Faculty Profiles - HIRAOKA Sakiko

Papers - HIRAOKA Sakiko

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Is presence or history of extracolonic primary malignancy a risk for colorectal Neoplasia? An analysis of patients who underwent colonoscopy Reviewed

Mitsuhiro Akita, Sakiko Hiraoka, Eisuke Kajia, Koji Takemoto, Yasuhiro Nagahara, Hiroshi Yamamot, Kazuhide Yamamoto, Jun Kato

Acta Medica Okayama 67 ( 5 ) 285 - 292 2013

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

Whether presence or history of extracolonic primary malignancy is a risk for colorectal neoplasia is not fully known. In this study, 26,452 first-time colonoscopy cases were examined using a colonoscopy database. Among the analyzed subjects, 3,026 (11%) subjects had history or concomitance of extracolonic primary malignancy, while the remaining 23,426 subjects did not. Colorectal neoplasia was observed in 39% of all the subjects. A crude comparison showed that the prevalence of any type of colorectal neoplasia was higher in subjects with extracolonic malignancy than in those without (42% vs. 39%, p = 0.0012). However, after adjusting for confounding factors, the odds ratios (ORs) of subjects with extracolonic malignancy for having colorectal neoplasia, advanced neoplasia, and cancer were all less than 1.0, and all significantly different from those of subjects without extracolonic malignancy. Analysis according to the type of extracolonic malignancy revealed that gastric cancer cases had a significantly lower risk for colorectal advanced neoplasia (OR: 0.81
95% CI: 0.67-0.99). Among major malignancies, only esophageal squamous cell cancer cases had increased risk for colorectal neoplasia (OR: 1.66
95% CI: 1.20-2.29). Patients with presence or history of extracolonic malignancy did not carry a higher risk of occurrence of colorectal neoplasia. © 2013 by Okayama University Medical School.

DOI： 10.18926/AMO/51864

Development of Invasive Colon Cancer with Microsatellite Instability in a Patient with Hyperplastic Polyposis Syndrome Reviewed

Joichiro Horii, Jun Kato, Takeshi Nagasaka, Sakiko Hiraoka, Dong-Sheng Sun, Kazuo Watanabe, Isao Fujita, Tatsuya Toyokawa, Jun Tomoda, Kazuhide Yamamoto

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 5 ) 451 - 454 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

The serrated pathway has recently been proposed as a route for the development of colorectal cancer with microsatellite instability. Hyperplastic polyposis syndrome is a rare syndrome defined by the presence of numerous serrated polyps, with a high risk of developing into colorectal cancer. We present here a case of hyperplastic polyposis syndrome developing into colorectal cancer with microsatellite instability from a serrated polyp. BRAF mutation and the loss of MLH1 protein were observed in the colorectal cancer, but not in the other serrated polyps around the colorectal cancer, suggesting that colorectal cancer with microsatellite instability develops rapidly from a specific serrated polyp with distinct molecular properties.

DOI： 10.1093/jjco/hys031

Externalization of Saw-Tooth Architecture in Small Serrated Polyps Implies the Presence of Methylation of IGFBP7 Reviewed

Eisuke Kaji, Toshio Uraoka, Jun Kato, Sakiko Hiraoka, Hideyuki Suzuki, Mitsuhiro Akita, Shunsuke Saito, Takehiro Tanaka, Nobuya Ohara, Kazuhide Yamamoto

DIGESTIVE DISEASES AND SCIENCES 57 ( 5 ) 1261 - 1270 2012.5

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

Serrated polyps have been considered to be precursors of colorectal cancer with microsatellite instability. However, the biological and/or morphological changes which occur during the course of serrated polyp to cancer remain to be elucidated.
Twenty-eight colorectal serrated polyps including five mixed polyps (MP) from 20 patients were observed by chromoendoscopy with magnification, and subsequently resected endoscopically. The presence of mutations in two genes (K-ras and BRAF) and the methylation status of six genes (MLH1-A, MLH1-C, ESR1, P16, SOCS1, and IGFBP7) were examined.
The 28 polyps included 32 histological serrated lesions (22 sessile serrated adenomas [SSA], six hyperplastic polyps [HP], and four traditional serrated adenoma [TSA]-like lesions). BRAF mutation was frequently observed in SSAs (19/22), while K-ras mutation was dominant in HPs (5/6). The externalization of saw-tooth architecture in serrated polyps was endoscopically observed more frequently in those with high levels of IGFBP7 methylation (P = 0.03). Moreover, the endoscopic finding was observed in five of six small serrated lesions (< 10 mm) which contained both BRAF mutation and high levels of IGFBP7 methylation. TSA-like lesions in small MPs demonstrated the endoscopic finding with no or little MLH1 methylation, while the counterparts in the mixed polyps had high levels of MLH1 methylation with relatively low levels of IGFBP7 methylation.
Our data suggests two distinct pathways may be involved in the early stages of the serrated pathway: one where MLH1 is primarily methylated, and a second where methylated IGFBP7 is associated with an externalization of saw-tooth architecture.

