Publications by authors named "Hock-Soo Ong"

51 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

Characteristics and Outcomes of Airway Involvement in Esophageal Cancer.

Ann Thorac Surg 2020 Nov 5. Epub 2020 Nov 5.

Department of Respiratory and Critical Care Medicine, Singapore General Hospital.

Background: Airway involvement, such as airway invasion, compression, and tracheobronchoesophageal fistula (TOF), in esophageal cancer is associated with significant morbidity. However, the risk factors and outcomes of airway complications remain unclear, with limited evidence to guide management.

Methods: We conducted a retrospective analysis of 804 patients diagnosed with esophageal cancer from 1998 to 2018 at a tertiary-care medical center. Patient demographics, treatment details, airway involvement based on bronchoscopic evaluation and/or CT imaging were recorded and analysed to determine risk factors and outcomes of airway involvement.

Results: The incidence of airway involvement and TOF was 36.6% and 13.1% respectively. Airway involvement was associated with reduced survival from the time of diagnosis (HR 1.52 (95% CI 1.30-1.79) and increased hospitalizations per year (4.53±4.80 versus 2.75±3.68, p<0.001). On multivariate analysis, mid- (OR 11.0 (95% CI 6.3-19.0)) and upper esophageal tumors (OR 8.5 (95% CI 4.7-15.6)), prior treatment with esophageal stenting (OR 17.8 (95% CI 4.1-77.6) and chemo- and/or radiotherapy were associated with development of airway involvement. In patients with TOF, treatment with chemotherapy (OR 0.34 (95% CI 0.20-0.60)) and combined airway and esophageal stenting (OR 0.48 (95% CI 0.25-0.91)) were independently associated with improved survival.

Conclusions: Airway involvement and TOF is common and associated with increased morbidity and poorer survival. Clinicians should remain vigilant for airway complications after treatment with esophageal stenting, chemo- or radiotherapy, especially with mid and upper esophageal cancers. In patients who develop TOFs, improved survival is seen when they are treated with airway stenting, esophageal stenting, or chemotherapy.
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http://dx.doi.org/10.1016/j.athoracsur.2020.10.015DOI Listing
November 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

A Descriptive Study of enteral tube feeding among adults in an acute care tertiary hospital-patient selection, characteristics and complications.

Clin Nutr ESPEN 2020 06 16;37:58-64. Epub 2020 Apr 16.

Division of Nursing, Singapore General Hospital, Singapore. Electronic address:

Background: It is vital to develop a better understanding of the use of different modalities for enteral feeding and its associated complications, given differences in funding support, community resources and infrastructure available to support home enteral feeding in an acute care tertiary hospital.

Aim: To provide a description of the clinical characteristics of patients on long-term enteral feeding and incidence of associated complications.

Methods: A retrospective case records review study design was adopted. Medical records of patients discharged from a tertiary hospital with long-term nasogastric tube (NGT) or percutaneous endoscopic gastrostomy (PEG) feeding for the first time during the period of January 2010 to June 2017 were reviewed. Data collected include patient's demographics, reason for enteral feeding, morbidity and nutritional status upon initiation of NGT and PEG feeding, readmission episodes and documented complications (associated with enteral feeding) within one-year post discharge.

Results: Records of 120 NGT and 118 PEG patients were analysed. Significant age and gender differences were found with older patients being more likely to be placed on NGT [NGT (Mean 79.1, SD 11.3) vs. PEG (Mean 67.1, SD 12.6)] and higher number of females in the NGT group as compared to the PEG group (NGT 59.2% vs. PEG 31.4%). Majority of patients were fed by caregivers in the NGT (99.2%) as compared to the PEG (51.7%) group. Patients with cancer were more likely to be on PEG feeding (NGT 5%, PEG 70.3%), whereas patients with stroke-related diagnoses were more likely to be on NGT feeding (NGT 48% vs. PEG 8.5%). The total Charlson Comorbidity score was also significantly different between the NGT (mean = 5.7; SD = 1.5) and PEG (mean = 4.5; SD = 2.0) groups. A higher number of patients with PEG feeding had no complications (47.5%) as compared to the NGT group (8.3%). Patients who received NGT feeding were more likely experience tube blockage [OR 0.03, 95% CI (0.001-0.72), p = 0.03], secondary displacement of tube [OR 0.04, 95% CI (0.002-0.72), p = 0.03] and accidental tube removal [OR 0.03, 95% CI (0.004-0.21), p < 0.001].

