記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy. Personalized medicine based on genetic mutations is required to improve its prognosis. The PI3K/AKT pathway plays a crucial role in cancer progression. While PI3K inhibitors have been developed for several malignancies, none have been clinically applied to PDAC. PIK3CA encodes the catalytic subunit of Class IA PI3K, and an activating mutation such as E545K and H1047R is oncogenic. In this study, we developed a novel pancreatic cancer mouse model with PIK3CAH1047R mutation, designated Ptf1acre/+; Rosa26-LSL-PIK3CAH1047R:p53loxP/loxP (PPC) mice. At 150 days of age, PPC mice developed PDAC and AKT was activated in their tumor epithelial cells. We established a pancreatic cancer cell line from PPC mice, and alpelisib, an inhibitor of PI3K p110α, inhibited the proliferation of PPC cells in vitro. Furthermore, PPC cells were subcutaneously transplanted into NOD/SCID mice, and alpelisib significantly reduced the tumor burden of PPC cells. Western blotting upon treatment with alpelisib revealed compensatory activation of ERK in PPC cells. Combination treatment with alpelisib and the MEK inhibitor PD98059 significantly inhibited cell proliferation. These data indicate that PIK3CA mutation may be oncogenic in PDAC and that PI3K inhibitors can be effective against such tumors. Dual inhibition of the PI3K/AKT and MEK/ERK pathways may enhance therapeutic effects in PI3K/AKT-activated pancreatic tumors.

DOI： 10.1371/journal.pone.0326491

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amoebic colitis is a parasitic gastrointestinal disease caused by Entamoeba histolytica (E. histolytica). In Japan, metronidazole (MNZ) monotherapy is often used and most cases are effective. However, we report a case of MNZ-insufficient amoebic colitis caused by residual cysts. A 73-year-old man had been staying in Southeast Asia for over a decade. He had undergone a screening colonoscopy and ulcerative lesions were observed in the cecum, and a biopsy confirmed amoeba parasites. The patient was treated with MNZ monotherapy. However, he forgot to take the medicine for several days, and the ulcerative lesions persisted. The patient was referred to our facility, and we performed a colonoscopy and confirmed trophozoites. Since we considered that previous treatment failure was due to the low oral dosage, we re-prescribed MNZ. A colonoscopy after 6 months showed that the ulcerative lesions persisted. We clinically diagnosed MNZ-insufficient amoebic colitis caused by residual cysts and prescribed MNZ and paromomycin (PRM) each for 10 days. One year later, no ulcerative lesions were observed. MNZ-insufficient amoebic colitis should be considered, when ulcerative lesions remain after MNZ administration and PRM is effective drug against cysts, and we propose a combination therapy of PRM to MNZ.

DOI： 10.1007/s12328-024-02083-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Cold snare polypectomy (CSP) is a common, simple, and safe procedure; however, it has a high rate of unclear margins. We analyzed the risk factors for unclear margins of colorectal polyp. METHODS: We retrospectively investigated colorectal polyps treated with CSP between July 2021 and July 2022, excluding those that could not be retrieved or pathologically nonneoplastic and hyperplastic polyps without margin evaluation. The clinicopathological features and risk factors for unclear margins were analyzed. Furthermore, the polyps were divided into two groups: those resected by experts and those resected by trainees. A 1 : 1 propensity score matching was performed. After matching, the risk factors for unclear margins in each group were analyzed as secondary outcomes. RESULTS: We analyzed 237 patients with 572 polyps; the margins were negative in 58.6% (negative group) and unclear in 41.4% (unclear group). The unclear margin was significantly higher at straddling folds ( P  = 0.0001), flexure points ( P  = 0.005), and in the procedures performed by trainees ( P  < 0.0001). Altogether, 198 propensity score matched pairs were explored for secondary outcomes. There were no significant differences in risk factors for unclear margins in the expert group, while in the trainee group, the unclear margin was significantly higher at the straddling folds ( P  = 0.0004) and flexure points ( P  = 0.005). CONCLUSIONS: We demonstrated that straddling folds, flexure points, and procedures performed by the trainees were significant risk factors for unclear margins, and we hypothesized that the rate of unclear margins will reduce as the trainees accumulate experience at difficult sites.

