Feasibility of intraoperative pathologic examination for sentinel lymph nodes during sentinel node navigation surgery in early gastric cancer: results of pathologic protocol for SENORITA trial.

BACKGROUND: During sentinel node navigation surgery in patients with gastric cancer, intraoperative pathologic examination of sentinel nodes is crucial in determining the extent of surgery. In this study, we evaluated the feasibility and accuracy of intraoperative pathologic protocols using data from a prospective, multicenter, randomized trial. METHODS: A retrospective analysis was conducted using data from the SEntinel Node ORIented Tailored Approach trials from 2013 to 2016. All sentinel lymph nodes were evaluated during surgery with hematoxylin-eosin (HE) staining using a representative section at the largest plane for lymph nodes. For permanent histologic evaluation, sentinel basin nodes were stained with HE and cytokeratin immunohistochemistry in formalin-fixed, paraffin-embedded (FFPE) sections and examined with HE for three deeper-step sections at 200-µm intervals. The failure rate of identification by frozen section and the metastasis rate in non-sentinel basins were investigated. RESULTS: Of the 237 patients who underwent sentinel node basin dissection, 30 had lymph node metastases on permanent pathology. Thirteen patients had macrometastasis confirmed in frozen sections as well as FFPE sections (failure rate: 0%). Patients with negative sentinel nodes in frozen sections but micrometastasis in FFPE sections had no lymph node recurrence during the follow-up period (0%, 0/6). However, in cases with tumor-positive nodes in frozen sections, metastases in non-sentinel basins were detected in the paraffin blocks (8.3%, 2/24). CONCLUSIONS: The single-section HE staining method is sufficient for detecting macrometastasis via intraoperative pathological examination. If a negative frozen-section result is confirmed, sentinel basin dissection can be performed safely. Otherwise, standard surgery is required.

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.

Clinical Efficacy of Laparoscopic Sentinel Node Navigation Surgery for Stomach Preservation in Patients With Early Gastric Cancer: 5-year Results of the SENORITA Trial.

OBJECTIVE: This study aimed to compare laparoscopic standard gastrectomy (LSG) and laparoscopic sentinel node navigation surgery (LSNNS) for EGC in terms of 5-year long-term oncologic outcomes. SUMMARY BACKGROUND DATA: The oncological safety of LSNNS for early gastric cancer (EGC) has not been confirmed. Three-year disease-free survival (DFS), which is the primary endpoint of the phase III multicenter randomized controlled clinical trial (SEntinel Node ORIented Tailored Approach [SENORITA] trial), did not show the non-inferiority of LSNNS relative to LSG. METHODS: The SENORITA trial, a multicenter randomized clinical trial, was designed to show that LSNNS is non-inferior to LSG in terms of 3-year DFS. In the present study, we collected 5-year follow-up data from 527 patients recruited in the SENORITA trial as the full analysis set (FAS). Disease-free survival (DFS), overall survival (OS), disease-specific survival (DSS), and recurrence patterns were evaluated using the FAS of both LSG (n=269) and LSNNS (n=258). RESULTS: The 5-year DFS was not significantly different between the LSG and LSNNS groups (P=0.0561). During the 5-year follow-up, gastric cancer-related events, such as metachronous cancer, were more frequent in the LSNNS group than in the LSG group. However, ten recurrent cancers in the remnant stomach of both groups were curatively resected by additional gastrectomy and one by additional endoscopic resection. Two of the 198 patients who underwent local resection for stomach preservation based on the LSNNS results developed distant metastasis. However, there was no statistically significant difference in the 5-year OS and DSS (P=0.7403 and P=0.9586, respectively) between the two groups. CONCLUSION: The 5-year DFS, DSS and OS did not differ significantly between the two groups. Considering the benefits of LSNNS on postoperative quality of life, LSNNS could be recommended as an alternative treatment option for EGC.

Unravelling interobserver variability in gastrointestinal glandular neoplasia: a contemporary study of US and Korean pathologists.

