Language：English   Publishing type：Research paper (scientific journal)  

Adenosine-to-inosine RNA editing is a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family. It has been discovered recently as an epigenetic modification dysregulated in human cancers. However, the clinical significance of RNA editing in patients with liver metastasis from colorectal cancer (CRC) remains unclear. The current study aimed to systematically and comprehensively investigate the significance of adenosine deaminase acting on RNA 1 (ADAR1) expression status in 83 liver metastatic tissue samples collected from 36 patients with CRC. The ADAR1 expression level was significantly elevated in liver metastatic tissue samples obtained from patients with right-sided, synchronous, or RAS mutant-type CRC. ADAR1-high liver metastasis was significantly correlated with remnant liver recurrence after hepatic metastasectomy. A high ADAR1 expression was a predictive factor of remnant liver recurrence (area under the curve = 0.72). Results showed that the ADAR1 expression level could be a clinically relevant predictive indicator of remnant liver recurrence. Patients with liver metastases who have a high ADAR1 expression requires adjuvant chemotherapy after hepatic metastasectomy.

DOI： 10.1038/s41598-023-29397-z

PubMed

researchmap

Language：English  

An annular pancreas is a rare anomaly of the pancreas, defined as pancreatic tissue that totally or partly encircles the duodenum, usually the descending portion. A 76-year-old man who was diagnosed with gastric cancer cT3N0M0 Stage IIB underwent laparoscopic distal gastrectomy with D2 lymph node dissection. Intraoperatively, the dorsal half of the duodenal bulb was seen to be half surrounded by the pancreas, and a non-typical annular pancreas was diagnosed. Because of the risk to the pancreas, it was considered impossible to perform anastomosis by a linear stapler as in the usual laparoscopic procedure. Therefore, we performed laparoscopically assisted distal gastrectomy and Billroth-I reconstruction using a circular stapler, and the surgery was completed without difficulties. His postoperative course was good despite the development of a pancreatic fistula, which was an International Study Group for Pancreas Fistula biochemical leak. Some APs can be diagnosed preoperatively, but the rarer subtypes such as ours are more difficult to visualize on imaging. In gastrectomy, it is both oncologically important and technically challenging to perform lymph node dissection around the pancreas. In this case with an especially proximal pancreas, a circular stapler was considered better suited for gastroduodenal anastomosis and required a broader field than that afforded by laparoscopy. A case of non-typical annular pancreas diagnosed during laparoscopic gastric surgery is described.

DOI： 10.18926/AMO/64368

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: Ulcerative colitis (UC) can develop colitis-associated colorectal neoplasm (CAN). Adenine-to-inosine RNA editing, which is regulated by adenosine deaminase acting on RNA (ADAR), induces the posttranscriptional modification of critical oncogenes, including antizyme inhibitor 1 (AZIN1), leading to colorectal carcinogenesis. Therefore, we hypothesized that ADAR1 might be involved in the development of CAN in UC. METHODS: We systematically analyzed a cohort of 139 UC cases (40 acute phase, 73 remission phase, 26 CAN). The degree of inflammation was evaluated using the Mayo endoscopic score (MES). RESULTS: The type 1 IFN-related inflammation pathway was upregulated in the rectum of active UC, rectum of UC-CAN, and tumor site of UC-CAN patients. ADAR1 expression was upregulated in the entire colon of CAN cases, while it was down-regulated in non-CAN MES0 cases. ADAR1 expression in the rectum predicted the development of CAN better than p53 or β-catenin, with an area under the curve of 0.93. The high expression of ADAR1 and high AZIN1 RNA editing in UC was triggered by type 1 IFN stimulation from UC-specific microbiomes, such as Fusobacterium in vitro analyses. The induction of AZIN1 RNA editing by ADAR1, whose expression is promoted by Fusobacterium, may induce carcinogenesis in UC. CONCLUSIONS: The risk of CAN can be evaluated by assessing ADAR1 expression in the rectum of MES0 UC patients, freeing UC patients from unnecessary colonoscopy and reducing their physical burden. RNA editing may be involved in UC carcinogenesis, and may be used to facilitate the prevention and treatment of CAN in UC.

DOI： 10.1093/ecco-jcc/jjac186

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A and subsequent accumulation of glycosphingolipids with terminal α-D-galactosyl residues. The molecular process through which this abnormal metabolism of glycosphingolipids causes multisystem dysfunction in Fabry disease is not fully understood. We sought to determine whether dysregulated DNA methylation plays a role in the development of this disease. In the present study, using isogenic cellular models derived from Fabry patient endothelial cells, we tested whether manipulation of α-galactosidase A activity and glycosphingolipid metabolism affects DNA methylation. Bisulfite pyrosequencing revealed that changes in α-galactosidase A activity were associated with significantly altered DNA methylation in the androgen receptor promoter, and this effect was highly CpG loci-specific. Methylation array studies showed that α-galactosidase A activity and glycosphingolipid levels were associated with differential methylation of numerous CpG sites throughout the genome. We identified 15 signaling pathways that may be susceptible to methylation alterations in Fabry disease. By incorporating RNA sequencing data, we identified 21 genes that have both differential mRNA expression and methylation. Upregulated expression of collagen type IV alpha 1 and alpha 2 genes correlated with decreased methylation of these two genes. Methionine levels were elevated in Fabry patient cells and Fabry mouse tissues, suggesting that a perturbed methionine cycle contributes to the observed dysregulated methylation patterns. In conclusion, this study provides evidence that α-galactosidase A deficiency and glycosphingolipid storage may affect DNA methylation homeostasis and highlights the importance of epigenetics in the pathogenesis of Fabry disease and, possibly, of other lysosomal storage disorders.

DOI： 10.1016/j.ymgmr.2022.100919

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Biliary tract cancer (BTC) is a Lynch syndrome (LS)-associated cancer with a high mortality rate. This study aimed to clarify the clinical features of BTC in individuals with LS and to discuss its management. METHODS: We obtained data from genetically verified Japanese individuals with LS who were diagnosed at a single institution, between January 2003 and April 2021. Moreover, 21 individuals with sporadic BTC (n=15) and LS associated BTC (n=6) underwent microsatellite instability (MSI) testing. RESULTS: Among 92 individuals with LS, 6 individuals with MLH1 variants developed BTCs (10 lesions, male/female, 2:1). The median age at diagnosis of initial BTC was 69 years (range, 34-78 years). Histological examination revealed a predominance of differentiated adenocarcinoma (89%). Then, 2 individuals had multiple BTCs. All available 7 BTC lesions showed high-frequency of microsatellite instability (MSI-H). MLH1 carriers showed a 7.2% cumulative risk of BTC development at an age of 70 years. Five of the six individuals died of BTC. CONCLUSIONS: MSI analysis could facilitate LS identification in individuals with BTC. Surveillance for BTC should be considered for MLH1 carriers in Japan.

DOI： 10.21037/jgo-22-165

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability-high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p < 0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p < 0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX-CRT regimen. CRT can promote proteomic diversity via RNA editing.

DOI： 10.1038/s41598-022-17773-0

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role and clinical significance in endometrial cancer (EC) remain unclear. METHODS: Adenosine Deaminase family Acting on RNA1 (ADAR1) expression and Antizyme inhibitor 1 (AZIN1) RNA editing were examined to clarify the correlation with clinicopathological parameters and prognosis in EC patients. The biological functions and inhibitory effects of ADAR1 knockdown were investigated in JHUCS-1 and TU-ECS-1 EC cell lines. RESULTS: ADAR1 showed significant association with worse histology (P = 0.006), and lymph vascular space involvement (P = 0.049) in EC. The level of AZIN1 RNA editing was also significantly associated with worse histology (P = 0.012). ADAR1 expression was significantly correlated with AZIN1 RNA editing level (R = 0.729, R2 = 0.547, P < 0.001). Multivariate analysis indicated that higher ADAR1 expression along with AZIN1 RNA editing is an independent predictor of prognosis in EC patients (P = 0.015). Knockdown of ADAR1 led to increased MDA-5, RIG-I, PKR, and IRF-7 expression, which in turn resulted in increased levels of Bak and apoptosis in EC cells. CONCLUSIONS: High ADAR1 expression along with AZIN1 RNA editing could be a predictor of worse prognosis in EC. ADAR1 could be a potential therapeutic target in EC patients.