DOI： 10.1097/MEG.0000000000002845

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/a-2496-2899

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/den.14949

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

UNLABELLED: This is the first registered intervention study for vonoprazan, high-dose amoxicillin, clarithromycin, and metronidazole 14-day concomitant therapy based on a susceptibility test of Helicobacter pylori. We conducted this study as a fourth-line rescue regimen in Japan. METHODS: Twenty patients who underwent three rounds of eradication therapies (first- or second-line 7-day triple therapy consisting of amoxicillin and clarithromycin, or metronidazole- and sitafloxacin-based third-line therapy) and had failed eradication based on a urea breath test or fecal antigen test were recruited. All patients underwent endoscopic examination and culture tests before starting eradication therapy. The intervention was concomitant therapy consisting of vonoprazan 20 mg bid, amoxicillin 500 mg qid, clarithromycin 400 mg bid, and metronidazole 250 mg bid for 14 days, which were modified based on the susceptibility test, and the resistant drugs were removed from the regimen. Patients with negative culture results were treated with quadruple therapy. The primary outcome was the eradication rate (UMIN000025765, jRCTs 031180208). RESULTS: The eradication rate of susceptibility-testing-based fourth-line eradication therapy was 63.2% (95%CI: 38.4-83.7%) in intent-to-treat analysis and 70.6% (95%CI: 44.0-89.7%) in per-protocol analysis. Thirteen patients received quadruple therapy, with eradication rates of 61.5% and 75.0%, respectively. No serious adverse events were reported. CONCLUSIONS: This vonoprazan-based concomitant therapy modified by the susceptibility test is a potential option as fourth-line eradication after first-line clarithromycin-based 7-day triple, second-line metronidazole-based 7-day triple, and third-line sitafloxacin-based 7-day triple therapy failure.

DOI： 10.3390/microorganisms12102104

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: In the absence of Helicobacter pylori (HP) infection, a characteristic gastric mucus adhesion may appear during the use of vonoprazan. We named this novel characteristic mucus "web-like mucus" (WLM). This study aimed to determine the incidence and risk factors for WLM. Methods: Between January 2017 and January 2022, 5665 patients were enrolled in this study. The patients were divided into a proton-pump inhibitor (PPI)-prescribed group (n = 2000), a vonoprazan-prescribed group (n = 268), and a no-PPI/vonoprazan-prescribed (n = 3397) group, and the presence of WLM was examined. After excluding four patients with autoimmune gastritis, the remaining 264 patients in the vonoprazan group were divided into WLM and non-WLM groups, and their clinical features were analyzed. Results: A total of 55 (21%) patients had WLM, all in the vonoprazan-prescribed group. There were no significant differences in factors such as, sex, age, chronic kidney disease, diabetes mellitus, HP eradication history, smoking, or alcohol consumption between the WLM and non-WLM groups. The median duration from the start of vonoprazan administration to the endoscopic detection of WLM was 2 (1-24) months. Conclusions: WLM appears to be a characteristic feature in patients treated with vonoprazan.

DOI： 10.3390/jcm13144070

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background and Objective: Rescue Helicobacter pylori eradication can be challenging. Rifabutin (RBT) demonstrates high activity against Helicobacter pylori and is incorporated into various rescue eradication regimens. This exploratory study was performed to evaluate the efficacy and safety of a rescue regimen comprising RBT, metronidazole (MNZ), and vonoprazan (VPZ). Methods: This prospective, single-center, single-arm, interventional study was performed in Japan. Eligible patients were those who underwent failed primary eradication treatment (7-day treatment with three drugs: VPZ or a proton pump inhibitor [PPI], amoxicillin [AMPC], and clarithromycin) and secondary eradication treatment (7-day treatment with three drugs: VPZ or a PPI, AMPC, and MNZ) and those who were unable to receive first- and second-line therapy because of penicillin allergy. Twenty Helicobacter pylori-positive patients were treated with RBT (150 mg twice daily), MNZ (250 mg twice daily), and VPZ (20 mg twice daily) for 10 days (RBT-MNZ-VPZ therapy). Eradication success was evaluated using the urea breath test. Drug susceptibility test results were available in 16 patients. This study is registered in the Japan Registry of Clinical Trials (jRCT031220504). Results: The intention-to-treat (ITT) and per-protocol (PP) eradication rates of RBT-MNZ-VPZ therapy were 70% (90% confidence interval [CI]: 49.2%-86.0%) and 72.2% (95% CI: 50.2%-88.4%), respectively. In the MNZ-susceptible subgroup, the ITT (n = 8) and PP (n = 7) eradication rates were 100% (90% CI: 68.8%-100%) and 100% (90% CI: 65.2%-100%). In the MNZ-resistant subgroup, the ITT (n = 8) and PP (n = 7) eradication rates were both 62.5% (90% CI: 28.9%-88.9%). All infections were RBT-susceptible. Conclusions: These findings suggest that RBT-MNZ-VPZ therapy may be a promising rescue regimen, especially in MNZ- and RBT-susceptible infections or patients with penicillin allergy.

