Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis.

BACKGROUND: Fibulin-3 (FBLN3) was recently presented as a promising novel biomarker for malignant pleural mesothelioma (MPM), warranting independent validation studies. METHODS: ELISA was used to measure cellular and secreted FBLN3 in cell lines, in plasma of xenograft tumour-bearing mice, in plasma from two independent series of MPM and non-MPM patients and in pleural fluid from a third series. Diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and Kaplan-Meier method, respectively. RESULTS: FBLN3 was expressed in all MPM and benign mesothelial cell lines tested, and a correlation was observed between cellular protein expression and secreted levels. Human FBLN3 was detectable in plasma of tumour-bearing mice, suggesting that MPM cells contribute to levels of circulating FBLN3. Plasma FBLN3 was significantly elevated in MPM patients from the Sydney cohort, but not the Vienna cohort, but the diagnostic accuracy was low (63%, (95% CI: 50.1-76.4) and 56% (95% CI: 41.5-71.0), respectively). Although FBLN3 levels in pleural effusions were not significantly different between cases and controls, FBLN3 levels in pleural effusion fluid were found to be independently associated with prognosis (hazard ratio of 9.92 (95% CI: 2.14-45.93)). CONCLUSIONS: These data confirm the potential prognostic value of pleural effusion FBLN3, but question the diagnostic value of this protein in MPM patients.

The freestyle aortic bioprosthesis: a systematic review.

BACKGROUND: The Medtronic Freestyle bioprosthesis (FSB) provides an alternative to other prostheses for both aortic valve and aortic root surgery. This paper is a systematic review of the post-operative outcomes in patients with aortic valve and/or aortic root disease following FSB implantation. METHODS: Electronic databases were searched for primary analysis, prospective randomised studies comparing the FSB with an alternative aortic prosthesis were included. Additionally, case series that included data for at least 100 individual operated patients were used for secondary analysis. RESULTS: Among three identified randomised studies, 199 FSB cases were compared with homografts, and stented and an alternative stentless bioprosthesis. The FSB showed comparable hospital mortality (4.5% vs. 5.3%) and eight-year actuarial survival (80±5.0% versus 77±6.0%) with the homograft (respectively) and comparable reduction in left ventricular mass index relative to other prosthesis types. Over 6000 individual patients were included in the selected 15 case series. Weighted mean operative mortality, neurological event rate and five-year actuarial survival was 5.2%, 5.5% and 77.8%, respectively. CONCLUSION: The FSB performed comparably against alternative prostheses regarding in-hospital mortality, long-term survival and reduction in left ventricular mass index. Included case series demonstrated robust post-operative outcomes in both the short and long term.

Geriatric cardiac surgery: chronology vs. biology.

Cardiac surgery is increasingly performed in elderly patients, and whilst the incidence of common risk factors associated with poorer outcome increases with age, recent studies suggest that outcomes in this population may be better than is widely appreciated. As such, in this review we have examined the current evidence for common cardiac surgical procedures in patients aged over 70 years. Coronary artery bypass grafting (CABG) in the elderly has similar early safety to percutaneous intervention, though repeat revascularisation is lower. Totally avoiding instrumentation of the ascending aorta with off-pump techniques may also reduce the incidence of neurological injury. Aortic valve replacement (AVR) significantly improves quality of life and provides excellent short- and long-term outcomes. Combined AVR and CABG carries higher risk but late survival is still excellent. Mini-sternotomy AVR in the elderly can provide comparable survival to full-sternotomy AVR. More accurate risk stratification systems are needed to appropriately select patients for transcatheter aortic valve implantation. Mitral valve repair is superior to replacement in the elderly, although choosing the most effective method is important for achieving maximal quality of life. Minimally-invasive mitral valve surgery in the elderly has similar postoperative outcomes to sternotomy-based surgery, but reduces hospital length of stay and return to activity. In operative candidates, surgical repair is superior to percutaneous repair. Current evidence indicates that advanced age alone is not a predictor of mortality or morbidity in cardiac surgery. Thus surgery should not be overlooked or denied to the elderly solely on the basis of their "chronological age", without considering the patient's true "biological age".

