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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.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.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.Patients were treated with R0 resection either by laparoscopic gastrectomy or open gastrectomy as the full analysis set of the KLASS-02 trial.Five-year OS and RFS rates, recurrence patterns, and long-term surgical complications were evaluated.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%]).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.ClinicalTrials.gov Identifier: NCT01456598.

Purpose: Gastric cancer peritoneal carcinomatosis is fatal. Delay in detection of peritoneal metastases contributes to high mortality, highlighting the need to develop biomarkers that can help identify patients at high risk for peritoneal recurrence or metastasis. Experimental Design: We performed a systematic discovery and validation for the identification of peritoneal recurrence prediction and peritoneal metastasis detection biomarkers by analyzing expression profiling datasets from 249 patients with gastric cancer, followed by analysis of 426 patients from three cohorts for clinical validation. Results: Genome-wide expression profiling identified a 12-gene panel for robust prediction of peritoneal recurrence in patients with gastric cancer (AUC = 0.95), which was successfully validated in a second dataset (AUC = 0.86). Examination of 216 specimens from a training cohort allowed us to establish a six gene–based risk-prediction model [AUC = 0.72; 95% confidence interval (CI): 0.66–0.78], which was subsequently validated in an independent cohort of 111 patients with gastric cancer (AUC = 0.76; 95% CI: 0.67–0.83). In both cohorts, combining tumor morphology and depth of invasion further improved the predictive accuracy of the prediction model (AUC = 0.84). Thereafter, we evaluated the performance of the identical six-gene panel for its ability to detect peritoneal metastasis by analyzing 210 gastric cancer specimens (prior 111 patients plus additional 99 cases), which discriminated patients with and without peritoneal metastasis (AUC = 0.72). Finally, our biomarker panel was also remarkably effective for identifying peritoneal micrometastasis (AUC = 0.72), and its diagnostic accuracy was significantly enhanced when depth of invasion was included in the model (AUC = 0.85). Conclusions: Our novel transcriptomic signature for risk stratification and identification of high-risk patients with peritoneal carcinomatosis might serve as an important clinical decision making in patients with gastric cancer.

Diffuse type gastric cancer (DGC), represented by low sensitivity to chemotherapy and poor prognosis, is a heterogenous malignancy in which patient subsets exhibit diverse oncological risk-profiles. This study aimed to develop molecular biomarkers for robust prognostic risk-stratification and improve survival outcomes in patients with diffuse type gastric cancer (DGC). We undertook a systematic and comprehensive discovery and validation effort to identify recurrence prediction biomarkers by analyzing genome-wide transcriptomic profiling data from 157 patients with DGC, followed by their validation in 254 patients from 2 clinical cohorts. Genome-wide transcriptomic profiling identified a 7-gene panel for robust prediction of recurrence in DGC patients (AUC = 0.91), which was successfully validated in an independent dataset (AUC = 0.86). Examination of 180 specimens from a training cohort allowed us to establish a gene-based risk prediction model (AUC = 0.78; 95% CI 0.71–0.84), which was subsequently validated in an independent cohort of 74 GC patients (AUC = 0.83; 95% CI 0.72–0.90). The Kaplan–Meier analyses exhibited a consistently superior performance of our risk-prediction model in the identification of high- and low-risk patient subgroups, which was significantly improved when we combined our gene signature with the tumor stage in both clinical cohorts (AUC of 0.83 in the training cohort and 0.89 in the validation cohort). Finally, for an easier clinical translation, we established a nomogram that robustly predicted prognosis in patients with DGC. Our novel transcriptomic signature for risk-stratification and identification of high-risk patients with recurrence could serve as an important clinical decision-making tool in patients with DGC.

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.

Sentinel node navigation surgery reduces the extent of gastric and lymph node dissection, and may improve quality of life. The benefit and harm of laparoscopic sentinel node navigation surgery (LSNNS) for early gastric cancer is unknown. The SENORITA (SEntinel Node ORIented Tailored Approach) trial investigated the pathological and surgical outcomes of LSNNS compared with laparoscopic standard gastrectomy (LSG) with lymph node dissection.The SENORITA trial was an investigator-initiated, open-label, parallel-assigned, non-inferiority, multicentre RCT conducted in Korea. The primary endpoint was 3-year disease-free survival. The secondary endpoints, morbidity and mortality within 30 days of surgery, are reported in the present study.A total of 580 patients were randomized to LSG (292) or LSNNS (288). Surgery was undertaken in 527 patients (LSG 269, LSNNS 258). LSNNS could be performed according to the protocol in 245 of 258 patients, and a sentinel node basin was detected in 237 (96·7 per cent) Stomach-preserving surgery was carried out in 210 of 258 patients (81·4 per cent). Postoperative complications occurred in 51 patients in the LSG group (19·0 per cent) and 40 (15·5 per cent) in the LSNNS group (P = 0·294). Complications with a Clavien-Dindo grade of III or higher occurred in 16 (5·9 per cent) and 13 (5·0 per cent) patients in the LSG and LSNNS groups respectively (P = 0·647).The rate and severity of complications following LSNNS for early gastric cancer are comparable to those after LSG with lymph node dissection. Registration number: NCT01804998 ( http://www.clinicaltrials.gov).La cirugía de navegación del ganglio centinela (sentinel node navigation surgery, SNNS) reduce la extensión de la resección gástrica y ganglionar, y puede mejorar la calidad de vida. Se desconoce el beneficio y el daño de la cirugía de navegación del ganglio centinela por vía laparoscópica (laparoscopic sentinel node navigation surgery, LSNNS) para el cáncer gástrico precoz. El ensayo clínico SENORITA investigó los resultados patológicos y quirúrgicos de LSNNS en comparación con la gastrectomía laparoscópica estándar (laparoscopic gastrectomy, LSG) con disección ganglionar (lymph node dissection, LND). MÉTODOS: El ensayo SENORITA fue un ensayo multicéntrico aleatorizado y controlado, iniciado por investigadores, abierto, con asignación a grupos paralelos y de no inferioridad llevado a cabo en Corea. El resultado primario fue la supervivencia libre de enfermedad a los 3 años. En el presente estudio, se describen los resultados secundarios correspondientes a morbilidad y mortalidad a los 30 días del postoperatorio.Un total de 580 pacientes fueron aleatorizados a LG (n = 292) o LSNNS (n = 288). La cirugía se realizó en 527 pacientes (LG 269, LSNNS 258). LSNNS pudo ser realizada de acuerdo con el protocolo en 245 de 258 pacientes y en 237 de 245 pacientes (96,7%) se detectó un ganglio centinela. La cirugía con preservación del estómago se realizó en 210 de 258 pacientes (81,4%). Las complicaciones postoperatorias se presentaron en 51 pacientes del grupo LSG (19,0%) y en 40 pacientes (15,5%) del grupo LSNNS (P = 0,294). Las complicaciones grado III o mayor de Clavien-Dindo se detectaron en 16 (5,9%) y 13 pacientes (5,0%) de los grupos LSG y LSNNS, respectivamente (P = 0,647). CONCLUSIÓN: El porcentaje y la gravedad de las complicaciones tras LSNNS para cancer gástrico precoz son comparables a la LSG con LND.

