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Background: For patients with gastric cancer, a well-balanced treatment that considers both oncological aspects and surgical risk is demanded. This study aimed to explore the optimal extent of lymph node dissection (LND) for patients with gastric cancer according to surgical risk, stratified by the risk calculator system produced by the Japan National Clinical Database (NCD)., Patients and Methods: We retrospectively evaluated 187 patients who underwent radical gastrectomy for gastric cancer. Using the median predicted anastomotic leak rate obtained by the NCD risk calculator as the cutoff value, we classified 97 and 90 patients as having high and low risks, respectively., Results: In low-risk patients, although limited LND reduced the postoperative intraabdominal infectious complications (IAIC), multivariate analysis revealed standard LND as an independent prognostic factor that improved Relapse-free survival (RFS). In high-risk patients, the rates of postoperative IAIC and RFS were similar between standard and limited LND. Pancreatic fistula was not observed in the limited dissection group., Conclusion: Limited LND might be the optimal treatment strategy for patients with gastric cancer with high surgical risk., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Background: Gastric cancer is primarily treated by surgery; however, little is known about the changes in the intraperitoneal immune environment and the prognostic impact of surgery. Surgical stress and cancer-associated inflammation cause immune cells to mobilize into the abdominal cavity via numerous cytokines. One such cytokine, CX3CR1, has various immune-related functions that remain to be fully explained. We characterized the intraperitoneal immune environment by investigating CX3CR1 + cells in intraperitoneal lavage fluid during gastric cancer surgery., Methods: Lavage fluid samples were obtained from a total of 41 patients who underwent gastrectomy. The relative expression of various genes was analyzed using quantitative real-time PCR. The association of each gene expression with clinicopathological features and surgical outcomes was examined. The fraction of CX3CR1 + cells was analyzed by flow cytometry. Cytokine profiles in lavage fluid samples were investigated using a cytometric beads array., Results: CX3CR1 high patients exhibited higher levels of perioperative inflammation in blood tests and more recurrences than CX3CR1 low patients. CX3CR1 high patients tended to exhibit higher pathological T and N stage than CX3CR1 low patients. CX3CR1 was primarily expressed on myeloid-derived suppressor cells and tumor-associated macrophages. In particular, polymorphonuclear myeloid-derived suppressor cells were associated with perioperative inflammation, pathological N, and recurrences. These immunosuppressive cells were associated with a trend toward unfavorable prognosis. Moreover, CX3CR1 expression was correlated with programmed death-1 expression., Conclusions: Our results suggest that CX3CR1 + cells are associated with an acute inflammatory response, tumor-promotion, and recurrence. CX3CR1 expression could be taken advantage of as a beneficial therapeutic target for improving immunosuppressive state in the future. In addition, analysis of intra-abdominal CX3CR1 + cells could be useful for characterizing the immune environment after gastric cancer surgery., (© 2024. The Author(s).)

Background/aim: Recently, there have been many reports on the use of preoperative body composition analysis to predict postoperative complications in gastric cancer surgery, most of which used 3D image analysis software for the measurements. This study aimed to evaluate the risk of postoperative infectious complications (PICs), especially pancreatic fistulas, using a simple measurement method incorporating only preoperative computed tomography images., Patients and Methods: A total of 265 patients with gastric cancer underwent laparoscopic or robot-assisted gastrectomy with lymph node dissection at Osaka Metropolitan University Hospital between 2016 and 2020. To simplify the measurement method, we measured the length of each region of the subcutaneous fat area (SFA). Each area included a) umbilical depth, b) thickness of the longest ventral subcutaneous fat, c) thickness of the longest dorsal subcutaneous fat, and d) thickness of the median dorsal subcutaneous fat (MDSF) measurements., Results: PICs occurred in 27 of 265 cases, of which pancreatic fistula was present in 9. SFA for pancreatic fistulas showed high diagnostic accuracy (area under the curve=0.922). Among the subcutaneous fat lengths, the MDSF was the most useful, and the optimal cut-off value was 16 mm. MDSF and non-expert surgeons were found to be independent risk factors for pancreatic fistula., Conclusion: Since the possibility of developing pancreatic fistula is high in cases with MDSF ≥16 mm, careful surgical strategies, such as having a skilled physician, are necessary., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Tumor heterogeneity has frequently been observed in gastric cancer (GC), but the correlation between patients' clinico-pathologic features and the tumoral heterogeneity of GC-associated molecules is unclear. We investigated the correlation between lymph node metastasis and the intra-tumoral heterogeneity of driver molecules in GC., Materials and Methods: We retrospectively analyzed the cases of 504 patients who underwent a gastrectomy at the Department of Gastroenterological Surgery, Osaka Metropolitan University and 389 cases drawn from The Cancer Genome Atlas (TCGA) data. We performed a clustering analysis based on eight cancer-associated molecules including HER2, c-Met, and p-Smad2 using the protein expression revealed by our immunohistochemical study of the patients' and TCGA cases. We determined the correlations between HER2 expression and the other molecules based on the degree of lymph node metastasis., Results: Immunohistochemical staining data showed that a 43 of the 504 patients with GC (8.5%) were HER2-positive. In the HER2-positive cases, the expressions of c-Met and p-Smad2 were increased in accord with the lymph-node metastatic level. The overall survival of the HER2-positive GC patients with both p-Smad2 and c-Met expression was significantly (p = 0.030) poorer than that of the patients with p-Smad2-negative and/or c-Met-negative expression. The results of the TCGA data analysis revealed that 58 of the 389 GC cases (14.9%) were ERBB2-positive. MET expression was more frequent in the N1 metastasis group than the N0 group. In the high lymph-node metastasis (N2 and N3) group, SMAD2 expression was more frequent, as was ERBB2 and MET expression., Conclusion: p-Smad2 and c-Met signaling might play important roles in lymph node metastasis in HER2-positive GC., (© 2022. The Author(s).)

This study examined whether the systemic inflammatory response present in the early phase of the postoperative state correlates with long-term outcomes and to identify markers in patients with stage II/III gastric cancer. 444 consecutive patients who underwent radical gastrectomy for stage II/III gastric cancer were retrospectively reviewed. We evaluated maximum serum C-reactive protein (CRP max ) and white blood cell count (WBC max ), defined as the maximum serum CRP level and maximum WBC count during the interval from surgery until discharge, as systemic inflammation markers. In univariate analyses, CRP max , WBC max and infectious complications were significantly associated with both overall survival (OS) (p < 0.001, p < 0.001 and p = 0.011, respectively) and relapse-free survival (RFS) (p < 0.001, p = 0.001 and p < 0.001, respectively). Multivariate analysis revealed that high-CRP max (> 9.2 mg/dL) was an independent prognostic factor for OS (hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.19-2.36, p = 0.003) and RFS (HR 1.56, 95% CI 1.12-2.18, p = 0.009), while WBC max and infectious complications were not. CRP max , which reflects the magnitude of systemic inflammation induced by surgical stress and postoperative complications in the early phase after surgery, may be a promising prognostic indicator in patients with stage II/III gastric cancer who undergo curative resection., (© 2022. The Author(s).)

