RNA expression of 6 genes from metastatic mucosal gastric cancer serves as the global prognostic marker for gastric cancer with functional validation.

BACKGROUND: Molecular analysis of advanced tumors can increase tumor heterogeneity and selection bias. We developed a robust prognostic signature for gastric cancer by comparing RNA expression between very rare early gastric cancers invading only mucosal layer (mEGCs) with lymph node metastasis (Npos) and those without metastasis (Nneg). METHODS: Out of 1003 mEGCs, all Npos were matched to Nneg using propensity scores. Machine learning approach comparing Npos and Nneg was used to develop prognostic signature. The function and robustness of prognostic signature was validated using cell lines and external datasets. RESULTS: Extensive machine learning with cross-validation identified the prognostic classifier consisting of four overexpressed genes (HDAC5, NPM1, DTX3, and PPP3R1) and two downregulated genes (MED12 and TP53), and enabled us to develop the risk score predicting poor prognosis. Cell lines engineered to high-risk score showed increased invasion, migration, and resistance to 5-FU and Oxaliplatin but maintained sensitivity to an HDAC inhibitor. Mouse models after tail vein injection of cell lines with high-risk score revealed increased metastasis. In three external cohorts, our risk score was identified as the independent prognostic factor for overall and recurrence-free survival. CONCLUSION: The risk score from the 6-gene classifier can successfully predict the prognosis of gastric cancer.

Distinctive Phenotypic and Microenvironmental Characteristics of Neuroendocrine Carcinoma and Adenocarcinoma Components in Gastric Mixed Adenoneuroendocrine Carcinoma.

This study aimed to conduct an in-depth examination of gene expression and microenvironmental profiles of gastric neuroendocrine carcinoma (NEC) and mixed adeno-NEC (MANEC). Tissue microarrays from 55 patients with gastric MANEC (N = 32) or NEC (N = 23) were analyzed using digital spatial profiling (GeoMx DSP, NanoString Technologies). Representative regions of interest were selected from the adenocarcinoma (ADC) portion (ADC-MANEC) and the NEC portion (NEC-MANEC) of the MANEC cores, and pure NEC (pNEC) cores. All regions of interest were separated into epithelial components and stromal components using the masking procedure in the GeoMx platform, followed by transcriptome analysis. Comparison of gene expression between ADC-MANEC and NEC-MANEC/pNEC identified several differentially expressed genes in the epithelial (including PEG10, MAP1B, STMN3, and AKT3) and stromal (FN1, COL1A1, SPARC, and BGN) components. Gene set enrichment analysis revealed that pathways related to the E2F target and G2M checkpoint were more enriched in NEC-MANEC and pNEC than in ADC-MANEC. Deconvolution analysis showed that the microenvironmental profile varied according to histologic differentiation. In ADC-MANEC, intraepithelial infiltrating immune cells were relatively more numerous, whereas fibroblasts in the stroma were more abundant in NEC-MANEC and pNEC. This study confirmed the distinct expression profile of each histologic component of MANEC according to its tumor vs stromal compartment using the DSP platform. Although each component of MANEC shares the same genetic origin, distinctive phenotypes should not be overlooked when managing patients with MANEC. This study provides a useful validation data set for future studies.

Safety and feasibility of single-incision laparoscopic distal gastrectomy in overweight and obese gastric cancer patients: a propensity score-matched analysis.