Conclusion: Overall, patients who received NGT feeding experienced more complications than those who had PEG feeding. The choice for NGT or PEG feeding may be influenced by patient related factors as well as the presence of caregivers, which need to be considered in the improvement of enteral nutrition services in the local context.
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http://dx.doi.org/10.1016/j.clnesp.2020.03.021DOI Listing
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

The Use of Bilayered Fascia Lata With an Interpositional Omental Flap for Autologous Repair of Contaminated Abdominal Fascial Defects.

Ann Plast Surg 2017 Nov;79(5):486-489

From the Department of Plastic, Reconstructive, and Aesthetic Surgery, Singapore General Hospital, Singapore.

Introduction: Contaminated abdominal fascial defects, such as those seen in enterocutaneous fistula, or wound dehiscence with mesh exposure, are a significant source of morbidity and present unique reconstructive challenges. We present our technique of using the fascia lata, augmented with an interpositional omental flap, for complete autologous reconstruction of contaminated fascial defects, and the postoperative results of 3 cases.

Methods: Three patients with contaminated abdominal defects underwent wound debridement/fistula resection and immediate reconstruction with fascia lata and omentum flap. Defect size ranged from 15 × 8 cm (120 cm) to 25 × 12 cm (300 cm). The fascia lata graft was inset using an underlay technique, and the omentum was tunneled through a subcostal slit in the semilunar line to augment the vascularity of the subcutaneous plane and protect the graft. Skin coverage was achieved by undermining and direct closure or local myocutaneous flaps.

Results: Three patients underwent abdominal wall reconstruction with our technique. The median follow-up was 12 months. There were no recurrent infections, fistulae, or herniae. All patients experienced full functional recovery with return to independent activities of daily living by 6 months postoperatively.

Conclusions: Since the use of synthetic material is contraindicated in contaminated abdominal fascial defects. We propose that our combination of fascia lata and an interpositional omental flap is a useful technique for the reconstruction of these challenging defects.
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http://dx.doi.org/10.1097/SAP.0000000000001192DOI Listing
November 2017

A Clinical Scoring System to Predict the Clinical Sequelae of Computed Tomography Diagnosed Intussusception.

World J Surg 2018 03;42(3):682-687

Department of Upper Gastrointestinal and Bariatric Surgery, Singapore General Hospital, 20 College Road, Level 5, Singapore, 169856, Singapore.

Introduction: Intussusception in adults is increasingly diagnosed on cross-sectional imaging with a lack of clear recommendations on management. The presence of an underlying lead point is a key to guiding management as its absence can predict spontaneous resolution. We studied adult patients with computed tomography (CT) diagnosed intussusception formulate a clinical scoring system to predict the risk of an underlying lead point.

Methodology: We performed a retrospective review of all adult patients who underwent CT scans of the abdomen and pelvis in our institution between 2001 and 2014. Independent associations of an underlying lead point were derived following multivariable analysis, from which a clinical scoring system was developed.

Results: We studied 140 patients. In multivariable analysis, six factors were found to be independently associated with the presence of an underlying lead point, namely gender, abdominal pain, CT evidence of colonic involvement, CT evidence of a lead point, distal diameter ≥27 mm and minimum wall thickness ≥3 mm. A nine-point clinical scoring system was developed, with a cutoff score of four or higher yielding a sensitivity and specificity of 0.75 and 0.81, respectively.

