Identification of maximal tumor size associated with negligible lymph node metastasis for endoscopic submucosal dissection of undifferentiated-type early gastric cancer.

BACKGROUND AND AIMS: When treating undifferentiated-type early gastric cancer (UD-EGC) that is limited to the mucosa (clinically T1a), endoscopic submucosal dissection (ESD) can be considered if the tumor is 2 cm or less and is not ulcerated. However, there is insufficient evidence to determine the relationships between tumor size and oncological safety of ESD in UD-EGC. METHODS: The pathology reports of Korean patients who were diagnosed with UD-EGC (n = 5286) were retrospectively reviewed. The cumulative incidence of lymph node metastasis (LNM) according to tumor size was evaluated in subgroups. The tumor-size cut-off was identified as the upper limit of the 95% confidence interval (CI) of cumulative LNM incidence that did not exceed 1.0%. RESULTS: We identified 1516 patients with non-ulcerated T1a tumors ≤2 cm in size. Among patients without lymphatic invasion, 1.5% (95% CI 0.91-2.16%) had LNM. In patients with poorly differentiated tubular adenocarcinoma (PD), LNM increased from 0 to 0.74% based on a tumor size of 1.0 cm. Regardless of tumor size, smaller percentages of undifferentiated-type (UD) and poorly cohesive carcinoma (PCC) patients experienced LNM than did those with PD. In non-ulcerated mucosal cancer without lymphatic invasion and tumor size ≤0.9 cm, no LNM was observed in patients with UD (95% CI 0-0.53%), PCC (95% CI 0-0.59%), or PD (95% CI 0-0.86%) histologic type. CONCLUSION: In patients diagnosed with non-ulcerated T1a UD-EGC, ESD can be performed if the tumor size is 0.9 cm or less, regardless of histologic type.

Prognostic and predictive impact of sex in locally advanced microsatellite instability high gastric or gastroesophageal junction cancer: An individual patient data pooled analysis of randomized clinical trials.

BACKGROUND: Surgery plus peri-operative/adjuvant chemotherapy is the standard of care for locally advanced GC/GEJC, though with unsatisfactory results. dMMR/MSI-high tumors have better prognosis and scant benefit from chemotherapy as compared to pMMR/MSS ones. The differential outcome of therapies in terms of safety and efficacy according to sex is still debated in GC/GEJC patients. METHODS: We previously performed an individual patient data pooled analysis of MAGIC, CLASSIC, ITACA-S, and ARTIST trials including GC/GEJC patients treated with surgery alone or surgery plus peri-operative/adjuvant chemotherapy to assess the value of MSI status. We performed a secondary analysis investigating the prognostic and predictive role of sex (female versus male) in the pooled analysis dataset in the overall population and patients stratified for MSI status (MSI-high versus MSS/MSI-low). Disease-free (DFS) and overall survival (OS) were calculated. RESULTS: Patients with MSI-high tumors had improved survival as compared to MSS/MSI-low ones irrespective of sex, whereas in those with MSS/MSI-low tumors, females had numerically longer OS and DFS (5-year OS was 63.2% versus 57.6%, HR 0.842; p = 0.058, and 5-year DFS was 55.8% versus 50.8%, HR 0.850; p = 0.0504 in female versus male patients). The numerical difference for the detrimental effect of chemotherapy in MSI-high GC was higher in females than males, while the significant benefit of chemotherapy over surgery alone was confirmed in MSS/MSI-low GC irrespective of sex. CONCLUSIONS: This pooled analysis including four randomized trials highlights a relevant impact of sex in the prognosis and treatment efficacy of MSI-high and MSS/MSI-low non-metastatic GC/GEJC.

Artificial Intelligence for Assessment of Endotracheal Tube Position on Chest Radiographs: Validation in Patients From Two Institutions.