DOI： 10.1007/s10620-011-2008-0

Detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography and computed tomography (FDG-PET/CT) Reviewed

Tomoko Hirakawa, Jun Kato, Yoshihiro Okumura, Keisuke Hori, Sakuma Takahashi, Hideyuki Suzuki, Mitsuhiro Akita, Reiji Higashi, Shunsuke Saito, Eisuke Kaji, Toshio Uraoka, Sakiko Hiraoka, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY 47 ( 2 ) 127 - 135 2012.2

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

The purpose of this study was to analyze the detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT).
Data for a total of 492 patients who had undergone both PET/CT and colonoscopy were analyzed. After the findings of PET/CT and colonoscopy were determined independently, the results were compared in each of the six colonic sites examined in all patients. The efficacy of PET/CT was determined using colonoscopic examination as the gold standard.
In all, 270 colorectal lesions 5 mm or more in size, including 70 pathologically confirmed malignant lesions, were found in 172 patients by colonoscopy. The sensitivity and specificity of PET/CT for detecting any of the colorectal lesions were 36 and 98%, respectively. For detecting lesions 11 mm or larger, the sensitivity was increased to 85%, with the specificity remaining consistent (97%). Moreover, the sensitivity for tumors 21 mm or larger was 96% (48/50). Tumors with malignant or high-grade pathology were likely to be positive with PET/CT. A size of 10 mm or smaller [odds ratio (OR) 44.14, 95% confidence interval (95% CI) 11.44-221.67] and flat morphology (OR 7.78, 95% CI 1.79-36.25) were significant factors that were associated with false-negative cases on PET/CT.
The sensitivity of PET/CT for detecting colorectal lesions is acceptable, showing size- and pathology-dependence, suggesting, for the most part, that clinically relevant lesions are detectable with PET/CT. However, when considering PET/CT for screening purposes caution must be exercised because there are cases of false-negative results.

DOI： 10.1007/s00535-011-0473-z

DNA Methylation of Colon Mucosa in Ulcerative Colitis Patients: Correlation with Inflammatory Status Reviewed

Shunsuke Saito, Jun Kato, Sakiko Hiraoka, Joichiro Horii, Hideyuki Suzuki, Reiji Higashi, Eisuke Kaji, Yoshitaka Kondo, Kazuhide Yamamoto

INFLAMMATORY BOWEL DISEASES 17 ( 9 ) 1955 - 1965 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background: Although DNA methylation of colonic mucosa in ulcerative colitis (UC) has been suggested, the majority of published reports indicate the correlation between methylation of colon mucosa and occurrence of UC-related dysplasia or cancer without considering the mucosal inflammatory status. The aim of this study was to verify whether mucosal inflammation-specific DNA methylation occurs in the colon of UC.
Methods: Of 15 gene loci initially screened, six loci (ABCB1, CDH1. ESR1, GDNF, HPP1, and MYOD1) methylated in colon mucosa of UC were analyzed according to inflammatory status using samples from 28 surgically resected UC patients.
Results: Four of six regions (CDH1, GDNF, HPP1, and MYOD1) were more highly methylated in the active inflamed mucosa than in the quiescent mucosa in each UC patient (P = 0.003, 0.0002, 0.02, and 0.048, respectively). In addition, when the methylation status of all samples taken from examined patients was stratified according to inflammatory status, methylation of CDHI and GDNF loci was significantly higher in active inflamed mucosa than in quiescent mucosa (P = 0.045 and 0.002, respectively). Multiple linear regression analysis revealed that active inflammation was an independent factor of methylation for CDHI and GDNF. DNA methyltransferase 1 and 3b were highly expressed in colon epithelial cells with active mucosa] inflammation, suggesting their involvement in inflammation-dependent methylation.
Conclusions: Methylation in colonic mucosa of UC was correlated with mucosal inflammatory status, suggesting the involvement of methylation due to chronic active inflammation in UC carcinogenesis.

