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Background Blood flow reversal is a possible mechanism for retrograde embolism in the setting of high‐risk atherosclerotic plaques in the descending aorta (DAo). Evidence suggests that pulse wave velocity (PWV) is a determinant of blood flow reversal and can be reduced by the destiffening effect of renin‐angiotensin system inhibitors (RASI). Purpose To evaluate the impact of antihypertensive therapy on in vivo changes in PWV and flow reversal in patients with cryptogenic stroke. Study Type Prospective. Population Sixteen patients (69 ± 9 years; 10 males) included after cryptogenic stroke. Field Strength/Sequence 3T. 4D flow sequence (temporal resolution = 19.6 msec) Assessment Patients underwent aortic MRI at baseline and at 6‐month follow‐up. Patients received standard‐of‐care antihypertensive therapy that were classified as RASI vs. non‐RASI medications (ie, destiffening vs. nondestiffening).We compared aortic PWV, flow reversal fraction (FRF), aortic measurements, cardiac function, and other aortic and cardiac measurements in the antihypertensive therapy groups. Statistical Tests Two‐tailed paired or unpaired Student's t ‐tests (normal distributions) or Wilcoxon tests (nonnormal distribution). Univariate correlations using Pearson correlation coefficients. Results There was a significant decrease in PWV in the RASI ( n = 10) group (9.4 ± 1.6 m/s vs. 8.3 ± 1.9 m/s; P < 0.05), as well as FRF (18.6% ± 4.1% vs. 16.3% ± 4.0%; P < 0.05) between baseline and the 6‐month MRI studies. There were no changes in PWV or FRF in the non‐RASI ( n = 6) group ( P = 0.146 and P = 0.32). A decrease in FRF was significantly correlated with a decrease in PWV ( r = 0.53; P < 0.05). Data Conclusion The findings of our study suggest that RASI therapy after cryptogenic stroke resulted in a decrease of blood flow reversal and aortic stiffness. Evidence Level 1 Technical Efficacy Stage 4

Background: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration. Methods: Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3–8.0; P =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6–269.1; P <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. Conclusions: This international multicenter study of CASQ2 -CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

BackgroundDoxorubicin and doxorubicin‐trastuzumab combination chemotherapy have been associated with cardiotoxicity that eventually leads to heart failure and may limit dose‐effective cancer treatment. Current diagnostic strategies rely on decreased ejection fraction (EF) to diagnose cardiotoxicity.PurposeThe aim of this study is to explore the potential of cardiac MR (CMR) imaging to identify imaging biomarkers in a mouse model of chemotherapy‐induced cardiotoxicity.MethodsA cumulative dose of 25 mg/kg doxorubicin was administered over three weeks using subcutaneous pellets (n = 9, Dox). Another group (n = 9) received same dose of Dox and a total of 10 mg/kg trastuzumab (DT). Mice were imaged at baseline, 5/6 weeks and 10 weeks post‐treatment on a 7T MRI system. The protocol included short‐axis cine MRI covering the left ventricle (LV) and mid‐ventricular short‐axis tissue phase mapping (TPM), pre‐ and post‐contrast T1 mapping, T2 mapping and Displacement Encoding with Stimulated Echoes (DENSE) strain encoded MRI. EF, peak myocardial velocities, native T1, T2, extracellular volume (ECV), and myocardial strain were quantified. N = 7 mice were sacrificed for histopathologic assessment of apoptosis at 5/6 weeks.ResultsGlobal peak systolic longitudinal velocity was reduced at 5/6 weeks in Dox (0.6 ± 0.3 vs 0.9 ± 0.3, p = 0.02). In the Dox group, native T1 was reduced at 5/6 weeks (1.3 ± 0.2 ms vs 1.6 ± 0.2 ms, p = 0.02), and relatively normalized at week 10 (1.4 ± 0.1 ms vs 1.6 ± 0.2 ms, p > 0.99). There was no change in EF and other MRI parameters and histopathologic results demonstrated minimal apoptosis in all mice (~1–2 apoptotic cell/high power field), suggesting early‐stage cardiotoxicity.ConclusionsIn a mouse model of chemotherapy‐induced cardiotoxicity using doxorubicin and trastuzumab, advanced CMR shows promise in identifying treatment‐related decrease in myocardial velocity and native T1 prior to the onset of cardiomyocyte apoptosis and reduction of EF.

