Yasuyuki Okada

Biomarkers for predicting the efficacy of anti-epidermal growth factor receptor antibody in the treatment of colorectal cancer.

Anti-epidermal growth factor receptor (EGFR) antibodies have been widely utilized as a standard treatment for metastatic colorectal cancer (CRC). Anti-EGFR antibodies bind competitively to EGFRs to inhibit receptor activation and subsequent signal transduction of the RAS/RAF/MEK pathway and PI3K/AKT pathway. By inhibiting EGFR-mediated signal transduction, anti-EGFR antibodies inhibit cell growth, invasion, metastasis and angiogenesis, and they induce apoptosis. The IgG1-type antibody cetuximab is also capable of inducing antibody-dependent cellular cytotoxicity. Several studies have shown that KRAS mutation is a useful biomarker for predicting the efficacy of anti-EGFR agents, and the major guidelines for the treatment of CRC recommend the use of anti-EGFR antibody only for the cancers with wild-type KRAS. Alterations of other genes, including BRAF, NRAS, PTEN and AKT, and EGFR expression/gene copy number have also been reported to be candidate biomarkers for predicting the efficacy of anti-EGFR agents. The predictive values of these biomarkers are still controversial and further investigations are required.

Linked color imaging enhances endoscopic detection of sessile serrated adenoma/polyps

Background and study aims  Although new image-enhanced endoscopy (IEE) technologies such as blue laser imaging (BLI), BLI-bright, and linked color imaging (LCI) have been developed, their utility for the detection of sessile serrated adenoma/polyps (SSA/Ps) is still unclear. This study aimed to evaluate the utility of BLI, BLI-bright, and LCI for SSA/P detection in still image examinations and in a prospective randomized controlled trial (RCT). Patients and methods  A group of 6 expert and non-expert endoscopists read 200 endoscopic still images containing SSA/P lesions using white light image (WLI), BLI, BLI-bright, and LCI. Color differences were calculated using the color space method. A prospective RCT of tandem colonoscopy with WLI and LCI was performed. Patients with SSA/P and those with a history of SSA/P that had been endoscopically removed were enrolled and randomly allocated to WLI-LCI or LCI-WLI groups. Additional endoscopic detection rates for SSA/P were compared between the 2 groups. Results  LCI showed the highest SSA/P detection rate among the 4 modes for both expert and non-expert endoscopists. The detection rate with LCI for the 6 expert endoscopists (mean 98.3 ± standard deviation 2.0 %) was significantly higher than that with WLI (86.7 ± 6.0 %, P  < 0.01). Likewise, the detection rate with LCI for the 6 non-expert endoscopists (92.3 ± 2.9 %) was significantly higher than that with WLI (72.7 ± 11.5 %, P  < 0.01). The color difference of SSA/P with LCI was the highest among the 4 modes, and was significantly higher than with WLI (median 15.9, (interquartile range 13.7 – 20.6) vs. 10.2, (7.6 – 14.2); P  < 0.0001). In the RCT, a total of 44 patients (WLI-LCI 22 vs. LCI-WLI 22) underwent colonoscopy. The additional detection rate for SSA/P in the second inspection in the WLI-LCI group (21.6 %, 8/37) was significantly higher than in the LCI-WLI group (3.2 %, 1/31; P  = 0.02). The small, flat, non-mucus and isochromatic SSA/Ps in the transverse colon were detected more frequently in the second inspection with LCI. Conclusions  LCI was the most sensitive mode for SSA/P detection among WLI, BLI, BLI-bright, and LCI in the still image examinations. Our RCT strongly suggests that LCI is superior to conventional WLI for SSA/P detection during colonoscopy. UMIN000017599.

The differing influence of several factors on the development of fatty liver with elevation of liver enzymes between genders with metabolic syndrome: A cross-sectional study