Nivolumab, an immune checkpoint blocker, has been approved for advanced gastric cancer (GC), but predictive factors of nivolumab's efficacy in patients with GC, especially immune cells such as tissue-resident memory T cells or those forming tertiary lymphoid structures (TLS), remain unclear. Tissue samples were obtained from surgically resected specimens of patients with GC who were treated with nivolumab as third-line or later treatment. Immunohistochemical staining was performed to detect the presence of TLS and CD103+ T cells and assess the association between TLSs and response to nivolumab treatment. A total of 19 patients were analyzed. In patients with partial response (PR) to nivolumab, numerous TLS were observed, and CD103+ T cells were found in and around TLS. Patients with many TLS experienced immune-related adverse events more often than those with few TLS (p = 0.018). The prognosis of patients with TLS high was better than those with TLS low. Patients with a combination of TLS high and CD103 high tended to have a better prognosis than other groups. Our results suggested that TLS status might be a predictor of nivolumab effectiveness., Competing Interests: The authors have declared that no competing interests exist.

Chemotherapy for elderly patients requires ingenuity in treatment to mitigate its high risk. Therefore, we investigated an upfront dose reduction in the first cycle of chemotherapy for unresectable/recurrent gastric cancers in patients over 80 years old. We examined 6 patients over 80 years old, who underwent S-1 plus L-OHP therapy(SOX)for unresectable/recurrent gastric cancer in our department between January 2020 and January 2021. There were no adverse events over Grade 3 in the upfront dose reduction group(U group), while 1 case(50.0%)in the normal dose group(N group)experienced an adverse event over Grade 3. Moreover, only the U group continued treatment for 4 or more courses, whereas none from the N group did. Partial response(PR)was achieved as a therapeutic effect in 3 patients of the U group. Only 2 cases of the U group advanced to the second-line regimen and both were able to transition to the third-line regimen. However, none were able to even transition to the second-line regimen in the N group. Therefore, it was suggested that by reducing the dose of chemotherapy from the first cycle for elderly patients over 80 years old, the incidence of adverse events can be kept low, which makes it possible to continue long-term chemotherapy.

Background: Gastric cancer (GC) patients frequently develop peritoneal metastasis. Recently, it has been reported that peritoneal mesothelial cells (PMCs) activated by GC cells acquire a migratory capacity and promote GC cell invasion. The invasiveness of PMCs reportedly depends on the activity of Tks5, an adaptor protein required for invadopodia formation. However, the relationship between clinicopathologic features and Tks5 expression in PMCs has been poorly documented. In this study, we evaluated the clinicopathologic significance of the Tks5 expression of PMCs in GC patients., Materials and Methods: A total of 110 GC patients who underwent gastrectomy were enrolled in this study. Tks5 expressions in PMCs from the greater omentum, lesser omentum and retroperitoneum were evaluated by immunohistochemistry. We analyzed the correlation between Tks5 expressions in PMCs and the patients' clinicopathologic features., Results: Tks5 expression was found in 71 (64.5%) of the 110 patients, while 39 (35.5%) were Tks5-negative. Tks5 positivity was significantly (p = 0.038) associated with a greater tumor depth (i.e., T3/4 compared with T1/T2). Peritoneal recurrence was found in 12 of 98 cases within 3 years of surgery. The 3-year peritoneal recurrence-free survival (PRFS) rate in Tks5-positive cases was significantly poorer than that in Tks5-negative cases (80.1% vs 97.4%, p = 0.024). Multivariate analysis revealed that Tks5 positivity and lymph node metastasis were independent factors for PRFS., Conclusion: Tks5 is frequently expressed in PMCs in advanced-stage gastric cancer. Tks5 might be a useful predictor for peritoneal recurrence in GC patients., Competing Interests: The authors have declared that no competing interests exist.

Several studies have reported that tissue-resident memory T cells (TRM cells) or tertiary lymphoid structures (TLSs) are associated with a good prognosis. The aim of this study was to clarify the association of TRM cells and TLSs in the tumor immune microenvironment in gastric cancer (GC). We performed immunohistochemical and immunofluorescence staining to detect the presence of CD103 + T cells and to assess the association between CD103 + T cells and TLSs. CD103 + T cells were observed in the tumor epithelium accompanied by CD8 + T cells and were associated with a better prognosis in GC. Furthermore, CD103 + T cells were located around TLSs, and patients with CD103 high had more rich TLSs. Patients who had both CD103 high cells and who were TLS-rich had a better prognosis than patients with CD103 low cells and who were TLS-poor. Moreover, for patients who received PD-1 blockade therapy, CD103 high and TLS-rich predicted a good response. Flow cytometry was performed to confirm the characteristics of CD103 + CD8 + T cells and showed that CD103 + CD8 + T cells in GC expressed higher levels of PD-1, granzyme B, and interferon-γ than CD103 - CD8 + T cells. Our results suggested that CD103 + CD8 + cells in GC are correlated with TLSs, resulting in enhanced antitumor immunity in GC., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Case 1: A 73-year-old man underwent total gastrectomy for residual gastric cancer, and final pathological diagnosis was pStage ⅠB. Adjuvant chemotherapy was not performed. CT findings showed multiple liver metastasis 16 months after procedure. S-1 and CDDP were administered for 28 months. Although chemotherapy regimen was changed to S-1, paclitaxel plus ramucirumab, nivolumab, irinotecan and S-1 plus oxaliplatin(SOX)after progression, he died 73 months after operation, and 57 months after recurrence. Case 2: A 72-year-old man was pointed out swelling of gastric lymph nodes in CT imaging. He was diagnosed as advanced gastric cancer with para-aortic lymph node metastasis by followed examination. S- 1 plus CDDP was administrated for 30 months. S-1 and SOX were administered after progressive findings, but he died 48 months after diagnosis. We report 2 cases of recurrent and advanced gastric cancer with long-term survival because of successful chemotherapy.

Background: Asporin (ASPN), a member of the proteoglycan family, has been shown to have a close correlation with cancer progression. It is not known whether ASPN is an oncogenic driver or a tumor suppressor in human gastric cancer. We sought herein to determine the relationship between ASPN expression and clinicopathological features of gastric cancer., Patients and Methods: A total of 296 gastric cancer patients (diffuse type, n = 144; intestinal type, n = 152) were enrolled. The ASPN expression level in each case was analyzed by immunohistochemistry., Results: ASPN was mainly found on stromal cells, especially on fibroblasts in tumor stroma, i.e., cancer-associated fibroblasts. The ASPN expression on either cancer cells or stromal cells was significantly high in macroscopic scirrhous-type tumors (p < 0.001) and histologically abundant stroma-type tumors (p < 0.001). Interestingly, a Kaplan-Meier survival curve of the 144 cases of diffuse-type gastric cancer revealed a significantly poorer prognosis in patients with ASPN-positive expression (p = 0.043; log rank) compared to those with ASPN-negative expression, but the prognoses were not significantly different in these subgroups of the 152 cases of intestinal-type gastric cancer. A multivariate analysis with respect to overall survival showed that ASPN expression on stromal cells and/or cancer cells was significantly correlated with overall survival in patients with diffuse-type gastric cancer (p = 0.041)., Conclusion: In gastric cancer, ASPN was expressed mainly on stromal cells and partially on cancer cells. ASPN expression on stromal cells and/or cancer cells might be a useful prognostic marker in patients with diffuse-type gastric cancer., (© 2021 S. Karger AG, Basel.)

A 69-year-old woman, who complained of appetite loss, was diagnosed with Type 3 gastric cancer, and a biopsy resulted in the diagnosis of adenocarcinoma(tub2-por), Group 5. Abdominal computed tomography (CT) revealed bulky metastatic lymph nodes around the stomach and the aorta. The diagnosis was cT4a, cN2, cM1(LYM), cStage ⅣB, and SP therapy(a combination of S-1 and cisplatin) was immediately administered. On the completion of 3 courses of SP therapy, both the primary tumor and lymph nodes markedly decreased in size. Based on this finding, D2 total gastrectomy, No. 16 lymph node dissection, splenectomy, and right adrenal tumor resection were performed. Histopathology showed no residual tumor cells in the stomach or lymph nodes. Postoperatively, she received S-1 therapy, which was discontinued on completion of the first course due to its side effects. She survived for over 7 years postoperatively without receiving chemotherapy and showed no recurrence.

