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Recent large-scale randomized controlled trials have shown that extended surgery does not significantly improve prognosis. The REGATTA trial (JCOG0705/KGCA01) explored the survival benefits of reduction gastrectomy in patients with advanced gastric cancer and a single non-curable factor but failed to demonstrate the superiority of gastrectomy plus chemotherapy over chemotherapy alone. 3 Terashima et al. 4 reported supplementary analysis aimed to explore the subgroups for which reduction gastrectomy might be beneficial with special reference to the tumor location and the country. Robotic surgical systems with three-dimensional camera and a high-precision instrument operation will perform more accurate and curative procedures even in advanced stage with less complications.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with frequent recurrence even after curative resection. The tumor microenvironment, which consists of non-cancer cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), was recently reported to promote several cancers, including ESCC. However, the role of CAF as a coordinator for tumor progression in ESCC remains to be elucidated. In our immunohistochemical investigation of ESCC tissues, we observed that the intensity of expression of two CAF markers—alpha smooth muscle actin (αSMA) and fibroblast activation protein (FAP)—in the tumor stroma was significantly correlated with the depth of tumor invasion, lymph node metastasis, advanced pathological stage, and poor prognosis. We co-cultured human bone marrow-derived mesenchymal stem cells (MSCs) with ESCC cells and confirmed the induction of FAP expression in the co-cultured MSCs. These FAP-positive MSCs (which we defined as CAF-like cells) promoted the cell growth and migration of ESCC cells and peripheral blood mononuclear cell-derived macrophage-like cells. CAF-like cells induced the M2 polarization of macrophage-like cells. A cytokine array and ELISA revealed that CAF-like cells secreted significantly more CCL2, Interleukin-6, and CXCL8 than MSCs. These cytokines promoted the migration of tumor cells and macrophage-like cells. The silencing of FAP in CAF-like cells attenuated cytokine secretion. We compared cell signaling of MSCs, CAF-like cells, and FAP-silenced CAF-like cells; PTEN/Akt and MEK/Erk signaling were upregulated and their downstream targets, NF-κB and β-catenin, were also activated with FAP expression. Silencing of FAP attenuated these effects. Cytokine secretion from CAF-like cells were attenuated by inhibitors against these signaling pathways. These findings indicate that the collaboration of CAFs with tumor cells and macrophages plays a pivotal role in tumor progression, and that FAP expression is responsible for the tumor promotive and immunosuppressive phenotypes of CAFs.

BackgroundThe aim of this retrospective study was to investigate the tumor characteristics, surgical details, and survival distribution of surgically resected cases of gastric cancer from the nationwide registry of the Japanese Gastric Cancer Association.MethodsData from 118,367 patients with primary gastric carcinoma who underwent resection between 2001 and 2007 were included in the survival analyses. The 5-year survival rates were calculated for various subsets of prognostic factors.ResultsThe median age of the patients was 67 years. The proportions of patients with pathological stage (Japanese Gastric Cancer Association) IA, IB, II, IIIA, IIIB, and IV disease were 44.0%, 14.7%, 11.7%, 9.5%, 5.0%, and 12.4% respectively. The death rate within 30 days of operation was 0.5%. The 5-year overall survival rate in the 118,367 patients who were treated by resection was 71.1%. The 5-year overall survival rates of patients with pathological stage IA, IB, II, IIIA, IIIB, and IV disease were 91.5%, 83.6%, 70.6%, 53.6%, 34.8%, and 16.4% respectively. The 5-year disease-specific survival rates in the patients with pT1 (mucosa) disease after D1+ dissection of lymph node station no. 7 (D1 + α), D1+ dissection of lymph node station nos. 7, 8, and 9 (D1+ β), and D2 lymphadenectomy were 99.4%, 99.6%, and 99.1% respectively. The 5-year disease-specific survival rates in the patients with pT1 (submucosa) disease after D1 + α, D1 + β, and D2 lymphadenectomy were 97.3%, 98.1%, and 96.9% respectively.ConclusionDetailed analyses of the data from more than 100,000 patients show the recent trends of the outcomes of gastric cancer treatment in Japan and provide baseline information for use by medical communities around world.