DOI： 10.1016/j.ygyno.2022.05.026

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Conventional imaging techniques are available for clinical identification of tumor sites. However, detecting metastatic tumor cells that are spreading from primary tumor sites using conventional imaging techniques remains difficult. In contrast, fluorescence-based labeling systems are useful tools for detecting tumor cells at the single-cell level in cancer research. The ability to detect fluorescent-labeled tumor cells enables investigations of the biodistribution of tumor cells for the diagnosis and treatment of cancer. For example, the presence of fluorescent tumor cells in the peripheral blood of cancer patients is a predictive biomarker for early diagnosis of distant metastasis. The elimination of fluorescent tumor cells without damaging normal tissues is ideal for minimally invasive treatment of cancer. To capture fluorescent tumor cells within normal tissues, however, tumor-specific activated target molecules are needed. This review focuses on recent advances in tumor-targeted fluorescence labeling systems, in which indirect reporter labeling using tumor-specific promoters is applied to fluorescence labeling of tumor cells for the diagnosis and treatment of cancer. Telomerase promoter-dependent fluorescence labeling using replication-competent viral vectors produces fluorescent proteins that can be used to detect and eliminate telomerase-positive tumor cells. Tissue-specific promoter-dependent fluorescence labeling enables identification of specific tumor cells. Vimentin promoter-dependent fluorescence labeling is a useful tool for identifying tumor cells that undergo epithelial-mesenchymal transition (EMT). The evaluation of tumor cells undergoing EMT is important for accurately assessing metastatic potential. Thus, tumor-targeted fluorescence labeling systems represent novel platforms that enable the capture of tumor cells for the diagnosis and treatment of cancer.

DOI： 10.1111/cas.15369

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Emerging evidence indicates that immunogenicity plays an important role in intrahepatic cholangiocarcinoma (ICC). Herein, we systematically evaluated the clinical relevance of immunogenicity in ICC. METHODS: Highly immunogenic ICCs identified in the public dataset and the Cancer Immunome Atlas (TCIA) were assessed to determine the prognostic impact of immunogenicity in ICC and key components after curative resection. We also investigated the clinical relevance of the immune milieu in ICC. RESULTS: Using the Gene Expression Omnibus dataset 89749 and TCIA, we identified CD8+/forkhead box P3 (FoxP3)+ tumour-infiltrating lymphocytes (TILs), T-cell immunoglobulin and mucin domain 3 (TIM-3) and human leukocyte antigen-A (HLA-A) in highly immunogenic ICCs. Immunohistochemical analysis of the in-house cohort showed that intratumoral FoxP3+ TILs correlated with CD8+ TILs (P = 0.045, Fisher's exact test) and that high FoxP3+/CD8+ ratio (FCR) was an important marker for poor survival (P < 0.001, log-rank test). Furthermore, the FCR was higher in tumour-free lymph nodes in ICCs with lymph node metastases than in those without lymph node metastases (P = 0.003, Mann-Whitney U test). CONCLUSIONS: FCR should be considered an important biomarker that represents the immune environment of ICC based on its potentially important role in tumour progression, especially lymph node metastasis.

DOI： 10.1038/s41416-022-01838-y

PubMed

researchmap

Language：English  

A 43-year-old female underwent pelvic magnetic resonance imaging for uterine myoma that incidentally revealed a 4.6 × 2.8 cm soft tissue mass in the anorectal region. Rectal endoscopy showed a submucosal tumor just above the anal canal. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed an anorectal tumor with very high FDG uptake. Aspiration cytology and needle biopsy were inconclusive, and the patient underwent trans-perineal tumor resection. The excised tumor was a 4.6 × 3.5 × 2.7 cm gray-white bifurcated nodular tumor. Light microscopy revealed fenestrated growth of poorly dysmorphic short spindle-shaped cells with eosinophilic sporophytes. Immunohistochemical staining was positive for αSMA and desmin, negative for CD117 (KIT) and S100, and the patient was diagnosed with benign leiomyoma. Tumor cells were also positive for glucose transporter-1 (GLUT1) immunohistochemically. It is important to keep in mind that FDG-PET/CT may show false-positive results even in benign anal leiomyoma for various reasons, including GLUT1 overexpression.

DOI： 10.1093/jscr/rjac101

PubMed

researchmap

Publishing type：Research paper (scientific journal)  

Objective: This study aimed to identify factors associated with outlet obstruction and high-output stoma (HOS) after ileostomy creation. Summary of background data: Ileostomy creation is effective in preventing leakage among patients undergoing low anterior resection for rectal cancer. However, major complications such as outlet obstruction and HOS can occur after surgery. Moreover, these complications cannot be prevented. Methods: This retrospective study included 34 patients with rectal cancer who underwent low anterior resection and ileostomy creation at Okayama University Hospital from January 2015 to December 2018. Then, the risk factors associated with outlet obstruction and HOS were analyzed. Results: Of 34 patients, 7 (21%) experienced outlet obstruction. In a multivariate logistic regression analysis, advanced T stage (P ¼ 0.10), ileostomy with a short horizontal diameter (P ¼ 0.01), and thick rectus abdominis (RA) muscle (P ¼ 0.0005) were considered independent risk factors for outlet obstruction. There was a significant correlation between outlet obstruction and HOS (P ¼ 0.03). Meanwhile, the independent risk factors of HOS were advanced T stage (P ¼ 0.03) and thick RA muscle (P ¼ 0.04). Conclusions: Thick RA muscle and advanced T stage were the common risk factors of outlet obstruction and HOS. Therefore, in high-risk patients, these complications can be prevented by choosing an appropriate ileostomy location according to RA muscle thickness and by preventing tubing into the ileostomy.

DOI： 10.9738/INTSURG-D-21-00012.1

Scopus

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Plastic and Reconstructive Surgery  

DOI： 10.53045/jprs.2022-0020

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Hyperthermia has been used for cancer therapy for along period of time, but has shown limited clinical efficacy. Induction-heating hyperthermia using the combination of magnetic nanoparticles (MNPs) and an alternating magnetic field (AMF), termed magnetic hyperthermia (MHT), has previously shown efficacy in an orthotopic mouse model of disseminated gastric cancer. In the present study, superparamagnetic iron oxide nanoparticles (SPIONs), atype of MNP, were conjugated with an anti-HER2 antibody, trastuzumab and termed anti-HER2-antibody-linked SPION nanoparticles (anti-HER2 SPIONs). Anti-HER2 SPIONs selectively targeted HER2-expressing cancer cells co-cultured along with normal fibroblasts and HER2-negative cancer cells and caused apoptosis only in the HER2-expressing individual cancer cells. The results of the present study show proof-of-concept of anovel hyperthermia technology, immuno-MHT for selective cancer therapy, that targets individual cancer cells.AbbreviationsAMF:alternating magnetic fieldDDW:double distilled waterDMEM:Dulbecco's Modified Eagle's Mediumf:frequencyFBS:fetal bovine serumFITC:Fluorescein isothiocyanateGFP:green fluorescent proteinH:amplitudeHsp:heat shock proteinMHT:magnetic hyperthermiaMNPs:magnetic nanoparticlesPI:propidium iodideRFP:red fluorescent proteinSPION:superparamagnetic iron oxide (Fe3O4) nanoparticle.

