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Purpose: Laparoscopic distal gastrectomy is now widely used in East Asia and worldwide with different preferences and outcomes. This study aimed to compare the short- and long-term outcomes and preferences between two high-volume gastric cancer centers in Korea and China., Methods: Patients who underwent laparoscopic-assisted distal gastrectomy (LADG) and totally laparoscopic distal gastrectomy (TLDG) for gastric cancer from Seoul National University Hospital (SNUH) and the First Affiliated Hospital of Nanjing Medical University (NMUH) from 2017 to 2020 were enrolled in this study., Results: A total of 1166 SNUH cases and 847 NMUH cases enrolled in this study. The overall complication rate of SNUH (14.49%) did not differ from that of NMUH after LADG or TLDG (12.28%). The anastomosis-related complications rate (2.74%) did not show a significant difference with that of NMUH (2.01%) either. The median postoperative hospital stay for SNUH (7,(7,10)) was shorter than that for NMUH (8,(7,9)). The 5-year overall survival (OS) rate of SNUH was not significantly different from that of NMUH., Conclusion: There was no significant difference in the overall complication rate, anastomosis-related complication rate, resected lymph nodes, and 5- year overall survival rate between SNUH and NMUH except for the postoperative stay. Both the LADG and TLDG achieved satisfactory short- and long-term outcomes when performed by surgeons with adequate experience., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interests. Ethical approval: The study was performed in accordance with the Declaration of Helsinki and was approved by the ethics committees of Seoul National University Hospital and the First Affiliated Hospital of Nanjing Medical University. Consent to participate: The patients were informed about sample collection and signed informed consent forms. All human samples used in this study were unidentified. Consent for publication: All authors of this article have directly participated in the planning and drafting, and all listed authors have read and approved the final version, including details and images., (© 2024. The Author(s).)

Microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits high tumor-infiltrating lymphocyte (TIL) density. Despite the recognized significance of the immune microenvironment in MSI-H GC, our understanding of TIL remains limited. This study aimed to investigate the clinicopathologic and prognostic implications of T cell subsets in MSI-H GC. Single immunohistochemistry (IHC) for CD8, TCF1, and CD103, and double IHC for CD8/TCF1 and CD8/CD103 were performed in 382 surgically resected MSI-H GC samples. Densities of single or double positive immune cells were quantified and correlated with clinicopathologic features and overall survival (OS). TCF1 + cell densities showed weak correlations with CD8 + and CD103 + cell densities, while CD8+/TCF1 + cell density moderately correlated with CD8+/CD103 + cell density (R 2  = 0.539, p < 0.001). Single IHC analyses showed no significant associations between CD8+, TCF1+, or CD103 + cell densities and OS (p > 0.05). Notably, elevated CD8+/TCF1 + cell density and a high CD8+/TCF1 + to CD8 + ratio correlated with less aggressive clinicopathologic features and improved OS (p = 0.017 and 0.001, respectively). Multivariable Cox-regression identified CD8+/TCF1 + to CD8 + ratio as an independent prognostic factor (p = 0.028). We demonstrated the prognostic significance of CD8+/TCF1 + to CD8 + ratio using double IHC in a large cohort of MSI-H GC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: This study aimed to develop and assess the feasibility and effectiveness of digital therapeutics for supportive care after gastrectomy., Materials and Method: The study included 39 patients with gastric cancer who underwent minimally invasive gastrectomy and were able to use a mobile application (app) on their smartphones. The developed research app automatically calculates and provides daily targets for calorie and protein intake based on the patient's body mass index (BMI). Patients recorded their daily diets, weights, and symptoms in the app and completed special questionnaires to assess the feasibility of the app in real-world clinical practice., Results: At the 10-week follow-up, the mean questionnaire scores for ease of learning, usability, and effectiveness of the app (primary endpoint) were 2.32±0.41, 2.35±0.43, and 2.4±0.39 (range: 0-3), respectively. Patients were classified as underweight (<18.5, n=4), normal (18.5-24.9, n=24), or overweight (≥25.0, n=11) according to predischarge BMI. Underweight patients showed higher compliance with app usage and a higher rate of achieving the target calorie and protein intake than normal weight and overweight patients (98% vs. 77% vs. 81%, p=0.0313; 102% vs. 75% vs. 61%, P=0.0111; 106% vs. 79% vs. 64%, P=0.0429). Two patients transitioned from underweight to normal weight (50.0%), one patient (4.3%) transitioned from normal weight to underweight, and two patients (22.2%) transitioned from overweight to normal weight., Conclusions: The mobile app is feasible and useful for postoperative supportive care in terms of ease of learning, usability, and effectiveness. Digital therapeutics may be an effective way to provide supportive care for postgastrectomy patients, particularly in terms of nutrition., Trial Registration: ClinicalTrials.gov Identifier: NCT04800991., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2024. Korean Gastric Cancer Association.)

Purpose: Hereditary diffuse gastric cancer (HDGC) presents a significant genetic predisposition, notably linked to mutations in the CDH1 and CTNNA1. However, the genetic basis for over half of HDGC cases remains unidentified. The aim of this study is to identify novel pathogenic variants in HDGC and evaluate their protein expression., Materials and Methods: Among 20 qualifying families, two were selected based on available pedigree and DNA. Whole genome sequencing (WGS) on DNA extracted from blood and whole exome sequencing on DNA from formalin-fixed paraffin-embedded tissues were performed to find potential pathogenic variants in HDGC. After selection of a candidate variant, functional validation, and enrichment analysis were performed., Results: As a result of WGS, three candidate germline mutations (EPHA5, MCOA2, and RHOA) were identified in one family. After literature review and in-silico analyses, the RHOA mutation (R129W) was selected as a candidate. This mutation was found in two gastric cancer patients within the family. In functional validation, it showed RhoA overexpression and a higher GTP-bound state in the RhoaR129W mutant. Decreased phosphorylation at Ser127/397 suggested altered YAP1 regulation in the Rho-ROCK pathway. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses linked RhoaR129W overexpression to changed migration/adhesion in MKN1 cell line. However, this RHOA mutation (R129W) was not found in index patients in other families., Conclusion: The RHOA mutation (R129W) emerges as a potential causative gene for HDGC, but only in one family, indicating a need for further studies to understand its role in HDGC pathogenesis fully.

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., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Gastric cancer exhibits molecular heterogeneity, with the microsatellite instability-high (MSI-H) subtype drawing attention for its distinct features. Despite a higher survival rate, MSI-H gastric cancer lack significant benefits from conventional chemotherapy. The immune checkpoint inhibitors, presents a potential avenue, but a deeper understanding of the tumor immune microenvironment of MSI-H gastric cancer is essential., Materials and Methods: We explored the molecular characteristics of CD8+ T-cell subtypes in three MSI-H and three microsatellite stable (MSS) gastric cancer samples using single-cell RNA sequencing and spatial transcriptome analysis., Results: In MSI-H gastric cancer, significantly higher proportions of effector memory T cell (Tem), exhausted T cell (Tex), proliferative exhausted T cell (pTex), and proliferative T cell were observed, while MSS gastric cancer exhibited significantly higher proportions of mucosal-associated invariant T cell and natural killer T cell. In MSI-H gastric cancer, Tex and pTex exhibited a significant upregulation of the exhaustion marker LAG3, as well as elevated expression of effector function markers such as IFNG, GZMB, GZMH, and GZMK, compared to those in MSS gastric cancer. The interferon γ (IFN-γ) signaling pathway of Tex and pTex was retained compared to those of MSS gastric cancer. The spatial transcriptome analysis demonstrates the IFN-γ signaling pathway between neighboring Tex and malignant cell, showcasing a significantly elevated interaction in MSI-H gastric cancer., Conclusion: Our study reveals novel finding indicating that IFN-γ signaling pathway is retained in Tex and pTex of MSI-H gastric cancer, offering a comprehensive perspective for future investigations into immunotherapy for gastric cancer.

