Preoperative Nonselective Chest Computed Tomography Prior to Primary Cardiac Surgery Results in Meaningful Change to Surgical Management: Systematic Review and Pooled Prevalence Meta-Analysis.

BACKGROUND: Routine screening chest computed tomography (CT) prior to primary cardiac surgery is advocated by some surgeons due to the purported benefits of identifying significant aortic calcification that impacts ongoing management, such as performing anaortic off-pump surgery or adjusting cannulation strategy. Additionally, axial imaging can identify incidental findings that may require concomitant or staged procedures such as ascending aortic dilatation or pulmonary lesions. The objective of this study was to quantify the impact that nonselective chest CT prior to primary cardiac surgery had on subsequent management. METHOD: A systematic review and pooled prevalence meta-analyses were performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Included studies performed non-selective chest CT prior to primary cardiac surgery. RESULTS: A total of eight studies, including 2,250 patients were included. The rate of mortality and stroke was low (1% and 2%, respectively). Calcification of the ascending aorta was identified in 15% of patients (95% confidence interval [CI] 5.0-26.0). A significant change to the surgical plan such as cannulation strategy, off-pump surgery, cancellation, or an additional procedure was required in 7% (95% CI 2.0-12.0). Clinically relevant incidental findings requiring in-patient management or follow-up were identified in 10% (95% CI 6.0-14.0). CONCLUSIONS: Nonselective CT chest prior to primary cardiac surgery identifies clinically relevant findings that result in a modification of the surgical plan in a significant population of patients to address the risk of stroke associated with aortic calcification as well as the identification of important incidental findings such as pulmonary lesions.

Synchronous Carotid Endarterectomy and Anaortic Off-Pump Coronary Artery Bypass Surgery.

BACKGROUND: There is ongoing debate regarding the optimal strategy and timing for the surgical management of patients with severe concomitant carotid and coronary artery disease. Anaortic off-pump coronary artery bypass (anOPCAB), which avoids aortic manipulation and cardiopulmonary bypass, has been shown to reduce the risk of perioperative stroke. We present the outcomes of a series of synchronous carotid endarterectomy (CEA) and anOPCAB. METHODS: A retrospective review was performed. The primary endpoint was stroke at 30 days post-operation. Secondary endpoints included transient ischaemic attack, myocardial infarction and mortality 30 days post-operation. RESULTS: From 2009 to 2016, 1,041 patients underwent anOPCAB with a 30-day stroke rate of 0.4%. The majority of patients had preoperative carotid-subclavian duplex ultrasound screening and 39 were identified with significant concomitant carotid disease who underwent synchronous CEA-anOPCAB. The mean age was 71±7.5 years. Nine patients (23.1%) had previous neurological events. Thirty (30) patients (76.9%) underwent an urgent operation. For CEA, a conventional longitudinal carotid endarterectomy with patch angioplasty was performed in all patients. For anOPCAB, total arterial revascularisation rate was performed in 84.6% and the mean number of distal anastomoses was 2.9±0.7. In the 30-day postoperative period, there was one stroke (2.63%), two deaths (5.26%), two transient ischaemic attacks (TIAs) (5.26%) and no myocardial infarction. Two patients experienced acute kidney injury (5.26%), one of which required haemodialysis (2.63%). Mean length of stay was 11.37±7.9 days. CONCLUSION: Synchronous CEA and anOPCAB is a safe and effective option for patients' severe concomitant disease. Preoperative carotid-subclavian ultrasound screening allows identification of these patients.

The Use of Intraoperative Transit Time Flow Measurement for Coronary Artery Bypass Surgery: Systematic Review of the Evidence and Expert Opinion Statements.

Transit time flow measurement (TTFM) allows quality control in coronary artery bypass grafting but remains largely underused, probably because of limited information and the lack of standardization. We performed a systematic review of the evidence on TTFM and other methods for quality control in coronary artery bypass grafting following PRISMA standards and elaborated expert recommendations by using a structured process. A panel of 19 experts took part in the consensus process using a 3-step modified Delphi method that consisted of 2 rounds of electronic voting and a final face-to-face virtual meeting. Eighty percent agreement was required for acceptance of the statements. A 2-level scale (strong, moderate) was used to grade the statements based on the perceived likelihood of a clinical benefit. The existing evidence supports an association between TTFM readings and graft patency and postoperative clinical outcomes, although there is high methodological heterogeneity among the published series. The evidence is more robust for arterial, rather than venous, grafts and for grafts to the left anterior descending artery. Although TTFM use increases the duration and the cost of surgery, there are no data to quantify this effect. Based on the systematic review, 10 expert statements for TTFM use in clinical practice were formulated. Six were approved at the first round of voting, 3 at the second round, and 1 at the virtual meeting. In conclusion, although TTFM use may increase the costs and duration of the procedure and requires a learning curve, its cost/benefit ratio seems largely favorable, in view of the potential clinical consequences of graft dysfunction. These consensus statements will help to standardize the use of TTFM in clinical practice and provide guidance in clinical decision-making.

