Purpose: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non–small cell lung
cancer (NSCLC) and are associated with sensitivity to treatment with ...gefitinib or erlotinib. Our study explored the relationship
between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes
of patients following treatment with gefitinib or erlotinib.
Experimental Design: Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon
19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined
for the two groups.
Results: We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an
exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months;
P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus
10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate
analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted 18 of
23 (78%) versus 3 of 9 (33%); P = 0.04. No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated
patients.
Conclusions: Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared
with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed
to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib,
erlotinib, and other EGFR inhibitors.
Longitudinal neuroimaging studies aid our understanding of recovery mechanisms in moderate-to-severe traumatic brain injury (TBI); however, there is a dearth of longitudinal functional connectivity ...research. Our aim was to characterize longitudinal functional connectivity patterns in two clinically important brain networks, the frontoparietal network (FPN) and the default mode network (DMN), in moderate-to-severe TBI. This inception cohort study of prospectively collected longitudinal data used resting-state functional magnetic resonance imaging (fMRI) to characterize functional connectivity patterns in the FPN and DMN. Forty adults with moderate-to-severe TBI (mean ± standard deviation SD; age = 39.53 ± 16.49 years, education = 13.92 ± 3.20 years, lowest Glasgow Coma Scale score = 6.63 ± 3.24, sex = 70% male) were scanned at approximately 0.5, 1-1.5, and 3+ years post-injury. Seventeen healthy, uninjured participants (mean ± SD; age = 38.91 ± 15.57 years, education = 15.11 ± 2.71 years, sex = 29% male) were scanned at baseline and approximately 11 months afterwards. Group independent component analyses and linear mixed-effects modeling with linear splines that contained a knot at 1.5 years post-injury were employed to investigate longitudinal network changes, and associations with covariates, including age, sex, and injury severity. In patients with TBI, functional connectivity in the right FPN increased from approximately 0.5 to 1.5 years post-injury (unstandardized estimate = 0.19, standard error SE = 0.07,
0.009), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.21, SE = 0.11,
0.009), and marginally declined afterwards (estimate = -0.10, SE = 0.06,
0.079). Functional connectivity in the DMN increased from approximately 0.5 to 1.5 years (estimate = 0.15, SE = 0.05,
0.006), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.19, SE = 0.08,
0.021), and was estimated to decline from 1.5 to 3+ years (estimate = -0.04, SE = 0.04,
0.303). Similarly, the left FPN increased in functional connectivity from approximately 0.5 to 1.5 years post-injury (estimate = 0.15, SE = 0.05,
0.002), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate = -0.18, SE = 0.07,
0.008), and was estimated to decline thereafter (estimate = -0.04, SE = 0.03,
0.254). At approximately 0.5 years post-injury, patients showed hypoconnectivity compared with healthy, uninjured participants at baseline. Covariates were not significantly associated in any of the models. Findings of early improvement but a tapering and possible decline in connectivity thereafter suggest that compensatory effects are time-limited. These later reductions in connectivity mirror growing evidence of behavioral and structural decline in chronic moderate-to-severe TBI. Targeting such declines represents a novel avenue of research and offers potential for improving clinical outcomes.
IMPORTANCE: Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women ...compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals. OBJECTIVE: To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET). DESIGN, SETTING AND PARTICIPANTS: This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women 61%) who underwent carbon 11–labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer’s Disease Neuroimaging Initiative (age range, 63-94 years; 55 women 51%) who underwent florbetapir and flortaucipir F 18 PET. MAIN OUTCOMES AND MEASURES: A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined. RESULTS: The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers 31%; 89 individuals 30% with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β male = −0.11 0.05; 95% CI, −0.21 to −0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β male, APOE ε4+ = −0.15 0.09; 95% CI, −0.32 to 0.01; P = .07). CONCLUSIONS AND RELEVANCE: Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.
The timing and length of burning seasons in different parts of the world depend on climate, land-cover characteristics, and human activities. In this study, global burned area estimates are used in ...conjunction with global gridded distributions of agricultural land-cover types (defined as the sum of cropland and pasture area) to separate the seasonality of agricultural burning practices from that of non-agricultural fire. The results presented in this study show that agricultural and non-agricultural land experience broadly different fire seasonality patterns that are not always linked to climate conditions. We highlight these differences on a regional basis, examining variations in both agricultural land cover and associated cultural practices to help explain our results. While we discuss two land-cover categories, the methods can be generalized to derive seasonality for any number of land uses or cover types. This will be useful as global fire models evolve to be fully interactive with land-use and land-cover change in the next generation of Earth system models.