AIMS: Interobserver variability in the assessment of gastric neoplasia biopsies between most Western and Eastern (predominantly represented by Japanese in the literature) pathologists has been documented. It is unknown if such variability exists between the US and Korean pathologists in the current era. METHODS: Ten gastrointestinal (GI) pathologists from the USA (n=5) and South Korea (n=5) evaluated 100 scanned images of gastric (n=50) and colorectal (n=50) neoplasia biopsies and answered multiple questionnaires. Consensus was defined as the answer chosen by the majority. Cohen's (κc) and Fleiss' kappa (κf) values were calculated between the consensus of the two groups and among the raters, respectively. RESULTS: Both groups reached a consensus in the majority of cases (74%-100%) with slight to perfect intergroup (κc=0.049-1.000) and no to substantial intragroup (κf=-0.083 to 0.660) agreements. For gastric neoplasia, Korean pathologists relied heavily on cytoarchitectural atypia, whereas the US pathologists focused on stromal invasion when diagnosing adenocarcinoma. For colorectal neoplasia, the Korean pathologists identified concurrent intramucosal carcinoma when diagnosing invasive adenocarcinoma, while the presence of desmoplasia was a prerequisite for the diagnosis of invasive adenocarcinoma for the US pathologists. CONCLUSIONS: For GI neoplasia biopsy interpretation, the diagnostic approach of Korean pathologists is similar to that of Eastern/Japanese pathologists. Consensus outperformed kappa statistics in capturing the magnitude of inter-rater and intergroup reliability, highlighting the potential benefit of consensus meetings to decrease the gap between Western and Eastern diagnostic approaches.

Tumour infiltrating lymphocytes and survival after adjuvant chemotherapy in patients with gastric cancer: post-hoc analysis of the CLASSIC trial.

BACKGROUND: Only a subset of gastric cancer (GC) patients with stage II-III benefits from chemotherapy after surgery. Tumour infiltrating lymphocytes per area (TIL density) has been suggested as a potential predictive biomarker of chemotherapy benefit. METHODS: We quantified TIL density in digital images of haematoxylin-eosin (HE) stained tissue using deep learning in 307 GC patients of the Yonsei Cancer Center (YCC) (193 surgery+adjuvant chemotherapy [S + C], 114 surgery alone [S]) and 629 CLASSIC trial GC patients (325 S + C and 304 S). The relationship between TIL density, disease-free survival (DFS) and clinicopathological variables was analysed. RESULTS: YCC S patients and CLASSIC S patients with high TIL density had longer DFS than S patients with low TIL density (P = 0.007 and P = 0.013, respectively). Furthermore, CLASSIC patients with low TIL density had longer DFS if treated with S + C compared to S (P = 0.003). No significant relationship of TIL density with other clinicopathological variables was found. CONCLUSION: This is the first study to suggest TIL density automatically quantified in routine HE stained tissue sections as a novel, clinically useful biomarker to identify stage II-III GC patients deriving benefit from adjuvant chemotherapy. Validation of our results in a prospective study is warranted.

Clinical Practice Guideline for Gastritis in Korea.

Gastritis is a disease characterized by inflammation of the gastric mucosa. It is very common and has various classification systems such as the updated Sydney system. As there is a lot of evidence that Helicobacter pylori infection is associated with the development of gastric cancer and that gastric cancer can be prevented by eradication, H. pylori gastritis has been emphasized recently. The incidence rate of gastric cancer in Korea is the highest in the world, and due to the spread of screening endoscopy, atrophic gastritis and intestinal metaplasia are commonly diagnosed in the general population. However, there have been no clinical guidelines developed in Korea for these lesions. Therefore, this clinical guideline has been developed by the Korean College of Helicobacter and Upper Gastrointestinal Research for important topics that are frequently encountered in clinical situations related to gastritis. Evidence-based guidelines were developed through systematic review and de novo processes, and eight recommendations were made for eight key questions. This guideline needs to be periodically revised according to the needs of clinical practice or as important evidence about this issue is published in the future.

Stomach tissue classification using autofluorescence spectroscopy and machine learning.