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/m 2 ) 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., (© 2024. The Author(s).)

Background: Vascularized gastroepiploic lymph node transfer (VGLNT) is a well-accepted surgical treatment for restoring physiological function in chronic lymphedema. However, the inclusion of substantial lymph nodes (LNs) in the flap remains uncertain. This study aimed to identify the anatomical basis for reliable flap harvest for VGLNT., Patients and Methods: The anatomy of perigastric station 4d LNs was studied in healthy cadavers (n = 15) and patients with early gastric cancer (EGC) (n = 27). The omentum was divided into three segments: proximal, middle, and distal from the origin of the right gastroepiploic vessels. The flap dimension, number, location, size of LNs, and caliber of the vessels were reviewed. Eight patients underwent VGLNT for upper/lower limb lymphedema., Results: The mean numbers of LNs in the proximal, middle, and distal segment were 2.5, 1.4, 0.5 in the cadavers, and 4.9, 2.7, 0.7 in the gastrectomy specimens, respectively. The proximal third included a significantly greater number of LNs than the distal third in the cadaveric (p = 0.024) and ECG (p = 0.016) specimens. A total of 95% of the LNs were located within proximal two-thirds of the flap from the vessel origin both in the cadavers (21.0 × 5.0 cm) and in the gastrectomy specimens (20 × 3.5 cm). In VGLNT, the transferred flap was 25.5 ± 6.9 × 4.1 + 0.7 cm in dimension, containing a mean number of 6.5 ± 1.9 LNs. At postoperative 6 months, the volumetric difference was significantly reduced by 22.8 ± 9.2% (p < 0.001)., Conclusions: This study provides a distinct distribution pattern of station 4d LNs. Inclusion of the proximal two-thirds of the flap, which carries majority of the LNs, is recommended for VGLNT., (© 2024. Society of Surgical Oncology.)

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., (© 2024. The Author(s).)

Background: This study aimed to investigate the oncologic long-term safety of proximal gastrectomy for upper-third advanced gastric cancer (AGC) and Siewert type II esophagogastric junction (EGJ) cancer., Methods: The study enrolled patients who underwent proximal gastrectomy (PG) or total gastrectomy (TG) with standard lymph node (LN) dissection for pathologically proven upper-third AGC and EGJ cancers between January 2007 and December 2018. Propensity score-matching with a 1:1 ratio was performed to reduce the influence of confounding variables such as age, sex, tumor size, T stage, N stage, and tumor-node-metastasis (TNM) stage. Kaplan-Meier survival analysis was performed to analyze oncologic outcome. The prognostic factors of recurrence-free survival (RFS) were analyzed using the Cox proportional hazard analysis., Results: Of the 713 enrolled patients in this study, 60 received PG and 653 received TG. Propensity score-matching yielded 60 patients for each group. The overall survival rates were 61.7 % in the PG group and 68.3 % in the TG group (p = 0.676). The RFS was 86.7 % in the PG group and 83.3 % in the TG group (p = 0.634). The PG group showed eight recurrences (1 anastomosis site, 1 paraaortic LN, 1 liver, 1 spleen, 1 lung, 1 splenic hilar LN, and 2 remnant stomachs). In the multivariate analysis, the operation method was not identified as a prognostic factor of tumor recurrence., Conclusion: The patients who underwent PG had a long-term oncologic outcome similar to that for the patients who underwent TG for upper-third AGC and EGJ cancer., (© 2024. The Author(s).)

Objective: The present study aimed to compare intraoperative and postoperative outcomes of laparoscopic-assisted distal gastrectomy versus totally laparoscopic distal gastrectomy (TLDG) Billroth I (BI) for gastric cancer and to assess the impact of the initial introduction phase of TLDG BI anastomosis., Patients and Methods: The study analyzed the prospectively collected data of patients who underwent laparoscopic distal gastrectomy BI from 2014 to 2021 at Seoul National University Hospital., Results: Among 1116 patients, laparoscopic-assisted distal gastrectomy BI was performed in 566 patients and TLDG BI was performed in 550 patients. The total laparoscopic arm had a faster mean operative time (190 vs 208 min; P < 0.001) and a shorter postoperative hospital stay (7.4 vs 7.9 d; P < 0.001). Local complications were higher in the total laparoscopic group (17.6% vs 9.9%; P = 0.008) during the early introduction phase., Conclusion: The total laparoscopic approach for BI reconstruction is safe and effective with faster operative time, shorter hospital stays, and less wound infection, but it may be associated with an increase in postoperative surgical complications and hospital stay in the early introduction phase., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Backgrounds & Aims: Precancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways that are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia., Methods: To assess the response to chemotherapeutic drugs, we used metaplastic and dysplastic organoids derived from Mist1-Kras mice and 20 human precancerous organoid lines established from patients with gastric cancer. Phospho-antibody array analysis and single-cell RNA-sequencing were performed to identify target cell populations and signaling pathways affected by pyrvinium, a putative anticancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo., Results: Although pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and signal transducer and activator of transcription 3 (STAT3) as well as STAT3-target genes. Single-cell RNA-sequencing data analyses revealed that pyrvinium specifically targeted CD133 + /CD166 + stem cell populations, as well as proliferating cells in dysplastic organoids. Pyrvinium inhibited metaplasia progression and facilitated the restoration of normal oxyntic glands in Mist1-Kras mice. Furthermore, pyrvinium exhibited suppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blocking of the MEK/ERK and STAT3 signaling pathways., Conclusions: Through its dual blockade of MEK/ERK and STAT3 signaling pathways, pyrvinium can effectively induce growth arrest in metaplasia and cell death in dysplasia. Therefore, our findings suggest that pyrvinium is a promising chemotherapeutic agent for reprogramming the precancerous milieu to prevent gastric cancer development., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The aim of this study was to audit the 22 items and assessed each item's predictive value on surgical outcomes., Background: The KLASS-02 trial revealed that the oncologic outcomes of laparoscopic distal gastrectomy are not inferior to open distal gastrectomy in patients with advanced gastric cancer. The surgeons participating in this trial were chosen based on the assessment scores from the KLASS-02-QC trial, which used 22 items for standardization of D2 lymphadenectomy and quality control., Methods: We reviewed proficiency scores (PSs) for 22 items for 20 surgeons who participated in KLASS-02. The surgeons were divided into 2 groups according to PS, and the perioperative outcomes of 924 patients enrolled in KLASS-02 were compared between groups. Each item's predictive value for perioperative outcome was then assessed using multivariable regression models., Results: Of the total 924 patients, 529 were operated on by high-score surgeons (high PS) and 395 were operated on by low-score surgeons (low-PS). High-PS group had less intraoperative blood loss, longer operation times, and fewer complications, major complications, reoperations, and shorter first flatus and hospital stay than low-PS group ( P =0.006, P <0.001, P <0.001, P <0.001, P =0.042, P =0.013, and P <0.001, respectively). Some items used in KLASS-02-QC predicted perioperative outcomes, such as intraoperative blood loss, major complications, reoperation, and hospital stay., Conclusions: Although this study only analyzed data associated with qualified surgeons, the 22 items effectively assessed the surgeons based on PS. A high score was associated with longer operation times, but better perioperative outcomes., Competing Interests: W.J.H. reported receiving grants from Medtronic and GC pharma, stocks from Hutom, and personal fees from SK Hynix (Wuxi) outside the submitted work. S.-U.H. reported receiving grants from the National R&D Program for Cancer Control and Ethicon Endo-Surgery, a Johnson & Johnson Company, during the study period. S.-H.K. reported receiving grants from Medtronic and Stryker outside the submitted work. D.J.P. reported receiving grants from Daewoong Pharmaceuticals, JW Pharmaceuticals, and Medtronic outside the submitted work. J.W.K. reported receiving grants from the DN Company Co. Ltd research fund outside the submitted work. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Prospective database is imperative in surgical outcome monitoring and has shown success in providing a comprehensive complication index to monitor surgical quality. This study aims to review whether prospective monitoring has an effect on postoperative complication rates, especially leakage after Billroth I (BI) anastomosis and to identify risk factors of anastomosis leakage after BI anastomosis., Materials and Methods: Patients who underwent distal gastrectomy with BI reconstruction at Seoul National University Hospital between January 2018 and April 2021 were enrolled. Clinicopathological characteristics and perioperative variables were retrieved. The risk factor that was statistically significant in univariate analysis was further analyzed by binomial logistic regression analysis., Results: BI leakage rate in three years has declined by half on a yearly basis from 5.7% to 1.8%. The leakage group patients were predominantly male (100%) when compared to the non-leakage group (67.6%) (p = 0.04). The BMI (25.00 ± 1.42 vs. 24.16 ± 3.15, p = 0.048) and CRP measured on POD#2 (16.47 ± 5.64 vs. 9.99 ± 5.42, p < 0.001) showed significant differences between the two groups. POD#2 CRP greater than 12.7 mg/dL was able to predict risk of anastomosis leak with sensitivity 73.3% and specificity 73.1%., Conclusion: Understanding variations in outcomes is important for improvements in surgical care, and through prospective monitoring and intra-departmental feedback, it is possible to reduce complication rates after gastrectomy. This study shows that age, gender and BMI are risk factors to BI leakage and POD#2 CRP greater than 12.7 mg/dL can be used to suspect leakage after BI anastomosis., Competing Interests: Declaration of competing interest None., (© 2023 Published by Elsevier Ltd.)

