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Objectives: A regimen of S-1 combined with oxaliplatin (SOX) has been widely used as the first-line regimen for advanced gastric cancer. To further improve the antitumor efficacy for gastric cancer patients with peritoneal metastasis, we added nab-paclitaxel to the established SOX regimen (NSOX). Nab-paclitaxel (nanoparticle albumin-bound paclitaxel) has effective transferability to tumor tissues and strong antitumor effects for peritoneal metastasis. We performed a phase 1 study of this regimen to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in patients with gastric cancer with peritoneal metastasis. Methods: The NSOX regimen involved 21-day cycles with escalated doses of nab-paclitaxel (50 [level 1] to 80 [level 4] mg/m2 on days 1 and 8) and fixed doses of oxaliplatin (100 mg/m2 on day 1) and S-1 (80 mg/m2/day for 2 weeks). Results: Six patients with gastric cancer with peritoneal metastasis were enrolled. The MTD was determined to be dose level 2, as 2 of 3 patients experienced dose-limiting toxicities (DLTs), grade 4 non-hematological toxicities. One patient experienced acute myocardial infarction, and the other patient developed jejunal perforation. There were no treatment-related deaths. No patients experienced DLTs, so the RD was determined to be dose level 1. Conclusions: The NSOX regimen was shown to be a tolerable regimen and may be a promising triplet therapy for patients with gastric cancer with peritoneal metastasis.

Endoscopic submucosal dissection (ESD) is a standard treatment for early gastric cancers (EGCs), but because of the obscured view and difficulty in submucosal lifting it is time consuming and poses high risk of perforation and bleeding in large lesions. In endoscopic submucosal tunnel dissection (ESTD) technique, good visualization of the submucosal layer can be achieved in the tunnel, it is, therefore, easy to discern the muscularis propria and visualize the vessels in the submucosal area. This study aims to evaluate the technical feasibility, efficacy, and safety of ESTD in comparison with conventional ESD (cESD) technique for treatment of EGCs. This is a single-center retrospective study of 799 consecutive patients with EGCs who underwent ESD. ESTD (n = 141) were performed between 2015 and 2018 and cESD (n = 658) were performed between 2003 and 2015. Using propensity scores to strictly balance the significant variables, we compared treatment outcomes. After matching, we enrolled 444 patients (n = 111 in ESTD group, n = 333 in cESD group). The resection speeds for lesions of the ESTD were faster than those of cESD (19.3 mm2/min versus 17.7 mm2/min, P = 0.009). There was no need to use additional countertraction by clip-with-line technique or snare for the submucosal dissection in the ESTD procedure. The incidence of perforation was significantly higher in the cESD group (6.0%) than in the ESTD group (0.9%) (P = 0.035). Among 799 patients, four patients who received non-curative ESD had recurrence of gastric cancer. ESTD technique is a safe and feasible treatment procedure for EGCs. It presents many theoretical advantages and may have definite benefits over cESD. ESTD may, therefore, be considered as the standard endoscopic treatment for EGCs.

Recent studies have found a negative impact of postoperative complications on long-term survival outcomes, but it has not been confirmed by data obtained from a prospective study with a large sample size. This study investigated the impact of postoperative complications on long-term survival outcomes, and considered the optimal definition of complication, using data from JCOG1001, which compared bursectomy and non-bursectomy for patients with cT3/4a locally advanced gastric cancer. This study included 1191 of 1204 patients enrolled in the JCOG1001 trial. Complications were graded by Clavien–Dindo (C-D) classification. Impact of the grade (≥ C-D grade II or ≥ grade III) or type (any or intra-abdominal infectious) of complication on survival outcome was evaluated by univariate and multivariable analyses using the Cox proportional hazard model. The incidence of any ≥ C-D grade II and ≥ grade III complication was 23.0% and 9.7%, respectively, and that of ≥ grade II and ≥ grade III intra-abdominal infectious complication was 13.4% and 6.9%, respectively. Multivariable analysis showed all four definitions of complications were independent prognostic factors for overall survival. Conversely, only any ≥ C-D grade III complication was found to be an independent prognostic factor for relapse-free survival (hazard ratio, 1.445; 95% confidence interval, 1.026–2.036; P = 0.035). Postoperative complications adversely affect the long-term survival outcomes of patients with cT3/4a gastric cancer. Any ≥ C-D grade III complication seems to be the most suitable definition of complication for predicting negative long-term survival outcomes.

Background Administration of landiolol hydrochloride was found to be associated with reduced incidence of atrial fibrillation (AF) after esophagectomy for esophageal cancer in our previous randomized controlled trial (RCT). In addition, reduced incidence of AF was associated with reduction of other complications. Meanwhile, the effects of postoperative AF and other complications on long-term survival following esophagectomy are not well understood. Materials and methods Between March 2014 and January 2016, 100 patients with esophageal cancer were registered in an RCT trial and randomly allocated to receive either administration of landiolol or a placebo. We analyzed data from this RCT to better understand the effect of postoperative AF and severe associated complications on overall survival (OS) after esophagectomy for cancer. We also examined whether prophylactic administration of landiolol hydrochloride directly affects prolonged survival in patients with esophageal cancer. Results The five-year rates of OS in the patients with and without AF were 60%, and 68.6%, respectively, there was no significant difference (P = 0.328). Five-year rates of OS of the patients with and without severe complications were 64.6%, and 67.5%, respectively (P = 0.995). The five-year rates of OS in the placebo and landiolol groups were 65.8% and 68%, respectively (P = 0.809). In multivariate analysis, high stage (stage III/IV) alone was an independent prognostic factor for esophageal cancer patients following esophagectomy. Conclusions New-onset AF and the other severe complications were not associated with poorer long-term survival following esophagectomy. In addition, administration of landiolol hydrochloride after esophagectomy did not contribute to prolonging the OS.

BackgroundCancer peptide vaccines show only marginal effects against cancers. Immune checkpoint inhibitors (ICIs) show significant curative effects in certain types of cancers, but the response rate is still limited. In this study, we aim to improve cancer peptide vaccination by targeting Ag peptides selectively to a dendritic cell (DC) subset, XCR1-expressing DCs (XCR1+DCs), with high ability to support CD8+T-cell responses.MethodsWe have generated a fusion protein, consisting of an Ag peptide presented with MHC class I, and an XCR1 ligand, XCL1, and examined its effects on antitumour immunity in mice.ResultsThe fusion protein was delivered to XCR1+DCs in an XCR1-dependent manner. Immunisation with the fusion protein plus an immune adjuvant, polyinosinic:polycytidylic acids (poly(I:C)), more potently induced Ag-specific CD8+T-cell responses through XCR1 than the Ag peptide plus poly(I:C) or the Ag protein plus poly(I:C). The fusion protein plus poly(I:C) inhibited the tumour growth efficiently in the prophylactic and therapeutic tumour models. Furthermore, the fusion protein plus poly(I:C) showed suppressive effects on tumour growth in synergy with anti-PD-1 Ab.ConclusionsCancer Ag targeting to XCR1+DCs should be a promising procedure as a combination anticancer therapy with immune checkpoint blockade.

