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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.

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.

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.

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 Our patient was a 21-year-old man with cerebral palsy and a history of laparoscopic fundoplication for hiatal hernia at the age of 11 years and gastrostomy at the age of 18 years. Case presentation The patient was referred to our department when his hematological examination revealed fever caused by an inflammatory response, and elevated amylase levels. Computed tomography examination revealed adhesions around the gastrostomy and dilation from the stomach to the upper jejunum. In addition, a wide range of adipose tissue intensity was seen around the pancreas, and he was diagnosed with adhesive intestinal obstruction and severe acute pancreatitis. Conservative treatment of the adhesive intestinal obstruction was performed. For the pancreatitis, we administered antibiotics and protease inhibitors, continuous hemodiafiltration, and intra-arterial therapy, and the patient's condition improved. On hospital day 24, we performed adhesiotomy to treat the adhesive intestinal obstruction. The patient's postoperative course was favorable, and he was transferred on hospital day 41. Conclusions Acute pancreatitis accompanying afferent loop obstruction has been reported after gastrectomy. In our patient, gas bloat syndrome and adhesive intestinal obstruction caused by fundoplication resulted in increased intestinal pressure, and it appeared that pancreatitis developed by a similar mechanism. In this report, we discuss our experience with this patient and a review of the literature.

To maintain the self-renewal of embryonic stem (ES) cells, several core transcription factors, including Oct3/4, STAT3, and Nanog, regulate the expression of their target genes. Zinc finger protein 57 (Zfp57) is specifically expressed in self-renewing ES cells and its expression level is reduced upon ES cell differentiation, suggesting that expression of this transcription factor is regulated by core transcription factors. In the present study, we investigated whether Zfp57 expression is regulated by Nanog. Nanog overexpression resulted in the upregulation of Zfp57. On the other hand, knockdown of Nanog reduced the expression level of Zfp57. In addition, we identified the Nanog-responsive region in the promoter of the Zfp57 gene. These results suggest that Nanog is an upstream regulator of Zfp57. Moreover, Nanog overexpression promoted the growth of ES cells in soft agar and this was suppressed by Zfp57 knockdown, suggesting that the Nanog/Zfp57 pathway plays a central role in anchorage-independent growth of ES cells. Interestingly, NANOG overexpression also led to the upregulation of ZFP57 in two human tumor cell lines. Taken together, our results suggest that Nanog positively regulates Zfp57 expression in multiple types of cells.

INTRODUCTIONDuodenal ulcer penetration into the liver is a rare, but serious complication. Its frequency was thought to have decreased owing to advances in therapies for peptic ulcers. However, we encountered a case in which the duodenal ulcer had penetrated into a previous hemihepatectomy site.PRESENTATION OF CASEA 69-year-old man with a history of left hemihepatectomy 20 months previously presented to the emergency room with sudden-onset abdominal pain and nausea. An upper gastrointestinal examination with a fiberscope revealed a giant ulcer in the duodenal bulb. In addition, a foreign body was detected at the ulcer floor and was strongly suspected of being a ligature from previous hemihepatectomy.DISCUSSIONThe presence of a gas-filled liver mass and bowel wall thickening with inflammatory changes are important imaging findings for prompt diagnosis of such a condition, but in this case, none of these were reported. Further, no definite abscess was found. Thus, the patient was treated conservatively with a proton pump inhibitor.CONCLUSIONThis case demonstrates the importance of using absorbable suture materials, adequate lavage in the postoperative peritoneal space and gastroduodenal mucosal protection postoperatively.