BACKGROUND: The technical challenges and safety concerns of single-incision laparoscopic gastrectomy for overweight and obese gastric cancer patients remain unclear. This study aimed to evaluate the safety and feasibility of single-incision laparoscopic distal gastrectomy (SIDG) compared to multiport laparoscopic distal gastrectomy (MLDG) in overweight and obese gastric cancer patients. METHODS: This study retrospectively analyzed overweight and obese patients (body mass index ≥ 25 kg/m2) and pathologic stage T1 primary gastric adenocarcinoma treated with either SIDG or MLDG. The SIDG and MLDG groups were propensity score matched at a 1:2 ratio using age, sex, height, body weight, American Society of Anesthesiologists classification, year of surgery, pathologic N stage, and anastomosis method as covariates. RESULTS: After 1:2 matching, the study included patients who underwent SIDG (n = 179) and MLDG (n = 358). No significant difference in the number of retrieved lymph nodes was found between the SIDG and MLDG groups (52.8 ± 19.3 vs. 53.9 ± 21.0, P = 0.56). Operation times were significantly shorter in the SIDG group (170.8 ± 60.0 min vs. 186.1 ± 52.6 min, P = 0.004). The postoperative hospital length of stay was comparable between the 2 groups (SIDG: 5.9 ± 3.4 days vs. MLDG: 6.3 ± 5.1 days, P = 0.23), as was postoperative complication rate (SIDG: 13.4% vs. MLDG: 12.8%, P = 0.89). CONCLUSIONS: SIDG was shown to be as safe and feasible as MLDG for overweight and obese gastric cancer patients, with comparable early postoperative complication rates without compromising operation time compared to MLDG.

Sex-dependent different clinicopathological characterization of Epstein-Barr virus-associated gastric carcinoma: a large-scale study.

BACKGROUND: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5-16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea. METHODS: A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV-ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed. RESULTS: A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan-Meier survival curve. However, this effect was evident only in males. CONCLUSIONS: EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females.

Single-port intragastric wedge resection using the tunnel method: a novel surgical approach for treating endophytic gastric subepithelial tumors.

BACKGROUND: Intragastric wedge resection is an effective method for treating endophytic gastric subepithelial tumors (SETs). However, retracting the stomach wall to the umbilicus is difficult in certain patients. In response, we developed a novel surgical technique for single-port intragastric wedge resection, which we termed the "tunnel method." METHODS: A transumbilical incision is made, and a wound retractor is applied. After diagnostic laparoscopy, a gastrostomy is made on the greater curvature, lower body. Another small wound retractor is inserted into the gastrostomy, and extracted through the transumbilical incision, creating a tunnel from the gastrostomy site to the umbilicus. Articulating laparoscopic instruments are inserted via the tunnel, and intragastric wedge resection is performed. We collected and analyzed the clinicopathologic and operative data of patients who underwent intragastric wedge resection via the tunnel method. RESULTS: Twenty-seven patients who underwent single-port intragastric wedge resection via the tunnel method in a single tertiary referral hospital were included in this study. The mean age of the patients was 54.6 ± 11.4 years, body mass index was 26.5 ± 3.4 kg/m2. Twenty-four (88.9%) patients had tumors located in the upper third of the stomach. The average operative time was 65.0 ± 24.2 min. None of the patients experienced Clavien-Dindo grade IIIa or higher postoperative complications. The average postoperative hospital stay length was 2.5 ± 0.8 days. Thirteen gastrointestinal stromal tumors, nine leiomyomas, and one neuroendocrine carcinoma, schwannoma, lipoma, spindle cell proliferative lesion, and fibrotic lesion were pathologically diagnosed. The average tumor size was 2.6 ± 1.3 cm. All cases had negative resection margins. CONCLUSIONS: Single-port intragastric wedge resection by the tunnel method is a feasible and safe approach for treating endophytic gastric SETs.

KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis.

Our previous work showed that KRAS activation in gastric cancer cells leads to activation of an epithelial-to-mesenchymal transition (EMT) program and generation of cancer stem-like cells (CSCs). Here we analyze how this KRAS activation in gastric CSCs promotes tumor angiogenesis and metastasis. Gastric cancer CSCs were found to secrete pro-angiogenic factors such as vascular endothelial growth factor A (VEGF-A), and inhibition of KRAS markedly reduced secretion of these factors. In a genetically engineered mouse model, gastric tumorigenesis was markedly attenuated when both KRAS and VEGF-A signaling were blocked. In orthotropic implant and experimental metastasis models, silencing of KRAS and VEGF-A using shRNA in gastric CSCs abrogated primary tumor formation, lymph node metastasis, and lung metastasis far greater than individual silencing of KRAS or VEGF-A. Analysis of gastric cancer patient samples using RNA sequencing revealed a clear association between high expression of the gastric CSC marker CD44 and expression of both KRAS and VEGF-A, and high CD44 and VEGF-A expression predicted worse overall survival. In conclusion, KRAS activation in gastric CSCs enhances secretion of pro-angiogenic factors and promotes tumor progression and metastasis.