Currently, gastric cancer is the third most common cause of cancer-associated mortality worldwide. Oncolytic virotherapy using herpes simplex virus (HSV) has emerged as a novel therapeutic strategy against cancer. Telomerase is activated in >90of malignant tumors, including gastric cancer, and human telomerase reverse transcriptase (hTERT) is one of the major components of telomerase enzyme. Therefore, in oncolytic HSV, placing the essential genes under the regulation of the hTERT promoter may enhance its antitumor efficacy. The present study examined the antitumor effect of fourth-generation oncolytic HSVs, which contain the ICP6 gene under the regulation of the hTERT promoter (T-hTERT). To examine the association between hTERT expression and prognosis in patients with gastric cancer, immunohistochemical analysis of resected tumor specimens was performed. The enhanced efficacy of T-hTERT was determined in human gastric cancer cell lines in vitro and in human gastric adenocarcinoma specimens in vivo. In in vitro experiments, enhanced cytotoxicity of T-hTERT was observed in MKN1, MKN28 and MKN45 cells compared with that of a third-generation oncolytic HSV, T-null. In particular, the cytotoxicity of T-hTERT was markedly enhanced in MKN45 cells. Furthermore, in vivo experiments demonstrated that 36.7 and 54.9% of cells were found to be lysed 48 h after infection with T-null or T-hTERT viruses at 0.01 pfu/cell, respectively. The T-hTERT-treated group exhibited considerably lower cell viability than the control [phosphate-buffered saline (-)] group. Therefore, employing oncolytic HSVs that contain the ICP6 gene under the regulation of the hTERT promoter may be an effective therapeutic strategy for gastric cancer. To the best of our knowledge, the present study was the first to describe the effect of an oncolytic HSV with ICP6 expression regulated by the hTERT promoter on gastric cancer cells.

Importance Robotic gastrectomy (RG) for gastric cancer may be associated with decreased incidence of intra-abdominal infectious complications, including pancreatic fistula, leakage, and abscess. Prospective randomized clinical trials comparing laparoscopic gastrectomy (LG) and RG are thus required. Objective To compare the short-term surgical outcomes of RG with those of LG for patients with gastric cancer. Design, Setting, and Participants In this phase 3, prospective superiority randomized clinical trial of RG vs LG regarding reduction of complications, 241 patients with resectable gastric cancer (clinical stages I-III) were enrolled between April 1, 2018, and October 31, 2020. Interventions LG vs RG. Main Outcomes and Measures The primary end point was the incidence of postoperative intra-abdominal infectious complications. Secondary end points were incidence of any complications, surgical results, postoperative courses, and oncologic outcomes. The modified intention-to-treat population excluded patients who had been randomized and met the postrandomization exclusion criteria. There was also a per-protocol population for analysis of postoperative complications. Results This study enrolled 241 patients, with 236 patients in the modified intention-to-treat population (150 men [63.6%]; mean [SD] age, 70.8 [10.7] years). There was no significant difference in the incidence of intra-abdominal infectious complications (per-protocol population: 10 of 117 [8.5%] in the LG group vs 7 of 113 [6.2%] in the RG group). Of 241 patients, 122 were randomly assigned to the LG group, and 119 patients were randomly assigned to the RG group. Two of the 122 patients (1.6%) in the LG group converted from LG to open surgery, and 4 of 119 patients (3.4%) in the RG group converted from RG to open or laparoscopic surgery, with no significant difference. Finally, 117 patients in the LG group completed the procedure, and 113 in the RG group completed the procedure; these populations were defined as the per-protocol population. The overall incidence of postoperative complications of grade II or higher was significantly higher in the LG group (23 [19.7%]) than in the RG group (10 [8.8%]) (P = .02). Even in analysis limited to grade IIIa or higher, the complication rate was still significantly higher in the LG group (19 [16.2%]) than in the RG group (6 [5.3%]) (P = .01). Conclusions and Relevance This study found no reduction of intra-abdominal infectious complications with RG compared with LG for gastric cancer. Trial Registration umin.ac.jp/ctr Identifier:UMIN000031536

The authors outline their stapling technique and retrospectively compare outcomes of laparoscopic staplers versus robotic staplers in patients undergoing robotic distal gastrectomy (RDG) with Billroth I gastroduodenostomy for gastric cancers.Of our 28 consecutive patients who underwent RDG, 18 underwent Billroth I gastroduodenostomy using laparoscopic staplers (fusion group); robotic staplers were used in the remaining 10 patients (robot group). All RDG procedures were performed using the da Vinci Surgical System.The duration of reconstruction was significantly longer for the robot group than for the fusion group. There were no conversions to conventional laparoscopy or open surgery in the fusion group, but 1 patient in the robot group required conversion to laparoscopic reconstruction for duodenal injury during anastomosis. No postoperative complications developed in the fusion group.Regarding short-term surgical outcomes, robotic-assisted laparoscopic stapling techniques for reconstruction after RDG are both feasible and safe for gastric cancers.

Currently, gastric cancer is the third most common cause of cancer-associated mortality worldwide. Oncolytic virotherapy using herpes simplex virus (HSV) has emerged as a novel therapeutic strategy against cancer. Telomerase is activated in >90of malignant tumors, including gastric cancer, and human telomerase reverse transcriptase (hTERT) is one of the major components of telomerase enzyme. Therefore, in oncolytic HSV, placing the essential genes under the regulation of the hTERT promoter may enhance its antitumor efficacy. The present study examined the antitumor effect of fourth-generation oncolytic HSVs, which contain the ICP6 gene under the regulation of the hTERT promoter (T-hTERT). To examine the association between hTERT expression and prognosis in patients with gastric cancer, immunohistochemical analysis of resected tumor specimens was performed. The enhanced efficacy of T-hTERT was determined in human gastric cancer cell lines in vitro and in human gastric adenocarcinoma specimens in vivo. In in vitro experiments, enhanced cytotoxicity of T-hTERT was observed in MKN1, MKN28 and MKN45 cells compared with that of a third-generation oncolytic HSV, T-null. In particular, the cytotoxicity of T-hTERT was markedly enhanced in MKN45 cells. Furthermore, in vivo experiments demonstrated that 36.7 and 54.9% of cells were found to be lysed 48 h after infection with T-null or T-hTERT viruses at 0.01 pfu/cell, respectively. The T-hTERT-treated group exhibited considerably lower cell viability than the control [phosphate-buffered saline (−)] group. Therefore, employing oncolytic HSVs that contain the ICP6 gene under the regulation of the hTERT promoter may be an effective therapeutic strategy for gastric cancer. To the best of our knowledge, the present study was the first to describe the effect of an oncolytic HSV with ICP6 expression regulated by the hTERT promoter on gastric cancer cells.

Oncolytic virotherapy is an encouraging treatment using herpes simplex virus (HSV) for gastric cancer patients. To treat gastric cancer, we generated and evaluated the efficacy of an attractive type of oncolytic HSV expressing the suppressor of cytokine signaling 3 (SOCS3). We constructed a third-generation type of oncolytic HSV (T-SOCS3) arming with SOCS3 by a bacterial artificial chromosome (BAC) system. We examined the viral replicative intensification and oncolysis of T-SOCS3 for human gastric cancer cell lines ex vivo. T-SOCS3 enhanced its replication and potentiated its cell-killing effect for MKN1 human gastric cancer cell lines, which are resistant to a non-armed third-generation type of oncolytic HSV (T-01) ex vivo. T-SOCS3 also induced the destruction within human gastric cancer specimens. Armed oncolytic HSVs expressing SOCS3 may be an efficacious therapeutic agent for gastric cancer treatment.