DOI： 10.1080/15384101.2021.1915604

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Magnetic hyperthermia (MHT), which combines magnetic nanoparticles (MNPs) with an alternating magnetic field (AMF), holds promise as a cancer therapy. There have been many studies about hyperthermia, most of which have been performed by direct injection of MNPs into tumor tissues. However, there have been no reports of treating peritoneal disseminated disease with MHT to date. In the present study, we treated peritoneal metastasis of gastric cancer with MHT using superparamagnetic iron oxide (Fe3O4) nanoparticle (SPION) coated with carboxydextran as an MNP, in an orthotopic mouse model mimicking early peritoneal disseminated disease of gastric cancer. SPIONs of an optimal size were intraperitoneally administered, and an AMF (390 kHz, 28 kAm-1) was applied for 10 minutes, four times every three days. Three weeks after the first MHT treatment, the peritoneal metastases were significantly inhibited compared with the AMF-alone group or the untreated-control group. The results of the present study show that MHT can be applied as a new treatment option for disseminated peritoneal gastric cancer.Abbreviations: AMF: alternating magnetic field; Cy1: cytology-positive; DMEM: Dulbecco's Modified Eagle's Medium; FBS: fetal bovine serum; H&E: hematoxylin and eosin; HIPEC: hyperthermic intraperitoneal chemotherapy; MEM: Minimum Essential Medium; MHT: magnetic hyperthermia; MNPs: magnetic nanoparticles; P0: macroscopic peritoneal dissemination; RFP: red fluorescent protein; SPION: superparamagnetic iron oxide (Fe3O4) nanoparticle.

DOI： 10.1080/15384101.2021.1919441

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

BACKGROUND: Mutations in the POLE gene result in an ultra-hypermutated phenotype in colorectal cancer (CRC); however, the molecular characterisation of epigenetic alterations remains unclear. We examined the genetic and epigenetic profiles of POLE-mutant CRC to elucidate the clinicopathological features of the associated genetic and epigenetic alterations. RESULTS: Tumour tissues (1,013) obtained from a cohort of patients with CRC were analysed to determine associations between the proofreading domain mutations of POLE with various clinicopathological variables, microsatellite instability (MSI) status, BRAF and KRAS mutations, and the methylation status of key regions of MLH1, MGMT, and SFRP2 promoters by calculating the methylation scores (range 0-6). Only four cases (0.4%) exhibited pathogenic POLE hotspot mutations (two p.P286R [c.857C > G], one p.V411L [c.1231G > C], and p.S459F [c.1376C > T] each), which were mutually exclusive to BRAF and KRAS mutations and MSI. CRC patients were divided into four subgroups: patients with POLE mutations (POLE, 0.4%, n = 4), patients with both MSI and extensive methylation in MLH1 (MSI-M, 2.9%, n = 29), patients with MSI but no extensive methylation in MLH1 (MSI-U, 3.6%, n = 36), and patients without MSI (non-MSI, 93.2%, n = 944). The POLE group was younger at diagnosis (median 52 years, P < 0.0001), with frequent right-sided tumour localisation (frequency of tumours located in the right colon was 100%, 93.1%, 36.1%, and 29.9% in POLE, MSI-M, MSI-U, and non-MSI, respectively; P < 0.0001), and was diagnosed at an earlier stage (frequency of stages I-II was 100%, 72.4%, 77.8%, and 46.6% in POLE, MSI-M, MSI-U, and non-MSI, respectively, P < 0.0001). The mean methylation score in POLE was not different from that in MSI-U and non-MSI, but the methylation signature was distinct from that of the other subgroups. Additionally, although the examined number of POLE-mutant tumours was small, the number of CD8-positive cells increased in tumours with partial methylation in the MLH1 gene. CONCLUSIONS: CRC patients with POLE proofreading mutations are rare. Such mutations are observed in younger individuals, and tumours are primarily located in the right colon. Diagnosis occurs at an earlier stage, and distinct epigenetic alterations may be associated with CD8 cell infiltration.

DOI： 10.1186/s13148-021-01104-7

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Scientific Information, Inc.  

Objective: Rare diseaseBackground: Juvenile polyposis syndrome is an uncommon, autosomal-dominant hereditary disease that is distinguished by multiple polyps in the stomach or intestinal tract. It is associated with a high risk of malignancy. Pathogenic variants in SMAD4 or BMPR1A account for 40% of all cases.Case Report: A 49-year-old woman underwent esophagogastroduodenoscopy because of exacerbation of anemia. She had numerous erythematous polyps in most parts of her stomach. Based on biopsy findings, juvenile polyposis syndrome (JPS) was suspected morphologically, but there was no evidence of malignancy. Colonoscopy showed stemmed hyperplastic polyps and an adenoma; video capsule endoscopy revealed no lesions in the small intestine. After preoperative surveillance, laparoscopic total gastrectomy with D1 lymph node dissection was performed to prevent malignant transformation. The pathological diagnosis was juvenile polyp-like polyposis with adenocarcinoma. In addition, a germline pathogenic variant in the SMAD4 gene was detected with genetic testing.Conclusions: JPS can be diagnosed with endoscopy and genetic testing. Further, appropriate surgical management may prevent cancer-related death in patients with this condition.

DOI： 10.12659/ajcr.932241

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Targeted therapies for malignant melanoma have improved patients' prognoses. A primary gastrointestinal malignant melanoma is very rare, with no standard treatment strategy. We treated a 78-year-old Japanese female with advanced primary gastrointestinal melanoma of the descending colon and gallbladder. We administered a multidisciplinary treatment: surgical resection of the descending colon and gallbladder tumors, resection of the metastatic lymph nodes behind the pancreas head, and immune checkpoint antibody-blockade therapy (nivolumab) for ~4 years. PET/CT demonstrated no recurrent lesion for > 3 years. Multidisciplinary therapies (e.g., surgery, chemotherapy, radiotherapy, target therapy, and immune checkpoint antibody-blockade therapy) can successfully treat primary gastrointestinal malignant melanoma.

DOI： 10.18926/AMO/61906

Web of Science

PubMed

researchmap

Language：English   Publisher：WILEY  

Web of Science

researchmap

Language：English   Publisher：WILEY  

Web of Science

researchmap

Language：English   Publisher：WILEY  

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

Accumulating evidence suggests that dysregulation of transcriptional enhancers plays a significant role in cancer pathogenesis. Herein, we performed a genome-wide discovery of enhancer elements in colorectal cancer (CRC). We identified PVT1 locus as a previously unrecognized transcriptional regulator in CRC with a significantly high enhancer activity, which ultimately was responsible for regulating the expression of MYC oncogene. High expression of the PVT1 long-non-coding RNA (lncRNA) transcribed from the PVT1 locus was associated with poor survival among patients with stage II and III CRCs (p < 0.05). Aberrant methylation of the PVT1 locus inversely correlated with the reduced expression of the corresponding the PVT1 lncRNA, as well as MYC gene expression. Bioinformatic analyses of CRC-transcriptomes revealed that the PVT1 locus may also broadly impact the expression and function of other key genes within two key CRC-associated signaling pathways - the TGFβ/SMAD and Wnt/β-Catenin pathways. We conclude that the PVT1 is a novel oncogenic enhancer of MYC and its activity is controlled through epigenetic regulation mediated through aberrant methylation in CRC. Our findings also suggest that the PVT1 lncRNA expression is a promising prognostic biomarker and a potential therapeutic target in CRC.

DOI： 10.1186/s12943-020-01277-4

Web of Science

PubMed

researchmap

Language：Japanese  

CiNii Article

CiNii Books

J-GLOBAL

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00393&link_issn=&doc_id=20200130110017&doc_link_id=issn%3D0016-593X%26volume%3D82%26issue%3D2%26spage%3D186&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0016-593X%26volume%3D82%26issue%3D2%26spage%3D186&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remains unclear. Here, we show the spatiotemporal visualization of CRC cells undergoing EMT using a fluorescence-guided EMT imaging system in which the mesenchymal vimentin promoter drives red fluorescent protein (RFP) expression. An inflammatory microenvironment including TNF-α, IL-1β, and cytokine-secreting inflammatory macrophages induced RFP expression in association with the EMT phenotype in CRC cells. In vivo experiments further demonstrated the distribution of RFP-positive CRC cells in rectal and metastatic tumors. Our data suggest that the EMT imaging system described here is a powerful tool for monitoring EMT in inflammatory microenvironment-CRC networks.

