Publications by authors named "Weng-Hoong Chan"

39 Publications

A functional network of gastric-cancer-associated splicing events controlled by dysregulated splicing factors.

NAR Genom Bioinform 2020 Jun 28;2(2):lqaa013. Epub 2020 Feb 28.

Centre for Computational Biology, Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.

Comprehensive understanding of aberrant splicing in gastric cancer is lacking. We RNA-sequenced 19 gastric tumor-normal pairs and identified 118 high-confidence tumor-associated (TA) alternative splicing events (ASEs) based on high-coverage sequencing and stringent filtering, and also identified 8 differentially expressed splicing factors (SFs). The TA ASEs occurred in genes primarily involved in cytoskeletal organization. We constructed a correlative network between TA ASE splicing ratios and SF expression, replicated it in independent gastric cancer data from The Cancer Genome Atlas and experimentally validated it by knockdown of the nodal SFs (,  and ). Each SF knockdown drove splicing alterations in several corresponding TA ASEs and led to alterations in cellular migration consistent with the role of TA ASEs in cytoskeletal organization. We have therefore established a robust network of dysregulated splicing associated with tumor invasion in gastric cancer. Our work is a resource for identifying oncogenic splice forms, SFs and splicing-generated tumor antigens as biomarkers and therapeutic targets.
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http://dx.doi.org/10.1093/nargab/lqaa013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671336PMC
June 2020

Systematic Review and Meta-Analysis of Prophylactic Transarterial Embolization for High-Risk Bleeding Peptic Ulcer Disease.

J Vasc Interv Radiol 2021 Jan 29. Epub 2021 Jan 29.

Department of Upper Gastrointestinal and Bariatric Surgery, Singapore General Hospital.

The present systematic review determined the role of transarterial embolization (TAE) as a prophylactic treatment in bleeding peptic ulcers after initial successful endoscopic hemostasis. PubMed and Ovid Medline databases were searched from inception until July 2019 for studies that included patients deemed high-risk based on Forrest Classification, Rockall score ≥ 5, or endoscopic evaluation in addition to those who underwent prophylactic TAE after initial successful endoscopic hemostasis. Meta-analysis was performed to compare patients who underwent endoscopic therapy (ET) and TAE with those who underwent ET alone. The primary outcomes measured included rates of rebleeding, reintervention, and 30-day mortality. Secondary outcome measures evaluated length of hospitalization, technical success rates, and complications associated with TAE. Of 916 publications, 5 were eligible for inclusion; 310 patients with high-risk peptic ulcer bleeding underwent prophylactic TAE, and 255 were compared against a control group of 580 patients that underwent standard treatment with ET alone. Patients who underwent ET with TAE had lower 30-day rebleeding rates (odds ratio [OR], 0.35; 95% confidence interval [CI] 0.15-0.85; P = .02; I = 50%). The ET with TAE group had a lower 30-day mortality rate (OR, 0.28; 95% CI, 0.10-0.83; P = .02; I = 58%). There was no difference in pooled reintervention rates (OR, 0.68; 95% CI, 0.43-1.08; P = .10; I = 0%) and length of hospitalization (mean difference, -0.32; 95% CI, -1.88 to 1.24; P = .69; I = 0%). Technical success rate of prophylactic TAE was 90.5% (95% CI, 83.09-97.98; I = 75.9%). Pooled proportion of overall complication rate was 0.18% (95% CI, 0.00-1.28; I = 0%). Prophylactic TAE has lower rebleeding and mortality with a good success rate and low complications. Prophylactic TAE after primary ET may be recommended for selected patients with high-risk bleeding ulcers; however, further studies should be performed to establish this as a routine tool in patients with bleeding peptic ulcer disease.
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http://dx.doi.org/10.1016/j.jvir.2020.12.005DOI Listing
January 2021

Small hiatal hernia and postprandial reflux after vertical sleeve gastrectomy: A multiethnic Asian cohort.

PLoS One 2020 6;15(11):e0241847. Epub 2020 Nov 6.

Division of Surgery, Department of Upper Gastrointestinal & Bariatric Surgery, Singapore General Hospital, Singapore, Singapore.

Background: Laparoscopic vertical sleeve gastrectomy (LSG) is a popular bariatric procedure performed in Asia, as obesity continues to be on the rise in our population. A major problem faced is the development of de novo gastroesophageal reflux disease (GERD) after LSG, which can be chronic and debilitating. In this study, we aim to assess the relationship between the presence of small hiatal hernia (HH) and the development of postoperative GERD, as well as to explore the correlation between GERD symptoms after LSG and timing of meals. In doing so, we hope to gain a better understanding about the type of reflux that occurs after LSG and take a step closer towards effectively managing this difficult to treat condition.

Methods: We retrospectively reviewed data collected from patients who underwent LSG in our hospital from Dec 2008 to Dec 2016. All patients underwent preoperative upper GI endoscopy, during which the identification of hiatal hernia takes place. Patients' information and reflux symptoms are recorded using standardized questionnaires, which are administered preoperatively, and again during postoperative follow up visits.

Results: Of the 255 patients, 125 patients (74%) developed de novo GERD within 6 months post-sleeve gastrectomy. The rate of de novo GERD was 57.1% in the group with HH, and 76.4% in the group without HH. Adjusted analysis showed no significant association between HH and GERD (RR = 0.682; 95% CI 0.419 to 1.111; P = 0.125). 88% of the patients who developed postoperative GERD reported postprandial symptoms occurring only after meals, and the remaining 12% of patients reported no correlation between the timing of GERD symptoms and meals.

Conclusion: There is no direct correlation between the presence of small hiatal hernia and GERD symptoms after LSG. Hence, the presence of a small sliding hiatal hernia should not be exclusion for sleeve gastrectomy. Electing not to perform concomitant hiatal hernia repair also does not appear to result in higher rates of postoperative or de novo GERD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241847PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647085PMC
January 2021

Branched-Chain Amino Acid Oxidation Is Elevated in Adults with Morbid Obesity and Decreases Significantly after Sleeve Gastrectomy.

