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Chronic inflammation contributes to tumor development by creating a local microenvironment that facilitates neoplastic transformation and potentiates the progression of cancer. Esophageal cancer (EC) is an inflammation-associated malignancy with a poor prognosis. The nature of the switch between chronic inflammation of the esophagus and EC-related immunological changes remains unclear. Here, we examined the dynamic alterations of immune cells at different stages of chronic esophagitis, Barrett’s esophagus (BE) and EC using an esophageal spontaneous carcinogenesis rat model. We also investigated the anticancer effects of metformin. To stimulate EC carcinogenesis, chronic gastroduodenal reflux esophagitis via esophagojejunostomy was induced in 120 rats in metformin-treated and non-treated (control) groups. After 40 weeks, BE and EC developed in 96.7% and 63.3% of the control group, and in 66.7% and 23.3% of the metformin-treated group, respectively. Flow cytometric analysis demonstrated that the balance of M1/M2-polarized or phospho-Stat3-positive macrophages, regulatory T, cytotoxic T, natural killer (NK), NK T cells, and Th17 T cells was dynamically changed at each stage of the disease and were resolved by metformin treatment. These findings clarify the immunity in esophageal carcinogenesis and suggest that metformin could suppress this disease by improving the immunosuppressive tumor microenvironment and immune evasion.

Palliative chemotherapy with best supportive care is a mainstay for patients with gastric cancer (GC) and distant metastasis. However, with advances in GC chemotherapy, multimodal treatment, including perioperative chemotherapy plus conversion surgery, has attracted attention as a new strategy to improve the outcome of patients with stage IV disease. Conversion surgery is defined as surgical treatment aimed at R0 resection after a good response to induction chemotherapy for tumors originally considered unresectable or marginally resectable for technical and/or oncological reasons. Various biological characteristics differ, depending on each metastatic condition in stage IV GC. The main metastatic pathways of GC can be divided into three categories: lymphatic, hematogenous, and peritoneal. In each category, considerable historical data on conversion surgery have demonstrated the benefits of individualized approaches. However, owing to the diversity of these conditions, a common definition, including the choice of induction chemotherapy, optimal timing of resection, and eligibility for conversion surgery, has not been established among surgical oncologists. Thus, we explore the current and future treatment options by reviewing the literature on this controversial topic comprehensively.

Background The multidisciplinary treatment including induction chemotherapy plus conversion surgery (CS) has attracted attention as a new strategy to improve the outcome of metastatic gastric cancer (MGC). However, it is unclear which patients achieve a good response to chemotherapy and successful CS. Tumor-infiltrating immune cells (TIICs) have been reported to be both prognostic and predictive biomarkers not only in immunotherapy but also in chemotherapy in many cancer types. However, there have been no reports on the usefulness of TIICs as biomarkers in conversion surgery for MGC. The aim of the present study was to evaluate the association between the TIICs and treatment outcome for the multidisciplinary treatment in MGC. Methods We retrospectively analyzed 68 MGC patients who received docetaxel plus cisplatin plus S-1 (DCS) therapy between April 2006 and March 2019 in our institute. The number of tumor-infiltrating CD4+, CD8+, Foxp3+lymphocytes, CD68+, CD163+macrophages in pre-treatment endoscopic biopsy samples were evaluated to investigate their predictive value for multidisciplinary treatment. Results Fifty patients underwent CS following DCS therapy (CS group), whereas 18 patients underwent DCS therapy alone (non-CS group). The median survival time (MST) of CS group was 33.3 months, which was significantly longer than the MST of 9.0 months in non-CS group (p +macrophages was extracted as an independent prognostic factor for overall survival in all patients. There were more cases of high infiltration of CD163+macrophages in non-CS group than in CS group. Furthermore, in CS group, pathological responders to DCS therapy showed low infiltration of CD163+ macrophages, and high infiltration of CD8+lymphocyte. CD163 low group showed a significant prolonged survival compared with CD163 high group in patients who underwent CS (p = 0.02). Conclusions The pre-treatment CD163+macrophages infiltration would be a pivotal biomarker for predicting prognosis and pathological response to multidisciplinary treatment among TIICs in MGC. Thus, for patients with low CD163+macrophage infiltration in pre-treatment biopsy sample, diagnostic imaging should be performed frequently during chemotherapy to avoid missing the optimal timing for CS, and CS should be aggressively considered as a treatment option if curative resection is deemed feasible.

This prospective multicenter non-randomized phase III study aims to evaluate the long-term outcome of sentinel node navigation surgery for early gastric cancer compared with conventional distal or total gastrectomy. Clinically diagnosed primary T1N0M0 gastric cancer patients with a single lesion (≤40 mm) and without previous endoscopic treatment will be enrolled in this study. Sentinel nodes are identified by dye and radioisotope tracers and are subjected to intraoperative rapid pathology. For patients with negative sentinel node metastasis, individualized surgery consisting of limited stomach resection and sentinel node basin dissection is performed, while standard gastrectomy with D2 lymph node dissection is employed for the positive sentinel node patients. A total of 225 patients will be accrued from 13 hospitals that have experience in sentinel node mapping. The primary endpoint is 5-year relapse-free survival. The secondary endpoints are overall survival, sentinel node detection rate, diagnostic accuracy for sentinel node, distribution of sentinel nodes and metastatic sentinel node/non-sentinel node, and postoperative quality of life.

Objective Severe acute pancreatitis is a serious disease, but its detailed mechanism has not yet been elucidated. We aimed to clarify the interaction between neutrophils and platelets in the pathogenesis of acute pancreatitis. Methods We induced acute pancreatitis in rats by injection of sodium taurocholate into the biliopancreatic duct and killed them over time. We observed the histological changes in pancreatic tissue with special attention to the dynamics of neutrophils and platelets. We also measured the concentrations of neutrophil- and platelet-derived factors in pancreatic tissue and blood samples. Results Neutrophils and platelets in the pancreatic tissue showed a similar pattern of migration. They initially spread in the interlobular connective tissue and finally into the lobules. The concentration of myeloperoxidase gradually increased in the inflamed pancreas until 24 hours and the concentration of thromboxane B2, plasminogen activator inhibitor 1, and CD41 also increased with time. Finally, the concentration of serum myeloperoxidase, citrullinated histone H3, and high-mobility group box 1 increased over time. Conclusions The interaction between neutrophils and platelets in pancreatic tissue plays an important role in the mechanism of advancing severity in acute pancreatitis. Circulating damage-associated molecular patterns induced by excessive local inflammation may lead to other organ injuries.

Extravasated platelet aggregation (EPA) serves an important role in the cancer microenvironment during cancer progression, and has been demonstrated to interact with tumor cells in several types of cancer. EPA induces epithelial-mesenchymal transition (EMT) via transforming growth factor-β, and also recruits immunosuppressive cells, including regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). However, the role of EPA in gastric cancer with peritoneal metastasis remains unknown. The present study analyzed the association between EPA and prognosis in patients with gastric cancer with peritoneal metastasis. The present study evaluated 62 patients diagnosed with advanced gastric cancer with peritoneal metastasis between 2001 and 2016. EPA, EMT, Treg cells and MDSCs in peritoneal metastatic lesions were detected by immunohistochemical evaluation of CD42b, SNAIL, FOXP3 and CD33, respectively. CD42b expression was observed in 56.5% (35/62) of peritoneal metastatic lesions. CD42b expression in peritoneal metastatic lesions was associated with poor overall survival compared with lower frequencies (hazard ratio, 2.03; 95% confidence interval, 1.12–3.69; P=0.018). SNAIL, FOXP3 and CD33 expression were not associated with overall survival, but CD33 expression was markedly higher in CD42b-positive patients (P=0.022). These results indicated that EPA affects immunosuppression by recruiting MDSCs in the tumor microenvironment via the secretion of soluble factors, resulting in tumor progression. EPA may be a novel therapeutic target for gastric cancer with peritoneal metastasis.

