Padraic MacMathuna

Do the benefits of metal stents justify the costs? A systematic review and meta-analysis of trials comparing endoscopic stents for malignant biliary obstruction.

Background A variety of stent designs has been studied for endoscopic stenting of the bile duct in patients with malignant biliary obstruction. Although metal stents are associated with longer patency, their costs are significantly higher than plastic stents. Aims To compare clinical outcome and cost-effectiveness of endoscopic metal and plastic stents for malignant biliary obstruction by a systematic review and meta-analysis of all randomized controlled trials in this area. Methods We conducted searches to identify all randomized controlled trials in any language from 1966 to 2006 using electronic databases and hand-searching of conference abstracts. Meta-analysis was performed with RevMan software [Review Manager (RevMan) version 4.2 for Windows. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2003]. Results Seven randomized controlled trials were identified that met the inclusion criteria, and 724 participants were randomized to either metal or plastic endoscopic stents. No significant difference between the two stent types in terms of technical success, therapeutic success, 30-day mortality or complications was observed. Metal stents were associated with a significantly less relative risk (RR) of stent occlusion at 4 months than plastic stents [RR, 0.44; 95% confidence interval (CI) 0.3, 0.63; P<0.01]. The overall risk of recurrent biliary obstruction was also significantly lower in patients treated with metal stents (RR, 0.52; 95% confidence interval 0.39, 0.69; P<0.01). The median incremental cost-effectiveness ratio of metal stents was

Lipoxin A4 and Aspirin-Triggered 15-Epi-Lipoxin A4 Antagonize TNF-α-Stimulated Neutrophil-Enterocyte Interactions In Vitro and Attenuate TNF-α-Induced Chemokine Release and Colonocyte Apoptosis in Human Intestinal Mucosa Ex Vivo

1820 per endoscopic retrograde cholangiopancreatography prevented. Conclusion Endoscopic metal stents for malignant biliary obstruction are associated with significantly higher patency rates than plastic stents as early as 4 months after insertion. Metal stents will be cost-effective if the unit cost of additional endoscopic retrograde cholangiopancreatographies per patient exceeds

Efficacy of IV Buscopan as a muscle relaxant in CT colonography

1820.

NET1-mediated RhoA activation facilitates lysophosphatidic acid-induced cell migration and invasion in gastric cancer.

Lipoxins (LXs) are lipoxygenase-derived eicosanoids and putative endogenous braking signals for inflammation in the gastrointestinal tract and other organs. Aspirin triggers the production of 15-epimers during cell-cell interaction in a cytokine-primed milieu, and aspirin-triggered 15-epi-5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA4) may contribute to the bioactivity profile of this prototype nonsteroidal anti-inflammatory drug in vivo. We determined the effect of LXA4, 15-(R/S)-methyl-11,12-dehydro-LXA4 methyl ester (15-(R/S)-methyl-LXA4), and stable analogs of LXA4 on TNF-α-stimulated neutrophil-enterocyte interaction in vitro and TNF-α-stimulated chemokine release, changes in mucosal architecture, and enterocyte apoptosis in cytokine-activated intact human colonic mucosa ex vivo. LXA4, 15-(R/S)-epi-LXA4, and 16-phenoxy-11,12-dehydro-17,18,19,20-tetranor-LXA4 methyl ester (16-phenoxy-LXA4) inhibited TNF-α-stimulated neutrophil adherence to epithelial monolayers at nanomolar concentrations. In parallel experiments involving human colonic mucosa ex vivo, LXA4potently attenuated TNF-α-stimulated release of the C-X-C chemokine IL-8, and the C-C chemokines monocyte-chemoattractant protein-1 (MCP-1) and RANTES. Exposure of strips of normal human colonic mucosa to TNF-α induced disruption of mucosa architecture and enhanced colonocyte apoptosis via a caspase-3-independent mechanism. Prior exposure of the mucosa strips to 15-(R/S)-methyl-LXA4 attenuated TNF-α-stimulated colonocyte apoptosis and protected the mucosa against TNF-α-induced mucosal damage. In aggregate, our data demonstrate that lipoxins and aspirin-triggered 15-epi-LXA4 are potent antagonists of TNF-α-mediated neutrophil-enterocyte interactions in vitro, attenuate TNF-α-triggered chemokine release and colonocyte apoptosis, and are protective against TNF-α-induced morphological disruption in human colonic strips ex vivo. Our observations further expand the anti-inflammatory profile of these lipoxygenase-derived eicosanoids and suggest new therapeutic approaches for the treatment of inflammatory bowel disease.

