yielded 96.8% of iterations in the right lower quadrant, representing higher benefits and lower costs. CONCLUSIONS: Our model results suggest that CTA and CTP are the preferred imaging strategy in SAH, compared with transcranial Doppler ultrasound, leading to improved clinical outcomes and lower health care costs.

Oxygen extraction fraction and stroke risk in patients with carotid stenosis or occlusion: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Increased oxygen extraction fraction on PET has been considered a risk factor for stroke in patients with carotid stenosis or occlusion, though the strength of this association has recently been questioned. We performed a systematic review and meta-analysis to summarize the association between increased oxygen extraction fraction and ipsilateral stroke risk. MATERIALS AND METHODS: A comprehensive literature search was performed. We included studies with baseline PET oxygen extraction fraction testing, ipsilateral stroke as the primary outcome, and at least 1 year of follow-up. A meta-analysis was performed by use of a random-effects model. RESULTS: After screening 2158 studies, 7 studies with 430 total patients with mean 30-month follow-up met inclusion criteria. We found that 6 of 7 studies were amenable to meta-analysis. Although 4 of the 6 studies independently did not reach statistical significance, meta-analysis revealed a significant positive relationship between abnormal oxygen extraction fraction and future ipsilateral stroke, with a pooled OR of 6.04 (95% CI, 2.58-14.12). There was no statistically significant difference in OR in the subgroup analyses according to testing method or disease site. CONCLUSIONS: Abnormal oxygen extraction fraction remains a powerful predictor of stroke in carotid stenosis or occlusion and is a valuable reference standard to compare and validate MR imaging-based measures of brain oxygen metabolism. However, there is a need for further evaluation of oxygen extraction fraction testing in patients with high-grade but asymptomatic carotid disease.

Does the location of the arterial input function affect quantitative CTP in patients with vasospasm?

BACKGROUND AND PURPOSE: In recent years, there has been increasing use of CTP imaging in patients with aneurysmal SAH to evaluate for vasospasm. Given the critical role of the arterial input function for generation of accurate CTP data, several studies have evaluated the effect of varying the arterial input function location in patients with acute stroke. Our aim was to determine the effect on quantitative CTP data when the arterial input function location is distal to significant vasospasm in patients with aneurysmal SAH. MATERIALS AND METHODS: A retrospective study was conducted of patients with aneurysmal SAH admitted from 2005 to 2011. Inclusion criteria were the presence of at least 1 anterior cerebral artery or MCA vessel with a radiologically significant vasospasm and at least 1 of these vessels without vasospasm. We postprocessed each CTP dataset 4 separate times by using standardized methods, only varying the selection of the arterial input function location in the anterior cerebral artery and MCA vessels. For each of the 4 separately processed examinations for each patient, quantitative data for CBF, CBV, and MTT were calculated by region-of-interest sampling of the vascular territories. Statistical analysis was performed by using a linear mixed-effects model. RESULTS: One hundred twelve uniquely processed CTP levels were analyzed in 28 patients (mean age, 52 years; 24 women and 4 men) recruited from January 2005 to December 2011. The average Hunt and Hess scale score was 2.89 ± 0.79. The average time to CTP from initial presentation was 8.2 ± 5.1 days. For each vascular territory (right and left anterior cerebral artery, MCA, posterior cerebral artery), there were no significant differences in the quantitative CBF, CBV, and MTT generated by arterial input function locations distal to significant vasospasm compared with nonvasospasm vessels (P > .05). CONCLUSIONS: Arterial input function placement distal to significant vasospasm does not affect the quantitative CTP data in the corresponding vascular territory or any other vascular territory in aneurysmal SAH.

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.