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Gastrointestinal stromal tumors (GIST) with KIT exon 11 deletions involving in codons 557–558 (KIT Δ557–558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with KIT Δ557–558. Whole-genome sequencing revealed that the high-risk malignant GISTs with KIT Δ557–558 (12 cases) had more structural variations (SV), single-nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with KIT Δ557–558 (six cases) and the high-risk (six cases) or low-risk (6 cases) GISTs with other KIT exon 11 mutations. The malignant GISTs with KIT Δ557–558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had LOH or CN-dependent expression reduction in CDKN2A. In addition, SVs with driver potential were detected in 75% of them, in which AKT3 and MGMT were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, SNAI2 upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with KIT Δ557–558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that KIT Δ557–558 mutations are associated with increased genomic instability in malignant GISTs. Significance: We present genomic and epigenomic insights into the malignant progression of GISTs with KIT exon 11 deletions involving in 557–558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation.

Genome-wide relationship between DNA methylation and gene expression in malignant GISTs with KIT Δ557–558.

Genes for expression signatures.

SVs identified in the 30 GIST cases in our study cohort.

Gastrointestinal stromal tumors (GIST) with KIT exon 11 deletions involving in codons 557–558 (KIT Δ557–558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with KIT Δ557–558. Whole-genome sequencing revealed that the high-risk malignant GISTs with KIT Δ557–558 (12 cases) had more structural variations (SV), single-nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with KIT Δ557–558 (six cases) and the high-risk (six cases) or low-risk (6 cases) GISTs with other KIT exon 11 mutations. The malignant GISTs with KIT Δ557–558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had LOH or CN-dependent expression reduction in CDKN2A. In addition, SVs with driver potential were detected in 75% of them, in which AKT3 and MGMT were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, SNAI2 upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with KIT Δ557–558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that KIT Δ557–558 mutations are associated with increased genomic instability in malignant GISTs.Significance:We present genomic and epigenomic insights into the malignant progression of GISTs with KIT exon 11 deletions involving in 557–558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation.

Circos plots of the 30 GIST genomes in our study cohort.

The robotic approach is especially promising for challenging surgeries, such as total gastrectomy. However, it remains unclear whether robotic total gastrectomy (RTG) is superior to conventional laparoscopic total gastrectomy (LTG). The present study aimed to clarify the impact of RTG on short- and long-term outcomes for patients with clinical stage I/IIA gastric cancer.This study included 98 patients with clinical stage I/IIA gastric cancer who underwent minimally invasive total gastrectomy from October 2013 to December 2020 at the Shizuoka Cancer Center. The short- and long-term outcomes of RTG were compared with those of LTG.This study included 36 RTG and 58 LTG patients. RTG was associated with a significantly longer operative time than LTG (p = 0.023). All complications tended to be lower in the RTG group than in the LTG group (2.8% and 15.5%, respectively; p = 0.083). There were no patients with anastomotic leakage in the RTG group. The multivariate analysis identified LTG as the only independent risk factor for postoperative complications (odds ratio, 6.620; 95% confidence interval, 1.132-126.4; p = 0.034). The survival of the RTG and LTG groups was equivalent.RTG reduced the risk of complications compared to LTG. Patients treated using the two approaches showed equivalent survival.

Gastric cancer (GC) has been classified based on molecular profiling like The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG), and attempts have been made to establish therapeutic strategies based on these classifications. However, it is difficult to predict the survival according to these classifications especially in radically resected patients. We aimed to establish a new molecular classification of GC which predicts the survival in patients undergoing radical gastrectomy. The present study included 499 Japanese patients with advanced GC undergoing radical (R0/R1) gastrectomy. Whole-exome sequencing, panel sequencing, and gene expression profiling were conducted (High-tech Omics-based Patient Evaluation [Project HOPE]). We classified patients according to TCGA and ACRG subtypes, and evaluated the clinicopathologic features and survival. Then, we attempted to classify patients according to their molecular profiles associated with biological features and survival (HOPE classification). TCGA and ACRG classifications failed to predict the survival. In HOPE classification, hypermutated (HMT) tumors were selected first as a distinctive feature, and T-cell-inflamed expression signature-high (TCI) tumors were then extracted. Finally, the remaining tumors were divided by the epithelial-mesenchymal transition (EMT) expression signature. HOPE classification significantly predicted the disease-specific and overall survival (p

The current study aimed to evaluate the ability of a modified version of the age-adjusted Charlson Comorbidity Index (mACCI) in predicting cause-specific survival (CSS) among patients with gastric cancer who underwent curative gastrectomy and compared it with the conventional ACCI.Patients who underwent gastrectomy for gastric cancer from 2007 to 2016 (n = 2885) were included. A mACCI was established by excluding scores for other malignancies, such as other cancers, leukemia, and lymphoma. After determining the optimal cutoff ACCI and mACCI values for CSS, clinicopathological factors and survival outcomes were assessed according to the ACCI and mACCI.Both ACCI and mACCI were identified as independent prognostic factors for overall survival (p 0.001 and p 0.001, respectively). However, only mACCI was identified as an independent prognostic factor for CSS (p 0.001). The present study suggested that mACCI was a better indicator of CSS in patients with gastric cancer who underwent curative gastrectomy than ACCI.Our findings showed that the mACCI was a strong predictor of CSS in patients with gastric cancer who underwent curative gastrectomy. We believe that the mACCI will become a novel marker that would guide treatment decisions for patients with gastric cancer suffering from comorbidities.