Safe preservation of the remnant stomach during distal gastrectomy in patients who have undergone distal pancreatectomy is important. During distal pancreatectomy, the splenic artery that supplies arterial blood to the cardiac part of stomach is resected. Previous reports suggested that blood flow to the remnant stomach may be insufficient when supplied by only the left inferior phrenic artery. In the present case, a 79-year-old woman who underwent distal pancreatectomy with splenectomy 20 years before she was diagnosed with gastric cancer and referred to our hospital. We performed laparoscopic distal gastrectomy and Roux-en-Y reconstruction because preoperative CT scan indicated a developed left inferior phrenic artery. To evaluate the blood supply, we employed indocyanine green fluorescence and were able to safely preserve the remnant stomach. Our experience suggests that indocyanine green fluorescence is potentially useful for evaluating blood flow to the remnant stomach.

Purpose The aim of this study was to clarify internal hernia (IH) characteristics after laparoscopic gastrectomy. Materials and methods This was a retrospective study of 1943 consecutive gastric cancer patients who underwent surgery at our institute between 2004 and 2015. Since 2013, our technique includes antecolic Roux-en-Y (RY) with closure of all mesenteric defects during laparoscopic total gastrectomy (LTG) as standard. Results Postoperative IH was only detected in patients who underwent total gastrectomy with RY reconstruction. Furthermore, the incidence of IH was significantly higher after LTG than after open total gastrectomy (4.9% vs. 1.0%; P=0.005). IH after LTG occurred in 8.0% of patients before standardization with closure of the mesenteric defects, but no IH was observed after standardization (P=0.047). Conclusions Closure of all mesenteric defects is recommended for gastric cancer patients who undergo LTG with antecolic RY. Registration number: UMIN000009163/000025029 (www.umin.ac.jp/ctr/).

Background Several studies have reported that the triangulating stapling method decreases the incidence of anastomotic stricture after esophagectomy, but no randomized, controlled trial has confirmed the efficacy of the triangulating stapling method for cervical esophagogastrostomy. We compared triangulating stapling and circular stapling for cervical esophagogastric anastomosis regarding the decrease in anastomotic stricture after esophagectomy for thoracic esophageal cancer. Methods Between August 2010 and April 2014, 100 patients enrolled in this randomized, controlled trial at the Wakayama Medical University Hospital were allocated randomly to either the circular stapling group (n = 49) or the triangulating stapling group (n = 51). The primary end point was the incidence of anastomotic stricture within 12 months postoperatively. This randomized, controlled trial was registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN000004848). Results There were no differences between the circular stapling and triangulating stapling groups in terms of clinical data. The amount of time required for esophagogastric anastomosis was slightly greater for the triangulating stapling group (22 minutes) than for the circular stapling group (18 minutes) (P = .028). Anastomotic stricture occurred in 8 patients (17%) in the circular stapling group and 9 patients (19%) in the triangulating stapling group (P = .935). The rate of anastomotic leakage was 11% for the circular stapling group and 2% for the triangulating stapling group (P = .073). Conclusion The triangulating stapling method for cervical anastomosis for thoracic esophageal cancer does not decrease the incidence of anastomotic stricture compared with the circular stapling method within 12 postoperative months but may affect the rate of anastomotic leakage.

Purpose Although S-1 based chemotherapy for patients with advanced gastric cancer has generally been accepted in Japan, discontinuations of treatment have been reported due to grade 3 or more adverse events. The present randomized phase II study was conducted to test whether alternate-day administration of S-1 would be comparably efficient and reduce adverse events compared with conventional daily administration in the first-line chemotherapy for advanced gastric cancer. Methods 132 patients with advanced gastric cancer were randomly assigned to 1:2 ratios to receive treatment with daily at a standard dose of 80 mg/m2/day or alternate-day administration group received S-1 on 4 days a week. The primary end point was progression-free survival (PFS), and the secondary end points were safety, overall survival, time to treatment failure (TTF), disease control rate, and response rate. Results The 6-month PFS rate of the alternate-day administration group was 20.9% and failed to show significant difference from the pre-specified threshold at 15% (p = 0.117), whereas that of the daily administration group was 39.1% and significantly higher than the threshold (p = 0.001). The hazard ratio of the alternate-day administration group compared with the daily administration group was 1.753 (95% confidence interval (CI) 1.15–2.68, p = 0.010). With regard to OS, the hazard ratio of the alternate-day administration group compared with the daily administration group was 1.487 (95% CI 0.97–2.29, p = 0.072). The median TTF were 4.2 and 2.8 months in the daily and alternate-day administration group, respectively (p = 0.007). Conclusion The alternate-day administration of S-1 was not recommended as the first-line therapy for patients with advanced gastric cancer.

Laparoscopic wedge resection of the stomach is an ideal procedure if the gastric gastrointestinal stromal tumors (GISTs) are located in the extraluminal stomach. When the tumor is located in the intraluminal stomach, two minimally invasive surgical procedures involving laparoscopic and endoscopic cooperative surgery (LECS) or endoscopic intragastric surgery (EIGS) are frequently performed. To date, there have been no comparative studies of LECS and EIGS in patients with intraluminal gastric GISTs regarding short-term and long-term outcomes. The aim of this study was to compare the safety and feasibility of LECS and EIGS in patients with intraluminal gastric GISTs. This was a single-center retrospective study of 46 consecutive patients with intraluminal gastric GISTs who underwent minimally invasive surgery. LECS (n = 21) was performed between 2013 and 2015 and EIGS (n = 26) was performed between 2001 and 2013. The overall incidence of perioperative complications was significantly higher in the EIGS group than in the LECS group (40 vs 4.8%; P = 0.006). In the EIGS group, three patients with intraoperative gastric mucosal injury were followed-up throughout surgical repair (12%). An esophageal tear was found in one patient during oral removal of tumor (4%). Postoperative gastric hemorrhage occurred in three patients (12%) and superficial surgical site infection was observed in three patients (12%). In the LECS group, anastomotic leakage requiring additional drainage was observed in one patient (4.8%). EIGS had less favorable results regarding median time to resumption of first oral intake (2 vs 1 days; P = 0.005). Two of 46 patients (4.3%), including one patient who underwent LECS and one patient who underwent EIGS developed recurrence. No cause-specific deaths were observed. LECS is a feasible and safe procedure for intraluminal gastric GISTs with regard to both short-term surgical and long-term oncological outcomes. Registration number: UMIN000026631.

CEACAM1 is associated with malignant potential of various cancers. The current study aims to clarify the association between carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression and malignant potential of gastric cancer and to address whether CEACAM1 cytoplasmic domain isoform balance modulates the properties of gastric cancer cells. Immunohistochemical analyses for CEACAM1 were performed in 235 patients with gastric cancer who underwent surgery. Risk factors for overall survival and peritoneal metastasis were calculated based on CEACAM1 expression in the gastric cancer tissue. Patients with CEACAM1 long (CEACAM1-L) or short (CEACAM1-S) cytoplasmic isoform dominance were compared with patients with null CEACAM1 expression in terms of overall survival. CEACAM1 transfected or knockdown gastric cancer cell line, NUGC3 and MKN7 cells, were examined by invasion assay and three dimensional (3D) culture, in order to clarify whether CEACAM1 modulate invasion, lumen formation and tumor growth of gastric cancer cells. Multivariate analysis demonstrated that gastric cancer without CEACAM1 is an independent prognostic factor and a risk factor for peritoneal dissemination. Patients with CEACAM1-S dominance had better prognosis than those with CEACAM1-L. CEACAM1-4L overexpression induced less invasion, more lumen formation, and less tumor growth of NUGC3 cells. CEACAM1-4S overexpression had less invasion and more lumen formations, but not less tumor growth. Knockdown of CEACAM1 expression had less invasion, but not less lumen formations of MKN7 cells. Loss of CEACAM1 is associated with poor prognosis and peritoneal dissemination of patients with gastric cancer. Expression of CEACAM1 in gastric cancer cells modulates invasiveness, lumen formation, and tumor growth.