Objectives Interleukin-17A (IL-17A) is pro-inflammatory cytokine and acts as profibrotic factor in the fibrosis of various organs. Fibrosis tumor-like peritoneal dissemination of gastric cancer interferes with drug delivery and immune cell infiltration because of its high internal pressure. In this study, we examined the relationship between IL-17A and tissue fibrosis in peritoneal dissemination and elucidated the mechanism of fibrosis induced by IL-17A using human peritoneal mesothelial cells (HPMCs) and a mouse xenograft model. Methods Seventy gastric cancer patients with peritoneal dissemination were evaluated. The correlation between IL-17A and fibrosis was examined by immunofluorescence and immunohistochemistry. A fibrosis tumor model was developed based on subcutaneous transplantation of co-cultured cells (HPMCs and human gastric cancer cell line MKN-45) into the dorsal side of nude mice. Mice were subsequently treated with or without IL-17A. We also examined the effect of IL-17A on HPMCs in vitro. Results There was a significant correlation between IL-17A expression, the number of mast cell tryptase (MCT)-positive cells, and the degree of fibrosis (r = 0.417, P Conclusions IL-17A derived from mast cells contributes to tumor fibrosis in peritoneal dissemination of gastric cancer. Inhibiting degranulation of mast cells might be a promising treatment strategy to control organ fibrosis.

Background Rhabdomyosarcoma (RMS), a malignant neoplasm that normally differentiates to form striated muscle, is the most common type of childhood soft tissue sarcoma. However, it infrequently occurs in adults and is uncommon in the liver. We herein report a case of RMS of the liver in an adult. Case presentation A 73-year-old woman was admitted to our institution for investigation of a hepatic mass. She had been followed for primary biliary cirrhosis for the past 20 years. A contrast-enhanced computed tomography scan of the abdomen showed a 12- × 10-cm heterogeneous low-density mass lesion containing cystic and solid components. A percutaneous liver biopsy was performed, and poorly differentiated cancer containing an RMS cell-like component was observed. The patient was diagnosed with RMS of the liver, and open surgery with right hepatic lobectomy was performed. Histopathological examination confirmed a diagnosis of pleomorphic RMS of the liver. The patient died of rapid progression of the tumor 6 months after the operation. Conclusions The tumor site in the present case is rare. The details of this case add to the current evidence base regarding establishment of the standard diagnosis and treatment of this rare condition. We recommend consideration of RMS as a differential diagnosis for hepatic tumors.

Introduction Platelets are one factor promoting tumor development. Conversely, lymphocytes are one factor for immune protection. The peripheral blood platelets-lymphocyte ratio (PLR) is useful as an inflammation/immune indicator to predict postoperative recurrence and prognosis of a variety of malignancies. The peripheral blood neutrophil-lymphocyte ratio (NLR) has also been reported as a useful inflammation/immune indicator. However, there are few studies evaluating the relationship between these peripheral blood indicators and the effectiveness of chemotherapy. Thus, we examined these relationships in gastric cancer patients. Patients and Methods Between 2005 and 2018, 41 gastric cancer patients treated with preoperative DCS therapy (docetaxel, cisplatin, and S-1) therapy followed by gastrectomy were evaluated. Data for peripheral blood tests prior to the initiation of chemotherapy were used. The effectiveness of chemotherapy was determined using Response Evaluation Criteria in Solid Tumors (RECIST) and the pathological response of primary lesions (Ef grade). The relationship between the blood test results and the effectiveness of chemotherapy was evaluated. Results Each optimal cut-off value of peripheral inflammation/immune indicators was calculated through ROC curves. Although the pathological responder (Ef grade 2 or 3) revealed significantly better prognosis than the non-responder (Ef grade 0-1b), no relationship was found between responder according to RECIST and prognosis (P=0.014, P=0.992). In univariate analysis, a low PLR (

Background: An artificial pancreas (AP) is useful for intensive insulin treatment (IIT). In this study, the safety and efficacy of an AP in the perioperative period of highly invasive hepato-biliary and pancreatic surgery (HBPS) was validated. Methods: Fifty patients underwent IIT with an AP during the HBPS perioperative period, including hepatectomy greater than two sectors (MH), pancreatoduodenectomy (PD), and liver transplantation (LT). The primary endpoint was occurrence of hypoglycemia (

Aim The present study aimed to examine the effects of prophylactic administration of recombinant human soluble thrombomodulin (rTM) for the prevention of sinusoidal obstruction syndrome (SOS). Materials and methods Crl:CD1 mice were allocated to the rTM, placebo, and control groups. The rTM group received an intraperitoneal administration of rTM, with intraperitoneal administration of monocrotaline (MCT) 1 h later. The placebo group received PBS instead of rTM, and the control group received PBS instead of rTM and MCT. Mice were sacrificed 48 h after MCT administration, and blood and liver tissues were evaluated. Immunostaining was performed using anti-CD42b and anti-SE-1 antibodies, and AZAN staining. Levels of plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS) in whole liver tissues were estimated using RT-PCR. Results Hematoxylin-eosin staining showed that SOS-related findings were markedly attenuated in the rTM group compared to the placebo group. CD42b immunostaining showed the presence of extravasated platelet activation (EPA) in the Disse space in the placebo group, but this was less noticeable in the rTM group. PAI-1 levels were significantly lower in the rTM group than in the placebo group in RT-PCR. However, eNOS levels were significantly higher in the rTM group than in the placebo group. Conclusion Administration of rTM may prevent SOS by protecting sinusoidal endothelial cells.

Na+/H+exchanger 5 (NHE5) is enriched in neurons and cycles between recycling endosomes and plasma membranes and transports protons to the endosomal lumen as well as to the extracellular space. Although NHE5 expression is undetectable in normal astrocytes, C6 glioma cells express NHE5 at an elevated level. Using C6 cells as a model, here we demonstrate that NHE5 has an important role in tumor growth and tumor cell proliferation and invasion. Glioma xenografts originating fromNHE5-knockdown cells exhibited significantly slower growth than those fromNHE1-knockdown cells and control cells. Histological characterization of the migration front ofNHE5-knockdown tumors revealed a less invasive and less proliferative appearance thanNHE1-knockdown and control tumors.NHE5-knockdown but notNHE1-knockdown led to downregulation of fetal bovine serum (FBS)-induced MET and EGFR signaling. Moreover, depletion of NHE5 but not NHE1 reduced the ability of cells to spread on collagen. We found that NHE5 depletion greatly abrogated endocytic recycling and the protein stability of β1-integrin, which in part accounted for the defective cell adhesion, spreading, and invasion ofNHE5-knockdown cells.

Esophageal squamous cell carcinomas (ESCCs) as well as adenocarcinomas (EACs) were developed in rat duodenal contents reflux models (reflux model). The present study aimed to shed light on the mechanism by which bile acid stimulation causes cancer onset and progression. Metabolomics analyses were performed on samples of neoplastic and nonneoplastic tissues from reflux models, and K14D, cultivated from a nonmetastatic, primary ESCC, and ESCC‐DR, established from a metastatic thoracic lesion. ESCC‐DRtca2M was prepared by treating ESCC‐DR cells with taurocholic acid (TCA) to accelerate cancer progression. The lines were subjected to comprehensive genomic analyses. In addition, protein expression levels of glucose‐6‐phosphate dehydrogenase (G6PD), nuclear factor kappa B (NF‐κB) (p65) and O‐linked N‐Acetylglucosamine (O‐GlcNAc) were compared among lines. Cancers developed in the reflux models exhibited greater hexosamine biosynthesis pathway (HBP) activation compared with the nonneoplastic tissues. Expression of O‐GlcNAc transferase (OGT) increased considerably in both ESCC and EAC compared with nonneoplastic squamous epithelium. Conversely, cell line‐based experiments revealed the greater activation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. G6PD overexpression in response to TCA exposure was observed. Both NF‐κB (p65) and O‐GlcNAc were expressed more highly in ESCC‐DRtca2M than in the other cell lines. Moreover, ESCC‐DRtca2M cells had additional chromosomal abnormalities in excess of ESCC‐DR cells. Overall, glucose metabolism was upregulated in both esophageal cancer tissue and cell lines. While bile acids are not mutagenic, chronic exposure seems to trigger NF‐κB(p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression. Glucose metabolism was upregulated in both esophageal cancer tissue and cell lines, and the HBP was activated in the former. The cell line‐based experiments demonstrated upregulation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. While bile acids are not mutagenic, chronic exposure seems to trigger G6PD overexpression and NF‐κB (p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression.

