A reduction in hospital length of stay reduces costs for colorectal surgery: an economic evaluation of the National Surgical Quality Improvement Program in Singapore.

PURPOSE: In 2017, the National Surgical Quality Improvement Program (NSQIP) was introduced in the Department of Colorectal Surgery at Singapore General Hospital as a pilot quality improvement initiative. This study aimed to examine the cost-effectiveness of NSQIP by evaluating its effects on surgical outcomes, length of stay (LOS), and costs. METHODS: We retrospectively reviewed patients undergoing colorectal surgery (2017-2020). Patients were divided into two cohorts: pre-NSQIP (2017-2018) and post-NSQIP (2019-2020). Outcomes evaluated were 30-day postoperative complications, LOS, and costs. Total cost-savings from NSQIP intervention's impact on LOS were estimated using a decision model with a one-way sensitivity analysis. Multivariate logistic regression was performed to identify factors for prolonged LOS. RESULTS: 1905 patients underwent colorectal surgery, with 996 in the pre-NSQIP cohort and 909 in the post-NSQIP cohort. A significant reduction in overall postoperative complications of 4.7% was observed in the post-NSQIP cohort (36.5% vs. 31.8%, p = 0.029). Patients in the post-NSQIP cohort had a shorter median LOS (8.0 vs. 6.0 days, p < 0.001). The implementation of NSQIP resulted in an 8.5% decrease in prolonged LOS > 6 days (p < 0.001), saving S$0.31 million on LOS. Total costs per case were reduced by 20.8% following NSQIP (S$39,539.05 vs. S$31,311.93, p < 0.001). CONCLUSION: Implementing NSQIP has significantly reduced overall postoperative complications, LOS, and costs and achieved cost savings following colorectal surgery.

Cost-savings of short stay sleeve gastrectomy and walk-in hydration clinic versus conventional inpatient care.

OBJECTIVE: We aim to evaluate the cost-saving of the short stay ward (SSW) versus conventional inpatient care following sleeve gastrectomy (LSG). We also compared the readmission rates pre- and post-inception of the intravenous hydration clinic and analyzed the cost-savings. METHODS: Patients who underwent LSG between December 2021 to March 2022 with SSW care were compared with standard inpatient care. Total costs were analyzed using univariate analysis. With a separate cohort of patients, 30-day readmission rates in the 12-months preceding and following implementation of the IV hydration clinic and associated cost-savings were evaluated. RESULTS: After matching on the propensity score to within ± 0.1, 20-subjects pairs were retained. The total cost per SSW-subject was significantly lower at $13,647.81 compared to $15,565.27 for conventional inpatient care (p = 0.0302). Lower average ward charges ($667.76 vs $1371.34, p < 0.0001), lower average daily treatment fee per case ($235.68 vs $836.54, p < 0.0001), and lower average laboratory investigation fee ($612.31 vs $797.21, p < 0.0001) accounted for the difference in costs between the groups. Thirty-day readmission rate reduced from 8.9 to 1.8% after implementation of the hydration clinic (p < 0.01) with decreased 30-day readmission cost (S$96,955.57 vs. S$5910.27, p < 0.01). CONCLUSION: SSW for LSG is cost-effective and should be preferred to inpatient management. Walk-in hydration clinics significantly reduced readmission rates and result in tremendous cost-savings.

Efficacy of laparoscopic fundoplication in patients with chronic cough and gastro-oesophageal reflux.

BACKGROUND: The outcome of anti-reflux surgery in patients with suspected gastro-oesophageal reflux-induced cough is frequently uncertain. The aims of this study were to assess the efficacy of laparoscopic fundoplication for controlling cough in patients with chronic cough without asthma, who have pathologic gastro-oesophageal reflux, and to identify predictors of response. METHODS: From a prospective database of 1598 patients who have undergone laparoscopic fundoplication, 66 (4%) with proven gastro-oesophageal reflux disease (GORD) and chronic cough without asthma were studied. All patients underwent gastroscopy and 24-h pH monitoring before operation. Heartburn and regurgitation were assessed using a modified DeMeester score. Severity of cough before and after surgery was self-assessed by the patient using a visual analog scale at a minimum of 12 months post-operatively (median 43 mo; range: 14-104 mo). Patients were considered to have responded to fundoplication if they had no cough or the cough had improved by 50% or more after operation. RESULTS: Cough and heartburn/regurgitation were relieved in 61% (40/66) and 90% (44/49) of the patients, respectively. The presence of typical GORD symptoms or oesophagitis, and pH study variables did not predict the response of the cough to fundoplication. CONCLUSION: Refinement in the aetiological diagnosis of chronic cough due to GORD is necessary for improved outcome. Patients diagnosed with GORD-related chronic cough need to be counseled regarding their expectations from anti-reflux surgery.