BACKGROUND AND OBJECTIVES: Determination of stomach tumor location and invasion depth requires delineation of gastric histological structure, which has hitherto been widely accomplished by histochemical staining. In recent years, alternative histochemical evaluation methods have been pursued to accelerate intraoperative diagnosis, often by bypassing the time-consuming step of dyeing. Owing to strong endogenous signals from coenzymes, metabolites, and proteins, autofluorescence spectroscopy is a favorable candidate technique to achieve this aim. MATERIALS AND METHODS: We investigated stomach tissue slices and block specimens using a fast fluorescence imaging scanner. To obtain histological information from broad and structureless fluorescence spectra, we analyzed tens of thousands of spectra with multiple machine-learning algorithms and built a tissue classification model trained with dissected gastric tissues. RESULTS: A machine-learning-based spectro-histological model was built based on the autofluorescence spectra measured from stomach tissue samples with delineated and validated histological structures. The scores from a principal components analysis were employed as input features, and prediction accuracy was confirmed to be 92.0%, 90.1%, and 91.4% for mucosa, submucosa, and muscularis propria, respectively. We investigated the tissue samples in both sliced and block forms using a fast fluorescence imaging scanner. CONCLUSION: We successfully demonstrated differentiation of multiple tissue layers of well-defined specimens with the guidance of a histologist. Our spectro-histology classification model is applicable to histological prediction for both tissue blocks and slices, even though only sliced samples were trained.

A Standardized Pathology Report for Gastric Cancer: 2nd Edition.

The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.

A standardized pathology report for gastric cancer: 2nd edition.

The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.

Risks and benefits of additional surgery for early gastric cancer in the upper third of the stomach meeting non-curative resection criteria after endoscopic submucosal dissection.

BACKGROUND: Additional surgery is recommended after non-curative endoscopic submucosal dissection for early gastric cancer. However, it is not easy to recommend for tumors located in the upper third of the stomach, because it would be a total or proximal gastrectomy. This study aimed to evaluate the actual risks and benefits of additional gastrectomy for upper third tumors. METHODS: We reviewed the clinicopathological data of patients who underwent total or proximal gastrectomy for early gastric cancer in the upper third of the stomach between March 2002 and January 2021. The incidence of lymph node metastasis and postoperative complications were calculated, and risk factors for lymph node metastasis were identified using logistic regression analysis. Survival rates were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: A total of 523 patients underwent total or proximal gastrectomy for early gastric cancer; 379 of them had tumors meeting the non-curative resection criteria for endoscopic submucosal dissection. The overall lymph node metastasis rate was 9.5%, and lymphovascular invasion was the only significant risk factor for lymph node metastasis (p < 0.001). The most common sites of lymph node metastasis were stations 1, 3, and 7, with their rates being 3.2%, 3.7%, and 3.2%, respectively. Overall and severe (Clavien-Dindo grade III or higher) postoperative complication rates were 21.1% and 14.0%, respectively, while postoperative mortality was 0.5% (2/379). The 5-year overall survival rates for patients with and without lymph node metastasis were 96.1% and 81.1%, respectively (p = 0.076). CONCLUSIONS: Before planning an additional gastrectomy after non-curative endoscopic resection for the upper third tumor, we should consider both the benefit of the 9.5% curability for lymph node metastasis and the risks of the 21% postoperative complications and 0.5% mortality.

A Comprehensive and Comparative Review of Global Gastric Cancer Treatment Guidelines.

Countries differ in their treatment expertise and research results regarding gastric cancer; hence, treatment guidelines are diverse based on evidence and medical situations. A comprehensive and comparative review of each country's guidelines is imperative to understand the similarities and differences among countries. We reviewed and compared five gastric cancer treatment guidelines in terms of endoscopic, surgical, perioperative, and palliative systemic treatment based on evidence levels and recommendation grades, as well as the postoperative follow-up strategies for each guideline. The Korean, Chinese, and European guidelines provided evidence and grading of the recommendations. The United States guidelines suggested categories for evidence and consensus. The Japanese guidelines suggested evidence and recommendations only for systemic treatment. The Korean and Japanese guidelines described endoscopic treatment, surgery, and lymphadenectomy in detail. The Chinese, United States, and European guidelines more intensively considered perioperative chemotherapy. In particular, the indications for chemotherapy and the regimens recommended by each guideline differed slightly. Considering their medical situations, each guideline had some diversity in terms of adopting evidence, which resulted in heterogeneous recommendations. This review will help medical personnel to comprehensively understand the diversity in gastric cancer treatment guidelines for each country in terms of evidence and recommendations.

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.