DOI： 10.1038/s41598-019-52816-z

Web of Science

PubMed

researchmap

Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.SABCS18-4330

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: Lynch syndrome (LS) is a predominantly inherited syndrome caused by a pathological germline mutation in one of the mismatch repair (MMR) genes. Whether breast cancer (BC) is one of the LS-associated tumors is controversial. The aim of this retrospective cohort study was to evaluate the clinical features of BC in Japanese patients with LS. METHODS: Of 38 mutation carriers, 4 females with BC were examined in this study. RESULTS: Two of the four patients had multiple BC. Their median age at the diagnosis of BC was 63 (range, 47-84) years. The TNM (6th revision) stages of the six BCs were as follows: stage I, 33% (2/6); stage IIA, 50% (3/6); and stage IIB, 17% (1/6). Histological examination revealed four scirrhous, one papillotubular, and one medullary carcinoma. The positive ratios for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth receptor 2 (HER2) were 83.3% (5/6), 83.3% (5/6), and 16.7% (1/6), respectively. Two of the three specimens showed MSI-H and one showed MSS. These MSI-H BCs had tumor-infiltrating lymphocytes. Two of the three specimens showed an absence of MLH1 and PMS2 proteins on immunohistochemistry. The cumulative risks for a person with LS to develop BC were 4.35% at the age of 50 years, 8.70% at 60 years, and 21.5% at 70 years. CONCLUSIONS: Our study results showed BC in Japanese females with LS to be an MSI-H tumor, which was ER and PgR positive and HER2 negative.

DOI： 10.1007/s12282-018-0931-z

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Chemoresistance in cancer is linked to a subset of cancer cells termed "cancer stem cells" (CSCs), and in particular, those expressing the CD44 variant appear to represent a more aggressive disease phenotype. Herein, we demonstrate that CD44v6 represents a CSC population with increased resistance to chemotherapeutic agents, and its high expression is frequently associated with poor overall survival (OS) and disease-free survival (DFS) in patients with colorectal cancer (CRC). CD44v6+ cells showed elevated resistance to chemotherapeutic drugs and significantly high tumor initiation capacity. Inhibition of CD44v6 resulted in the attenuation of self-renewal capacity and resensitization to chemotherapeutic agents. Of note, miRNA profiling of CD44v6+ spheroid-derived CSCs identified a unique panel of miRNAs indicative of high self-renewal capacity. In particular, miR-1246 was overexpressed in CD44v6+ cells, and associated with poor OS and DFS in CRC patients. We demonstrate that CD44v6+ CSCs induced chemoresistance and enhance tumorigenicity in CRC cells, and this was in part orchestrated by a distinct panel of miRNAs with dysregulated profiles. These findings suggest that specific miRNAs could serve as therapeutic targets as well as promising prognostic biomarkers in patients with colorectal neoplasia.

DOI： 10.1172/jci.insight.125294

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) and its clinical significance remains unclear. Herein, we systematically analyzed a large cohort of 627 colorectal cancer (CRC) specimens, and investigated the expression pattern of ADAR1 and its biological significance on the antizyme inhibitor 1 (AZIN1) RNA editing levels. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues vs. normal mucosa, and these findings correlated with the increased expression of mesenchymal markers, Vimentin (ρ = 0.44) and Fibroblast activation protein (ρ = 0.38). Intriguingly, ADAR1 expression was specifically upregulated in both cancer cells and fibroblasts from cancerous lesions. Conditioned medium from cancer cells led to induction of ADAR1 expression and activation of AZIN1 RNA editing in fibroblasts (p < 0.05). Additionally, edited AZIN1 enhanced the invasive potential of fibroblasts. In conclusion, we provide novel evidence that hyper-editing of AZIN1 enhances the invasive potential of CAFs within the TME in colon and is an important predictor of tumor invasiveness in CRC.

DOI： 10.1016/j.canlet.2018.12.009

Web of Science

PubMed

researchmap

Language：English   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

DOI： 10.1016/j.ymgme.2018.12.345

Web of Science

researchmap

Language：Japanese   Publisher：The Japanese Society for Familial Tumors  

Neurofibromatosis type 1 (NF1) is a complex autosomal dominant disorder caused by germline variants in the NF1 tumor suppressor gene characterized by multiple caféau lait spots and cutaneous neurofibromas. Therefore, NF1 predisposes patients to benign and malignant tumor development. We report a 54-year-old NF1 male with multiple gastrointestinal stromal tumors (GIST) in the small intestine. We resected a part of the small intestine with larger tumors, but left the part with small tumors to avoid short bowel syndrome. Histological examination revealed spindle cells with eosinophilic cytoplasm. The tumors were positive for KIT on immunopathological examination. They were smaller than 3.5 cm and their mitotic activity was less than 5/50 in high-power fields. We left 17 GIST that were smaller than 10 mm, but no progression has been detected to date. (<250 words)

DOI： 10.18976/jsft.19.2_77

CiNii Article

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

BACKGROUND: Adenosine-to-inosine (A-to-I) RNA editing is catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes. Recent evidence suggests that RNA editing of antizyme inhibitor 1 (AZIN1) RNA is emerging as a key epigenetic alteration underlying cancer pathogenesis. METHODS: We evaluated AZIN1 RNA editing levels, and the expression of its regulator, ADAR1, in 280 gastric tissues from 140 patients, using a RNA editing site-specific quantitative polymerase chain reaction assays. We also analyzed the clinical significance of these results as disease biomarkers in gastric cancer (GC) patients. RESULTS: Both AZIN1 RNA editing levels and ADAR1 expression were significantly elevated in GC tissues compared with matched normal mucosa (P < 0.0001, 0.0008, respectively); and AZIN1 RNA editing was positively correlated with ADAR1 expression. Elevated expression of ADAR1 significantly correlated with poor overall survival (P = 0.034), while hyper-edited AZIN1 emerged as an independent prognostic factor for OS and disease-free survival in GC patients [odds ratio (OR):1.98, 95% CI 1.17-3.35, P = 0.011, OR: 4.55, 95% CI 2.12-9.78, P = 0.0001, respectively]. Increased AZIN1 RNA editing and ADAR1 over-expression were significantly correlated with key clinicopathological factors, such as advanced T stage, presence of lymph node metastasis, distant metastasis, and higher TNM stages in GC patients. Logistic regression analysis revealed that hyper-editing status of AZIN1 RNA was an independent risk factor for lymph node metastasis in GC patients [hazard ratio (HR):3.03, 95% CI 1.19-7.71, P = 0.02]. CONCLUSIONS: AZIN1 RNA editing levels may be an important prognostic biomarker in GC patients, and may serve as a key clinical decision-making tool for determining preoperative treatment strategies in GC patients.

DOI： 10.1186/s12967-018-1740-z

Web of Science

PubMed

researchmap

Language：English   Publisher：WILEY  

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Gastric cancer patients positive for peritoneal cytology are at increased risk of tumor recurrence, but although a certain proportion of cytology-positive patients relapse rapidly with aggressive progression, others survive longer with conventional chemotherapies. This heterogeneity makes it difficult to stratify patients for more intensive therapy and poses a substantial challenge for the implementation of precision medicine. We developed a new approach to identify biologically malignant subpopulations in cytology-positive gastric cancer patients, using a green fluorescent protein (GFP)-expressing attenuated adenovirus in which the telomerase promoter regulates viral replication (TelomeScan, OBP-401). The fluorescence emitted from TelomeScan-positive cells was successfully quantified using a multi-mode microplate reader. We then analyzed clinical peritoneal washes obtained from 68 gastric cancer patients and found that patients positive for TelomeScan had a significantly worse prognosis. In 21 cytology-positive patients, the median survival time of those who were TelomeScan positive (235 days) was significantly shorter than that for those who were TelomeScan negative (671 days; P = 0.0062). This fluorescent virus-guided cytology detects biologically malignant cancer cells from the peritoneal washes of gastric cancer patients and may thus be useful for both therapy stratification and precision medicine approaches based on genetic profiling of disseminated cells.