J Nutr 2020 12;150(12):3180-3189

USDA/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Background: Plasma concentrations of branched-chain amino acids (BCAAs) are elevated in obese individuals with insulin resistance (IR) and decrease after bariatric surgery. However, the metabolic mechanisms are unclear.

Objectives: Our objectives are to compare leucine kinetics between morbidly obese and healthy-weight individuals cross-sectionally, and to prospectively evaluate changes in the morbidly obese after sleeve gastrectomy. We hypothesized that leucine oxidation is slower in obese individuals and increases after surgery.

Methods: Ten morbidly obese [BMI (in kg/m2) ≥32.5, age 21-50 y] and 10 healthy-weight participants (BMI <25), matched for age (median ∼30 y) but not gender, were infused with [U-13C6] leucine and [2H5] glycerol to quantify leucine and glycerol kinetics. Morbidly obese participants were studied again 6 mo postsurgery. Primary outcomes were kinetic parameters related to BCAA metabolism. Data were analyzed by nonparametric methods and presented as median (IQR).

Results: Participants with obesity had IR with an HOMA-IR (4.89; 4.36-8.76) greater than that of healthy-weight participants (1.32; 0.99-1.49; P < 0.001) and had significantly faster leucine flux [218; 196-259 compared with 145; 138-149 μmol · kg fat-free mass (FFM)-1 · h-1], oxidation (24.0; 17.9-29.8 compared with 16.1; 14.3-18.5 μmol · kg FFM-1 · h-1), and nonoxidative disposal (204; 190-247 compared with 138; 129-140 μmol · kg FFM-1 · h-1) (P < 0.017 for all). After surgery, the morbidly obese had a marked improvement in IR (3.54; 3.06-6.08; P = 0.008) and significant reductions in BCAA concentrations (113; 95-157 μmol/L) and leucine oxidation (9.37; 6.85-15.2 μmol · kg FFM-1 · h-1) (P = 0.017 for both). Further, leucine flux in this group correlated significantly with IR (r = 0.78, P < 0.001).

Conclusions: BCAA oxidation is not impaired but elevated in individuals with morbid obesity. Plasma BCAA concentrations are lowered after surgery owing to slower breakdown of body proteins as insulin's ability to suppress proteolysis is restored. These findings suggest that IR is the underlying cause and not the consequence of elevated BCAAs in obesity.
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http://dx.doi.org/10.1093/jn/nxaa298DOI Listing
December 2020

Resolution of Erosive Esophagitis After Conversion from Vertical Sleeve Gastrectomy to Roux-en-Y Gastric Bypass.

Obes Surg 2020 Dec 15;30(12):4751-4759. Epub 2020 Aug 15.

Department of Upper Gastrointestinal & Bariatric Surgery, Division of Surgery, Singapore General Hospital, Academia, 20 College Road, Singapore, 169856, Singapore.

Background: Laparoscopic sleeve gastrectomy (LSG) has become the preferred bariatric procedure in many countries. However, there is one shortcoming of LSG in the long-term follow-up, and this is the onset of gastro-esophageal reflux disease (GERD) and erosive esophagitis (EE). Conversion to Roux-en-Y gastric bypass (RYGB) is considered an option in patients unresponsive to medical therapy. Currently, there is no evidence of EE improvement or resolution after conversion surgery. In this study, we objectively evaluate the effectiveness of RYGB in management of EE with upper endoscopy (EGD) to identify the significant variables in patients with GERD symptoms post LSG refractory to medical therapy and require conversion surgery.

Methods: Over a period of 11 years (2008-2019) at Singapore General Hospital, we retrospectively reviewed a prospectively collected database of a cohort of patients whom had conversion surgery to RYGB for refractory GERD and EE after LSG. Patient's endoscopic findings and demographic and anthropometric data were analyzed.

Results: We identified a total of 14 patients who underwent LSG to RYGB conversions for endoscopic proven erosive esophagitis in our unit during the study period. Eight patients (57.1%) had concurrent hiatal hernia repaired. Nine (64.3%) patients were females. The median age of patients in this cohort was 44 (range 30-61) years. Mean weight and BMI were 87.7 kg (± 19.2) and 32.8 (± 3.09) kg/m2, respectively, on the day of conversion surgery. The median time between LSG and revision to RYGB was 36 (range 6-68) months. Seven patients (50%) had complete resolution of GERD symptoms after conversion, and 6 patients (42.9%) had partial resolution. Six out of 7 patients had complete resolution of EE. There were 4 anastomotic strictures (28.6%). Older patients, Indian ethnicity, present of hiatal hernia and lower weight loss after initial LSG were more likely to undergo conversion surgery.

Conclusion: Conversion to RYGB after LSG is clinically relevant and may be a feasible solution if patients have ongoing GERD refractory to medical therapy. Ninety-three percent of our patients achieved complete resolution of their GERD symptoms and significant improvement of erosive esophagitis with significant weight loss after conversion. This study has important implications as LSG is increasingly being performed and a proportion of these will need revision surgery for various reasons, particularly GERD which is extremely prevalent.
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http://dx.doi.org/10.1007/s11695-020-04913-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429122PMC
December 2020

Associations of Bariatric Interventions With Micronutrient and Endocrine Disturbances.

JAMA Netw Open 2020 06 1;3(6):e205123. Epub 2020 Jun 1.

Department of Upper Gastrointestinal and Bariatric Surgery, Singapore General Hospital, Singapore.

Importance: Few studies have described the longitudinal trajectories of serum levels of micronutrients whose deficiencies are associated with serious sequelae following bariatric procedures, such as anemia, osteoporotic fractures, and neuropathies. Furthermore, previous studies comparing laparoscopic sleeve gastrectomy (LSG) vs Roux-en-Y gastric bypass (LRYGB) or one-anastomosis gastric bypass (OAGB) procedures may have been limited by selection and confounding biases.

