RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future.

While activating RET fusions are identified in various cancers, lung cancer represents the most common RET fusion-positive tumor. The clinical drug development of RET inhibitors in RET fusion-positive lung cancers naturally began after RET fusions were first identified in patient tumor samples in 2011, and thereafter paralleled drug development in RET fusion-positive thyroid cancers. Multikinase inhibitors were initially tested with limited efficacy and substantial toxicity. RET inhibitors were then designed with improved selectivity, central nervous system penetrance, and activity against RET fusions and most RET mutations, including resistance mutations. Owing their success to these rationally designed features, the first-generation selective RET tyrosine kinase inhibitors (TKIs) had higher response rates, more durable disease control, and an improved safety profile compared to the multikinase inhibitors. This led to lung and thyroid cancer, and later tumor-agnostic regulatory approvals. While next-generation RET TKIs were designed to abrogate uncommon on-target (e.g., solvent front mutation) resistance to selpercatinib and pralsetinib, many of these drugs lacked the selectivity of the first-generation TKIs, raising the question of what the future holds for drug development in RET-dependent cancers.

Multi-level alignment processes in the sustainment of a youth substance use treatment model following a federal implementation initiative: A mixed method study.

INTRODUCTION: Government agencies have identified evidence-based practice (EBP) dissemination as a pathway to high-quality behavioral health care for youth. However, gaps remain about how to best sustain EBPs in treatment organizations in the U.S., especially in resource-constrained settings like publicly-funded youth substance use services. One important, but understudied, determinant of EBP sustainment is alignment: the extent to which multi-level factors that influence sustainment processes and outcomes are congruent, consistent, and/or coordinated. This study examined the role of alignment in U.S. states' efforts to sustain the Adolescent Community Reinforcement Approach (A-CRA), an EBP for youth substance use disorders, during the COVID-19 pandemic. METHODS: In this mixed methods study, the qualitative investigation preceded and informed the quantitative investigation. We interviewed state administrators and providers (i.e., supervisors and clinicians) from 15 states that had completed a federal A-CRA implementation grant; providers also completed surveys. The sample included 50 providers from 35 treatment organizations that reported sustaining A-CRA when the COVID-19 pandemic began, and 20 state administrators. In qualitative thematic analyses, we applied the EPIS (Exploration, Preparation, Implementation, Sustainment) framework to characterize alignment processes that interviewees described as influential on sustainment. We then used survey items to quantitatively explore the associations described in qualitative themes, using bivariate linear regressions. RESULTS: At the time of interview, staff from 80 % of the treatment organizations (n = 28), reported sustaining A-CRA. Providers from both sustainer and non-sustainer organizations, as well as state administrators, described major sources of misalignment when state agencies ceased technical assistance post-grant, and because limited staff capacity conflicted with A-CRA's training model, which was perceived as time-intensive. Participants described the pandemic as exacerbating preexisting challenges, including capacity issues. Sustainer organizations reported seeking new funding to help sustain A-CRA. Quantitative associations between self-rated extent of sustainment and other survey items mostly followed the pattern predicted from the qualitative findings. CONCLUSIONS: The COVID-19 pandemic amplified longstanding A-CRA sustainment challenges, but treatment organizations already successfully sustaining A-CRA pre-pandemic largely continued. There are missed opportunities for state-level actors to coordinate with providers on the shared goal of EBP sustainment. A greater focus on alignment processes in research and practice could help states and providers strengthen sustainability planning.

Serial Cell-Free DNA Sequencing in ROS1 Fusion-Positive Lung Cancers During Treatment With Entrectinib.

