After propensity score matching in long-term oncologic outcomes of robotic gastrectomy for gastric cancer compared with laparoscopic gastrectomy”

Randomized phase III trial of gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer, the short-term safety and surgical results: Japan Clinical Oncology Group Study (JCOG0501) Abstract Background The prognosis of patients with linitis plastica (type 4) and large (≥ 8 cm) ulcero-invasive-type (type 3) gastric cancer is extremely poor, even after extended surgery and adjuvant chemotherapy. Given the promising results of our previous phase II study evaluating neoadjuvant chemotherapy (NAC) with S-1 plus cisplatin (JCOG0210), we performed a phase III study to confirm the efficacy of NAC in these patients, with the safety and surgical results are presented here. Methods Eligible patients were randomized to gastrectomy plus adjuvant chemotherapy with S-1 (Arm A) or NAC followed by gastrectomy + adjuvant chemotherapy (Arm B). The primary endpoint was the overall survival (OS). This trial is registered at the UMIN Clinical Trials Registry as C000000279. Results From February 2007 to July 2013, 300 patients were randomized (Arm A 149, Arm B 151). NAC was completed in 133 patients (88%). Major grade 3/4 adverse events during NAC were neutropenia (29.3%), nausea (5.4%), diarrhea (4.8%), and fatigue (2.7%). Gastrectomy was performed in 147 patients (99%) in Arm A and 139 patients (92%) in Arm B. The operation time was significantly shorter in Arm B than in Arm A (median 255 vs. 240 min, respectively; p = 0.024). There were no significant differences in Grade 2–4 morbidity and mortality (25.2% and 1.3% in Arm A and 15.8% and 0.7% in Arm B, respectively). Conclusions NAC for type 4 and large type 3 gastric cancer followed by D2 gastrectomy can be safely performed without increasing the morbidity or mortality.

Epigenetic downregulation of MUC17 by H. pylori infection facilitates NF-κB-mediated expression of CEACAM1-3S in human gastric cancer Abstract Background and aims Helicobacter pylori invades the mucosal barrier and infects the mucins of gastric epithelial cells. However, whether gastric carcinogenesis caused by H. pylori infection involves the membrane-bound mucins is unclear. This study explored the role of mucin 17 (MUC17) in gastric cancer (GC) associated with H. pylori infection. Methods The expression of MUC17 and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) was examined in human GC cells and tissues with H. pylori infection. Gain- and loss-of-function assays were performed to assess the role of MUC17 in regulating CEACAM1 in H. pylori-infected GC cells. Results MUC17 was downregulated in H. pylori-infected GC cells and tissues in association with poor survival of GC patients. Downregulation of MUC17 was attributable to MUC17 promoter methylation mediated by DNA methyltransferase 1 (DNMT1) H. pylori-enhanced GC cell proliferation and colony formation associated with MUC17 downregulation. Gain- and loss-of-function assays showed that MUC17 inhibited the H. pylori-enhanced GC cell growth by preventing the translocation of H. pylori CagA into GC cells. Moreover, MUC17 downregulated the expression of CEACAM1 variant 3S (CEACAM1-3S) in GC cells and tissues with H. pylori infection. Additionally, MUC17 downregulated CEACAM1 promoter activity via attenuation of NF-κB activation in GC cells. Conclusions MUC17 was epigenetically downregulated in GC with H. pylori infection. MUC17 inhibited H. pylori CagA translocation via attenuation of NF-κB-mediated expression of CEACAM1-3S in GC cells. Thus, MUC17 may serve as a valuable prognostic biomarker for H. pylori-associated GC.

Duodenal stump reinforcement might reduce both incidence and severity of duodenal stump leakage after laparoscopic gastrectomy with Roux-en-Y reconstruction for gastric cancer Abstract Background Although duodenal stump leakage (DSL) is a relatively rare complication after gastrectomy with Roux-en-Y (R-Y) reconstruction, it is difficult to treat and can be fatal. We investigated the impact of duodenal stump reinforcement on DSL after laparoscopic gastrectomy with R-Y reconstruction for gastric cancer. Methods This retrospective study of 965 patients with gastric cancer who underwent laparoscopic distal or total gastrectomy (LDG or LTG) with R-Y reconstruction compared surgical outcomes between two groups, the duodenal stump reinforcement group (reinforcement group) (n = 895) and that without duodenal stump reinforcement (non-reinforcement group) (n = 70). Results Mean operative duration was significantly longer in the reinforcement than in the non-reinforcement group (LDG; 291 min versus 258 min, p < 0.001, LTG; 325 min versus 285 min, p < 0.001). DSL occurred less frequently in the reinforcement than in the non-reinforcement group (0.67% vs. 5.71%, p < 0.001). Furthermore, non-reinforcement was an independent risk factor for DSL in multiple logistic regression analysis with adjustment for potential confounding factors. Patients with DSL in the non-reinforcement group all required re-operation, while all but one patient with DSL in the reinforcement group recovered with conservative management. Conclusions Duodenal stump reinforcement in laparoscopic gastrectomy with R-Y reconstruction may reduce the risk of DSL development and minimize its severity.