Objective: To appraise the spectrum and temporal course of micronutrient deficiencies associated with bone metabolism and erythropoiesis after LSG vs OAGB or LRYGB procedures, using the propensity score as a balancing score.

Design, Setting, And Participants: This prospective, longitudinal comparative effectiveness study was conducted at a high-volume bariatric unit in Singapore from September 1, 2008, to November 30, 2017, with a cutoff date for analysis of September 2018. Patients who underwent adjustable gastric banding, biliopancreatic diversion procedures, and intragastric balloon procedures were excluded. All other patients who underwent bariatric procedures were included. Data were analyzed from September 23 to 30, 2018.

Main Outcomes And Measures: Serial assessment of 13 biochemical parameters at 12 time points for up to 5 years after bariatric procedure. Inverse probability-of-treatment weights were used to obtain estimates of the mean associations of variables assessed with the bariatric surgical interventions. Longitudinal trajectories were analyzed using mixed-effects generalized linear models to apportion the temporal variation of serum micronutrients into fixed-effects and random-effects components.

Results: A total of 688 patients were included in this study, of whom 499 underwent LSG (mean [SD] age, 41.5 [11.3] years; 318 [63.7%] women) and 189 underwent OAGB or LRYGB (mean [SD] age, 48.6 [9.4] years; 112 [59.3%] women). There were no differences during follow-up among patients who underwent LSG vs those who underwent OAGB or LRYGB in intact parathyroid hormone levels (mean difference, 7.05 [95% CI, -28.67 to 42.77] pg/mL; P = .70), serum 25-hydroxyvitamin D levels (mean difference, -0.72 [95% CI, -1.56 to 0.12] ng/mL; P = .09), or phosphate levels (mean difference, 0.006 [95% CI, -0.052 to 0.064] mg/dL; P = .83). Hemoglobin levels were a mean 0.63 (95% CI, 0.41 to 0.85) g/dL higher among patients who underwent LSG compared with those who underwent OAGB or LRYGB (P < .001), despite no differences in iron concentration levels (mean difference, 1.50 [95% CI, -1.39 to 4.39] µg/dL; P = .31), total iron-binding capacity (mean difference, 4.36 [95% CI, -5.25 to 13.98] µg/dL; P = .37), or ferritin levels (mean difference, 3.0 [95% CI, -13.0 to 18.9] ng/mL; P = .71). Compared with patients who underwent LSG procedures, patients who underwent OAGB or LRYGB had higher folate levels (mean difference, 2.376 [95% CI, 1.716 to 3.036] ng/mL; P < .001) but lower serum magnesium levels (mean difference, -0.25 [95% CI, -0.35 to -0.16] mg/dL; P < .001) and zinc levels (mean difference, -7.58 [95% CI, -9.92 to -5.24] µg/dL; P < .001).

Conclusions And Relevance: These findings suggest that LSG vs OAGB or LRYGB procedures have differential associations with various micronutrient and metabolic parameters. These differences should be recognized in guidelines for postbariatric nutritional surveillance and prevention.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.5123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284307PMC
June 2020

Randomized control trial comparing an Alvarado Score-based management algorithm and current best practice in the evaluation of suspected appendicitis.

World J Emerg Surg 2020 05 1;15(1):30. Epub 2020 May 1.

Department of General Surgery, Singapore General Hospital, Singapore, Singapore.

Background: An objective algorithm for the management of suspected appendicitis guided by the Alvarado Score had previously been proposed. This algorithm was expected to reduce computed tomography (CT) utilization without compromising the negative appendectomy rate. This study attempts to validate the proposed algorithm in a randomized control trial.

Methods: A randomized control trial comparing the management of suspected acute appendicitis using the proposed algorithm compared to current best practice, with the rate of CT utilization as the primary outcome of interest. Secondary outcomes included the percentage of missed diagnosis, negative appendectomies, length of stay in days, and overall cost of stay in dollars.

Results: One hundred sixty patients were randomized. Characteristics such as age, ethnic group, American Society of Anesthesiologist score, white cell count, and symptom duration were similar between the two groups. The overall CT utilization rate of the intervention arm and the usual care arm were similar (93.7% vs 92.5%, p = 0.999). There were no differences in terms of negative appendectomy rate, length of stay, and cost of stay between the intervention arm as compared to the usual care arm (p = 0.926, p = 0.705, and p = 0.886, respectively). Among patients evaluated with CT, 75% (112 out of 149) revealed diagnoses for the presenting symptoms.

Conclusion: The proposed AS-based management algorithm did not reduce the CT utilization rate. Outcomes such as missed diagnoses, negative appendectomy rates, length of stay, and cost of stay were also largely similar. CT utilization was prevalent as 93% of the study cohort was evaluated by CT scan.

Trial Registration: The study has been registered at ClinicalTrials.gov (NCT03324165, Registered October 27 2017).
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http://dx.doi.org/10.1186/s13017-020-00309-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193351PMC
May 2020

Preoperative Weight Loss via Very Low Caloric Diet (VLCD) and Its Effect on Outcomes After Bariatric Surgery.

Obes Surg 2020 Jun;30(6):2099-2107

Department of Endocrinology, Singapore General Hospital, Singapore, Singapore.

Introduction: The effect of preoperative weight loss via very low caloric diet (VLCD) on long-term weight loss post-bariatric surgery (BS) is conflicting. We analysed its impact on weight loss and other outcomes post-BS.

Methods: Patients (n = 306) who underwent sleeve gastrectomy or gastric bypass from 2008 to 2018 were studied. VLCD was prescribed for 14 days preoperatively. Patients were followed up for 5 years. Postoperative weight loss was compared in patients with preoperative weight gain or weight loss < 5% (WL < 5%), and weight loss ≥ 5% (WL ≥ 5%). Preoperative WL compared weight before and after VLCD; postoperative WL compared post-VLCD weight and follow-up weight. Total weight loss (TWL) encompassed pre- and postoperative WL.