Totally implantable vascular access devices (TIVADs) are often used to administer chemotherapy by prolonged intravenous infusion. The objective of the present study was to investigate the incidence of long-term complications and identify risk factors associated with TIVAD placement in patients with gastric cancer. A total of 121 patients with gastric cancer who had undergone 150 TIVAD placement procedures for chemotherapy or supportive care were enrolled in the present retrospective cohort study. A number of risk factors were analyzed, including age, sex, hypertension, diabetes mellitus, history of thrombosis, body mass index, disease stage, and site and purpose of TIVAD. In total, 40 TIVADs (26.7%) developed long-term complications, of which 27 (18.0%) were infections, seven (4.7%) were catheter-related deep vein thrombosis (CR-DVT), and six (4.0%) were obstructions. Chemotherapy was associated with an increased rate of infectious adverse events (odds ratio 2.925; 95% CI, 1.104-7.750; P=0.031) according to the multivariate analysis. CR-DVT occurred more frequently in upper arm ports than in chest wall ports; however, this difference was not statistically significant (7.5 vs. 0.0%; P=0.084) according to the univariable analysis. All CR-DVTs developed in the upper arm sites. Chemotherapy and the upper arm site were associated with long-term complications in patients with TIVAD. However, further studies are needed to confirm the findings of the present study and to determine the reasons for the high incidence of long-term complications in these patients.

A gastrointestinal-airway fistula (GAF) after esophagectomy is a very serious postoperative complication that can cause severe respiratory complications due to digestive juice inflow. Generally, GAF is managed by invasive surgical treatment; less-invasive treatment has yet to be established. We performed esophageal stent placement (ESP) in three cases of GAF after esophagectomy. We assessed the usefulness of ESP through our clinical experience. All GAFs were successfully managed by ESP procedures. After the procedure, the stent positioning and expansion were appropriately evaluated by radiological assessments over time. The stent was removed after endoscopic confirmation of fistula closure on days 8, 23, and 71. Only one patient with a long-term indwelling stent developed a manageable secondary gastrobronchial fistula as a procedure-related complication. In conclusion, ESP was shown to be a less-invasive and effective therapeutic modality for the treatment of GAF.

Background The embryonic stem cell-specific transcription factor, ZFP57, has been shown to play an important role in tumor formation. In this study, we examined if ZFP57 is involved in colorectal cancer metastasis. Materials and methods First, we used colorectal cancer cell lines to perform in vivo metastatic experiments with nude mice. Next, we carried out immunohistochemical analysis of clinical specimens of colorectal cancers. Results In liver metastatic experiments using human colorectal cancer HT29 and HCT116 cells, liver polymetastases occurred at high frequency in ZFP57-overexpressing HT29 and HCT116 cells, whereas both control cells only resulted in oligometastases. Next, we analyzed ZFP57 expression using clinical specimens. Liver metastasis-positive cases were more frequently associated with ZFP57 overexpression than negative cases in primary lesions of colorectal cancer, and the overexpression was particularly remarkable in tumor invasive lesions. Furthermore, ZFP57 overexpression was significantly correlated not only with liver metastasis but also with lymph node metastasis. In addition, the expression level of ZFP57 was significantly correlated with that of the metastasis-related gene NANOG. We also found that ZFP57 overexpression reduced the progression-free survival rate of patients with colorectal cancer. Conclusions This study demonstrated that ZFP57 plays an important role in the hematogenous metastasis of colorectal cancer, suggesting that it could be used as a novel treatment target.

The number of ABO-incompatible living donor liver transplantations (ABO-I LDLT) has increased owing to the use of preoperative rituximab for immunosuppression. However, controversy remains regarding adequate immunosuppression owing to rejection and infection. Here, we present 5 cases of our ABO-I LDLT experience, emphasizing rejection and infectious complications, retrospectively. The treatment protocol included prophylactic rituximab followed by plasma exchange prior to transplantation, splenectomy, and immunosuppressive and prophylactic antibiotic regimens after transplantation. Four of the 5 patients also received local infusion therapy via the portal vein. Neither hyperacute nor antibody-mediated rejection occurred. All grafts were functioning well at discharge. Rehospitalization was required for 2 patients due to severe infection within 6 months of transplantation. Invasive aspergillosis was successfully treated in 1 patient, but the other patient died from severe sepsis with overwhelming postsplenectomy infection syndrome. Our results confirm that, although improved immunosuppressive therapy markedly reduces rejection in ABO-I LDLT, it is also associated with an increased risk of various life-threatening infections.

Background Neutrophil extracellular traps (NETs) play a crucial role in host defense, but excess and prolonged interaction of NETs with platelets can cause severe inflammation and host organ damage. Modification of histone H3 by citrullination is involved in in vitro NET formation. The phosphodiesterase III inhibitor, cilostazol (Ciz), which has a protective effect on liver sinusoidal endothelial cells and inhibits platelet aggregation, may prevent organ damage caused by excess NETosis. In this study, we investigated whether citrullinated histone H3 (H3Cit) could serve as a biomarker for the detection of critical liver damage in sepsis and the efficacy of phosphodiesterase-III inhibition for preventing the liver dysfunction induced by NETosis. Materials and methods Mice injected with lipopolysaccharide (LPS; 1 mg/kg) were used as a sepsis model with or without treatment with Ciz (200 mg/kg). H3Cit, myeloperoxidase, and neutrophil elastase levels were measured by immunohistochemistry. We evaluated H3Cit-positive neutrophils in the peripheral blood by flow cytometry. Results Immunohistochemistry revealed that H3Cit-, neutrophil elastase-, and myeloperoxidase-positive cell numbers in the livers peaked at 12 h after LPS administration. However, flow cytometry showed a significant increase in H3Cit-positive neutrophils in the peripheral blood only 4 h after LPS injection. Treatment with Ciz significantly ameliorated all parameters. Conclusions H3Cit is a useful biomarker for early detection of NETosis or liver dysfunction, and Ciz may be an effective treatment for septic liver damage.

Chemotherapy, including preoperative chemotherapy, plays an important role in the treatment of esophageal cancer. However, although docetaxel, cisplatin, and fluorouracil (DCF) therapy has a powerful antitumor effect, the associated adverse events make it difficult to maintain the patient’s general condition. Oral mucositis is an important adverse effect of chemotherapy, and its severity, frequency, and impact on patient quality of life should not be underestimated. This study evaluated the role of oral cryotherapy for prophylaxis of oral mucositis caused by DCF therapy. We retrospectively examined the incidence and severity of adverse events, including mucositis, in 72 patients with esophageal cancer treated with DCF. Fifty-eight patients received cryotherapy during docetaxel administration and 14 received no cryotherapy. The incidence of mucositis of all grades and grade 3 was significantly lower in the cryotherapy group compared with the no-cryotherapy group (24.1% vs. 71.4%, P

Background The correlation between tumor location and lymphatic flow distribution in gastric cancer has been previously reported, and PTD (Proximal – Transitional – Distal) classification was proposed. Our group updated and developed the nPTD classification. Method We retrospectively studied gastric cancer patients who underwent the dye method sentinel node biopsy from 1993 to 2020. The inclusion criteria were a single lesion type 0 cancer of ≤5 cm in the long axis, clinically node-negative, and invasion within the proper muscle layer pathologically. In this study, the distribution of dyed lymphatic flow was evaluated for each occupied area of the tumor. Results We included 416 patients in this study. The tumors located in the watershed of the right and left gastroepiploic arteries near greater curvature had extensive lymphatic flow; therefore, a newly circular region with a diameter of 5 cm is set on the watershed of the greater curvature between P and T zone as the ‘n’ zone. In addition, for cancers located in the lesser P curvature, lymphatic flow to the greater curvature was not observed. Therefore, the P zone was divided into two: the lesser curvature side (PL) and the greater curvature side (PG). Conclusions The advantage of the nPTD classification is that it provides not only proper nodal dissection but also adequate function-preserving gastrectomy. If the tumor is localized within the PL, the proximal gastrectomy resection area can be further reduced. In contrast, for cancers located in the ‘n’ zone, near-total gastrectomy is required because of the extensive lymphatic flow.