Gastric cancer mortality rates among US and foreign-born persons: United States 2005–2014 Abstract Background Historically, foreign-born individuals in the US have had an elevated risk of dying from gastric cancer when compared to US-born individuals. This is primarily due to factors that occur prior to their immigration to the US, including diet and underlying risk of H. pylori infection. Methods National mortality data from 2005 to 2014 were obtained from the CDC’s National Center for Health Statistics. Annual population estimates were obtained from the US Census Bureau’s American Community Survey for foreign-born and US-born persons. Age-adjusted gastric cancer mortality rates and rate ratios (RR) were calculated stratified by birth place, age, race/ethnicity, and geographic location. Results From 2005 to 2014, 111,718 deaths from malignant gastric cancer occurred in the US, of which 24,583 (22%) occurred among foreign-born individuals. Overall, foreign-born individuals had higher mortality rates compared with US-born individuals (RR 1.82; 95% CI 1.80, 1.85) and this difference remained after stratifying by sex, age, and geographic location. However, this finding was primarily driven by the low rate of gastric cancer mortality among US-born whites, with similar mortality rates observed among all other foreign-born and US-born groups. Gastric cancer mortality rates significantly decreased during the study period overall (AAPC − 2.50; 95% CI − 3.21, − 1.79) with significant declines observed among US-born (AAPC − 2.81; 95% CI − 3.55, − 2.07) and the foreign-born (AAPC − 2.53; 95% CI − 3.20, − 1.86) population. Conclusions Efforts directed at reducing the prevalence of gastric cancer risk factors could help reduce the elevated burden observed among foreign-born individuals and US-born minority groups.

Digital image analysis-based scoring system for endoscopic ultrasonography is useful in predicting gastrointestinal stromal tumors Abstract Background When gastric mesenchymal tumors (GMTs) measuring 2–5 cm in size are found, whether to undergo further treatment or not is controversial. Endoscopic ultrasonography (EUS) is useful for the evaluation of malignant potential of GMTs, but has limitations, such as subjective interpretation of EUS images. Therefore, we aimed to develop a scoring system based on the digital image analysis of EUS images to predict gastrointestinal stromal tumors (GISTs). Methods We included 103 patients with histopathologically proven GIST, leiomyoma or schwannoma on surgically resected specimen who underwent EUS examination between January 2007 and June 2018. After standardization of the EUS images, brightness values, including the mean (Tmean), indicative of echogenicity, and the standard deviation (TSD), indicative of heterogeneity, in the tumors were analyzed. Results Age, Tmean, and TSD were significantly higher in GISTs than in non-GISTs. The sensitivity and specificity were almost optimized for differentiating GISTs from non-GISTs when the critical values of age, Tmean, and TSD were 57.5 years, 67.0, and 25.6, respectively. A GIST-predicting scoring system was created by assigning 3 points for Tmean ≥ 67, 2 points for age ≥ 58 years, and 1 point for TSD ≥ 26. When GMTs with 3 points or more were diagnosed as GISTs, the sensitivity, specificity, and accuracy of the scoring system were 86.5%, 75.9%, and 83.5%, respectively. Conclusions The scoring system based on the information of digital image analysis is useful in predicting GISTs in case of GMTs that are 2–5 cm in size.