BACKGROUND. Timely and accurate interpretation of chest radiographs obtained to evaluate endotracheal tube (ETT) position is important for facilitating prompt adjustment if needed. OBJECTIVE. The purpose of our study was to evaluate the performance of a deep learning (DL)-based artificial intelligence (AI) system for detecting ETT presence and position on chest radiographs in three patient samples from two different institutions. METHODS. This retrospective study included 539 chest radiographs obtained immediately after ETT insertion from January 1 to March 31, 2020, in 505 patients (293 men, 212 women; mean age, 63 years) from institution A (sample A); 637 chest radiographs obtained from January 1 to January 3, 2020, in 302 patients (157 men, 145 women; mean age, 66 years) in the ICU (with or without an ETT) from institution A (sample B); and 546 chest radiographs obtained from January 1 to January 20, 2020, in 83 patients (54 men, 29 women; mean age, 70 years) in the ICU (with or without an ETT) from institution B (sample C). A commercial DL-based AI system was used to identify ETT presence and measure ETT tip-to-carina distance (TCD). The reference standard for proper ETT position was TCD between greater than 3 cm and less than 7 cm, determined by human readers. Critical ETT position was separately defined as ETT tip below the carina or TCD of 1 cm or less. ROC analysis was performed. RESULTS. AI had sensitivity and specificity for identification of ETT presence of 100.0% and 98.7% (sample B) and 99.2% and 94.5% (sample C). AI had sensitivity and specificity for identification of improper ETT position of 72.5% and 92.0% (sample A), 78.9% and 100.0% (sample B), and 83.7% and 99.1% (sample C). At a threshold y-axis TCD of 2 cm or less, AI had sensitivity and specificity for critical ETT position of 100.0% and 96.7% (sample A), 100.0% and 100.0% (sample B), and 100.0% and 99.2% (sample C). CONCLUSION. AI identified improperly positioned ETTs on chest radiographs obtained after ETT insertion as well as on chest radiographs obtained of patients in the ICU at two institutions. CLINICAL IMPACT. Automated AI identification of improper ETT position on chest radiographs may allow earlier repositioning and thereby reduce complications.

The Clinical Implication of Conversion Surgery in Patients with Stage IV Gastric Cancer Who Received Systemic Chemotherapy.

With the advances in chemotherapy and immunotherapy, a small subset of patients may be eligible for conversion surgery after achieving tumor regression with chemotherapy. This is a retrospective cohort study of 118 patients with stage IV gastric cancer who received palliative chemotherapy and conversion surgery with a negative resection margin at Samsung Medical Center. Baseline features included comorbidities, body mass index (BMI), carcinoembryonic antigen (CEA) level, primary tumor size, biopsy histology, distant metastatic sites, and molecular markers-HER2, MSI/MMR, PD-L1, and EBV. Post-chemotherapy features included BMI, CEA level, chemotherapy regimen, objective response to chemotherapy, and number of preoperative chemotherapy cycles. Post-operational features included tumor size, histologic differentiation and Lauren's classification, pathologic tumor and nodal stages, invasion of lymphatics/vessels/nerves, peritoneal cytology, and the receipt of postoperative chemotherapy. Of 118 patients, 60 patients received total gastrectomy and 58 patients received subtotal gastrectomy. In all, 21 patients achieved a pathologic complete response, and 97 patients achieved downstaging to yp stage I, II, or III. Before conversion surgery, patients received first-line capecitabine/oxaliplatin (62%), HER2 inhibitors combined with chemotherapy (18%), immune checkpoint inhibitors (15%), and inhibitors of MET or VEGFR2 (5%). In the multivariable analysis, BMI at the time of diagnosis, either HER2 positive, high MSI, or deficient MMR, and the use of targeted agents were significant prognostic factors. Conversion surgery could be considered in patients with stage IV gastric cancer regardless of the initial disease burden. BMI and molecular markers are important prognostic factors that can be used to select candidates.

Role of reduction gastrectomy in patients with gastric cancer with a single non-curable factor: Supplementary analysis of REGATTA trial.