PURPOSE: Patients with metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC) are effectively treated with entrectinib, a multikinase inhibitor. Whether serial targeted gene panel sequencing of cell-free DNA (cfDNA) can identify response and progression along with mechanisms of acquired resistance to entrectinib is underexplored. METHODS: In patients with ROS1 fusion-positive NSCLC, coclinical trial plasma samples were collected before treatment, after two cycles, and after progression on entrectinib (global phase II clinical trial, ClinicalTrials.gov identifier: NCT02568267). Samples underwent cfDNA analysis using MSK-ACCESS. Variant allele frequencies of detectable alterations were correlated with objective response per RECIST v1.1 criteria. RESULTS: Twelve patients were included, with best response as partial response (n = 9, 75%), stable disease (n = 2, 17%), and progressive disease (PD; n = 1, 8%). A ROS1 fusion was variably detected in cfDNA; however, patients without a ROS1 fusion in cfDNA had no other somatic alterations detected, indicative of possible low cfDNA shedding. Clearance of the enrolling ROS1 fusion or concurrent non-ROS1 alterations (TP53, CDH1, NF1, or ARID1A mutations) was observed in response to entrectinib therapy. Radiologic PD was accompanied by redemonstration of a ROS1 fusion or non-ROS1 alterations. On-target resistance was rare; only one patient acquired ROS1 G2032R at the time of progression. Several patients acquired new off-target likely oncogenic alterations, including a truncating alteration in NF1. CONCLUSION: Serial cfDNA monitoring may complement radiographic assessments as determinants of response and resistance to entrectinib in ROS1 fusion-positive lung cancers in addition to detecting putative resistance mechanisms on progression.

Basket Trials: Past, Present, and Future.

Large-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development.

Tumor-agnostic genomic and clinical analysis of BRAF fusions identify actionable targets.

BACKGROUND: Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course. PATIENTS/METHODS: We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, intact BRAF kinase domain). RESULTS: We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5' fusion partners spanning 52 histologies. 39 fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. 24 patients spanning multiple histologies were treated with MAPK-directed therapies of which 20 were evaluable for RECIST. Best response was partial response (N=2), stable disease (N=11), and progressive disease (N=7). The median time on therapy was 1 month with MEK plus BRAF inhibitors ([N=11], range 0-18 months) and 8 months for MEK inhibitors ([N=14], range 1-26 months). 9 patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N=6), Erdheim-Chester disease (N=1), extraventricular neurocytoma (N=1), melanoma (N=1)]. Fifteen patients had acquired BRAF fusions. CONCLUSIONS: BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy underscoring the importance of post-progression biopsies to optimize treatment at relapse in these patients.

Breaking the Mold: Trailblazing Melanoma Therapy Beyond Checkpoint Through Innovative Approaches.

Melanoma has long been a difficult malignancy to treat with low response rates to standard chemotherapies. In recent years, the use of immune checkpoint inhibitors have demonstrated promising results, paving the way for the use of the rapidly developing novel immune targeting therapies. In this review, we look beyond immune checkpoint inhibitor treatments and summarize several emerging treatment strategies for melanoma, including neoantigen vaccines, conventional antibody drug-conjugates, and bispecific T-cell engager therapies.

Phase II Study of Osimertinib in Patients With Epidermal Growth Factor Receptor Mutations: Results From the NCI-MATCH ECOG-ACRIN (EAY131) Trial Subprotocol E.

PURPOSE: The National Cancer Institute Molecular Analysis for Therapy Choice trial is a signal-finding genomically driven platform trial that assigns patients with any advanced refractory solid tumor, lymphoma, or myeloma to targeted therapies on the basis of next-generation sequencing results. Subprotocol E evaluated osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with EGFR mutations. METHODS: Eligible patients had EGFR mutations (T790M or rare activating) and received osimertinib 80 mg once daily. Patients with lung cancer with EGFR T790M were excluded. The primary end point was objective response rate (ORR), and the secondary end points were 6-month progression-free survival (PFS), overall survival, and toxicity. RESULTS: A total of 19 patients were enrolled: 17 were evaluable for toxicity and 13 for efficacy. The median age of the 13 included in the efficacy analysis was 63 years, 62% had Eastern Cooperative Oncology Group performance status 1, and 31% received >three previous systemic therapies. The most common tumor type was brain cancers (54%). The ORR was 15.4% (n = 2 of 13; 90% CI, 2.8 to 41.0) and 6-month PFS was 16.7% (90% CI, 0 to 34.4). The two confirmed RECIST responses were observed in a patient with neuroendocrine carcinoma not otherwise specified (EGFR exon 20 S768T and exon 18 G719C mutation) and a patient with low-grade epithelial carcinoma of the paranasal sinus (EGFR D770_N771insSVD). The most common (>20%) treatment-related adverse events were diarrhea, thrombocytopenia, and maculopapular rash. CONCLUSION: In this pretreated cohort, osimertinib did not meet the prespecified end point threshold for efficacy, but responses were seen in a neuroendocrine carcinoma with an EGFR exon 20 S768T and exon 18 G719C mutation and an epithelial carcinoma with an EGFR D770_N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

Activating Point Mutations in the MET Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors.