Minimally invasive mitral valve surgery using single dose antegrade Custodiol cardioplegia.

OBJECTIVE: Our unit began a minimally invasive mitral surgery (MIMS) program utilising antegrade Custodiol solution as the sole cardioplegia. The aim of this paper is to report our results of this program. PATIENTS/METHODS: Early clinical outcomes were identified and assessed for the first consecutive 100 MIMS patients with comparisons made to a historical group operated via a sternotomy (n=113). The efficacy of myocardial protection was assessed using surrogate outcomes of myocardial protection with serial sodium concentrations also analysed. RESULTS: Six hours postoperatively 12 patients required inotropic support. Peak troponin-I in the first 24 hours was 5.1 (0.8-40 µg/L [median(range)]. Sodium levels decreased following administration of Custodiol but by six hours postoperatively the sodium had returned to greater than 130 mmol/L in all but five patients. Blood transfusion was smaller in the MIMS versus historical group (RBC 17% vs. 65%). MIMS patients had a shorter duration of ventilation, hospital stay and one-year mortality rate (0%). CONCLUSIONS: In this series of patients undergoing MIMS, single dose antegrade Custodiol offers satisfactory and safe myocardial protection. Early clinical outcomes were also satisfactory. Whilst our findings are observational, they nevertheless support the use of this less invasive approach to mitral surgery using single dose Custodiol for myocardial protection.

Anaortic off-pump coronary artery bypass grafting in the elderly and very elderly.

BACKGROUND: Elderly patients undergoing surgical revascularisation may disproportionately benefit from avoiding manipulation of the ascending aorta and cardiopulmonary bypass. In this multi-centre observational study, we sought to determine the 30-day outcomes of anaortic off-pump coronary artery bypass (OPCAB) in an elderly and very-elderly population. METHODS: Data were prospectively collected for all patients aged >70 years old (y) undergoing anaortic OPCAB at three hospitals between January 2002 and October 2011. Analysis was carried out on two age sub-groups (70-79 y vs. ≥80 y). Multiple logistic regression was used to identify predictors of post-operative 30-day mortality. RESULTS: In total, 1135 patients >70 years underwent anaortic OPCAB - 817 (72%) patients were aged 70-79 y while 318 (28%) were aged ≥80 y. The rate of mortality and morbidity for both groups was low: 30-day mortality (70-79 y: 1.8%; ≥80 y: 2.8%) or permanent stroke (70-79 y: 0.2%; ≥80 y: 0.9%). Chronic lung disease, a history of previous myocardial infarction and left main disease were independent predictors of 30-day mortality. CONCLUSIONS: OPCAB is associated with low rates of 30-day mortality and peri-operative stroke in this elderly and very elderly patient cohort. Anaortic OPCAB can provide excellent short-term post-operative outcomes and may give the elderly and very elderly population the opportunity to benefit from surgical coronary revascularisation.

Off-pump coronary artery bypass grafting in elderly and high-risk patients--a review.

Elderly and high-risk patients are increasingly being considered for myocardial revascularisation. Most trials comparing the various options for revascularisation exclude elderly and 'high-risk' patients. We have reviewed the options for myocardial revascularisation for elderly patients, and for patients with a number of common 'high-risk' co-morbidities--diabetes mellitus, renal insufficiency, poor left ventricular ejection fraction, peripheral vascular disease, left main coronary artery disease and chronic obstructive pulmonary disease--with a focus on coronary artery bypass grafting without the use of cardiopulmonary bypass and aortic manipulation.

Anaortic, total-arterial, off-pump coronary artery bypass surgery: how to do it.

Several large series have demonstrated that performing off-pump coronary artery bypass surgery without manipulating the ascending aorta (anaortic) utilising all-arterial grafts provides superior protection against neurological injury. Recent series comparing percutaneous coronary intervention (PCI) with surgical revascularisation have demonstrated superior results for surgery over PCI. However, a significant criticism of coronary artery surgery remains the higher incidence of neurological injury when compared to PCI. We present a simple and reproducible technique for anaortic, total-arterial off-pump coronary artery revascularisation.

