[Show abstract][Hide abstract] ABSTRACT: Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia-dysplasia-neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett's esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC).
Annals of Surgical Oncology 10/2014; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Robot-assisted general surgery operations are being performed more frequently. This review investigates whether robotic assistance results in significant advantages or disadvantages for the operative treatment of gastro-oesophageal reflux disease and achalasia.Methods
The electronic databases (Medline, Embase, PubMed) were searched for original English language publications for antireflux surgery and Heller's myotomy between January 1990 and December 2013.ResultsThirty-three publications included antireflux operations and 20 included Heller's myotomy. The publications indicate that the safety and effectiveness of robotic surgery is similar to that of conventional minimally invasive surgery for both operations. The six randomized trials of robot-assisted versus laparoscopic antireflux surgery showed no significant advantages but significantly higher costs for the robotic method. Gastric perforation during non-redo robotic fundoplication occurred in four trials.Conclusions
No consistent advantage for robot-assisted antireflux surgery has been demonstrated, and there is an increased cost with current robotic technology. A reported advantage for robotic in reducing the perforation rate during Heller's myotomy for achalasia remains unproven. Gastric perforation during robotic fundoplication may be due to the lack of haptic feedback combined with the superhuman strength of the robot.
ANZ Journal of Surgery 08/2014; · 1.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Robot-assisted surgery is a technically feasible alternative to open and laparoscopic surgery, which is being more frequently used in general surgery. We undertook this review to investigate whether robotic assistance provides a significant benefit for oesophagogastric cancer surgery.Methods
Electronic databases were searched for original English-language publications for robotic-assisted gastrectomy and oesophagectomy between January 1990 and October 2013.ResultsSixty-one publications were included. Thirty-five included gastrectomy, 31 included oesophagectomy and five included both operations. Several publications suggest that robot-assisted subtotal gastrectomy can be as safe and effective as an open or laparoscopic procedure, with equal outcomes with regard to the number of lymph nodes resected, overall morbidity and perioperative mortality, and length of hospital stay. Robotic assistance is associated with longer operation times but also with less blood loss in some reports. A significant benefit for robotic assistance has not been shown for the more extensive operations of oesophagectomy or total gastrectomy with D2-lymphadenectomy. There are very few oncologic data regarding local recurrence or long-term survival for any of the robotic operations.Conclusions
No significant differences in morbidity, mortality or number of lymph node harvested have been shown between robot-assisted and laparoscopic gastrectomy or oesophagectomy. Robotic surgery, with its relatively short learning curve, may facilitate reproducible minimally invasive surgery in this field but operation times are reportedly longer and cost differences remain unclear. Randomized trials with oncologic outcomes and cost comparisons are needed.
ANZ Journal of Surgery 05/2014; · 1.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and aims
Bariatric surgery improves health outcomes in the obese and reduces some aspects of obesity-associated systemic inflammation. Little is known however about its effects on circulating TNF-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin level, which regulate apoptosis and are implicated in atherogenesis. Our objective was to identify whether circulating TRAIL and osteoprotegerin levels are influenced by the energy restriction and weight loss that follows bariatric surgery in obese patients with glucose disorders.
15 morbidly obese individuals with type 2 diabetes mellitus (T2D) or glucose intolerance were recruited for bariatric surgery. Participants were assessed for weight, waist circumference and BMI at baseline, then 2 and 12 weeks following energy restriction with bariatric surgery. Laparoscopic adjustable gastric band placement was performed. Fasted blood samples were collected and an oral glucose tolerance test was performed at each visit. Metabolic parameters and plasma chemistries were assessed. Circulating TRAIL, osteoprotegerin and leptin levels were measured.
A significant increase in circulating TRAIL levels was observed at 12 weeks relative to baseline in participants who suppressed leptin levels. The percentage change in TRAIL was inversely related to the percentage change in fasting insulin and HOMA-β. In contrast, osteoprotegerin levels and the osteoprotegerin:TRAIL ratio were significantly reduced following bariatric surgery. The change in osteoprotegerin:TRAIL ratio positively related to the percentage change in fasting glucose.
Energy restriction after bariatric surgery is associated with increased circulating TRAIL levels and reduced osteoprotegerin levels and osteoprotegerin:TRAIL ratio in obese humans with dysglycaemia. Changes in the TRAIL and osteoprotegerin:TRAIL ratio related to changes in fasting insulin, suggesting a possible role in glucose improvements after bariatric surgery. Mechanistic studies will clarify the role of TRAIL and osteoprotegerin in health and disease.
[Show abstract][Hide abstract] ABSTRACT: Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.
[Show abstract][Hide abstract] ABSTRACT: The effect of the laparoscopic adjustable gastric band (LAGB) on the esophagus has been the subject of few studies despite recognition of its clinical importance. The aim of this study was to investigate the frequency and clinical effect of esophageal dysmotility and dilatation after LAGB.
We undertook a retrospective analysis of 50 consecutive patients with no dysmotility on perioperative video contrast swallow who underwent primary LAGB operation. All patients had serial focused postoperative contrast studies for band adjustments at least 6 months post-LAGB. Clinical and radiological outcomes were assessed.
Median follow-up time was 18 months (range 7-39 months), and the median number of contrast swallows per patient was 5. The mean excess weight loss (EWL) overall was 47 % (standard deviation (SD) 22.3). Radiological abnormalities were recorded in 17 patients (34 %, 95 % confidence interval (CI) 21-49 %), of whom 15 had radiological dysmotility and 7 had esophageal dilatation (five patients had both dysmotility and dilatation). Of these 17 patients, six (35 %) developed significant symptoms of dysphagia, gastroesophageal reflux disease (GERD) or regurgitation requiring fluid removal. In comparison, 12 of 33 (36 %) patients without radiological abnormalities developed symptoms requiring fluid removal (p = 1.00). Patients with radiological abnormalities were significantly older than those without these abnormalities. Symptoms were alleviated by removing fluid in most patients.
The LAGB operation results in the development of radiological esophageal dysmotility in a significant proportion of patients. It is not clear if these changes are associated with an increased risk of significant symptoms. Fluid removal can reverse these abnormalities and their associated symptoms.
[Show abstract][Hide abstract] ABSTRACT: The contribution of immune cells to the inflammasome that characterises type 2 diabetes mellitus and obesity is under intense research scrutiny. We hypothesised that early changes in glucose metabolism following gastric banding surgery may relate to systemic inflammation, particularly cell-mediated immunity.
Obese participants (BMI 43.4 ± 4.9 kg/m(2), n = 15) with diabetes or impaired glucose tolerance (IGT) underwent laparoscopic adjustable gastric banding surgery. Measurements taken before, and at 2 and 12 weeks after surgery included: fasting glucose, glucose levels 2 h after a 75 g oral load, glucose incremental AUC, oral glucose insulin sensitivity index (OGIS), circulating immune cell numbers and activation, and adipokine levels. Subcutaneous and visceral adipose tissue were collected at surgery, and macrophage number and activation measured.
There were significant reductions in fasting and 2 h glucose, as well as improved OGIS at 2 and 12 weeks. At 12 weeks, 80% of the diabetic participants reverted to normal glucose tolerance or IGT, and all IGT participants had normalised glucose tolerance. The 12 week fall in fasting glucose was significantly related to baseline lymphocyte and T lymphocyte numbers, and to granulocyte activation, but also to the magnitude of the 12 week reduction in lymphocyte and T lymphocyte numbers and TNF-α levels. In a model that explained 75% of the variance in the change in fasting glucose, the 12 week change in T lymphocytes was independently associated with the 12 week fall in fasting glucose.
Rapid improvements in glucose metabolism after gastric banding surgery are related to reductions in circulating pro-inflammatory immune cells, specifically T lymphocytes. The contribution of immune cell-mediated inflammation to glucose homeostasis in type 2 diabetes and its improvement after bariatric surgery require further investigation.
[Show abstract][Hide abstract] ABSTRACT: Esophageal adenocarcinoma develops in response to severe gastresophageal reflux disease through the precursor lesion Barrett's esophagus, in which the normal squamous epithelium is replaced by a columnar lining. The incidence of esophageal adenocarcinoma in the USA has increased by over 600% in the past 40 y and the overall survival rate remains less than 20% in the community. This review highlights some of the signaling pathways for which there is some evidence of a role in the development of esophageal adenocarcinoma. An increasingly detailed understanding of the biology of this cancer has emerged recently, revealing that in addition to the well-recognized alterations in single genes such as p53, p16, APC and telomerase, there are interactions between the components of the reflux fluid, the homeobox gene Cdx2 and the Wnt, Notch and Hedgehog signaling pathways.