Background: REGATTA trial failed to demonstrate the survival benefit of reduction gastrectomy in patients with advanced gastric cancer with a single non-curable factor. However, a significant interaction was found between the treatment effect and tumor location in the subset analysis. Additionally, the treatment effect appeared to be different between Japan and Korea. This supplementary analysis aimed to elucidate the effect of reduction surgery based on tumor location and country. Methods: Multivariable Cox regression analyses in each subgroup were performed to estimate the hazard ratio (HRadj), including the following variables as explanatory variables: country, age, sex, incurable factor, cT, cN, primary tumor, performance status, histological type, and macroscopic type. Results: Patients (95 in Japan and 80 in Korea) were randomized to chemotherapy alone (86 patients) or gastrectomy plus chemotherapy (89 patients). The subgroup analysis according to the country revealed a worse overall survival in gastrectomy plus chemotherapy arm in Japan (hazard ratio: 1.32, 95% confidence interval: 0.85-2.05), but not in Korea (hazard ratio: 0.85.95% confidence interval: 0.52-1.40). Overall survival was better in distal gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 0.69, 95% confidence interval: 0.42-1.13), and worse in total gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 1.34, 95% CI: 0.93-1.94), which was more remarkable in Korea than in Japan. Conclusions: Primary chemotherapy is a standard of care for advanced gastric cancer; however, the survival benefits from reduction by distal gastrectomy remained controversial.

Meso-jejunal lymph node dissection has a survival benefit in patients with remnant gastric cancer.

BACKGROUND: Clinical benefits of the meso-jejunal lymph node (MJLN) dissection in remnant gastric cancer (RGC) patients have not been fully established. Hence, in this retrospective study, we evaluated the survival benefit of MJLN dissection and prognostic significance of MJLN metastasis in RGC patients who underwent gastrojejunostomy reconstruction after their initial gastrectomy. METHODS: We retrospectively reviewed 391 patients who underwent surgery for RGC at our institution between 1996 and 2019. Among them, 60 patients had MJLN dissection. The index value of the survival benefit gained by dissection of the MJLN was calculated by multiplying the frequency of metastasis at the MJLN station and the 5-year overall survival rate (5YOS) of patients with metastasis at that station. When the metastatic rate or 5YOS exceeded 10%, dissection was recommended. An index value of dissection greater than 1.0 was considered significant. RESULTS: Total metastatic rate of MJLN was 35% (n = 21/60). Patients with MJLN metastasis had advanced pathologic stage compared to patients in the no-metastasis group (p < 0.001). In T2-T4 RGC patients, the metastatic rate of MJLN was 48.6% (n = 17/35), and their 5YOS was 28.4%. The calculated index value was 13.8. Also, patients with MJLN metastasis had a poorer overall survival than those without metastasis. MJLN metastasis was an independent prognostic factor of overall survival in multivariate analysis (HR 6.77, 95%CI 2.21-20.79, p = 0.001). CONCLUSION: MJLN dissection should be considered for advanced RGC patients who underwent gastrojejunostomy after distal gastrectomy during their initial surgery according to the index value.

Prognostic Significance of Esophagogastric Junction Invasion in Patients with Adenocarcinoma of the Cardia or Subcardia.

