Citations

121 Background: We evaluated the role of pre-treatment pulmonary function testing (PFT) in predicting the likelihood of cardiac and/or pulmonary toxicity for esophagus cancer patients receiving trimodality therapy. Methods: From 2007 to 2013, 64 patients with esophageal cancer received trimodality therapy at a single tertiary center with pre-treatment PFTs. The odds ratio of pre-treatment PFT as a predictor of cardiopulmonary toxicity was assess with univariate analysis (UVA). FEV1 (forced expiratory volume in 1 second) and DLCO (diffusion capacity for carbon monoxide) were assessed per 0.5-unit decrease. Percent FEV1 and DLCO predicted were assessed per 10% decrease. Results: The median age was 62 years (range, 41-79) with 88% male patients. A total of 70% of patients had adenocarcinoma with 66% having stage 3 disease. Most patients were former (43%) or current smokers (32%) and 18% had COPD. One or more cardiac comorbidities were observed in 54% of patients. The median RT dose was 50 Gy and the most frequent concurrent chemotherapy was cisplatin/5FU (53%). The median pre-treatment FEV1 and DLCO was 2.8 liters (range, 1-4.9) and 22.5 mL/min/mmHg (range, 17.2-25.5), respectively. This correlated to a median percent predicted value for FEV1 and DLCO of 85% (range, 30-124%) and 81.5% (range, 49-119%), respectively. The overall rate of any cardiac and pulmonary toxicity was 35% and 50%, respectively. Percent predicted value of both FEV1 and DLCO was statistically associated with pulmonary but not cardiac toxicity (Table). Conclusions: Patients with compromised pre-treatment pulmonary function are at higher risk of developing post-treatment pulmonary toxicities. Pulmonary function testing should be routinely performed prior to initiation of trimodality therapy for patient risk stratification. [Table: see text]

114 Background: Clinical staging of early esophageal neoplasia traditionally involves histological confirmation and imaging with endoscopic ultrasound (EUS), CT, and PET which have low sensitivity and specificity for staging esophageal cancer (EC). Endoscopic submucosal dissection (ESD) therapy is traditionally used for treatment, but not diagnosis as it is felt to be technically challenging and have a high risk for complications. We applied a new articulating endoscopic knife that permits safe ESD (ESD-CC) to evaluate early neoplasia with potential curative resection. Methods: We performed a retrospective study of patients undergoing ESD to stage or treat suspected early EC (cT1-T2). Clinical stage was done by EUS, CT, and PET. Two expert GI pathologists reviewed all histology. Lesions were examined with high resolution white light endoscopy and narrow band imaging. ESD was done with 1:200,000 epinephrine and methylene blue dye injection for lifting and staining the submucosal space. A 5mm, scissors-like articulated knife was used to perform ESD and hemostasis. Complications during post-ESD observation or follow-up were recorded. Results: A total of 35 patients who underwent ESD-CC were included with median age 70 (IQR 12), 26 males (74%), and followed for a median 3.4 months (IQR 6.4). This group consisted of 32 potential adenocarcinomas and 3 squamous cell cancers. The clinical Pre-ESD diagnoses were cT1 EC (24, 69%) and suspected EC in Barrett’s esophagus (BE) (11, 31%). The cT1 EC cases had ESD staged at least T1b (5, 21%), T1a (11, 46%), EC in situ (1, 4%), and dysplastic BE (7, 29%). The suspected EC cases had ESD staged at least T1b (1, 9%), T1a (2, 18%), and DBE (8, 73%). ESD-CC up-staged 4 (11%), down-staged 10 (29%), and confirmed prior diagnosis in 21 (60%). No complications including bleeding, perforation, or stricture formation regardless of size of ESD, age of patient, or co-morbidities. Conclusions: Staging of early esophageal cancer can be improved using ESD with an articulating knife, without increase in complications. ESD may be used as a staging modality in early esophageal cancer.

Acquisition of self-reactive effector CD4+ T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3–dependent amplification loop that exacerbates autoimmune inflammation. In experimental myocarditis, we show that effector organ–accumulating autoreactive IL-3+ CD4+ T cells stimulate IL-3R+ tissue macrophages to produce monocyte-attracting chemokines. The newly recruited monocytes differentiate into antigen-presenting cells that stimulate local IL-3+ CD4+ T cell proliferation, thereby amplifying organ inflammation. Consequently, Il3−/− mice resist developing robust autoimmune inflammation and myocardial dysfunction, whereas therapeutic IL-3 targeting ameliorates disease. This study defines a mechanism that orchestrates inflammation in myocarditis, describes a previously unknown function for IL-3, and identifies IL-3 as a potential therapeutic target in patients with myocarditis.

Background It has been observed that trauma patients have elevated plasma procoagulant activity that could be assigned to an elevated concentration of tissue factor (TF). However, in many instances there is a discrepancy between the levels of TF and the procoagulant activity observed. We hypothesized that factor XIa (FXIa) could be responsible for this additional activity and that the presence and levels of both proteins could correlate with trauma severity. Methods Citrate plasma from 98 trauma patients (47 blunt, 17 penetrating, and 34 thermal) were evaluated in clotting assays for the presence of FXIa and TF activity using respective inhibitory antibodies. Results When the three trauma patient groups were divided into two cohorts (Injury Severity Score [ISS] > 25 and ISS ≤ 25), higher frequencies and concentrations of both TF and FXIa were observed for all the more severe injury subgroups. Conclusions The majority of trauma patients have active FXIa in their plasma, with a significant fraction having active TF as well. Additionally, both TF and FXIa frequency and concentration directly relate to trauma severity. These data suggest the use of these two proteins as potential markers for the stratification of trauma patients.

Objective Surveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett’s oesophagus (BE) are currently empiric and not based on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines. Design Data on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies. Results 594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4–4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI −7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia). Conclusions BE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.

Background: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a “virtual proteomic” approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. Methods: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651). Results: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-β predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08–1.58; P =0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66–0.94; P =0.008) per 1-SD increment in platelet-derived growth factor receptor-β. Conclusions: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.

Isolated aortic mural thrombus (AMT) is an infrequent occurrence in the setting of an otherwise normal aorta and is a similarly rare occurrence in Takayasu arteritis (TAK). As such, consensus on optimal treatment strategy does not exist, however, invariably necessitates anticoagulation. We report a case of a 21-year-old female who presented with acute chest pain with an isolated descending thoracic AMT on imaging. Diagnosis was elusive after an exhaustive, multidisciplinary evaluation including structural, hypercoagulable, and rheumatologic etiologies. After hypertension control and anticoagulation, she was asymptomatic without embolic sequelae. We proceeded with thoracic aortic resection with interposition reconstruction for the dual function of treatment and definitive diagnosis revealing TAK. This demonstrates a curious presentation of TAK with an equally atypical complication managed with surgery.