Background Tumor‐infiltrating lymphocytes (TILs) and other immune cells have been reported as a prognostic factor in several tumors, including gastric cancer, and they play an important role in antitumor effect at the primary site. There were few reports on the immune status in peritoneal metastatic lesions for gastric cancer. Aims The aims of this study were to assess the prognostic significance of TILs (CD4, CD8, CD19, regulatory T cells [Tregs]), and myeloid‐derived suppressor cells (MDSCs) in peritoneal metastatic lesions. Methods We retrospectively investigated 60 patients for gastric cancer with peritoneal metastasis who were treated between 2009 and 2016 in our institute. Immunohistochemistry for CD4, CD8, CD19, FOXP3, and CD33 was performed in the peritoneal metastatic lesions. The absolute numbers of immune cells and ratios were evaluated, and the relationship between immune‐related marker and overall survival (OS) was investigated. Results A high infiltration of CD8+ lymphocytes or high CD8/CD33 ratio was a better prognosis for OS in univariate analysis using all immunologic variables (P = .012, P = .001). In multivariate analysis for clinical and immunologic variables, high CD8/CD33 ratio was identified as an independent prognostic factor for OS (Hazard ratio: 0.291, 95% confidence interval: 0.126‐0.670, P = .004). Conclusion High CD8/CD33 ratio and high infiltration of CD8+ lymphocytes in peritoneal metastatic lesions were favorable prognoses for gastric cancer patients with peritoneal metastasis. It is necessary to modify the immune microenvironment result to increase the level of CD8+ lymphocytes in the peritoneal metastatic lesions.

BackgroundPeritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients.MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6 J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with α-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+cells was significantly lower in PM lesions than in primary lesions (P +cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P = 0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P P = 0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P P ConclusionsThis model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

Background Postoperative pancreatic fistula (POPF) is a serious complication after gastric cancer surgery. The current study aimed to investigate the significance of the anatomic location of the pancreas as a predictor for POPF in both laparoscopic gastrectomy (LG) and open gastrectomy (OG). Methods In total, 233 patients with gastric cancer were assessed retrospectively. We measured the maximum vertical (P-L height; PLH) and horizontal length (P-L depth; PLD) between the upper border of pancreas and the root of left gastric artery on a preoperative CT in the sagittal direction. The maximum length of the vertical line between the surface of the pancreas and the aorta (P-A length), previously reported as prognostic factor of POPF, was also measured. We investigated the correlations between these parameters and the incidence of POPF in LG and OG groups. Results Among the patients in this study, 118 underwent OG and 115 underwent LG. In LG, the median PLH and P-A length in patients with POPF were significantly longer compared with those without POPF (p = 0.026, 0.034, respectively), but not in OG. There was no significant difference in the median PLD between the patients with or without POPF in both LG and OG. The multivariate analysis demonstrated that PLH (odds ratio [OR] 4.19, 95% confidence interval [CI] 1.57–11.3, P = 0.004) and P-A length (OR 4.06, 95%CI 1.05–15.7, P = 0.042] were independent factors for predicting POPF in LG. However, intraoperative blood loss (OR 2.55, 95%CI 1.05–6.18, P = 0.038) was extracted as an independent factor in OG. The median amylase level in the drained fluid (D-Amy) were significantly higher in patients with high PLH(≥12.4 mm) or high P-A length (≥45 mm) compared with those with low PLH or low P-A length in LG. However, there were no differences in the D-Amy levels by PLH or P-A length in OG patients. Conclusions The anatomic location of the pancreas is a specific and independent predictor of POPF in LG but not in OG. PLH is a simple parameter that can evaluate the anatomic position of the pancreas, and it may be useful for preventing POPF after LG.

Background and Objectives: Although cholangiolocellular carcinoma is considered a combined hepatocellular and cholangiocarcinoma, we feel that this classification is not appropriate. Therefore, we compared the diagnostic imaging findings, surgical prognosis, and pathological features of cholangiolocellular carcinoma with those of other combined hepatocellular and cholangiocarcinoma subtypes, hepatocellular carcinoma, and cholangiocarcinoma. Methods: The study patients included 7 with classical type combined hepatocellular and cholangiocarcinoma; 8 with stem cell feature, intermediate type combined hepatocellular and cholangiocarcinoma; 13 with cholangiolocellular carcinoma; 58 with cholangiocarcinoma; and 359 with hepatocellular carcinoma. All patients underwent hepatectomy or living-related donor liver transplantation from 2001 to 2014. Results: cholangiolocellular carcinoma could be distinguished from hepatocellular carcinom, other combined hepatocellular and cholangiocarcinoma subtypes, and cholangiocarcinoma by the presence of intratumoral Glisson’s pedicle, hepatic vein penetration, and tumor-staining pattern on angiography-assisted CT. Cholangiolocellular carcinoma was associated with a significantly lower SUV-max than that of cholangiocarcinoma on FDG-PET. Hepatocellular carcinoma, classical type, and cholangiolocellular carcinoma had significantly better prognoses than stem cell feature, intermediate type and cholangiocarcinoma. A cholangiocarcinoma component was detected in cholangiolocellular carcinoma that progressed to the hepatic hilum, and the cholangiocarcinoma component was found in perineural invasion and lymph node metastases. Conclusions: From the viewpoint of surgeon, cholangiolocellular carcinoma should be classified as a good-prognosis subtype of biliary tract carcinoma because of its tendency to differentiate into cholangiocarcinoma during its progression, and its distinctive imaging and few recurrence rates different from other combined hepatocellular and cholangiocarcinoma subtypes.

Background Choriocarcinomas are usually classified as either gestational or non-gestational. Primary choriocarcinomas in the gastrointestinal tract, especially primary choriocarcinomas in the esophagus, are extremely rare. We report a case of a rare primary esophageal choriocarcinoma mixed with squamous cell carcinoma-like components in association with Barrett’s adenocarcinoma. Case presentation A 58-year-old man visited the hospital, complaining of hematemesis and tarry stools. In emergency upper gastrointestinal endoscopy, a bleeding esophageal tumor was observed. Additionally, a contrast computed tomography (CT) scan showed a large hypervascular tumor 4.8 cm in diameter in the left kidney. He came to our institution for further examination and treatment of the esophageal tumor and kidney lesion. The patient had an easy bleeding elevated tumor 2 cm in diameter at the left wall of the middle thoracic esophagus and a left renal carcinoma. Histopathological diagnosis of the biopsy specimen of the esophageal tumor was a poorly differentiated carcinoma. However, a precise histological type diagnosis could not be obtained. In June 2016, mediastinoscopic transhiatal esophagectomy and posterior mediastinal gastric tube reconstruction were performed to treat his esophageal tumor. Histopathologically, most of the tumor comprised hCG-positive syncytiotrophoblasts. Therefore, we confirmed it as a primary esophageal choriocarcinoma. Furthermore, the tumor contained a poorly differentiated squamous cell carcinoma-like component that was also diagnosed as a choriocarcinoma using immunohistochemical staining and there was a small Barrett’s esophageal adenocarcinoma lesion in the Barrett's epithelium near the tumor. Three months after surgery, a CT scan demonstrated multiple lung metastatic nodules and multiple intrahepatic masses. Needle biopsy from the lung nodule showed a choriocarcinoma. Despite chemotherapy, the metastatic choriocarcinoma regrew rapidly and multiple bone metastases appeared. He died because of his esophageal choriocarcinoma 13 months after primary resection. Conclusions We encountered an extremely rare case of esophageal choriocarcinoma combined with squamous cell carcinoma-like components in association with a simultaneous Barrett’s adenocarcinoma that we followed for the entire course of his disease, from resection to end of life. Esophageal choriocarcinomas are rare with peculiar characteristics and very poor prognoses. Additional cases are needed to establish an appropriate future treatment.