ABSTRACT Objectives: Clinical features of eosinophilic esophagitis (EoE) have been well‐described in the literature, however, characterization of features experienced by patients with other eosinophilic gastrointestinal diseases (EGIDs) is lacking. Using data collected from a patient contact registry, we sought to characterize and contrast patient‐reported gastrointestinal and extragastrointestinal symptoms and comorbidities in non‐EoE EGIDs, including eosinophilic gastritis, gastroenteritis and colitis, relative to EoE. Methods: We conducted a cross‐sectional study of contact registry data collected from 2015 to 2018. Statistical comparisons were made using chi‐square (categorical measures) and the Mann‐Whitney U test (continuous measures). Multivariable analyses were used to evaluate associations between treatment and feelings of isolation. Results: Of the 715 reporting an EGID diagnosis (n = 525 EoE; n = 190 non‐EoE EGID), a higher proportion of those with a non‐EoE EGID reported more frequent specific and nonspecific gastrointestinal symptoms, including nausea, abdominal pain, diarrhea, constipation, and bloating ( P < 0.01 for all). Participants with a non‐EoE EGID were more likely to report higher frequency of fatigue, isolation, and deep muscle or joint pain ( P < 0.01 for all). Specific food elimination and elemental formula treatments were associated with increased odds of more frequent (at least weekly) feelings of isolation for participants with EoE (adjusted odds rtaio [aOR]: 2.4; 95% confidence interval [CI]: 1.5‐‐4.1 for specific food elimination and adjusted OR: 1.9; 95% CI: 1.2‐‐3.3 for elemental formula). Conclusions: Significant differences exist in the symptoms and comorbidities experienced between those with EoE versus non‐EoE EGIDs. Additional investigation is needed to elucidate the factors that may contribute to the high disease burden of these poorly understood conditions.

Background: Preclinical studies and pilot patient studies have shown that chronic infarctions can be detected and characterized from cardiac magnetic resonance without gadolinium-based contrast agents using native-T1 maps at 3T. We aimed to investigate the diagnostic capacity of this approach for characterizing chronic myocardial infarctions (MIs) in a multi-center setting. Methods: Patients with a prior MI (n=105) were recruited at 3 different medical centers and were imaged with native-T1 mapping and late gadolinium enhancement (LGE) at 3T. Infarct location, size, and transmurality were determined from native-T1 maps and LGE. Sensitivity, specificity, receiver-operating characteristic metrics, and inter- and intraobserver variabilities were assessed relative to LGE. Results: Across all subjects, T1 of MI territory was 1621±110 ms, and remote territory was 1225±75 ms. Sensitivity, specificity, and area under curve for detecting MI location based on native-T1 mapping relative to LGE were 88%, 92%, and 0.93, respectively. Native-T1 maps were not different for measuring infarct size (native-T1 maps: 12.1±7.5%; LGE: 11.8±7.2%, P =0.82) and were in agreement with LGE ( R 2 =0.92, bias, 0.09±2.6%). Corresponding inter- and intraobserver assessments were also highly correlated (interobserver: R 2 =0.90, bias, 0.18±2.4%; and intraobserver: R 2 =0.91, bias, 0.28±2.1%). Native T1 maps were not different for measuring MI transmurality (native-T1 maps: 49.1±15.8%; LGE: 47.2±19.0%, P =0.56) and showed agreement ( R 2 =0.71; bias, 1.32±10.2%). Corresponding inter- and intraobserver assessments were also in agreement (interobserver: R 2 =0.81, bias, 0.1±9.4%; and intraobserver: R 2 =0.91, bias, 0.28±2.1%, respectively). While the overall accuracy for detecting MI with native-T1 maps at 3T was high, logistic regression analysis showed that MI location was a prominent confounder. Conclusions: Native-T1 mapping can be used to image chronic MI with high degree of accuracy, and as such, it is a viable alternative for scar imaging in patients with chronic MI who are contraindicated for LGE. Technical advancements may be needed to overcome the imaging confounders that currently limit native-T1 mapping from reaching equivalent detection levels as LGE.

Background: Four-dimensional (D) flow magnetic resonance imaging (MRI) is limited by time-consuming and nonstandardized data analysis. We aimed to test the efficiency and interobserver reproducibility of a dedicated 4D flow MRI analysis workflow. Materials and Methods: Thirty retrospectively identified patients with bicuspid aortic valve (BAV, age=47.8±11.8 y, 9 male) and 30 healthy controls (age=48.8±12.5 y, 21 male) underwent Aortic 4D flow MRI using 1.5 and 3 T MRI systems. Two independent readers performed 4D flow analysis on a dedicated workstation including preprocessing, aorta segmentation, and placement of four 2D planes throughout the aorta for quantification of net flow, peak velocity, and regurgitant fraction. 3D flow visualization using streamlines was used to grade aortic valve outflow jets and extent of helical flow. Results: 4D flow analysis workflow time for both observers: 5.0±1.4 minutes per case (range=3 to 10 min). Valve outflow jets and flow derangement was visible in all 30 BAV patients (both observers). Net flow, peak velocity, and regurgitant fraction was significantly elevated in BAV patients compared with controls except for regurgitant fraction in plane 4 (91.1±29.7 vs. 62.6±19.6 mL/s, 37.1% difference; 121.7±49.7 vs. 90.9±26.4 cm/s, 28.9% difference; 9.3±10.1% vs. 2.0±3.4%, 128.0% difference, respectively; P <0.001). Excellent intraclass correlation coefficient agreement for net flow: 0.979, peak velocity: 0.931, and regurgitant fraction: 0.928. Conclusion: Our study demonstrates the potential of an efficient data analysis workflow to perform standardized 4D flow MRI processing in under 10 minutes and with good-to-excellent reproducibility for flow and velocity quantification in the thoracic aorta.

