記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: S-1 monotherapy had previously been widely used as a second-line treatment for pancreatic cancer (PC) after gemcitabine-based chemotherapy mainly in Japan. Based on the results of the NAPOLI-1 trial, the recommended second-line therapy is now liposomal irinotecan plus fluorouracil/folinic acid (nal-IRI + 5-FU/LV). However, there have been no studies comparing nal-IRI + 5-FU/LV therapy with S-1 monotherapy. METHODS: The main objective of this study was to compare overall survival (OS) in patients treated with nal-IRI + 5-FU/LV and those treated with S-1 monotherapy as second-line treatments, using the inverse probability of treatment weighting (IPTW) method. This study was conducted in 31 institutions participating in Japan Oncology Network in Hepatobiliary and Pancreas. To minimize potential biases due to the retrospective design, IPTW analysis was performed with multiple imputation, and imputed IPTW-adjusted hazard ratios and corresponding 95% confidence intervals (CIs) were estimated using a Cox proportional hazards model and combined into pooled estimates. RESULTS: A total of 463 metastatic PC patients were enrolled in this study (257 in the S-1 monotherapy group and 206 in the nal-IRI + 5-FU/LV group). The median OS was 7.50 months (95% CI 4.18-12.69 months) in the nal-IRI + 5-FU/LV group and 5.72 months (95% CI 2.76-10.79 months) in the S-1 monotherapy group. In the IPTW-adjusted Cox proportional hazards model, nal-IRI + 5-FU/LV was associated with a significant OS benefit (pooled IPTW-adjusted hazard ratio, 0.779; 95% CI 0.399-0.941; p = 0.025). CONCLUSION: These findings support the use of nal-IRI + 5-FU/LV as standard second-line treatment for PC patients after gemcitabine-based chemotherapy.

DOI： 10.1007/s00535-024-02186-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Objectives: Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) often requires fistula dilation owing to the placement of a large diameter of the delivery stent. The recently developed delivery devices, which are as thin as 5.9/6.0 Fr, may save the need for fistula dilation. Therefore, we investigated whether large fistula dilation would be required or not in the case of this newly developed thin-diameter delivery stents. Methods: We conducted a retrospective study involving 33 patients implemented with a self-expandable metal stent (SEMS) during EUS-HGS. The patients were categorized based on the delivery device diameter into thin (n = 13; delivery device diameter: 5.9/6.0 Fr) and thick (n = 20; delivery device diameter: 8.5 Fr) groups. We compared the initial rate of success, technical success, and clinical success between the thin and thick groups. The initial rate of success was defined as successful stent placement without a balloon or large diameter mechanical dilation. Results: The rate of the initial stenting success was significantly higher in the thin group (100% [13/13]) compared with that in the thick group (65.0% [13/20]) (p = 0.027). In the thick group, seven cases with technical difficulty in terms of stent placement could be successfully completed with additional fistula dilation with a 9 Fr bougie dilator or 4 mm balloon dilator; this resulted in a technical success of 100% in both groups ultimately. The rate of clinical success was 100% and 95.0% in the thin and thick groups, respectively (p = 1.00). Conclusions: Thin delivery stents may facilitate stent placement without the need for a balloon fistula or large-diameter mechanical dilation.

DOI： 10.3390/jcm13216328

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Objectives: The usefulness of dual-energy computed tomography (DECT) for low absorption in the parenchymal phase and contrast effects in the delayed phase for pancreatic cancer is not clear. Therefore, the diagnostic capability of low-KeV images obtained using DECT for pancreatic cancer in the pancreatic parenchymal and delayed phases was evaluated quantitatively and qualitatively. Methods: Twenty-five patients with pancreatic cancer who underwent contrast-enhanced DECT were included. A total of 50 and 70 KeV CT images, classified as low-keV and conventional CT-equivalent images, were produced, respectively. The tumor-to-pancreas contrast (Hounsfield units [HU]) in the pancreatic parenchymal and delayed phases was calculated by subtracting the CT value of the pancreatic tumor from that of normal parenchyma. Results: The median tumor-to-pancreas contrast on 50 KeV CT in the pancreatic parenchymal phase (133 HU) was higher than that on conventional CT (68 HU) (p < 0.001). The median tumor-to-pancreas contrast in the delayed phase was -28 HU for 50 KeV CT and -9 HU for conventional CT (p = 0.545). For tumors < 20 mm, the tumor-to-pancreas contrast of 50 KeV CT (-39 HU) had a significantly clearer contrast effect than that of conventional CT (-16.5 HU), even in the delayed phase (p = 0.034). Conclusions: These 50 KeV CT images may clarify the low-absorption areas of pancreatic cancer in the pancreatic parenchymal phase. A good contrast effect was observed in small pancreatic cancers on 50 KeV delayed-phase images, suggesting that DECT is useful for the visualization of early pancreatic cancer with a small tumor diameter.

