Academy of Medicine, Singapore clinical guideline on the use of sedation by non-anaesthesiologists during gastrointestinal endoscopy in the hospital setting.

INTRODUCTION: In Singapore, non-anaesthesiologists generally administer sedation during gastrointestinal endoscopy. The drugs used for sedation in hospital endoscopy centres now include propofol in addition to benzodiazepines and opiates. The requirements for peri-procedural monitoring and discharge protocols have also evolved. There is a need to develop an evidence-based clinical guideline on the safe and effective use of sedation by non-anaesthesiologists during gastrointestinal endoscopy in the hospital setting. METHODS: The Academy of Medicine, Singapore appointed an expert workgroup comprising 18 gastroenterologists, general surgeons and anaesthesiologists to develop guidelines on the use of sedation during gastrointestinal endoscopy. The workgroup formulated clinical questions related to different aspects of endoscopic sedation, conducted a relevant literature search, adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology and developed recommendations by consensus using a modified Delphi process. RESULTS: The workgroup made 16 recommendations encompassing 7 areas: (1) purpose of sedation, benefits and disadvantages of sedation during gastrointestinal endoscopy; (2) pre-procedural assessment, preparation and consent taking for sedation; (3) Efficacy and safety of drugs used in sedation; (4) the role of anaesthesiologist administered sedation during gastrointestinal endoscopy; (5) performance of sedation; (6) post-sedation care and discharge after sedation; and (7) training in sedation for gastrointestinal endoscopy for non-anaesthesiologists. CONCLUSION: These recommendations serve to guide clinical practice during sedation for gastrointestinal endoscopy by non-anaesthesiologists in the hospital setting.

A case report of wound site seeding following cholecystectomy for dysplastic gallbladder.

Wound site metastasis following cholecystectomy is an uncommon but well recognised complication following laparoscopic surgery for unsuspected gallbladder carcinoma. We describe a case of implantation of dysplastic cells with subsequent malignant transformation at the incision site 3 years post-cholecystectomy for an inflamed gallbladder. Histopathological examination of this tumour confirmed adenocarcinoma of pancreatobiliary origin, possibly secondary to gallbladder cells implantation and subsequent carcinomatous change. Unlike previously reported cases, the present case has two unique features: Firstly, the histology of the resected gallbladder at the initial operation was that of a low-grade dysplasia and not carcinoma; and secondly, there was a long interval between initial surgery and subsequent development of the wound site tumour. This case highlights that careful handling of the specimen tissue intraoperatively is paramount as cells implanted in the wound site can survive and undergo malignant transformation. All new masses occurring along the surgical wound site should be followed up and investigated to exclude implanted tumours.

Gelsolin-Cu/ZnSOD interaction alters intracellular reactive oxygen species levels to promote cancer cell invasion.

The actin-binding protein, gelsolin, is a well known regulator of cancer cell invasion. However, the mechanisms by which gelsolin promotes invasion are not well established. As reactive oxygen species (ROS) have been shown to promote cancer cell invasion, we investigated on the hypothesis that gelsolin-induced changes in ROS levels may mediate the invasive capacity of colon cancer cells.Herein, we show that increased gelsolin enhances the invasive capacity of colon cancer cells, and this is mediated via gelsolin's effects in elevating intracellular superoxide (O2.-) levels. We also provide evidence for a novel physical interaction between gelsolin and Cu/ZnSOD, that inhibits the enzymatic activity of Cu/ZnSOD, thereby resulting in a sustained elevation of intracellular O2.-. Using microarray data of human colorectal cancer tissues from Gene Omnibus, we found that gelsolin gene expression positively correlates with urokinase plasminogen activator (uPA), an important matrix-degrading protease invovled in cancer invasion. Consistent with the in vivo evidence, we show that increased levels of O2.- induced by gelsolin overexpression triggers the secretion of uPA. We further observed reduction in invasion and intracellular O2.- levels in colon cancer cells, as a consequence of gelsolin knockdown using two different siRNAs. In these cells, concurrent repression of Cu/ZnSOD restored intracellular O2.- levels and rescued invasive capacity.Our study therefore identified gelsolin as a novel regulator of intracellular O2.- in cancer cells via interacting with Cu/ZnSOD and inhibiting its enzymatic activity. Taken together, these findings provide insight into a novel function of gelsolin in promoting tumor invasion by directly impacting the cellular redox milieu.

