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.
(要約)
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.
(要約)
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.
(キーワード)
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.
(要約)
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, 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.
(要約)
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.
Reported rates of delayed bleeding (DB) after endoscopic resection using direct oral anticoagulants (DOACs) are high and heterogeneous. This large-scale multicenter study analyzed cases of DB after colorectal endoscopic submucosal dissection related to various types of DOACs in Japan (the ABCD-J study) with those associated with warfarin. We retrospectively reviewed 1019 lesions in patients treated with DOACs and 459 lesions in patients treated with warfarin among 34,455 endoscopic submucosal dissection cases from 47 Japanese institutions between 2012 and 2021. The DB rate (DBR) with each DOAC was compared with that with warfarin. Risk factors for DB in patients treated with DOACs or warfarin were also investigated. The mean tumor sizes in the DOAC and warfarin groups were 29.6 ± 14.0 and 30.3 ± 16.4 mm, respectively. In the DOAC group, the DBR with dabigatran (18.26%) was significantly higher than that with apixaban (10.08%, P = .029), edoxaban (7.73%, P = .001), and rivaroxaban (7.21%, P < .001). Only rivaroxaban showed a significantly lower DBR than warfarin (11.76%, P = .033). In the multivariate analysis, heparin bridging therapy (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.27-3.73, P = .005), rectal location (2.01, 1.28-3.16, P = .002), and procedure time ≥55 minutes (2.43, 1.49-3.95, P < .001) were significant risk factors for DB in the DOAC group. The DB risk in the DOAC group (OR, (95% CI)) was 2.13 (1.30-3.50) and 4.53 (2.52-8.15) for 1 and 2 significant risk factors, respectively. Dabigatran was associated with a higher DBR than other DOACs, and only rivaroxaban was associated with a significantly lower DBR than warfarin.
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.
(要約)
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.
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.
(要約)
<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>
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.
(要約)
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.
(要約)
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.
(要約)
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.
(要約)
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.
(要約)
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.
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, 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.
(要約)
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.
(要約)
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.
(要約)
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.
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.
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.
(要約)
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.
(要約)
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.
(要約)
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.
(キーワード)
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.
(要約)
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.
(要約)
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.
(要約)
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.
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.
(要約)
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.
(キーワード)
Breast Neoplasms / Female / Genetic Association Studies / Hamartoma Syndrome, Multiple / Humans / Intestinal Polyps / Japan / Male / Middle Aged / PTEN Phosphohydrolase / Risk
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.
(要約)
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.
(要約)
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.
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.
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.
(要約)
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.
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.
(要約)
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.
(要約)
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.
(要約)
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.
(要約)
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.
(要約)
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.
(要約)
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.
(要約)
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.
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.
(要約)
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
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.
(要約)
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.
(要約)
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.
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.
(要約)
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.
(要約)
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.
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.
(要約)
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.
Ayumi Sasaki, Mayumi Sugimoto, Narumi Tokaji, Makoto Irahara, Koichi Okamoto, Hisanori Uehara and Shoji Kagami : Efficacy of an elimination diet in a patient with eosinophilic gastroenteritis : a pediatric case with multiple food allergies., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 201-204, 2019.
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.
(要約)
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.
(要約)
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.
(要約)
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.
(要約)
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.
(要約)
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.
(要約)
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.
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.
(要約)
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.
(要約)
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.
(要約)
Forty-nine patients were enrolled from November 2011 to April 2014, and 43 were eligible. The overall RR was 79.1%, including two cases of a complete response (4.7%), and 32 cases of a partial response (74.4%). Nine cases had stable disease (20.9%) but none showed progressive disease. Of the 43 cases, 15 cases (34.9%) underwent curative conversion surgery. The median PFS was 350 days (95% CI 240-416 days) and median OS was 722 days (95% CI 411 days-not reached). Grade 3/4 neutropenia developed in 79.1%, and febrile neutropenia in 34.9%, of patients. Non-hematological grade 3/4 adverse events were anorexia (25.6%), nausea (4.7%), and diarrhea (9.3%).
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.
(要約)
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.
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.
(要約)
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.
(要約)
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
(要約)
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
(要約)
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.
A Frank Sinicrope, Koichi Okamoto, M Pashtoon Kasi and Hisato Kawakami : Molecular Biomarkers in the Personalized Treatment of Colorectal Cancer., Clinical Gastroenterology and Hepatology, Vol.14, No.5, 651-658, 2016.
(要約)
Colorectal cancer (CRC) is a disease in which pathogenesis is influenced by genetic and epigenetic events that occur with tumor initiation and progression. Large variation exists in individual patient prognosis and response to chemotherapy, caused by molecular heterogeneity. Certain biomarkers have been identified that can predict clinical outcome beyond tumor staging, and inform treatment selection. Molecular testing is routinely performed in clinical practice for the selection of patients for targeted biological agents or immunotherapy, and is advocated for prognostic stratification. Estimating prognosis can avoid undertreatment or overtreatment and also guide the intensity of patient follow-up. Classifiers of CRC have been developed that integrate genetic and/or epigenetic features. The mutational status of KRAS and BRAF(V600E) oncogenes combined with analysis of the DNA mismatch repair system with/without the CpG island methylator phenotype (CIMP) has been shown to identify colon cancer subtypes with distinct clinical features and prognoses. Gene expression profiling has also been used to subtype CRCs and can overcome the limitations of single/limited gene testing. A recent effort identified 4 consensus molecular subtypes of biological relevance that were associated with different patient outcomes. Efforts to validate and refine these subtypes to include additional genomic features are ongoing. The focus of this article is to highlight molecular markers that can inform clinical decision-making in patients with CRC.
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.
(要約)
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.
(要約)
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.
Koichi Okamoto, Aziz Zaanan, Hisato Kawakami, Khashayarsha Khazaie, Shengbing Huang and A Frank Sinicrope : Mutant KRAS Upregulates BCL-XL via STAT3 to Confer Apoptosis Resistance that is Reversed by BIM Induction and BCL-XL Antagonism., The Journal of Biological Chemistry, 2015.
(要約)
In colorectal cancers (CRC) with oncogenic KRAS mutations, inhibition of downstream MEK/ERK signaling has shown limited efficacy due, in part, due to failure to induce a robust apoptotic response. We studied the mechanism of apoptosis resistance in mutant KRAS cells and sought to enhance the efficacy of a KRAS-specific MEK/ERK inhibitor, GDC-0623. GDC-0623 was shown to potently upregulate BIM expression to a greater extent vs other MEK inhibitors in isogenic KRAS HCT116 and mutant KRAS SW620 colon cells. ERK silencing enhanced BIM upregulation by GDC-0623 that was due to its loss of phosphorylation at Ser(69), confirmed by a BIM-EL phosphorylation-defective mutant (S69G) that increased protein stability and blocked BIM induction. Despite BIM and BIK induction, isogenic KRAS mutant vs wild-type cells remained resistant to GDC-0623-induced apoptosis due, in part, to upregulation of BCL-XL. KRAS knockdown by a doxycycline-inducible shRNA attenuated BCL-XL expression. BCL-XL knockdown sensitized KRAS mutant cells to GDC-0623-mediated apoptosis as did the BH3 mimetic ABT-263. GDC-0623 plus ABT-263 induced a synergistic apoptosis by a mechanism that includes release of BIM from its sequestration by BCL-XL. Furthermore, mutant KRAS activated p-STAT3 (Tyr(705)) in the absence of IL-6 secretion, and STAT3 knockdown reduced BCL-XL mRNA and protein expression. These data suggest that BCL-XL upregulation by STAT3 contributes to mutant KRAS-mediated apoptosis resistance. Such resistance can be overcome by potent BIM induction and concurrent BCL-XL antagonism to enable a synergistic apoptotic response.
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.
(要約)
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.
(要約)
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.
(キーワード)
Adult / Aged / Aged, 80 and over / Endoscopy, Gastrointestinal / Female / Gastric Mucosa / Humans / Male / Middle Aged / Platelet Aggregation Inhibitors / Retrospective Studies / Stomach Diseases / Young Adult
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.
(要約)
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.
Koichi Okamoto, Aziz Zaanan, Hisato Kawakami, Shengbing Huang and A Frank Sinicrope : Reversal of Mutant KRAS-Mediated Apoptosis Resistance by Concurrent Noxa/Bik Induction and Bcl-2/Bcl-xL Antagonism in Colon Cancer Cells., Molecular Cancer Research : MCR, Vol.13, No.4, 659-669, 2014.
(要約)
This novel study reveals a promising treatment strategy to overcome apoptosis resistance in KRAS-mutant colorectal cancer by concurrent upregulation of Noxa/Bik and antagonism of Bcl-xL.
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.
(要約)
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.
Park Myung Jae, David Tougeron, Shengbing Huang, Koichi Okamoto and A Frank Sinicrope : Beclin 1 and UVRAG confer protection from radiation-induced DNA damage and maintain centrosome stability in colorectal cancer cells., PLoS ONE, Vol.9, No.6, e100819, 2014.
(要約)
Beclin 1 interacts with UV-irradiation-resistance-associated gene (UVRAG) to form core complexes that induce autophagy. While cells with defective autophagy are prone to genomic instability that contributes to tumorigenesis, it is unknown whether Beclin1 or UVRAG can regulate the DNA damage/repair response to cancer treatment in established tumor cells. We found that siRNA knockdown of Beclin 1 or UVRAG can increase radiation-induced DNA double strand breaks (DSBs), shown by pATM and H2Ax, and promote colorectal cancer cell death. Furthermore, knockdown of Beclin 1, UVRAG or ATG5 increased the percentage of irradiated cells with nuclear foci expressing 53BP1, a marker of nonhomologous end joining but not RAD51 (homologous recombination), compared to control siRNA. Beclin 1 siRNA was shown to attenuate UVRAG expression. Cells with a UVRAG deletion mutant defective in Beclin 1 binding showed increased radiation-induced DSBs and cell death compared to cells with ectopic wild-type UVRAG. Knockdown of Beclin 1 or UVRAG, but not ATG5, resulted in a significant increase in centrosome number (-tubulin staining) in irradiated cells compared to control siRNA. Taken together, these data indicate that Beclin 1 and UVRAG confer protection against radiation-induced DNA DSBs and may maintain centrosome stability in established tumor cells.
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.
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.
(要約)
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.
(キーワード)
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
Koichi Okamoto, Huang Shengbing, Chunrong Yu and A Frank Sinicrope : p62/sequestosome-1 up-regulation promotes ABT-263-induced caspase-8 aggregation/activation on the autophagosome., The Journal of Biological Chemistry, Vol.288, No.47, 33654-33666, 2013.
(要約)
Autophagy and apoptosis regulate cancer cell viability in response to cytotoxic stress; however, their functional relationship remains unclear. p62/sequestosome 1 is a multifunctional protein and a signaling hub that shuttles ubiquitinated proteins to the lysosome during autophagy. Autophagy inhibition up-regulates p62, and prior data suggest that p62 may mediate apoptosis. Here, we demonstrate that p62 can regulate a caspase-8-dependent apoptosis in response to the BH3 mimetic agent, ABT-263. Up-regulation of p62 was shown to enhance ABT-263-induced caspase-8 activation that was Bax-dependent and resulted from mitochondrial amplification. Dependence upon caspase-8 was confirmed using caspase-8-deficient cells and by caspase-8 siRNA. Ectopic wild-type p62, but not p62 mutants with loss of ability to promote apoptosis, was shown to co-localize with caspase-8 and to promote its self-aggregation in ABT-263-treated cells, shown using a bimolecular fluorescence complementation assay. Endogenous p62 co-localized with caspase-8 in the presence of ABT-263 plus an autophagy inhibitor. Caspase-8 was shown to interact and co-localize with the autophagosome marker, LC3II. Knockdown of p62 attenuated binding between caspase-8 and LC3II, whereas p62 overexpression enhanced the co-localization of caspase-8 aggregates with LC3. LC3 knockdown did not affect interaction between caspase-8 and p62, suggesting that p62 may facilitate caspase-8 translocation to the autophagosomal membrane. A direct activator of caspase-8, i.e., TRAIL, alone or combined with ABT-263, induced caspase-8 aggregation and co-localization with p62 that was associated with a synergistic drug interaction. Together, these results demonstrate that up-regulation of p62 can mediate apoptosis via caspase-8 in the setting of autophagy inhibition.
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.