The case of a neuroendocrine tumor arising from an upside-down stomach due to a large hiatal hernia is rare but occasionally encountered in clinical practice. As we experienced such a case and successfully treated by simultaneous laparoscopic distal gastrectomy and hernia repair with fundoplication, we here report our experience. A 79-year-old woman was referred to our hospital with suspicion of a stomach submucosal tumor. Detailed examination revealed the submucosal tumor in diameter of 20mm located on the middle third of stomach, and the pathology of biopsy showed the positivity for Chromogranin-A and Synaptophysin. CT scan also demonstrated the large hiatal hernia with prolapsing the almost whole stomach and transverse colon to the left thoracic cavity. We diagnosed that as Rindi classification type III neuroendocrine tumor and complex esophageal hiatal hernia, and we planned laparoscopic distal gastrectomy and hernia repair with fundoplication. Laparoscopy showed the prolapse of almost whole stomach and colon through the esophageal hilum to left thoracic cavity. We pull them back to abdominal cavity and divided the hernia sac at the level of hilum. After distal gastrectomy, we managed to close the enlarged esophageal hilum without using artificial mesh by suturing the crus of diaphragm. We added the Toupet fundoplication to remnant stomach, and reconstructed the digestive tract by means of Roux-en-Y method. There were no findings of passage obstruction or regurgitation in the peroral contrast examination. The patient was discharged 7 days after surgery with good postoperative course. Simultaneous laparoscopic gastrectomy and esophageal hiatus hernia repair was successfully performed. Enlarged esophageal hilum could be closed without using the artificial mesh even for the patient with an upside-down stomach, and Toupet fundoplication could be added for a small remnant stomach after distal gastrectomy. Therefore, our procedure was considered to be a safe and feasible minimally invasive surgery for such patients.

Resection for hepatic recurrence after gastrectomy in patients with gastric cancer may be curative; however, the prediction of hepatic recurrence remains intractable. Therefore, we aimed to explore predictive markers for hepatic recurrence in gastric and gastroesophageal junction cancer based on genetic information. This study recruited 154 patients who underwent curative gastrectomy for pathological stage II or III primary gastric and gastroesophageal junction adenocarcinoma. Genes associated with hepatic recurrence were comprehensively analyzed using whole-exome sequencing and gene expression profiling (GEP), followed by immunohistochemistry analysis for MAGEA10. The cumulative incidences of hepatic recurrence, relapse-free survival, and overall survival were evaluated. A total of 12 patients with early hepatic recurrences were found within 2 years of surgery. Although there were no distinct gene mutations in recurrent patients, upregulation of MAGEA10 was identified in patients with early hepatic recurrence using GEP analysis. Immunostaining for MAGEA10 stained the cell nuclei in 29 (18.8%) of 154 samples. Furthermore, protein expression of MAGEA10 on immunohistochemistry was significantly related to a high MAGEA10 mRNA expression, high cumulative incidences of hepatic recurrence, and poor relapse-free survival. Overall survival did not differ significantly between positive and negative immunohistochemical staining for MAGEA10. The sensitivity and specificity of MAGEA10 staining for early hepatic recurrence were 58.3% and 84.5%, respectively. MAGEA10 represents a promising predictive marker for early hepatic recurrence after curative gastrectomy for gastric and gastroesophageal junction cancer.

421 Background: The prevalence of gastric cancer is higher in males than in females. Reports have revealed that female gastric cancer patients exhibit some distinctive features, such as a high proportion of undifferentiated cancer and poor survival outcomes. The therapeutic effects of anti-PD-1 antibody have also been reported to be different between males and females. However, precise differences in molecular profiling features between males and females are yet to be reported. To elucidate sex differences in the clinicopathological and molecular biological characteristics of gastric cancer, we performed whole-exon sequencing and comprehensive gene expression analysis. Methods: We compared the clinicopathological factors and disease-specific survival (DSS) in 499 patients who underwent gastrectomy for gastric cancer between January 2014 and April 2019, excluding those with special types of gastric cancer and R2 resection. We also performed whole-exome sequencing using peripheral blood and tumor tissue, gene panel testing, and transcriptome analysis of tumor and nontumor tissues. Results: Among the 499 patients, 358 were male and 141 were female. Women had significantly more undifferentiated and M-region cancers (P < 0.05 for both). In terms of gene mutations, TP53 mutations were significantly more common in males (P = 0.002), whereas CDH1 (P = 0.005), PIK3CA (P = 0.046), and ERBB3 (P = 0.021) mutations were significantly more common in females. Expression profiles reflecting the tumor microenvironment were classified into two groups: T cell high group (290 patients) and T cell low group (209 patients), via cluster analysis. Men in the T-cell high group had significantly better DSS than those in the T-cell low group (P = 0.005), whereas no significant difference was observed among women in the T-cell high and low groups (P = 0.402). Among the 136 genes significantly upregulated in the T-cell high group, CCL18 (P = 0.048) gene was significantly upregulated in males and CD8A (P = 0.026) gene was upregulated in females. Conclusions: TP53 mutations were more common in male patients with gastric cancer, whereas CDH1, PIK3CA, and ERBB3 mutations were more common in female patients with gastric cancer. Additionally, women did not demonstrate good survival outcomes even in the T-cell high group considered to have enhanced tumor immunity.

468 Background: The American Joint Committee on Cancer (AJCC) has increasingly recognized the need for individual risk prediction model for the era of tailored therapy. This study aimed to develop a postoperative gastric cancer nomogram for prediction of overall survival (OS). Methods: The nomogram was developed using data of 4,990 patients with primary gastric cancer who underwent macroscopically complete resection (residual tumor: R0 or R1) at Shizuoka Cancer Center (Shizuoka, Japan), and it was created with a multivariable Cox proportional hazard regression model. Fifteen pathological or host-related variables (age, sex tumor location, tumor size, macroscopic type, histology, depth (pT), number of positive nodes (pN), number of negative nodes, location of positive nodes, lymphovascular invasion, lavage cytology (CY), tumor margin, serum CEA and serum CA19-9) were collected. They are recommended to collect and register by the AJCC. The model was validated internally using measures of discrimination (Harrell’s C-index), calibration and decision curve analysis. A stage-specific subset survival analysis of the three risk groups (low, intermediate, high) calculated using the nomogram was performed. Results: In the development procedure, multivariable analysis for OS selected 11 variables for constructing the nomogram. The developed nomogram showed good discrimination, with a C-index of 0.812; that of the American Joint Committee on Cancer (AJCC) pathological stage was 0.756. The nomogram performed well in the calibration and decision curve analyses. A stage-specific subset survival analysis of the three risk groups calculated using the nomogram also showed the superiority of nomogram-prediction when compared to AJCC ordinal staging. Conclusions: This new postoperative risk model accurately predicts OS in gastric cancer and can be used for patient counseling in clinical practice and clinical trial eligibility determination.