Supplemental Digital Content is available in the text, Laparoscopic lymph node dissection around the peripancreatic area for gastric cancer (GC) remains challenging because of drawbacks in laparoscopic surgery including the limited range of movement, amplification of hand tremors, and inconvenient surgical positioning. In some cases of laparoscopic gastrectomy (LG), therefore, postoperative pancreatic fistula (POPF) occurs. Robotic surgery, on the other hand, plays an essential role in ergonomics and offers advantages, such as motion scaling, less fatigue, tremor filtering, 7 degrees of motion in the robotic instruments assisted by the wrist-like instruments tips, and three-dimensional vision. Robotic gastrectomy (RG) may enable surgeons to overcome the drawbacks associated with laparoscopic surgery. This study compares the safety and feasibility of short-term surgical outcomes of RG and LG for patients with GC. This was a single-center retrospective study of 659 consecutive patients with GC who received minimally invasive surgery. LG (n = 639) was performed between 2013 and 2017 and RG (n = 20) was performed in 2017. Lymphadenectomy without touching the pancreas was basically performed during RG using assisting articulating forceps. Overall incidence of postoperative complications higher than Clavien–Dindo grade 2 was not significantly different (LG group 5.9%, RG group 5.0%). In RG group, POPF, intra-abdominal abscess, and anastomotic leakage were not found, but postoperative bleeding requiring interventional catheter embolization occurred in 1 patient. In LG, POPF was found in 4.7%. Amylase levels in drainage fluid on postoperative day 1 were significantly lower in the RG group (238.5 IU/L) than in the LG group (884.5 IU/L) (P = .028). Regarding short-term surgical outcomes, RG is feasible, safe, and ideal treatment procedure for GC. Our robotic procedure without touching the pancreas may be associated with decreased incidence of POPF.

Summary Background We investigated the superiority of docetaxel plus cisplatin and S-1 compared with cisplatin and S-1 in chemotherapy-naive patients with advanced gastric cancer. Methods In this open-label, phase 3, randomised controlled trial, patients were recruited from 56 hospitals in Japan. We enrolled individuals aged 20–75 years who had unresectable or recurrent gastric cancer, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had received no previous chemotherapy (except adjuvant chemotherapy completed 24 weeks before reccurence), radiotherapy, or hormonal therapy, could take drugs orally, and had adequate organ function. Patients were randomly assigned (1:1) to receive docetaxel plus cisplatin and S-1 (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1 intravenously, and S-1 40–60 mg twice a day orally for 2 weeks, every 4 weeks) or cisplatin and S-1 (cisplatin 60 mg/m2 intravenously on day 8, and S-1 40–60 mg orally twice a day for 3 weeks, every 5 weeks). Randomisation was done centrally with the minimisation method, with a random component balancing for institution, ECOG performance status (0 vs 1), disease status at enrolment (unresectable vs recurrent), measurable lesion (yes vs no), number of metastatic sites (0–1 vs ≥2), and histological type (differentiated vs undifferentiated). Neither investigators or patients were masked to the study treatment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with UMIN-CTR, number UMIN000007652. Findings Between April 3, 2012, and March 18, 2016, 741 patients were randomly assigned to receive docetaxel plus cisplatin and S-1 (n=370) or cisplatin and S-1 (n=371). Median overall survival was 14·2 months (95% CI 12·9–15·9) in the docetaxel plus cisplatin and S-1 group and 15·3 months (14·2–16·2) in the cisplatin and S-1 group (hazard ratio [HR] 0·99 [95% CI 0·85–1·16]; one-sided stratified log-rank p=0·47). The most common grade 3 or worse adverse events were neutropenia (209 [59%] of 357 patients in the docetaxel plus cisplatin and S-1 group vs 117 [32%] of 365 patients in the cisplatin and S-1 group), leukopenia (120 [34%] vs 60 [16%]), and anorexia (94 [26%] vs 81 [22%]). The deaths of one patient in the cisplatin and S-1 group and in three patients in the docetaxel plus cisplatin and S-1 group were deemed treatment-related. Interpretation The addition of docetaxel to cisplatin and S-1 did not improve overall survival in chemotherapy-naive Japanese patients with advanced gastric cancer. Therefore, cisplatin and S-1 remains the standard first-line chemotherapy. Funding Ministry of Health, Labour and Welfare and Japan Agency for Medical Research and Development.

Background Several studies have reported that the triangulating stapling method decreases the incidence of anastomotic stricture after esophagectomy. Our previous randomized controlled trial, however, could not confirm the superiority of the triangulating stapling (TS) method over the circular stapling (CS) method in terms of postoperative anastomotic stricture rate. Recently, the functional end-to-end stapling (FEES) method for cervical anastomosis after esophagectomy was developed, and lower anastomotic stricture rates with FEES have been reported than for our previously experienced anastomotic methods. To investigate the optimal anastomotic method, we now compare the TS method with the FEES method for cervical anastomosis regarding decrease in anastomotic stricture after esophagectomy for thoracic esophageal cancer. Methods This is a randomized, single-center clinical trial designed to examine the superiority of the FEES method over the TS method for esophageal cancer patients. The primary endpoint is reduction of anastomotic stricture of cervical esophagogastric anastomosis within 12 months after esophagectomy. Secondary endpoints include overall postoperative morbidity within the first 12 months after esophagectomy, incidence of anastomotic leakage, aspiration pneumonia, or reflux esophagitis, and quality of life assessment as measured by the FACT-E at 12 months after esophagectomy. The incidence rate of anastomotic stricture of the TS method was 20% and this rate of the FEES method was estimated to be 4% in our preliminary study. We calculated sample size with a beta error of 0.20 and an alpha error of 0.05. We have been enrolling 125 patients in this trial to either the TS group or the FEES group since January 2017. Discussion This study should help to define the optimal anastomotic method for cervical esophagogastric anastomosis after esophagectomy in patients with esophageal cancer. The FEES method, if proven to be superior to the TS method, can be implemented routinely for esophageal cancer patients with gastric-conduit reconstruction after esophagectomy. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN 000025632). Registered on 13 January 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3201-2) contains supplementary material, which is available to authorized users.