OBJECTIVE To qualify surgeons to participate in a randomized trial comparing laparoscopic and open distal D2 gastrectomy for advanced gastric cancer. SUMMARY OF BACKGROUND DATA No studies have sought to qualify surgeons for a randomized trial comparing laparoscopic and open D2 gastrectomy for advanced gastric cancer. METHODS We conducted a multicenter prospective observational study evaluating unedited videos of laparoscopic and open D2 gastrectomy performed by 27 surgeons. Surgeons performed 3 of each laparoscopic and open distal gastrectomies with D2 lymphadenectomy for gastric cancer. Five peers reviewed each unedited video using a video assessment form. Based on experts' review of videos, a separate review committee decided surgeons as "Qualified" or "Not-qualified." RESULTS Twelve surgeons (44.4%) were qualified on initial evaluation whereas the other 15 surgeons were not. Another 9 surgeons were finally qualified after re-evaluation. The median score for Qualified was significantly higher than Not-qualified (P < 0.001).Significant differences between Qualified and Not-qualified were noted both in operation type and in all evaluation area of surgical skill, perigastric, and extra-perigastric lymphadenectomy, although the inter-rater variability of the assessment score was low (kappa = 0.285). However, Not-qualified surgeons' scores improved upon re-evaluation of resubmitted videos.When compared laparoscopy with open surgery, median scores were similar between the 2 groups (P = 0.680). However, open gastrectomy scores for surgical skills were significantly higher than for laparoscopic surgery (P = 0.016). CONCLUSIONS Our surgeon quality control study for gastrectomy represents a milestone in surgical standardization for surgical clinical trials. Our methods could also serve as a system for educating surgeons and assessing surgical proficiency.

OBJECTIVE To compare long-term outcomes between robotic and LG approaches using propensity score weighting based on a generalized boosted method to control for selection bias. SUMMARY OF BACKGROUND DATA Minimally invasive surgical approaches for GC are increasing, yet limited evidence exists for long-term outcomes of robotic gastrectomy (RG). METHODS Patients (n = 2084) with GC stages I-III who underwent LG or RG between 2009 and 2017 were analyzed. Generalized boosted method was used to estimate a propensity score derived from all available preoperative characteristics. Long-term outcomes were compared using the adjusted Kaplan-Meier method and the weighted Cox proportional hazards regression model. RESULTS After propensity score weighting, the population was balanced. Patients who underwent RG showed reduced blood loss (16 mL less, P = 0.025), sufficient lymph node harvest from the initial period, and no changes in surgical outcomes over time. With 52-month median follow-up, no difference was noted in 5-year overall survival in unweighted [91.5% in LG vs 94% in RG; hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.46-1.1; P = 0.126] and weighted populations (94.2% in LG vs 93.2% in RG; HR, 0.88; 95% CI, 0.52-1.48; P = 0.636). There were no differences in 5-year recurrence-free survival (RFS), with unweighted 5-year RFS of 95.4% for LG and 95.2% for RG (HR, 0.95; 95% CI, 0.55-1.64; P = 0.845) and weighted 5-year RFS of 96.3% for LG and 95.3% for RG (HR, 1.24; 95% CI, 0.66-2.33; P = 0.498). CONCLUSIONS After balancing covariates, RG demonstrated reliable surgical outcomes from the beginning. Long-term survival after RG and LG for GC was similar.

BACKGROUND We aimed to evaluate the safety and efficacy of a clinical pathway (CP) for enhanced recovery after surgery (ERAS) in gastric cancer patients, including early oral feeding and discharge on postoperative day 4. METHODS We performed a prospective, single-center, phase II clinical trial. Based on proposed indications for an ERAS CP in our retrospective study, we enrolled 133 patients younger than 65 years who were undergoing minimally invasive subtotal gastrectomy. The primary endpoint was the ERAS CP completion rate. Secondary endpoints included complication, mortality, hospital stay, and readmission. RESULTS Among 133 patients, six patients were dropped out from this study. The ERAS CP completion rate (77.2%, 98 of 127) was comparable to the historical control group that completed a conventional CP (85.4%, P = .085). The postoperative complication incidence (13.4%, 15 of 127) was also similar to that of the conventional CP group (9.5%, P = .174). We identified reduced hospital stays (4.7 ± 1.3 vs 7.2±2.3 days; P

PURPOSE To compare postoperative complications, long-term survival, and quality of life (QOL) after laparoscopic sentinel node navigation surgery (LSNNS) and laparoscopic standard gastrectomy (LSG). METHODS Five hundred eighty patients with preoperatively diagnosed stage IA gastric adenocarcinoma (≤ 3 cm) were assigned to undergo either LSG or LSNNS. Observers were not blinded to patient grouping. The primary outcome was 3-year disease-free survival (3y-DFS). Secondary outcomes included postoperative complications, QOL, 3-year disease-specific survival (3y-DSS), and 3-year overall survival (3y-OS). RESULTS In total, 527 patients were included in the modified intention-to-treat analysis population for the primary outcome (LSG, 269; LSNNS, 258). Stomach-preserving surgery was performed in 210 patients (81%) in the LSNNS group. During the median follow-up duration, the 3y-DFS rates in the LSG and LSNNS groups were 95.5% and 91.8%, respectively (difference: 3.7%; 95% CI, –0.6 to 8.1). Three patients with recurrence and five with metachronous gastric cancer in the LSNNS group underwent standard surgery. Two patients with distant metastasis in both groups were treated with palliative chemotherapy. The 3y-DSS and 3y-OS rates in the LSG and LSNNS groups were 99.5% and 99.1% ( P = .59) and 99.2% and 97.6% ( P = .17), respectively. Postoperative complications occurred in 19.0% of the LSG group and 15.5% of the LSNNS group ( P = .294). The LSNNS group showed better physical function ( P = .015), less symptoms ( P < .001), and improved nutrition than the LSG group. CONCLUSION LSNNS did not show noninferiority to LSG for 3y-DFS, with a 5% margin. However, the 3y-DSS and 3y-OS were not different after rescue surgery in cases of recurrence/metachronous gastric cancer, and LSNNS had better long-term QOL and nutrition than LSG.

The importance of methylation in the tumorigenic responses of nonhistone proteins, such as TP53, PTEN, RB1, AKT, and STAT3, has been emphasized in numerous studies. In parallel, the corresponding nonhistone protein methyltransferases have been acknowledged in the pathophysiology of cancer. Thus, this study aimed to explore the pathological role of a nonhistone methyltransferase in gastric cancer (GC), identify nonhistone substrate protein, and understand the underlying mechanism. Interestingly, among the 24 methyltransferases and methyltransferase family 16 (MTF16) proteins, EEF1AKMT3 (METTL21B) expression was prominently lower in GC tissues than in normal adjacent tissues and was associated with a worse prognosis. In addition, EEF1AKMT3-knockdown induced gastric tumor invasiveness and migration. Through gain and loss-of-function studies, mass spectrometry analysis, RNA-seq, and phospho-antibody array, we identified EEF1AKMT3 as a novel tumor-suppressive methyltransferase that catalyzes the monomethylation of MAP2K7 (MKK7) at K296, thereby decreasing the phosphorylation, ubiquitination, and degradation of TP53. Furthermore, EEF1AKMT3, p-MAP2K7, and TP53 protein levels were positively correlated in GC tissues. Collectively, our results delineate the tumor-suppressive function of the EEF1AKMT3/MAP2K7/TP53 signaling axis and suggest the dysregulation of the signaling axis as potential targeted therapy in GC.

