Usefulness of intraoperative ultrasound examination for laparoscopic right-side colon cancer surgery: a propensity score-matched study.

Complete mesocolic excision (CME) with central vascular ligation (CVL) in laparoscopic surgery for right-sided colon cancer (RSCC) requires a precise understanding of the vascular anatomy. The efficacy of intraoperative ultrasound (IUS) in the identification of blood vessels for RSCC surgery was not evaluated. The aim of this study was to compare the intraoperative and short-term outcomes of CME with CVL with or without IUS by laparoscopic surgery for RSCC. We performed IUS on 26 patients of RSCC and compared with a total of 124 patients who underwent the surgery for RSCC at our institution. Propensity score matching (PSM) was performed to reduce the confounding effects to imbalances in the use of IUS. The IUS identified the main feeding artery and the accompanying vein in all 26 cases. After PSM, the amount of intraoperative blood loss in the IUS group was significantly lower than that in the conventional group (5 ml vs. 30 ml, p = 0.035) and no significant difference of the postoperative complications was observed. The IUS reduced the risk of bleeding in the surgery for RSCC. The IUS is a safe and feasible technique that help the surgeons for anatomical understandings under real-time condition in the laparoscopic surgery of RSCC.

Identification of novel lactic acid bacteria with enhanced protective effects against influenza virus.

Lactic acid bacteria (LAB) exert health-beneficial effects by regulating innate immunity in the intestinal tract. Due to growing health awareness, the demand for LAB and studies have focused on identifying beneficial LAB strains is increasing, especially those that stimulate innate immunity. In this study, the LAB strain D279 (NITE_BP-03645, Latilactobacillus sakei) was isolated from among 741 LAB strains that were analyzed for their ability to induce interleukin 12 (IL-12) production and was subsequently characterized. D279 induced the highest expression of IL-12 among the screened LABs. Furthermore, D279 significantly activated antiviral genes and preferentially induced interferon (IFN)λ expression in vitro, which plays a critical role in the epithelial tissue, thereby conferring strong anti-influenza potency without inflammation. However, it decreased the IFNα levels. The administration of pasteurized D279 to mice resulted in strong anti-influenza potency, with higher natural killer (NK) cell activity and a lower viral load in the lung than in the control. Importantly, none of the D279-administered mice were sacrificed during the viral infection tests. These results suggest that D279 administration confers beneficial effects by regulating innate immunity and that it may be relevant for commercial use in the future.

Predictive value of the Naples prognostic score on postoperative outcomes in patients with rectal cancer.

PURPOSE: The Naples prognostic score (NPS) is a prognostic index based on the nutritional and inflammatory status. However, its utility in predicting postoperative complications (POCs) has not been examined in rectal cancer (RC). We evaluated the predictive value of the preoperative NPS for POCs in RC. METHODS: We retrospectively analyzed 235 patients who underwent surgery for RC. The NPS was calculated based on serum albumin, serum total cholesterol, the neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR). Severe POCs were defined as Clavien-Dindo classification grade ≥ III. The optimal cut-off value of the NPS was determined by a receiver operator characteristic (ROC) curve analysis. The NPS, NLR, LMR, platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP)-to-albumin ratio (CAR), Glasgow prognostic score (GPS), Onodera prognostic nutritional index (PNI) and controlling nutritional status score (CONUT) were investigated as inflammation-based and/or nutritional markers. Predictors of severe POCs were analyzed by logistic regression modeling. RESULTS: Severe POCs were observed in 64 patients (27.2%). Male sex, operation time (> 257 min), blood loss (≥ 30 mL), albumin (< 4.0 g/dL), CRP (≥ 1.0 mg/dL), total cholesterol (≤ 180 mg/dL), NPS (≥ 2), LMR (≥ 3.48), PLR (≥ 103.6), CAR (> 0.025), GPS (≥ 1), PNI (< 48.1) and CONUT (≥ 2) were significantly associated with severe POCs. The multivariate analysis revealed that male sex, operation time (> 257 min), and a high NPS (≥ 2) were independent predictors of severe POCs. The ROC curve analysis revealed that the NPS had the greatest predictive value among the inflammation-based and/or nutritional markers. CONCLUSION: The NPS is a valuable predictor of severe POCs in RC.