Esophageal cancer has a poor prognosis despite the fact that surgical techniques have been advanced and optimized, and systemic multimodality approaches have progressed recently. Adding chemotherapy, radiotherapy, and immunotherapy to the basic surgical approach have been shown to have therapeutic benefit for esophageal cancer. This review describes the latest development of chemoradiotherapy, chemotherapy, and immunotherapy, which have contributed to the reduction in esophageal cancer growth and improved the survival of patients. Chemoradiation is a treatment option for resectable esophageal cancer to preserve the esophagus for patients who cannot tolerate surgery. Moreover, a combination of chemoradiotherapy and salvage surgery could extend the survival of patients. The effects of a triplet chemotherapy regimen are currently being verified in some Phase III studies for unresectable advanced/recurrent esophageal cancer. In addition, with the great promise of immune checkpoint inhibitors, strategies that incorporate the use of immunotherapy may shift from the metastatic setting to the neoadjuvant/adjuvant setting as a result of clinical trials. More precise comprehension of the molecular biology of esophageal cancer is expected to further control disease progression using multimodality treatments in the future.

BackgroundAlthough laparoscopic total gastrectomy (LTG) is considered a technically demanding procedure with safety issues, it has been performed in several hospitals in Japan. Data from a nationwide web-based data entry system for surgical procedures (NCD) that started enrollment in 2011 are now available for analysis.MethodsA retrospective cohort study was conducted using data from 32,144 patients who underwent total gastrectomy and were registered in the NCD database between January 2012 and December 2013. Mortality and morbidities were compared between patients who received LTG and those who underwent open total gastrectomy (OTG) in the propensity score-matched Stage I cohort and Stage II–IV cohort.ResultsThere was no significant difference in mortality rate between LTG and OTG in both cohorts. Operating time was significantly longer in LTG while the blood loss was smaller. In the Stage I cohort, LTG, performed in 33.6% of the patients, was associated with significantly shorter hospital stay but significantly higher incidence of readmission, reoperation, and anastomotic leakage (5.4% vs. 3.6%, p < 0.01). In the Stage II–IV cohort, LTG was performed in only 8.8% of the patients and was associated with significantly higher incidence of leakage (5.7% vs. 3.6%, p < 0.02) although the hospital stay was shorter (15 days vs. 17 days, p < 0.001).ConclusionLTG was more discreetly introduced than distal gastrectomy, but remained a technically demanding procedure as of 2013. This procedure should be performed only among the well-trained and informed laparoscopic team.

BackgroundEsophageal neuroendocrine carcinoma (ENEC) is an extremely rare type of tumor characterized by a high malignant potential, rapid growth, and poor prognosis. Because the standard therapy for ENEC has been poorly defined, we herein aimed to attain a clear view of the current state of treatment for ENEC by performing a large-scale, multicenter study.MethodsWe conducted a questionnaire-based, retrospective clinical review of 142 patients with ENEC treated at 37 hospitals accredited by the Japan Esophageal Society from January 2010 to December 2015.ResultsThe most frequent main treatment performed was an operation, followed by chemoradiotherapy, chemotherapy, and endoscopic submucosal dissection. Among the 67 patients who underwent surgery, 28 (19.7%) were not accurately diagnosed with NEC or a combined NEC tumor by pretreatment biopsy. The 5-year overall survival rate of all patients was 33.2%. Among patients with Stages III and IV disease, the prognosis was significantly better in patients who underwent chemoradiotherapy than in patients who underwent other treatments. Among patients with Stages I and II disease, however, there was no difference in survival rates between those who underwent surgery and chemoradiotherapy.ConclusionsThis nationwide survey is a valuable report of the current status of treatment of ENEC in a limited number of cases experienced at each participating institution. The survival benefit obtained from surgery was considered to be limited, especially for Stages III and IV ENEC. Accurate pretreatment histological diagnosis is essential to determine the most appropriate treatment strategy for patients with ENEC.