(要約)
The mean number of ACF in the 8-week manumycin A group (72.9 ± 20.1) was significantly lower than in the vehicle group (155.6 ± 56.7, P < 0.01), and it was significantly lower even in the 4-week manumycin A group than in the vehicle group (92.2 ± 13.0 vs 222.3 ± 83.3, P < 0.01). The positive rate for phosphorylated ERK in the manumycin A group (13.5 ± 19.2%) was significantly lower than in the vehicle group (50.2 ± 19.8%, P < 0.01). The positive rate for Ki-67 in the manumycin A group (2.2 ± 3.4%) was significantly lower than in the vehicle group (14.7 ± 8.2%, P < 0.01). There were significantly more terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in tissue samples from the manumycin A group versus the vehicle group (8.6 ± 9.7% vs 2.9 ± 2.0%, P < 0.05).
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.
(要約)
NG was found in 62 cases (0.94%) out of 6623 patients who underwent endoscopy, with a mean age of 47.3 ± 13.3 years. Female patients were present at a significantly higher rate in the elderly group (P < 0.001). The grade of neutrophil infiltration in the greater curvature of the upper gastric body was recognized at a significantly higher rate in the elderly group (P < 0.05). PG II was present at a higher rate and PG I/II at a lower rate in the elderly group (P < 0.05). The odds ratio for the risk of gastric cancer in patients with NG was 2.1 (95% confidence interval 0.3-15.3) in the elderly group.
(キーワード)
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.
(要約)
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.
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.
(要約)
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.
(キーワード)
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.
Yutaka Saito, Hiroshi Kawano, Yoji Takeuchi, Ken Ohata, Shiro Oka, Kinichi Hotta, Koichi Okamoto, Kiyoaki Homma, Toshio Uraoka, Takashi Hisabe, Kyung Dong Chang and Ping-Hong Zhou : Current status of colorectal endoscopic submucosal dissection in Japan and other Asian countries: progressing towards technical standardization., Digestive Endoscopy, Vol.24 Suppl 1, 67-72, 2012.
(要約)
There were no significant differences with regards to clinical results between the two periods although the perforation rate decreased from 3.3% to 2.4%. In addition, colorectal ESD has become increasingly standardized technically at specialized referral centers not only in Japan, but several other Asian referral institutions as well.
(キーワード)
Adult / Aged / Aged, 80 and over / Colorectal Neoplasms / Dissection / Endoscopy, Gastrointestinal / 女性 (female) / Health Care Surveys / Humans / Intestinal Mucosa / Intraoperative Complications / 日本 (Japan) / 男性 (male) / Middle Aged / Surveys and Questionnaires / Young Adult
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.
(要約)
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.
(要約)
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.
(要約)
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.
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.
(要約)
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.
Yoshitaka Imoto, Naoki Muguruma, Tetsuo Kimura, Eriko Aoyagi, Koichi Okamoto, Seisuke Okamura, Susumu Ito, Nobuya Sano and Mitsuo Shimada : Relationship between mucin expression and preoperatie bile juice cytology in biliary tract carcinoma, The Journal of Medical Investigation : JMI, Vol.54, No.1-2, 41-47, 2007.
(要約)
The present study evaluated correlations between preoperative bile juice cytology and mucin expression of surgical specimens in biliary tract carcinoma. Twenty-five patients with biliary tract carcinoma surgically treated at our hospital, whose bile juice cytology had been evaluated before operation, were allocated to this study. Biliary cytology was classified into three categories based on the Papanicolaou classification. Immunohistochemical staining of tissues was performed using MUC1 and MUC2 monoclonal antibodies. Lesions showing MUC1 expression of ++ or higher and MUC2 expression of - were classified as Group A, and the remaining lesions as Group B. According to the epithelial site, preoperative cytology was highly correlated in Group A, while it was negative in Group B (p<0.05). In the advanced site of carcinomas, preoperative cytology tended to highly be positive in Group A, while it tended to be negative in Group B (p<0.05). These results suggest that the bile juice cytology results are affected by characteristics of mucin expression in the tissue. Based on the possibility that mucin expression correlates with the prognosis of each carcinoma, a positive cytological result suggests a poor prognosis for the carcinoma, which may be informative for predicting the post-operative courses and choosing treatments.