Comparison of perioperative outcomes between bipolar sealing, ultrasonic shears and a hybrid device during laparoscopic gastrectomy for early gastric cancer: a prospective, multicenter, randomized study.

BACKGROUND: Although EBDs are essential for minimally invasive surgery, well-established prospective randomized studies comparing EBDs are scarce. This study aimed to compare the intraoperative inflammatory response and short-term surgical outcomes among different energy-based devices (EBDs) in laparoscopic distal gastrectomy (LDG). METHODS: Patients with clinical stage I gastric cancer scheduled for LDG at two different medical centers were prospectively randomized into three groups: ultrasonic shears (US), advanced bipolar (BP) and ultrasonic-bipolar hybrid (HB). The C-reactive protein (CRP) level, operation time, intraoperative blood loss (IBL), laboratory tests, cytokines (interleukin (IL)-6 and IL-10), hospital stay, and complication rate were analyzed. A novel semiquantitative measurement method using indocyanine green (ICG) and a near-infrared camera measured the amount of lymphatic leakage. RESULTS: The primary endpoint, the CRP level, was significantly lower in the BP (n = 60) group than in the US (n = 57) or HB (n = 57) group [9.03 ± 5.55 vs. 11.12 ± 5.02 vs. 12.67 ± 6.14, p = 0.001, on postoperative day (POD) 2 and 7.48 vs. 9.62 vs. 9.48, p = 0.026, on POD 4]. IBL was significantly lower in BP than in US or HB (26.3 ± 25.3 vs. 43.7 ± 42.0 vs. 34.9 ± 37.0, p = 0.032). Jackson-Pratt drainage triglycerides were significantly lower in BP than in US (53.6 ± 33.7 vs. 84.2 ± 59.0, p = 0.11; HB: 71.3 ± 51.4). ICG fluorescence intensity, operation time, laboratory results, cytokines, hospital stay, and complication rate were not significantly different among the 3 groups. CONCLUSION: BP showed a lower postoperative CRP level and less IBL than US and HB, suggesting less collateral thermal damage and better sealing function. Surgeons may consider this when selecting EBDs for laparoscopic surgery.

Postoperative pain and quality of life after single-incision distal gastrectomy versus multiport laparoscopic distal gastrectomy for early gastric cancer - a randomized controlled trial.

BACKGROUND: Although it has been more than ten years since its first introduction, single-incision distal gastrectomy (SIDG) still lacks solid evidence and there are also no reports on patient quality of life (QOL). This study evaluates the postoperative outcomes and patient QOL of SIDG compared to multiport laparoscopic distal gastrectomy (MLDG). METHODS: This study was designed as a prospective phase II randomized controlled study. Patients diagnosed with early gastric cancer in the distal 2/3rd of the stomach were randomized to either multiport or single-port group. Primary endpoint was pain using the visual analogue scale on postoperative day (POD) 1. Other outcomes include operative data, complications, and patient QOL using the EORTC C30 and STO22 modules. RESULTS: A total of 43 patients in the SIDG group and 40 patients in the MLDG group were enrolled from September 2017 to February 2020. Mean operation time was 154.3 ± 53.3 min in the MLDG group and 148.9 ± 50.1 min in the SIDG group (p = 0.631). There was no difference in POD1 pain scores between the two groups (MLDG = 4.0 ± 1.3, SIDG = 4.3 ± 1.3, p = 0.372). Mean hospital stay was 5.5 (range 4-12) days in the MLDG group and 5 (range 4-17) days in the SIDG group (p = 0.993). There was no statistical significance in postoperative QOL scores. CONCLUSION: Unlike previous reports, there was no difference in POD1 pain scores between SIDG and MLDG. Nevertheless, SIDG did not increase short-term morbidity compared to MLDG and had similar outcomes in QOL.