Conclusion: Our clinical scoring system provides a quantitative tool to predict the likelihood of an underlying lead point in CT-diagnosed intussusception in adults to help guide management.
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http://dx.doi.org/10.1007/s00268-017-4196-zDOI Listing
March 2018

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

Surgical Strategy and Outcomes in Duodenal Gastrointestinal Stromal Tumor.

Ann Surg Oncol 2017 Jan 13;24(1):202-210. Epub 2016 Sep 13.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: The surgical management of duodenal gastrointestinal stromal tumors (DGIST) is poorly characterized. Limited resection may be technically feasible and oncologically safe, but anatomic considerations may compromise the resection margins due to the proximity of critical structures, thereby necessitating more extensive resections such as pancreaticoduodenectomy.

Methods: Patients undergoing surgery for DGIST at two institutions from 1994 to 2014 were identified. Clinicopathologic and survival data were analyzed to compare outcomes in patients treated with limited or radical resection.

Results: Sixty patients underwent surgery for DGIST. Pancreaticoduodenectomy was performed in 38 % while the rest underwent limited resections. The most common type of limited resection was wedge resection and primary closure (49 %) followed by segmental resection with an end-to-end or side-to-side duodenojejunostomy (27 %). The pancreaticoduodenectomy group tended to have larger tumors with the majority located in D2/3 (87 %) and at the mesenteric border (91 %). The pancreaticoduodenectomy group also had significantly greater intraoperative blood loss, longer operative time, longer hospital stay, and higher 90-day morbidity and readmission rates. The 5-year relapse-free survival, recurrence-free survival, and overall survival for the pancreaticoduodenectomy versus limited resection were 81 versus 56 % (p = 0.05), 64 versus 53 % (p = 0.5), and 76 versus 72 % (p = 0.6), respectively. A surgical algorithm based on the location and size of the tumor is proposed.

Conclusions: Limited resection of DGIST is safe, but may be associated with lower 5-year relapse-free survival. Pancreaticoduodenectomy is recommended for selected patients with DGIST when an R0 resection cannot be performed without removing the ampulla or part of the pancreas.
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http://dx.doi.org/10.1245/s10434-016-5565-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199143PMC
January 2017

Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia.

Nat Med 2016 06 2;22(6):666-71. Epub 2016 May 2.

Genome Institute of Singapore, Agency for Science Technology and Research, Singapore.

Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia.
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http://dx.doi.org/10.1038/nm.4093DOI Listing
June 2016

Blood neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios are independent prognostic factors for surgically resected gastrointestinal stromal tumors.

Surgery 2016 Apr 11;159(4):1146-56. Epub 2015 Dec 11.

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

Background: Recent studies have demonstrated that the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are prognostic for various malignancies; however, there are limited data to date demonstrating their usefulness for gastrointestinal stromal tumors (GISTs). The aim of this study was to determine whether NLR and PLR are prognostic for GIST.

Methods: Three hundred patients who underwent operative resection for primary localized GIST with preoperative results for neutrophil, platelet, and lymphocyte counts available were retrospectively reviewed. Optimal cutoff values for high NLR (≥ 3.0) and PLR (≥ 275) in predicting recurrence-free survival (RFS) were determined. Prognostic factors of RFS were determined using univariate and multivariate Cox regression analyses for the 266 patients who did not receive adjuvant imatinib.

Results: On univariate analyses, tumor size, mitotic count, location, and both a high NLR and PLR were significant prognostic indicators of decreased RFS (hazard ratio [HR], 2.89 [95% CI; 1.609-5.179 P < .001] and HR, 3.572 [95% CI, 2.094-6.096; P < .001], respectively). On multivariate analyses, tumor size, mitotic count, tumor location, and both high NLR and PLR were independent prognostic factors of RFS in GIST. Both a high NLR and PLR were significant prognostic factors for GISTs within the National Institutes of Health (NIH) and Armed Forces Institute of Pathology (AFIP) high-risk categories. Addition of NLR or PLR to the NIH or AFIP improved the accuracy of these systems.