Gastric cancer surgery for obese patients is regarded as a technically challenging procedure. The morbidity after gastrectomy has been reported to be significantly higher in patients with high visceral fat area (VFA). Robotic gastrectomy (RG) is expected to be advantageous for complicated operations. However, whether RG is superior to conventional laparoscopic gastrectomy (LG) for patients with visceral fat obesity remains unclear. The present study aimed to clarify the impact of RG on the short- and long-term outcomes of patients with high VFAs.This study included 1306 patients with clinical stage I/II gastric cancer who underwent minimally invasive gastrectomy between January 2012 and December 2020. The patients were subclassified according to VFA. The short- and long-term outcomes of RG were compared with those of LG in two VFA categories.This study included 394 (high-VFA, 151; low-VFA, 243) and 882 patients (high-VFA, 366; low-VFA, 516) in the RG and LG groups, respectively. RG was associated with a significantly longer operative time than LG (high-VFA, P 0.001; low-VFA, P 0.001). The incidence rates of overall and intra-abdominal infectious complications in the high-VFA patients were lower in the RG group than in the LG group (P = 0.019 and P = 0.048, respectively) but not significantly different from those in the low-VFA patients. In the multivariate analysis, LG was identified as the only independent risk factor of overall (odds ratio [OR] 3.281; P = 0.012) and intra-abdominal infectious complications (OR 3.462; P = 0.021) in the high-VFA patients. The overall survival of high-VFA patients was significantly better in the RG group than in the LG group (P = 0.045).For patients with visceral fat obesity, RG appears to be advantageous to LG in terms of reducing the risk of complications and better long-term survival.

Gallstones are known to occur quite frequently after gastrectomy. Most of the studies about postoperative cholelithiasis have focused on open gastrectomy, whereas laparoscopic gastrectomy has recently gained popularity as a type of minimally invasive surgery (MIS). Hence, the efficacy of MIS in preventing post-gastrectomy gallstone formation remains to be elucidated. This study aimed to evaluate the risk of gallstone formation after MIS for clinical stage I/IIA gastric cancer. A total of 1166 patients undergoing gastrectomy for clinical stage I/IIA gastric cancer between 2009 and 2016 were included in this study. Gallstones were detected on abdominal ultrasound and/or computed tomography. Multivariate logistic regression analysis was used to determine factors associated with postoperative gallstone formation. Gallstone formation was observed in 174 patients (15%), of whom 22 (2%) experienced symptomatic cholelithiasis. In multivariate analysis, the following were identified as risk factors for post-gastrectomy gallstone formation: open approach with an odds ratio (OR) of 1.670 and a 95% confidence interval (CI) of 1.110–2.510 (P = 0.014), older age (OR 1.880; 95% CI 1.290–2.730; P

Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification‐dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high‐risk GIST) and less malignant GIST (low‐ and very low‐risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K‐related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST., Signaling pathways involved in 65 GIST samples were investigated. Pathways were curated by genetic alterations, including oncogenic mutations and amplification‐dependent expression enhancement for oncogenes, and loss of heterozygosity and expression reduction for tumor suppressor genes. Malignant GIST with metastasis and high‐risk showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K and the cell cycle.

While paraaortic lymph node (PAN) dissection (PAND) has been found to be efficacious for patients with extensive lymph node metastasis (ELM) of locally advanced gastric cancer (LGC), the optimal indications for PAND remain to be elucidated. Thus, the prognostic factors among these patients were evaluated.A total of 35 patients with ELM of LGC who underwent gastrectomy with D2 and PAND between August 2008 and December 2019 were included and evaluated for long-term outcomes and prognostic factors.Preoperative chemotherapy was administered to 33 patients [neoadjuvant chemotherapy (NAC), n = 26; palliative chemotherapy followed by conversion surgery, n = 7], none of whom suffered surgical mortality. The pathological analysis identified PAN metastasis in 11 patients (31.4%). The 5-year overall and relapse-free survival (RFS) survival were 66.4% and 52.6%, respectively. Locoregional recurrence was found in one patient. The multivariate analysis revealed that NAC (P = 0.011) and 3 metastatic PANs on preoperative imaging (P = 0.017) were independently associated with RFS.D2 and PAND after NAC can be a promising approach for patients with ELM of LGC. In particular, patients with a limited number of metastatic PANs can be considered good candidates for PAND.

Robotic gastrectomy (RG) has been developed to address the drawbacks of laparoscopic gastrectomy (LG); however, whether or not RG is superior to conventional LG remains to be seen. The present study aimed to clarify the impact of RG on clinical stage I/II gastric cancer patients. The present study included 1208 patients with clinical stage I/II gastric cancer who had minimally invasive gastrectomy from January 2012 to March 2020 at the Shizuoka Cancer Center. The short- and long-term outcomes of RG and LG were compared after propensity score matching. This study involved 835 LG and 345 RG patients. After propensity score matching, there were 342 patients each in the RG and LG groups, with an improved balance of confounding factors between the two groups. RG was associated with a significantly longer operative time and lower amylase concentration in the drainage fluid on the first postoperative day than LG. Furthermore, the incidence of intra-abdominal infectious complications in the RG was lower than that in the LG (4.4% vs. 9.4%; P = 0.015). The survival of the RG and LG groups was equivalent. RG reduced the risk of intra-abdominal infectious complications in comparison with LG in the propensity score-matched analysis. Patients treated by the two approaches showed equivalent survival.