On the introduction of robot-assisted thoracoscopic esophagectomy (RATE), we refined the robotic system application to enhance our surgical experience obtained through thoracoscopic esophagectomy (TE) in the lateral decubitus position (LDP). Herein, we evaluate our methods introduced to optimize RATE in the LDP. We performed RATE in the LDP with camera rotation and manual hand control assignment to reproduce the surgical view and manipulation of open esophagectomy. Forty patients underwent RATE between July 2018 and August 2020. After the initial 30 cases (initial RATE group), we optimized the port arrangement and robot settings in the most recent ten cases (recent RATE group). The surgical results of RATE were compared with those of 30 patients underwent TE between April 2014 and May 2019 selected by propensity score-matched analysis based on cStage (TE group). Operative duration was significantly longer in the initial RATE group than the TE group and the recent RATE group. Thoracic blood loss was significantly less in the initial RATE group than the TE group. Console time was significantly shorter in the recent RATE group than the initial RATE group. There was no surgical mortality in RATE and the surgical morbidity rate was similar in the three groups. Camera rotation and manual hand control assignment during RATE in the LDP reproduced the surgical view and manipulation of open esophagectomy and TE in the LDP. The robotic platform enabled meticulous dissection and reduced blood loss, but was initially time-consuming. Optimization of the port arrangement minimized operative duration.

BACKGROUND Severe pericentral zone (zone 3)-based liver injury (LI) may become intractable, with allograft dysfunction after liver transplantation. The phosphodiesterase-3 inhibitor, milrinone, has been reported to attenuate hepatic ischemia-reperfusion injury (IRI). This study clarified how hepatic IRI involved zone 3-based LI, in which zone milrinone was effective, and whether milrinone could improve small intestinal injury (SII) with hepatic IRI. MATERIAL AND METHODS Rats were divided into sham, ischemia-reperfusion (IR), or IR+milrinone groups (n=13 per group). Milrinone was administered intraportally via intrasplenic injection, and whole hepatic ischemia was induced for 30 min. Five hours after reperfusion, serum chemistry and histopathological findings were compared. Expression of CD34 for the detection of altered sinusoidal endothelium as sinusoidal capillarization and cleaved caspase-3 as an apoptosis marker were analyzed via immunohistochemistry. Survival rates were examined after 45 min of whole hepatic ischemia. RESULTS Serum aspartate aminotransferase and direct bilirubin levels were significantly decreased in the IR+milrinone group compared with those of the IR group. The degree of LI, sinusoidal capillarization and apoptosis at zone 3 in the IR group was significantly increased compared with those at the periportal zone (zone 1). These findings at zone 3 in the IR group were improved in the IR+milrinone group. SII with villus congestion and apoptosis in the IR group was significantly attenuated in the IR+milrinone group. The 7-day survival rate was significantly elevated in the IR+milrinone group as compared with that of the IR group. CONCLUSIONS A hepatic IRI model caused zone 3-based LI and SII, which were attenuated by intraportal administration of milrinone.

Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with a-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P=0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (PP=0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (PPConclusionsThis model is the first immunocompetent mouse model to accurately reflect the TME of human clinical PM. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

The impacts of post‑operative abdominal infectious complications increase hematogenous distant metastasis and result in poor long‑term survival after curative resection. Even if curative resection can be performed, the presence of circulating tumor cells is affected. The liver, the most common site of metastases, is an important organ in innate immune surveillance. However, the molecular mechanisms of distant hematogenous metastasis are not yet fully known. Platelets are crucial components in the tumor microenvironment that function to promote tumor progression and metastasis. The purpose of this study was to identify the effect of platelets on escape from innate immune surveillance in post‑operative abdominal infectious complications. Platelet adherence was assessed by co‑culturing human pancreatic cancer cells including transforming growth factor (TGF‑β)‑treated BxPC‑3. CD44 isoform, transcription factors and epithelial‑mesenchymal transition markers were examined using western blotting. We also assessed whether cancer cells surrounded by activated platelets could escape from innate immune surveillance, using infectious and non‑infectious mouse models injected intraperitoneally with LPS. Platelets were found to preferentially adhere to mesenchymal cells rather than epithelial cells. BxPC‑3 epithelial cells showed upregulation of CD44‑variant and epithelial splicing regulatory protein 1 (ESRP‑1) expression. However, Panc‑1 mesenchymal cells and TGF‑β‑treated BxPC‑3 cells showed upregulation of CD44‑standard and zinc finger E‑box‑binding homeobox 1 (ZEB‑1) expression and a reduction in ESRP‑1. In the non‑infectious model, cancer cells were not found in the liver. In the infectious model, although epithelial cells without platelet adhesion were in an apoptotic state, mesenchymal cells showed many viable cancer cells surrounded by activated platelets. Cancer cells were suggested to have phenotypic plasticity through the switching of CD44 isoforms. Mesenchymal cells, which express CD44‑standard, could escape from immune surveillance by becoming surrounded by adhered activated platelets. Therefore, it may be necessary to administer antiplatelet agents to prevent distant hematogenous metastasis when post‑operative abdominal infectious complications occur.

Mechanisms of peritoneal metastasis (PM) formation remain unclear. It has long been considered that the establishment of PM is a multi-step process. Here are the recent new concepts of the formation of PM, in terms of three patterns of PM: trans-mesothelial, trans-lymphatic, and superficial growing metastasis. Trans-mesothelial metastasis is established through detachment of cancer cells, adhesion on distant peritoneal surface, invasion into submesothelial tissue, and proliferation. Trans-lymphatic metastasis develops by the migration of peritoneal free cancer cells (PFCCs) into omental milky spots and/or initial lymphatic vessels. Superficial growing metastasis is established by growing of PFCCs on the peritoneal surface after trapping or adhesion to pocket-like structure or pouch in pelvic cavity or in peritoneum absorbed by negative pressure generated omental milky spots or initial lymphatic vessels.

Background Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens. Methods Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Results Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6–7.4 versus 3.6 months, 95% CI 2.8–5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42–0.78; p = 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without. Conclusions In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials. Electronic supplementary material The online version of this article (10.1007/s10120-018-0899-6) contains supplementary material, which is available to authorized users.

Sachio Fushida,1 Jun Kinoshita,1 Katsunobu Oyama,1 Takashi Fujimura,2 Tomoya Tsukada,3 Takahisa Yamaguchi,1 Itasu Ninomiya,1 Tetsuo Ohta1 1Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan; 2Department of Surgery, Toyama City Hospital, Toyama, Japan; 3Department of Surgery, Toyama Prefectural Central Hospital, Toyama, Japan Background: Scirrhous gastric cancer (SGC) is highly invasive and metastatic because of its interactions with stromal cells, such as fibroblasts and macrophages, and extracellular matrix, leading to a higher incidence of peritoneal metastasis (PM) than other gastric cancers (GCs). Taxane-based intraperitoneal chemotherapy (IPC) is a promising therapy for PM. We retrospectively analyzed outcomes of multidisciplinary therapies that included IPC for SGC. Patients and therapy: Of 1,679 GC patients treated between 1990 and 2012, we analyzed 119 patients who underwent multidisciplinary therapy for SGC. Patients without PM received gastrectomy with lymphadenectomy and resection of involved adjacent organs followed by intraoperative IPC using cisplatin. Patients with PM received chemotherapy using fluorouracil, with or without methotrexate plus IPC using cisplatin before 2000, and S-1 plus IPC using paclitaxel or docetaxel since 2000. Results: Of the 119 patients, 73 (61%) had PM and 63 (53%) had positive peritoneal lavage cytology. Of the 89 gastrectomy patients, 30 (34%) had macroscopic residual tumors (R2). Of the patients treated since 2000, 66 (100%) received S-1 plus taxanes and 44 patients (67%) received taxane-based IPC. Median survival time was significantly longer in the post-2000 group (22.8 months) than in the pre-2000 group (9.5 months). In univariate analysis, lavage cytology, PM, taxane-based IPC, gastrectomy, and R2 resection were significant prognostic factors. However, only R2 resection was an independent prognostic factor in multivariate analysis (hazard ratio: 5.53, 95% CI: 2.05–14.93). Conclusion: As use of taxane-based IPC is not an independent prognostic factor, new multidisciplinary therapies are necessary to avoid R2 resections. Keywords: peritoneal metastasis, intraperitoneal chemotherapy, taxanes