Cryobiopsy for Identification of Usual Interstitial Pneumonia and Other Interstitial Lung Disease Features. Further Lessons from COLDICE, a Prospective Multicenter Clinical Trial.

Rationale: Transbronchial lung cryobiopsy (TBLC) is an emerging technique for interstitial lung disease diagnosis. Good histopathologic agreement between TBLC and surgical lung biopsy (SLB) was demonstrated in the COLDICE (Cryobiopsy versus Open Lung Biopsy in the Diagnosis of Interstitial Lung Disease Alliance) study; however, diagnostic confidence was frequently lower for TBLC than SLB. Objectives: To characterize specific features of TBLC predictive of usual interstitial pneumonia (UIP) in corresponding SLB and to identify clinical indices predictive of biopsy concordance. Methods: The COLDICE study was a prospective, multicenter study investigating diagnostic agreement between TBLC and SLB. The participants underwent both procedures with blinded pathologist analysis of specimens, applying international guideline criteria. The TBLC features predictive of UIP in the paired SLB and predictive features of overall concordance were analyzed. Measurements and Main Results: A total of 65 patients (66.1 ± 9.3 yr; FVC, 84.7 ± 14.2%; DlCO, 63.4 ± 13.8%) participated in the COLDICE study. UIP was identified in 33/65 (50.8%) SLB, and 81.5% were concordant with corresponding TBLC (κ, 0.61; 95% confidence interval [CI], 0.38-0.77). The UIP guideline criteria of "predominantly subpleural or paraseptal fibrosis" was infrequently reported in TBLC (8/33, 24.2%), whereas "patchy fibrosis," "fibroblast foci," and the "absence of alternative diagnostic features" were frequently observed in TBLC. The combination of these three features strongly predicted UIP in paired SLB (odds ratio [OR], 23.4; 95% CI, 6.36-86.1; P < 0.0001). Increased numbers of TBLC samples predicted histopathologic concordance with SLB (OR, 1.8; 95% CI, 1.08-3.01; P = 0.03). The predictors of discordance included older age, family history, and radiologic asymmetry. Conclusions: Subpleural and/or paraseptal fibrosis were not essential for diagnosing UIP in TBLC, provided that other guideline criteria features were present. The diagnostic accuracy of TBLC was strengthened when increased numbers of samples were taken. Clinical trial registered with www.anzctr.org.au (ACTRN12615000718549).

Minimally invasive off-pump anaortic coronary artery bypass (MACAB).

BACKGROUND: Minimally invasive direct coronary artery bypass has enabled coronary artery bypass graft to compete with the appeal of less invasive percutaneous coronary procedures. Favorable results of coronary artery bypass surgery performed without the use of cardiopulmonary bypass and without touching the aorta (anOPCAB) have enabled the development and use of minimally invasive methods. METHODS: Between 2016 and 2021, 112 patients underwent multivessel coronary bypass surgery performed using a minimally invasive method through a small thoracotomy in the left chest with off-pump, anaortic, and all-arterial grafts (Minimally Invasive Off-Pump Anaortic Coronary Artery Bypass [MACAB]). Patient data were collected and retrospectively analyzed. Eight series from the literature using the multivessel mini-OPCAB and MACAB technique were also evaluated. RESULTS: Collectively, from the literature, 2729 patients underwent an average of 2.4 bypasses with an early mortality rate of 0.7% and a stroke rate of 0.16%. In our MACAB case series, 112 patients underwent an average of 2.9 bypasses with a mortality rate of 1.8% and a stroke rate of 0%. CONCLUSION: MACAB can be performed safely by experienced surgeons and reduces neurological injury and surgical trauma and may be a good alternative for multivessel stenting. Simulation systems are essential for its dissemination, and teams dedicated to coronary surgery-with subspecialty expertise-are necessary to achieve good outcomes.