DOI： 10.1002/ibd.21573

Is sigmoidoscopy sufficient for evaluating inflammatory status of ulcerative colitis patients? Reviewed

Jun Kato, Motoaki Kuriyama, Sakiko Hiraoka, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 26 ( 4 ) 683 - 687 2011.4

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

Background and Aims:
An adequate range of colonic observations for precise evaluation of inflammation in ulcerative colitis (UC) patients has not been reported.
Methods:
Retrospective analysis of 545 colonoscopic examinations of UC patients was carried out. Severity of mucosal inflammation was evaluated using the Mayo score of endoscopic index at each location (rectum, sigmoid colon, descending colon, and the oral side of the splenic flexure) in each patient. The colonic site with maximum inflammation was determined for each patient.
Results:
Of 545 patients, 319 (59%) had maximum inflammation in the rectum, 79 (14%) in the sigmoid colon, 70 (13%) in the descending colon, and 77 (14%) on the oral side of the splenic flexure. Severe inflammatory activity (Mayo 3) was observed more frequently in patients who had maximum activity in the descending colon or the more proximal portion than those who had this in the rectum or sigmoid colon (42% vs 25%, P < 0.0001). The first-attack patients were significantly more frequently found in patients with maximum severity in the descending colon or the oral side of splenic flexure than those with maximum severity in the rectum or sigmoid colon (P = 0.016). Moreover, among 134 patients with no inflammation in the rectum and sigmoid colon, 54 (40%) had inflamed mucosa in the descending colon or the more proximal portion.
Conclusions:
Sigmoidoscopy is not sufficient for evaluating inflammation in UC patients. In particular, colonoscopy is necessary for first-attack patients and patients who have a discrepancy between rectosigmoid observation and symptoms.

DOI： 10.1111/j.1440-1746.2010.06562.x

Analysis of K-ras, BRAF, and PIK3CA mutations in laterally-spreading tumors of the colorectum Reviewed

Eisuke Kaji, Jun Kato, Hideyuki Suzuki, Mitsuhiro Akita, Joichiro Horii, Shunsuke Saito, Reiji Higashi, Shin Ishikawa, Motoaki Kuriyama, Sakiko Hiraoka, Toshio Uraoka, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 26 ( 3 ) 599 - 607 2011.3

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

Background and Aims: Laterally-spreading tumors (LST) are a newly-recognized category of colorectal neoplasia, and are defined as lesions larger than 10 mm in diameter and extending circumferentially rather than vertically. However, genetic features of this new category of tumors are not fully elucidated. The aim of this study was to evaluate genetic alterations in LST.
Methods: We examined K-ras, BRAF, and phosphoinositide-3-kinase catalytic-alpha polypeptide (PIK3CA) mutations in 101 LST, including 68 LST-granular type (LST-G) and 33 LST-non-granular type by direct sequencing. As controls, we examined these gene mutations in 66 protruded colon adenomas (10 mm or larger) and 44 advanced colon cancers.
Results: K-ras, BRAF, and PIK3CA mutations were observed in 59 (58%), zero (0%), and three (3%) LST, respectively. LST-G morphology in the right-sided colon was significantly correlated with the existence of K-ras mutations, whereas a size of 20 mm or larger was the only predictor of mutations in the left-sided colorectum. The frequency of K-ras mutations in LST was particularly marked in the left-sided colorectum compared to protruded adenomas or advanced cancers (LST vs protruded adenomas, P < 0.001; LST vs advanced cancers, P = 0.002), whereas in the right-sided colon, K-ras mutations were equally frequent. PIK3CA mutations were not familiar in either LST (3%) or advanced cancers (9%).
Conclusions: K-ras mutations were involved in colorectal LST in different manners according to tumor location.