DOI： 10.3390/jcm13133774

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In clinical cases of pancreas divisum, endoscopic retrograde cholangiopancreatography often necessitates cannulation of the pancreatic duct through the minor papilla. Nevertheless, this procedure can be challenging because of the small size of the minor papilla and the difficulty in visualizing the ductal orifice. A new image-enhanced endoscopy technique called texture and color enhancement imaging (TXI) has been developed, which enhances texture, brightness, and color compared with white-light imaging, resulting in subtle differences in the surface mucosa. Herein, we describe the case of a 73-year-old man with pancreas divisum in whom TXI was useful in identifying the orifice of the minor papilla. He was referred to our hospital with repetitive acute exacerbation of chronic pancreatitis. Since contrast-enhanced computed tomography revealed a pancreatic stone in the main pancreatic duct, endoscopic retrograde cholangoepancreatography was performed as a therapeutic intervention. Despite the initial difficulty in identifying the orifice of the minor papilla on white-light imaging, TXI enhanced its visibility successfully, enabling dorsal pancreatic duct cannulation via the minor papilla. Subsequently, endoscopic pancreatic sphincterotomy was performed and a 6Fr plastic stent was placed. Post-endoscopic therapy, the patient's abdominal pain was relieved. TXI was useful in identifying the minor papilla orifice and led to successful cannulation.

DOI： 10.1002/deo2.358

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: To date, no randomized trials have compared the efficacy of 7-day vonoprazan, amoxicillin, and metronidazole triple therapy (VAM) versus 7-day vonoprazan, amoxicillin, and clarithromycin triple therapy (VAC) as a first-line treatment for Helicobacter pylori eradication. This study was performed to compare the efficacy of VAM and VAC as first-line treatments. METHODS: This prospective multicenter randomized trial was performed in Japan and involved 124 H. pylori-positive patients without a history of eradication. Patients without antibiotic resistance testing of H. pylori were eligible. The patients were randomized to receive either VAC (vonoprazan 20 mg + amoxicillin 750 mg + clarithromycin 200 or 400 mg twice a day) or VAM (vonoprazan 20 mg + amoxicillin 750 mg + metronidazole 250 mg twice a day) for 7 days, with stratification by age and sex. Eradication success was evaluated using the 13C-urea breath test. We evaluated safety using patient questionnaires (UMIN000025773). RESULTS: The intention-to-treat and per-protocol eradication rates of VAM were 91.3% (95% confidence interval [CI], 82.0-96.7%) and 92.6% (95% CI, 83.7-97.6%), respectively, and those of VAC were 89.1% (95% CI, 77.8-95.9%) and 96.1% (95% CI, 86.5-99.5%), respectively. No significant difference was observed between VAM and VAC in either analysis (P = 0.76 and P = 0.70, respectively). Abdominal fullness was more frequent in patients who received VAM than VAC. CONCLUSIONS: These findings suggest that VAM as a first-line treatment in Japan can be categorized as grade B (intention-to-treat cure rate of 90-95%) and have potential as a first-line national insurance -approved regimen.

DOI： 10.1002/jgh3.13069

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: An esophageal diverticulum is a relatively rare disease, with reports of treatment for esophageal cancer in the diverticulum even rarer. CASE PRESENTATION: The case involved a 72-year-old male with a chief complaint of dysphagia. He was diagnosed with an esophageal diverticulum (Zenker's diverticulum) measuring 10 cm in diameter. Five years later, an upper gastrointestinal endoscopy revealed an iodine-unstained 0-IIb lesion of 20 mm in diameter with type B1 vessels in the diverticulum. An endoscopic biopsy and CT revealed it to be squamous cell carcinoma, cT1a-EP/LPM N0 M0, cStage 0. Because the lesion was in the diverticulum and endoscopic resection was difficult with the risk of perforation, surgical resection was set as the course of treatment. Diverticulectomy was performed via a cervical approach, using a stapler, and the patient was discharged on the 16th day without any complications. The pathological diagnosis was pTis-EP, ly0, v0, R0. CONCLUSIONS: We think this case is very rare and diverticulectomy of early esophageal cancer in the diverticulum is available and safe.

DOI： 10.1186/s44215-023-00123-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: The incidence of metachronous gastric cancer (MGC) after endoscopic treatment for early gastric cancer (EGC) is high, but a method of risk assessment for MGC based on endoscopic findings has not been established. In this study, we focused on endoscopic intestinal metaplasia (IM) and investigated the risk for MGC after endoscopic submucosal dissection (ESD) for EGC. METHODS: This retrospective observational study involved patients who underwent curative ESD for EGC from April 2015 to January 2021. We assessed endoscopic IM using the pretreatment endoscopic examination images. The severity of endoscopic IM was classified into four levels: 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Four different gastric areas were evaluated. We divided the patients into a low-score group and a high-score group, and compared the cumulative incidence of MGC. RESULTS: In total, 156 patients who met the inclusion criteria were followed up for at least 12 months after ESD, and MGC developed in 14 patients during a mean period oof 41.5 months. The endoscopic IM scores in the lesser curvature of the antrum, lesser curvature of the corpus, and greater curvature of the corpus were higher in patients with MGC than in those without MGC. In the corpus, the 5-year cumulative incidence of MGC was significantly higher in the high-score group than in the low-score group (29.8% vs 10.0%, P = 0.004). CONCLUSION: The severity of endoscopic corpus IM was associated with MGC. Thus, patients with severe corpus IM at the time of ESD require careful examination and intensive follow-up.

DOI： 10.1002/jgh3.12989

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Helicobacter pylori (HP) infection causes chronic inflammation and atrophy of the gastric mucosa and thus a high risk of gastric cancer (GC). With the increasing success of HP infection treatment, a larger number of GCs that develop after eradication can be assessed. Several studies have shown that epithelium with low-grade atypia (ELA) is a frequent characteristic of these GCs, but the origin of this condition is unknown. In this study, we compared the mucin phenotype, cellular proliferation, and p53 staining in ELA and cancerous tissues obtained from patients with GC with and without HP eradication. METHODS: The study population consisted of 23 patients with GC that developed after successful HP eradication therapy (eradicated group) and 24 patients with GC and HP infection (infected group). The prevalence of ELA was determined by hematoxylin and eosin staining. Tumor tissue and ELA samples were further analyzed by immunohistochemical staining for Muc5AC, Muc2, p53, and Ki-67. RESULTS: The ELA coverage rate was significantly higher in the eradicated group than in the infected group. Gastric-type mucin was frequently expressed by the ELA, and the mucin phenotypes of ELA and cancerous areas differed in 75% of cases. The Ki-67 labeling index was consistently lower in ELA than in the cancerous mucosa. Fourteen of 21 (66.7%) cancerous lesions, but only 3 ELA samples, were p53-positive. CONCLUSION: In most cases, ELA on the surfaces of GCs seems to have originated from normal gastric cells, not from cancer cells.

DOI： 10.1159/000521875

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cigarette smoking, alcohol consumption, and Lugol-voiding lesions (LVLs) are the major causative risk factors of esophageal squamous cell carcinoma (ESCC); however, reports on ESCC cases unrelated to these risk factors are very limited. Here, we investigated the clinicopathological features and etiology of such cases. METHODS: We retrospectively analyzed 704 consecutive superficial ESCC tumors of 512 patients who were treated with endoscopic submucosal dissection. The enrolled patients were divided into two groups-the very low-risk (VLR)-group and risk (R)-group-based on the presence of the abovementioned risks. Clinical, endoscopic, and pathological characteristics and genetic findings were assessed in both groups. RESULTS: The VLR-group consisted of 21 (4.1%) patients, who were characteristically female. Patients in the VLR-group presented gastroesophageal reflux disease (GERD), hiatal hernia, and non-open-type atrophic gastritis, and were negative for Helicobacter pylori. We found unique endoscopic features-frequently observed in the posterior wall of the middle thoracic esophagus-with a linear shape that closely resembled the erosion-like form of GERD. Additionally, histopathological examination showed that these tumors presented atypical nuclei limited to the basal and parabasal layer, sequential to the surrounding changes that presented pathological chronic inflammation of esophagitis. Evaluation of somatic mutations in cancer-related genes using next-generation sequencing revealed that the positive carcinogenic potential (TP53 mutation) of the tumors was relatively frequent in the VLR-group. CONCLUSIONS: Our study suggests that ESCC without major causative factors is related to GERD, with no remarkable oncogenic difference.

