Citations

Abstract Background First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy. Methods Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible. Results A total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively). Conclusions Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.

Background: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia. Objective: To determine whether CMBs on antemortem MRI correlate with CAA. Methods: We reviewed 54 consecutive participants with antemortem T2*GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By a clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs. Results: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal/cortical components correlated with number of lobar CMBs. Conclusion: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOE ɛ4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA.

Background: Atrial fibrillation (AF) is an established risk factor for ischemic stroke, but it can be paroxysmal and may go undiagnosed. An artificial intelligence (AI)-enabled ECG acquired during normal sinus rhythm was recently shown to detect silent AF. The objective of this study was to determine if AI-ECG AF score is associated with presence of cerebral infarcts. Methods: Participants from a population-based study ages 30 to 95 years with T2 fluid attenuation inversion recovery (FLAIR) MRI obtained between October 10, 2011, and November 2, 2017 were considered for inclusion. Participants without ECG were excluded. AI-ECG score was calculated using most recent ECG with normal sinus rhythm at the time of MRI. Presence of infarcts was determined on FLAIR MRI scans. Logistic regression was run to evaluate the relationship between AI-ECG AF score and presence of cerebral infarcts. Similar analyses were performed using history of AF rather than AI-ECG AF score as predictor. Age and sex were included as covariates. We also examined whether a high-threshold AI-ECG score was associated with infarcts. In a prior study, an AI-ECG AF score > 0.5 was associated with a cumulative incidence of AF of 21.5% at 2 years and 52.2% at 10 years. Results: This study included 1,373 individuals. Average age was 69.6 years and 53% of participants were male. There were 136 (10%) individuals with ECG-confirmed AF; 1237 (90%) participants had no AF history. Of participants with AF, 23% (n=31) were on anticoagulation, 47% (n=64) were on antiplatelet and 18% (n=24) were on dual therapy. Only 1.3% (n=16) of patients without AF were on anticoagulation and 47% (n=578) were on antiplatelet therapy. Ischemic infarcts were detected in 214 (15.6%) patients. As a continuous measure AI-ECG was associated with infarcts but not after adjusting for age and sex (p=0.46). AI-ECG AF score > 0.5 was associated with infarcts ( p < 0.001); even after adjusting for age and sex ( p = 0.03). History of AF was also associated with infarcts after adjusting for age and sex ( p = 0.018). Conclusion: AI-ECG AF score and history of AF were associated with presence of cerebral infarcts after adjusting for age and sex. This tool could be useful in select patients with cryptogenic stroke but further investigation would be required.

Background: Cerebral microbleeds (CMBs) are associated with cognitive decline, but their importance outside of clinical cerebral amyloid angiopathy is less well understood, as are the mechanisms of their impact on cognition. In a community-based dementia-free cohort, we evaluate cross-sectional associations between CMB patterns and cerebral amyloid β (Aβ) deposition, measured by florbetapir PET. Methods: ARIC-PET recruited nondemented individuals from 3 US sites. Participants completed 3T brain MRI with T2*GRE (with CMBs read for presence, frequency, location (lobar vs subcortical), and pattern, as well as florbetapir (Aβ) PET (global cortical standardized uptake value ratio >1.2 as a positive scan). Multivariable (see Table) logistic regression models of Aβ+ scans evaluated CMB presence, frequency, location, and pattern, in separate models. Effect modification by sex, race, APOE status, and cognition (normal vs mild cognitive impairment) was evaluated. Results: Nearly 25% of the 322 individuals included had CMBs. No significant associations were found between CMBs (presence or number) and Aβ positivity, but a pattern of isolated lobar CMBs or superficial siderosis was associated with over a 4-fold higher odds of elevated Aβ vs having no CMBs, without a similar elevated risk in those with isolated subcortical CMBs or mixed subcortical + either lobar CMBs or superficial siderosis. Although no significant interactions were found, a mixed pattern was nonsignificantly protective (OR estimates 0.4-0.6) and lobar only CMBs had a (nonsignificantly) higher risk (OR up to 6.4) of Aβ for three subgroups: women (vs men); Blacks (vs whites), APOE ε4 noncarriers (vs carriers), and cognitively normal (vs MCI). Conclusions: A lobar-only pattern of CMBs is most strongly associated with brain Aβ, with no elevated risk for a mixed CMB pattern. Further study is needed to understand differences in these CMB patterns and their meaning across distinct demographic subgroups.

AbstractIntroductionWe determined whether cerebrospinal fluid (CSF) neurofilament light (NfL), neurogranin (Ng), and total‐tau (t‐tau) differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH).MethodsAnalyses included 536 non‐demented Mayo Clinic Study of Aging participants with CSF NfL, Ng, t‐tau, amyloid beta (Aβ)42 and longitudinal MRI scans. Linear mixed models assessed longitudinal associations between CSF markers and MRI changes.ResultsHigher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t‐tau was associated with decreasing temporal lobe and Alzheimer's disease (AD) meta region of interest (ROI) cortical thickness. There was no association between Ng and any MRI measure. CSF Aβ42 interacted with Ng for declines in temporal lobe and AD meta ROI cortical thickness and cingulum FA.DiscussionCSF NfL predicts changes in white matter integrity, t‐tau reflects non‐specific changes in cortical thickness, and Ng reflects AD‐specific synaptic and neuronal degeneration.

