Future Science Ltd. Acta Medica Okayama 2056-5623 Concordance of acquired mutations between metastatic lesions and liquid biopsy in metastatic colorectal cancer FSO757 EN Fumitaka Taniguchi Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Akihiro Nyuya Department of Clinical Oncology, Kawasaki Medical School Toshiaki Toshima Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Kazuya Yasui Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Yoshiko Mori Department of Clinical Genetics & Digestive Tract & General Surgery, Saitama Medical Center, Saitama Medical University, Makoto Okawaki Department of Clinical Oncology, Kawasaki Medical School Hiroyuki Kishimoto Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Yuzo Umeda Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Toshiyoshi Fujiwara Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Hiroaki Tanioka Department of Clinical Oncology, Kawasaki Medical School Yoshiyuki Yamaguchi Department of Clinical Oncology, Kawasaki Medical School Ajay Goel Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center Takeshi Nagasaka Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences Aim: To evaluate whether PCR-reverse sequence-specific oligonucleotide can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Materials & methods: We examined acquired mutations in chemoresistant lesions and blood obtained from four patients with RAS wildtype metastatic colorectal cancer who underwent treatment with anti-epidermal growth factor receptor antibodies. Results: In one patient, metastatic lesions harbored diverse acquired mutations in KRAS in all seven metastases; the two acquired mutations were detectable in blood collected after the patient acquired resistance. None of the other patients exhibited liquid biopsy mutations, except one, with a BRAF mutation confirmed in primary tumor and peritoneal dissemination. Conclusion: Liquid biopsy based on PCR-reverse sequence-specific oligonucleotide is a successful procedure for capturing acquired mutations with precise information on the RAS mutational spectrum. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 129 2 2017 家族性大腸腺腫症術後20年後に小腸癌を発症した1例 111 114 EN Yuusaku Sugihara Department of Gastroenterology and Hepatology, Okayama University Hospital Seiji Kawano Department of Gastroenterology and Hepatology, Okayama University Hospital Keita Harada Department of Gastroenterological Surgery, Okayama University Hospital Shiho Takashima Department of Gastroenterology and Hepatology, Okayama University Hospital Daisuke Takei Department of Gastroenterological Surgery, Okayama University Hospital Toshihiro Inokuchi Department of Gastroenterology and Hepatology, Okayama University Hospital Masahiro Takahara Department of Gastroenterology and Hepatology, Okayama University Hospital Sakiko Hiraoka Department of Gastroenterology and Hepatology, Okayama University Hospital Yoshiko Mori Division of Endoscopy, Okayama University Hospital Hiroyuki Kishimoto Division of Endoscopy, Okayama University Hospital Takeshi Nagasaka Division of Endoscopy, Okayama University Hospital Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Hospital A 58-year-old Japanese man visited a local clinic for the evaluation of a stomachache. He was diagnosed with intestinal obstruction. His medical history included a proctocolectomy at the age of 38 years, due to familial adenomatous polyposis (FAP). He was referred to our institution, where he underwent a computed tomography examination and endoscopy of the small intestine. The pathological diagnosis was adenocarcinoma. No invasive or metastatic lesions were observed. Therefore, partial resection of the ileum with lymphadenectomy and reconstruction of the ileostomy were performed. Pathological examination revealed that the tumor was type 2, pT3 (SS) , pN1, pPM0, pDM0, pRM0, INFb, ly1, v1, pEX0, PN0. Twenty-nine days after the surgery, the patient was diagnosed with lung metastasis and he underwent lung radiofrequency ablation. We suggest that long-term follow-up is necessary for patients after surgery for FAP, because of the risk of malignant disease developing in other organs. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 70 6 2016 Acute Bowel Injury due to Cryoablation for Renal Cell Carcinoma: Correlated Radiologic and Pathologic Findings 511 514 EN Hideo Gobara Department of Radiology,Okayama University Hospital Takao Hiraki Department of Radiology,Okayama University Hospital Toshihiro Iguchi Department of Radiology,Okayama University Hospital Hiroyasu Fujiwara Department of Radiology,Okayama University Hospital Takeshi Nagasaka Department of Gastroenterological Surgery, Okayama University Hospital Hiroyuki Kishimoto Department of Gastroenterological Surgery, Okayama University Hospital Takehiro Tanaka Department of Pathology, Okayama University Hospital Susumu Kanazawa Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science Case Report 10.18926/AMO/54817 An 87-year-old Japanese man underwent percutaneous cryoablation (PCA) therapy for his renal cell tumor. We displaced the colon from the tumor using hydrodissection. Computed tomography (CT) immediately after PCA was indicative of iceball extension to the colon wall, and a discontinuous enhancement of the colon wall was observed. We therefore performed an emergency surgery. On laparotomy, we observed a dark-purple area on the affected area of the colon, and the resected specimen showed focal, deep ulceration on the mucosal surface. Photomicrography revealed mucosal necrosis, submucosal hemorrhage, and necrotic foci in the muscularis propria, corresponding to the discontinuous colon wall enhancement on CT and the deep ulceration and dark-purple area on laparotomy. He recovered from surgery and was discharged without any complications. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 70 4 2016 Single Center Prospective Phase II Trial of CT-guided Radiofrequency Ablation for Pulmonary Metastases from Colorectal Cancer (SCIRO-1401) 317 321 EN Jun Sakurai Center for Innovative Clinical Medicine, Okayama University Hospital Yusuke Matsui Department of Radiology, Okayama University Hospital Takao Hiraki Department of Radiology, Okayama University Hospital Toshihiro Iguchi Department of Radiology, Okayama University Hospital Hiroyasu Fujiwara Department of Radiology, Okayama University Hospital Hideo Gobara Department of Radiology, Okayama University Hospital Toshiharu Mitsuhashi Center for Innovative Clinical Medicine, Okayama University Hospital Takeshi Nagasaka Department of Gastroenterological Surgery Transplant and Surgical Oncology, Okayama University Hospital Susumu Kanazawa Susumu Kanazawa Department of Radiology, Okayama University Hospital Clinical Study Protocols 10.18926/AMO/54512 The present single center prospective phase II clinical trial is designed to evaluate the efficacy and safety of percutaneous radiofrequency (RF) ablation for colorectal lung metastases. Patients who have colorectal lung metastases without extrapulmonary metastases are included in this study. The primary endpoint is 3-year overall survival (OS) after RF ablation. The secondary endpoints are the prevalence of adverse events within 4 weeks, local tumor progression rate, 1- and 5-year OS, cause-specific survival, and relapse-free survival. The recruitment of patients commenced in July 2014, and the enrolment of 45 patients is intended over the 3 years of study period. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 69 5 2015 A Case-matched Comparative Study of Laparoscopic and Open Total Proctocolectomy for Ulcerative Colitis 267 273 EN Ryo Inada Takeshi Nagasaka Yoshitaka Kondo Ayako Watanabe Toshiaki Toshima Nobuhito Kubota Satoru Kikuchi Michihiro Ishida Shinji Kuroda Yoshiko Mori Hiroyuki Kishimoto Toshiyoshi Fujiwara Original Article 10.18926/AMO/53672 The aim of this single-institution, retrospective, observational case-control study was to evaluate the safety and feasibility of laparoscopic proctocolectomy (PC) for ulcerative colitis (UC), by comparing it with a case-control series of open PC. Twenty UC patients who underwent laparoscopic PC were retrospectively compared with the open PC group of 12 patients matched for age, sex, and urgency of the operation. In the laparoscopic PC group, the operative time was significantly longer, but the amount of blood loss was significantly smaller. The open PC patients underwent an intraoperative blood transfusion significantly more often, and the serum C-reactive protein level on the first postoperative day was significantly higher in the open PC group. In the laparoscopic PC group, the rate of severe postoperative morbidities, grades 3 and 4 on the Clavien-Dindo classification, was significantly lower, and the median length of hospital stay was significantly shorter. Laparoscopic PC for patients with UC showed superior perioperative outcomes to open PC, except for longer operative time. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 127 2 2015 超高齢者（95歳）の進行盲腸癌に対して腹腔鏡下回盲部切除を施行した1例 117 121 EN Ayako Watanabe Ryo Inada Takeshi Nagasaka Tomohiko Yagi Hijiri Matsumoto Toshiaki Toshima Satoru Kikuchi Shinshi Kuroda Yoshitaka Kondo Yoshiko Mori Hiroyuki Kishimoto Toshiyoshi Fujiwara We report a successful laparoscopic resection of a cecal tumor in a 95-year-old Japanese man. The patient visited an initial hospital with a complaint of constipation in March 2014. Computed tomography scan and colonoscopy showed a stenotic ileocecal cancer with pericolic lymph node metastases, and he was referred to our department for management. Since his general condition was maintained, we performed a laparoscopic ileocecal resection with regional lymph node dissection for the patient. The operation achieved curative resection, and the tumor was diagnosed as a moderately differentiated adenocarcinoma and graded as pStage IIIa (pT3, pN0, pM0) according to the Japanese Classification of Colorectal Carcinoma, eighth edition. He was discharged on the 11th postoperative day without perioperative complications. Several large-scale randomized controlled trials （RCTs） revealed that laparoscopic surgeries for colorectal cancers have some advantages compared to open surgeries, including superior short-term outcomes and comparable long-term outcomes. Unfortunately, since these RCTs did not include enough elderly patients, the safety and feasibility of laparoscopic surgery for extremely elderly patients are still unknown. With respect to less-invasive procedures, these advantages of laparoscopic surgery are also thought to be the advantages for elderly colorectal cancer patients. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 69 2 2015 Aggressive Multimodality Treatment for Advanced Rectal Cancer 113 118 EN Ryo Inada Takeshi Nagasaka Toshiaki Toshima Yoshiko Mori Yoshitaka Kondo Hiroyuki Kishimoto Takao Hiraki Taihei Oshiro Yukihide Kanemitsu Toshiyoshi Fujiwara Case Report 10.18926/AMO/53340 A case of advanced rectal cancer treated by aggressive local and systemic treatment who has survived more than 7 years from initial recurrence is presented. A 55-year-old woman was diagnosed with advanced lower rectal cancer and underwent a low anterior resection with complete removal of all regional lymph nodes and total mesorectal excision. The tumor was diagnosed as a moderately differentiated adenocarcinoma, pStage IIIB (T3, N2a, M0). Twenty-six months after the initial surgery, local recurrence in the pelvis was detected by computed tomography, and total pelvic exenteration with distal sacrectomy (TPES) was performed after systemic chemotherapy with a molecular-targeted drug. Six months after the TPES, multiple lung metastases were detected. Consequently, the patient underwent radiofrequency ablation (RFA) and chemotherapy. The disease has since been controlled for 38 months. As volume control is essential for cancer treatment, it may be important to combine appropriate local therapy with systemic therapy to metastatic or recurrent sites in order to achieve much longer disease control. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1525-0016 2014 Biological Ablation of Sentinel Lymph Node Metastasis in Submucosally Invaded Early Gastrointestinal Cancer EN Satoru Kikuchi Hiroyuki Kishimoto Hiroshi Tazawa Yuuri Hashimoto Shinji Kuroda Masahiko Nishizaki Takeshi Nagasaka Yasuhiro Shirakawa Shunsuke Kagawa Yasuo Urata Robert M Hoffman Toshiyoshi Fujiwara Currently, early gastrointestinal cancers are treated endoscopically, as long as there are no lymph node metastases. However, once a gastrointestinal cancer invades the submucosal layer, the lymph node metastatic rate rises to higher than 10%. Therefore, surgery is still the gold standard to remove regional lymph nodes containing possible metastases. Here, to avoid prophylactic surgery, we propose a less-invasive biological ablation of lymph node metastasis in submucosally invaded gastrointestinal cancer patients. We have established an orthotopic early rectal cancer xenograft model with spontaneous lymph node metastasis by implantation of green fluorescent protein (GFP)-labeled human colon cancer cells into the submucosal layer of the murine rectum. A solution containing telomerase-specific oncolytic adenovirus was injected into the peritumoral submucosal space, followed by excision of the primary rectal tumors mimicking the endoscopic submucosal dissection (ESD) technique. Seven days after treatment, GFP signals had completely disappeared indicating that sentinel lymph node metastasis was selectively eradicated. Moreover, biologically treated mice were confirmed to be relapse-free even 4 weeks after treatment. These results indicate that virus-mediated biological ablation selectively targets lymph node metastasis and provides a potential alternative to surgery for submucosal invasive gastrointestinal cancer patients. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0172-6390 61 130 2014 Management Of Peritoneal Effusion by Sealing with a Self-Assembling Nanofiber Polypeptide Following Pelvic Surgery 349 353 EN Yoshitaka Kondo Takeshi Nagasaka Satoru Kobayashi Naoya Kobayashi Toshiyoshi Fujiwara Background/Aims: PuraMatrix is a synthetic material consisting of 16-amino acid peptides that self-assemble into nanofibers, previously used as a scaffold for functional cell cultures. We conducted a clinical study to determine the safety and sealing properties of PuraMatrix in post-operative lymphorrhea following pelvic surgery in humans. Methodology: A total of 20 patients who underwent rectal cancer resection were analyzed. The study group (n = 10) consisted of patients who received PuraMatrix, matched with a control group (n = 10) of patients operated on conventionally. Results: During the 2 to 3 month follow-up period, there were no abnormal findings or adverse events in any the patients who received PuraMatrix. We found that the patients who received PuraMatrix had significantly reduced post-operative drainage volumes compared with the patients in the control group. Conclusions: PuraMatrix is a safe and effective bio-compatible sealing material for the management of post-operative peritoneal effusion following pelvic surgery. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 2014 Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnostics EN Kunitoshi Shigeyasu Hiroshi Tazawa Yuuri Hashimoto Yoshiko Mori Masahiko Nishizaki Hiroyuki Kishimoto Takeshi Nagasaka Shinji Kuroda Yasuo Urata Ajay Goel Shunsuke Kagawa Toshiyoshi Fujiwara 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. No potential conflict of interest relevant to this article was reported.

Academic Press Inc Elsevier Science Acta Medica Okayama 0022-4804 178 2 2012 Jejunal interposition reconstruction with a stomach preserving esophagectomy improves postoperative weight loss and reflux symptoms for esophageal cancer patients 700 707 EN Eiji Yamada Yasuhiro Shirakawa Tomoki Yamatsuji Leon Sakuma Munenori Takaoka Takako Yamada Kazuhiro Noma Kazufumi Sakurama Yasuhiro Fujiwara Shunsuke Tanabe Takeshi Nagasaka Toshiyoshi Fujiwara Yoshio Naomoto Background: Conventional reconstruction after an esophagectomy uses a gastric tube, which commonly causes several postoperative complaints such as gastric acid reflux in long-term survival cases. Intestinal interposition between the remnant esophagus and the stomach is an option to reduce complaints, and in this study, the advantages of jejunal interposition reconstruction with a stomach preserving esophagectomy (SPE) were assessed. Materials and methods: Eleven cases of jejunal interposition with an SPE and 16 cases with gastric tube reconstruction as a control were subject to a comparison of operation time, amount of bleeding, postoperative quality of life, and endoscopic findings. Results: The SPE group had a longer operation time (SPE: 560 +/- 121 min, control 414 +/- 83 min, P = 0.038), whereas there was no significant difference in blood loss. Postoperative weight loss was significantly recovered in the SPE group (SPE versus control = 94.0 +/- 5.4% versus 87.5 +/- 4.7% at 3 mo, P = 0.017; 97.2 +/- 7.5% versus 85.0 +/- 5.2% at 6 mo, P = 0.010), and there was a significant decrease in the occurrence of reflux symptoms such as heartburn, odynophagia, and cough when jejunal interposition with an SPE was done. Furthermore, reflux esophagitis and Barrett's epithelium were found in six out of 12 cases (50%) of the control group by postoperative endoscopy, while no cases in the SPE group had either condition (P < 0.01). Conclusions: This reconstruction method is a promising option to improve postoperative quality of life, mainly due to the long-term elimination of reflux esophagitis, which assists in the recovery of postoperative weight loss. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1078-0432 19 23 2013 A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem-like Cells in S/G(2)/M Phases 6495 6505 EN Shuya Yano Hiroshi Tazawa Yuuri Hashimoto Yasuhiro Shirakawa Shinji Kuroda Masahiko Nishizaki Hiroyuki Kishimoto Futoshi Uno Takeshi Nagasaka Yasuo Urata Shunsuke Kagawa Robert M. Hoffman Toshiyoshi Fujiwara Purpose: Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem-like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem-like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem-like cells. Experimental Design: We established CD133(+) cancer stem-like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent cancer stem-like cells. We visualized the treatment dynamics of OBP-301 killing of quiescent cancer stem-like cells in dormant tumor spheres and xenografts using a fluorescent ubiquitination cell-cycle indicator (FUCCI). Results: CD133(+) gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133(+) cancer stem-like cells resistant to chemoradiotherapy. OBP-301 induced cell-cycle mobilization from G(0)-G(1) to S/G(2)/M phases and subsequent cell death in quiescent CD133(+) cancer stem-like cells by mobilizing cell-cycle-related proteins. FUCCI enabled visualization of quiescent CD133(+) cancer stem-like cells and proliferating CD133(-) non-cancer stem-like cells. Three-dimensional visualization of the cell-cycle behavior in tumor spheres showed that CD133(+) cancer stem-like cells maintained stemness by remaining in G(0)-G(1) phase. We showed that OBP-301 mobilized quiescent cancer stem-like cells in tumor spheres and xenografts into S/G(2)/M phases where they lost viability and cancer stem-like cell properties and became chemosensitive. Conclusion: Oncolytic adenoviralinfection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent cancer stem-like cells. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 5 4 2013 CD14 upregulation as a distinct feature of non-alcoholic fatty liver disease after pancreatoduodenectomy 189 195 EN Daisuke Satoh Takahito Yagi Takeshi Nagasaka Susumu Shinoura Yuzo Umeda Ryuichi Yoshida Masashi Utsumi Takehiro Tanaka Hiroshi Sadamori Toshiyoshi Fujiwara AIM: To investigate the pathogenesis of non-alcoholic fatty liver disease (NAFLD) after pancreatoduodenectomy (PD). METHODS: A cohort of 82 patients who underwent PD at Okayama University Hospital between 2003 and 2009 was enrolled and the clinicopathological features were compared between patients with and without NAFLD after PD. Computed tomography (CT) images were evaluated every 6 mo after PD for follow-up. Hepatic steatosis was diagnosed on CT when hepatic attenuation values were 40 Hounsfield units. Liver biopsy was performed for 4 of 30 patients with NAFLD after PD who consented to undergo biopsies. To compare NAFLD after PD with NAFLD associated with metabolic syndrome, liver samples were obtained from 10 patients with NAFLD associated with metabolic syndrome [fatty liver, n = 5; non-alcoholic steatohepatitis (NASH), n = 5] by percutaneous ultrasonography-guided liver biopsy. Double-fluorescence immunohistochemistry was applied to examine CD14 expression as a marker of lipopolysaccharide (LPS)-sensitized macrophage cells (Kupffer cells) in liver biopsy specimens. RESULTS: The incidence of postoperative NAFLD was 36.6% (30/82). Univariate analysis identified cancer of the pancreatic head, sex, diameter of the main pancreatic duct, and dissection of the nerve plexus as factors associated with the development of NAFLD after PD. Those patients who developed NAFLD after PD demonstrated significantly decreased levels of serum albumin, total protein, cholesterol and triglycerides compared to patients without NAFLD after PD, but no glucose intolerance or insulin resistance. Liver biopsy was performed in four patients with NAFLD after PD. All four patients showed moderate-to-severe steatosis and NASH was diagnosed in two. Numbers of cells positive for CD68 (a marker of Kupffer cells) and CD14 (a marker of LPS-sensitized Kupffer cells) were counted in all biopsy specimens. The number of CD68+ cells in specimens of NAFLD after PD was significantly increased from that in specimens of NAFLD associated with metabolic syndrome specimens, which indicated the presence of significantly more Kupffer cells in NAFLD after PD than in NAFLD associated with metabolic syndrome. Similarly, more CD14+ cells, namely, LPS-sensitized Kupffer cells, were observed in NAFLD after PD than in NAFLD associated with metabolic syndrome. Regarding NASH, more CD68+ cells and CD14+ cells were observed in NASH after PD specimens than in NASH associated with metabolic syndrome. This showed that more Kupffer cells and more LPS-sensitized Kupffer cells were present in NASH after PD than in NASH associated with metabolic syndrome. These observations suggest that after PD, Kupffer cells and LPS-sensitized Kupffer cells were significantly upregulated, not only in NASH, but also in simple fatty liver. CONCLUSION: NAFLD after PD is characterized by both malnutrition and the up-regulation of CD14 on Kupffer cells. Gut-derived endotoxin appears central to the development of NAFLD after PD. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 2 2013 消化器がんと分子標的治療薬 145 152 EN Takeshi Nagasaka Toshiyoshi Fujiwara No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 1 2013 一次治療でセツキシマブ不耐となった後，三次治療での再使用により奏功した進行大腸癌の一例 51 55 EN Ryo Inada Takeshi Nagasaka Yoshiko Mori Yuzo Umeda Nobuhito Kubota Tatsuya Morikawa Yoshitaka Kondo Futoshi Uno Yu Sadamori Takahito Yagi Toshiyoshi Fujiwara 　A 55-year-old man who had been diagnosed with rectal cancer with multiple liver metastases and lymph node metastases on colonoscopy and computed tomography (CT) was referred to Okayama University Hospital for treatment. Based on the diagnosis of non-curative rectal cancer, we planned to perform systematic chemotherapy after surgical resection. We