514 Background: The 21- gene Breast Recurrence Score predicts benefit from adjuvant chemotherapy in estrogen receptor positive (ER+), HER-2 negative (-) breast cancer (BC). We aimed to examine whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NAC). Methods: We identified patients with stage I-III ER+/HER2− BC treated with NAC from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤ 40 years. The 21-gene assay was performed on tumor specimens removed prior to NAC either as part of clinical care or retrospectively for research. Pathologic complete response (pCR) was defined as no residual invasive tumor (ypT0/is ypN0). The relationship between Recurrence Score result (RS) and pCR was evaluated using logistic regression modeling. Results: 76 women in the cohort had undergone NAC for ER+, HER2- BC and were eligible for this analysis: 5 had undergone clinical 21-gene assay testing, 71 had banked specimens retrospectively tested. Median age at diagnosis was 36.7 (24.3-40). Most tumors were of ductal histology (78%), high grade (51%), progesterone receptor (PgR) positive (86%), ≥T2 (88%), clinically node positive (74%), and anthracycline and taxane containing protocols were administered in 86% of cases. RS ranged between 5-75 with 50% > 25 and only 4 < 11. Mean RS was significantly higher among tumors achieving pCR vs. non-pCR response (51.9 vs. 26.6, pwilcoxon= 0.0005). pCR rate in patients with RS > 25 was 21% (8/38) vs. 5% in patients with RS < 25 (2/38), with both pCRs in the <25 group in patients with RS 21-25. In univariable analysis, PgR negativity (odds ratio (OR) 5.62, 95% confidence interval (CI) 1.27-24.89, p = 0.02), high grade (OR 9.03, 95%CI 1.07-76.32, p = 0.04) and higher RS as a continuous variable (OR 1.08, 95%CI 1.04-1.13, p = 0.0003) were associated with a greater likelihood of pCR. In multivariable analysis only RS remained significantly associated with pCR (OR: 1.07, 95%CI 1.01-1.12, p = 0.01): a 7% increase in the odds of pCR for every 1-point increase in RS. Conclusions: In young women with ER+, HER2- BC who received NAC, higher pretreatment RS was associated with an increased likelihood of pCR. Genomic expression profiling assays may have a role in decision-making in young women in need of neoadjuvant therapy. For women with low likelihood of benefiting from NAC, alternative approaches are clearly warranted. Given the demonstrated efficacy of neoadjuvant endocrine therapy in post-menopausal women, further evaluation in young women should be pursued.

AbstractBackgroundBuccal squamous cell carcinoma (SCC) is a locoregionally aggressive malignancy, representing a small subset of oral cancers in North America. We investigated the prognostic value of several clinicopathologic factors in a cohort of patients diagnosed with buccal SCC.MethodsBetween years 1992 and 2017, 52 patients were diagnosed with conventional buccal SCC. Archival surgical pathology material was retrospectively reviewed for reportable findings according to the latest reporting guidelines published by the College of American Pathologists. Clinical data were obtained through chart review.ResultsThe majority of patients were of older age, current or past smokers, and without specific gender predilection. Most presented at a clinically advanced stage and were treated with surgery alone, or surgery followed by adjuvant radiotherapy. The tumor recurred in about 40% of patients, and almost half of the patients died from the disease by the end of the follow‐up period. The worst pattern of invasion (WPOI) was associated with greater depth of invasion (DOI) (P = .031) and perineural invasion (P < .001). In univariate analyses, older age (P = .004), positive nodal status (P = .047), lymphovascular invasion (P = .012), perineural invasion (P = .05), and WPOI‐5 (P = .015) were adverse predictors of 5‐year overall survival (OS). In multivariate analysis, older age (P = .011), WPOI‐5 (P < .001), and perineural invasion (P = .001) remained statistically significant independent prognosticators of worse 5‐year OS.ConclusionsOlder age, WPOI‐5, and perineural invasion are significant prognosticators of worse OS. WPOI is associated with DOI, a finding which may have important implications for the pathogenesis and biologic behavior of the disease.