ABSTRACT
BACKGROUND: Brain bases and progression of methotrexate-associated neurotoxicity and cognitive disturbances remain unknown. We tested whether brain abnormalities worsen in proportion to intrathecal methotrexate(IT-MTX) doses. METHODS: In this prospective, longitudinal study, we recruited 19 patients with newly diagnosed acute lymphoblastic leukemia 4-to-20 years of age and 20 matched controls. We collected MRI and neuropsychological assessments at a pre-methotrexate baseline and at week 9, week 22, and year 1 during treatment. RESULTS: Patients had baseline abnormalities in cortical and subcortical gray matter(GM), white matter(WM) volumes and microstructure, regional cerebral blood flow, and neuronal density. Abnormalities of GM, blood flow, and metabolites worsened in direct proportions to IT-MTX doses. WM abnormalities persisted until week 22 but normalized by year 1. Brain injuries were localized to dorsal and ventral attentional and frontoparietal cognitive networks. Patients had cognitive deficits at baseline that persisted at 1-year follow-up. CONCLUSIONS: Baseline abnormalities are likely a consequence of neuroinflammation and oxidative stress. Baseline abnormalities in WM microstructure and volumes, and blood flow persisted until week 22 but normalized by year 1, likely due to treatment and its effects on reducing inflammation. The cytotoxic effects of IT-MTX, however, likely contributed to continued, progressive cortical thinning and reductions in neuronal density, thereby contributing to enduring cognitive deficits. IMPACT: Brain abnormalities at a pre-methotrexate baseline likely are due to acute illness. The cytotoxic effects of intrathecal MTX contribute to progressive cortical thinning, reductions in neuronal density, and enduring cognitive deficits. Baseline white matter abnormalities may have normalized via methotrexate treatment and decreasing neuroinflammation. Corticosteroid and leucovorin conferred neuroprotective effects. Our findings suggest that the administration of neuroprotective and anti-inflammatory agents should be considered even earlier than they are currently administered. The neuroprotective effects of leucovorin suggest that strategies may be developed that extend the duration of this intervention or adapt it for use in standard risk patients.
ABSTRACT
BACKGROUND: Characterizing the appeal of flavored e-cigarette solutions by tobacco product use status can inform regulations to reduce vaping in those who never smoked without discouraging adopting e-cigarettes as a quit-smoking aid. METHODS: Adults aged 21+ who currently use tobacco products (N = 119) self-administered standardized puffs of eight non-tobacco flavored and two tobacco-flavored e-cigarette solutions using a pod-style device. Participants rated appeal (0-100 scale) following each administration. Mean differences in flavor appeal ratings were compared between four groups: people who never smoked/currently vape, formerly smoked/currently vape, currently smoke/currently vape, and currently smoke/do not vape (with interest in vaping). RESULTS: The Global Flavor (all non-tobacco vs. tobacco)×Group interaction (p = .028) revealed higher appeal for non-tobacco vs. tobacco flavors in adults who never smoked/currently vape (B[95 %CI] = 13.6[4.1-23.1]), formerly smoked/currently vape (B[95 %CI] = 11.6[4.2-18.9]), and currently smoke/currently vape (B[95 %CI] = 9.3[2.5-11.6]), but not adults who currently smoke/never vaped (B[95 %CI] = -0.1[-5.1 to 4.9]). In flavor-specific analyses, adults who never smoked/currently vape rated strawberry (p = .022), peppermint (p = .028), and menthol (p = .028) more appealing than tobacco flavors. Among adults who formerly smoked/currently vape, strawberry (p < .001), peppermint (p = .009), and vanilla (p = .009), were more appealing than tobacco. Adults who currently smoked/currently vape rated peppermint (p = .022) and vanilla (p = .009) as more appealing than tobacco. No non-tobacco flavors were more appealing than tobacco in adults who currently smoke/never vaped. CONCLUSIONS: E-cigarette sales restrictions on non-tobacco flavors, including menthol, may eliminate products preferred by adults who vape, including those who never smoked, without discouraging adults who currently smoke and never vaped from trying e-cigarettes.