This study was performed to clarify the optimal therapeutic strategy for recurrent disease after esophagectomy. We investigated the prognosis of 37 patients who developed recurrence among 128 patients who underwent curative thoracoscopic esophagectomy (TE) at Kanazawa University Hospital. The prognostic factors after recurrence were examined by univariate and multivariate analyses. Of these 37 recurrences, 29 patients underwent local therapy (surgery, 10 patients; surgery followed by radiation, 2 patients; radiation, 17 patients). Radiation includes intensity-modulated radiation therapy, chemoradiation, and simple radiation therapy. Seventeen patients (58.6%) were considered to have undergone successful therapy by disappearance or diminishment of the targeted region without regrowth. Eleven of 17 patients (64.7%) showed repeat recurrence at another site. Multiple local therapy was performed for repeat recurrence or uncontrollable first therapy. Finally, 57 local therapies were performed. Using multimodal local therapy, 37 (64.9%) of 57 recurrences were successfully managed. The 12 patients treated by surgery as the initial therapy showed the most favorable survival. Seventeen patients who underwent successful initial therapy showed better survival than others. Multiple or miscellaneous organ metastasis, abdominal lymphatic recurrence and best supportive care at recurrence were statistically significant negative variables for survival after recurrence. Performance of surgery and successful therapy as the initial recurrence were statistically significant positive variables for survival after recurrence. Multivariate analysis showed that successful therapy at the initial recurrence was the only independent variable for survival after recurrence. Multimodal local therapy for repeat recurrence after TE contributes to the improvement of survival after recurrence.

Background Acetaminophen is used in multimodal therapy for postoperative pain management. However, the additional effects of acetaminophen in combination with thoracic epidural analgesia (TEA) are not well understood. This prospective, multicenter randomized study was conducted to evaluate the efficacy of routine intravenous (i.v.) acetaminophen in combination with TEA for the management of postoperative pain in gastric cancer surgery. Methods A total of 120 patients who underwent distal gastrectomy were randomly assigned in a 1:1 ratio to receive i.v. acetaminophen every 6 h and TEA during the first 3 postoperative days (acetaminophen group) or TEA alone (control group). The primary endpoint was the sum of TEA rescue doses during the first 2 postoperative days. Results Final analysis included 58 patients in the acetaminophen group and 56 patients in the control group. The median number of TEA rescue doses was significantly lower in the acetaminophen group compared with the control group (3.0 vs. 8.0, p = 0.013). The median area under the curve (AUC) of the pain scores at coughing was significantly less in the acetaminophen group compared with the control group (285 vs. 342, p = 0.046) without an increase in postoperative complications. TEA rescue doses and pain score AUCs were significantly reduced by acetaminophen in patients who underwent open gastrectomy (p = 0.037 and 0.045), whereas there was no significant difference between patients who underwent laparoscopic gastrectomy in the two groups. Conclusions In gastric cancer surgery patients, routine i.v. acetaminophen in combination with TEA provides superior postoperative pain management compared with TEA alone.

Summary: Background/Objective: The neutrophil-to-lymphocyte ratio (NLR) is a simple index that represents systemic inflammatory change. The number of platelets is also known to reflect both post-transplant graft regeneration and dysfunction. Thus, we aimed to investigate the usefulness of NLR and platelet number in predicting the clinical course after adult-to-adult living donor liver transplantation (AA-LDLT) in the acute postoperative period in recipients. Methods: Between January 1999 and December 2013, 61 patients underwent their first AA-LDLT at our institute. We retrospectively analyzed their clinical data, including NLR and number of platelets, until postoperative day 14, and evaluated their ability to predict prognosis after AA-LDLT. Results: The optimal cutoff values of postoperative maximum NLR and maximum platelets to predict prognosis were 50 and 80 × 103/μL, respectively. The 1- and 5-year survival rates were 87.5% and 79.1% in the normal maximum NLR group, respectively, and 46.2% for both in the high maximum NLR group (p = 0.0033). The 1- and 5-year survival rates, respectively, were 90.9% and 84.1% in the high maximum platelets group and 47.1% and 41.2% in the low maximum platelets group (p

Background Prostaglandin E2 is one of the potential products that promotes development of tumors and also is a strong inducer of M2 phenotype macrophages, which contribute to tumor development in the immunosuppressed microenvironment. Hangeshashinto (TJ-14), a Japanese traditional medicine (Kampo medicine), has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2. We previously developed a surgical rat reflux model of esophageal cancer and used this well-established animal model to investigate the action of TJ-14 in preventing esophageal cancer. We also assessed the effect of TJ-14 on the downregulation of prostaglandin E2 production, utilizing esophageal squamous cell carcinoma cell line exposed to bile acid. Methods An end-to-side esophagojejunostomy was performed for the reflux model. A daily oral diet was subsequently administered, consisting of either diet-incorporated TJ-14 or standard diet as a control group. The rats were killed at 40 weeks after surgery. The incidence of esophageal cancer, Barrett's metaplasia, and proliferative hyperplasia were assessed histologically. CD163, a M2 phenotype macrophage marker, was assessed with immunohistochemistry. Prostaglandin E2 enzyme immunoassay and lactate dehydrogenase assay were performed on chenodeoxycholic acid or gastroesophageal reflux contents exposed to esophageal squamous cell carcinoma cell line. Results Sixty-seven percent of the controls (n = 12) developed esophageal cancer, but animals that received TJ-14 (n = 10) had a cancer incidence of 10% (P = .007). Barrett's metaplasia was found in 83% of the rats in the control group and 50% of the rats in the TJ-14 indicating a protective tendency of TJ-14 (P = .095). All of the rats developed proliferative hyperplasia. The number of M2 phenotype macrophage were significantly decreased in the TJ-14 group compared to the control group in both Barrett's metaplasia and esophageal cancer lesions. TJ-14 inhibited chenodeoxycholic acid or gastroesophageal reflux content–induced prostaglandin E2 production in esophageal squamous cell carcinoma cell. Conclusion TJ-14 reduced the incidence of reflux-induced esophageal cancer and the infiltration of M2 macrophages in a surgical rat model or suppressed prostaglandin E2 production in esophageal squamous cell carcinoma cell. Further investigation is required regarding the potential clinical use of TJ-14 as an esophageal cancer chemopreventive agent.

Mitsuyoshi Okazaki,1 Sachio Fushida,1 Tomoya Tsukada,1 Jun Kinoshita,1 Katsunobu Oyama,1 Tomoharu Miyashita,1 Itasu Ninomiya,1 Shinichi Harada,2 Tetsuo Ohta1 1Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan; 2Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Ishikawa, Japan Background: In patients with gastric cancer, one of the greatest obstacles to effective chemotherapy is the development of chemoresistance. It has been previously reported that hypoxia-inducible factor-1 alpha (HIF-1α) is associated with acquisition of chemoresistance, and more recent studies have also noted an association of pyruvate kinase muscle 1 (PKM1) and chemoresistance. The purpose of this study was to identify the effect of HIF-1α and PKM1 expression on the development of acquired chemoresistance using a paclitaxel (PTX)-resistant gastric cancer cell line.Materials and methods: A cancer cell line resistant to PTX was established from MKN45 cells by stepwise exposure to drug (rMKN45-PTX). The expressions of HIF-1α, apoptosis, vascular endothelial growth factor (VEGF), multidrug transporters and glycolytic enzyme were examined by Western blotting, enzyme-linked immunosorbent assay and immunohistochemistry. We also assessed the tumor proliferation by subcutaneous tumor and peritoneal dissemination of mouse xenograft model.Results: The resistance index was 6.1 by determining as the ratio of the 50% growth inhibition (IC50) of rMKN45-PTX/IC50 of MKN45. Expression of nuclear factor kappa B and HIF-1α was increased in rMKN45-PTX cells compared with the parent cells. Expression of Bax and caspase-3 was significantly downregulated, whereas expression of Bcl-xL, P-glycoprotein, multidrug resistance-associated protein and VEGF was increased in rMKN45-PTX. The expression level of PKM1 was upregulated in rMKN45-PTX, leading to an increase in the PKM1/PKM2 ratio. Using xenograft models, we demonstrated that mouse subcutaneous tumors derived from rMKN45-PTX were significantly larger than those derived from MKN45 cells.Conclusion: Under the stress of chemotherapeutic agent exposure, high expression of HIF-1α affects various downstream genes. Although the underlying mechanism is unknown, our data suggest that PKM1 is also a molecular target for gastric cancer treatment. Keywords: HIF-1α, PKM1, chemoresistance, gastric cancer