Natural Orifice Transluminal Endoscopic One-Anastomosis Gastric Bypass: a Feasibility Study Using Human Cadavers.

BACKGROUND: Endoscopic bariatric therapies (EBT) has emerged as an effective treatment in the management of the patient with obesity. Unfortunately, most procedures involve only the restriction of gastric volume without altering the underlying metabolism. The objective of this study was to investigate the practicability and limitations of the metabolic altering procedures: "One anastomosis gastric bypass (OAGB)" with "natural orifice transluminal endoscopic surgery (NOTES)" on human cadavers. METHODS: We performed OAGB with NOTES approach in 3 human cadavers. The steps of the procedure can be divided as follows: step 1, endoscopic sleeve gastroplasty (ESG); step 2, trans-gastric access to peritoneal cavity; step 3, identification of suitable loop of jejunum; step 4, introduction of the jejunal loop into the stomach; step 5, creation of the gastro-jejunostomy with lumen-apposing metal stent (LAMS); step 6, gastric pylorus occlusion with overstitch. RESULTS: We performed OAGB with NOTES in 3 human cadavers with bypassed bilio-pancreatic limb of 55, 75, and 105 cm from the pylorus. The average weight for the cadavers was 64.9 kg (61.2-71.7 kg). The mean procedure time was 157 min. The optimal bypassed length for the procedure was 105 cm. CONCLUSIONS: This study has provided proof-of-principle in a pre-clinical cadaveric model that NOTES approach can be used to perform OAGB and, therefore, merits additional evaluation and consideration in surviving porcine model.

Academy of Medicine, Singapore clinical guideline on endoscopic surveillance and management of gastric premalignant lesions.

Gastric cancer (GC) has a good prognosis, if detected at an early stage. The intestinal subtype of GC follows a stepwise progression to carcinoma, which is treatable with early detection and intervention using high-quality endoscopy. Premalignant lesions and gastric epithelial polyps are commonly encountered in clinical practice. Surveillance of patients with premalignant gastric lesions may aid in early diagnosis of GC, and thus improve chances of survival. An expert professional workgroup was formed to summarise the current evidence and provide recommendations on the management of patients with gastric premalignant lesions in Singapore. Twenty-five recommendations were made to address screening and surveillance, strategies for detection and management of gastric premalignant lesions, management of gastric epithelial polyps, and pathological reporting of gastric premalignant lesions.

Centile Charts for Monitoring of Weight Loss Trajectories After Bariatric Surgery in Asian Patients.

BACKGROUND: Following bariatric surgery, accurate charting of weight loss and regain is crucial. Various preoperative factors affect postoperative weight loss, including age, sex, ethnicity, and surgical type. These are not considered by current weight loss metrics, limiting comparison of weight loss outcomes between patients or centers and across time. METHODS: Patients (n=1022) who underwent sleeve gastrectomy (n=809) and gastric bypass (n=213) from 2008 to 2020 in a single center were reviewed. Weight loss outcomes (% total weight loss) were measured for 60 months postoperatively. Longitudinal centile lines were plotted using the post-estimation predictions of quantile regression models, adjusted for type of procedure, sex, ethnicity, and baseline BMI. RESULTS: Median regression showed that %TWL was 1.0% greater among males than females (ß = +1.1, 95% CI: +0.6 to +1.7, P = <0.0001). Participants who underwent SG had less %TWL compared to GB (ß = -1.3, 95% CI: -1.9 to -0.8, P < 0.0001). There was a trend towards less %TWL among the Indian and Malay participants compared to Chinese. Age and diabetes were not significant predictors. Reference centile charts were produced for the overall cohort, as well as specific charts adjusted for type of bariatric procedure, sex, ethnicity, and baseline BMI. CONCLUSION: Centile charts provide a clinically relevant method for monitoring of weight trajectories postoperatively and aid in realistic and personalised goal setting, and the early identification of "poor responders". This is the first study to present post-bariatric surgery centile charts for an Asian cohort.

Natural orifice transluminal endoscopic one-anastomosis gastric bypass: a feasibility study using porcine model.