Selecting the optimal treatment for left main coronary disease: The importance of identifying subgroups of patients.

Randomized trials of stenting versus surgery for patients with unprotected left main (LM) coronary stenosis have largely shown similar survival between the two interventions. However, patients with LM stenosis represent a heterogeneous group in which subgroups likely to benefit from one therapy more than another are difficult to identify. Increasing coronary disease burden is the most accepted subgrouping for identifying optimal therapy but this can be defined in more detail allowing greater discrimination. Competitive flow reduces bypass graft patency in patients with isolated LM stenosis and complex bifurcation stenoses reduce the effectiveness of coronary stenting. The evidence for LM stenosis subgroupings is presented.

Concomitant anaortic OPCAB and transfemoral TAVR for high-risk patients: A case series.

BACKGROUND: Combined on-pump coronary artery bypass (ONCAB) and surgical aortic valve replacement (SAVR) is the treatment of choice for concomitant severe aortic stenosis and coronary artery disease not amenable to percutaneous coronary intervention. Extensive aortic calcification and atheromatous disease may prohibit cardiopulmonary bypass and aortic cross-clamping. In these cases, anaortic off-pump coronary artery bypass (OPCAB) is a Class I (EACTS 2018) and Class IIA (AHA 2021) indication for surgical coronary revascularization. Transcatheter aortic valve replacement (TAVR) has similar benefits when compared with SAVR for this population (Partner 2 & 3). Herewith we describe a case series of concomitant Anaortic OPCAB and TAVR via the transfemoral approach for patients with coronary artery and valve disease considered too high risk for traditional coronary artery bypass grafting and SAVR due to severe aortic disease. METHODS/RESULTS: Eight patients underwent anaortic OPCAB and transfemoral TAVR during the same anesthetic in a hybrid operating room. Seven patients with multivessel disease had anaortic OPCAB via a sternotomy using composite grafts, one patient with LAD disease had anaortic OPCAB using a Da Vinci-assisted MIDCAB approach. All patients then had an Edwards Sapien 3 TAVR placed percutaneously via the common femoral artery. There was no 30 mortality or CVA in the series and all patients were discharged to home or a rehabilitation facility on Day 4-13. CONCLUSIONS: Combined anaortic OPCAB and transfemoral TAVR is a safe and feasible approach to treating concomitant extensive coronary artery disease and severe aortic stenosis. The aortic no-touch technique provides benefits in the elderly high-risk patients by reducing the risk of postoperative myocardial infarction and cerebrovascular stroke.

Assessing potential for aortoiliac vascular injury from venoarterial extracorporeal membrane oxygenation cannulae: An in vitro particle image velocimetry study.

Limb ischemia is a major complication associated with peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO). The high velocity jet from arterial cannulae can cause "sandblasting" injuries to the arterial endothelium, with the potential risk of distal embolization and end organ damage. The aim of this study was to identify, for a range of clinically relevant VA-ECMO cannulae and flow rates, any regions of peak flow velocity on the aortic wall which may predispose to vascular injury, and any regions of low-velocity flow which may predispose to thrombus formation. A silicone model of the aortic and iliac vessels was sourced and the right external iliac artery was cannulated. Cannulae ranged from 15 to 21 Fr in size. Simulated steady state ECMO flow rates were instituted using a magnetically levitated pump (CentriMag pump). Adaptive particle image velocimetry was performed for each cannula at 3, 3.5, 4, and 4.5 L/min. For all cannulae, in both horizontal and vertical side hole orientations, the peak velocity on the aortic wall ranged from 0.3 to 0.45 m/s, and the regions of lowest velocity flow were 0.05 m/s. The magnitude of peak velocity flow on the aortic wall was not different between a single pair versus multiple pairs of side holes. Maximum velocity flow on the aortic wall occurred earlier at a lower pump flow rate in the vertical orientation of distal side holes compared to a horizontal position. The presence of multiple paired side holes was associated with fewer low-velocity flow regions, and some retrograde flow, in the distal abdominal aorta compared to cannulae with a single pair of side holes. From this in vitro visualization study, the selection of a cannula design with multiple versus single pairs of side holes did not change the magnitude of peak velocity flow delivered to the vessel wall. Cannulae with multiple side holes were associated with fewer regions of low-velocity flow in the distal abdominal aorta. Further in vivo studies, and ideally clinical data would be required to assess any correlation of peak velocity flows with incidence of vascular injury, and any low-velocity flow regions with incidence of thrombosis.

