Yasushi Sato and Tetsuji Takayama : 癌性腹膜炎 / Carcinomatous peritonitis, プレシジョン, 2019.
10.
Tetsuji Takayama, Yasushi Sato and Naoki Muguruma : Role of Alcohol and Metabolic Diseases in Colorectal Carcinogenesis., Springer-Verlag, Singapore, 2019.
11.
Yasushi Sato and Tetsuji Takayama : Chapter 4. Upper Gastrointestinal Cancer Adjuvant Chemotherapy: Current Practices, Efficacy and Future Directions, Nova Science Publishers, Sep. 2018.
12.
Yasushi Sato and Tetsuji Takayama : 第4章 消化器癌薬物療法の進歩 胃癌, 先端医療技術研究所, Aug. 2018.
13.
Koichi Okamoto, Tetsuo Kimura, Naoki Muguruma, Susumu Ito and Tetsuji Takayama : 赤外線蛍光内視鏡を用いた新しい診断法の開発., Technical Information Institute Co., Ltd., Sep. 2017.
Masahiro Sogabe, Toshiya Okahisa, Miwako Kagawa, Motoko Sei, Hiroyuki Ueda, reiko yokoyama, Kaizo Kagemoto, Hironori Tanaka, Yoshifumi Kida, Fumika Nakamura, Tetsu Tomonari, Koichi Okamoto, Yutaka Kawano, Hiroshi Miyamoto, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Association of metabolic dysfunction-associated steatotic liver disease with erosive esophagitis development: a longitudinal observational study., Journal of Gastroenterology and Hepatology, Vol.39, No.6, 1107-1114, 2024.
(Summary)
Although erosive esophagitis (EE) is associated with fatty liver and metabolic dysregulation, the association between EE and metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. Thus, this study aimed to investigate the longitudinal association between MASLD and EE. We included 1578 patients without EE at baseline who underwent more than two health checkups over 2 years. Generalized estimation equations were used to analyze associations between MASLD and EE according to repeated measures at baseline and most recent stages. EE development rates in men and women were 14.5% and 7.2%, respectively. After adjusting for lifestyle habits, the odds ratios of MASLD for EE development in men and women were 1.907 (95% confidence interval [CI]: 1.289-2.832, P < 0.005) and 1.483 (95% CI: 0.783-2.811, P = 0.227), respectively. In the subgroup analysis, after adjusting for lifestyle habits, among men and women aged 50 years with more than three MASLD components, the odds ratios for EE development were 2.408 (95% CI: 1.505-3.855, P < 0.001) and 2.148 (95% CI: 1.093-4.221, P < 0.05), respectively. After adjusting for various factors, the significant risk factors for EE development were different between men and women. The influence of MASLD and other factors on EE development differed by sex and age. Particularly, patients aged 50 years with MASLD and with an increased number of MASLD components should be considered at increased risk for EE.
Masahiro Sogabe, Toshiya Okahisa, Miwako Kagawa, Motoko Sei, Hiroyuki Ueda, reiko yokoyama, Kaizo Kagemoto, Hironori Tanaka, Yoshifumi Kida, Fumika Nakamura, Tetsu Tomonari, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Association of variabilities in body mass index and waist circumference with newly achieved remission of metabolic dysfunction-associated fatty liver disease., Diabetes & Metabolic Syndrome, Vol.18, No.5, 103036, 2024.
(Summary)
Although body weight reduction is recommended to ameliorate nonalcoholic fatty liver disease, the effects of body mass index (BMI) and waist circumference (WC) variability on newly achieved remission of metabolic dysfunction-associated fatty liver disease (MAFLD) remain unclear. We aimed to investigate the longitudinal association between BMI and WC variabilities and newly achieved MAFLD remission in both sexes. Among 26,952 patients, 1823 with MAFLD diagnosed by ultrasonography and with >2 health checkups over >2 years from April 2014 to March 2021 were included in this observational cohort study. A generalized estimation equation model analyzed the association between BMI and WC and newly achieved MAFLD remission according to repeated measures at baseline and the most recent stage. Rates of MAFLD remission in male and female patients were 7.4 % and 6.0 %, respectively. Regarding decreased BMI variability, newly achieved MAFLD remission prevalence among the subgroups differed significantly between sexes (p < 0.001). In male patients, a decrease in BMI variability of ≥1.5 kg/m and WC variability of ≥4.2 cm had adjusted odds ratios (ORs) of 5.215 and 2.820, respectively, for newly achieved MAFLD remission. Among female patients, regular exercise and breakfast consumption were accelerating factors for newly achieved MAFLD remission. Non-invasive liver fibrosis scores significantly differed between MAFLD and newly achieved MAFLD remission, including in the subgroups (p < 0.01 and p < 0.001, respectively). Reducing BMI and WC variabilities in male patients and improving lifestyle habits in female patients may accelerate MAFLD remission.
(Keyword)
Humans / Male / Female / Body Mass Index / Middle Aged / Non-alcoholic Fatty Liver Disease / Waist Circumference / Adult / Remission Induction / Follow-Up Studies / Prognosis / Metabolic Diseases
Koichi Okamoto, Tomoyuki Kawaguchi, Kaizo Kagemoto, Yoshifumi Kida, Yasuhiro Mitsui, Fumika Nakamura, Kouzou Yoshikawa, Masahiro Sogabe, Yasushi Sato, Joji Shunto, Yoshimi Bando, Mitsuo Shimada and Tetsuji Takayama : Gastric fundic gland polyposis and cancer development after eradication of Helicobacter pylori in patient with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)., Gastric Cancer, Vol.27, No.3, 635-640, 2024.
(Summary)
A 44-year-old woman with gastric cancer (GC) and fundic gland polyposis (FGPs) was referred to our hospital for further diagnosis and treatment. She successfully underwent eradication therapy for Helicobacter pylori (HP) 6 years ago, but did not exhibit FGPs at that time. When she underwent an esophagogastroduodenoscopy 2, 4, and 5 years after the eradication of HP, her imaging results revealed the existence of FGPs which gradually increased in her gastric fundus and body. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) was suspected and a mutational analysis was performed, revealing an APC promoter 1B variant c.-191T > C. A robotic total gastrectomy with lymphadenectomy was performed. Histopathological analysis of the surgical specimens revealed GC with no lymph node metastasis. GAPPS is characterized by GC and FGPs. However, our case shows different gastric phenotypes that are dependent on the status of HP infection.
Masahiro Sogabe, Toshiya Okahisa, Miwako Kagawa, Takanori Kashihara, shota Fujimoto, Tomoyuki Kawaguchi, reiko yokoyama, Kaizo Kagemoto, Hironori Tanaka, Yoshifumi Kida, Tetsu Tomonari, Yutaka Kawano, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Impact of alcohol consumption on metabolic dysfunction-associated fatty liver disease development and remission: A longitudinal cohort study., European Journal of Clinical Investigation, Vol.Online ahead of print., e14221, 2024.
(Summary)
The influence of alcohol intake on metabolic dysfunction-associated fatty liver disease (MAFLD) development and remission remains unclear; thus, we aimed to investigate their longitudinal associations. This observational cohort study included 6349 patients who underwent more than two health check-ups over >2 years between April 2013 and March 2021. Generalized estimation equations were used to analyse the longitudinal associations between changes in alcohol intake and MAFLD according to repeated measures at baseline and the most recent stage. The MAFLD development and remission rates were 20.4 and 5.1 and 9.1 and 4.7% in men and women, respectively. Although alcohol consumption was not a significant factor for MAFLD development, consuming 0.1-69.9 g/week (odds ratio [OR]: 0.672, 95% confidence interval [CI]: 0.469-0.964, p < .05) and ≥280 g/week were significant factors for MAFLD development in males (OR: 1.796, 95% CI: 1.009-3.196, p < .05) and females (OR: 16.74, 95% CI: 3.877-72.24, p < .001). Regardless of quantity and frequency, alcohol consumption was not a significant factor for MAFLD remission. Several noninvasive liver fibrosis scores were significantly associated with alcohol intake quantity and frequency in males with MAFLD development and remission (p < .05). The nonalcoholic fatty liver disease fibrosis score differed significantly between males with and without reduced alcohol intake (p < .05) who showed MAFLD remission. Although the influence of alcohol intake on MAFLD development and remission differed, alcohol consumption was not beneficial for MAFLD remission in either sex. Alcohol intake reduction or cessation is recommended to prevent liver fibrosis, even in those who achieve MAFLD remission.
Masahiro Sogabe, Toshiya Okahisa, Miwako Kagawa, Motoko Sei, Kaizo Kagemoto, Hironori Tanaka, Yoshifumi Kida, Fumika Nakamura, Tetsu Tomonari, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Association of metabolic dysfunction-associated fatty liver disease with gallstone development: A longitudinal study., Journal of Gastroenterology and Hepatology, Vol.39, No.4, 754-761, 2024.
(Summary)
The influence of metabolic dysfunction-associated fatty liver disease on gallstone development remains unclear. We aimed to investigate the longitudinal association between metabolic dysfunction-associated fatty liver disease and gallstone development in both men and women. This observational cohort study included 5398 patients without gallstones who underwent > 2 health check-ups between April 1, 2014, and March 31, 2020. A generalized estimation equation model was used to analyze the association between metabolic dysfunction-associated fatty liver disease and gallstone development according to repeated measures at baseline and most recent stage. After adjustment, the odds ratios of metabolic dysfunction-associated fatty liver disease for gallstone development in men and women were 3.019 (95% confidence interval [CI]: 1.901-4.794) and 2.201 (95% CI: 1.321-3.667), respectively. Among patients aged 50 years, the odds ratio for gallstone development was significantly enhanced with increasing metabolic dysfunction-associated fatty liver disease component numbers in both sexes; however, no significance was observed in those aged < 50 years. Other significant risk factors for gallstone development were age (odds ratio: 1.093, 95% CI: 1.060-1.126) and waist circumference (odds ratio: 1.048, 95% CI: 1.018-1.079) in men and age (odds ratio: 1.035, 95% CI: 1.003-1.067) and current smoking (odd ratio: 5.465, 95% CI: 1.881-15.88) in women. Although the risk factors for gallstone development differed between sexes, metabolic dysfunction-associated fatty liver disease was common. Paying attention to an increase in the number of metabolic dysfunction-associated fatty liver disease components in patients aged 50 years is important for gallstone prevention.
Ryo Shinomiya, Yasushi Sato, Takanori Yoshimoto, Tomoyuki Kawaguchi, Akihiro Hirao, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : A case of treatmentresistant advanced gastric cancer with FGFR2gene alteration successfully treated with pemigatinib., International Cancer Conference Journal, Vol.13, 240-244, 2024.
Yuya Ueki, Hideki Otsuka, Tamaki Otani, Ryosuke Kasai, Youichi Otomi, Daiki Ikemitsu, Shota Azane, Yamato Kunikane, Takanori Bandoh, Noritake Matsuda, Yasuyuki Okada, Tetsuji Takayama and Masafumi Harada : Combined visual and quantitative assessment of somatostatin receptor scintigraphy for staging and restaging of neuroendocrine tumors, Japanese Journal of Radiology, Vol.42, No.5, 519-535, 2024.
(Summary)
Somatostatin receptor scintigraphy (SRS) using In-DTPA-DPhe-octreotide (pentetreotide) has become an integral part of neuroendocrine neoplasm management. The lack of precise quantification is a disadvantage of SRS. This study aimed to adapt the standardized uptake value (SUV) to SRS, establish the SUV range for physiological uptake in the liver, kidney, and spleen, and elucidate the utility of combined visual and quantitative SRS assessment for staging and restaging of neuroendocrine tumors (NETs). This study included 21 patients with NETs who underwent In-pentetreotide SRS. The SUV of physiological and pathological uptake was calculated using bone single-photon emission computed tomography (SPECT) quantitative analysis software (GI-BONE). For visual analysis, the primary and metastatic lesions were scored visually on planar and SPECT images using a five-point scale. We assessed the relationships between the SUVs of the liver, kidney, and spleen in the dual phase, and among quantitative indices, visual score, and pathological lesions classification. Sixty-three NEN lesions were evaluated. The mean ± standard deviation maximum SUVs (SUVmax) were liver: 4 h, 2.6 ± 1.0; 24 h, 2.2 ± 1.0; kidney: 4 h, 8.9 ± 1.8; 24 h, 7.0 ± 2.0; and spleen; 4 h, 11.3 ± 4.5; 24 h, 11.5 ± 7.6. Higher SUVmax was significantly associated with higher visual scores on dual-phase SPECT (4 h, p < 0.001; 24 h, p < 0.001) (4 h: scores 3 and 4, p < 0.05; scores 3 and 5: p < 0.01; scores 4 and 5: p < 0.01; 24 h: scores 3 and 4, p = 0.0748; scores 3 and 5: p < 0.01; scores 4 and 5: p < 0.01). We adapted the SUV to SRS and established the range of SUV for physiological uptake in the liver, kidney, and spleen. Combined visual and quantitative assessment is useful for imaging individual lesions in greater detail, and may serve as a new tumor marker of SRS for staging and restaging of NETs.
Akinari Kasai, Jinsei Miyoshi, Yasushi Sato, Koichi Okamoto, Hiroshi Miyamoto, Takashi Kawanaka, Chisato Tonoiso, Masafumi Harada, Masakazu Goto, Takahiro Yoshida, Akihiro Haga and Tetsuji Takayama : A novel CT-based radiomics model for predicting response and prognosis of chemoradiotherapy in esophageal squamous cell carcinoma., Scientific Reports, Vol.14, No.1, 2039, 2024.
(Summary)
No clinically relevant biomarker has been identified for predicting the response of esophageal squamous cell carcinoma (ESCC) to chemoradiotherapy (CRT). Herein, we established a CT-based radiomics model with artificial intelligence (AI) to predict the response and prognosis of CRT in ESCC. A total of 44 ESCC patients (stage I-IV) were enrolled in this study; training (n = 27) and validation (n = 17) cohorts. First, we extracted a total of 476 radiomics features from three-dimensional CT images of cancer lesions in training cohort, selected 110 features associated with the CRT response by ROC analysis (AUC ≥ 0.7) and identified 12 independent features, excluding correlated features by Pearson's correlation analysis (r ≥ 0.7). Based on the 12 features, we constructed 5 prediction models of different machine learning algorithms (Random Forest (RF), Ridge Regression, Naive Bayes, Support Vector Machine, and Artificial Neural Network models). Among those, the RF model showed the highest AUC in the training cohort (0.99 [95%CI 0.86-1.00]) as well as in the validation cohort (0.92 [95%CI 0.71-0.99]) to predict the CRT response. Additionally, Kaplan-Meyer analysis of the validation cohort and all the patient data showed significantly longer progression-free and overall survival in the high-prediction score group compared with the low-prediction score group in the RF model. Univariate and multivariate analyses revealed that the radiomics prediction score and lymph node metastasis were independent prognostic biomarkers for CRT of ESCC. In conclusion, we have developed a CT-based radiomics model using AI, which may have the potential to predict the CRT response as well as the prognosis for ESCC patients with non-invasiveness and cost-effectiveness.
Yutaka Kawano, Maki Tanaka, Yasushi Sato, Shigekazu Sugino, Jun Suzuki, Masaki Fujishima, Eri Okumura, Hideo Takekoshi, Osamu Uehara, Shintaro Sugita, Yoshihiro Abiko, Tetsu Tomonari, Hironori Tanaka, Hidekatsu Takeda and Tetsuji Takayama : Acanthopanax senticosus ameliorates steatohepatitis through HNF4 alpha pathway activation in mice., Scientific Reports, Vol.14, No.1, 110, 2024.
(Summary)
Non-alcoholic fatty liver disease is a common liver disease worldwide, and is associated with dysregulation of lipid metabolism, leading to inflammation and fibrosis. Acanthopanax senticosus Harms (ASH) is widely used in traditional medicine as an adaptogen food. We examined the effect of ASH on steatohepatitis using a high-fat diet mouse model. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet with ASH extract (ASHE). After 6 weeks, liver RNA transcriptome sequencing (RNA-Seq) was performed, followed by Ingenuity Pathway Analysis (IPA). Our findings revealed that mice fed a high-fat diet with 5% ASHE exhibited significantly reduced liver steatosis. These mice also demonstrated alleviated inflammation and reduced fibrosis in the liver. IPA of RNA-Seq indicated that hepatocyte nuclear factor 4 alpha (HNF4 alpha), a transcription factor, was the activated upstream regulator (P-value 0.00155, z score = 2.413) in the liver of ASHE-fed mice. Adenosine triphosphate binding cassette transporter 8 and carboxylesterase 2, downstream targets of HNF4 alpha pathway, were upregulated. Finally, ASHE-treated HepG2 cells exposed to palmitate exhibited significantly decreased lipid droplet contents. Our study provides that ASHE can activate HNF4 alpha pathway and promote fat secretion from hepatocytes, thereby serving as a prophylactic treatment for steatohepatitis in mice.
Yasuyuki Okada, Koichi Okamoto, 谷 直也, 和田 浩典, Tomoyuki Kawaguchi, 野田 和克, 宮本 佳彦, 春藤 譲治, Hisanori Uehara and Tetsuji Takayama : A CASE OF GASTRIC NEUROENDOCRINE TUMOR IN A PATIENT WITH AUTOIMMUNE GASTRITIS COMPLICATED BY TYPE 3 AUTOIMMUNE POLYENDOCRINE SYNDROME TYPE 3, Gastroenterological Endoscopy, Vol.66, No.3, 259-265, 2024.
Tetsu Tomonari, Joji Tani, Yasushi Sato, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Yutaka Kawano, Asahiro Morishita, Koichi Okamoto, Masahiro Sogabe, Hiroshi Miyamoto, Tsutomu Masaki and Tetsuji Takayama : Clinical Features and Outcomes of Conversion Therapy in Patients with Unresectable Hepatocellular Carcinoma., Cancers, Vol.15, No.21, 5221, 2023.
(Summary)
<jats:p>This retrospective multicenter study analyzed 244 patients with unresectable hepatocellular carcinoma treated with lenvatinib (LEN) and atezolizumab + bevacizumab (Atezo + Bev) to examine the characteristics, treatment courses, and prognoses. The cases of patients who could achieve HCC downstaging from Barcelona Clinic Liver Cancer (BCLC) stage B or C to A or zero indicated the need for conversion therapy. The patients' prognoses with and without conversion therapy were compared. Of the 244 patients, 12 (4.9%) underwent conversion therapy, six out of 131 (4.6%) were treated with LEN, and six out of 113 (5.3%) were treated with Atezo + Bev. Eleven patients (91.7%) with a modified albumin bilirubin (mALBI) grade 1 or 2a and BCLC-B stage showed significantly higher rates of transition during conversion therapy (p < 0.05). The patients undergoing conversion therapy had a significantly longer median overall survival rate than those receiving chemotherapy alone (1208 [1064–NA] vs. 569 [466–704] days, p < 0.01). A comparison of the patients who achieved a partial response with and without conversion was evaluated using propensity score matching to reduce the confounding factors, showing a significant survival benefit in the conversion group (1208 [1064–NA] vs. 665 days, p < 0.01). Among the patients with u-HCC who were treated with LEN and Atezo + Bev, those with mALBI 1 + 2a and BCLC-B were likely to achieve conversion therapy with downstaging.</jats:p>
Tetsuji Takayama, Naoki Muguruma, Masanori Igarashi, shozo Ohsumi, Shiro Oka, Fumihiko Kakuta, Yoshiaki Kubo, Hideki Kumagai, Mika Sasaki, Tamotsu Sugai, Kokichi Sugao, Yuko Takeda, Hisashi Doyama, Kouji Bannno, Suguru Fukahori, Yoichi Furukawa, Takahiro Horimatsu, Ishikawa Hideki, Takeo Iawama, Yasushi Okazaki, Yutaka Saito, Nariaki Matsuura, Michihiro Mutoh, Naohiro Tomita, Takashi Akiyama, Toshiki Yamamoto, Hideyuki Ishida and Nakayama Yoshiko : Clinical Guidelines for Diagnosis and Management of Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in Children and Adults-Secondary Publication., Journal of the Anus, Rectum and Colon, Vol.7, No.4, 284-300, 2023.
(Summary)
Cowden syndrome (CS)/ hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.
Yusaku Shimamoto, Yoji Takeuchi, Shingo Ishiguro, Shin-Ichi Nakatsuka, Hiroshi Yunokizaki, Yasumasa Ezoe, Takeshi Nakajima, Kumiko Tanaka, Ryu Ishihara, Tetsuji Takayama, Teruhiko Yoshida, Kokichi Sugano, Michihiko Mutoh and Hideki Ishikawa : Genotype-phenotype correlation for extracolonic aggressive phenotypes in patients with familial adenomatous polyposis., Cancer Science, Vol.114, No.12, 4596-4606, 2023.
(Summary)
Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can be explained by the localization of the adenomatous polyposis coli (APC) variant, but few reports provide definitive findings about genotype-phenotype correlations. Therefore, we investigated FAP patients and the association between the severe phenotypes and APC variants. Of 247 FAP patients, 126 patients from 85 families identified to have APC germline variant sites were extracted. These sites were divided into six groups (Regions A to F), and the frequency of severe comorbidities was compared among the patient phenotypes. Of the 126 patients, the proportions of patients with desmoid tumor stage ≥III, number of FGPs ≥1000, multiple gastric neoplasms, gastric neoplasm with high-grade dysplasia, and Spigelman stage ≥III were 3%, 16%, 21%, 12%, and 41%, respectively, while the corresponding rates were 30%, 50%, 70%, 50%, and 80% in patients with Region E (codons 1398-1580) variants. These latter rates were significantly higher than those for patients with variants in other regions. Moreover, the proportion of patients with all three indicators (desmoid tumor stage ≥III, number of FGPs ≥1000, and Spigelman stage ≥III) was 20% for those with variants in Region E and 0% for those with variants in other regions. Variants in Region E indicate aggressive phenotypes, and more intensive management is required.
Reiko Yokoyama, Yasushi Sato, Fumika Nakamura, Kaizo Kagemoto, Yasuhiro Mitsui, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Efficacy of immune checkpoint inhibitors in patients with anorectal melanoma in association with immune-related adverse events: a case series., Clinical Journal of Gastroenterology, Vol.Online ahead of print., 2023.
(Summary)
Anorectal melanoma (AM) is a rare subtype of mucosal melanoma with a poor prognosis. Given its rarity compared to its cutaneous counterpart, the benefits and side effects of immune checkpoint inhibitor (ICI) therapy and the relationship between side effects and prognosis remain unclear. Herein, we describe the clinical presentation of five patients with AM treated with ICI as well as their relationship to the treatment course and the development of immune-related adverse events (irAEs). Three patients received sequential or concurrent administrations of nivolumab and ipilimumab, one received nivolumab alone, and one received ipilimumab alone. The response rate (RR) and disease control rate (DCR) were 40% and 80%, respectively. Pituitary and hepatic dysfunctions were the most common irAEs observed (40% each), followed by thyroid, diarrhea, and renal dysfunctions (20% each). The RR was 67% in patients with irAEs while no response was observed in patients without irAEs. DCR was 100% and 50% in patients with and without irAEs, respectively. Overall survival was 34 months in irAE and 8.75 months in non-irAE cases, with a longer survival trend in irAE cases. ICI therapy was effective and well-tolerated by AM patients, with potentially better outcomes for those who experienced irAEs compared to those who did not.
Tamotsu Sagawa, Yasushi Sato, Hiroyuki Nagashimia, Kohichi Takada, Mamoru Takahashi, Masahiro Hiarakawa, Kyoko Hamaguchi, Fumito Tamura, Koshi Fujikawa, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Hilar/mediastinal and cutaneous drug-induced sarcoidosis-like reaction associated with immune checkpoint inhibitors in metastatic colorectal cancer: a case report., Frontiers in Immunology, Vol.14, 1203621, 2023.
(Summary)
Immune checkpoint inhibitors (ICIs) are the standard treatment for metastatic colorectal cancer (mCRC) with high microsatellite instability (MSI-H). Among immune-related adverse events (irAEs), drug-induced sarcoidosis-like reactions (DISR) are often difficult to differentiate from cancer progression. This is a case of a woman in her mid-60s, with mCRC (RAS wild/BRAF mutant/MSI-H) and abdominal lymph node metastasis, treated with four courses of ipilimumab + nivolumab every 3 weeks, followed by nivolumab every 2 weeks as third-line treatment. After treatment, the original lymph node metastases shrank, but hilar/mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epithelioid granulomas without necrosis, indicating a sarcoidosis-like reaction. Fluorodeoxyglucose-positron emission tomography scan showed abnormal subcutaneous accumulation in bilateral forearms and bilateral knee joints. Biopsy of the cutaneous lesions was also performed, which revealed epithelioid granulomas. As the patient had no symptoms in other organs, no specific therapeutic intervention was administered. After the discontinuation of immunotherapy, the sarcoidosis-like reaction regressed without cancer relapse. Clinicians should be aware of the possibility of DISR as an irAE during the ICI treatment of mCRC. In suspected cases of DISR following ICI therapy, it is important to differentiate between cancer progression and DISR through histological diagnosis for the subsequent strategy, as radiological and serological findings are not definitive.
Tamotsu Sagawa, Yasushi Sato, Masahiro Hirakawa, Kyoko Hamguchi, Fumito Tamura, Hiroyuki Nagashima, Koshi Fujikawa, Koichi Okamoto, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Case Report: Longitudinal monitoring of clonal evolution by circulating tumor DNA for resistance to anti-EGFR antibody in a case of metastatic colorectal cancer., Frontiers in Oncology, Vol.13, 1203296, 2023.
(Summary)
Treatment with anti-EGFR antibody has been shown to prolong survival in patients with RAS wild-type metastatic colorectal cancer (mCRC). However, even patients who initially respond to anti-EGFR antibody therapy, almost without exception, develop resistance to the therapy and then fail to respond. Secondary mutations in the mitogen-activated protein (MAPK) signaling pathway (mainly in NRAS and BRAF) have been implicated in anti-EGFR resistance. However, the process by which resistant clones develop during therapy has not been elucidated, and considerable intrapatient and interpatient heterogeneity exists. Circulating tumor DNA (ctDNA) testing has recently allowed the noninvasive detection of heterogeneous molecular alterations that underlie the evolution of resistance to anti-EGFR. In this report, we describe our observation of genomic alterations in and in a patient with acquired resistance to anti-EGFR antibody drugs by tracking clonal evolution using serial ctDNA anaylsis. A 54-year-old woman was initially diagnosed with sigmoid colon cancer with multiple liver metastases. After receiving first-line mFOLFOX + cetuximab, second-line FOLFIRI + ramucirumab, third-line trifluridine/tipiracil + bevacizumab, fourth-line regorafenib, and fifth-line CAPOX + bevacizumab, she was rechallenged with CPT-11 + cetuximab. The best response to anti-EGFR rechallenge therapy was a partial response. in the ctDNA was assessed during treatment. The status changed from wild type to mutant type, back to wild type, and again to mutant type ( codon 61) during the course of treatment. In this report, tracking of ctDNA allowed us to describe clonal evolution in a case in which we observed genomic alterations in and in a patient who acquired resistance to anti-EGFR antibody drugs during treatment. It is reasonable to consider repeat molecular interrogation during progression in patients with mCRC by using ctDNA analysis, which could help to identify patients who may benefit from a rechallenge strategy.
Masahiro Sogabe, Toshiya Okahisa, Miwako Kagawa, Hiroyuki Ueda, Kaizo Kagemoto, Hironori Tanaka, Yoshifumi Kida, Tetsu Tomonari, Tatsuya Taniguchi, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Influence of alcohol on newly developed metabolic dysfunction-associated fatty liver disease in both sexes: A longitudinal study., Clinical Nutrition, Vol.42, No.5, 810-816, 2023.
(Summary)
The influence of changes in alcohol consumption on newly developed metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. We investigated the influence of alcohol consumption on newly developed MAFLD in both sexes. This observational cohort study included 4071 patients who underwent more than two health check-ups between 2015 and 2020 over an interval of more than a year. Generalised estimating equations were used for analyses. At baseline, the rates of drinking and MAFLD between men and women were 72.5% versus 41.7% and 42.2% versus 22.1%, respectively. At the most recent stage, the rates of an increase in alcohol consumption for men and women were 13.3% and 8.7%, respectively, and 311/1192 (26.1%) men and 155/1566 (9.9%) women had newly developed MAFLD. The odds ratio (OR) for drinking in patients with newly developed MAFLD was 0.863 (men) (95% confidence interval [CI], 0.676-1.102, p = 0.237) and 1.041 (women) (95% CI, 0.753-1.439, p = 0.808); the OR for women who drank 140-279.9 g/week was 2.135 (95% CI, 1.158-3.939, p < 0.05) and that for all drinking categories among women was >1. Several non-invasive fibrosis scores were significantly associated with the quantity of alcohol consumption in patients with newly developed MAFLD (p < 0.005). Alcohol consumption had no significant protective effect against newly developed MAFLD in both sexes, regardless of quantity. Conversely, alcohol consumption ≥140 g/week was a risk factor for newly developed MAFLD in women. The development of liver fibrosis with increased alcohol intake should be considered in patients with MAFLD.
Tetsu Tomonari, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Masahiro Sogabe, Yutaka Kawano, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato and Tetsuji Takayama : A case of complete response with rechallenge-lenvatinib plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma refractory to multiple molecular-targeted agent treatments., Clinical Journal of Gastroenterology, Vol.16, No.3, 438-443, 2023.
(Summary)
The efficacy of lenvatinib (LEN) plus transcatheter arterial chemoembolization (LEN-TACE) has been reported, but its effect on unresectable hepatocellular carcinoma (HCC) refractory to LEN therapy has not been demonstrated. We report a case of HCC refractory to multiple molecular-targeted agents (MTA) treatments, including LEN, that was successfully treated with LEN-TACE. A 59-year-old man was referred to our department with multiple HCCs and a background of hepatitis B virus infection. TACE was the initial treatment. However, he was determined to be TACE-refractory, and multitargeted therapy was initiated. LEN was started at 12 mg/day but resulted in progressive disease (PD) after 13 months of the administration. The response to second-line sorafenib was PD after 2 months. Third-line therapy with atezolizumab + bevacizumab was stopped after one course because of an immune-related adverse event (i.e., dermatitis). The response to fourth-line regorafenib was PD at 2 months, and the response to fifth-line cabozantinib was PD after 6 months. The efficacy of LEN-TACE was recently reported; therefore, we decided to attempt LEN-TACE therapy as a salvage line. After obtaining the patient's consent to repeat LEN and TACE, treatment was initiated. The tumor markers levels markedly reduced after LEN-TACE therapy. After three additional TACE treatments with continued LEN administration, the tumor marker levels normalized, and complete response was determined based on RECIST guidelines. LEN-TACE therapy may effectively treat unresectable advanced HCC in the LEN-rechallenge setting and may be a treatment option as a last-line therapeutic option.
1,3a,6a-Triazapentalene (TAP) is a compact fluorescent chromophore whose fluorescence properties vary greatly depending on the substituents on the TAP ring. This study investigated the photo-induced cytotoxicities of various TAP derivatives. Among the derivatives, 2-p-nitrophenyl-TAP showed significant cytotoxicity to HeLa cells under UV irradiation but no cytotoxicity without UV. In addition, the photo-induced cytotoxicity of 2-p-nitirophenyl-TAP was found to be cancer cell selective and effective against HeLa cells and HCT 116 cells. Under UV irradiation, 2-p-nitrophenyl-TAP generated reactive oxygen species (ROS) that induced an apoptosis and ferroptosis in cancer cells. Therefore, it was revealed that 2-p-nitrophenyl-TAP is the most compact dye that can generate ROS by photoirradiation.
Although several angiogenesis-related factors are reportedly involved in the pathogenesis of ulcerative colitis (UC), the mechanisms by which they contribute to disease are unclear. We first examined the expression of angiogenesis-related factors in inflamed colorectal tissue of UC patients using antibody array, and identified the 5 factors with highest expression, which included matrix metalloproteinase-8, urokinase-type plasminogen activator (uPA), angiostatin/plasminogen, hepatocyte growth factor and endoglin. Subsequent real-time PCR experiments using additional colorectal tissues revealed that uPA mRNA levels were significantly higher in inflamed tissues than in non-inflamed tissues, and significantly correlated with the severity of UC. Mirror section immunohistochemistry revealed that uPA was expressed in the neutrophils of inflamed colorectal tissues. We administered dextran sulfate sodium (DSS) in drinking water to uPA knockout (uPA) mice, and found that the disease activity index in uPA mice was marginally lower and the histological score in uPA mice was significantly lower than those in wild-type mice, suggesting the importance of uPA in colitis. When an uPA-selective inhibitor, UK122, was administered to DSS-treated C57BL6J mice, the disease activity index and histological score in those mice were significantly lower compared with control mice. Multiple cytokine/chemokine assay using colorectal tissues from uPA and UK122-treated mice revealed significantly lowered level of RANTES. In conclusion, uPA was highly expressed in neutrophils of the inflamed mucosa of UC patients, and the expression level correlated with the severity of UC. Genetic uPA deletion or pharmacological uPA blockade significantly ameliorated colitis in mice, concomitant with downregulation of RANTES.
Tetsu Tomonari, Joji Tani, Chikara Ogawa, Akihiro Deguchi, Tomonori Senoh, Akio Moriya, Hiroshi Shibata, Hiroshi Fukuno, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Masahiro Sogabe, Yutaka Kawano, Akihiro Morishita, Koichi Takaguchi, Hiroshi Miyamoto, Yasushi Sato, Tsutomu Masaki and Tetsuji Takayama : Multicenter retrospective study of Initial treatment outcome and feasibility of initiating dose reduction of cabozantinib in unresectable hepatocellular carcinoma., Hepatology Research, Vol.53, No.2, 172-178, 2023.
(Summary)
Cabozantinib (CAB), a multiple kinase inhibitor, has been approved for use in patients with previously treated unresectable hepatocellular carcinoma (uHCC). However, real-world clinical data are lacking, particularly clinical data regarding dose modifications of CAB. We analyzed the clinical outcomes of CAB in uHCC and compared treatment outcomes between the full- and reduced-dose groups. This multicenter, observational study included patients with uHCC who were treated with CAB from March 2021 to April 2022. Patient characteristics, efficacy, and safety were compared between the full- and reduced-dose groups. Twenty-six patients from eight institutes were analyzed. Cabozantinib was administered as a third-line or later treatment in 25 (96.2%) patients and postimmunotherapy in 21 (80.5%) patients. There were 15 patients in the full-dose group (60 mg CAB) and 11 in the reduced-dose group (40 or 20 mg CAB). The objective response rate (ORR) and disease control rate (DCR) were not significantly different between the two groups. The ORR was 6.7% for the full-dose group and 9.1% for the reduced-dose group, and the DCR was 53.4% and 81.8%, respectively. Progression-free survival analysis showed no significant differences between the two groups. The incidence of decreased appetite, fatigue, and diarrhea, and the rate of discontinuation and dose reduction, was significantly higher in the full-dose group. Our study suggests that the efficacy and safety of CAB in real-world clinical practice are comparable to those of the phase III trial (CELESTIAL), and that dose reduction of CAB may be a safer treatment option.
Tetsu Tomonari, Joji Tani, Yasushi Sato, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Akihiro Morishita, Koichi Okamoto, Masahiro Sogabe, Hiroshi Miyamoto, Naoki Muguruma, Tsutomu Masaki and Tetsuji Takayama : Initial therapeutic results of atezolizumab plus bevacizumab for unresectable advanced hepatocellular carcinoma and the importance of hepatic functional reserve., Cancer Medicine, Vol.12, No.3, 2646-2657, 2023.
(Summary)
We analyzed the association between the modified albumin-bilirubin (mALBI) grade and therapeutic efficacy of atezolizumab plus bevacizumab (Atezo+Bev) for the treatment of unresectable hepatocellular carcinoma (u-HCC). In this retrospective observational study, we included 71 u-HCC patients treated with Atezo+Bev between September 2020 and September 2021. Patients were grouped corresponding to the mALBI grade at the start of treatment (mALBI 1+2a or mALBI 2b+3) and analyzed for therapeutic effect and the transition rate to secondary treatment. According to the Response Evaluation Criteria in Solid Tumors, the overall response rate was significantly higher for the mALBI 1+2a group, than for the mALBI 2b+3 group, with 26.2% and 3.4%, respectively. The progression-free survival (PFS) was significantly longer in the mALBI 1+2a group (10.5 months) than in the mALBI 2b+3 group (3.0 months). In the multivariate analysis, an mALBI of 1+2a was found to be an independent factor of PFS. The rate of second-line treatment with multi-targeted agents was also significantly higher in the mALBI 1+2a group. In real-world practice, Atezo+Bev treatment might have higher therapeutic efficacy in u-HCC patients with mALBI 1+2a.
Yasushi Sato, Yasuyuki Okada, Yasuteru Fujino, Tomoyuki Kawaguchi, Yoshifumi Kida, Yasuhiro Mitsui, Hironori Tanaka, Tetsu Tomonari, Shinji Kitamura, Koichi Okamoto, Yutaka Kawano, Hiroshi Miyamoto, Masahiro Sogabe and Tetsuji Takayama : Clinical Outcomes of Comprehensive Genomic Profiling Tests for Gastrointestinal Cancers: Experience from Tokushima University Hospital., The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 154-159, 2023.
(Summary)
In Japan, cancer genome profiling (CGP) for cancer patients without standard treatment has been covered by public insurance since June 2019. This study analyzed data of 122 patients with gastrointestinal tumors who underwent CGP to clarify cancer genome medicine's current status and possible problems at the Tokushima University Hospital. The major types of cancer included pancreatic (n=30), colorectal (n=25), biliary tract (n=15), gastric (n=11), and hepatocellular carcinoma (n=8). CGP tests included F1CDx in 70 patients (57%), F1LCDx in 36 (30%), TSO500 in 14 (11%), and NCC Oncopanel in 2 (2%). Actionable gene alterations were identified in 72 patients (59%), but only 5 patients (4%) were treated for pancreatic (n=1), colorectal (n=3), and small bowel cancers (n=1). The main reasons for not receiving genotype-matched therapy included the lack of appropriate drugs or clinical trials that matched the actionable gene alterations (n=40) and the inability to participate in clinical trials (n=10). There is still not a sufficient number of patients receiving genotype-matched treatment for gastrointestinal cancers. To promote cancer genome medicine in regional areas, attempts to improve access to genotype-matched therapies are required, as well as to promote the development of new molecular-targeted drugs and clinical trials for these drugs. J. Med. Invest. 70 : 154-159, February, 2023.
Megumi Yamasaki, Yasushi Sato, Koichi Okamoto, Akira Fukuya, Tomoyuki Kawaguchi, Kazuyoshi Noda, Kaizo Kagemoto, Yasuhiro Mitsui, Hiroshi Miyamoto and Tetsuji Takayama : Two cases of anal squamous cell carcinoma achieving complete response after docetaxel + cisplatin + S1 (DCS) induction chemotherapy followed by chemoradiation., Clinical Journal of Gastroenterology, Vol.16, No.2, 180-186, 2022.
(Summary)
Anal squamous cell carcinoma (ASCC) is an uncommon tumor. However, its incidence is increasing worldwide. Surgical resection of locally advanced cases requires permanent anal prosthesis. Thus, chemoradiotherapy (CRT) is preferred as the first-line treatment; however, high local recurrence rate remains an issue. Here, we describe two cases of locally advanced ASCC treated with docetaxel + cisplatin + S-1 (DCS) followed by CRT with S-1 that showed complete response. The two patients, aged 69 and 65 years, were diagnosed with ASCC (cStage IIIB) at our hospital. Due to extensive lymph node metastases, the patients were treated with triple induction chemotherapy (DCS) followed by CRT with S-1. Positron emission tomography/computed tomography performed six months after starting the treatment showed disappearance of tumors, indicating a complete response. The patients continued to receive S-1 for one year and achieved relapse-free long-term survival since the completion of treatment. Therefore, induction chemotherapy with DCS, prior to CRT with S-1 may benefit patients with locally advanced ASCC.
Masahiro Sogabe, Toshiya Okahisa, Miwako Kagawa, Hiroyuki Ueda, Kaizo Kagemoto, Hironori Tanaka, Yoshifumi Kida, Tetsu Tomonari, Tatsuya Taniguchi, Hiroshi Miyamoto, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Influence of Alcohol Consumption on the Development of Erosive Esophagitis in Both Sexes: A Longitudinal Study., Nutrients, Vol.14, No.22, 4760, 2022.
(Summary)
The influence of changes in alcohol consumption on erosive esophagitis (EE) development in both sexes is unclear. This observational study investigated sex differences in the influence of alcohol consumption on EE development, and included 2582 patients without EE at baseline from 13,448 patients who underwent >2 health check-ups over >1 year. The rates of non-drinkers who started drinking, and drinkers who abstained from drinking, who increased, and who decreased their weekly alcohol consumption were 7.2%, 9.7%, 14.7%, and 24.1% and 7.3%, 17.8%, 12.8%, and 39.0% in men and women, respectively. In the final cohort, 211/1405 (15.0%) men and 79/1177 (6.7%) women newly developed EE. The odds ratio (OR) for drinking in EE development was 1.252 (95% confidence interval (CI), 0.907-1.726) among men and 1.078 (95% CI, 0.666-1.747) among women. Among men aged <50 years, the OR for drinking ≥70 g/week in EE development was 2.825 (95% CI, 1.427-5.592), whereas among women, the OR for drinking ≥140 g/week in EE development was 3.248 (95% CI, 1.646-6.410). Among participants aged <50 years, the OR for daily drinking in EE development was 2.692 (95% CI, 1.298-5.586) among men and 4.030 (95% CI, 1.404-11.57) among women. The influence of alcohol consumption on EE development differed between the sexes. We recommend no alcohol consumption for individuals aged <50 years to avoid EE development. Daily drinkers should be assessed for EE development.
hironori wada, Yasuteru Fujino, Kaizo Kagemoto, Yoshifumi Kida, Yasuyuki Okada, Yasuhiro Mitsui, Koichi Okamoto, Yasushi Sato, Yoshimi Bando, Hiroshi Miyamoto and Tetsuji Takayama : Gastric cancer genome profiling reveals HER2 false-negative status and informs a successful trastuzumab treatment strategy, The Japanese Journal of Gastro-enterology, Vol.119, No.10, 937-945, 2022.