Phase III trials have shown the non-inferiority of minimally invasive distal gastrectomy (MIDG) comparison with open distal gastrectomy (ODG) in patients with gastric cancer; however, it remains unclear whether MIDG is also effective in the elderly. This study aimed to clarify the efficacy of MIDG in elderly gastric cancer patients. This study included 316 patients older than 75 years with clinical stage I/IIA gastric cancer who underwent distal gastrectomy from August 2008 to December 2016 at the Shizuoka Cancer Centre. The long-term outcomes between MIDG and ODG were compared after propensity score matching. After propensity score matching, there were 97 patients each in the MIDG and ODG groups, with an improved balance of confounding factors between the two groups. MIDG was associated with significantly longer operative time and a lower level of blood loss than ODG. The incidence of complications was comparable between the two groups. Survival outcomes were better in the MIDG group than in the ODG group (overall survival; P = 0.034, relapse-free survival; P = 0.027). In the multivariable analysis, ODG [hazard ratio (HR) 1.971, P = 0.046], being 80 years or older (HR 2.285, P = 0.018), male sex (HR 2.428, 95% P = 0.024), and poor physical status (HR 2.324, P = 0.022) were identified as independent prognostic factors for overall survival. We found that MIDG showed better efficacy than ODG in elderly gastric cancer patients. MIDG is an acceptable option for elderly patients.

The outcomes of robotic gastrectomy (RG) for gastric cancer remain unclear due to a lack of prospective studies. We had previously designed and conducted a prospective phase II study of RG that showed favorable short-term outcomes. Herein, we aimed to determine the long-term outcomes of RG for clinical stage I gastric cancer. This single-center, prospective phase II study enrolled patients with clinical stage I gastric cancer undergoing RG. The survival outcomes, which were the secondary endpoints of the study, were evaluated. Between December 2012 and April 2015, 120 patients were enrolled in this study. The 5-year overall survival (OS) was 96.7% (95% confidence interval [CI] 91.5–98.7%). The 5-year recurrence-free (RFS) and disease-specific survival (DSS) rates were 96.7% (95% CI 91.5–98.7%) and 99.2% (95% CI 94.3–99.9%), respectively. When confining the analysis to distal and pylorus-preserving gastrectomy, the 5-year OS, RFS, and DSS were 98.1% (95% CI 92.7–99.5%), 98.1% (95% CI 92.7–99.5%), and 100%, respectively. Only one patient died due to relapse of gastric cancer, while three died from other causes. Long-term outcomes of RG was comparable to those of open and laparoscopic gastrectomy when the surgeries were performed by experienced surgeons in a high-volume center.

Postoperative intra-abdominal infectious complication (PIIC) after gastrectomy for gastric cancer worsens in-hospital death or long-term survival. However, the methodology for PIIC preoperative risk assessment remains unestablished. We aimed to develop a preoperative risk model for postgastrectomy PIIC. We collected 183,936 patients’ data on distal or total gastrectomy performed in 2013–2016 for gastric cancer from the Japanese National Clinical Database and divided into development (2013–2015; n = 140,558) and validation (2016; n = 43,378) cohort. The primary outcome was the incidence of PIIC. The risk model for PIIC was developed using 18 preoperative factors: age, sex, body mass index, activities of daily living, 12 comorbidity types, gastric cancer stage, and surgical procedure in the development cohort. Secondarily, we developed another model based on the new scoring system for clinical use using selected factors. The overall incidence of PIIC was 4.7%, including 2.6%, 1.7%, and 1.3% in anastomotic leakage, pancreatic fistula, and intra-abdominal abscess, respectively. Among the 18 preoperative factors, male [odds ratio, (OR) 1.92], obesity (OR, 1.52–1.96), peripheral vascular disease (OR, 1.55), steroid use (OR, 1.83), and total gastrectomy (OR, 1.89) strongly correlated with PIIC incidence. The entire model using the 18 factors had good discrimination and calibration in the validation cohort. We selected eight relevant factors to create a simple scoring system, using which we categorized the patients into three risk groups, which showed good calibration. Using nationwide clinical practice data, we created a preoperative risk model for postgastrectomy PIIC for gastric cancer.

Introduction Recent reports on gene expression profiling (GEP) show several genes associated with malignant progression of GIST. However, genes associated with malignant transformation have not been clarified. Here, we aimed to reveal distinct genes in aggressive malignant GIST, using comprehensive gene expression analysis. Materials and methods We investigated GEP obtained by microarrays for 43 gastric GISTs, which mostly harbored KIT and PDGFRA mutations and integrated clinicopathological risk information. RT-PCR and immunohistochemistry were performed for FZD7, a receptor of Wnt ligands. Results GEP divided 43 gastric GISTs into two clusters. A cluster included seven of eight high-risk GISTs (88%) in modified NIH classification and was defined as high-risk cluster; the other cluster was defined as low-risk cluster. The number of probes with over 3-fold changes between the two clusters was 1,177, in which probes corresponding to 16 oncogenes were included. Genes involved in the Wnt signaling pathway were the most abundant among the 16 oncogenes. Focusing on 73 Wnt signaling pathway genes of the 21,578 probes, 12 upregulated and 5 downregulated genes were found in the high-risk cluster. Major cascade genes promoting the Wnt/β-catenin signaling pathway, including WNT11, FZD family, and DVL2, were upregulated in the high-risk cluster. SNAI1, SNAI2, and BIRC5, which are activated by this pathway and increase cell proliferation, were also upregulated. These gene expression alterations were consistent in the positive direction of this pathway. GISTs in high-risk cluster strongly expressed FZD7. Conclusion Wnt/β-catenin signaling pathway may play an important role in malignant transformation of indolent GIST.