Currently, the immunotherapy approved for gastric cancer is immune checkpoint blockade( ICB) therapy. The effects of ICB depend on the T cell-mediated immune response elicited at the cancer site. Based on the results of previous clinical trials, it is clear that an enhanced immune response to cancer improves prognosis. Thus, the development of biomarkers to predict local immune responses may increase the significance of future immunotherapy for gastric cancer. Biomarker research has clearly progressed with the rapid development of genetic analysis technologies, enabling the analysis of data from clinical trials. Not only the molecular biomarkers known to date for ICB biomarkers, but immune cells that influence ICB therapy are also reviewed in this article.

Tertiary lymphoid structures (TLSs), which consist of B cells, T cells, follicular dendritic cells and high endothelial venules, have recently been found to be associated with effective antitumor immune responses in patients with cancer. Tumor‑infiltrating T cells and B cells have each been demonstrated to be associated with survival in patients with cancer. We hypothesized that TLSs, an assembly of immune cells, may be important for the initiation and/or maintenance of T cell and B cell responses against tumors. The aim of the present study was to examine the cellular mechanism of B cells in TLSs within gastric cancer and to understand the antitumor immune response of TLSs. Each B cell subset in a tumor was examined using flow cytometry to evaluate B cell differentiation and the functional status of B cells. In addition, B cell clonality was investigated by analyzing the B cell antigen receptor gene using PCR, and the function and formation/maintenance of TLSs were evaluated using reverse transcription‑quantitative PCR. Tumor‑infiltrating B cells were more differentiated compared with that in distant non‑tumor tissues and tumor‑draining lymph nodes. The PCR results revealed specific BCR gene expression in tumor‑infiltrating B cells. The expression of co‑stimulatory factors, CD80 and CD86, was observed, in addition to the constantly expressed major histocompatibility complex molecules (HLA‑ABC and HLA‑DR). CD70 was expressed in addition to CD27 in both CD20+ B cells and CD8+ T cells, indicating that these factors are activated together through their interaction. The mRNA expression levels of CCL21, CXCL13, PD‑L1, perforin and granzyme B in TLSs was significantly higher compared with that in non‑TLSs. The majority of tumor‑infiltrating B cells in gastric cancer exist in the form of TLSs around the tumor and have been antigen‑sensitized and differentiated, and proliferated in TLSs but not in the lymph nodes. In addition, B cells in TLSs might primarily function as antigen‑presenting cells and be associated with the induction of cytotoxic T cells.

Background: Although many studies have identified several inflammation-based and/or nutritional markers with prognostic value for patients with various types of cancer, the optimal markers and cut-off values for these markers remain obscure. Therefore, this retrospective study aimed to identify optimal markers and their cutoffs., Methods: We compared prognostic values among established preoperative inflammation-based and/or nutritional markers in 225 patients who underwent R0 resection for stage III gastric cancer. Inflammation-based and/or nutritional markers comprised C-reactive protein to albumin ratio (CAR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic nutritional index (PNI), Glasgow prognostic score (GPS), and prognostic index (PI). Time-dependent receiver operating characteristic curves were analyzed to assess predictive ability and to determine the optimal cut-off values. Prognostic factors predicting overall survival (OS) and cancer specific survival (CSS) were analyzed using Cox proportional hazards models., Results: Multivariate analyses revealed that CAR and PLR cut-off values of 0.47 and 172, respectively, were independent prognostic factors for overall survival (OS) (HR, 2.257; 95% CI, 1.180-4.319; p = 0.014 and HR, 1.478; 95% CI, 1.025-2.133; p = 0.037, respectively) and cancer-specific survival (CSS) (HR, 2.771; 95% CI, 1.398-5.493; p = 0.004 and HR, 1.552; 95% CI, 1.029-2.341; p = 0.036, respectively). These results were different from those we previously reported in patients with stage II., Conclusions: Among inflammation-based and/or nutritional markers, CAR and PLR were independent prognostic factors of OS and CSS in patients with stage III gastric cancer. The optimal markers and their cut-off values should be determined in specific populations.

Background: Peritoneal recurrence is one of the most frequent recurrent diseases in gastric cancer. Although the exposure of cancer cells to the serosal surface is considered a common risk factor for peritoneal recurrence, there are some cases of peritoneal recurrence without infiltration to the serosal surface even after curative surgery. This study sought to clarify the risk factors of peritoneal recurrence in the absence of invasion to the serosal surface., Materials and Methods: Ninety-six patients with gastric cancer who underwent curative surgery were enrolled. In all 96 cases, the depth of tumor invasion was subserosal (T3). The microscopic distance from the tumor invasion front to the serosa (DIFS) was measured using tissue slides by H&E staining and pan-cytokeratin staining. E-cadherin expression was evaluated by immunohistochemical staining., Results: Among the 96 patients, 16 developed peritoneal recurrence after curative surgery. The DIFS of the tumors with peritoneal recurrence (156±220 μm) was significantly shorter (p = 0.011) than that without peritoneal recurrence (360±478 μm). Peritoneal recurrence was significantly correlated with DIFS ≤234 μm (p = 0.023), but not with E-cadherin expression. The prognosis of DIFS ≤234 μm was significantly poorer than that of DIFS >234 μm (log rank, p = 0.007). A multivariate analysis of the patients' five-year overall survival revealed that DIFS ≤234 μm and lymph node metastasis were significantly correlated with survival (p = 0.005, p = 0.032, respectively)., Conclusion: The measurement of the DIFS might be useful for the prediction of peritoneal recurrence in T3-gastric cancer patients after curative surgery., Competing Interests: The authors have declared that no competing interests exist.

Tumor‑associated neutrophils (TANs) have an immunosuppressive function and play an important role in tumor progression. However, the detailed mechanism is largely unknown. The present study investigated the immunosuppressive ability of TANs in gastric cancer. Tumor tissue culture supernatant (TTCS) and non‑tumor tissue culture supernatant (NTCS) were purified and added to neutrophils. Expression of programmed cell death ligand‑1 (PDL‑1), 7‑amino‑actinomycin D and human leukocyte antigen‑DR (HLA‑DR), and the levels of hydrogen peroxide (H2O2) were determined. Levels of programmed cell death‑1 (PD‑1) and CD25 were assessed in T cells co‑cultured with neutrophils. Furthermore, CD4+ T cells were co‑cultured with dendritic cells and neutrophils to examine their proliferation. CD15 and PD‑1 immunohistochemical staining was also performed to explore the positional relationship. The results revealed that the neutrophils incubated with TTCS showed upregulation of PDL‑1 expression, as well as a decreases in the ratio of apoptotic cells, expression of HLA‑DR, and levels of H2O2. CD4+ T cells co‑cultured with neutrophils conditioned with TTCS showed a decrease in proliferation, upregulation of PD‑1 expression, and downregulation of CD25 expression. IHC showed that PD‑1+ T cells formed clusters and TANs infiltrated around the clusters. In conclusion, neutrophils in gastric cancer tissue inhibit the proliferation of CD4+ T cells and may form a local immunosuppressive environment through the PD‑1/PDL‑1 pathway.