Background: Neoadjuvant treatment is recommended for large GISTs due to their friability and risk of extensive operations; however, studies on the indications and long-term results of this approach are lacking., Methods: Patients with large (≥ 10 cm) gastric GISTs were enrolled from multiple centers in Korea and Japan after a pathologic confirmation of c-KIT ( +) GISTs. Imatinib (400 mg/d) was given for 6-9 months preoperatively, and R0 resection was intended. Postoperative imatinib was given for at least 12 months and recommended for 3 years., Results: A total of 56 patients were enrolled in this study, with 53 patients receiving imatinib treatment at least once and 48 patients undergoing R0 resection. The 5-year overall survival and progression-free survival rates were 94.3% and 61.6%, respectively. Even patients with stable disease by RECIST criteria responded well to preoperative imatinib treatment and could undergo R0 resection, with most being evaluated as partial response by CHOI criteria. The optimal reduction in tumor size was achieved with preoperative imatinib treatment for 24 weeks or more. No resumption of imatinib treatment was identified as an independent prognostic factor for recurrence after R0 resection. No additional size criteria for a higher risk of recurrence were identified in this cohort with a size of 10 cm or more., Conclusions: Neoadjuvant imatinib treatment is an effective treatment option for gastric GISTs 10 cm or larger. Postoperative imatinib treatment is recommended even after R0 resection to minimize recurrence., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: A gene or variant has pleiotropic effects, and genetic variant identification across multiple phenotypes can provide a comprehensive understanding of biological pathways shared among different diseases or phenotypes. Discovery of genetic loci associated with multiple diseases can simultaneously support general interventions. Several meta-analyses have shown genetic associations with gastric cancer (GC); however, no study has identified associations with other phenotypes using this approach., Methods: Here, we applied disease network analysis and gene-based analysis (GBA) to examine genetic variants linked to GC and simultaneously associated with other phenotypes. We conducted a single-nucleotide polymorphism (SNP) level meta-analysis and GBA through a systematic genome-wide association study (GWAS) linked to GC, to integrate published results for the SNP variants and group them into major GC-associated genes. We then performed disease network and expression quantitative trait loci (eQTL) analyses to evaluate cross-phenotype associations and expression levels of GC-related genes., Results: Seven genes (MTX1, GBAP1, MUC1, TRIM46, THBS3, PSCA, and ABO) were associated with GC as well as blood urea nitrogen (BUN), glomerular filtration rate (GFR), and uric acid (UA). In addition, 17 SNPs regulated the expression of genes located on 1q22, 24 SNPs regulated the expression of PSCA on 8q24.3, and rs7849820 regulated the expression of ABO on 9q34.2. Furthermore, rs1057941 and rs2294008 had the highest posterior causal probabilities of being a causal candidate SNP in 1q22, and 8q24.3, respectively., Conclusions: These findings identified seven GC-associated genes exhibiting a cross-association with GFR, BUN, and UA., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: We aimed to determine the molecular and immune microenvironment characteristics of HER2-positive gastric cancer (GC) related to the patient's response to first-line trastuzumab-based treatment., Methods: Eighty-three cases of HER2-positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post-treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor-infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression-free survival (PFS) analysis was performed., Results: Group 1 showed frequent amplification of G1/S cell cycle checkpoint-related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune-related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle-related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p < 0.05), or immune-related including high density of CD3 - CD57 + NK cells and PD-L1 combined positive score ≥5 (p < 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p < 0.001)., Conclusion: HER2-positive GC with favorable response to trastuzumab were characterized by cell cycle-related gene alterations and increased CD3 - CD57 + NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2-positive GC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Pylorus-preserving gastrectomy (PPG) is a surgical treatment option for cT1N0M0 gastric cancer located in the middle third of the stomach. However, data for the long-term post-PPG clinical outcomes related to metachronous gastric neoplasms (mGNs) in the residual stomach are currently lacking. Therefore, we aimed to evaluate the safety of PPG by focusing on mGNs., Methods: In this single-center, retrospective study, we reviewed the data for 362 patients who underwent PPG with a 3-cm antral cuff and 139 who underwent endoscopic submucosal dissection (ESD) for middle-third gastric cancer between January 2013 and December 2015. The histopathologic features of the antrum in the ESD group, which could not be determined in the PPG group, were analyzed to investigate the risk factors for mGNs. The estimated and actual incidence of mGNs in the antrum were compared in the PPG group., Results: The incidence of mGNs was 6.5% (9/139) in the ESD group. The presence of a synchronous adenoma (odds ratio [OR], 8.46; 95% confidence interval [CI], 1.55-46.34), carcinoma (OR, 15.71; 95% CI, 2.67-92.56) and moderate-to-severe intestinal metaplasia (OR, 9.77; 95% CI, 1.14-83.92) were associated with a higher risk of overall mGNs. However, when confined to the antrum, no significant association was observed between these factors and mGNs. In the ESD group, 2 of 9 mGNs (1.4%) were located at the 3-cm antral cuff. In the PPG group, both mGNs (0.6%) were located in the proximal remnant stomach., Conclusion: Pylorus-preserving gastrectomy was a safe therapeutic option with regard to the occurrence of metachronous adenomas or carcinomas in our series. Despite the low mGN incidence in the 3-cm antral cuff after PPG, the presence of synchronous neoplasms or moderate-to-severe intestinal metaplasia was a risk factor for mGNs in the ESD group; thus, further studies on longer antral cuffs with long-term follow-up are needed., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The benefit of regular follow-up after curative resection for gastric cancer is controversial as there is no evidence that it will improve survival. This study assessed whether regular follow-up leads to improved survival in patients after surgery for gastric cancer., Methods: A secondary analysis was undertaken of patients who participated in an RCT of laparoscopic versus open distal gastrectomy for advanced gastric cancer between November 2011 and April 2015. Depending on whether patients were compliant with the initial trial follow-up protocol or not, they were analysed as having had either regular or irregular follow-up. Clinicopathological characteristics, recurrence patterns, detection, treatments, and survival were compared between the groups., Results: The regular and irregular follow-up groups comprised 712 and 263 patients respectively. Disease recurrence within 36 months was more common in the regular group than in the irregular group (17.0 versus 11.4 per cent; P = 0.041). Recurrence patterns did not differ between the groups. The 3-year recurrence-free survival rate was worse in the regular than in the irregular group (81.2 versus 86.5 per cent; P = 0.031). However, the 5-year overall survival rate was comparable (84.5 versus 87.5 per cent respectively; P = 0.160). Multivariable analysis revealed that type of follow-up was not an independent factor affecting 5-year overall survival., Conclusion: Regular follow-up after radical gastrectomy was not associated with improved overall survival., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Patients undergoing proximal gastrectomy (PG) with double-tract reconstruction (DTR) have been reported to have an incidence of reflux esophagitis that is as low as that observed after total gastrectomy (TG). It is unclear whether PG has an advantage over TG for the treatment of patients with upper early gastric cancer (GC)., Objective: To evaluate the effect of laparoscopic PG with DTR (LPG-DTR) vs laparoscopic TG (LTG) on levels of hemoglobin and vitamin B12 supplementation required among patients with clinically early GC in the upper third of the stomach (upper-third early GC)., Design, Setting, and Participants: This multicenter open-label superiority randomized clinical trial was conducted at 10 institutions in Korea. A total of 138 patients with upper-third cT1N0M0 GC were enrolled between October 27, 2016, and September 9, 2018. Follow-up ended on December 3, 2020., Interventions: Patients were randomized to undergo either LPG-DTR or LTG., Main Outcomes and Measures: The primary co-end points were change in hemoglobin level and cumulative amount of vitamin B12 supplementation at 2 years after LPG-DTR or LTG. The secondary end points included morbidity, postoperative reflux esophagitis, quality of life, overall survival, and disease-free survival. Quality of life outcomes were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) 30-item core questionnaire (C30) and the EORTC QLQ stomach cancer-specific questionnaire at 3 months, 12 months, and 24 months., Results: Among 138 patients (mean [SD] age, 60.0 [10.9] years; 87 men [63.0%]; all of Asian race and Korean ethnicity), 68 (mean [SD] age, 56.7 [10.4] years; 39 men [57.4%]) were randomized to receive LPG-DTR and 69 (mean [SD] age, 61.3 [11.3] years; 48 men [69.6%]) were randomized to receive LTG. The mean (SD) changes in hemoglobin levels from baseline to month 24 were -5.6% (7.4%) in the LPG-DTR group and -6.9% (8.3%) in the LTG group, for an estimated difference of -1.3% (95% CI, -4.0% to 1.4%; P = .35). The mean (SD) cumulative amount of vitamin B12 supplementation was 0.4 (1.3) mg in the LPG-DTR group and 2.5 (3.0) mg in the LTG group, for an estimated difference of 2.1 mg (95% CI, 1.3-2.9 mg; P < .001). The late complication rates in the LPG-DTR and LTG groups were 17.6% and 10.1%, respectively (P = .31). The incidence of reflux esophagitis was not different between the LPG-DTR and LTG groups (2.9% vs 2.9%; P = .99). Compared with the LTG group, the LPG-DTR group had better physical functioning scores (85.2 [15.6] vs 79.9 [19.3]; P = .03) and social functioning scores (89.5 [17.9] vs 82.4 [19.4]; P = .03) on the EORTC QLQ-C30. Two-year overall survival (98.5% vs 100%; P = .33) and disease-free survival (98.5% vs 97.1%; P = .54) did not significantly differ between the LPG-DTR vs LTG groups., Conclusions and Relevance: In this study, patients with upper-third early GC who received LPG-DTR required less vitamin B12 supplementation than those who received LTG, with no increase in complication rates and no difference in overall and disease-free survival rates. There was no difference in change in hemoglobin level between groups. In addition, the LPG-DTR group had better physical and social functioning than the LTG group. These findings suggest that LPG-DTR may be as safe as LTG and may be a function-preserving procedure for the treatment of patients with upper-third early GC., Trial Registration: ClinicalTrials.gov Identifier: NCT02892643.