Preoperative wait time is affected by various factors, and a certain time is needed before surgery. There is a concern that cancer treatment delay can lead to poor survival. The present study aimed to evaluate the impact of preoperative wait time on survival in patients with clinical stage (cStage) II/III gastric cancer. The study included patients with cStage II/III primary gastric cancer undergoing surgery between 2002 and 2012. Preoperative wait time was defined as the time from endoscopy for initial diagnosis to surgery. Patients were divided into the following three groups according to wait time: short wait group (≤ 30 days), intermediate wait group (> 30 and ≤ 60 days), and long wait group (> 60 and ≤ 90 days). Patient characteristics and survival were compared among the groups. This study included 467 male (67%) and 229 female (33%) patients, and the median patient age was 67 years. The numbers of cStage II and III patients were 332 (48%) and 364 (52%), respectively. The median wait time was 45 days. The body mass index was lower in the short wait group than in the other groups. A shorter wait time tended to be associated with a more advanced cStage. Although survival was significantly worse in the short wait group than in the long wait group, wait time was not identified as an independent prognostic factor in multivariate analysis. Preoperative wait time up to 90 days does not affect survival in patients with cStage II/III gastric cancer.

Preoperative malnutrition can worsen morbidity and mortality; however, the role of postgastrectomy nutritional status remains unclear. Our purpose was to clarify whether malnutrition after gastrectomy could predict long-term survival. Patients with pathological stage I, II, and III gastric cancer who underwent gastrectomy between 2002 and 2013 were included. The nutrition risk index (NRI) was evaluated before and at 1, 3, 6 and 12 months after gastrectomy. The patients were divided into normal (NRI > 97.5) or malnutrition (NRI ≤ 97.5) groups, and we compared the correlations of clinicopathological characteristics, surgical treatment, and overall survival between the two groups. Among the 760 participants, patients in the malnutrition group were significantly older and had higher incidences of comorbidity and advanced cancer than the patients in the normal group. Multivariate analysis showed that overall survival was poorer in the malnutrition group before gastrectomy [hazard ratio (HR) 1.68] and at 1 month (HR 1.77), 3 months (HR 2.18), 6 months (HR 1.81) and 12 months (HR 2.17) after gastrectomy (all p

The standard treatment for clinical submucosal invasive (cT1b) early gastric cancer is gastrectomy. However, Japanese gastric cancer treatment guidelines list endoscopic submucosal dissection (ESD) as an option for treating limited early gastric cancer cases. ESD can be curative depending on the pathological characteristics of resected specimens. Thus, we aimed to clarify the benefits and disadvantages of preceding ESD for early gastric cancer. We retrospectively analyzed patients who underwent ESD or curative gastrectomy for cT1b gastric cancer with differentiated adenocarcinoma 30 mm or less in diameter. Patients who underwent ESD irrespective of undergoing gastrectomy were assigned to the ESD group (n = 107), and those who underwent gastrectomy without undergoing ESD were assigned to the non-ESD group (n = 181). Clinicopathological characteristics were assessed, and the short-term and long-term outcomes of patients were compared. The criteria for curative resection were satisfied by 83 patients (28.8%), and preceding ESD did not affect the surgical outcomes of gastrectomy. Two patients (1.9%) who underwent ESD had an unscheduled total gastrectomy. The en bloc and complete resection rates of ESD were 99.0% and 84.1% respectively. Nine patients (8.4%) experienced intraprocedure perforation and postprocedure bleeding caused by ESD. Overall survival (hazard ratio 1.38; P = 0.302) and cause-specific survival (hazard ratio 0.96; P = 0.944) were comparable between groups. The stomach was preserved in 28.8% of patients, and preceding ESD did not show obvious disadvantages. Therefore, diagnostic ESD should be considered as an initial treatment for limited cT1b gastric cancer cases.

Studies to identify predictive biomarkers of adjuvant chemotherapy with S-1 after gastrectomy in Stage II/III gastric cancer patients have been done; however, more clarity and understanding are needed. Our aim in the present study was to identify biomarkers predicting benefit due to S-1 adjuvant chemotherapy using comprehensive gene expression analysis. We retrospectively analyzed 102 patients receiving adjuvant chemotherapy with S-1 and 46 patients not receiving S-1 adjuvant chemotherapy after gastrectomy for gastric cancer treatment between January 2014 and December 2016. Hierarchical clustering analysis was performed based on the gene expression data obtained using cDNA microarray. Differentially expressed genes (DEGs) were identified using thresholds of absolute fold changes of > 4.0 and a false discovery rate P value of

Patients with stage I gastric cancer tend to wait for surgery. Although the cancer may progress during such a delay, effects of wait time for surgery on survival remain inconsistent. Here, we evaluated the safety of surgical wait time on survival of patients with clinical stage I gastric cancer.The outcomes of 556 patients who underwent gastrectomy for clinical stage I gastric cancer between January 2007 and December 2011 were retrospectively evaluated. Patients were stratified into three groups based on wait time: short- (61 days, n = 185), intermediate- (61-90 days, n = 218), and long-wait (91-180 days, n = 153) groups. Clinicopathological findings and survival were compared among the groups.The median wait time was 72 days. Age and comorbidities differed among the groups, but clinical and pathological cancer stages did not. Overall survival was comparable; the 5-year overall survival was 90.2%, 93.6%, and 88.8% in the short-, intermediate-, and long-wait groups, respectively. Multivariate analysis revealed that wait time was not an independent prognostic factor for overall survival. Adjusted hazard ratios (HRs) were 0.69 (p = 0.262) and 1.03 (p = 0.926) in the intermediate- and long-wait groups, respectively, with short wait time as the reference. Relapse-free survival was comparable among the groups (intermediate-wait HR = 0.80, p = 0.476; long-wait HR = 1.10, p = 0.740).A half-year wait time for surgery was not independently associated with survival of patients with clinical stage I gastric cancer and may therefore be acceptable.

