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BackgroundThe long-term outcomes of type 4 and large type 3 gastric cancer patients with positive peritoneal lavage cytology (CY1) remain unsatisfying. We evaluated our treatment strategy of conversion therapy for CY1 patients without peritoneal dissemination (P0).MethodsDiagnostic staging laparoscopy (DSL) was performed before treatment. Chemotherapy was applied for DSL-diagnosed P0CY1. The re-evaluation of peritoneal metastasis by staging laparoscopy (re-SL) was performed when a response to chemotherapy was identified by gastroscopy and/or CT. Gastrectomy with radical lymphadenectomy was applied as conversion therapy when peritoneal lavage cytology-negative (CY0) and P0 were diagnosed with re-SL, with the aim of achieving R0 resection. Chemotherapy was continued as palliative treatment in patients for whom re-SL was not applicable or when re-SL did not confirm P0CY0. The long-term outcomes were retrospectively evaluated.ResultsBetween 2009 and 2015, 214 patients with type 4 and large type 3 gastric cancer underwent DSL in the Cancer Institute Hospital. Thirty-nine patients were initially diagnosed with P0CY1. Seven patients received palliative gastrectomy first due to outlet obstruction or other reasons. Thirty-two patients received chemotherapy first. Among them, 13 patients underwent gastrectomy as conversion therapy and 19 were treated with palliative chemotherapy. The 3-year survival rate of patients who underwent conversion therapy, palliative chemotherapy and palliative gastrectomy was 76.9% [95% confidence interval (CI) 47.8–92.4%], 10.5% (95% CI 1.9–42.3%), and 0%, respectively.ConclusionConversion therapy might be a promising treatment for P0CY1 type 4 and large type 3 gastric cancer patients. Re-SL was useful for selecting candidates for R0 resection.

BackgroundDouble-flap technique (DFT) has received increased attention as an anastomotic procedure preventing reflux esophagitis after laparoscopic proximal gastrectomy (LPG) for upper-third gastric cancer. However, incidence of anastomotic stricture still remains high. This study was a retrospective review aimed to demonstrate details of surgical outcomes and to assess risk factors for anastomotic complications using pre-operative CT image after LPG with DFT (LPG–DFT).MethodsPatient background data, surgical outcomes, post-operative courses, and complications for patients who underwent LPG–DFT from January 2013 to June 2017 were collected. In addition to the details of short-term outcomes, risk factors for anastomotic stricture and gastroesophageal reflux were analyzed.ResultsThe study sample was 147 patients, including 139 patients with upper-third gastric cancer and 8 patients with submucosal tumor of the upper-third stomach. The overall morbidity rate was 12.2% (18/147), and 97.3% (143/147) of the patients achieved R0 resection. Twelve (8.3%) patients required endoscopic balloon dilatation for anastomotic stenosis, and six (4.2%) suffered regurgitation grade ≥ B in the Los Angeles classification. Multivariate analysis revealed that diameter of the esophagus < 18 mm on pre-operative CT image and the presence of short-term complications were found to be independent risk factors for post-operative anastomotic stenosis. No specific risk for gastroesophageal reflux was identified.ConclusionsThe incidence rate of anastomotic complications after LPG–DFT was far lower than that reported after conventional esophagogastrostomy. Alternative anastomotic method may be considered for patients with diameter of the esophagus < 18 mm on pre-operative CT image. Prevention of short-term complications may lessen post-operative stricture.