(Summary)
Intratumoral HER2 heterogeneity is a well-described gastric cancer feature and may explain many false-negative results related to this oncogene. An 81-year-old man was diagnosed at our hospital with stage IV gastric cancer with multiple lymph node metastases. Immunohistochemistry (IHC) analysis indicated that the primary tumor was HER2-negative. After a chemotherapy course, we submitted a pretreatment biopsy specimen for comprehensive cancer genome profiling (CGP) to determine the last-line therapy. This revealed HER2 amplification. The specimen was reevaluated using fluorescence in situ hybridization and IHC with deeper-cut specimens, which confirmed that the tumor was indeed HER2-positive. Therefore, the patient was treated with chemotherapy plus trastuzumab, which elicited tumor shrinkage and conferred long-term survival. Our current data underscore the CGP importance, which can provide more accurate tumor profilings and inform subsequent treatment decisions.
Hideki Ishikawa, Masayoshi Yamada, Yasushi Sato, Shinji Tanaka, Chino Akiko, Masahiro Tajika, Hisashi Doyama, Tetsuji Takayama, Yoshio Ohda, Takahiro Horimatsu, Yasushi Sano, Kohji Tanakaya, Hiroaki Ikematsu, Yoshihisa Saida, Hideyuki Ishida, Yoji Takeuchi, Hiroshi Kashida, Shinsuke Kiriyama, Shinichiro Hori, Kyowon Lee, Jun Tashiro, Nozomu Kobayashi, Takeshi Nakajima, Sadao Suzuki and Michihiro Mutoh : Intensive endoscopic resection for downstaging of polyp burden in patients with familial adenomatous polyposis (J-FAPP Study III): a multicenter prospective interventional study., Endoscopy, Vol.55, No.4, 344-352, 2022.
(Summary)
IDP in patients with mild-to-moderate FAP could have the potential to be a useful means of preventing colorectal cancer without implementing colectomy. However, if the IDP protocol was proposed during a much longer term, it may not preclude the possibility that a large proportion of colectomies may still need to be performed.
Masahiro Sogabe, Toshiya Okahisa, Takeshi Kurihara, Miwako Kagawa, Hiroyuki Ueda, Tomoyuki Kawaguchi, Akira Fukuya, Kaizoh Kagemoto, Hironori Tanaka, Yoshifumi Kida, Tetsu Tomonari, Tatsuya Taniguchi, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Comparison of the role of alcohol consumption and qualitative abdominal fat on NAFLD and MAFLD in males and females., Scientific Reports, Vol.12, No.1, 16048, 2022.
(Summary)
The clinical difference between nonalcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) between the two sexes is unclear. This study aimed to determine the influences of alcohol consumption and qualitative abdominal fat between male and female patients with NAFLD and MAFLD. This cross-sectional study examined 11,766 participants who underwent health check-ups comparing lifestyle habits, biochemical features, and noninvasive liver fibrosis scores, between non-MAFLD and MAFLD groups. Furthermore, differences in alcohol consumption and qualitative abdominal fat were examined between male and female patients with NAFLD and MAFLD. The prevalence of metabolic dysregulation, ratio of visceral fat area to subcutaneous fat area, and noninvasive liver fibrosis scores were significantly higher in male patients with MAFLD than in those with NAFLD (p < 0.05), but these were not significantly different in female patients. Among male patients with an alcohol consumption of > 70 g/week, several noninvasive liver fibrosis scores were significantly higher in the MAFLD group than in the NAFLD group (all p < 0.05). The influences of alcohol consumption and qualitative abdominal fat on NAFLD and MAFLD were different between sexes. The development of liver fibrosis should be considered in male patients with MAFLD who exceed mild drinking.
Hironori Wada, Yasushi Sato, Shota Fujimoto, Koichi Okamoto, Masahiro Bando, Tomoyuki Kawaguchi, Hiroshi Miyamoto, Naoki Muguruma, Katsuhisa Horimoto, Yui Matsuzawa, Michihiro Mutoh and Tetsuji Takayama : Resveratrol inhibits development of colorectal adenoma via suppression of LEF1; comprehensive analysis with connectivity map., Cancer Science, Vol.113, No.12, 4374-4384, 2022.
(Summary)
Although many chemopreventive studies on colorectal tumors have been reported, no effective and safe preventive agent is currently available. We searched for candidate preventive compounds against colorectal tumor comprehensively from United States Food and Drug Administration (FDA)-approved compounds by using connectivity map (CMAP) analysis coupled with in vitro screening with colorectal adenoma (CRA) patient-derived organoids (PDOs). We generated CRA-specific gene signatures based on the DNA microarray analysis of CRA and normal epithelial specimens, applied them to CMAP analysis with 1309 FDA-approved compounds, and identified 121 candidate compounds that should cancel the gene signatures. We narrowed them down to 15 compounds, and evaluated their inhibitory effects on the growth of CRA-PDOs in vitro. We finally identified resveratrol, one of the polyphenolic phytochemicals, as a compound showing the strongest inhibitory effect on the growth of CRA-PDOs compared with normal epithelial PDOs. When resveratrol was administered to Apc mice at 15 or 30 mg/kg, the number of polyps (adenomas) was significantly reduced in both groups compared with control mice. Similarly, the number of polyps (adenomas) was significantly reduced in azoxymethane-injected rats treated with 10 or 100 mg/resveratrol compared with control rats. Microarray analysis of adenomas from resveratrol-treated rats revealed the highest change (downregulation) in expression of LEF1, a key molecule in the Wnt signaling pathway. Treatment with resveratrol significantly downregulated the Wnt-target gene (MYC) in CRA-PDOs. Our data demonstrated that resveratrol can be the most effective compound for chemoprevention of colorectal tumors, the efficacy of which is mediated through suppression of LEF1 expression in the Wnt signaling pathway.
Beibei Ma, Hiroyuki Ueda, Koichi Okamoto, Masahiro Bando, Shota Fujimoto, Yasuyuki Okada, Tomoyuki Kawaguchi, Hironori Wada, Hiroshi Miyamoto, Mitsuo Shimada, Yasushi Sato and Tetsuji Takayama : TIMP1 promotes cell proliferation and invasion capability of right-sided colon cancers via the FAK/Akt signaling pathway., Cancer Science, Vol.113, No.12, 4244-4257, 2022.
(Summary)
Although right-sided colorectal cancer (CRC) shows a worse prognosis than left-sided CRC, the underlying mechanism remains unclear. We established patient-derived organoids (PDOs) from left- and right-sided CRCs and directly compared cell proliferation and invasion capability between them. We then analyzed the expression of numerous genes in signal transduction pathways to clarify the mechanism of the differential prognosis. Cell proliferation activity and invasion capability in right-sided cancer PDOs were significantly higher than in left-sided cancer PDOs and normal PDOs, as revealed by Cell Titer Glo and transwell assays, respectively. We then used quantitative RT-PCR to compare 184 genes in 30 pathways among right-sided and left-sided cancer and normal PDOs and found that the TIMP1 mRNA level was highest in right-sided PDOs. TIMP1 protein levels were upregulated in right-sided PDOs compared with normal PDOs but was downregulated in left-sided PDOs. TIMP1 knockdown with shRNA significantly decreased cell proliferation activity and invasion capability in right-sided PDOs but not in left-sided PDOs. Moreover, TIMP1 knockdown significantly decreased pFAK and pAkt expression levels in right-sided PDOs but not in left-sided PDOs. A database analysis of The Cancer Genome Atlas revealed that TIMP1 expression in right-sided CRCs was significantly higher than in left-sided CRCs. Kaplan-Meier survival analysis showed significantly shorter overall survival in high-TIMP1 patients versus low-TIMP1 patients with right-sided CRCs but not left-sided CRCs. Our data suggest that TIMP1 is overexpressed in right-sided CRCs and promotes cell proliferation and invasion capability through the TIMP1/FAK/Akt pathway, leading to a poor prognosis. The TIMP1/FAK/Akt pathway can be a target for therapeutic agents in right-sided CRCs.
(Keyword)
Humans / Prognosis / Signal Transduction / Colorectal Neoplasms / Colonic Neoplasms / Cell Proliferation / Tissue Inhibitor of Metalloproteinase-1
Yosuke Iwakawa, Kouzou Yoshikawa, Koichi Okamoto, Tetsuji Takayama, Takuya Tokunaga, Toshihiro Nakao, Masaaki Nishi, Chie Takasu, Hideya Kashihara, Yuuma Wada, Toshiaki Yoshimoto, Shoko Yamashita and Mitsuo Shimada : Four cases of gastric adenocarcinoma and proximal polyposis of the stomach treated by robotic total gastrectomy, Surgical Case Reports, Vol.8, No.1, 70, 2022.
(Summary)
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare disease and characterized by a unique point mutation in the promoter 1B region of the adenomatous polyposis coli (APC) gene. There are two aims in surgery for GAPPS; the first is prophylactic gastrectomy, and the second is excising concurrent cancer. We performed robotic total gastrectomy (RTG) for four cases of GAPPS. Case 1 was a woman in her 40 s whose sister had died from gastric cancer. Mutational analysis revealed mutation of APC exon 1B. We performed prophylactic gastrectomy. Case 2 was a woman in her 30 s who had a mutation of APC exon 1B, and preoperative biopsy revealed suspected adenocarcinoma. Case 3 was a woman in her 40 s who was diagnosed with gastric cancer with multiple polyps in the stomach and a mutation of APC exon 1B. Case 4 was a woman in her 20 s in whom biopsy revealed low-grade dysplasia of a raised lesion. She had a mutation in APC exon 1B. We performed RTG with D1 + lymphadenectomy in all patients, and there were no intraoperative complications. Patients with GAPPS are mainly followed regularly with repeat biopsy, and tumors are detected in an early stage. As the safety of robotic surgery for the early gastric cancer is reported, RTG is an option for these patients. This is the first report of RTG for GAPPS patients.
Fumika Nakamura, Yasushi Sato, Koichi Okamoto, Yasuteru Fujino, Yasuhiro Mitsui, kaizo kagemoto, Tomoyuki Kawaguchi, Hiroshi Miyamoto, Naoki Muguruma, Tomoko Sonoda, Koichi Tsuneyama and Tetsuji Takayama : Colorectal carcinoma occurring via the adenoma-carcinoma pathway in patients with serrated polyposis syndrome., Journal of Gastroenterology, Vol.57, No.4, 286-299, 2022.
(Summary)
Although serrated polyposis syndrome (SPS) is associated with an increased colorectal cancer (CRC) risk, the carcinogenic mechanisms remain unknown. We investigated clinicopathological characteristics and genetic abnormalities in colorectal polyps and CRC to elucidate carcinogenic mechanisms in SPS. We retrospectively analyzed clinicopathological features of colorectal polyps in 44 SPS patients, and examined mutations of genes including APC, RAS, BRAF, and TP53, and microsatellite instability (MSI) in CRC tissues. Of the 44 patients, 25 (56%) fulfilled WHO criterion 1, 11 (25%) fulfilled criterion 2, and 8 (18%) fulfilled both. A total of 956 polyps were observed; 642 (67%) hyperplastic polyps (HP), 204 (21%) sessile serrated lesions (SSL), 10 (1%) traditional serrated adenoma (TSA), and 100 (11%) adenomas. The median numbers of polyps (/patient) were 10.5 (IQR 2.75-23) HPs, 4.0 (2.0-6.0) SSLs, 0 (0-0) TSA, and 1 (0-3.3) adenoma. SSL and HP located preferentially in the proximal and distal colon, respectively. Twenty-two CRCs were found in 18 patients. Based on the histological coexistence of SSL/TSA, BRAF mutation and MSI, 5 CRCs (26%) were classified as serrated-neoplasia pathway. Conversely, based on the coexistence of adenoma, APC/RAS and TP53 mutations, 11 CRCs (58%) were classified as adenoma-carcinoma pathway. The remaining three were unclassifiable. Most CRCs through adenoma-carcinoma pathway were located in the left-side colorectum and patients bearing those met criterion 2, characterized by many HP and advanced adenomas. Adenoma was a significant risk factor for CRC. Our results suggest that more than half of the CRCs, particularly those in the left-side colorectum, developed through the adenoma-carcinoma pathway in SPS patients. Adenoma was a risk factor for CRCs, suggesting its importance in colorectal carcinogenesis.
Noriaki Murayama, Koichi Okamoto, Tadahiko Nakagawa, Jinsei Miyoshi, Kensei Nishida, Tomoyuki Kawaguchi, kaizo kagemoto, Shinji Kitamura, Beibei Ma, Hiroshi Miyamoto, Naoki Muguruma, Mitsuyasu Yano, Koichi Tsuneyama, Takahiro Fujimori, Yasushi Sato and Tetsuji Takayama : miR-144-3p/miR-451a promotes lymphovascular invasion through repression of PTEN/p19 in rectal neuroendocrine tumors., Journal of Gastroenterology and Hepatology, Vol.37, No.5, 919-927, 2022.
(Summary)
Although rectal neuroendocrine tumor (NET-G1) have potential metastatic capability, even among small tumors, no predictive biomarker for invasion and metastasis has been reported. We analyzed microRNA (miRNA) expression profiles in rectal NET-G1 tissues with and without lymphovascular invasion (LVI). Moreover, we then investigated their target genes to clarify the mechanism of invasion/metastasis in NET-G1. miRNA array analysis was performed using seven rectal NET-G1 tissues with LVI and seven without LVI. miRNA expression was confirmed by quantitative real-time PCR. A NET cell line H727 was transfected with miRNA mimic or target gene small interfering RNA, and migration and invasion assays were performed. The expression levels of miR-144-3p and miR-451a were significantly higher in NET-G1 with LVI versus without LVI, as determined by miRNA array analysis and RT-qPCR. A significant correlation was observed between miR-144-3p and miR-451a expression levels, strongly suggesting miR144/451 cluster overexpression in NET-G1 with LVI. Bioinformatic analysis of target genes revealed that miR-144-3p and miR-451a directly interact with PTEN and p19 mRNA, respectively. Immunohistochemistry revealed significantly lower expression of PTEN and p19 in NET-G1 tissues with LVI than in those without LVI. The miR-144-3p and miR-451a mimic significantly increased cell migration/invasion capability, respectively. Knockdown of PTEN and p19 induced significant augmentation of cell invasion and migration capability, respectively. Our data suggest that overexpression of miR-144/miR-451 cluster promotes LVI via repression of PTEN and p19 in rectal NET-G1 cells. miR-144/451 cluster may be a novel biomarker for predicting invasion/metastasis in rectal NET-G1.
Yasutsugu Shimohara, Yuji Urabe, Shiro Oka, Hisabe Takahashi, Atsushi Yamada, Hiro-o Matsushita, Bunichiro Kato, Hirotsugu Sakamoto, Joichiro Horii, Daisuke Watanabe, Hirotsugu Ega, Fumika Nakamura, Akiko Chino, Hironori Yamamoto, Tetsuji Takayama, Takayuki Matsumoto, Hideki Ishikawa and Shinji Tanaka : Clinicopathological characteristics of colorectal serrated polyposis syndrome (SPS): results of a multicenter study by the SPS Study Group in Japan., Journal of Gastroenterology, Vol.57, No.4, 300-308, 2022.
(Summary)
Serrated polyposis syndrome (SPS), a type of colorectal polyposis characterized by multiple serrated polyps, is associated with a high risk of colorectal carcinoma (CRC). This study aimed to clarify the clinicopathological characteristics of SPS in Japan. We investigated the clinicopathological characteristics of patients with SPS from the "Multicenter Study on Clinicopathological Characteristics of SPS (UMIN 000032138)" by the Colorectal Serrated Polyposis Syndrome (SPS) Study Group. In this study, patients were diagnosed with SPS based on the 2019 World Health Organization (WHO) SPS diagnostic criteria. Ninety-four patients were diagnosed with SPS in 10 institutions between January 2001 and December 2017. The mean number (± standard deviation [SD]) of resected lesions per patient was 11.3 ± 13.8. The mean age at diagnosis of SPS was 63.3 ± 11.6 years, and 58 patients (61.7%) were male. Eighty-seven (92.6%) and 16 (17.0%) patients satisfied WHO diagnostic criteria I and II, respectively. Nine patients (9.6%) satisfied both criteria I and II. Carcinoma (T1-T4) were observed in 21 patients (22.3%) and 24 lesions. Of the 21 patients with CRC, 19 (90.4%) satisfied diagnostic criterion I, 1 (4.8%) satisfied diagnostic criterion II, and 1 (4.8%) satisfied diagnostic criteria I and II. There was no notable difference in the prevalence of CRC among patients who met diagnostic criterion I, II, and both I and II. Patients with SPS have a high risk of CRC and should undergo regular surveillance colonoscopy. Raising awareness of this syndrome is crucial.
Satoshi Teramae, Naoki Muguruma, Koichi Okamoto, Kumiko Oseto, Ryutaro Nishikawa, Takayuki Tanoue, Keiji Hirata, Shunichi Yanai, Takayuki Matsumoto, Seiji Shimizu, Jun Miwa, Yu Sakaki, Kazuo Yashima, Hiroyuki Ohnuma, Yasushi Sato, Yoshitaka Kitayama, Yoshio Ohda, Atsushi Yamauchi, Yoji Sanomura, Kumiko Tanaka, Yoshiaki Kubo, Hideki Ishikawa, Yoshimi Bando, TOmoko Sonoda and Tetsuji Takayama : Cancer risk and genotype-phenotype correlation in Japanese patients with Cowden syndrome., International Journal of Clinical Oncology, Vol.27, No.4, 639-647, 2022.
(Summary)
Cowden syndrome (CS) is an autosomal-dominant hereditary disorder caused by a germline PTEN variant and characterized by multiple hamartomas and a high risk of cancers. However, no detailed data on CS in Asian patients nor genotype-phenotype correlation have been reported. We performed the first Japanese nationwide questionnaire survey on CS and obtained questionnaire response data on 49 CS patients. Patients included 26 females (median age 48 years). The incidence of breast, thyroid, endometrium, and colorectal cancer was 32.7%, 12.2%, 19.2% (among females), and 6.1%, respectively. The incidence of any cancers was relatively high among all patients (46.9%, 23/49), and particularly female patients (73.1%, 19/26), compared with previous reports from Western countries. Gastrointestinal (GI) polyps were more frequently found throughout the GI tract compared with previous studies. PTEN variants were detected in 95.6% (22/23) of patients; 12 in the N-terminal region (11 in phosphatase domain) and 10 in the C-terminal (C2 domain) region. The incidence of cancer in the C2 domain group was significantly higher than in the N-terminal region (phosphatase) group. All female patients with C2 domain variant had breast cancer. Our data suggest that Japanese patients with CS, particularly female patients and patients with C2 domain variant may have a high risk of cancers.
(Keyword)
Breast Neoplasms / Female / Genetic Association Studies / Hamartoma Syndrome, Multiple / Humans / Intestinal Polyps / Japan / Male / Middle Aged / PTEN Phosphohydrolase / Risk
Masahiro Sogabe, Yumiko Izaki, Toshiya Okahisa and Tetsuji Takayama : Improvement of acceptability in patients undergoing esophagogastroduodenoscopy using auditory and visual stimulation., The Journal of Medical Investigation : JMI, Vol.69, No.1-2, 8-18, 2022.
(Summary)
Esophagogastroduodenoscopy (EGD) has become an indispensable examination to discover upper gastrointestinal diseases, including cancer, and perform endoscopic treatment. However, many individuals who undergo the procedure have feelings of anxiety and fear regarding EGD. Although the use of medication for sedation during EGD is useful for reducing anxiety and the stability of hemodynamics, sedation may increase the likelihood of complications. Several noninvasive distractions have been introduced to decrease pain and anxiety during endoscopic examinations;however, most assessments of these distractions evaluated subjective items such as impression. We herein add the results of our studies using objective items and review the effectiveness of distractions for EGD. J. Med. Invest. 69 : 8-18, February, 2022.
Yasushi Sato, Koichi Okamoto, Hiroshi Miyamoto and Tetsuji Takayama : Chemotherapy in older adults with gastrointestinal cancer:Current practices and future directions in Japan., The Journal of Medical Investigation : JMI, Vol.69, No.1.2, 25-30, 2022.
(Summary)
Chemotherapy for cancer has significantly improved owing to the increasing number of effective chemotherapeutic agents and supportive care. Recently, the number of older cancer patients has rapidly increased owing to the aging of the global population. However, in most cases, it is difficult to treat those using similar dosages or schedules as that of younger patients because older patients generally have unfavorable factors, such as decreased performance status and physical and cognitive conditions, thus increasing the incidence of complications and side effects. Chemotherapy for gastrointestinal cancers has made significant progress in recent years with the introduction of molecular-targeted agents and immunotherapy. However, clinical trials showed limited evidence regarding the efficacy of chemotherapy in older cancer patients, accounting for half of all patients, making it difficult to develop a well-established treatment strategy. This review aimed to evaluate the current state of chemotherapy for gastrointestinal cancer in older adults. Furthermore, the limitations and future perspectives were discussed. J. Med. Invest. 69 : 25-30, February, 2022.
Masanori Takehara, Hiroshi Miyamoto, Yasuteru Fujino, Tetsu Tomonari, Tatsuya Taniguchi, Shinji Kitamura, Koichi Okamoto, Masahiro Sogabe, Yasushi Sato, Naoki Muguruma, Yoshimi Bando and Tetsuji Takayama : Long-Term Survival due to Chemotherapy including Paclitaxel in a Patient with Metastatic Primary Splenic Angiosarcoma., Case Reports in Gastroenterology, Vol.15, No.3, 910-918, 2021.
(Summary)
A primary splenic angiosarcoma is a rare type of soft tissue sarcoma and is associated with an extremely poor prognosis. In this study, we describe the case of a patient who was diagnosed with metastatic primary splenic angiosarcoma and survived for about 2 years. A 62-year-old female was referred to us for the treatment of splenic angiosarcoma with disseminated intravascular coagulation (DIC) and multiple liver and bone metastases. Paclitaxel therapy resulted in recovery from DIC and enabled her to continue sequential treatment through to sixth-line chemotherapy. We reviewed all splenic angiosarcoma case reports which were described as stage IV to date and compared with our case. From these data, we found that the median overall survival was 105 days, and the prognosis of splenic angiosarcoma of stage IV was worse than conventional case series. Splenectomy was performed in more patients than chemotherapy as a treatment. Moreover, various chemotherapeutic regimens were used. These data suggest that administering chemotherapy including paclitaxel to patients with splenic angiosarcoma might improve their prognosis.
The mechanism of resistance to sorafenib in hepatocellular carcinoma (HCC) remains unclear. We analyzed miRNA expression profiles in sorafenib-resistant HCC cell lines (PLC/PRF5-R1/R2) and parental cell lines (PLC/PRF5) to identify the miRNAs responsible for resistance. Drug sensitivity, migration/invasion capabilities, and epithelial-mesenchymal transition (EMT) properties were analyzed by biochemical methods. The clinical relevance of the target genes to survival in HCC patients were assessed using a public database. Four miRNAs were significantly upregulated in PLC/PRF5-R1/-R2 compared with PLC/PRF5. Among them, miR-125b-5p mimic-transfected PLC/PRF5 cells (PLC/PRF5-miR125b) and showed a significantly higher IC50 for sorafenib compared with controls, while the other miRNA mimics did not. PLC/PRF5-miR125b showed lower E-cadherin and higher Snail and vimentin expression-findings similar to those for PLC/PRF5-R2-which suggests the induction of EMT in those cells. PLC/PRF5-miR125b exhibited significantly higher migration and invasion capabilities and induced sorafenib resistance in an in vivo mouse model. Bioinformatic analysis revealed ataxin-1 as a target gene of miR-125b-5p. PLC/PRF5 cells transfected with ataxin-1 siRNA showed a significantly higher IC50, higher migration/invasion capability, higher cancer stem cell population, and an EMT phenotype. Median overall survival in the low-ataxin-1 patient group was significantly shorter than in the high-ataxin-1 group. In conclusion, miR-125b-5p suppressed ataxin-1 and consequently induced Snail-mediated EMT and stemness, leading to a poor prognosis in HCC patients.
Lenvatinib is a multi-targeted tyrosine kinase inhibitor available for the treatment of unresectable hepatocellular carcinoma (HCC). We herein report an 84-year-old-man with interstitial pneumonia caused by lenvatinib. Four months after the start of lenvatinib administration for HCC, chest computed tomography revealed bilateral ground-glass opacity. However, he continued to take lenvatinib for four more months until he complained of dyspnea on exertion. This is a case of lenvatinib-induced interstitial pneumonia that progressed relatively slowly with a long asymptomatic period despite the appearance of pneumonia on image findings.
(Keyword)
Aged, 80 and over / Carcinoma, Hepatocellular / Humans / Liver Neoplasms / Lung Diseases, Interstitial / male / Phenylurea Compounds / Quinolines
Yusaku Shimamoto, Shingo Ishiguro, Yoji Takeuchi, Nakatsuka Shin-Ichi, Hiroshi Yunokizaki, Yasumasa Ezoe, Takeshi Nakajima, Kenshi Matsuno, Hiroko Nakahira, Kumiko Tanaka, Ryu Ishihara, Tetsuji Takayama, Teruhiko Yoshida and Hideki Ishikawa : Gastric neoplasms in patients with familial adenomatous polyposis: endoscopic and clinicopathological features., Gastrointestinal Endoscopy, Vol.94, No.6, 1030-1042, 2021.
(Summary)
Gastric neoplasms in patients with familial adenomatous polyposis occur at a high rate and can cause death. The endoscopic findings of gastric neoplasms in these patients are characteristic, but not well recognized. To identify the relevant characteristics to enable early detection, we retrospectively investigated endoscopic findings of gastric neoplasms in patients with familial adenomatous polyposis, then compared the clinical, histopathological, and genetic features among subgroups. Of 234 patients with 171 pedigrees at 2 institutes, 56 (24%) cases (133 gastric neoplasms) with 44 pedigrees were examined. Immunostaining was performed for histopathological evaluation by one blinded pathologist. According to the endoscopic findings, gastric neoplasms were divided into 4 types (L, UM-W, UM-T, and UM-R) and their clinicopathological features were examined. Of the cases, 93% could be classified into a single type. Among histological phenotypes, high-grade dysplasia was present in 26% (Type L), 41% (Type UM-W), 0% (Type UM-T), and 22% (Type UM-R). The immunological phenotype comprised the gastric type in 69% (93% in Type UM); it comprised the intestinal phenotype, including the mixed type, in 31% (61% in Type L). Moreover, 96% of the patients had concurrent duodenal neoplasms. Adenomatous polyposis coli gene status was identified in 93% of the patients; the pathogenic variant was detected in 98% but did not influence any endoscopic features. Gastric neoplasms in patients with familial adenomatous polyposis were stratified into 4 types according to their endoscopic findings. The endoscopic phenotype was related to the histopathological phenotype, but not to germline variants.
Misato Takao, Tatsuro Yamaguchi, Hidetaka Eguchi, Takeshi Yamada, Yasushi Okazaki, Naohiro Tomita, Tadashi Noizu, Tomoyuki Momma, Tetsuji Takayama, Kohji Tanakaya, Kiwamu Akagi and Hideyuki Ishida : APC germline variant analysis in the adenomatous polyposis phenotype in Japanese patients., International Journal of Clinical Oncology, Vol.26, No.9, 1661-1670, 2021.
(Summary)
Familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by multiple colonic polyps, is caused by a germline pathogenic variant of the APC gene. However, this variant is not detected in up to 30% of patients with the adenomatous polyposis phenotype. We performed next-generation sequencing (NGS) to identify the causative genes in FAP patients with 10 or more polyps. For patients in whom the APC germline variant was not able to be identified, we screened for APC mosaicism using high-coverage NGS of APC with DNA from leucocytes and/or frozen tissue. The pathogenic APC germline variant was found in 93.3%, 71.6%, and 17.1% of patients with profuse-type polyposis, sparse-type polyposis, and oligo-polyposis, respectively. The APC germline variant detection rate in patients with FAP-related diseases was 69.7% for fundic gland polyposis, 79.7% for duodenal adenoma, 94.7% for desmoid tumor, and 71.4% for thyroid cancer, with increasing numbers of extracolonic lesions associated with an increasing APC germline variant detection rate. A mosaic test detected nine patients with APC mosaicism. A comparison of APC-associated polyposis with APC mosaicism showed that patients with APC mosaicism had a low frequency of duodenal adenoma and a family history of colonic polyposis. We determined the detection rate of the APC germline variant by phenotype and identified APC mosaicism. Genetic testing of FAP patients is important because it can help with surgical decision-making, monitoring, and genetic counseling. Furthermore, genetic testing by NGS proved to be an effective method of detecting APC germline variants.
Masahiro Sogabe, Toshiya Okahisa, Takeshi Kurihara, Miwako Kagawa, Kaizoh Kagemoto, Yoshifumi Kida, Tetsu Tomonari, Tatsuya Taniguchi, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato, Masahiko Nakasono and Tetsuji Takayama : Differences in Several Factors in the Development of Erosive Esophagitis Among Patients at Various Stages of Metabolic Syndrome: A Cross-Sectional Study., Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy, Vol.14, 1589-1600, 2021.
Hideki Ishikawa, Michihiro Muto, Yasushi Sato, Hisashi Doyama, Masahiro Tajika, Shinji Tanaka, Takahiro Horimatsu, Yoji Takeuchi, Hiroshi kashida, Jun Tashiro, Yasumasa Ezoe, Takeshi Nakajima, Hiroaki Ikemitsu, Shinichiro Hori, Sadao Suzuki, Takahiro Otani, Tetsuji Takayama, Yoshio Ohda, Kanae Mure, Keiji Wakabayashi and Toshiyuki Sakai : Chemoprevention with low-dose aspirin, mesalazine, or both in patients with familial adenomatous polyposis without previous colectomy (J-FAPP Study IV): a multicentre, double-blind, randomised, two-by-two factorial design trial., The Lancet. Gastroenterology & Hepatology, Vol.6, No.6, 474-481, 2021.
(Summary)
The only established treatment for preventing colorectal cancer in patients with familial adenomatous polyposis (FAP) is colectomy, which greatly reduces patient quality of life. Thus, an alternative method is warranted. In this trial, we aimed to clarify the individual and joint effects of low-dose aspirin and mesalazine on the recurrence of colorectal polyps in Japanese patients with FAP. This was a randomised, double-blind, placebo-controlled, multicentre trial with a two-by-two factorial design done in 11 centres in Japan. Eligible patients were aged 16-70 years and had a history of more than 100 adenomatous polyps in the large intestine, without a history of colectomy. Before the study, patients underwent endoscopic removal of all colorectal polyps of at least 5·0 mm in diameter. Randomisation was done with a minimisation method with a random component to balance the groups with respect to the adjustment factors of sex, age (<30 years vs ≥30 years), or smoking status at the time of entry. Patients and researchers were masked to the treatment group. There were four groups: aspirin (100 mg per day) plus mesalazine (2 g per day), aspirin (100 mg per day) plus mesalazine placebo, aspirin placebo plus mesalazine (2 g per day), or aspirin placebo plus mesalazine placebo. Treatment was continued until 1 week before 8 month colonoscopy. The primary endpoint was the incidence of colorectal polyps of at least 5·0 mm at 8 months and was assessed in the intention-to-treat population. Safety was assessed in the ITT population. We also did a per-protocol analysis including only patients who took at least 70% of the allocated study drug. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000018736, and is complete. Between Sept 25, 2015, and March 13, 2017, 104 patients were randomly assigned to receive either aspirin or aspirin placebo (n=52) or mesalazine or mesalazine placebo (n=52). Two patients withdrew from the aspirin plus mesalazine placebo group. 26 (50%) of 52 patients who received no aspirin had colorectal polyps of at least 5·0 mm at 8 months, as did 15 (30%) of the 50 patients who received any aspirin, 21 (42%) of the 50 patients who received no mesalazine, and 20 (38%) of the 52 patients who received any mesalazine. The adjusted odds ratio for polyp recurrence was 0·37 (95% CI 0·16-0·86) in the patients who received any aspirin and 0·87 (95% CI 0·38-2·00) in any who received mesalazine. The most common adverse events were grade 1-2 upper gastrointestinal symptoms in three (12%) of 26 patients who received aspirin plus mesalazine, one (4%) of 24 patients who received aspirin plus mesalazine placebo, and one (4%) of 26 patients who received mesalazine plus aspirin placebo. There was one grade 4 event in the mesalazine plus aspirin placebo group, but not related to the treatment. Low-dose aspirin safely suppressed the recurrence of colorectal polyps larger than 5·0 mm in patients with FAP. These results suggest an effect of low-dose aspirin for FAP and could be an alternative method for preventing colorectal cancer in FAP. Japan Agency for Medical Research and Development.
Tetsu Tomonari, Yasushi Sato, Joji Tani, Akira Hirose, Chikara Ogawa, Akihiro Morishita, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Koichi Okamoto, Masahiro Sogabe, Hiroshi Miyamoto, Naoki Muguruma, Kazushige Uchida, Tsutomu Masaki and Tetsuji Takayama : Comparison of therapeutic outcomes of Sorafenib and Lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular-targeted agent sequential therapy: A propensity score-matched analysis., Hepatology Research, Vol.51, No.4, 472-481, 2021.
(Summary)
The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts). The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], P <0.01; progression-free survival: 10 months [LEN] vs. 5.1 months [SOR], P <0.01). No significant intergroup differences were noted in the rate of transition to secondary MTA treatments (SOR: 58.7%; LEN: 48.4%), adverse events (SOR: 86%; LEN: 95%), and maintenance of the Child-Pugh (CP) score during treatment. Compared to non-MTA treatments, secondary MTA treatment achieved a greater improvement in survival ( 4.3 months vs. 2.8 months, P=0.0047). Multivariate analysis demonstrated that the CP score (P <0.01) and alpha-fetoprotein level (P <0.01) were independent prognostic factors. Both SOR and LEN treatments showed a clinically comparable therapeutic efficacy as the first-line treatments for u-HCC patients in an MTA sequential therapy.
Yasuyuki Okada, Naoki Takahashi, Tetsuji Takayama and Ajay Goel : LAMC2 promotes cancer progression and gemcitabine resistance through modulation of EMT and ATP-binding cassette transporters in pancreatic ductal adenocarcinoma., Carcinogenesis, Vol.42, No.4, 546-556, 2021.
(Summary)
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis. Gemcitabine remains an effective option for the majority of PDAC patients. Unfortunately, currently no reliable prognostic and predictive biomarkers of therapeutic response are available for the patients with PDAC. Laminin γ2 (LAMC2) is overexpressed in several cancers, and its high expression facilitates cancer development and chemoresistance. However, its functional role in PDAC remains unclear, and a better understanding of this will likely help improve the prognosis of PDAC patients. This study aimed to elucidate the clinical and biological role of LAMC2 in PDAC. We first analyzed the expression levels of LAMC2 by real-time reverse transcription PCR in a cohort of 114 PDAC patients. Interestingly, higher expression of LAMC2 significantly correlated with poor survival in PDAC cohort. In addition, elevated LAMC2 expression served as a potential prognostic marker for survival. Subsequently, functional characterization for the role of LAMC2 in PDAC was performed by small interfering RNA knockdown in pancreatic cancer (PC) cell lines. Interestingly, inhibition of LAMC2 in PC cells enhanced the gemcitabine sensitivity and induction of apoptosis. Moreover, it inhibited colony formation ability, migration and invasion potential. Furthermore, LAMC2 regulated the expression of epithelial-mesenchymal transition (EMT) phenotype. In addition, LAMC2 significantly correlated with genes associated with the expression of ATP-binding cassette (ABC) transporters in PC cells and PDAC patients. In conclusion, these results suggest that LAMC2 regulates gemcitabine sensitivity through EMT and ABC transporters in PDAC and may be a novel therapeutic target in PDAC patients.
Yasuyuki Okada, Satoshi Nisiwada, Kensuke Yamamura, Masayuki Sho, Hideo Baba, Tetsuji Takayama and Ajay Goel : Identification of laminin γ2 as a prognostic and predictive biomarker for determining response to gemcitabine-based therapy in pancreatic ductal adenocarcinoma., European Journal of Cancer, Vol.146, 125-134, 2021.
(Summary)
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. While the extracellular matrix component plays an integral role in PDAC pathogenesis and mediating chemoresistance, its role in predicting response to chemotherapy in patients with PDAC remains unclear. We performed a systematic biomarker discovery by analysing genome-wide transcriptomic profiling data from 423 patients (GSE71729, GSE21501 and The Cancer Genome Atlas [TCGA]) for predicting overall survival (OS). This was subsequently validated in two independent clinical cohorts of 270 patients with PDAC (training cohort, n = 121, and validation cohort, n = 149). In addition, we investigated endoscopic ultrasound-fine needle aspiration biopsy specimens from 51 patients with PDAC with an unresectable cancer for predicting therapeutic response to gemcitabine-based therapy. After rigorous bioinformatic analysis, we identified laminin γ2 (LAMC2) to be a significant prognostic factor in all three PDAC data sets (GSE71729: hazard ratio [HR] = 2.04, P = 0.002; GSE21501: HR = 2.17, P = 0.031; TCGA: HR = 2.57, P < 0.001). High LAMC2 expression in patients with PDAC was associated with a significantly poor OS and relapse-free survival in both the training (P < 0.001, P < 0.001) and validation cohorts (P = 0.001, P = 0.026). More importantly, LAMC2 expression robustly identified patients with PDAC and unresectable disease and those who responded to gemcitabine-based therapy (area under the curve = 0.79; 95% confidence interval [CI], 0.65-0.89). The univariate logistic regression analysis revealed that high LAMC2 expression was the only factor that predicted poor response to gemcitabine in patients with PDAC (odds ratio = 4.90; 95% CI, 1.45-16.6; P = 0.011). We conclude that LAMC2 is a novel prognostic and predictive biomarker for gemcitabine-based therapy in both the adjuvant and palliative setting; which could have significant impact on precision and individualised treatment of patients with PDAC.
Motoki SUGASAKI, Naoki TOKUNAGA, Akishige IKEGAME, Takayuki NAKAO, Masahiro Oura, Hirokazu Miki, Kojiro Nagai and Tetsuji Takayama : A case of congenital prekallikrein deficiency discovered by preoperative screening, Japanese Journal of Medical Technology, Vol.70, No.1, 132-137, 2021.
Hironori Tanaka, Yoshihito Saijyo, Tetsu Tomonari, Takahiro Tanaka, Tatsuya Taniguchi, Shusuke Yagi, Koichi Okamoto, Hiroshi Miyamoto, Masahiro Sogabe, Yasushi Sato, Naoki Muguruma, Koichi Tsuneyama, Masataka Sata and Tetsuji Takayama : An Adult Case of Congenital Extrahepatic Portosystemic Shunt Successfully Treated with Balloon-occluded Retrograde Transvenous Obliteration, Internal Medicine, Vol.60, No.12, 1839-1845, 2021.
(Summary)
A 42-year-old woman visited our hospital due to syncope. Contrast-enhanced CT revealed portosystemic shunt, portal vein hypoplasia, and multiple liver nodules. The histological examination of a liver biopsy specimen exhibited portal vein hypoplasia and revealed that the liver tumor was positive for glutamine synthetase. The patient was therefore diagnosed with congenital extrahepatic portosystemic shunt type II, and with focal nodular hyperplasia (FNH)-like nodules. She had the complication of severe portopulmonary hypertension and underwent complete shunt closure by balloon-occluded retrograde transvenous obliteration (B-RTO). The intrahepatic portal vein was well developed at 1 year after B-RTO, and multiple liver nodules completely regressed. Her pulmonary hypertension also improved.
Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor lesion of colon cancer. Although the relevance of DNA hypermethylation in the SSA/P-cancer sequence is well documented, the role of DNA hypomethylation is unknown. We investigated the biological relevance of DNA hypomethylation in the SSA/P-cancer sequence by using 3-dimensional organoids of SSA/P. We first analyzed hypomethylated genes using datasets from our previous DNA methylation array analysis on 7 SSA/P and 2 cancer in SSA/P specimens. Expression levels of hypomethylated genes in SSA/P specimens were determined by RT-PCR and immunohistochemistry. We established 3-dimensional SSA/P organoids and performed knockdown experiments using a lentiviral shRNA vector. DNA hypomethylation at CpG sites of the gene was quantitated by MassARRAY analysis. The mean number of hypomethylated genes in SSA/P and cancer in SSA/P was 41.6 ± 27.5 and 214 ± 19.8, respectively, showing a stepwise increment in hypomethylation during the SSA/P-cancer sequence. S100P, S100α2, PKP3, and MUC2 were most commonly hypomethylated in SSA/P specimens. The mRNA and protein expression levels of S100P, S100α2, and MUC2 were significantly elevated in SSA/P compared with normal colon tissues, as revealed by RT-PCR and immunohistochemistry, respectively. Among these, mRNA and protein levels were highest for S100P. Knockdown of the S100P gene using a lentiviral shRNA vector in 3-dimensional SSA/P organoids inhibited cell growth by >50% (p < 0.01). The mean diameter of SSA/P organoids with S100P gene knockdown was significantly smaller compared with control organoids. MassARRAY analysis of DNA hypomethylation in the S100P gene revealed significant hypomethylation at specific CpG sites in intron 1, exon 1, and the 5'-flanking promoter region. These results suggest that DNA hypomethylation, including S100P hypomethylation, is supposedly associated with the SSA/P-cancer sequence. S100P overexpression via DNA hypomethylation plays an important role in promoting cell growth in the SSA/P-cancer sequence.