Results: WL was < 5% in 87.3% and ≥ 5% in 12.7%. There was no significant difference in complication rate, duration of surgery or length of stay, regardless of surgical type. Patients with WL < 5% lost more weight postoperatively compared with WL ≥ 5% for up to 60 months (%postoperative WL at 1 month: WL < 5% = 13.7%, WL ≥ 5% = 10%, p = <0.001; 60 months: WL < 5% = 30.6%, WL ≥ 5% = 23.9%, p = 0.041). However, when TWL and percentage of excess body mass index loss (%EBMIL) were measured, there was no difference beyond 6 months. A predictive multivariable model for 1-year %EBMIL was formed. Significant variables included pre-VLCD BMI and preoperative WL, and the relationship between the two.

Conclusion: Preoperative WL via VLCD was associated with reduced postoperative WL after BS, with no significant effect on complications, long-term TWL or %EBMIL. This challenges the notion that preoperative WL via VLCD should be mandated for better postoperative outcomes.
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http://dx.doi.org/10.1007/s11695-020-04446-yDOI Listing
June 2020

Attitudes and perceptions of the general public on obesity and its treatment options in Singapore.

Obes Res Clin Pract 2019 Jul - Aug;13(4):404-407. Epub 2019 Apr 8.

Obesity and Metabolic Unit, Bowyer Block A Level 1, Singapore General Hospital, Outram Road, Singapore 169608, Singapore; Department of Endocrinology, Singapore General Hospital, 20 College Rd., Singapore 169856, Singapore.

Data on attitudes and perceptions towards obesity are lacking in Asia. Participants who attended an obesity public forum were surveyed concerning obesity and its treatment options. Although obesity is generally accepted as a disease with biological underpinnings such as hormonal imbalances and slow metabolic rate, it is also regarded as an issue of personal responsibility. 65.1% believed that weight-loss medications are dangerous. 20.6% thought that pharmacotherapy is effective for weight loss, whereas 41.1% were unsure. Most believed that bariatric surgery could improve health (81.9%) and diabetes control (74.0%) although 64.1% were unsure of its risks.
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http://dx.doi.org/10.1016/j.orcp.2019.03.007DOI Listing
June 2020

Endoscopic partial reversal of complicated single anastomosis gastric bypass.

Endoscopy 2019 05 21;51(5):E108-E110. Epub 2019 Feb 21.

Department of Upper Gastrointestional and Bariatric Surgery, Singapore General Hospital, Singapore.

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http://dx.doi.org/10.1055/a-0841-9831DOI Listing
May 2019

Correlation Between Symptomatic Gastro-Esophageal Reflux Disease (GERD) and Erosive Esophagitis (EE) Post-vertical Sleeve Gastrectomy (VSG).

Obes Surg 2019 01;29(1):207-214

Department of Upper Gastrointestinal & Bariatric Surgery, Division of Surgery, Singapore General Hospital, Academia, 20 College Road, Singapore, 169856, Singapore.

Background: Laparoscopic sleeve gastrectomy (LSG) has become the preferred bariatric procedure in many countries. However, there is one shortcoming of LSG in the long-term follow-up and this is the onset of GERD and erosive esophagitis (EE). Current evidence of the effect of SG on GERD did not consolidate to a consensus. In this study, we objectively evaluate the incidence of EE 1 year post-LSG with upper endoscopy (EGD) and try to identify the significant variables and possible underlying mechanisms of the EE post-LSG.

Methods: Over a period of 5 years (2011-2016) at Singapore General Hospital, we retrospectively reviewed a prospectively collected database of a cohort of patients whom had LSG by a single surgeon who routinely performed EGD pre-operative and 1 year post-operative to assess EE and hiatal hernia. Patient's endoscopic findings and demographic and anthropometric data were analyzed.

Results: We identified a total of 97 obese patients who underwent LSG at our hospital by studied surgeon. Sixty-three patients (64.9% of original sample) were finally evaluated in the present study, 40 (59.7%) of whom were female. The mean (range) age of patients was 38.2 (18-66) years, and mean BMI was 36.3 ± 4.1 kg/m. Median time to follow-up EGD was 13 months (range, 12-15). Following LSG, there was a significant decrease in both BMI (42.1 ± 1.2 vs. 29.9 ± 1.0 kg/m) and percentage excess weight loss of 56.6 ± 3.6%. The prevalence of EE on endoscopy increased from 9 (14.3%) to 28 (44.4%) patients. Of which 15 (23.8%) were grade A, 11 (17.5%) were grade B, and 2 (3.2%) were grade C. There was no correlation between GERD symptoms with EE; however, our study found a trend suggesting higher prevalence of EE with a sleeve diameter measuring > 2 cm wide (p = 0.069).

Conclusion: Although LSG is effective in treating obesity and its metabolic syndromes, the prevalence of EE increased significantly 1 year after the surgery. Since we do not fully understand the long-term impact of chronic esophagitis in post-sleeve population, we recommend follow-up EGD assessment post-operatively and treat the esophagitis if present.
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http://dx.doi.org/10.1007/s11695-018-3509-0DOI Listing
January 2019

Comprehensive Assessment of the Effects of Sleeve Gastrectomy on Glucose, Lipid, and Amino Acid Metabolism in Asian Individuals with Morbid Obesity.

Obes Surg 2019 01;29(1):149-158

Department of Endocrinology, The Academia Level 3, Singapore General Hospital, 20 College Road, Singapore, 169856, Singapore.

Background: Obesity-induced insulin resistance leads to abnormalities in glucose, lipid, and amino acid metabolism. Our study examined the differences in insulin-mediated glucose, amino acid, and lipid metabolism between morbidly obese subjects with non-obese controls and the associated changes following sleeve gastrectomy (SG).

