Yushi Ogawa

Efficiency of endocytoscopy in differentiating types of serrated polyps

BACKGROUND Accurate endoscopic criteria are needed to differentiate serrated polyps, including hyperplastic polyp (HP), sessile serrated adenoma/polyp (SSA/P), and traditional serrated adenoma (TSA), because some are precursors of colorectal cancers. OBJECTIVE To determine the endocytoscopic features of each type of serrated polyp, especially the shapes of lumens and nuclei. DESIGN Retrospective study. SETTING Single, tertiary-care referral center. PATIENTS Patients who underwent removal of serrated polyps from May 2005 to December 2012. INTERVENTION Endocytoscopy was performed. Endocytoscopic images were evaluated by assessing the shapes of the lumens and nuclei of the target lesions. MAIN OUTCOME MEASUREMENTS The significant endocytoscopic features in differentiating among types of serrated polyps. RESULTS Of the 58 eligible lesions, 27 were classified as HP, 12 as SSA/P, and 19 as TSA. Most HPs (77.8%) had star-like lumens, and most SSA/Ps (83.3%) had oval lumens. The lumens of TSAs were serrated (31.6%) or villous (68.4%), with both shapes seen only in TSAs. Most HPs (92.6%) and SSA/Ps (75.0%) had small, round nuclei, and all TSAs had fusiform nuclei. Features significantly differentiating TSAs from HPs and SSA/Ps were the presence of fusiform nuclei (P < .001) and villous (P < .001) and serrated (P = .002) lumens. The presence of oval lumens was significantly characteristic of SSA/Ps (P < .001), and the presence of star-like lumens was significantly characteristic of HPs (P < .001). LIMITATIONS Retrospective design. Single-center study. CONCLUSION The shape of lumens and nuclei on endocytoscopy can efficiently differentiate among the different types of serrated polyps. ( CLINICAL TRIAL REGISTRATION NUMBER UMIN Clinical Trials Registry UMIN000007850.).

Diagnosis of sessile serrated adenomas/polyps using endocytoscopy (with videos)

Sessile serrated adenomas/polyps (SSA/P) are considered to be precursors of colorectal cancers. They therefore need to be distinguished from hyperplastic polyps, and should be treated similarly to adenomas. Various endoscopic classifications for discriminating SSA/P have recently been proposed and validated, including the ‘Type II‐O’ pit pattern in magnifying chromoendoscopy and the ‘varicose microvascular vessel’ in narrow‐band imaging. However, there is currently no diagnostic consensus on the endoscopic appearance of SSA/P. Endocytoscopy (EC) is an emerging modality with diagnostic potential for SSA/P. EC is a type of a contact light microscopy, which allows in vivo visualization of cells and nuclei facilitating precise, real‐time pathological prediction. SSA/P show oval gland lumens with small round nuclei in EC, indirectly reflecting the pathological features. EC has shown a sensitivity of 83.3% and a specificity of 97.8% for the diagnosis of SSA/P. EC is also a promising tool for the diagnosis of SSA/P with cytological dysplasia because of its ability to detect morphological changes in nuclei, which is the most important factor determining the presence of dysplasia in the lesion. However, clinical data validating the usefulness of EC are lacking, and further studies are required.

Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer

Yes-associated protein 1 (YAP1) acts as an oncogene through dephosphorylation and nuclear translocation, and nuclear accumulation of YAP1 is associated with poor prognosis in gastric cancer (GC). We previously identified ivermectin, an antiparasitic drug, as a YAP1 inhibitor. Here, we aimed to clarify whether ivermectin had antitumor effects on GC through inhibition of YAP1. First, we evaluated the antiproliferative effects of ivermectin on human GC cells using in vitro proliferation assays and a xenograft mouse model. YAP1-knockdown assays were performed to assess whether the sensitivity to ivermectin depended on YAP1 expression. Next, we explored the mechanism through which ivermectin regulated YAP1 expression or localization by immunoblotting and reverse transcription-quantitative polymerase chain reaction for YAP1 and the downstream gene CTGF. Finally, the clinical significance of YAP1 expression was examined using three independent GC datasets. We found that MKN1 GC cells were most sensitive to ivermectin, whereas MKN7 cells were most resistant. In MKN1 xenografts, ivermectin suppressed tumor growth, and the sensitivity of MKN1 cells to ivermectin was decreased by YAP1 knockdown. Ivermectin inhibited YAP1 nuclear expression and CTGF expression in MKN1 cells but not MKN7 cells. Moreover, ivermectin decreased YAP1 mRNA expression, thereby inhibiting nuclear accumulation of YAP1 in MKN1 cells. In survival analysis, low YAP1 mRNA expression was associated with a better prognosis in three independent GC datasets. In conclusion, we identified ivermectin as a potential antitumor agent and found a promising novel therapeutic strategy for inhibition of GC progression by blocking YAP1 expression.