DOI： 10.1111/cas.13760

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Adenosine-to-inosine (A-to-I) RNA editing, a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family, is a recently discovered epigenetic modification dysregulated in human cancers. However, the clinical significance and the functional role of RNA editing in colorectal cancer (CRC) remain unclear. We have systematically and comprehensively investigated the significance of the expression status of ADAR1 and of the RNA editing levels of antizyme inhibitor 1 (AZIN1), one of the most frequently edited genes in cancers, in 392 colorectal tissues from multiple independent CRC patient cohorts. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues when compared with corresponding normal mucosa. High levels of AZIN1 RNA editing emerged as a prognostic factor for overall survival and disease-free survival and were an independent risk factor for lymph node and distant metastasis. Furthermore, elevated AZIN1 editing identified high-risk stage II CRC patients. Mechanistically, edited AZIN1 enhances stemness and appears to drive the metastatic processes. We have demonstrated that edited AZIN1 functions as an oncogene and a potential therapeutic target in CRC. Moreover, AZIN1 RNA editing status could be used as a clinically relevant prognostic indicator in CRC patients.

DOI： 10.1172/jci.insight.99976

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Verlag  

BACKGROUND: Trastuzumab when combined with fluoropyrimidine and cisplatin was proven to improve survival in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) in the ToGA study. The safety and efficacy of trastuzumab in combination with docetaxel and S-1 have not yet been evaluated. METHODS: This study was a multicenter, phase II study. Patients with chemotherapy-naïve HER2-positive advanced or metastatic GC were eligible. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 and 6 mg/kg in subsequent cycles. Docetaxel was administered intravenously at 40 mg/m2 on day 1 of each cycle. S-1 was administered at a dosage based on body surface area for 14 days in a 3-weekly cycle. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 23 patients were enrolled. Median PFS was 6.7 months (95% CI 4.1-10.1). The response rate (RR) was 39.1%. Median overall survival (OS) and time to treatment failure (TTF) were 17.5 and 4.4 months, respectively. Major grade 3-4 adverse events were neutropenia (39.1%), leukopenia (30.4%), and febrile neutropenia (8.7%). CONCLUSION: Trastuzumab in combination with docetaxel and S-1 showed effective antitumor activity and manageable toxicities as first-line treatment for patients with HER2-positive GC.

DOI： 10.1007/s00280-017-3505-4

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

DOI： 10.1016/j.ymgme.2017.12.356

Web of Science

researchmap

Language：English   Publisher：WILEY  

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

BACKGROUND: Emerging evidence indicates that small nucleolar RNAs (snoRNAs) play a central role in oncogenesis. Herein, we systematically evaluated expression profiles of snoRNAs in colorectal cancer (CRC) and investigated their clinical and functional role in this malignancy. METHODS: We compared expression levels of snoRNAs between cancer and normal tissues using publicly available datasets and identified the most differentially expressed and commonly upregulated snoRNAs in CRC. These results were examined in 489 colorectal tissues to assess their clinical significance, followed by a series of in vitro and in vivo experiments to evaluate the functional role of candidate snoRNAs. RESULTS: Using multiple RNA profiling datasets, we identified consistent overexpression of SNORA21 in CRC. In the clinical validation cohorts, the expression level of SNORA21 was upregulated in colorectal adenomas and cancers. Furthermore, elevated SNORA21 emerged as an independent factor for predicting poor survival. Both in vitro and in vivo experiments revealed that CRISPR/Cas9-mediated inhibition of SNORA21 expression resulted in decreased cell proliferation and invasion through modulation of multiple cancer related pathways. CONCLUSIONS: We systematically identified SNORA21 as a key oncogenic snoRNA in CRC, which plays an important role in cancer progression, and might serve as an important prognostic biomarker in CRC.

DOI： 10.1016/j.ebiom.2017.07.009

Web of Science

PubMed

researchmap

Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2017-4720

Web of Science

researchmap

Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2017-3356

Web of Science

researchmap

Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2017-5711

Web of Science

researchmap

Language：English   Publisher：OXFORD UNIV PRESS  

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Cancer has emerged as a leading cause of mortality worldwide, claiming more than 8 million lives annually. Gastrointestinal cancers account for about 35% of these mortalities. Recent advances in diagnostic and treatment strategies have reduced mortality among patients with gastrointestinal cancer, yet a significant number of patients still develop late-stage cancer, where treatment options are inadequate. Emerging interests in "liquid biopsies" have encouraged investigators to identify and develop clinically relevant noninvasive genomic and epigenomic signatures that can be exploited as biomarkers capable of detecting premalignant and early-stage cancers. In this context, microRNAs (miRNA), which are small, noncoding RNAs that are frequently dysregulated in cancers, have emerged as promising entities for such diagnostic purposes. Even though the future looks promising, current approaches for detecting miRNAs in blood and other biofluids remain inadequate. This review summarizes existing efforts to exploit circulating miRNAs as cancer biomarkers and evaluates their potential and challenges as liquid biopsy-based biomarkers for gastrointestinal cancers. Clin Cancer Res; 23(10); 2391-9. ©2017 AACR.

DOI： 10.1158/1078-0432.CCR-16-1676

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: Dysregulated expression of miRNAs has emerged as a hallmark feature in human cancers. Exportin-5 (XPO5), a karyopherin family member, is a key protein responsible for transporting precursor miRNAs from the nucleus to the cytoplasm. Although XPO5 is one of the key regulators of miRNA biogenesis, its functional role and potential clinical significance in colorectal cancer remains unclear.Experimental Design: The expression levels of XPO5 were initially assessed in three genomic datasets, followed by determination and validation of the relationship between XPO5 expression and clinicopathologic features in two independent colorectal cancer patient cohorts. A functional characterization of XPO5 in colorectal cancer was examined by targeted gene silencing in colorectal cancer cell lines and a xenograft animal model.Results: XPO5 is upregulated, both at mRNA and protein levels, in colorectal cancers compared with normal tissues. High XPO5 expression is associated with worse clinicopathologic features and poor survival in colorectal cancer patient cohorts. The siRNA knockdown of XPO5 resulted in reduced cellular proliferation, attenuated invasion, induction of G1-S cell-cycle arrest, and downregulation of key oncogenic miRNAs in colorectal cancer cells. These findings were confirmed in a xenograft animal model, wherein silencing of XPO5 resulted in the attenuation of tumor growth.Conclusions: XPO5 acts like an oncogene in colorectal cancer by regulating the expression of miRNAs and may be a potential therapeutic target in colorectal cancer. Clin Cancer Res; 23(5); 1312-22. ©2016 AACR.

DOI： 10.1158/1078-0432.CCR-16-1023

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function. Transcriptome data analysis revealed not only previously identified mechanisms such as Let-7 regulation by H19, but also RB1-E2F1 function and β-catenin activity as essential upstream regulators mediating H19 function. Our experimental data showed that H19 affects phosphorylation of RB1 protein by regulating gene expression of CDK4 and CCND1. We further demonstrated that reduced CDK8 expression underlies changes of β-catenin activity, and identified that H19 interacts with macroH2A, an essential regulator of CDK8 gene transcription. However, the relevance of H19-macroH2A interaction in CDK8 regulation remains to be experimentally determined. We further explored the clinical relevance of above mechanisms in clinical samples, and showed that combined analysis of H19 with its targets improved prognostic value of H19 in CRC.