Background: To evaluate whether insertion of self-biodegradable stent into the pylorus to prevent delayed-gastric emptying after pylorus-preserving gastrectomy is feasible and safe through porcine experiment., Methods: Self-biodegradable dumbbell-shaped pyloric stents were designed from absorbable suture materials: poly(glycolide-co-caprolactone) (PGCL) or poly-p-dioxanone (PPDO). After gastrotomy on ten pigs, each stent was inserted: two shams, four PGCL stents, and four PPDO stents. Body weight (Bwt), body temperature (BT), complete blood cell (CBC) count, and plain X-ray were evaluated. On postoperative day (POD) 13, euthanasia was performed for histologic evaluation., Results: Operation was successfully performed in all ten pigs. Without tagging suture, both stents migrated before POD 3. The migration was delayed up to POD 13, when the tagging sutures (-t) were applied between stent and stomach wall. Self-degradation of PGCL started from POD 3, and stents were completely excreted from the abdomen by POD 8. Although PPDO were also weakened as self-degradation progressed, its shape was maintained in gastrointestinal tract for 13 days. Unexpected sudden death occurred in the pig with PPDO-t2 on POD 10, which is more likely due to acute volvulus rather than stent-related complication. There was no significant difference between three groups in terms of Bwt, BT, CBC, and histology (sham vs. PGCL vs. PPDO, all p > 0.05)., Conclusion: The concept of biodegradable stents made of absorbent suture material seems feasible in porcine experiment. Among them, PGCL which has shown rapid absorption, appears to be a more suitable material for transient pyloric absorbable stent when considering safety aspect., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Importance: The long-term safety of laparoscopic distal gastrectomy for locally advanced gastric cancer (AGC) remains uncertain given the lack of 5-year follow-up results., Objective: To compare the 5-year follow-up results in patients with clinically AGC enrolled in the Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS)-02 randomized clinical trial who underwent laparoscopic or open distal gastrectomy., Design, Setting, and Participants: The KLASS-02, a multicenter randomized clinical trial, showed that laparoscopic surgery was noninferior to open surgery for patients with locally AGC. The present study assessed the 5-year follow-up results, including 5-year overall survival (OS) and relapse-free survival (RFS) rates and long-term complications, in patients enrolled in KLASS-02. From November 21, 2011, to April 29, 2015, patients aged 20 to 80 years diagnosed preoperatively with locally AGC were enrolled. Final follow-up was on June 15, 2021. Data were analyzed June 24 to September 9, 2021., Interventions: Patients were treated with R0 resection either by laparoscopic gastrectomy or open gastrectomy as the full analysis set of the KLASS-02 trial., Main Outcomes and Measures: Five-year OS and RFS rates, recurrence patterns, and long-term surgical complications were evaluated., Results: This study enrolled a total of 1050 patients. A total of 974 patients were treated with R0 resection; 492 (50.5%) in the laparoscopic gastrectomy group (mean [SD] age, 59.8 [11.0] years; 351 men [71.3%]) and 482 (49.5%) in the open gastrectomy group (mean [SD] age, 59.4 [11.5] years; 335 men [69.5%]). In patients who underwent laparoscopic and open distal gastrectomy, the 5-year OS (88.9% vs 88.7%) and RFS (79.5% vs 81.1%) rates did not differ significantly. The most common types of recurrence were peritoneal carcinomatosis (73 of 173 [42.1%]), hematogenous metastases (36 of 173 [20.8%]), and locoregional recurrence (23 of 173 [13.2%]), with no between-group differences in types of recurrence at each cancer stage. The correlation between 3-year RFS and 5-year OS at the individual level was highest in patients with stage III gastric cancer (ρ = 0.720). The late complication rate was significantly lower in the laparoscopic than in the open surgery group (32 of 492 [6.5%] vs 53 of 482 [11.0%]). The most common type of complication in both groups was intestinal obstruction (13 of 492 [2.6%] vs 24 of 482 [5.0%])., Conclusions and Relevance: The 5-year outcomes of the KLASS-02 trial support the 3-year results, which is the noninferiority of laparoscopic surgery compared with open gastrectomy for locally AGC. The laparoscopic approach can be recommended in patients with locally AGC to achieve the benefit of low incidence of late complications., Trial Registration: ClinicalTrials.gov Identifier: NCT01456598.