Conclusion: High NLR and PLR were independent prognostic factors of RFS in GIST. NLR and PLR would be useful as a preoperative prognostic tool and its incorporation into current prognostication systems improved their accuracy.
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http://dx.doi.org/10.1016/j.surg.2015.10.021DOI Listing
April 2016

SETD2 histone modifier loss in aggressive GI stromal tumours.

Gut 2016 12 3;65(12):1960-1972. Epub 2015 Sep 3.

Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore, Singapore.

Background: GI stromal tumours (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients.

Objectives: We sought to identify genetic alterations associated with high-risk GIST, explore their molecular consequences, and test their utility as prognostic markers.

Designs: Exome sequencing of 18 GISTs was performed (9 patients with high-risk/metastatic and 5 patients with low/intermediate-risk), corresponding to 11 primary and 7 metastatic tumours. Candidate alterations were validated by prevalence screening in an independent patient cohort (n=120). Functional consequences of SETD2 mutations were investigated in primary tissues and cell lines. Transcriptomic profiles for 8 GISTs (4 SETD2 mutated, 4 SETD2 wild type) and DNA methylation profiles for 22 GISTs (10 SETD2 mutated, 12 SETD2 wild type) were analysed. Statistical associations between molecular, clinicopathological factors, and relapse-free survival were determined.

Results: High-risk GISTs harboured increased numbers of somatic mutations compared with low-risk GISTs (25.2 mutations/high-risk cases vs 6.8 mutations/low-risk cases; two sample t test p=3.1×10). Somatic alterations in the SETD2 histone modifier gene occurred in 3 out of 9 high-risk/metastatic cases but no low/intermediate-risk cases. Prevalence screening identified additional SETD2 mutations in 7 out of 80 high-risk/metastatic cases but no low/intermediate-risk cases (n=29). Combined, the frequency of SETD2 mutations was 11.2% (10/89) and 0% (0/34) in high-risk and low-risk GISTs respectively. SETD2 mutant GISTs exhibited decreased H3K36me3 expression while SETD2 silencing promoted DNA damage in GIST-T1 cells. In gastric GISTs, SETD2 mutations were associated with overexpression of HOXC cluster genes and a DNA methylation signature of hypomethylated heterochromatin. Gastric GISTs with SETD2 mutations, or GISTs with hypomethylated heterochromatin, showed significantly shorter relapse-free survival on univariate analysis (log rank p=4.1×10).

Conclusions: Our data suggest that SETD2 is a novel GIST tumour suppressor gene associated with disease progression. Assessing SETD2 genetic status and SETD2-associated epigenomic phenotypes may guide risk stratification and provide insights into mechanisms of GIST clinical aggressiveness.
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http://dx.doi.org/10.1136/gutjnl-2015-309482DOI Listing
December 2016

A Rare Cause of Abdominal Pain. Left Paraduodenal Hernia.

Gastroenterology 2015 Sep 29;149(3):551-2. Epub 2015 Jul 29.

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

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http://dx.doi.org/10.1053/j.gastro.2015.05.047DOI Listing
September 2015

Validation of the MSKCC Gastrointestinal Stromal Tumor Nomogram and Comparison with Other Prognostication Systems: Single-Institution Experience with 289 Patients.

Ann Surg Oncol 2015 Oct 5;22(11):3597-605. Epub 2015 Feb 5.

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

Purpose: To validate the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic nomogram in a single-institution cohort of patients with gastrointestinal stromal tumors (GISTs), and to compare its predictive accuracy against other established risk classification systems, including the National Institutes of Health (NIH), Armed Forces Institute of Pathology (AFIP), and Joensuu criteria.