DOI： 10.1016/j.ebiom.2016.10.026

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

PURPOSE: Although limited understanding exists for the presence of specific genetic mutations and aberrantly methylated genes in pancreatobiliary intraductal papillary mucinous neoplasms (IPMNs), the fundamental understanding of the dynamics of methylation expansion across CpG dinucleotides in specific gene promoters during carcinogenesis remains unexplored. Expansion of DNA methylation in some gene promoter regions, such as EFEMP1, one of the fibulin family, with tumor progression has been reported in several malignancies. We hypothesized that DNA hypermethylation in EFEMP1 promoter would expand with the tumor grade of IPMN. METHODS: A sample of 65 IPMNs and 30 normal pancreatic tissues was analyzed. IPMNs were divided into the following three subsets according to pathological findings: 31 with low-grade dysplasia (low grade), 11 with high-grade dysplasia (high grade), and 23 with associated invasive carcinoma (invasive Ca). Mutations in the KRAS or GNAS genes were analyzed by Sanger sequencing, and methylation status of two discrete regions within the EFEMP1 promoter, namely region 1 and region 2, was analyzed by bisulfite sequencing and fluorescent high-sensitive assay for bisulfite DNA (Hi-SA). Expression status of EFEMP1 was investigated by immunohistochemistry (IHC). RESULTS: KRAS mutations were detected in 39, 55, and 70 % of low-grade, high-grade, and invasive Ca, respectively. GNAS mutations were observed in 32, 55, and 22 % of low-grade, high-grade, and invasive Ca, respectively. The methylation of individual regions (region 1 or 2) in the EFEMP1 promoter was observed in 84, 91, and 87 % of low-grade, high-grade, and invasive Ca, respectively. However, simultaneous methylation of both regions (extensive methylation) was exclusively detected in 35 % of invasive Ca (p = 0.001) and five of eight IPMNs (63 %) with extensive methylation, whereas 20 of 57 (35.1 %) tumors of unmethylation or partial methylation of the EFEMP1 promoter region showed weak staining EFEMP1 in extracellular matrix (p = 0.422). In addition, extensive EFEMP1 methylation was particularly present in malignant tumors without GNAS mutations and associated with disease-free survival of patients with IPMNs (p < 0.0001). CONCLUSIONS: Extensive methylation of the EFEMP1 gene promoter can discriminate invasive from benign IPMNs with superior accuracy owing to their stepwise accumulation of tumor progression.

DOI： 10.1007/s00432-016-2164-x

Web of Science

PubMed

researchmap

Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2016-768

Web of Science

researchmap

Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2016-952

Web of Science

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

DOI： 10.1016/S0016-5085(16)33429-1

Web of Science

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

DOI： 10.1016/S0016-5085(16)33430-8

Web of Science

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

0

DOI： 10.1016/S0016-5085(16)30456-5

Web of Science

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

DOI： 10.1016/S0016-5085(16)32142-4

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Mutations in TGFBR2, a component of the transforming growth factor (TGF)-β signaling pathway, occur in high-frequency microsatellite instability (MSI-H) colorectal cancer (CRC). In mouse models, Tgfbr2 inactivation in the intestinal epithelium accelerates the development of malignant intestinal tumors in combination with disruption of the Wnt-β-catenin pathway. However, no studies have further identified the genes influenced by TGFBR2 inactivation following disruption of the Wnt-β-catenin pathway. We previously described CDX2P-G19Cre;Apcflox/flox mice, which is stochastically null for Apc in the colon epithelium. In this study, we generated CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice, with simultaneous loss of Apc and Tgfbr2. These mice developed tumors, including adenocarcinoma in the proximal colon. We compared gene expression profiles between tumors of the two types of mice using microarray analysis. Our results showed that the expression of the murine homolog of GSDMC was significantly upregulated by 9.25-fold in tumors of CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice compared with those of CDX2P-G19Cre;Apcflox/flox mice. We then investigated the role of GSDMC in regulating CRC tumorigenesis. The silencing of GSDMC led to a significant reduction in the proliferation and tumorigenesis of CRC cell lines, whereas the overexpression of GSDMC enhanced cell proliferation. These results suggested that GSDMC functioned as an oncogene, promoting cell proliferation in colorectal carcinogenesis. In conclusion, combined inactivation of both Apc and Tgfbr2 in the colon epithelium of a CRC mouse model promoted development of adenocarcinoma in the proximal colon. Moreover, GSDMC was upregulated by TGFBR2 mutation in CRC and promoted tumor cell proliferation in CRC carcinogenesis, suggesting that GSDMC may be a promising therapeutic target.

DOI： 10.1371/journal.pone.0166422

Web of Science

PubMed

researchmap

Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2015-2301

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

BACKGROUND: Molecular-based companion diagnostic tests are being used with increasing frequency to predict their clinical response to various drugs, particularly for molecularly targeted drugs. However, invasive procedures are typically required to obtain tissues for this analysis. Circulating tumour cells (CTCs) are novel biomarkers that can be used for the prediction of disease progression and are also important surrogate sources of cancer cells. Because current CTC detection strategies mainly depend on epithelial cell-surface markers, the presence of heterogeneous populations of CTCs with epithelial and/or mesenchymal characteristics may pose obstacles to the detection of CTCs. METHODS: We developed a new approach to capture live CTCs among millions of peripheral blood leukocytes using a green fluorescent protein (GFP)-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401, TelomeScan). RESULTS: Our biological capturing system can image epithelial and mesenchymal tumour cells with telomerase activities as GFP-positive cells. After sorting, direct sequencing or mutation-specific PCR can precisely detect different mutations in KRAS, BRAF and KIT genes in epithelial, mesenchymal or epithelial-mesenchymal transition-induced CTCs, and in clinical blood samples from patients with colorectal cancer. CONCLUSIONS: This fluorescence virus-guided viable CTC capturing method provides a non-invasive alternative to tissue biopsy or surgical resection of primary tumours for companion diagnostics.

DOI： 10.1136/gutjnl-2014-306957

Web of Science

PubMed

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

BACKGROUND: To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown. METHODS: This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox's proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS). RESULTS: By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis. CONCLUSIONS: CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer.

DOI： 10.1371/journal.pone.0130409

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBLISHING GROUP INC  

To apply an individualized oncological approach to gastric cancer patients, the accurate diagnosis of disease entities is required. Peritoneal metastasis is the most frequent mode of metastasis in gastric cancer, and the tumor-node-metastasis classification includes cytological detection of intraperitoneal cancer cells as part of the staging process, denoting metastatic disease. The accuracy of cytological diagnosis leaves room for improvement; therefore, highly sensitive molecular diagnostics, such as an enzyme immunoassay, reverse transcription polymerase chain reaction, and virus-guided imaging, have been developed to detect minute cancer cells in the peritoneal cavity. Molecular targeting therapy has also been spun off from basic research in the past decade. Although conventional cytology is still the mainstay, novel approaches could serve as practical complementary diagnostics to cytology in near future.

DOI： 10.3748/wjg.v20.i47.17796

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag Tokyo  

A 70-year-old female experienced sudden onset of back pain on the right side and was admitted to our hospital in December 2010. Abdominal computed tomography revealed an S7 hepatic mass measuring 7 cm in diameter accompanied by a subcapsular hematoma. Emergency angiography confirmed the diagnosis of a ruptured hepatic mass, and hemostasis was carried out by embolization of A8 and A7 of the liver. A right hepatic lobectomy was carried out 39 days following transarterial embolization. Although almost all aspects of the tumor were necrotic, residual tumor cells stained positive for HMB-45, and negative for α-SMA, S-100, CD 34, c-kit, CAM 5.2, and hepatocytes. The MIB-1 index was 2 %. Pathological diagnosis was hepatic angiomyolipoma (HAML). The patient has shown no signs of recurrence at 42 months following surgery. Here, we report on this case of spontaneous HAML rupture and discuss therapeutic strategies for HAML and ruptured hepatic tumors.

DOI： 10.1007/s12328-014-0517-z

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Lynch syndrome is an autosomal dominant disease associated with a high incidence of colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, bile duct and brain tumors. The syndrome can also include sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel. The lifetime risk for bile duct cancer in patients with Lynch syndrome is approximately 2 %. The present report describes a case of Lynch syndrome with metachronous bile duct cancer diagnosed at an early stage. The patient was a 73-year-old Japanese male who underwent a successful left lobectomy of the liver, and there was no sign of recurrence for 2 years postoperative. However, this patient harbored a germline mutation in MLH1, which prompted diagnostic examinations for noncolorectal tumors when a periodic surveillance blood examination showed abnormal values of hepatobiliary enzymes. Although most patients with bile duct cancer are diagnosed at an advanced stage, the bile duct cancer was diagnosed at an early stage in the present patient due to the observation of the gene mutation and the preceding liver tumor. This case illustrates the importance of continuous surveillance for extracolonic tumors, including bile duct cancer, in patients with Lynch syndrome.

DOI： 10.1007/s00595-013-0669-3

Web of Science

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Lynch syndrome is an inherited syndrome associated with the development of colorectal and various other cancers. A 65- year-old male underwent a laparoscopic-assisted right hemi-colectomy for ascending colon cancer (cStage II). Histologically, his tumor was diagnosed as a poorly differentiated adenocarcinoma. Lymphocytic reactions, such as tumor-infiltrating lymphocytes (TIL), and Crohn's-like reactions, were observed. Genetic testing revealed the presence of a pathogenic mutation in the MLH1. In the Lynch syndrome, the most frequently observed findings include the accumulation of mutations, and an early onset of familial colon cancer. Although the case presented here did not show the typical clinical findings of Lynch syndrome, histological examination of the lymphocytic reactions proved useful for screening for Lynch syndrome. Herein, we establish the important role of the pathologist in alerting the clinician to the possibility of Lynch syndrome when the findings of TIL and Crohn's-like reactions are detected.

Scopus

PubMed

J-GLOBAL

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

Lynch syndrome is an inherited autosomal dominant disorder caused by germ-line mutation of mismatch repair genes, in which a malignant tumor develops at a young age in the colon, endometrium, stomach, or other tissues. A 54-year-old patient with gastric cancer received pylorus-preserving gastrectomy, and a genetic examination confirmed a pathological variation of the MLH1 gene. Five years after surgery, an upper gastrointestinal endoscopy revealed a residual 0 -IIa+IIc gastric tumor approximately 2 cm in size extending from the anastomotic site to the lesser curvature side of the stomach. The remaining stomach was completely removed. The final diagnosis was T1b (SM) N1M0, StageIB gastric cancer. Microsatellite instability was positive, and we attributed the cancer to Lynch syndrome. In Lynch syndrome, the risk of multicentric gastric cancer is higher than normal, and for the initial therapy, preventive total gastrectomy should be considered as an option.

Scopus

PubMed

J-GLOBAL

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

We present a case in which combination chemotherapy was used to successfully treat hepatocellular carcinoma (HCC) with rapid progression of lymph node (LN) metastases after liver resection. In addition, epithelial to mesenchymal transition (EMT) markers were examined immunohistochemically. A 43-year-old man who had been diagnosed with HCC showed an enlarged LN near the hepatic artery proper. After extended left lobectomy with lymphadenectomy in the hepatoduodenal ligament, he experienced rapid progression of metastases to the para-aortic and mediastinal LN. Partial remission was achieved after induction and maintenance of combination chemotherapy using etoposide, carboplatin, epirubicin and 5-fluorouracil. As a consequence of this treatment, the patient survived 10 months. Immunohistochemical studies demonstrated that HCC cells in the metastatic LN showed low expression of E-cadherin and high expression of N-cadherin and vimentin, indicating EMT. Combination chemotherapy may prove effective for patients with HCC accompanied by LN metastases that show features of EMT.

DOI： 10.1111/hepr.12080

Web of Science

PubMed

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

0

Web of Science

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Web of Science

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

0

Web of Science

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Web of Science

researchmap

Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

0

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

PURPOSE: Peritoneal dissemination is the most frequent and life-threatening mode of metastasis and recurrence in patients with gastric cancer. A multicenter phase II study was designed to evaluate the efficacy and tolerability of S-1 and docetaxel combination chemotherapy regimen for the treatment of advanced or recurrent gastric cancer patients with peritoneal dissemination. METHODS: Nineteen patients with histologically confirmed unresectable or recurrent gastric cancer with peritoneal dissemination were enrolled. Oral S-1 at 80 mg/m(2)/day was administered twice daily for 2 weeks, followed by 1 drug-free week. Docetaxel infusion at 40 mg/m(2) was performed on day 1, simultaneous with S-1 administration. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary endpoints were the response rates and safety status. RESULTS: Patients received a median of 4 cycles of the S-1 and docetaxel regimen (range 1-43). The disease control rate was 73.7 % (14/19). Median overall survival was 459 days (15.3 months), while median time to progression was 212 days (7.1 months). Neutropenia was the most common type of toxicity (n = 7, 36.8 %). CONCLUSIONS: Combination chemotherapy with S-1 and docetaxel is a tolerable and effective treatment for advanced or recurrent gastric cancer patients with peritoneal dissemination.

DOI： 10.1007/s00280-013-2086-0

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-2385

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OKAYAMA UNIV MED SCHOOL  

Secreted frizzled-related protein 2, (SFRP2) is a Wnt inhibitor whose promoter CpGs were recently found to be methylated at high frequency in colorectal cancers (CRCs). We hypothesized that the pattern of SFRP2 methylation may differ throughout the promoter during progressive tumorigenesis. Using combined bisulfite restriction analysis (COBRA), two methylation-sensitive regions (Regions A and B) of the SFRP2 promoter were investigated in 569 specimens of colorectal tissue:222 CRCs, 103 adenomatous polyps (APs), 208 normal colonic mucosa from CRC patients (N-Cs), and 36 normal colonic mucosa from subjects with no evidence of colorectal neoplasia at colonoscopy (N-Ns). Extensive (including both Regions A and B) and partial (either Region A or B) SFRP2 methylation levels were found in 61.7% and 24.8% of CRCs, 8.7% and 37.9% of APs, 3.9% and 39.9% of N-Cs, and 0% and 30.6% of N-Ns, respectively. Extensive methylation of the SFRP2 promoter was present primarily in CRCs, while partial methylation was common in APs. Whereas APs with the KRAS mutant showed no correlation to any pattern of SFRP2 methylation, extensive methylation of the SFRP2 promoter was significantly associated with KRAS mutant CRCs (p＜.0001), suggesting that genetic alteration in the RAS-RAF pathway might precede the spread of CpG methylation through the SFRP2 promoter, which is observed in over 60% of advanced colorectal tumors.