Yoko Tadatsu, Naoki Muguruma, Susumu Ito, Masaya Tadatsu, Yoshihiro Kusaka, Koichi Okamoto, Yoshitaka Imoto, Hiromi Taue, Shigeki Sano and Yoshimitsu Nagao : Optimal Labeling Condition of Antibodies Available for Immunofluorescence Endoscopy, The Journal of Medical Investigation : JMI, Vol.53, No.1/2, 52-60, 2006.
(要約)
In recent years, labeled antibodies have been used for diagnostic imaging in many studies. In this study, we investigated the mode of binding in antibodies labeled with ICG derivatives newly developed for the diagnosis of microcarcinomas, and evaluated the optimal binding molar ratio between the labeling compounds and antibody. MUC 1 antibody and ICG derivatives (ICG-ATT and ICG-sulfo-OSu) were used. ICG derivatives non-covalently bound to the antibody were removed with ethyl acetate, and the ratio of ICG derivatives covalently bound to the labeled antibody was confirmed. During purification of the labeled antibody, the amount of each labeling compound reacting with 1 molecule of the antibody varied as follows: 4, 8, 16, and 32 molar equivalents. Subsequently, the intensity of fluorescence was evaluated by spectroscopy and infrared fluoroscopy. The ratio of residual ICG derivative labeling the antibody was 67.4% for ICG-ATT and 65.0% for ICG-sulfo-OSu. When fluorescent antibody labeled with ICG-ATT at an F/P ratio of 2.94 or 4.18 was used, specific and clear fluorescent images of the antigen were obtained. When ICG-ATT-labeled antibody at an F/P ratio of 6.50 or 6.75 was used, the fluorescence intensity decreased and the fluorescent images of antigen became unclear. It was found that the ICG-ATT-labeled antibody was a more specific and sensitive marker than ICG-sulfo-OSu-labeled antibody, and that lower binding molar ratios of ICG-ATT were more useful for labeling the antibody.
Mayuko Takagawa, Naoki Muguruma, Kaori Oguri, Yoshitaka Imoto, Koichi Okamoto, Kunio II and Susumu Ito : Prediction of Prognosis in Gallbladder Carcinoma by Mucin and p53 Immunohistochemistry, Digestive Diseases and Sciences, Vol.50, No.8, 1410-1413, 2005.
(要約)
Mucin core proteins are known to be present in various organs and are specifically expressed with carcinogenesis and closely associated with the prognoses of various malignant tumors in the digestive tract such as colorectal cancer. The present study evaluated correlations between mucin and p53 expression and prognosis of gallbladder cancer using surgically resected tissue specimens from 26 patients with gallbladder carcinoma surgically treated at our hospital. Immunohistochemical staining was performed using MUC 1, MUC2, and p53 monoclonal antibody. The level of antigen expression in the lesion was classified into four stages: none(-), slight(+), moderate (++), and severe (+ + +). According to the UICC classification, histopathological grading, levels of T, N, and M factors, and tumor stages were compared with regard to the correlations with mucin and p53 expression. All cases were classified into two groups according to the results of mucin immunohistochemistry: group A (MUC1, > or = ++; and MUC2, < or = +) and group B (MUC1, < ++; or MUC2, > +). Postoperative survival periods were compared between the two groups and p53-positive and -negative groups. Neither histological grading nor T factor correlated with mucin or p53 expression, respectively. Moreover, neither N factor nor M factor correlated with mucin or p53 expression. Furthermore, stage grouping did not correlate with mucin or p53 expression. However, when the correlation between the postoperative survival period and mucin expression was evaluated, the mean postoperative surgical period was significantly shorter in Group A than in Group B (1.02 years in Group A vs 2.92 years in Group B; P = 0.016). There was no relationship between postoperative survival period and p53 positivity. Mucin expression was independent of various tumor growth factors and clearly reflected the prognosis of gallbladder cancer. Because the relative malignancy of gallbladder cancer could be evaluated by examining the level of glycoprotein expression in tumor tissue, mucin could be a more important marker than p53 for predicting prognosis in gallbladder carcinoma using surgically resected tissue specimens.