DOI： 10.3390/tomography10100117

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Positron emission tomography (PET) is an important imaging modality, especially in oncology. [18F]fluorodeoxyglucose PET (FDG-PET) is the most used cancer PET imaging. However, since the elevated glucose use by cancers, termed the Warburg effect, is usually only moderate, FDG often does not provide a strong or well-delineated signal. Malignancies have a stronger addiction to methionine, known as the Hoffman effect, and thus [11C]methionine PET (MET-PET) has demonstrated superiority over FDG-PET in gliomas and other brain tumors. Our team is pioneering the use of MET-PET for tumors of the trunk for both better detection of cancer and to determine candidates for methionine-restriction therapy. The present study provides examples of cancers of organs in the trunk in which MET-PET outperforms FDG-PET in detecting and delineating primary and metastatic cancer. PATIENTS AND METHODS: In all cases, MET-PET and FDG-PET were performed simultaneously. An evaluation of the images was conducted by a nuclear medicine physician. RESULTS: Four cases, including prostate, bladder, esophageal, and breast cancer demonstrated the superiority of MET-PET compared to FDG-PET. CONCLUSION: MET-PET can out-perform FDG PET for accurate detection of primary and metastatic cancer in the trunk and can determine the extent of methionine addiction of cancer, thereby indicating whether cancer patients can benefit from methionine-restriction therapy.

DOI： 10.21873/anticanres.17216

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Pancreatic cancer has a very poor prognosis with a 5-year survival rate of less than 5% among patients with distant metastasis, a figure that has not improved over many decades. Only 10 to 20% patients are candidates for curative surgery at presentation due to the aggressive nature and asymptomatic progression of pancreatic cancer. Although first-line chemotherapy, such as FOLFIRINOX and gemcitabine + nab paclitaxel, improved the median survival from 8.5 to 11.1 months, more effective treatments are immediately needed. The aim of the present study was to evaluate the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet combined with first-line chemotherapy on a patient with stage IV metastatic pancreatic cancer. CASE REPORT: A 63-year-old female was diagnosed with metastatic pancreatic cancer in October 2023. The patient started FOLFIRINOX as first-line chemotherapy in combination with methionine restriction, which comprised o-rMETase 250 units twice a day and a low-methionine diet. The patient was monitored using computed tomography and CA19-9 blood tests. After five months from the start of combination therapy, the size of the primary tumor decreased by 40% along with liver-metastasis regression. The CA19-9 blood marker decreased by 86%. The patient sustains a high performance status and continues the combination therapy without severe side effects. CONCLUSION: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with first-line chemotherapy, was highly effective in a patient with inoperable stage IV pancreatic cancer.

DOI： 10.21873/anticanres.17215

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although handheld ultrasound devices (HUDs) are commonplace, their ability to diagnose fecal retention (FR) remains unclear. This prospective observational study examined HUDs' usefulness in diagnosing FR in patients with constipation in a palliative care setting. Between 10 December 2020 and 30 June 2022, we compared rectal ultrasonographic findings obtained using HUDs with clinical manifestations in 64 males and 70 females (48%, 52%, 68 ± 11 years old) with constipation who had undergone computed tomography (CT). FR was diagnosed using a HUD and compared with CT and digital rectal examination (DRE) results. In total, 42 (31%), 42 (31%), and 41 (31%) patients were diagnosed using HUDs, CT, and DRE, respectively. Thirty-nine (93%) patients in the CT group were also diagnosed with FR using HUDs. A total of 89 of 92 patients with a negative CT diagnosis also had a negative HUD diagnosis. Among the 41 patients in the DRE group, 37 were also diagnosed with FR using HUDs. Among 93 patients with a negative DRE diagnosis, 86 had a negative HUD diagnosis. The sensitivity, specificity, positive predictive value, and negative predictive value of HUDs for CT were 93%, 97%, 93%, and 97%, respectively. Those of HUDs for DRE were 88%, 94%, 86%, and 95%, respectively. The concordance rates for FR diagnosis were 128/134 for CT and HUDs and 123/134 for DRE and HUDs. HUD was useful for diagnosing FR in this setting. HUDs could provide valuable support for appropriate treatment selection. Developing a constipation treatment algorithm based on rectal ultrasonographic findings is warranted in the future.