Background: We investigated the superiority of docetaxel plus cisplatin and S-1 (DCS) compared with cisplatin plus S-1 (CS) in chemotherapy-naive patients with advanced gastric cancer. Methods: This randomised, open-label, phase 3 trial was conducted at 56 hospitals in Japan. Patients were randomised (1:1) to receive DCS (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1, and S-1 40-60 mg twice a day for 2 weeks, every 4 weeks) or CS (cisplatin 60 mg/m2 on day 8, and S-1 40-60 mg twice a day for 3 weeks, every 5 weeks). The primary endpoint was overall survival in the intention-to-treat population. The study is registered with UMIN-CTR, number UMIN000007652. Findings: Between April 3, 2012, and March 18, 2016, 741 patients were randomised to DCS (n=370) or CS (n=371). Median overall survival was 14·2 months (95% CI 12·9-15·9) in the DCS group and 15·3 months (14·2-16·2) in the CS group (hazard ratio [HR] 0·99, 95% CI 0·85-1·16; one-sided stratified log-rank p=0·47). Median progression-free survival was 7·4 months for DCS and 6·5 months for CS (HR 0·99; 95% CI, 0·86-1·15; p=0·92), and the overall response rate was 59% for DCS and 56% for CS (p=0·50). In the safety analysis set, the most common grade 3 or worse adverse events were neutropenia (209 [58%] of 358 patients in the DCS group vs 117 [32%] of 367 patients in the CS group), leukopenia (120 [34%] vs 60 [16%]), and anorexia (94 [26%] vs 81 [22%]). Interpretation: DCS did not improve overall survival in chemotherapy-naive Japanese patients with advanced gastric cancer. Therefore, CS remains the standard first-line chemotherapy. Trial Registration Number: The study is registered with UMIN-CTR, number UMIN000007652. Funding: Ministry of Health, Labour and Welfare, and Japan Agency for Medical Research and Development. Declaration of Interest: YY reports personal fees from Taiho, Chugai, Eli Lilly (EL), Yakult, Nipponkayaku, Ono, Eisai, Bristol-Myers Squibb (BMS), Janssen, 1 AMED and research grant from Daiichi-Sankyo (DS). NB has received grants and honoraria from Taiho and BMS, and honoraria from Ono, Chugai, EL. JM, HF, and SK reports grants and non-financial support from MHLW and AMED, and SK personal fees from Johnson & Johnson (J&J). SI reports personal fees and others from EL and Chugai, personal fees from Taiho and Ono, others from BMS, Eisai, DS, Novartis, Merck-Serono (MS), Bayer, Otsuka. SK reports grants and personal fees from EL, Taiho, Ono, BMS, grants from Boehringer-Ingelheim (BI), personal fees from Chugai, MS, Bayer, Eisai, and Yakult. KS reports grants and personal fees from EL, Ono, Novartis, Yakult, personal fees from Astellas, BMS, Takeda, Pfizer, Novartis, and Abbvie, grants from Dainippon-Sumitomo, DS, Taiho, Chugai, and MSD. TT reports grants from AMED, Ono, BMS, Takeda, personal fees from MS and Takeda. HH reports grants from AstraZeneca, DS, Dainippon-Sumitomo, EL, MS, MSD, Taiho, Chugai, Eisai, LSK BioPharma, Incyte, Pfizer, BI, Beigene, Ono, and BMS. TY reports personal fees from Ono, BMS, EL, Taiho, Chugai, Yakult, DS, NipponKayaku, Olympus, Covidien, J&J, and Terumo. MS reports personal fees from Taiho, Chugai, EL, Ono, DS, Yakult, Merck Sharp and Dohme. MT reports personal fees from Taiho, Chugai, Ono, BMS, Yakult, Takeda, EL, Pfizer, and DS. NN, MA, KC, HH, MN, and HY have nothing to disclose. Ethical Approval: The trial protocol was approved by the JCOG Protocol Review Committee and the institutional review boards of each participating centre.

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist: recommended items to address in a clinical trial protocol and related documents*. (DOC 124 kb)

// Toshiyasu Ojima 1 , Masaki Nakamura 1 , Mikihito Nakamori 1 , Masahiro Katsuda 1 , Keiji Hayata 1 , Junya Kitadani 1 , Shimpei Maruoka 1 , Toshio Shimokawa 2 and Hiroki Yamaue 1 1 Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan 2 Clinical Study Support Center, Wakayama Medical University, Wakayama, Japan Correspondence to: Hiroki Yamaue, email: yamaue-h@wakayama-med.ac.jp Keywords: squamous cell carcinoma; esophageal cancer; docetaxel; cisplatin; S-1 Received: December 06, 2018 Accepted: January 03, 2019 Published: January 25, 2019 ABSTRACT Background: Although triplet regimen of docetaxel, cisplatin, and 5-FU (DCF) reportedly yields high response rates for metastatic squamous cell carcinoma of the esophagus (SCCE), it has severe toxicity. In our previous phase II trial, grade 3/4 toxicities of neutropenia occurred in 68.8% of the patients. Development of chemotherapeutic regimen that does not impair quality of life of the patients with metastatic SCCE is therefore needed. A novel chemotherapeutic regimen combining docetaxel, cisplatin, and alternate-day administration of S-1 (modified DCS) may be associated with reduction of severe adverse effects. Methods: This study is a single center phase I/II trial of chemotherapy using modified DCS regimen for patients with recurrent/unresectable SCCE. The phase I trial adopts a ‘3 + 3 patient cohort’, dose-escalating study design. In the phase II trial, the primary endpoint is evaluation of the overall response rate (ORR). Secondary endpoints are evaluation of drug-related toxicity, overall survival (OS), and progression-free survival (PFS). Results: In the phase I trial, the recommended dose for docetaxel, cisplatin, and S-1 were 40 mg/m 2 (day 1), 50 mg/m 2 (day 1), and 80 mg/m 2 /day, respectively. In the phase II trial (n = 50), the ORR was 54 %. The median OS and PFS were 10 and 4 months, respectively. Grade 3/4 adverse events included neutropenia (26%), leukopenia (14%), anorexia (10%) and febrile neutropenia (6%). Conclusion: The modified DCS therapy for patients with advanced SCCE is feasible and safe in both chemotherapeutic and perioperative periods. Registration number: UMIN000016364.

Gastric cancer with extensive lymph node metastasis is commonly considered unresectable, with a poor prognosis. We previously reported the results of the use of cisplatin and S-1 as preoperative chemotherapy for gastric cancer with extensive lymph node metastasis; docetaxel, cisplatin, and S-1 (DCS) have now been investigated for the same purpose.Patients received two or three 28-day cycles of DCS therapy (docetaxel at 40 mg/mBetween July 2011 and May 2013, 53 patients were enrolled, of whom 52 were eligible. The clinical RR was 57.7 % [30/52, 80 % confidence interval 47.9-67.1 %, p = 0.89], and R0 resection was achieved in 84.6 % of patients (44/52). Common grade 3 or grade 4 adverse events during DCS therapy were leukocytopenia (18.9 %), neutropenia (39.6 %), and hyponatremia (15.1 %). The common grade 3 or grade 4 surgical morbidity was abdominal infection (10.2 %). The pathological RR was 50.0 % (26/52).Preoperative DCS therapy was feasible but did not show a sufficient RR. Preoperative cisplatin and S-1 therapy is still considered the tentative standard treatment for this population until survival results are known.

Postoperative chylothorax is a rare, but serious complication after esophagectomy for esophageal cancer. Because the surgical treatment for chylothorax, which involves the ligation of the thoracic ducts, is not necessarily a reliable treatment, it is important to have alternative options for the conservative treatment of chylothorax. We treated three patients with chylothorax after esophagectomy using a conservative treatment with administration of octreotide and etilefrine. Octreotide acts on lymph ductal endothelial cells with somatostatin receptors and reduces leakage of lymph fluids by contracting the smooth muscle of the lymph duct. Etilefrine contracts the smooth muscle, which decreases chyle flow output by reducing the diameter of the main lymph ducts. All three patients recovered fully without surgical treatment. We consider the combination of octreotide and etilefrine to be a safe and effective treatment for chylothorax after esophagectomy.