Hypoalbuminemia for the prediction of venous thromboembolism and treatment of direct oral anticoagulants in metastatic gastric cancer patients Abstract Background Venous thromboembolism (VTE) is highly associated with advanced gastric cancer (AGC) and is sometimes lethal. Predictors of VTE have not been identified, and the efficacy and safety of direct oral anticoagulants (DOACs) for AGC-associated VTE remain to be clarified. Methods A total of 188 AGC patients who started chemotherapy during the period from January 2014 to December 2017 in our institutions were retrospectively examined for the incidence of VTE, risk factors for VTE, and the efficacy and safety of DOAC-based anticoagulant therapy for VTE. Results Thirty-four patients (18%) were diagnosed with VTE at the start or during the course of chemotherapy (VTE group). More VTE group patients had a history of abdominal surgery and had moderate–severe ascites (32% versus 17%, 32% versus 14%, respectively) than non-VTE group patients (NVTE group). The mean serum albumin concentrations in the VTE group were significantly lower than NVTE group (3.38 mg/dL vs 3.65 mg/dL, respectively). Multivariate analysis showed that hypoalbuminemia was significantly correlated with VTE (P = 0.012). In the VTE group, 29 patients (85%) received anticoagulant therapy, including 24 patients treated with DOACs. No lethal VTE was observed in any patients. Thirteen patients (45%) terminated DOACs because of anemia or bleeding events, of whom eleven developed major bleeding. Median overall survivals of the VTE and NVTE groups were 9.63 months and 11.5 months, respectively (P = 0.262). Conclusion Hypoalbuminemia appears to be a risk factor for AGC-associated VTE. DOACs are effective to AGC-associated VTE, but careful observation of bleeding events is required.

Identification of different gene expressions between diffuse- and intestinal-type spheroid-forming gastric cancer cells Abstract Background Three-dimensional in vitro spheroid models are unique because they are considered for enrichment of specific cell populations with self-renewal ability. In this study, we explored the different mechanisms of gastric cancer spheroid-forming cells according to the Lauren classification. Methods We isolated and enriched cells with self-renewal ability using spheroid-forming methods from gastric cancer cell lines. The expression of candidate target genes was investigated using western blot and qRT-PCR analysis. Lentiviral shRNA knockdown of target gene expression was performed and the effects on spheroid, colony forming, and tumorigenic ability were analyzed. Results The SNU-638, SNU-484, MKN-28, and NCI-N87 successfully formed spheroid from single cell and enriched for self-renewal ability from 11 gastric cancer cell lines, including diffuse and intestinal types. The expression of SOX2 and E-cadherin increased in spheroid-forming cells in a diffuse-type cell line (SNU-638 and SNU-484), but not in the intestinal type (MKN-28 and NCI-N87). In contrast, ERBB3 expression was only increased in intestinal-type spheroid cells. The depletion of each candidate target gene expression suppressed self-renewal ability to grow as spheroids and colonies in a soft agar assay. In particular, down-regulated ERBB3 in the intestinal-type cell lines inhibited tumor growth in a mouse xenograft model. We found that high ERBB3 gene expression correlates with decreased survival in the intestinal type of gastric cancer. Conclusions Our results suggest that diffuse- and intestinal-type spheroid-forming cells express genes differently. Our data suggest that these candidate genes from spheroid-forming cells can be used in applications in targeted therapy.

Oncological feasibility of laparoscopic subtotal gastrectomy compared with laparoscopic proximal or total gastrectomy for cT1N0M0 gastric cancer in the upper gastric body Abstract Background The upper gastric body is of particular interest in relation to gastrectomy because this area includes a border; that is, both distal and proximal gastrectomy for early gastric cancer can involve this area. Laparoscopic subtotal gastrectomy (LsTG) is reported to be suitable procedure compared with laparoscopic proximal and total gastrectomy (LPG, LTG), regarding postoperative nutritional status and surgical safety. However, whether LsTG is an oncologically acceptable procedure for early gastric cancer in the upper gastric body is unclear. Methods We analyzed 215 patients with cT1N0M0 gastric cancer limitedly located in the upper gastric body. The frequency of conversion from each intended procedure to an alternative procedure, the width of the pathological margin, the incidence of lymph node metastasis at each station and the 3-year overall survival (OS) and relapse-free survival (RFS) were evaluated. Results LsTG was planned for 65 patients, and LPG for 72 and LTG for 78, respectively. Conversion to other procedures was required in about 10% of patients for whom LsTG or LPG was planned. The width of the pathological margin in patients who underwent LsTG was significantly shorter than patients who underwent the others. No patients who underwent LsTG, LPG or LTG had metastases in station no. 2 or 4sa lymph node. The 3-year OS and RFS rates of patients for whom each procedure was planned were not different. Conclusions LsTG could be an oncologically acceptable procedure for cT1N0M0 gastric cancer in the upper gastric body. LsTG could be one option for such disease.

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