Prognostic significance of the Naples prognostic score in colorectal cancer patients undergoing curative resection: a propensity score matching analysis.

BACKGROUND: Systemic inflammation is recognized as a hallmark of cancer that contributes to tumor development and progression in various malignancies. The Naples prognostic score (NPS) was established as a prognostic indicator for colorectal cancer (CRC). This study aims to examine the predictive value of the NPS for survival in CRC patients undergoing curative resection by a propensity score matching (PSM) analysis. METHODS: A total of 533 CRC patients were enrolled in this study. Overall survival (OS) and disease-free survival (DFS) were compared between high-NPS and low-NPS groups. A time-dependent receiver operator characteristic (ROC) curve analysis was conducted to calculate the area under curve (AUC) of the NPS for OS. A multivariable Cox-proportional hazards regression analysis and PSM analysis were used to identify independent prognostic factors for OS and DFS. We compared the predictive value of the NPS to that of the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), Onodera prognostic nutritional index (PNI), and controlling nutritional status score (CONUT) for OS. RESULTS: High-NPS was significantly associated with worse OS and DFS. After PSM, 123 patients were included in each group. A multivariate analysis revealed that Age ≥ 68, ASA-PS ≥ 3, high NPS and undifferentiated tumor type were independently associated with OS, while high NPS, advanced T and N stage were independently associated with DFS after PSM. The NPS had the greatest AUC for OS in comparison to the NLR, LMR, PNI and CONUT. CONCLUSIONS: We successfully validated the prognostic utility of the NPS for CRC patients after curative resection.

Establishment of a gastric cancer cell line with high microsatellite instability, OCUM-13, derived from Borrmann type-2 primary tumor.

Gastric cancer (GC) with microsatellite instability (MSI) has been reported to be sensitive to immunotherapy, however some of GC cases with MSI remain resistant to immunotherapy. Cancer cell lines showing MSI might be useful for the analysis of mechanisms of immunotherapy, while only a few GC cell lines with MSI are available so far. In this study, we established a unique GC cell line with MSI, OCUM-13, from a primary GC with abundant tumor-infiltrating lymphocytes. MSI assay indicated that OCUM-13 cells as well as the primary tumor showed a band shift in more than 3 of 5 microsatellite loci, suggesting that OCUM-13 did have high MSI. The subcutaneous inoculation of OCUM-13 cells into mice performed tumor formation. Insulin-like growth factor 1 receptor inhibitor decreased the growth of OCUM-13 cells. The newly established cell line with MSI, OCUM-13, might be useful for the analysis of cancer therapy for GC with MSI.

The Surgical Apgar Score Predicts Postoperative Complications in Elderly Patients After Surgery for Colorectal Cancer.

OBJECTIVE: The surgical Apgar score (SAS) has been validated as a risk assessment tool for postoperative complications. However, the utility of the SAS in elderly patients with colorectal cancer remains unclear. In this study, we evaluated the utility of the SAS for predicting the severe complications in elderly patients with colorectal cancer. METHODS: We retrospectively analyzed 295 patients underwent radical surgery for colorectal cancer in elderly patients ≥75 years old. The SAS was calculated based on 3 intraoperative parameters: estimated blood loss (EBL), lowest mean arterial pressure, and lowest heart rate. Severe complications were defined as Clavien-Dindo classification grade ≥ IIIa. We divided all patients into 2 groups according to with or without severe complications. The optimal cut-off value of SAS for severe complications has been determined by receiver operator characteristic curve. Predictors for severe complications were analyzed by logistic regression modeling. RESULTS: Severe complications were observed in 57 patients (19.3%). Male, rectal cancer, operation time (>240 minutes), EBL (≥120 mL), and a low SAS (≤6) were significantly associated with severe complications in univariate analysis. A multivariate analysis revealed that male, rectal cancer, and a low SAS (≤6) were independent predictors for severe complications. CONCLUSIONS: A low SAS (≤6) was associated with severe complications after colorectal cancer surgery in elderly patients. The SAS is a valuable predictor for severe complications in elderly patients with colorectal cancer.

Usefulness of the skeletal muscle index in postoperative ileus of colorectal cancer patients: a retrospective cohort study.