BackgroundPylorus-preserving gastrectomy (PPG) is a function-preserving procedure for cT1N0 gastric cancer located in the middle-third of stomach, which is currently performed through a laparoscopic approach (LPPG). PPG is sometimes associated with a crucial problem during the early postoperative course, designated gastric stasis. However, information regarding gastric stasis remains to be fully elucidated.MethodsThe study included 897 patients who underwent LPPG between 2005 and 2017. Early postoperative gastric stasis (E-stasis) was defined when the following conditions were fulfilled: upper abdominal distension, remnant stomach fullness on radiography image, and period of starvation exceeding 72 h within 1 month postoperatively. To evaluate long-term outcomes of E-stasis, late postoperative food residue (L-residue) was defined as grade 2 or higher food residue endoscopically according to the RGB (residue, gastritis, bile) classification at 1 year postoperatively. Risk factors and long-term outcomes of E-stasis were retrospectively analyzed.ResultsE-stasis was the most common complication during the early postoperative course. E-stasis occurred in 68 (7.6%) patients. Multivariate analysis identified age (≥ 61 years), DM, and postoperative intraabdominal infection as risk factors. At 1 year postoperatively, relative body weight ratio and postoperative serum albumin in the patients who experienced E-stasis was significantly lower than those in the other patients (P = 0.042 and 0.011, respectively). Of the patients who suffered from E-stasis, 42.5% experienced L-residue.ConclusionsE-stasis after LPPG occurs in 7.6% of patients. Age, DM, and intraabdominal infection are significantly related to E-stasis. E-stasis is associated with poorer nutritional and functional outcomes even at 1 year postoperatively.

Background Laparoscopic pylorus-preserving gastrectomy (LPPG) is performed for cT1N0 gastric cancer as a function-preserving surgery, but reflux esophagitis can develop as a mid- to long-term complication postoperatively. We aimed to clarify the incidence rate of this complication and the factors correlated with it. Methods Patients with gastric cancer who underwent LPPG between 2005 and 2017 were analyzed. Postoperative reflux esophagitis was evaluated with esophagogastroduodenoscopy; patients were diagnosed as having reflux esophagitis with erosive esophagitis using the modified Los Angeles classification. The incidence rate of postoperative reflux esophagitis was estimated; factors correlated with postoperative reflux esophagitis were analyzed using the logistic regression model. Results During the study period, 813 patients underwent LPPG for gastric cancer, and 127 (15.6%) of them developed grade B or more severe postoperative reflux esophagitis. The factors correlated with postoperative reflux esophagitis were male sex (odds ratio, 2.68; 95% confidence interval, 1.77–4.05; P < 0.001), preoperative grade A reflux esophagitis (odds ratio, 3.05; 95% confidence interval, 1.28–7.27; P = 0.012), body mass index of ≥ 23 kg/m 2 at 1 year postoperatively (odds ratio, 2.18; 95% confidence interval, 1.34–3.53; P = 0.002), postoperative hiatal hernia (odds ratio, 4.35; 95% confidence interval, 2.35–8.04; P < 0.001), and long-term stasis (odds ratio, 1.58; 95% confidence interval, 1.01–2.47; P = 0.044). Conclusions Careful attention should be paid in performing LPPG and in postoperative management after LPPG for gastric cancer patients with those risk factors.

Tumors consist of heterogeneous cell populations that contain cancer cell subpopulations with anticancer drug‐resistant properties called “persister” cells. While this early‐phase drug tolerance is known to be related to the stem cell‐like characteristic of persister cells, how the stem cell‐related pathways contribute to drug resistance has remained elusive. Here, we conducted a single‐cell analysis based on the stem cell lineage‐related and gastric cell lineage‐related gene expression in patient‐derived gastric cancer cell models. The analyses revealed that 5‐fluorouracil (5‐FU) induces a dynamic change in the cell heterogeneity. In particular, cells highly expressing stem cell‐related genes were enriched in the residual cancer cells after 5‐FU treatment. Subsequent functional screening identified aldehyde dehydrogenase 1A3 (ALDH1A3) as a specific marker and potential therapeutic target of persister cells. ALDH1A3 was selectively overexpressed among the ALDH isozymes after treatment with 5‐FU or SN38, a DNA topoisomerase I inhibitor. Attenuation of ALDH1A3 expression by RNA interference significantly suppressed cell proliferation, reduced the number of persister cells after anticancer drug treatment and interfered with tumor growth in a mouse xenograft model. Mechanistically, ALDH1A3 depletion affected gene expression of the mammalian target of rapamycin (mTOR) cell survival pathway, which coincided with a decrease in the activating phosphorylation of S6 kinase. Temsirolimus, an mTOR inhibitor, reduced the number of 5FU‐tolerant persister cells. High ALDH1A3 expression correlated with worse prognosis of gastric cancer patients. These observations indicate that the ALDH1A3‐mTOR axis could be a novel therapeutic target to eradicate drug‐tolerant gastric cancer cells. Using a single‐cell analysis of patient‐derived gastric cancer cells, we identified aldehyde dehydrogenase 1A3 (ALDH1A3) as a therapeutic target of anticancer drug‐tolerant persister cells. ALDH1A3 knockdown significantly suppressed cell proliferation and reduced the number of persister cells after treatment with 5‐fluorouracil (5‐FU) and SN38. Mechanistically, ALDH1A3 depletion downregulated the mTOR cell survival pathway, and an mTOR inhibitor reduced the number of drug‐tolerant persister cells.