The present study aimed to investigate whether the Janus‑activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a critical mechanism underlying the cancer‑associated fibroblast (CAF)‑induced chemoresistance of gastric cancer (GC). In addition, the present study tried to suggest a natural product to compromise the effects of CAF on the chemoresistance of GC. The results of cell proliferation assay revealed that the conditioned medium (CM) collected from CAFs further increased resistance to 5‑fluorouracil (5‑FU) in GC cell lines. Secretome analysis revealed that the levels of several secreted proteins, including C‑C motif chemokine ligand 2, C‑X‑C motif chemokine ligand 1, interleukin (IL)‑6 and IL‑8, were increased in the CM from CAFs co‑cultured with cancer cells compared to CM from cancer cells. Western blot analysis revealed that CAFs activated the JAK/STAT3 signaling pathway in cancer cells. The experimental models revealed that curcumin abrogated the CAF‑mediated activation of the JAK/STAT3 signaling pathway in GC cells.

IntroductionPatients who underwent curative gastrectomy for gastric cancer are regularly followed-up for the early detection of recurrence and postoperative symptom management. However, there is a lack of evidence with regard to proper surveillance intervals and diagnostic tools. This study aims to evaluate whether frequent surveillance tests have a survival benefit or improve the quality of life in patients who underwent curative resection for advanced gastric cancer.Methods and analysisThe STOFOLUP trial is an investigator-initiated, parallel-assigned, multicentre randomised controlled trial involving 16 hospitals in the Republic of Korea. Patients (n=886) diagnosed with pathological stage II or III gastric adenocarcinoma will be randomised to either the 3-month or the 6-month group at a 1:1 ratio, stratified by trial site and tumour stage. Patients allocated to the 3-month group will undergo an abdominal CT scan every 3 months postoperatively and those allocated to the 6-month group will undergo CT every 6 months. The primary endpoint is 3-year overall survival and the secondary endpoints are quality of life, as assessed using KOrean QUality of life in Stomach cancer patients Study group-40, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the stomach cancer-specific module (STO22), and nutritional outcomes. Other survival data including data concerning 3-year disease-free survival, recurrence-free survival, gastric cancer-specific survival and postrecurrence survival will also be estimated. The first patient was enrolled on July 2021 and active patient enrolment is currently underway.Ethics and disseminationThis study has been approved by the Institutional Review Board of eight of the participating hospitals (NCC 2021-0085, KBSMC2021-01-059, SMC 2021-01-140, KC21OEDE0082, 4-2021-0281, AJIRB-MED-INT-20-608, 2021-0515 and H-2102-093-1198). This study will be disseminated through peer-reviewed publications, national or international conferences.Trial registration numberNCT04740346.

The aim of the study was to evaluate the short-term outcomes of KLASS-02-RCT, a multicenter randomized controlled trial comparing laparoscopic distal gastrectomy (LDG) with D2 lymphadenectomy with open distal gastrectomy (ODG).Although several benefits of laparoscopic gastric cancer surgery have been reported, strong evidence is still limited, especially in locally advanced gastric cancer which requires extensive lymph node dissection.Enrollment criteria included histologically confirmed cT2-4a and N0-1 gastric adenocarcinoma. Thirty-day morbidity, 90-day mortality, postoperative pain, and recovery were compared between LDG and ODG groups.A total of 1050 patients were randomly assigned to LDG (n = 526) or ODG group (n = 524) between November 2011 and April 2015. After excluding patients who received bypass or no surgery, 1011 patients were analyzed as actual treatment group. Mean number of totally retrieved lymph nodes was similar in both groups (LDG = 46.6 vs ODG = 47.4, P = 0.451). Early morbidity rate was significantly lower after LDG (16.6%) than after ODG (24.1%; P = 0.003). Postoperative analgesics use and patients' reported pain score were significantly lower after LDG. First day of flatus was earlier after LDG (3.5 vs 3.7 d, P = 0.025) and postoperative hospital stay was shorter in LDG group (8.1 vs 9.3 d, P = 0.005). Ninety days' mortality rate was similar in both groups (LDG = 0.4% vs ODG = 0.6%, P = 0.682).Laparoscopic distal gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer shows benefits in terms of lower complication rate, faster recovery, and less pain compared with open surgery.

Linear-shaped gastroduodenostomy (LSGD) is a new method of intracorporeal reconstruction that is simpler to perform and associated with a lower rate of bile reflux than delta-shaped anastomosis. Here, we analyzed the learning curve of LSGD in totally laparoscopic distal gastrectomy. The cumulative sum method was used to retrospectively analyze consecutive gastric cancer patients undergoing intracorporeal gastroduodenostomy after distal gastrectomy between January 2009 and May 2016. The duration of surgery, postoperative complications, hospital stay, and endoscopic findings in the postoperative period and the first, third, and fifth year were evaluated according to the two phases of the learning curve (learning period versus mastery period). Data from 222 patients were included in the analysis. The LSGD learning period was 29 cases. The surgical time in mastery period was significantly shorter than the learning period (124.9 ± 34.5 versus 168.2 ± 42.0 min, p

Background Delayed detection of tumours contributes to poor prognosis in patients with gastric cancer (GC). The invasive nature of endoscopy and the absence of an effective serum markers highlight the need to develop novel, noninvasive biomarkers. Methods We performed biomarker discovery and validation to identify candidate genes in three gene expression data sets. After validating the gene panel in clinical tissues, we translated the gene panel into serum samples by performing training and validation in 89 samples from GC patients and 54 from healthy donors in two independent cohorts. Results We identified a nine-gene panel in the discovery phase, with subsequent validation in tissue specimens. Using a serum training cohort, we developed a 5-gene risk prediction formulae for the diagnosis of GC; bootstrapped analysis exhibited an AUC of 0.896. We validated this 5-gene biomarker panel using an independent serum cohort, yielding an AUC of 0.947. This biomarker panel successfully identified GC, regardless of tumour histology. Notably, biomarker performance for detection of stage 1 and 2 GC displayed an AUC of 0.928 and 0.980 in both serum cohorts. Conclusions We identified a novel 5-gene biomarker panel for noninvasive diagnosis of GC, which might serve as a potential diagnostic tool for early detection.

Introduction Textbook outcome is a composite quality measurement of short-term outcomes for evaluating complex surgical procedures. We compared textbook outcome and survival of robotic total gastrectomy(RTG) with those of laparoscopic total gastrectomy(LTG).Methods We retrospectively reviewed 395patients(RTG,n = 74;LTG,n = 321) who underwent curative total gastrectomy for gastric cancer via minimally invasive approaches from 2009 to 2018. We performed propensity score matched analysis to adjust for potential selection bias. Textbook outcome included a negative resection margin, no intraoperative complication, retrieved lymph nodes > 15, no severe complication, no reintervention, no unplanned intensive care unit admission, hospitalisation ≤ 21days, no readmission after discharge, and no postoperative mortality. Survival outcomes included 5-year overall and relapse-free survival rates.Results After matching, 74patients in each group were selected. Textbook outcome was similar in the RTG and LTG groups(70.3% and 75.7%,respectively), although RTG required a longer operative time. The quality metric least often achieved was the presence of severe complications in both groups(77.0% in both groups). There were no differences in the 5-year overall survival rate(90.7% and 85.9%,respectively;log-rank P = 0.144) and relapse-free survival rate between the RTG and LTG groups(89.5% and 85.2%,respectively;log-rank P = 0.167).Conclusion Textbook outcome and survival outcome of RTG were comparable to those of LTG for gastric cancer.