Tomoyuki Kawaguchi, Koichi Okamoto, Shota Fujimoto, Masahiro Bando, Hironori Wada, Hiroshi Miyamoto, Yasushi Sato, Naoki Muguruma, Katsuhisa Horiimoito and Tetsuji Takayama : Lansoprazole Inhibits the Development of Sessile Serrated Lesions by Inducing G1 Arrest via Skp2/p27 Signaling Pathway., Journal of Gastroenterology, Vol.59, No.1, 11-23, 2021.
(Summary)
Although the serrated-neoplasia pathway reportedly accounts for 15-30% of colorectal cancer (CRC), no studies on chemoprevention of sessile serrated lesions (SSLs) have been reported. We searched for effective compounds comprehensively from a large series of compounds by employing Connectivity Map (CMAP) analysis of SSL-specific gene expression profiles coupled with in vitro screening using SSL patient-derived organoids (PDOs), and validated their efficacy using a xenograft mouse model of SSL. We generated SSL-specific gene signatures based on DNA microarray data, and applied them to CMAP analysis with 1309 FDA-approved compounds to select candidate compounds. We evaluated their inhibitory effects on SSL-PDOs using a cell viability assay. SSL-PDOs were orthotopically transplanted into NOG mice for in vivo evaluation. The signal transduction pathway was evaluated by gene expression profile and protein expression analysis. We identified 221 compounds by employing CMAP analysis of SSL-specific signatures, which should cancel the gene signatures, and narrowed them down to 17 compounds. Cell viability assay using SSL-PDOs identified lansoprazole as having the lowest IC50 value (47 µM) among 17 compounds. When SSL-PDO was orthotopically transplanted into murine intestinal tract, the tumor grew gradually. Administration of lansoprazole to mice inhibited the growth of SSL xenograft whereas the tumor in control mice treated with vehicle alone grew gradually over time. The Ki67 index in xenograft lesions from the lansoprazole group was significantly lower compared with the control group. Cell cycle analysis of SSL-PDOs treated with lansoprazole exhibited a significant increase in G1 phase cell population. Microarray and protein analysis revealed that lansoprazole downregulated Skp2 expression and upregulated p27 expression in SSL-PDOs. Our data strongly suggest that lansoprazole is the most effective chemopreventive agent against SSL, and that lansoprazole induces G1 cell cycle arrest by downregulating Skp2 and upregulating p27 in SSL cells.
Tamotsu Sagawa, Yasushi Sato, Masahiro Hirakawa, Kyoko Hamaguchi, Akira Fukuya, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma, Koshi Fujikawa, Yasuo Takahashi and Tetsuji Takayama : Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab., Scientific Reports, Vol.10, No.1, 19815, 2020.
(Summary)
The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27-0.74; p < 0.001]. In patients with left-sided tumours, treatment with chemotherapy plus cetuximab yielded longer OS than chemotherapy plus bevacizumab (50.6 vs 27.8 months, HR 0.55; 95% CI 0.32-0.97; p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32-0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28-0.68, p < 0.001, respectively). Moreover, ETS and/or high DpR achieved in patients with right-sided mCRC receiving chemotherapy plus cetuximab were associated with significantly better OS than in those lacking ETS and with low DpR (34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.
Jun Okazaki, Toshihito Tanahashi, Yasushi Sato, Jinsei Miyoshi, Tadahiko Nakagawa, Tetsuo Kimura, Hiroshi Miyamoto, Yasuteru Fujino, Fumika Nakamura, Masanori Takehara, beibei ma, Masahiro Bando, Shinji Kitamura, Koichi Okamoto, Naoki Muguruma, Masahiro Sogabe and Tetsuji Takayama : MicroRNA-296-5p Promotes Cell Invasion and Drug Resistance by Targeting Bcl2-Related Ovarian Killer, Leading to a Poor Prognosis in Pancreatic Cancer., Digestion, Vol.101, No.6, 794-806, 2020.
(Summary)
Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive invasion, early metastasis, and resistance to chemotherapy, leading to a poor prognosis. To clarify the molecular mechanism of these malignant characteristics, we performed a genome-wide microRNA (miRNA) array analysis utilizing micro-cancer tissues from patients with unresectable PDAC (stage IV), obtained by endoscopic ultrasound-fine needle aspiration (EUS-FNA). The expression profiles of 2,042 miRNAs were determined using micro-cancer tissues from 13 patients with unresectable PDAC obtained by EUS-FNA. The relationship between individual miRNA levels and overall survival (OS) was analyzed. Possible target genes for miRNAs were bioinformatically analyzed using the online database miRDB. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and PK-8 were transfected with miRNA mimic or small interfering RNA, and cell invasion, epithelial-mesenchymal transition (EMT), and apoptosis markers were examined. miRNA and mRNA expressions were examined by quantitative polymerase chain reaction. Of 2,042 miRNAs, the 10 that exhibited the lowest correlation coefficient (p 0.005) between miRNA expression level and OS among the patients were identified. The miRDB and expression analysis in cancer cell lines for the 10 miRNAs identified miR-296-5p and miR-1207-5p as biomarkers predictive of shorter survival (p < 0.0005). Bioinformative target gene analysis and transfection experiments with miRNA mimics showed that Bcl2-related ovarian killer (BOK), a pro-apoptotic gene, is a target for miR296-5p in pancreatic cancer cells; transfection of miR-296-5p mimic into PANC-1, MIA PaCa-2, and PK-8 cells resulted in significant suppression of BOK mRNA and protein expression. These transfectants showed significantly higher invasion capability compared with control cells, and knock down of BOK in pancreatic cancer cells similarly enhanced invasion capability. Transfectants of miR-296-5p mimic also exhibited aberrant expression of EMT markers, including vimentin and N-cadherin. Moreover, these transfectants showed a significantly lower apoptosis rate in response to 5-fluorouracil and gemcitabine with a decrease of BOK expression, suggesting a role of miR-296-5p in drug resistance. These results suggest that miR-296-5p is a useful biomarker for a poor prognosis in patients with PDAC, and that the miR-296-5p/BOK signaling axis plays an important role in cell invasion, drug resistance, and EMT in PDACs.
Shota Fuimoto, Naoki Muguruma, Michiyasu Nakao, Hidenori ANDO, Takanori Kashihara, Yoshihiko Miyamoto, Koichi Okamoto, Shigeki Sano, Tatsuhiro Ishida, Yasushi Sato and Tetsuji Takayama : Indocyanine green-labeled dasatinib as a new fluorescent probe for molecular imaging of gastrointestinal stromal tumors., Journal of Gastroenterology and Hepatology, Vol.36, No.5, 1253-1262, 2020.
(Summary)
It is difficult to differentiate gastrointestinal stromal tumors (GISTs) from other subepithelial lesions under gastrointestinal endoscopy. Because most GISTs express tyrosine kinase receptor c-KIT, fluorescence-labeled c-KIT-specific tyrosine kinase inhibitors seem to be useful agents for molecular imaging of GIST. We aimed to develop a near-infrared fluorescent imaging technology for GIST targeting c-KIT using the novel fluorescent probe indocyanine green-labeled dasatinib (ICG-dasatinib) and to investigate the antitumor effect of ICG-dasatinib on GIST cells. Indocyanine green-labeled dasatinib was synthesized by labeling linker-induced dasatinib with ICG derivative 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione. Human GIST cell lines GIST-T1 and GIST-882M were incubated with ICG-dasatinib and observed by fluorescent microscopy. GIST cells were incubated with ICG-dasatinib, unlabeled dasatinib, or imatinib, and cell viabilities were evaluated. Subcutaneous GIST model mice or orthotopic GIST model rats were intravenously injected with ICG-dasatinib and observed using an IVIS Spectrum. Strong fluorescent signals of ICG-dasatinib were observed in both GIST cell lines in vitro. IC50 values for ICG-dasatinib, unlabeled dasatinib, and imatinib were 13.9, 1.17, and 16.2 nM in GIST-T1 and 26.6, 3.63, and 47.6 nM in GIST-882M cells, respectively. ICG-dasatinib accumulated in subcutaneous xenografts in mice. Fluorescent signals were also observed in liver and gallbladder, indicating biliary excretion; however, fluorescence intensity of tumors was significantly higher than that of intestine after washing. Strong fluorescent signals were observed in orthotopic xenografts through the covering normal mucosa in rats. Indocyanine green-labeled dasatinib could visualize GIST cells and xenografted tumors. The antitumor effect of ICG-dasatinib was preserved to the same degree as imatinib.
Tetsu Tomonari, Yasushi Sato, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Masahiro Sogabe, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma, Yu Saitou, Satoru Imura, Yoshimi Bando, Mitsuo Shimada and Tetsuji Takayama : Conversion therapy for unresectable hepatocellular carcinoma after lenvatinib Three case reports., Medicine, Vol.99, No.42, e22782, 2020.
(Summary)
Lenvatinib (LEN) is a novel potent multi-tyrosine kinase inhibitor, approved as first-line treatment for unresectable hepatocellular carcinoma (HCC). Considering its high objective response rate, LEN therapy could be expected to achieve downstaging of tumors and lead to conversion therapy with hepatectomy or ablation. However, the feasibility of conversion therapy after LEN treatment in unresectable HCC remains largely unknown. Here, we reported 3 cases of unresectable HCC: case 1, a 69-year-old man diagnosed with ruptured HCC; case 2, a 72-year-old woman with nonalcoholic steatohepatitis-based HCC; and case 3, a 73-year-old man with a history of alcoholic cirrhosis-based HCC. In all cases, cirrhosis was classified as Child-Pugh 5 and modified albumin-bilirubin grade 1 or 2a. HCC was diagnosed as Barcelona Clinic Liver Cancer (BCLC) stage B. In all cases, LEN was initiated after conventional-transcatheter arterial embolization enforcement, while maintaining liver function. In all cases, the main tumor size decreased after 6 months of LEN treatment and no satellite nodes were detected, indicating downstaging of HCC to BCLC stage A. Subsequently, conversion hepatectomy or ablation was performed. After successful conversion therapy, the general condition of the patients was good, without tumor recurrence during the observation period (median 10 months). This study demonstrated that LEN enables downstaging of HCC and thus represents a bridge to successful surgery or ablation therapy. In particular, LEN treatment may facilitate the possibility for conversion therapy of initially unresectable HCC, while maintaining the hepatic functional reserve.
Masahiro Sogabe, Toshiya Okahisa, Takeshi Kurihara, Masanori Takehara, Kaizoh Kagemoto, Jun Okazaki, Yoshifumi Kida, Akihiro Hirao, Hironori Tanaka, Tetsu Tomonari, Tatsuya Taniguchi, Koichi Okamoto, Masahiro Nakasono and Tetsuji Takayama : Differences among patients with and without nonalcoholic fatty liver disease having elevated alanine aminotransferase levels at various stages of metabolic syndrome., PLoS ONE, Vol.15, No.8, e0238388, 2020.
(Summary)
The prevalence of nonalcoholic fatty liver disease (NAFLD) in the non-obese population has increased and NAFLD is not always recognized in individuals with metabolic syndrome (MS). The risk of cirrhosis is higher in patients having NAFLD with elevated alanine aminotransferase (ALT) levels than in those having NAFLD with normal ALT levels. To measure the differences in clinical factors associated with NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and to measure differences in metabolites between MS subjects with and without NAFLD having elevation of ALT. Among 7,054 persons undergoing health check-ups, we included 3,025 subjects who met the selection criteria. We measured differences in clinical factors for NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and compared metabolites between subjects with and without NAFLD having elevation of ALT in 32 subjects with MS. The prevalence of NAFLD and NAFLD having elevation of ALT was significantly progressively greater in subjects with Non-MS, Pre-MS, and MS (p <0.001, respectively). In the Non-MS group, there were significant differences between subjects with and without NAFLD having elevation of ALT with respect to body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, hemoglobin A1c, uric acid, aspartate aminotransferase (AST); In the Pre-MS group, there were significant differences in BMI, hypertension, AST, and gamma-glutamyl transpeptidase (GGT); In the MS group, there were significant differences in HDL-C, impaired glucose tolerance, AST, and GGT. There were significant differences in levels of metabolites of nicotinamide, inosine, and acetyl-L-carnitine between MS subjects with and without NAFLD having elevation of ALT (all p <0.05). Although NAFLD having elevation of ALT is important for development of NAFLD, differences in factors associated with NAFLD having elevation of ALT at various stages of MS should be considered. Additionally, several metabolites may play roles in the identification of risk for NAFLD in individuals with MS.
Recently, immune checkpoint inhibitors(ICI)have been approved for use in advanced gastric cancer(AGC)based on the positive results of ATTRACTION‐2 trial in Japan. There has been accumulating evidence that the development of immune-related adverse events(irAE)may be associated with a response to ICI therapy, particularly in lung cancer, although little is known about these correlations in gastrointestinal cancer. To investigate the efficacy and irAE of ICI treatment and their correlation in AGC, we retrospectively examined 29 patients with AGC who received nivolumab therapy in our departments. Among them, 15 patients(52%)developed irAEs including 4 patients(14%)for grade 3 irAEs ; liver dysfunction(n＝2), type 1 diabetes mellitus(n＝2) and adrenal insufficiency(n＝1). The median overall survival was12．0months in the irAE group and 3．25 months in the non-irAE group(p＝0．164), which suggested the relationship between the effects and irAEs in ICI treatment of AGC. Further research is required to understand the implications of irAE characteristics on ICI response in GCA patients.
藤井 有美子, 小林 誠司, 大西 芳明, Katsuya Tanaka, Naoki Muguruma and Tetsuji Takayama : Assessment of accidental events in images during capsule endoscopy, Shikoku Acta Medica, Vol.76, No.3,4, 159-164, 2020.
(Summary)
Recently, there have been some reports of electromagnetic interference during capsule endoscopy(CE)in regards to other medical devices and facility environment. These accidental events have not been analyzed sufficiently although academic societies and related ministries are proposing guidelines with cautious attention. Based on this, detailed analyses and development of solution are required. In this study, we review our experience with cases of accidental events during CE and assessed the causes and preventive solutions. A total of149CE cases(male :89, female :60, mean age :56±18 8)from January 2017 until December 2019 were analyzed retrospectively. Four cases(2%)with defective images were noted. Detailed events were as follows ;1 disorder of the sensor array, 2 recorder freezes, and 1 electromagnetic interference. These mechanical and electromagnetic troubles should be assessed and shared among medical staffs and manufacturers to propose possible solutions and perform CE safely.
Tetsu Tomonari, Yasushi Sato, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Masahiro Sogabe, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : Sorafenib as second-line treatment option after failure of lenvatinib in patients with unresectable hepatocellular carcinoma, JGH Open, Vol.4, No.6, 1135-1139, 2020.
(Summary)
Abstract Background and Aim Currently, there is no molecular-targeted agent that has demonstrated evidence of efficacy in patients with unresectable hepatocellular carcinoma (u-HCC) who have developed resistance to treatment with lenvatinib (LEN). In this real-world study, we aimed to investigate the therapeutic effect and safety of sorafenib (SOR) in patients with u-HCC after progression on treatment with LEN. Methods (Patients) and Results A total of 13 patients with u-HCC (12 males and 1 female), who were treated with SOR after progression on LEN, were enrolled in this retrospective study. Therapeutic efficacy was evaluated via contrast-enhanced computerized tomography at 8 weeks after the initiation of SOR therapy according to modified response evaluation criteria in solid tumors (mRECIST) and RECIST. According to mRECIST, the objective response rate (ORR) and disease control rate (DCR) were 15.3
Although pancreatic cancer often invades into peripancreatic adipose tissue, little is known about the cancer-adipocyte interaction. We first investigated the ability of adipocytes to de-differentiate to cancer-associated adipocytes (CAAs) by co-culturing with pancreatic cancer cells. We then examined the effects of CAA-conditioned media (CAA-CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3-L1 adipocytes were co-cultured with pancreatic cancer cells (PANC-1) using Transwell system, adipocytes lost their lipid droplets and morphologically changed to fibroblast-like cells (CAA). Adipocyte-specific marker mRNA levels significantly decreased but those of fibroblast-specific markers appeared, characteristic findings of CAA, as revealed by real-time PCR. When PANC-1 cells were cultured with CAA-CM, significantly higher migration/invasion capability, chemoresistance, and epithelial-mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC-1 cells cultured with CAA-CM, and found 78.5-fold higher expression of SAA1 compared with control cells. When SAA1 gene in PANC-1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1-positive group was significantly shorter than in the SAA1-negative group (p=0.013). In conclusion, we demonstrated that pancreatic cancer cells induced de-differentiation in adipocytes toward CAA, and CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer.
Hironori Tanaka, Koichi Okamoto, Yasushi Sato, Takahiro Tanaka, Tetsu Tomonari, Fumika Nakamura, Yasuteru Fujino, Yasuhiro Mitsui, Hiroshi Miyamoto, Naoki Muguruma, Akinori Morita, Hitoshi Ikushima and Tetsuji Takayama : Synergistic anti-tumor activity of miriplatin and radiation through PUMA-mediated apoptosis in hepatocellular carcinoma., Journal of Gastroenterology, Vol.55, No.11, 1072-1086, 2020.
(Summary)
The prognosis for patients with unresectable advanced hepatocellular carcinoma (HCC) is poor. Miriplatin is a hydrophobic platinum compound that has a long retention time in lesions after transarterial chemoembolization (TACE). We investigated anti-tumor activity of miriplatin combined with irradiation on HCC cells, and its underlying mechanism of apoptosis. We also analyzed the effectiveness of miriplatin-TACE and radiotherapy for locally advanced HCC. Human HCC cell lines HepG2 and HuH-7 were treated with DPC (active form of miriplatin) and radiation, and synergy was evaluated using a combination index (CI). Apoptosis-related proteins and cell cycles were analyzed by western blotting and flowcytometry. We retrospectively analyzed treatment outcomes in 10 unresectable HCC patients with vascular/bile duct invasion treated with miriplatin-TACE and radiotherapy. DPC or X-ray irradiation decreased cell viability dose-dependently. DPC plus irradiation decreased cell viability synergistically in both cell lines (CI < 1, respectively). Cleaved PARP expression was induced much more strongly by DPC plus irradiation than by each treatment alone. Expression of p53 up-regulated modulator of apoptosis (PUMA) was significantly induced by the combination, and knockdown of PUMA with siRNA significantly decreased apoptosis in both cell lines. DPC plus irradiation caused sub-G1, G2/M, and S phase cell arrest in those cells. The combination of miriplatin-TACE and radiotherapy showed a high response rate for patients with locally advanced HCC despite small number of patients. Miriplatin plus irradiation had synergistic anti-tumor activity on HCC cells through PUMA-mediated apoptosis and cell cycle arrest. This combination may possibly be effective in treating locally advanced HCC.
Tetsu Tomonari, Yasushi Sato, Hironori Tanaka, Takahiro Tanaka, Yasuteru Fujino, Yasuhiro Mitsui, Akihiro Hirao, Tatsuya Taniguchi, Koichi Okamoto, Masahiro Sogabe, Hiroshi Miyamoto, Naoki Muguruma, Harumi Kagiwada, Masashi Kitazawa, Kazuhiro Fukui, Ktsuhisa Horimoto and Tetsuji Takayama : Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma including after treatment with sorafenib: Real-world evidence and in vitro assessment via protein phosphorylation array., Oncotarget, Vol.11, No.26, 2531-2542, 2020.
(Summary)
The efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line LEN treatment, investigated the sensitivity of a SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and assessed their signal transduction pathways by protein array analysis. We retrospectively enrolled 57 patients with unresectable HCC. Fifty-three radiologically evaluated patients comprised 34 molecular-targeted agent (MTA)-naive (first-line), nine intolerant to SOR (second-line), and 10 resistant to regorafenib (third-line). The objective response rates (ORRs) were 61.8% in first-line, 33.3% in second-line, and 20.0% in third-line groups. The overall survival (OS) in the first-line was significantly longer than that in the third-line group ( < 0.05). Patients with better liver functional reserves (child score, ALBI grade) exhibited higher ORR and longer OS. The IC of LEN against PLC/PRF5-R2 was significantly higher than that against PLC/PRF5. LEN significantly inhibited more LEN-related signal transduction pathways in PLC/PRF5 than in PLC/PRF5-R2 cells. This suggests that LEN is active and safe as a second/third-line treatment for unresectable HCC. LEN seems more effective for patients with HCC with better hepatic reserve functions or before MTA-resistance is acquired because of the partial cross-resistance to SOR.
Toshiya Okahisa, Masahiro Sogabe, Tadahiko Nakagawa, Kumiko Tanaka, Tetsu Tomonari, Tatsuya Taniguchi, Akira Takahashi, Yohsuke Kinouchi, Junji Nishioka, Naoki Igata, Hiroaki Yanagawa, takatoshi Komatsu, Yoshiaki Ohnishi, Masashi Fukuhara, Masashi Ishikawa, Hiroshi Shibata, Hirohiko Shinomiya, Masahiko Nakasono, Fumiko Kishi, Keiko Komai, Yayoi Tatsuki, Toru Murashima, Yoshihiro Deguchi, Hiroshi Aramaki, Hideyuki Fukumitsu and Tetsuji Takayama : Development of a novel automatic ascites filtration and concentration equipment with multi-ring-type roller pump units for cell-free and concentrated ascites reinfusion therapy., Artificial Organs, Vol.44, No.8, 856-872, 2020.
(Summary)
Cell-free and concentrated ascites reinfusion therapy (CART) is an effective therapy for refractory ascites. However, CART is difficult to perform as ascites filtration and concentration is a complicated procedure. Moreover, the procedure requires the constant assistance of a clinical engineer or/and the use of an expensive equipment for the multi-purpose blood processing. Therefore, we developed a CART specialized equipment (mobility CART [M-CART]) that could be used safely with various safety measures and automatic functions such as automatic washing of clogged filtration filter and self-regulation of the concentration ratio. Downsizing, lightning of the weight, and automatic processing in M-CART required the use of newly developed multi-ring-type roller pump units. This equipment was approved under Japanese regulations in 2018. In performing 41 sessions of CART (for malignant ascites, 22 sessions; and hepatic ascites, 19 sessions) using this equipment in 17 patients, no serious adverse event occurred. An average of 4494 g of ascites was collected and the total amount of ascites was processed in all the sessions without any trouble. The mean weight of the processed ascites was 560 g and the mean concentration ratio was 8.0. The ascites were processed at a flow rate of 50 mL/min. The mean ascites processing time was 112.5 minutes and a 106.5-minutes (95.2%) ascites processing was performed automatically. The operator responded to alarms or support information 3.2 times on average (3.1 minutes, 2.1% of ascites processing time). Human errors related to ascites processing were detected by M-CART at 0.4 times per session on average and were appropriately addressed by the operator. The frequencies of automatic washing of clogged filtration filter and self-regulation of the concentration ratio were 31.7% and 53.7%, respectively. The mean recovery rates (recovery dose) of protein, albumin, and immunoglobulin G were 72.9%, 72.9%, and 71.2% (65.9 g, 34.9 g, and 13.2 g), respectively. Steroids were administered in 92.7% of the sessions to prevent fever and the mean increase in body temperature was 0.53°C. M-CART is a compact and lightweight automatic CART specialized equipment that can safely and easily process a large quantity of ascites without the constant assistance of an operator.
Tadahiko Nakagawa, Yasushi Sato, Toshihito Tanahashi, Yasuhiro Mitsui, Yoshifumi Kida, Yasuteru Fujino, Misato Hirata, Shinji Kitamura, Hiroshi Miyamoto, Koichi Okamoto, Naoki Muguruma, Yoshimi Bando and Tetsuji Takayama : JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8., Gastric Cancer, Vol.23, No.3, 426-436, 2020.
(Summary)
Jumonji domain-containing protein 2A (JMJD2A) of the JMJD2 family of histone lysine demethylases has been implicated in tumorigenesis. However, its expression and role in gastric cancer (GC) drug resistance remain unknown. Here, we investigated the role of JMJD2A in GC chemotherapeutic susceptibility and its clinical relevance in GC. We selected 12 relevant genes from previously identified gene signatures that can predict GC susceptibility to docetaxel, cisplatin, and S-1 (DCS) therapy. Each gene was knocked down using siRNA in GC cell lines, and cell viability assays were performed. JMJD2A expression in GC cell lines and tissues was assessed using qRT-PCR and immunohistochemistry, respectively. A JMJD2A downstream target related to drug susceptibility was examined using whole-gene expression array and immunoprecipitation. Among the 12 candidate genes, down-regulation of JMJD2A showed the maximum effect on GC susceptibility to anti-cancer drugs and increased the IC values for 5-FU, cisplatin, and docetaxel 15.3-, 2.7-, and 4.0-fold, respectively. JMJD2A was universally expressed in 12 GC cell lines, and its overexpression in GC tissue was positively correlated with tumor regression in 34 DCS-treated patients. A whole-gene expression array of JMJD2A-knockdown GC cells demonstrated a significant decrease in the expression of pro-apoptotic coiled-coil domain containing 8 (CCDC8), a downstream target of JMJD2A. Direct interaction between CCDC8 and JMJD2A was verified using immunoprecipitation. CCDC8 inhibition restored drug resistance to docetaxel, cisplatin, and S-1. Our results indicate that JMJD2A is a novel epigenetic factor affecting GC chemotherapeutic susceptibility, and JMJD2A/CCDC8 is a potential GC therapeutic target.
Masahiro Sogabe, Toshiya Okahisa, Akira Fukuya, Kaizoh Kagemoto, Yasuyuki Okada, Yuka Adachi, Takeshi Kurihara, Toru Nii, Satoshi Teramae, Hironori Tanaka, Tetsu Tomonari, Koichi Okamoto, Hiroshi Miyamoto, Masahiko Nakasono and Tetsuji Takayama : Effects of audio and visual distraction on patients' vital signs and tolerance during esophagogastroduodenoscopy: a randomized controlled trial., BMC Gastroenterology, Vol.20, No.1, 122, 2020.
(Summary)
Esophagogastroduodenoscopy (EGD) provides an indispensable and unambiguous inspection allowing the discovery upper gastrointestinal lesions. However, many patients are anxious about undergoing EGD. Few studies have investigated the influence on patients' vital signs and tolerance during EGD using subjective and objective assessments. This study was a prospective randomized controlled study that investigated the influence of audio and visual distraction on EGD. We randomly divided 289 subjects who underwent EGD into 4 groups (control group, audio group, visual group, combination group) and examined their vital signs, heart rate variability (HRV), psychological items, and acceptance of distraction. Pulse rate (PR) at post-distraction and post-EGD in the 3 distraction groups were significantly lower than those of control group (p < 0.001 and p < 0.01, respectively). Blood pressure (BP) during and post-EGD was significantly higher than that at pre-EGD in control group (p < 0.05), but no significant elevation of BP was observed during the latter half of EGD and post-EGD in the 3 distraction groups. BP at post-distraction improved significantly compared to pre-distraction in the 3 distraction groups (p < 0.05). There was a significant difference in the low-frequency (LF) power/ high-frequency (HF) power at post-distraction and post-EGD among the 4 groups (p < 0.001 and p < 0.001, respectively). The LF power/HF power at post-distraction and post-EGD in the 3 distraction groups was significantly lower than that in control group (p < 0.05). Several items of profile of mood states (POMS) and the impression of EGD at post-distraction improved significantly compared to those at pre-distraction among the 3 distraction groups (p < 0.05). Visual analog scale (VAS) of willingness for the next use of distraction in the 3 distraction groups was excellent because VAS was more than 70. Distractions effectively improved psychological factors, vital signs and some of HRV at pre and post-EGD. Distractions may suppress BP elevation during the latter half of EGD and lead to stability of HRV on EGD. This prospective trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029637. Registered on 20 October 2017.
Seiko Aadachi, Takahiro Hamoya, Gen Fujii, Takumi Narita, Masami Komiya, Shingo Miyamoto, Yurie Kurokawa, Maiko Takahashi, Tetsuji Takayama, Hideki ishikawa, Kosuke Tashiro and Michihiro Mutoh : Theracurmin inhibits intestinal polyp development in Apc-mutant mice by inhibiting inflammation-related factors., Cancer Science, Vol.111, No.4, 1367-1374, 2020.
(Summary)
Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Therefore, it is important to establish useful methods for preventing CRC. One prevention strategy involves the use of cancer chemopreventive agents, including functional foods. We focused on the well-known cancer chemopreventive agent curcumin, which is derived from turmeric. However, curcumin has the disadvantage of being poorly soluble in water due to its high hydrophobicity. To overcome this problem, the formation of submicron particles with surface controlled technology has been applied to curcumin to give it remarkably improved water solubility, and this derived compound is named Theracurmin. To date, the preventive effects of Theracurmin on hereditary intestinal carcinogenesis have not been elucidated. Thus, we used Apc-mutant mice, a model of familial adenomatous polyposis, to evaluate the effects of Theracurmin. First, we showed that treatment with 10-20 µM Theracurmin for 24 hours reduced nuclear factor-κB (NF-κB) transcriptional activity in human colon cancer DLD-1 and HCT116 cells. However, treatment with curcumin mixed in water did not change the NF-κB promoter transcriptional activity. As NF-κB is a regulator of inflammation-related factors, we next investigated the downstream targets of NF-κB: monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-6. We found that treatment with 500 ppm Theracurmin for 8 weeks inhibited intestinal polyp development and suppressed MCP-1 and IL-6 mRNA expression levels in the parts of the intestine with polyps. This report provides a proof of concept for the ongoing Theracurmin human trial (J-CAP-C study).
Kaizoh Kagemoto, Yutaka Saito, Yasuhiko Mizuguchi, Taku Sakamoto, Hirokazu Taniguchi, Shigeki Sekine and Tetsuji Takayama : Optical biopsy in real time by endocytoscopy: a case of juvenile polyp., Endoscopy, Vol.52, No.4, E142-E143, 2019.
Yoshihiko Miyamoto, Naoki Muguruma, Shota Fujimoto, Yasuyuki Okada, Yoshifumi Kida, Fumika Nakamura, Kumiko Tanaka, Tadahiko Nakagawa, Shinji Kitamura, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato and Tetsuji Takayama : Epidermal growth factor receptortargeted molecular imaging of colorectal tumors: Detection and treatment evaluation of tumors in animal models., Cancer Science, Vol.110, No.6, 1921-1930, 2019.
(Summary)
To overcome the problem of overlooking colorectal tumors, a new and highly sensitive modality of colonoscopy is needed. Moreover, it is also important to establish a new modality to evaluate viable tumor volume in primary lesions of colorectal cancer (CRC) during chemotherapy. Therefore, we carried out molecular imaging of colorectal tumors targeting epidermal growth factor receptor (EGFR), which is highly expressed on tumor cells, for evaluating chemotherapeutic efficacy and for endoscopic detection of colorectal adenomas. We first attempted to image five CRC cell lines with various levels of EGFR expression using an Alexa Fluor-labeled anti-EGFR monoclonal antibody (AF-EGFR-Ab). A strong fluorescence signal was observed in the cells depending on the level of EGFR expression. When nude mice xenografted with LIM1215 CRC cells, which highly express EGFR, were i.v. injected with AF-EGFR-Ab, a strong fluorescence signal appeared in the tumor with a high signal to noise ratio, peaking at 48 hours after injection and then gradually decreasing, as shown using an IVIS Spectrum system. When the xenografted mice were treated with 5-fluorouracil, fluorescence intensity in the tumor decreased in proportion to the viable tumor cell volume. Moreover, when the colorectum of azoxymethane-treated rats was observed using a thin fluorescent endoscope with AF-EGFR-Ab, all 10 small colorectal adenomas (3 mm) were detected with a clear fluorescence signal. These preliminary results of animal experiments suggest that EGFR-targeted fluorescent molecular imaging may be useful for quantitatively evaluating cell viability in CRC during chemotherapy, and also for detecting small adenomas using a fluorescent endoscope.
Chisato Tonoiso, Hitoshi Ikushima, Akiko Kubo, Takashi Kawanaka, Shunsuke Furutani, Takaharu Kudoh, Takahiro Yoshida, Hiroshi Miyamoto, Masafumi Harada, Tetsuji Takayama and Akira Tangoku : Clinical outcomes and prognostic factors of definitive radiotherapy for esophageal cancer, The Journal of Medical Investigation : JMI, Vol.66, No.1, 2, 99-105, 2019.
(Summary)
Purpose To assess the treatment results of definitive radiotherapy for esophageal cancer at Tokushima University Hospital and clarify the prognostic factors. Methods Seventy consecutive patients with esophageal cancer who underwent definitive radiotherapy between May 2004 and March 2012 were included in the present study. Local control rate, overall survival rate, and radiation morbidity were examined and univariate and multivariate analyses were performed to investigate prognostic factors. Results The 5-yearoverall survival rates of stages I, II, III, and IVA were 81%, 71%, 0%, and 9%, respectively. Performance status, clinical stage, and neoadjuvant chemotherapy were significant prognostic factors. A past history of interstitial pneumonia was associated with severe radiation-induced lung injury. Conclusions Patients who underwent definitive chemoradiotherapy for esophageal cancer in stage I/II showed good prognosis. However, treatment results of the patients in stage III/IV were not satisfactory, and those who could not undergo surgery after neoadjuvant chemotherapy had the worst prognosis.J.Med.Invest.66:99-105, February, 2019.
(Keyword)
esophageal cancer / radiotherapy / chemoradiotherapy
Hiroshi Miyamoto, Kumiko Tanaka, Fumika Nakamura, Takahiro Ikeda, Shinji Kitamura, Tetsuo Kimura, Koichi Okamoto, Masahiro Sogabe, Naoki Muguruma, Yoshimi Bando and Tetsuji Takayama : Massive hemobilia following plastic stent removal in common bile duct cancer associated with primary sclerosing cholangitis (with video)., Clinical Journal of Gastroenterology, Vol.12, No.1, 2019.
(Summary)
Hemobilia is defined as bleeding into the biliary tract. Herein, we report a very rare case of massive hemobilia following plastic stent (PS) removal in common bile duct (CBD) cancer. A 72-year-old man with primary sclerosing cholangitis had undergone repeated insertion of a PS into the CBD. Biliary tract biopsy was performed based on suspicion of combined CBD cancer. Biopsy revealed poorly differentiated adenocarcinoma of the CBD. One month after the biliary tract biopsy, he was admitted for acute cholangitis, and endoscopic retrograde cholangiography was performed for the exchange of the PS. When one of the two biliary PSs was removed, spurting bleeding from the major papilla began abruptly. The massive bleeding caused the patient to be in a pre-shock state. A retrieval balloon catheter was compressed against the papilla for hemostasis. Although he was treated conservatively, the patient developed a bloody discharge. Upper gastrointestinal endoscopy revealed that the pulsatile bleeding beside the PSs started immediately after the removal of the coagula. Emergent contrast-enhanced computed tomography showed right hepatic artery aneurysm across the CBD. Therefore, transarterial embolization was performed. The patient's post-therapeutic course was uneventful. He received chemotherapy, but died about a half year after hemobilia occurred.
Yasushi Sato, Tamotsu Sagawa, Hiroyuki Ohnuma, Masahiro Hiarakawa, Yasuo Takahashi, Kyoko Hamaguchi, Koshi Fujikawa, Takayuki Nobuoka, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma, Ichiro Takemasa and Tetsuji Takayama : A dose-escalation study of docetaxel, oxaliplatin, and S-1 (DOS) as a first-line therapy for patients with unresectable metastatic gastric cancer., Cancer Chemotherapy and Pharmacology, Vol.83, No.1, 161-167, 2019.
(Summary)
The aim of this study was to determine the recommended dose (RD) for a docetaxel/oxaliplatin/S-1 (DOS) regimen in patients with unresectable gastric cancer and to preliminarily evaluate its efficacy. Previously untreated patients with histologically proven unresectable metastatic gastric cancer were enrolled (n = 16). Docetaxel and oxaliplatin were administered intravenously on day 8 and S-1 was administered orally twice a day on days 1-14. Each cycle was repeated every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle. Three dose escalations of DOS were employed in this study: level 1 (50/100/80 mg/m), level 2 (50/130/80 mg/m), and level 3 (60/130/80 mg/m). According to the 3 + 3 dose-escalating schedule, we determined that the RD and maximum tolerated dose for this regimen were level 1 and level 2, respectively. The DLTs were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) for patients with measurable lesions and consisted of two complete responses and five partial responses. Five patients underwent conversion surgery. The median follow-up time was 19 months with median survival time and progression-free survival being 19.6 months and 7.6 months, respectively. The results from this study demonstrated the safety and tolerability of DOS in unresectable metastatic gastric cancer patients and revealed promising preliminary efficacy with a high conversion rate. A phase II trial of DOS regimen using the identified RD is ongoing.
Masahiro Sogabe, Toshiya Okahisa, Yumi Adachi, Masanori Takehara, Shinichi Hamada, Jun Okazaki, Yasuteru Fujino, akira fukuya, Akihiro Hirao, Kaizoh Kagemoto, Akihiro Hirao, Koichi Okamoto, Masahiko Nakasono and Tetsuji Takayama : The influence of various distractions prior to upper gastrointestinal endoscopy: a prospective randomized controlled study., BMC Gastroenterology, Vol.18, No.1, 132, 2018.
(Summary)
Although many patients still have anxiety about upper gastrointestinal (GI) endoscopy, there have been few reports on the influence of distractions for a person who is going to undergo upper GI endoscopy soon. This study was a prospective randomized controlled study investigating the influence of distractions, such as auditive and visual distractions using subjective and objective assessments including autonomic nervous function prior to upper GI endoscopy. 206 subjects who underwent upper GI endoscopy as regular health check-ups were divided randomly into 4 groups prior to upper GI endoscopy; group 1 (control group), group 2 (auditive group), group 3 (visual group), and group 4 (combination group). We measured vital signs, autonomic nervous function, profile of mood state (POMS), and the impression for upper GI endoscopy pre- and post-distraction in the 4 groups. There was no significant difference in vital signs between 5 and 15 min after sitting in group 1, however, several vital signs in all distraction groups improved significantly after distraction (Pulse rate (P): p < 0.001 in group 4; blood pressure: p < 0.05 in group 2, 3, 4) and the rate of decrease in P and diastolic blood pressure was highest in group 4 (p < 0.001). Several scores of POMS and the impression for upper GI endoscopy post-distraction improved significantly compared to pre-distraction between distraction groups and the satisfaction for distraction was highest in group 4 (p < 0.01). Regarding autonomic nerve function, the low- frequency power/ high- frequency power ratio post-distraction was significantly lower than that pre-distraction in all distraction groups (p < 0.001). Although auditive distraction alone and visual distraction alone were effective, a combination distraction was more effective than any other distraction by subjective and objective assessments. These distractions, which were simple and safe, may play an assistive role in the stability of physical and psychological conditions prior to upper GI endoscopy. This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000022801 . Registered on 10 July 2016.
Kaizo Kagemoto, Koichi Okamoto, Tohshi Takaoka, Yasushi Sato, Shinji Kitamura, Tetsuo Kimura, Masahiro Sogabe, Hiroshi Miyamoto, Naoki Muguruma, Koichi Tsuneyama and Tetsuji Takayama : Detection of aberrant crypt foci with image-enhanced endoscopy., Endoscopy International Open, Vol.6, No.8, E924-E933, 2018.
(Summary)
Conventional detection of aberrant crypt foci (ACF) with dye-spraying and magnifying observation is labor- and skill-intensive. We performed a prospective non-inferiority study to investigate the utility of image-enhanced endoscopy (IEE) for detection of ACF. Patients with a history of colorectal neoplasm were eligible. The number of ACF in the lower rectum was counted first using IEE magnification with narrow-band imaging (NBI) or blue-laser imaging (BLI), and subsequently using the methylene blue method. The primary endpoint was the ACF detection rate with IEE, i. e., the number of ACF detected with IEE relative to the number of ACF detected with methylene blue. The secondary endpoints were bowel preparation time, ACF detection time, and the detection rate with NBI or BLI. A total of 40 patients were enrolled (NBI 20 and BLI 20). The overall detection rate for ACF with IEE was 81.7 % (503/616; 95 %CI 78.8 - 84.6 %), meeting the primary endpoint. The detection rate for ACF with BLI (84.9 %, 258/304) was significantly higher than with NBI (78.5 %, 245/312; < 0.05). Both bowel preparation time and ACF detection time were significantly shorter with IEE versus the methylene blue method ( < 0.01, respectively). The detection rates for dysplastic and non-dysplastic ACF with IEE were 84.4 % (27/32) and 80.3 % (469/584), respectively. IEE is able to detect ACF during colonoscopy with sensitivity non-inferior to that of the conventional methylene blue method. IEE is simpler than the methylene blue method and is therefore a potentially useful new tool for ACF detection.
Yasuhiro Mitsui, Reiko Yokoyama, Shota Fujimoto, Kaizoh Kagemoto, Shinji Kitamura, Koichi Okamoto, Naoki Muguruma, Yoshimi Bando, Hidetaka Eguchi, Yasushi Okazaki, Hideyuki Ishida and Tetsuji Takayama : First report of an Asian family with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) revealed with the germline mutation of the APC exon 1B promoter region., Gastric Cancer, Vol.21, No.6, 1058-1063, 2018.
(Summary)
A 48-year-old Japanese female with left hypochondralgia presented at our hospital. Esophagogastroduodenoscopy (EGD) revealed gastric cancers and carpeting fundic gland polyposis (FGPs) without Helicobacter pylori infection. Computed tomography showed multiple liver metastases. Total colonoscopy revealed a colonic tubular adenoma but not polyposis. She was diagnosed as having advanced gastric cancer with liver metastasis and received chemotherapy. Her mother had died from gastric cancer, and her elderly brother and niece had FGPs as revealed by EGD. Thus, the pedigree was diagnosed as gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Germline mutation analysis exhibited a point mutation in exon1B of the APC gene (c.-191T > C). Adenocarcinoma showed a gastric mucinous phenotype and was positive for a somatic mutation of p53, suggesting that p53 mutation may play a role in FGPs carcinogenesis. This is the first family with GAPPS in Asia in whom germline mutation of APC exon 1B has been detected.