BackgroundThe incidence of metachronous multiple gastric cancer (MMGC) after gastrectomy remains unclear. This study evaluated the incidences of MMGC according to specific gastrectomy types, including pylorus-preserving gastrectomy (PPG), proximal gastrectomy (PG), and function-preserving gastrectomy (FPG), which was categorized as segmental gastrectomy and local resection.MethodsWe conducted a questionnaire survey of the Japanese Society for Gastro-Surgical Pathophysiology members, who were asked to report their institutional numbers of radical gastrectomy cases for cancer between 2003 and 2012. The cases were categorized according to whether the remnant stomach’s status was followed for > 5 years, confirmation of MMGC, time to diagnosis, and treatment for MMGC. We calculated the “precise incidence” of MMGC by dividing the number of MMGC cases by the number of cases in which the status of remnant stomach was followed up for > 5 years.ResultsThe responses identified 33,731 cases of gastrectomy. The precise incidences of MMGC were 2.35% after distal gastrectomy (DG), 3.01% after PPG, 6.28% after PG (p < 0.001), and 8.21% after FPG (p < 0.001). A substantial proportion of MMGCs (36.4%) was found at 5 years after the initial surgery. The rates of MMGC treatment using endoscopic submucosal dissection were 31% after DG, 28.6% after PPG, 50.8% after PG (p < 0.001), and 67.9% after FPG (p < 0.001).ConclusionsThe incidence of MMGC was 2.4% after DG, and higher incidences were observed for larger stomach remnants. However, the proportion of cases in which MMGC could be treated using endoscopic submucosal dissection was significantly higher after PG and FPG than after DG.

Background Postoperative complications such as anastomotic leakage were reported to be a major independent prognostic factor for long-term survival in gastrointestinal malignancies. This study sought to clarify the prognostic significance of postoperative inflammatory complications specifically for patients with gastric cancer. Methods This study included 1,395 patients who underwent curative resection for gastric cancer from 2005 to 2008. Complications were evaluated according to the Clavien-Dindo classification. Overall survival (OS) and disease-specific mortality (DSM) were compared between complication and no-complication groups. Presence of complications was modeled by the Cox proportional hazard model for OS and the Fine and Gray competing risk regression model for DSM to assess the correlation between complication and prognosis. Results The median follow-up time was 3.1 years. Two hundred seven patients (14.8 %) had complications of grade 2 or higher. Of 131 patients who died within this period, 87 died of gastric cancer. The 3-year OS in the complication group was 84.1 % compared to 93.1 % in the no-complication group ( P  < 0.0001). The cumulative incidence of DSM was also significantly worse in patients with complications ( P  < 0.0001). Multivariate analysis identified the same significant increasing risk of complication for both OS (hazard ratio 1.88; 95 % confidence interval 1.26–2.80) and DSM (hazard ratio 1.90; 95 % confidence interval 1.19–3.02). Conclusions Postoperative complications that can cause prolonged inflammation have an obvious impact not only on the OS but also on the DSM of patients with gastric cancer even if the tumor is resected curatively.