Toward stroke-free coronary surgery: The role of the anaortic off-pump bypass technique.

Surgical coronary revascularization remains the preferred strategy in a significant portion of patients with coronary artery disease due to superior long-term outcomes. However, there is a significant risk of perioperative neurologic injury that has influenced guideline recommendations. These complications occur in 1%-5% of patients, ranging from overt neurologic deficits with permanent disability, to subtle cerebral defects noted on neuroimaging that may result in slow cognitive and functional decline. The primary mechanism by which these events occur is thromboembolism from manipulation of the ascending aorta. This occurs during cardiopulmonary bypass, aortic cross-clamping, and partial occlusion clamping (side clamp). Elderly patients and patients with aortic atheroma are, therefore, at significantly increased risk. Initial surgical techniques addressed this by aggressively debriding or replacing the ascending aorta during coronary artery bypass grafting (CABG). Strategies then moved toward minimizing aortic manipulation through pump-assisted beating heart surgery and off-pump surgery with partial occlusion clamping or proximal anastomosis devices. Finally, anaortic off-pump CABG aims to avoid all manipulation of the ascending aorta through advanced off-pump grafting techniques combined with in situ and composite grafts. This has been demonstrated to result in the greatest reduction in risk. Establishing successful anaortic off-pump CABG programs requires subspecialization and focused interest groups dedicated to advancing CABG outcomes.

Five-Year Survival of Transcatheter Aortic Valve Implantation in High-Risk Patients.

BACKGROUND: Although transcatheter aortic valve implantation (TAVI) has become the standard treatment for severe aortic stenosis in high-risk patients in Australia, there is still limited data on long term survival. METHODS: All patients undergoing TAVI at a single tertiary institution between September 2009 and December 2015 were included. The primary outcome was survival, by linkage of patients with the National Death Index of the Australian Institute of Health and Welfare. Post-procedure data and echocardiographic measurements were retrospectively analysed for all patients. RESULTS: A total of 186 patients were included. It was a high-risk patient population (mean EuroSCORE 31.5±20.5, mean age 83.0±8.2 years). Valve prostheses used were Edwards SAPIEN (ES) (Edwards, Irvine, CA, USA) in 16.1%, Edwards SAPIEN XT (ESXT) in 74.2%, and Medtronic CoreValve (MCV) (Medtronic, Minneapolis, MN, USA) in 9.7%. Median survival time for the entire cohort was 68.2 months (95% Confidence Interval [CI]; Lower Limit [LL] 58.0 months, Upper Limit [UL] not defined). The 2- and 5-year estimates of survival were 85% (LL 80%, UL 90%) and 56% (LL 48%, UL 66%), respectively. There was no statistically significant difference in median survival between the ES and ESXT valves, or implantation approach. Survival was greater in patients with creatinine <200 µmol/L compared to >200 µmol/L (68.8 months [LL 61.4, UL n/a] vs 48.0 months [LL 25.5, UL n/a]). Over the study period, there was a statistically significant trend in increasing mean transvalvular gradient (ES: 1.66 mmHg/yr, p=0.0058; ESXT: 2.50 mmHg/yr, p≤0.001) and maximum velocity (ESXT: 0.16 m/s/yr, p=0.004) and decreasing valve area (ESXT: -0.07 cm2/yr, p<0.001). There was substantial attrition of patient echocardiographic follow-up (number of echocardiograms followed up at 5 years=6, number at risk=41). CONCLUSIONS: This study has demonstrated acceptable survival in a high-risk cohort of patients undergoing TAVI, with comparable results to larger international experiences. There was a trend for worsening haemodynamics that needs to be monitored. Future studies need to examine patient quality of life and the performance of newer generation prostheses.

Replicable brain signatures of emotional bias and memory based on diffusion kurtosis imaging of white matter tracts.