Background Nonalcoholic fatty liver disease (NAFLD) is known to be strongly associated with obesity, visceral fat, metabolic syndrome (MS), lifestyle, and lifestyle-related diseases in both males and females. However, the prevalence of NAFLD, MS, and clinical backgrounds is different between males and females. Objective We conducted a cross-sectional study to examine the differing influence of lifestyle-related factors and visceral fat on fatty liver (FL) with elevation of liver enzymes between males and females with MS. Methods We enrolled 42,134 persons who underwent a regular health check-up, and after excluding subjects who fulfilled excluding criteria, the remaining subjects were 2,110 persons with MS. We examined the differing influence of lifestyle-related factors and visceral fat on FL with elevation of alanine aminotransferase (ALT) (ALT elevation was defined as ALT level of ≥31 IU/l in the present study). Results The odds rations for FL with ALT elevation were as follows: WC, 1.83 (95% confidence interval (CI) 1.36–2.46); dyslipidemia, 1.89 (95% CI 1.34–2.68); hemoglobin A1c, 1.36 (95% CI 1.00–1.85); visceral fat type MS (V-type MS), 5.78 (95% CI 4.29–7.80); and light drinker, 0.56 (95% CI 0.41–0.78) in males with MS and BMI, 2.18 (95% CI 1.43–3.33); WC, 1.85 (95% CI 1.27–2.70); diastolic blood pressure, 1.69 (95% CI 1.16–2.45); triglyceride, 2.22 (95% CI 1.56–3.17); impaired glucose tolerance, 1.66 (95% CI 1.11–2.47); and V-type MS, 3.83 (95% CI 2.57–5.70) in females with MS. The prevalence of FL with ALT elevation and ALT was significantly higher in V-type MS than in the subcutaneous fat type MS in both males and females with MS (P < 0.001). Conclusion Although V-type MS and WC is a common significant predictor of an increased prevalence of FL with ALT elevation in both males and females with MS, gender, lifestyle-related factors, and MS type in individuals with MS should be considered for the development of FL with ALT elevation.

EGFR Downregulation after Anti-EGFR Therapy Predicts the Antitumor Effect in Colorectal Cancer

Anti-EGFR mAb is reported to induce EGFR internalization in colorectal cancer cells. However, the biological relevance of EGFR internalization with anti-EGFR mAb is unknown. Therefore, the relevance of EGFR downregulation with anti-EGFR mAb to antitumor activity in colorectal cancer cells was investigated. Quantification of EGFR on the cell surface before cetuximab treatment was assessed by flow cytometry, and its growth-inhibitory effects were measured by Trypan blue exclusion, in 10 RAS, BRAF wild-type colorectal cancer cell lines, but there was no significant correlation between EGFR number and its growth-inhibitory effect. However, a significant correlation existed between the percentage decrease in the number of EGFRs after cetuximab treatment and its growth-inhibitory effect in those cell lines. Treatment with TGFα, a ligand for EGFR, induced EGFR internalization in colorectal cancer cells, but most EGFRs subsequently recycled to the cell surface, consistent with previous studies. While cetuximab treatment induced EGFR internalization, most receptors subsequently translocated into the late endosome, leading to lysosomal degradation, as revealed by immunoblotting and double immunofluorescence. Cetuximab-sensitive colorectal cancer cells showed greater EGFR internalization, stronger cell growth inhibition, and more augmented apoptotic signals than nonsensitive cells. IHC for EGFR, performed using an EGFR pharmDx Kit (mouse anti-human EGFR mAb clone 2-18C9), in clinical specimens before and after anti-EGFR mAb therapy in 13 colorectal cancer patients showed a significant correlation between the response to anti-EGFR mAb and decreased staining after therapy. Implications: This report clearly demonstrates that anti-EGFR mAb facilitates internalization and subsequent degradation of EGFRs in lysosomes, which is an important determinant of the efficacy of anti-EGFR mAb treatment for colorectal cancer. Mol Cancer Res; 15(10); 1445–54. ©2017 AACR.

Endoscopic submucosal dissection through a gastrostomy for early gastric cancer in patients with pharyngeal stenosis

e 1. Endoscopic submucosal dissection (ESD) through the gastrostomy (case 2). A, Dilation of the gastrostomy was done with a 27F dilator. B, C, A r gastroscope with a water jet function was inserted from the stoma under direct vision through the transnasal endoscope (B, view from the oral C, view from the stoma). D, A protruding, 3-cm lesion was noted. E, The lesion was lifted with thin biopsy forceps to reveal the submucosa. F, ESD an insulated tip knife was conducted successfully.

Tu1725 Angiogenesis-Related Factors At the Residual Inflammation in Patients With Ulcerative Colitis in Clinical Remission Stage

Angiogenesis-Related Factors At the Residual Inflammation in Patients With Ulcerative Colitis in Clinical Remission Stage Miwako Kagawa, Toshiya Okahisa, Yoshifumi Takaoka, Yasuteru Fujino, Jinsei Miyoshi, Toshi Takaoka, Tetsu Tomonari, Shinji Kitamura, Yasuyuki Okada, Kaizo Kagemoto, Masanori Takehara, Kumiko Tanaka, Sayo Matsumoto, Tomofumi Teramae, Hiroshi Miyamoto, Naoki Muguruma, Tetsuji Takayama