Methods: We retrospectively reviewed 289 patients who underwent surgical resection for primary localized GISTs without adjuvant imatinib therapy and compared the actuarial recurrence-free survival (RFS) with the predicted RFS.

Results: Tumors >5 cm in size, with high mitotic index, and which had ruptured were significantly associated with recurrent disease. The 2-year RFS was 77.2 % [95 % confidence interval (CI) 71.6-81.8], and the 5-year RFS was 67.9 % (95 % CI 61.7-73.4). The concordance probability of the nomogram of 2-year RFS was 0.71 (SE 0.02), and 5-year RFS was 0.71 (SE 0.19). The 2-year and 5-year MSKCC nomogram probability calculations and the AFIP criteria gave a better estimation of RFS compared to the NIH (p < 0.001) and Joensuu (p < 0.001) criteria. There was no significant difference between the predictive accuracy of the nomogram compared to the AFIP criteria.

Conclusions: The MSKCC nomogram slightly underestimated the probability of RFS after surgical resection of GISTs. It was associated with a significantly better predictive accuracy compared to the NIH and Joensuu. This study suggests that there is a wider than expected prognostic divergence between gastric GISTs versus GISTs arising from the small intestine.
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http://dx.doi.org/10.1245/s10434-015-4400-zDOI Listing
October 2015

Anticoagulation in the treatment of portovenous emboli after cyanoacrylate injection for a bleeding gastric varix.

Singapore Med J 2015 Jan;56(1):e14-6

Department of Anaesthesiology, Academia Level 5, Singapore General Hospital, Outram Road, Singapore 169608.

We herein report the use of endoscopic n-butyl-2-cyanoacrylate injections to obliterate a gastric varix, which led to cyanoacrylate embolisation in the splenic and portal veins in a single patient. Cyanoacrylate embolisation is a known but uncommonly reported complication of endoscopic sclerotherapy. This case report illustrates the successful management of this complication (i.e. cyanoacrylate embolisation in the splenic and portal veins) with anticoagulation and analyses the presentation and management of other cases of cyanoacrylate embolisation reported in the literature.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325574PMC
http://dx.doi.org/10.11622/smedj.2015016DOI Listing
January 2015

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

Characterization of Insulin-Secreting Porcine Bone Marrow Stromal Cells Ex Vivo and Autologous Cell Therapy In Vivo.

Cell Transplant 2015 24;24(7):1205-20. Epub 2014 Mar 24.

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

Cell therapy could potentially meet the need for pancreas and islet transplantations in diabetes mellitus that far exceeds the number of available donors. Bone marrow stromal cells are widely used in clinical trials mainly for their immunomodulatory effects with a record of safety. However, less focus has been paid to developing these cells for insulin secretion by transfection. Although murine models of diabetes have been extensively used in gene and cell therapy research, few studies have shown efficacy in large preclinical animal models. Here we report optimized conditions for ex vivo expansion and characterization of porcine bone marrow stromal cells and their permissive expression of a transfected insulin gene. Our data show that these cells resemble human bone marrow stromal cells in surface antigen expression, are homogeneous, and can be reproducibly isolated from outbred Yorkshire-Landrace pigs. Porcine bone marrow stromal cells were efficiently expanded in vitro to >10(10) cells from 20 ml of bone marrow and remained karyotypically normal during expansion. These cells were electroporated with an insulin expression plasmid vector with high efficiency and viability, and secreted human insulin and C-peptide indicating appropriate processing of proinsulin. We showed that autologous insulin-secreting bone marrow stromal cells implanted and engrafted in the liver of a streptozotocin-diabetic pig that modeled type 1 diabetes resulted in partial, but significant, improvement in hyperglycemia that could not be ascribed to regeneration of endogenous β-cells. Glucose-stimulated insulin secretion in vivo from implanted cells in the treated pig was documented by a rise in serum human C-peptide levels during intravenous glucose tolerance tests. Compared to a sham-treated control pig, this resulted in significantly reduced fasting hyperglycemia, a slower rise in serum fructosamine, and prevented weight loss. Taken together, this study suggests that bone marrow stromal cells merit further development as autologous cell therapy for diabetes.
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http://dx.doi.org/10.3727/096368914X679363DOI Listing
April 2016

A rare case of two synchronous gastric duplication cysts in an adult.