Susumu Ito, Koichi Okamoto, Naoki Muguruma, T. Kimura, H. Yano, Y. Imoto, M. Kaji, R. Aoki and Seisuke Okamura : A Novel Diagnostic Method for Evaluation of Vascular Lesions in the Digestive Tract Using Infrared Fluorescence Endoscopy, Endoscopy, Vol.37, No.1, 52-57, 2005.
(要約)
We have developed an infrared fluorescence endoscope to evaluate gastrointestinal vascular lesions. Infrared endoscopy (IRE) after intravenous administration of indocyanine green (ICG) is used at present to examine vascular lesions such as esophageal varices. However, no previous study has compared the sensitivity of infrared fluorescence endoscopy (IRFE) with that of IRE. In this study, we compared the usefulness of IRFE and IRE. For IRFE we used an infrared endoscope equipped with excitation and barrier filters and an intensified charge-coupled device camera. In preliminary experiments, the observable tissue depth was assessed by wrapping increasing numbers of layers of commercially available pork around a syringe containing a uniform concentration of ICG or by changing the concentration of ICG in a syringe covered by a piece of pork of uniform thickness. In the clinical part of the study, ICG was administered intravenously at different concentrations to patients with esophageal varices and the resulting infrared fluorescent images were evaluated. The preliminary experiments revealed that the depth of tissue that could be visualized was significantly greater in IRFE than it was in IRE (11.2 mm in IRFE vs. approximately 3.2 mm in IRE). Clear infrared fluorescence was obtained by IRFE at lower concentrations of ICG than the concentrations required to obtain clear images using IRE. In the clinical part of the study, clear infrared fluorescence was observed in a region where esophageal varices had been detected by conventional endoscopy when ICG was administered in doses of 0.005 mg/kg to 0.01 mg/kg, which was lower than the doses used in IRE. Compared with conventional IRE, IRFE facilitated the observation of deeper layers, and esophageal varices were observed by IRFE following the intravenous administration of a markedly reduced dose of ICG. IRFE, in combining the characteristics of reflected infrared light and fluorescence, may be a useful novel procedure in the diagnosis of vascular lesions in the gastrointestinal tract.
Koichi Okamoto, Naoki Muguruma, Rika Aoki, Yasunori Sato, Jiro Nakamoto, Yoshitaka Imoto, Seisuke Okamura, Susumu Ito, Hiroshi Okitsu and Toshiaki Sano : A Treatment Using ST1571 for Jejunal Gastrointestinal Stromal Tumor (GIST) Accompanied with Liver Metastas and Peritoneal Dissemination, Internal Medicine, Vol.43, No.12, 1151-1156, 2004.
(要約)
A 64-year-old man with a chief complaint of melena visited our emergency outpatient clinic. After several examinations, he was diagnosed as a gastrointestinal stromal tumor (GIST) with liver metastasis. Surgical resection of the jejunal lesion and postoperative adjuvant therapy with STI571 for one year was performed. Due to recent immunohistological studies and introduction of STI571, the diagnosis, treatment, and prognosis of GIST are about to change profoundly. Further accumulation of cases is necessary to investigate the diagnosis, treatment, and prognosis of GIST.
Masaya Tadatsu, Susumu Ito, Naoki Muguruma, Yoshihiro Kusaka, Kumi Inayama, Termi Bando, Yoko Tadatsu, Koichi Okamoto, Kunio Ii, Yoshimitsu Nagao, Shigeki Sano and Hiromi Taue : A New Infrared Fluorescent-Labeling Agent and Labeled Antibody for Diagnosing Microcancers, Bioorganic & Medicinal Chemistry, Vol.11, No.15, 3289-3294, 2003.
(要約)
We have developed infrared fluorescent labeling agents and infrared-ray fluorescence endoscopes to establish a novel diagnostic technique. Since the fluorescence intensity of the initial labeled antibody (ICG-sulfo-OSu-labeled antibody) was not sufficient for practical use, we synthesized indocyanine green acylthiazolidinethione (ICG-ATT), which was expected to label various target molecules having amino groups efficiently. To confirm imaging of infrared fluorescence intensity of ICG-ATT- and ICG-sulfo-OSu-labeled anti-MUC1 antibodies, cotton thread was soaked in various concentrations of the antibody solution in 0.1M PBS, and observed under the epi-illumination infrared fluorescence microscope. Localization and the intensity of infrared fluorescence and DAB coloring was compared in paraffin sections of human gastric mucosa. In the study of cotton threads, both labeled antibodies showed relatively clear infrared fluorescence, and significant difference was not observed between the two antibodies. ICG-ATT-labeled anti-MUC1 antibody produced stronger staining than that by ICG-sulfo-OSu-labeled antibody. Localization pattern of infrared fluorescent staining was in good agreement with that by the conventional method with oxidized DAB staining. ICG-ATT is useful as a fluorescent-labeling agent for diagnosis of microcancers by infrared fluorescence endoscopes.