Methods: Non-obese controls and individuals with morbid obesity and scheduled for SG were recruited. Metabolic assessments were performed for all subjects at baseline and at 6 months after SG for eight subjects. The hyperinsulinemic-euglycemic clamp technique together with comprehensive metabolomic profiling was used to quantify insulin-mediated glucose, amino acid, and lipid metabolism.

Results: Eleven morbidly obese non-diabetic subjects scheduled for SG and nine non-obese controls were recruited. Compared to controls, obese subjects had significantly lower glucose uptake (4.4 ± 0.6 vs. 17.3 ± 2.4 mg/kg FFM/min per μU/mL·100) and higher concentration of branched-chain amino acids (BCAAs, 332.5 ± 26.8 vs. 235.3 ± 11.0 μM), non-esterified fatty acid (52.9 ± 9.9 vs. 25.6 ± 6.7 μM), and lipid-related acylcarnitines (intermediate chain 389.8 ± 32.5 vs. 285.9 ± 20.5; long chain 301.7 ± 22.1 vs. 236.0 ± 13.3 nM) during insulin clamp. Body weight significantly reduced at 6 months after bariatric surgery (92.5 ± 6.3 vs. 115.2 ± 6.9 kg), together with improvements in insulin-mediated glucose uptake, and suppression of BCAAs, non-esterified fatty acids, and lipid-related metabolites.

Conclusions: Morbid obesity in Asian individuals was associated with impairment in the regulatory actions of insulin on glucose, amino acid, and lipid metabolism, and these obesity-induced regulatory dysfunctions improved significantly 6 months after SG.
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http://dx.doi.org/10.1007/s11695-018-3487-2DOI Listing
January 2019

Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma.

Cancer Discov 2017 06 20;7(6):630-651. Epub 2017 Mar 20.

Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.

Promoter elements play important roles in isoform and cell type-specific expression. We surveyed the epigenomic promoter landscape of gastric adenocarcinoma, analyzing 110 chromatin profiles (H3K4me3, H3K4me1, H3K27ac) of primary gastric cancers, gastric cancer lines, and nonmalignant gastric tissues. We identified nearly 2,000 promoter alterations (somatic promoters), many deregulated in various epithelial malignancies and mapping frequently to alternative promoters within the same gene, generating potential pro-oncogenic isoforms (). Somatic promoter-associated N-terminal peptides displaying relative depletion in tumors exhibited high-affinity MHC binding predictions and elicited potent T-cell responses , suggesting a mechanism for reducing tumor antigenicity. In multiple patient cohorts, gastric cancers with high somatic promoter usage also displayed reduced T-cell cytolytic marker expression. Somatic promoters are enriched in PRC2 occupancy, display sensitivity to EZH2 therapeutic inhibition, and are associated with novel cancer-associated transcripts. By generating tumor-specific isoforms and decreasing tumor antigenicity, epigenomic promoter alterations may thus drive intrinsic tumorigenesis and also allow nascent cancers to evade host immunity. We apply epigenomic profiling to demarcate the promoter landscape of gastric cancer. Many tumor-specific promoters activate different promoters in the same gene, some generating pro-oncogenic isoforms. Tumor-specific promoters also reduce tumor antigenicity by causing relative depletion of immunogenic peptides, contributing to cancer immunoediting and allowing tumors to evade host immune attack. .
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http://dx.doi.org/10.1158/2159-8290.CD-16-1022DOI Listing
June 2017

Prognostic significance of KIT exon 11 deletion mutation in intermediate-risk gastrointestinal stromal tumor.

Asia Pac J Clin Oncol 2017 Jun 17;13(3):115-124. Epub 2016 Oct 17.

Department of Medical Oncology, The Canberra Hospital, Garran, Australia.

Aim: Benefit of adjuvant imatinib therapy following curative resection in patients with intermediate-risk gastrointestinal stromal tumor (GIST) is unclear. GIST-specific exon mutations, in particular exon 11 deletions, have been shown to be prognostic. We hypothesize that specific KIT mutations may improve risk stratification in patients with intermediate-risk GIST, identifying a subgroup of patients who may benefit from adjuvant therapy.

Methods: In total, 142 GIST patients with complete clinicopathologic and mutational data from two sites were included. Risk classification was based on the modified National Institute of Health (NIH) criteria.

Results: In this cohort, 74% (n = 105) of patients harbored a KIT mutation; 61% (n = 86) were found in exon 11 of which nearly 70% were KIT exon 11 deletions (n = 60). A total of 18% (n = 25) of cases were classified as having intermediate-risk disease. Univariate analysis confirmed tumor size, mitotic index, nongastric origin, presence of tumor rupture and modified NIH criteria were adversely prognostic for relapse-free survival (RFS). Among KIT/PDGFRA mutants, KIT exon 11 deletions had a significantly worse prognosis (hazard ratio 2.31; 95% confidence interval, 1.30-4.10; P = 0.003). Multivariate analysis confirmed KIT exon 11 deletion (P = 0.003) and clinical risk classification (P < 0.001) as independent adverse prognostic factors for RFS. Intermediate-risk patients harboring KIT exon 11 deletions had RFS outcomes similar to high-risk patients.

Conclusion: The presence of KIT exon 11 deletion mutation in patients with intermediate-risk GIST is associated with an inferior clinical outcome with RFS similar to high-risk patients.
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http://dx.doi.org/10.1111/ajco.12603DOI Listing
June 2017

Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity.

Nat Commun 2016 Sep 28;7:12983. Epub 2016 Sep 28.

Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.

Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments. Somatic gain super-enhancers are associated with complex chromatin interaction profiles, expression patterns correlated with patient outcome and dense co-occupancy of the transcription factors CDX2 and HNF4α. Somatic super-enhancers are also enriched in genetic risk SNPs associated with cancer predisposition. Our results reveal a genome-wide reprogramming of the GC enhancer and super-enhancer landscape during tumorigenesis, contributing to dysregulated local and regional cancer gene expression.
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http://dx.doi.org/10.1038/ncomms12983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052795PMC
September 2016

Laparoscopic wedge resection for suspected large (≥5 cm) gastric gastrointestinal stromal tumors.

Surg Endosc 2017 05 8;31(5):2271-2279. Epub 2016 Sep 8.

Department of Upper Gastrointestinal and Bariatric Surgery, Singapore General Hospital, Singapore, Singapore.

Background: Laparoscopic wedge resection (LWR) for small gastric gastrointestinal stromal tumors (GIST) is now widely accepted, but its application for large GISTs remains controversial. This study aims to evaluate the feasibility and safety of LWR for suspected large (≥5 cm) gastric GISTs.

Methods: Retrospective review of 82 consecutive patients who underwent attempted LWR for suspected gastric GIST. LWR for large (≥5 cm) (n = 23) tumors was compared with LWR for small (<5 cm) tumors (n = 59). The 23 patients with LWR for large tumors were also compared to 36 consecutive patients who underwent open wedge resection (OWR) for large tumors.

Results: Comparison between patients who underwent LWR for large versus small tumors demonstrated that resection of large tumors was associated with a longer operating time. There was no difference in other perioperative outcomes, and oncological outcomes such as frequency of close margins (≤1 mm) and recurrence-free survival. Comparison between patients who underwent LWR versus OWR for large tumors showed that LWR was associated with decreased median time to fluid or solid diet, shorter postoperative stay but longer operating times. There was no difference in oncological outcomes.

Conclusion: LWR for suspected large gastric GIST is feasible and safe. It is associated with similar short-term outcomes with LWR for small tumors and favorable short-term outcomes over OWR for large tumors without compromising on oncological outcomes.
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http://dx.doi.org/10.1007/s00464-016-5229-7DOI Listing
May 2017

Factors associated with and consequences of open conversion after laparoscopic distal pancreatectomy: initial experience at a single institution.

ANZ J Surg 2017 Dec 21;87(12):E271-E275. Epub 2016 Jul 21.

Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital, Singapore.

Background: Laparoscopic distal pancreatectomy (LDP) is increasingly adopted today. This study aims to determine factors associated with and consequences of open conversion after LDP.

Methods: Retrospective review of the first 40 consecutive LDP performed for pancreatic tumors from 2006 to 2015 was performed. Individual surgeon volume was stratified by ≤5 versus >5 cases and institution experience was stratified by two time periods 2006-2010 and 2011-2015.

Results: Two high-volume surgeons performed 19 cases with an average case volume of ≥2/year whereas 10 low-volume surgeons performed 21 cases with an average case volume of <1/year. Median age of patients was 57.6 (range, 21-78) years. LDP was performed for malignancy in four (10%) patients. The median tumor size was 25 (range, 8-75) mm. Eight patients (20%) underwent subtotal pancreatectomies and seven (17.5%) had concomitant surgeries. Eleven (27.5%) LDP were spleen-saving procedures. Ten (25%) procedures were converted to open. Twenty-nine (72.5%) patients experienced 90-day/in-hospital morbidity of which eight (20%) were major (>grade II). There were 24 (60%) pancreatic fistulas of which 10 (25%) were grade B. Univariate analyses demonstrated that splenectomy (10 (34.5%) versus 0, P = 0.025), individual surgeon volume (<5 cases) (8 (38.1%) versus 2 (10.15%), P = 0.044) and institution experience (5 (55.6%) versus 5 (16.1%), P = 0.016) were factors associated with open conversion after LDP. Open conversion was associated with an increased rate of intra-operative blood transfusion (P = 0.053).

Conclusions: Splenectomy, institution experience and individual surgeon volume were the factors associated with open conversion after LDP.
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http://dx.doi.org/10.1111/ans.13661DOI Listing
December 2017

Primary melanoma of the esophagus, a diagnostic challenge.

Asian J Surg 2015 Oct 19;38(4):236-8. Epub 2013 Feb 19.

Department of General Surgery, Singapore General Hospital, Singapore.

Primary melanoma of the esophagus is a rare condition. Its diagnosis can be challenging, as its presentation is similar to that of other esophageal malignancies, especially when melanin is not evidently expressed in the melanoma. We report a case of esophageal melanoma in a 59-year-old Chinese male, whose histological diagnosis was confirmed from the esophagectomy specimen.
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http://dx.doi.org/10.1016/j.asjsur.2012.11.001DOI Listing
October 2015

Abundant copy-number loss of CYCLOPS and STOP genes in gastric adenocarcinoma.

Gastric Cancer 2016 Apr 24;19(2):453-465. Epub 2015 Jul 24.

Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.

Background: Gastric cancer, a leading cause of cancer death worldwide, has been little studied compared with other cancers that impose similar health burdens. Our goal is to assess genomic copy-number loss and the possible functional consequences and therapeutic implications thereof across a large series of gastric adenocarcinomas.

Methods: We used high-density single-nucleotide polymorphism microarrays to determine patterns of copy-number loss and allelic imbalance in 74 gastric adenocarcinomas. We investigated whether suppressor of tumorigenesis and/or proliferation (STOP) genes are associated with genomic copy-number loss. We also analyzed the extent to which copy-number loss affects Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS (CYCLOPS) genes-genes that may be attractive targets for therapeutic inhibition when partially deleted.

Results: The proportion of the genome subject to copy-number loss varies considerably from tumor to tumor, with a median of 5.5 %, and a mean of 12 % (range 0-58.5 %). On average, 91 STOP genes were subject to copy-number loss per tumor (median 35, range 0-452), and STOP genes tended to have lower copy-number compared with the rest of the genes. Furthermore, on average, 1.6 CYCLOPS genes per tumor were both subject to copy-number loss and downregulated, and 51.4 % of the tumors had at least one such gene.