The detection of cytokeratins in lymph nodes of Duke's B colorectal cancer subjects predicts a poor outcome.

The aim of this study was to examine the efficacy of IV Buscopan as a muscle relaxant in CT colonography in terms of colonic distension and polyp detection, and to determine its particular efficacy in patients with diverticular disease. Seventy-three consecutive patients were randomised to receive IV Buscopan or no muscle relaxant prior to CT colonography. CT colonography was performed using a Siemens Somatom 4-detector multislice CT scanner. The following parameters were recorded: degree of colonic distension using a 4-point scale; diagnostic adequacy of colonic distension; presence or absence of diverticular disease; and presence of colonic polyps. Accuracy of polyp detection was assessed using subsequent conventional colonoscopy as a gold standard. There was no significant difference between the two groups in the number of segments that were deemed to be optimally or adequately distended (p=0.37). Although IV Buscopan did improve distension of certain segments, this effect was not sufficient to improve the number of diagnostically adequate studies in the Buscopan group (p=0.14). In patients with diverticular disease, IV Buscopan did not have any significant effect on segments affected by diverticulosis but was associated with an improvement in distension of more proximal segments. There was no significant difference between the two groups in terms of polyp detection (p=0.34). The addition of prone scanning to supine scanning was found to be the most useful technique for maximising colonic distension. Intravenous Buscopan at CT colonography does not improve the overall adequacy of colonic distension nor the accuracy of polyp detection. In patients with sigmoid diverticular disease IV Buscopan improves distension of more proximal colonic segments and may be useful in selected cases, but our results do not support its routine use for CT colonography.The aim of this study was to examine the efficacy of IV Buscopan as a muscle relaxant in CT colonography in terms of colonic distension and polyp detection, and to determine its particular efficacy in patients with diverticular disease. Seventy-three consecutive patients were randomised to receive IV Buscopan or no muscle relaxant prior to CT colonography. CT colonography was performed using a Siemens Somatom 4-detector multislice CT scanner. The following parameters were recorded: degree of colonic distension using a 4-point scale; diagnostic adequacy of colonic distension; presence or absence of diverticular disease; and presence of colonic polyps. Accuracy of polyp detection was assessed using subsequent conventional colonoscopy as a gold standard. There was no significant difference between the two groups in the number of segments that were deemed to be optimally or adequately distended (p=0.37). Although IV Buscopan did improve distension of certain segments, this effect was not sufficient to improve the number of diagnostically adequate studies in the Buscopan group (p=0.14). In patients with diverticular disease, IV Buscopan did not have any significant effect on segments affected by diverticulosis but was associated with an improvement in distension of more proximal segments. There was no significant difference between the two groups in terms of polyp detection (p=0.34). The addition of prone scanning to supine scanning was found to be the most useful technique for maximising colonic distension. Intravenous Buscopan at CT colonography does not improve the overall adequacy of colonic distension nor the accuracy of polyp detection. In patients with sigmoid diverticular disease IV Buscopan improves distension of more proximal colonic segments and may be useful in selected cases, but our results do not support its routine use for CT colonography.

Net1 and Myeov: computationally identified mediators of gastric cancer

The most lethal aspects of gastric adenocarcinoma (GA) are its invasive and metastatic properties. This aggressive phenotype remains poorly understood. We have recently identified neuroepithelial cell transforming gene 1 (NET1), a guanine exchange factor (GEF), as a novel GA-associated gene. Neuroepithelial cell transforming gene 1 expression is enhanced in GA and it is of functional importance in cell invasion. In this study, we demonstrate the activity of NET1 in driving cytoskeletal rearrangement, a key pathological mechanism in gastric tumour cell migration and invasion. Neuroepithelial cell transforming gene 1 expression was increased 10-fold in response to treatment with lysophosphatidic acid (LPA), resulting in an increase in active levels of RhoA and a 2-fold increase in cell invasion. Lysophosphatidic acid-induced cell invasion and migration were significantly inhibited using either NET1 siRNA or a RhoA inhibitor (C3 exoenzyme), thus indicating the activity of both NET1 and RhoA in gastric cancer progression. Furthermore, LPA-induced invasion and migration were also significantly reduced in the presence of cytochalasin D, an inhibitor of cytoskeletal rearrangements. Neuroepithelial cell transforming gene 1 knockdown resulted in AGS cell rounding and a loss of actin filament organisation, demonstrating the function of NET1 in actin organisation. These data highlight the importance of NET1 as a driver of tumour cell invasion, an activity mediated by RhoA activation and cytoskeletal reorganisation.