BACKGROUND: There has been no comparison of the prognoses of Korean patients who underwent curative surgery for cancer located at the cardia or subcardia of the stomach. We performed this comparison and further investigated the prognostic significance of esophagogastric junction (EGJ) invasion in patients. METHODS: The medical records of patients (n = 511) who were diagnosed with cardia or subcardia cancer and underwent surgery between January 2010 and May 2019 were retrospectively reviewed. Patients were further categorized into four groups for analysis: subcardia gastric cancer (sGC; subcardia cancer without EGJ invasion; n = 97), AEG (adenocarcinoma of the esophagogastric junction) type III (subcardia cancer with EGJ invasion, n = 54), AEG type II without EGJ invasion (n = 158), and AEG type II with EGJ invasion (n = 202). We compared the overall survival of the four groups using a gastric cancer staging system and evaluated the prognostic significance of EGJ invasion with multivariate analysis. RESULTS: The median follow-up of patients was 46.0 months (range: 0-124 months). There was significant difference in overall survival curves among the four groups (p < 0.001). Subgroup analysis showed a significant difference in overall survival between the groups with and without EGJ invasion (p < 0.001). Cancers with EGJ invasion were more frequently in the cardia (p < 0.001), had a larger size (p < 0.001), and showed a more advanced pathologic stage (stages II and III; 67.6% versus 33.7%, p < 0.001) than those without EGJ invasion. EGJ invasion and the pathologic stage were significant independent prognostic factors of overall survival in cardia and subcardia cancer patients (hazard ratio 2.24, 95% confidence interval 1.32-3.81, p = 0.003). CONCLUSION: The overall survival between patients with cardia or subcardia cancer was significantly different according to EGJ invasion. EGJ invasion was an independent prognostic factor and should be considered for staging. Additional research is needed to apply this feature to gastric and esophageal cancer classification.

Predictive Value of KLASS-02-QC Assessment Score on KLASS-02 Surgical Outcomes: Validation of Surgeon Quality Control and Standardization for D2 Lymphadenectomy.

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.

Standard follow-up after curative surgery for advanced gastric cancer: secondary analysis of a multicentre randomized clinical trial (KLASS-02).

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.

Determining the precise extent of sentinel basins during laparoscopic gastrectomy for early gastric cancer.

PURPOSE: By analyzing sentinel basin dissection (SBD) data from the SEntinel Node ORIented Tailored Approach (SENORITA) trial, we sought to determine the precise extent of the sentinel basin (SB) without a tracer. MATERIALS AND METHODS: This study investigated SB length in patients (n = 25) who underwent laparoscopic SBD for early gastric cancer (EGC) in the SENORITA trial. SB length along the greater curvature (GC) and lesser curvature (LC) was measured intraoperatively before performing SBD. RESULTS: In all 25 cases, along the LC of the stomach, the lengths of the SB were 3.7 cm [2.0-5.0] (median [min-max]) proximally and 3.0 cm [2.3-5.5] distally; along the GC side, the lengths of the SB were 6.8 cm [3.5-11.0] proximally and 7.0 cm [3.8-9.5] distally from the tumors. The SB length at the GC or LC side was not significantly different between subgroups categorized by tumor depth, size, and longitudinal location. When tumors were located at the anterior wall of the stomach, the length of the proximal SB (10.0 cm [9.0-11.0]) at the GC side was the longest. In cases with several sentinel lymph nodes (SLNs), the lengths of the SB at the GC side were significantly longer than those with fewer SLNs. However, the lengths of the SB were similar on the LC side regardless of the number of SLNs. CONCLUSIONS: This pilot study had some limitations of a small number of enrolled patients, the lack of research on the specific station of SLNs, and the inaccurate indication for sentinel node navigation surgery (SNNS) without tracer. Nevertheless, the present study which reported the extents of SBs might be the first step towards simplifying procedures in laparoscopic SNNS for stomach preservation in EGC.

Trends in vitamin D level and risk of vitamin D deficiency after gastrectomy for gastric cancer: A retrospective study of a single high-volume center experience.