performed a low anterior resection of a 36×35 mm upper rectal moderately differentiated adenocarcinoma with wil-type KRAS. After the resection, a FOLFIRI regimen with cetuximab was given as the first-line chemotherapy. Although metastatic lesions in the liver showed shrinkage, we decided to switch regimens because of intolerable adverse events. A modified FOLFOX6 regimen with bevacizumab was administered as the second-line treatment. There were no signs of disease progression until eight months later, when positron emission tomography (PET)/CT scans revealed that the new metastatic lesions appeared. As the third-line treatment, an irinotecan with cetuximab regimen was administered, leading to a good response for over 12 months. 　We experienced a successful rechallenge with cetuximab for a case with metastatic rectal cancer. For patients with wild-type KRAS colorectal cancer, rechallenge with cetuximab-based chemotherapy can be an effective therapeutic option. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 125 1 2013 予後不良な経過をたどったBRAF遺伝子変異を伴うStage Ⅳ大腸癌の１例 47 50 EN Ryo Inada Takeshi Nagasaka Kiyoto Takehara Masahiro Sugihara Yoshiko Mori Yuzo Umeda Nobuhito Kubota Tatsuya Morikawa Yoshitaka Kondo Futoshi Uno Yu Sadamori Takahito Yagi Toshiyoshi Fujiwara 　A 79-year-old woman visited a previous hospital with a complaint of general fatigue. The patient was diagnosed with cecal cancer with multiple liver metastases and lymph node metastases on colonoscopy, abdominal ultrasonography and CT scan, and was referred to our division for treatment. Based on the diagnosis of non-curative colonic cancer, we planned to perform systematic chemotherapy after local surgical treatment. We performed an ileocecal resection, and the specimen showed poorly differentiated adenocarcinoma with mutation in the BRAF oncogene. After the surgical treatment, the tumor grew rapidly and the patient died from cancer on the 19th postoperative day without having the opportunity to undergo chemotherapy. 　Multiple genetic and epigenetic alterations in oncogenes and tumor suppressor genes are involved in the process of colorectal carcinogenesis. Some of the alterations have been identified as predictive and prognostic biomarkers. A mutation in the BRAF oncogene was reported to be associated with a very unfavorable prognosis in colorectal cancers. Some of the cases with rapid progression are suggested to have the BRAF oncogene mutation. According to our experience, chemotherapy before surgical treatment might improve the prognosis of cases with the BRAF mutation. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 65 3 2011 Expansion of CpG Methylation in the SFRP2 Promoter Region during Colorectal Tumorigenesis 169 177 EN Masanori Takeda Takeshi Nagasaka Sun Dong-Sheng Hiroyuki Nishie Tetsuhiro Oka Eiji Yamada Yoshiko Mori Kunitoshi Shigeyasu Tatsuya Morikawa Satoshi Mizobuchi Toshiyoshi Fujiwara Original Article 10.18926/AMO/46628 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. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 122 2 2010 便中メチル化DNA検出による消化器がんスクリーニング：消化器がんを非侵襲的にスクリーニングすることは可能か？ 107 112 EN Takeshi Nagasaka Noriaki Tanaka Dong-Sheng Sun Yoshio Naomoto Nagahide Mastubara Takahito Yagi Toshiyoshi Fujiwara No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 60 5 2006 Detection of Fecal DNA Methylation for Colorectal Neoplasia : Does It Lead to an Optimal Screening Test? 249 256 EN Takeshi Nagasaka Ajay Goel Nagahide Matsubara Noriaki Tanaka Review 10.18926/AMO/30741 Aberrant promoter methylation, an 'epigenetic' form of genomic instability that leads to transcriptional silencing of tumor suppressor genes, is increasingly being recognized as a crucial component in the evolution of human cancers. With our limited knowledge of the molecular basis and timing of the initiation of altered methylation events in the stepwise progression of cancers, the biggest challenge we currently face is to identify novel biomarkers and technologies for the timely screening of patients carrying such alterations. One such strategy would be to develop tests for the detection of fecal DNA methylation patterns that will improve the sensitivity of noninvasive screening tests for colorectal neoplasia, and moreover, will decrease both mortality and the incremental costs of treating colorectal cancers. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 117 2 2005 大腸癌におけるKRAS，BRAF 遺伝子突然変異とDNA メチル化 97 103 EN No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 2004 Hypermethylation of ο6-Methylguanine-DNA Methyltransferase Promoter May Predict Nonrecurrence after Chemotherapy in Colorectal Cancer Cases EN Takeshi Nagasaka No potential conflict of interest relevant to this article was reported.