Tricuspid leaflet repair: innovative solutions.

Tricuspid regurgitation (TR) represents a significant disease process and when severe, is associated with increased mortality. Recent guidelines support a more aggressive approach to tricuspid valve (TV) surgery, especially when encountered with left-sided valvular pathology. While annuloplasty has been the standard treatment for TR, it may not provide as effective or durable a repair compared to annuloplasty combined with TV repair techniques. Several of these approaches are discussed including bicuspidalization, anterior leaflet augmentation, edge to edge repair, neochords, leaflet resection and combined approaches. Although patient cohorts in most of the studies examining these techniques are small, the long-term durability of TV repair is significant.

miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention.

Characterization of the hypercoagulable state following severe orthopedic trauma.

BACKGROUND: Acute traumatic coagulopathy develops in seriously injured patients, which is followed by a paradoxical hypercoagulable state. The hypercoagulable state contributes to venous thromboembolism, and yet, there are no sensitive tests available to detect it. The aim of this study was to characterize the hypercoagulable state caused by major orthopedic trauma using the overall hemostatic potential (OHP) assay. METHODS: Major orthopedic trauma patients admitted during a 7-month period in 2012 were included in the study. Blood samples were drawn 1 hour before surgery, then 1, 7, 24 hours and 3, 5, 10, and 42 days postoperatively. The assay parameters were determined and analyzed according to injury severity (polytrauma or nonpolytrauma), type of surgical intervention, and shock status. Values were compared with 20 healthy controls. RESULTS: Forty-one consecutive patients were enrolled (age, 41.5 ± 2.7 years; 70% male; Injury Severity Score [ISS], 21.5 ± 2.1). Hypercoagulability based on OHP was present in the preoperative sample compared with the controls (OHP, 13.8 ± 1.4 U vs. 8.1 ± 0.5 U; p = 0.020) and then further elevated after surgery (1 hour postoperative, 17.8 ± 2.0 U vs. preoperative, 13.8 ± 1.4 U, p = 0.008). Polytrauma patients were more hypercoagulable than nonpolytrauma at the preoperative sample time (17.7 ± 2.6 U vs. 10.7 ± 1.2 U, p = 0.040) and postoperative period (24.3 ± 3.4 U vs. 11.9 ± 1.4 U, p = 0.006). The OHP for patients undergoing open pelvic surgery (28.3 ± 3.0 U) was higher than both intramedullary nailing (16.2 ± 2.0 U) and percutaneous pelvic surgery (17.0 ± 1.7 U) on Day 5 (p < 0.05). Patients demonstrated a higher OHP than controls did at all time points, except at 6 weeks (patients, 10.8 ± 1.7 U vs. controls, 8.1 ± 0.5 U; p = 0.400). CONCLUSION: The OHP assay detected the hypercoagulable state following major orthopedic trauma and surgical intervention, which was present for 10 days postoperatively. The extent of hypercoagulability could be associated with polytrauma and the type of surgical intervention; however, further studies are needed to confirm this. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Bilateral internal mammary arteries: evidence and technical considerations.

Bilateral internal mammary artery (BIMA) grafts are used for coronary revascularisation by only a minority of surgeons, despite a growing body of evidence suggesting improved survival when compared to use of only one internal mammary artery with additional saphenous vein grafts. Herein we review the evidence supporting revascularisation with BIMA and suggest reasons why the majority of surgeons use only one internal mammary artery. We discuss technical considerations, various graft combinations and the use of BIMA to facilitate anaortic off-pump coronary artery bypass (OPCAB).

The Impact of Hemolysis on Cell-Free microRNA Biomarkers.

