Citations

Background Myocardial strain imaging is a sensitive echocardiographic technique for identifying ventricular dysfunction. The aim of this study was to describe a reference range for right ventricular ( RV ) strain in subjects without cardiopulmonary disease and to report these values from a systematic review and meta‐analysis of the current literature. Methods Prospective online measurement of RV free wall longitudinal systolic strain using speckle tracking echocardiography ( STE ) was performed in 116 subjects with normal echocardiograms and without cardiopulmonary disease or risk factors. A systematic search of studies in EMBASE and Medline reporting RV strain values was performed through February 2014. Results The mean age was 48 ± 16 years and 58% were female. Mean RV strain was −26 ± 4%. Ten studies involving a total of 486 patients met our inclusion criteria. The mean age range was 43–57 years and 59% were female. All prior studies were performed with offline strain analysis, and 9 used a GE Healthcare strain analysis software system. The weighted estimate of RV free wall strain measured using tissue Doppler imaging (4 studies) was −27 ± 1% (95% confidence interval [ CI ] −30% to −25%) and with STE (8 studies, including the current study data) −27 ± 2% (95% CI −29% to −24%), respectively. Conclusions A reference range for RV strain in subjects without cardiopulmonary disease is presented. These data may help facilitate the routine clinical measurement of RV strain in patients referred for right heart echocardiography assessment.

Abstract Phosphaturic mesenchymal tumours ( PMTs ) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour‐induced osteomalacia ( TIO ) through secretion of phosphatonins including fibroblast growth factor 23 ( FGF23 ). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1–FGFR1 fusion gene in three out of four PMTs by next‐generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT‐PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1–FGFR1 fusion out of an additional 11 PMTs . Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded protein's oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia‐inducing FGFR1 fusion genes, which are ligand‐independent, the FN1–FGFR1 chimeric protein was predicted to preserve its ligand‐binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

SummaryVenous thromboembolism (VTE) has an increased incidence in patients with multiple myeloma (MM), especially during chemotherapy. Mechanisms including upregulation of procoagulant factors, such as factor VIII, have been postulated. The National Cancer Institute of Canada Clinical Trials Group MY.10 phase III clinical trial compared thalidomide‐prednisone to observation for 332 patients with MM post‐autologous stem cell transplantation (ASCT), with a primary endpoint of overall survival and various secondary endpoints including the incidence of VTE. One hundred and fifty‐three patients had biomarker data, including D‐dimer, factor VIII and thrombin anti‐thrombin (TAT) levels collected post‐ASCT at baseline and 2 months after intervention investigating in‐vivo thrombin generation. Differences between the time‐points included a significant reduction over time in D‐dimer, factor VIII and TAT levels in the observation group and sustained elevation of D‐dimer, significant increase in factor VIII and reduction in TAT levels in the thalidomide‐prednisone group. Eight VTE events were reported in this subset of study patients, all in the thalidomide‐prednisone arm, with a trend to increase in D‐dimer levels over time in those patients with VTE. This study provides physiological and clinical evidence for an increased risk of VTE associated with thalidomide‐prednisone maintenance therapy post‐ASCT for MM.