Feasibility and safety of pure single-incision laparoscopic total and proximal gastrectomy for early gastric cancer: propensity score-matched comparison to multiport totally laparoscopic approach.

BACKGROUND: There have been few studies regarding the feasibility and safety of pure single-incision laparoscopic total gastrectomy (SITG) or proximal gastrectomy (SIPG) for early gastric cancer (EGC). The purpose of this study was to analyze the surgical outcome of all consecutive SITG or SIPG cases compared with multiport laparoscopic total gastrectomy (MLTG) or proximal gastrectomy (MLPG) for EGC. METHODS: We analyzed all consecutive SITG or SIPG cases with double-tract reconstruction for ECG, including the initial case, between March 2013 and December 2021. SITG/SIPG was performed on patients without significant systemic comorbidities through a 3-4 cm vertical transumbilical incision. SITG/SIPG was matched to multiport laparoscopic total or proximal gastrectomy (MLTG/MLPG) cases performed in the same period using a 1:3 propensity score matching, including sex, body mass index (BMI), age and type of resection, year of operation, and institution as covariates. We compared perioperative clinicopathological characteristics and early postoperative morbidity within 1 month after surgery between the SITG/SIPG and MLTG/MLPG groups. RESULTS: In total, 21 patients with SITG and 15 patients with SIPG were compared with those with MLTG (n = 264) and MLPG (n = 220). No conversion to an open or multiport approach occurred in the SITG/SIPG group. After matching, operation time was similar between SITG/SIPG and MLTG/MLPG (223.9 ± 63.5 min vs 234.8 ± 68.7 min, P = 0.402). Length of stay was not significantly different between SITG/SIPG and MLTG/MLPG (11.9 ± 15.4 days vs 8.4 ± 5.0 days, P = 0.210). The average number of retrieved lymph nodes was not significantly different between SITG and MLTG (53.1 ± 16.3 vs 63.2 ± 27.5, P = 0.115), but it was significantly higher in SIPG than MLPG (59.6 ± 27.2 vs 46.0 ± 19.7, P = 0.040). The overall complication rate (30.6% vs 25.9%, P = 0.666) and Clavien-Dindo grade III or higher complication rates (13.9% vs 6.5%, P = 0.175) were not significantly different between the SITG/SIPG and MLTG/MLPG groups. CONCLUSION: Cautious adoption of SITG/SIPG procedures for EGC is feasible and safe.

Comprehensive Molecular Characterization of Adenocarcinoma of the Gastroesophageal Junction Between Esophageal and Gastric Adenocarcinomas.

OBJECTIVE: To investigate the molecular characteristics of AGEJ compared with EAC and gastric adenocarcinoma. SUMMARY OF BACKGROUND DATA: Classification of AGEJ based on differential molecular characteristics between EAC and gastric adenocarcinoma has been long-standing controversy but rarely conducted due to anatomical ambiguity and epidemiologic difference. METHODS: The molecular classification model with Bayesian compound covariate predictor was developed based on differential mRNA expression of EAC (N = 78) and GCFB (N = 102) from the Cancer Genome Atlas (TCGA) cohort. AGEJ/cardia (N = 48) in TCGA cohort and AGEJ/upper third GC (N = 46 pairs) in Seoul National University cohort were classified into the EAC-like or GCFB-like groups whose genomic, transcriptomic, and proteomic characteristics were compared. RESULTS: AGEJ in both cohorts was similarly classified as EAC-like (31.2%) or GCFB-like (68.8%) based on the 400-gene classifier. The GCFB-like group showed significantly activated phosphoinositide 3-kinase-AKT signaling with decreased expression of ERBB2. The EAC-like group presented significantly different alternative splicing including the skipped exon of RPS24, a significantly higher copy number amplification including ERBB2 amplification, and increased protein expression of ERBB2 and EGFR compared with GCFB-like group. High-throughput 3D drug test using independent cell lines revealed that the EAC-like group showed a significantly better response to lapatinib than the GCFB-like group (P = 0.015). CONCLUSIONS: AGEJ was the combined entity of the EAC-like and GCFB-like groups with consistently different molecular characteristics in both Seoul National University and TCGA cohorts. The EAC-like group with a high Bayesian compound covariate predictor score could be effectively targeted by dual inhibition of ERBB2 and EGFR.