Shota Fujimoto, Naoki Muguruma, Koichi Okamoto, Takeshi Kurihara, Yasushi Sato, Yoshihiko Miyamoto, Shinji Kitamura, Hiroshi Miyamoto, Takahiro Taguchi, Koichi Tsuneyama and Tetsuji Takayama : A Novel Theranostic Combination of Near-infrared Fluorescence Imaging and Laser Irradiation Targeting c-KIT for Gastrointestinal Stromal Tumors., Theranostics, Vol.8, No.9, 2313-2328, 2018.
(Summary)
It is difficult to distinguish gastrointestinal stromal tumors (GISTs) from other types of submucosal tumors under conventional gastrointestinal endoscopy. We aimed to detect GISTs by molecular fluorescence imaging using a near-infrared (NIR) photosensitizer (IR700)-conjugated anti-c-KIT antibody and to treat GISTs by photoimmunotherapy with NIR irradiation as a non-invasive theranostic procedure. We also investigated the therapeutic mechanisms. Human GIST cell lines GIST-T1 and GIST-882M were incubated with IR700-conjugated anti-c-KIT antibody, IR700-12A8, and observed by confocal laser microscopy. Mice with GIST-T1 xenografts or rats with orthotopic xenografts were injected with IR700-12A8 or AF488-conjugated antibody, and observed under IVIS or autofluorescence imaging (AFI) endoscopy. GIST cells were treated with IR700-12A8 and NIR light and vivo, and cell viability, histology and apoptosis were evaluated. Strong red fluorescence of IR700-12A8 was observed on the cell membrane of GIST cells and was gradually internalized into the cytoplasm. Tumor-specific accumulation of IR700-12A8 was observed in GIST-T1 xenografts in mice. Under AFI endoscopy, a strong fluorescence signal was observed in orthotopic GIST xenografts in rats through the normal mucosa covering the tumor. The percentage of dead cells significantly increased in a light-dose-dependent manner and both acute necrotic and late apoptotic cell death was observed with annexin/PI staining. Cleaved PARP expression was significantly increased after IR700-12A8-mediated NIR irradiation, which was almost completely reversed by NaN. All xenograft tumors (7/7) immediately regressed and 4/7 tumors completely disappeared after IR700-12A8-mediated NIR irradiation. Histologic assessment and TUNEL staining revealed apoptosis in the tumors. NIR fluorescence imaging using IR700-12A8 and subsequent NIR irradiation could be a very effective theranostic technology for GIST, the underlying mechanism of which appears to involve acute necrosis and supposedly late apoptosis induced by singlet oxygen.
It has been reported that some single-nucleotide polymorphisms (SNPs) in lipid regulators such as apolipoproteins and cell surface molecules for hepatitis C virus (HCV) entry into hepatocytes are associated with HCV infection. However, it is unknown how HCV infection is affected by altered lipid metabolism resulting from the SNPs. We investigated the relationship between these SNPs and HCV infection status, and also analyzed the mechanism by which these SNPs mediate HCV infection via lipid metabolism alterations. Serum lipid and apolipoprotein profiles were tested in 158 HCV-positive and 220 HCV-negative subjects. We selected 22 SNPs in five lipid regulator genes which were related to HCV entry into hepatocytes and to lipid metabolism (APOA1, APOB, SR-B1, LDLR, and APOE), and their polymorphisms were analyzed using the PCR-sequence-specific oligonucleotide probe-Luminex method. An APOB N4311S (g.41553a > g) SNP, rs1042034, was significantly associated with HCV positivity; the HCV positivity rate for the minor allele AA genotype was significantly higher than for genotype AG + GG (P = 0.016). Other SNPs except for APOB P2712L SNP rs676210, which is in linkage disequilibrium with rs1042034, showed no significant difference in genotype distribution. The serum level of low density lipoprotein-cholesterol (LDL-C) in the genotype AA group was significantly lower than in the genotype non-AA group (P = 0.032), whereas the triglyceride (TG) level was significantly higher (P = 0.007). An APOB SNP, rs1042034, is closely associated with HCV infection through lipid metabolism alteration. The minor allele AA genotype might contribute to facilitating serum LDL uptake into hepatocytes via LDLR by modifying their affinity and interaction and may have an influence on HCV infection by their entry to the liver through the LDLR.
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). 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. 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 %, < 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 %, < 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); < 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; = 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. 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.
Yasushi Sato, Masahiro Hirakawa, Hiroyuki Ohnuma, Minoru Takahashi, Tetsuro Okamoto, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma, Tomohisa Furuhata, Ichiro Takemasa, Junji Kato and Tetsuji Takayama : A triplet combination with capecitabine/oxaliplatin/irinotecan (XELOXIRI) plus cetuximab as first-line therapy for patients with metastatic colorectal cancer: a dose escalation study., Cancer Chemotherapy and Pharmacology, Vol.80, No.6, 1133-1139, 2017.
(Summary)
The addition of cetuximab to triplet chemotherapy can increase treatment efficacy for patients with metastatic colorectal cancer (mCRC). We explored the dose-limiting toxicity and feasibility of a triweekly capecitabine, oxaliplatin, irinotecan, plus cetuximab (XELOXIRI plus cetuximab) regimen in patients with wild-type KRAS mCRC. Patients received oxaliplatin (100 mg/m, day 1), capecitabine (1700 mg/m per day from day 2 to 15), irinotecan (100, 120, and 150 mg/m for dose levels 1, 2, 3, respectively, on day 1), and cetuximab (400 mg/m, day 1 and, thereafter, 250 mg/m every week), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first 2 treatment cycles to determine the maximum tolerated dose (MTD) and the recommended dose (RD). Twelve patients received a median of 7 cycles of therapy (range 2-10). The DLT was grade 4 neutropenia, observed in 1 of 6 patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m. Most common grade ≥ 3 toxicities were neutropenia (50%), diarrhea (17%), and febrile neutropenia (8%). The response rate was 83% (complete and partial response: 1 and 9 patient(s), respectively), including 4 conversion cases. The combination of XELOXIRI and cetuximab is feasible and has an acceptable toxicity profile; neutropenia was the DLT. The RD of irinotecan is 150 mg/m. The observed response rate was promising and warrants further investigation.
Yasuyuki Okada, Tetsuo Kimura, Tadahiko Nakagawa, Koichi Okamoto, Akira Fukuya, Takahiro Goji, Shota Fujimoto, Masahiro Sogabe, Hiroshi Miyamoto, Naoki Muguruma, Yasushi Tsuji, Toshiya Okahisa and Tetsuji Takayama : EGFR Down-regulation After anti-EGFR Therapy Predicts the Anti-tumor Effect in Colorectal Cancer., Molecular Cancer Research : MCR, Vol.15, No.10, 1445-1454, 2017.
(Summary)
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 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. 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. .
Gastric xanthomas are frequently observed in the stomach as small yellowish plaques or nodules. A close relationship among Helicobacter pylori infection, atrophic gastritis, and xanthomas has been reported. We assessed the clinicopathological features of gastric cancer with or without xanthomas. A total of 91 patients who were diagnosed as having early gastric cancer were enrolled. We evaluated the gastritis status using scores for gastritis and atrophy, positivity of H. pylori infection, the prevalence rate of xanthomas, and the clinicopathological features of gastric cancer. Gastric xanthomas were observed in 72.5% of early gastric cancer cases. Scores for gastritis and atrophy were significantly higher in the xanthoma-positive group than those in the xanthoma-negative group. A higher prevalence of differentiated-type adenocarcinoma was found in the xanthoma-positive group. Among the cases with multiple gastric xanthomas, the prevalence of males was significantly higher than that of females. A high prevalence rate of gastric xanthomas in gastric cancer cases was shown. Xanthomas were highly associated with age, the severities of gastritis and atrophy, and differentiated-type adenocarcinoma. Regardless of the eradication of H. pylori, xanthomas may be useful predictive markers for the development of differentiated-type adenocarcinoma.
The rectal tonsil is a rare polypoid lesion exclusively found in the rectum and is considered a reactive proliferation of the lymphoid tissue. Although this lesion is benign, we recommend that it should be differentiated from carcinoid or polypoid type of mucosaassociated lymphoid tissue (MALT) lymphomas, based on gross findings. In this case report, we describe a case of rectal lesions with a unique appearance in a 41-year-old man. Colonoscopy revealed two 5-mm-sized nodules located opposite from each other on the left and right sides of the lower rectum. Endoscopic mucosal resection was conducted. Histopathologically, both lesions were mainly located in the submucosa and consisted of prominent lymphoid follicles with germinal centers of various sizes. No immunoreactivity of Bcl-2 was seen in the germinal centers. Immunohistochemical staining for kappa and lambda light chains revealed a polyclonal pattern. Therefore, these lesions were diagnosed as rectal tonsils.
Naoki Uemura, Shohei Kikuchi, Yasushi Sato, Hiroyuki Ohnuma, Koichi Okamoto, Hiroshi Miyamoto, Masahiro Hirakawa, Tamotsu Sagawa, Koshi Fujikawa, Yasuo Takahashi, Toshinori Okuda, Shinya Minami, Minoru Takahashi, Tetsuro Okamoto, Kohichi Takada, Koji Miyanisi, Tetsuji Takayama and Junji Kato : A phase II study of modified docetaxel, cisplatin, and S-1 (mDCS) chemotherapy for unresectable advanced gastric cancer., Cancer Chemotherapy and Pharmacology, Vol.80, No.4, 707-713, 2017.
(Summary)
Modified DCS therapy showed high clinical efficacy sufficient enough to attempt conversion therapy against unresectable gastric cancer. Modified DCS showed fewer toxicities, but careful management of these is still essential.
Naoki Muguruma, Koichi Okamoto, Tadahiko Nakagawa, Katsutaka Sannomiya, Shota Fujimoto, Yasuhiro Mitsui, Tetsuo Kimura, Hiroshi Miyamoto, Jun Higashijima, Mitsuo Shimada, Yoko Horino, Shinya Matsumoto, Kenjiro Hanaoka, Tetsuo Nagano, Makoto Shibutani and Tetsuji Takayama : Molecular imaging of aberrant crypt foci in the human colon targeting glutathione S-transferase P1-1., Scientific Reports, Vol.7, No.1, 6536, 2017.
(Summary)
Aberrant crypt foci (ACF), the earliest precursor lesion of colorectal cancers (CRCs), are a good surrogate marker for CRC risk stratification and chemoprevention. However, the conventional ACF detection method with dye-spraying by magnifying colonoscopy is labor- and skill-intensive. We sought to identify rat and human ACF using a fluorescent imaging technique that targets a molecule specific for ACF. We found that glutathione S-transferase (GST) P1-1 was overexpressed in ACF tissues in a screening experiment. We then synthesized the fluorogenic probe, DNAT-Me, which is fluorescently quenched but is activated by GSTP1-1. A CRC cell line incubated with DNAT-Me showed strong fluorescence in the cytosol. Fluorescence intensities correlated significantly with GST activities in cancer cell lines. When we sprayed DNAT-Me onto colorectal mucosa excised from azoxymethane-treated rats and surgically resected from CRC patients, ACF with strong fluorescent signals were clearly observed. The ACF number determined by postoperative DNAT-Me imaging was almost identical to that determined by preoperative methylene blue staining. The signal-to-noise ratio for ACF in DNAT-Me images was significantly higher than that in methylene blue staining. Thus, we sensitively visualized ACF on rat and human colorectal mucosa by using a GST-activated fluorogenic probe without dye-spraying and magnifying colonoscopy.
Masahiro Sogabe, Toshiya Okahisa, Masahiko Nakasono, Hiroshi Fukuno, Yoshihiko Miyamoto, Yasuyuki Okada, Jun Okazaki, Jinsei Miyoshi, Tetsu Tomonari, Tatsuya Taniguchi, Takahiro Goji, Shinji Kitamura, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : 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., PLoS ONE, Vol.12, No.6, e0177925, 2017.
(Summary)
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. 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. 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). 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). 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.
S Bando, Takeshi Soeki, Tomomi Matsuura, Takeshi Tobiume, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Takashi Iwase, Hirotsugu Yamada, Tetsuzo Wakatsuki, Michio Shimabukuro, Naoki Muguruma, Tetsuji Takayama, I Kishimoto, Kenji Kangawa and Masataka Sata : Plasma brain natriuretic peptide levels are elevated in patients with cancer, PLoS ONE, Vol.12, No.6, e0178607, 2017.
(Summary)
Natriuretic peptides have been proposed as biomarkers of cardiovascular disease, especially heart failure. Brain natriuretic peptide (BNP) has also been shown to be upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in cardiac myocytes. Although we often measure plasma BNP levels in cancer patients, it remains unknown whether cancer-related inflammation affects the plasma BNP levels. We investigated the relationship between the BNP and human cancers. We retrospectively studied 2,923 patients in whom the plasma BNP levels and serum C-reactive protein (CRP) were measured and echocardiography was performed. Patients with clinically evident heart failure (NYHA II or higher), heart disease requiring medical treatment or surgery, renal dysfunction, and inflammatory disease were excluded. There were 234 patients in the final analysis. Blood sampling was performed before surgery and chemotherapy. In addition, we evaluated the relationship between the inflammation and plasma BNP levels in mouse models of colon cancer. Of the 234 patients, 80 were diagnosed with cancer. Both the plasma BNP and serum CRP levels were significantly higher in cancer patients than those without. There were no significant differences in the echocardiographic parameters. There was a significant positive correlation between the plasma BNP and serum CRP levels in cancer patients (r = 0.360, P<0.01) but not in those without. In cancer patients, only the CRP correlated with the BNP independent of the age, creatinine level, hypertension, and body mass index. In addition, in nude mice with subcutaneous colon cancer, the plasma BNP level was elevated compared with that in non-cancer mice, and there was a significant relationship between the plasma BNP and serum levels of the inflammatory markers. In cancer patients, as well as colon cancer model mice, the plasma BNP levels were elevated, possibly due to cancer-related inflammation. The effect of cancer on the BNP levels should be considered when using BNP as an indicator of heart failure in cancer patients.
Jun Okazaki, Naoki Muguruma, Shinji Kitamura, Tetsuo Kimura, Koichi Okamoto, Hiroshi Miyamoto, Kazuhiro Kishi, Yoshimi Bando, Takeshi Kondo, Itsuro Endo, Masahiro Abe and Tetsuji Takayama : Paraneoplastic hypocalcemia developed in gastric cancer accompanied by osteoblastic metastasis, Internal Medicine, Vol.56, No.11, 1345-1349, 2017.
(Summary)
Paraneoplastic syndromes are generally defined as clinical disorders associated with malignant diseases, and hypocalcemia associated with cancer is a rare condition. A woman in her 60s was referred to our hospital for the further examination of massive ascites due to carcinoma of unknown primary origin. She complained of numbness around her lips, and marked hypocalcemia of 5.0 mg/dL was noted. After two courses of chemotherapy, computed tomography showed a decrease in the ascites, and her serum calcium level increased. Although hypocalcemia is a very rare condition in patients with gastric cancer, serum calcium values should be evaluated when neurological symptoms are observed.
Shinji Kitamura, Toshihito Tanahashi, Eriko Aoyagi, Tadahiko Nakagawa, Koichi Okamoto, Tetsuo Kimura, Hiroshi Miyamoto, Yasuhiro Mitsui, Kazuhito Rokutan, Naoki Muguruma and Tetsuji Takayama : Response Predictors of S-1, Cisplatin, and Docetaxel Combination Chemotherapy for Metastatic Gastric Cancer: Microarray Analysis of Whole Human Genes., Oncology, Vol.93, No.2, 127-135, 2017.
(Summary)
The aim of this study was to identify biomarkers for predicting the efficacy of docetaxel, cisplatin, and S-1 (DCS) therapy for advanced gastric cancer using microarrays of biopsy specimens before chemotherapy. Nineteen samples were taken from 19 patients with unresectable metastatic gastric cancer who received DCS as a first-line therapy. Laser capture microdissection was performed, and total cellular RNA was extracted from each microdissected sample. Whole-gene expression was analyzed by microarray, and the difference in mRNA expression observed with the microarrays was confirmed by quantitative real-time PCR. Immunohistochemical staining was performed using clinical tissue sections obtained by endoscopic biopsy. Eleven patients were identified as early responders and 8 patients as nonresponders to DCS therapy. Twenty-nine genes showed significant differences in relative expression ratios between tumor and normal tissues. A classifier set of 29 genes had high accuracy (94.7%) for distinguishing gene expression between 11 early responders and 8 nonresponders. Decreasing the size of the classifier set to 4 genes (PDGFB, PCGF3, CISH, and ANXA5) increased the accuracy to 100%. Expression levels by real-time PCR for validation were well correlated with those 4 genes in microarrays. The genes identified may serve as efficient biomarkers for personalized cancer-targeted therapy.
Conversion therapy is an option for unresectable metastatic gastric cancer when distant metastases are controlled by chemotherapy; however, the feasibility and efficacy remain unclear. This study aimed to assess the feasibility and efficacy of conversion therapy in patients with initially unresectable gastric cancer treated with docetaxel, cisplatin, and S-1 (DCS) chemotherapy by evaluating clinical outcomes. One hundred unresectable metastatic gastric cancer patients, enrolled in three DCS chemotherapy clinical trials, were retrospectively evaluated. The patients received oral S-1 (40 mg/m2 b.i.d.) on days 1-14 and intravenous cisplatin (60 mg/m2) and docetaxel (50-60 mg/m2) on day 8 every 3 weeks. Conversion therapy was defined when the patients could undergo R0 resection post-DCS chemotherapy and were able to tolerate curative surgery. Conversion therapy was achieved in 33/100 patients, with no perioperative mortality. Twenty-eight of the 33 patients (84.8 %) achieved R0 resection, and 78.8 % were defined as histological chemotherapeutic responders. The median overall survival (OS) of patients who underwent conversion therapy was 47.8 months (95 % CI 28.0-88.5 months). Patients who underwent R0 resection had significantly longer OS than those who underwent R1 and R2 resections (P = 0.0002). Of the patients with primarily unresectable metastases, 10 % lived >5 years. Among patients who underwent conversion therapy, multivariate analysis showed that the pathological response was a significant independent predictor for OS. DCS safely induced a high conversion rate, with very high R0 and pathological response rates, and was associated with a good prognosis; these findings warrant further prospective investigations.
Koichi Okamoto, Naoki Muguruma, Kaizo Kagemoto, Yasuhiro Mitsui, Daisaku Fujimoto, Shinji Kitamura, Tetsuo Kimura, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Efficacy of hybrid endoscopic submucosal dissection (ESD) as a rescue treatment in difficult colorectal ESD cases., Digestive Endoscopy, Vol.29, No.suppl.2, 45-52, 2017.
(Summary)
Endoscopic submucosal dissection (ESD), which provides a higher en bloc resection rate than conventional endoscopic mucosal resection (EMR), is considered to be a useful treatment option for large colorectal tumors. However, colorectal ESD is not widely used because of its technical difficulty, risk of complications and time required. To overcome these drawbacks, a simpler modified technique, ESD with snaring (hybrid ESD), has been developed. The aim of the present study was to retrospectively compare the safety and efficacy of hybrid ESD and conventional ESD for colorectal tumors. Between September 2008 and June 2016, ESD was carried out on 137 lesions and hybrid ESD on 27 lesions. All hybrid ESD cases were carried out as a rescue treatment in difficult ESD cases. We retrospectively investigated procedure time, and the rates of en bloc resection, perforation, bleeding, and local recurrence. In the hybrid ESD group, procedure time was shorter compared with the ESD group (108 ± 59.5 min vs 122 ± 72.2 min), but the en bloc resection rate was lower (66.7% vs 94.2%). However, there were no significant differences in procedure time, or in rates of en bloc resection, perforation and bleeding between the two groups. Local recurrence did not develop in any of our cases. Hybrid ESD as a rescue treatment in difficult ESD cases may be less effective for en bloc resection of large colorectal tumors. Indication for hybrid ESD may be limited to scheduled treatment from the outset and emergency cases with patients who present unstable vital signs during ESD.
Although des-gamma-carboxy prothrombin (DCP) is a well-known tumor marker for hepatocellular carcinoma (HCC), the mechanism of DCP production is unclear. This study aimed to investigate the mechanism how DCP is produced in HCC cells. Levels of mRNA and DCP were analyzed by real-time polymerase chain reaction and electro-chemiluminescence immunoassay respectively. Secreted alkaline phosphatase (SEAP) expression vectors including deletion mutants of the prothrombin gene promoter were constructed for reporter gene assay. The transcription factors bound to DNA fragments were analyzed by mass spectrometry. An electrophoretic mobility shift assay (EMSA) was performed using a biotin end-labeled DNA. The prothrombin mRNA levels in all 5 DCP producing cell lines were appreciably high. However, those in 2 DCP non-producing cell lines were below detectable levels. A SEAP vector with -2985 to +27 showed a very high transcription activity in DCP-producing Huh-1 cells. However, transcription abruptly decreased when the vector with -2955 to +27 was transfected, and then remained at the similar levels with larger deletion mutants, indicating the existence of a cis-element at -2985 to -2955 (31-bp). Mass spectrometry analysis identified the protein that bound to the 31-bp DNA as poly-(ADP-ribose) polymerase-1 (PARP-1). Knockdown of the PARP-1 gene by small interfering RNA in Huh-1 cells induced marked inhibition of prothrombin gene transcription. The EMSA clearly showed that PARP-1 specifically binds to the 31-bp DNA fragment in the prothrombin gene promoter. Our data suggest that PARP-1 activates prothrombin gene transcription and that the excessive prothrombin gene transcription induces DCP production in DCP-producing HCC cells.
Naoki Muguruma, Kumiko Tanaka, satoshi teramae and Tetsuji Takayama : Colon capsule endoscopy: toward the future., Clinical Journal of Gastroenterology, Vol.10, No.1, 1-6, 2017.
(Summary)
Colon capsule endoscopy is a wireless and minimally invasive technique for visualization of the whole colon. With recent improvements of technical features in second-generation systems, a more important role for colon capsule endoscopy is rapidly emerging. Although several limitations and drawbacks are yet to be resolved, its usefulness as a tool for colorectal cancer screening and monitoring disease activity in inflammatory bowel diseases has become more apparent with increased use. Further investigations, including multicenter trials, are required to evaluate the substantial role of the colon capsule in managing colorectal diseases.
(Keyword)
Capsule Endoscopes / Capsule Endoscopy / Colonic Diseases / Colonic Polyps / Colonoscopy / Colorectal Neoplasms / Early Detection of Cancer / Equipment Design / Humans / Inflammatory Bowel Diseases
Yuri Matsumoto, Hiroshi Miyamoto, Akira Fukuya, Fumika Nakamura, Takahiro Goji, Shinji Kitamura, Tetsuo Kimura, Koichi Okamoto, Masahiro Sogabe, Naoki Muguruma, Mitsuo Shimada, Yoshimi Bando and Tetsuji Takayama : Hemosuccus pancreaticus caused by a mucinous cystic neoplasm of the pancreas., Clinical Journal of Gastroenterology, Vol.10, No.2, 185-190, 2017.
(Summary)
Hemosuccus pancreaticus is a gastrointestinal hemorrhage through the main pancreatic duct. Here, we report a rare case of hemosuccus pancreaticus due to a mucinous cystic neoplasm of the pancreas. A 62-year-old woman who had been followed for a branch duct intraductal papillary mucinous neoplasm visited our emergency room due to severe abdominal pain and bloody discharge. Computed tomography revealed that the pancreatic cyst increased the tension of the wall and a high-density area indicative of bleeding into the cyst was observed. Endoscopy showed opening of and hemorrhaging from the papilla of Vater. The patient was diagnosed with hemosuccus pancreaticus caused by hemorrhaging into the cyst from the branch duct intraductal papillary mucinous neoplasm. Based on this diagnosis, elective distal pancreatectomy was performed. The histopathological diagnosis was a mucinous cystic neoplasm with intermediate-grade dysplasia based upon the pathological findings that fibrous ovarian-type stroma existed abundantly and the stroma cells were positive for progesterone receptor and inhibin. Hemosuccus pancreaticus caused by a mucinous cystic neoplasm is extremely rare and there has been only one case reported to date. In conclusion, it should be recognized that pancreatic cystic neoplasms including mucinous cystic neoplasms may cause hemosuccus pancreaticus.
(Keyword)
Ampulla of Vater / female / Gastrointestinal Hemorrhage / Humans / magnetic resonance imaging / Middle Aged / Neoplasms, Cystic, Mucinous, and Serous / Pancreatic Cyst / Pancreatic Ducts / Pancreatic Neoplasms / Tomography, X-Ray Computed
Yasuteru Fujino, Shunsaku Takeishi, Kensei Nishida, Koichi Okamoto, Naoki Muguruma, Tetsuo Kimura, Shinji Kitamura, Hiroshi Miyamoto, Akiko Fujimoto, Jun Higashijima, Mitsuo Shimada, Kazuhito Rokutan and Tetsuji Takayama : Downregulation of miR-100/miR-125b is associated with lymph node metastasis in early colorectal cancer with submucosal invasion., Cancer Science, Vol.108, No.3, 390-397, 2017.
(Summary)
A majority of early colorectal cancers (CRCs) with submucosal invasion undergo surgical operation, despite a very low incidence of lymph node metastasis. Our study aimed to identify microRNAs (miRNAs) specifically responsible for lymph node metastasis in submucosal CRCs. MicroRNA microarray analysis revealed that miR-100 and miR-125b expression levels were significantly lower in CRC tissues with lymph node metastases than in those without metastases. These results were validated by quantitative real-time PCR in a larger set of clinical samples. The transfection of a miR-100 or miR-125b inhibitor into colon cancer HCT116 cells significantly increased cell invasion, migration, and MMP activity. Conversely, overexpression of miR-100 or miR-125b mimics significantly attenuated all these activities but did not affect cell growth. To identify target mRNAs, we undertook a gene expression array analysis of miR-100-silenced HCT116 cells as well as negative control cells. The Ingenuity Pathway Analysis, TargetScan software analyses, and subsequent verification of mRNA expression by real-time PCR identified mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 receptor (IGF1R) as direct, and Fas and X-linked inhibitor-of-apoptosis protein (XIAP) as indirect candidate targets for miR-100 involved in lymph node metastasis. Knockdown of each gene by siRNA significantly reduced the invasiveness of HCT116 cells. These data clearly show that downregulation of miR-100 and miR-125b is closely associated with lymph node metastasis in submucosal CRC through enhancement of invasion, motility, and MMP activity. In particular, miR-100 may promote metastasis by upregulating mTOR, IGF1R, Fas, and XIAP as targets. Thus, miR-100 and miR-125b may be novel biomarkers for lymph node metastasis of early CRCs with submucosal invasion.
Koichi Okamoto, Shinji Kitamura, Tetsuo Kimura, Tadahiko Nakagawa, Masahiro Sogabe, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : Clinicopathological Characteristics of Serrated Polyps as Precursors to Colorectal Cancer: Current Status and Management., Journal of Gastroenterology and Hepatology, Vol.32, No.2, 358-367, 2017.
(Summary)
Serrated polyps have long been thought to lack malignant potential in the human colorectum. However, identification of the serrated pathway to colorectal cancer based on molecular biology has improved our understanding of the pathogenesis of colorectal cancers. Accordingly, serrated polyps such as traditional serrated adenoma and sessile serrated adenoma/polyps (SSA/P) are now considered to be precursor lesions of the serrated pathway. Recently, serrated polyps were classified into three subtypes, consisting of hyperplastic polyp, SSA/P, and traditional serrated adenoma, according to the World Health Organization classification. It has been suggested that SSA/P in the proximal colon are a precursor lesion of pathogenesis of colorectal cancer and are characterized by BRAF mutation and a CpG island methylator phenotype with or without microsatellite instability. However, SSA/P is more challenging to detect by colonoscopy and is likely to account for some interval cancers, particularly in the proximal colon because it presents flat or sessile, isochroous appearance, and occasionally has a mucous cap. Furthermore, the possibility has been raised that pathologists misclassify SSA/P as hyperplastic polyp. It is important for gastroenterologists to recognize the endoscopic features of serrated polyps to facilitate their detection and removal and also to establish postpolypectomy surveillance guidelines. In this review, we discuss the recent classification of serrated polyps; the molecular characteristics of the serrated pathway; appropriate diagnostic methods using endoscopy, including a new image-enhanced endoscopic technique; and management of these lesions.
Tetsuo Kimura, Hiroshi Miyamoto, Akira Fukuya, Shinji Kitamura, Koichi Okamoto, Masako Kimura, Naoki Muguruma, Tetsuya Ikemoto, Mitsuo Shimada, Akiko Yoneda, Yoshimi Bando, Makoto Takishita and Tetsuji Takayama : Neuroendocrine carcinoma of the pancreas with similar genetic alterations to invasive ductal adenocarcinoma., Clinical Journal of Gastroenterology, Vol.9, No.4, 261-265, 2016.
(Summary)
Neuroendocrine carcinoma (NEC) of the pancreas is very rare, and its origin is not fully elucidated. Here, we present a case of a small-size NEC of the pancreas that is genetically similar to invasive ductal adenocarcinoma (IDA). A 65-year-old man was referred to our hospital due to obstructive jaundice and found to have a 12-mm solid tumor in the pancreas head. The tumor exhibited low vascularity on enhanced computed tomography, and endoscopic retrograde pancreatographic imaging revealed an irregular obstruction in a branch duct of the pancreas. The patient was thereby diagnosed with a pancreatic ductal cancer, and stomach-preserving pancreaticoduodenectomy with regional lymph node resection was performed. Histochemical analysis of the resected tumor showed that the neoplastic cells with scanty cytoplasm and hyperchromatic nuclei strongly expressed chromogranin A and synaptophysin. The Ki-67 index was 40 % in the most proliferative tumor regions, and the tumor was diagnosed as a NEC of the pancreas. However, in the analysis of genetic alterations of the tumor tissue, the neoplastic cells showed altered KRAS, TP53, and SMAD4/DPC4, suggesting that the NEC in our case is genetically related to IDA. Our data suggest that poorly differentiated IDAs may transform into NECs.
K Yamazaki, M Nagase, H Tamagawa, S Ueda, T Tamura, K Murata, T Nakajima Eguchi, E Baba, M Tsuda, T Moriwaki, T Esaki, Y Tsuji, K Muro, K Taira, T Denda, S Funai, K Shinozaki, H Yamashita, N Sugimoto, T Okuno, T Nishina, T Umeki, T Kurimoto, Tetsuji Takayama, A Tsuji, M Yoshida, A Hosokawa, Y Shibata, K Suyama, M Okabe, K Suzuki, N Seki, K Kawakami, M Sato, K Fujikawa, T Hirashima, T Shimura, K Taku, T Otsuji, F Tamura, E Shinozaki, K Nakashima, H Hara, T Tsushima, M Ando, S Morita, N Boku and I Hyodo : Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G)., Annals of Oncology, Vol.27, No.8, 1539-1546, 2016.
(Summary)
FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. UMIN000001396.
Masahiro Sogabe, Toshiya Okahisa, Tetsuo Kimura, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : Influence of metabolic syndrome on upper gastrointestinal disease., Clinical Journal of Gastroenterology, Vol.9, No.4, 191-202, 2016.
(Summary)
A recent increase in the rate of obesity as a result of insufficient physical exercise and excess food consumption has been seen in both developed and developing countries throughout the world. Additionally, the recent increased number of obese individuals with lifestyle-related diseases associated with abnormalities in glucose metabolism, dyslipidemia, and hypertension, defined as metabolic syndrome (MS), has been problematic. Although MS has been highlighted as a risk factor for ischemic heart disease and arteriosclerotic diseases, it was also recently shown to be associated with digestive system disorders, including upper gastrointestinal diseases. Unlike high body weight and high body mass index, abdominal obesity with visceral fat accumulation is implicated in the onset of various digestive system diseases because excessive visceral fat accumulation may cause an increase in intra-abdominal pressure, inducing the release of various bioactive substances, known as adipocytokines, including tumor necrosis factor-α, interleukin-6, resistin, leptin, and adiponectin. This review article focuses on upper gastrointestinal disorders and their association with MS, including obesity, visceral fat accumulation, and the major upper gastrointestinal diseases.
Tetsuji Takayama, Hiroshi Miyamoto and Naoki Muguruma : Prevention of colorectal cancer, The Japanese Journal of Gastro-enterology, Vol.113, No.7, 1168-1175, 2016.
Yoshihiko Miyamoto, Naoki Muguruma, Tetsuo Kimura, Koichi Okamoto, Masahiro Sogabe, Hiroshi Miyamoto, Seiya Kohno, Masahiko Nakasono, Hiroshige Hayashi, Yoshimi Bando and Tetsuji Takayama : Protein-losing enteropathy in a patient with familial adenomatous polyposis and advanced colon cancer., Clinical Journal of Gastroenterology, Vol.9, No.3, 134-139, 2016.
(Summary)
A 29-year-old female visited a hospital because of increasingly severe lower leg edema. She was diagnosed as having multiple polyps in the stomach and colon by gastroscopy and sigmoidoscopy as well as multiple liver tumors by abdominal CT. She was referred to our hospital for further examination. Total colonoscopy revealed a type 2 tumor in the transverse colon and more than 200 polyps distributed throughout the colorectum. Biopsies of the tumor and polyps showed histological characteristics of adenocarcinoma and tubulovillous adenoma, respectively. Thus, she was diagnosed as having metastatic colon cancer derived from familial adenomatous polyposis (FAP). Laboratory tests showed a marked hypoalbuminemia of 1.1 g/dl. The fecal alpha-1 anti-trypsin test showed abnormal clearance (62.1 ml/day), and scintigraphy using 99mTc-human serum albumin revealed protein loss in the whole colon. Multiple ligation probe amplification analysis of the APC gene identified a germline duplication of exons 11-13. Direct sequencing of the reverse transcription PCR products of APC mRNA revealed a deletion of 25 base pairs and a tandem duplication of exons 11-13. This case was considered to be protein-losing enteropathy resulting from numerous colonic tubulovillous adenomas and advanced colon cancer in a FAP patient with unusual mutational events in APC.
Miwako Kagawa, Yasuteru Fujino, Naoki Muguruma, Noriaki Murayama, Koichi Okamoto, Shinji Kitamura, Tetsuo Kimura, Kazuhiro Kishi, Hiroshi Miyamoto, Hisanori Uehara and Tetsuji Takayama : Localized amyloidosis of the stomach mimicking a superficial gastric cancer., Clinical Journal of Gastroenterology, Vol.9, No.3, 109-113, 2016.
(Summary)
A 73-year-old man was referred to our hospital for further examination of a depressed lesion in the stomach found by cancer screening gastroscopy. A barium upper gastrointestinal series showed an area of irregular mucosa measuring 15 mm on the anterior wall of the gastric body. Esophagogastroduodenoscopy revealed a 15 mm depressed lesion on the anterior wall of the lower gastric body. We suspected an undifferentiated adenocarcinoma from the appearance and took some biopsies. However, histology of the specimens revealed amyloidal deposits in the submucosal layer without malignant findings. Congo red staining was positive for amyloidal protein and green birefringence was observed under polarized light microscopy. Congo red staining with prior potassium permanganate incubation confirmed the light chain (AL) amyloid type. There were no amyloid deposits in the colon or duodenum. Computed tomography of the chest, abdomen, and pelvis showed no remarkable findings. Thus, this case was diagnosed as a localized gastric amyloidosis characterized by AL type amyloid deposition in the mucosal or submucosal layer. As the clinical outcome of gastric AL amyloidosis seems favorable, this case is scheduled for periodic examination to recognize potential disease progression and has been stable for 2 years.
Tomohiro Kubo, Yutaka Kawano, Nobuaki Himuro, Shintaro Sugita, Yasushi Sato, Kazuma Ishikawa, Kohichi Takada, Kazuyuki Murase, Koji Miyanishi, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Takayuki Nobuoka, Koichi Hirata, Tetsuji Takayama, Mitsuru Mori, Tadashi Hasegawa and Junji Kato : BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer., Gastric Cancer, Vol.19, No.3, 827-837, 2016.
(Summary)
Preoperative chemotherapy is a promising strategy for downstaging advanced gastric cancer before radical resection, although severe adverse events can occur and clinical outcomes are often unsatisfactory. To identify predictive biomarkers of drug sensitivity, we used a well-designed functional apoptosis assay and assessed the correlations between chemosensitivity and clinical outcomes. Drug sensitivity to docetaxel, cisplatin, and 5-fluorouracil was examined in 11 gastric cancer cell lines. BCL2-homology domain 3 (BH3) profiling was performed and assessed for correlations with drug sensitivity. Immunohistochemical staining of clinical gastric cancer specimens was performed before preoperative chemotherapy, and correlations with histopathological responses and clinical outcomes were assessed. BIM (BCL2L11)-BH3 profiling results correlated with docetaxel sensitivity and BAK protein expression, whose knockdown caused docetaxel resistance. The BAK expression indexes of 69 gastric cancer specimens before preoperative chemotherapy (including docetaxel treatment) were determined by multiplying numerical values describing the degrees of BAK positivity and staining intensity observed. Patients whose specimens showed good chemotherapeutic histopathological responses had higher BAK indexes than those with poor responses. Patients with BAK index values 3 showed improved progression-free survival (HR, 2.664; 95 % CI, 1.352-5.248; P = 0.005) and overall survival (HR, 3.390; 95 % CI, 1.549-7.422; P = 0.002). BH3 profiling clearly showed that BIM expression, which depends on BAK expression, correlated with docetaxel sensitivity. BAK expression in gastric cancer is thus predictive of chemotherapeutic responses to docetaxel and clinical prognosis in patients treated with preoperative chemotherapy.
Tetsuo Kimura and Tetsuji Takayama : Diagnostic and therapeutic approach to pancreatic cancer, Shikoku Acta Medica, Vol.72, No.1-2, 13-18, 2016.
(Summary)
Pancreatic cancer is the fourth leading cause of cancer death in Japan and the incidence and mortality rates have been increasing year by year. Despite the significant progress has been made in management of pancreatic cancer, further preclinical and clinical research studies are needed to advance our clinical approach to this aggressive cancer. Recent advance in diagnostic modalities including MDCT, MRCP and EUS-FNA allow early detection and accurate preoperative staging of the disease. Although surgery remains the only curative treatment for pancreatic cancer, increasing evidence now suggest that further significant improvements to overall survival can be achieved via new chemotherapeutic options such as FOLFIRINOX and gemcitabine/nabpaclitaxel regimen. This review will provide an overview of clinical practice for pancreatic cancer.
Masahiro Sogabe, Toshiya Okahisa, Tadahiko Nakagawa, Hiroshi Fukuno, Masahiko Nakasono, Tetsu Tomonari, Takahiro Tanaka, Hironori Tanaka, Tatsuya Taniguchi, Naoki Muguruma and Tetsuji Takayama : Influence of light alcohol consumption on lifestyle-related diseases: a predictor of fatty liver with liver enzyme elevation in Japanese females with metabolic syndrome., BMC Gastroenterology, Vol.16, No.1, 17, 2016.
(Summary)
Although heavy drinking is known to lead to liver injury, some recent studies have reported that light alcohol consumption (LAC) may play a protective role against fatty liver in the general population, and may even play a protective role against non-alcoholic fatty liver disease (NAFLD) in males with metabolic syndrome (MS). However, the association between LAC and fatty liver with liver enzyme elevation in females with MS is unclear. Participants of this study were 20,853 females who underwent a regular health check-up between April 2008 and March 2012 at our hospital. Enrolled subjects were 1141 females with MS, who underwent all necessary tests and drank less than 20 g/day of alcohol. We investigated the presence of fatty liver with liver enzyme elevation, defined in this study as alanine aminotransferase (ALT) levels ≧31 IU/I, and the association between LAC and fatty liver with ALT elevation. There was no significant difference in the prevalence of fatty liver and ALT between light drinkers and non-drinkers. The prevalence of individuals receiving a treatment for dyslipidemia and impaired glucose tolerance (IGT) was significantly lower in light drinkers than in non-drinkers. Body mass index (BMI), waist circumference (WC), diastolic blood pressure (DBP), triglyceride (TG), uric acid (UA), IGT, and visceral fat type MS (V-type MS) were significant predictors of the prevalence of fatty liver with ALT elevation in logistic regression analysis. The odds ratio [OR] (95 % confidence interval [CI], p value) for fatty liver with ALT elevation were as follows: BMI, 2.181 (1.445-3.293, p <0.001); WC, 1.853 (1.280-2.684, p <0.01); DBP, 1.604 (1.120-2.298, p <0.05); TG, 2.202 (1.562-3.105, p <0.001); UA, 2.959 (1.537-5.698, p <0.01); IGT, 1.692 (1.143-2.506, p <0.01); and V-type MS, 3.708 (2.529-5.437, p <0.001). There was no significant difference in the prevalence of fatty liver with ALT elevation in females with MS between light drinkers and non-drinkers, suggesting that other factors such as BMI, WC, V-type MS, and lifestyle-related disease may be more important than LAC for the prevalence of fatty liver with ALT elevation.
Tetsu Tomonari, Shunsaku Takeishi, Tatsuya Taniguchi, Takahiro Tanaka, Hironori Tanaka, Shota Fujimoto, Tetsuo Kimura, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : MRP3 as a novel resistance factor for sorafenib in hepatocellular carcinoma, Oncotarget, Vol.7, No.6, 7207-7215, 2016.