Background & Aims: Dysplasia carries a high risk of cancer development; however, the cellular mechanisms for dysplasia evolution to cancer are obscure. We have previously identified 2 putative dysplastic stem cell (DSC) populations, CD44v6 neg /CD133 + /CD166 + (double positive [DP]) and CD44v6 + /CD133 + /CD166 + (triple positive [TP]), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of noncancerous Trop2 + /CD133 + /CD166 + DSCs initially developed in the transition from precancerous metaplasia to dysplasia in the stomach., Methods: Dysplastic organoids established from active Kras-induced mouse stomachs were used for transcriptome analysis, in vitro differentiation, and in vivo tumorigenicity assessments of DSCs. Cell heterogeneity and genetic alterations during clonal evolution of DSCs were examined by next-generation sequencing. Tissue microarrays were used to identify DSCs in human dysplasia. We additionally evaluated the effect of casein kinase 1 alpha (CK1α) regulation on the DSC activities using both mouse and human dysplastic organoids., Results: We identified a high similarity of molecular profiles between DP- and TP-DSCs, but more dynamic activities of DP-DSCs in differentiation and survival for maintaining dysplastic cell lineages through Wnt ligand-independent CK1α/β-catenin signaling. Xenograft studies demonstrated that the DP-DSCs clonally evolve toward multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Last, growth and survival of both mouse and human dysplastic organoids were controlled by targeting CK1α., Conclusions: These findings indicate that the DSCs are de novo gastric cancer-initiating cells responsible for neoplastic transformation and a promising target for intervention in early induction of gastric cancer., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Several studies have previously reported that laparoscopic surgery using an energy sealing device generates hazardous surgical smoke. However, the droplets appearing on the surface of peritoneal fluid irrigated with saline, after dissection phase of laparoscopic gastrectomy were ignored for a long time. This study aimed to investigate the composition and clinical significance of these droplet particles., Methods: This study prospectively enrolled 15 patients with early gastric cancer (cT1NanyM0) who were scheduled for laparoscopic gastrectomy. Floating phases of peritoneal irrigation fluid containing droplets in dissected area were retrieved before and after surgical dissection. Using gas chromatography analysis, the areas under the peak were compared between the samples retrieved before and after surgical dissection. We also analyzed if the area value with significant change was related to the inflammatory response., Results: In gas chromatography, the area values after laparoscopic surgical dissection were significantly increased in 10 out of 37 kinds of fatty acids, compared to those before surgical dissection. The significant increase in area value of α-linoleic and eicosadienoic acids were positively correlated with the elevated level of C-reactive protein at postoperative day 2 (Spearman's ρ = 0.843, P < 0.001; Spearman's ρ = 0.785, P = 0.001)., Conclusions: The lipid droplets, generated after laparoscopic lymphadenectomy during gastric cancer surgery, contained various types of fatty acids, and some of them have been found to be associated with inflammatory response., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Surgical resection with lymphadenectomy and perioperative chemotherapy is the universal mainstay for curative treatment of gastric cancer (GC) patients with locoregional disease. However, GC survival remains asymmetric in West- and East-world regions. We hypothesize that this asymmetry derives from differential clinical management. Therefore, we collected chemo-naïve GC patients from Portugal and South Korea to explore specific immunophenotypic profiles related to disease aggressiveness and clinicopathological factors potentially explaining associated overall survival (OS) differences. Clinicopathological and survival data were collected from chemo-naïve surgical cohorts from Portugal (West-Europe cohort [WE-C]; n = 170) and South Korea (East-Asia cohort [EA-C]; n = 367) and correlated with immunohistochemical expression profiles of E-cadherin and CD44v6 obtained from consecutive tissue microarrays sections. Survival analysis revealed a subset of 12.4% of WE-C patients, whose tumors concomitantly express E-cadherin&#95;abnormal and CD44v6&#95;very high, displaying extremely poor OS, even at TNM stages I and II. These WE-C stage-I and -II patients tumors were particularly aggressive compared to all others, invading deeper into the gastric wall (P = .032) and more often permeating the vasculature (P = .018) and nerves (P = .009). A similar immunophenotypic profile was found in 11.9% of EA-C patients, but unrelated to survival. Tumours, from stage-I and -II EA-C patients, that display both biomarkers, also permeated more lymphatic vessels (P = .003), promoting lymph node (LN) metastasis (P = .019), being diagnosed on average 8 years earlier and submitted to more extensive LN dissection than WE-C. Concomitant E-cadherin&#95;abnormal/CD44v6&#95;very-high expression predicts aggressiveness and poor survival of stage-I and -II GC submitted to conservative lymphadenectomy., (© 2021 UICC.)