Safety and Efficacy of Intraperitoneal Paclitaxel Plus Intravenous Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) for Gastric Cancer with Peritoneal Metastasis.

BACKGROUND: Peritoneal metastasis (PM) remains a major obstacle in the treatment of stage IV gastric cancer. This is a dose-escalation study of intraperitoneal (IP) paclitaxel combined with intravenous (IV) fluorouracil, leucovorin, and oxaliplatin (FOLFOX) to determine the recommended phase II dose in gastric cancer patients. METHODS: Patients with gastric adenocarcinoma and PM were enrolled. The recommended phase II dose of IP paclitaxel was determined using the standard "3 + 3" dose escalation with planned doses ranging from 40 to 100 mg/m2. IV FOLFOX was administered on the same day (oxaliplatin 100 mg/m2 (day 1), leucovorin 100 mg/m2 (day 1), fluorouracil 2,400 mg/m2 over 46 hours (day 1)). Both IP and IV regimens were repeated every 2 weeks. RESULTS: Among the 13 patients, there was no DLT at 40 and 60 mg/m2. Two patients had grade 3 febrile neutropenia at 80 mg/m2, and the recommended phase II dose was 60 mg/m2. Other patients underwent IP paclitaxel and FOLFOX without serious adverse events. Seven patients underwent second-look diagnostic laparoscopy, and the average change in PCI score was -7.0 ± 9.7. Conversion surgery rate was 23.1% (n = 3). The median overall survival was 16.6 months (95% confidence interval, 16.6-N/A), and progression-free survival was 9.6 months (95% confidence interval, 4.7-N/A). All adverse events were tolerable and manageable. CONCLUSIONS: The biweekly regimen of IP paclitaxel and FOLFOX is safe and the recommended dose of IP paclitaxel for a phase II trial is 60 mg/m2.

Glucose metabolic profiles evaluated by PET associated with molecular characteristic landscape of gastric cancer.

BACKGROUND: Although FDG-PET is widely used in cancer, its role in gastric cancer (GC) is still controversial due to variable [18F]fluorodeoxyglucose ([18F]FDG) uptake. Here, we sought to develop a genetic signature to predict high FDG-avid GC to plan individualized PET and investigate the molecular landscape of GC and its association with glucose metabolic profiles noninvasively evaluated by [18F]FDG-PET. METHODS: Based on a genetic signature, PETscore, representing [18F]FDG avidity, was developed by imaging data acquired from thirty patient-derived xenografts (PDX). The PETscore was validated by [18F]FDG-PET data and gene expression data of human GC. The PETscore was associated with genomic and transcriptomic profiles of GC using The Cancer Genome Atlas. RESULTS: Five genes, PLS1, PYY, HBQ1, SLC6A5, and NAT16, were identified for the predictive model for [18F]FDG uptake of GC. The PETscore was validated in independent PET data of human GC with qRT-PCR and RNA-sequencing. By applying PETscore on TCGA, a significant association between glucose uptake and tumor mutational burden as well as genomic alterations were identified. CONCLUSION: Our findings suggest that molecular characteristics are underlying the diverse metabolic profiles of GC. Diverse glucose metabolic profiles may apply to precise diagnostic and therapeutic approaches for GC.

Should total omentectomy be performed for advanced gastric cancer?: The role of omentectomy during laparoscopic gastrectomy for advanced gastric cancer.