DOI： 10.1111/j.1440-1746.2010.06485.x

Serum Folate and Homocysteine Levels Are Associated With Colon Tumorigenesis in End-Stage Renal Disease Patients Reviewed

Eisuke Kaji, Jun Kato, Shunsuke Saito, Keita Harada, Kenji Kuwaki, Masashi Tatsukawa, Tamiya Morikawa, Sakiko Hiraoka, Hiroshi Matsushima, Kazuhide Yamamoto

NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL 63 ( 2 ) 202 - 211 2011

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

The aim of this study was to evaluate the effect of folate and homocysteine on colon tumorigenesis by performing colonoscopy and examining serum folate and homocysteine levels in end-stage renal disease (ESRD) patients. We performed colonoscopy in 72 ESRD patients who were undergoing hemodialysis and also measured their serum folate and homocysteine levels. Serum folate and homocysteine concentrations of the 72 ESRD patients were 6.0 +/- 3.9 g/l and 37.3 +/- 25.5 mol/l, respectively. Colorectal neoplasia was detected in 47 (65%) of the patients. Compared to a control group, ESRD patients had significantly more and larger neoplasia (P = 0.002 and 0.001, respectively). Multivariate analysis revealed that ESRD patients with lower levels of serum homocysteine had significantly more and larger neoplasia than those with higher levels (P = 0.02 and 0.03, respectively). In addition, patients with a shorter duration of hemodialysis were likely to have larger neoplasia. ESRD patients had higher than normal serum homocysteine levels. Interestingly, patients with lower homocysteine levels were likely to carry more and larger colorectal neoplasia. These results suggest that suppression of folate metabolism and an elevated serum homocysteine concentration are inversely associated with colon tumorigenesis in ESRD patients.

DOI： 10.1080/01635581.2011.523501

TOLERABILITY AND USEFULNESS OF MERCAPTOPURINE IN AZATHIOPRINE-INTOLERANT JAPANESE PATIENTS WITH ULCERATIVE COLITIS Reviewed

Motoaki Kuriyama, Jun Kato, Hideyuki Suzuki, Mitsuhiro Akita, Sakiko Hiraoka, Hiroyuki Okada, Kazuhide Yamamoto

DIGESTIVE ENDOSCOPY 22 ( 4 ) 289 - 296 2010.10

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

Background and Aim:
Azathioprine (AZA) and mercaptopurine (6-MP) are established as effective therapeutic drugs for the induction and maintenance of remission in patients with ulcerative colitis (UC). However, AZA is often intolerable due to adverse effects. Evidence regarding the approach of switching from AZA to 6-MP in patients of Asian ethnicity is lacking. We assessed the tolerability and usefulness of 6-MP in Japanese UC patients who had shown intolerance to AZA.
Methods:
One-hundred and ten UC patients who had been treated with AZA and/or 6-MP from January 1985 to October 2008 were examined retrospectively.
Results:
Among 110 patients, 107 were treated first with AZA; only three were treated first with 6-MP. Thirty-five (33%) of the 107 patients were intolerant of AZA, with adverse effects including myelosuppression (8/35, 23%), hepatotoxicity (8/35, 23%), and abdominal symptoms (6/35, 17%). Among 35 AZA-intolerant patients, 23 were switched to 6-MP treatment. The cumulative probability of colectomy was significantly higher in patients not treated with 6-MP than in patients treated with 6-MP (log-rank test, P = 0.0002). Among the 26 patients (23 AZA-intolerant and three AZA-untreated) treated with 6-MP, 22 (85%) could tolerate the therapy. Adverse effects due to 6-MP were abdominal symptoms (2/4), myelosuppression (1/4), and rash (1/4). The median initial dose of 6-MP was 20 mg/day, and the median final dose was 30 mg/day.
Conclusions:
6-MP was tolerated in 83% of AZA-intolerant patients, and it was effective for maintenance therapy of UC patients. 6-MP treatment should be considered in AZA-intolerant patients.

DOI： 10.1111/j.1443-1661.2010.01009.x

Prediction of flare-ups of ulcerative colitis using quantitative immunochemical fecal occult blood test Reviewed

Motoaki Kuriyama, Jun Kato, Koji Takemoto, Sakiko Hiraoka, Hiroyuki Okada, Kazuhide Yamamoto