Diffusion MRI (dMRI) is sensitive to anisotropic diffusion within bundles of nerve axons and can be used to make objective measurements of brain networks. Many brain disorders are now recognised as being caused by network dysfunction or are secondarily associated with changes in networks. There is therefore great potential in using dMRI measures that reflect network integrity as a future clinical tool to help manage these conditions. Here, we used dMRI to identify replicable, robust and objective markers that meaningfully reflect cognitive and emotional performance. Using diffusion kurtosis analysis and a battery of cognitive and emotional tests, we demonstrated strong relationships between white matter structure across networks of anatomically and functionally specific brain regions with both emotional bias and emotional memory performance in a large healthy cohort. When the connectivity of these regions was examined using diffusion tractography, the terminations of the identified tracts overlapped precisely with cortical loci relating to these domains, drawn from an independent spatial meta-analysis of available functional neuroimaging literature. The association with emotional bias was then replicated using an independently acquired healthy cohort drawn from the Human Connectome Project. These results demonstrate that, even in healthy individuals, white matter dMRI structural features underpin important cognitive and emotional functions. Our robust cross-correlation and replication supports the potential of structural brain biomarkers from diffusion kurtosis MRI to characterise early neurological changes and risk in individuals with a reduced threshold for cognitive dysfunction, with further testing required to demonstrate clinical utility.

New Onset Atrial Fibrillation Following Transcatheter and Surgical Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

BACKGROUND: New-onset atrial fibrillation (NOAF) is a well-recognised, although variably reported complication following surgical aortic valve replacement (SAVR). Rates of NOAF following transcatheter aortic valve implantation (TAVI) seem to be notably less than SAVR, even though this population is typically older and of higher risk. The aim of this study was to determine the prevalence of NOAF in both these populations and associated postoperative outcomes. METHODS: We conducted a systematic review and meta-analysis of studies reporting rates of NOAF post SAVR or TAVI, along with early postoperative outcomes. Twenty-five (25) studies with a total of 13,010 patients were included in the final analysis. RESULTS: The prevalence of NOAF post SAVR was 0.4 (95% CI 0.36-0.44) and post TAVI 0.15 (95% CI 0.11-0.18). NOAF was associated with an increased risk of postoperative cerebrovascular accident (CVA) for SAVR and TAVI (RR 1.44 95% CI 1.01-2.06 and RR 2.24 95% CI 1.46-3.45 respectively). NOAF was associated with increased mortality in the TAVI group (RR 3.02 95% CI 1.55-5.9) but not the SAVR group (RR 1.00, 95% CI 0.54-1.84). Hospital length of stay was increased for both TAVI and SAVR patients with NOAF (MD 2.54 days, 95% CI 2.0-3.00) and (MD 1.64 days, 95% CI 0.04-3.24 respectively). CONCLUSIONS: The prevalence of NOAF is significantly less following TAVI, as compared to SAVR. While NOAF is associated with increased risk of postoperative stroke for both groups, for TAVI alone NOAF confers increased risk of early mortality.

New Strategies for Surgical Myocardial Revascularization.

We summarize the evidence on the new strategies for coronary artery bypass grafting (CABG). Hybrid CABG implies surgical grafting of the left anterior descending artery and percutaneous treatment of the other target vessels, with the promise of combining the durable benefits of surgery with the less invasive approach of percutaneous coronary interventions. Robotic CABG and minimally invasive CABG are performed through minimal incision or port access with dedicated equipment and instruments. Anaortic coronary artery bypass refers to off-pump CABG using only in-situ grafts. The use of multiple arterial grafts has been shown to improve patency and is potentially associated with better clinical outcomes. All these techniques require dedicated training and are more complex than conventional CABG but can significantly improve the results of surgery. Validation of the results of these new approaches in large randomized trials is a priority for the surgical community.

Extracorporeal membrane oxygenation support in refractory perioperative anaphylactic shock to rocuronium: a report of two cases.

In recent years, extracorporeal membrane oxygenation has become increasingly common in the treatment of in-hospital cardiac arrest in non-cardiac surgery patients. This includes cardiac arrest secondary to perioperative anaphylactic shock refractory to standard advanced life support protocols, which is a rare but catastrophic event associated with significant mortality. Neuromuscular blocking drugs are most commonly implicated in perioperative anaphylaxis, with rocuronium playing a major role. In this article, we report two cases of young and otherwise fit and well patients who experienced a perioperative arrest secondary to rocuronium anaphylaxis before elective surgery; both patients did not respond to conventional advanced life support, but survived neurologically intact after institution of urgent veno-arterial extracorporeal membrane oxygenation.

Bilateral Versus Single Internal Mammary Artery Use in Coronary Artery Bypass Grafting: A Propensity Matched Analysis.