(Summary)
The mechanism of resistance of hepatocellular carcinoma (HCC) to sorafenib is unknown and no useful predictive biomarker for sorafenib treatment has been reported. Accordingly, we established sorafenib-resistant HCC cells and investigated the underlying mechanism of resistance to sorafenib. Sorafenib-resistant cell lines were established from the HCC cell line PLC/PRF5 by cultivation under continuous exposure to increasing concentration of sorafenib. The IC50 values of the 2 resistant clones PLC/PRF5-R1 and PLC-PRF5-R2 were 9.2±0.47 M (1.8-fold) and 25±5.1 M (4.6-fold) respectively, which were significantly higher than that of parental PLC/PRF5 cells (5.4±0.17 M) (p < 0.01 respectively), as determined by MTT assay. Western blot analysis of signal transduction-related proteins showed no significant differences in expression of AKT/pAKT, mTOR/pmTOR, or ERK/pERK between the 2 resistant clones versus parent cells, suggesting no activation of an alternative signal transduction pathway. Likewise, when expression of membrane transporter proteins was determined, there were no significant differences in expression levels of BSEP, MDR1, MRP2, BCRP, MRP4 and OCT1 between resistant clones and parent cells. However, the expression levels of MRP3 in the 2 resistant clones were significantly higher than that of parent cells. When MRP3 gene was knocked down by siRNA in PLC-PRF5-R2 cells, the sensitivity of the cells to sorafenib was restored. In the analysis of gene mutation, there was no mutation in the activation segment of Raf1 kinase in the resistant clones. Our data clearly demonstrate that the efflux transporter MRP3 plays an important role in resistance to sorafenib in HCC cells.
Jinsei Miyoshi, Hiroshi Miyamoto, Takahiro Goji, Tatsuya Taniguchi, Tetsu Tomonari, Masahiro Sogabe, Tetsuo Kimura, Shinji Kitamura, Koichi Okamoto, Yasuteru Fujino, Naoki Muguruma, Toshiya Okahisa and Tetsuji Takayama : Serum diamine oxidase activity as a predictor of gastrointestinal toxicity and malnutrition due to anticancer drugs., Journal of Gastroenterology and Hepatology, Vol.30, No.11, 1582-1590, 2015.
(Summary)
Objective evaluation of intestinal mucosal damage due to anticancer drugs is generally difficult. Serum diamine oxidase (DAO) activity is reported to reflect the integrity and maturity of the small intestinal mucosa. Therefore, we investigated whether serum DAO activity is an indicator of gastrointestinal toxicity or nutritional status in patients receiving chemotherapy. We prospectively enrolled 20 patients with unresectable metastatic gastric cancer who received oral S-1 (80 mg/m(2) ) on days 1-14, and intravenous cisplatin (60 mg/m(2) ) and docetaxel (50 mg/m(2) ) on day 8 every 3 weeks. Serum DAO activity was measured by colorimetry. Gastrointestinal toxicity was evaluated by CTCAE v4.0. Endoscopic examination and biopsy of duodenal mucosa assessed mucosal damage. Malnutrition was evaluated by measuring serum total protein and albumin levels. Serum DAO activity decreased step-by-step significantly during anticancer drug treatment and recovered after drug holidays. In all 14 patients who experienced diarrhea, serum DAO activity significantly decreased prior to diarrhea onset. Percent decrease in DAO activity was significantly correlated with severity of diarrhea. Significant correlation was observed between percent decrease in DAO activity and percent decrease in duodenal villus height or surface area from baseline. There were also significant correlations between percent decrease in serum DAO activity at day 14 and percent decrease in serum total protein or albumin levels at day 21 from baseline. Serum DAO activity sensitively indicates gastrointestinal damage prior to symptom onset and can be a useful predictor of intestinal mucosal damage and nutritional status in patients receiving chemotherapy.
Hiroyuki Ohnuma, Yasushi Sato, Masahiro Hirakawa, Yutaka Okagawa, Takahiro Osuga, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Tamotsu Sagawa, Masakazu Hori, Masanori Someya, Kensei Nakata, Koh-ichi Sakata, Tetsuji Takayama and Junji Kato : A Phase 1/2 Study of Definitive Chemoradiation Therapy Using Docetaxel, Nedaplatin, and 5-Fluorouracil (DNF-R) for Esophageal Cancer., International Journal of Radiation Oncology*Biology*Physics, Vol.93, No.2, 382-390, 2015.
(Summary)
Patient survival in esophageal cancer (EC) remains poor. The purpose of this study was to investigate a regimen of definitive chemoradiation therapy (CRT) that exerts good local control of EC. We performed a phase 1/2 study to assess the safety and efficacy of CRT with docetaxel, nedaplatin, and 5-fluorouracil (DNF-R). Eligible patients presented with stage IB to IV EC. Patients received 2 cycles of docetaxel (20, 30, or 40 mg/m(2)) and nedaplatin (50 mg/m(2)) on days 1 and 8 and a continuous infusion of 5-fluorouracil (400 mg/m(2)/day) on days 1 to 5 and 8 to 12, every 5 weeks, with concurrent radiation therapy (59.4 Gy/33 fractions). The recommended dose (RD) was determined using a 3 + 3 design. In the phase 1 study, the dose-limiting toxicities were neutropenia and thrombocytopenia. The RD of docetaxel was determined to be 20 mg/m(2). In the phase 2 study, grade 3 to 4 acute toxicities included neutropenia (42.8%), febrile neutropenia (7.14%), thrombocytopenia (17.9%), and esophagitis (21.4%). Grade 3 to 4 late radiation toxicity included esophagostenosis (10.7%). The complete response rate was 82.1% (95% confidence interval: 67.9-96.3%). Both the median progression-free survival and overall survival were 41.2 months. DNF-R showed good tolerability and strong antitumor activity, suggesting that it is a potentially effective therapeutic regimen for EC.
Takahiro Goji, Tetsuo Kimura, Hiroshi Miyamoto, Masanori Takehara, kaizo Kagamoto, Yasuyuki Okada, Jun Okazaki, Yoshifumi Takaoka, Yoshihiko Miyamoto, Yasuhiro Mitsui, Tatsunao Sueuchi, Kumiko Tanaka, Yasuteru Fujino, Sayo Matsumoto, Toshi Takaoka, Shinji Kitamura, Koichi Okamoto, Masako Kimura, Masahiro Sogabe, Naoki Muguruma, Toshiya Okahisa, Yasuhiro Sato, Tamotsu Sagawa, Koji Fujikawa, Yasushi Sato, Hitoshi Ikushima and Tetsuji Takayama : A Phase I/II Study of Fixed-dose-rate Gemcitabine and S-1 with Concurrent Radiotherapy for Locally Advanced Pancreatic Cancer, Cancer Chemotherapy and Pharmacology, Vol.76, No.3, 615-620, 2015.
(Summary)
This study was conducted to identify the maximum-tolerated dose (MTD) of fixed-dose-rate gemcitabine (FDR-gem) administered concurrently with S-1 and radical radiation for locally advanced pancreatic cancer (LAPC) and to provide efficacy and safety data. Patients with unrespectable pancreatic cancer confined to the pancreatic region were treated with FDR-gem (300-400 mg/m(2), 5 mg/m(2)/min) on days 1, 8, 22, and 29 and 60 mg/m(2) of S-1 orally on days 1-14, 22-35. A total radiation dose of 50.4 Gy (1.8 Gy/day, 28 fractions) was delivered concurrently. Twenty-five patients were enrolled; all were evaluable for toxicity assessment. In phase I, eight patients were treated in sequential cohorts of three to five patients per dose level. The MTD was reached at level 2, and dose-limiting toxicities were neutropenia and thrombocytopenia. The recommended doses were 300 mg/m(2) of gemcitabine and 60 mg/m(2) of S-1 daily. The overall response rate was 25% and disease control rate (partial response plus stable disease) was 92%. The progression-free survival was 11.0 months. The median overall survival and 1-year survival rates were 16.0 months and 73%, respectively. The combination of FDR-gem and S-1 with radiation is a feasible regimen that shows favorable antitumor activity with an acceptable safety profile in patients with LAPC.
Masahiro Sogabe, Toshiya Okahisa, Masahiko Nakasono, Yasuteru Fujino, Yasuhiro Mitsui, Yoshihumi Takaoka, Tetsuo Kimura, Koichi Okamoto, Naoki Muguruma and Tetsuji Takayama : Investigation of Gastroduodenal Mucosal Injury in Japanese Asymptomatic Antiplatelet Drug Users, Medicine, Vol.94, No.26, e1047, 2015.
(Summary)
Antiplatelet drugs are widely used for the prevention of cardiovascular disease and cerebral vascular disorders. Although there have been several studies on gastroduodenal mucosal injury with gastrointestinal (GI) symptoms such as GI bleeding, in antiplatelet drug users (including low-dose aspirin (LDA)), there have been few reports on the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users. This study was a cross-sectional study elucidating the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Subjects were 186 asymptomatic Japanese antiplatelet drug users who underwent a regular health checkup. Subjects were divided into those with and without gastroduodenal mucosal injury endoscopically, and the association between gastroduodenal mucosal injury and other data in asymptomatic antiplatelet drug users was investigated.The prevalence of males and drinkers were significantly higher in subjects with gastroduodenal mucosal injury than in those without. In addition, the prevalence of proton pump inhibitor (PPI) users was significantly lower in subjects with gastroduodenal mucosal injury than in subjects without gastroduodenal mucosal injury. Logistic regression analysis showed PPI (odds ratios: 0.116; 95% confidence intervals: 0.021-0.638; P < 0.05) was a significant predictor of a decreased prevalence of gastroduodenal mucosal injury and closed-type (C-type) atrophy (3.172; 1.322-7.609; P < 0.01) was a significant predictor of an increased prevalence of severe gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Gender and lifestyle, such as drinking, may have an impact on risk of gastroduodenal mucosal injury in asymptomatic subjects taking antiplatelet drugs. Although PPI is a significant predictor of a decreased prevalence of gastroduodenal mucosal injury, including in asymptomatic antiplatelet drug users, status of gastric atrophy should also be considered against severe gastroduodenal mucosal injury.
(Keyword)
Adult / Aged / Aged, 80 and over / Endoscopy, Gastrointestinal / Female / Gastric Mucosa / Humans / Male / Middle Aged / Platelet Aggregation Inhibitors / Retrospective Studies / Stomach Diseases / Young Adult
Yasuhiro Mitsui, Yasushi Sato, Hiroshi Miyamoto, Yasuteru Fujino, Toshi Takaoka, Jinsei Miyoshi, Miwako Kagawa, Hiroyuki Ohnuma, Masahiro Hirakawa, Tomohiro Kubo, Takahiro Osuga, Tamotsu Sagawa, Yasuhiro Sato, Yasuo Takahashi, shinichi Katsuki, Toshinori Okuda, Rishu Takimoto, Masayoshi Kobune, Takayuki Nobuoka, Koichi Hirata, Junji Kato and Tetsuji Takayama : Trastuzumab in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: feasibility and preliminary efficacy., Cancer Chemotherapy and Pharmacology, Vol.76, No.2, 375-382, 2015.
(Summary)
We previously reported that a triplet combination of docetaxel, cisplatin, and S-1 (DCS) is active against metastatic gastric cancer with a very high response rate of 87.1 % in a phase II study. Recently, the efficacy of trastuzumab (T-mab) for the treatment of HER2-positive gastric cancer has been reported. Therefore, we investigated the feasibility and preliminary efficacy of DCS + T-mab (DCS-T) for unresectable HER2-positive metastatic gastric cancer. Patients received oral S-1 (40 mg/m(2) b.i.d.) on days 1-14, intravenous cisplatin (60 mg/m(2)), docetaxel (50 mg/m(2)), and T-mab (8 mg/kg in the first cycle and 6 mg/kg in the second cycle and thereafter) on day 8 every 3 weeks. The study included 16 patients: median age, 60 (34-76) years; males/females, 11:5; intestinal-type/diffuse-type histology, 11:5; and HER2 3+/2+(FISH+), 13:3. The completion rate until the third cycle was 87.5 % (14/16) (95 %CI 71.3-103.7 %). Adverse events of grade 3/4 severity during the first 3 cycles were: leukopenia/neutropenia, 50.0:75.0 %; febrile neutropenia, 12.5 %; diarrhea, 12.5 %; and stomatitis, 12.5 %. All of these side effects were manageable and well controlled. There were no treatment-related deaths. The overall response rate was 93.8 % (15/16), and the response rate in patients with measurable lesions was 100 % (15/15). The median cycle to response was only 1 (1-3 cycles). Non-curative factors disappeared in 56.3 % (9/16) of patients, and conversion surgery (R0 resection) was performed in all these cases. Pathological response rates in primary and metastatic lesions were 88.9 % (8/9) and 100 % (9/9), respectively. The median PFS and OS were not reached during the median follow-up time of 18.3 months ranged from 11.0 to 34.3 months. DCS-T was feasible in patients with unresectable HER2-positive metastatic gastric cancer. The observed response was very promising and warrants further investigation. UMIN000005603.
Masahiro Sogabe, Toshiya Okahisa, Tatsuya Taniguchi, Tetsu Tomonari, Takahiro Tanaka, Hironori Tanaka, Masahiko Nakasono and Tetsuji Takayama : Light alcohol consumption plays a protective role against non-alcoholic fatty liver disease in Japanese men with metabolic syndrome., Liver International, Vol.35, No.6, 1707-1714, 2015.
(Summary)
Although excess alcohol consumption has been believed to cause liver injury, light alcohol consumption (LAC) has been reported to play a protective role against fatty liver in recent studies. However, the association between non-alcoholic fatty liver disease (NAFLD) and LAC in men with metabolic syndrome (MS) is unclear. The aim of this study was to examine the association between NAFLD and LAC in men with MS. Subjects were 1055 men with MS who underwent a regular health check-up and drank less 20 g/day of alcohol. A distinction was made between non-drinkers and light drinkers and the association between NAFLD and LAC in men with MS was elucidated. NAFLD was referred as fatty liver with alanine aminotransferase (ALT) levels 31 IU/L in this study. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and the prevalence of NAFLD were significantly lower in light drinkers than in non-drinkers. Logistic regression analysis showed body mass index (BMI), waist circumference (WC), uric acid (UA), haemoglobin A1c (HbA1c), visceral fat type MS and LAC (odds ratios: 0.654; 95% confidence intervals: 0.473-0.906; <0.05) were significant predictors of the prevalence of NAFLD. The prevalence of NAFLD in light drinkers was significantly lower than in non-drinkers, and supporting previous reports studying the general population, LAC is one of the significant predictors of a decreased prevalence of NAFLD in men with MS.
(Keyword)
Abdomen / Adult / Aged / Alanine Transaminase / Alcohol Drinking / Asian Continental Ancestry Group / Aspartate Aminotransferases / Body Mass Index / Hemoglobin A, Glycosylated / Humans / Intra-Abdominal Fat / Japan / Logistic Models / Male / Metabolic Syndrome X / Middle Aged / Multivariate Analysis / Non-alcoholic Fatty Liver Disease / Odds Ratio / Surveys and Questionnaires / Uric Acid / Waist Circumference
Naoki Muguruma, Shinji Kitamura, Tetsuo Kimura, Hiroshi Miyamoto and Tetsuji Takayama : Endoscopic Management of Nonvariceal Upper Gastrointestinal Bleeding: State of the Art., Clinical Endoscopy, Vol.48, No.2, 96-101, 2015.
(Summary)
Nonvariceal upper gastrointestinal (GI) bleeding is one of the most common reasons for hospitalization and a major cause of morbidity and mortality worldwide. Recently developed endoscopic devices and supporting apparatuses can achieve endoscopic hemostasis with greater safety and efficiency. With these advancements in technology and technique, gastroenterologists should have no concerns regarding the management of acute upper GI bleeding, provided that they are well prepared and trained. However, when endoscopic hemostasis fails, endoscopy should not be continued. Rather, endoscopists should refer patients to radiologists and surgeons without any delay for evaluation regarding the appropriateness of emergency interventional radiology or surgery.
Takuji Ohmoto, Nobuyuki Yoshitani, Kazuchika Nishitsuji, Tetsuji Takayama, Yuto Yanagisawa, Motohiro Takeya and Naomi Sakashita : CD44-expressing undifferentiated carcinoma with rhabdoid features of the pancreas: molecular analysis of aggressive invasion and metastasis., Pathology International, Vol.65, No.5, 264-270, 2015.
(Summary)
Carcinoma with rhabdoid features is a rare malignant tumor with a poor prognosis whose molecular mechanism for aggressive behavior is unclear. We describe an undifferentiated pancreatic carcinoma with rhabdoid features that demonstrated extensive invasion and metastasis. Examination of a 63-year-old man with back pain disclosed a retroperitoneal tumor with multiple metastases. Lymph node biopsy revealed an undifferentiated carcinoma of unknown origin. Intensive chemotherapy was ineffective; the patient died 3 months after initial symptoms. Autopsy showed that the tumor displaced the retroperitoneal space: it diffusely invaded and destroyed the pancreas and duodenum. Histology demonstrated tumor cells with eccentric vesicular nuclei, large nucleoli, juxtanuclear eosinophilic inclusions, and poor cell adhesion. Immunohistochemistry showed that tumor cells expressed cytokeratin and vimentin, and electron microscopy confirmed a perinuclear mass of intermediate fibrils and lipid droplets, which indicated an undifferentiated carcinoma with rhabdoid features. Tumor tissue contained hyaluronan; tumor cells strongly expressed CD44, matrix metalloproteinase-9, hypoxia-inducible factor-1, hyaluronan synthase 2, and acyl-CoA:cholesterol acyltransferase 1 and had a high Ki-67(+) ratio. Since hyaluronan is a ligand for CD44, formation of CD44-hyaluronan complex on the cell surface activates CD44 and this activation may explain why the tumor manifested aggressive invasion and metastasis throughout the clinical course.
A 60-year-old male presented to our hospital for further investigation of abnormal findings on an upper gastrointestinal series. Esophagogastroduodenoscopy demonstrated atrophic gastritis and a submucosal tumor (SMT) at the anterior wall of the antrum. The patient was positive for serum anti-Helicobacter pylori (H. pylori) antibody and H. pylori eradication therapy was performed. Five months later, the SMT showed a remarkable morphological change in that an ulcer had developed on its apex, and partial gastrectomy was performed. Pathological examination suggested an inflammatory fibroid polyp (IFP), and genetic analysis revealed no mutation in the platelet-derived growth factor receptor alpha gene. This case suggests that H. pylori infection plays an important role in the etiology of IFPs.
Satoshi Teramae, Hiroshi Miyamoto, Naoki Muguruma, Yasuyuki Okada, Takahiro Goji, Shinji Kitamura, Tetsuo Kimura, Masako Kimura, Yoshimi Bando and Tetsuji Takayama : Insulin-like growth factor II-producing metastatic colon cancer with recurrent hypoglycemia., Clinical Journal of Gastroenterology, Vol.8, No.1, 35-40, 2015.
(Summary)
A 45-year-old man was referred to our hospital and found to have a tubular adenocarcinoma of the descending colon with multiple liver metastases. During hospitalization, the patient suffered recurrent hypoglycemic attacks that required intravenous 50% glucose infusion. He was diagnosed with non-islet cell tumor hypoglycemia (NICTH) because the colon cancer tissue obtained by biopsy was strongly stained for insulin-like growth factor-II (IGF-II) by immunohistochemistry. He received chemotherapy with oxaliplatin, 5-FU and leucovorin (FOLFOX) plus bevacizumab (Bmab), and showed a partial response. As the metastatic lesions decreased in size, the hypoglycemic attacks gradually disappeared. Subsequently, he received outpatient chemotherapy and maintained a high quality of life for about 10 months. Western blot analysis of IGF-II in serum at the time of admission showed a high-molecular-weight form of IGF-II, which was considered to have caused hypoglycemia. This patient presents a very rare case of colorectal cancer associated with NICTH syndrome due to production of high-molecular-weight IGF-II by cancer cells. It is important to investigate IGF-II expression in cancer tissues for establishing the diagnosis of NICTH in cases with intractable hypoglycemia complicated by advanced cancer.
(Keyword)
Adenocarcinoma / Blotting, Western / Colonic Neoplasms / Humans / Hypoglycemia / Immunohistochemistry / Insulin-Like Growth Factor II / Liver Neoplasms / Male / Middle Aged / Recurrence
Atsushi Inoue, Koichi Okamoto, Yasuteru Fujino, Tadahiko Nakagawa, Naoki Muguruma, Katsutaka Sannomiya, Yasuhiro Mitsui, Toshi Takaoka, Shinji Kitamura, Hiroshi Miyamoto, Toshiya Okahisa, Takahiro Fujimori, Issei Imoto and Tetsuji Takayama : B-RAF mutation and accumulated gene methylation in aberrant crypt foci (ACF),sessile serrated adenoma/polyp (SSA/P) and cancer in SSA/P., British Journal of Cancer, Vol.112, No.2, 403-412, 2015.
(Summary)
Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor of colon cancer with microsatellite instability (MSI). However, the developmental mechanism of SSA/P remains unknown. We performed genetic analysis and genome-wide DNA methylation analysis in aberrant crypt foci (ACF), SSA/P, and cancer in SSA/P specimens to show a close association between ACF and the SSA/P-cancer sequence. We also evaluated the prevalence and number of ACF in SSA/P patients. ACF in the right-side colon were observed in 36 patients with SSA/Ps alone, 2 with cancers in SSA/P, and 20 normal subjects and biopsied under magnifying endoscopy. B-RAF mutation and MSI were analysed by PCR-restriction fragment length polymorphism (RFLP) and PCR-SSCP, respectively, in 15 ACF, 20 SSA/P, and 2 cancer specimens. DNA methylation array analysis of seven ACF, seven SSA/P, and two cancer in SSA/P specimens was performed using the microarray-based integrated analysis of methylation by isochizomers (MIAMI) method. B-RAF mutations were frequently detected in ACF, SSA/P, and cancer in SSA/P tissues. The number of methylated genes increased significantly in the order of ACF<SSA/P<cancer. The most commonly methylated genes in SSA/P were PQLC1, HDHD3, RASL10B, FLI1, GJA3, and SLC26A2. Some of these genes were methylated in ACF, whereas all genes were methylated in cancers. Immunohistochemistry revealed their silenced expression. Microsatellite instability and MLH1 methylation were observed only in cancer. The prevalence and number of ACF were significantly higher in SSA/P patients than in normal subjects. A significant correlation was seen between the numbers of SSA/P and ACF in SSA/P patients. Our results suggest that ACF are precursor lesions of the SSA/P-cancer sequence in patients with SSA/P, where ACF arise by B-RAF mutation and methylation of some of the six identified genes and develop into SSA/Ps through accumulated methylation of these genes.
Masahiro Sogabe, Toshiya Okahisa, Akira Yamanoi and Tetsuji Takayama : Subtypes of metabolic syndrome and of other risk factors in Japanese women with erosive esophagitis., Medicine, Vol.93, No.28, e276, 2014.
(Summary)
Obesity and metabolic syndrome (MS) are strongly associated with erosive esophagitis (EE). The prevalence of MS and EE, and the distribution of adipose tissue have been known to differ markedly between men and women. Although the prevalence of EE in men with MS is known to be higher in visceral fat type MS (V-type MS) than in subcutaneous fat type MS (S-type MS), the association between EE and the types of MS in women with MS is unclear. This study was a cross-sectional study elucidating the association between EE and the types of MS in women with MS. Subjects were 454 women with MS who underwent a regular health check-up. A distinction was made between V-type MS and S-type MS and the prevalence of EE and the association between EE and other data were elucidated. Although there were some significant different factors in characteristics between V-type MS and S-type MS, there was no significant difference in the prevalence of EE between V-type MS and S-type MS. The presence of Helicobacter pylori (H. pylori) was significantly lower than in subjects with EE (13.7%) than in subjects without EE (41.9%). The frequency of hiatal hernia was significantly higher in subjects with EE (60.8%) than in subjects without EE (24.6%). Logistic regression analysis showed hiatal hernia (odds ratio: 4.673; 95% confidence interval: 2.448-8.920; P<0.001), hemoglobin A1c (HbA1c) (2.325; 1.110-4.870; P<0.05), and the presence of H. pylori (0.239; 0.101-0.567; P<0.005) were significant predictors of the prevalence of EE. V-type MS may not be such an important factor for the prevalence of EE in women with MS as in men with MS. The absence of H. pylori, hiatal hernia, and HbA1c may be more important for the prevalence of EE than the types of MS in women with MS.
Yasuteru Fujino, Naoki Muguruma, Shinji Kitamura, Yasuhiro Mitsui, Tetsuo Kimura, Hiroshi Miyamoto, Hisanori Uehara, Koichi Kataoka and Tetsuji Takayama : Perineurioma in the sigmoid colon diagnosed and treated by endoscopic resection, Clinical Journal of Gastroenterology, Vol.7, No.5, 392-396, 2014.
(Summary)
Perineuriomas are rare benign peripheral nerve sheath tumors in the gastrointestinal tract. We recently encountered a submucosal lesion in the sigmoid colon that was resected by endoscopic mucosal resection and was then diagnosed as perineurioma by immunohistochemistry. A 51-year-old female with a positive test for fecal occult blood was referred to our hospital for screening colonoscopy. Colonoscopy identified a submucosal lesion, approximately 15 mm in diameter, in the sigmoid colon. Endoscopic ultrasound showed a 15-mm tumor with a strong acoustic shadow. Endoscopic mucosal resection was performed in order to make a precise diagnosis as well as removal. The specimen revealed spindle cell proliferation without atypia, and immunostaining revealed that the spindle cells were positive for collagen type IV and glut-1, and the lesion was diagnosed as a colonic perineurioma with no malignancy. Gastroenterologists as well as pathologists should be aware of this type of submucosal lesion, and immunohistochemical evaluation is highly recommended when an unusual mesenchymal tumor is found.
Miyamoto Yoshihiko, Naoki Muguruma, Seisuke Okamura, Okada Yasuyuki, Shinji Kitamura, Koichi Okamoto, Takahiro Goji, Yoneda Akiko, Noriko Kagawa and Tetsuji Takayama : A pedunculated submucosal lesion in the stomach with inverted downgrowth, Internal Medicine, Vol.53, No.15, 1625-1628, 2014.
(Summary)
A 70-year-old man with a gastric lesion was referred to our hospital because of an unusual pedunculated lesion in the gastric body. Endoscopic ultrasound showed scattered cystic lesions within a heterogeneous area confined to the submucosal layer. Endoscopic mucosal resection was performed to obtain a precise diagnosis, as well as for removal. The lesion was histopathologically diagnosed as a heterotopic submucosal gland. We herein describe this rare type of gastric polyp and provide a literature review.
Hirao Akihiro, Tetsu Tomonari, Tanaka Hironori, Kumiko Tanaka, Kagawa Miwako, Tanaka Takahiro, Tatsuya Taniguchi, Harada Rie, Momoko Sato, Naoki Muguruma and Tetsuji Takayama : Development of a renal subcapsular hematoma during angiography for diagnosis and subsequent treatment of hepatocellular carcinoma, Clinical Journal of Gastroenterology, Vol.7, No.2, 185-188, 2014.
(Summary)
A renal subcapsular hematoma rarely occurs without a history of trauma. It has been reported as a complication of urological interventions and also reported to occur spontaneously in patients with renal malignancies. However, there are no previous reports of renal subcapsular hematomas occurring in connection with abdominal angiography. We report here a case of a renal subcapsular hematoma that developed and was recognized during abdominal angiography for treatment of hepatocellular carcinoma (HCC). An 80-year-old male was referred to our hospital for transarterial embolization for multiple HCCs. His past medical history included hypertension. His laboratory data showed slightly decreased number of platelets and hepaplastin test due to liver cirrhosis. When computed tomography angiography was performed, a 7-cm subcapsular hematoma developed and was recognized over the right kidney during the procedure. He was successfully managed supportively with blood transfusion, tranexamic acid and antibiotics. Since thrombocytopenia and hypertension are reportedly risk factors for hematoma formation, careful manipulation is required during angiography in HCC patients with liver cirrhosis and hypertension. It must be kept in mind that rare complications, such as a renal subcapsular hematoma, can happen during abdominal angiography for diagnostic and interventional treatment of HCC.
Shinji Kitamura, Naoki Muguruma, Koichi Okamoto, Fumika Nakamura, Yasuyuki Okada, Tetsuo Kimura, Hiroshi Miyamoto and Tetsuji Takayama : Endoscopic submucosal dissection through a gastrostomy for early gastric cancer in patients with pharyngeal stenosis., Gastrointestinal Endoscopy, Vol.79, No.2, 206-207, 2014.
Hideki Ishikawa, Michihiro Mutoh, Sadao Suzuki, Shinkan Tokudome, Yoshihisa Saida, Takashi Abe, Shozo Okamura, Masahiro Tajika, Takashi Joh, Shinji Tanaka, Shin-Ei Kudo, Takahisa Matsuda, Masaki Iimuro, Tomomi Yukawa, Tetsuji Takayama, Yasushi Sato, Kyowon Lee, Shinji Kitamura, Motowo Mizuno, Yasushi Sano, Nobuhisa Gondo, Kenji Sugimoto, Masato Kusunoki, Chiho Goto, Nariaki Matsuura, Toshiyuki Sakai and Keiji Wakabayashi : The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial., Gut, Vol.63, No.11, 1755-1759, 2014.
(Summary)
Low-dose, enteric-coated aspirin tablets reduced colorectal tumour recurrence in an Asian population. The results are consistent with those obtained from other randomised controlled trials in Western countries. THE CLINICAL TRIAL REGISTRY WEBSITE AND THE CLINICAL TRIAL NUMBER: http://www.umin.ac.jp (number UMIN000000697).
Yasuyuki Okada, Hiroshi Miyamoto, Takahiro Goji and Tetsuji Takayama : Biomarkers for predicting the efficacy of anti-epidermal growth factor receptor antibody in the treatment of colorectal cancer., Digestion, Vol.89, No.1, 18-23, 2014.
Momoko Sato, Naoki Muguruma, Nakagawa Tadahiko, Koichi Okamoto, Tetsuo Kimura, Shinji Kitamura, Hiromi Yano, Sannomiya Katsutaka, Takahiro Goji, Hiroshi Miyamoto, Toshiya Okahisa, Hiroaki Mikasa, Wada Satoshi, Iwata Masao and Tetsuji Takayama : High antitumor activity of pladienolide B and its derivative in gastric cancer, Cancer Science, Vol.105, No.1, 110-116, 2014.
(Summary)
The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6-4.0) and 1.2 ± 1.1 (range, 0.4-3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction.
(Keyword)
Aged / Aged, 80 and over / Animals / Antineoplastic Agents / Apoptosis / Cell Line, Tumor / Cyclin E / Cyclin-Dependent Kinase Inhibitor p16 / Epoxy Compounds / Female / Humans / Macrolides / Male / Mice / Mice, SCID / Middle Aged / RNA Splicing / Random Allocation / Stomach Neoplasms / Xenograft Model Antitumor Assays
Toshihiro Omoya, Masako Shiba, Shingo Hibino, Rika Aoki, Shinji Kitamura, Naoki Muguruma and Tetsuji Takayama : Twig tea impaction in the colon causing abdominal pain, Clinical Journal of Gastroenterology, Vol.6, No.6, 438-441, 2013.
(Summary)
We describe a case of lower abdominal pain caused by a twig tea impaction at the rectosigmoid junction after inadvertent ingestion. The foreign body was detected and successfully dislodged from the colonic wall with grasping forceps during colonoscopy. The post-procedural course was uneventful, and the patient was discharged 10 days after the removal. Colonic injury, including perforation due to foreign body ingestion, must be considered in patients presenting with unexplained symptoms and findings, even when they do not recall any foreign body ingestion.
(Keyword)
abdominal pain / foreign body / endoscopic removal
Naoki Muguruma, Hiroshi Miyamoto, Toshiya Okahisa and Tetsuji Takayama : Endoscopic Molecular Imaging: Status and Future Perspective., Clinical Endoscopy, Vol.46, No.6, 603-610, 2013.
(Summary)
During the last decade, researchers have made great progress in the development of new image processing technologies for gastrointestinal endoscopy. However, diagnosis using conventional endoscopy with white light optical imaging is essentially limited, and ultimately, we still rely on the histopathological diagnosis from biopsy specimens. Molecular imaging represents the most novel imaging methods in medicine, and the future of endoscopic diagnosis is likely to be impacted by a combination of biomarkers and technology. Endoscopic molecular imaging can be defined as the visualization of molecular characteristics with endoscopy. These innovations will allow us not only to locate a tumor or dysplastic lesion but also to visualize its molecular characteristics and the activity of specific molecules and biological processes that affect tumor behavior and/or its response to therapy. In the near future, these promising technologies will play a central role in endoluminal oncology.
Koichi Okamoto, Takaoka Toshi, Naoki Muguruma, Tetsuji Takayama and Niitsu Yoshiro : Endoscopy of aberrant crypt foci: the expert approach, Video Journal and Encyclopedia of GI Endoscopy, Vol.1, 357-358, 2013.
Miho Tsuda, Koichi Okamoto, Naoki Muguruma, Katsutaka Sannomiya, Tadahiko Nakagawa, Hiroshi Miyamoto, Shinji Kitamura, Takahiro Goji, Tetsuo Kimura, Toshiya Okahisa, Keisuke Izumi and Tetsuji Takayama : Suppressive effect of RAS inhibitor manumycin A on aberrant crypt foci formation in the azoxymethane-induced rat colorectal carcinogenesis model., Journal of Gastroenterology and Hepatology, Vol.28, No.10, 1616-1623, 2013.
(Summary)
Manumycin A suppressed ACF formation in the AOM-induced colorectal carcinogenesis model, demonstrating that RAS inhibitors may be very effective for chemoprevention of colorectal cancers.
Shinji Kitamura, Mitsugi Yasuda, Naoki Muguruma, Koichi Okamoto, Hisashi Takeuchi, Yoshimi Bando, Hiroshi Miyamoto, Toshiya Okahisa, Mitsuyasu Yano, Ryusuke Torisu and Tetsuji Takayama : Prevalence and characteristics of nodular gastritis in Japanese elderly., Journal of Gastroenterology and Hepatology, Vol.28, No.7, 1154-1160, 2013.
(Summary)
NG in the elderly was also suggested to be a risk factor for gastric cancer as well as in the young.
(Keyword)
Age Factors / Aged / Aged, 80 and over / Asian Continental Ancestry Group / Gastritis / Gastroscopy / Humans / Japan / Prevalence / Risk Factors / Stomach Neoplasms
Koichi Okamoto, Naoki Muguruma, Shinji Kitamura, Masako Shiba and Tetsuji Takayama : Lessons from imperfect endoscopic submucosal dissection of rectal tumor., Digestive Endoscopy, Vol.25, No.Suppl 2, 31-36, 2013.
(Summary)
Endoscopic mucosal resection (EMR) is a standard endoscopic treatment for gastrointestinal tumors, but resections done in a piecemeal fashion are difficult to diagnose pathologically as curative resections, and the local recurrence rate is relatively high. Recently, endoscopic submucosal dissection (ESD) for colorectal tumors, which provides a higher complete resection rate than conventional EMR, has rapidly come into widespread use in Japan. However, colorectal ESD is still technically difficult and has complications such as perforation, and the procedure time is longer than that of conventional EMR. We report herein a case in which a rectal tumor was resected with an inappropriate specimen due to imperfect ESD. This lesion had severe fibrosis in the submucosal layer because the lesion had been injected with a solution for EMR in another hospital, which resulted in non-lifting signs, and had been subjected to many biopsies. During the ESD in our hospital, the submucosal layer was not clearly identified, and a small injury was caused in the specimen. A precise diagnosis based on histopathological findings could not be made because of the inappropriate specimen. Thus, expertise in both the diagnostic and the therapeutic aspects is required before treating large colorectal tumors.
Hirakawa Masahiro, Yasushi Sato, Ohnuma Hiroyuki, Tetsuji Takayama, Sagawa Tamotsu, Nobuoka Takayuki, Harada Keisuke, Hiroshi Miyamoto, Sato Yasuhiro, Takahashi Yasuo, Katsuki Shinichi, Hirayama Michiaki, Takahashi Minoru, Ono Michihiro, Maeda Masahiro, Takada Kohichi, Hayashi Tsuyoshi, Sato Tsutomu, Miyanishi Koji, Takimoto Rishu, Kobune Masayoshi, Hirata Koichi and Kato Junji : A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin,and S-1 for locally advanced resectable gastric cancer: nucleotide excision repair (NER) as potential chemoresistance marker, Cancer Chemotherapy and Pharmacology, Vol.71, No.3, 789-797, 2013.
(Summary)
The combination of docetaxel, cisplatin, and S-1 (DCS) chemotherapy is expected to be a promising regimen for advanced gastric cancer. This study was performed to evaluate the efficacy and safety of neoadjuvant DCS chemotherapy for locally advanced resectable gastric cancer. Patients with locally advanced gastric cancer received 2 courses of preoperative chemotherapy with S-1 (40 mg/m(2) b.i.d.) on days 1-14 and docetaxel (60 mg/m(2)) plus cisplatin (60 mg/m(2)) on day 8 every 3 weeks, followed by standard curative surgery within 4-8 weeks. The primary endpoint was R0 resectability. Expression of damage DNA binding protein complex subunit 2 (DDB2)/excision repair cross-complementing 1 (ERCC1) in the pretreated tumor tissues was examined by immunohistochemistry. A total of 43 patients received neoadjuvant chemotherapy. The response rate was 74.4%, and disease control ratio was 100%. Grade 4 neutropenia developed in 53.5% of patients and febrile neutropenia in 16.3%. Non-hematological grade 3/4 adverse events were anorexia (23.3%), nausea (14.0%), and diarrhea (23.3%), but these were generally transient and manageable. The proportion of R0 resections in the 43 eligible patients was 90.7%, and a pathological response was found in 65.9% of patients. There were no treatment-related deaths and no major surgical complications. The accuracy of the combination of DDB2 and ERCC1 expression for predicting chemoresistance was 82.5%. Preoperative treatment with DCS combination for locally advanced gastric cancer demonstrated a sufficient R0 resection rate and a good pathological response with manageable toxicities. The DDB2/ERCC1-high phenotype, as determined by immunohistochemistry, may be useful predictor of resistance to DCS chemotherapy.
Koichi Okamoto, Seisuke Okamura, Naoki Muguruma, Shinji Kitamura, Tetsuo Kimura, Yoshitaka Imoto, Hiroshi Miyamoto, Toshiya Okahisa and Tetsuji Takayama : Endoscopic submucosal dissection for early gastric cancer using a cross-counter technique., Surgical Endoscopy, Vol.26, No.12, 3676-3681, 2012.
(Summary)
Endoscopic submucosal dissection (ESD) in early gastric cancer has rapidly come into widespread use. However, since complications such as bleeding and perforation often occur, and the procedure time is longer for ESD than endoscopic mucosal resection (EMR), development of safer and more reliable technique is required. The subjects comprised 45 patients with lesions diagnosed histologically as early gastric cancer. They were divided into three groups: cross-counter technique group (CC, n = 15), peroral traction-assisted ESD with suture material group (PT, n = 15), and no-traction group (NT, n = 15). ESD was carried out by two endoscopists who had experienced fewer than 30 cases of ESD. To compare safety and efficacy of a new traction method (CC group) for ESD in early gastric cancer with other methods (PT group and NT group), procedure time, dissected area per unit time, complete resection rate, perforation rate, and bleeding rate were evaluated. There was no significant difference among these three groups in terms of complications, complete resection rate or procedure time. The dissection area per unit time was 22.4, 15.7, and 13.5 mm(2)/min in the CC, PT, and NT groups, respectively, and there was a significant difference between the CC and NT groups (p = 0.007). The cross-counter technique shortened the treatment time for endoscopists without abundant experience in gastric ESD, and it is considered a useful method to institute in order to introduce ESD.
(Keyword)
Aged / Aged, 80 and over / Early Medical Intervention / Equipment Design / Female / Gastric Mucosa / Gastroscopes / Gastroscopy / Humans / Male / Middle Aged / Stomach Neoplasms
Naoki Muguruma, Seisuke Okamura, Y Imoto, T Sueuchi, Koichi Okamoto, H Fujimoto, K Arita, Takanori Hirose and Tetsuji Takayama : Perineurioma: an uncommon lesion in the gastrointestinal tract., Endoscopy, Vol.44, No.Suppl 2 UCTN, E182-3, 2012.
Koichi Okamoto, Naoki Muguruma, Shinji Kitamura, Tetsuo Kimura and Tetsuji Takayama : Endoscopic submucosal dissection for large colorectal tumors using a cross-counter technique and a novel large-diameter balloon overtube., Digestive Endoscopy, Vol.24, No.Suppl.1, 96-99, 2012.
(Summary)
Endoscopic submucosal dissection (ESD) in early gastric cancer (EGC), which provides a higher complete resection rate than conventional endoscopic mucosal resection (EMR), has rapidly come into widespread use. However, colorectal ESD is not widely used because of its technical difficulty and complications such as perforation, and the procedure time is longer than that of conventional EMR. Development of safer and more reliable devices as well as technique modifications are therefore required. The aim of our study is to compare safety and efficacy of a new traction method, the cross-counter technique, for large colorectal tumors combined with a balloon overtube. A total of 30 patients with large colorectal tumors were analyzed retrospectively; 15 patients for the cross-counter technique group (CC group) and 15 patients for the no-traction group (NT group). Procedure time, complete resection rate, perforation rate and bleeding rate were assessed. The procedure time was 126 ± 42.2 min and 165 ± 61.3 min in the CC and NT groups, respectively, and there was a significant difference between the two groups (P < 0.05). There were no significant differences in complete resection rate, perforation rate and bleeding rate between the two groups. The cross-counter technique shortened the treatment time in colorectal ESD without any complication.