Abstract BACKGROUND Anticoagulation protocols used during mechanical circulatory support call for titration of antiplatelet agents. We compared the precision and reliability of 5 platelet function tests in healthy volunteers and donors on daily antiplatelet therapy to distinguish their efficacy for titrating antiplatelet therapy. METHODS We assessed arachidonic acid–induced platelet function by light transmission aggregometry (LTA), Multiplate impedance aggregometry, VerifyNow, and platelet mapping by thromboelastography (TEG PM). We assessed ADP-induced platelet function by the same methods and flow cytometry. Forty healthy volunteers and 10–13 volunteers on daily aspirin and/or clopidogrel therapy were evaluated. We compared tests for intraassay precision, interassay precision (samples from 2 separate blood draws), and reliability coefficient. RESULTS For arachidonic acid–induced platelet aggregation in healthy volunteers, intra- and interassay CVs were ≤10% for all methods. Intra- and interassay precision among donors on daily aspirin was ≤30% for all methods except LTA (38% interassay CV) and TEG PM (95% intraassay and 104% interassay CV). For ADP-induced platelet function, intra- and interassay precision was ≤10% and ≤30% for all methods. Only Multiplate demonstrated moderate or greater (R > 0.40) reliability coefficients for arachidonic acid–induced platelet function among all subjects. All methods of ADP-induced platelet function, except TEG PM, demonstrated substantial or greater (R > 0.60) reliability among all subjects. CONCLUSIONS TEG PM is least suited to monitor effects of antiplatelet agents. Multiplate impedance aggregometry was the only method to demonstrate an acceptable reliability coefficient among healthy volunteers and donors on both aspirin and clopidogrel therapy.

Pancreatectomy is associated with significant morbidity and unpredictable outcome, with few diagnostic tools to determine, which patients gain the most benefit from this treatment, especially before the operation. This study aimed to define a preoperative signature panel of serum markers to indicate response to pancreatectomy for pancreatic cancer. Over 1000 patients with pancreatic cancer treated at two independent high‐volume institutions were included in this study and were divided into three groups, including resected, locally advanced and metastatic. Eight serum tumor markers most commonly used in gastrointestinal cancers were analyzed for patient outcome. Preoperative CA19‐9 independently indicated surgical response in pancreatic cancer. Patients with CA19‐9 ≥1000 U/mL generally had a poor surgical benefit. However, a subset of these patients still achieved a survival advantage when CA19‐9 levels decreased postoperatively. CEA and CA125 in the presence of CA19‐9 ≥1000 U/mL could independently predict the non‐decrease of CA19‐9 postoperatively. The combination of the three markers was useful for predicting a worse surgical outcome with a median survival of 5.1 months vs. 23.0 months (p < 0.001) for the training cohort and 7.0 months vs. 18.2 months (p < 0.001) for the validation cohort and also suggested a higher prevalence of early distant metastasis after surgery. Resected patients with this proposed signature showed no survival advantage over patients in the locally advanced group who did not receive pancreatectomy. Therefore, a preoperative serum signature of CEA+/CA125+/CA19‐9 ≥1000 U/mL is associated with poor surgical outcome and can be used to select appropriate patients with pancreatic cancer for pancreatectomy.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on translational research on Barrett's esophagus that address evidence for genetic instability in esophageal cancer; the role of microsatellite instability; the use of histologic and serum Doublecortin‐like kinase 1 expression for progression of Barrett's esophagus to adenocarcinoma; the oxidative stress in Barrett's tumorigenesis; the genomic alterations in esophageal cancer; in vivo modeling in Barrett's esophagus; epigenetic and transcriptional regulation in Barrett's esophagus and esophageal adenocarcinoma; and normal and disordered regeneration in Barrett's esophagus.

Abstract The serine/cysteine protease inhibitor SCCA1 (SERPINB3) is upregulated in many advanced cancers with poor prognosis, but there is limited information about whether it makes functional contributions to malignancy. Here, we show that SCCA1 expression promoted oncogenic transformation and epithelial–mesenchymal transition (EMT) in mammary epithelial cells, and that SCCA1 silencing in breast cancer cells halted their proliferation. SCCA1 overexpression in neu+ mammary tumors increased the unfolded protein response (UPR), IL6 expression, and inflammatory phenotypes. Mechanistically, SCCA1 induced a prolonged nonlethal increase in the UPR that was sufficient to activate NF-κB and expression of the protumorigenic cytokine IL6. Overall, our findings established that SCCA1 contributes to tumorigenesis by promoting EMT and a UPR-dependent induction of NF-κB and IL6 autocrine signaling that promotes a protumorigenic inflammation. Cancer Res; 74(21); 6318–29. ©2014 AACR.