BACKGROUND: Bilateral internal mammary artery (BIMA) grafts have demonstrated superior long-term outcomes compared with single internal mammary artery (SIMA) grafts. Despite this, BIMA remains widely underutilised due to perceived technical challenges and concerns regarding wound healing. We sought to examine the morbidity and mortality associated with BIMA use in a propensity-matched cohort of patients. METHODS: From 2009 to 2016, 3,594 consecutive patients underwent coronary artery bypass surgery at three affiliated institutions. Thirty-day (30) mortality and morbidity data were collected prospectively. Propensity-score matched analyses were performed for BIMA versus SIMA use controlling for a number of preoperative characteristics. RESULTS: Overall, 29% of procedures were performed off pump, with a greater proportion in the BIMA group (43% vs. 21%, p<0.001). In the propensity-score analysis consisting of 820 matched pairs, there were similar rates of 30-day mortality (1.3% BIMA vs. 0.9% SIMA, p=0.48) and deep sternal wound infection (1.1% BIMA vs. 0.9% SIMA, p=0.84). The rate of superficial sternal wound infection trended towards being higher in the BIMA group (2.6% vs. 1.3%, p=0.077). The rates of red blood cell transfusions (27.4% vs. 27%, p=0.217), other blood product transfusions (18% vs. 20%, p=0.217), and reoperation for bleeding (2.9% vs. 2.1%, p=0.349) were similar. CONCLUSIONS: Bilateral internal mammary artery use was associated with similar rates of deep sternal wound infection compared to SIMA use, with a preponderance of superficial sternal wound infections that did not result in increased mortality or transfusion requirements. The use of BIMA should be more widely considered for coronary artery bypass surgery.

Structural Heart Disease Australia (SHDA).

Structural Heart Disease Australia (SHDA) is a rapidly evolving multidisciplinary group of health care professionals which provides a forum focussed on understanding the rapidly advancing management of structural cardiac disease via Free Open Access Medical Education (FOAM).

Neurocognitive and Psychiatric Issues Post Cardiac Surgery.

Neurocognitive and psychiatric complications are common following cardiac surgery and impact on patient quality of life, recovery from surgery, participation in rehabilitation and long-term mortality. Postoperative cognitive decline, depressive disorders, post-traumatic stress disorder and neurocognitive impairment related to silent brain infarcts have all been linked to the perioperative period of cardiac surgery, and potentially have serious consequences. The accurate assessment of these conditions, particularly in determining the aetiology, and impact on patients is difficult due to the poorly recognised nature of these complications as well as similarities in presentation with postoperative delirium. This review aims to summarise current understanding surrounding psychiatric disturbances following cardiac surgery including the impact on patient quality of life and long-term outcomes.

KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets. METHODS: Utilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy. RESULTS: We identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epithelioid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the (normal) mesothelial line MeT-5A, and was also upregulated in patient tumor samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration. CONCLUSION: These functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and potentially druggable targets.

A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma.

BACKGROUND: We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM). METHODS: Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series (n=97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts. RESULTS: Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P=0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P=0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC. CONCLUSIONS: Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.

Use of multi-velocity encoding 4D flow MRI to improve quantification of flow patterns in the aorta.

PURPOSE: To show that the use of a multi-velocity encoding (VENC) 4D-flow approach offers significant improvements in the characterization of complex flow in the aorta. Four-dimensional flow magnetic resonance imaging (MRI) (4D-flow) can be used to measure complex flow patterns and dynamics in the heart and major vessels. The quality of the information derived from these measures is dependent on the accuracy of the vector field, which is limited by the vector-to-noise ratio. MATERIALS AND METHODS: A 4D-flow protocol involving three different VENC values of 150, 60, and 20 cm/s was performed on six control subjects and nine patients with type-B chronic aortic dissection at 3T MRI. Data were processed using a single VENC value (150 cm/s) or using a fused dataset that selected the lowest appropriate VENC for each voxel. Performance was analyzed by measuring spatial vector angular correlation, magnitude correlation, temporal vector conservation, and "real-world" streamline tracing performance. RESULTS: The multi-VENC approach provided a 31% improvement in spatial and 53% improvement in temporal precision of velocity vector measurements during the mid-late diastolic period, where 99% of the flow vectors in the normal aorta are below 20 cm/s. In low-flow conditions this resulted in practical improvements of greater than 50% in pathline tracking and streamline tracing quantified by streamline curvature measurements. CONCLUSION: A multi-VENC 4D-flow approach provides accurate vector data across normal physiological velocities observed in the aorta, dramatically improving outputs such as pathline tracking, streamline estimation, and further advanced analyses.