Singapore Med J 2013 Apr;54(4):e91-2

Department of General Surgery, Changi General Hospital, 2, Simei Street 3, Singapore.

This report describes a rare case of two synchronous gastric duplication cysts in a 56-year-old woman. The larger gastric duplication cyst was identified on ultrasonography and computed tomography, whereas the smaller duplication cyst was identified on gastroscopic examination. The patient underwent open surgical excision of the cysts and had an uneventful recovery.
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http://dx.doi.org/10.11622/smedj.2013090DOI Listing
April 2013

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

A rare cause of gastrointestinal haemorrhage: gastric invasion by hepatocellular carcinoma.

J Surg Case Rep 2013 Jan 15;2013(1). Epub 2013 Jan 15.

Department of General Surgery, Singapore General Hospital, Singapore.

Patients with hepatocellular carcinoma (HCC) are predisposed to upper gastrointestinal (GI) haemorrhage with bleeding gastro-oesophageal varices and peptic ulcers being the common aetiologies. On rare occasions, HCC with direct invasion into the upper GI tract can lead to haemorrhage. Recognizing the possibility of invasive HCC causing upper GI haemorrhage is of paramount importance as acute management differs from the usual aetiologies. We describe a 76-year-old lady with long-standing liver cirrhosis who presented with upper GI haemorrhage due to an HCC invading into the greater curvature of the stomach. Trans-arterial embolization was performed which led to successful cessation of bleeding. Direct invasion of the GI tract by HCC causing haemorrhage is an extremely rare condition. Compared with endoscopic therapy, trans-arterial embolization offers the best chance of successful haemostasis and should be considered first-line therapy in these patients.
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http://dx.doi.org/10.1093/jscr/rjs050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579534PMC
January 2013

Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma.

J Hepatol 2012 Mar 23;56(3):595-601. Epub 2011 Oct 23.

Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, Singapore.

Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death. Although sorafenib has been shown to improve survival of patients with advanced HCC, this improvement is modest and patients eventually have refractory disease. This study aims at investigating the antitumor, antiangiogenesis and antimetastatic activities of dovitinib in preclinical models of HCC.

Methods: 21-0208 and SK-HEP1 cells as well as patient-derived HCC models were employed to study the antitumor effect of dovitinib. Changes of biomarkers relevant to FGFR/VEGFR/PDGFR pathways were determined by Western blotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry.

Results: Treatment of SK-HEP1 cells with dovitinib resulted in G2/M cell cycle arrest, inhibition of colony formation in soft agar and blockade of bFGF-induced cell migration. Dovitinib inhibited basal expression and FGF-induced phosphorylation of FGFR-1, FRS2-α and ERK1/2. In vivo, dovitinib potently inhibited tumor growth of six HCC lines. Inhibition of angiogenesis correlated with inactivation of FGFR/PDGFR-β/VEGFR-2 signaling pathways. Dovitinib also caused dephosphorylation of retinoblastoma, upregulation of p-histone H2A-X and p27, and downregulation of p-cdk-2 and cyclin B1, which resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. In an orthotopic model, dovitinib potently inhibited primary tumor growth and lung metastasis and significantly prolonged mouse survival.

Conclusions: Dovitinib demonstrated significant antitumor and antimetastatic activities in HCC xenograft models. This study provides a compelling rationale for clinical investigation in patients with advanced HCC.
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http://dx.doi.org/10.1016/j.jhep.2011.09.017DOI Listing
March 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