Cancer biology & therapy 06/2013; 14(9). · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bariatric surgery may be an effective treatment for obese heart failure patients, enabling access to cardiac transplantation and/or improvement of symptoms. We report the outcomes of two morbidly obese patients with end-stage heart failure, where obesity precluded cardiac transplantation and underwent laparoscopic gastric banding. A 42 year-old male with idiopathic dilated cardiomyopathy weighing 124.4kg (BMI 42kg/m(2)) lost 34kg and was successfully transplanted 11 months later. A 40 year-old woman with familial dilated cardiomyopathy weighing 105kg (BMI 40kg/m(2)) lost 14kg with sufficient symptomatic resolution to no longer require cardiac transplantation. In selected patients with severe heart failure and concomitant morbid obesity, bariatric surgery may be a reasonable treatment option.
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that the extracellular matrix play important roles in intercellular communications and contribute to the development of a number of diseases, including diseases of the gastrointestinal tract. The present study examined the structural characteristics and alterations of the extracellular matrix of the mucosa stroma in the Barrett's esophagus metaplasia-dysplasia-adenocarcinoma sequence.
A total of 41 esophageal tissue specimens (15 esophageal adenocarcinoma, 10 Barrett's esophagus intestinal metaplasia, seven dysplasia and nine normal esophagus) were studied. The present study used transmission electron microscopy and computerized quantitative electron-microscopic analysis in order to investigate the characteristics of the extracellular matrix of the mucosa.
The study revealed that marked structural alterations of the mucosa stroma, relating to changes in the distribution and appearance of collagen fibers as well as to changes in numbers of matrix microvesicles, occur in Barrett's esophagus and esophageal adenocarcinoma. It was found that there were 3.1 times more microvesicles in the stroma in Barrett's esophagus than in the stroma of the normal esophagus (P<0.0001) and that there were 5.8 times more microvesicles in esophageal adenocarcinoma than in the normal esophagus (P<0.0001). There were 1.9 times more microvesicles in esophageal adenocarcinoma than in Barrett's esophagus (P=0.0043).
The study demonstrates distinctive alterations of the mucosa stroma extracellular matrix in the metaplasia-dysplasia-adenocarcinoma sequence. The findings suggest that the redistribution of collagen fibers and increases in numbers of matrix microvesicles may play roles in the formation of specialized intestinal metaplasia and the development of adenocarcinoma.
Journal of Gastroenterology and Hepatology 05/2012; 27(9):1498-504. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Weight loss after bariatric surgery reduces cardiac risk and morbidity. We examined weight loss effects on arterial stiffness in morbidly obese subjects, in relation to cytokines, circulating and subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)-based immune cells and gene expression. Obese subjects with type 2 diabetes mellitus (T2D) or impaired glucose tolerance (n = 14, mean±SEM body mass index 42.9kg/m(2)) underwent 24 weeks' caloric restriction, with gastric banding at 12 weeks. Measures were: arterial augmentation index (AIx), insulin resistance, circulating cytokines, immune cell activation markers, and SAT and VAT cytokine gene expression. Weight loss reduced AIx by 20% (p = 0.007), with falls in s-selectin (p = 0.001) and inter-cellular adhesion molecule (p = 0.04). Improved AIx related to reduced surface expression of the interleukin (IL)-2 receptor on T-lymphocytes (TL-IL2R) and granulocyte adhesion markers (r = 0.59, 0.64, respectively, p < 0.04). Higher VAT expression of interferon-γ and monocyte chemoattractant protein-1 associated with a blunted AIx response. A model of TL-IL2R expression, waist, weight and insulin resistance explained 73% of the variance in AIx reduction (p = 0.005). In morbidly obese dysglycaemic subjects, modest weight loss reduces arterial stiffness, the magnitude of which relates to improved markers of inflammation.