Background: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at least one cognitive domain compared to 42.9% of controls ( H = 7.13, p = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I ( p = 0.044), Logical Memory II ( p = 0.011), and Trail Making Test –B ( p = 0.032), and APOE ɛ4 genotype was associated with worse performance on Logical Memory I ( p = 0.022); these relationships did not differ between LLD and ND. Conclusion: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer’s disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD.

AbstractIntroductionThis study evaluated the diagnostic accuracy of the Cogstate Brief Battery (CBB) for mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) in a population‐based sample.MethodsParticipants included adults ages 50+ classified as cognitively unimpaired (CU, n = 2866) or MCI (n = 226), and a subset with amyloid (A) and tau (T) positron emission tomography who were AD biomarker negative (A–T–) or had prodromal AD (A+T+).ResultsDiagnostic accuracy of the Learning/Working Memory Composite (Lrn/WM) for discriminating all CU and MCI was moderate (area under the curve [AUC] = 0.75), but improved when discriminating CU A–T– and MCI A+T+ (AUC = 0.93) and when differentiating MCI participants without AD biomarkers from those with prodromal AD (AUC = 0.86). Conventional cut‐offs yielded lower than expected sensitivity for both MCI (38%) and prodromal AD (73%).DiscussionClinical utility of the CBB for detecting MCI in a population‐based sample is lower than expected. Caution is needed when using currently available CBB normative data for clinical interpretation.

Background: Medicare reimbursement trends across multiple surgical subspecialties have been analyzed; however, little has been reported regarding the long-term trends in reimbursement of hand surgery procedures. The aim of this study is to analyze trends in Medicare reimbursement for commonly performed hand surgeries. Methods: Using the Centers for Medicare and Medicaid Services Physician and Other Supplier Public Use File, we determined the 20 hand surgery procedure codes most commonly billed to Medicare in 2016. Reimbursement rates were collected and analyzed for each code from The Physician Fee Schedule Look-Up Tool for years 2000 to 2019. We compared the change in reimbursement rate for each procedure to the rate of inflation in US dollars, using the Consumer Price Index (CPI) over the same time period. Results: The reimbursement rate for each procedure increased on average by 13.9% during the study period while the United States CPI increased significantly more by 46.7% ( P < .0001). When all reimbursement data were adjusted for inflation to 2019 dollars, the average reimbursement for all included procedures in this study decreased by 22.6% from 2000 to 2019. The average adjusted reimbursement rate for all procedures decreased by 21.92% from 2000 to 2009 and decreased by 0.86% on average from 2009 to 2019 ( P < .0001). Conclusion: When adjusted for inflation, Medicare reimbursement for hand surgery has steadily decreased over the past 20 years. It will be important to consider the implications of these trends when evaluating healthcare policies and the impact this has on access to hand surgery.

ABSTRACT BACKGROUND There is limited data regarding financial trends for procedural reimbursement in stroke care. A comprehensive understanding of such trends is important as continued progress is made to advance agreeable reimbursement models in the care of stroke patients. OBJECTIVE To evaluate monetary trends in Medicare reimbursement rates for commonly utilized procedures in stroke care from 2000 to 2019. METHODS The Centers for Medicare & Medicaid Services was queried for the included Current Procedural Terminology (CPT) codes and reimbursement data were extracted. The CPT codes compiled were the most commonly performed procedures for stroke-related International Classification of Diseases (ICD)-10 codes at our institution (I60-I63). Additionally, data were collected for alteplase and telestroke codes. The rate of change between procedures was compared utilizing an unpaired Student's t -test. All monetary data were adjusted for inflation to 2019 US dollars utilizing the US Consumer Price Index. RESULTS After adjusting for inflation, the average reimbursement for stroke (ICD I60-I63) procedures decreased by 11.2% from 2000 to 2019 (average of −0.43% per year). The adjusted reimbursement rate for included telestroke codes decreased by 12.1% from 2010 to 2019 (average of −1.4% per year). From 2005 to 2019, the reimbursement for alteplase rose by 163.98% (average of +7.3% per year). CONCLUSION When adjusted for inflation, Medicare reimbursement for common stroke procedures has decreased from 2000 to 2019. In contrast, reimbursement for alteplase has increased markedly. It is important to be aware of these trends in order to contextualize healthcare economic analyses and inform discussions.

Abstract Introduction The Frontotemporal Lobar Degeneration Module (FTLD‐MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD‐MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring. Methods Linear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 185), non‐fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data. Results Among PPAs, the FTLD‐MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change. Discussion The FTLD‐MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring.