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BACKGROUND: This study aimed to clarify the significance of the crosstalk between hypoxia-inducible factor-1α (HIF-1α) and the Wnt/β-catenin pathway in oesophageal squamous cell carcinoma (ESCC). METHODS: The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. RESULTS: The expression level of HIF-1α, β-catenin, and TCF4/TCF7L2 in T.Tn and TE1 cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, migration/invasion and epithelial–mesenchymal transition (EMT) progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth, angiogenesis, and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-catenin and TCF4/TCF7L2 were increased in ESCC tumour tissues compared to the corresponding non-tumour tissues. High levels of HIF-1α and TCF4/TCF7L2 expression were correlated with aggressive phenotypes and poor prognosis in ESCC patients. CONCLUSIONS: HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/β-catenin pathway.

Esophageal cancer (EC) is a malignant cancer that still has a poor prognosis, although its prognosis has been improving with the development of multidisciplinary treatment modalities such as surgery, chemotherapy and radiotherapy. Therefore, identifying specific molecular markers that can be served as biomarkers for the prognosis and treatment response of EC is highly desirable to aid in the personalization and improvement of the precision of medical treatment. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+)-dependent proteins consisting of seven members (SIRT1-7). These proteins have been reported to be involved in the regulation of a variety of biological functions including apoptosis, metabolism, stress response, senescence, differentiation and cell cycle progression. Given the variety of functions of sirtuins, they are speculated to be associated in some manner with cancer progression. However, while the role of sirtuins in cancer progression has been investigated over the past few years, their precise role remains difficult to characterize, as they have both cancer-promoting and cancer-suppressing properties, depending on the type of cancer. These conflicting characteristics make research into the nature of sirtuins all the more fascinating. However, the role of sirtuins in EC remains unclear due to the limited number of reports concerning sirtuins in EC. We herein review the current findings and future prospects of sirtuins in EC.

Recent progress of large-scale international studies has provided comprehensive catalogs of somatic mutations in cancers. Additionally, it has become evident that allelic imbalance in the abundance of somatic mutations between DNA and RNA were pervasive in various types of cancer. However, the allelic imbalance of the abundance of somatic mutations in esophageal squamous cell carcinoma (ESCC) has not been fully analyzed.We performed exome sequencing for 25 Japanese patients with ESCC to detect a comprehensive catalog of somatic mutations in ESCC. Additionally, we performed mRNA sequencing to evaluate the allelic imbalance of the identified somatic mutations at the transcriptional level by comparing the mutant allele frequencies between RNA and DNA.The exome sequencing showed that TP53 and ZNF750 were significantly mutated genes. The expression levels of TP53 and ZNF750 were different depending on the mutation status. In almost all the tumors with missense mutations in TP53 and ZNF750, the mutant allele frequencies were higher in the RNA sequencing than those in the exome sequencing, indicating that the mutant alleles were preferentially expressed. By examining the allelic imbalances for all the identified missense mutations, we demonstrated that genes showing preferential expressions of the mutant alleles were involved in the pathways including cell cycle, cell death, and chromatin modification.The results of this study suggest that the allelic imbalance of the abundance of somatic mutations plays important roles in the initiation and progression of ESCC by modulating cancer-related biological pathways.

Introduction: Antidiabetic drug metformin exerts various antitumor effects on different cancers. Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer and new treatment strategy is required. In this study, we performed a comprehensive gene expression analysis of ESCC cell lines treated with metformin, which provided helpful information on the antitumor effects of metformin in ESCC. Next, we selected a promising gene among them and examined its effects on ESCC properties. Methods: We examined metformin-induced mRNA expression changes in two human ESCC cell lines by performing next-generation sequencing (NGS) and pathway analysis. Heat shock protein family A (Hsp70) member 6 (HSPA6) expression in surgical specimens obtained from 83 ESCC patients who underwent curative operations was evaluated immunohistochemically and analyzed. Results: Metformin upregulated mRNA expression of the many genes, including HSPA6, a cancer immune-related gene, and inhibited mRNA expression of the other many genes. Pathway analysis indicated major canonical pathways and upstream regulators related to metformin. The result indicated HSPA6 as a promising biomarker. HSPA6 expression correlated with disease-free survival (DFS) of the patients with all stage ESCC (p = 0.021), especially with stage I/II ESCC (p < 0.001). With stage III, low HSPA6 expression was not associated with poor DFS (p = 0.918). Multivariate analysis indicated that independent low HSPA6 expression was an independent poor prognostic factor of stage I/II ESCC (p < 0.001). However, HSPA6 expression did not correlate with the clinicopathological characteristics, including age, sex, tumor depth, lymph node metastasis, tumor stage, and tumor markers of the patients with stage I/II ESCC. Conclusions: This NGS analysis detected prospective candidate genes, including HSPA6. Our results indicate that HSPA6 is a promising biomarker of the recurrence risk of stage I/II ESCC. Further studies on HSPA6 would lead to better treatment.

Introduction: Immune checkpoint inhibitors (ICIs) are expected to improve the prognosis of gastric cancer (GC). Also, hepatic steatosis has been reported to be associated with cancer cachexia and is expected to be a cancer biomarker. The purpose of this study was to evaluate prognostic impact of hepatic steatosis in ICI therapy for GC. Methods: Unresectable or recurrent GC treated with ICIs was investigated. Using unenhanced CT, the liver-to-spleen CT attenuation ratio (LSR) was calculated as a parameter of hepatic steatosis. LSR was compared with the presence of sarcopenia and inflammatory markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR). These parameters were also compared with disease-specific survival (DSS) and progression-free survival (PFS). Associations of LSR with insulin-like growth factor 1 (IGF-1) and growth hormone were also evaluated. Results: A total of 70 patients were investigated. LSR of sarcopenia patients was significantly lower than that of non-sarcopenic ones (p = 0.02). LSR showed significant negative correlations with NLR, PLR, and MLR (p = 0.003, 0.03, 0.01, respectively). Lower LSR was significantly associated with a higher level of serum IGF-1 (p = 0.03). In univariate analysis, LSR was significantly correlated with DSS and PFS (both p < 0.0001), and multivariate analysis demonstrated that LSR was the independent prognostic factor for both DSS and PFS (both p = 0.01). ROC analysis demonstrated that LSR >1.263 was a good predictive marker for favorable DSS (>5.3 months) with an AUC of 0.80. Conclusion: Hepatic steatosis can be a promising prognostic biomarker for ICI therapy of GC, associated with sarcopenia and the elevation of inflammatory markers. Our data suggested that GC with steatohepatitis might be less responsive to ICI therapy.

Hypoxia inducible factor -1α (HIF-1α) and Wnt/β-catenin signal pathway has been reported to be involved in tumor progression in various types of cancers. However, the molecular mechanism by which HIF-1α regulate malignant features in esophageal squamous cell carcninoma (ESCC) are still poorly understood. This study aimed to clarify the significance of the crosstalk between HIF-1α and the Wnt/β-catenin pathway in ESCC. The oncogenic role of HIF-1α in ESCC was investigated using in vitro and in vivo assays. The clinicopathological significance of HIF-1α, β-catenin and TCF4/TCF7L2 in ESCC were evaluated using quantitative real-time PCR and immunohistochemistry. Then we performed qRT-PCR, western blotting, Cell Counting-8 assay, trans-well assay, flow cytometry, immunofluorescence, Co-IP and ChIP assays, chemo resistance test in vitro, tumor xenograft model in vivo. The expression level of HIF-1α, β-catenin, and TCF4/TCF7L2 in ESCC cell lines were elevated under hypoxia in vitro. HIF-1α knockdown suppressed proliferation, igration/invasion and EMT progression, induced G0/G1 cell cycle arrest, promoted apoptosis and inhibited 5-fluorouracil chemoresistance in vitro. In vivo assays showed that HIF-1α is essential in maintaining tumour growth and 5-fluorouracil chemoresistance. Mechanically, we identified the complex between HIF-1α and β-catenin, HIF-1α can directly bind to the promoter region of TCF4/TCF7L2. The mRNA level of HIF-1α, β-catenin and TCF4/TCF7L2 were increased in ESCC tumor tissues. High levels of HIF-1α and TCF4/TCF7L2 were correlated with poor prognosis in ESCC. HIF-1α serves as an oncogenic transcriptional factor in ESCC, probably by directly targeting TCF4/TCF7L2 and activating the Wnt/β-catenin pathway. Our study clarifies the critical role of HIF-1α in ESCC progression.

Subtotal gastrectomy (SG) has become a general option for distal gastric cancer. However, the availability of an organ-preserving approach for the treatment of remnant gastric cancer (RGC) is still controversial. Thus, the objective of the present study was to assess the safety and efficacy of SG for RGC by integrating data from published articles. We searched the PubMed, Cochrane Library, and Web of Science databases for studies that compared SG versus total gastrectomy (TG) for RGC published from the inception of the databases until May 2020. A meta-analysis was performed using the Review Manager Version 5.0 software program from the Cochrane Collaboration. Three retrospective cohort studies with 144 patients were included. The meta-analysis revealed that the operative time of the SG group was significantly shorter than that in the TG group (MD: -34.84. 95% CI: -59.97- -9.71, P = 0.007). There was no significant difference in intraoperative blood loss (MD: -109.19. 95% CI: -240.37-21.99, P =0.10), length of postoperative hospital stay (MD: 0.40. 95% CI: -3.03-3.83, P = 0.82), postoperative complications (RR: 1.41. 95% CI: 0.76-2.63, P = 0.28), or recurrence (RR: 2.33, 95% CI: 0.48-11.44, P = 0.30). SG for RGC tended to be correlated with favorable 5-year overall survival; however, the association was not statistically significant (HR: 0.89, 95% CI: 0.63-1.26, P = 0.51). Organ-preserving approaches such as SG may be a safe and feasible treatment option for early-stage RGC.

Esophageal squamous cell carcinoma (ESCC) is a malignant cancer with a poor prognosis. Chemoradiotherapy is one of the most important strategies for patients with locally advanced unresectable ESCC; however, its therapeutic effect is unsatisfactory. Tumor-initiating cells (TICs) have been reported to be resistant to conventional chemotherapy and radiotherapy so far. Therefore, we aimed to develop a treatment strategy targeting TICs in ESCC to improve radiosensitivity.First, we validated aldehyde dehydrogenase 1 (ALDH1) as a TIC marker and investigated its ability to mediate resistance in human ESCC cell lines using flow cytometry, Western blotting, and functional analyses. Then, we focused on disulfiram (DSF), an aldehyde dehydrogenase inhibitor, used to treat alcohol use disorder. We investigated the effect of DSF and copper (II) D-gluconate (Cu) on the radiosensitivity of ESCC in xenograft mouse models.ALDH1-positive cells showed an upregulation of SOX2 and Nanog, exhibiting much stronger tumor-initiating properties than ALDH1-negative cells. Furthermore, inhibition of ALDH1 attenuated the tumor-initiating properties of ESCC cell lines. Our results also showed that ALDH1-positive cells were resistant to chemotherapy and radiotherapy, and the inhibition of ALDH1 led to the mitigation of therapeutic resistance. Our in vitro and in vivo studies revealed that the DSF/Cu complex could radiosensitize ALDH1-positive ESCC cells and downregulate the phosphoinositide 3-kinase/Akt pathway.ALDH1 inhibition by the DSF/Cu complex enhances the radiosensitivity of TICs in ESCC. The drug repositioning approach using disulfiram is a potential treatment option to overcome radioresistance in patients with locally advanced ESCC.

Background/Aim: Several articles have assessed the prognostic significance of the expression of sirtuin 1 (SIRT1) in esophageal squamous cell carcinoma (ESCC). However, evidence in this field is insufficient. Thus, we conducted a meta-analysis to investigate the prognostic and clinical impact of SIRT1 expression in ESCC. Materials and Methods: We searched the PubMed, Cochrane Library, and Web of Science databases for articles on the expression of SIRT1 and clinicopathological features in patients with ESCC. A meta-analysis was conducted. Results: Four studies with 429 patients were included. The meta-analysis revealed a significant relationship between the high expression of SIRT1 and higher T-stage (odds ratio=2.39. 95% confidence interval=1.12-5.13, p=0.02), more advanced TNM stage (odds ratio=2.35. 95% confidence interval=1.20-4.60, p=0.01), and a poor overall survival (hazard ratio=1.90, 95% confidence interval=1.45-2.47, p

In actual surgical research, case-matched studies are frequently conducted as an alternative to randomized controlled trials (RCTs). However, it is still unclear what differences there are between RCTs and case-matched studies in upper gastrointestinal surgery, and clarifying them is a very important clinical issue. Thus, the purpose of this study was to investigate estimated treatment effects between RCTs, case-matched studies, and cohort studies regarding laparoscopic distal gastrectomy (LDG) for advanced gastric cancer (AGC).We searched the PubMed, Cochrane Central Register of Controlled Trials, and Web of Science databases for studies that compared LDG versus open distal gastrectomy for AGC published from the inception of the databases until July 2021. A meta-analysis was performed using the Review Manager version 5.3 software program from the Cochrane Collaboration, and six short-term outcomes and three long-term outcomes were assessed.Twenty-three studies with 13698 patients were included. There was no difference in estimated treatment effects between RCTs and case-matched studies for all outcomes except for the number of retrieved lymph nodes and postoperative complications. In terms of intraoperative blood loss, postoperative hospital stay, number of retrieved lymph nodes, and recurrence, observational studies tended to overestimate the treatment effects.The estimated treatment effects of LDG for AGC in the case-matched study were almost the same as in the RCTs. However, to assess the true magnitude of the treatment effect, the design and actual implementation of the analysis must be critically evaluated.

Granulomatous appendicitis is uncommon. It can be caused by infectious or systemic disorders, such as Crohn’s disease (CD) and sarcoidosis. It is therefore essential to investigate systematic causes of granulomatous appendicitis after surgery by appropriate examinations. It is also rare for acute appendiceal inflammation to develop due to active CD. We herein report a case of CD presenting as granulomatous appendicitis. The patient was a 28-year-old man who arrived at the emergency room with right lower abdominal pain. Computed tomography showed a low-density lesion with a clear boundary and a small high-density spot in its center behind the cecum. Acute appendicitis with abscess formation was suspected and conservative treatment was started. After 3 consecutive days of conservative treatment there was no improvement in his condition. We therefore performed open appendectomy. Histopathological examination showed numerous noncaseous epithelioid granulomas in the wall of the appendix. Specific staining revealed no evidence of acid-fast bacilli or fungi. During follow-up after discharge, colonoscopy demonstrated erosion from the cecum to the transverse colon. A colon biopsy showed severe inflammation with cryptitis, Paneth cells, and a granulomatous lesion. The patient was therefore diagnosed with CD and treatment with mesalazine was started. Careful examination is necessary to diagnose and properly treat patients with granulomatous inflammation of the appendix.

Background/aim Gastric cancer (GC) with peritoneal metastasis remains difficult to treat. The anti-diabetic drug metformin exerts various antitumor effects via the 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway and nuclear factor-kappa B (NF-ĸB). Therefore, we evaluated the antitumor effects of metformin for GC in vitro and on peritoneal metastasis. Materials and methods The human GC cell lines MKN1, MKN45, KATO-III and SNU-1 were used. The antiproliferative effect was evaluated in vitro with 0.5 mM or 25 mM glucose and in vivo using tumor xenograft peritoneal models of metastasis. The protein expression of AMPK, liver kinase B1 (LKB1) and NF-ĸB in tumors was examined by western blotting. Results Metformin inhibited cell proliferation in all GC lines and sensitivity was increased under low-glucose conditions in vitro. Metformin also suppressed peritoneal metastasis. In tumors, metformin reduced the numbers of proliferating cells and NF-ĸB expression, but a similar trend was not noted for AMPK. Conclusion Metformin may be a useful drug for the treatment of GC with peritoneal metastasis.

Aim Application of laparoscopic approaches for the treatment of remnant gastric cancers (RGC) is still controversial. Therefore, in the present study, the safety and effectiveness of laparoscopic gastrectomy (LG) for RGC was investigated. Methods A total of 27 patients who underwent gastrectomy for RGC from June 2008 to September 2017 were enrolled in this study. A comprehensive review of the literature on LG for RGC published before December 2017 using the PubMed database was carried out. Results Laparoscopic gastrectomy was carried out in seven patients, and open gastrectomy (OG) was done in the remaining 20 patients. LG was associated with significantly less intraoperative blood loss (70 ± 71 vs. 1066 ± 1428 g; P

We determined the serum concentrations of Programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2) in patients with esophageal squamous cell carcinoma (ESCC). Blood samples were collected from 85 patients with histologically proved ESCC. Serum levels of PD-1, PD-L1, and PD-L2 were measured using enzyme linked immunosorbent assays. Correlations between serum PD-1, PD-L1, and PD-L2 concentration and tumor depth, number of lymph node metastases, organ metastasis status, or disease stage were assessed and five-year survival rates according to clinicopathological characteristics were calculated. The concentration of PD-1 was not differed according to tumor progression. On the other hand, the average concentration of PD-L1 in patients with T3/T4 disease was 15.6 (12.2–18.3) pg/mL (25–75%), and this was significantly higher than that in patients with Tis/T1/T2 disease (p = 0.020). Similarly, PD-L1 levels were significantly higher in patients with positive lymph nodes than in cases with negative lymph node involvement (p = 0.006) and were higher in patients with organ metastasis (p = 0.123) and in more advanced stage (p = 0.006). Similar tendency was observed regarding PD-L2 concentrations. PD-L2 concentration was higher in T3, T4 cases (p = 0.008), in LN positive cases (p = 0.032), and in more advanced stage (p = 0.024). Our data showed that a concentration of PD-L1 in peripheral blood was high in advanced cancer and high concentration of PD-L1 predicted disease progression and also poor survival in patients with ESCC.

Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer that has proven difficult to treat despite multidisciplinary therapy, and a new treatment strategy is demanded. Metformin is used for type 2 diabetes mellitus and its antitumor effects have been reported recently. Metformin exerts antitumor effects in various respects, such as inhibiting inflammation, tumor growth and epithelial-mesenchymal transition (EMT). However, few reports have described the efficacy of metformin on ESCC, and their findings have been controversial. We analyzed the antitumor effects of metformin and clarified its effects on anti-inflammation, growth suppression and EMT inhibition. Activation of nuclear factor kappa B (NF-κB), the major transcription factor induced by inflammation, was investigated by immunostaining. We found that localization of NF-κB in the nucleus was reduced after metformin treatment. This suggests that metformin inhibited the activation of NF-κB. Metformin inhibited tumor growth and induced apoptosis in ESCC cell lines. Associated with EMT, we examined cell motility by a wound healing assay and the epithelial marker E-cadherin expression of various ESCC cell lines by western blotting. Metformin inhibited cell motility and induced E-cadherin expression. In conclusion, metformin showed multiple antitumor effects such as growth suppression, invasion inhibition, and control of EMT by inhibiting NF-κB localization on ESCC. Further exploration of the marker of treatment efficacy and combination therapy could result in the possibility for novel treatment to use metformin on ESCC.

Objective: ZNF750, an epidermal differentiation regulator, has been suggested to act as a tumor suppressor of esophageal squamous cell carcinoma (ESCC). Although a correlation between the epidermal differentiation gene and resistance to chemoradiotherapy (CRT) has been posited, no data regarding the ZNF750 status in ESCC have been reported. The aim of the present study was to evaluate the relationship between ZNF750 expression and response to CRT in ESCC. Methods: Eighty-seven patients who had been pathologically diagnosed with ESCC were evaluated in the present study. All patients underwent neoadjuvant CRT, followed by curative esophagectomy. The expression of ZNF750 in pretreatment biopsy samples was immunohistochemically investigated and compared to the histopathological effectiveness of CRT in surgical specimens. Results: High expression of ZNF750 was closely correlated with good sensitivity to CRT (p = 0.016). A univariate analysis showed that high/intermediate expression of ZNF750 was a significant predictive factor for good sensitivity to CRT (p = 0.006). High/intermediate expression of ZNF750 (30% or more) remained an independent predictive factor for sensitivity to CRT in a multivariate analysis (p = 0.033). Conclusions: ZNF750 expression predicts sensitivity to CRT and can be a biomarker that reliably predicts the response of ESCC to CRT.

Genome medicine has been attractingmuch of attention in Japan. The combination of molecular targetingdrug s and somatic mutations has been developed for cancer treatment, which was introduced clinically with evidence by cancer type. Several cancer somatic mutations can be identified in a single test inexpensively using next-generation sequencing(NGS). Drug approval not based on organs but on cancer genome analysis has been practiced mainly in the United States, and is also being implemented in Japan. However, cancer treatment strategies using molecular targeting drugs and the associated diagnosis are limited in each type of cancer. Furthermore, the benefit of NGS, which is an improved and inexpensive technique, is still insignificant in Japan. However, the clinical biobank system was initiated in 2011 to prepare the era of cancer genome medicine in our department. The quality of biological samples was strictly controlled by the standardized sampling procedures, which can be used by the researchers accordingto their convenience. Furthermore, the cooperative research involvingcommercial corporations has been started.

Gastric cancer (GC) with peritoneal metastasis remains difficult to treat. The anti-diabetic drug metformin exerts various antitumor effects via the 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway and nuclear factor-kappa B (NF-ĸB). Therefore, we evaluated the antitumor effects of metformin for GC in vitro and on peritoneal metastasis.The human GC cell lines MKN1, MKN45, KATO-III and SNU-1 were used. The antiproliferative effect was evaluated in vitro with 0.5 mM or 25 mM glucose and in vivo using tumor xenograft peritoneal models of metastasis. The protein expression of AMPK, liver kinase B1 (LKB1) and NF-ĸB in tumors was examined by western blotting.Metformin inhibited cell proliferation in all GC lines and sensitivity was increased under low-glucose conditions in vitro. Metformin also suppressed peritoneal metastasis. In tumors, metformin reduced the numbers of proliferating cells and NF-ĸB expression, but a similar trend was not noted for AMPK.Metformin may be a useful drug for the treatment of GC with peritoneal metastasis.

Objective: ZNF750, a transcriptional regulator of epidermal differentiation, has been identified as a tumor suppressor in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to investigate the clinical and prognostic significance of ZNF750 expression and to evaluate the effect of ZNF750 knockdown on cell proliferation, migration, and invasion in ESCC. Methods: A total of 124 patients with ESCC who underwent curative esophagectomy were evaluated in this study. The expression of ZNF750 in surgical specimens was immunohistochemically assessed and used in the analysis of clinicopathological features and overall survival (OS). The molecular role of ZNF750 was investigated by ZNF750 knockdown using small interfering RNA (siRNA) in ESCC cell lines. Results: Low ZNF750 expression had a significant correlation with positive lymph node metastasis (p = 0.028). Furthermore, there was a significant relationship between low expression of ZNF750 in ESCC and a poor OS, and a multivariate analysis showed that low ZNF750 expression was an independent prognostic factor (p = 0.020). The cell growth, migration, and invasion were significantly increased by downregulation of ZNF750. Conclusions: The low expression of ZNF750 was significantly associated with a poor prognosis, and ZNF750 expression may, therefore, be a reliable prognostic biomarker in ESCC.

Acute pancreatitis reportedly occurs in about 15 % of cases of branch duct (BD)-intraductal papillary mucinous neoplasms (IPMNs), with two-thirds of BD-IPMNs being located in the head or uncinate process of the pancreas. However, the surgical indications and optimal treatment methods for BD-IPMNs have not been established. A 59-year-old Japanese male with epigastralgia was admitted to our hospital. A multidetector row computed tomography (MDCT) scan disclosed grade I acute pancreatitis. Magnetic resonance cholangiopancreatography disclosed a 1.5-cm BD-IPMN in the uncinate process. Two months after discharge, the epigastralgia recurred, and MDCT again revealed grade I pancreatitis. Due to the repeated episodes of pancreatitis, we performed ductal branch-oriented pancreatic resection. To detect the inferior branch of the Wirsung duct and avoid the development of a pancreatic fistula, we injected indigo carmine into the tumor which confirmed ligation of the inferior branch. Histopathologically, the tumor proved to be an adenoma. The postoperative course was uneventful in both the short- and long-term follow-up and, to date, there has been no recurrence of pancreatitis, or diabetes mellitus during the 6 years since pancreatectomy. This procedure is one of the methods that can be used for the successful resection of a BD-IPMN in the uncinate process that caused recurrent acute pancreatitis.

A 44-year-old man consulted an internist because of abnormalities in an upper gastrointestinal series. It showed an elevated lesion with central depression in the greater curvature of the middle part of the stomach. Upper gastrointestinal endoscopy showed an elevated lesion with central depression, bridging hold, and no abnormalities of the gastric mucosa in the greater curvature of the middle part of the stomach. Endoscopic ultrasonography showed a submucosal tumor derived from the muscle layer of the stomach. Computed tomography showed a 22-mm tumor in the upper part of the stomach. Integrated position emission tomography/computed tomography (PET/CT) showed an intense tracer uptake by the tumor. Based on these findings, a gastrointestinal stromal tumor was suspected and laparoscopic endoscopic cooperative surgery was performed. A histopathological examination showed lymphoplasmacytic infiltration and fibrosis, and an immunohistochemical analysis showed the infiltration of IgG4-positive lymphoplasmacytic cells. The probable diagnosis was IgG4-related sclerosing disease of the stomach. We herein describe a rare case of probable IgG4-related sclerosing disease which presented as a gastric submucosal tumor. PET/CT is a useful imaging technique for the diagnosis and follow-up of this disease.

Exosomes play important roles in cancer progression. Although its contents (e.g., proteins and microRNAs) have been focused on in cancer research, particularly as potential diagnostic markers, the exosome behavior and methods for exosome quantification remain unclear. In the present study, we analyzed the tumor-derived exosome behavior and assessed the quantification of exosomes in patient plasma as a biomarker for esophageal squamous cell carcinoma (ESCC). A CD63-GFP expressing human ESCC cell line (TE2-CD63-GFP) was made by transfection, and mouse subcutaneous tumor models were established. Fluorescence imaging was performed on tumors and plasma exosomes harvested from mice. GFP-positive small vesicles were confirmed in the plasma obtained from TE2-CD63-GFP tumor-bearing mice. Patient plasma was collected in Chiba University Hospital (n=86). Exosomes were extracted from 100 µl of the plasma and quantified by acetylcholinesterase (AChE) activity. The relationship between exosome quantification and the patient clinical characteristics was assessed. The quantification of exosomes isolated from the patient plasma revealed that esophageal cancer patients (n=66) expressed higher exosome levels than non-malignant patients (n=20) (P=0.0002). Although there was no correlation between the tumor progression and the exosome levels, exosome number was the independent prognostic marker and low levels of exosome predicted a poor prognosis (P=0.03). In conclusion, exosome levels may be useful as an independent prognostic factor for ESCC patients.

The current report presents the case of a 46-year-old woman with phyllodes tumor metastasis to the anterior chest wall treated by radiation therapy. Although the lesion was not controlled with surgery and chemotherapy, the tumor size markedly reduced after radiation therapy, and bleeding and foul odor from the tumor stopped. Radiation therapy for phyllodes tumor appears to be an effective treatment and should be recognized as one choice of palliative medicine.

A 63-year-old man who had been admitted to another institute with sepsis and renal failure was referred to our hospital after computed tomography (CT) findings showed thickening of the walls in the sigmoid colon and a defect in contrast enhancement in the portal and inferior mesenteric veins. Emergency sigmoid colon resection with D2 lymphadenectomy was performed after detection of perforation due to sigmoid colon cancer. The histopathological diagnosis was adenosquamous carcinoma, pSS, int, INF b, ly1, v0, pN2, pStage IIIband inferior mesenteric vein thrombosis. He was discharged on day 12, and we administered anticoagulant warfarin therapy.

A 70-year-old woman was admitted for difficulty in swallowing. Esophageal cancer (MtLt, type 3, T4N3M0, cStage IVa) was diagnosed in May 2010. The cancer was unresectable, and chemoradiotherapy (CRT) with TS-1 was initiated in June 2010, and a partial response (PR) was observed. After CRT, TS-1 was continued, but a brain metastasis was detected owing to the development of right hemiplegia in April 2012. Craniotomy and tumorectomy were performed, and the right hemiplegia improved. Pathological examination of the brain tumor indicated squamous cell carcinoma. Because of a recurrence of brain metastasis, a gamma knife procedure was performed in May 2012. Subsequently, several recurrences of brain metastases were diagnosed, and a total of 7 gamma knife procedures were performed up to January 2014. Although systemic chemotherapy (5-fluorouracil and cisplatin [FP], 5 courses)was administered, the patient showed progressive lung metastases in February 2013. The chemotherapy regimen was changed from FP to docetaxel (TXT), but the lung metastases continued to progress up to June 2013. The patient died in March 2014. Patients with esophageal cancer and metastases to the brain have poor prognosis, but the present patient survived approximately 2 years after first diagnosis of metastases to the brain after multidisciplinary therapy.

A 63-year-old man was admitted for an abdominal mass. Computed tomography revealed an abscess (21 × 20 cm) in the abdominal wall and a tumor in the sigmoid colon. Thus, cancer of the sigmoid colon complicated by an abscess of the abdominal wall was diagnosed. The abscess was drained and transverse colostomy was performed with curative intent. After the intervention, chemotherapy (XELOX×3) was administered. Three months later, sigmoidectomy was performed and the stoma was closed. Macroscopic and microscopic examination of the resected specimen detected no remnants of cancer. In patients with advanced colon cancer and abdominal wall involvement, a two-stage operation and preoperative chemotherapy may be considered essential when curative resection is performed.

In recent years, large-scale international studies have provide comprehensive catalogues of genomic alterations in cancers including Esophageal Squamous Cell Cancer(ESCC). They revealed that some gene associated with cell cycle/apoptosis pathway, NOTCH pathway, WNT pathway, such as TP53 and NOTCH1, harbored genetic abnormalities frequently. As the next step clinical sequencing studies are starting to evaluate efficacy of using targeted agents to patients with specific molecular aberrations. We performed exome sequencing and RNA sequencing for 25 Japanese patients with esophageal squamous cell carcinoma (ESCC) to provide a comprehensive catalogue of genomic abnormalities in ESCC and found TP53 and ZNF750 significantly mutated genes. Additionally, we performed allele specific expression analysis of TP53, integrating mRNA sequencing data into the information of genomic abnormality. This analysis revealed that levels of expression changes depending on mutation types and nearly mono-allelic expression of TP53 was a common signature of ESCC patients with somatic mutations. And pattern of mono-allelic expression was dependent on mutation types. We expanded this analysis to all genes with somatic SNV mutations and revealed that mutant allele specific expression was observed in other genes including ZNF750, and many of them were belonged to cancer pathway in KEGG database. About TP53, our investigation might provide better understanding of the involvement of somatic mutations. And fluctuations in transcriptional regulation of TP53 could be predicted based on type of somatic mutation. In addition to this, analysis of allele specific expression suggested that not only somatic mutation of DNA, but also mutant allele expression should be considered to understand cancer genetic pathophysiology better and build more effective therapeutic strategies. Citation Format: Masahiko Takahashi, Hirofumi Nakaoka, Yasunori Akutsu, Naoyuki Hanari, Kentaro Murakami, Masayuki Kano, Yasunori Matsumoto, Ryota Otsuka, Nobufumi Sekino, Masaya Yokoyama, Itsuro Inoue, Hisahiro Matsubara. Analysis of allele specific expression in esophageal squamous cell carcinoma with combination of exome sequencing and mRNA Sequencing [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B07.