Diabetes & Vascular Disease Research 04/2012; · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Barrett’s esophagus is a multistage polyclonal disease that is associated with the development of adenocarcinoma of the esophagus
and csophagogastric junction. Telomerase activation is associated with cellular immortality and carcinogenesis, and increased
expression of the telomerase reverse transcriptase catalytic subunit (hTERT) has been used for the early detection of malignant
diseases. To identify’ biomarkers associated with each stage of the Barrett’s process, relative mRNA expression levels of
hTERT were measured using a quantitative reverse transcription-polymerase chain reaction method (ABI 7700 Sequence Detector
(TaqMan system) in Barrett’s intestinal metaplasia (n —14), Barrett’s dysplasia (n =10), Barrett’s adenocarcinoma (n = 14),
and matching normal squamous esophagus tissues (n = 32). hTERT expression was significantly increased at all stages of Barren’s
esophagus, including the intestinal metaplasia stage, compared to normal tissues from patients without cancer (intestinal
metaplasia vs. normal esophagus, P <0.0001; dysplasia, P = 0.001; adenocarcinoma, P = 0.007; all Alann-Whitney U test). hTERT
expression levels were significantly higher in adenocarcinoma tissues than in intestinal metaplasia tissues (P = 0.003), and
were higher in dysplasia compared with intestinal metaplasia tissues (P = 0.056). hTERT levels were also significantly higher
in histologically normal squamous esophagus tissues from cancer panents than in normal esophagus tissues from patients vrith
no cancer (P = 0.013). Very high expression levels ([hTERT × 100: β-actin] >20) were found only in patients with cancer. These
findings suggest that telomerase activation is an important early event in the development of Barrett’s esophagus and esophageal
adenocarcinoma, that very high telomerase levels may be a clinically useful biomarker for the detection of occult adenocarcinoma,
and that a widespread cancer ‘field’ effect is present in the esophagus of patients with Barrett’s cancer.
Journal of Gastrointestinal Surgery 04/2012; 4(2):135-142. · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mechanistic reasoning suggests that since antireflux surgery treats the gastroesophageal reflux that is the major known risk factor for Barrett's esophagus, it should have a beneficial effect on the biology of Barrett's disease. Due to a lack of adequate data, whether this is the case remains uncertain. Most studies, including several large population-based cohort studies, are observational studies that are subject to bias. Selection bias could be present, for example, if the patients undergoing one treatment had worse disease than those undergoing the comparator treatment, which seems possible for antireflux surgery and acid suppression medication therapy. A systematic review also suggests publication bias. The published data indicate that surgeons should not claim that antireflux surgery prevents the progression of Barrett's. Well-conducted prospective studies with postoperative pH studies suggest, however, that effective surgery may reduce the risk of Barrett's progression whereas ineffective surgery provides no benefit.
[Show abstract][Hide abstract] ABSTRACT: The origin of smooth muscle cells in developing atherosclerotic lesions is a controversial topic with accumulating evidence indicating that at least some arterial smooth muscle cells might originate from bone marrow-derived smooth muscle cell precursors circulating in the blood. The stem cell markers currently used for the identification of stem cells in the arterial intima can be expressed by a number of different cell types residing in the arterial wall, such as mast cells, endothelial cells and dendritic cells, which can make interpretation of the data obtained somewhat ambiguous. In the present study we examined whether the putative intestinal stem cell marker Musashi-1 is expressed in the arterial wall. Using a multiplexed tandem polymerase chain reaction method (MT-PCR) and immunohistochemistry, Musashi-1 expression was revealed in human coronary arterial wall tissue segments, and this finding was followed by the demonstration of significantly higher expression levels of Musashi-1 in atherosclerotic plaques compared with those in undiseased intimal sites. Double immunohistochemistry demonstrated that in the arterial wall Musashi-1 positive cells either did not display any specific markers of cells that are known to reside in the arterial intima or Musashi-1 was co-expressed by smooth muscle α-actin positive cells. Some Musashi-1 positive cells were found along the luminal surface of arteries as well as within microvessels formed in atherosclerotic plaques by neovascularization, which supports the possibility that Musashi-1 positive cells might intrude into the arterial wall from the blood and might even represent circulating smooth muscle cell precursors.
[Show abstract][Hide abstract] ABSTRACT: Barrett's esophagus is an acquired metaplastic abnormality in which the normal stratified squamous epithelium lining of the esophagus is replaced by an intestinal-like columnar epithelium. While in itself a benign and asymptomatic disorder, the clinical importance of this relatively common condition relates to its role as a precursor lesion to esophageal adenocarcinoma, the incidence of which has dramatically increased in Western populations in recent years. Although known to arise as a consequence of chronic gastroesophageal reflux, the cellular and molecular mechanisms underlying development Barrett's esophagus and its progression to cancer remain unclear.