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.

Brief Report: Tyrosine Kinase Inhibitors for Lung Cancers That Inhibit MATE-1 Can Lead to "False" Decreases in Renal Function.

INTRODUCTION: Select tyrosine kinase inhibitors (TKIs) used to treat oncogene-driven lung cancers also inhibit MATE-1. When MATE-1 is blocked, creatinine is retained in the serum. Elevated creatinine levels raise the specter of drug-induced intrarenal insufficiency despite the lack of true renal injury. We conducted a systematic analysis of MATE-1 inhibitor (MATEi)-treated patients to comprehensively characterize this phenomenon. METHODS: Patients with oncogene-driven lung cancer treated with a wide variety of MATEi TKIs (brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib, and tepotinib) were eligible for an analysis of renal dysfunction. Acute kidney injury was classified on the basis of creatinine levels (Kidney Disease: Improving Global Outcomes criteria) as stage 1 (≥1.5× but <2× baseline), stage 2 (≥2× but <3× baseline), or stage 3 (>3× baseline). When available, cystatin C, a marker of kidney function unaffected by MATE-1, was used to evaluate the glomerular filtration rate (GFR). RESULTS: We identified 863 patients receiving MATEi TKIs including crizotinib (39%, n = 333), lorlatinib (17%, n = 144), cabozantinib (10%, n = 87), selpercatinib (10%, n = 82), capmatinib (9%, n = 77), brigatinib (6%, n = 53), entrectinib (5%, n = 45), tepotinib (5%, n = 41), and pralsetinib (0.1%, n = 1). Of the 90 patients (10%) with acute kidney injury, Kidney Disease: Improving Global Outcomes stages 1, 2, and 3 were observed in 72% (n = 65), 21% (n = 19), and 7% (n = 6) of patients, respectively. Concurrently drawn creatinine and cystatin C levels on TKI therapy were available for 17 patients. In most cases (n = 15 of 17), the calculated GFR was higher using cystatin C versus creatinine. The percentage of patients whose GFR was higher using cystatin C versus creatinine by less than 10 mL/min, 10 to 19 mL/min, 20 to 29 mL/min, and more than or equal to 30 mL/min was 27% (n = four of 15), 20% (n = three of 15), 20% (n = three of 15), and 33% (n = five of 15), respectively. Long-term data in three patients that spanned 3 years revealed that GFR was higher using cystatin C versus creatinine in 96% (n = 49 of 51) of all time points. Using a virtual clinical trial GFR cutoff of 40 mL/min, the percentage of eligible patients rose from 41% (n = seven of 17) using creatinine calculations to 71% (n = 12 of 17) using cystatin C calculations. CONCLUSIONS: The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine level seems elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.

Computed Tomographic Evaluation of Safe Corridors for Pin Placement in Rabbit Thoracolumbar Vertebrae and Sacrum.

OBJECTIVE: The aim of this study was to identify safe corridors for pin placement in the terminal thoracic vertebrae, lumbar vertebrae and sacrum of rabbits using computed tomography (CT) in cadaveric models. STUDY DESIGN: Computed tomographic imaging of 25 adult New Zealand white rabbit (Oryctolagus cuniculi) cadavers was evaluated. Safe insertion corridors at the cranial and caudal end cortical sections (ECS) of the vertebrae were determined using a multiplanar reconstruction software. Pins were placed to allow maximal bone purchase within the safe corridors. Post-procedure CT imaging was performed to evaluate the pin position. RESULTS: The median safe corridor height in the thoracic and lumbar cranial ECS (2.54 mm; 1.39-3.97 mm) was significantly lower than that of caudal ECS (3.98 mm; 1.66-5.53 mm; p < 0.001). The mean widths of the left and right sacral safe corridors were not significantly different. Of the 99 pins placed, 70.7% of the pins were appropriately placed without vertebral canal impingement. Errors included partial canal impingement (12.1%), complete canal impingement (5.1%), inadequate bone purchase (7.1%), placement into the intervertebral disc space (1.0%) or in the incorrect ECS than intended (4.0%). The odds ratio of successful pin insertion without canal impingement was 2.77 (95% confidence interval, 1.04-7.43; p < 0.05) times higher in the caudal ECS than in the cranial ECS. CONCLUSION: The corridor identified in this study can be used as a guideline for pin placement in the thoracic and lumbar vertebrae of New Zealand white rabbits. Further biomechanical studies are required.