DOI： 10.1007/s00535-021-01815-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: To assess the efficacy and safety of 7-day Helicobacter pylori rescue treatment consisting of a vonoprazan (VPZ), metronidazole (MNZ), and sitafloxacin (STFX) regimen (VPZ-MNZ-STFX therapy) in patients with penicillin allergy. METHODS: This was a registered prospective intervention study. Patients with penicillin allergy who were diagnosed with H. pylori infection and had a history of H. pylori eradication were eligible for inclusion. Seventeen patients were prospectively treated with VPZ 20 mg bid, MNZ 250 mg bid, and STFX 100 mg bid for 7 days. Safety was evaluated using a questionnaire on adverse effects. RESULTS: The eradication rate of 7-day VPZ-MNZ-SFTX therapy was 88.2% (95% confidence interval: 63.6-98.5%; n = 17) in both intention-to-treat and per-protocol analyses. On the questionnaire, 25% of patients reported experiencing diarrhea, with a score of 2 or 3. All patients undergoing VPZ-MNZ-STFX therapy completed 100% of their medication course. CONCLUSION: Rescue H. pylori eradication with VPZ-MNZ-STFX therapy is effective and well tolerated in patients with penicillin allergy (UMIN000016335, jRCTs031180133).

DOI： 10.1002/jgh3.12492

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Although colorectal endoscopic submucosal dissection (ESD) has become a standardized procedure worldwide, the difficulty of the procedure is well known. However, there have been no studies assessing the causes of treatment interruption. The present study aimed to evaluate the factors involved in the interruption of colorectal ESD. METHODS: We retrospectively analyzed 1116 consecutive superficial colorectal neoplasms of 1012 patients who were treated with ESD between August 2008 and September 2018. The clinicopathological characteristics and treatment outcomes were analyzed. RESULTS: Interrupted ESD was reported in 14 lesions (1.3%) of the total study population. Univariate analysis of clinical characteristics indicated that age, 0-I macroscopic-type tumor, and tumor location on the left side colon were risk factors for interruption. Multivariate analysis revealed that 0-I macroscopic-type tumor was the sole preoperative independent risk factor for interruption. Univariate analysis revealed that the presence of muscle-retracting sign (MRS), deep submucosal tumor invasion, and intermediate invasive growth pattern represented the etiology of interruption. Multivariate analysis indicated that MRS can be a sole key sign for the interruption. Additionally, the resectability and curability of 0-I type tumors were significantly inferior to those of predominantly lateral spreading tumors. Observations of 0-I macroscopic-type tumors, MRS, and submucosal deep invasion were significantly more frequent in interrupted cases. Conventional endoscopic images without magnification endoscopy were more associated with interruption than irregular surfaces or Vi pit patterns in cases with 0-I type tumors. CONCLUSION: ESD of 0-I type tumors is highly disruptive, and undiagnosable submucosal infiltration can reduce the curability.

DOI： 10.1007/s00464-020-08042-0

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記述言語：日本語   出版者・発行元：(一社)日本消化器内視鏡学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/meg.0000000000001788