Background/aim: We have previously reported that chemokine (C-X-C motif) receptor 2 (CXCR2) signaling was associated with the malignant progression of gastric cancer (GC). We thus examined the clinicopathological significance of CXCR2 ligands, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8, in GC., Patients and Methods: The expression of CXCR2 ligands in 590 GC cases was investigated by immunohistochemistry., Results: The expression was as follows: CXCL1, 46.2% (257/557); CXCL2, 20.7% (122/590); CXCL3, 17.1% (101/589); CXCL5/CXCL6, 2.9% (17/589); CXCL7, 36.4% (215/590); and CXCL8 1.7% (10/585) of the cases. High invasion depth was correlated with CXCL1 expression. Lymph node metastasis and peritoneal cytology positivity were correlated with high expression of CXCL1 and CXCL7. The prognoses of the CXCL1-positive patients were significantly poorer than those of the CXCL1-negative patients (p<0.001)., Conclusion: Among the CXCR2 ligands, CXCL7 and especially CXCL1, might play an important role in the malignant progression of GC via CXCR2 signaling., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Thrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic significance of THBS4 expression in gastric carcinoma (GC)., Materials and Methods: We retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting., Results: THBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor., Conclusion: THBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients., Competing Interests: The authors have declared that no competing interests exist.

Background/aim: Multiplex gene panel tests using next-generation sequencing (NGS) are clinically available for gastric cancer (GC). The NGS tests can reveal unexpected pathogenic variants to be associated with hereditary diseases, i.e., secondary genetic findings. We investigated whether GC patients at high risk of having hereditary gastric cancer (HGC) can be identified by their clinicopathological variables before they undergo NGS cancer gene panel tests., Patients and Methods: The cases of 2,286 patients with GC treated at our hospital during the years 1999-2017 were retrospectively analyzed; of them, 143 patients were identified as being at high risk of having HGC (HR-HGC), and the remaining 2,143 patients were classified as having sporadic gastric cancer (SGC)., Results: Compared to the SGC group, the HR-HGC status was significantly associated with younger age, female gender, macroscopic type IV and a histologically diffuse type. In a multivariate analysis, being young (i.e., ≤50 years old) was an independent risk factor for HR-HGC., Conclusion: Female and young patients with diffuse-type GC are closely associated with a high risk of having HGC, and these factors might predict the detection of secondary genetic findings by NGS testing., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: In gastrectomy, postoperative elevation of C-reactive protein (CRP) is thought to be useful for predicting complications. Laparoscopic gastrectomy (LG) is less invasive than laparotomy and the elevation of CRP is also mild. Postoperative complications such as anastomotic leakage not only increase the severity of the condition, but also carry a poor prognosis when treatment is delayed. Early treatment is therefore necessary., Method: This retrospective study examined the relationship between occurrence of complications and the ratio of CRP levels on postoperative days 1 and 3 (CRP ratio) for 449 gastric cancer patients who underwent LG in the Department of Gastrointestinal Surgery at Osaka City University Hospital between 2006 and 2016., Results: We observed that factors associated with postoperative complications were preoperative renal failure and CRP ratio. No significant associations with surgical procedure, operation time, bleeding volume, age, obesity, measured CRP concentration, or white blood cell count were evident. The optimal cut-off for CRP ratio to predict postoperative complications from the receiver operating characteristic curve was 2.13., Conclusion: Our results suggested that the risk of severe postoperative complications after LG could be predicted using the CRP ratio.

Background: Our aim was to determine factors predictive of long-term post-gastrectomy outcomes in older adults with pathological stage I gastric cancer (GC)., Methods: A total of 175 patients with resected pathological stage I GC at two institutions were reviewed, each ≥75 years old at the time of gastrectomy and full participants in a 5-year follow-up program. The procedures were undertaken between January 2006 and December 2011. Patients were divided into two groups: survivors and non-survivors at postoperative Year 5. Univariate and multivariate analyses were applied to identify independent predictors of 5-years survival, including preoperative, surgical, and histopathologic variables., Results: Multivariate analysis of overall survival (OS) at 5 years indicated that prognostic nutritional index (PNI) <45 and the American Society of Anesthesiologists physical status (ASA-PS) 3 were independently associated with unfavorable outcomes. A clinical score consisting of 1-point each for these two variables proved useful in predicting survival after gastrectomy (5-year OS: 0 point, 86.6%; 1-point, 51.6%; 2-point, 33.3%; p < .001, area under the curve [AUC] = 0.757)., Conclusions: Long-term survival of older adults with pathological stage I GC is unfavorable in patients displaying both ASA-PS 3 and PNI < 45. A simple scoring method, based on combined ASA-PS/PNI determinations, provides an accurate prognostic prediction for these patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The RAINBOW trial showed that paclitaxel(PTX)plus ramucirumab(RAM)therapy improved the survival of patients with advanced gastric cancer, previously treated with chemotherapy. We retrospectively investigated 33 patients with unresectable or recurrent gastric cancer who underwent PTX plus RAM treatment as second- or third-line chemotherapy between September 2015 and December 2017. The median age was 68(45-84)years with 22 patients(67%)aged 65 years or older. Seventeen patients had unresectable and 16 patients had recurrent gastric cancer. ECOG PS was 2 in 5 patients(16%). PTX plus RAM was administered as second-line therapy for 24 patients, and as third-line therapy for 9 patients. Best overall response was partial response(PR)in 4 patients, stable disease(SD)in 14 patients, and progressive disease(PD)in 9 patients. Response rate(RR)and disease control rate(DCR)were 14.8% and 66.7%, respectively. Grade 3/4 adverse events were observed in 28(85%)of(leucopenia·neutropenia[64%], neuropathy[9%], etc). Median follow-up period was 7.3(0.4- 22.4)months. Median OS and PFS were 9.3(0.4-22.4)months and 4.7(0.4-22.4)months, respectively. We conclude that PTX plus RAM therapy is useful for treating unresectable or recurrent gastric cancer. In clinical practice, we have many opportunities to provide PTX plus RAM therapy for patients of older age and poorer PS; careful attention to adverse events is essential in such cases.

Background: Sarcopenia is known to have an important influence on postoperative complications in several diseases, and on the prognosis of patients with cancer. However, whether sarcopenia is associated with complications and prognosis after gastrectomy in patients with gastric cancer remains controversial. This study evaluated the impact of the preoperative muscle mass on postoperative complications of gastric cancer surgery., Materials and Methods: The muscle mass of 153 patients who underwent gastrectomy for gastric cancer from January 2014 to August 2016 was assessed before surgery by a multifrequency bioelectrical impedance analysis (In Body 3.0; Biospace, Tokyo, Japan) and was expressed as the muscle mass index (MMI). Sarcopenia was defined as an MMI value of one standard deviation or more below the gender-specific mean MMI. Complications of Clavien-Dindo grade 2 or more were defined as significant postoperative complications. The impact of preoperative sarcopenia on postoperative infectious complications was analyzed by univariate and multivariate analyses., Results: A total of 153 patients were analyzed, sarcopenia was present in 24 out of 153 patients (15.7%). Thirty (19.6%) patients developed postoperative complications, 20 (13.1%) of which were infectious complications. Sarcopenia was significantly associated with age, body mass index, serum albumin, pulmonary disease in comorbidities, operative time, surgical approach, and postoperative complications. The univariate analyses revealed that male sex, sarcopenia, total gastrectomy, laparotomy, and intraoperative blood loss were associated with postoperative infectious complications. In the multivariate analyses, sarcopenia and intraoperative blood loss ≥400 ml were independently associated with postoperative infectious complications., Conclusion: Preoperative sarcopenia was found to be an independent risk factor for postoperative infectious complications in gastric cancer patients., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Endoscopic submucosal dissection (ESD) of lesions using expanded indications for early gastric cancer (EGC) has been accepted as an alternative treatment for cases without lymph node metastasis. We herein report a rare case of metastatic lymph node tissue in mixed adenoneuroendocrine carcinoma (MANEC) after curative ESD using the expanded pathological criteria. A 70-year-old man underwent ESD for two EGC lesions. A pathological examination revealed lesions that required curative resection based on the expanded pathological criteria of the Japanese classification of gastric carcinoma. However, lymph node metastasis was detected at 26 months after ESD. Additional surgical resection was performed and MANEC was pathologically diagnosed in the metastatic lymph node. The patient subsequently underwent additional chemotherapy and remains alive at 2 years after surgery. Even though MANEC is a rare tumor, this case suggests that periodic follow-up is important when patients undergo curative resection by ESD based on the expanded indications because of the high malignant potential and the poor prognosis.