Few current preoperative risk assessment tools provide essential, optimized treatment for gastric cancer. The purpose of this study was to develop and validate a nomogram that uses preoperative data to predict survival and risk assessments. A survival prediction model was constructed using data from a developmental cohort of 1251 patients with stage I to III gastric cancer who underwent curative resection between January 2005 and December 2008 at Ajou University Hospital, Korea. The model was internally validated for discrimination and calibrated using bootstrap resampling. To externally validate the model, data from a validation cohort of 2012 patients with stage I to III gastric cancer who underwent surgery at multiple centers in Korea between January 2001 and June 2006 were analyzed. Analyses included the model’s discrimination index (C-index), calibration plots, and decision curve that predict overall survival. Eight independent predictors, including age, sex, clinical tumor size, macroscopic features, body mass index, histology, clinical stages, and tumor location, were considered for developing the nomogram. The discrimination index was 0.816 (adjusted C-index) in the developmental cohort and 0.781 (adjusted C-index) in the external validation cohort. Additionally, in both the developmental and validation datasets, age and tumor size were significantly correlated with each other and were independent indicators for survival (P < 0.05). We developed a new nomogram by using the most common and significant preoperative parameters that can help to identify high-risk patients before treatment and help clinicians to make appropriate decisions for patients with stage I to III gastric cancer.

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.

Few studies have presented evidence pertaining to the adequate minimum number of adjuvant chemotherapy (AC) cycles required to achieve an oncologic benefit for gastric cancer. From January 2012 to December 2013, data from patients who underwent curative radical gastrectomy and consequently received AC for pathologic stage 2 or 3 gastric cancer at 27 institutions in South Korea were analyzed. The study enrolled 925 patients, 661 patients (71.5%) who completed 8 cycles of AC and 264 patients (28.5%) who did not. Compared with the mean disease-free survival (DFS) of the patients who completed 8 AC cycles (69.3 months), the mean DFS of patients who completed 6 AC cycles (72.4 months; p = 0.531) and those who completed 7 AC cycles (63.7 months; p = 0.184) did not differ significantly. However, the mean DFS of the patients who completed 5 AC cycles (48.2 months; p = 0.016) and those who completed 1–4 AC cycles (62.9 months; p = 0.036) was significantly lower than the DFS of those who completed 8 AC cycles. In the multivariate Cox proportional hazards analysis, the mean DFS was significantly affected by advanced stage, large tumor size, positive vascular invasion, and number of completed AC cycles (1–5 cycles: hazard ratio 1.45; 95% confidence interval 1.01–2.08; p = 0.041). The current multicenter observational cohort study showed that the mean DFS for 6 or 7 AC cycles was similar to that for 8 AC cycles as an adjuvant treatment for gastric cancer.

IMPORTANCE: The incidence of gallstones has been reported to increase after gastrectomy. However, few studies have been conducted on the prevention of gallstone formation in patients who have undergone gastrectomy. OBJECTIVE: To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) in preventing gallstone formation after gastrectomy in patients with gastric cancer. DESIGN, SETTING, AND PARTICIPANTS: The PEGASUS-D study (Efficacy and Safety of DWJ1319 in the Prevention of Gallstone Formation after Gastrectomy in Patient with Gastric Cancer: A Multicenter, Randomized, Double-blind, Placebo-controlled Study) was a randomized, double-blind, placebo-controlled clinical trial conducted at 12 institutions in the Republic of Korea. Adults (aged ≥19 years) with a diagnosis of gastric cancer who underwent total, distal, or proximal gastrectomy were enrolled between May 26, 2015, and January 9, 2017; follow-up ended January 8, 2018. Efficacy was evaluated by both the full analysis set, based on the intention-to-treat principle, and the per-protocol set; full analysis set findings were interpreted as the main results. INTERVENTIONS: Eligible participants were randomly assigned to receive 300 mg of UDCA, 600 mg of UDCA, or placebo at a ratio of 1:1:1. Ursodeoxycholic acid and placebo were administered daily for 52 weeks. MAIN OUTCOMES AND MEASURES: Gallstone formation was assessed with abdominal ultrasonography every 3 months for 12 months. Randomization and allocation to trial groups were carried out by an interactive web-response system. The primary end point was the proportion of patients developing gallstones within 12 months after gastrectomy. RESULTS: A total of 521 patients (175 received 300 mg of UDCA, 178 received 600 mg of UDCA, and 168 received placebo) were randomized. The full analysis set included 465 patients (311 men; median age, 56.0 years [interquartile range, 48.0-64.0 years]), with 151 patients in the 300-mg group, 164 patients in the 600-mg group, and 150 patients in the placebo group. The proportion of patients developing gallstones within 12 months after gastrectomy was 8 of 151 (5.3%) in the 300-mg group, 7 of 164 (4.3%) in the 600-mg group, and 25 of 150 (16.7%) in the placebo group. Compared with the placebo group, odds ratios for gallstone formation were 0.27 (95% CI, 0.12-0.62; P = .002) in the 300-mg group and 0.20 (95% CI, 0.08-0.50; P

Gastrokine 1 (GKN1) is a stomach-specific tumor suppressor that is secreted into extracellular space as an exosomal cargo protein. The objective of this study was to investigate the uptake and tumor-suppressive pathways of exosome-associated GKN1 protein in gastric epithelial cells. Immunofluorescent and Western blot analysis were used to investigate gastric-specific uptake of HFE-145-derived exosomes. Binding affinity of HFE-145 derived exosomes with integrin proteins was examined using protein microarray chip. Tumor suppressor activities of exosome-carrying GKN1 protein were analyzed using transwell co-culture, MTT assay, BrdU incorporation, immunoprecipitation, and Western blot analysis. HFE-145-derived exosomes were internalized only into HFE-145 gastric epithelial cells and gastric cancer cells. Gastric-specific uptake of stomach-derived exosomes required integrin α6 and αX proteins. Clathrin and macropinocytosis increased the uptake of exosomes into gastric epithelial cells, whereas caveolin inhibited the uptake of exosomes. Transwell co-culture of AGS cells with HFE-145 cells markedly inhibited viability and proliferation of AGS cells. Following uptake of HFE-145-derived exosomes in recipient cells, GKN1 protein bound to HRas and inhibited the binding of HRas to b-Raf and c-Raf which subsequently downregulated HRas/Raf/MEK/ERK signaling pathways in AGS, MKN1 cells, and MKN1-derived xenograft tumor tissues. In addition, exosomal GKN1 protein suppressed both migration and invasion of gastric cancer cells by inhibiting epithelial–mesenchymal transition. Gastric-specific uptake of exosomes derived from gastric epithelial cells requires integrin α6 and αX proteins in both gastric epithelial cells and exosomes. Exosomal GKN1 protein inhibits gastric carcinogenesis by downregulating HRas/Raf/MEK/ERK signaling pathways.

We conducted an RNA sequencing study to identify novel gene fusions in 80 discovery dataset tumors collected from young patients with diffuse gastric cancer (DGC). Twenty-five in-frame fusions are associated with DGC, three of which (CLDN18-ARHGAP26, CTNND1-ARHGAP26, and ANXA2-MYO9A) are recurrent in 384 DGCs based on RT-PCR. All three fusions contain a RhoGAP domain in their 3’ partner genes. Patients with one of these three fusions have a significantly worse prognosis than those without. Ectopic expression of CLDN18-ARHGAP26 promotes the migration and invasion capacities of DGC cells. Parallel targeted RNA sequencing analysis additionally identifies TACC2-PPAPDC1A as a recurrent and poor prognostic in-frame fusion. Overall, PPAPDC1A fusions and in-frame fusions containing a RhoGAP domain clearly define the aggressive subset (7.5%) of DGCs, and their prognostic impact is greater than, and independent of, chromosomal instability and CDH1 mutations. Our study may provide novel genomic insights guiding future strategies for managing DGCs., Diffuse Gastric Cancer (DGC) is increasingly being considered separate to intestinal type gastric cancer; several fusions events have been reported as drivers of the disease but few of those have been subsequently validated. Here the authors perform RNA-seq on early-onset DGC patients who had not been treated with chemotherapy or radiation and identify a previously unknown fusion.