Cell-free microRNAs in plasma and serum have become a promising source of biomarkers for various diseases. Despite rapid progress in this field, there remains a lack of consensus regarding optimal quantification methods, reference genes, and quality control of samples. Recent studies have shown that hemolysis occurring during blood collection has substantial impact on the microRNA content in plasma/serum. To date, the impact of hemolysis has only been investigated for a limited number of microRNAs, mainly the red blood cell (RBC)-enriched miRs-16 and -451. In contrast, the effect of hemolysis on other microRNAs - in particular those proposed as biomarkers - has not been addressed. In this study we profiled the microRNA content of hemolyzed and non-hemolyzed plasma as well as RBCs to obtain a profile of microRNAs in the circulation affected or unaffected by hemolysis. Profiling by TaqMan Array Microfluidic Cards was used to compare three pairs of hemolyzed and non-hemolyzed plasma (with varying degrees of hemolysis) and one RBC sample. A total of 136 microRNAs were detectable in at least two of the samples, and of those 15 were at least twofold elevated in all three hemolyzed samples. This number increased to 88 microRNAs for the sample with the highest level of hemolysis, with all of these also detected in the RBC profile. Thus these microRNAs represent a large proportion of detectable microRNAs and those most likely to be affected by hemolysis. Several of the hemolysis-susceptible microRNAs (e.g., miRs-21, -106a, -92a, -17, -16) have also been previously proposed as plasma/serum biomarkers of disease, highlighting the importance of rigorous quality control of plasma/serum samples used for measurement of circulating microRNAs. As low-level hemolysis is a frequent occurrence during plasma/serum collection it is critical that this is taken into account in the measurement of any candidate circulating microRNA.

Systematic review of robotic-assisted, totally endoscopic coronary artery bypass grafting.

BACKGROUND: Advancements in surgical robotic technology over the last two decades have enabled coronary artery bypass grafting to be performed totally endoscopically, and have the potential to significantly change clinical practice in the future. METHODS: A systematic review of studies reporting clinical outcomes of total endoscopic coronary artery bypass grafting (TECABG) was performed. RESULTS: 14 appraised studies included 880 beating heart TECABGs, 360 arrested heart TECABGs, 633 one-vessel operations and 357 two-vessel operations. Patients were generally low-risk. There was a significant learning curve. The weighted means for short-term beating heart and arrested heart TECABG results respectively were: intraoperative exclusion rate of 5.7% and 1.9%, intraoperative conversion rate of 5.6% and 15.0%, all-cause mortality of 1.2% and 0.4%, stroke of 0.7% and 0.8%, myocardial infarction of 0.8% and 1.8%, new onset atrial fibrillation of 10.7% and 5.1% and post-operative reintervention rate of 2.6% and 2.3%. The overall rate of short term postoperative graft patency for beating heart and arrested heart TECABG was 98.3% and 96.4% respectively. CONCLUSIONS: Appropriate patient selection was important in minimizing the risk of intraoperative and postoperative complications. Short-term outcomes of both beating and arrested heart TECABG were acceptable, but results so far have been heterogeneous. There were fewer studies reporting intermediate to long-term outcomes, but results were encouraging, and further investigation and development of the procedure is warranted.

Off-pump coronary artery bypass surgery induces prolonged alterations to host neutrophil physiology.

Persistent alteration to host polymorphonuclear cell (PMN) physiology has been demonstrated after cardiac surgery performed with cardiopulmonary bypass (CPB). However, to date, PMN physiology and function beyond the first 24 h have not been investigated after cardiac surgery performed without CPB (off-pump coronary artery bypass grafting [OPCAB]). Blood samples of 15 patients were collected preoperatively and on days 1, 3, and 5 after OPCAB. Expression of CD11b, CD18, CBRM1/5, and CD62L were assessed by flow cytometry under resting conditions and after stimulation with formyl methionyl-leucyl-phenylalanine (fMLF), and respiratory burst activity was also measured. Under resting conditions, PMN CD11b, CBRM1/5, and CD62L expressions were minimally altered by surgery. Compared with the response of preoperative PMNs, PMNs assayed on days 3 and 5 after OPCAB demonstrated a significantly blunted increase in the expression of CD11b and CBRM1/5 after fMLF, significantly diminished shedding of CD62L in response to platelet-activating factor and fMLF, and diminished superoxide production after stimulation on day 3. The alteration of PMN function after OPCAB implies that cardiac surgical trauma without CPB directly modulates host PMN physiology.