Background/aim: The clinical significance of postoperative neutrophil lymphocyte ratio (NLR) remains unclear. The aim of this study was to examine the impact of postoperative NLR on prediction for postoperative recurrence of gastric cancer., Patients and Methods: A retrospective analysis was performed on data from 170 patients with Stage II/III gastric cancer who underwent surgery followed by adjuvant chemotherapy using S-1 between 2006 and 2015. Postoperative NLR was calculated every 6 months and the data at the time of recurrence or last survival were used for analysis., Results: Postoperative NLR was associated with Prognostic nutritional index (PNI) and modified Glasgow Prognostic Score (mGPS). In multivariate analysis, we found that elevated CA19-9, CEA and NLR were independent predictive markers. The patients with low values of both NLR and CEA after surgery had the most favorable prognosis., Conclusion: The postoperative NLR might be one of the surrogate markers for recurrence after curative surgery for patients with Stage II/III gastric cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Tumor-Associated Neutrophils (TANs) may be able to induce lymphangiogenesis and angiogenesis, although the detailed roles of TANs remain unclear. The Neutrophil-Lymphocyte Ratio (NLR) is an inflammation-based prognostic factor for gastric cancer. This study aimed to investigate the distribution of CD15 + neutrophils in the primary tumor and Tumor-Draining Lymph Nodes (TDLNs), and to examine the association of TANs with the clinicopathological features (including NLR) of patients with gastric cancer., Results: Immunohistochemical staining showed that the median number of CD15 + TANs was 18 and 24 per high-power field (HPF) in primary tumors and TDLNs, respectively. Patients were divided into high and low infiltration groups based on the median number. A high number of infiltrating CD15 + TANs in the primary tumors and in the TDLNs were associated with depth of invasion and lymph node metastasis. Kaplan-Meier analysis revealed that a poor overall survival was associated with high numbers of CD15 + TANs, and the multivariate analyses revealed that a high number of CD15 + TANs in the TDLNs was an independent prognostic factor. The numbers of CD15 + TANs in the primary tumors and TDLNs showed weak positive correlation. The number of CD15 + TANs in the primary tumors was positively correlated with the preoperative NLR, (P = 0.001, R = 0.327) and immunohistochemical staining revealed that C-X-C motif chemokine receptor 2 (CXCR2) + neutrophils might be the origin of the CD15 + TANs. Flow cytometry analysis indicated that infiltrating neutrophils increased in the tumor and TDLN compared to non-cancerous tissue. Neutrophils treated with cancer supernatant upregulated TWIST and IL-6 genes in vitro., Conclusion: Our findings suggested that local infiltration of CD15 + TANs may be correlated with inflammation in TDLNs and systemic response to cause metastasis in gastric carcinoma.

Background/aims: Lysyl oxidase (LOX) family members play a key role in modifying the primary tumor microenvironment by crosslinking collagens and elastin in the extracellular matrix. The aim of this study was to analyze the LOX-like (LOXL)1, LOXL3, and LOXL4 expressions in gastric cancer tissue by immunohistochemical staining., Methods: The correlations between the clinicopathological features of 597 primary gastric carcinomas and LOX family members - LOXL1, LOXL3, and LOXL4 - were investigated by immunohistochemical studies. The effect of the transforming growth -factor β1 (TGFβ1) on the expressions of LOXL1, LOXL3, and LOXL4 in gastric cancer was examined using diffuse-type gastric cancer cell lines in vitro., Results: The expressions of LOXL1, LOXL3, and LOXL4 were correlated with T invasion, lymph node metastasis, and lymphatic and venous invasion. LOXL1 expression was associated with histological intestinal-type and expanding growth patterns. The overall survival of patients with LOXL1-, LOXL3-, or LOXL4-positive cancer was poorer than those with negative cancer. LOXL3 and LOXL4 mRNA expressions were significantly high in diffuse-type gastric cancer cells with high invasion ability. TGFβ decreased the LOXL1 expression and increased LOXL3 and LOXL4 expression., Conclusion: LOXL1, LOXL3, and LOXL4 expressions are associated with distant metastasis of gastric cancer., (© 2018 S. Karger AG, Basel.)

Background: We sought to clarify the clinical value of the examination of cancer cells exposed to gastric serosa by our novel method of serosal stamp cytology and a real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis., Method: A total of 70 patients who underwent gastrectomy were enrolled. Stamp cytology specimens were obtained by stamping the gastric serosa at the primary gastric tumor lesion, followed by Papanicolaou's staining. Samples obtained by brushing the serosa at the primary gastric tumor were analyzed by our RT-PCR of carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20)., Results: Among the 70 patients, 11 patients were diagnosed as stamp cytology-positive. Eight and five patients were found to be CEA-positive and CK20-positive, respectively. Since 21 of the 70 patients were either stamp cytology-positive or RT-PCR analysis-positive, these 21 patients were considered to be positive for cancer cells exposed to serosa of primary gastric tumor. The 3-year recurrence-free survival rate of the patients with a single positive result by our method (41.7%) was significantly (log rank p = 0.0002) worse than that of the patients with both negative results (81.0%). Our method showed 58.8% sensitivity and 79.2% specificity. A multivariate analysis revealed that a stamp cytology and/or RT-PCR result was an independent prognostic factor for recurrence., Conclusion: The examination of cancer cells exposed to gastric serosa by our serosal stamp cytology and RT-PCR system will be useful for the identification of patients at high risk for peritoneal recurrence after curative surgery for gastric cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to determine the impact of preoperative skeletal muscle mass on short- and long-term outcomes of patients with gastric cancer (GC) who undergo gastrectomy., Methods: A total of 569 patients subjected to gastrectomy for GC at our institution between January 2007 and December 2013 were reviewed and skeletal muscle index (SMI) was measured via cross-sectional, image-based muscle assessment. Computed tomography (CT) and the volume analyzer SYNAPSE VINCENT were required. Patients were divided into two groups, with the first quartile serving as the cut-point for both men and women. Clinicopathologic features and short- and long-term outcomes were compared., Results: In multivariate analysis, SMI emerged as an independent predictor of 5 year overall survival (OS) and cancer-specific survival (CSS) in patients with GC. In subgroup analysis, by stage, patients with stage I disease and low (vs. high) SMI demonstrated significantly worse 5 year OS. The incidence of postoperative complications did not differ significantly by group., Conclusions: Preoperative SMI, measured in cross-section using CT, is a useful nutritional determinant that may predict OS and CSS in patients with GC who undergo gastrectomy. In our view, nutritional support for sarcopenic patients with stage I GC, aimed at retaining or adding skeletal muscle mass, may improve survival. Our analysis showed no relationship between preoperative SMI and postoperative complications.