Superior sulcus non-small cell lung cancers (Pancoast tumors): Current outcomes after multidisciplinary management.

OBJECTIVE: Despite neoadjuvant chemoradiotherapy, Pancoast tumors still present surgical and oncologic challenges. To optimize outcomes, we used a multidisciplinary care paradigm with medical and radiation oncology, and involvement of spine neurosurgery for most T3 and all T4 tumors. Spine neurosurgery permitted resection of transverse process for T3 and vertebral body resection for T4 tumors. METHODS: Retrospective analysis of single institution, prospective database of patients undergoing resection for cT3 4M0 Pancoast tumors. Patients were grouped as cT3 with combined resection with spine neurosurgery (T3 Neuro), cT3 without spine neurosurgery (T3 NoNeuro), and cT4. Overall survival, progression-free survival were analyzed by Kaplan-Meier and compared between groups using log-rank test. Cumulative incidence of local-regional and distant recurrence were compared using Gray test. P value <.05 was considered significant. RESULTS: From 2000 to 2021, 155 patients underwent surgery: median age was 58 years, and 81 were (52%) men. Most patients received neoadjuvant platinum-based neoadjuvant chemoradiotherapy (n = 127 [82%]). Operations were 48 cT3 Neuro, 41 cT3 NoNeuro, 66 cT4. R0 resection was achieved in 49 (94%) cT3 NoNeuro, 35 (85%) cT3 Neuro, and 57 (86%) cT4 patients (P = .4). Complete or major pathologic response occurred in 71 (55%) patients. Lower local-regional cumulative incidence was seen in cT3 Neuro versus cT3 NoNeuro (P = .05) and after major pathologic response. Overall survival and progression-free survival were associated with complete response, pathologic stage, and nodal status but not cT category. CONCLUSIONS: This treatment paradigm was associated with a high frequency of R0 resection, complete response, and major pathologic response. cT3 and cT4 tumors had similar outcomes. Novel therapies are needed to improve complete response.

Lorlatinib Tolerability and Association With Clinical Outcomes in Patients With Advanced ALK- or ROS1-Rearranged NSCLC: A Brief Report.

Introduction: Treatment with lorlatinib for patients with advanced ALK- and ROS1-rearranged NSCLC (ALK+ and ROS1+ NSCLC) is associated with a unique set of adverse events (AEs) often requiring dose reduction. However, the impact of dose reductions on outcomes remains unclear and is mainly limited to analyses from prospective studies of lorlatinib in the first-line setting. Methods: We reviewed the course of 144 patients with advanced ALK- or ROS1-rearranged NSCLC treated with lorlatinib in the second-line or later setting to assess the frequency of dose reductions resulting from treatment-related AEs (TRAEs) and the association between dose reductions and progression-free survival (PFS) and overall survival (OS). Results: A total of 58 patients (40%) had TRAE-related dose reductions, most (59%) owing to neurocognitive AEs or neuropathy. Among all patients, the median PFS was 8.1 months (95% confidence interval [CI]: 6.4-11.8); the median OS was 20.7 months (95% CI: 16.3-30.5). Among patients who were started on lorlatinib 100 mg/d (n = 122), a Cox regression model with the occurrence of a dose reduction as a time-dependent covariate indicated no association between dose reduction and PFS (hazard ratio = 0.86, 95% CI: 0.54-1.39) or OS (hazard ratio = 0.78, 95% CI: 0.47-1.30). Conclusions: Lorlatinib dose reductions were not associated with inferior clinical outcomes in this multicenter analysis. Prompt identification of lorlatinib TRAEs and implementation of dose reductions may help maximize tolerability without compromising outcomes.

Early-stage anaplastic lymphoma kinase (ALK)-positive lung cancer: a narrative review.