DOI： 10.18926/AMO/46628

Web of Science

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

CiNii Article

CiNii Books

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)山口県医師会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(株)日本臨床社  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

researchmap

Language：Japanese   Publisher：(株)へるす出版  

researchmap

Language：Japanese   Publisher：(一社)日本腹部救急医学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：Japanese   Publisher：(一社)日本臨床検査医学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：Japanese   Publisher：(一社)日本臨床検査医学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

researchmap

Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本臨床薬理学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

researchmap

Language：Japanese   Publisher：(一社)日本ハイパーサーミア学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

上皮間葉転換(EMT)可視化プローベを用い、間葉型大腸癌がhybrid E/Mで最も化学療法抵抗性であるかをイメージングによって明らかにするとともに、時間的にEMTマーカーを追跡した。Vimentinプロモーター下に赤色蛍光タンパク遺伝子(rfp)がドライブさせるEMT可視化プローベを作成した。大腸癌細胞株HCT116、RKOにEMT可視化プローベを導入した。大腸癌の代表的な抗癌剤5-FU、オキサリプラチン(L-OHP)、シスプラチン(CDDP)、イリノテカン(CPT-11)を曝露させた。その結果、RKOではL-OHP、CDDP、5-FUの順で赤色を呈するEMTを起こし、HCT116では5-FU、L-OHP、CDDPの順でEMTを起こした。また、時間軸では化学療法後48時間するとEMTを起こし赤色になったが、化学療法終了後48時間経過するとEMTを起こし無色に戻った。化学療法施行前にEMT阻害剤で前治療しておくと、化学療法に曝露しても赤色にならず(EMTは阻害され)、さらに化学療法への感受性も増加していた。

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本癌学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本癌学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本遺伝性腫瘍学会  

症例は54歳男性.大量出血を伴う小腸多発GIST(Gastrointestinal stromal tumor)を認めて緊急入院となった.姉が神経線維腫症1型(neurofibromatosis type 1:NF1)と診断されており,患者にもおよそ20個の神経線維腫を疑う腫瘤とcafe au lait斑を6個以上認めたためNF1と診断した.出血コントロール目的に開腹手術を行ったが,GISTはおよそ20個多発しており,大量小腸切除を避けるために10mm以上の腫瘍のみ外科的切除を行い,多発微小腫瘍は経過観察とした不完全切除を選択した.切除標本の病理検査では紡錘形核と好酸性胞体を有する紡錘形細胞が密に錯綜する腫瘍を認め,免疫染色でKIT陽性.核分裂数は5以下/50HPFsであり低悪性度GISTと診断した.NF1に伴うGISTは比較的予後が良いとの報告もあるが,このような多発微小病変については明らかな治療指針がない.今後さらなる症例の集積と検討を要する.(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J03931&link_issn=&doc_id=20200310200005&doc_link_id=10.18976%2Fjsft.19.2_77&url=https%3A%2F%2Fdoi.org%2F10.18976%2Fjsft.19.2_77&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

Language：English   Publisher：日本癌学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：English   Publisher：日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本ストーマ・排泄リハビリテーション学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一財)日本消化器病学会  

researchmap

Language：English   Publisher：日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本癌治療学会  

J-GLOBAL

researchmap

Language：English   Publisher：日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本胃癌学会  

researchmap

Language：Japanese   Publisher：(株)羊土社  

アデノウイルスは本来ヒトの細胞に感染・増殖し、最終的に感染した細胞をさまざまな機序により破壊する。近年の遺伝子工学技術の進歩により、アデノウイルスの増殖能にがん選択性をもたせることで新たながん治療薬としての臨床開発が進められている。本稿では、われわれが独自に開発したテロメラーゼ活性選択的に制限増殖するアデノウイルス製剤を用いたがん治療法・診断法に関する研究成果や臨床応用について概説する。がん細胞の無制限な増殖能に関連するテロメラーゼを標的とすることで多くのがん患者に対する治療・診断技術の開発が期待される。(著者抄録)

J-GLOBAL

researchmap

Language：Japanese   Publisher：Okayama Medical Association  

DOI： 10.4044/joma.128.179

CiNii Article

CiNii Books

researchmap

Other Link： http://ousar.lib.okayama-u.ac.jp/54612

Language：Japanese   Publisher：(一社)山口県医師会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

肝腫瘍として見つかり,肝切除術後に原発不明神経内分泌癌(neuroendocrine carcinoma;以下,NECと略記)と診断された症例を経験したので報告する.症例は67歳の男性で,肝S6に20mm大の腫瘤と肝門部リンパ節腫大が確認された.腫瘍が増大傾向にあり,PET-CTでもFDG集積が確認されたため,肝S6亜区域切除および肝門部リンパ節郭清を行った.切除標本でNECと診断され,肝S6に主病変以外にも12個の腫瘍があった.肝門部リンパ節転移もあり,原発不明NECの肝転移およびリンパ節転移と診断した.その後多発肝転移再発を認め,化学療法,オクトレオチド投与,肝ラジオ波焼灼術や肝動脈化学塞栓術による加療を行った.予後不良と考えられたが,術後34ヵ月の生存が得られた.NECは予後不良とされるが,集学的治療により生存期間延長が期待できる可能性がある.(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01117&link_issn=&doc_id=20150420340002&doc_link_id=10.5833%2Fjjgs.2014.0022&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.2014.0022&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese  

J-GLOBAL

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2015&ichushi_jid=J01117&link_issn=&doc_id=20150420340002&doc_link_id=10.5833%2Fjjgs.2014.0022&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.2014.0022&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(株)癌と化学療法社  

Lynch症候群は、若年で大腸、子宮内膜、胃などに悪性腫瘍を高率に発症する常染色体優性遺伝性疾患である。症例は59歳、男性。54歳時、胃癌に対して幽門保存胃切除術を施行し、後の遺伝子検査でMLH1の病的変異を確認した。術後5年目の上部消化管内視鏡で吻合部から小彎側にかけて約2cm大の0-IIa+IIcの残胃癌を指摘された。遠隔転移認めず、残胃全摘を施行した。最終診断は、T1b(SM)N1M0、Stage IBであった。高頻度マイクロサテライト不安定性を認め、Lynch症候群による発がんと思われた。Lynch症候群においては多発胃癌のリスクが通常より高く、初回治療で予防的胃全摘術も選択肢として考慮し得る。(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00296&link_issn=&doc_id=20141217480274&doc_link_id=%2Fab8gtkrc%2F2014%2F004112%2F274%2F2264-2265%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2014%2F004112%2F274%2F2264-2265%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)癌と化学療法社  

Lynch症候群は大腸の他、様々な臓器に発癌する遺伝性腫瘍症候群である。症例は65歳、男性。上行結腸癌の診断にて、腹腔鏡補助下結腸右半切除術を施行した。病理検査では低分化腺癌を認め、さらに腫瘍内にリンパ球浸潤、腫瘍周囲のクローン様リンパ球浸潤などの組織所見を認めた(fStage II)。遺伝子検査で病的遺伝子変異(MLH1 exon 5 1.2kb del)を認め、Lynch症候群と確定診断した。Lynch症候群では、大腸癌の家系内集積と若年発生が高頻度に認められる。自験例ではこのようなリンチ症候群の典型的な所見に乏しかったが、組織学的所見がLynch症候群のスクリーニングに有用であった。腫瘍内リンパ球浸潤やクローン様リンパ球反応などの組織所見を認める場合、病理医が臨床医にLynch症候群の可能性を指摘することが重要と考えられた。(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00296&link_issn=&doc_id=20141217480051&doc_link_id=%2Fab8gtkrc%2F2014%2F004112%2F051%2F1602-1604%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2014%2F004112%2F051%2F1602-1604%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(NPO)日本食道学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本乳癌学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J03156&link_issn=&doc_id=20140714130049&doc_link_id=10.3919%2Fjjsa.75.1717&url=https%3A%2F%2Fdoi.org%2F10.3919%2Fjjsa.75.1717&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本遺伝性腫瘍学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：MARY ANN LIEBERT, INC  

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本臨床外科学会  

J-GLOBAL

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本癌治療学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本癌治療学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本遺伝性腫瘍学会  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J00192&link_issn=&doc_id=20130527120004&doc_link_id=10.11280%2Fgee.55.1650&url=https%3A%2F%2Fdoi.org%2F10.11280%2Fgee.55.1650&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(一社)日本遺伝性腫瘍学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Article

CiNii Books

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本外科学会  

J-GLOBAL

researchmap

Language：English   Publisher：日本癌学会  

researchmap

Language：English   Publisher：日本癌学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器外科学会