In silico gene expression analysis – an overview

Objectives The objectives of this study were to examine the frequency of lymph node micrometastases detected by keratin immunohistochemistry and their relationship with survival behaviour. Methods A total of 133 consecutive patients staged as Dukes B, who had curative resection for colorectal cancer (CRC), comprised the study population. Patients who had died of a non‐CRC‐related cause or who became lost to follow‐up were excluded, resulting in an amended population of 100. Study end‐points were defined as disease‐free survival of 5 years or CRC‐related death. Paraffin‐embedded lymph node sections were stained with a commercial cytokeratin antibody using a standard avidin‐biotin technique. Results One quarter of subjects had micrometastases. Fifty‐six per cent of subjects with positive lymph nodes had an adverse outcome, compared with 11% of subjects with negative nodes. A highly significant association was found between lymph node cytokeratin expression and mortality in both the univariate (log rank P = 0.0001) and multivariate (Cox proportional hazards P= 0.0123) analysis. Conclusions Lymph node micrometastases detected by this inexpensive and simple technique are significantly associated with mortality in Dukes B CRC. This technique may be used to select patients for adjuvant chemotherapy. Eur J Gastroenterol Hepatol 12:549‐552

Aggressive multiple myeloma presenting as mesenteric panniculitis

Gastric adenocarcinoma (GA) is a significant cause of mortality worldwide. The molecular mechanisms of GA remain poorly characterised. Our aim was to characterise the functional activity of the computationally identified genes, NET 1 and MYEOV in GA. Digital Differential Display was used to identify genes altered expression in GA-derived EST libraries. mRNA levels of a subset of genes were quantitated by qPCR in a panel of cell lines and tumour tissue. The effect of pro- and anti-inflammatory stimuli on gene expression was investigated. Cell proliferation and invasion were measured using in an in-vitro GA model following inhibition of expression using siRNA. In all, 23 genes not previously reported in association with GA were identified. Two genes, Net1 and Myeov, were selected for further analysis and increased expression was detected in GA tissue compared to paired normal tissue using quantitative PCR. siRNA-mediated downregulation of Net1 and Myeov resulted in decreased proliferation and invasion of gastric cancer cells in vitro. These functional studies highlight a putative role for NET1 and Myeov in the development and progression of gastric cancer. These genes may provide important targets for intervention in GA, evidenced by their role in promoting invasion and proliferation, key phenotypic hallmarks of cancer cells.

Pathophysiology of Portal Hypertension

Efforts aimed at deciphering the molecular basis of complex disease are underpinned by the availability of high throughput strategies for the identification of biomolecules that drive the disease process. The completion of the human genome-sequencing project, coupled to major technological developments, has afforded investigators myriad opportunities for multidimensional analysis of biological systems. Nowhere has this research explosion been more evident than in the field of transcriptomics. Affordable access and availability to the technology that supports such investigations has led to a significant increase in the amount of data generated. As most biological distinctions are now observed at a genomic level, a large amount of expression information is now openly available via public databases. Furthermore, numerous computational based methods have been developed to harness the power of these data. In this review we provide a brief overview of in silico methodologies for the analysis of differential gene expression such as Serial Analysis of Gene Expression and Digital Differential Display. The performance of these strategies, at both an operational and result/output level is assessed and compared. The key considerations that must be made when completing an in silico expression analysis are also presented as a roadmap to facilitate biologists. Furthermore, to highlight the importance of these in silico methodologies in contemporary biomedical research, examples of current studies using these approaches are discussed. The overriding goal of this review is to present the scientific community with a critical overview of these strategies, so that they can be effectively added to the tool box of biomedical researchers focused on identifying the molecular mechanisms of disease.

Mechanisms and Consequences of Portal Hypertension

Mesenteric panniculitis is a rare disease of the bowel mesentery, characterized by tumor-like infiltration by chronic inflammatory cells, fat necrosis, and fibrosis. Reported cases cited clinical presentation ranging from abdominal pain to fever of unknown origin, the majority of which were idiopathic and associated with a benign prognosis. We report the case of a 43-yr-old male who presented with malaise, weight loss, microcytic anemia, and a high erythrocyte sedimentation rate. Radiographic and histological investigations revealed typical features of mesenteric panniculitis. Initial treatment with high-dose oral prednisolone led to rapid and complete resolution of symptomatology, radiographic, and laboratory anomalies. Within 6 months, the patient presented again with anemia, renal failure, and hypercalcemia. A diagnosis of IgA kappa chain myeloma was made. Despite chemotherapy and restoration of normocalcemia, he died from refractory pulmonary edema. This is the first report of a hematological malignancy initially presenting with features of mesenteric panniculitis culminating in an aggressive course and a fatal outcome.