BACKGROUND: In the era of minimally invasive surgery, laparoscopic partial omentectomy (LPO) has seen widespread use as a curative surgical procedure for early gastric cancer. However, scientific evidence of the extent of omentectomy during laparoscopic gastrectomy remains unclear for advanced gastric cancer (AGC). METHODS: We analyzed 666 eligible patients who underwent laparoscopic gastrectomy for AGC with curative intent between 2014 and 2018. Surgical outcome and postoperative prognosis were compared between LPO and laparoscopic total omentectomy (LTO) groups after 2:1 propensity score matching with age, sex, body mass index, tumor size, pT stage, pN stage, gastrectomy type, and clinical T stage as covariates. RESULTS: After extensive matching, there was no significant difference in pathologic or clinical stages between the LPO (n = 254) and LTO (n = 177) groups. LPO provided a significantly shorter operation time than LTO (199.2 ± 64.8 vs. 248.1 ± 68.3 min, P < 0.001). Pulmonary complication within postoperative 30 days was significantly lower in the LPO group (4.4 vs. 10.3%, P = 0.018). In multivariate analysis, LTO was the independent risk factor for pulmonary complication (odds ratio [OR] 2.53, 95% confidence interval [95% CI] 1.12-5.73, P = 0.025), which became more obvious in patients with a Charlson's comorbidity index of 4 or higher (OR 27.43, 95% CI 1.35-558.34, P = 0.031). The 5-year overall survival rate (OS) and 3-year recurrence-free survival (RFS) rates were not significantly different between the two groups, even after stage stratification. CONCLUSION: LPO provided significantly shorter operation time and less pulmonary complication than LTO without compromising 5-year OS and 3-year RFS for AGC. LTO was the independent risk factor for pulmonary complications, which became more evident in patients with severe comorbidities.

Postoperative morbidity and quality of life between totally laparoscopic total gastrectomy and laparoscopy-assisted total gastrectomy: a propensity-score matched analysis.

BACKGROUND: This study aimed to evaluate the surgical outcome and quality of life (QoL) of totally laparoscopic total gastrectomy (TLTG) compared with laparoscopy-assisted total gastrectomy (LATG) in patients with clinical stage I gastric cancer. METHODS: From 2012 to 2018, EGC patients who underwent TLTG (n = 223), including the first case with intracorporeal hemi-double stapling, were matched to those who underwent LATG (n = 114) with extracorporeal circular stapling, using 2:1 propensity score matching (PSM). Prospectively collected morbidity was compared between the TLTG and LATG groups in conjunction with the learning curve. The European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaires QLQ-C30, STO22, and OG25 were prospectively surveyed during postoperative 1 year for patient subgroups. RESULTS: After PSM, grade I pulmonary complication rate was lower in the TLTG group (n = 213) than in the LATG group (n = 111) (0.5% vs. 5.4%, P = 0.007). Other complications were not different between the groups. The learning curve of TLTG was overcome at the 26th case in terms of the comprehensive complication index. The TLTG group after learning curve showed lower grade I pulmonary complication rate than the matched LATG group (0.5% vs. 4.7%, P = 0.024). Regarding postoperative QoL, the TLTG group (n = 63) revealed less dysphagia (P = 0.028), pain (P = 0.028), eating restriction (P = 0.006), eating (P = 0.004), odynophagia (P = 0.023) than the LATG group (n = 21). Multivariate analyses for each QoL item demonstrated that TLTG was the only common independent factor for better QoL. CONCLUSIONS: TLTG reduced grade I pulmonary complications and provided better QoL in dysphagia, pain, eating, odynophagia than LATG for patients with clinical stage I gastric cancer.