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Persistent Helicobacter pylori (H. pylori) infection causes chronic inflammation, atrophy of the gastric mucosa, and a high risk of developing gastric cancer. In recent years, awareness of eradication therapy has increased in Japan. As H. pylori infections decrease, the proportion of gastric cancers arising from H. pylori uninfected gastric mucosa will increase. The emergence of gastric cancer arising in H. pylori uninfected patients though rarely reported, is a concern to be addressed and needs elucidation of its clinicopathological features. AIM: To evaluate the clinicopathological features of early gastric cancer in H. pylori-uninfected patients. METHODS: A total of 2462 patients with 3375 instances of early gastric cancers that were treated by endoscopic submucosal dissection were enrolled in our study between May 2000 and September 2019. Of these, 30 lesions in 30 patients were diagnosed as H. pylori-uninfected gastric cancer (HpUIGC). We defined a patient as H. pylori-uninfected using the following three criteria: (1) The patient did not receive treatment for H. pylori, which was determined by investigating medical records and conducting patient interviews; (2) Lack of endoscopic atrophy; and (3) The patient was negative for H. pylori after being tested at least twice using various diagnostic methods, including serum anti-H. pylori-IgG antibody, urease breath test, rapid urease test, and microscopic examination. RESULTS: The frequency of HpUIGC was 1.2% (30/2462) for the patients in our study. The study included 19 males and 11 females with a mean age of 59 years. The location of the stomach lesions was divided into three sections; upper third (U), middle third (M), lower third (L). Of the 30 lesions, 15 were U, 1 was M, and 14 were L. Morphologically, 17 lesions were protruded and flat elevated type (0-I, 0-IIa, 0-IIa + IIc), and 13 lesions were flat and depressed type (0-IIb, 0-IIc). The median tumor diameter was 8 mm (range 2-98 mm). Histological analysis revealed that 22 lesions (73.3%) were differentiated type.The HpUIGC lesions were classified into fundic gland type adenocarcinoma (7 cases), foveolar type well-differentiated adenocarcinoma (8 cases), intestinal phenotype adenocarcinoma (7 cases), and pure signet-ring cell carcinoma (8 cases). Among 30 HpUIGCs, 24 lesions (80%) were limited to the mucosa; wherein, the remaining 6 lesions showed submucosal invasion. One of the submucosal invasive lesions showed more than 500 μm invasion. The mucin phenotype analysis identified 7 HpUIGC with intestinal phenotype and 23 with gastric phenotype. CONCLUSION: We elucidated the clinicopathological characteristics of HpUIGC, revealing recognition not only undifferentiated-type but also differentiated-type. In addition, intestinal phenotype tumors were also observed and could be an important tip.

DOI： 10.3748/wjg.v26.i20.2618

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: E-cadherin (Cdh1) is a key molecule for adherence required for maintenance of structural homeostasis. Loss of E-cadherin leads to poor prognosis and the development of resistance to chemotherapy in pancreatic cancer. Here, we evaluated the physiological and pathologic roles of E-cadherin in the pancreas. METHODS: We crossbred Ptf1a-Cre mice with Cdh1f/f mice to examine the physiological roles of E-cadherin in the pancreas. In addition, we crossbred these mice with LSL-KrasG12D/+ mice (PKC) to investigate the pathologic roles of E-cadherin. We also generated a tamoxifen-inducible system (Ptf1a-CreERT model). Organoids derived from these models using lentiviral transduction were analyzed for immunohistochemical features. Established cell lines from these organoids were analyzed for migratory and invasive activities as well as gene expression by complementary DNA microarray analyses. RESULTS: None of the Ptf1a-Cre mice crossbred with Cdh1f/f mice survived for more than 28 days. We observed aberrant epithelial tubules that resembled the structure of acinar-to-ductal metaplasia after postnatal day 6, showing features of pancreatitis. All of the PKC mice died within 10 days. We observed tumorigenicity with increasing stroma-like aggressive tumors. Ptf1a-CreERT models showed that deletion of E-cadherin led to earlier pancreatic intraepithelial neoplasm formation. Cells established from PKC organoids had greater migratory and invasive activities, and these allograft tumors showed a poorly differentiated phenotype. Gene expression analysis indicated that Hdac1 was up-regulated in PKC cell lines and a histone deacetylase 1 inhibitor suppressed PKC cell proliferation. CONCLUSIONS: Under physiological conditions, E-cadherin is important for maintaining the tissue homeostasis of the pancreas. Under pathologic conditions with mutational Kras activation, E-cadherin plays an important role in tumor formation via the acquisition of tumorigenic activity.