Background and Objective: While anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard of care treatment for metastatic ALK-positive non-small cell lung cancer (NSCLC), the benefit of moving ALK inhibitors to earlier disease stages is unclear. The objective of this review is to summarize the literature regarding the prevalence and prognosis of early-stage ALK-positive NSCLC and the utility of targeted therapies, immunotherapy, and chemotherapy in the neoadjuvant and adjuvant settings. Methods: We identified the references for this narrative review through a literature search of papers about early stage ALK-positive NSCLC using PubMed and clinicaltrials.gov. Last search was run on July 3, 2022. There were no language or time frame restrictions. Key Content and Findings: The incidence of oncogenic ALK alterations in early-stage NSCLC ranges from 2-7%, and ALK-positive NSCLC patients are more likely to be younger and never or light smokers. Studies on the prognostic impact of ALK in early-stage disease have had conflicting results. ALK TKIs are not approved in the neoadjuvant or adjuvant setting and there is a lack of large, randomized trial results. Several trials are currently accruing but results are not expected for several years. Conclusions: Attempts at large, randomized trials to evaluate the benefit of ALK TKIs in the adjuvant and neoadjuvant has been hampered by slow recruitment given the rarity of ALK alterations, lack of universal genetic testing, and the rapid pace of drug development. Expanded lung cancer screening recommendations, liberalization of surrogate endpoints (i.e., pathological complete response and major pathological response), growth of multicenter national clinical trials, and new diagnostic technologies (i.e., cell-free DNA liquid biopsies) provide hope of generating much needed data to definitively answer the question of the utility of ALK-directed therapies in the early-stage setting.

Long-Term Patient-Reported Outcomes of Visual Field Defects and Compensatory Mechanisms in Patients After Cerebral Hemispherectomy.

BACKGROUND: In cases of intractable epilepsy resistant to drug therapy, hemispherectomy is often the only treatment option to mitigate seizures; however, the true long-term subjective visual outcomes are relatively unexplored. In this study, we sought to determine and characterize patient-reported visual function years after hemispherectomy. METHODS: This was an observational study conducted on a large cohort of children with seizure disorder treated with cerebral hemispherectomy. An online survey was sent to parents with questions to assess subjective visual function with a variety of questions from presence of visual field defects after hemispherectomy, to improvement over time, compensatory mechanisms used, and development of strabismus. RESULTS: This survey was emailed to 248 parents of previously evaluated children who agreed to be re-surveyed, 48 (20%) of which responded. The average age at hemispherectomy was approximately 5 (±4) years, and the average time after hemispherectomy was 7 (±5) years. Thirty-nine patients (81%) were seizure-free after 1 surgery and 85% (n = 41) were seizure-free after ≥1 surgeries. Thirty-four (71%) experienced a visual field defect after surgery, but 25 (52%) experienced subjective improvement over time. Thirty-eight (79%) used compensatory mechanisms, such as head tilting, with 16 (33%) patients experiencing subjective improvement over time. Twenty-seven (56%) patients experienced a decrease in visual acuity after surgery with 12 (25%) experiencing subjective improvement over time. CONCLUSION: In a large cohort examining patient-reported visual outcomes years after hemispherectomy, most patients experienced strabismus and/or visual field defects. However, more than half reported improvements and compensatory mechanisms (exotropic strabismus and ipsilateral esotropic strabismus) over time, presumably to enhance visual field function. By exploring subjective visual and cognitive function, this paper uniquely characterizes patient-reported improvements over time, and provides motivation for larger longitudinal studies using more quantitative measures of visual function and improvement after hemispherectomy.

Racial Differences in Atrial Cardiopathy Phenotypes in Ischemic Stroke Patients.