BACKGROUND & AIMS: Post-gastrectomy vitamin D deficiency can result in osteoporosis and fractures, which can decrease patient quality of life and increase their socioeconomic burden. However, because there is no consensus around preoperative measurement and regular postoperative monitoring of serum vitamin D [25(OH)vitD] level for gastric cancer patients, we performed a retrospective study with a single high-volume center experience. METHODS: We reviewed a database of 614 gastric cancer patients who underwent curative gastrectomy between December 2015 and December 2019. Multivariate analyses were performed to identify risk factors for 25(OH)vitD deficiency after one year postoperative (n = 546). A linear mixed model was used to evaluate changes between preoperative (n = 585) and postoperative (6 [n = 504] and 12 months [n = 572]) 25(OH)vitD values. RESULTS: Preoperative 25(OH)vitD deficiency occurred in 67.7% of patients with gastric cancer. Patients who underwent postoperative chemotherapy for advanced pathologic disease were more likely to be 25(OH)vitD deficient at postoperative year one than those who did not receive chemotherapy (P = 0.005). Postoperative chemotherapy was an independent risk factor along with preoperative 25(OH)vitD level for one year postoperative 25(OH)vitD deficiency (P = 0.002). Meanwhile, there was significant change in 25(OH)vitD level after surgery according to reconstruction (increased in Billroth I group compared to gastrojejunostomy group, P = 0.016), pathologic stage (increased in stage I group, decreased in stage II and III group, P = 0.005), postoperative chemotherapy (increased in non-chemotherapy group, decreased in chemotherapy group, P = 0.001), and season of surgery (increased when the blood tests were performed at summer, decreased when tested in non-summer season, P = 0.009). CONCLUSION: More than half of gastric cancer patients had preoperative 25(OH)vitD deficiency, and those who had postoperative chemotherapy were at risk for 25(OH)vitD deficiency one year after surgery. There was a significant change in 25(OH)vitD level after surgery according to reconstruction method and postoperative chemotherapy. Preoperative measurement and regular postoperative monitoring should be considered for high-risk patients.

Accuracy of preoperative clinical staging for locally advanced gastric cancer in KLASS-02 randomized clinical trial.

Purpose: The discrepancy between preoperative and final pathological staging has been a long-standing challenge for the application of clinical trials or appropriate treatment options. This study aimed to demonstrate the accuracy of preoperative staging of locally advanced gastric cancer using data from a large-scale randomized clinical trial. Materials and methods: Of the 1050 patients enrolled in the clinical trial, 26 were excluded due to withdrawal of consent (n = 20) or non-surgery (n = 6). The clinical and pathological staging was compared. Risk factor analysis for underestimation was performed using univariate and multivariate analyses. Results: Regarding T staging by computed tomography, accuracy rates were 74.48, 61.62, 58.56, and 85.16% for T1, T2, T3 and T4a, respectively. Multivariate analysis for underestimation of T staging revealed that younger age, ulcerative gross type, circular location, larger tumor size, and undifferentiated histology were independent risk factors. Regarding nodal status estimation, 54.9% of patients with clinical N0 disease were pathologic N0, and 36.4% of patients were revealed to have pathologic N0 among clinical node-positive patients. The percentage of metastasis involvement at the D1, D1+, and D2 lymph node stations significantly increased with the advanced clinical N stage. Among all patients, 29 (2.8%), including 26 with peritoneal seeding, exhibited distant metastases. Conclusions: Estimating the exact pathologic staging remains challenging. A thorough evaluation is mandatory before treatment selection or trial enrollment. Moreover, we need to set a sufficient case number when we design the clinical trial considering the stage migration.

Efficacy of S-1 or Capecitabine Plus Oxaliplatin Adjuvant Chemotherapy for Stage II or III Gastric Cancer after Curative Gastrectomy: A Systematic Review and Meta-Analysis.

Background: Adjuvant chemotherapy (AC) regimens tegafur/gimeracil/oteracil (S-1) and capecitabine plus oxaliplatin (CAPOX) have predominated, however, there has been a lack of studies on their differences in efficacy. Methods: We conducted pairwise meta-analyses comparing the efficacy of S-1 and CAPOX regimens for overall survival (OS) and disease-free survival (DFS) in stage II or III GC patients. Results: Three studies were enrolled and analyzed using a forest plot for meta-analysis. Two of them were propensity score matching studies, and the remaining one was a retrospective observational study. In all stages, the five-year OS was not different between the two regimens (HR 0.96, 95% CI 0.78-1.17; p = 0.56). Additionally, the 5-year DFS was not different at any stage (HR 1.00, 95% CI 0.85-1.18; p = 0.21). After omitting the retrospective observational study, the five-year OS (HR 1.40, 95% CI 0.53-3.73) and DFS (HR 1.41, 95% CI 0.57-3.44) of S-1 tended to be better in stage II, and the five-year OS (HR 0.81, 95% CI 0.56-1.16) and DFS (HR 0.85, 95% CI 0.63-1.13) of CAPOX tended to be better in stage III, without statistical significance. Conclusions: In the present meta-analysis, the five-year OS and DFS for stage II or III GC patients were comparable between S-1 and CAPOX regimens as AC.