Journal of Gastroenterology and Hepatology 12/2010; 26(4):639-48. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Widespread applicability of tissue-based mRNA expression screening for Barrett esophagus (BE) is likely to require (1) accurate methods for assaying archival formalin-fixed, paraffin-embedded (FFPE) histopathology specimens taken at endoscopy, and (2) validation studies of promising biomarkers in different patient cohorts.
30 genes were significantly differentially expressed by histopathology tissue type. The direction and magnitude of the differences were very similar to those found in previous studies using fresh frozen tissues. Novel upregulated genes were TSPAN8 (also known as CO-029), TSPAN24 (CD151), EGR1 and TCIRG1. Novel downregulated genes were DPYD, TSPAN29 (CD9) and Ets1. Strong associations between histopathology type and gene expression were observed with the overexpressed genes: cyclo-oxygenase-2 (COX-2), for which histopathology type explained 77.7% of the variation in expression, TSPAN1 (73.5%), TSPAN8 (62.9%), SPARC (62.1%), MMP7 (50.8%); and the under-expressed genes ADH7 (53.7%), APC (58.2%), RAR-gamma (51.3%).
mRNA was isolated from 54 FFPE small endoscopic biopsies from patients with Barrett intestinal metaplasia (BE), esophageal adenocarcinoma (EAC), or control patients with a normal squamous-lined esophagus. Multiplexed tandem PCR (MT-PCR) was used to quantitate 50 selected candidate genes for BE and control genes in duplicate. Principal component analysis (PCA) was conducted to explore the presence of global differences in gene expression profiles. One-way analysis of variance (ANOVA) of the transformed data was used to identify genes that were differentially expressed between different histological subtypes. Differentially expressed genes with a fold change of ≥2 (upregulated) or ≤-2 (downregulated) are reported with the p value for each comparison (EAC vs. normal, EAC vs. BE and BE vs. normal). The Benjamini-Hochberg method was used to control the false discovery rate at 0.01 for all comparisons.
Alterations in expression of select genes are strongly associated with BE or EAC or both. This study's findings for many highly differentially expressed genes are very similar to those previously reported, suggesting that these genes should be tested further in longitudinal studies for their potential role as biomarkers of progression to more advanced Barrett disease.
Cancer biology & therapy 07/2010; 10(2):172-9. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: C1q, an element of the first component of complement, is known to be expressed by interdigitating and follicular dendritic cells in the spleen, where it has been suggested that C1q is involved in capturing immune complexes. The present study investigated whether C1q is expressed in Barrett's esophagus and esophageal adenocarcinoma and, if so, whether its expression is associated with dendritic cells.
Endoscopic biopsy or operative surgical specimens were obtained from 15 patients with Barrett's esophagus, 13 patients with esophageal adenocarcinoma and 12 patients whose biopsy specimens did not show the presence of specialized intestinal metaplasia or adenocarcinoma. Barrett's esophagus was diagnosed by the presence of a macroscopic area of columnar-lined esophagus as well as microscopic intestinal metaplasia with goblet cells. Immunohistochemistry utilizing anti-C1q and markers for dendritic cells and macrophages was performed on sections of tissue samples embedded in paraffin. Double immunostaining with C1q/CD83 and C1q/CD68 was used to analyze the possible co-localization of C1q with dendritic cells and macrophages. The expression of C1q by dendritic cells and macrophages was also examined in in vitro studies using reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting.
In all specimens studied, C1q expression was detected as being distributed irregularly throughout the lamina propria. A computerized quantitative analysis showed that C1q expression was significantly higher in tissue specimens without specialized intestinal-type metaplasia than in Barrett's esophagus specimens and specimens with adenocarcinoma. Double immunostaining revealed that dendritic cells and macrophages expressed C1q in all analyzed esophageal specimens. The expression of C1q by dendritic cells and macrophages was also demonstrated in in vitro studies using RT-PCR and Western blotting.
The findings suggest that reduced levels of the expression of C1q by dendritic cells and macrophages in the esophagus may play a role in the formation of immune responses associated with the formation of specialized intestinal metaplasia and the development of adenocarcinoma.
Journal of Gastrointestinal Surgery 05/2010; 14(8):1207-13. · 2.36 Impact Factor