Vascular endothelial growth factor C (VEGF-C) is the only factor known to cause lymphangiogenesis. We studied the correlation between VEGF-C and vascular endothelial growth factor receptor-3 (VEGFR-3) expression of 85 primary gastric cancers by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, and the results were correlated with the number of lymphatic vessels, stained with anti-VEGFR-3 antibody. RT-PCR and immunohistology demonstrated that VEGF-C was mainly produced from cancer cells, but not from stromal elements. Morphologically, VEGFR-3 expression was detected in the endothelial cells of the stromal lymphatic vessels. There was a statistically positive correlation between the incidence of VEGF-C and VEGFR-3 mRNA expression in the primary tumours (P=0.0002). The number of VEGFR-3-positive lymphatic vessels in VEGF-C mRNA positive tumours was significantly larger than that in VEGF-C-negative tumours. The number of VEGFR-3-positive vessels in the tumour stroma was closely related to the grade of lymphatic invasion of gastric cancer. These results strongly indicate that VEGF-C may induce the proliferation of lymphatic vessels in the stroma of primary gastric cancer via activation of VEGFR-3, expressed on the endothelial cells of lymphatic vessels. In these circumstances, cancer cells can easily invade the lymphatic vessel, because of the increase of the contact points of cancer cells with the lymphatic vessels.

Background. The most common cause of noncurative resection and recurrence in gastric cancer is peritoneal seeding. However, the results of treatment of peritoneal dissemination with chemotherapy have been poor with 5-year survival rates of 0%. Methods. A new in vitro thermochemosensitivity test was performed on gastric cancer cells obtained from 19 surgically resected specimens by using tetrazolium-based colorimetric assay (MTT assay). A novel treatment of the intraoperative chemohyperthermia was undertaken in 83 patients with gastric cancer with peritoneal dissemination. After aggressive resection of primary tumor, lymph nodes, and peritoneal metastases, warmed saline solution containing mitomycin C 30 mg, etoposide 150 mg, and cisplatin 300 mg was introduced into the peritoneal cavity via a closed circuit continuous hyperthermic peritoneal perfusion (CHPP) for 60 minutes to keep the abdominal temperature at 42° to 43° C by means of a heat exhange mechanism. Results. The in vitro thermochemosensitivity test showed that 43° C enhanced the cytotoxic effects on gastric cancer cells under clinically achievable drug concentrations. During CHPP, drug concentrations of cisplatin, mitomycin C, and etoposide in the perfusate remained statistically higher than in the peripheral venous circulation. Among 43 evaluable patients with residual peritoneal seeding, eight (19%) and nine (21%) exhibited complete response and partial response, respectively. The overall 1- and 5-year survival rates were 43% and 11%, respectively. Patients who underwent complete resection survived significantly longer than those with residual disease, and those with complete response had a significantly better prognosis than did those with partial response or nonresponders. One-year survival rates of patients with complete response, partial response, and nonresponders were 88%, 27%, and 22%, respectively. Five patients survived longer than 5 years. Conclusions. Our triple treatment combining surgery and CHPP is an effective therapy for selected patients with gastric cancer with peritoneal dissemination.

Background: Major histocompatibility complex class 1-related chain A/B (MIC A/B), expressed on the cell-surface of cancer cells, functions as a ligand for NKG2D, an important immunoreceptor expressed on gamma delta (γδ) T cells. We investigated the effect of gemcitabine (GEM), a key drug for pancreatic cancer treatment, on the expression of cellsurface MIC A/B in pancreatic cancer cells and resulting cytotoxity of γδ T cells. Materials and Methods: We investigated the effect of GEM on the upregulation of cell-surface MICA/ B expression by flow cytometry, utilizing seven pancreatic cancer cell lines. MICA and CD16 (γδ T and NK cells) expression from resected pancreatic cancer patient specimens, which received neoadjuvant chemotherapy (NAC) with GEM, was analyzed by immunohistochemistry. Results: At a concentration not affecting cell growth, GEM increased the MICA/B expression effectively on all pancreatic cancer cell lines. Furthermore, GEM increased the MICA/B expression at a cytostatic concentration but did not increase the MICA/B expression at a cytotoxic concentration in the PANC-1 cell line (Fig.1A,B). Moreover, cytotoxic activity of γδT cells against PANC-1 was detected and function via NKG2D and MICA/B interaction. Immunohistochemical staining demonstrated that MICA expression in tumor cells (Fig.1C) and CD16 positive cells surrounding tumors (Fig.1D) were significantly higher in the NAC group compared to that of the control group. There was a significant correlation between NAC and MICA expression (p=0.002), as well as NAC and CD16 positive cell expression (p=0.001). Conclusion: The present results indicate that low dose GEM-induced MICA/B expression activates innate immune function, rather than cytotoxicity in pancreatic cancer.