Background and aim Sinusoidal obstruction syndrome (SOS) is a serious drug-induced liver injury. However, the pathophysiology of the disease remains unclear. This study investigated the effects of cilostazol (CZ), a phosphodiesterase III inhibitor, in a monocrotaline (MCT)-induced rat model of SOS. Methods Male Wistar rats were administrated MCT to induce SOS. Rats were divided into control, MCT, and MCT + CZ groups. In the MCT + CZ group, CZ was administered at 48 h, 24 h, and 30 min prior to and 8 h and 24 h after MCT administration. The MCT group was treated with water instead of CZ. At 48 h after MCT administration, blood and liver samples were collected to assess biochemistry and liver histology. Expression of rat endothelial cell antigen, CD34, CD41, P-selectin, and caspase-3 in the liver were analyzed. Plasminogen activator inhibitor-1 (PAI-1) in hepatocytes was analyzed using western blotting and polymerase chain reaction. Results In the MCT group, macroscopic findings showed a dark-red liver surface. Histological findings showed sinusoidal dilatation, coagulative necrosis of hepatocytes, and endothelial damage of the central vein. These changes were attenuated in the MCT + CZ group. Elevated serum transaminase and decreased platelet counts were observed in the MCT + CZ group compared with those in the MCT group. Treatment with CZ reduced MCT-induced damage to the liver sinusoidal endothelial cells, inhibited extravasated platelet aggregation, and suppressed hepatocyte apoptosis around the central vein. CZ attenuated hepatic PAI-1 protein and mRNA levels. Conclusions Cilostazol attenuated MCT-induced SOS by preventing damage to liver sinusoidal endothelial cells and extravasated platelet aggregation. Hepatic PAI-1 levels were suppressed with CZ treatment.

Background Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, is a form of drug-induced liver injury, the initial morphological changes associated with which occur in liver sinusoidal endothelial cells (LSECs). Recombinant human soluble thrombomodulin (rTM) is reported to have anti-inflammatory and cytoprotective effects. Therefore, we investigated the ability of rTM to protect endothelial cells and enhance their functions in a monocrotaline (MCT)-induced model of SOS. Materials and methods Human umbilical vein endothelial cells were assessed in vitro following administration of MCT (2-4 mM) with/without rTM (10-100 ng/ml) to investigate the effect of rTM on cell proliferation and apoptosis. In vivo experiments were performed with Crl:CD1 mice divided into three groups: rTM (rTM + MCT), placebo (control diluent + MCT), and control (control diluent only). LSECs [cluster of differentiation (CD) 31+CD34+ vascular endothelial growth factor receptor 3 (VEGFR3)+ cells] from these mice were identified using fluorescence-activated cell sorting and assessed by quantitative real-time polymerase chain reaction (qPCR). Results In vitro, caspase-3 and -7 activities were significantly lower and cell viability (as assessed by MTT assays) significantly higher in the rTM group than in the placebo group. Moreover, levels of p-AKT increased upon rTM administration. In vivo, damage to LSECs in zone 3 of the hepatic acinus was attenuated and the number of LSECs were maintained in the rTM group, in contrast to the placebo group. Furthermore, expression of Nos3 (encoding endothelial nitric oxide synthase) was higher and that of plasminogen activator inhibitor 1 (Pai1) lower in LSECs from mice in the rTM group than in those from the placebo group. Conclusion rTM can attenuate SOS by protecting LSECs and enhancing their functions.

Thoracoscopic esophagectomy (TE) is widely performed as a minimally invasive technique in the management of esophageal cancer. The aim of this study was to estimate the efficacy of intrathoracic carbon dioxide (CO2) insufflation during TE in the left lateral position. From January 2010 to April 2016, 58 patients with esophageal cancer underwent TE without intrathoracic CO2 insufflation (Group N) and 37 patients with esophageal cancer underwent TE with intrathoracic CO2 insufflation (Group C). The operation results and respiratory parameters during the thoracic procedure were compared in both groups. A satisfactory surgical field was obtained by CO2 insufflation. There was no difference in the duration of the thoracic procedure or number of dissected mediastinal lymph nodes between the two groups. The amount of thoracic blood loss in Group C was significantly less than that in Group N (P

BACKGROUND Congestion of the small intestine, which induces mucosal damage via apoptosis, is a common pathophysiological change in hepato-biliary-pancreatic surgery, including liver transplantation. Small intestinal mucosal damage can trigger postoperative complications via various pathways. Therefore, we investigated the efficacy of intermittent portal venous clamping, which we named congestive preconditioning (CPC), for decreasing congestive re-outflow injury (CRoI) of the small intestine. MATERIAL AND METHODS Small intestinal CRoI was induced in rats by clamping the portal vein (PV) for 30 min, followed by re-outflow. The CPC group underwent 3 episodes of 5 min PV clamping and 5 min re-outflow before CRoI. The Control group underwent CRoI after 30 min simple laparotomy without any preconditioning. Survival and histological changes in the small intestine after CRoI were analyzed. The histological changes were compared CPC group to Control group using a scoring system that expressed histopathological severity. Also, small intestinal apoptosis and expression of apoptosis-related genes were analyzed by immunohistochemistry. RESULTS The survival rate of the CPC group was significantly higher than Control group. Histological scoring of small intestinal damage was significantly lower in the CPC group after 6 h of CRoI. Expression of anti-apoptotic gene, Bcl-xL was significantly increased, but pro-apoptotic gene caspase-3 and apoptotic cells did not differ significantly between the CPC group and Control group. CONCLUSIONS Induction of CPC for small intestinal CRoI was effective, which suggests that an anti-apoptotic pathway is involved in the beneficial mechanism.

Background Scirrhous gastric cancer is an intractable disease with a high incidence of peritoneal dissemination and obstructive symptoms (e.g., ileus, jaundice, and hydronephrosis) arising from accompanying marked fibrosis. Microenvironmental interactions between cancer cells and cancer-associated fibroblasts are the suggested cause of the disease. We elucidated the mechanisms of tumor growth and fibrosis using human peritoneal mesothelial cells (HPMCs) and investigated the effects of tranilast treatment on cells and a xenograft mouse model of fibrosis. Methods HPMCs were isolated from surgically excised omentum and their interaction with MKN-45 gastric cancer cells was investigated using co-culture. Furthermore, a fibrosis tumor model was developed based on subcutaneous transplantation of co-cultured cells into the dorsal side of nude mice to form large fibrotic tumors. Mice were subsequently treated with or without tranilast. Results The morphology of HPMCs treated with transforming growth factor (TGF)-β1 changed from cobblestone to spindle-type. Moreover, E-cadherin was weakly expressed whereas high levels of α-smooth muscle actin expression were observed. TGF-β-mediated epithelial–mesenchymal transition-like changes in HPMCs were inhibited in a dose-dependent manner following tranilast treatment through inhibition of Smad2 phosphorylation. In the mouse model, tumor size decreased significantly and fibrosis was inhibited in the tranilast treatment group compared with that in the control group. Conclusions Tranilast acts on the TGF-β/Smad pathway to inhibit interactions between cancer cells and cancer-associated fibroblasts, thereby inhibiting tumor growth and fibrosis. This study supports the hypothesis that tranilast represents a novel strategy to prevent fibrous tumor establishment represented by peritoneal dissemination.