OBJECTIVE: To test the hypothesis that thrombogenic atrial cardiopathy may be relevant to stroke-related racial disparities, we compared atrial cardiopathy phenotypes between Black versus White ischemic stroke patients. METHODS: We assessed markers of atrial cardiopathy in the Greater Cincinnati/Northern Kentucky Stroke Study, a study of stroke incidence in a population of 1.3 million. We obtained ECGs and reports of echocardiograms performed during evaluation of stroke during the 2010/2015 study periods. Patients with atrial fibrillation (AF) or flutter (AFL) were excluded. Investigators blinded to patients' characteristics measured P-wave terminal force in ECG lead V1 (PTFV1), a marker of left atrial fibrosis and impaired inter-atrial conduction, and abstracted left atrial diameter from echocardiogram reports. Linear regression was used to examine the association between race and atrial cardiopathy markers after adjustment for demographics, body mass index, and vascular comorbidities. RESULTS: Among 3,426 ischemic stroke cases in Black or White patients without AF/AFL, 2,391 had a left atrial diameter measurement (mean, 3.65 ±0.70 cm). Black race was associated with smaller left atrial diameter in unadjusted (ß coefficient, -0.11; 95% CI, -0.17 to -0.05) and adjusted (ß, -0.15; 95% CI, -0.21 to -0.09) models. PTFV1 measurements were available in 3,209 patients (mean, 3,434 ±2,525 µV*ms). Black race was associated with greater PTFV1 in unadjusted (ß, 1.59; 95% CI, 1.21 to 1.97) and adjusted (ß, 1.45; 95% CI, 1.00 to 1.80) models. CONCLUSIONS: We found systematic Black-White racial differences in left atrial structure and pathophysiology in a population-based sample of ischemic stroke patients. CLASSIFICATION OF EVIDENCE: This study provides class II evidence that the rate of atrial cardiopathy is greater among Black people with acute stroke compared to White people.

Gastrointestinal Disorders and Risk of First-Ever Ischemic Stroke.

BACKGROUND AND PURPOSE: Recent studies suggest that alteration of the normal gut microbiome contributes to atherosclerotic burden and cardiovascular disease. While many gastrointestinal diseases are known to cause disruption of the normal gut microbiome in humans, the clinical impact of gastrointestinal diseases on subsequent cerebrovascular disease remains unknown. We conducted an exploratory analysis evaluating the relationship between gastrointestinal diseases and ischemic stroke. METHODS: We performed a retrospective cohort study using claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We included only beneficiaries ≥66 years of age. We used previously validated diagnosis codes to ascertain our primary outcome of ischemic stroke. In an exploratory manner, we categorized gastrointestinal disorders by anatomic location, disease chronicity, and disease mechanism. We used Cox proportional hazards models to examine associations of gastrointestinal disorder categories and ischemic stroke with adjustment for demographics and established vascular risk factors. RESULTS: Among a mean of 1 725 246 beneficiaries in each analysis, several categories of gastrointestinal disorders were associated with an increased risk of ischemic stroke after adjustment for established stroke risk factors. The most notable positive associations included disorders of the stomach (hazard ratio, 1.17 [95% CI, 1.15-1.19]) and functional (1.16 [95% CI, 1.15-1.17]), inflammatory (1.13 [95% CI, 1.12-1.15]), and infectious gastrointestinal disorders (1.13 [95% CI, 1.12-1.15]). In contrast, we found no associations with stroke for diseases of the anus and rectum (0.97 [95% CI, 0.94-1.00]) or neoplastic gastrointestinal disorders (0.97 [95% CI, 0.94-1.00]). CONCLUSIONS: In exploratory analyses, several categories of gastrointestinal disorders were associated with an increased risk of future ischemic stroke after adjustment for demographics and established stroke risk factors.

Stroke Risk Following Takotsubo Cardiomyopathy.

BACKGROUND AND PURPOSE: Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is an increasingly recognized cause of left ventricular dysfunction. Previously considered a benign disease, Takotsubo cardiomyopathy may be a risk factor of ischemic stroke based on recent small, single-center case series. The strength and temporal profile of this association remains uncertain. METHODS: We performed a cohort-crossover study using administrative claims data on all emergency department visits and acute care hospitalizations from 2005 to 2015 in California, New York, and Florida. We identified patients with Takotsubo cardiomyopathy, excluding those with a prior or concomitant stroke diagnosis. We compared the risk of ischemic stroke in the first year after Takotsubo cardiomyopathy to the risk of ischemic stroke in the second year after Takotsubo cardiomyopathy. Takotsubo cardiomyopathy and ischemic stroke were ascertained using previously validated ICD-9-CM codes. Absolute risks and odds ratios (OR) were calculated using McNemar test for matched data. RESULTS: Among 5283 patients with Takotsubo cardiomyopathy (mean age, 67 years; 92% female), we identified 49 ischemic strokes during the first year after Takotsubo cardiomyopathy versus 19 ischemic strokes during the second year after. The risk of stroke was significantly higher in the year after Takotsubo cardiomyopathy (absolute increase, 0.6%; 95% CI: 0.2-0.9; OR: 2.6; 95% CI: 1.5-4.6) as compared to the control period. CONCLUSION: We found a heightened risk of ischemic stroke in the year after a diagnosis of Takotsubo cardiomyopathy, although the absolute risk increase was small.

