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The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA.We conducted a randomized controlled trial of CHB patients on NA12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 μg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg)1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg200 IU/mL, qHBsAg100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT).A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P.0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P.001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P.0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy).ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511.

Our objective was to examine differences in cytokine/chemokine response in chronic hepatitis B(CHB) patients to understand the immune mechanism of HBsAg loss (functional cure) during antiviral therapy. We used an unbiased machine learning strategy to unravel the immune pathways in CHB nucleo(t)side analogue-treated patients who achieved HBsAg loss with peg-interferon-α(peg-IFN-α) add-on or switch treatment in a randomised clinical trial. Cytokines/chemokines from plasma were compared between those with/without HBsAg loss, at baseline, before and after HBsAg loss. Peg-IFN-α treatment resulted in higher levels of IL-27, IL-12p70, IL-18, IL-13, IL-4, IL-22 and GM-CSF prior to HBsAg loss. Probabilistic network analysis of cytokines, chemokines and soluble factors suggested a dynamic dendritic cell driven NK and T cell immune response associated with HBsAg loss. Bayesian network analysis showed a dominant myeloid-driven type 1 inflammatory response with a MIG and I-TAC central module contributing to HBsAg loss in the add-on arm. In the switch arm, HBsAg loss was associated with a T cell activation module exemplified by high levels of CD40L suggesting T cell activation. Our findings show that more than one immune pathway to HBsAg loss was found with peg-IFN-α therapy; by myeloid-driven Type 1 response in one instance, and T cell activation in the other.

Detection of pre-neoplastic gastric mucosal changes and early gastric cancer (EGC) by white-light endoscopy (WLE) is often difficult. In this study we investigated whether combined autofluorescence imaging (AFI) and narrow band imaging (NBI) can improve detection of pre-neoplastic lesions and early gastric cancer in high-risk patients.Chinese patients who were 50-years-old or above with dyspepsia were examined by both high-resolution WLE and combined AFI followed by NBI (AFI-NBI), consecutively in a prospective randomized cross-over setting, by two experienced endoscopists. The primary outcome was diagnostic ability of the two methods for patients with pre-neoplastic lesions such as intestinal metaplasia (IM) and mucosal atrophy.Sixty-five patients were recruited. One patient with large advanced gastric cancer was found and excluded from the analysis. Among the remaining 64 patients, 38 (59%) had IM; of these, 26 (68%) were correctly identified by AFI-NBI (sensitivity 68%, specificity 23%) and only 13 (34%) by WLE (sensitivity 34%, specificity 65%). AFI-NBI detected more patients with IM than did WLE (p=0.011). Thirty-one patients (48%) had mucosal atrophy. Ten patients (32%) were identified by AFI-NBI (sensitivity 32%, specificity 79%) and four patients (13%) by WLE (sensitivity 13%, specificity 88%) (p=0.100). No dysplasia or EGC was found.AFI-NBI identified significantly more patients with IM than did WLE. Our result warrants further studies to define the role of combined AFI-NBI endoscopy for detection of precancerous conditions.

Peritoneal recurrence after gastrectomy for gastric cancer is common and the prognosis is dismal. Recent evidence suggests that extensive peritoneal lavage with large volume of normal saline after surgery before abdominal closure can reduce the risk of peritoneal recurrence and improve overall survival. This study aims to evaluate the benefit of extensive intraoperative peritoneal lavage. This is a prospective, open-label, multicentre randomised controlled trial involving 15 international centres in China, Korea, Japan, Malaysia and Singapore. Patients with cT3/4 stomach cancer undergoing curative resection are randomised to either extensive peritoneal lavage (10 l of saline) or standard lavage (≤2 l of saline). The primary outcome is overall survival and secondary outcomes include disease-free survival and peritoneal recurrence. The minimum sample size is 600 subjects with 300 per arm completing 3 years follow-up. The data will be analysed on an intention-to-treat basis, assuming a two-sided test with a 5% level of significance.