Conclusions: The enrichment of STOP genes in regions of copy-number loss indicates that their deletion may contribute to gastric carcinogenesis. Furthermore, the presence of several deleted and downregulated CYCLOPS genes in some tumors suggests potential therapeutic targets in these tumors.
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http://dx.doi.org/10.1007/s10120-015-0514-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824836PMC
April 2016

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

J Am Coll Surg 2015 Feb 25;220(2):218-24. Epub 2014 Oct 25.

Department of General Surgery, Singapore General Hospital, Singapore.

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.
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http://dx.doi.org/10.1016/j.jamcollsurg.2014.10.010DOI Listing
February 2015

Clinical outcome and cost comparison between laparoscopic and open appendicectomy.

Ann Acad Med Singap 2014 Sep;43(9):464-8

Department of General Surgery, Singapore General Hospital, Singapore.

Introduction: Local data comparing laparoscopic appendicectomy (LA) and open appendicectomy (OA) is lacking. We perform a cost and outcome comparison between LA and OA.

Materials And Methods: A retrospective review of all appendicectomies performed for suspected appendicitis from July 2010 to December 2010 was conducted. Patient demographics, duration of surgery, complication rates, total cost of stay (COS) and length of stay (LOS) were compared between LA and OA.

Results: A total of 198 patients underwent appendicectomy during the duration of study; 82 LA and 116 OA. There were 115 males (58.1%) and 83 females (41.9%). Median age was 33 years. Patients who underwent LA were significantly younger (P <0.001) with a greater proportion of females (P <0.0001) and were more likely to be negative appendicectomies (18.3% vs. 6.9%, P = 0.023). Duration of surgery was significantly longer in LA patients (86 min vs. 74 min, P = 0.003). LOS in the LA group was shorter by 1.3 days compared to OA (2.0 days vs. 3.3 days, P <0.0001). The differences in operative duration and LOS between LA and OA remained significant on multivariate analysis (P = 0.001 and P = 0.008, respectively). The COS (P = 0.359), wound infection rates (P = 0.528) and complication rates (P = 0.131) were not significantly different between the 2 groups.

Conclusion: LA is associated with a shorter LOS while its cost is equivalent to OA. From the perspective of utilisation of healthcare resources, LA appears to be superior.
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September 2014

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

ANZ J Surg 2016 Jun 7;86(6):464-8. Epub 2014 Oct 7.

Department of Upper Gastrointestinal and Bariatric Surgery, Singapore General Hospital, Singapore.

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.
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http://dx.doi.org/10.1111/ans.12866DOI Listing
June 2016

Nanoscale chromatin profiling of gastric adenocarcinoma reveals cancer-associated cryptic promoters and somatically acquired regulatory elements.

Nat Commun 2014 Jul 10;5:4361. Epub 2014 Jul 10.

1] Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore [3] Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore [4] Cellular and Molecular Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.

Chromatin alterations are fundamental hallmarks of cancer. To study chromatin alterations in primary gastric adenocarcinomas, we perform nanoscale chromatin immunoprecipitation sequencing of multiple histone modifications in five gastric cancers and matched normal tissues. We identify hundreds of somatically altered promoters and predicted enhancers. Many cancer-associated promoters localize to genomic sites lacking previously annotated transcription start sites (cryptic promoters), driving expression of nearby genes involved in gastrointestinal cancer, embryonic development and tissue specification. Cancer-associated promoters overlap with embryonic stem cell regions targeted by polycomb repressive complex 2, exhibiting promoter bivalency and DNA methylation loss. We identify somatically acquired elements exhibiting germline allelic biases and non-coding somatic mutations creating new promoters. Our findings demonstrate the feasibility of profiling chromatin from solid tumours with limited tissue to identify regulatory elements, transcriptional patterns and regulatory genetic variants associated with cancer.
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http://dx.doi.org/10.1038/ncomms5361DOI Listing
July 2014

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

ANZ J Surg 2013 Oct 27;83(10):748-52. Epub 2013 Jan 27.

Department of General Surgery, Singapore General Hospital, Singapore.

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.
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http://dx.doi.org/10.1111/ans.12076DOI Listing
October 2013

Giant omental lipoma.

Singapore Med J 2012 Jun;53(6):e131-2

Department of General Surgery, Singapore General Hospital, Singapore.

A 58-year-old Chinese woman presented with deranged liver function tests, which was discovered incidentally during surveillance for statins therapy. Ultrasonography and computed tomography revealed a large lipoma originating from the greater omentum, which was treated with surgical resection. This case is reported due to the rare occurrence of omental lipomas.
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June 2012

Characterization of the human gastric fluid proteome reveals distinct pH-dependent protein profiles: implications for biomarker studies.

J Proteome Res 2011 Oct 22;10(10):4535-46. Epub 2011 Sep 22.

Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre , Singapore.

Gastric fluid is a source of gastric cancer biomarkers. However, very little is known about the normal gastric fluid proteome and its biological variations. In this study, we performed a comprehensive analysis of the human gastric fluid proteome using samples obtained from individuals with benign gastric conditions. Gastric fluid proteins were prefractionated using ultracentrifuge filters (3 kDa cutoff) and analyzed by two-dimensional gel electrophoresis (2-DE) and multidimensional LC-MS/MS. Our 2-DE analysis of 170 gastric fluid samples revealed distinct protein profiles for acidic and neutral samples, highlighting pH effects on protein composition. By 2D LC-MS/MS analysis of pooled samples, we identified 284 and 347 proteins in acidic and neutral samples respectively (FDR ≤1%), of which 265 proteins (72.4%) overlapped. However, unlike neutral samples, most proteins in acidic samples were identified from peptides in the filtrate (i.e., <3 kDa). Consistent with this finding, immunoblot analysis of six potential gastric cancer biomarkers rarely detected full-length proteins in acidic samples. These findings have important implications for biomarker studies because a majority of gastric cancer patients have neutral gastric fluid compared to noncancer controls. Consequently, sample stratification, choice of proteomic approaches, and validation strategy can profoundly affect the interpretation of biomarker findings. These observations should help to refine gastric fluid biomarker studies.
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http://dx.doi.org/10.1021/pr200349zDOI Listing
October 2011

Impact of the introduction of laparoscopic wedge resection as a surgical option for suspected small/medium-sized gastrointestinal stromal tumors of the stomach on perioperative and oncologic outcomes.