Background Patients' quality of life (QoL) deteriorates remarkably after gastrectomy. Billroth I reconstruction following distal gastrectomy has the physiological advantage of allowing food to pass through the duodenum. It was hypothesized that Billroth I reconstruction would be superior to Roux-en-Y reconstruction in terms of long-term QoL after distal gastrectomy. This study compared two reconstructions in a multicentre prospective randomized clinical trial to identify the optimal reconstruction procedure. Methods Between January 2009 and September 2010, patients who underwent gastrectomy for gastric cancer were randomized during surgery to Billroth I or Roux-en-Y reconstruction. The primary endpoint was assessment of QoL using the Functional Assessment of Cancer Therapy – Gastric (FACT-Ga) questionnaire 36 months after surgery. Results A total of 122 patients were enrolled in the study, 60 to Billroth I and 62 to Roux-en-Y reconstruction. There were no differences between the two groups in terms of postoperative complications or mortality, and no significant differences in FACT-Ga total score (P = 0·496). Symptom scales such as epigastric fullness (heaviness), diarrhoea and fatigue were significantly better in the Billroth I group at 36 months after gastrectomy (heaviness, P = 0·040; diarrhoea, P = 0·046; fatigue, P = 0·029). The rate of weight loss in the third year was lower for patients in the Billroth I group (P = 0·046). Conclusion The choice of anastomotic reconstruction after distal gastrectomy resulted in no difference in long-term QoL in patients with gastric cancer. Registration number: NCT01065688 (http://www.clinicaltrials.gov).

The aim of this study was to compare the oncologic results of endoscopic submucosal dissection (ESD) for early gastric cancers (EGC) in remnant stomachs (RS) with results of ESD for EGC in normal stomachs (NS).From 2002 to 2013, ESD was performed for 583 EGC lesions. ESD of the RS was performed for 34 lesions.Two patients with EGC in the NS and 1 patient with EGC in the RS died from these gastric cancers. In all patients, the ESD treatments were considered outside of indications according to the pathologic results. The 5-year cause-specific survival rate was 99.5% for EGC patients with NS and 96.2% for EGC patients with RS. The 5-year overall survival rates were 88.4% for patients with NS and 58.4% for patients with RS.On the basis of the favorable long-term oncologic outcomes, ESD for EGC in the RS can be considered feasible in clinical practice.

381 Background: Pathological response rate (pRR) is a common endpoint for assessing the efficacy of neo-adjuvant chemotherapy (NAC) in patients with advanced gastric cancer (GC). We performed supplementary analysis to investigate if pRR can be a surrogate endpoint using data from JCOG0501. Methods: Patients with type 4 and large type 3 resectable GC were randomized either surgery plus adjuvant S-1 (arm A) or NAC (S-1 plus cisplatin) plus surgery plus S-1 (arm B) in JCOG0501. Histological type (sig vs non-sig) was evaluated using preoperative biopsy specimen. Cox proportional hazards model was utilized to assess the effects of covariates for overall survival (OS). Pathological response was defined as Grade1b-3 according to the Japanese Gastric Cancer Association grading. Results: Among 286 (147 in arm A and 139 in arm B) patients who underwent surgery, 132 patients with complete pathological data in arm B were evaluated. Macroscopic tumor response (PR) was observed in 47 patients (36%) and pathological response (Grade 0/1a/1b/2/3) was 15/40/30/44/3, respectively. As shown in the table, pathological response was significantly better OS after adjusting other factors (HR, 0.51 [95% CI 0.30-0.87], p = 0.014). Conclusions: pRR may be used as a surrogate endpoint for future clinical trials in type 4 and large type 3 GC. Clinical trial information: C000000279. [Table: see text]

Tumor-derived peptides can induce antitumor cytotoxic T lymphocyte(CTL)response. However, the effects are limited. We aimed to overcome this limitation by selectively delivering antigen peptides to an XC chemokine receptor 1-expressing dendritic cell subset(XCR1+DC)that is notable for its exceptional ability to generate CTL response. To do that, we designed a vaccine(mXCL1-OVA peptide vaccine)that consisted of a murine XCR1 ligand(XCL1)and an ovalbumin(OVA)-derived MHC class I-restricted antigen. When co-injected with the immune adjuvant polyinosinic-polycytidylic acid(poly[I: C]), mXCL1-OVA peptide vaccine showed much greater antigen-specific cytotoxic T cell(CTL)response than either OVA protein plus poly(I: C)or OVA peptide plus poly(I: C). Furthermore, mXCL1-OVA peptide vaccine plus poly(I: C)showed more prominent antitumor effects against OVA-expressing melanoma(B16-OVA)than other vaccines with regard to growth inhibition. Thus, our results suggest that chemokine-directed antigen delivery to DC subsets with high CTL-inducing ability is a promising method for generating effective antitumor immunity.

Purpose We outline our reinforced stapling technique for reconstruction after laparoscopic distal gastrectomy (LDG). We also investigated the safety and feasibility of short-term surgical outcomes of this technique for patients with gastric cancer (GC). Materials and methods This is a retrospective study of 24 consecutive patients with GC who underwent reinforced stapling technique for reconstruction after LDG at our institute between 2016 and 2017. We adopted intracorporeal anastomosis, namely delta-shaped Billroth I gastroduodenostomy or Roux-en-Y gastrojejunostomy, using reinforced staples with polyglycolic acid sheets (Neoveil). Results No anastomosis-related complications (anastomotic leakage, anastomotic stricture, postoperative gastrointestinal bleeding) were found in our 24 consecutive patients. Conclusions Reinforced stapling for reconstruction after LDG is a feasible and safe procedure for GC with regard to short-term surgical outcomes.

Background and study aims Interventional endoscopic treatments including the application of glue are becoming more frequently used for the treatment of esophageal fistulas. However, there are no prospective studies of endoscopic treatment for esophageal fistulas. This prospective study aims to investigate the efficacy and safety of endoscopic injection of alpha-cyanoacrylate monomer for intractable esophageal fistulas. Patients and methods This single-center prospective phase II trial included patients with more than 1 wk of conservative medical treatment for intractable esophageal fistulas after esophagectomy. In the image-guided therapy suite, a mixture of alpha-cyanoacrylate monomer and oily contrast agent in a ratio of 0.3 to 1.7 mL was endoscopically injected through the fistula. Results Twenty-five patients who underwent esophagectomy at Wakayama Medical University Hospital were enrolled in this study. The primary disease was esophageal cancer in 16 patients (64 %) and gastric cancer in the remaining 9 patients (36 %). Complete closure of the esophageal fistula was performed in 22 patients after endoscopic injection of alpha-cyanoacrylate monomer. The overall success rate was 88 %. There was no fistula recurrence in any successful closure cases. Three patients with failed esophageal fistula closure had esophageal cancer with cervical esophageal fistulas and required reoperation of the fistulectomy under general anesthesia. No complications associated with this endoscopic treatment were detected. Conclusions Endoscopic treatment with injection of alpha-cyanoacrylate monomer facilitated healing of post-esophagectomy fistula in 88 % of patients without complications. This suggests that the treatment is effective and safe for patients with esophageal fistulas.