Roux-en-Y reconstruction after distal gastrectomy can result in delayed gastric emptying, called Roux stasis syndrome (RSS). The cause of RSS has not been completely identified. This study retrospectively investigated the development of RSS.Between April 2008 and March 2014, we performed 138 procedures with distal gastrectomy using Roux-en-Y reconstruction. The development of RSS was analyzed and examined for correlations with the length of the operation, amount of blood loss, and surgical procedure.RSS was observed in 16 of the 138 patients. There were no relationships between the length of the operation or amount of blood loss and the development of RSS according to the Mann-Whitney U test. There were also no significant differences in the development of RSS between the patients treated with laparotomy and laparoscopic surgery, end-to-side, side-to-side, or end-to-end anastomosis or isoperistaltic or antiperistaltic anastomosis, as determined using the chi-square test. However, the development of RSS tended to lower in the patients who underwent laparoscopic surgery, side-to-side anastomosis, and isoperistaltic anastomosis. In addition, there was a significant difference between the patients who received antecolic and retrocolic reconstruction (p=0.005).Our findings suggest that antecolic reconstruction correlates with a lower likelihood of developing RSS.

We report a case of patient who is alive 10 years after total gastrectomy and partial liver resection for gastric cancer and liver metastasis, respectively. The patient is 69-year-old man who was examined in another hospital for nausea, tarry stool, and weight loss. Diagnosis by stomach fluoroscopy revealed gastric cancer and he was admitted to our hospital in September 2002. Computed tomography (CT) scan and ultrasonography (US) revealed liver metastasis in S7. Distant metastases were not detected. The patient underwent distal gastrectomy, transverse colon partial resection, and a hepatic partial resection in October 2002. Pathological findings showed SI, N1, and M1. Though adjuvant chemotherapy was given, a local recurrence was detected in the liver in February 2003. Hepatic arterial infusion (HAI) was started in April 2003. After 8 courses, HAI was discontinued because of hepatic artery obstruction. No additional distant metastases were found. Therefore, transdiaphragmatic radiofrequency ablation (RFA) was performed by thoracotomy. Currently, the patient is treatment free and remains alive after 10 years with no recurrence.

Exosomes are small membrane vesicles (30-100 nm) and are thought to play an important role in tumor progression, chemoresistance, dormancy etc. However, the exosome dynamics and transportation between cancer cells and the other cells are still unclear. In addition, although it is common method to quantify exosomes using standard protein quantification methods, it is actually incorrect. In this study, we assessed the exosome dynamics with mouse model and quantify plasma exosome by cholesteryl ester transfer protein activity, which is known to be enriched within exosomes. We analyzed the relationship between exosome quantification and clinical characters in ESCC patients. In order to image and analyze the movement of cancer cell-derived exosomes, green fluorescent protein (GFP)-tagged CD63, which is a general marker of exosomes, was expressed in human esophageal squamous cancer cell line TE2. Mouse model of human ESCC were then established by s.c. injection of TE2-CD63-GFP or TE2 cell lines. Eight weeks after injection, the tumor, blood and other organs were harvested and imaged with fluorescence. Our data indicates tumor derived exosome can emitted from the tumor and circulate in the blood flow. Quantification of plasma exosome in ESCC patients (n = 64) and no malignant patient (n = 10) were performed by measurement of cholesteryl ester protein activity, and then analyzed the relationship between the exosome number and the patients’ clinical characteristics, such as age, sex, TNM classification, prognosis, tumor marker. Our data indicates the exosome number was higher in ESCC patients than no malignant patients (P = 0.0014). Althogh there were no difference in tumor depth, lymph node status, distant metastasis, the exosome number can be a prognostic marker for ESCC (P = 0.04). Citation Format: Yasunori Matsumoto, Masayuki Kano, Yasunori Akutsu, Naoyuki Hanari, Isamu Hoshino, Kentaro Murakami, Akihiro Usui, Hiroshi Suito, Masahiko Takahashi, Ryota Otsuka, Hisahiro Matsubara. Usefulness of exosome quantification by cholesteryl ester transfer protein activity as a biomarker for human esophageal squamous cell carcinoma (ESCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 487.