Use of endocytoscopy for identification of sessile serrated adenoma/polyps and hyperplastic polyps by quantitative image analysis of the luminal areas

Background and study aims  Recent studies that used magnifying chromoendoscopy and endocytoscopy (EC) to investigate endoscopic features of sessile serrated adenoma/polyps (SSA/Ps) suggested that a dilated crypt opening was an important indicator of SSA/Ps. However, no studies to date have measured the actual extent of dilatation. Hence, we investigated retrospectively the luminal areas using EC to determine a cutoff value for differentiating SSA/Ps from hyperplastic polyps (HPs). Patients and methods  A total of 101 lesions, including 25 SSA/Ps, 66 HPs, and 10 normal mucosal samples, assessed by an integrated-type EC were collected. For each lesion, 1 image that showed the widest lumen was selected and the average area of the contiguous 3 lumens were calculated. The cutoff value differentiating SSAPs from HPs was determined by receiver operating curve (ROC) analysis. Results  The mean luminal areas of SSA/Ps and HPs were 4152 μm 2 and 2117 μm 2 , respectively. ROC analysis found that a luminal area cutoff of 3068 μm 2 had a sensitivity of 80.0 %, a specificity of 77.3 %, an accuracy of 78.0 %, and an area under the ROC curve of 0.865. Furthermore, a cutoff of ≥ 556 μm 2 was found to accurately distinguish between HPs and normal mucosa (sensitivity 98.5 %, specificity 100 %, accuracy 98.7 %, and AUC 0.998). Conclusions  EC analysis of the luminal area is useful for differentiating between SSAPs and HPs. This approach could be adapted for computer-aided diagnosis of SSA/P.

Abstract 1972: Identification of novel candidate driver genes of colorectal cancer on chromosome 7p

Background Colorectal cancer (CRC) is one of the most prevalent types of cancer. The high mortality rate of CRC is a serious problem. Hence it is urgently necessary to identify novel molecular target to improve the mortality rate. Amplification of chromosome 7p is frequent in CRC, and it has been considered to harbor driver genes that promote tumorigenesis or tumor progression by the gain of function. The aim of this study is to identify novel candidate driver genes on chromosome 7p and to clarify the clinical significance of their expression in CRC. Material and Methods 1. We selected the candidate genes that satisfied the following criteria using CRC data from The Cancer Genome Atlas (TCGA). 1) The DNA copy number and mRNA expression is positively correlated with each other, 2) overexpressed in the tumor tissues compared to the normal tissues. 2. The mRNA expression of the candidate genes was measured in 108 surgically-resected CRC tissues and the paired normal tissues in our hospital by quantitative RT-PCR. The differences of mRNA expression between CRC tissues and normal tissues were analyzed by Mann Whitney U-test. 3. Survival analysis between high and low expression group of the candidate genes was performed by Kaplan-Meier method. Correlation between the mRNA expression of the candidate genes and the clinicopathological factors were analyzed by Fisher’s exact test. 4. We performed Gene Set Enrichment Analysis (GSEA) in CRC data from TCGA to clarify the correlation between the candidate genes and gene sets that are associated with tumorigenesis or tumor progression. Results DEAD Box Helicase56 (DDX56), ATP-dependent RNA helicases involved in several aspects of RNA metabolism including mRNA splicing and transport, transcription, translation and remodeling of ribonucleoprotein complexes, was satisfied with the criteria. The expression of DDX56 was significantly higher in CRC tissues than in normal colon tissues (p Conclusions We identified DDX56 as a promising driver gene of CRC on chromosome 7p. DDX56 expression was positively associated with lymphatic invasion and distant metastasis, and was an independent poor prognostic factor. Furthermore, DDX56 may be involved in tumor progression through stimulating cell-cycle. DDX56 could be a therapeutic target as well as a poor prognostic biomarker in CRC. Note: This abstract was not presented at the meeting. Citation Format: Yuta Kouyama, Yushi Ogawa, Takaaki Masuda, Yukihiro Yoshikawa, Miwa Noda, Hiroaki Wakiyama, Kuniaki Sato, Sho Nambara, Qingjiang Hu, Shinya Kidogami, Tomoko Saito, Shotaro Sakimura, Naoki Hayashi, Yohsuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Koshi Mimori. Identification of novel candidate driver genes of colorectal cancer on chromosome 7p [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1972. doi:10.1158/1538-7445.AM2017-1972

Mo1936 Characteristics of Colorectal Tumours in Asymptomatic Patients With Negative Immunochemical Faecal Occult Blood Test Results

The immunochemical faecal occult blood test (iFOBT) is a simple, non-invasive colorectal cancer (CRC) screening method for reducing CRC-related mortality. However, the sensitivity of iFOBT is imperfect and certain colonic neoplasms that require removal may be missed. The aim of this study was to investigate the incidence and character- istics of CRC in asymptomatic, iFOBT-negative patients who underwent opportunistic screening. A total of 919 subclinical patients (276 iFOBT-positive and 643 iFOBT-negative) in the health screening program of our hospital underwent total colonoscopy (TCS) within 2 years after iFOBT. The patients were divided into an iFOBT-positive and an iFOBT-negative group and the TCS findings were compared between the two groups. Although the incidence of advanced neoplasia (CRC, high‑grade dysplasia, adenoma sized ≥10 mm and tubulovil- lous adenoma) was significantly higher in the iFOBT‑positive group, these lesions were also found in 6.3% of iFOBT-nega- tive patients. The lesions tended to be proximally located and non-protruding. In conclusion, screening with iFOBT remains clinically significant. However, colonoscopy is indispensable for reducing the incidence and mortality of CRC.