INTRODUCTION: Endoscopic bariatric therapies (EBT) are emerging as effective therapies in the management of overweight patient with or without metabolic syndrome. Unfortunately most procedures only restrict the gastric volume without altering the underlying metabolism which is seen in surgical patients. The aim of this study was to investigate the feasibility and limitations of a natural orifice trans-luminal endoscopic surgery (NOTES) one anastomosis gastric bypass (OAGB). METHODS: NOTES OAGB was performed in three porcine models. The steps of the procedure can be divide as follows: (1) Endoscopic sleeve gastroplasty. (2) Trans-gastric access to peritoneal cavity. (3) Identification of a loop of jejunum. (4) Introduction of the jejunal loop into the stomach. (5) Creation of the gastro-jejunostomy with lumen-apposing metal stent (LAMS). (6) Closure of gastric pylorus with overstitch system. RESULTS: All the animals underwent successful NOTES of OAGB. The mean weight for the animals was 34.3 kg (32-37 kg). The mean procedure time was 250 min (300 min for first animal and 180 min for third animal). The average bypassed bilio-pancreatic limb was 98 cm (range 65-130 cm). CONCLUSIONS: This study has provided proof-of-principle in a preclinical model that a NOTES approach can be used to perform OAGB and, therefore, merits additional evaluation and consideration.

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

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; I2 = 50%). The ET with TAE group had a lower 30-day mortality rate (OR, 0.28; 95% CI, 0.10-0.83; P = .02; I2 = 58%). There was no difference in pooled reintervention rates (OR, 0.68; 95% CI, 0.43-1.08; P = .10; I2 = 0%) and length of hospitalization (mean difference, -0.32; 95% CI, -1.88 to 1.24; P = .69; I2 = 0%). Technical success rate of prophylactic TAE was 90.5% (95% CI, 83.09-97.98; I2 = 75.9%). Pooled proportion of overall complication rate was 0.18% (95% CI, 0.00-1.28; I2 = 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.

Characteristics and Outcomes of Airway Involvement in Esophageal Cancer.

BACKGROUND: Airway involvement, such as airway invasion, compression, and tracheobronchoesophageal fistula (TEF), 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: This retrospective analysis included 804 patients with a diagnosis of esophageal cancer from 1998 to 2018 at a tertiary care medical center (Singapore General Hospital, Singapore). Patients' demographics, treatment details, and airway involvement, as determined by bronchoscopic evaluation or computed tomographic imaging, were recorded and analyzed to determine risk factors and outcomes of airway involvement. RESULTS: The incidence of airway involvement and TEF was 36.6% and 13.1%, respectively. Airway involvement was associated with reduced survival from the time of diagnosis (hazard ratio, 1.52; 95% confidence interval [CI], 1.30 to 1.79) and increased hospitalizations per year (4.53 ± 4.80 vs 2.75 ± 3.68; P < .001). On multivariate analysis, midesophageal tumors (odds ratio [OR], 11.0; 95% CI, 6.3 to 19.0) and upper esophageal tumors (OR, 8.5; 95% CI, 4.7 to 15.6), previous treatment with esophageal stenting (OR, 17.8; 95% CI, 4.1 to 77.6), and chemotherapy or radiotherapy were associated with development of airway involvement. In patients with TEF, treatment with chemotherapy (OR, 0.34; 95% CI, 0.20 to 0.60) and combined airway and esophageal stenting (OR, 0.48; 95% CI, 0.25 to 0.91) were independently associated with improved survival. CONCLUSIONS: Airway involvement and TEF are common and are associated with increased morbidity and poorer survival. Clinicians should remain vigilant for airway complications after treatment with esophageal stenting, chemotherapy, or radiotherapy, especially in patients with midesophageal and upper esophageal cancers. In patients with TEFs, survival is improved when they are treated with airway stenting, esophageal stenting, or chemotherapy.

Associations of Bariatric Interventions With Micronutrient and Endocrine Disturbances.

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.

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

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).

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

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.

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

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 (PTBP1, ESRP2 and MBNL1). 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.

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

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.

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

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.

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

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 (RASA3). Somatic promoter-associated N-terminal peptides displaying relative depletion in tumors exhibited high-affinity MHC binding predictions and elicited potent T-cell responses in vitro, 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.Significance: 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. Cancer Discov; 7(6); 630-51. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.

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

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.

Surgical Strategy and Outcomes in Duodenal Gastrointestinal Stromal Tumor.

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.

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

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.

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

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.