DOI： 10.3390/diagnostics14151626

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Breast cancer is the most common and the deadliest cancer among women in the world. Treatment options for HER2-positive metastatic breast cancer patients are limited. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), has recently been introduced as second-line chemotherapy for HER2-positive metastatic breast cancer. The aim of the present study was to evaluate the efficacy of methionine restriction with oral recombinant methioninase (o-rMETase) and a low-methionine diet combined with T-DXd, on a patient with HER2-positive recurrent stage IV breast cancer. CASE REPORT: A 66-year-old female was diagnosed with HER2-positive metastatic breast cancer. Computed tomography (CT) indicated peritoneal dissemination, thickening of the sigmoid colon and splenic flexure and widespread bone metastases. The patient was previously treated with fulvestrant, trastuzumab, pertuzumab, paclitaxel and capecitabine which were ineffective. T-DXd was administered as a second-line chemotherapy. Since the patient experienced strong side effects, the dose of T-Dxd was decreased. The patient began methionine restriction using o-rMETase and a low-methionine diet along with T-DXd. After the start of the combined treatment, CA15-3 and CA27.29, tumor markers for breast cancer, decreased rapidly from a very high level. The levels of both tumor markers are currently normal. Additionally, peritoneal-dissemination nodules, ascites and the thickness of the sigmoid colon and splenic flexure are no longer detected on CT. The patient maintains a high performance status, without severe side effects of the combination treatment. CONCLUSION: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with T-DXd as second-line chemotherapy, was highly effective in a patient with HER2-positive stage IV breast cancer.

DOI： 10.21873/anticanres.16946

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) serves as a novel and effective treatment option for somatostatin receptor-positive unresectable liver metastases of pancreatic neuroendocrine tumors (PNETs). However, there are few reported cases of surgical resection for initially unresectable liver metastases of PNET that were converted to resectable after PRRT. Here we report a case where PRRT and somatostatin analogs (SSAs) led to a pathological complete response of initially unresectable multiple liver metastases following PNET resection. CASE PRESENTATION: A 52-year-old man underwent pylorus-preserving pancreaticoduodenectomy for PNET at age 40 and subsequent hepatectomies for resectable liver metastases at 44 and 47 years of age. At age 48, a follow-up examination revealed unresectable multiple liver metastases, and PRRT with 177Lu-DOTATATE therapy was initiated. After four cycles of PRRT, most liver metastases diminished according to imaging studies, and the remaining two hepatic lesions continued to shrink with additional lanreotide. Conversion surgery for liver metastases was successfully performed, revealing no viable tumor cells in tissue specimens. Seventeen months after surgery, imaging showed no detectable residual tumor or recurrence. We present a review of the relevant literature that highlights the significance of our findings. CONCLUSIONS: This rare case highlights the pathological complete response of initially unresectable multiple liver metastases achieved by PRRT and SSAs following PNET resection, suggesting their potential as a multimodality treatment option for unresectable PNET.

DOI： 10.1186/s40792-024-01839-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glycosylation changes in cancer proteins have been associated with malignant transformation. However, techniques for analyzing site-specific glycosylation changes in target proteins obtained from clinical tissue samples are insufficient. To overcome these problems, we developed a targeted N-glycoproteomic approach consisting of immunoprecipitation, glycopeptide enrichment, LC/MS/MS, and structural assignment using commercially available analytical software followed by manual confirmation. This approach was applied to the comparative site-specific glycosylation analysis of lysosome-associated membrane glycoprotein 1 (LAMP1) between breast cancer (BC) tumors and normal tissues adjacent to tumors. Extensive determination of glycan heterogeneity from four N-glycosylation sites (Asn84/103/249/261) in LAMP1 identified 262 glycoforms, and revealed remarkable diversity in tumor glycan structures. A significant increase in N-glycoforms with multiple fucoses and sialic acids at Asn84/249 and high-mannose-type glycans at Asn103/261 were observed in the tumor. Principal component analysis revealed that tumors of different subtypes have independent distributions. This approach enables site-specific glycopeptide analysis of target glycoprotein in breast cancer tissue and become a powerful tool for characterizing tumors with different pathological features by their glycan profiles.