Smad4 and p53 synergize in suppressing autochthonous intestinal cancer.

BACKGROUND: Smad4 and p53 mutations are the most common mutations in human colorectal cancers (CRCs). We evaluated whether and how they are synergistic in intestinal carcinogenesis using novel autochthonous mouse models. METHOD: To recapitulate human CRCs, we generated Villin-Cre;Smad4F / F ;Trp53F / F mice. We then compared the intestinal phenotype of Villin-Cre;Smad4F / F ;Trp53F / F mice (n = 40) with Villin-Cre;Smad4F / F (n = 30) and Villin-Cre;Trp53F / F mice (n = 45). RESULTS: Twenty-week-old Villin-Cre;Smad4F / F ;Trp53F / F mice displayed spontaneous highly proliferative intestinal tumors, and 85% of mice developed adenocarcinomas. p21 was downregulated in the intestinal mucosa in Villin-Cre;Smad4F / F ;Trp53F / F mice than in Villin-Cre;Smad4F / F and Villin-Cre;Trp53F / F mice. Villin-Cre;Smad4F / F ;Trp53F / F mice displayed multistep intestinal tumorigenesis and Wnt activation. Long-term CWP232291 (small-molecule Wnt inhibitor) treatment of Villin-Cre;Smad4F / F ;Trp53F / F mice suppressed intestinal tumorigenesis and progression. CWP232291 treatment downregulated cancer stem cell (CSC) tumor markers including CD133, Lgr-5, and Sca-1. CWP232291 treatment reduced the CSC frequency. Small-molecule Wnt inhibitors reduced intestinal CSC populations and inhibited their growth, along with Bcl-XL downregulation. Furthermore, BH3I-1, a Bcl-XL antagonist, increasingly inhibited intestinal CSCs than bulk tumor cells. CONCLUSION: Smad4 loss and p53 loss are synergistic in autochthonous intestinal carcinogenesis, by downregulating p21 and activating Wnt/ß-catenin pathway.

Development and validation of deep learning classifiers to detect Epstein-Barr virus and microsatellite instability status in gastric cancer: a retrospective multicentre cohort study.

BACKGROUND: Response to immunotherapy in gastric cancer is associated with microsatellite instability (or mismatch repair deficiency) and Epstein-Barr virus (EBV) positivity. We therefore aimed to develop and validate deep learning-based classifiers to detect microsatellite instability and EBV status from routine histology slides. METHODS: In this retrospective, multicentre study, we collected tissue samples from ten cohorts of patients with gastric cancer from seven countries (South Korea, Switzerland, Japan, Italy, Germany, the UK and the USA). We trained a deep learning-based classifier to detect microsatellite instability and EBV positivity from digitised, haematoxylin and eosin stained resection slides without annotating tumour containing regions. The performance of the classifier was assessed by within-cohort cross-validation in all ten cohorts and by external validation, for which we split the cohorts into a five-cohort training dataset and a five-cohort test dataset. We measured the area under the receiver operating curve (AUROC) for detection of microsatellite instability and EBV status. Microsatellite instability and EBV status were determined to be detectable if the lower bound of the 95% CI for the AUROC was above 0·5. FINDINGS: Across the ten cohorts, our analysis included 2823 patients with known microsatellite instability status and 2685 patients with known EBV status. In the within-cohort cross-validation, the deep learning-based classifier could detect microsatellite instability status in nine of ten cohorts, with AUROCs ranging from 0·597 (95% CI 0·522-0·737) to 0·836 (0·795-0·880) and EBV status in five of eight cohorts, with AUROCs ranging from 0·819 (0·752-0·841) to 0·897 (0·513-0·966). Training a classifier on the pooled training dataset and testing it on the five remaining cohorts resulted in high classification performance with AUROCs ranging from 0·723 (95% CI 0·676-0·794) to 0·863 (0·747-0·969) for detection of microsatellite instability and from 0·672 (0·403-0·989) to 0·859 (0·823-0·919) for detection of EBV status. INTERPRETATION: Classifiers became increasingly robust when trained on pooled cohorts. After prospective validation, this deep learning-based tissue classification system could be used as an inexpensive predictive biomarker for immunotherapy in gastric cancer. FUNDING: German Cancer Aid and German Federal Ministry of Health.