Background Laparoscopic gastrectomy is more frequently associated with postoperative pancreatic fistula than is open gastrectomy. We assumed that compression of the pancreas with various devices to obtain a proper operative view is associated with the higher incidence of PF in LG and that the extent of the compression differs depending on the anatomical position of the pancreas. The present study aimed to elucidate the correlation between the anatomical position of the pancreas and PF after LG for gastric cancer. Methods Patients who underwent LG for gastric cancer from 2005 to 2019 were retrospectively reviewed. Two anatomical parameters representing the height of the slope looking down the celiac artery from the top of the pancreas (P-A length) and the steepness of the slope (UP-CA angle) were measured in computed tomography sagittal projections. The correlation between PF and (1) P-A length, (2) UP-CA angle, and (3) other clinicopathological factors was analyzed using a logistic regression model. Results Among 3485 patients, grade ≥ II PF was observed in 140 (4.0%) patients. The UP-CA angle [odds ratio (OR), 2.472; 95% confidence interval (CI), 1.725–3.543; P  < 0.001], a high BMI (OR 2.339; 95% CI 1.634–3.348; P  < 0.001), and male sex (OR 2.602; 95% CI 1.590–4.257; P  < 0.001) were independently correlated with grade ≥ II PF. Conclusions The present study identified a significant correlation between anatomical position of the pancreas and PF after LG. High BMI and male sex were also significantly correlated with PF after LG.

Purpose Deciding palliative treatment for gastric bleeding from incurable gastric cancer (IGC) is worrying considering different patient situations and the lack of comprehensive assessment of palliative treatment. We evaluated the clinical outcomes and prognostic factors after palliative treatment for gastric bleeding from IGC. Methods We enrolled 48 consecutive patients with gastric bleeding from IGC who underwent palliative surgery (PS) or palliative radiotherapy (PRT). Results Of the 48 patients, 23 underwent PS and 25 received PRT. More patients who had an Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≥ 2 or who received chemotherapy underwent PRT than underwent PS. Severe complications were observed in 2 (8.6%) patients after PS. After PRT, 22 patients achieved hemostasis (88%), but rebleeding was found in 10 (40%). Chemotherapy was introduced after palliative treatment for 21 (91.3%) patients in the PS group and 17 (68%) patients in the PRT group. The median survival time (MST) of patients with and without chemotherapy after PS was 12.5 and 3.1 months, respectively ( p  ≤ 0.001), while the MST of patients with and without chemotherapy after PRT was 6.5 and 1.6 months ( p  < 0.001). Multivariate analyses identified ECOG-PS, tumor size, and chemotherapy after palliative treatment as independent risk factors. Conclusions Palliative treatment strategies for gastric bleeding should be determined with consideration of the general condition, previous chemotherapy, and chemotherapy after palliative treatment.

BackgroundWhether splenectomy for splenic hilar lymph node (No. 10) dissection in type 4 gastric cancer involving the greater curvature is necessary is not established. Patients with type 4 gastric cancer often experience peritoneal relapse, despite curative surgery, and total gastrectomy with splenectomy is frequently associated with infectious complications.MethodPatients with cT2–T4 gastric cancer in the upper or middle third of the stomach, or both, involving the greater curvature who underwent R0 total gastrectomy with splenectomy between 2006 and 2016 were selected. Clinicopathological findings, postoperative complications, the incidence of lymph node metastasis, and the therapeutic value index of each station were compared between type 4 and non-type 4 gastric cancer.ResultsWe enrolled 50 patients with type 4 and 60 with non-type 4. The former had a significantly higher proportion of the undifferentiated type and larger and deeper tumors. The overall incidence of Grade III or higher complications was 20.9%. The incidence of No. 10 metastasis was 26.0% in type 4 and 31.7% in non-type 4. Although the therapeutic value index of the No. 10 was 13.7 in type 4 and 15.0 in non-type 4, the index of type 4 ranked just below several peri-gastric stations and seventh, while that in non-type 4 ranked second.ConclusionSplenectomy for No. 10 dissection may be oncologically valid for type 4 gastric cancer involving the greater curvature. A safer procedure for No. 10 dissection should be established.