Tumor-associated macrophages of the M2 phenotype promote tumor proliferation and are associated with a poor prognosis in patients with various malignancies, including gastric cancer with peritoneal dissemination. The present study assessed whether paclitaxel (PTX) suppresses M2 macrophages, by acting as a Toll-like receptor 4 (TLR4) agonist. Macrophages derived from the THP-1 monocytic cell line and peripheral blood mononuclear cell (PBMC)-derived macrophages were cultured with gastric cancer cells in medium containing PTX, at a concentration that did not affect cell proliferation. The effects of PTX on macrophage expression of CD204, a marker of M2 macrophages and NOS2, a marker of M1 macrophages, was evaluated by western blotting. The ability of PTX to stimulate intranuclear translocation of NF-κB was determined by evaluating the expression of the p65 subunit of NF-κB. In THP-1 macrophages, low-dose PTX (1 and 5 nM) inhibited the expression of CD204, enhanced the expression of NOS2, and significantly suppressed the phosphorylation of Stat3, which is essential for the M2 phenotype. Low-dose PTX also inhibited CD204 expression in primary macrophages derived from PBMCs. PTX treatment of THP-1 macrophages for 1 h induced marked intranuclear translocation of NF-κB p65. Low-dose PTX inhibited the M2 phenotype and induced the M1 phenotype via TLR4 signaling, suggesting that low-dose PTX can alter the macrophage phenotype, whereas clinical doses can kill cancer cells. These results suggest that the anticancer effects of PTX are due both to its cytotoxic and immunomodulatory activities.

New and effective treatments for advanced gastric cancer are urgently needed. Cyclins E and D1 form a complex with cyclin-dependent kinase 2, 4, or 6 to regulate G1-S transition. The G1-S regulatory genes encoding cyclin E (CCNE1), cyclin D1 (CCND1), and CDK6 (CDK6) are frequently amplified in gastric cancer and may therefore influence molecularly targeted therapies against ERBB2 or EGFR when coamplified. A total of 179 formalin-fixed and paraffin-embedded gastric cancer specimens were examined for these gene amplifications by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Amplification of at least 1 G1-S regulatory gene was found in 35 tumors (CCNE1 amplification, 15% of samples; CCND1, 6%; CDK6, 1%). In 13 of the 35 tumors, dual-color fluorescence in situ hybridization identified coamplification of the G1-S regulatory genes with ERBB2, EGFR, and/or KRAS in single cancer nuclei. The observation that cells with G1-S regulatory gene amplification contained clonal subpopulations with coamplification of ERBB2, EGFR, or KRAS in 5 early and 3 advanced cancers suggests that amplification of the G1-S regulatory genes represents an early event, which precedes ERBB2, EGFR, or KRAS amplification. Amplified CCNE1, CCND1, and CDK6 in advanced gastric cancer may be potentially useful as direct targets for molecular therapy or for combination therapy with ERBB2 or EGFR inhibitors. Multiplex ligation-dependent probe amplification could be a useful tool for identification of patients who would benefit from such therapies. © 2016 Elsevier Inc., Embargo Period 12 months

Background/aim The aim of the study was to evaluate the status of extravasated platelet activation (EPA) surrounding podoplanin (PDPN)-positive cancer-associated fibroblasts (CAFs) in pancreatic cancer stroma by neoadjuvant chemotherapy. Patients and methods A total of 74 patients were enrolled in this study. We investigated CD42b and PDPN expression in the groups of untreated, gemcitabine (GEM) alone, GEM plus S-1 (GS) and GEM plus nab-paclitaxel (GnP). Results CD42b expression in surrounding CAFs was observed in 58% patients. CD42b expression was significantly correlated with PDPN expression. CD42b-positive cases were significantly lower in the group treated with GnP than in the untreated group and groups treated with GEM alone or GS. PDPN expression was reduced in the GnP group, as revealed by markedly disorganized collagen and a low density of PDPN-positive fibroblasts. There was a significantly lower CD42b expression and fewer PDPN-positive fibroblasts in the GnP group than in untreated, GEM alone, and GS groups, but there was no significant difference between the latter three groups. Conclusion There is a significant association between EPA and PDPN-positive CAFs in pancreatic cancer stroma. Our data suggest that the GnP regimen decreases EPA through PDPN-positive CAF depletion.

Background/aim Local recurrence of hepatocellular carcinoma (HCC) after thermal coagulation therapy may be associated with an aggressive phenotypic change. This study focused on the thermal effects on HCC cells and evaluated the heat shock response and phenotypic changes after heat treatment. Materials and methods HepG2 and HuH7 cells were used. After heat treatment at 37-50°C for 5-30 min, we assessed their survival rate, induction of heat shock protein (HSP)70 promoter, proliferation rate, induction of the epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related markers. Results Induction of HSP70 promoter per surviving cell was maximized after 10 min of heat treatment at 48°C. Induction of EMT and CSC-related markers was also observed. Conclusion Sub-lethal heat treatment causes large heat shock response to surviving HCC cells and induce EMT-like and CSC-like phenotypic changes that might contribute to increased aggressiveness.

Summary Background: Neoadjuvant Intraperitoneal/ Systemic Chemotherapy (NIPS) is considered effective method to treat Peritoneal Metastasis (PM) from Gastric Cancer (GC). The objective of the present study is to verify the effect of NIPS on Lymph Node Metastasis (LNM). Methods: During the last 18 years, we enrolled 107 and 136 patients who underwent D2-gastrectomy after NIPS and D2-gastrectomy alone (non-NIPS group), respectively. Results: The total number of LNMs in the non-NIPS group and NIPS group was 14.8 ± 13.9 and 4.6 ± 5.9, respectively (P NIPS is a very effective method to control LNM from GC. After intraperitoneal administration of chemotherapeutic drug, extremely higher concentrations of chemotherapeutic drug are absorbed through omental milky spots, and the efferent lymphatic fluid drain into the regional lymph nodes of stomach. As a result, regional LNM of stomach are exposed with extremely higher concentrations of chemotherapeutic drugs than systemic chemotherapy. This feature of the lymphatic circulation accounts for the much greater effects of NIPS on LNM. Synopsis: Neoadjuvant intraperitoneal/systemic chemotherapy is effective not only peritoneal metastasis but also lymph node metastasis from gastric cancer. Keywords: Gastric cancer; Lymph node metastasis; Neoadjuvant intraperitoneal/systemic chemotherapy

In this review, Japanese experience of cytoreductive surgery and perioperative chemotherapy is described. The new concept of peritoneal metastasis (PM) type, i.e., trans-mesothelial, trans-lymphatic, and superficial growing metastasis type was proposed in 2012. Surgeons should perform peritonectomy according to the type of PM. Since 1980, Japanese surgical oncologists have been spearheading the use of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemoperfusion (HIPEC) as treatment for PM from gastric cancer. Two RCTs were conducted to verify the effect of HIPEC for the prophylaxis of peritoneal recurrence after curative resection of advanced gastric cancer. These two studies indicated that HIPEC is effective in preventing peritoneal recurrence of gastric cancer with serosal invasion. In 2002, intraperitoneal chemotherapy using taxans was developed for the treatment of PM from gastric cancer and led to the development of neoadjuvant intraperitoneal/systemic chemotherapy (NIPS), which was reported in 2006. In 2009, extensive intra-operative peritoneal lavage (EIPL) was developed, and contributed to the remarkable improvement in survival of patients with positive lavage cytology as demonstrated by prospective randomized clinical trials. In 2017, the Peritoneal Surface Oncology Group International proposed the value of complete cytoreduction and peritoneal cancer index cut-off as independent prognostic factors after CRS for gastric cancer with PM. Founded in 2016, the Japanese/Asian School of Peritoneal Surface Oncology (JASPSO) trains beginners to perform CRS and HIPEC safely. Sixteen students have already graduated from JASPSO and started to perform the treatment in their home countries.