PRODIGY: A Phase III Study of Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 Versus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer.

PURPOSE: Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS: Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 every 6 weeks for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 every 3 weeks for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS: Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION: PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

Recent updates and current issues of sentinel node navigation surgery for early gastric cancer.

With the increase in the incidence of early gastric cancer (EGC), several endoscopic and laparoscopic approaches, such as endoscopic submucosal dissection and function-preserving gastrectomy, have been accepted as standard treatments. Sentinel node navigation surgery (SNNS) is an ideal surgical option for preservation of most parts of the stomach and consequent maintenance of normal gastric function to improve quality of life in patients with EGC. Although many previous studies and clinical trials have demonstrated the safety and feasibility of the sentinel node concept in gastric cancer, the clinical application of SNNS is debatable. Several issues regarding technical standardization and oncological safety need to be resolved. Recently several studies to resolve these problems are being actively performed, and SNNS might be an important surgical option in the treatment of gastric cancer in the future.

Risk factors for lymph node metastasis in early gastric cancer without lymphatic invasion after endoscopic submucosal dissection.

BACKGROUND: Lymphatic invasion (LI) is a potent risk factor for lymph node metastasis (LNM) in early gastric cancer (EGC) after endoscopic submucosal dissection (ESD). However, there are also other risk factors for LNM. Hence, to identify the need for additional surgery in some case of EGC without LI, the present study aimed to identify the risk factors for LNM in patients with EGC without LI. METHODS: Data from 2284 patients diagnosed with EGC who underwent curative surgery at National Cancer Center in Korea from January 2012 to May 2019 were collected. The clinicopathological characteristics of patients with EGC without LI were compared on the basis of LNM status. RESULTS: There were 339 (17.1%) and 1648 (82.9%) patients with and without LI respectively. Among these patients with and without LI, 118 (34.8%) and 91 (5.5%) patients presented with LNM, respectively. In patients with EGC without LI, tumor size larger than 3 cm (OR = 2.12, 95% CI = 1.22-3.68; p = 0.007), submucosal invasion (OR = 4.14, 95% CI = 2.57-6.65; p < 0.001), and undifferentiated histologic type (OR = 2.33, 95% CI = 1.45-3.76; p < 0.001) were significant risk factors for LNM. Rates of LNM in patients meeting absolute, expanded, and beyond expanded criteria without LI were 0%, 1.5% (OR = 3.27, 95% CI = 0.18-59.41; p = 0.423), and 7.3% respectively. When the expanded criteria were divided into four subtypes patients with EGC, without LI within each subtype did not show significant risk of incidence of LNM compared to the absolute criteria. CONCLUSIONS: The current expanded criteria for endoscopic resection (ER) are tolerable in cases without LI, even though minimal risk LNM exists. Therefore, additional surgery may not be needed for patients meeting expanded criteria for ER.

Feasibility of Non-Exposure Simple Suturing Endoscopic Full-Thickness Resection in Comparison with Laparoscopic Endoscopic Cooperative Surgery for Gastric Subepithelial Tumors: Results of Two Independent Prospective Trials.

Recently, nonexposure simple suturing endoscopic full-thickness resection (NESS-EFTR) method was developed to avoid tumor exposure to the peritoneal cavity. The aim of this study is to compare the short-term outcomes of the NESS-EFTR method with those of laparoscopic and endoscopic cooperative surgery (LECS) for gastric subepithelial tumors (SETs). A prospective single-center trial of LECS for gastric SETs was performed from March 2012 to October 2013 with a separate prospective trial of NESS-EFTR performed from August 2015 to June 2017, enrolling 15 patients each. Among the 30 enrolled patients, 14 who underwent LECS and 11 who underwent NESS-EFTR were finally included in the analysis. The rate of complete resection and successful closure was 100% in both groups. The operating time was longer for NESS-EFTR group than for LECS (110 vs. 189 min; p < 0.0001). There were no postoperative complications except one case of transient fever in the NESS-EFTR group. One patient in the LECS group had peritoneal seeding of gastrointestinal stromal tumor at 17 months postoperatively, and there was no other recurrence. Although NESS-EFTR had long operating and procedure times, it was feasible for patients with gastric SETs requiring a nonexposure technique.