DOI： 10.1016/j.jcmgh.2019.09.001

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記述言語：日本語   出版者・発行元：(一社)日本消化器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Tokyo  

DOI： 10.1007/s10120-017-0734-5

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.gie.2017.10.038

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Hindawi Limited  

<italic>Background</italic>. Vonoprazan affords more clinical benefits than proton pump inhibitors (PPIs) during the healing of gastroduodenal ulcers. However, it remains controversial whether vonoprazan is more effective than PPIs when used to heal artificial ulcers arising after endoscopic submucosal dissection (ESD). <italic>Aim</italic>. This study investigated the effects of vonoprazan compared with esomeprazole on the healing of post-ESD artificial ulcers. <italic>Methods</italic>. Sixty patients who underwent gastric ESD between May 2015 and May 2017 were randomized to treatment with vonoprazan (V group) or esomeprazole (E group) for 8 weeks. Upper endoscopy was performed at 4 and 8 weeks after ESD, and drug effects were estimated based on the ulcer healing rates and shrinkage rates. <italic>Results</italic>. Fifty-three patients were analyzed. The respective 4- and 8-week ulcer healing rates did not differ significantly between V and E groups (8.0 versus 11.5%, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.669</mml:mn></mml:math>; 88.9 versus 84.6%, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.420</mml:mn></mml:math>). Similarly, the respective 4- and 8-week ulcer shrinkage rates did not differ significantly between V and E groups (96.8 versus 97.5%, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.656</mml:mn></mml:math>; 100 versus 100%, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.257</mml:mn></mml:math>). <italic>Conclusion</italic>. The healing of artificial ulcers after ESD did not differ using vonoprazan or esomeprazole. Both vonoprazan and esomeprazole were effective when used to promote artificial ulcer healing after ESD.

DOI： 10.1155/2018/1615092

PubMed

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その他リンク： http://downloads.hindawi.com/journals/grp/2018/1615092.xml

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stomach cancer rarely develops in patients with familial adenomatous polyposis (FAP), and Helicobacter pylori infection may increase the risk of FAP-related gastric cancer. We describe the case of a 64-year-old woman who developed multiple synchronous early gastric cancers without H. pylori infection. Nine cancer lesions were successfully treated by endoscopic submucosal dissection. An immunohistochemical analysis revealed that the tumors were positive for mucin (MUC)2, MUC6, and CDX2, but negative for MUC5AC, suggesting that the tumors were gastrointestinal mixed type. Periodical endoscopic surveillance is important for the detection of cancers at an early stage.

DOI： 10.2169/internalmedicine.8735-16

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although Helicobacter-induced gastric inflammation is the major predisposing factor for gastric carcinogenesis, the precise mechanism by which chronic gastritis causes gastric cancer remains unclear. Intestinal and spasmolytic polypeptide-expressing metaplasia (SPEM) is considered as precancerous lesions, changes in epithelial tissue stem/progenitor cells after chronic inflammation has not been clarified yet. In this study, we utilized three-dimensional gastric epithelial cell culture systems that could form organoids, mimicking gastric epithelial layer, and characterized the changes in epithelial cells after chronic Helicobacter felis infection. METHODS: We used three mice model; 1) long-term H. felis infection, 2) H. felis eradication, and 3) MNU chemical carcinogenesis model. We performed cRNA microarray analysis after organoid culture, and analyzed the effects of chronic gastric inflammation on tissue stem cells, by the size of organoid, mRNA expression profile and immunohistochemical analysis. RESULTS: The number of organoids cultured from gastric epithelial cells was significantly higher in organoids isolated from H. felis-infected mice compared with those from uninfected gastric mucosa. Based on the mRNA expression profile, we found that possible stem cell markers such as Cd44, Dclk1, and genes associated with the intestinal phenotype, such as Villin, were increased in organoids isolated from H. felis-infected mucosa compared with the control. The upregulation of these genes were cancelled after H. felis eradication. In a xenograft model, tumors were generated only from organoids cultured from carcinogen-treated gastric mucosa, not from H. felis infected mucosa or control organoids. CONCLUSIONS: Our results suggested that, as a possible mechanism of gastric carcinogenesis, chronic inflammation induced by H. felis infection increased the number of tissue stem/progenitor cells and the expression of stem cell markers. These findings suggest that chronic inflammation may alter the direction of differentiation toward undifferentiated state and that drawbacks may enable cells to redifferentiate to intestinal metaplasia or neoplasia.

DOI： 10.1186/s12876-017-0706-6

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一社)日本消化器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3748/wjg.v23.i30.5557

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本胆道学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3748/wjg.v22.i36.8242

Web of Science

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/00365521.2016.1216591

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：英語   出版者・発行元：(一社)日本胃癌学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(公社)神奈川県医師会  

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