Gastrokine 1 (GKN1) plays important roles in maintaining mucosal homeostasis, and in regulating cell proliferation and differentiation. Here, we determined whether GKN1 is a potential theragnostic marker for gastric cancer. We identified GKN1 binding proteins using the protein microarray assay and investigated whether GKN1 is one of the exosomal cargo proteins by western blot, immunoprecipitation, and immunofluorescent assays. Cell proliferation and apoptosis were analyzed by MTT, BrdU incorporation, flow cytometry, and western blot assays. We further validated the functional relevance of exosomal GKN1 in MKN1-injected xenograft mice. The possibility of serum GKN1 as a diagnostic marker for gastric cancer was determined by ELISA assay. In protein microarray assay, GKN1 binding to 27 exosomal proteins was clearly observed. GKN1 was expressed in exosomes derived from HFE-145 gastric epithelial cells by western blot and immunofluorescent assays, but not in exosomes from AGS and MKN1 gastric cancer cells. Exosomes carrying GKN1 inhibited cell proliferation and induced apoptosis in both AGS and MKN1 cells, and exosomes carrying GKN1-treated nude mice-bearing MKN1 xenograft tumors exhibited significantly reduced tumor volume and tumor weight. Silencing of clathrin markedly down-regulated the internalization of exosomal GKN1. Interestingly, serum GKN1 concentrations in patients with gastric cancer were significantly lower than those in healthy individuals and patients with colorectal and hepatocellular carcinomas. The GKN1 is secreted and internalized in the gastric epithelium by exosome-driven transfer, which inhibits gastric tumorigenesis and supports the clinical application of GKN1 protein in gastric cancer diagnosis and treatment.

Gastric signet ring cell carcinoma (SRC) has shown a favorable outcome in early stages but has a worse prognosis than non-SRC in advanced stages. However, the cause for this stage-dependent prognostic impact has not been determined. This study aimed to compare clinicopathologic features and recurrence patterns between gastric SRC and non-SRC in a cohort of Eastern patients. This study reviewed the prospectively collected data of 764 patients undergoing curative resection for gastric cancer from 2005 to 2008. The demographics, clinicopathologic characteristics, disease-specific survival (DSS) rate, and recurrence-free survival (RFS) rate of the patients were analyzed. The SRC patients (n = 176) had a worse prognosis than the non-SRC patients (n = 588), especially in stages T3 and T4. Peritoneal recurrence and the incidence of neural invasion (NI) were significantly increased in the SRC patients, albeit only in stages T3 and T4. In the T3 and T4 patients with NI, peritoneal recurrence occurred more frequently in SRC than in non-SRC (28.7% vs. 13.7%; p = 0.001), but not in the T3 and T4 patients without NI. Only in the patients with NI, SRC led to a significantly shorter DSS (67.6 vs. 90.7 months; p = 0.008) and RFS (67.1 vs. 80.3 months; p = 0.036) than non-SRC. This report is the first to present the relationship between NI and peritoneal recurrence as the cause of stage-dependent prognoses for SRC. A better understanding of NI may lend insight into cancer spread and recurrence, especially in gastric SRC.

Background: The application of laparoscopic surgery using instruments that are 3 mm or less in diameter for patients with early gastric cancer (EGC) has not yet been established. We aimed to evalua...

The effects of cancer-associated fibroblasts (CAF) on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAF and GC cells have not been applied in a clinical setting. Here, we examined if inhibition for Axl receptor tyrosine kinase (AXL) can suppress CAF-induced aggressive phenotype in GC. We investigated the function of CAF-derived growth arrest-specific 6 (GAS6), a major ligand of AXL, on the migration and proliferation of GC cells. The effect of the AXL inhibitor, BGB324, on the CAF-induced aggressive phenotype of GC cells was also investigated. In addition, we performed immunohistochemistry to examine the expression of phosphorylated AXL protein in 175 GC tissues and evaluated its correlation with the prognosis. The qPCR and western blot analysis showed that GAS6 expression was higher in CAF relative to other cells. We found that co-culture with CAF increased the phosphorylation of AXL (P-AXL), differentiation into a mesenchymal-like phenotype, and cell survival in GC cell lines. When the expression of AXL was genetically inhibited in GC cells, the effect of CAF was reduced. BGB324, a small molecule inhibitor of AXL, suppressed the effects of CAF on GC cell lines. In GC tissues, high levels of P-AXL were significantly associated with poor overall survival (P = 0.022). We concluded that CAF are a major source of GAS6 and that GAS6 promotes an aggressiveness through AXL activation in GC. We suggested that an AXL inhibitor may be a novel agent for GC treatment.

The role of palliative surgical resection in recurrent or metastatic gastric cancer is still controversial. A retrospective review was conducted on 689 patients who received palliative chemotherapy for recurrent (n = 307) or primary metastatic (n = 382) gastric cancer. Among 131 patients (89 primary metastatic and 42 recurrent) with surgical resection before chemotherpay, 75 underwent gastrectomy, 42 metastasectomy, and 14 gastrectomy with metastasectomy. The median overall survival (OS) of patients who underwent surgical resection was significantly longer than that of patients who received chemotherapy alone (18 vs. 9 months, p p p p pensity score matching. In addition, the median OS of patients who underwent gross complete resection (n = 54) was significantly longer than that of patients who underwent incomplete resection (n = 77) (30 vs. 15 months, p = 0.002). The present study suggests that judicious use of surgical resection before chemotherapy in recurrent or metastatic gastric cancer patients may result in a favorable outcome, especially when complete resection is achievable.

Background Although the tumor stroma in solid tumors like gastric cancer (GC) plays a crucial role in chemo-resistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. The present study aims to determine whether cancer-associated fibroblasts (CAFs), a major component of the tumor stroma, confer chemotherapeutic resistance to GC cells, and to discover potential targets to improve chemo-response in GC. Methods To identify CAF-specific proteins and signal transduction pathways affecting chemo-resistance in GC cells, secretome and transcriptome analyses were performed. We evaluated the inhibiting effect of CAF-specific protein in in vivo and in vitro models and investigated the expression of CAF-specific protein in human GC tissues. Results Secretome and transcriptome data revealed that interleukin-6 (IL-6) is a CAF-specific secretory protein that protects GC cells via paracrine signaling. Furthermore, CAF-induced activation of the Janus kinase 1-signal transducer and activator of transcription 3 signal transduction pathway confers chemo-resistance in GC cells. CAF-mediated inhibition of chemotherapy-induced apoptosis was abrogated by the anti-IL-6 receptor monoclonal antibody tocilizumab in various experimental models. Clinical data revealed that IL-6 was prominently expressed in the stromal portion of GC tissues, and IL-6 upregulation in GC tissues was correlated with poor responsiveness to chemotherapy. Conclusions Our data provide plausible evidence for crosstalk between GC cells and CAFs, wherein IL-6 is a key contributor to chemoresistance. These findings suggest the potential therapeutic application of IL-6 inhibitors to enhance the responsiveness to chemotherapy in GC. Electronic supplementary material The online version of this article (10.1186/s12943-019-0972-8) contains supplementary material, which is available to authorized users.