Background: The effectiveness of subcostal transversus abdominis plane block (TAPB) in laparoscopic gastric cancer surgery is unknown. We aimed to investigate its opioid-sparing and pain-relief effects in laparoscopic gastrectomy for gastric cancer., Method: One hundred and twelve patients undergoing elective laparoscopic gastrectomy were randomised to the TAPB or control group. The TAPB group received ultrasound-guided bilateral subcostal TAPB at the end of surgery, while the control group did not. We investigated fentanyl consumption administered via intravenous patient-controlled analgesia and as a rescue analgesic, the numeric rating scale (NRS) pain scores at rest and during coughing, and the opioid-related side effects at 6, 12, 24, and 48 h postoperatively. The primary outcome was cumulative fentanyl consumption at 24 h postoperatively., Results: The study included 53 patients in each group. The cumulative fentanyl consumption 24 h postoperatively was significantly lower in the TAPB group than in the control group (median difference -170 mcg, P = 0.03, 95% CI -360 to -15 mcg). Subcostal TAPB also significantly reduced the resting NRS score at 48 h postoperatively (median difference -1, 95% CI -1 to 0, P = 0.01) and coughing NRS score at all time points (all median difference -1, 95% CI -2 to 0, P < 0.01, P  = 0.02, 0.01, and 0.01, respectively). However, it did not reduce the occurrence of opioid-related side effects, except the use of antiemetics during the first 6 h postoperatively (TAPB, 1.9% vs. Control, 15.1%, P = 0.03)., Conclusion: Ultrasound-guided bilateral subcostal TAPB provides efficient postoperative analgesia with an opioid-sparing effect after laparoscopic gastrectomy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: Using indocyanine green (ICG) fluorescence imaging and tissue marking dyes (TMDs), perigastric lymphatic mapping and their pathological correlation were examined to see whether ICG staining covers all metastatic lymph nodes (LNs) in advanced gastric cancer (AGC)., Methods: Patients with AGC who underwent open distal or total gastrectomy were enrolled. ICG was serially injected intraoperatively into the subserosa along the greater and lesser curvatures. Stomach specimens were examined under a near-infrared camera. ICG-stained LNs were named, excised, and tattooed with different colored TMDs to retrace the exact location after pathological examinations., Results: A total of 687 LNs and 69 LN stations were examined from 11 patients. The map of the perigastric lymphatic network showing the topography of ICG-stained and ICG-unstained LNs, including metastatic information, was successfully reconstructed. The average number of ICG-stained and ICG-unstained LNs were 23.6 ± 12.3 (37.8%) and 38.8 ± 17.1 (62.2%), respectively. LN metastases were present in 28 LN stations of 8 patients. Of 8 cases with LN metastases, 40% (11.1-75% per case) of metastatic LNs were stained by ICG. Of 28 metastatic LN stations, 21 (75.0%) were covered by ICG, and actual metastatic LNs were stained in 16 LN stations (57.1%). In 4/8 cases (50%), all metastatic LN stations showed ICG signals., Conclusions: ICG fluorescence imaging and TMD are useful tools for visualizing the perigastric lymphatic network and retracing the exact location of ICG-stained LNs in AGC. However, ICG imaging is still not recommended for selective LN dissection in AGC because of the limited staining of perigastric LNs., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare. The paper is not based on a previous communication to a society or meeting., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Although FDG-PET is widely used in cancer, its role in gastric cancer (GC) is still controversial due to variable [ 18 F]fluorodeoxyglucose ([ 18 F]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 [ 18 F]FDG-PET., Methods: Based on a genetic signature, PETscore, representing [ 18 F]FDG avidity, was developed by imaging data acquired from thirty patient-derived xenografts (PDX). The PETscore was validated by [ 18 F]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 [ 18 F]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., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Stratification of patients who undergo curative resection for early gastric cancer (EGC) is warranted due to the heterogeneity in the risk of developing extragastric recurrence (EGR). Therefore, we aimed to stratify the need for postoperative surveillance for EGR detection in patients with EGC by developing a model for predicting EGR-free survival., Methods: This retrospective cohort study included patients who underwent postoperative surveillance after curative resection of EGC (n = 4149). Cox proportional hazard models were used to identify predictors to build a model for predicting EGR-free survival. Bootstrap-corrected c-index and calibration plots were used for internal and external (n = 2148) validations., Results: A risk-scoring system was constructed using variables significantly associated with EGR-free survival: pathologic T stage (pT1b[sm1], hazard ratio [HR] 4.928; pT1b[sm2], HR 5.235; pT1b[sm3], HR 7.748) and N stage (pN1, HR 4.056; pN2, HR 9.075; pN3, HR 30.659). Patients were dichotomized into a very-low-risk group or a low-or-greater-risk group. The 5-year EGR-free survival rates differed between the two groups (99.9 vs. 97.3%). The discriminative performance of the model was 0.851 (Uno's c-index) and 0.751 in the internal and external cohorts, respectively. The calibration slope was 0.916 and 1.131 in the internal and external cohorts, respectively., Conclusions: Our model for predicting EGR-free survival based on the pathologic T and N stages may be useful for stratifying patients who have undergone curative surgery for EGC. The results suggest that patients in the very-low-risk group may be spared from postoperative surveillance considering their extremely high EGR-free survival rate., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: There remain concerns about the safety and functional benefit of laparoscopic pylorus-preserving gastrectomy (LPPG) compared with laparoscopic distal gastrectomy (LDG). This study evaluated short-term outcomes of a randomized clinical trial (RCT) comparing LPPG with LDG for gastric cancer., Methods: The Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS)-04 trial was an investigator-initiated, open-label, parallel-assigned, superiority, multicentre RCT in Korea. Patients with cT1N0M0 cancer located in the middle third of the stomach at least 5 cm from the pylorus were randomized to undergo LPPG or LDG. Participants, care givers and those assessing the outcomes were not blinded to group assignment. Outcomes were 30-day postoperative morbidity rate and death at 90 days., Results: Some 256 patients from nine institutions were randomized (LPPG 129 patients, LDG 127 patients) between July 2015 and July 2017 and outcomes for 253 patients were analysed. Postoperative complications within 30 days were seen in 19.3 and 15.5 per cent in the LPPG and LDG groups respectively (P = 0·419). Postoperative pyloric stenosis was observed in nine (7.2 per cent) and two (1·5 per cent) patients in the LPPG and LDG groups (P = 0·026) respectively. In multivariable analysis higher BMI was a risk factor for postoperative complications (odds ratio 1·17, 95 per cent c.i. 1·04 to 1·32; P = 0·011). Death at 90 days was zero in both groups., Conclusion: Postoperative complications and mortality was comparable in patients undergoing LPPG and LDG. Registration number: NCT02595086 (http://www.clinicaltrials.gov)., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© 2021. The Author(s).)

Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both cancer cells and the tumor microenvironment (TME). We develop a 30-gene prediction model to determine the responsiveness to 5-FU and oxaliplatin-based chemotherapy and confirm the significant poor survival outcomes among cases classified as non-responder-like in three independent GC cohorts. Our study may inform clinical decision-making when designing treatment strategies., (© 2021. The Author(s).)

Introduction: With the introduction of new therapeutic options for gastric cancer treatment, more precise preoperative staging of gastric cancer is needed. The purpose of this study was to evaluate the role of endoscopic ultrasonography (EUS) for improving the accuracy of clinical T staging by computed tomography (CT) for gastric cancer., Materials and Methods: A total of 2636 patients underwent stomach protocol CT (S-CT) and EUS, followed by gastrectomy for primary gastric adenocarcinoma between September 2012 and February 2018 at Seoul National University Hospital. The results of preoperative S-CT and EUS were compared to the postoperative pathologic staging., Results: The overall accuracy of S-CT and EUS for T staging were 69.4% and 70.4%, respectively. When T staging was divided into T1-2 and T3-4 for clinically advanced gastric cancer (AGC), the positive predictive value for T3-4 using S-CT, EUS, and a combination of both modalities was 73.8%, 79.3%, and 85.6%, respectively. In 114 cases of indeterminate lesions between cT1 and cT2 by S-CT, EUS had a better prediction rate than the final decision based on endoscopy or the agreement between the two experts (Match rate: EUS vs. final decision, 69.3% vs. 58.8%)., Conclusion: EUS can be a complementary diagnostic tool to clinical T staging of gastric cancer by CT for selecting T3-4 lesion., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Malnutrition after gastrectomy is associated with a poor prognosis; however, no accurate model for predicting post-gastrectomy malnutrition exists. Hence, we conducted a retrospective study to develop a prediction model identifying gastric cancer patients at high risk of malnutrition after gastrectomy., Method: Gastric cancer patients who underwent curative gastrectomy with more than one weight measurement during a 3-year follow-up period were included. Malnutrition was defined as body mass index (BMI) < 18.5 kg/m 2 according to the European Society of Clinical Nutrition and Metabolism diagnostic criteria. BMI-loss pattern was analyzed using a group-based trajectory model. A prediction model for malnutrition 6 months after gastrectomy was developed based on significant risk factors, and then validated., Results: Overall, 1421 patients were examined. The BMI-loss trajectory model showed significant BMI loss at 6 months after gastrectomy. Severe BMI loss (mean 21.5%; n = 109) was significantly associated with the elderly, female sex, higher preoperative BMI, advanced cancer stage, open surgery, total gastrectomy, Roux-en-Y reconstruction, chemotherapy, and postoperative complications (all p < 0.05). Malnutrition 6 months after gastrectomy was observed in 152 (11.9%) of 1281 patients. Preoperative BMI, sex, and type of operation were included in the final prediction model as predictive factors (p < 0.05). The C-index of the developmental set and bootstrap validation of the prediction model was 0.91 (95% confidence interval 0.89-0.94) and 0.91, respectively., Conclusion: The prediction model for the risk of malnutrition 6 months after gastrectomy was accurately developed, with three independent risk factors: low preoperative BMI, female sex, and total or proximal gastrectomy.