There is no evidence that strict follow-up using cross-sectional imaging after curative gastrectomy benefits survival; however, nonperitoneal recurrence detected early might be treated with additional surgery. The present study examined whether early detection of recurrence by imaging modalities could increase survival, particularly in patients with nonperitoneal recurrence. We retrospectively analyzed 218 patients with recurrent gastric cancer after curative gastrectomy performed from 2002 to 2014. The patients were divided into an asymptomatic group (n = 117) and a symptomatic group (n = 101), according to the presence of symptoms at the time of recurrence, to compare clinicopathological characteristics and long-term survival. Peritoneal recurrence was less frequent in the asymptomatic group (22.2%) than in the symptomatic group (62.4%), the median time to recurrence was shorter (12.7 months vs 18.9 months; P

It has been reported that postoperative complications after curative surgery for gastric cancer adversely affect long-term survival; however, postoperative complications may confound other patient characteristics or tumor factors associated with survival outcome. In the present study, covariates were adjusted by propensity score matching to clarify whether postoperative complications truly affect survival outcome. The present study was performed on 1541 patients who underwent curative gastrectomy for gastric cancer between 2002 and 2009. Patients were divided into two groups based on the occurrence (174 patients) or absence (1367 patients) of postoperative intra-abdominal infectious complications. Survival outcomes were compared between groups using propensity score matching analysis. Most clinicopathological characteristics differed significantly between the two groups, but these differences disappeared after propensity score matching. After matching, overall survival was significantly poorer in patients with postoperative intra-abdominal infectious complications [hazard ratio (HR) 1.43, 95 % confidence interval (CI) 1.02–2.00; p = 0.036], as was relapse-free survival (HR 1.42, 95 % CI 1.03–1.96; p = 0.034). Intra-abdominal infectious complications adversely affected survival outcome when patients were matched by propensity scores, which included demographic data as covariates. Thus, it is important to avoid the development of intra-abdominal infectious complications to improve long-term survival.

4562 Background: There are three major reconstruction methods after gastrectomy for distal gastric cancer; Billroth-I (B-I), Roux-en-Y (RY) and pylorus-preserving gastrectomy (PPG). These procedures can affect postoperative health-related quality-of-life (HRQoL), but the method is often selected due to physician’s preference or each institutional policy without solid evidence. We aimed to explore differences in HRQoL after each reconstruction procedure selected in JCOG0912, a phase III noninferiority trial comparing open and laparoscopic distal gastrectomies for stage I gastric cancer. Methods: Among 33 institutions participated in JCOG0912, 4 major cancer centers were selected for HRQoL assessment. HRQoL was assessed using the EORTC QLQ-C30 and STO22 before (baseline) and at 1, 3, 12, and 36 months after surgery as preplanned exploratory analysis. Results: Excluding 2 patients who didn’t answer the questionnaire, 590 patients were analyzed in this study. For reconstruction, B-I was performed for 222 patients (37.7%), RY for 178 (30.2%) and PPG for 189 (32.1%). Proportion of the opted reconstruction procedures was not different in open and laparoscopic gastrectomies. Global health status (GHS) scores of QLQ-C30 were not different among 3 groups at any time point. In comparison of B-I and RY, B-I was better than RY in constipation, while RY was better than B-I in diarrhea and reflux symptoms. In comparison of B-I and PPG, B-I was better than PPG in constipation and reflux symptoms, while PPG was better than B-I in diarrhea. When comparing RY and PPG, RY was better than PPG in constipation and reflux symptoms, while PPG was better than RY in taste (table). Conclusions: GHS scores were similar regardless of the reconstruction procedure, however postoperative symptoms including reflux, constipation, and diarrhea were various according to reconstruction methods. [Table: see text]

290 Background: In patients with gastric cancer (GC), the most common double cancer is colorectal cancer (CRC). However, the meaning of screening colonoscopy has not been established. The aim of this retrospective study was to evaluate the useful of screening colonoscopy in preoperative patients with GC. Methods: This study included 689 patients who received screening colonoscopy before gastric surgery between 2012 and 2016. Multivariate analysis using logistic regression model was conducted to elucidate independent risk factors of CRC. Then, we investigated the clinicopathological factors for CRC. Results: Colorectal adenomas and CRC were observed in 315 patients (46%) and 37 patients (5.4%), respectively. The clinical T classification of the CRC were as follows; Tis: 24 patients (65%), T1: 8 patients (21%), T2: 2 patients (6%), and T3: 3 patients (8%). In multivariate analysis, male (OR 5.04, 95% C.I. 1.29-19.6, p = 0.020) was revealed as risk factor for affecting CRC. The treatments for CRC were as follows; EMR was performed in 27 patients, simultaneous resection with GC was performed in 9 patients, resection after gastrectomy was performed in 1 patient, respectively. Pathological stage of CRC was as follows; Stage 0: 24 patients, Stage I: 10 patients, and Stage IIA: 3 patients, respectively. As for the patients who underwent surgery for CRC, all of them received radical colectomy. No patient died for CRC who received colonoscopy before gastric surgery. Conclusions: Screening colonoscopy is useful for GC patients. Because most of the synchronous CRC were found early stage and curatively treated.

Robotic surgery using da Vinci®Surgical System which has the high resolution 3-dimensional images, the forceps with 7 degrees freedom, the function for prevention of tremors and motion scaling enables to perform meticulous operation circumventing the action of forceps movement which is the major problem in conventional laparoscopic surgery. In 2003, initial robotic gastrectomy for gastric cancer has been reported. Since then robotic gastrectomy has been developed mainly in Japan, Korea and Italy. From January 2012, we launched robotic gastrectomy at our institute as prospective clinical phase II trials to clarify the safety of robotic gastrectomy. The results of these trials have already been published and the safety of robotic gastrectomy was confirmed. In the several retrospective analyses, robotic gastrectomy has been reported to show longer operation time, less blood loss and lower morbidity compared with conventional laparoscopic surgery. However, the superiority of robotic gastrectomy to laparoscopic gastrectomy has not yet been demonstrated in terms of short- and long-term outcomes in a randomized controlled trial. Since robotic gastrectomy has been approved in Japanese health insurance system at April 2018, it is expected to rapidly expand throughout the country in the near future. Therefore, it is urgent matter to establish an evidence and educational program. In this article, the current status and future perspective about robotic surgery for gastric cancer are presented.