We compared high-sensitivity KRAS mutation testing with direct sequencing for predicting the efficacy of antiepidermal growth factor receptor antibodies in patients with metastatic colorectal cancer (mCRC). We analyzed the KRAS status in 61 tumors from cetuximab-treated mCRC patients by both direct sequencing and a high-sensitivity method: 2-step PCR restriction fragmentation length polymorphism (RFLP). Therapeutic effects in each mutational status were evaluated. The incidences of KRAS mutations determined by direct sequencing and 2-step PCR RFLP were 34.4 and 52.5%, respectively (p = 0.02). Patients were categorized into 3 groups [W/W, wild-type by both methods (n = 29); W/M, wild-type by direct sequencing, detected mutation by 2-step PCR RFLP (n = 11); M/M, mutant-type by both methods (n = 21)]. The response rate for cetuximab in the W/M group (0%) was the same as that in the M/M group, and was significantly lower than in the W/W group (41.4%) (p < 0.001). Progression-free survival in the W/M group (11.0 weeks) was similar to that in the M/M group (8.0 weeks), and was significantly shorter than in the W/W group (18.0 weeks) (p < 0.002). High-sensitivity KRAS mutation testing is useful for selecting true responders to cetuximab.
Takeuchi Hisashi, Tetsuo Kimura, Koichi Okamoto, Aoyagi Eriko, Hiroshi Miyamoto, Masako Kaji, Hidetaka Takenaka, Seisuke Okamura, Yasushi Sato, Kato Junji, Toshiya Okahisa and Tetsuji Takayama : A mechanism for abnormal angiogenesis in human radiation proctitis: analysis of expression profile for angiogenic factors, Journal of Gastroenterology, Vol.47, No.1, 56-64, 2012.
(Summary)
Radiation proctitis is an increasingly prevalent problem, with many patients being treated with radiotherapy for pelvic cancers. However, the mechanisms by which radiation proctitis develops in humans are not well understood. In this study, the expression profiles of angiogenic factors were analyzed to clarify their role in the etiology of radiation proctitis. Rectal biopsies were taken from 8 patients with radiation proctitis and 8 normal subjects. Protein lysates of the tissues were applied to an antibody array for angiogenesis-related factors. The mRNA level of each factor was evaluated by Taqman real-time PCR. Immunohistochemistry was performed using the labeled streptavidin biotin method. Antibody array analysis revealed 2.12- to 7.31-fold higher expression levels of angiogenin, fibroblast growth factor 1 (FGF1), endoglin, matrix metalloproteinase (MMP)-8, urokinase-type plasminogen activator (uPA) and maspin in radiation proctitis tissues compared with normal rectal mucosa. The mRNA level of each factor in radiation proctitis tissue was significantly higher than in normal rectal mucosa, suggesting their transcriptional activation. Immunohistochemical staining showed strong expression of angiogenin and maspin in rectal epithelia, MMP-8 and uPA in infiltrating lymphocytes, FGF1 in fibroblasts and endoglin in endothelial cells. The expression of VEGF was not evident. Our results suggest that in radiation proctitis, MMP-8 and uPA cooperatively degrade the extracellular matrix and basement membrane to provide space for angiogenesis. Simultaneously, angiogenin and FGF1 promote endothelial cell proliferation, and endoglin induces vessel formation, culminating in angiogenesis. Inhibitors of angiogenic factors such as angiogenin and FGF1 may be effective for treating radiation proctitis.
Naoki Muguruma, Koichi Okamoto, Tetsuo Kimura, Kazuhiro Kishi, Toshiya Okahisa, Seisuke Okamura and Tetsuji Takayama : Endoscopic ablation therapy for gastrointestinal superficial neoplasia., Digestive Endoscopy, Vol.24, No.3, 139-149, 2011.
(Summary)
In Japan, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been widely accepted and standardized for the treatment of gastrointestinal superficial neoplasia. In contrast, mucosal ablation techniques are more common in Western countries and a variety of endoscopic ablation modalities, including argon plasma coagulation (APC), photodynamic therapy (PDT) and lasers, are used. Recently developed modalities such as radiofrequency ablation (RFA) and cryotherapy are also available for the treatment of superficial lesions such as dysplasia of Barrett's esophagus. Although we should understand that the completeness of destruction of neoplastic tissue can only be judged at follow up, endoscopic ablation is a viable alternative to endoscopic resection for dysplasia and early-stage malignancies, especially for poor candidates of surgery or endoscopic resection.
Tetsuji Takayama, Hiroyuki Nagashima, Masahiro Maeda, Shuichi Nojiri, Michiaki Hirayama, Yoichiro Nakano, Yasuo Takahashi, Yasushi Sato, Hitoshi Sekikawa, Mitsuru Mori, Tomoko Sonoda, Tetsuo Kimura, Junji Kato and Yoshiro Niitsu : Randomized double-blind trial of sulindac and etodolac to eradicate aberrant crypt foci and to prevent sporadic colorectal polyps., Clinical Cancer Research, Vol.17, No.11, 3803-3811, 2011.
(Summary)
On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer. Experimental design: Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted. ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed. ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer.
Yasushi Sato, Tetsuji Takayama, Tamotsu Sagawa, Masahiro Hirakawa, Hiroyuki Ohnuma, Koji Miyanishi, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Koichi Okamoto, Hisashi Takeuchi and Junji Kato : Argon plasma coagulation treatment of hemorrhagic radiation proctopathy: the optimal settings for application and long-term outcome., Gastrointestinal Endoscopy, Vol.73, No.3, 543-549, 2011.
(Summary)
No standard treatment exists for hemorrhagic radiation proctopathy (HRP). Recently it was reported that argon plasma coagulation (APC) is effective for HRP. However, previous studies documented complications such as ulcers, strictures, and perforations in as many as 20% of APC-treated patients. The aim of this study was to determine the optimal parameters for APC by using swine rectum and to assess the safety and effectiveness of APC in HRP patients. Prospective case series. University teaching hospital. Sixty-five patients with HRP were prospectively enrolled between 2000 and 2010. APC for HRP. Optimal APC parameters, number of treatments, success rate, complications, clinical remissions. APC in swine rectal wall ex vivo was optimal with a 40-W current, 1.2-L/min gas flow rate, and 2-second application, which was sufficient to treat the submucosal telangiectasia but did not adversely affect the muscle layer. Sixty-five patients (46 men, 19 women; median age 72 years) with HRP occurring at a mean of 20 months after radiotherapy were studied. Proctopathy was classified as grade A (mild) in 7 patients (10.8%), grade B (moderate) in 41 (63.1%), and grade C (severe) in 17 (26.2%). The treatment success rate was 98.5% after a median of 2 (range 1-5) APC sessions. The median clinical score for rectal bleeding was significantly decreased after APC (P < .0001), and the hemoglobin level was significantly increased (P < .0001). APC was well tolerated, and no significant side effects or complications occurred. During a mean follow-up of 34.6 months (range 3.6 -121.1 months), 4 patients (6.3%) had minor recurrent rectal bleeding and 60 (93.8%) remained in remission. Nonrandomized study. HRP treatment with optimal APC settings yields a high success rate and long-lasting clinical remission with no significant complications.
Tetsuji Takayama, T Hayashi, H Ishiwatari, H Ihara, Y Kawano, K Takada, K Miyanishi, M Kobune, R Takimoto, T Sonoda, J Kato and Y Niitsu : Suppressive effect of sulindac on branch duct-intraductal papillary mucinous neoplasms., Journal of Gastroenterology, Vol.44, No.9, 964-975, 2009.
(Summary)
When considering surgery for branch duct-intraductal papillary mucinous neoplasms (BD-IPMNs) with suspected malignancy, it should be recognized that these lesions are frequently multifocal and are usually found in elderly patients with potential comorbidities that could affect the outcome of surgery. Clinical trials of chemoprevention have been conducted for a wide variety of malignancies. Twenty-two BD-IPMN patients participated in the trial at our institution from June 2004 to January 2007. Ten of the 22 patients who rejected surgical therapy although their lesions or clinical symptoms met the criteria for surgical resection of the International Association of Pancreatology guidelines were assigned to the treatment group. Sulindac (150 mg twice daily) and omeprazole (20 mg once daily) were administered to these patients for 18 months. The remaining 12 patients comprised the control group. Branch duct diameter and mural nodule heights were monitored by either magnetic resonance cholangiopancreatography (MRCP) or computed tomography (CT) and by endoscopic ultrasonography (EUS). Both branch duct diameter and mural nodule height of BD-IPMNs in the treatment group were significantly reduced, while those in the control group were unchanged. Immunohistochemical staining for cyclooxygenase-1 and -2 was negative in hyperplasia, adenoma and carcinoma portions of resected pancreatic specimens but was clearly positive for glutathione-S-transferase pi (GST-pi), suggesting that GST-pi is a putative target molecule for sulindac. Although a larger scale randomized controlled study is needed in future, the present results suggest the promise of chemoprevention of carcinoma derived from BD-IPMNs by sulindac.
(Keyword)
Adenocarcinoma, Mucinous / Adenocarcinoma, Papillary / Aged / Aged, 80 and over / Anti-Ulcer Agents / Antineoplastic Agents / Carcinoma, Pancreatic Ductal / Cholangiopancreatography, Magnetic Resonance / Drug Delivery Systems / Endosonography / Female / Glutathione S-Transferase pi / Humans / Male / Middle Aged / Omeprazole / Pancreatic Neoplasms / Sulindac / Tomography, X-Ray Computed
Fecal tagging computed tomographic colonography (ftCTC) reduces the discomfort and the inconvenience of patients associated with bowel cleansing procedures before CT scanning. In conventional colonic polyp detection techniques for ftCTC, a digital bowel cleansing (DBC) technique is applied to detect polyps in tagged fecal materials (TFM). However, DBC removes the surface of soft tissues and hampers polyp detection. We developed a colonic polyp detection method for CT colonographic examination that enables the detection of polyps surrounded by air and polyps surrounded by TFM without DBC. CT values inside the polyps surrounded by air and polyps surrounded by TFM tend to gradually increase (blob structure) and decrease (inverse-blob structure) from outward to inward, respectively. We developed blob and inverse-blob structure enhancement filters based on the eigenvalues of a Hessian matrix to detect polyps using their intensity characteristic. False-positive elimination is performed using three feature values: volume, maximum value of filter outputs, and standard deviation of CT values inside the polyp candidates. The proposed method is applied to 104 cases of ftCTC images that include 57 polyps larger than 6 mm in diameter. The sensitivity of the method was 91.2% (52/57) with 11.4 false positives per case. The proposed method detects polyps with high sensitivity and 11.4 false positives per case without adverse effects on the DBC.
H Takahashi, Tetsuji Takayama, K Yoneda, H Endo, H Iida, M Sugiyama, K Fujita, M Yoneda, M Inamori, Y Abe, S Saito, K Wada, H Nakagama and A Nakajima : Association of visceral fat accumulation and plasma adiponectin with rectal dysplastic aberrant crypt foci in a clinical population., Cancer Science, Vol.100, No.1, 29-32, 2009.
(Summary)
The association between obesity and the risk of colorectal cancer (CRC) cannot be easily evaluated because CRC itself is associated with a gradual loss of bodyweight. Aberrant crypt foci (ACF) can be classified as dysplastic ACF or non-dysplastic ACF by magnifying colonoscopy, and dysplastic ACF are thought to be a biomarker of CRC. Ninety-four participants who underwent colonoscopy at Yokohama City University Hospital, Japan, were enrolled in the current study. We detected 557 ACF, including 67 dysplastic ACF (12.0%). Univariate regression analysis was conducted to determine correlations between the number of dysplastic ACF and various potential risk factors, including patient age, waist circumference, body mass index, visceral fat area (VFA), and plasma adiponectin level. The results of multiple regression analysis revealed that the number of dysplastic ACF correlated with age (correlation coefficient r=0.212, P=0.0383) and plasma adiponectin level (r=-0.201, P=0.0371), even after adjustments for sex, waist circumference, body mass index, and VFA. Our univariate correlation analysis data showed a significant correlation with the number of dysplastic ACF with VFA (r=0.238, P=0.0209), no correlation with subcutaneous fat area, and an inverse correlation with the plasma level of adiponectin (r=-0.258, P=0.0118). Thus, our results suggest that aging and visceral fat accumulation could correlate moderately with colorectal carcinogenesis. The novelty of our study lies in the finding that visceral fat accumulation and a low plasma adiponectin level may promote colorectal carcinogenesis; therefore, these obesity-related parameters may serve as novel targets for CRC prevention.
Yasushi Sato, Tetsuji Takayama, D Takahari, T Sagawa, T Sato, S Abe, T Kogawa, T Nikaido, K Miyanishi, S Takahashi, J Kato and Y Niitsu : Successful treatment for gastro-intestinal bleeding of Osler-Weber-Rendu disease by argon plasma coagulation using double-balloon enteroscopy., Endoscopy, Vol.40, No.Suppl 2, E228-229, 2008.
Masayuki Shono, Ichiro Shimizu, Eriko Aoyagi, Tatsuya Taniguchi, Hidetaka Takenaka, Momoko Ishikawa, Mari Urata, Katsutaka Sannomiya, Katsuyoshi Tamaki, Nagakatsu Harada, Yutaka Nakaya and Tetsuji Takayama : Reducing Effect of Feeding Powdered Nacre of Pinctada maxima on the Visceral Fat of Rats, Bioscience, Biotechnology, and Biochemistry, Vol.72, No.10, 2761-2763, 2008.
(Summary)
An abdominal fat accumulation complicated by high blood triglycerides is regarded as a risk factor of metabolic syndrome. Feeding powdered nacre, mother of pearl, from Pinctada maxima, resulted in reduced body weight, visceral fat amount, and blood triglyceride level without influencing the food intake, body length, or amount of muscular tissue, suggesting that nacre powder specifically could decrease visceral fat.
T Sagawa, Y Yamada, M Takahashi, Yasushi Sato, M Kobune, R Takimoto, J Fukaura, S Iyama, T Sato, K Miyanishi, T Matsunaga, Tetsuji Takayama, J Kato, K Sasaki, H Hamada and Y Niitsu : Treatment of hepatocellular carcinoma by AdAFPep/rep, AdAFPep/p53, and 5-fluorouracil in mice., Hepatology, Vol.48, No.3, 828-840, 2008.
(Summary)
Although conditionally replicable adenovirus (CRAd) has been used in the clinical treatment of hepatocellular carcinoma (HCC), it suffers from the inherent drawback of having relatively low antitumor activity. Here, we have sought to overcome this drawback. First, we combined CRAd (AdAFPep/Rep) driven by alpha-fetoprotein enhancer/promoter (AFPep) with a replication-incompetent adenovirus carrying a p53 transgene that is also driven by AFPep. The synergism of this combination produced a significantly improved tumoricidal effect on the human HCC cell line Hep3B, which has a relatively short doubling time in comparison with other human HCC cell lines, through the transactivation of p53 by early region 1A transcribed by AdAFPep/Rep. This synergistic interaction was augmented by the addition of a subtumoricidal dose (0.5 microg/mL) of 5-fluorouracil (5-FU), which enhanced p53 expression and facilitated the release of virions from tumor cells. When relatively large (10-mm-diameter) Hep3B tumors grown in nude mice were injected with the two viruses in combination, they showed significantly impaired growth in comparison with those treated with each virus separately. The growth suppression effect of the virus combination was enhanced by a low dose (600 microg) of 5-FU. Survival of the tumor-bearing mice treated with these three agents was significantly longer than that of control mice. Moreover, the tumor completely disappeared with the repeated injection of these agents. CONCLUSION: This combination strategy holds promise for the treatment of relatively large and rapidly growing HCCs that may be encountered clinically.
S Takahashi, K Miyanishi, K Takada, Y Kawano, T Sagawa, Yasushi Sato, R Takimoto, Tetsuji Takayama, J Kato, M Omatsu, T Hasegawa, M Kojiro and Y Niitsu : Case report of a focal nodular hyperplasia-like nodule present in cirrhotic liver., Hepatology Research, Vol.38, No.5, 521-528, 2008.
(Summary)
An 81-year-old female was referred to Sapporo Medical University Hospital because of a nodular lesion 20 mm in diameter found in the liver S8 during follow-up for type C liver cirrhosis. Abdominal ultrasonography showed a capsule-like structure, and contrast computed tomography revealed hypervascularity at the early phase and inner pooling of the contrast medium with ring enhancement at the late phase. Magnetic resonance T2-weighted imaging (T2WI) demonstrated a hyperintensity nodule with further hyperintensity signals in some parts of the nodule, and the signal pattern differed from that of typical fibrosis. SPIO-magnetic resonance imaging showed partial hypointensity signals by T2WI, which indicated the presence of Kupffer cells. Angiography did not show a spoke-wheel pattern. The results by imaging modalities indicated that the nodule was atypical for hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH), and liver nodule biopsy was performed for histological diagnosis. Compared with the background liver, the nodule revealed high cellular density, cellular dysplasia at the periphery, a pseudo-crypt structure and irregular hepatic cord arrangement in some parts of the nodule. Among them, there was immature fibrous tissue containing arterioles with muscular hypertrophy. There has been no report of well-differentiated HCC with a central scar, and this case was presumed to be an FNH-like nodule with dysplasia physically associated with cirrhotic tissue.
A Fujimi, T Matsunaga, M Kobune, Y Kawano, T Nagaya, I Tanaka, S Iyama, T Hayashi, T Sato, K Miyanishi, T Sagawa, Yasushi Sato, R Takimoto, Tetsuji Takayama, J Kato, S Gasa, H Sakai, E Tsuchida, K Ikebuchi, H Hamada and Y Niitsu : Ex vivo large-scale generation of human red blood cells from cord blood CD34(+) cells by co-culturing with macrophages., International Journal of Hematology, Vol.87, No.4, 339-350, 2008.
(Summary)
We generated red blood cells (RBC) from cord blood (CB) CD34+ cells using a four-phase culture system. We first cultured CB CD34+ cells on telomerase gene-transduced human stromal cells in serum-free medium containing stem cell factor (SCF), Flt-3/Flk-2 ligand, and thrombopoietin to expand CD34+ cells (980-fold) and the total cells (10,400-fold) (first phase). Expanded cells from the first phase were liquid-cultured with SCF, interleukin-3 (IL-3), and erythropoietin (EPO) to expand (113-fold) and differentiate them into erythroblasts (second phase). To obtain macrophages for the next phase, we expanded CD34+ cells from a different donor using the same coculture system. Expanded cells from the first phase were liquid-cultured with granulocyte-macrophage colony stimulating factor, macrophage-colony stimulating factor (M-CSF), IL-3, and SCF to generate monocytes/macrophages (75-fold), which were incubated with type AB serum and M-CSF to fully differentiate them into macrophages. Erythroblasts were then co-cultured with macrophages in the presence of EPO to expand (threefold) and fully differentiate them (61% orthochromatic erythroblasts plus 39% RBC) (third phase). RBC were purified from erythroblasts and debris through a deleukocyting filter to generate 6.0 x 10(12) RBC from 1.0 unit of CB (3.0 transfusable units). Qualitatively, these RBC showed a hemoglobin content, oxygenation of hemoglobin, and in vivo clearance similar to those of adult peripheral RBC. Finally, an almost complete enucleation of orthochromatic erythroblasts (99.4%) was achieved by the cultivation method recently described by Miharada et al. in the absence of macrophages and cytokines (fourth phase). RBC were purified from remnant erythroblasts and debris by passage through a deleukocyting filter to generate 1.76 x 10(13) RBC from 1.0 unit of CB (8.8 transfusable units), the highest yield ever reported. Thus, this method may be useful for generating an alternative RBC supply for transfusions, investigating infectious agents that target erythroid cells, and as a general in vitro hematopoietic model system.
S Iyama, T Matsunaga, T Sato, K Murase, N Araki, R Takimoto, M Kobune, T Sagawa, Tetsuji Takayama and Y Niitsu : Successful treatment of chronic myeloproliferative disease-unclassifiable (CMPD-U) with no chromosomal abnormalities by imatinib mesylate., Internal Medicine, Vol.47, No.8, 791-794, 2008.
(Summary)
We report a chronic myeloproliferative disease-unclassifiable (CMPD-U) patient who achieved hematological remission following imatinib mesylate (imatinib). Chromosomal and molecular analyses demonstrated no genetic abnormalities of c-abl, bcr-abl, c-kit or platelet-derived growth factor receptor (PDGFR) genes from hematopoietic cells. Although there has been one report of CMPD-U patient with chromosomal abnormalities of the PDGFR gene having complete hematologic responses upon treatment with imatinib, there have not been similar reports of patients without chromosomal abnormalities. This is the first case report of a CMPD-U patient with no chromosomal abnormalities who completely responded to treatment with imatinib.
Ying Yuan, Ichiro Shimizu, Mi Shen, Eriko Aoyagi, Hidetaka Takenaka, Tatuzo Itagaki, Mari Urata, Katsutaka Sannnomiya, Nao Kohno, Katsuyoshi Tamaki, Masayuki Shono and Tetsuji Takayama : Effects of estradiol and progesterone on the proinflammatory cytokine production by mononuclear cells from patients with chronic hepatitis C., World Journal of Gastroenterology : WJG, Vol.14, No.14, 2200-2207, 2008.
(Summary)
To investigate the effects of estradiol (E2) and progesterone on the unstimulated and oxidative stress-stimulated production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-8, and macrophage chemotactic protein (MCP)-1 by peripheral blood mononuclear cells (PBMCs) from patients with chronic hepatitis C and healthy controls. The PBMCs were separated from age-matched 72 males and 71 females with and without chronic hepatitis C, who were divided into two groups based on a mean menopausal age of 50 years. Oxidative stress was induced by hydrogen peroxide in the cells incubated in serum-free media. Cytokines in the culture supernatant were measured by an enzyme-linked immunosorbent assay. The highest levels of the spontaneous production of TNF-alpha, IL-1beta, IL-8, and MCP-1 by the unstimulated PBMCs were in the older male patients with chronic hepatitis C and the lowest levels were in the pre-menopausal female healthy controls. E2 inhibited the cytokine production by the unstimulated PBMCs from the older male and post-menopausal female patients, which was further stimulated by progesterone. The exposure to hydrogen peroxide in the PBMCs from the younger male and pre-menopausal female healthy subjects induced the production of cytokines. The change rates of the hydrogen peroxide-stimulated cytokine production were suppressed by E2 and enhanced by progesterone. These findings suggest that E2 may play a favorable role in the course of persistent liver injury by preventing the accumulation of monocytes-macrophages and by inhibiting proinflammatory cytokine production, whereas progesterone may counteract the favorable E2 effects.
Yasushi Sato, K Murase, J Kato, M Kobune, T Sato, Y Kawano, R Takimoto, K Takada, K Miyanishi, T Matsunaga, Tetsuji Takayama and Y Niitsu : Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone., Nature Biotechnology, Vol.26, No.4, 431-442, 2008.
(Summary)
There are currently no approved antifibrotic therapies for liver cirrhosis. We used vitamin A-coupled liposomes to deliver small interfering RNA (siRNA) against gp46, the rat homolog of human heat shock protein 47, to hepatic stellate cells. Our approach exploits the key roles of these cells in both fibrogenesis as well as uptake and storage of vitamin A. Five treatments with the siRNA-bearing vitamin A-coupled liposomes almost completely resolved liver fibrosis and prolonged survival in rats with otherwise lethal dimethylnitrosamine-induced liver cirrhosis in a dose- and duration-dependent manner. Rescue was not related to off-target effects or associated with recruitment of innate immunity. Receptor-specific siRNA delivery was similarly effective in suppressing collagen secretion and treating fibrosis induced by CCl(4) or bile duct ligation. The efficacy of the approach using both acute and chronic models of liver fibrosis suggests its therapeutic potential for reversing human liver cirrhosis.
Yasushi Sato, Tetsuji Takayama, Tamotsu Sagawa, Tsutomu Sato, Kumiko Okamoto, Shou Takahashi, Seiichiro Abe, Satoshi Iyama, Kazuyuki Murase, Junji Kato and Yoshiro Niitsu : [An advanced metastatic breast cancer patient successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy]., Japanese Journal of Cancer and Chemotherapy, Vol.35, No.3, 471-473, 2008.
(Summary)
We reported here a case of advanced breast cancer successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy. A 56-year-old male was referred to our hospital for treatment of recurrent metastatic breast cancer. When he was admitted, his general condition was poor due to massive intraperitoneal metastasis. We administered TAC chemotherapy (docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2), every 3 weeks). During chemotherapy, he showed no major adverse effects except grade 3 neutropenia, which could be easily managed with G-CSF administration. Metastatic lesions almost disappeared after 4 cycles of TAC. TAC therapy was considered to be acceptable as salvage therapy for a metastatic male breast cancer patient.
Huiwei Huang, Jianghong He, Ying Yuan, Eriko Aoyagi, Hidetaka Takenaka, Tatuzo Itagaki, Katsutaka Sannomiya, Katsuyoshi Tamaki, Nagakatsu Harada, Masayuki Shono, Ichiro Shimizu and Tetsuji Takayama : Opposing effects of estradiol and progesterone on the oxidative stress-induced production of chemokine and proinflammatory cytokines in murine peritoneal macrophages., The Journal of Medical Investigation : JMI, Vol.55, No.1-2, 133-141, 2008.
(Summary)
In inflammatory and oxidative liver injury, virus proteins and reactive oxygen species are involved in the regulation of proinflammatory cytokine production by macrophages. This study investigated the effects of estradiol (E2) and progesterone on the unstimulated and oxidative stress-stimulated production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, macrophage inflammatory protein (MIP)-2, and macrophage chemotactic protein (MCP)-1 by peritoneal macrophages isolated from male and female mice. E2 inhibited the cytokine production of TNF-alpha, IL-1beta, MIP-2, and MCP-1 by the unstimulated macrophages from males and females, which was then further stimulated by progesterone. The exposure to hydrogen peroxide in the macrophages from both sexes induced the production of cytokine. The hydrogen peroxide-stimulated cytokine production was suppressed by E2 and enhanced by progesterone. The sex hormone effects on the unstimulated and stimulated macrophages were blocked by their receptor antagonists and showed no significant difference between male and female subjects. These findings suggest that E2 may play a favorable role in the course of persistent liver injury, by inhibiting proinflammatory cytokine production, which, in addition, progesterone may counteract the favorable E2 effects through their receptors.
T Matsunaga, F Fukai, S Miura, Y Nakane, T Owaki, H Kodama, M Tanaka, T Nagaya, R Takimoto, Tetsuji Takayama and Y Niitsu : Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia., Leukemia, Vol.22, No.2, 353-360, 2008.
(Summary)
We investigated whether FNIII14, a 22-mer peptide derived from fibronectin (FN) that potently impairs interaction of FN with beta1-integrin, could overcome cell adhesion-mediated drug resistance (CAM-DR) induced by very late antigen (VLA)-4-to-FN interaction in acute myelogenous leukemia (AML). Two AML cell lines, U937 cells and HL-60 cells, and fresh leukemic cells from six AML patients with high alpha4-integrin expression exhibited CAM-DR to cytosine arabinoside (Ara C) through VLA-4-to-FN interaction, while fresh leukemic cells from two AML patients with low alpha4-integrin expression did not display CAM-DR to Ara C. FNIII14 impaired VLA-4-to-FN interaction and restored sensitivity to Ara C in the CAM-DR leukemic cells. In these CAM-DR leukemic cells, upregulation of Bcl-2, which was induced through the focal adhesion kinase/Akt signal pathway upon VLA-4-to-FN interaction, was inhibited by FNIII14 treatment. In a mouse model of minimal residual disease (MRD) in bone marrow, 100% survival was achieved by combining FNIII14 with Ara C, whereas Ara C alone prolonged survival only slightly. The myelosuppression induced by Ara C was not augmented by the combination of FNIII14 in mouse experiments. Thus, the combination of anticancer drugs and FNIII14 holds promise to eradicate MRD in bone marrow after chemotherapy.
Takehiro Kukitsu, Tetsuji Takayama, Koji Miyanishi, Atsushi Nobuoka, Shinichi Katsuki, Yasushi Sato, Rishu Takimoto, Takuya Matsunaga, Junji Kato, Tomoko Sonoda, Sumio Sakamaki and Yoshiro Niitsu : Aberrant Crypt Foci as Precursors of the Dysplasia-Carcinoma Sequence in Patients with Ulcerative Colitis., Clinical Cancer Research, Vol.14, No.1, 48-54, 2008.
(Summary)
Long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer, but surveillance of colitis-associated cancer by detecting the precancerous lesion dysplasia is often difficult because of its rare occurrence and normal-looking appearance. In sporadic colorectal cancer, aberrant crypt foci (ACF) have been reported by many investigators to be precursor lesions of the adenoma-carcinoma sequence. In the present study, we analyzed the genetic background of ACF to determine whether they could be precursors for dysplasia, and we examined the usefulness of endoscopic examination of ACF as a surrogate marker for surveillance of colitis-associated cancer. ACF were examined in 28 UC patients (19 patients with UC alone and 9 patients with UC and dysplasia; 2 of those patients with dysplasia also had cancer) using magnifying endoscopy. K-ras, APC, and p53 mutations were analyzed by two-step PCR RFLP, in vitro--synthesized protein assay, and single-strand conformation polymorphism, respectively. Methylation of p16 was analyzed by methylation-specific PCR. ACF that appeared distinct endoscopically and histologically were identified in 27 out of 28 UC patients. They were negative for K-ras, APC, and p53 mutations but were frequently positive for p16 methylation (8 of 11; 73%). In dysplasia, K-ras and APC mutations were negative but p53 mutation (3 of 5; 60%) and p16 methylation (3 of 5; 60%) were positive. There was a significant stepwise increase in the number of ACF from patients with UC alone to patients with dysplasia and to patients with cancer. Univariate and multivariate analyses showed significant correlations between ACF and dysplasia. We have disclosed an ACF-dysplasia-cancer sequence in colitis-associated carcinogenesis similar to the ACF-adenoma-carcinoma sequence in sporadic colon carcinogenesis. This study suggests the use of ACF instead of dysplasia for the surveillance of colitis cancer and warrants further evaluation of ACF as a surveillance marker in large-scale studies.
J Kato, K Miyanishi, M Kobune, T Nakamura, K Takada, R Takimoto, Y Kawano, S Takahashi, M Takahashi, Yasushi Sato, Tetsuji Takayama and Y Niitsu : Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C., Journal of Gastroenterology, Vol.42, No.10, 830-836, 2007.
(Summary)
We have previously demonstrated that in patients with chronic hepatitis C (CHC), iron depletion improves serum alanine aminotransferase (ALT) levels as well as hepatic oxidative DNA damage. However, it has not been determined whether continuation of iron depletion therapy for CHC favorably influences its progression to hepatocellular carcinoma (HCC). We conducted a cohort study on biopsy-proven CHC patients with moderate or severe liver fibrosis who failed to respond to previous interferon (IFN) therapy or had conditions for which IFN is contradicted. Patients were divided into two groups: subjects in group A (n = 35) underwent weekly phlebotomy (200 g) until they reached a state of mild iron deficiency, followed by monthly maintenance phlebotomy for 44-144 months (median, 107 months), and they were advised to consume a low-iron diet (5-7 mg iron/day); group B (n = 40) comprised CHC patients who declined to receive iron depletion therapy. In group A, during the maintenance phase, serum ALT levels decreased to less than 60 IU/l in all patients and normalized (<40 IU/l) in 24 patients (69%), whereas in group B no spontaneous decrease in serum ALT occurred. Hepatocarcinogenesis rates in groups A and B were 5.7% and 17.5% at the end of the fifth year, and 8.6% and 39% in the tenth year, respectively. Multivariate analysis revealed that iron depletion therapy significantly lowered the risk of HCC (odds ratio, 0.57) compared with that of untreated patients (P = 0.0337). Long-term iron depletion for CHC patients is a promising modality for lowering the risk of progression to HCC.
Tetsuji Takayama, Yasushi Sato, T Sagawa, T Okamoto, H Nagashima, Y Takahashi, H Ohnuma, G Kuroiwa, K Miyanishi, R Takimoto, T Matsunaga, J Kato, K Yamaguchi, K Hirata and Y Niitsu : Phase I study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer., British Journal of Cancer, Vol.97, No.7, 851-856, 2007.
(Summary)
The aim of this dose escalation study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs) and preliminary efficacy of docetaxel, S-1 and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Seventeen patients received oral S-1 (40 mg m(-2) bid) on days 1-14, intravenous cisplatin (60 mg m(-2)) and docetaxel (60, 70 or 80 mg m(-2) depending on DLT) on day 8 every 3 weeks. The MTD of this combination was presumed to be docetaxel 70 mg m(-2). At this dose level, 40% of the patients (two of five) developed grade 4 neutropenia and 20% (one of five) exhibited grade 3 nausea during the first course. Therefore, the recommended dose of docetaxel was defined as 60 mg m(-2). The DLT was neutropenia. The response rate (RR) was 88.2% (15 of 17), consisting of one complete response and 14 partial responses. There were two stable diseases but no progressive disease. Of these 15 responders, four (23.5%) with high VEGF expression showed rapid tumour regression and achieved downstaging, leading to subsequent curative gastrectomy. Three of these have been disease free for about 3 years, suggesting a complete cure. In conclusion, this regimen was tolerable and showed a quite high RR, with an appreciable downstaging rate in metastatic gastric cancer.
Tamotsu Sagawa, Yasushi Sato, Tetsuji Takayama, Masahiro Hirakawa, Seiichiro Abe, Satoshi Iyama, Koji Miyanishi, Yutaka Kawano, Kohichi Takada, Tokiko Nakamura, Junji Kato and Yoshiro Niitsu : [A case of resection of synchronous multiple liver metastases from colorectal cancer after hepatic infusion chemotherapy and systemic chemotherapy]., Japanese Journal of Cancer and Chemotherapy, Vol.34, No.9, 1481-1484, 2007.
(Summary)
A 70-year-old man was admitted for tranverse colon cancer with multiple liver metastases. Hepatic arterial infusion chemotherapy and systemic chemotherapy (FOLFOX 4) were conducted postoperatively. Thirteen months after the first surgery, liver metastases became resectable and hepatectomy was performed. Though multiple liver metastases were unresectable at the time of the first examination, hepatectomy was possible followed by hepatic arterial infusion chemotherapy and systemic chemotherapy.
Tamotsu Sagawa, Yasushi Sato, Tetsuji Takayama, Hiroyuki Kuroda, Masahiro Hirakawa, Seiichiro Abe, Satoshi Iyama, Sumio Sakamaki, Junji Kato and Yoshiro Niitsu : [Fifth-line chemotherapy for metastatic gastric cancer--a case responding to modified FOLFOX 6]., Japanese Journal of Cancer and Chemotherapy, Vol.34, No.9, 1467-1471, 2007.
(Summary)
According to the National Comprehensive Cancer Network (NCCN) clinical practice guideline for gastric cancer (2006, the first edition), 5-FU/Leucovorin (LV), 5-FU-based, cisplatin (CDDP)-based, oxaliplatin (L-OHP)-based, taxane-based, and irinotecan (CPT-11)-based, ECF are recommended. We used modified FOLFOX 6 (mFOLFOX 6) for pretreatment, that is oxaliplatin-based chemotherapy, for a patient who had received 5-FU-based, CDDPbased, taxane-based, and CPT-11-based treatment for an unresectable gastric cancer case responding to mFOLFOX 6. A 73-year-old male admitted to our hospital for treatment of advanced gastric cancer was diagnosed to be inoperable. A combination chemotherapy docetaxel and CDDP and S-1 as first-line treatment, CPT-11 and CDDP as second-line treatment, weekly paclitaxel treatment as third-line treatment, and MTX and 5-FU as fourth-line treatment were performed. He had progressed after 5-FU-based, CDDP-based, taxane-based, and CPT-11-based chemotherapy. There are no effective approved drugs for gastric cancer in Japan. Oxaliplatin was reportedly effective for metastatic gastric cancer, but it is still non-approved in Japan. After receiving an explanation of oxaliplatin-based therapy, he gave informed consent. Oxaliplatin-based therapy for this patient was then evaluated and approved under an institutional review board of Higashi Sapporo Hospital. mFOLFOX 6 used for the oxaliplatin-based therapy. After 2 courses of mFOLFOX 6, he showed a partial response. Oxaliplatin-based treatment was thought to be promising for previously CDDP-treated patients with unresectable gastric cancers.
Yasushi Sato, Tetsuji Takayama, Tomomi Nikaido, Yuko Wada, Tamotsu Sagawa, Seiichiro Abe, Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Hironobu Araki, Yasuhiro Sato, Junji Kato, Yoshiro Niitsu and Hideki Chiba : Report of an autopsy case of colon cancer with amyotrophic lateral sclerosis., The Japanese Journal of Gastro-enterology, Vol.104, No.9, 1365-1370, 2007.
(Summary)
Amyotrophic lateral sclerosis (ALS) is a degenerative disease involving both upper and lower motor neurons and the pathogenesis of this disorder is still unknown. To date, few reports have suggested that motor neuron diseases may have a paraneoplastic origin. However, it is still under discussion whether ALS occurring in cancer patients is paraneoplastic. A 60-year-old man with rectal cancer (Stage IV) having multiple lung, liver and para-aortic lymph node metastases underwent anterior resection of the rectum as palliative surgery. He was referred to our hospital for adjuvant chemotherapy. Lung and lymph node metastases decreased after 2 courses of chemotherapy using CPT-11 and 5-FU/LV but liver metastases were enlarged, following up increase in CEA. Thereafter, he suffered from muscle weakness in hands, arms, and legs and results of neurophysiologic studies were compatible with primary lateral sclerosis (ALS). For second line chemotherapy, he was treated with low-dose CDDP/5-FU over 6 courses. As a result, the size the of metastatic lesions markedly reduced and CEA was decreased to the normal level. Although significant tumor reduction was observed, his neurological symptoms rapidly progressed. He died of aspiration pneumonia 8 months after onset of the disease. Autopsy revealed that his neuropathological findings were compatible with ALS, and it was thought to be the primary cause of death in the because of absence of cancer progression. In this case the neurological syndrome was not affected by cancer therapy. Thus our case does not support the hypothesis that ALS in associated with cancer and the relationship between both disorders remains uncertain.
K Kuribayashi, K Nakamura, M Tanaka, T Sato, J Kato, K Sasaki, R Takimoto, K Kogawa, T Terui, Tetsuji Takayama, T Onuma, T Matsunaga and Y Niitsu : Essential role of protein kinase C {zeta} in transducing a motility signal induced by superoxide and a chemotactic peptide, fMLP., The Journal of Cell Biology, Vol.176, No.7, 1049-1060, 2007.
(Summary)
Under various pathological conditions, including infection, malignancy, and autoimmune diseases, tissues are incessantly exposed to reactive oxygen species produced by infiltrating inflammatory cells. We show augmentation of motility associated with morphological changes of human squamous carcinoma SASH1 cells, human peripheral monocytes (hPMs), and murine macrophage-like cell line J774.1 by superoxide stimulation. We also disclose that motility of hPMs and J774.1 induced by a chemotactic peptide (N-formyl-methionyl-leucyl-phenylalanine [fMLP]) was inhibited by superoxide dismutase or N-acetylcystein, indicating stimulation of motility by superoxide generated by fMLP stimulation. In these cells, protein kinase C (PKC) zeta was activated to phosphorylate RhoGDI-1, which liberated RhoGTPases, leading to their activation. These events were inhibited by dominant-negative PKCzeta in SASH1 cells, myristoylated PKCzeta peptides in hPMs and J774.1, or a specific inhibitor of RhoGTPase in SASH1, hPMs, and J774.1. These results suggest a new approach for manipulation of inflammation as well as tumor cell invasion by targeting this novel signaling pathway.
Tamotsu Sagawa, Yasushi Sato, Seiichiro Abe, Toshinori Okuda, Naoko Araki, Daisuke Takahari, Tetsuro Okamoto, Tetsuji Takayama, Junji Kato and Yoshiro Niitsu : [Anaphylactic reaction to oxaliplatin--a case of colon cancer]., Japanese Journal of Cancer and Chemotherapy, Vol.33, No.13, 2093-2096, 2006.
(Summary)
Oxaliplatin (L-OHP) is a new third-generation platinum which is efficacious in treating advanced unresectable recurrent colorectal cancer as a first-line regimen. The marketing authorization was given in Japan in March, 2005. Its increased use has resulted in rare serious adverse effects, including anaphylactic shock. We experienced a case that developed anaphylactic shock by L-OHP. We report a 69-year-old man who was treated for recurrent colorectal cancer who underwent systemic chemotherapy with FOLFOX 4. After eight cycles he developed severe L-OHP associated neuropathy and lung metastases was a progressive tendency. The FOLFOX 4 regimen was discontinued and another modality, FOLFIRI regimen, was used. After eight cycles of FOLFIRI regimen, lung and liver metastases showed progressive disease for response assessment by RECIST criteria. Although a patient was stopped L-OHP for neurotoxicity, neuropathy was disappeared after 4 months interval. Therefore, we reintroduced L-OHP, FOLFOX 4 regimen. Anaphylactic shock occurred in the second cycle of reintroduction of the FOLFOX 4 regimen (total 10 cycles), 30 minutes after infusion of L-OHP. L-OHP infusion was immediately withdrawn and he was treated with intravenous hydroxyzine hydrochloride and methylprednisolone. The anaphylaxis symptoms resolved in 30 minutes. Chemotherapy based on L-OHP for unresectable recurrence colorectal cancer causes anaphylactic shock as a rare severe complication. The prediction factor is not proved. We should take steps for early detection of anaphylactic reaction and perform the appropriate treatment.
Takuya Matsunaga, Ikuta Tanaka, Masayoshi Kobune, Yutaka Kawano, Maki Tanaka, Kageaki Kuribayashi, Satoshi Iyama, Tsutomu Sato, Yasushi Sato, Rishu Takimoto, Tetsuji Takayama, Junji Kato, Takafumi Ninomiya, Hirofumi Hamada and Yoshiro Niitsu : Ex vivo large scale generation of human platelets from cord blood CD34+ cells., Stem Cells, Vol.24, No.12, 2877-2887, 2006.