DOI： 10.1093/jb/mvae001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Irinotecan (IRN), a topoisomerase I inhibitor and pro-drug of SN-38, is first-line treatment of colon cancer as part of FOLFIRI and FOLFOXIRI combination chemotherapy. However, IRN causes dose-limiting adverse events such as neutropenia and diarrhea. Dose reductions are sometimes required, which reduce efficacy. Recombinant methioninase (rMETase) targets the fundamental basis of cancer, methionine addiction, known as the Hoffman effect, and enhances the efficacy of numerous chemotherapy drugs. The present study determined the efficacy of rMETase when administered in combination with IRN. MATERIALS AND METHODS: Cell viability was assessed by cultivating the HCT-116 human colorectal cancer cell line in 96-well plates at 1×103 cells per well in Dulbecco's modified Eagle's medium (DMEM). Subsequently, HCT-116 cells were treated with increasing concentrations of SN-38, the active form of IRN, ranging from 0.5 nM to 32 nM, and/or rMETase ranging from 0.125 to 8 U/ml. After treatment for 72 h, the half-maximal inhibitory concentration (IC50) of SN-38 alone and rMETase alone for HCT-116 cells were determined. Using the IC50 concentration of rMETase, we determined the IC50 of SN-38 in combination with rMETase. Cell viability was determined with the cell-counting Kit-8 with the WST-8 reagent.. RESULTS: The IC50 of rMETase alone for the HCT-116 cells was 0.55 U/ml, and the IC50 of IRN (SN-38) alone was 3.50 nM. rMETase at 0.55 U/ml lowered the IC50 of SN-38 to 0.232 nM (p<0.0001), a 15-fold reduction. CONCLUSION: rMETase and IRN are strongly synergistic, giving rise to the possibility of lowering the effective dose of IRN for the treatment of patients with colon cancer, thereby reducing its severe toxicity. This new strategy will allow more patients with cancer to be effectively treated with IRN.

DOI： 10.21873/anticanres.16785

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Gliomas are the most common and recalcitrant malignant primary brain tumors. All cancer types are addicted to methionine, which is a fundamental and general hallmark of cancer known as the Hoffman effect. Particularly glioma cells exhibit methionine addiction. Because of methionine addiction, [11C]-methionine positron emission tomography (MET-PET) is widely used for glioma imaging in clinical practice, which can monitor the extent of methionine addiction. Methionine restriction including recombinant methioninase (rMETase) and a low-methionine diet, has shown high efficacy in preclinical models of gliomas, especially in combination with chemotherapy. The aim of the present study was to determine the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet, combined with radiation and temozolomide (TMZ), on a teenage female patient with high-grade glioma. CASE REPORT: A 16-year-old girl was diagnosed with high-grade glioma. Magnetic resonance imaging (MRI) showed a left temporal-lobe tumor with compression to the left lateral ventricle and narrowing of sulci in the left temporal lobe. After the start of methionine restriction with o-rMETase and a low-methionine diet, along with TMZ combined with radiotherapy, the tumor size shrunk at least 60%, with improvement in the left lateral ventricle and sulci. The patient's condition remains stable for 19 months without severe adverse effects. CONCLUSION: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with radiation and TMZ as first-line chemotherapy, were highly effective in a patient with high-grade glioma.

DOI： 10.21873/invivo.13591

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Primary small bowel carcinoma in pregnant women is extremely rare. Small bowel cancer is difficult to diagnose because of its rarity, lack of specific clinical symptoms, and particular anatomical features. We experienced a case of primary small bowel adenocarcinoma with ovarian metastasis during pregnancy. This is the first reported case of a patient with small bowel adenocarcinoma whose pregnancy continued to term and ended in delivery. CASE PRESENTATION: A 32-year-old pregnant woman developed abdominal pain, and imaging examination revealed an ovarian tumor at 29 weeks of gestation. We performed laparotomy and resected the ovarian tumor, which was initially suspected to be primary ovarian cancer. The patient continued the pregnancy to term. A detailed examination of the abdominal cavity during cesarean delivery at 37 weeks revealed that the primary lesion was located in the small bowel. CONCLUSION: It is important to recognize that the small bowel may be the primary site of metastatic ovarian cancer. Detailed and careful examination is necessary to diagnose small bowel cancer during pregnancy.

DOI： 10.1159/000540524

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Colorectal cancer (CRC) is the third-leading cause of death in the world. Although the prognosis has improved due to improvement of chemotherapy, metastatic CRC is still a recalcitrant disease, with a 5-year survival of only 13%. Irinotecan (IRN) is used as first-line chemotherapy for patients with unresectable CRC. However, there are severe side effects, such as neutropenia and diarrhea, which are dose-limiting. We have previously shown that methionine restriction (MR), effected by recombinant methioninase (rMETase), lowered the effective dose of IRN of colon-cancer cells in vitro. The aim of the present study was to evaluate the efficacy of the combination of low-dose IRN and MR on colon-cancer in nude mice. MATERIALS AND METHODS: HCT-116 colon-cancer cells were cultured and subcutaneously injected into the flank of nude mice. After the tumor size reached approximately 100 mm3, 18 mice were randomized into three groups; Group 1: untreated control on a normal diet; Group 2: high-dose IRN on a normal diet (2 mg/kg, i.p.); Group 3: low-dose IRN (1 mg/kg i.p.) on MR effected by a methionine-depleted diet. RESULTS: There was no significant difference between the control mice and the mice treated with high-dose IRN, without MR. However, low-dose IRN combined with MR was significantly more effective than the control and arrested colon-cancer growth (p=0.03). Body weight loss was reversible in the mice treated by low-dose IRN combined with MR. CONCLUSION: The combination of low-dose IRN and MR acted synergistically in arresting HCT-116 colon-cancer grown in nude mice. The present study indicates the MR has the potential to reduce the effective dose of IRN in the clinic.