Phase 2 of extracellular RNA communication consortium charts next-generation approaches for extracellular RNA research.

The extracellular RNA communication consortium (ERCC) is an NIH-funded program aiming to promote the development of new technologies, resources, and knowledge about exRNAs and their carriers. After Phase 1 (2013-2018), Phase 2 of the program (ERCC2, 2019-2023) aims to fill critical gaps in knowledge and technology to enable rigorous and reproducible methods for separation and characterization of both bulk populations of exRNA carriers and single EVs. ERCC2 investigators are also developing new bioinformatic pipelines to promote data integration through the exRNA atlas database. ERCC2 has established several Working Groups (Resource Sharing, Reagent Development, Data Analysis and Coordination, Technology Development, nomenclature, and Scientific Outreach) to promote collaboration between ERCC2 members and the broader scientific community. We expect that ERCC2's current and future achievements will significantly improve our understanding of exRNA biology and the development of accurate and efficient exRNA-based diagnostic, prognostic, and theranostic biomarker assays.

Clinical Significance of Preoperative Hematological Parameters in Patients with D2-Resected, Node-Positive Stomach Cancer.

The purpose of the present study was to investigate the clinical significance of preoperative hematological parameters in patients with advanced stomach cancer, and to explore who might benefit from adjuvant concurrent chemoradiotherapy (CCRT) compared to chemotherapy alone. Among 1032 patients with node-positive stomach cancer who had a confirmed diagnosis after complete D2 resection, and who received adjuvant chemotherapy alone or CCRT, a total of 692 patients was selected using propensity score matching. Among absolute neutrophil count, absolute lymphocyte count (ALC), absolute monocyte count (AMC), platelet count, neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio, AMC was the most relevant prognostic factor for overall survival and recurrence-free survival (hazard ratio (HR) 1.674, 95% confidence interval (CI) 1.180-2.376; HR 1.908, 95% CI 1.650-2.695, respectively). In a subgroup with a high ALC, patients treated with adjuvant CCRT had a favorable recurrence-free survival (HR 0.620, 95% CI 0.393-0.980) compared to those treated with chemotherapy alone. Further study is needed to confirm our findings and to develop tailored adjuvant treatment.

Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer: 5-Year Outcomes of the KLASS-02 Randomized Clinical Trial.

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.

Feasibility of Gastric Tumor Xenograft (GTX)-derived Cell Lines for Individualized Anti-cancer Drug Screening.

BACKGROUND/AIM: Because there are ongoing efforts to identify and develop novel drugs in the treatment of refractory gastric cancer, it is necessary to develop effective preclinical studies. Here, the preclinical efficacy of gastric tumor xenograft (GTX)-derived cell line models for the personalized treatment of gastric cancer was investigated. MATERIALS AND METHODS: Anti-cancer drugs were scanned with high-throughput screening (HTS) using pre-established GTX-derived cell lines. The efficacy of a selected drug (afatinib) was re-confirmed in vivo and intracellular signaling pathways were investigated in xenograft tumor cell lysates using western blotting. Validation studies, such as cell proliferation and caspase activity assays, were also conducted in vitro with GTX-derived cell lines. RESULTS: HTS indicated that afatinib was effective in one of the five GTX-derived cell lines (GTX-087). A xenograft mouse model was established from GTX-087, and administration of afatinib at 1 mg/20 g body weight/day per oral resulted in tumor-suppressive activity in vivo. The RAS-ERK pathway was inactivated by an increase in Bax and cleaved caspase-3 in this xenograft model. In vitro cell proliferation assay also revealed that afatinib was able to suppress the growth of the GTX-087 cell line. Caspase activity assay confirmed that afatinib had an apoptotic role on GTX-087 and showed that caspase-3/7 activity increased in a time dependent manner. CONCLUSION: The GTX-derived cell line model might be useful for estimating novel drug responses and could be an alternative to patient-derived xenograft animal models.

