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Mehner C.,Mayo Medical School | Miller E.,Mayo Medical School | Khauv D.,Mayo Medical School | Oberg A.L.,Mayo Medical School | And 6 more authors.
Molecular Cancer Research | Year: 2014

Pancreatic ductal adenocarcinoma (PDA) arises at the convergence of genetic alterations in KRAS with a fostering microenvironment shaped by immune cell influx and fibrotic changes; identification of the earliest tumorigenic molecular mediators evokes the proverbial chicken and egg problem. Matrix metalloproteinases (MMP) are key drivers of tumor progression that originate primarily from stromal cells activated by the developing tumor. Here, MMP3, known to be expressed in PDA, was found to be associated with expression of Rac1b, a tumorigenic splice isoform of Rac1, in all stages of pancreatic cancer. Using a large cohort of human PDA tissue biopsies specimens, both MMP3 and Rac1b are expressed in PDA cells, that the expression levels of the two markers are highly correlated, and that the subcellular distribution of Rac1b in PDA is significantly associated with patient outcome. Using transgenic mouse models, coexpression of MMP3 with activated KRAS in pancreatic acinar cells stimulates metaplasia and immune cell infiltration, priming the stromal microenvironment for early tumor development. Finally, exposure of cultured pancreatic cancer cells to recombinant MMP3 stimulates expression of Rac1b, increases cellular invasiveness, and activation of tumorigenic transcriptional profiles. Implications: MMP3 acts as a coconspirator of oncogenic KRAS in pancreatic cancer tumorigenesis and progression, both through Rac1b-mediated phenotypic control of pancreatic cancer cells themselves, and by giving rise to the tumorigenic microenvironment; these findings also point to inhibition of this pathway as a potential therapeutic strategy for pancreatic cancer. ©2014 AACR.


Ho R.C.M.,National University Hospital Singapore | Zaw M.H.,Thoracic and Vascular Surgery | Mak A.,National University of Singapore
American Journal of Geriatric Psychiatry | Year: 2011

Obective: High homocysteine (Hct) has been causatively linked to Alzheimer disease (AD) and vascular dementia (VaD) in old age, but research methodologies and outcome measures are heterogeneous. It remains unclear whether the findings can be generalized across studies. Methods: Random-effects meta-analyses were conducted on studies examining the relationship between Hct level and risk of developing dementia/cognitive decline between comparison groups. Meta-regression identified patient-and trial-related factors, which may contribute to heterogeneity. Results: Seventeen relevant studies (6,122 participants; 13 cross-sectional and fourprospective studies) were included. Compared with controls, Hct was significantly elevated in AD (pooled standardized mean difference [SMD]: 0.59; 95% confidence interval [CI]: 0.38-0.80; significant heterogeneity: τ = 0.105) and VaD (pooled SMD: 1.30; 95% CI: 0.75-1.84; significant heterogeneity: τ = 0.378). Meta-regression identified mean age as significant moderator for AD versus controls and mean age and mean folate levels as significant moderators for VaD versus controls. Hct was significantly higher in VaD relative to AD (pooled SMD: 0.48; 95% CI: 0.23-0.73; moderately significant heterogeneity: τ = 0.076); proportion of men and mean folate levels were significant moderators. High-Hct level was not associated with risk of developing dementia in prospective studies (pooled odds ratio: 1.34; 95% CI: 0.94-1.91, nonsignificant heterogeneity: τ = 0.048). Conclusion: Individuals with AD and VaD have higher Hct levels than controls; however, a causal relationship between high-Hct level and risk of developing dementia is not supported. More prospective studies and randomized controlled trials are required to test the therapeutic benefits of lowering Hct levels. © 2011 American Association for Geriatric Psychiatry.


Reibetanz J.,Visceral | Jurowich C.,Visceral | Erdogan I.,University of Würzburg | Nies C.,Marienhospital Osnabruck | And 5 more authors.
Annals of Surgery | Year: 2012

Objective: Adrenocortical carcinoma (ACC) is a rare malignancy with an unfavorable prognosis. The impact of a locoregional lymph node dissection (LND) has never been defined in this disease. We report the disease-specific outcome of patients treated with or without LND during primary adrenalectomy. Methods: The medical records of patients followed by the German ACC Registry were retrospectively reviewed. Patients with incomplete resection or distant metastases were excluded. Only if the histologic analysis retrieved 5 or more lymph nodes, an intended LND was assumed (LND group). The predefined primary end point of the study was disease-specific survival. Results: Of 283 included patients, 47 patients (16.6%) were treated with LND, whereas 236 patients (83.4%) underwent surgery without LND. Patients who underwent LND had a larger median tumor size (12.0 cm, range: 2.3-30 cm vs 10.0 cm, range: 4.0-39 cm, P = 0.007) and were more often treated by multivisceral resection (LND: 47.8% vs no-LND: 18.1%; P < 0.001). The other baseline characteristics (age, sex, endocrine activity, Weiss score, Ki-67 index, and adjuvant treatment) did not differ significantly. Median follow-up of all patients still alive was 40 months (range: 6-326). Multivariate analysis adjusted for age, tumor stage, multivisceral resection, adjuvant treatment, and lymph nodes status on preoperative imaging demonstrated a significantly reduced risk for tumor recurrence (hazard ratio: 0.65; 95% confidence interval: 0.43-0.98; P = 0.042) and for disease-related death (hazard ratio: 0.54; 95% confidence interval: 0.29-0.99; P = 0.049) in LND patients when compared with no-LND patients. Conclusions: Our retrospective data indicate that locoregional LND improves tumor staging and leads to a favorable oncologic outcome in patients with localized ACC. © 2012 by Lippincott Williams & Wilkins.