Laparoscopy-assisted endoscopic full-thickness resection (LAEFTR) has been suggested as an alternative to laparoscopic wedge resection in the treatment of gastric subepithelial tumors (SETs). It is expected to minimize the resection of the tissue surrounding the tumors and maintain the function of the remnant stomach. Here, we performed a prospective pilot study to evaluate the efficacy of laparoscopy-assisted endoscopic full-thickness resection (LAEFTR) for patients with gastric SETs.We enrolled twelve patients who were diagnosed with gastric SETs with an intraluminal growth pattern or which is located in the gastric antrum between October 2011 and September 2013. LAEFTR was performed endoscopically using an endoscopic knife to make an incision half way around the tumor circumference and a laparoscopic resection around the remaining tumor circumference, followed by its laparoscopic removal. The feasibility, safety, and effectiveness of LAEFTR for gastric SETs were evaluated.The median size of the tumors in twelve patients was 22 mm (21-33). Of the 12 patients, 8 received LAEFTR, while the others underwent conventional laparoscopic wedge resection, since their tumor outlines were clearly visible in laparoscopic view. In 8 patients who underwent LAEFTR, the mean total operation time (endoscopic procedure time/laparoscopic procedure time) were 117 (37/41) min. The tumors were completely resected with clear margin, and there was no perioperative and postoperative complications.LAEFTR currently seems to be the ideal treatment modality of intraluminal gastric SETs where their resection margins are difficult to define under laparoscopic guidance alone.

It has been reported that serum insulin-like growth factor-binding protein 2 (IGFBP2) levels are elevated in various types of cancers. However, the clinicopathologic and prognostic implications of circulating IGFBP2 have never been investigated in gastric cancer. We tested IGFBP2 levels in the sera of 118 gastric cancer patients and 34 healthy controls using enzyme-linked immunosorbent assay (ELISA). The mean serum IGFBP2 level was significantly elevated in the gastric cancer patients compared to controls (805.23 ± 590.56 ng/ml vs. 459.61 ± 277.01 ng/ml; P < 0.001). Serum IGFBP2 levels were significantly higher in larger (> 6 cm) tumors (956.8 ± 734.0 ng/ml vs. 548.6 ± 364.0 ng/ml; P = 0.007) and in higher (T3/4) T stages (854.8 ± 621.4 ng/ml vs. 546.5 ± 315.1 ng/ml; P = 0.037). Multivariate Cox analysis showed that higher serum IGFBP2 level (> 400.01 ng/ml) was an independent prognostic factor predicting worse overall survival in patients with gastric cancer (hazard ratio (HR): 3.749, P = 0.034). When we divided patients into four groups based on blood IGFBP2 levels, survival was stratified. The HRs for death in the 3rd and 4th quartiles of serum IGFBP2 levels in comparison to that in the 1st quartile were 2.527 (P = 0.043) and 3.092 (P = 0.012). In conclusion, circulating IGFBP2 has potential as a biomarker predicting prognosis for gastric cancer patients.

The aim of this study was to evaluate the prognostic significance of the intratumor stromal proportion in gastric signet ring cell (SRC) carcinomas. Cancer stroma, as exemplified by cancer-associated fibroblasts (CAFs), plays critical roles in cancer proliferation, invasion, and metastasis. One hundred seventy-five SRC carcinoma cases were classified according to the intratumor desmoplastic stromal proportion to then analyze the clinicopathologic characteristics of stroma-rich cases. We also investigated the impact of CAFs on the migration as well as on the phenotypic changes of gastric SRC carcinomas in vitro. Furthermore, we performed RNA sequencing of a pair of CAFs and normal-tissue-associated fibroblasts. Stroma-rich SRC carcinomas (64 of 175 cases, 36.5%) were associated with female patients (P = 0.045), large tumor size (P = 0.007), higher T category (P

AT-rich interactive domain 1A (ARID1A) is frequently mutated in gastric cancers, and loss of ARID1A expression is considered a poor prognostic factor in various cancers. However, in practice, ARID1A shows various expression patterns, and our understanding of its significance is limited. We performed immunohistochemistry for ARID1A, MLH1, and pS6 using whole tissue blocks of 350 gastric cancers and classified the ARID1A expression as follows: retained (63.7%), reduced (17.7%), complete loss (14.9%), and partial loss (3.7%). Complete/partial loss was more common in poorly differentiated histology (P < .001), and reduced or complete loss of ARID1A was frequent in cases with MLH1 loss (P < .001). The ARID1A-reduced group showed only slightly inferior disease-free survival (DFS; P = .254) and overall survival (OS; P = .377) compared to those of the ARID1A-retained group, whereas the group with complete loss showed significantly worse DFS (hazard ratio [HR], 1.732; P = .015) and OS (HR, 1.751; P = .013). Worse DFS (HR, 2.672; P = .005) and OS (HR, 2.531; P = .002) were also noted in the group with partial loss. High expression of pS6 was observed more frequently in groups showing altered ARID1A expression patterns (P < .001). In conclusion, reduced ARID1A expression is not a major prognostic determinant, although it may lead to AKT pathway activation. Tumor cells lacking ARID1A expression may influence the prognosis even if they constitute only a small proportion of the tumor sample. Our data provide an enhanced roadmap for understanding ARID1A with implications for future research and therapeutics.

Metastasis-associated in colon cancer-1 (MACC1), a newly identified oncogene, promotes tumor proliferation and invasion via the MET pathway. The purpose of this study is to determine the clinical significance of MACC1 and MET expression in the long-term survival and recurrence in a large cohort of gastric carcinoma patients following curative resection. We evaluated the prognostic value of MACC1 and MET expression using immunohistochemistry in 331 gastric adenocarcinoma patients. MACC1-positive patients had lower overall survival (OS) or event-free survival (EFS) rates than MACC1-negative patients (P=0.039 and P=0.044, respectively), while MET positivity itself was not associated with either OS or EFS. Multivariate analysis identified the expression level of MACC1 protein as an independent negative prognostic factor for OS or EFS (P=0.021 and P=0.016, respectively). This study suggests that MACC1 is an independent prognostic factor in gastric adenocarcinoma and that the prognostic impact of MACC1 may be associated with MACC1 partners other than MET.

Discoidin domain receptor 1 (DDR1) is activated by fibrillar (triple-helical) collagens and collagen IV, which are major components of tumor stroma; thus, DDR1 might be a critical mediator of communication between cancer cells and stroma. The aim of this study was to investigate the effect of DDR1 inhibition on stroma-induced peritoneal metastasis in gastric carcinoma. We analyzed by immunohistochemistry the correlation between DDR1 expression and the pattern of recurrence in gastric carcinoma tissues from a previously characterized and established gastric carcinoma patient cohort. We also cocultured human gastric carcinoma cell lines with gastric cancer–associated fibroblasts (CAF) and investigated DDR1 expression and activation. We evaluated CAF-induced tumorigenic properties of gastric carcinoma cell lines and the effect of a DDR1-specific inhibitor in organotypic cultures and in a peritoneal seeding xenograft animal model. The expression of DDR1 in gastric cancer tissues was positively associated with early recurrence (P = 0.043) and a high incidence of peritoneal recurrence (P = 0.036). We confirmed that coculturing with CAFs elevated DDR1 protein expression in gastric carcinoma cell lines and enhanced gastric carcinoma cell line spheroid formation in organotypic cultures in a tumor cell DDR1-dependent manner. Coimplantation of CAFs with gastric carcinoma cells enhanced peritoneal tumor formation in vivo, an effect that was sensitive to pharmacologic inhibition of DDR1. Implications: This study highlights that CAF-induced elevation of DDR1 expression in gastric carcinoma cells enhances peritoneal tumorigenesis, and that inhibition of DDR1 is an attractive strategy for the treatment of gastric carcinoma peritoneal metastasis. Mol Cancer Res; 16(10); 1590–600. ©2018 AACR.