Background/aim: Lymph node metastasis is the most important prognostic factor for patients with gastric cancer. Increasing evidence suggests that lymphatic endothelial cells (LECs) regulate immune responses. The aim of this study was to examine the effect of LECs on the activation of CD4 + T cells., Materials and Methods: We examined the impact of cancer cells on the phenotype and production of cytokines of LECs derived from tumor-draining lymph nodes., Results: We showed that LECs inhibited CD4 + T cell production of cytokines, such as IL-2, IL-10, and INF-γ. The mRNA expression of programmed death-ligand 1 (PD-L1) and indoleamine 2, 3-dioxygenase (IDO) by LECs were significantly up-regulated when the LECs and CD4 + T cells were co-cultured with cells of the gastric cancer cell line, OCUM12., Conclusion: Intranodal LECs may be a key player in the induction of immune tolerance against cancer and in facilitating metastasis through lymphatic vessels in gastric cancer., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We retrospectively investigated the efficacy and safety of S-1 and oxaliplatin(SOX)as the first-line chemotherapy in patients with metastatic/recurrent gastric cancer. A total of 27 patients who received SOX as the first-line chemotherapy in our hospital were considered for the study. The SOX chemotherapy schedule consisted of 1 course every 3 weeks. S-1 was administered orally, at 80-120mg-body, every day for 14 days. Oxaliplatin was infused at 100mg/m2 on day 1 of each course. The median number of treatment courses was 7. The response rate and disease control rate were 47.6% and 76.2%, respectively. The observed adverse events of Grade 3 or more included neutropenia(33.3%); peripheral neuropathy and anorexia(11.1%); thrombocytopenia(7.4%); and anemia, diarrhea, fatigue, and hypercalcemia(3.7%). The median overall survival was not achieved, and the 1-year survival rate was 63.2%. Therefore, SOX is an effective and feasible first-line chemotherapy that is easily available for ambulatory treatment of patients with metastatic/recurrent gastric cancer.

Background: Preoperative nutritional status may predict short- and long-term outcomes of patients with cancer., Objective: The aim of this study was to clarify the impact of preoperative nutritional status on outcomes of elderly patients who have undergone gastrectomy for gastric cancer (GC)., Methods: A review examining 147 patients treated for GC by gastrectomy at our institution between January 2004 and December 2011 was conducted. Onodera's prognostic nutritional index (PNI) was invoked, using an optimal cutpoint to stratify patients by high (PNI > 43.8; n = 84) or low (PNI ≤ 43.8; n = 63) nutritional status. Clinicopathologic features and short- and long-term outcomes, including the cause of death, were compared., Results: In multivariate analysis, low PNI was identified as an independent correlate of poor 5-year overall survival (OS). In subgroup analysis, 5-year OS rates for patients with stage 1 GC were significantly worse in the low PNI (vs. high PNI) patient subset, which also posed a significantly higher risk of death from other disease; however, 5-year cancer-specific survival and PNI were unrelated. Deaths from recurrence in both groups were statistically similar, and morbidity rates did not differ significantly by group., Conclusions: PNI is useful in predicting long-term outcomes of elderly patients surgically treated for GC, helping to identify those at high risk of death from other disease. In an effort to improve patient outcomes, nutritional status and oncologic staging merit attention.

Tumor lymphangiogenesis is a major prognostic indicator of gastric cancer. Tumor-induced inflammation has been shown to attract tumor-associated macrophages that affect lymphangiogenesis. However, detailed mechanisms of macrophage-induced lymphangiogenesis have not been elucidated. Here, we evaluated the interaction between tumor-associated macrophages and lymphatic endothelial cells (LECs) derived from lymph nodes (LNs) of human gastric cancer. Lymphatic endothelial cells were directly or indirectly cocultured with macrophages from healthy human blood, with or without the supernatant of the gastric cancer cell line, OCUM-12. We analyzed the effect of cancer pretreated macrophages and of macrophages from metastatic LNs of gastric cancer on LECs. We observed morphological changes of LECs in coculture and assessed the gene expression of possible lymphangiogenic molecules of macrophages and LECs after contact coculture, and of cancer pretreated macrophages, by quantitative RT-PCR. Specimens of metastatic LN of gastric cancer were immunofluorescently stained. We found that tubulogenesis of LECs was observed only in the contact coculture model. OCUM-12 cells promoted macrophage-induced tubulogenesis of LECs. Relative gene expression of MMP and adhesion molecules was significantly upregulated in both capillary-forming LECs and cocultured macrophages. Cancer pretreated macrophages upregulated lymphangiogenic factors including inflammatory cytokines, MMPs, adhesion molecules, and vascular endothelial growth factor-C. Blocking of intercellular adhesion molecule-1 and macrophage activation suppressed tubulogenesis of LECs. Immunohistochemistry showed macrophages localized around lymphatic vessels. Our results suggested that interaction between LECs and macrophages may be an important initial step of tumor lymphangiogenesis developing LN metastasis. Understanding of its mechanisms could be useful for future therapeutics of gastric cancer., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The necessity of additional gastrectomy for patients not meeting the inclusion criteria after endoscopic submu cosal dissection (ESD) is controversial. The aim of this study was to elucidate the risk factors for lymph node metastasis (LNM) and residual cancer (RC) in patients not meeting the inclusion criteria after ESD and to determine additional treatment strategies., Methods: Of 1443 gastric cancer patients who underwent ESD between 2004 and 2013, 167 patients diagnosed as having a lesion not meeting the inclusion criteria after ESD were retrospectively analyzed. Of the 167 cases, 100 cases underwent additional gastrectomy, and 67 cases were observed without surgery., Results: Overall, 9.0 % (9/100) and 9.0 % (9/100) of patients not meeting the inclusion criteria after ESD presented with LNM and RC, respectively, but neither was observed in 83 patients (83.0 %). Multivariate analysis revealed that lymphovascular involvement (LVI) (OR 38.38; 95 % CI 1.94-761.43, p = 0.017) and undifferentiated type (OR 45.58; 95 % CI 2.88-720.94, p = 0.007) were independent risk factors for LNM, and positive horizontal margin was an independent risk factor for RC (OR 9.48; 95 % CI 1.72-52.13, p = 0.010). In differentiated types without LVI, no cases had LNM (0/38) in the additional gastrectomy group, and there was no lymph node or distant recurrence (0/39) in the observation group., Conclusions: Additional treatment is necessary for patients with LVI, undifferentiated type, and positive horizontal margin. Careful follow-up may be acceptable for patients with the differentiated type without LVI, especially for the elderly or patients with severe comorbidities.

Remnant gastric cancer (RGC) and gastric stump cancer after distal gastrectomy (DG) are recognized as the same clinical entity. In this review, the current knowledges as well as the non-settled issues of RGC are presented. Duodenogastric reflux and denervation of the gastric mucosa are considered as the two main factors responsible for the development of RGC after benign disease. On the other hand, some precancerous circumstances which already have existed at the time of initial surgery, such as atrophic gastritis and intestinal metaplasia, are the main factors associated with RGC after gastric cancer. Although eradication of Helicobacter pylori (H. pylori) in remnant stomach is promising, it is still uncertain whether it can reduce the risk of carcinogenesis. Periodic endoscopic surveillance after DG was reported useful in detecting RGC at an early stage, which offers a chance to undergo minimally invasive endoscopic treatment or laparoscopic surgery and leads to an improved prognosis in RGC patients. Future challenges may be expected to elucidate the benefit of eradication of H. pylori in the remnant stomach if it could reduce the risk for RGC, to build an optimal endoscopic surveillance strategy after DG by stratifying the risk for development of RGC, and to develop a specific staging system for RGC for the standardization of the treatment by prospecting the prognosis.