Evaluation of Lymph Node Metastasis Among Adults With Gastric Adenocarcinoma Managed With Total Gastrectomy.

Importance: It is unclear whether proximal gastrectomy (PG) can replace total gastrectomy (TG), even in cases of advanced gastric carcinoma. Objectives: To evaluate the oncologic safety of PG based on the lymph node (LN) metastasis rate and develop a selection diagram for PG eligibility. Design, Setting, and Participants: In this cohort study, a retrospective analysis of a prospective database of gastric carcinoma surgery was performed including procedures that took place between December 1, 2000, and December 31, 2015, in the National Cancer Center, Korea, a high-volume carcinoma center with a structured database and accurate long-term follow-up. Among 9952 patients who underwent surgery for gastric carcinoma, 2347 underwent TG. Six-hundred fifty-five (564 in a second statistical analysis) had gastric carcinoma in the upper third of the stomach. The inclusion criteria were age 18 to 85 years, histologically proven adenocarcinoma (any size or differentiation) located in the upper third of the stomach, curative R0 TG performed, and postoperative follow-up for at least 3 years. Exclusion criteria included Borrmann type 4 carcinoma, T4 category, use of neoadjuvant chemotherapy, and a history of other carcinomas. Data analysis was performed from December 1, 2019, to May 30, 2020. Exposures: Total gastrectomy and LN dissection. Main Outcomes and Measures: The primary end point was the rate of LN metastasis at LN stations 4d, 5, and 6, which are usually not dissected during PG. Results: Among the 655 study patients, the mean (SD) age was 57.7 (11.9) years, and 462 (70.5%) were men. Only those with poorly differentiated cT3 category carcinomas had an increased incidence of LN metastasis at stations 4d (2 of 32 [6.3%]) and 11d (T3N0: 2 of 22 [9.1%], T3N1: 3 of 27 [11.1%]), independent of tumor size. For cT1-T3N0/1M0 category carcinomas, the incidence of station 5 LN metastasis was 0, irrespective of tumor size and differentiation. The LN metastasis rate at stations 4d and 6 for cT1-T3N0/1M0 differentiated tumors was also 0. Tumor size greater than or equal to 4.1 cm was associated with significantly increased LN metastasis compared with tumors less than 4.1 cm (40.0% vs 20.4%, P = .001). Conclusions and Relevance: The findings of this study suggest that PG can be safely performed for cT1-T2N0/1M0 tumors less than 4.1 cm in diameter that are located in the upper third of the stomach. The cT3N0/1M0-differentiated tumors less than 4.1 cm may also be eligible for PG, whereas poorly differentiated cT3 tumors and any cT4 or cN2/3 diseases require TG.

Clinicopathologic Features of Submucosal Papillary Gastric Cancer Differ from Those of Other Differentiated-Type Histologies.

Background/Aims: Papillary gastric cancer (GC) is classified as differentiated adenocarcinoma, together with well-differentiated (WD) and moderately differentiated (MD) adenocarcinoma. This study evaluated the risk of lymph node metastasis (LNM) in submucosal (SM) invasive papillary GC compared with other differentiated early GC types. Methods: This retrospective study involved three tertiary hospitals and enrolled 1,798 lesions with differentiated SM invasive GC treated with curative gastrectomy between March 2001 and December 2012. All pathology slides were reviewed, and clinicopathologic findings associated with LNM, including tumor size, location, gross type, ulceration, depth and width of SM invasion, and lymphovascular invasion (LVI), were analyzed. Results: The proportion of SM papillary GC was 2.8% (n=51). SM papillary GC was associated with larger tumor size and deeper and wider SM invasion than other differentiated GC types. LNM was significantly higher in the papillary type than in the MD and WD types. LNM was found in 27.5% of SM papillary GC patients (WD: 9.0%, MD: 21.2%). LVI was the only significant risk factor for LNM in SM papillary GC. The depth or width of SM invasion was not associated with LNM in papillary GC. Lower third location or elevated gross appearance was significantly associated with LVI. Conclusions: SM papillary GC had the highest LNM rate, with features different from those of other differentiated SM invasive GCs. The treatment strategy for SM papillary GC should be carefully approached, especially for lesions located in the lower third or of the elevated gross type.