(Summary)
In the present investigation, we generated platelets (PLTs) from cord blood (CB) CD34(+) cells using a three-phase culture system. We first cultured 500 CB CD34(+) cells on telomerase gene-transduced human stromal cells (hTERT stroma) in serum-free medium supplemented with stem cell factor (SCF), Flt-3/Flk-2 ligand (FL), and thrombopoietin (TPO) for 14 days. We then transferred the cells to hTERT stroma and cultured for another 14 days with fresh medium containing interleukin-11 (IL-11) in addition to the original cytokine cocktail. Subsequently, we cultured the cells in a liquid culture medium containing SCF, FL, TPO, and IL-11 for another 5 days to recover PLT fractions from the supernatant, which were then gel-filtered to purify the PLTs. The calculated yield of PLTs from 1.0 unit of CB (5 x 10(6) CD34(+) cells) was 1.26 x 10(11) - 1.68 x 10(11) PLTs. These numbers of PLTs are equivalent to 2.5-3.4 units of random donor-derived PLTs or 2/5-6/10 of single-apheresis PLTs. The CB-derived PLTs exhibited features quite similar to those from peripheral blood in morphology, as revealed by electron micrographs, and in function, as revealed by fibrinogen/ADP aggregation, with the appearance of P-selectin and activated glycoprotein IIb-IIIa antigens. Thus, this culture system may be applicable for large-scale generation of PLTs for future clinical use.
T Oku, S Iyama, T Sato, Yasushi Sato, M Tanaka, T Sagawa, K Kuribayashi, T Sumiyosi, K Murase, T Machida, T Okamoto, T Matsunaga, Tetsuji Takayama, M Takahashi, J Kato, H Hamada and Y Niitsu : Amelioration of murine dextran sulfate sodium-induced colitis by ex vivo extracellular superoxide dismutase gene transfer., Inflammatory Bowel Diseases, Vol.12, No.7, 630-640, 2006.
(Summary)
Although the etiology of inflammatory bowel disease has not been fully clarified, reactive oxygen species is speculated to be involved. Extracellular superoxide dismutase (EC-SOD), an isozyme of SODs, is known to function mainly in body fluids. We investigated the efficacy of an ex vivo EC-SOD gene transfer into dextran sulfate sodium (DSS)-induced colitis mice. Experimental colitis was induced by providing Balb/c mice with DSS in sterile distilled water provided as desired. The syngenic fibroblasts were obtained from Balb/c mice embryos and retrovirally transduced with the hEC-SOD gene. These engineered cells were confirmed to secrete EC-SOD in culture medium by enzyme-linked immunosorbent assay and were inoculated subcutaneously in the backs of DSS-treated mice. Mucosal injury of the colon was evaluated by the disease activity index (DAI: body weight, rectal bleeding, and stool consistency), grading of histologic disease severity, and levels of cytokine (tumor necrosis factor-alpha, interleukin-1beta) production. 8-Hydroxydeoxyguanosine (8-OHdG) levels in the mucosal tissue were assessed by immunohistochemical staining. Malondialdehyde (MDA) was measured using a colorimetric assay. A significant improvement was observed in DAI score and histologic severity as well as in mucosal tissue levels of inflammatory cytokines, 8-OHdG, and MDA of mice treated with the EC-SOD gene as compared with those without gene therapy, not only in a mild colitis model but also in a severe colitis model. Survival of treated mice in these models was significantly prolonged. Ex vivo transfer of the EC-SOD gene was feasible for treatment of DSS-induced colitis.
Yasushi Sato, J Kato, R Takimoto, K Takada, Y Kawano, K Miyanishi, M Kobune, Y Sato, Tetsuji Takayama, T Matsunaga and Y Niitsu : Hepatitis C virus core protein promotes proliferation of human hepatoma cells through enhancement of transforming growth factor-{alpha} expression via activation of NF-{kappa}B., Gut, Vol.55, No.12, 1801-1808, 2006.
(Summary)
Hepatitis C virus (HCV) infection is a major cause of human hepatocellular carcinoma (HCC). The precise mechanism of hepatocarcinogenesis in humans by HCV is currently unclear. It was recently shown, however, that transgenic mice with the HCV core gene often develop HCC, suggesting tumorigenic activity of the HCV core protein. Further, the HCV core protein expressed in HepG2 cells transfected with the core gene was shown to stimulate proliferation of transfectants through activation of nuclear factor-kappaB (NF-kappaB). The downstream target molecule(s) of NF-kappaB activated by the HCV core protein to evoke cell proliferation is not yet identified. Transforming growth factor (TGF) alpha, which is often overexpressed in various tumour tissues such as HCC, has been shown to stimulate hepatocyte proliferation through activation of the mitogen-activated protein kinase or extracellular signal-related protein kinase (MAPK/ERK) cascade. To explore the possibility that TGFalpha might be a target molecule for NF-kappaB activated by the HCV core, and that TGFalpha participates in the growth promotion of the core transfectants in an autocrine manner, activating the MAPK/ERK pathway. A HCV core expression vector was transfected into human hepatoma Huh-7, HepG2 and Hep3B cells. NF-kappaB activity was examined by an electrophoretic mobility shift assay. TGFalpha transcription was assessed by a luciferase reporter assay. TGFalpha protein was determined by immunoblot and ELISA. MAPK/ERK activity was examined by an in vitro kinase assay. Cell proliferation was assessed by a water-soluble tetrazolium salt-1 assay. In the HCV core transfectants, NF-kappaB bound to the kappaB site in the TGFalpha proximal promoter region, resulting in an increase in TGFalpha transcription. Immunoblot as well as ELISA showed increased TGFalpha expression in the HCV core transfectants. SN50, a specific inhibitory peptide for NF-kappaB, cancelled HCV core-induced TGFalpha expression. HCV core protein increased cell proliferation as well as ERK activity of the HCV core transfectants as compared with the mock transfectants. The growth-promoting activity and activation of ERK by the HCV core protein were negated by treatment with anti-TGFalpha antibodies. These results suggest that the HCV core protein promotes proliferation of human hepatoma cells by activation of the MAPK/ERK pathway through up regulation of TGFalpha transcription via activation of NF-kappaB. Our finding provides a new insight into the mechanism of hepatocarcinogenesis by HCV infection.
Tetsuji Takayama, K Miyanishi, T Hayashi, Yasushi Sato and Y Niitsu : Colorectal Cancer: genetics of development and metastasis., Journal of Gastroenterology, Vol.41, No.3, 185-192, 2006.
(Summary)
It has been well documented that there are two major pathways in colorectal carcinogenesis. One is the chromosomal instability pathway (adenoma-carcinoma sequence), which is characterized by allelic losses on chromosome 5q (APC), 17p (p53), and 18q (DCC/SMAD4), and the other is a pathway that involves microsatellite instability. Recent progress in molecular biology, however, has shown that colorectal carcinogenesis is not necessarily clearly divided into these two pathways, but is in fact more complicated. Other routes, including the transforming growth factor-beta/SMAD pathway, the serrated pathway, and the epigenetic pathway, have been reported. Cross talk among these pathways has also been reported. In the invasion and metastasis steps of colorectal cancers, many more genes have now been identified as being involved in proteolysis, adhesion, angiogenesis, and cell growth. Recently accumulated evidence indicates that colorectal cancer is a genetically heterogeneous and complicated disease.
Yasushi Sato, Tetsuji Takayama, T Sagawa, T Okamoto, K Miyanishi, T Sato, H Araki, S Iyama, S Abe, K Murase, R Takimoto, H Nagakura, M Hareyama and Y Niitsu : A phase I/II study of nedaplatin and 5-fluorouracil with concurrent radiotherapy in patients with esophageal cancer., Cancer Chemotherapy and Pharmacology, Vol.58, No.5, 570-576, 2006.
(Summary)
To determine the recommended dose (RD) of cis-diammine-glycolatoplatinum (nedaplatin) when given concurrently with 5-FU and high dose radiation therapy in the treatment of esophageal cancer. The purpose of the phase II trial is to determine efficacy and further define the side effect profile. Twenty-six patients with clinical stage I to IVA squamous cell carcinoma of the esophagus were enrolled in a non-surgical treatment comprised of a fixed dose of fluorouracil (400 mg/m2 administered as continuous intravenous infusion on days 1-5 and days 8-12) plus escalating doses of nedaplatin (40 mg/m2 in level 1, 50 mg/m2 in level 2, or 60 mg/m2 in level 3 on days 1 and 8), repeated twice every 3 weeks with concurrent radiotherapy (60 Gy). Between July 1998 and February 2004, a total of 26 patients entered this trial, all of whom were considered evaluable for toxicity assessment. In phase I of the study, 12 patients were treated in sequential cohorts of three to six patients per dose level. The maximum tolerated dose was reached at level 3 with two grade 4 neutropenia and one grade 4 thrombocytopenia. Thus, the recommended dosing schedule is level 2. Of the 20 patients treated at the RD level 2, including 6 patients of the RD phase I portion, 8 out of 20 patients (40%) had grade 3-4 neutropenia, 5 patients (25.0%) had grade 3-4 thrombocytopenia, 4 patients (20.0%) had grade 3 anemia and 4 patients (20.0%) had grade 3-4 esophagitis. Other toxicities were relatively mild and usually of grade 2 or less. Objective responses were noted in the 26 patients (overall response rate, 88.5%) including 11 (42.3%) complete remissions. The 1- and 3-year survival rates were 65.1 and 37.2%, respectively, with a median survival time of 21.2 months. The combination of nedaplatin and 5-FU with radiation is a feasible regimen that shows promising antitumor activity with an acceptable safety profile in patients with esophageal cancer.
T Akiyama, T Matsunaga, T Terui, K Miyanishi, I Tanaka, T Sato, H Kuroda, R Takimoto, Tetsuji Takayama, J Kato, N Yamauchi, K Kogawa, S Sakamaki, Y Hirayama, K Kohda and Y Niitsu : Involvement of transforming growth factor-beta and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis., Leukemia, Vol.19, No.9, 1558-1566, 2005.
(Summary)
We investigated the cause of myelofibrosis and proliferation of megakaryocytes in myelodysplastic syndrome with myelofibrosis (MDS-MF (+)). Plasma-transforming growth factor-beta1 (PTGF-beta1) concentrations closely correlated with myelofibrosis grade in MDS-MF (+) and were higher than those in idiopathic myelofibrosis (IMF), essential thrombocythemia (ET), idiopathic thrombocytopenic purpura (ITP), MDS-without MF (MDS-MF (-)) or healthy volunteers (HV). Peripheral blood mononuclear cells from MDS-MF (+) patients expressed more TGF-beta1 mRNA than those from IMF, MDS-MF (-) or HV. When we immunostained bone marrow specimens of MDS-MF (+) for TGF-beta, the intensity of blasts was apparently higher than that of megakaryocytes, while in MDS-MF (-), megakaryocytes were immunostained with a similar intensity as that in MDS-MF (+), but blasts were negative for staining. In IMF, megakaryocytes, monocytes and small mononuclear cells representing CD34+ cells were all similarly stained with a much lower intensity than that of blasts in MDS-MF (+). The number of bone marrow megakaryocytes were increased the most in MDS-MF (+), followed by ET, ITP, MDS-MF (-) and NHL and correlated with plasma thrombopoietin (TPO) levels or with plasma TGF-beta1 levels, respectively, in each disease. Thus, in MDS-MF (+), both myelofibrosis and the increased megakaryocytes were ascribed to overproduction of TGF-beta1 from blasts.
Tetsuji Takayama, M Miyanishi, T Hayashi, T Kukitsu, K Takanashi, T Kogawa, T Abe and Y Niitsu : Aberrant crypt foci: detection, gene abnormalities, and clinical usefulness, Clinical Gastroenterology and Hepatology, Vol.3, No.7 Suppl 1, S42-S45, 2005.
(Summary)
Human aberrant crypt foci (ACF) were first identified as lesions consisting of large thick crypts in colonic mucosa of surgical specimens after staining with methylene blue. Previously we succeeded in identifying ACF by using magnifying endoscopy and analyzed the number, size, and dysplastic features of ACF in normal controls and patients with adenoma or cancer patients. On the basis of these analyses, we strongly suggested that ACF, particularly dysplastic ACF, are precursor lesions of the adenoma-carcinoma sequence in humans. In most sporadic ACF, K-ras mutations were positive, but APC mutations were negative irrespective of nondysplastic or dysplastic features. Conversely, in most ACF from familial adenomatous polyposis patients, APC mutations were positive but K-ras mutations were negative. These results may suggest that the molecular mechanism of sporadic colon carcinogenesis is not necessarily the same as that of familial adenomatous polyposis. It was shown that ACF acquired resistance to apoptosis induced by bile salts, whereas normal colonic epithelial cells are turning over consistently by apoptosis. This apoptosis resistance was closely associated with glutathione S-transferase P1-1 expression. One of the most important clinical applications of ACF observation with magnifying endoscopy is its use as a target lesion for chemoprevention. Because ACF are tiny lesions, they should be eradicated during a short time by administration of chemopreventive agents. In fact, we performed an open chemopreventive trial of sulindac and found that the number of ACF was reduced markedly in 2 months. We currently are proceeding with a randomized double-blind trial targeting ACF.
R Takimoto, J Kato, T Terui, K Takada, G Kuroiwa, J Wu, H Ohnuma, D Takahari, M Kobune, Yasushi Sato, Tetsuji Takayama, T Matsunaga and Y Niitsu : Augmentation of Antitumor Effects of p53 Gene Therapy by Combination with HDAC Inhibitor., Cancer Biology & Therapy, Vol.4, No.4, 421-428, 2005.
(Summary)
We have previously shown that the HDAC inhibitors (HDACI) activate the p53 molecule through acetylation of 320 and 373 lysine residues, upregulate PIG3 and NOXA and induce apoptosis in cancer cells expressing wild and pseudo-wild type p53 genes (Terui T, et al. Cancer Res 2003; 63:8948-54). It has also been reported that expression of the Coxsackie adenovirus receptor and subsequent transfection efficiency of the adenovirus in cancer cells were enhanced by HDACI treatment. In this study, we extended these observations to explore the combination effect of adenoviral vector carrying wild type p53 (Ad-p53) gene therapy with a HDACI, sodium butyrate (SB), on xenografted human gastric cancer cells (KATO-III) and hepatocellular carcinoma cells (HuH7) in nude mice. We first confirmed an increased expression of Coxsackie adenovirus receptors with an associated increment of transgene (X-gal) expression by SB treatment in KATO-III cells. We then injected Ad-p53 into subcutaneous tumors of KATO-III and HuH7 combined with intraperitoneal administration of SB and found a significantly higher growth suppressive effect than single treatments of each. Even a complete regression of tumors was observed in three of five mice treated with this combination while with single treatment no tumor regression was observed. Tumors treated with the combination showed higher numbers of TUNEL positive cells than those treated with a single modality. Moreover, necrotic changes were more evident in tumors treated with the combination than separately, a compatible finding to the observation that vascularity revealed by CD34 staining was poorer in tumors treated with the combination than those treated with p53 gene or SB alone. This was further supported by the finding that BAI-1 (brain specific angiogenesis inhibitor-1), an inhibitor of vascularization, was induced by SB treatment in KATO-III and HuH7 cells transfected with Ad-p53. Thus SB was shown to be an efficient potentiator of p53 gene therapy for cancer.
Yasushi Sato, H Araki, J Kato, K Nakamura, Y Kawano, M Kobune, T Sato, K Miyanishi, Tetsuji Takayama, M Takahashi, R Takimoto, S Iyama, T Matsunaga, S Ohtani, A Matsuura, H Hamada and Y Niitsu : Human mesenchymal stem cells xenografted directly to rat liver differentiated into human hepatocytes without fusion., Blood, Vol.106, No.2, 756-763, 2005.
(Summary)
Hepatic transdifferentiation of bone marrow cells has been previously demonstrated by intravenous administration of donor cells, which may recirculate to the liver after undergoing proliferation and differentiation in the recipient's bone marrow. In the present study, to elucidate which cellular components of human bone marrow more potently differentiate into hepatocytes, we fractionated human bone marrow cells into mesenchymal stem cells (MSCs), CD34+ cells, and non-MSCs/CD34- cells and examined them by directly xenografting to allylalcohol (AA)-treated rat liver. Hepatocyte-like cells, as revealed by positive immunostaining for human-specific alpha-fetoprotein (AFP), albumin (Alb), cytokeratin 19 (CK19), cytokeratin 18 (CK18), and asialoglycoprotein receptor (AGPR), and by reverse transcription-polymerase chain reaction (RT-PCR) for expression of AFP and Alb mRNA, were observed only in recipient livers with MSC fractions. Cell fusion was not likely involved since both human and rat chromosomes were independently identified by fluorescence in situ hybridization (FISH). The differentiation appeared to follow the process of hepatic ontogeny, reprogramming of gene expression in the genome of MSCs, as evidenced by expression of the AFP gene at an early stage and the albumin gene at a later stage. In conclusion, we have demonstrated that MSCs are the most potent component in hepatic differentiation, as revealed by directly xenografting into rat livers.
K Yamaguchi, H Shibuya, K Sasaki, K Takashima, Yasushi Sato, Y Arimura, Tetsuji Takayama, Itsuro Endo, Y Shinomura, Y Niitsu and K Hirata : Clinical evaluation of laparoscopy-assisted distal gastrwctomy for early gastric cancer., Tumor Research, Vol.40, 37-45, 2005.
199.
Tamotsu Sagawa, Minoru Takahashi, Tsutomu Sato, Yasushi Sato, Yue Lu, Tetsuya Sumiyoshi, Yasuyuki Yamada, Satoshi Iyama, Junki Fukaura, Katsunori Sasaki, Hirofumi Hamada, Koji Miyanishi, Tetsuji Takayama, Junji Kato and Yoshiro Niitsu : Prolonged survival of mice with multiple liver metastases of human colon cancer by intravenous administration of replicable E1B-55K-deleted adenovirus with E1A expressed by CEA promoter., Molecular Therapy, Vol.10, No.6, 1043-1050, 2004.
(Summary)
Liver is the most preferential site for metastasis of colon cancer. We, in the present study, constructed a self-replicable adenovirus in which E1A is driven by a CEA promoter and E1B-55K is deleted from the E1B region (AdCEAp/Rep) and examined its effects on multiple metastases of a human colon cancer cell in a mouse xenograft model. We first showed effective replication of the virus in various CEA-producing human colon cancer cells (M7609, HT-29) and subsequent lysis of the infected cells in vitro. We then demonstrated that a single intratumoral injection of the virus (1 x 10(8) PFU/100 microl) induced a complete regression of subcutaneous tumors (M7609) inoculated into nude mice. Further, we demonstrated that systemic administration of the virus (1 x 10(8) PFU/100 microl) through the tail vein to nude mice, which 1 week prior had been inoculated with tumor cells (colon carcinoma cell line HT-29) via the spleen and showed apparent multiple metastases in the liver, effectively suppressed the metastasis formation. The mean survival time of the treated mice was significantly longer than that of the controls. Thus, the systemic administration of AdCEAp/Rep was considered to be effective on multiple liver metastases of CEA-positive colon cancer in a xenograft model.
Tsutomu Sato, Takuya Matsunaga, Masaya Kida, Kazuhiro Morii, Takuro Machida, Yutaka Kawano, Kiminori Nakamura, Kageaki Kuribayashi, Kohichi Takada, Satoshi Iyama, Yasushi Sato, Tetsuji Takayama, Minoru Takahashi, Junji Kato, Manabu Chokki and Yoshiro Niitsu : Interleukin-11 as an osteoprotegerin-inducing factor in culture medium of blastic cells from a patient with acute megakaryocytic leukemia complicated with osteosclerosis., American Journal of Hematology, Vol.77, No.1, 62-66, 2004.
(Summary)
We came across a rare case of acute megakaryocytic leukemia, the clinical course of which was relatively chronic and nonaggressive. This case was complicated with generalized severe osteosclerosis (OS). The medium in which blastic cells from the patient were cultured showed a strong activity to enhance the expression of an osteosclerotic cytokine, osteoprotegerin (OPG), as revealed by real-time quantitative RT-PCR and Western blot analysis. The OPG-inducing activity of the culture medium was neutralized by the anti-interleukin-11 (IL-11) antibody. These results indicate that IL-11 produced by the blasts was a causative factor of the OS observed in this patient.
A Nobuoka, Tetsuji Takayama, K Miyanishi, T Sato, T Hayashi, T Kukitsu, K Takanashi, Yasushi Sato, M Takahashi, T Okamoto, T Matsunaga, J Kato, M Oda, T Azuma and Y Niitsu : Glutathione S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid., Gastroenterology, Vol.127, No.2, 428-443, 2004.
(Summary)
Aberrant crypt foci, precursors of colonic adenoma, are frequently positive for glutathione-S-transferase P1-1. Because deoxycholic acid is an apoptosis-inducing xenobiotic in the colon, we examined the possibility that aberrant crypt foci, through the cytoprotecting function of glutathione-S-transferase P1-1, resist deoxycholic acid-induced apoptosis, thereby surviving to become adenomas and subsequently cancer. Glutathione-S-transferase P1-1 or cyclooxygenase-2 expression and the percentage of apoptotic cells in aberrant crypt foci were examined by immunohistochemistry and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, respectively. Glutathione-S-transferase P1-1 was transfected into colon cancer cells (M7609) and human lung fibroblasts, and deoxycholic acid-induced apoptosis was evaluated by a dye-uptake assay and flow cytometry. Binding of deoxycholic acid to glutathione-S-transferase P1-1 was analyzed by circular dichroism and immunoprecipitation. Caspase activities were determined by colorimetric protease assay, and sulindac binding to glutathione-S-transferase P1-1 was determined by inhibition assay of glutathione-S-transferase P1-1 activity. Aberrant crypt foci showed positive immunostaining for glutathione-S-transferase P1-1 but negative staining for cyclooxygenase-2. The percentage of apoptotic cells in aberrant crypt foci was significantly lower than in healthy epithelium, and the difference became more apparent with deoxycholic acid treatment. The impaired sensitivity of aberrant crypt foci to deoxycholic acid was restored by the glutathione-S-transferase P1-1-specific inhibitor gamma-glutamyl-S-(benzyl)cysteinyl-R-phenylglycine diethylester. By transfection of glutathione-S-transferase P1-1, M7609 cells became more resistant to deoxycholic acid-induced apoptosis than mock transfectants. Direct binding of glutathione-S-transferase P1-1 to deoxycholic acid was proven by circular dichroism and by immunoprecipitation. The aberrant crypt foci in adenoma patients treated with sulindac, which was shown to bind to glutathione-S-transferase P1-1, underwent apoptosis in 4 days and mostly regressed in 2-3 months. Glutathione-S-transferase P1-1 protects aberrant crypt foci from deoxycholic acid-induced apoptosis and may play a pivotal role in early colon carcinogenesis.
Tsutomu Sato, Takuro Machida, Sho Takahashi, Satoshi Iyama, Yasushi Sato, Kageaki Kuribayashi, Kohichi Takada, Takatomi Oku, Yutaka Kawano, Tetsuro Okamoto, Rishu Takimoto, Takuya Matsunaga, Tetsuji Takayama, Minoru Takahashi, Junji Kato and Yoshiro Niitsu : Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells., The Journal of Immunology, Vol.173, No.1, 285-296, 2004.
(Summary)
Generation of reactive oxygen species (ROS) and activation of caspase cascade are both indispensable in Fas-mediated apoptotic signaling. Although ROS was presumed to affect the activity of the caspase cascade on the basis of findings that antioxidants inhibited the activation of caspases and that the stimulation of ROS by itself activated caspases, the mechanism by which these cellular events are integrated in Fas signaling is presently unclear. In this study, using human T cell leukemia Jurkat cells as well as an in vitro reconstitution system, we demonstrate that ROS are required for the formation of apoptosome. We first showed that ROS derived from mitochondrial permeability transition positively regulated the apoptotic events downstream of mitochondrial permeability transition. Then, we revealed that apoptosome formation in Fas-stimulated Jurkat cells was clearly inhibited by N-acetyl-L-cysteine and manganese superoxide dismutase by using both the immunoprecipitation and size-exclusion chromatography methods. To confirm these in vivo findings, we next used an in vitro reconstitution system in which in vitro-translated apoptotic protease-activating factor 1 (Apaf-1), procaspase-9, and cytochrome c purified from human placenta were activated by dATP to form apoptosome; the formation of apoptosome was markedly inhibited by reducing reagents such as DTT or reduced glutathione (GSH), whereas hydrogen peroxide prevented this inhibition. We also found that apoptosome formation was substantially impaired by GSH-pretreated Apaf-1, but not GSH-pretreated procaspase-9 or GSH-pretreated cytochrome c. Collectively, these results suggest that ROS plays an essential role in apoptosome formation by oxidizing Apaf-1 and the subsequent activation of caspase-9 and -3.
Takatomi Oku, Tetsuji Takayama, Yasuhiro Sato, Yasushi Sato, Koichi Takada, Tsuyoshi Hayashi, Minoru Takahashi, Mitsugu Kuroda, Junji Kato and Yoshiro Niitsu : A case of Gardner syndrome with a mutation at codon 1556 of APC: a suggested case of genotype-phenotype correlation in dental abnormality., European Journal of Gastroenterology & Hepatology, Vol.16, No.1, 101-105, 2004.
(Summary)
A 25-year-old man with suspected Gardner syndrome was introduced to our hospital by a dentist who, during examination of the patient, had found dental dysplasias and multiple osteomas of the jaw. Radiographs, endoscopy and biopsies revealed adenomatous polyposis of the colon. Genetic analysis of peripheral lymphocytes revealed a one-base deletion at codon 1556 in exon 15 of APC, which caused a frame shift and a premature stop at codon 1564. The pedigree analysis demonstrated five patients in his family who presented with dental abnormality and osteomas in addition to adenomatous polyposis of the colon. Although the relationship between the location of APC mutations and dental abnormalities remains controversial, this case supports the hypothesis that a mutation at around codon 1556 of APC is closely associated with dental abnormality and osteomas.
Tamotsu Sagawa, Yasushi Tsuji, Norihiro Takayanagi, Yasuo Hirayama, Sumio Sakamaki, Hiroki Chiba, Takaharu Nakajima, Satoshi Iyama, Takatomi Oku, Tetsuya Sumiyoshi, Yasushi Sato, Minoru Takahashi, Tetsuji Takayama and Yoshiro Niitsu : [A case responding to weekly paclitaxel (TXL) therapy as third line chemotherapy for scirrhous type gastric cancer]., Japanese Journal of Cancer and Chemotherapy, Vol.30, No.5, 707-710, 2003.
(Summary)
A 67-year-old female was admitted to our hospital in May, 2001 for examination. She was diagnosed with advanced gastric cancer that was inoperable due to peritoneal dissemination. Seventeen courses of sequential MTX and 5-FU therapy, and 2 courses of TS-1 plus CDDP were carried out. A partial response (PR) and prolonged NC were obtained after these chemotherapies. However, pleural effusion and ascites appeared again, and we diagnosed progressive disease. As a third line chemotherapy for this patient, paclitaxel (TXL) was administered. Treatment consisted of two 3-week courses of paclitaxel 70 mg per m2 on day 1 of each week, with a 1-week break between the courses. Two weeks after the start of this therapy, pleural effusion and ascites had completely disappeared. Paclitaxel is considered to be promising for advanced gastric cancers, as second or third line chemotherapy with paclitaxel for patients with inoperable gastric cancer seems to be effective in improving QOL.
Tamotsu Sagawa, Yasushi Tsuji, Norihiro Takayanagi, Yasuo Hirayama, Sumio Sakamaki, Hiroki Chiba, Satoshi Iyama, Takatomi Oku, Yasushi Sato, Minoru Takahashi, Tetsuji Takayama and Yoshiro Niitsu : [A case of irinotecan-resistant colon cancer responding to chronotherapy with oxaliplatin, 5-FU, l-LV]., Japanese Journal of Cancer and Chemotherapy, Vol.30, No.4, 537-543, 2003.
(Summary)
We report a case of irinotecan-resistant colon cancer responding to chronotherapy with oxaliplatin (L-OHP), 5-FU, l-LV (l-Leucovorin). A 72-year-old man was examined at a certain hospital because of constipation and appetite loss. Chest computed tomography (CT) revealed lung metastases, and abdominal CT revealed liver metastases. He was then referred to our hospital. A colonoscopy revealed type 2 tumor in the colon, at the hepatic flexure. We diagnosed adenocarcinoma of the colon with metastases to the liver and lung. Resection of the primary lesion was performed, and chemotherapy consisting of systemic administration of CPT-11, 5-FU and l-LV was performed. After 2 courses of combined treatment with CPT-11/5-FU/l-LV, CT revealed considerable reduction of the metastatic tumors. However, after 3 courses of combined treatment, progressive disease was observed and new brain and bone metastases were detected. We imported and used a non-approved/pending drug, oxaliplatin from the Remedy and Health Corporation, with informed consent from the patient and his family and our clinical ethics committee. Chronotherapeutic schedules have been performed, from which the safety and activity of oxaliplatin against advanced colorectal cancer was reported. Our patient received a 5-day course of chronomodulated 5-FU and l-LV (750 and 300 mg/body/day, respectively; peak delivery rate at AM 4:00 hours) with L-OHP on the first day of each course (100 mg/body, as a 6-hour infusion). Each course was again repeated every 21 days. A partial response was observed in the liver and lung metastases. These results indicate that chronomodulated 5-FU and LV with L-OHP therapy could be an effective regimen for cases of irinotecan-resistant colon cancer.
(Keyword)
Aged / Antineoplastic Combined Chemotherapy Protocols / Bone Neoplasms / Camptothecin / Chronotherapy / Colonic Neoplasms / Drug Evaluation / Drug Resistance, Neoplasm / Fluorouracil / Humans / Leucovorin / Liver Neoplasms / Lung Neoplasms / Male / Organoplatinum Compounds
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12722689
T Sagawa, Tetsuji Takayama, T Oku, T Hayashi, H Ota, T Okamoto, H Muramatsu, S Katsuki, Yasushi Sato, J Kato and Y Niitsu : Argon plasma coagulation for successful treatment of early gastric cancer with intramucosal invasion., Gut, Vol.52, No.3, 334-339, 2003.
(Summary)
APC is a safe and effective modality for treatment of early gastric cancer with intramucosal invasion untreatable by surgical resection or EMR. However, further observations are necessary to determine the long term prognosis of patients undergoing this treatment.
G Kuroiwa, Tetsuji Takayama, Yasushi Sato, Y Takahashi, T Fujita, A Nobuoka, T Kukitsu, J Kato, S Sakamaki and Y Niitsu : Primary intestinal lymphangiectasia successfully treated with octreotide., Journal of Gastroenterology, Vol.36, No.2, 129-132, 2001.
(Summary)
A 21-year-old man with diarrhea and edema was admitted to our hospital and diagnosed with protein-losing enteropathy caused by primary intestinal lymphangiectasia. He was placed, in turn, on a low-fat diet, an elemental diet, and, subsequently, fasting therapy with total parenteral nutrition (TPN) support. However, his symptoms were not relieved, but, rather were exacerbated. On the 45th day of hospitalization, octreotide therapy was initiated. After 2 weeks of treatment, his clinical symptoms, as well as hypoproteinemia and hypoalbuminemia, gradually became alleviated. The improvement was confirmed in terms of scintigraphy, endoscopy, and histology of the duodenum. The patient remained healthy until 6 months after the commencement of octreotide treatment, when he discontinued octreotide at his own discretion, at which point the symptoms recurred. Resumption of the drug, however, again brought about remission, which has continued until the present, March 2000. Thus, octreotide therapy is one modality which may be useful for refractory primary intestinal lymphangiectasia.
T Goji, Seisuke Okamura, H Takeuchi, Tetsuo Kimura, Shinji Kitamura, Katsuyoshi Tamaki, Koichi Okamoto, Masako Kaji, Naoki Muguruma, Toshiya Okahisa, J Shunto and Tetsuji Takayama : Migrated Endoclip and Stone Formation after Cholecystectomy: A Case Treated by Endoscopic Sphincterotomy, Internal Medicine, Vol.48, No.23, 2015-2017, 2009.
(Summary)
Endoclip migration into the common bile duct following laparoscopic cholecystectomy (LC) is an extremely rare complication. Migrated endoclip into the common bile duct can cause obstruction, serve as a nidus for stone formation, and cause cholangitis. We report a case of cholangitis due to a migrated endoclip and consequent choledocholithiasis 6 years after LC, which was successfully treated by endoscopic extraction.
(Keyword)
Aged / Cholecystectomy / Common Bile Duct / Foreign-Body Migration / Gallstones / Humans / Male / Postoperative Complications / Sphincterotomy, Endoscopic / Surgical Instruments
Naoki Muguruma and Tetsuji Takayama : Endoscopic Sclerotherapy with Aluminum Potassium Sulfate and Tannic Acid: An Effective and Less Invasive Strategy for Internal Hemorrhoids, Clinical Endoscopy, Vol.52, No.6, 521-522, 2019.
Yasushi Sato, Koichi Okamoto, Yoshifumi Kida, Yasuhiro Mitsui, Yutaka Kawano, Masahiro Sogabe, Hiroshi Miyamoto and Tetsuji Takayama : Overview of Chemotherapy for Gastric Cancer., Journal of Clinical Medicine, Vol.12, No.4, 1336, Feb. 2023.
(Summary)
Gastric cancer (GC) is one of the most clinically challenging cancers worldwide. Over the past few years, new molecular-targeted agents and immunotherapy have markedly improved GC prognosis. Human epidermal growth factor receptor 2 (HER2) expression is a key biomarker in first-line chemotherapy for unresectable advanced GC. Further, the addition of trastuzumab to cytotoxic chemotherapy has extended the overall survival of patients with HER2-positive advanced GC. In HER2-negative GC, the combination of nivolumab, an immune checkpoint inhibitor, and a cytotoxic agent has been demonstrated to prolong the overall survival of GC patients. Ramucirumab and trifluridine/tipiracil, which are second- and third-line treatments for GC, and trastuzumab deruxtecan, an antibody-drug conjugate for HER2-positive GC, have been introduced in clinics. New promising molecular-targeted agents are also being developed, and combination therapy comprising immunotherapy and molecular-targeted agents is expected. As the number of available drugs increases, it is important to understand the target biomarkers and drug characteristics and select the optimal therapy for each patient. For resectable disease, differences in the extent of standard lymphadenectomy between Eastern and Western countries have led to different standard treatments: perioperative (neoadjuvant) and adjuvant therapy. This review aimed to summarize recent advances in chemotherapy for advanced GC.
Satoshi Teramae, Kumiko Tanaka, Koichi Okamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : Cowden症候群(IV. 各論 消化管ポリポーシス)., Nihon Rinsho. Japanese Journal of Clinical Medicine, Vol.80, No.7, 241-246, Jul. 2022.
5.
石川 秀樹, Tetsuji Takayama, Kumiko Tanaka and 竹内 洋司 : 家族性大腸腺腫症における空腸・回腸腫瘍(IV. 各論 消化管ポリポーシス)., Nihon Rinsho. Japanese Journal of Clinical Medicine, Vol.80, No.7, 225-228, Jul. 2022.
6.
Yasushi Sato, Koichi Okamoto, Tomoyuki Kawaguchi, Fumika Nakamura, Hiroshi Miyamoto and Tetsuji Takayama : Treatment Response Predictors of Neoadjuvant Therapy for Locally Advanced Gastric Cancer: Current Status and Future Perspectives., Biomedicines, Vol.10, No.7, 1614, Jul. 2022.
(Summary)
Neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (LAGC) has been recognized as an effective therapeutic option because it is expected to improve the curative resection rate by reducing the tumor size and preventing recurrence of micrometastases. However, for patients resistant to NAC, not only will operation timing be delayed, but they will also suffer from side effects. Thus, it is crucial to develop a comprehensive strategy and select patients sensitive to NAC. However, the therapeutic effect of NAC is unpredictable due to tumor heterogeneity and a lack of predictive biomarkers for guiding the choice of optimal preoperative treatment in clinical practice. This article summarizes the related research progress on predictive biomarkers of NAC for gastric cancer. Among the many investigated biomarkers, metabolic enzymes for cytotoxic agents, nucleotide excision repair, and microsatellite instability, have shown promising results and should be assessed in prospective clinical trials. Noninvasive liquid biopsy detection, including miRNA and exosome detection, is also a promising strategy.
Yasushi Sato and Tetsuji Takayama : 化学療法 術前化学療法 治療反応性予測因子(V.胃癌の治療)., Nihon Rinsho. Japanese Journal of Clinical Medicine, Vol.80, No.3, 281-287, Mar. 2022.
10.
Yoshiro Niitsu, Yasushi Sato and Tetsuji Takayama : Implications of glutathione-S transferase P1 in MAPK signaling as a CRAF chaperone: In memory of Dr. Irving Listowsky., Proceedings of the Japan Academy. Series B, Physical and biological sciences, Vol.98, No.2, 72-86, 2022.
(Summary)
Glutathione-S transferase P1 (GSTP1) is one of the glutathione-S transferase isozymes that belong to a family of phase II metabolic isozymes. The unique feature of GSTP1 compared with other GST isozymes is its relatively high expression in malignant tissues. Thus, clinically, GSTP1 serves as a tumor marker and as a refractory factor against certain types of anticancer drugs through its primary function as a detoxifying enzyme. Additionally, recent studies have identified a chaperone activity of GSTP1 involved in the regulation the function of various intracellular proteins, including factors of the growth signaling pathway. In this review, we will first describe the function of GSTP1 and then extend the details onto its role in the mitogen-activated protein kinase signal pathway, referring to the results of our recent study that proposed a novel autocrine signal loop formed by the CRAF/GSTP1 complex in mutated KRAS and BRAF cancers. Finally, the possibilities of new therapeutic approaches for these cancers by targeting this complex will be discussed.
Naohiro Tomita, Hideyuki Ishida, Tetsuji Takayama and Rectum Society for Cancer of the Colon Japanese : Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2020 for the Clinical Practice of Hereditary Colorectal Cancer., International Journal of Clinical Oncology, Vol.26, No.8, 1353-1419, Jun. 2021.
(Summary)
Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.
Takanori Kashihara, Naoki Muguruma, Shota Fujimoto, Yoshihiko Miyamoto, Yasushi Sato and Tetsuji Takayama : Recent Advances in Molecular Imaging of Colorectal Tumors., Digestion, Vol.102, No.1, 57-64, Dec. 2020.
(Summary)
Recent endoscopic studies have revealed that small colorectal tumors are often overlooked during colonoscopy, indicating that more sensitive detection methods are needed. Molecular imaging has received considerable attention as a new endoscopic technique with high sensitivity. It generally employs a fluorescence-labeled compound that specifically binds to a molecule on the tumor. Fluorescent probes for molecular imaging are largely classified as 2 types: a fluorescence-labeled antibody targeting a molecule specifically expressed on the tumor cell surface such as epidermal growth factor receptor or vascular endothelial growth factor (VEGF); and a fluorescence-labeled small molecule compound targeting a molecule specifically expressed in tumor cells including c-Met, glutathione S-transferase, γ-glutamyltranspeptidase, cathepsin, or endothelin A receptor. These probes successfully detected colorectal tumors in several animal studies. Moreover, 3 recent human clinical trials evaluating endoscopic molecular imaging for colorectal tumors have been reported. In one study, a Cy5-labeled synthetic peptide against c-Met was developed, and fluorescent endoscopic observation with this probe detected a greater number of colorectal adenomas than with white light observation. Another trial used IR800-labeled anti-VEGF antibody, which sensitively detected human colorectal adenomas by fluorescent endoscopy. Last, a fluorescent probe with synthetic peptide against BRAF-positive cells was able to visualize sessile serrated lesions. The fluorescent probes accumulated at very high levels in colorectal tumor cells but at lower levels in surrounding nonneoplastic mucosa. Key Messages: We expect that molecular imaging techniques with fluorescent probes will soon lead to the establishment of a highly sensitive endoscopic method for colorectal tumor detection.
Tetsuji Takayama, Takahiro Goji, Tatsuya Taniguchi and A Inoue : Chemoprevention of colorectal cancer-experimental and clinical aspects-., The Journal of Medical Investigation : JMI, Vol.56, No.1-2, 1-5, Feb. 2009.
(Summary)
Colorectal cancer is a leading cause of cancer-related mortality worldwide. Therefore, an appropriate prevention strategy should be urgently established. Chemoprevention involves the use of oral agents to suppress the development of cancer. Recent progress in the molecular analysis of colorectal cancer has revealed many candidate molecules for chemoprevention. Many new agents targeting these molecules have also been developed. These agents are largely classified into three categories: 1) Signal transduction modulators including epidermal growth factor (EGF) receptor inhibitors, anti-vascular endothelial growth factor (VEGF) antibodies, and inhibitors of oncogene products. 2) Epigenetic modulators including peroxisome proliferative activated receptor (PPAR)-gamma agonists, estrogen receptor (ER)-beta, and histone deacetylase inhibitors. 3) Anti-inflammatory modulators including cyclooxygenase (COX)-2, EP 1-4, and NF-kB. Of these agents, some actually proceeded to human clinical trials, and have been shown to be active chemopreventive agents.
阿部 清一郎, Tetsuji Takayama, 佐川 保, Yasushi Sato and 新津 洋司郎 : 【早期大腸癌の取り扱い】大腸ポリープの取り扱い どのようなポリープを取るか，取った後どうするか, 消化器の臨床, Vol.10, No.1, 45-49, Feb. 2007.