BACKGROUND: Postoperative complications of colorectal cancer mainly include infections (surgical site infection, remote infection, etc.), post-operative ileus (POI), and anastomosis leakage. POI reportedly prolongs the hospital stay and increases medical costs. Therefore, predicting POI is very important. There have been some reports on the relationships between sarcopenia and postoperative complications in colorectal cancer patients, but none have been limited to POI. We therefore conducted a retrospective clinical study with a logistic regression analysis to confirm the risk factors for ileus after colorectal cancer surgery. METHODS: We retrospectively analyzed 213 patients who underwent elective oncological colorectal surgery for colorectal cancer from November 2017 to July 2021. The skeletal muscle mass (SMM, kg) was estimated using a whole-body bioelectrical impedance analysis (BIA), and the skeletal muscle index (SMI) was calculated as the SMM/height2. We divided all patients into 2 groups based on a low SMI (male < 8.958 kg/m2, female < 8.443 kg/m2) or normal SMI. Preoperative and intraoperative factors as well as, postoperative outcomes were then compared between the two groups. RESULTS: The median (range) age of the 213 included patients was 72.0 (33-91) years old. Complications were noted in 96 patients (45.1%), including 21 (9.9%) with POI. There were 68 (31.9%) low SMI patients. POI occurred significantly more frequently in low SMI patients (19.1%) than in normal SMI patients (5.5%) (p = 0.005). In the multivariate analysis, bleeding (p = 0.039) and a low SMI (p = 0.031) were significantly associated with POI. In addition, a propensity score matching analysis was performed to further reduce the selection bias. As a result, a low SMI was the only independent POI predictor among the 78 matched cases. CONCLUSION: A preoperative low SMI in colorectal cancer patients was considered a risk factor for POI.

Candidate Oncogenes, ARHGAP4, NOS3, and OR51B5, for the Development of Scirrhous-type Gastric Cancer.

BACKGROUND/AIM: Scirrhous-type gastric cancer (SGC), one of the most intractable cancer subtypes, is characterized by rapid cancer cell proliferation and infiltration accompanied by extensive stromal fibrosis. One of the reasons for its poor prognosis may be the lack of molecular target drugs for SGC, because of the unknown driver genes. Exploration of somatic mutations in the human samples of SGC using next-generation sequencing (NGS) has been hampered by abundant fibrous tissues in these samples. Therefore, this study aimed to determine a novel oncogene by RNA-sequencing using SGC cell lines, avoiding contamination with fibrosis. MATERIALS AND METHODS: In silico analysis of RNA-sequencing public data of the gastric cancer cell line, and RNA- sequencing using five of our unique SGC cell lines, OCUM1, OCUM2MLN, OCUM8, OCUM12, and OCUM14 were performed. RESULTS: We found three differentially expressed genes, ARHGAP4, NOS3, and OR51B5 that are significantly over-expressed in SGC cells. Immunohistochemical analysis indicated that the protein expression levels of these three genes were significantly higher in SGC than in other types of gastric cancer. The prognosis of patients with positive expression of these three genes was significantly poorer than those with negative expression. In particular, ARHGAP4 expression was an independent predictor of poor prognosis and recurrence. CONCLUSION: ARHGAP4, NOS3, and OR51B5 may be candidate driver genes for SGC. ARHGAP4 may be a promising molecular target for SGC.

Significance of tumor heterogeneity of p-Smad2 and c-Met in HER2-positive gastric carcinoma with lymph node metastasis.

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.

Lipocalin-2 negatively regulates epithelial-mesenchymal transition through matrix metalloprotease-2 downregulation in gastric cancer.

