Elective colorectal cancer surgery in nonagenarians and postoperative outcomes.

OBJECTIVES: The population of very elderly patients is increasing, and nonagenarians have significantly higher mortality rates and poorer rates of survival than younger patients. Meanwhile, recent studies have shown colorectal cancer surgery in nonagenarian patients to be feasible regarding postoperative outcomes. This retrospective study aims to evaluate the postoperative outcomes of nonagenarians in the latest clinical settings. METHODS: Consecutive nonagenarian patients who underwent elective colorectal cancer surgery between 2018 and 2020 retrospectively enrolled (Trial registration number: UMIN000046296 on December 7th, 2021). Clinicopathological data and short-term postoperative outcomes were collected for statistical analysis. RESULTS: This study included 81 nonagenarian patients (31 males, 50 females). Postoperative complications occurred in 21 patients (25.9%), and 3 patients died within 90 days (3.7%). Multivariate analysis revealed prognostic nutritional index was a significant predictor of postoperative complications (OR 2.99, 95% CI 0.78-9.10, P = 0.048), and performance status ≥ 3 could be an independent risk factor of 90-day mortality (HR 32.30, 95% CI 3.20-326.10, P = 0.032). CONCLUSIONS: Short-term outcomes after surgical treatment for nonagenarian patients with colorectal cancer were acceptable. Low prognostic nutritional index was closely related to postoperative complications and poor performance status could also lead to 90-day mortality. In aging populations, risk stratification to prevent poorer postoperative outcomes in nonagenarian patients is needed.

Oncolytic virotherapy with human telomerase reverse transcriptase promoter regulation enhances cytotoxic effects against gastric cancer.

[This retracts the article DOI: 10.3892/ol.2021.12751.].

Short-term Outcomes of Robotic Gastrectomy vs Laparoscopic Gastrectomy for Patients With Gastric Cancer: A Randomized Clinical Trial.

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.

Oncolytic virotherapy with human telomerase reverse transcriptase promoter regulation enhances cytotoxic effects against gastric cancer.

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 with SOCS3 enhances viral replicative potency and oncolysis for gastric cancer.

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.

Phase 1 Study of Combined Chemotherapy of Nab-Paclitaxel, S-1, and Oxaliplatin for Gastric Cancer with Peritoneal Metastasis (NSOX Study).

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.

Impact of postoperative complications on survival outcomes in patients with gastric cancer: exploratory analysis of a randomized controlled JCOG1001 trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Endoscopic submucosal tunnel dissection versus conventional endoscopic submucosal dissection for early gastric cancers: outcomes of 799 consecutive cases in a single institution.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Postoperative atrial fibrillation does not impact on overall survival after esophagectomy in patients with thoracic esophageal cancer: results from a randomized, double-blind, placebo-controlled trial.

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.

Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade.

BACKGROUND: Cancer 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. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: Cancer Ag targeting to XCR1+ DCs should be a promising procedure as a combination anticancer therapy with immune checkpoint blockade.

Laparoscopic Billroth I Gastroduodenostomy in Robotic Distal Gastrectomy for Gastric Cancers: Fusion Surgery.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Regarding short-term surgical outcomes, robotic-assisted laparoscopic stapling techniques for reconstruction after RDG are both feasible and safe for gastric cancers.

Loss of CEACAM1 is associated with poor prognosis and peritoneal dissemination of patients with gastric cancer.

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.

Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial.

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.

Robotic radical lymphadenectomy without touching the pancreas during gastrectomy for gastric cancer.

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.

Triplet chemotherapy with docetaxel, cisplatin and S-1 for unresectable advanced squamous cell carcinoma of the esophagus: phase I/II trial results.

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/m2 (day 1), 50 mg/m2 (day 1), and 80 mg/m2/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.

Triangulating stapling vs functional end-to-end stapling for cervical esophagogastric anastomosis after esophagectomy for thoracic esophageal cancer: study protocol for a randomized controlled trial.

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.

Conversion Surgery for Gastric Cancer with Peritoneal Metastasis Based on the Diagnosis of Second-Look Staging Laparoscopy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 < 0.001). We observed no difference in overall survival between patients who underwent CS and patients with CY0P0 at the first SL (P = 0.913). All patients with P1 received chemotherapy. As peritoneal metastasis of five patients (15.2%) disappeared by chemotherapy, those patients underwent the CS (R0). The survival of patients who underwent CS was significantly longer than those who did not (MST; 31 vs. 10 months, respectively, P = 0.034). CONCLUSION: This study suggests that conversion surgery contributes to improvement in survival of patients with peritoneal metastasis.

[In Vivo Antigen Delivery to Dendritic Cells-A Novel Peptide Vaccine for Cancer Therapy].

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.

Endoscopic treatment of esophageal fistulas after esophagectomy with injection of an alpha-cyanoacrylate monomer: a phase II study.

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.