Background/aim Although the efficacy is limited, standard therapy for Stage II/III esophageal cancer in Japan includes neoadjuvant chemotherapy with cisplatin plus 5-fluorouracil. A phase II trial was conducted on patients with resectable advanced esophageal cancer obtaining neoadjuvant chemotherapy with docetaxel, cisplatin plus S-1 (DCS). Patients and methods A total of 40 patients were enrolled, each treated by the following DCS regimen: docetaxel 40 mg/m2, cisplatin 60 mg/m2 on day 1, and S-1 80 mg/m2 on days 1-14, repeated every four weeks, for a maximum of three cycles. Results Clinical response rate was 76% and the pathological response rate (Grade 2/3) was 33%. Hematological toxicities of Grade 3/4 were leukopenia 50%, neutropenia 68%, and febrile neutropenia 18%. Conclusion Neoadjuvant chemotherapy with DCS is a feasible therapeutic strategy for patients with advanced thoracic esophageal squamous cell carcinoma.

Background Laparoscopic gastrectomy (LG) has several benefits as a treatment of gastric cancer (GC), including reduced pain, early recovery of intestinal function, and shorter hospital stay. LG still has several drawbacks, however, including limited range of movement, amplification of hand tremors, and inconvenient surgical positioning. Around the peripancreatic area, laparoscopic lymph node dissection, therefore, remains challenging; postoperative pancreatic fistula occurs in around 4–7% of patients undergoing LG. Robotic surgery, on the other hand, plays a role in ergonomics and offers several advantages, including 7° of wrist-like motion, less fatigue, tremor filtering, motion scaling, and three-dimensional vision. In our previous retrospective study, we compared the safety and feasibility of surgical outcomes of LG and robotic gastrectomy (RG) for patients with GC. In our previous results, in the LG group, intra-abdominal infectious complications were found in 11%. In the RG group, however, none were found. Our RG procedure may be associated with decreased incidence of intra-abdominal infectious complications. Prospective randomized controlled trials (RCTs) comparing LG and RG are required, however. We begin an RCT to compare short-term surgical and long-term oncological outcomes of LG and RG for GC patients. Methods This is a randomized, single-center clinical trial. All included patients are adults with primary carcinoma of the stomach, in whom the tumor is considered surgically resectable (stages I–III). Included in this trial are 240 patients with GC. The primary endpoint is to assess the incidence of postoperative intra-abdominal infectious complications including pancreatic fistula, intra-abdominal abscess, and anastomotic leakage. Secondary endpoints include the incidence of any complications (both related and unrelated to surgery), surgical results, postoperative course, and oncological outcomes. Discussion Although its short-term outcomes have been proven comparable to LG in comparative studies, use of RG remains restricted, partly due to the lack of informative RCTs pertaining to it. To evaluate the surgical and oncological outcomes of RG, we therefore undertake a prospective RCT. The obtained results will be useful for reducing the restrictions and for adaptive expansion of RG for patients with GC. Trial registration University Hospital Medical Information Network Clinical Trials Registry, ID: UMIN000031536. Registered on 1 March 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-2810-5) contains supplementary material, which is available to authorized users.

Patients with positive peritoneal cytology (CY1) or peritoneal dissemination (P1) have significantly poor prognosis. We performed pre-therapeutic staging laparoscopy (SL) to diagnose peritoneal metastasis for patients with advanced gastric cancer. When peritoneal metastasis disappears by chemotherapy for patients with CY1 or P1, we have intention to perform conversion surgery (CS). This study aims to clarify the clinical significance of CS for such patients. We retrospectively analyzed clinical outcomes of 115 patients with advanced gastric cancer (large type 3, type 4, serosa-invasion) who underwent SL between 2005 and 2014. Disappearance of peritoneal metastasis was confirmed by second-look SL. CY0P0, CY1P0, and P1 were found in 56, 26, and 33 patients, respectively. In patients with CY1P0, 12 patients (66.7%) underwent CS (R0) as peritoneal cytology turned negative. All cases received S-1-based regimens, with median five treatment courses. The survival of patients with CS was significantly longer than those without CS (median survival time (MST); 41 vs. 11 months, respectively, P

Our previous trial with a docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen showed high response rates in metastatic squamous cell carcinoma of the esophagus (SCCE). The observed increased toxicity of the DCF regimen, however, was clinically harmful. S-1, an oral anticancer drug, has been approved as a combination therapy for SCCE, and alternate-day regimen with S-1 has shown lower levels of toxicity. This prospective single-center phase I/II trial examines the efficacy and toxicity of a combination of docetaxel, cisplatin, and an alternate-day regimen of S-1 (modified DCS) for patients with metastatic SCCE. We use a two-stage design. Phase I is undertaken to determine the maximum tolerated dose and the recommended dose. The phase I trial adopts a three-patient cohort with escalating dose study design. In the phase II trial, the primary endpoint is the assessment of the overall response rate (Response Evaluation Criteria in Solid Tumors 1.1). The secondary endpoints are the evaluation of drug-related toxicity (National Cancer Institute Common Toxicity Criteria 4.0), overall survival, and progression-free survival. Fifty patients with metastatic SCCE participate in the phase II section. This study protocol is the first to test the effects of the modified DCS regimen for metastatic SCCE.

Compared with total gastrectomy, proximal gastrectomy (PG) has potential advantages from a nutritional perspective, such as anemia and postoperative loss of body weight. However, PG is associated with some postoperative functional disorders, such as reflux esophagus (13–31%) and anastomotic stenosis (3–29%).1 We therefore developed a new procedure for fundoplication during esophago-gastrostomy after robotic PG (RPG). We performed RPG for early gastric cancer localized in the upper third of the stomach using the da Vinci Surgical System (Intuitive, Sunnyvale, CA). After RPG conclusion, intracorporeal esophago-gastrostomy was performed by side-to-side anastomosis using a linear 45 mm stapling device, Endo GIA purple cartridge.2 The post-excisional hole in the esophago-gastrostomy was closed with interrupted single-layered sutures by robotic suturing technique. Fundoplication was created by wrapping the remnant stomach around 180 degrees of the circumference of the esophagus; the remnant stomach was wrapped from the esophageal posterior wall towards the esophageal anterior wall. Four stitches were used for fixation. We did not add a bougie of esophago-gastrostomy when fashioning the wrap. In addition, we did not perform pyloroplasty. In our series with 15 patients, there were no postoperative complications. No patients had reflux symptoms. Our technique using the fundoplication with “clockwise” rotation attempts to prevent reflux by use of intragastric pressure to flatten the lower end of the esophagus into a valvate shape. Indeed, in fluoroscopic findings 4 days after surgery, there was no reflux to the esophagus of the contrast medium. In endoscopic findings 3 months after surgery, anastomotic stenosis was absent. We observed no endoscopic findings of reflux esophagitis. Formation of the pseudo-fornix was confirmed by wrapping the remnant stomach. RPG followed by fundoplication with 180-degree wrap may be a promising procedure for reflux esophagitis prevention.3,4 However, long-term follow-up is required to show benefits of this new procedure.4

Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist: recommended items to address in a clinical trial protocol and related documents*. (DOC 121 kb)