Purpose: The role of peritoneal washing cytology in determining further treatment strategies after surgery for gastric cancer remains unclear. One reason for this is the fact that optimal procedures to increase the accuracy of predicting peritoneal metastasis have not been established. The aim of this study was to evaluate the efficacy of cytology using samples harvested from two different abdominal cavity sites during gastric cancer surgery. Materials and Methods: We prospectively recruited 108 patients who were clinically diagnosed with locally advanced gastric cancer (higher than cT1 stage disease). Peritoneal washing fluids were collected from the pouch of Douglas and the subphrenic area. Patients were prospectively followed up for 2 years to determine the recurrence and survival rates. Results: Thirty-three patients dropped out of the study for various reasons, so 75 patients were included in the final analysis. Seven patients (9.3%) showed positive cytology findings, of whom, three showed peritoneal recurrence. Tumor size was the only factor associated with positive cytology findings (P=0.037). The accuracy and specificity of cytology for predicting peritoneal recurrence were 90.1% and 94.2%, respectively, whereas the sensitivity was 50.0%. The survival rate did not differ between patients with positive cytology findings and those with negative cytology findings (P=0.081). Conclusions: Peritoneal washing cytology using samples harvested from two different sites in the abdominal cavity was not able to predict peritoneal recurrence or survival in gastric cancer patients. Further studies will be required to determine whether peritoneal washing cytology during gastric cancer surgery is a meaningful procedure.

BACKGROUND The clinicopathological significance of oncofetal mRNA-binding protein, human insulin-like growth factor II mRNA-binding protein 3 (IMP3), in gastric carcinoma (GC) is not fully understood. MATERIALS AND METHODS Tissue microarray blocks with specimens from 346 patients with GC were constructed to evaluate the clinicopathological role of IMP3 expression in GC. These results were validated with an online dataset of 876 patients from the Kaplan-Meier Plotter. Sera from 15 controls and 57 patients with GC were collected in order to compare the levels of serum IMP3 between groups. RESULTS High expression of IMP3 was significantly associated with poor prognosis. Survival curves from the Kaplan-Meier Plotter showed that high IMP3 expression was significantly related to worse disease-free survival and overall survival. CONCLUSION Tissue overexpression of IMP3 might be used as a predictor of advanced disease or lymph node metastasis, and is associated with poorer prognosis in GCs.

PURPOSE It is hypothesized that robotic gastrectomy may surpass laparoscopic gastrectomy after the operators acquire long-term experience and skills in the manipulation of robotic arms. This study aimed to evaluate the long-term learning curve of robotic distal gastrectomy (RDG) for gastric cancer compared with laparoscopic distal gastrectomy (LDG). MATERIALS AND METHODS From October 2008 to December 2015, patients who underwent LDG (n=809) were matched to patients who underwent RDG (n=232) at a 1:1 ratio, by using a propensity score matching method after stratification for the operative year. The surgical outcomes, such as trends of operative time, blood loss, and complication rate, were compared between the two groups. RESULTS The RDG group showed a longer operative time (171.3 minutes vs. 147.6 minutes, P

Determining resection margins for gastric cancer, which are not exposed to the serosal surface of the stomach, is the most important procedure during totally laparoscopic gastrectomy (TLG). The aim of this protocol is to introduce a procedure for intraoperative gastroscopy, in order to directly mark tumors during TLG for gastric cancer in the middle third of the stomach. Patients who were diagnosed with adenocarcinoma in the middle third of the stomach were enrolled in this case series. Before surgery, additional gastroscopy for tumor localization is not performed. Under general anesthesia, laparoscopic mobilization of the stomach is performed first. After the first portion of the duodenum is mobilized from the pancreas and clamped, the surgeon moves to the other side for the gastroscopic procedure. On the insertion of a gastroscope through the oral cavity into the stomach, 2 - 3 cc of indigo carmine is administered via an endoscopic injector into the gastric muscle layer at the proximal margin of the stomach. The location of stained serosa in the laparoscopic view is used to guide distal subtotal gastrectomy, however, total gastrectomy is performed if the tumor is too close to the esophagogastric junction. A specimen is sampled after distal gastrectomy to confirm sufficient length from resection margin to tumor before reconstruction. In our case series, all patients had tumor-free margins and required no additional resection. There was no morbidity related to the gastroscopic procedure, and the time required for the procedure has gradually decreased to about five minutes. Intraoperative gastroscopy for tumor localization is an accurate and tolerated method for gastric cancer patients undergoing totally laparoscopic distal gastrectomy.

Compared to end-to-side anastomosis with a circular stapler, the overlap method is favored for intracorporeal esophagojejunostomy because it facilitates handling of the stapler, even in narrow spaces, and wider anastomosis. However, it associates with technical difficulties during anastomosis, including difficult traction on the esophageal stump that necessitates stay sutures. Here, we introduce a new modified overlap method that employs knotless barbed sutures (MOBS) and report the outcomes of our case series. All consecutive patients who underwent intracorporeal esophagojejunostomy in 2015–2016 were included. All patients underwent surgery as follows: After esophageal transection with a linear stapler, two V-loc 90 sutures (Covidien, Mansfield, MA, USA) were sutured in the center of the stapled line. The opening was made between the two threads, and the intraluminal space was identified. The jejunum was ascended toward the esophageal stump by inserting a 45-mm-long linear staple. The anastomosis was made at the space between the right and left crura. After firing the linear stapler, the entry hole was closed bidirectionally using the pre-sutured threads. Forty patients underwent MOBS (27 by laparoscopy; 13 by robot). Mean total operative and MOBS procedural times were 180.6 and 22.4 min, respectively. Mean hospital stay was 6.9 days. Two patients had major complications (5.0 %). There were no anastomosis-related complications. Laparoscopy and robot subgroups did not differ in mean MOBS procedural times (22.2 vs. 22.7 min, p = 0.787). MOBS is a safe and feasible method that is a good option for intracorporeal esophagojejunostomy after laparoscopic gastrectomy.

Hospital volume is known to be a crucial factor in reducing postoperative morbidity and mortality in laparoscopic gastrectomy for gastric cancer. However, it is unclear whether surgeon’s individual experience can overcome the effect of hospital volume. Clinicopathologic data of initial 50 laparoscopic gastrectomy cases were collected from six gastric cancer surgeons. Half of the six surgeons worked in high-volume centers, and the other half worked in low-volume hospitals. Perioperative outcomes were compared between the high-volume centers and the low-volume hospitals. Three low-volume hospitals in this study contained significantly more male and older patients with a higher American Society of Anesthesiologists score than high-volume centers. Although high- and low-volume hospitals mainly used laparoscopy-assisted and totally laparoscopic approach, respectively, there were no differences between the two groups in the extent of resection, operating time, estimated blood loss, and number of collected lymph nodes. Postoperative recovery such as duration to soft diet and hospital stay did not differ between the high- and the low-volume hospitals. No significant difference was found in postoperative morbidities by Clavien–Dindo classification. There was no mortality reported in both groups of the enrolled hospitals. Hospital volume is not a decisive factor in affecting postoperative morbidity and mortality for well-trained beginners in laparoscopic surgery for gastric cancer.