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.
(要約)
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.
(キーワード)
Aged / Cholecystectomy / Common Bile Duct / Foreign-Body Migration / Gallstones / Humans / Male / Postoperative Complications / Sphincterotomy, Endoscopic / Surgical Instruments
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.
(要約)
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.
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.
(要約)
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.
Susumu Ito, Naoki Muguruma, Tetsuo Kimura, Hiromi Yano, Yoshitaka Imoto, Koichi Okamoto, Masako Kaji, Shigeki Sano and Yoshimitsu Nagao : Principle and Clinical Usefulness of the Infrared Fluorescence Endoscopy, The Journal of Medical Investigation : JMI, Vol.53, No.1/2, 1-8, Feb. 2006.
(要約)
Since there is no infrared fluorescence materials in the living body, infrared fluorescence labeling materials are very useful for making a diagnosis of a micro cancer. We have developed an infrared fluorescence endoscope (IRFE) and indocyanin green (ICG)-derivative as infrared fluorescence labeling materials to evaluate gastrointestinal neoplastic lesions. The study aims were to apply an IRFE and to demonstrate its usefulness in detecting cancerous tissue using an antibody coupled with ICG-derivative. IRFE consisted of an infrared endoscope equipped with excitation (710-790 nm) and barrier (810-920 nm) filters and an intensified CCD camera. We have developed ICG N-hydroxy sulfo succinimide ester (ICG-sulfo-OSu) and 3-ICG-acyl-1, 3-thiazolidine-2-thione (ICG-ATT) as an infrared fluorescent-labeling reagent. ICG-derivative-labeled mouse anti-human carcinoembryonic antigen (CEA) antibody and MUC1 antibody were employed in this study. Moreover, we examined the ability of a reinforcement agent, octylglucoside, to intensity fluorescence from the labeled antibody. Biopsy specimens of gastric cancer were stained with anti-CEA antibody by the avidin-biotinylated peroxidase complex method. Among the positive specimens, freshly resected stomach from three cases were used for the infrared (IR) imaging analysis. The incubation of freshly resected stomach specimens with ICG-anti-CEA antibody-complex resulted in positive staining of the tumor sites by IRFE, and the IR fluorescent images correlated well with the tumor sites. The immunohistochemical studies suggested that the intensity of IR fluorescence of ICG-ATT-MUC1 was stronger than that of ICG-sulfo-OSu. In tumor sections, the reinforcement agent intensified fluorescence, ever at low antibody concentrations. Therefore, we conclude that an anti-CEA (and/or MUC1) antibody with affinity for cancerous lesions and labeled with ICG-derivative can be imaged with this IRFE. Specific antibodies tagged with ICG-derivative with the reinforcement agent can label cancer cells and generate a strong enough fluorescent signal to detect small cancers when examined with an IR fluorescence endoscope.
Naoki Muguruma, Koichi Okamoto and Tetsuji Takayama : Advanced Endoscopic Imaging in Colorectal Lesions, Korea International Digestive Endoscopy Congress 2019, Aug. 2019.
(キーワード)
Colorectal cancer / Image-enhanced endoscopy / Molecular imaging
11.
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.
12.
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.
14.
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.
15.
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.
16.
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.
17.
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.
18.
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.
19.
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.
20.
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.
23.
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.
24.
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.
25.
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.
26.
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.
27.
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.
28.
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.
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.
32.
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.
33.
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.
34.
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.
35.
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.
国内講演発表:
1.
岡本 耕一, 吉本 貴則, 高山 哲治 : <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, 2024年11月.
2.
岡本 耕一, 吉本 貴則 : <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, 2024年11月.
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.
41.
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.
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.
58.
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.
59.
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.
60.
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.
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.
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.
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.