Gelsolin-mediated activation of PI3K/Akt pathway is crucial for hepatocyte growth factor-induced cell scattering in gastric carcinoma.

In gastric cancer (GC), the main subtypes (diffuse and intestinal types) differ in pathological characteristics, with diffuse GC exhibiting early disseminative and invasive behaviour. A distinctive feature of diffuse GC is loss of intercellular adhesion. Although widely attributed to mutations in the CDH1 gene encoding E-cadherin, a significant percentage of diffuse GC do not harbor CDH1 mutations. We found that the expression of the actin-modulating cytoskeletal protein, gelsolin, is significantly higher in diffuse-type compared to intestinal-type GCs, using immunohistochemical and microarray analysis. Furthermore, in GCs with wild-type CDH1, gelsolin expression correlated inversely with CDH1 gene expression. Downregulating gelsolin using siRNA in GC cells enhanced intercellular adhesion and E-cadherin expression, and reduced invasive capacity. Interestingly, hepatocyte growth factor (HGF) induced increased gelsolin expression, and gelsolin was essential for HGF-medicated cell scattering and E-cadherin transcriptional repression through Snail, Twist and Zeb2. The HGF-dependent effect on E-cadherin was found to be mediated by interactions between gelsolin and PI3K-Akt signaling. This study reveals for the first time a function of gelsolin in the HGF/cMet oncogenic pathway, which leads to E-cadherin repression and cell scattering in gastric cancer. Our study highlights gelsolin as an important pro-disseminative factor contributing to the aggressive phenotype of diffuse GC.

Endoscopic self-expandable metallic stenting for palliation of malignant gastric outlet obstruction in Southeast Asia.

BACKGROUND: Malignant gastric outlet obstruction (GOO) is a pre-terminal event in the natural history of gastric and pancreaticobiliary cancers. The use of endoscopic placement of self-expandable metallic stents (SEMS) is a less invasive alternative palliative option for these patients. This is the first study in Southeast Asia to evaluate the clinical efficacy and safety of endoscopic SEMS placement in patients with malignant GOO. METHODS: A retrospective review of our department's database in endoscopic SEMS placement for the treatment of malignant GOO was performed. Twenty-four patients with advanced or metastatic malignancy that underwent placement of SEMS for treatment of malignant GOO between January 2003 and July 2013 were analysed. The GOO severity score was used as an objective means of assessing patients' oral intake. RESULTS: Technical success rate was 100%. All patients resumed oral intake of liquids within the same day of stent placement. Clinical success was achieved in 21 patients (87.5%). There was a significant improvement of GOO severity score from 0.62 ± 1.0 (mean ± standard deviation) before stent placement to 2.04 ± 0.86 after stent placement (P < 0.001). Complication rate was 12.5%. Stent-related complications observed include stent migration (two patients) and tumour ingrowth (one patient). Serious complications such as gastrointestinal haemorrhage or perforation did not occur in any patients. The median survival after stent placement was 57 days (95% confidence interval, 12.2-101.8 days). None of the patients died from stent-related complications. CONCLUSION: Endoscopic SEMS placement is a minimally invasive, safe and effective option for the palliation of malignant GOO.

Prospective comparison of the Alvarado score and CT scan in the evaluation of suspected appendicitis: a proposed algorithm to guide CT use.

BACKGROUND: Although computed tomography (CT) has reduced negative appendectomy rates, its radiation risk remains a concern. We compared the performance statistics of the Alvarado Score (AS) with those of CT scan in the evaluation of suspected appendicitis, with the aim of identifying a subset of patients who will benefit from CT evaluation. STUDY DESIGN: We performed prospective data collection on 350 consecutive patients with suspected appendicitis who were evaluated with CT scans. The AS for each patient was scored at admission and correlated with eventual histology and CT findings. The sensitivity, specificity, and positive likelihood ratios were determined for various AS and for CT scan. The AS ranges that benefitted most from CT evaluation were determined by comparing the positive likelihood ratios of CT scan with each of the AS cutoff values. RESULTS: The study included 134 males (38.3%) and 216 females (61.7%). The overall prevalence of appendicitis was 44.3% in the total study population; 37.5% in females and 55.2% in males. There were 168 patients (48%) who underwent surgery, with a negative appendectomy rate of 7.7%. Positive likelihood ratio of disease was significantly greater than 1 only in patients with an AS of 4 and above. An AS of 7 and above in males and 9 and above in females has a positive likelihood ratio comparable to that of CT scan. CONCLUSIONS: Evaluation by CT is beneficial mainly in patients with AS of 6 and below in males and 8 and below in females. We propose an objective management algorithm with the AS guiding subsequent evaluation.