In contrast to mitochondria in healthy cells, which utilize oxidative phosphorylation, malignant cells undergo elevated glycolysis for energy production using glucose. The objectives of this study were to evaluate whether the expression of various molecules, including pyruvate dehydrogenase kinase-1 (PDK-1), is involved in the altered glucose metabolism associated with gastric cancer prognosis and to assess the role of a therapeutic agent in targeting glucose metabolism in gastric cancer. Immunohistochemistry was performed on gastric cancer tissues obtained from 152 patients who underwent curative resection to assess the expression of hypoxia-inducible factor-1α (HIF-1α), glucose transporter-1 (GLUT-1), hexokinase-2 (HK-2) and PDK-1. In an in vitro analysis, the lactate production and glucose uptake levels, cellular viability and 5-fluorouracil (5-FU) responses were evaluated before and after treatment with dichloroacetate (DCA), a PDK-1 inhibitor, in the MKN45 and AGS gastric cancer cell lines and in the non-cancerous HEK293 cell line. GLUT-1 and PDK-1 expression was significantly associated with tumor progression, although only PDK-1 expression was an independent prognostic factor for patients who received 5-FU adjuvant treatment. There was no significant difference in cell viability between the HEK293 and gastric cancer cell lines following DCA treatment. However, DCA treatment reduced lactate production and increased responsiveness to 5-FU in MKN45 cells, which expressed high levels of PDK-1 in comparison to the other cell lines. Thus, PDK-1 may serve as a biomarker of poor prognosis in patients with gastric cancer. In addition, PDK-1 inhibitors such as DCA may be considered an additional treatment option for patients with PDK-1-expressing gastric cancers.

This study aimed to verify the long-term outcome of a minimally invasive endoscopic or laparoscopic approach for the treatment of gastric gastrointestinal stromal tumor (GIST).This single-center study involved a retrospective review of gastric tumors that were pathologically confirmed as GIST. A total of 84 patients who underwent minimally invasive endoscopic or laparoscopic resection for gastric GIST were enrolled from February 2002 to June 2007. These demographics, tumor characteristics, and outcomes were analyzed for identification of outcomes and feasibility of endoscopic or laparoscopic resection.Of 84 patients, 27 and 57 patients underwent endoscopic and laparoscopic resection, respectively. The average tumor size was 3.1 ± 1.7 cm. With a mean follow-up of 40.5 ± 20.7 months, 82 (97.7%) patients were disease free. Two patients, both of whom underwent laparoscopic resection, were alive with peritoneal recurrence. Two (7.4%) and 6 (10.5%) patients, respectively, had postoperative complications after endoscopic resection and laparoscopic resection. There was no significant difference in the operative morbidity according to tumor size. There was no postoperative mortality.Laparoscopic surgery for gastric GIST is safe and feasible, even in large (5 cm) tumors. Because endoscopic resection showed good results without recurrence, this approach can be useful in selected cases with a high operative risk or a need for preservation of organ function.

Purpose: As the proportion of early gastric cancer (EGC) has recently been increased, minimally invasive treatment is currently accepted as main therapy for EGC. Accurate preoperative staging is very important in determining treatment options. To know the accuracy of endoscopic ultrasonography (EUS), we compared the depth of invasion of the tumor with preoperative EUS and postoperative pathologic findings. Materials and Methods: We retrospectively analyzed 152 patients who underwent EUS before laparoscopic gastrectomy. The preoperative EUS results were compared with the pathological findings. Results: The overall proportion of coincidence for depth of invasion between EUS and pathologic results was 41.4%. Univariate analysis showed that the rate of corrected prediction of EUS for tumor depth significantly decreased for the lesions more than 3cm in diameter (P=0.033), and those with a depressed morphology (P=0.035). In multivariate analysis, the depressed type (P=0.029, OR=2.873) and upper lesion (P=0.035, OR=2.151) was the significantly independent factors influencing the inaccurate prediction of EUS for tumor depth. Conclusions: When we decide the treatment modality considering the clinical depth of invasion by EUS, the possibility of discordance with pathologic results should be considered for the lesions located in the upper third of the stomach and with a depressed morphology.

Background This study evaluated the feasibility and safety of robotic surgery in gastrectomy for gastric cancer. Methods Between April and October 2009, 12 patients who were diagnosed with stage I gastric cancer underwent robot-assisted distal gastrectomy (RADG) using the da Vinci System (Intuitive Surgical, Sunnyvale, CA). The clinical and pathological characteristics of the patients and surgical outcome were analyzed. Results All procedures were completed successfully, with no laparoscopic or open conversion. The mean operating time was 253 minutes (range 170–365), and the mean blood loss was 135 mL (range 30–500). The resection margin was negative in all specimens, and a mean of 46 (range 21–115) lymph nodes was retrieved. The mean time to resume a soft diet and hospital stay was 4.6 and 6.6 days, respectively. Acute pancreatitis occurred in 1 patient and resolved with conservative management. Conclusions In our initial experience, RADG was feasible, enabling a fast patient recovery and good operative outcome.

Purpose: Gastric cancer surgery is a common operation in East Asia, such as Korea and Japan, and there has been a significant increase in the need for this procedure due to the aging population. As a result, surgery for the treatment of gastric cancer for elderly patients is expected to increase. This study examined the effect of old age on gastric cancer surgery, and analyzed the operative risk factors for elderly patients. Materials and Methods: From November 2008 to August 2010, 590 patients, who underwent a curative resection for gastric cancers, were enrolled. Patients who underwent palliative or emergency surgery were excluded. A retrospective analysis of the correlation between surgical outcomes and age was performed. The elderly were defined as patients who were over the age of 65 years. Results: The mean age of all patients was 58.3 years, and complications occurred in 87 cases (14.7%). The most common complication was wound infection and severe complications requiring surgical, endoscopic, or radiologic intervention developed in 52 cases (8.8%). The rate of complications increased with increasing age of the patients. Univariate analysis revealed age, comorbidity, extent of resection, operation time, and combined resection to be associated with surgical complications. In particular, age over 75 years old, operation time, and comorbidity were predictive factors in multivariate analysis. In the elderly, only comorbidity was associated with surgical complications Conclusions: The patients’ age is the most important factor for predicting surgical complications. Surgeons should pay an attention to the performance of gastric cancer surgery on elderly patients. In particular, it must be performed carefully for elderly patients with a comorbidity.

Background To date, early oral feeding after gastrectomy for gastric cancer has not been accepted universally. Therefore, we performed a randomized clinical trial to determine whether early oral feeding after curative surgery for gastric cancer can be tolerated and whether it has an effect on recovery. Methods From July 2008 to February 2009, 58 patients were enrolled and 4 were excluded according to set criteria. The patients in the early feeding group began a liquid diet on the second postoperative day, and then were fed a soft diet from the third day until the day they were discharged. The patients in the control group began a liquid diet on the fourth day. The primary endpoint of this study was the duration of postoperative hospitalization. Results No significant differences were found in the clinico-operative characteristics between the 2 groups. The duration of hospitalization (P = .044) and time until flatus (P = .036) in the early group were decreased significantly. With regard to the rates of morbidity, cost of hospitalization, postoperative symptoms, and pain scales, no significant differences were found. The quality of life scores were decreased significantly at the fatigue (P = .007) and nausea and vomiting (P = .048) immediately after operation in the early feeding group. Conclusion Early oral feeding after gastric cancer surgery is feasible and can result in shorter hospitalization and improvements in several aspects of quality of life in the early postoperative period.