Background: Tumor-associated macrophages (TAMs) correlate with lymphangiogenesis in primary lesions and with lymph node (LN) metastasis of several cancers. However, the association of TAMs in regional LNs with lymphatic spread of cancer remains unclear. The purpose of this study was to evaluate the distribution of TAMs in draining LNs and the impact of TAMs on the establishment of LN metastasis of gastric cancer., Methods: The number and distribution of TAMs in regional LNs that were obtained from 49 patients who underwent radical surgery for gastric cancer at Osaka City University Hospital in 2011 were assessed. TAMs were defined as immunohistochemically CD163 positive cells. The association of the TAM density with lymph node metastasis and the lymphatic drainage route of the stomach were investigated., Results: A high density of TAMs was significantly associated with pathologically positive lymph nodes and pathological TNM stage. The density of TAMs was increased in LNs with micro metastasis compared with those without metastasis. There was a significant, positive correlation between TAM number and lymphatic vessel density in LNs. In nonmetastatic LNs, TAMs were likely to accumulate in the neighborhood of the primary lesion. In addition, the density of TAMs in distant LNs was significantly increased in patients in whom LN metastasis was observed in perigastric LNs., Conclusions: Accumulated TAMs may induce lymphangiogenesis and prepare an environment that facilitates cancer proliferation in LNs. Our findings might provide a conceptual framework for understanding the lymphatic spreading of cancer and for designing future therapeutic strategies for gastric cancer.

Background: Preoperative nutritional status not only correlates with the incidence of postoperative complications but also may be indicative of long-term outcomes for patients with cancer. The impact of preoperative nutritional status on outcomes for patients undergoing gastrectomy for gastric cancer (GC) was investigated., Methods: The study reviewed 594 patients treated for GC by gastrectomy at the authors' hospital between January, 2004 and December, 2010. Onodera's prognostic nutritional index (PNI) was invoked, using an optimal cut point to group patients as having high (PNI > 45; n = 449) or low (PNI ≤ 45; n = 145) nutritional status. Clinicopathologic features, perioperative results, and long-term outcomes, including cause of death, were compared., Results: Multivariate analysis of 5-year overall survival (OS) and disease-specific survival (DSS) indicated that low PNI was independently associated with unfavorable outcomes for patients with GC. In subgroup analysis, the 5-year OS and DSS rates for patients with GC at stages 1 and 2 were significantly worse in the low PNI group than in the high PNI group. Although wound and extrasurgical field infections also tended to be more frequent in the low PNI group, postoperative intraabdominal infections did not differ significantly by group., Conclusions: Preoperative PNI may have merit as a gauge of prognosis for patients with GC at stages 1 and 2, but PNI and postoperative morbidity showed no correlation in this setting.

Aim: This study evaluated the clinicopathological significance of autophagy, an intracellular degradation system, in gastric cancer., Materials and Methods: The expression levels of three autophagy-related proteins, namely light chain 3 (LC3), Beclin 1 and p62, were analyzed by immunohistochemistry using samples from 510 patients with primary gastric cancer., Results: LC3, Beclin 1, and p62 expression was positive in 79 (15.5%), 126 (24.7%) and 251 (49.2%) out of 510 carcinomas, respectively. Autophagy was defined when samples were positive for at least two out of the three proteins. Autophagy-positive cases were 113 (22.1%) out of the 510. Autophagy determined by LC3, Beclin 1, and p62 significantly correlated with lymph node metastasis, vessel invasion, and hepatic metastasis. A Kaplan-Meier survival curve showed that autophagy was significantly associated with poor survival of patients with gastric cancer, especially for those with disease at stage I. Multivariate analysis indicated that autophagy was an independent prognostic factor., Conclusion: Autophagy promotes the progression of gastric cancer at an early clinical stage., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: The cell surface receptor programmed death-1 (PD1) and its ligand (PDL1) have been detected in various cancer types. It has been reported that expression of PDL1 and PD1 in a tumor is associated with poor prognosis of the patient. In the present study, we retrospectively examined tumor expression of PDL1 and intratumoral PD1(+) cell infiltration, and assessed their relationship with patient prognosis according to the pathological stage of gastric cancer., Materials and Methods: PDL1 and PD1 expression in primary tumors from 431 patients was evaluated using immunohistochemistry. The association between the expression of PDL1/PD1 and clinicopathological features was assessed., Results: High expression of PDL1 was observed in 128 (29.6%) patients. PDL1 expression was correlated with tumor infiltration of PD1(+) cells. In multivariate analysis, PDL1 expression was associated with worse overall survival. In subset analysis, PDL1 expression was significantly associated with survival in patients with stage II/III gastric cancer. In conclusion, PDL1 was an independent prognostic factor for patients with stage II/III gastric cancer. Our results suggested that patients with stage II/III gastric cancer might be appropriate for PD1/PDL1-targeted therapy., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Tumour cells and stromal cells interact in the tumour microenvironment; moreover, stromal cells can acquire abnormalities that contribute to tumour progression. However, interactions between lymphatic endothelial cells (LECs) and tumour cells are largely unexamined. In this study, we aimed to determine whether tumour-specific LECs inhabit the tumour microenvironment and examine their influence on this microenvironment., Methods: We isolated normal LECs (NLECs) from a non-metastatic lymph node and tumour-associated LECs (TLECs) from cancerous lymph nodes. We examined proliferative and migratory potency, growth factor production, and gene expression of each type of LEC. Moreover, we developed a co-culture system to investigate the interactions between gastric cancer cells and LECs., Results: When compared with NLEC, TLECs had an abnormal shape, high proliferative and migratory abilities, and elevated expression of genes associated with inflammation, cell growth, and cell migration. NLECs co-cultured with gastric cancer cells from the OCUM12 cell line acquired TLEC-like phenotypes. Also, OCUM12 cells co-cultured with TLECs expressed high levels of genes responsible for metastasis., Conclusions: Our results demonstrated that LECs interacted with tumour cells and obtained abnormal phenotypes that could have important roles in tumour progression.

We report a case of long-term survival with complete remission after hepatic arterial infusion chemotherapy (HAIC) for liver metastasis from gastric cancer. A 62-year-old man underwent radical distal gastrectomy with D2 lymphadenectomy for an advanced gastric cancer. Solitary liver metastasis in the S2/3 segment was detected 26 months after initial surgery. The patient underwent HAIC with systemic chemotherapy. Serum CEA levels rapidly decreased, and CT scan showed disappearance of the tumor with complete clinical response 8 months after HAIC. HAIC was performed 83 times in total, until the hepatic artery proper was adequately obstructed. No severe adverse effects were observed during HAIC treatment. The patient is still disease-free without further chemotherapy more than 12 years after HAIC. Our experience suggests that HAIC should be considered as a treatment option in patients with resectable liver metastasis from gastric cancer. However, further studies are needed to verify the validity of HAIC for resectable liver metastasis from gastric cancer.

Studies of tumor-infiltrating immune cells have revealed that immune escape plays an important role in tumor growth. The aim of the present study was to investigate the impact of metastasis affecting CD4+ T cell subsets in human clinical samples. Single-cell suspensions derived from tumor-draining lymph node (TDLN) and primary cancer specimens were assessed by flow cytometry, qRT-PCR and immunohistochemistry. In the CD4+ T cell subsets detected in TDLN, effector T cells (TE) in metastatic TDLN (mTDLN) was significantly lower than that in metastatic-free TDLN (mfTDLN). TE in mfTDLN were increased compared with normal controls. Similarly, effector memory T cells (TEM) in mTDLN was significantly lower than in control and mfTDLN. There was a significantly positive correlation between the proportion of TEM in TDLN and number of tumor-infiltrating CD4+ and CD8+ T cells. Th1 to Th2 ratio was lower in mTDLN, and Treg in mTDLN was significantly higher than in mfTDLN. CD4+ T cell and TE subsets in TDLN were significantly affected by metastasis. Immunosuppressive cells exhibit increased migration to TDLN, in which a subset of CD4+ TE is skewed towards immune tolerance in the tumor microenvironment.