WORLD JOURNAL OF GASTROENTEROLOGY 16 ( 9 ) 1110 - 1114 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：W J G PRESS

AIM: To examine the feasibility of predicting the flare-up of ulcerative colitis (UC) before symptoms emerge using the immunochemical fecal occult blood test (I-FOBT).
METHODS: We prospectively measured fecal hemoglobin concentrations in 78 UC patients using the I-FOBT every 1 or 2 mo.
RESULTS: During a 20 mo-period, 823 fecal samples from 78 patients were submitted. The median concentration of fecal hemoglobin was 41 ng/mL (range: 0-392500 ng/mL). There were three types of patients with regard to the correlation between I-FOBT and patient symptoms; the synchronous transition type with symptoms (44 patients), the unrelated type with symptoms (19 patients), and the flare-up predictive type (15 patients). In patients with the flare-up predictive type, the values of I-FOBT were generally low during the study period with stable symptoms. Two to four weeks before the flare-up of symptoms, the I-FOBT values were high. Thus, in these patients, I-FOBT could predict the flare-up before symptoms emerged.
CONCLUSION: Flare-up could be predicted by I-FOBT in approximately 20% of UC patients. These results warrant periodical I-FOBT in UC patients. (C) 2010 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v16.i9.1110

Specific endoscopic features of ulcerative colitis complicated by cytomegalovirus infection Reviewed

Hideyuki Suzuki, Jun Kato, Motoaki Kuriyama, Sakiko Hiraoka, Kenji Kuwaki, Kazuhide Yamamoto

WORLD JOURNAL OF GASTROENTEROLOGY 16 ( 10 ) 1245 - 1251 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：W J G PRESS

AIM: To identify specific colonoscopic findings in patients with ulcerative colitis (UC) complicated by cytomegalovirus (CMV) infection.
METHODS: Among UC patients who were hospitalized due to exacerbation of symptoms, colonoscopic findings were compared between 15 CMV-positive patients and 58 CMV-negative patients. CMV infection was determined by blood test for CMV antigenemia. Five aspects of mucosal changes were analyzed (loss of vascular pattern, erythema, mucosal edema, easy bleeding, and mucinous exudates) as well as five aspects of ulcerative change (wide mucosal defect, punched-out ulceration, longitudinal ulceration, irregular ulceration, and cobblestone-like appearance). Sensitivity, specificity, positive predictive value, and negative predictive value of each finding for CMV positivity were determined.
RESULTS: The sensitivity of irregular ulceration for positive CMV was 100%. The specificity of wide mucosal defect was 95%. Punched-out ulceration and longitudinal ulceration exhibited relatively high sensitivity and specificity (more than 70% for each).
CONCLUSION: Specific colonoscopic findings in patients with UC complicated by CMV infection were identified. These findings may facilitate the early diagnosis of CMV infection in UC patients. (C) 2010 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v16.i10.1245

Methylation status of normal background mucosa is correlated with occurrence and development of neoplasia in the distal colon Reviewed

Sakiko Hiraoka, Jun Kato, Joichiro Horii, Shunsuke Saito, Keita Harada, Hideyuki Fujita, Motoaki Kuriyama, Koji Takemoto, Toshio Uraoka, Kazuhide Yamamoto

HUMAN PATHOLOGY 41 ( 1 ) 38 - 47 2010.1

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

The aim of this study is to evaluate the methylation status of normal colonic mucosa in relation to the stage of neoplasia arising from the mucosa. The methylation status of 2 age-related loci (ESR1 and MYOD1) and global methylation (the mean of Alu and Sat2) in the normal colonic mucosa of 156 patients with and without colorectal neoplasia were examined. The distal colon and proximal colon were analyzed separately because neoplasia is biologically and clinically different between these sites. The methylation status was determined by MethyLight using percentage of methylated reference (PMR). In the distal colon, methylation of the age-related loci decreased as the stage of neoplasia increased (patients with no neoplasia or with adenoma <= 9 mm versus patients with advanced adenoma or with invasive cancer: ESR1-PMR median, 21.0 versus 15.7; P = .015; MYOD1-PMR median, 5.35 versus 3.80; P = .0037, respectively). Interestingly, global methylation was inversely correlated with the stage of neoplasia (59.7 versus 61.5; P = .054). In contrast, the proximal colon showed no significant correlations. The methylation of MYOD1 in the normal mucosa was significantly correlated with K-ras mutation in neoplastic tissue arising from the mucosa. Specific epigenetic changes in normal colonic mucosa may be correlated with the occurrence and development of neoplasia in the distal colon. (c) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2009.06.002

Methylation of estrogen receptor 1 in colorectal adenomas is not age-dependent, but is correlated with K-ras mutation Reviewed

Joichiro Horii, Sakiko Hiraoka, Jun Kato, Shunsuke Saito, Keita Harada, Hideyuki Fujita, Eisuke Kaji, Kazuhide Yamamoto