This study describes and evaluates the Fire Including Natural & Agricultural Lands model (FINAL) which, for the first time, explicitly simulates cropland and pasture management fires separately from ...non-agricultural fires. The non-agricultural fire module uses empirical relationships to simulate burned area in a quasi-mechanistic framework, similar to past fire modeling efforts, but with a novel optimization method that improves the fidelity of simulated fire patterns to new observational estimates of non-agricultural burning. The agricultural fire components are forced with estimates of cropland and pasture fire seasonality and frequency derived from observational land cover and satellite fire datasets. FINAL accurately simulates the amount, distribution, and seasonal timing of burned cropland and pasture over 2001–2009 (global totals: 0.434×106 and 2.02×106 km2 yr−1 modeled, 0.454×106 and 2.04×106 km2 yr−1 observed), but carbon emissions for cropland and pasture fire are overestimated (global totals: 0.295 and 0.706 PgC yr−1 modeled, 0.194 and 0.538 PgC yr−1 observed). The non-agricultural fire module underestimates global burned area (1.91×106 km2 yr−1 modeled, 2.44×106 km2 yr−1 observed) and carbon emissions (1.14 PgC yr−1 modeled, 1.84 PgC yr−1 observed). The spatial pattern of total burned area and carbon emissions is generally well reproduced across much of sub-Saharan Africa, Brazil, Central Asia, and Australia, whereas the boreal zone sees underestimates. FINAL represents an important step in the development of global fire models, and offers a strategy for fire models to consider human-driven fire regimes on cultivated lands. At the regional scale, simulations would benefit from refinements in the parameterizations and improved optimization datasets. We include an in-depth discussion of the lessons learned from using the Levenberg–Marquardt algorithm in an interactive optimization for a dynamic global vegetation model.
This is a phase II, multicenter, open-label study of chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) and age > or = 70 years who were treated with erlotinib and evaluated to ...determine the median, 1-year, and 2-year survival. The secondary end points include radiographic response rate, time to progression (TTP), toxicity, and symptom improvement.
Eligible patients with NSCLC were treated with erlotinib 150 mg/d until disease progression or significant toxicity. Tumor response was assessed every 8 weeks by computed tomography scan using Response Evaluation Criteria in Solid Tumors. Tumor samples were analyzed for the presence of somatic mutations in EGFR and KRAS.
Eighty eligible patients initiated erlotinib therapy between March 2003 and May 2005. There were eight partial responses (10%), and an additional 33 patients (41%) had stable disease for 2 months or longer. The median TTP was 3.5 months (95% CI, 2.0 to 5.5 months). The median survival time was 10.9 months (95% CI, 7.8 to 14.6 months). The 1- and 2- year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. EGFR mutations were detected in nine of 43 patients studied. The presence of an EGFR mutation was strongly correlated with disease control, prolonged TTP, and survival.
Erlotinib monotherapy is active and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Erlotinib merits consideration for further investigation as a first-line therapeutic option in elderly patients.
Introduction
The apolipoprotein E (APOE) genotype is a driver of cognitive decline and dementia. We used causal mediation methods to characterize pathways linking the APOE genotype to late‐life ...cognition through Alzheimer's disease (AD) and non‐AD neuropathologies.
Methods
We analyzed autopsy data from 1671 individuals from the Religious Orders Study, Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS) studies with cognitive assessment within 5 years of death and autopsy measures of AD (amyloid beta (Aβ), neurofibrillary tangles), vascular (athero/arteriolo‐sclerosis, micro‐infarcts/macro‐infarcts), and non‐AD neurodegenerative neuropathologies (TAR DNA protein 43 TDP‐43, Lewy bodies, amyloid angiopathy, hippocampal sclerosis).
Results
The detrimental effect of APOE ε4 on cognition was mediated by summary measures of AD and non‐AD neurodegenerative neuropathologies but not vascular neuropathologies; effects were strongest in individuals with dementia. The protective effect of APOE ε2 was partly mediated by AD neuropathology and stronger in women than in men.
Discussion
The APOE genotype influences cognition and dementia through multiple neuropathological pathways, with implications for different therapeutic strategies targeting people at increased risk for dementia.
Highlights
Both apolipoprotein E (APOE) ε2 and APOE ε4 effects on late‐life cognition are mediated by AD neuropathology.
The estimated mediated effects of most measures of AD neuropathology were similar.
Non–Alzheimer's disease (AD) neurodegenerative pathologies mediate the effect of ε4 independently from AD.
Non‐AD vascular pathologies did not mediate the effect of the APOE genotype on cognition.
The protective effect of APOE ε2 on cognition was stronger in women.
Objectives
Amyloid‐beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and ...interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated.
Methods
One hundred thirty‐seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ (11C‐Pittsburgh compound B) and tau (18F‐flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex‐wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites.
Results
Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map‐level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies.
Interpretation
Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1–3 ANN NEUROL 2019;85:181–193.
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