Purpose: Patients who have undergone gastrectomy have unique symptoms that are not appropriately assessed using currently available tools. This study developed and validated a symptom-focused quality of life (QoL) questionnaire for patients who have received gastrectomy for gastric cancer., Materials and Methods: Based on a literature review, patient interviews, and expert consultation by the KOrean QUality of life in Stomach cancer patients Study group (KOQUSS), the initial item pool was developed. Two large-scale developmental studies were then sequentially conducted for exploratory factor analyses for content validity and item reduction. The final item pool was validated in a separate cohort of patients and assessed for internal consistency, test-retest reliability, construct validity, and clinical validity., Results: The initial questionnaire consisted of 46-items in 12 domains. Data from 465 patients at 11 institutions, followed by 499 patients at 13 institutions, were used to conduct item reduction and exploratory factor analyses. The final questionnaire (KOQUSS-40) comprised 40 items within 11 domains. Validation of KOQUSS-40 was conducted on 413 patients from 12 hospitals. KOQUSS-40 was found to have good model fit. The mean summary score of the KOQUSS-40 was correlated with the EORTC QLQ-C30 and STO22 (correlation coefficients, 0.821 and 0.778, respectively). The KOQUSS-40 score was also correlated with clinical factors, and had acceptable internal consistency (> 0.7). Test-retest reliability was greater than 0.8., Conclusion: The KOQUSS-40 can be used to assess QoL of gastric cancer patients after gastrectomy and allows for a robust comparison of surgical techniques in clinical trials.

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., (© 2021 John Wiley & Sons Ltd.)

Background: Tumor localization during totally laparoscopic gastrectomy is challenging owing to the invisibility of tumors on the serosal surface. We aimed to evaluate the clinical significance of intra-operative gastroscopy in totally laparoscopic partial gastrectomy., Methods: We reviewed 1084 gastric cancer patients who underwent either intra- or extracorporeal partial gastrectomy between 2014 and 2018. The intracorporeal group with intra-operative gastroscopy (intra-operative gastroscopy group, n = 187), the intracorporeal group without intra-operative gastroscopy (non-intra-operative gastroscopy group, n = 267), and the extracorporeal group (n = 630) were evaluated for the adequacy of surgical resection margins. We assessed whether total gastrectomy could be avoided according to the performance of intra-operative gastroscopy if the tumor was located within 3-5 cm away from the gastroesophageal junction., Results: The proximal margin positivity was lesser in the intra-operative gastroscopy group than in the non-intra-operative gastroscopy group (0% versus 2.2%; P = 0.045) but similar to that in the extracorporeal group (0% versus 0.6%; P = 0.579). The number of cases with proximal resection margins < 1 cm was lower in the intra-operative gastroscopy group than in the non-intra-operative gastroscopy group (3.7% versus 9.4%; P = 0.025) but comparable with that in the extracorporeal group (3.7% versus 4.1%; P = 0.815). Among 94 patients with lesions located within 3-5 cm apart from the gastroesophageal junction, the intra-operative gastroscopy group (n = 47) had fewer patients who underwent total gastrectomy than the non-intra-operative gastroscopy group (n = 47) (12.8% versus 44.7%; P = 0.001). Intra-operative gastroscopy was the only independent factor that prevented total gastrectomy (P = 0.001)., Conclusion: Intra-operative gastroscopy can provide margin safety during intracorporeal partial gastrectomy, avoiding unnecessary total gastrectomy.

Background: Laparoscopic distal gastrectomy for early gastric cancer has been widely accepted, but laparoscopic total gastrectomy has still not gained popularity because of technical difficulty and unsolved safety issue. We conducted a single-arm multicenter phase II clinical trial to evaluate the safety and the feasibility of laparoscopic total gastrectomy for clinical stage I proximal gastric cancer in terms of postoperative morbidity and mortality in Korea. The secondary endpoint of this trial was comparison of surgical outcomes among the groups that received different methods of esophagojejunostomy (EJ)., Methods: The 160 patients of the full analysis set group were divided into three groups according to the method of EJ, the extracorporeal circular stapling group (EC; n = 45), the intracorporeal circular stapling group (IC; n = 64), and the intracorporeal linear stapling group (IL; n = 51). The clinicopathologic characteristics and the surgical outcomes were compared among these three groups., Results: There were no significant differences in the early complication rates among the three groups (26.7% vs. 18.8% vs. 17.6%, EC vs. IC vs. IL; p = 0.516). The length of mini-laparotomy incision was significantly longer in the EC group than in the IC or IL group. The anastomosis time was significantly shorter in the EC group than in the IL group. The time to first flatus was significantly shorter in the IL group than in the EC group. The long-term complication rate was not significantly different among the three groups (4.4% vs. 12.7% vs. 7.8%; EC vs. IC vs. IL; p = 0.359), however, the long-term incidence of EJ stenosis in IC group (10.9%) was significantly higher than in EC (0%) and IL (2.0%) groups (p = 0.020)., Conclusions: The extracorporeal circular stapling and the intracorporeal linear stapling were safe and feasible in laparoscopic total gastrectomy, however, intracorporeal circular stapling increased EJ stenosis.

Background and Aims: Guidelines propose different extents of macroscopic proximal margin for gastric cancer and frozen margin investigation in selected cases, but data is lacking. This study was to evaluate the necessary extent of macroscopic proximal margin, accuracy of frozen margin investigation, and prognostic impact of tumor-free proximal margin length in pT2-pT4 gastric cancer., Study Design: Proximal and distal frozen margins were routinely investigated intraoperatively in all pT2-pT4 gastric cancers resected between 2011 and 2017. Macroscopic and microscopic proximal margin lengths were correlated. For R0-resections, survival analysis was performed for distal gastrectomy (DG) with microscopic proximal margin length ≤3 cm versus >3 cm., Results: Overall, 1484 patients were included. Microscopic proximal margin lengths were macroscopically more often misestimated in diffuse histology (P = 0.0004), but extent of underestimation in centimeter was similar to intestinal and mixed/undetermined type (P = 0.134). Fifteen cases (1.0%) resulted in R1-resection, 10 at distal, and 5 at proximal margin but none with macroscopic proximal margin ≥3 cm and negative frozen section. Overall agreement of frozen margin and final pathology was 2951/2968 (99.4%). Proximal margin length in DG did not correlate with survival or recurrence in R0-resected patients., Discussion: Diffuse histology is at higher risk for underestimation of proximal margin length, but extent of underestimation is similar in other Laurén subtypes. If ≥3 cm macroscopic proximal margin length is applied with intraoperative frozen margin confirmation, R1-resection can be avoided., Conclusion: In pT2-T4a gastric cancer, proximal margin of ≥3 cm plus frozen margin confirmation provides high oncological safety. In DG patients with R0-resection, proximal margin length does not correlate with survival or recurrence.

Purpose: We aimed to investigate the usefulness of near-infrared indocyanine green (ICG)-enhanced fluorescence guidance for infrapyloric LN dissection in laparoscopic distal gastrectomy., Methods: This study enrolled patients with early gastric cancer scheduled for laparoscopic distal gastrectomy. After intraoperative submucosal injection of ICG (0.1 mg/mL), LN dissection was conducted under near-infrared ICG fluorescence guidance. The operation time, bleeding events during infrapyloric LN dissection were analyzed. Cases were retrospectively 1:3 propensity-score matched to patients who underwent laparoscopic distal gastrectomy without ICG injection., Results: The mean time from midline omentectomy to exposure of the right gastroepiploic vein was significantly shorter in the ICG group (n = 20) than in the non-ICG group (n = 60) (13.05 ± 5.77 vs 18.68 ± 7.92 min; p = 0.001), and the incidence of bleeding during infrapyloric LN dissection was lower in the ICG group (20% vs 68.3%, p < 0.001). The two groups did not differ significantly regarding the number of LNs retrieved from the infrapyloric area (p = 0.434)., Conclusions: Near-infrared ICG fluorescence guidance facilitates safe and fast infrapyloric LN dissection in laparoscopic distal gastrectomy.