Use and Removal of Inferior Vena Cava Filters in Patients With Acute Brain Injury.

BACKGROUND: Few data exist regarding the rate of inferior vena cava (IVC) filter retrieval among brain-injured patients. METHODS: We conducted a retrospective cohort study using inpatient claims between 2009 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We included patients aged ≥65 years who were hospitalized with acute brain injury. The primary outcome was the retrieval of IVC filter at 12 months and the secondary outcomes were the association with 30-day mortality and 12-month freedom from pulmonary embolism (PE). We used Current Procedural Terminology codes to ascertain filter placement and retrieval and International Classification of Diseases, Ninth Revision, Clinical Modification codes to ascertain venous thromboembolism (VTE) diagnoses. We used standard descriptive statistics to calculate the crude rate of filter placement. We used Cox proportional hazards analysis to examine the association between IVC filter placement and mortality and the occurrence of PE after adjustment for demographics, comorbidities, and mechanical ventilation. We used Kaplan-Meier survival statistics to calculate cumulative rates of retrieval 12 months after filter placement. RESULTS: Among 44 641 Medicare beneficiaries, 1068 (2.4%; 95% confidence interval [CI], 2.3%-2.5) received an IVC filter, of whom 452 (42.3%; 95% CI, 39.3%-45.3) had a diagnosis of VTE. After adjusting for demographics, comorbidities, and mechanical ventilation, filter placement was not associated with a reduced risk of mortality (hazard ratio [HR], 1.0; 95% CI, 0.8-1.3) regardless of documented VTE. The occurrence of pulmonary embolism at 12 months was associated with IVC filter placement (HR, 3.19; 95% CI, 1.3-3.3) in the most adjusted model. The cumulative rate of filter retrieval at 12 months was 4.4% (95% CI, 3.1%-6.1%); there was no significant difference in retrieval rates between those with and without VTE. CONCLUSIONS: In a large cohort of Medicare beneficiaries hospitalized with acute brain injury, IVC filter placement was uncommon, but once placed, very few filters were removed. IVC filter placement was not associated with a reduced risk of mortality and did not prevent future PE.

Differences in Diagnostic Evaluation in Women and Men After Acute Ischemic Stroke.

Background Sex differences have been found in stroke risk factors, incidence, treatment, and outcomes. There are conflicting data on whether diagnostic evaluation for stroke may differ between men and women. Methods and Results We performed a retrospective cohort study using inpatient and outpatient claims between 2008 and 2016 from a nationally representative 5% sample of Medicare beneficiaries. We included patients ≥65 years old and hospitalized with ischemic stroke, defined by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM diagnosis codes. Logistic regression was used to determine the association between female sex and the odds of diagnostic testing and specialist evaluation, adjusted for age, race, and number of Charlson comorbidities. Among 78 822 patients with acute ischemic stroke, 58.3% (95% CI, 57.9-58.6%) were women. Female sex was associated with decreased odds of intracranial vessel imaging (odds ratio [OR]: 0.94; 95% CI, 0.91-0.97), extracranial vessel imaging (OR: 0.89; 95% CI, 0.86-0.92), heart-rhythm monitoring (OR: 0.92; 95% CI, 0.87-0.98), echocardiography (OR: 0.92; 95% CI, 0.89-0.95), evaluation by a neurologist (OR: 0.94; 95% CI, 0.91-0.97), and evaluation by a vascular neurologist (OR: 0.94; 95% CI, 0.90-0.97), after adjustment for age, race, and comorbidities. These findings were unchanged in separate sensitivity analyses excluding patients who died during the index hospitalization or were discharged to hospice and excluding patients with atrial fibrillation diagnosed before their index stroke. Conclusions In a nationally representative cohort of Medicare beneficiaries, we found that women with acute ischemic stroke were less likely to be evaluated by stroke specialists and less likely to undergo standard diagnostic testing compared with men.