A novel treatment strategy for lapatinib resistance in a subset of HER2-amplified gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 13-23% of all GC cases and patients with HER2 overexpression exhibit a poor prognosis. Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, is an effective agent to treat HER2-amplified breast cancer but it failed in gastric cancer (GC) clinical trials. However, the molecular mechanism of lapatinib resistance in HER2-amplified GC is not well studied. METHODS: We employed an unbiased, genome-scale screening with pooled CRISPR library on HER2-amplified GC cell lines to identify genes that are associated with resistance to lapatinib. To validate the candidate genes, we applied in vitro and in vivo pharmacological tests to confirm the function of the target genes. RESULTS: We found that loss of function of CSK or PTEN conferred lapatinib resistance in HER2-amplified GC cell lines NCI-N87 and OE19, respectively. Moreover, PI3K and MAPK signaling was significantly increased in CSK or PTEN null cells. Furthermore, in vitro and in vivo pharmacological study has shown that lapatinib resistance by the loss of function of CSK or PTEN, could be overcome by lapatinib combined with the PI3K inhibitor copanlisib and MEK inhibitor trametinib. CONCLUSIONS: Our study suggests that loss-of-function mutations of CSK and PTEN cause lapatinib resistance by re-activating MAPK and PI3K pathways, and further proved these two pathways are druggable targets. Inhibiting the two pathways synergistically are effective to overcome lapatinib resistance in HER2-amplified GC. This study provides insights for understanding the resistant mechanism of HER2 targeted therapy and novel strategies that may ultimately overcome resistance or limited efficacy of lapatinib treatment for subset of HER2 amplified GC.

Network analyses of associations between cancer-related physical and psychological symptoms and quality of life in gastric cancer patients.

OBJECTIVE: This study applied network analyses to illustrate patterns of associations between cancer-related physical and psychological symptoms (CPPS) and quality of life (QOL) before and after surgery. METHODS: Participants consisted of 256 gastric cancer patients admitted for curative section surgery at the surgical department in a teaching hospital in Korea between May 2016 and November 2017. Participants completed the survey, including MD Anderson Symptom Inventory, Hospital Anxiety and Depression Scale, and Functional Assessment of Cancer Therapy-Gastric Cancer before surgery (T0), 1 week after surgery (T1), and 3-6 months after surgery (T2). RESULTS: Three networks featured several salient connections with varying magnitudes between CPPS and QOL across all time points. Particularly, anxiety was tightly connected to emotional wellbeing (EWB) across all time points and physical wellbeing (PWB) at T1. On the other hand, depression was connected to functional wellbeing at T0 and T2, gastric cancer concerns (CS) at T1, and PWB at T2. Distress and sadness were the most central symptoms in the three networks. Other central symptoms included shortness of breath at T0, fatigue at T0 and T1, and PWB and CS at T2. Anxiety, depression, and EWB served as bridges connecting CPPS to QOL across all time points with varying degrees of importance, as did PWB at T1 and T2. CONCLUSIONS: Treating psychological distress and enhancing EWB and PWB can be high impact intervention targets throughout the cancer trajectory.

Preservation of hepatic branch of the vagus nerve reduces the risk of gallstone formation after gastrectomy.

BACKGROUND: Injury to the vagus nerve has been proposed to be associated with occurrence of gallstones after gastrectomy. We investigated the effect of preservation of hepatic branch of the vagus nerve on prevention of gallstones during laparoscopic distal (LDG) and pylorus-preserving gastrectomy (LPPG). METHODS: Preservation of the vagus nerve was reviewed of cT1N0M0 gastric cancer patients underwent LDG (n = 323) and LPPG (n = 144) during 2016-2017. Presence of gallstones was evaluated by ultrasonography (US) and computed tomography (CT). Incidences of gallstones were compared between the nerve preserved (h-DG, h-PPG) group and sacrificed (s-DG, s-PPG) group. Clinicopathological features were also compared. RESULTS: The 3-year cumulative incidence of gallstones was lower in the h-DG (2.7%, n = 85) than the s-DG (14.6%, n = 238) (p = 0.017) and lower in the h-PPG (1.6%, n = 123) than the s-PPG (12.9%, n = 21) (p = 0.004). Overall postoperative complication rate was similar between the h-DG and s-DG (p = 0.861) as well as between the h-PPG and s-PPG (p = 0.768). The number of retrieved lymph nodes station #1 and 3-year recurrence-free survival were not significantly different between the preserved group and sacrificed group. Injury to the vagus nerve (p = 0.001) and high body mass index (BMI) (≥ 27.5 kg/m2) (p = 0.040) were found to be independent risk factors of gallstone formation in multivariate analysis. CONCLUSIONS: Preservation of hepatic branch of the vagus nerve can be recommended for LDG as well as LPPG of early gastric cancer patients to reduce postoperative gallstone formation.