Breitenbach I.,Thoracic and Vascular Surgery | Harringer W.,Thoracic and Vascular Surgery | Tsui S.,Papworth Hospital | Amorim M.J.,Hospital Of Sao Joao | And 4 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2012

Objectives: To compare the decrease in left ventricular mass index (LVMI) by magnetic resonance imaging (MRI) versus transthoracic echocardiography (TTE) after aortic valve replacement (AVR) for severe aortic stenosis with Epic and Epic Supra stented porcine bioprostheses (St Jude Medical, Inc, St Paul, Minn). Methods: This prospective multicenter study enrolled 149 patients who underwent AVR between January 2006 and February 2008. TTE and cardiac MRI measurements of LVMI were made at baseline and at 6 months of follow-up and were compared. Changes in mean pressure gradients were examined using TTE. Results: TTE measurements of LVMI were 48% to 63% higher than the MRI measurements. A decrease in LVMI from 137 ± 32 to 95 ± 16 g/m2 with the Epic and from 139 ± 29 to 104 ± 28 g/m2 with the Epic Supra valves (P < .0001 for both comparisons) was measured by TTE. Cardiac MRI revealed decreases in LVMI from 84 ± 20 to 64 ± 12 g/m 2 and from 86 ± 27 to 64 ± 17 g/m2 with the Epic and Epic Supra valves, respectively (P < .0001 for both comparisons). TTE revealed a significant regression of mean pressure gradients from 51.6 ± 15.3 to 15.5 ± 5.2 mm Hg with the Epic and from 46.7 ± 19.4 to 17.9 ± 12.8 mm Hg with the Epic supra (P < .0001 for both comparisons). Conclusions: A significant decrease in LVMI was measured after AVR with all sizes of both bioprosthetic models. Because of the overestimation of the decrease in LVMI by the Devereux formula, as well as the higher accuracy and reproducibility of cardiac MRI measurements, the latter should be preferred to TTE. An ultimate validation of this thesis could only be done comparing each of these modalities with pathologic examination. Copyright © 2012 by The American Association for Thoracic Surgery.


PubMed | University of Graz, Medical University of Graz and Thoracic and Vascular Surgery
Type: Journal Article | Journal: Annals of biomedical engineering | Year: 2015

One goal of cardiac research is to perform numerical simulations to describe/reproduce the mechanoelectrical function of the human myocardium in health and disease. Such simulations are based on a complex combination of mathematical models describing the passive mechanical behavior of the myocardium and its electrophysiology, i.e., the activation of cardiac muscle cells. The problem in developing adequate constitutive models is the shortage of experimental data suitable for detailed parameter estimation in specific functional forms. A combination of shear and biaxial extension tests with different loading protocols on different specimen orientations is necessary to capture adequately the direction-dependent (orthotropic) response of the myocardium. In most experimental animal studies, where planar biaxial extension tests on the myocardium have been conducted, the generated shear stresses were neither considered nor discussed. Hence, in this study a method is presented which allows the quantification of shear deformations and related stresses. It demonstrates an approach for experimenters as to how the generation of these shear stresses can be minimized during mechanical testing. Experimental results on 14 passive human myocardial specimens, obtained from nine human hearts, show the efficiency of this newly developed method. Moreover, the influence of the clamping technique of the specimen, i.e., the load transmission between the testing device and the tissue, on the stress response is determined by testing an isotropic material (Latex). We identified that the force transmission between the testing device and the specimen by means of hooks and cords does not influence the performed experiments. We further showed that in-plane shear stresses definitely exist in biaxially tested human ventricular myocardium, but can be reduced to a minimum by preparing the specimens in an appropriate manner. Moreover, we showed whether shear stresses can be neglected when performing planar biaxial extension tests on fiber-reinforced materials. The used method appears to be robust to quantify normal and shear deformations and corresponding stresses in biaxially tested human myocardium. This method can be applied for the mechanical characterization of any fiber-reinforced material using planar biaxial extension tests.


Willems S.,University Hospital Brussels | Vanhulle A.,Thoracic and Vascular Surgery | Deruyter L.,Thoracic and Vascular Surgery
Acta Chirurgica Belgica | Year: 2011

Appendiceal diverticulitis is a rare pathologic entity that usually simulates acute appendicitis. However, it can present as a separate clinical entity that should be part of the differential diagnosis of right lower quadrant abdominal pain. Pre-operative diagnosis is rarely described but is important in preventing perforation and subsequent abdominal sepsis. We present a case of an atypical right iliac fossa pain syndrome caused by histologically proven appendiceal diverticulitis, pre-operatively diagnosed by computed tomography.