BACKGROUND: Although the role of Lipocalin-2 (LCN2) in cancer development has been focused on recent studies, the molecular mechanisms and clinical relevance of LCN2 in gastric cancer (GC) still remain unclear. METHODS: Transcriptome analysis of GC samples from public human data was performed according to Lauren's classification and molecular classification. In vitro, Western blotting, RT-PCR, wound healing assay and invasion assay were performed to reveal the function and mechanisms of LCN2 in cell proliferation, migration and invasion using LCN2 knockdown cells. Gene set enrichment analysis (GSEA) of GC samples from public human data was analyzed according to LCN2 expression. The clinical significance of LCN2 expression was investigated in GC patients from public data and our hospital. RESULTS: LCN2 was downregulated in diffuse-type GC, as well as in Epithelial-Mesenchymal Transition (EMT) type GC. LCN2 downregulation significantly promoted proliferation, invasion and migration of GC cells. The molecular mechanisms of LCN2 downregulation contribute to Matrix Metalloproteinases-2 (MMP2) stimulation which enhances EMT signaling in GC cells. GSEA revealed that LCN2 downregulation in human samples was involved in EMT signaling. Low LCN2 protein and mRNA levels were significantly associated with poor prognosis in patients with GC. LCN2 mRNA level was an independent prognostic factor for overall survival in GC patients. CONCLUSIONS: LCN2 has a critical role in EMT signaling via MMP2 activity during GC progression. Thus, LCN2 might be a promising therapeutic target to revert EMT signaling in GC patients with poor outcomes.

CXCR2 signaling might have a tumor-suppressive role in patients with cholangiocarcinoma.

BACKGROUND: We reported that chemokine C-X-C motif receptor 2 (CXCR2) signaling appears to play an important role in the pathogenic signaling of gastric cancer (GC), and although CXCR2 may have a role in other solid cancers, the significance of CXCR2 in cholangiocarcinoma (CCA) has not been evaluated. Herein, we determined the clinicopathologic significance of CXCL1-CXCR2 signaling in CCA. MATERIALS AND METHODS: Two human CCA cell lines, OCUG-1 and HuCCT1, were used. CXCR2 expression was examined by western blotting. We investigated the effects of CXCL1 on the proliferation (by MTT assay) and migration activity (by a wound-healing assay) of each cell line. Our immunohistochemical study of the cases of 178 CCA patients examined the expression levels of CXCR2 and CXCL1, and we analyzed the relationship between these expression levels and the patients' clinicopathologic features. RESULTS: CXCR2 was expressed on both CCA cell lines. CXCL1 significantly inhibited both the proliferative activity and migratory activity of both cell lines. CXCL1 and CXCR2 were immunohistochemically expressed in 73% and 18% of the CCA cases, respectively. The CXCL1-positive group was significantly associated with negative lymph node metastasis (p = 0.043). The CXCR2-positive group showed significantly better survival (p = 0.042, Kaplan-Meier). A multivariate logistic regression analysis revealed that CXCR2 expression (p = 0.031) and lymph node metastasis (p = 0.004) were significantly correlated with the CCA patients' overall survival. CONCLUSION: CXCR2 signaling might exert a tumor-suppressive effect on CCA cells. CXCR2 might be a useful independent prognostic marker for CCA patients after surgical resection.

Hard Palate Metastasis from Rectal Adenocarcinoma.

The most common sites of metastasis from colorectal cancer are liver, lungs, and peritoneum. Oral cavity metastasis is extremely rare, accounting for only 1-2% of all oral cancers. We report the case of a 71-year-old male who presented with hard palate metastasis 20 months after his initial diagnosis for T4N1M1 rectal adenocarcinoma according to the UICC TNM classification. To the best of our knowledge, hard palate metastasis from colorectal cancer has never been previously reported in the literature. The hard palate metastasis deteriorates oral function, resulted in unfavorable prognosis. Early detection of oral cavity metastasis could lead to the opportunities for additional treatment and improve outcomes following treatment.

The impact of the surgical Apgar score on oncological outcomes in patients with colorectal cancer: a propensity score-matched study.

BACKGROUND: The surgical Apgar score (SAS) predicts postoperative complications (POCs) following gastrointestinal surgery. Recently, the SAS was reported to be a predictor of not only POCs but also prognosis. However, the impact of the SAS on oncological outcomes in patients with colorectal cancer (CRC) has not been fully examined. The present study therefore explored the oncological significance of the SAS in patients with CRC, using a propensity score matching (PSM) method. METHODS: We retrospectively analyzed 639 patients who underwent radical surgery for CRC. The SAS was calculated based on three intraoperative parameters: estimated blood loss, lowest mean arterial pressure, and lowest heart rate. All patients were classified into 2 groups based on the SAS (≤6 and >6). The association of the SAS with the recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) was analyzed. RESULTS: After PSM, each group included 156 patients. Univariate analyses revealed that a lower SAS (≤6) was significantly associated with a worse OS and CSS. A multivariate analysis revealed that the age ≥75 years old, ASA-Physical Status ≥3, SAS ≤6, histologically undifferentiated tumor type, and an advanced pStage were independent factors for the OS, and open surgery, a SAS ≤6, histologically undifferentiated tumor type and advanced pStage were independent factors for the CSS. CONCLUSIONS: A lower SAS (≤6) was an independent prognostic factor for not only the OS but also the CSS in patients with CRC, suggesting that the SAS might be a useful biomarker predicting oncological outcomes in patients with CRC.