National cancer screening program for gastric cancer in Korea: Nationwide treatment benefit and cost.

BACKGROUND: The purpose of this study was to evaluate the nationwide benefit and cost of the national cancer screening program (NCSP) for gastric cancer treatment. METHODS: For this nationwide, population-based study, the Korean National Health Insurance Big Data Base, which included gastric cancer-related treatment information and the costs for all patients with gastric cancer who were 40 years old or older between 2004 and 2013, was restructured. Patients with gastric cancer who participated in the NCSP at least once (the screening group) were compared with those who did not participate in the NCSP (the nonscreening group). RESULTS: The screening group (n = 116,775) spent significantly less on medical care expenses than the nonscreening group (n = 74,927) during the 5 years since the initial treatment (P < .0001). The screening group presented a significantly better prognosis for 5 and 9 years than the nonscreening group (P < .0001). The screening group revealed a 41% decreased hazard ratio (P < .0001) for death in comparison with the nonscreening group; the prognostic benefit became more obvious when treatment was started within the first 4 months after screening. The age-standardized mortality rate ratio of the screening group versus the nonscreening group was 0.62 (P < .0001). The NCSP for gastric cancer required an average of 22,169,769 Korean Republic won (US $20,309) for 1 life-year saved, which was less than the average gross domestic product (GDP) per capita in Korea. CONCLUSIONS: The screening group had significantly lower medical care expenses and showed a significantly better prognosis than the nonscreening group. On the basis of the GDP per capita, the NCSP for gastric cancer was cost-effective for treatment prognosis.

Alterations in the Rho pathway contribute to Epstein-Barr virus-induced lymphomagenesis in immunosuppressed environments.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV+-DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV+-DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV+-DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV+-DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2, and Rho pathway transcriptomic activation. Targeting the Rho pathway using a Rho-associated protein kinase (ROCK) inhibitor, fasudil, markedly decreased tumor growth in EBV+-DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.

microRNA-30a arbitrates intestinal-type early gastric carcinogenesis by directly targeting ITGA2.

BACKGROUND: Spasmolytic polypeptide-expressing metaplasia (SPEM) is considered a precursor lesion of intestinal metaplasia and intestinal-type gastric cancer (GC), but little is known about microRNA alterations during metaplasia and GC developments. Here, we investigate miR-30a expression in gastric lesions and identify its novel target gene which is associated with the intestinal-type GC. METHODS: We conducted in situ hybridization and qRT-PCR to determine miR-30a expression in gastric tissues. miR-30a functions were determined through induction or inhibition of miR-30a in GC cell lines. A gene microarray was utilized to confirm miR-30a target genes in GC, and siRNA-mediated target gene suppression and immunostaining were performed. The Cancer Genome Atlas data were utilized to validate gene expressions. RESULTS: We found down-regulation of miR-30a during chief cell transdifferentiation into SPEM. MiR-30a level was also reduced in the early stage of GC, and its level was maintained in advanced GC. We identified a novel target gene of miR-30a and ITGA2, and our results showed that either ectopic expression of miR-30a or ITGA2 knockdown suppressed GC cell proliferation, migration, and tumorigenesis. Levels of ITGA2 inversely correlated with levels of miR-30a in human intestinal-type GC. CONCLUSION: We found down-regulation of miR-30a in preneoplastic lesions and its tumor-suppressive functions by targeting ITGA2 in GC. The level of ITGA2, which functions as an oncogene, was up-regulated in human GC. The results of this study suggest that coordination of the miR-30a-ITGA2 axis may serve as an important mechanism in the development of gastric precancerous lesions and intestinal-type GC.