Pylorus-preserving gastrectomy (PPG) has the postoperative advantages of a better quality of life and less weight loss than distal gastrectomy. However, postoperative delayed gastric emptying (DGE) due to antral hypomotility can be a problem. Although preserving the infra-pyloric vein (IPV) is reported to improve congestion of the antrum and prevent DGE, the benefits of this procedure have not been confirmed. The present study aimed to clarify the preventive effect on DGE of preserving the IPV. A total of 148 patients [IPV-preserved (IPVP): 78 patients and IPV-non-preserved (IPVN): 70 patients] who underwent laparoscopic and robotic PPG (LRPPG) for early gastric cancer were enrolled in this study. The clinicopathologic characteristics and incidence of DGE were compared between the groups. The nutritional risk index (NRI) at 1, 2, and 3 years after the operation and the relapse-free survival (RFS) were also compared. There were no significant differences in the clinicopathological characteristics between the two groups. DGE was observed in 15 of 148 patients (10.1%). The incidence of DGE did not differ markedly between the 2 groups (IPVP vs. IPVN; 11.5% vs. 8.6% p = 0.596). There were no significant differences in other complications between the groups either (IPVP vs. IPVN; 19.2% vs. 21.4%; p = 0.838). The NRI and 3-year RFS were not significantly different between the two groups. Regarding LRPPG, preserving the IPV did not help prevent DGE and resulted in no significant difference in the outcomes.

The incidence of postoperative delirium is reported to range from 9 to 87%; however, no report has focused on cases of postoperative delirium in gastric cancer surgery alone. Therefore, we investigated the incidence of and risk factors for postoperative delirium after gastrectomy in patients with gastric cancer. A total of 1037 patients who underwent surgery were included in the study. Patients were divided into two groups—those with (delirium group) or without (non-delirium group) postoperative delirium—and their backgrounds were compared. The short-term outcomes and the overall survival were also investigated. Postoperative delirium was observed in 47 of 1037 patients (4.5%). A multivariate analysis revealed that male gender, age ≥ 75 years, a history of cerebrovascular disease, and the habitual use of sleeping pills were independent predictive factors for postoperative delirium. The postoperative hospital stay was significantly longer in the postoperative delirium group than in the non-delirium group. Postoperative delirium was significantly associated with postoperative complications. The 3-year overall survival was 74.3% in the delirium group and 85.5% in the non-delirium group (log-rank p = 0.006). A multivariate analysis revealed that postoperative delirium was an independent prognostic factor, along with the age and cancer stage. The incidence of postoperative delirium was 4.5% in gastric cancer patients. Male gender, age ≥ 75 years, a history of cerebrovascular disease, and the habitual use of narcoleptic agents were risk factors for postoperative delirium after gastrectomy in gastric cancer patients. Postoperative delirium was strongly associated with other postoperative complications and a poor survival after surgery.

Randomized controlled trials, including the Japan Clinical Oncology Group (JCOG) 0912 trial, have shown the safety of laparoscopy-assisted distal gastrectomy (LADG) for select healthy patients. It is unclear whether LADG is feasible in patients who do not meet trial eligibility criteria. The present study retrospectively reviewed 547 patients with clinical stage I gastric cancer who underwent distal or pylorus-preserving gastrectomy. Of these, 185 were identified as not fulfilling the eligibility criteria of JCOG 0912; the short-term surgical outcomes between LADG and open distal gastrectomy (ODG) were compared in this group before and after propensity score matching. Patients who were not eligible for inclusion in the trial comprised 33.8% of the total. After matching, there were 59 patients each in the LADG and ODG groups, with an improved balance of confounding factors between the two groups. LADG was associated with significantly longer operation time, less blood loss, and shorter postoperative hospital stay than ODG. The rate of overall postoperative complications of Clavien–Dindo Grade II or higher did not differ significantly between the LADG and ODG groups (23.7 vs. 18.6%, respectively; p = 0.653). The incidence of pneumonia (6.8 vs. 5.1%), intra-abdominal infectious complications (5.1 vs. 3.4%), and stasis syndrome (5.1 vs. 3.4%) was also comparable between the two groups. LADG was as safe as ODG in patients who did not meet the eligibility criteria of JCOG 0912. LADG could be a standard treatment option for patients with stage I gastric cancer, regardless of their general condition.

Although sigmoid volvulus (SV) causes acute obstruction, its pathogenesis and mechanism of torsion are unknown, and few reports have described its pathological findings. Here, we evaluated the clinicopathological characteristics of volvulus and factors contributing to volvulus of the sigmoid colon.We compared 14 patients with SV (10 men and 4 women; median age, 78.5 years) with 14 age- and sex-matched control patients for differences in clinical characteristics, focusing on dysmotility (enteric visceral myopathy, neuropathy, and mesenchymopathy).Of the 14 SV patients, 7 had recurrent volvulus, 11 had an associated condition, and 5 required emergency surgery. Atrophy and fibrosis of the inner muscle were more prevalent in the SV than control patients (p = 0.041). Median extent (per centimeter of muscularis propria) of the myenteric plexus (12.5 versus 17.5, p 0.001) and submucous plexus (15.0 versus 25.5, p 0.001) was lower in the SV patients, as were the median numbers of myenteric (9.7 versus 30.4, p 0.001) and submucous ganglion cells (10.0 versus 23.2, p 0.001). Inflammatory neuropathy was more prevalent in the SV than control patients (p = 0.046); whereas, the prevalence of mesenchymopathy did not differ (p = 0.481).A decrease in the extent of enteric plexus and ganglion cells precedes the clinical manifestation of SV. Although further elucidation is needed, this decrease may play an important role in the diagnosis of SV and in identifying the mechanism leading to torsion in SV.