PubMed | University of Kuala Lumpur, AKH Inc., Medicity, View Medical and 4 more.
Type: | Journal: The journal of vascular access | Year: 2016

Medical education and training in dialysis access skills remains complex and inadequate as learners come from diverse backgrounds and from various specialties so that appropriate training is limited. As a result, a system of progressive education including live lectures, and hands on training has emerged, but there is controversy as to what constitutes the best educational model.Presently there is no recognized or structured training in vascular access during residency or fellowships. Here we present a model of dialysis access training for beginner to advanced surgeons.A structured hands-on and didactic surgery training certification course consisting of a one week curriculum with 49 hours of ACCME credit hours has been in effect for one year. The learning impact and the performance outcome are high but with limited attendance capacity. Pre- and post- training test results attest to training effectiveness. To increase access, an off-site training curriculum has been initiated, entailing 1-2 days (8-15 credit hours) consisting of didactic lectures and surgical training. This teaching module has moderate learning impact for 50-100 attendees.Finally, a tiered, web-based training curriculum (10 ACCME credit hours) can accommodate an unlimited number of learners, but has a lower skills learning impact.The future dialysis access training must also accommodate learners with diverse individual backgrounds, and different levels of professional (skill) development. To be effective and accessible, a variety of educational system, for example on site or web based is needed. Collaborative initiatives for global dialysis access training are currently underway.


PubMed | Stadtspital Triemli, University of Zürich, Thoracic and Vascular Surgery and Stadtspital Waid
Type: Journal Article | Journal: Asian cardiovascular & thoracic annals | Year: 2016

A 23-year-old woman presented with a mediastinal paraganglioma and multiple pulmonary chondromas following antral gastric resection for gastrointestinal stromal tumor. These tumors form the Carney triad, a rare disorder of unknown genetic background. First described in 1977, approximately 120 cases have been documented in the literature. The tumors do not harbor the specific c-kit or PDGFRA gene mutations often found in sporadic gastrointestinal stromal tumor. In most cases, gastric gastrointestinal stromal tumor is the first tumor to be detected, with secondary tumors appearing years later. Even if it is rare, Carney triad should be suspected in young patients with history of gastrointestinal stromal tumor.


Breitenbach I.,Thoracic and Vascular Surgery | Wimmer-Greinecker G.,Herz und Gefasszentrum Bad Bevensen | Bockeria L.A.,Bakoulev Scientific Center for Cardiovascular Surgery | Sadowski J.,Jagiellonian University | And 5 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2010

Objective: To evaluate the modular sutureless Arbor Trilogy Aortic Valve System (Arbor Surgical Technologies, Irvine, Calif), designed for minimally invasive aortic valve replacement. Methods: In a prospective multicenter study, 32 patients with severe aortic valve stenosis underwent aortic valve replacement with the Trilogy valve between 2006 and 2008. Concomitant coronary artery bypass grafting was performed in 6 patients. Transthoracic echocardiography was performed at baseline, at discharge, at 4 to 6 months, at 11 to 14 months, and annually thereafter. Results: Valve implantation was successful in 30 patients. The procedure was converted to conventional aortic valve replacement in 2 patients. Mean bypass time was 111 ± 42 minutes, and crossclamp time was 70 ± 23 minutes. Valve implantation took 21 ± 7 minutes. The transvalvular gradients at discharge were 10 ± 3 mm Hg (mean) and 20 ± 7 mm Hg (peak), and the effective orifice area was 1.9 ± 0.4 cm2. At 2-year follow-up, gradients were 7 ± 3 mm Hg (mean) and 14 ± 4 mm Hg (peak), and the effective orifice area was 1.9 ± 0.3 cm2. There was no intraoperative mortality: Two patients died of causes unrelated to the valve during follow-up. One redo aortic valve replacement was performed at 22 months for prosthetic valve endocarditis. Conclusions: Sutureless aortic valve replacement is feasible and safe with the Trilogy System. After an initial learning curve, the modular valve design allows a more rapid and simple implantation compared with conventional stented tissue valves. The simplicity may also facilitate a greater adoption of minimally invasive aortic valve replacement by a broader spectrum of surgeons. Copyright © 2010 by The American Association for Thoracic Surgery.


PubMed | Thoracic and Vascular Surgery and UZ Brussels
Type: Journal Article | Journal: Acta chirurgica Belgica | Year: 2016

Iatrogenic intrapericardial diaphragmatic hernia after creation of a pericardial-peritoneal window is a very rare entity. We present the clinical case of an acute intestinal bowel obstruction due to herniation of small bowel into the pericardial sac. After laparoscopic reduction of the herniated small bowel, the diaphragmatic defect was successfully repaired using the hepatic falciform ligament.

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