Aim: The present study aimed to examine the survival benefit of adjuvant chemotherapy for the patients with stage IB gastric cancer according to the second English edition of the Japanese Classification of Gastric Carcinoma (2nd JCGC)., Patients and Methods: In total, 201 consecutive patients who underwent curative surgery for stage IB gastric cancer according to the 2nd JCGC were retrospectively analyzed., Results: Seventy-four (36.8%) received adjuvant chemotherapy, and 72 (35.8%) had stage II diseases as defined by the 3rd JCGC. The 5-year overall survival (OS) was 86.9%. Multivariate analysis showed that adjuvant chemotherapy was an independent prognostic factor. In the sub-group analysis by stage according to the 3rd JCGC, those with stage II disease had better OS in the adjuvant-chemotherapy group than in the group treated with surgery alone (5-year OS 94.5% vs. 73.9%, p=0.002)., Conclusion: Among patients with stage IB gastric cancer by 2nd JCGC, and especially patients with stage II defined by the 3rd JCGC, should be considered for adjuvant-chemotherapy., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The aim of this study was to clarify the operative mortality and long-term survival of gastrectomy for elderly patients with gastric cancer., Methods: A total of 461 patients who underwent gastrectomy for gastric cancer in our hospital were classified as elderly group (≥80 years-old, 95 patients) and control group (60-69 years-old, 366 patients)., Results: The frequency of comorbidities was significantly (P < 0.05) higher in elderly group (74.7%) than that in the control group (49.5%). No significant difference of the postoperative complication rate was found between the elderly group (23.2%) and the control group (23.2%). Adjuvant chemotherapy was 9.5% in the elderly group, which was significantly less than 29.0% of the control group (P < 0.05). Stage II and III elderly patients had worse disease specific survival (DSS) than controls did. In the elderly, overall survival (OS) was significantly worse than DSS in stage I patients (P < 0.05)., Conclusions: The operative complication rate of elderly patients was comparable to the control group. Comorbidity and occurrence of secondary malignant disease should be followed for elderly patients at stage I. For stage II and III disease patients, a novel drug which is acceptable for the elderly is needed as a postoperative therapy., (© 2015 Wiley Periodicals, Inc.)

Aim: To present a series of seven cases of gastric small cell carcinoma (GSCC) treated surgically and to illustrate the clinicopathological features and clinical course., Patients and Methods: Among 1,832 patients with gastric cancer who underwent gastric resection between 1997 and 2012, we reviewed the clinical records of 7 patients with histopathological diagnoses of GSCC., Results: No patients had preoperative confirmation of GSCC from endoscopic biopsy. Curative resection (R0) was achieved in 5 patients (71.4%). Two out of the 5 patients with curative resection survived more than four years. Two out of 3 patients who received weekly paclitaxel had progression-free survival of more than 10 months. The median survival time for the whole patient group was 14 months and the 3-year survival rate was 25.0%., Conclusion: Curative surgery with adjuvant chemotherapy may be essential to improve the prognosis of GSCC, and weekly paclitaxel chemotherapy may represent a promising chemotherapy for GSCC., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Unlabelled: BACKGROND/AIM: Recent evidence indicates that inflammation is a hallmark of cancer. Tumor-associated neutrophils (TANs) contribute to tumor invasion. However, whether TANs and lymph node metastasis are related is unknown. Intranodal lymphatic vessel density (LVD) is significantly correlated with tumor progression, lymph node metastasis in gastric cancer. Herein, we investigated the effects of TANs in regional lymph nodes., Materials and Methods: We investigated the association of the density of TANs in regional lymph nodes with clinicopathological features by immunohistochemistry. Furthermore, we examined the prognostic value of TANs in lymph nodes., Results: The number of TANs in regional lymph nodes was positively correlated with intranodal LVD and micrometastases. Patients with higher cluster of differentiation 15(+) TAN counts had significantly poorer prognosis than those with lower counts., Conclusion: Our results suggest that TANs in regional lymph nodes promote the invasion of lymph nodes by cancer cells via augmentation of lymphangiogenesis and thereby contribute to tumor progression., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Brain metastasis from gastric cancer is fairly uncommon and prognosis is dismal. We report a case of early gastric cancer with brain metastasis arising 8 years after gastrectomy., Case Presentation: A 78-year-old Japanese female presented to our hospital complaining of dizziness, 8 years after undergoing gastrectomy for gastric cancer. Histopathological type of the tumor was well-differentiated adenocarcinoma. Final TNM classification was T1b(sm1)N0M0, and pathological stage was IA. Further examination revealed a metastatic tumor in the cerebellum and multiple liver metastases. The brain metastasis was treated using radiotherapy and steroid. Systemic treatment for liver metastases was performed using the oral fluoropyrimidine drug S-1. Neurological symptoms decreased, enabling the patient to be discharged from hospital. However, chemotherapy was discontinued due to loss of appetite and general fatigue. She died 5 months after the diagnosis of brain metastasis due to progressive disease., Conclusions: Cases of brain metastasis arising 8 years after gastrectomy for early gastric cancer have rarely reported. Aggressive treatment for brain metastases may be effective for improvement of the damage to neurological function and quality of life.

Prostaglandin D2 (PGD2) has been demonstrated to have antitumor effects on cancer cells. PGD2 acts through two major receptors of DP1 and DP2, as well as through the peroxisome proliferator-activated receptor γ (PPARγ) via the PGD2 metabolite, 15-deoxy-Δ12-14-PGJ2. The expression levels of DP1, DP2, and PPARγ were analyzed by immunohistochemistry on 277 primary gastric carcinomas. Either DP1- or DP2-positive cases were regarded as DP-positive. DP-Positive tumour was significantly associated with lymph mode metastasis, lymphatic invasion, and venous invasion. PPARγ positivity was not associated with any clinicopathological factors of gastric cancer. DP-Negative and PPARγ-positive cases were significantly associated with T category, lymph metastasis, and lymphatic invasion. The prognosis of DP-negative and PPARγ-positive cases was better than that of the other cases. These findings suggest that DP and PPARγ signaling influence the invasiveness of cancer cells. DP and PPARγ can be used as a potential marker for gastric cancer progression., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Introduction: Peritumoral lymphangiogenesis is significantly correlated with lymph node metastasis and poor prognosis in various cancers. However, there are few reports concerning the role of intranodal lymphangiogenesis in lymphatic metastasis. The aim of this study was to examine the association of lymphangiogenesis in regional lymph nodes with the progression of gastric cancer., Materials and Methods: Lymphatic vessel density (LVD) was immunohistochemically estimated in 1,596 lymph nodes from 52 patients who underwent gastrectomy., Results: Intranodal LVD was significantly correlated with the size of metastasis and the progression of cancer. Patients in the high LVD group had significantly poorer prognosis relative to patients in the low LVD group. Furthermore, expression of VEGF-C mRNA was significantly up-regulated in lymph nodes of pathological node positive patients compared to node negative patients., Discussion: Thus, intranodal lymphangiogenesis was correlated with nodal metastasis and poor prognosis of patients with gastric cancer. Lymphangiogenesis in regional lymph nodes plays an early role in spreading of tumor cells through the lymphatic system to distant organs in gastric cancer.