Clinical application of dendritic cell (DC) vaccine therapy is hindered by the need for a large quantity of DCs generated from peripheral blood monocytes of the patient. We investigated whether genetically modified human induced pluripotent stem cell (iPSC)-derived dendritic cells (hiPSDCs) expressing carcinoembryonic antigen (CEA) could induce CEA-specific cytotoxic T cells in a human model and whether genetically modified mouse iPSDCs (miPSDCs) expressing CEA showed an actual antitumor effect using a CEA transgenic mouse model. We differentiated hiPSDCs from iPSCs of three healthy donors and transduced CEA cDNA into the hiPSDCs. The surface marker expression, cytokine secretion and migratory capacity of the hiPSDCs were equivalent to those of human monocyte-derived DCs (hMoDCs). Cytotoxic T cells activated by hiPSDCs-CEA exhibited CEA-specific cytotoxic activity against the target cells expressing CEA. Furthermore, in the CEA transgenic mouse model, cytotoxic T cells activated in mice immunized with miPSDCs-CEA displayed CEA-specific cytotoxic activity against MC38-CEA. In the subcutaneous tumour model, vaccination with miPSDCs-CEA achieved a significant growth inhibitory effect on MC38-CEA. No adverse events caused by the administration of miPSDCs were observed. Genetic modification of iPSDCs, inducing the expression of CEA, is a promising tool for clinical applications of vaccine therapy for treating gastrointestinal cancer patients.

The aim of this study was to examine the feasibility of performing combined laparoscopic resection in patients with synchronous gastric and colorectal cancer.Thirty-six consecutive patients with synchronous gastric and colorectal cancer who underwent simultaneous combined resection were enrolled in this retrospective study.Six patients underwent laparoscopic combined resection (lap group), whereas the other 30 patients underwent conventional open combined surgery (open group). Although the operative time was longer in the lap group than in the open group, there were no differences in the amount of intraoperative bleeding. Although there were no differences in the rates of postoperative complications between the 2 groups, the postoperative hospital stay was significantly shorter in the lap group. During a mean follow-up of 35 months, all 6 patients who underwent laparoscopic combined resection survived without any signs of recurrence.Simultaneous laparoscopic resection is a feasible procedure in patients with synchronous gastric and colorectal cancer.

Postoperative internal hernia (IH) is a potentially life-threatening acute protrusion of viscus through an iatrogenic mesenteric defect. In our retrospective study of 1943 consecutive gastric cancer (GC) patients who had undergone surgery, the incidence of IH after laparoscopic total gastrectomy (LTG) was 4.9%.1 This high incidence seems to be caused by decreased adhesion formation after LTG. There is no consensus regarding orifice management during robotic total gastrectomy (RTG). We therefore developed a new procedure for IH prevention during RTG. We performed RTG with antecolic Roux-en-Y reconstruction using the da Vinci S system (Intuitive, Sunnyvale, CA). We chose an intracorporeal side-to-side esophagojejunostomy (overlap method).2 First, mesenteric defect of jejunojejunostomy was closed under direct vision following retrieval of the stomach. Second, the esophagus hiatus and Petersen’s defect were closed under laparoscopic vision using robotic suture.3 Finally, the duodenal stump and the Roux limb were fixed to prevent torsion of the Roux limb. We performed this procedure on five patients between May and October 2017. The median duration of surgery was 395 min (range, 319–442 min), median bleeding was 60 ml (range, 35–140 ml). There were no anastomosis-related complications higher than Clavien-Dindo grade II in any patients.4 Although the follow-up period is less than 1 year, no IH after RTG has been observed in any patients. Regarding short-term surgical outcomes, this procedure is recommended for GC patients who undergo RTG. However, more long-term follow-up for patients who have undergone RTG with closure of all mesenteric defects is required.

There have been no comparative studies of open gastrojejunostomy (OGJ) and laparoscopic gastrojejunostomy (LGJ) in gastric cancer (GC) patients with gastric outlet obstruction (GOO) to explore both short- and long-term outcomes. The aim of this study was to compare the safety and feasibility of short-term oral intake as well as the long-term oncological outcome of OGJ and LGJ. This was a retrospective study of 53 consecutive unresectable GC patients who underwent GJ for GOO in our institute. OGJ (n = 23) was performed between 2010 and 2012 and LGJ (n = 30) was performed between 2013 and 2015. We found a higher rate of postoperative delayed gastric emptying in the OGJ group than in the LGJ group (26.1 vs 0%; P = 0.004). OGJ had more unfavorable results regarding the median time to resumption of oral feeding (4 vs 2 days; P

This study aimed to determine risk factors for postoperative complications of gastric endoscopic submucosal dissection (ESD).This retrospective study included 647 lesions in 580 consecutive patients who underwent ESD for gastric noninvasive neoplasia from January 1, 2002 through December 31, 2011.The overall perforation rate was 5.1%. Multivariate logistic regression analysis indicated that perforation was significantly associated with tumors in the greater curvature of the stomach (P0.0001), scars in tumor lesions (P=0.002), long operative time (P=0.007), and tumors in the remnant stomach (P=0.036). The bleeding rate after gastric ESD was 3.9%. Multivariate logistic regression analysis indicated a statistically significant association between postoperative bleeding and oral anticoagulant or antiplatelet drugs (P0.0001), dialysis (P=0.009), and use of antihypertensive drugs (P=0.015).It is important to perform gastric ESD with particular care in patients with risk factors.

Peritoneal dissemination is frequently detected in patients with advanced gastric cancer. The peritoneal cavity is a compartment in which an immunologic host-tumor interaction can occur. There are no reports on the relationship between IL-17 expression in peritoneal lavage and prognosis in gastric cancer patients. Therefore, we investigated the expression of IL-17 mRNA in peritoneal lavage from gastric cancer patients and assessed the association of its expression with clinicopathological parameters and prognosis. Peritoneal lavage was obtained from 114 patients with gastric cancer at initial surgery. Seventy-nine patients underwent curative resection. Among these 79 patients, IL-17 mRNA expression was associated with the depth of tumor invasion (p

It is generally accepted that the difficulty in obtaining a sufficient number of functional dendritic cells (DCs) is a serious problem in DC-based immunotherapy. Therefore, we used the induced pluripotent stem (iPS) cell-derived DCs (iPSDCs). If the therapeutic efficacy of iPSDCs is equivalent to that of bone marrow-derived DCs (BMDCs), then the aforementioned problems may be solved. In our study, we induced iPSDCs from iPS cells and examined the capacity for maturation of iPSDCs compared to that of BMDCs in addition to the capacity for migration of iPSDCs to regional lymph nodes. We adenovirally transduced the hgp100 gene, natural tumor antigens, into DCs and immunized mice once with the genetically modified DCs. The cytotoxic activity of CD8 (+) cytotoxic T lymphocytes (CTLs) was assayed using a (51) Cr-release assay. The therapeutic efficacy of the vaccination was examined in a subcutaneous tumor model. Our results showed that iPSDCs have an equal capacity to BMDCs in terms of maturation and migration. Furthermore, hgp100-specific CTLs were generated in mice immunized with genetically modified iPSDCs. These CTLs exhibited as high a level of cytotoxicity against B16 cells as BMDCs. Moreover, vaccination with the genetically modified iPSDCs achieved as high a level of therapeutic efficacy as vaccination with BMDCs. Our study clarified experimentally that genetically modified iPSDCs have an equal capacity to BMDCs in terms of tumor-associated antigen-specific therapeutic antitumor immunity. This vaccination strategy may therefore be useful for future clinical application as a cancer vaccine.