Purpose: It is unclear whether laparoscopic distal gastrectomy for locally advanced gastric cancer is oncologically equivalent to open distal gastrectomy. The noninferiority of laparoscopic subtotal gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer compared with open surgery in terms of 3-year relapse-free survival rate was evaluated., Patients and Methods: A phase III, open-label, randomized controlled trial was conducted for patients with histologically proven locally advanced gastric adenocarcinoma suitable for distal subtotal gastrectomy. The primary end point was the 3-year relapse-free survival rate; the upper limit of the hazard ratio (HR) for noninferiority was 1.43 between the laparoscopic and open distal gastrectomy groups., Results: From November 2011 to April 2015, 1,050 patients were randomly assigned to laparoscopy (n = 524) or open surgery (n = 526). After exclusions, 492 patients underwent laparoscopic surgery and 482 underwent open surgery and were included in the analysis. The laparoscopy group, compared with the open surgery group, suffered fewer early complications (15.7% v 23.4%, respectively; P = .0027) and late complications (4.7% v 9.5%, respectively; P = .0038), particularly intestinal obstruction (2.0% v 4.4%, respectively; P = .0447). The 3-year relapse-free survival rate was 80.3% (95% CI, 76.0% to 85.0%) for the laparoscopy group and 81.3% (95% CI, 77.0% to 85.0%; log-rank P = .726) for the open group. Cox regression analysis after stratification by the surgeon revealed an HR of 1.035 (95% CI, 0.762 to 1.406; log-rank P = .827; P for noninferiority = .039). When stratified by pathologic stage, the HR was 1.020 (95% CI, 0.751 to 1.385; log-rank P = .900; P for noninferiority = .030)., Conclusion: Laparoscopic distal gastrectomy with D2 lymphadenectomy was comparable to open surgery in terms of relapse-free survival for patients with locally advanced gastric cancer. Laparoscopic distal gastrectomy with D2 lymphadenectomy could be a potential standard treatment option for locally advanced gastric cancer.

Patient-derived xenografts (PDX) have emerged as an important translational research tool for understanding tumor biology and enabling drug efficacy testing. They are established by transfer of patient tumor into immune compromised mice with the intent of using them as Avatars; operating under the assumption that they closely resemble patient tumors. In this study, we established 27 PDX from 100 resected gastric cancers and studied their fidelity in histological and molecular subtypes. We show that the established PDX preserved histology and molecular subtypes of parental tumors. However, in depth investigation of the entire cohort revealed that not all histological and molecular subtypes are established. Also, for the established PDX models, genetic changes are selected at early passages and rare subclones can emerge in PDX. This study highlights the importance of considering the molecular and evolutionary characteristics of PDX for a proper use of such models, particularly for Avatar trials.

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.

Background: Scarce data are available on the characteristics of postoperative organ failure (POF) and mortality after gastrectomy. We aimed to describe the causes of organ failure and mortality related to gastrectomy for gastric cancer and to identify patients with POF who are at a risk of failure to rescue (FTR)., Methods: The study examined patients with POF or in-hospital mortality in Seoul National University Hospital between 2005 and 2014. We identified patients at a high risk of FTR by analyzing laboratory findings, complication data, intensive care unit records, and risk scoring including Acute Physiology and Chronic Health Evaluation (APACHE) IV, Sequential Organ Failure Assessment (SOFA) score, and Simplified Acute Physiology Score (SAPS) 3 at ICU admission., Results: Among the 7304 patients who underwent gastrectomy, 80 (1.1%) were identified with Clavien-Dindo classification (CDC) grade ≥ IVa. The numbers of patients with CDC grade IVa, IVb, and V were 48 (0.66%), 11 (0.15%), and 21 (0.29%), respectively. Pulmonary failure (43.8%), surgical site complication (27.5%), and cardiac failure (13.8%) were the most common causes of POF and mortality. Cancer progression (100%) and cardiac events (45.5%) showed high FTR rates. In univariate analysis, acidosis, hypoalbuminemia, SOFA, APACHE IV, and SAPS 3 were identified as risk factors for FTR (P < 0.05). Finally, SAPS 3 was identified as an independent predictive factor for FTR., Conclusions: Cancer progression and acute cardiac failure were the most lethal causes of FTR. SAPS 3 is an independent predictor of FTR among POF patients after gastrectomy.

Tumor-promoting inflammation is a hallmark of cancer and is highly associated with tumor progression, angiogenesis, and metastasis. Tumor-associated macrophages (TAMs) are major drivers of tumor-promoting inflammation, but due to the complexity of the tumor microenvironment, the detailed regulatory mechanisms are still under investigation. Here, we investigated a novel role for transglutaminase 2 (TGM2) in the development of tumor-promoting inflammation and recruitment of TAMs to gastric cancer (GC) tissues. When estimated by array comparative genomic hybridization and droplet digital PCR, the copy numbers of the TGM2 gene were amplified in 13.6% (14/103) of GC patients and positively associated with TGM2 expression. Gene set enrichment analysis of expression microarray data for GC samples with high or low TGM2 expression showed that increased TGM2 expression was associated with tumor-promoting inflammation in GC. In addition, the expression of TGM2 was correlated with the expression of markers for macrophages, neutrophils, blood vessels, and lymphatic vessels. Overexpression of TGM2 in GC cells augmented the IL-1β-induced secretion of macrophage-recruiting chemokines and NF-κB activation. TGM2 protein levels were associated with the expression levels of the macrophage marker CD163 in human GC tissue samples. Moreover, GC patients with high expression of TGM2 had a worse prognosis than those with low expression of TGM2. These results suggest TGM2 as a novel regulator of the tumor microenvironment of GC and provide a promising target for constraining tumor-promoting inflammation.

There are still lot of controversies whether aberrant left hepatic artery (ALHA) originating from left gastric artery should be ligated or preserved during gastric cancer (GC) surgery. We aimed to investigate this issue. We reviewed ALHA cases who had laparoscopic gastrectomy for gastric cancer at Seoul National University Hospital (SNUH) from 2012 to 2016. Type of ALHA variants using Michel's classification of hepatic arterial anatomy and diameter of each vessel were evaluated by 2 radiologists. Postoperative hepatic function and surgical outcome were collected until 6 months after surgery. Results showed that if the diameter of ALHA was larger than 1.5 mm, a transient elevation of SGOT and SGPT on postoperative day 2 was observed in the ligated cases. No differences were observed in operation time, amount of blood loss, overall complication rate, hospital stay, and number of lymph nodes retrieved between the ligated and preserved replaced left hepatic artery (RLHA) and accessory left hepatic artery (acLHA) group. In this study, we conclude that ligation of ALHA seems to be safe as none of the patients suffered adverse outcome. A transient rise in postoperative SGOT and SGPT levels were seen after ligating ALHA >1.5 mm in diameter regardless of subtype.

Background: Development of high-performance serum biomarkers will likely improve treatment outcomes of patients with gastric cancer (GC). We previously identified the candidate serum markers, anosmin 1 (ANOS1), dihydropyrimidinase-like 3 (DPYSL3), and melanoma-associated antigen D2 (MAGE-D2) and evaluated their clinical significance through a single-center retrospective analysis. Here we conducted a prospective multicenter observational study aimed at validating the diagnostic performance of these potential markers., Methods: We analyzed serum levels before and after surgery of the three potential biomarkers in patients with GC and healthy volunteers. Quantification of serum and GC tissue levels was performed using an ELISA., Results: Area under the curve (AUC) values that discriminated patients with GC from healthy controls were - 0.7058, 0.6188, and 0.5031 for ANOS1, DPYSL3, and MAGED2, respectively. The sensitivity and specificity of the ANOS1 assay were 0.36 and 0.85, respectively. The AUC value of ANOS1 that discriminated patients with stage I GC from healthy controls was 0.7131. Serum ANOS1 levels were significantly elevated in patients with stage I GC compared with those of healthy controls (median 1179 ng/ml and 461 ng/ml, respectively, P < 0.0001) and decreased after resection of primary GC lesions (P < 0.0001). The combination of serum ANOS1 and DPYSL3 levels increased the AUC value that discriminated patients with GC from healthy controls. Serum levels of ANOS1 did not significantly correlate with those of carcinoembryonic antigen, carbohydrate antigen 19-9, or other markers of inflammation., Conclusions: Serum levels of ANOS1 may serve as a useful diagnostic tool for managing GC.