[A Case of Rectal Cancer and Multiple Lung Metastases That Had Complete Response Treated by XELOX plus Bevacizumab after Primary Lesion Resection].

A 54-year-old woman visited our hospital complaining of abdominal distension. Endoscopic examination revealed type 3 tumor in the rectum located 15 cm from the anal edge. Enhanced computed tomography showed multiple ground glass-like shadows in both lungs that were suspected of multiple metastases. We diagnosed as having rectal cancer with multiple lung metastases. After placing the stent transanally to release the intestinal obstruction, we performed laparoscopic high anterior resection. Then, the patient received chemotherapy with 10 courses of XELOX plus bevacizumab and 9 courses of the regimen without oxaliplatin. A whole-body CT revealed complete response. And while taking capecitabine the patient remains well and without recurrence. We describe the present case with reference to the literature.

Dipeptidyl Peptidase-4 from Cancer-associated Fibroblasts Stimulates the Proliferation of Scirrhous-type Gastric Cancer Cells.

BACKGROUND/AIM: Cancer-associated fibroblasts (CAFs) may promote the malignancy of human scirrhous gastric cancer (SGC) cells. We conducted the present study to identify novel growth factors from CAFs. MATERIALS AND METHODS: OCUM-12 and 2 CAF cell lines were used. The proliferation of cancer cells was determined by the number of cancer cells or the MTT assay. The growth factor(s) were purified and characterized by the gel filtration chromatography and protein array. RESULTS: The molecular weight of the growth-stimulating factor was estimated to be approximately 66-669 kDa. Protein array of conditioned medium (CM) from CAFs indicated that dipeptidyl peptidase-4 (DPP-4) was one of the growth factors. The addition of CM increased the phosphorylation of C-X-C chemokine receptor 4 (CXCR4). The DPP-4 inhibitor significantly inhibited the growth-stimulating activity of CM. CONCLUSION: DPP-4 from CAFs might be one of the growth-stimulating factors for SGC through CXCR4.

Gastric cancer stem cells survive in stress environments via their autophagy system.

Cancer stem cells (CSCs) play an important role in the progression of carcinoma and have a high potential for survival in stress environments. However, the mechanisms of survival potential of CSCs have been unclear. The aim of this study was to clarify the significance of autophagy systems of CSCs under stress environments. Four gastric cancer cell line were used. Side population (SP) cells were sorted from the parent cells, as CSC rich cells. The expression of stem cell markers was examined by RT-PCR. The viability of cancer cells under starvation and hypoxia was evaluated. The expression level of the autophagy molecule LC3B-II was examined by western blot. The numbers of autophagosomes and autolysosomes were counted by electron microscope. SP cells of OCUM-12 showed a higher expression of stem cell markers and higher viability in starvation and hypoxia. Western blot and electron microscope examinations indicated that the autophagy was more induced in SP cells than in parent cells. The autophagy inhibitor significantly decreased the viability under the stress environments. These findings suggested that Cancer stem cells of gastric cancer might maintain their viability via the autophagy system. Autophagy inhibitors might be a promising therapeutic agent for gastric cancer.

Preoperative C-reactive protein to albumin ratio predicts anastomotic leakage after esophagectomy for thoracic esophageal cancer: a single-center retrospective cohort study.