World J Surg 2010 Aug;34(8):1847-52

Department of Surgery, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore.

Background: The present study is designed to determine the feasibility and impact of the introduction of laparoscopic wedge resection as a surgical option for the treatment of suspected small/medium-sized (<7 cm) gastric gastrointestinal stromal tumors (GISTs).

Methods: The study involved a retrospective review of 53 consecutive patients who underwent laparoscopic or open wedge resection of a suspected gastric GIST. It was divided into two consecutive time periods wherein laparoscopic resection was a surgical option only in the latter period. Comparisons were made between the outcomes of patients who underwent laparoscopic versus open wedge resection and the outcomes of patients treated during the two consecutive time periods (to determine the impact of the introduction of laparoscopic wedge resection),

Results: Fourteen patients (26%) underwent laparoscopic wedge resection with 1 conversion. The pathological exam showed that 41 patients (77%) had a GIST. Laparoscopic resection was significantly associated with a longer operative time, an earlier return of bowel function, earlier resumption of liquid and solid diet, decreased duration of parenteral or epidural analgesia use, and shorter postoperative hospitalization compared to open resection. There was no statistical difference in the rate of R1 resection and actuarial recurrence-free survival for the two approaches. Comparison between the two time periods demonstrated that the introduction of the laparoscopic approach in the latter period resulted in an earlier return of bowel function, earlier resumption of liquid and solid diet, and decreased duration of parenteral or epidural analgesia.

Conclusions: Laparoscopic wedge resection for gastric GIST can be safely adopted. It is associated with a more favorable perioperative outcome than the open approach. Its introduction as a surgical option has resulted in an improvement in perioperative outcomes without compromising oncologic safety at our institution.
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http://dx.doi.org/10.1007/s00268-010-0590-5DOI Listing
August 2010

Oncogenic pathway combinations predict clinical prognosis in gastric cancer.

PLoS Genet 2009 Oct 2;5(10):e1000676. Epub 2009 Oct 2.

Duke-NUS Graduate Medical School, Singapore.

Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB, and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms.
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http://dx.doi.org/10.1371/journal.pgen.1000676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748685PMC
October 2009

Recurrent giant fibrovascular polyp of the esophagus.

World J Gastroenterol 2009 Aug;15(29):3697-700

Department of General Surgery, Singapore General Hospital, Singapore.

Giant fibrovascular polyps of the esophagus and hypopharynx are rare benign esophageal tumors. They arise most commonly in the upper esophagus and may, rarely, originate in the hypopharynx. They can vary significantly in size. Even though they are benign, they may be lethal due to either bleeding or, rarely, asphyxiation if a large polyp is regurgitated. Patients commonly present with dysphagia or hematemesis. The polyps may not be well visualized on endoscopy and imaging plays a vital role in aiding diagnosis as well as providing important information for pre-operative planning, such as the location of the pedicle, the vascularity of the polyp and the tissue elements of the mass. They can also be recurrent in rare cases, especially if the resection margins of the base are involved. We review the recent literature and report a case of a 61-year-old man with a recurrent giant esophageal fibrovascular polyp with illustrative contrast barium swallow, CT and intra-operative images, who required several surgeries via a combination of endoscopic, trans-oral, trans-cervical, trans-thoracic and trans-abdominal approaches.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721250PMC
http://dx.doi.org/10.3748/wjg.15.3697DOI Listing
August 2009

The distinctive gastric fluid proteome in gastric cancer reveals a multi-biomarker diagnostic profile.

BMC Med Genomics 2008 Oct 25;1:54. Epub 2008 Oct 25.

Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Republic of Singapore.

Background: Overall gastric cancer survival remains poor mainly because there are no reliable methods for identifying highly curable early stage disease. Multi-protein profiling of gastric fluids, obtained from the anatomic site of pathology, could reveal diagnostic proteomic fingerprints.

Methods: Protein profiles were generated from gastric fluid samples of 19 gastric cancer and 36 benign gastritides patients undergoing elective, clinically-indicated gastroscopy using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry on multiple ProteinChip arrays. Proteomic features were compared by significance analysis of microarray algorithm and two-way hierarchical clustering. A second blinded sample set (24 gastric cancers and 29 clinically benign gastritides) was used for validation.

Results: By significance analysyis of microarray, 60 proteomic features were up-regulated and 46 were down-regulated in gastric cancer samples (p < 0.01). Multimarker clustering showed two distinctive proteomic profiles independent of age and ethnicity. Eighteen of 19 cancer samples clustered together (sensitivity 95%) while 27/36 of non-cancer samples clustered in a second group. Nine non-cancer samples that clustered with cancer samples included 5 pre-malignant lesions (1 adenomatous polyp and 4 intestinal metaplasia). Validation using a second sample set showed the sensitivity and specificity to be 88% and 93%, respectively. Positive predictive value of the combined data was 0.80. Selected peptide sequencing identified pepsinogen C and pepsin A activation peptide as significantly down-regulated and alpha-defensin as significantly up-regulated.

Conclusion: This simple and reproducible multimarker proteomic assay could supplement clinical gastroscopic evaluation of symptomatic patients to enhance diagnostic accuracy for gastric cancer and pre-malignant lesions.
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http://dx.doi.org/10.1186/1755-8794-1-54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2584050PMC
October 2008