Alvarado score: a guide to computed tomography utilization in appendicitis.

BACKGROUND: Although useful in evaluation of suspected appendicitis, not all patients require computed tomography (CT) evaluation. Clinical stratification of patients who benefit from CT evaluation is essential. We utilize the Alvarado score (AS) to stratify patients with suspected appendicitis into subgroups who benefit from CT evaluation and propose an objective algorithm with AS guiding CT utilization. METHODS: This study is a retrospective review of medical records of all patients admitted for suspected appendicitis over a 6-month duration. Relevant data were recorded. The AS for each patient was determined retrospectively and correlated with histological and CT findings. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were determined for various ASs and for CT. RESULTS: Three hundred fifty-eight patients were studied, with 167 males (46.6%) and 191 females (53.4%). Prevalence of appendicitis was 50% (179 patients). Two hundred fourteen patients (59.8%) had CT performed. Surgery was performed for 206 patients (57.5%). Overall negative appendicectomy rate was 13.1%. Patients who underwent CT evaluation had a negative appendicectomy rate of 5.7% compared to 17.9% in those without CT evaluation (P = 0.009). CT scan had a sensitivity and specificity of 92.6% and 96.9%, respectively. An AS greater than 3 had a sensitivity superior to CT (95.5%), while an AS of 9 or greater had a specificity superior to CT (100%). CONCLUSIONS: In suspected appendicitis, patients who benefit from CT evaluation are those with the AS ranging from 4 to 8. We propose a management algorithm with the AS guiding the necessity for CT evaluation.

Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase-type plasminogen activator cascade.

Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell motility and plasticity. Although initially regarded as a tumor suppressor, gelsolin expression in certain tumors correlates with poor prognosis and therapy-resistance. In vitro, gelsolin has anti-apoptotic and pro-migratory functions and is critical for invasion of some types of tumor cells. We found that gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues, as examined by immunohistochemistry. Although gelsolin contributes to lamellipodia formation in migrating cells, the mechanisms by which it induces tumor invasion are unclear. Gelsolin's influence on the invasive activity of colorectal cancer cells was investigated using overexpression and small interfering RNA knockdown. We show that gelsolin is required for invasion of colorectal cancer cells through matrigel. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion-promoting genes in colorectal cancer cells, including the matrix-degrading urokinase-type plasminogen activator (uPA). Conversely, gelsolin knockdown reduces uPA levels, as well as uPA secretion. The enhanced invasiveness of gelsolin-overexpressing cells was attenuated by treatment with function-blocking antibodies to either uPA or its receptor uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. In summary, our data reveals novel functions of gelsolin in colorectal tumor cell invasion through its modulation of the uPA/uPAR cascade, with potentially important roles in colorectal tumor dissemination to metastatic sites.

Heat-shock protein 60 translocates to the surface of apoptotic cells and differentiated megakaryocytes and stimulates phagocytosis.

Heat-shock protein 60 (Hsp60) is a highly conserved stress protein which has chaperone functions in prokaryotes and mammalian cells. Hsp60 is associated with the mitochondria and the plasma membrane through phosphorylation by protein kinase A, and is incorporated into lipid membranes as a protein-folding chaperone. Its diverse intracellular chaperone functions include the secretion of proteins where it maintains the conformation of precursors and facilitates their translocation through the plasma membrane. We report here that Hsp60 is concentrated in apoptotic membrane blebs and translocates to the surface of cells undergoing apoptosis. Hsp60 is also enriched in platelets derived from terminally differentiated megakaryocytes and expressed at the surface of senescent platelets. Furthermore, the exposure of monocytic U937 cells to Hsp60 enhanced their phagocytic activity. Our results suggests that externalized Hsp60 in apoptotic cells and senescent platelets influences events subsequent to apoptosis, such as the clearance of apoptotic cells by phagocytes.