Background Amputation neuromas (ANs) are reactive hyperplasia of nerve tissues that occur after a trauma or surgery involving the peripheral nerves. Only two previous reports of ANs occurring around the stomach and post gastrectomy have been reported. We report the case of a patient with AN near the remnant stomach who underwent distal gastrectomy for gastric cancer. Case presentation A 76-year-old man underwent distal gastrectomy, D1+ lymphadenectomy, and Billroth-I reconstruction for early gastric cancer in another hospital at 63 years of age. A regular gastrointestinal endoscopic follow-up examination after gastrectomy revealed an ulcerative lesion on the lesser curvature of the remnant stomach, which was diagnosed as remnant gastric cancer based on the histopathological examination. Then, he was transferred to our hospital. An upper gastrointestinal series and endoscopy revealed an 18-mm Type 0-IIc lesion on the lesser curvature of the remnant stomach with an estimated depth within the mucosa (T1a). An abdominal contrast-enhanced computed tomography (CT) failed to detect the primary lesion; however, a slightly enhanced 13 × 10-mm nodule was detected near the lesser curvature of the remnant stomach. An endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) of the nodule showed no cancer cell; thus, endoscopic submucosal dissection (ESD) for the remnant gastric cancer was performed. Histopathological examination revealed noncurative resection due to T1b2 and UL (+). We planned an additional surgical resection. Before the resection, CT was performed, which had a 3-month interval with a previous CT, showing an enlargement of the nodule to 16 × 12 mm. We diagnosed the nodule as a lymph node metastasis and performed resection of the remnant stomach, D2 lymphadenectomy, splenectomy, and Roux-en-Y reconstruction. The nodule was later diagnosed as AN based on the histopathological examination. There was no residual cancer in the resected specimen. Conclusions We report AN mimicking lymph node metastasis near the remnant stomach of a patient with remnant gastric cancer. When nodules appear in the previous operative field, the possibility of ANs should be considered, although the incidence may be quite low.

Background Studies to identify predictive biomarkers of adjuvant chemotherapy with S-1 after gastrectomy in Stage II/III gastric cancer patients have been done; however, more clarity and understanding are needed. Our aim in the present study was to identify biomarkers predicting benefit due to S-1 adjuvant chemotherapy using comprehensive gene expression analysis. Methods We retrospectively analyzed 102 patients receiving adjuvant chemotherapy with S-1 and 46 patients not receiving S-1 adjuvant chemotherapy after gastrectomy for gastric cancer treatment between January 2014 and December 2016. Hierarchical clustering analysis was performed based on the gene expression data obtained using DNA microarrays. Differentially expressed genes (DEGs) were identified using thresholds of absolute fold changes (FCs) of > 4.0 and a false discovery rate (FDR) P value of Results Hierarchical clustering analysis in patients treated with S-1 adjuvant chemotherapy revealed two clusters with favorable and unfavorable survival outcomes. We identified 147 upregulated DEGs and 192 downregulated DEGs in the favorable outcome group. GO analysis to identify significantly upregulated genes showed enrichment in immune-related genes and GO terms. Upregulation of these immune-related genes was not associated with survival in patients not receiving S-1 adjuvant chemotherapy. Conclusions The upregulation and enrichment of immune-related genes and GO terms may be a predictive biomarker in patients who would benefit from adjuvant S-1 chemotherapy to treat Stage II/III gastric cancer. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Terashima: Honoraria (self): Taiho; Honoraria (self): Chugai; Honoraria (self): Yakult; Honoraria (self): ONo; Honoraria (self): BMS; Honoraria (self): Eli-Lilly; Honoraria (self): Takeda; Honoraria (self): Daiichi-Sankyo; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Nihon Kayaku; Honoraria (self): Pfizer. All other authors have declared no conflicts of interest.

49 Background: Immune checkpoint inhibitors (ICPIs) have provided clinical benefit for various malignancies. A new attempt was recently made to combine PD-1/PD-L1 inhibitors and other ICPIs. In order to establish a new strategy for ICPI combination therapy, we must first understand the expression patterns of PD-L1 and other ICP molecules. To identify possible candidate agents for application in combination therapy with PD-1/PD-L1, we analyzed the expression patterns of ICP molecules in gastric cancer. Methods: Tumor samples were obtained from 278 patients who underwent gastrectomy for gastric cancer from 2014 to 2016, and a comprehensive gene expression analysis using a DNA microarray. We analyzed the TCGA dataset to identify the candidate ICP molecules in relation to PD-L1. The immune landscape was evaluated according to the expression patterns of known immune cell markers reported by Bindea et al. Results: Seven ICP molecules ( PD-L2, IDO1, CD80, ICOS, CTLA4, LAG3 and TIM3) were coexpressed with PD-L1 in the TCGA dataset. In our cohort, all of these molecules were also coexpressed (R > 0.5, P < 0.0001). Using a cluster analysis based on these gene expression profiles, patients were divided into Group A, characterized by the co-overexpression of PD-L1 and other ICP molecules, and Group B, characterized by the underexpression of PD-L1. In Group A, PD-L2 (R = 0.67) and IDO1 (R = 0.61) were particularly strongly associated with the PD-L1 expression. In Group B, elevated expressions of CTLA4 and ICOS were predominantly observed, and these expressions were strongly correlated with each other (R = 0.90). The tumor stage was significantly more advanced in Group B than in Group A (P = 0.02). Accordingly, Group A exhibited a better survival outcome than Group B. The immune landscape of Group A was particularly enriched for Th1, NK CD56dim and activated dendritic cells. Conclusions: PD-L1 and several immune checkpoint molecules tend to be coexpressed in gastric cancer. The combination of PD-L1/-L2 and IDO1 target agents may be a new strategy for treating gastric cancer with PD-L1 overexpression. In contrast, the underexpression of PD-L1 might be an indication for the use of CTLA4- and/or ICOS-directed therapies.