BackgroundGiven the worldwide popularization of conventional minimally invasive esophagectomy (C-MIE), robot-assisted MIE (RAMIE) can be expected to provide a finer procedure. However, controversy remains regarding whether RAMIE is superior to C-MIE in preventing recurrent laryngeal nerve (RLN) palsy. Considering the shallow learning curve for RAMIE, a novel procedure for lymphadenectomy along the RLN during RAMIE is needed.MethodsBased on a logical and simple understanding of the left upper mediastinum anatomy, the authors developed a novel “modified bascule method” for RAMIE that could simplify lymphadenectomy along the left RLN and prevent it from being touched and stretched. Between 2018 and 2020, 46 patients with esophageal carcinoma underwent RAMIE using this method at Kobe University.ResultsThe modified bascule method was used to perform RAMIE for 29 men and 17 women with a median age of 67 years (range, 49–82 years). The median thoracoscopic procedure time was 438 min (range, 344–625 min), and the median console time was 351 min (range 273–518 min). The study harvested a median of 24 (range, 8–34) lymph nodes from the thoracic portion and 4 (range, 0–10) lymph nodes from along the left RLN. The mortality rate was 0%. Postoperative left RLN palsy classified as Clavien–Dindo (C–D) grade 1 or higher was observed for 9 patients (19%), whereas grade 2 or higher was not seen (0%). Pneumonia and anastomotic leakage rates higher than C–D grade 2 were respectively 13% and 19%.ConclusionsThe novel modified bascule method for RAMIE can promote feasible lymphadenectomy along the left RLN even when performed during the learning period.

BackgroundLaparoscopic distal gastrectomy (LDG) is becoming the standard procedure for gastric cancer. However, supporting evidence thus far has been derived primarily from randomized control trials conducted by centers of excellence. In the present study we used the National Clinical Database (NCD) in Japan to prospectively accumulate data from diverse types of hospitals and examine whether LDG is a safe and valid standard procedure.MethodsFrom the NCD, 169 institutions were selected to form a cohort that was considered to be representative of Japan. From August 2014 to July 2015, 5288 patients who underwent LDG were registered prospectively, and clinical data were acquired through the NCD. To compare surgical outcomes between open distal gastrectomy (ODG) and LDG, we adjusted for confounding factors using propensity score matching, ultimately retrieving data from 1067 patients in each group.ResultsThere were no significant differences in the number of in-hospital deaths in the ODG and LDG groups (3/1067 vs. 6/1067; P = 0.51) or in the number of reoperations (20/1067 vs. 29/1067; P = 0.19). However, the length of hospital stay was significantly shorter in the LDG. Although wound infection and dehiscence were more common in the ODG group, LDG was more often associated with grade B or higher pancreatic fistulas.ConclusionThe safety and minimal invasiveness of LDG were confirmed in the present Japanese nationwide survey. However, care must be taken to prevent the formation of pancreatic fistulas with LDG, and further improvements in surgical quality are warranted in this regard.

Wnt5a‐Ror2 signaling has been shown to play important roles in promoting aggressiveness of various cancer cells in a cell‐autonomous manner. However, little is known about its function in cancer‐associated stromal cells, including mesenchymal stem cells (MSCs). Thus, we examined the role of Wnt5a‐Ror2 signaling in bone marrow‐derived MSCs in regulating proliferation of undifferentiated gastric cancer cells. Coculture of a gastric cancer cell line, MKN45, with MSCs either directly or indirectly promotes proliferation of MKN45 cells, and suppressed expression of Ror2 in MSCs prior to coculture inhibits enhanced proliferation of MKN45 cells. In addition, conditioned media from MSCs, treated with control siRNA, but not siRNAs against Ror2, can enhance proliferation of MKN45 cells. Interestingly, it was found that expression of CXCL16 in MSCs is augmented by Wnt5a‐Ror2 signaling, and that recombinant chemokine (C‐X‐C motif) ligand (CXCL)16 protein can enhance proliferation of MKN45 cells in the absence of MSCs. In fact, suppressed expression of CXCL16 in MSCs or an addition of a neutralizing antibody against CXCL16 fails to promote proliferation of MKN45 cells in either direct or indirect coculture with MSCs. Importantly, we show that MKN45 cells express chemokine (C‐X‐C motif) receptor (CXCR)6, a receptor for CXCL16, and that suppressed expression of CXCR6 in MKN45 cells results in a failure of its enhanced proliferation in either direct or indirect coculture with MSCs. These findings indicate that Wnt5a‐Ror2 signaling enhances expression of CXCL16 in MSCs and, as a result, enhanced secretion of CXCL16 from MSCs might act on CXCR6 expressed on MKN45, leading to the promotion of its proliferation. We examined the role of Wnt5a‐Ror2 signaling in bone marrow‐derived mesenchymal stem cells (MSCs) in regulating proliferation of undifferentiated gastric cancer cell line, MKN45 cells. Our findings show that Wnt5a‐Ror2 signaling enhances expression of CXCL16 in MSCs and as a result enhanced secretion of CXCL16 from MSCs might act on CXCR6 expressed on MKN45, leading to the promotion of its proliferation.