CANCER SCIENCE 100 ( 6 ) 1005 - 1011 2009.6

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

The promoter region of estrogen receptor 1 (ESR1) has been shown to be methylated in normal colorectal mucosa in an age-dependent manner. However, the methylation of this region in colorectal tumors has not sufficiently been investigated. The methylation status of ESR1 in 105 colorectal adenoma tissues was examined by MethyLight and presented as the percentage of methylated references (PMR). Factors that affect the PMR of ESR1 in adenomas were determined using parameters including patient age, sex, past history of malignancy, family history of colorectal cancer, smoking and drinking habits, clinical characteristics of adenomas (location, size, macroscopic appearance, and histology), and K-ras mutation. Multiple linear regression revealed that the PMR was not correlated with patient age. K-ras mutation was significantly correlated with the higher methylation status of ESR1 in adenoma (t-value = 3.21, P = 0.0018), whereas alcohol exposure was significantly correlated with lower methylation status (t-value = -2.37, P = 0.02). Because methylation of O(6)-methylguanine DNA methyltransferase (MGMT) has been reported to be correlated with K-ras G-to-A transition, methylation of ESR1 was compared with that of MGMT with regard to K-ras mutation. Contrary to expectations, methylation of MGMT was not significantly correlated with K-ras G-to-A transition, but that of ESR1 was strongly correlated with K-ras G-to-A transition. Thus, the methylation status of ESR1 in adenomas was not correlated with patient age, but was associated with K-ras mutation, suggesting that methylation of ESR1 in tumors functions differently from that in normal colon mucosa. (Cancer Sci 2009; 100: 1005-1011).

DOI： 10.1111/j.1349-7006.2009.01140.x

Ratio of Platelet Reduction is an Early Predictive Factor for the Effectiveness of Leukocytapheresis for Ulcerative Colitis Patients Reviewed

Koji Takemoto, Motoaki Kuriyama, Jun Kato, Hideyuki Suzuki, Shin Ishikawa, Sakiko Hiraoka, Kazuhide Yamamoto

THERAPEUTIC APHERESIS AND DIALYSIS 13 ( 1 ) 6 - 13 2009.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Leukocytapheresis is effective for ulcerative colitis (UC), and both peripheral leukocyte and platelet counts decrease during apheresis. While leukocyte counts increase and overshoot after finishing the apheresis procedure, platelet reduction continues even after apheresis. The aim of this study is to elucidate the impact of the overshoot of leukocyte and continuous platelet reduction on the efficacy of leukocytapheresis for UC. Leukocyte and platelet counts before and one hour after each leukocytapheresis session of 43 UC cases were examined (31 entered remission, but 12 did not). The correlation between the efficacy of leukocytapheresis and leukocyte overshoot or platelet reduction was examined. The average increase ratio of leukocytes in the initial five sessions of the responders was not significantly different from that of the non-responders (95% vs. 92%, P = 0.28). In contrast, the average decrease ratio of platelets in the initial five sessions of the responders was significantly higher than that of the non-responders (34% vs. 27%, P = 0.0041). Moreover, the platelet reduction at the third and fourth apheresis sessions in the responders was remarkably greater than that in the non-responders (33% vs. 20%, P = 0.0018). The efficiency of platelet reduction could be a predictive factor for the efficacy of leukocytapheresis.

DOI： 10.1111/j.1744-9987.2009.00649.x

A case of small early cancer of sigmoid colon, which recurred with liver metastasis 18 months after surgical resection Reviewed

Keita Harada, Jun Kato, Koji Takemoto, Toshio Uraoka, Sakiko Hiraoka, Hiroyuki Yanai, Kazuhide Yamamoto

Journal of Japanese Society of Gastroenterology 106 ( 5 ) 660 - 667 2009

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

A 74-year-old man was referred to our hospital with positive fecal occult blood test. Colonoscopic examination revealed a 7-mm 0-Is type polyp in the sigmoid colon. Endoscopic mucosal resection for this lesion completely removed the lesion and the histologic diagnosis was well differentiated adenocarcinoma. Cancer cells invaded the submucosa to a depth of 900μm, and vascular invasion was found. Therefore, the patient underwent additional surgical resection with lymph node dissection. During follow-up, however, serum CEA increased beyond the normal limit 18 months after surgical operation, and a 15-mm single liver metastasis was found through enhanced CT scan abdominal imaging, the FDG-PET scan, and ultrasonography. We have to pay attention to metachronous liver metastasis especially when the vascular invasion is suspected in the resected sample, even if the lesion is completely removed.