Background & Aims It is not clear how the duration of upper endoscopy affects the detection of cancer or premalignant lesions that increase the risk for gastric cancer. We investigated whether the length of time spent performing esophagogastroduodenoscopy (EGD) affects the detection of important pathologic features of the stomach. Methods We collected data from 837 symptomatic patients, during a 3-month period in 2010, who underwent a first diagnostic EGD at a tertiary university hospital in Singapore. Endoscopists were classified as fast or slow based on the mean amount of time it took them to perform a normal EGD examination. We used logistic regression to compare between groups the numbers of intestinal metaplasias, gastric atrophies, dysplasias, and cancers detected, using histologic analysis of biopsy samples collected during endoscopy as the standard. Results Of 224 normal endoscopies, the mean duration was 6.6 minutes (range, 2–32 min). When we used 7 minutes as the cut-off time, 8 endoscopists were considered to have short mean examination times (mean duration, 5.5 ± 2.1 min; referred to as fast endoscopists ), and 8 endoscopists were considered to have long mean examination times (mean duration, 8.6 ± 4.2 min; referred to as slow endoscopists ). Eleven cancers and 81 lesions considered to pose risks for cancer were detected in 86 patients; 1.3% were determined to be cancer, 1.0% were determined to be dysplasia, and 8.7% were determined to be intestinal metaplasia and/or gastric atrophy. Slow endoscopists were twice as likely to detect high-risk lesions as fast endoscopists (odds ratio, 2.50; 95% confidence interval, 1.52–4.12), regardless of whether they were endoscopy staff or trainees. The slow endoscopists also detected 3-fold more neoplastic lesions (cancer or dysplasia; odds ratio, 3.42; 95% confidence interval, 1.25–10.38). Conclusions Endoscopists with mean EGD examination times longer than 7 minutes identified a greater number of high-risk gastric lesions than faster endoscopists. Examination time may be a useful indicator of quality assessment for upper endoscopy. Studies are required to test these findings in different populations.

Diffuse gastric cancer (DGC) is a poorly differentiated adenocarcinoma characterized by infiltration of signet ring cells into the stomach wall and a lack of tumor mass formation. DGC has rapid disease progression with a dismally poor prognosis and is resistant to chemo- and radiotherapy. There is no available targeted therapy, and preclinical models that reliably predict clinical activity of novel compounds are also lacking. In addition, molecular analyses of DGC have been hampered by difficulty in obtaining primary tumors of sufficient tumor cellularity without contaminating normal fibroblasts. To overcome the scarcity of cancer cells and the abundance of surrounding stromal tissue, we isolated cancer cells from malignant ascites of DGC patients. Red blood cells were removed by Ficoll separation and CD45+ hematopoietic cells were depleted using antibody-conjugated magnetic beads. Exome sequencing was performed on cancer cells and peripheral blood cells from the same patient to identify somatic alterations in DGC. We also generated patient-derived xenografts (PDX) using isolated cancer cells to establish preclinical cancer models for DGC. Exome sequencing revealed FGFR2 and KRAS amplifications as well as p53 mutations. Cancer cells isolated from malignant ascites formed subcutaneous tumors that recapitulated the histology of primary DGC tumors with characteristic signet ring cells and intracellular mucin. FGFR2 amplification in PDX tumors was confirmed by fluorescence in situ hybridization (FISH), with correspondingly high levels of FGFR2 transcripts and protein expression. We performed drug treatments on PDX tumors using FGFR2 inhibitor AZD4547 and found that FGFR2 amplification status alone was sufficient to predict the sensitivity of PDX tumors to AZD4547. Tumor volume of FGFR2-amplified tumors decreased or remained the same following AZD4547 treatment compared to vehicle-treated tumors which showed increased tumor volume. In contrast, AZD4547 treatment had little or no effect on tumor growth of non-FGFR2 amplified tumors. Furthermore, these PDX tumors regardless of FGFR2 amplification status responded poorly to cisplatin, a standard drug currently used for treatment of DGC. In conclusion, we report a high prevalence of FGFR2 gene amplification in DGC and the establishment of reliable PDX models that can predict tumor response to targeted therapy. Citation Format: Wen Min Lau, Zhijiang Zang, Eileen Teng, Kakoli Das, Wei Peng Yong, Ming Teh, Tania Chia, Jin Wei Tan, Amy Tay, Asim Shabbir, Koji Kono, Jimmy So, Patrick Tan, Shing Leng Chan. Clinical relevance of FGFR2 amplification in diffuse gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1228. doi:10.1158/1538-7445.AM2014-1228