Custodiol for myocardial protection and preservation: a systematic review.

INTRODUCTION: Custodiol cardioplegia is attractive for minimally invasive cardiac surgery, as a single dose provides a long period of myocardial protection. Despite widespread use in Europe, there is little data confirming its efficacy compared with conventional (blood or crystalloid) cardioplegia. There is similar enthusiasm for its use in organ preservation for transplant, but also a lack of data. This systematic review aimed to assess the evidence for the efficacy of Custodiol in myocardial protection and as a preservation solution in heart transplant. METHODS: Electronic searches were performed of six databases from inception to October 2013. Reviewers independently identified studies that compared Custodiol with conventional cardioplegia (blood or extracellular crystalloid) in adult patients for meta-analysis; large case series that reported results using Custodiol were analyzed. Next, we identified studies that compared Custodiol with other organ preservation solutions for organ preservation in heart transplant. RESULTS: Fourteen studies compared Custodiol with conventional cardioplegia for myocardial protection in adult cardiac surgery. No difference was identified in mortality; there was a trend for increased incidence of ventricular fibrillation in the Custodiol group that did not reach statistical significance. No difference was identified in studies that compared Custodiol with other solutions for heart transplant. CONCLUSIONS: Despite widespread clinical use, the evidence supporting the superiority of Custodiol over other solutions for myocardial protection or organ preservation is limited. Large randomised trials are required.

ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma.

INTRODUCTION: Epigenetic inactivation of tumor suppressor genes is involved in the development of malignant pleural mesothelioma (MPM). ZIC1, a potential tumor suppressor gene involved in regulating cell growth and apoptosis, was investigated in MPM cell lines and tumors. METHODS: ZIC1 expression and promoter methylation were evaluated in MPM cell lines and tumor samples by quantitative polymerase chain reaction (PCR), Combined Bisulfite Restriction Analysis, and methylation-specific PCR. ZIC1 was reexpressed in cell lines and functional effects were assessed. miRNA expression was quantified by microarray and reverse transcription quantitative PCR. ZIC1 knockdown and miRNA inhibitors were used to study the relationship between ZIC1 and miRNA expression and confirmed by chromatin immunoprecipitation PCR. RESULTS: ZIC1 expression was low in MPM cells, and was correlated with ZIC1 promoter methylation and reversed upon decitabine treatment. ZIC1 reexpression inhibited proliferation and invasion in MPM cells whereas knockdown enhanced the growth of MeT-5A. In MPM tumor samples ZIC1 expression was either low or undetectable, with promoter methylation observed in 16 of 24 cases. The overexpression of miR-23a and miR-27a was reduced by ZIC1 reexpression, with inhibitors of miR-23a or miR-27a reducing colony formation. miR-23a overexpression was also associated with shorter survival of MPM patients. CONCLUSION: ZIC1 is down-regulated in MPM through promoter methylation and acts as a tumor suppressor through down-regulation of its direct targets miR-23a and miR-27a.

Cardiac surgery versus stenting: what is better for the patient?

Patterns of myocardial revascularization have changed significantly over the past decade. There has been a relative decrease of coronary artery bypass grafting (CABG) compared with percutaneous coronary intervention (PCI) and some patients are undergoing PCI for coronary lesions traditionally reserved for CABG. The mid- to long-term results of several trials comparing PCI with CABG have recently been published. For three-vessel disease, CABG is superior to PCI, with lower rates of major adverse cardiac events. PCI may be equivalent to CABG for three-vessel disease in the lowest disease complexity tercile (SYNTAX score <22; ∼20% of patients). This review focuses on the most recent evidence for myocardial revascularization in patients with multi-vessel and left main coronary artery disease.