(Summary)
大腸ポリープの大部分を占める腺腫は前癌病変であることから，基本的に内視鏡的切除の適応である．ただし，腫瘍径5mm未満の微小ポリープについては必ずしも切除する必要はないと思われる．また，大腸ポリープ切除後のサーベイランスについては米国でガイドラインが発表されており，腺腫の個数，サイズ，組織学的悪性度に応じたサーベイランス期間が示されている．わが国においてもポリープ切除後の適切なサーベイランス期間を調べるためにJapan Polyp Study Workgroupによるrandomized control trialが開始され，その結果が待たれる．(著者抄録)
(Keyword)
*大腸ポリープ(外科的療法) 集団サーベイランス 臨床試験 内視鏡的粘膜切除術 ヒト
29.
Yasushi Sato, 佐川 保, Tetsuji Takayama and 新津 洋司郎 : 【食道・胃・十二指腸疾患】治療 食道癌・胃癌の外来化学療法 外来化学療法施設が普及した今日的指針, Medical Practice, Vol.23, No.8, 1409-1414, Aug. 2006.
Hironori Tanaka, Tetsu Tomonari, Ryo Shinomiya, Mai Yonezawa, Yutaka Kawano and Tetsuji Takayama : Usefulness of shear wave elastography for evaluation of HCC recurrence after ablation., APASL2024, Kyoto, Mar. 2024.
2.
Yutaka Kawano, Maki Tanaka, Yasushi Sato, Tetsu Tomonari, Hironori Tanaka, Takeshi Mitsuhashi and Tetsuji Takayama : Activation of HNF4α pathway by treatment with botanical plant, Acanthopanax Senticosus, ameliorates steatohepatitis in high-fat fed mice model., AASLD2023, Boston, Nov. 2023.
Tomoyuki Kawaguchi, Koichi Okamoto, shota fujimoto, Masahiro Bando, hironori wada, Hiroshi Miyamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : Lansoprazole as an effective chemopreventive agent for serrated-neoplasia pathway; A comprehensive analysis using connectivity map., DDW2023, May 2023.
5.
Yasushi Sato, Kazuyoshi Noda, Yasuyuki Okada, Kensei Nishida, Yutaka Kawano, Toshihito Tanahashi, Masanori Takehara, Yasuteru Fujino, Koichi Okamoto, Hiroshi Miyamoto and Tetsuji Takayama : Exosomal miR-199a-3p secreted from cancer-associated adipocytes promote pancreatic cancer progression., DDW2023, Chicago, May 2023.
6.
Yutaka Kawano, Maki Tanaka, Yasushi Sato, Tetsu Tomonari, Hironori Tanaka, Takeshi Mitsuhashi and Tetsuji Takayama : Activation of HNF4α pathway by treatment with botanical plant, Acanthopanax senticosus, ameliorates steatohepatitis in high-fat fed mice model., DDW2023, Chicago, May 2023.
7.
Tetsuji Takayama, Yoshifumi Kida, Toshiya Okahisa, Yasushi Sato, Masahiro Bando, shota Fujimoto, Tomoyuki Kawaguchi, Fumika Nakamura, Koichi Okamoto, Hiroshi Miyamoto, Koichi Tsuneyama and Masahiro Sogabe : The relevance of urokinase-type plasminogen activator in pathogenesis of ulcerative colitis., WCOG2022 (World Congress of Gastroenterology), Dubai, Dec. 2022.
8.
Toshiya Okahisa, Masahiro Sogabe, Ryosuke Ogata, Takatoshi Komatsu, Yoshiaki Ohnishi, Hiroyuki Ueda, Tomoyuki Kawaguchi, Akira Fukuya, Yoshifumi Kida, Tetsu Tomonari, Hiroshi Miyamoto and Tetsuji Takayama : Concentration Ratio Self-regulation Function of Ascites Filtration and Concentration Equipment for Cell-free and Concentrated Ascites Reinfusion Therapy, ASAIO 67th Annual Conference, Chicago, Jun. 2022.
9.
Hironori Tanaka, Tetsu Tomonari, Reika Matsumoto, Kazuyoshi Noda, Tatsuya Taniguchi and Tetsuji Takayama : Usefulness of shear wave elastography for evaluation of hepatocellular carcinoma recurrence after ablation therapy., ACTA 2021(7th conference on Tumor Ablation), Oct. 2021.
10.
Yasutsugu Shimohata, Yuji Urabe, Shiro Oka, Takashi Hisabe, Atsushi Yamada, Hiro-O Matsushita, Hirotsugu Sakamoto, Joichiro Horii, Daisuke Watanabe, Hirotsugu Eda, Fumika Nakamura, Hironori Yamamoto, Tetsuji Takayama, Takayuki Matsumoto, Shinji Tanaka and Hideki Ishikawa : Clinicopathological Characteristics of Serrated Polyposis Syndrome: Results of a Multicenter Study by the Colorectal Serrated Polyposis Syndrome (SPS) Study Group in Japan., Digestive Disease Week2021, May 2021.
11.
Yasuyuki Okada, Fuduan Peng, Jose Perea, Luis Bujanda, Tetsuji Takayama, Wei Li and Ajay Goel : Identification of a Novel Epigenetic Signature for the Identification of Patients with Synchronous Colorectal Cancers., Digestive Disease Week2021, May 2021.
12.
Yasuyuki Okada, Ya Cui, Satoshi Nishiwada, Eunsung Jun, Fuminori Sonohara, SongCheol Kim, Yasuhiro Koreda, Masayuki Sho, Wei Li, Tetsuji Takayama and Ajay Goel : Expression Profiling Identifies a Novel miRNA-based Signature for Predicting Local Recurrence in Patients with Pancreatic Ductal Adenocarcinoma., Digestive Disease Week2021, May 2021.
13.
Yasuyuki Okada, Goel Ajay, Nishiwada Satoshi, Takahashi Naoki and Tetsuji Takayama : LAMC2 promotes progression and gemcitabine resistance through modulation of EMT and ATP-binding transporters in pancreatic ductal adenocarcinoma, AACR annual meeting 2021, Apr. 2021.
14.
Hiroyuki Ueda, Yasuhiro Mitsui, Makoto Takishita, Mitsuyasu Yano, Masanori Takehara, Akira Fukuya, Tomoyuki Kawaguchi, Kazuyoshi Noda, Shinji Kitamura, Koichi Okamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : Clinicopathologial Analysis of Six Families with Gastric Adenocarcinoma and Proximal Polyposis of the stomach (GAPPS)., DDW2020, May 2020.
15.
Yasushi Sato, Kumiko Tanaka, Ishikawa Hideki, Satoshi Teramae, Fumika Nakamura, Yasuhiro Mitsui, Kagemoto Kaizo, Hiroshi Miyamoto, Koichi Okamoto, Naoki Muguruma, Ohmiya Naoki, Mutoh Michihiro and Tetsuji Takayama : Small- intestinal involvement in familial adenomatous polyposis: characteristics and genotype- phenotype correlation from a Japanese cohort study, DDW, May 2020.
16.
Yasushi Sato, Tetsu Tomonari, Hironori Tanaka, Takahiro Tanaka, Hirao Akihiro, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma, Kagiwada Harumi, Kitazawa Masashi, Fukui Kazuhiko, Horimoto Katsuhisa and Tetsuji Takayama : Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma beyond progression of sorafenib treatment: A real-world evidence and in vitro assessment with protein phosphorylation array, ASCO Gastrointestinal Cancers Symposium(ASCO-GI 2020), San Francisco, Jan. 2020.
Yasushi Sato, Hideki Ishikawa and Tetsuji Takayama : Capsule endoscopy for small intestinal surveillance in patients with familial adenomatous polyposis., JDDW2019(第27回日本消化器関連学会週間), Kobe, Nov. 2019.
18.
Hiroshi Miyamoto, Jun Okazaki and Tetsuji Takayama : The relationship between poor prognosis in pancreatic cancer with miR-296-5p/BOK signaling axis according to a genome-wide microRNA array analysis using micro-tissues by EUS-FNA., JDDW2019(第27回日本消化器関連学会週間), Kobe, Nov. 2019.
19.
Naoki Muguruma, Daisaku Fujimot, Tomoyuki Kawaguchi, Kaizoh Kagemoto, Satoshi Teramae, Yoshifumi Kida, Hironori Wada, Fumika Nakamura, Yasuteru Fujino, Shinji Kitamura, Koichi Okamoto, Hiroshi Miyamoto, Toshihito Tanahashi, Hiroshi Miyamoto, Yasushi Sato and Tetsuji Takayama : Linked Color Imaging Improves Detection Rate of Sessile Serrated Adenoma/Polyp in the Colon: A Prospective Randomized Controlled Trial., UEG Week 2019, Barcelona, Oct. 2019.
20.
Shinji Kitamura, Mototsugu Kato, Kenro Kawada, Masanori Takehara, Kaizo Kagemoto, Fumika Nakamura, Hironori Wada, Naoki Muguruma, Osamu Dohi, Shoko Ono, Hideki Ishikawa and Tetsuji Takayama : Linked Color Imaging for the Detection of Gastric Neoplasm in High Risk Patients: A Prospective Multicenter Randomized Controlled Trial (LCI-FIND Trial)., UEG Week2019, Barcelona, Oct. 2019.
21.
Yasushi Sato, Tadahiko Nakagawa, Toshihito Tanahashi, Shinji Kitamura, Hiroshi Miyamoto, Koichi Okamoto, Naoki Muguruma and Tetsuji Takayama : JMJD2A is a novel epigenetic factor of chemotherapeutic susceptibility in gastric cancer., The ESMO Congress 2019, Barcelona, Sep. 2019.
Naoki Muguruma, Fujimoto Daisaku, Yasuteru Fujino, Kashihara Takanori, Kazuyoshi Noda, Fukuya Akira, Takehara Masanori, Hirao Akihiro, Hironori Tanaka, Takahiro Tanaka, Tetsu Tomonari and Tetsuji Takayama : Linked Color Imaging System in the Endoscopic Detection of Sessile Serrated Adenoma/Polyp, Korea International Digestive Endoscopy Congress 2019, Aug. 2019.
(Keyword)
Image-enhanced endoscopy / Linked color imaging / Sessile serrated adenoma/polyp
23.
Naoki Muguruma, Koichi Okamoto and Tetsuji Takayama : Advanced Endoscopic Imaging in Colorectal Lesions, Korea International Digestive Endoscopy Congress 2019, Aug. 2019.
(Keyword)
Colorectal cancer / Image-enhanced endoscopy / Molecular imaging
24.
Naoki Igata, J nishioka, T Komatsu, S Kobayashi, Y Ohnishi, M Fukuhara, Hironori Tanaka, Tetsu Tomonari, Tetsuji Takayama, Masahiro Sogabe and Toshiya Okahisa : Drainage with Normal Saline in Two Directions for Washing of the Clogging Filter During Cell-free and Concentrated Ascites Reinfusion Therapy., The 65th Annual Conference of American Society for Artificial Internal Organs (ASAIO), San Francisco, Jun. 2019.
25.
junji nishioka, T Komatsu, S Kobayashi, Y Ohnishi, M Fukuhara, Hironori Tanaka, Tetsu Tomonari, Tetsuji Takayama, Masahiro Sogabe and Toshiya Okahisa : Development of Multiple Point Bowel-sound Analysis System (MPBAS) for the Optimization of the Bowel Sound Measurement Position., The 65th Annual Conference of American Society for Artificial Internal Organs (ASAIO), San Francisco, Jun. 2019.
26.
Hironori Tanaka, Tetsu Tomonari, Takahiro Tanaka, Akihiro Hirao, Fumika Nakamura, Kumiko Tanaka, Koichi Okamoto, Yasushi Sato, Masahiro Sogabe, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : Therapeutic efficacy of chemoradiotherapy with Miriplatin for hepatocellular carcinoma., digestive disease week2019, San Diego, May 2019.
27.
Jinsei Miyoshi, Noriaki Murayama, Kumiko Tanaka, Takahiro Tanaka, Fumika Nakamura, Yasuteru Fujino, Keiichiro Matsumura, Miwako Kagawa, Tetsu Tomonari, Shinji Kitamura, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : Development of a Novel Mirna-Based Signature to Predict Invasion and Metastasis in Rectal Neuroendocrine Tumors., digestive disease week2019, Vol.156, No.6, 133, San Diego, May 2019.
Jun Okazaki, Toshihito Tanahasi, Yasushi Sato, Jinsei Miyoshi, Tadahiko Nakagawa, Tetsuo Kimura, Hiroshi Miyamoto, Yasuteru Fujino, Fumika Nakamura, Masanori Takehara, Masahiro Bando, Shinji Kitamura, Koichi Okamoto, Naoki Muguruma, Masahiro Sogabe and Tetsuji Takayama : Interaction Between Pancreatic Cancer Cells and Adipocytes Promote Pancreatic Cancer Progression Through Overexpression of Saa1., digestive disease week2019, San Diego, May 2019.
29.
Tetsuji Takayama, Toshihito Tanahashi, Koichi Okamoto, Shota Fujimoto, Tadahiko Nakagawa, Kaizoh Kagemoto, Yasuyuki Okada, Fumika Nakamura, Yasuteru Fujino, Shinji Kitamura, Hiroshi Miyamoto, Yasushi Sato and Naoki Muguruma : S100P as a novel hypomethylation target in Sessile Serrated Adenoma(SSA/P)-cancer sequence: A genome-wide DNA methylation array analysis., UEG Week2018, Wien, Oct. 2018.
30.
Toshiya Okahisa, Masahiro Sogabe, Mayu Uyama, Tadahiko Nakagawa, Tetsu Tomonari, Tatsuya Taniguchi, Koichi Okamoto, Tetsuji Takayama, Takaaki Shimohata, Takashi Uebanso, Kazuaki Mawatari, Akira Takahashi, Takahiro Emoto, Masatake Akutagawa, M Yamada and M Fukuhara : Development Of A Multi-Ring Type Roller Pump Unit Equipped To A Compact And Convenient Ascites Purification Machine For Cell-Free And Concentrated Ascites Reinfusion Therapy (CART)., ASAIO 64th Annual Conference, Washington, D.C., Jun. 2018.
31.
Jinsei Miyoshi, Noriaki Murayama, Tadahiko Nakagawa, Tetsu Tomonari, Shinji Kitamura, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : Mir-144-3P/451A as a Novel Biomarker for Predicting Recurrence and Metastasis in Rectal Neuroendocrine Tumors Through Targeting Pten/P19., Digestive Disease Week 2018, Washington, D.C., Jun. 2018.
32.
Fumika Nakamura, Koichi Okamoto, Kumiko Tanaka, Yasuteru Fujino, Jinsei Miyoshi, Shinji Kitamura, Hiroshi Miyamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : Clinicopathological Analyses of Colorectal Polyps and Cancers in Serrated Polyposis Syndrome., DIgestive Disease Week2018, Washington, D.C., Jun. 2018.
33.
Shota Fujimoto, Naoki Muguruma, Michiyasu Nakao, Yoshihiko Miyamoto, Tatsuhiro Ishida, Shigeki Sano and Tetsuji Takayama : Near-Infrared Molecular Imaging of Gastrointestinal Stromal Tumors using a Novel Fluorescent Probe Indocyanine Green (ICG)-Labeled Dasatinib., Digetive Disease Week2018, Washington, D.C., Jun. 2018.
34.
Yasushi Sato, Tamotsu Sagawa, Yasuo Takahashi, Hiroyuki Ohnuma, Kyoko Hamaguchi, Masahiro Hirakawa, Koshi Fujikawa, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : A dose-escalation study of docetaxel, oxaliplatin and S-1 (DOS) as a first-line therapy for patients with unresectable metastatic gastric cancer., 2018 Gastrointestinal Cancers Symposium, San Francisco, Jan. 2018.
35.
Yasushi Sato, Hiroyuki Ohnuma, Koichi Okamoto, Hiroshi Miyamoto, Masahiro Hirakawa, Naoki Uemura, Shohei Kikuchi, Tamotsu Sagawa, Koji Fujikawa, Yasuo Takahashi, Toshinori Okuda, Shinya Minami, Minoru Takahashi, Tetsuro Okamoto, Junji Kato and Tetsuji Takayama : Phase II study of modified docetaxel, cisplatin and S-1 (mDCS) combination chemotherapy in patients with unresectable metastatic gastric cancer, ESMO 2017 Congress, Madrid, Spain, Madrid, Sep. 2017.
36.
Daisaku Fujimoto, Kaizo Kagemoto, Yasuyuki Okada, Hironori Tanaka, Satoshi Teramae, Akihiro Hirao, Fumika Nakamura, Shinji Kitamura, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : Usefulness of Linked Color Imaging System in Endoscopic Diagnosis of Sessile Serrated Adenoma/Polyp: A Novel Image Enhanced Technique., Digestive Disease Week2017, Chicago, May 2017.
Naoki Muguruma, Koichi Okamoto, Shota Fujimoto, Tadahiko Nakagawa, Katsutaka Sannomiya, Yasuhiro Mitsui, Tetsuo Kimura, Hiroshi Miyamoto, Mitsuo Shimada, Yoko Horino, Shinya Matsumoto, Kenjiro Hanaoka and Tetsuji Takayama : Optical Molecular Imaging of Aberrant Crypt Foci in the Human Colon by Glutathione S-Transferase-Activated Fluorogenic Probe., Digestive Disease Week2017, Chicago, May 2017.
39.
Shota Fujimoto, Naoki Muguruma, Koichi Okamoto, Misaki Miwa, Yoshihiko Miyamoto, Yoshifumi Takaoka, Koichi Tsuneyama and Tetsuji Takayama : A New Theranostic Combination of Fluorescent Molecular Imaging and Laser Therapy Targeting C-Kit in Gastrointestinal Stromal Tumors., Digestive Disease Week2017, Chicago, May 2017.
40.
Masanori Takehara, Naoki Muguruma, Koichi Okamoto, Kazuyoshi Noda, Kaizo Kagemoto, Yuri Matsumoto, Tadahiko Nakagawa, Shunsaku Takeishi, Jun Okazaki, Daisaku Fujimoto, Shinji Kitamura, Tetsuo Kimura, Hiroshi Miyamoto and Tetsuji Takayama : Endoscopic Resection is safe and effective for rectal carcinoid tumors., The First World Congress of Gastrointestinal Endoscopy,, Hyderabad, Feb. 2017.
41.
Tomoyuki Kawaguchi, Naoki Muguruma, Koichi Okamoto, Kumiko Tanaka, Satoshi Teramae, Yasuhiro Mitsui, Yoshifumi Takaoka, Tatsunao Sueuchi, Takahiro Goji, Shinji Kitamura, Masako Kimura, Tetsuo Kimura, Hiroshi Miyamoto and Tetsuji Takayama : Assessment of small bowel capsule endoscopy and APC gene mutation in familial adenomatous polyposis., The First World Congress of Gastrointestinal Endoscopy, Hyderabad, Feb. 2017.
42.
Masahiro Sogabe, Toshiya Okahisa, Tadahiko Nakagawa, Noriaki Murayama, Masanori Takehara, Kaizo Kagemoto, Yoshifumi Takaoka, Tetsu Tomonari, Tatsuya Taniguchi, Tetsuo Kimura, Naoki Muguruma and Tetsuji Takayama : Influence of Lifestyle and Lifestyle-Related Disease on Nonalcoholic Fatty Liver Disease in Japanese With Metabolic Syndrome, Digestive Disease Week2016, San Diego, May 2016.
43.
Tatsuya Taniguchi, Hironori Tanaka, Takahiro Tanaka, Tetsu Tomonari, Kazuhiro Kishi, Hiroshi Miyamoto, Naoki Muguruma, Masahiro Sogabe, Tadahiko Nakagawa and Tetsuji Takayama : Des-g-carboxy Prothrombin (DCP) Is Produced by Overexpression of Prothrombin Gene in Hepatocellular Carcinoma, Digestive Disease Week2016, San Diego, May 2016.
44.
Tetsu Tomonari, Shunsaku Takeishi, Tatsuya Taniguchi, Takahiro Tanaka, Hironori Tanaka, Tetsuo Kimura, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : MRP3 As a Novel Resistance Factor for Sorafenib in Hepatocellular Carcinoma, Digestive Disease Week2016, San Diego, May 2016.
45.
Yoshihiko Miyamoto, Naoki Muguruma, Shota Fujimoto, Tadahiko Nakagawa, Shinji Kitamura, Tetsuo Kimura, Koichi Okamoto, Masahiro Sogabe, Toshiya Okahisa and Tetsuji Takayama : Molecular Imaging Targeting Epidermal Growth Factor Receptor in Detection and Evaluation of Therapeutic Efficacy for Colorectal Cancer, Digestive Disease Week2016, San Diego, May 2016.
46.
Tetsuji Takayama, Naoki Muguruma and Koichi Okamoto : Chemoprevention for Colorectal Cancer targeting Aberrant Crypt Foci, The 5th International Forum,The 102nd General Meeting of the Japanese Society of Gastroenterology, Tokyo, Apr. 2016.
Tatsuya Taniguchi, Tetsu Tomonari and Tetsuji Takayama : Des-γ-carboxy prothrombin (DCP) producing mechanism based on PARP-1 in hepatocellular carcinoma, 第23回消化器関連学会週間, Tokyo, Oct. 2015.
49.
Tadahiko Nakagawa, Yoshifumi Takaoka, Hironori Tanaka, Kumiko Tanaka, Tetsuji Takayama, Takaaki Shimohata, Takashi Uebanso, Kazuaki Mawatari, Akira Takahashi, Masatake Akutagawa, Takahiro Emoto, Yohsuke Kinouchi, Toru Murashima, Satoru Yamaji, Zenji Tanaka, Masahiro Sogabe and Toshiya Okahisa : Roller Pump Circulation System For Preventing Filter Clogging During Cell-free and Concentrated Ascites Reinfusion Therapy (cart)., The 61th Annual Conference of American Society for Artificial Internal Organs(ASAIO), Chicago, Jun. 2015.
50.
Tatsuya Taniguchi, Tetsu Tomonari, Hironori Tanaka, Takahiro Tanaka, Kazuhiro Kishi, Hiroshi Miyamoto, Naoki Muguruma, Masahiro Sogabe, Toshiya Okahisa, Tadahiko Nakagawa and Tetsuji Takayama : Des-G-Carboxy Prothrombin (DCP) Is Induced by PARP-1 in Hepatocellular Carcinoma, Digestive Disease Week 2015, Washington, D.C., May 2015.
Rai Shimoyama, Tetsuo Kimura, Toshi Takaoka, Kazuki Sakamoto, Shunji Kawamoto, Koji Yoshizaki, Yuji Negoro, Fuminori Goda, Akihito Tsuji, Tsuyoshi Nakayama, Hiroshi Miyamoto, Tetsuji Takayama and Yoshihiro Niitsu : A phase II trial of panitumumab with irinotecan and S-1 (IRIS) as second-line treatment in patients with wild-type KRAS metastatic colorectal cancer., 2015 Gastrointestinal Cancers Symposium, San Francisco, Jan. 2015.
53.
Naoki Muguruma, Miyamoto Yoshihiko, Fujimoto Shota, Okada Yasuyuki, Shinji Kitamura, Tetsuo Kimura, Koichi Okamoto, Hiroshi Miyamoto and Tetsuji Takayama : Optical Molecular Imaging and Assessment of Therapeutic Response of Colorectal Cancer Targeting Epidermal Growth Factor Receptor, World Congress of Molecular Imaging 2014, Sep. 2014.
54.
Kagawa Miwako, Toshiya Okahisa, Takaoka yoshifumi, Yasuteru Fujino, Jinsei Miyoshi, Takaoka Toshi, Tetsu Tomonari, Shinji Kitamura, Okada Yasuyuki, Kagemoto Kaizo, Takehara Masanori, Kumiko Tanaka, Matsumoto Sayo, Teramae Tomofumi, Hiroshi Miyamoto, Naoki Muguruma, Tetsuji Takayama and Takaoka Toshi : Angiogenesis-Related Factors At the Residual Inflammation in Patients With Ulcerative Colitis in Clinical Remission Stage, Digestive Disease Week2014, Chicago, May 2014.
55.
Noboru Niki, Yoshiki Kawata, Hidenobu Suzuki, Masafumi Harada, Hideki Otsuka, Junji Ueno, Mitsuo Shimada, Tetsuji Takayama, Masahiro Abe, Haruimi Itoh, Kenji Eguchi, Masahiko Kusumoto, Takaaki Tsuchida, Hironobu Ohmatsu, Masashi Takahashi, Yasutaka Nakano, Hiroaki Sakai and Yuichi Takiguchi : Computer-aided diagnosis based on computational anatomical models:Progress overview FY2009-2013, The 5th International Symposium on the Project ``Computational Anatomy'', 39-43, Mar. 2014.
56.
Yasushi Sato, Tetsuji Takayama, Hiroyuki Ohnuma, Masahiro Hirakawa, Takahiro Osuga, Hiroshi Miyamoto, Tamotsu Sagawa, Yasuhiro Sato, Yasuo Takahashi, Shinichi Katsuki, Kohichi Takada, Tokunori Okuda, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Takayuki Nobuoka, Koichi Hirata and Junji Kato : Trastuzumab (T-mab) in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: Feasibility and preliminary efficacy., 2014 Gastrointestinal Cancers Symposium, San Francisco, Jan. 2014.
57.
Akina Nakanishi, Toshiya Okahisa, Emi Umezu, Tadahiko Nakagawa, Miwako Kagawa, Toshi Takaoka, Takahiro Goji, Hiromi Yano, Shinji Kitamura, Takahiro Goji, Hiroshi Miyamoto, Naoki Muguruma and Tetsuji Takayama : Expression of Thymidline EMT via ERK 1/2 Signal Patway in Ulcerative Colitis, DDW2013,Orland, Orange County Convention Center, Orlando, May 2013.
58.
Yasuteru Fujino, Koichi Okamoto, Naoki Muguruma, Jun Okazaki, Yasuyuki Okada, Hironori Tanaka, Jinsei Miyoshi, Toshi Takaoka, Shinji Kitamura, Hiroshi Miyamoto, Toshiya Okahisa and Tetsuji Takayama : Usefulness of a new sphincterotome for the endoscopic submucosal dissection of colorectal neoplasms, DDW2013, Orlando, May 2013.
59.
Noboru Niki, Yoshiki Kawata, Hidenobu Suzuki, Masafumi Harada, Hideki Otsuka, Junji Ueno, Mitsuo Shimada, Tetsuji Takayama, Masahiro Abe, Harumi Itoh, Masahiro Kaneko, Kenji Eguchi, Masahiko Kusumoto, Takaaki Tsuchida, Hironobu Ohmatsu, Masashi Takahashi, Yasutaka Nakano, Hiroaki Sakai and Yuichi Takiguchi : Computer-Aided Diagnosis Based on Computational Anatomical Models: Progress Overview FY2012, he 4th International Symposium on the Project ``Computational Anatomy'', 45-51, Feb. 2013.
60.
Noboru Niki, Yoshiki Kawata, Hidenobu Suzuki, Masafumi Harada, Hideki Otsuka, Junji Ueno, Mitsuo Shimada, Tetsuji Takayama, Masahiro Abe, Harumi Itoh, Masahiro Kaneko, Kenji Eguchi, Masahiko Kusumoto, Takaaki Tsuchida, Hironobu Ohmatsu, Masashi Takahashi, Yasutaka Nakano, Hiroaki Sakai and Yuichi Takiguchi : Computer-aided diagnosis based on computational anatomical models: progress overview FY2011, The 3rd International Symposium on the Project ``Computational Anatomy'', 35-42, Mar. 2012.
61.
Atsushi Inoue, Koichi Okamoto, Yasuteru Fujino, Jinsei Miyoshi, Takahiro Tanaka, Tetsuo Kimura, Masako Kaji, Hiroshi Miyamoto, Toshiya Okahisa, Seisuke Okamura and Tetsuji Takayama : Aberrant Crypt Foci in Patients With Sessile Serrated Adenomas, Digestive Disease Week2011, Chicago, May 2011.
62.
T Tonoiso, Tetsuji Takayama and et.al : Developmental Mechanism of Human Radiation Proctitis:Analysis of Expression profilefor Angiogenic Factors, Digestive Disease Week 2011, Chicago, May 2011.
63.
Hidetaka Takenaka, Katsuyoshi Tamaki, Tatsuya Taniguchi, Tetsu Tomonari, Rie Harada, Katsutaka Sannomiya, Momoko Sato, Toshiya Okahisa, Seisuke Okamura and Tetsuji Takayama : Radiofrequency ablation using a balloon catheter for hepatocellular carcinoma adjacent to the gastrointestinal tract:Experimental and Clinical Study, Digestive Disease Week 2011, Chicago, Chicago, May 2011.
64.
Noboru Niki, Yoshiki Kawata, Hidenobu Suzuki, Masafumi Harada, Hideki Otsuka, Junji Ueno, Mitsuo Shimada, Tetsuji Takayama, Masahiro Abe, Harumi Itoh, Masahiro Kaneko, kenji Eguchi, Masahiko Kusumoto, Takaaki Tsuchida, Hironobu Ohmatsu, Masashi Takahashi, Yasutaka Nakano and Hiroaki Sakai : Computer-aided diagnosis based on computational anatomical models: progress overview FY2010, The 2nd International Symposium on the Project ``Computational Anatomy'', 95-100, Mar. 2011.
65.
Masako Kaji, Tetsu Tomonari, Kagawa Miwako, Saito Azusa, Tsuda Miho, Harada Rie, Tetsuo Kimura, Shinji Kitamura, Hiromi Yano, Koichi Okamoto, Niki Miyako, Toshiya Okahisa, Seisuke Okamura and Tetsuji Takayama : Usefulness of electrocolonography for evaluation of colonic motility, Digestive Disease Week 2010, New Orleans, May 2010.
66.
Toshiya Okahisa, Tsuda Miho, Tetsu Tomonari, Inoue Atsushi, Tetsuo Kimura, Shinji Kitamura, Hiromi Yano, Takeuchi Hisashi, Koichi Okamoto, Niki Miyako, Masako Kaji, Seisuke Okamura, Kanno Ryota, Shinsuke Konaka, Takahiro Emoto, Masatake Akutagawa and Tetsuji Takayama : Vascular patterns assessed by vascular analysis software are predictive of relapse in patients with inactive ulcerative colitis, Digestive Disease Week 2010, New Orleans, May 2010.
67.
Yasushi Sato, Tetsuji Takayama, Tamotsu Sagawa, Yasuo Takahashi, Hiroyuki Ohnuma, Syunichi Okubo, Naoaki Shintani, Shingo Tanaka, Masaya Kida, Yasuhiro Sato, Hidetoshi Ohta, Koji Miyanishi, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Koji Yamaguchi, Koichi Hirata, Yoshiro Niitsu and Junji Kato : Phase II study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer., Cancer Chemotherapy and Pharmacology, Vol.66, No.4, 721-728, 2010.
(Summary)
We evaluated the activity and toxicity of docetaxel, cisplatin, and S-1 (DCS) combination chemotherapy in patients with unresectable metastatic gastric cancer.
Koichi Okamoto, takanori yoshimoto and Tetsuji Takayama : <ワークショップ>胃癌を発症したGastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)の臨床病理学的特徴., JDDW2024, Nov. 2024.
Tetsu Tomonari, Hironori Tanaka, Tatsuya Taniguchi, Yutaka Kawano, Hiroshi Miyamoto and Tetsuji Takayama : 悪性肝腫瘍に対するEmprint Ablation Systemの治療成績., 日本超音波医学会第96回学術集会, May 2023.
58.
Kaizo Kagemoto, Koichi Okamoto and Tetsuji Takayama : Sessile serrated lesion(SSL)に対する内視鏡的切除法の検討, 第105回日本消化器内視鏡学会総会, May 2023.
59.
takanori yoshimoto, Koichi Okamoto and Tetsuji Takayama : Gastric adenocarcinoma and proximal polyposis of the stomach(GAPPS)における褪色調平坦/隆起型病変の意義., 第105回日本消化器内視鏡学会総会, May 2023.
Koichi Okamoto, 和田 浩典 and Tetsuji Takayama : Gastric adenocarcinoma and proximal polyposis of the stomach(GAPPS)7 家系の臨床病理学的検討., 第103回日本消化器内視鏡学会総会, May 2022.
87.
Tetsu Tomonari, Hironori Tanaka and Tetsuji Takayama : 切除不能進行肝癌に対する根治的Combination therapyの有効性., 第58回日本肝癌研究会, May 2022.
88.
Tetsu Tomonari, 谷 丈二 and Tetsuji Takayama : Cancer free及びSequential治療を見据えたアテゾリズマブ・ベバシズマブ療法の治療戦略., 第58回日本肝癌研究会, May 2022.
Akinari Kasai, Jinsei Miyoshi, Akihiro Haga, Takashi Kawanaka, Koichi Okamoto, Naoki Muguruma, Yasushi Sato and Tetsuji Takayama : CT-based AI radiomics model for predicting complete response and progression free survival of chemoradiothearapy in ESCC., 第80回日本癌学会学術総会, Oct. 2021.
107.
Beibei Ma, Hiroyuki Ueda, Naoki Muguruma, Koichi Okamoto, Tomoyuki Kawaguchi, Akira Fukuya, Yoshifumi Kida, Yasuyuki Okada, Tatsuya Taniguchi, Yasushi Sato and Tetsuji Takayama : Activation of EGFR signaling pathway in the left-side colorectal cancerLeft-side vs. right-side cancer organoids., 第80回日本癌学会学術総会, Sep. 2021.
108.
Rei Mizobuchi, Hironori Tanaka, Naoya Tani, Kazuyoshi Noda, Takahiro Tanaka, Tetsu Tomonari, Tatsuya Taniguchi, Tomomi Matsuura, Masataka Sata and Tetsuji Takayama : 超音波観察を併用することで安全に治療した高度腎機能低下を合併した猪瀬型肝性脳症の1例, 第263回徳島医学会学術集会, Aug. 2021.
Tetsu Tomonari, Hironori Tanaka and Tetsuji Takayama : Therapeutic strategy of lenvatinib for hepatocelluar carcinoma in intermediate-stage., 第57回日本肝癌研究会, Jul. 2021.
Recently, immune checkpoint inhibitors(ICI)have been approved for use in advanced gastric cancer(AGC)based on the positive results of ATTRACTION‐2 trial in Japan. There has been accumulating evidence that the development of immune-related adverse events(irAE)may be associated with a response to ICI therapy, particularly in lung cancer, although little is known about these correlations in gastrointestinal cancer. To investigate the efficacy and irAE of ICI treatment and their correlation in AGC, we retrospectively examined 29 patients with AGC who received nivolumab therapy in our departments. Among them, 15 patients(52%)developed irAEs including 4 patients(14%)for grade 3 irAEs ; liver dysfunction(n＝2), type 1 diabetes mellitus(n＝2) and adrenal insufficiency(n＝1). The median overall survival was12．0months in the irAE group and 3．25 months in the non-irAE group(p＝0．164), which suggested the relationship between the effects and irAEs in ICI treatment of AGC. Further research is required to understand the implications of irAE characteristics on ICI response in GCA patients.
Tetsuji Takayama, Koichi Okamoto and Naoki Muguruma : Surrogate marker for chemoprevention study on colorectal cancer Molecular imaging of aberrant crypt foci., 第78回日本癌学会学術総会, Sep. 2019.
171.
Tadahiko Nakagawa, Toshihito Tanahashi, yoshihiko miyamoto, Jun Okazaki, masanori takehara, noriaki murayama, Jinsei Miyoshi, Tatsuya Taniguchi, Yoshimi Bando, Koichi Okamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : JMJD2A (KDM4A) sensitizes metastatic gastric cancer to chemotherapy by cooperating CCDC8., 第78回日本癌学会学術総会, Sep. 2019.
172.
yoshihiko miyamoto, Naoki Muguruma, yasuyuki okada, Hironori Tanaka, Jun Okazaki, Koichi Okamoto, Yasushi Sato and Tetsuji Takayama : EGFR-targeted molecular imaging for detection and treatment evaluation of colorectal tumors in animal model., 第78回日本癌学会学術総会, Sep. 2019.
173.
Hironori Tanaka, Koichi Okamoto, 岡田 泰行, 宮本 佳彦, Yasuhiro Mitsui, Fumika Nakamura, Jinsei Miyoshi, Yasuteru Fujino, Takahiro Tanaka, Tetsu Tomonari, Shinji Kitamura, Hiroshi Miyamoto, Naoki Muguruma, Yasushi Sato and Tetsuji Takayama : Therapeutic efficacy of miriplatin in combination with radiotherapy for advanced hepatocellular carcinoma., 第17回日本臨床腫瘍学会学術集会, Jul. 2019.
Tetsu Tomonari, Takahiro Tanaka and Tetsuji Takayama : 切除不能進行肝癌に対するレンバチニブの有効性と安全性の検討., 第105回日本消化器病学会総会, May 2019.
184.
Kumiko Tanaka, 石川 秀樹 and Tetsuji Takayama : 家族性大腸腺腫症における小腸病変の解析., 第105回日本消化器病学会総会, May 2019.
185.
Yasuhiro Mitsui, 津保 友香 and Tetsuji Takayama : 切除不能進行神経内分泌癌に対するIrinotecan+Cisplatin併用療法の臨床的有用性とサロゲートマーカーの検討., 第105回日本消化器病学会総会, May 2019.
186.
Jinsei Miyoshi, Goel Ajay and Tetsuji Takayama : 血清miRNAパネルを用いた食道腺癌の早期診断モデルの構築., 第105回日本消化器病学会総会, May 2019.
187.
Yasushi Sato, Kazuhiro Kishi and Tetsuji Takayama : 消化管腫瘍における免疫チェックポイント阻害薬の経験―自己免疫疾患関連副作用(irAE)の相違から―., 第105回日本消化器病学会総会, May 2019.
188.
Tatsunao Sueuchi, Toshiya Okahisa and Tetsuji Takayama : 過敏性腸症候群患者に対するアロマ療法施行時の腸蠕動音解析., 第105回日本消化器病学会総会, May 2019.
189.
Yasuhiro Mitsui, Shinji Kitamura, Koichi Okamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : Clinicopathological characteristics of Gastric adenocarcinoma with proximal polyposis of the stomach., 第91回日本胃癌学会総会, Mar. 2019.
Yasuhiro Mitsui, Kumiko Tanaka, 寺前 智史, Shinji Kitamura, Koichi Okamoto, Yasushi Sato, Naoki Muguruma and Tetsuji Takayama : Gastric adenocarcinoma with proximal polyposis of the stomach(GAPPS)におけるAPC 遺伝子生殖細胞系列変異および臨床病理学的特徴., 第24回日本家族性腫瘍学会学術集会, Jun. 2018.
222.
Fumika Oi, Masanobu Haraguchi, Yohsuke Kinouchi, Tadahiko Nakagawa, RYUTO TAMAI, Koichi Okamoto, Tetsuji Takayama, Masahiro Sogabe, Toshiya Okahisa, Masatake Akutagawa and Takahiro Emoto : Small Animal Extracorporeal Circulation with Irradiation Models and Studying Responses, Transactions of the Japanese Society for Medical and Biological Engineering, Vol.annual 56, 171, Jun. 2018.
(Summary)
<p>We made an extracorporeal circulation (ECC) with light emitting diode (LED) irradiation system on adult male SD rats. We used three wave lengths of each LED which main wave lengths are 365nm, 465nm, 515nm. ECC was derived to ECC with irradiation. This system is consisted of a tubing line, a roller pump and an irradiation device. Animals were divided into not-irradiated group and other groups. We took the blood tests at pre-circulation with irradiation and post-circulation with irradiation. We compared Experimental data between pre-circulation with irradiation and post- circulation with irradiation.</p>
Hiroyuki Ohnuma, Teppei Matsuno, Chisa Fujita, Masahiro Hirakawa, Koji Miyanishi, Koichi Okamoto, Hiroshi Miyamoto, Yasushi Sato, Tetsuji Takayama and Junji Kato : [WS4-5] Efficacy of DCS±T/DOS combination chemotherapy for gastric cancer with peritoneal metastasis, Workshop 4 Treatment of gastric cancer patients with peritoneal dissemination 90th Annual Meeting of the Japanese Gastric Cancer Association, Mar. 2018.
232.
Shinji Kitamura, Naoki Muguruma, Yasushi Sato and Tetsuji Takayama : New Traction Method with Endoloop for ESD., 第90回日本胃癌学会総会, Mar. 2018.
Daisaku Fujimoto, Naoki Muguruma and Tetsuji Takayama : Usefulness of linked color imaging in endoscopic diagnosis of SSA/P: A novel image enhancment technique., 第24回日本消化器関連学会週間, Nov. 2016.
Tetsuo Kimura, Naoki Muguruma and Tetsuji Takayama : Suppressive effect of the farnesyltransferase inhibitor for aberrant crypt foci as a precursor of colorectal cancer., 第56回日本消化器病学会大会(JDDW2014), Oct. 2014.
Koichi Okamoto, Yoshitaka Imoto and Tetsuji Takayama : Endoscopic submucosal dissection for early gastric cancer using a cross-counter technique, 第83回日本消化器内視鏡学会, May 2012.
Optimization of therapeutic strategy for esophageal squamous cell carcinoma based on modeling of intratumoral heterogeneity using omics data and genome editing (Project/Area Number: 26293304 )
Development of a novel high sensitivity molecular imaging for ACF (Project/Area Number: 26293176 )
In vivo molecular imaging targeting epidermal growth factor receptor in detection for colorectal cancer developed in ulcerative colitis (Project/Area Number: 25461034 )
Scientific Support Programs for Cancer Research Grant-in-Aid for Scientific Research on Innovative Areas (Project/Area Number: 221S0001 )
Computer-Aided Diagnosis Based on Computational Anatomical Models (Project/Area Number: 21103005 )
Molecular analysis of differentiation mechanism of hMSC into hepatocyte and application to liver regeneration therapy (Project/Area Number: 18590740 )
A role of mutated H-ferritin gene in famial gastric cancer -Analysis of mechanism using mutated H-ferritin transgenic mouse- (Project/Area Number: 17590663 )