Age-related methylation in normal colon mucosa differs between the proximal and distal colon in patients who underwent colonoscopy Reviewed

Joichiro Horii, Sakiko Hiraoka, Jun Kato, Keita Harada, Kenji Kuwaki, Hideyuki Fujita, Shinichi Toyooka, Kazuhide Yamamoto

CLINICAL BIOCHEMISTRY 41 ( 18 ) 1440 - 1448 2008.12

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Objectives: To examine the difference in the methylation status ill normal colon mucosa between the proximal and distal colon. in relation to the correlation between the methylation status of normal mucosa and characteristics of neoplasia.
Design and methods: Paired biopsy specimens of normal mucosa from the proximal and distal colon of 82 patients who underwent colonoscopy were obtained. The methylation status of the promoter region of estrogen receptor 1 (ESR1) and myogenic differentiation 1 (MYOD1) was examined.
Results: Normal mucosa was more highly methylated ill the distal than in the proximal colon in both ESR1 and MYOD1 loci (p<0.0001 and p = 0.0009, respectively). Advanced characteristics of polyps in the distal colon were frequently observed in patients with lower methylation of ESR1 in the distal colon normal mucosa.
Conclusions: Methylation levels in normal mucosa differ between the proximal and distal colon, and lower methylation of ESR1 in the distal colon normal mucosa may correlate with advanced features of neoplasia in the distal colon. (c) 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clinbiochem.2008.08.089

Genetic and epigenetic alterations of Ras signalling pathway in colorectal neoplasia: analysis based on tumour clinicopathological features. International journal

K Harada, S Hiraoka, J Kato, J Horii, H Fujita, K Sakaguchi, Y Shiratori

British journal of cancer 97 ( 10 ) 1425 - 31 2007.11

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

Activation of RAS signalling induced by K-ras/BRAF mutations is a hallmark of colorectal tumours. In addition, Ras association domain families 1 and 2 (RASSF1 and RASSF2), the negative regulators of K-ras, are often inactivated by methylation of the promoter region in those tumours. However, reports showing differences in the occurrence of these alterations on the basis of tumour characteristics have been scarce. We analysed K-ras/BRAF mutations and the methylation status of RASSF1 and RASSF2 promoter regions in 120 colorectal adenomas with respect to their clinicopathological features. K-ras/BRAF mutations and RASSF2 methylation were observed in 49 (41%) and 30 (25%) of the samples, respectively, while RASSF1 methylation was observed in only 3 (2.5%). Adenomas with RASSF2 methylation often carried K-ras/BRAF mutations simultaneously (22 out of 30, P<0.01). Multivariate analysis revealed that the concomitance of these alterations was frequently observed in serrated adenomas (odds ratio (OR) 11.11; 95% confidence interval (CI) 1.96-63.00), but rarely in adenomas located in the sigmoid or descending colon (OR 0.13; 95% CI 0.03-0.58). A comparison between adenomas and cancers showed a significantly higher prevalence of these alterations in cancers than in adenomas in the proximal colon (58 vs 27%, P=0.02). Frequency and the time point of the occurrence of Ras signalling disorders differ according to colorectal neoplasia's characteristics, particularly the location.

Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells Reviewed

Hideyuki Fujita, Jun Kato, Joichiro Horii, Keita Harada, Sakiko Hiraoka, Hidenori Shiraha, Kohsaku Sakaguchi, Yasushi Shiratori