Clinicopathologic and genomic characteristics of mucinous gastric adenocarcinoma.

BACKGROUND: Mucinous gastric adenocarcinoma (MGC) is a rare but distinctive histologic subtype of gastric cancer (GC). The clinico-pathologic and genomic characteristics of MGC have not been well evaluated. METHODS: We collected individual data from five cohorts targeting the microsatellite instability (MSI) of GC (n = 5089) to evaluate the clinico-pathologic characteristics of MGC. In addition, public genomic databases were used for genomic analysis. The characteristics of MGC were compared with those of non-mucinous GC (NMGC). RESULTS: MGC (n = 158, 3.1%) showed distinctive characteristics in terms of age, sex, and TNM stage compared to NMGC (n = 4931). MGC was frequently associated with MSI-high (OR: 2.24, 95% confidence interval [CI] 1.44-3.40, p < 0.001), while mutually exclusive to the Epstein-Barr virus type. The prognosis of MGC was better than that of NMGC (adj.HR: 0.731, 95% CI 0.556-0.962, p = 0.025). There was no clear benefit from postoperative chemotherapy in MGC. TP53 was the main driver mutation in the MGC without recurrent variants. MGC was related to high expression of GPR120 and B3GNT6 and moderate regulation of epithelial-mesenchymal transition (EMT)-up signature with a high EMT-down signature, and those characteristics was related to favorable prognosis of GC (log-rank p = 0.044, p < 0.001, p < 0.001, respectively). MSI-H of MGC was associated with low cancer-associate fibroblasts but high CD274 (PD-L1) expression compared to microsatellite stable MGC, suggesting that immune checkpoint inhibitors may be useful for the MSI-H of MGC. CONCLUSION: MGC could be a surrogate for performing MSI but not the EBV test in GC. Further, its genetic characteristics lead to a favorable prognosis for MGC.

Laparoscopic Sentinel Node Navigation Surgery for Stomach Preservation in Patients With Early Gastric Cancer: A Randomized Clinical Trial.

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.

A preoperative risk prediction model for high malignancy potential gastrointestinal stromal tumors of the stomach.

BACKGROUND: Gastric gastrointestinal stromal tumors (GISTs) exhibit various degrees of aggression and malignant potential. However, no systematic preoperative evaluation strategy to predict the malignancy potential of gastric GISTs has yet been developed. This study aimed to develop a reliable and easy-to-use preoperative risk-scoring model for predicting high malignancy potential (HMP) gastric GISTs. METHODS: The data of 542 patients with pathologically confirmed gastric GISTs who underwent resection were reviewed. Multivariate logistic regression analysis was used to identify significant predictors of HMP. The risk-scoring system (RSS) was based on the predictive factors for HMP, and its performance was validated using a split-sample approach. RESULTS: A total of 239 of 542 (44.1%) surgically resected gastric GISTs had HMP. Multivariate analysis demonstrated that tumor size, location, and surface changes were independent risk factors for HMP. Based on the accordant regression coefficients, the presence of surface ulceration was assigned 1 point. Tumor sizes of 4-6 cm and > 6 cm were assigned 2 and 5 points, respectively. Two points were assigned to cardia or fundus locations. A score of 3 points was the optimal cut-off value for HMP prediction. HMP were found in 19.8% and 82.7% of the low and high-risk groups of the RSS, respectively. The area under the receiver-operating characteristic curve for predicting HMP was 0.81 (95% confidence interval (CI) 0.75-0.86). Discrimination was good after validation (0.75, 95% CI 0.69-0.81). CONCLUSION: This simple RSS could be useful for predicting the malignancy potential of gastric GISTs and may aid preoperative clinical decision making to ensure optimal treatment.