BACKGROUND: Postoperative anastomotic leakage (AL) is associated with not only prolonged hospital stay and increased medical costs, but also poor prognosis in esophageal cancer. Several studies have addressed the utility of various inflammation-based and/or nutritional markers as predictors for postoperative complications. However, none have been documented as specific predictors for AL in esophageal cancer. We aimed to identify predictors of AL after esophagectomy for thoracic esophageal cancer, focusing on preoperative inflammation-based and/or nutritional markers. METHODS: We retrospectively analyzed 295 patients who underwent radical esophagectomy for thoracic esophageal squamous cell carcinoma between June 2007 and July 2020. As inflammation-based and/or nutritional markers, Onodera prognostic nutritional index, C-reactive protein (CRP)-to-albumin ratio (CAR) and modified Glasgow prognostic score were investigated. Optimal cut-off values of inflammation-based and/or nutritional markers for AL were determined by receiver operating characteristic curves. Predictors for AL were analyzed by logistic regression modeling. RESULTS: AL was observed in 34 patients (11.5%). In univariate analyses, preoperative body mass index (≥ 22.1 kg/m2), serum albumin level (≤ 3.8 g/dL), serum CRP level (≥ 0.06 mg/dL), CAR (≥ 0.0139), operation time (> 565 min) and blood loss (≥ 480 mL) were identified as predictors of AL. Multivariate analyses revealed higher preoperative CAR (≥ 0.0139) as an independent predictor of AL (p = 0.048, odds ratio = 3.02, 95% confidence interval 1.01-9.06). CONCLUSION: Preoperative CAR may provide a useful predictor of AL after esophagectomy for thoracic esophageal squamous cell carcinoma.

EMMPRIN in extracellular vesicles from peritoneal mesothelial cells stimulates the invasion activity of diffuse-type gastric cancer cells.

Peritoneal metastasis of gastric cancer (GC) results in extremely poor prognoses. The peritoneal cavity is covered by a monolayer of peritoneal mesothelial cells (PMCs). Interactions between GC cells and PMCs might play a pivotal role in peritoneal metastasis. Extracellular vesicles (EVs) correlate with intercellular communication. Although intercellular communication between cancer cells and PMCs might be associated with the peritoneal metastatic process, the role of EVs from PMCs remains unclear. We investigated the effects of EVs from PMCs on GC cells. Three GC cell lines (OCUM-12, NUGC-3, and MKN74) and four mesothelial cell lines were used. The effects of EVs derived from the PMCs on the invasion and migration of GC cells were evaluated by Matrigel invasion assay. Factors contained in the PMC EVs were analyzed; extra-cellular matrix metalloproteinase inducer (EMMPRIN) was detected in the EVs. The effects of an EMMPRIN inhibitor on the invasion-stimulating activity of EVs were examined. The EMMPRIN expressions of 110 GCs were evaluated by immunohistochemistry. PMC EVs significantly promoted the invasion of diffuse-type GC cells, i.e., OCUM-12 and NUGC-3 cells. EMMPRIN in the EVs stimulated the invasion of OCUM-12 and NUGC-3 cells. The invasion-stimulating activity of PMC EVs was inhibited by the EMMPRIN inhibitor. A high EMMPRIN expression in PMCs was significantly associated with worse cancer-specific survival and peritoneal-recurrence-free survival. EMMPRIN in EVs from PMCs might stimulate the malignant progression of diffuse-type GC. EMMPRIN might be a useful prognostic marker of recurrence in GC patients.

The clinicopathologic significance of Tks5 expression of peritoneal mesothelial cells in gastric cancer patients.

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.

Brazilian green propolis promotes TNFR2 expression on regulatory T cells.

FoxP3+ regulatory T cells (Tregs) are needed to suppress inflammatory diseases and maintain immune homeostasis. The suppressive function of Tregs can be used to control autoimmune or inflammatory diseases; therefore, it is well studied how Tregs can be artificially up- or downregulated in vitro and in vivo, by using antibodies, chemical compounds, foods, and natural resources. Propolis is a famous functional food that has an anti-inflammatory effect. However, the influences of propolis on Treg function have not been fully evaluated so far. Here, we demonstrated that Brazilian green propolis increases TNFR2 expression in Tregs via the IRF4/cMyc axis, and artepillin C was a major effective component of propolis on Tregs. These results indicate that propolis and artepillin C have the potential as Treg activators via TNFR2 expression and may be useful for the prevention and/or therapy of autoimmune or inflammatory diseases.