ONCOLOGY REPORTS 18 ( 5 ) 1129 - 1137 2007.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Patients with sporadic microsatellite instable colorectal cancers, in most of which the function of the hMLH1 mismatch repair gene is impaired, do not gain a survival benefit from 5-fluorouracil (5-FU)-based chemotherapy. However, the effect of hMLH1 on the cytotoxicity induced by 5-FU has not yet been sufficiently confirmed. In this study, we assessed the effect of hMLH1 on cytotoxicity and apoptosis induced by 5-FU using newly developed cell lines. We constructed two cell lines: SW480 (originally hMLH1-proficient), in which the expression of hMLH1 was reduced using a small interfering RNA (siRNA) technique, and HCT116 (originally hMLH1-deficient), in which the expression of hMLH1 can be regulated by doxycycline. Using these, cell lines, a clonogenic survival assay, 4',6-diamidino-2-phenylindole (DAPI) staining and an Annexin-V assay were performed. Moreover, the incorporation of 5-FU into DNA was determined using tritium-labeled 5-FU. In both of our two cell lines, hMLH1-deficient cells exhibited approximately 2.4-fold clonal surviving fraction compared to hMLH1-proficient cells for 10 days after the administration of 5-FU. Additionally, hMLH1-deficient cells treated with 5-FU exhibited 34-45% less apoptosis than hMLH1-proficient cells according to the results of DAPI staining and Annexin-V assay. Furthermore, hMLH1-deficient cells treated with 5-FU exhibited an approximately 2-fold greater incorporation of 5-FU into DNA than control cells, suggesting that the recognition of 5-FU-incorporated DNA is impaired in hMLH1-deficient cells, resulting in reduced apoptosis. Our conclusions were that decreased expression of hMLH1 in colon cancer cells reduced the apoptosis induced by 5-M, suggesting that hMLH1 is a key determinant of 5-FU chemosensitivity.

Centrifugal leukocytapheresis therapy for ulcerative colitis without concurrent corticosteroid administration Reviewed

H Okada, R Takenaka, S Hiraoka, C Makidono, S Hori, J Kato, H Okazaki, H Kawamoto, M Mizuno, Y Shiratori

THERAPEUTIC APHERESIS AND DIALYSIS 10 ( 3 ) 242 - 246 2006.6

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

Corticosteroid administration is an important therapy for active ulcerative colitis. However, long-term corticosteroid use is associated with serious complications such as osteoporosis, diabetes, and growth retardation. The effect of combination therapy corticosteroid plus leukocytapheresis has been previously reported, but that of leukocytapheresis with no corticosteroid is unknown. We carried out a preliminary study of six patients (two men and four women) with active ulcerative colitis (severe in two, moderately severe in four) who did not respond to 5-aminosalicylate derivatives, but refused corticosteroid use. Centrifugal leukocytapheresis was carried out once per week totaling four sessions per course. Treatment was considered effective when patients experienced clinical remission, which was defined as a frequency of diarrhea of four times or less and absence of visible blood in the stool, after one course. Leukocytapheresis was effective in five of six patients(83%). With cases stratified by severity, both severe cases and three of four moderately severe cases showed effectiveness. Clinical activity scores according to Lichtiger et al. in cases where leukocytapheresis was effective decreased from 9.8 to 6.6 at 1 week (P < 0.0001), declining further 2.4 at the end of the course. No obvious complications of leukocytapheresis were noted except for a decrease in hemoglobin by 1 g/dL. Centrifugal leukocytapheresis without corticosteroid treatment can induce remission in patients with active ulcerative colitis, and might be particularly beneficial for patients in whom adverse effects preclude the use of corticosteroids.

DOI： 10.1111/j.1744-9987.2006.00379.x

Therapeutic efficacy of leukocytapheresis in a pregnant woman with severe active ulcerative colitis Reviewed

H. Okada, C. Makidono, R. Takenaka, S. Hiraoka, A. Fujiwara, J. Kato, Y. Kawahara, H. Kawamoto, M. Mizuno, Y. Shiratori

DIGESTION 74 ( 1 ) 15 - 18 2006

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

Leukocytapheresis has recently been used to induce remission in patients with ulcerative colitis (UC) who fail to respond to corticosteroids. We could not find a report in the literature on leukocytapheresis for UC with gestational exacerbation. We have recently encountered this unique condition and report the details here. A 30-year-old Japanese woman with left-sided severe UC was corticosteroid-dependent and had recurrence of the active disease during tapering of corticosteroid. She declined any dose increase and the use of any immunosuppressive agent because she was in the 13th week of pregnancy. Then, concomitant leukocytapheresis was performed without increasing the corticosteroid dose. Recovery was rapid and dramatic. Mucous and bloody stool decreased after the first session, and she had remission 2 weeks later. She underwent a total of four sessions without complications. After 6 weeks, she was discharged from our hospital and underwent maintenance treatment as an outpatient with mesalazine and corticosteroid tapering. Subsequently, she gave birth to a healthy baby girl by an uncomplicated vaginal delivery while keeping the remitted stage of UC. Copyright (c) 2006 S. Karger AG, Basel.

DOI： 10.1159/000095478

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