DOI： 10.21873/invivo.13539

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The risk and prognosis of pancreatobiliary cancer and in patients with autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC) remain unclear. Therefore, we retrospectively investigated the risk of pancreatobiliary cancer and prognosis in patients with AIP and IgG4-SC. METHODS: Patients with AIP and IgG4-SC at seven centers between 1998 and 2022 were investigated. The following data were evaluated: (1) the number of cancers diagnosed and standardized incidence ratio (SIR) for pancreatobiliary and other cancers during the observational period and (2) prognosis after diagnosis of AIP and IgG4-SC using standardized mortality ratio (SMR). RESULTS: This study included 201 patients with AIP and IgG4-SC. The mean follow-up period was 5.7 years. Seven cases of pancreatic cancer were diagnosed, and the SIR was 8.11 (95% confidence interval [CI]: 7.29-9.13). Three cases of bile duct cancer were diagnosed, and the SIR was 6.89 (95% CI: 6.20-7.75). The SMR after the diagnosis of AIP and IgG4-SC in cases that developed pancreatobiliary cancer were 4.03 (95% CI: 2.83-6.99). CONCLUSIONS: Patients with autoimmune pancreatitis and IgG4-SC were associated with a high risk of pancreatic and bile duct cancer. Patients with AIP and IgG4-SC have a worse prognosis when they develop pancreatobiliary cancer.

DOI： 10.1002/jhbp.1404

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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: Fully covered self-expandable metallic stents (SEMS) are laser-cut (L) or braided (B); however, which is more effective for distal malignant biliary obstruction (DMBO) has been unclear. We compared the clinical outcomes of using L- type and B-type stents because we believe that recurrent biliary obstruction (RBO) is less likely to occur with L-type stents. METHODS: Patients diagnosed with unresectable DMBO were randomly assigned to groups L and B in a stratified block fashion, and outcomes were compared. The primary outcome was the rate of RBO within 1 year; secondary outcomes were adverse events, clinical success rate, time to RBO (TRBO), and overall survival. RESULTS: Of the 60 enrolled participants, 56 (group L: 27, group B: 29) were included. The rates of RBO within 1 year were 44.4% and 17.2% in groups L and B, respectively (odds ratio 2.57 [95% confidence interval {CI}: 1.045-6.353]). Early adverse events, which improved with conservative treatment, included pancreatitis (n=4) in group L and pancreatitis (n=3) and cholecystitis (n=1) in group B (p=0.913). The median TRBO (220 days [95% CI: 56-272] versus 418 days [95% CI: 232-454]) was significantly longer in group B than in group L (log-rank test, p=0.0118). The median overall survival (L: 158 days, B: 204 days) after stenting was not significantly different between the groups (p=0.8544). CONCLUSIONS: In the setting of DMBO, braided (B)-type stents are associated with less recurrent obstruction than laser-cut-type (L) stents, although there was no difference in safety.

DOI： 10.1016/j.gie.2023.11.057

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/PURPOSE: There is currently no consensus on the use of endoscopic papillectomy (EP) for early stage duodenal ampullary adenocarcinoma. This study aimed to evaluate the feasibility of EP for patients with early stage duodenal ampullary adenocarcinoma. METHODS: Patients who underwent EP for ampullary adenocarcinomas were investigated. Complete and clinical complete resection rates were evaluated. Clinical complete resection was defined as either complete resection or resection with positive or unknown margins but no cancer in the surgically resected specimen, or no recurrence on endoscopy after at least a 1-year follow-up. RESULTS: Adenocarcinoma developed in 30 patients (carcinoma in situ [Tis]: 21, mucosal tumors [T1a(M)]: 4, tumors in the sphincter of Oddi [T1a(OD)]: 5). The complete resection rate was 60.0% (18/30) (Tis: 66.7% [14/21], T1a[M]: 50.0% [2/4], and T1a[OD]: 40.0% [2/5]). The mean follow-up period was 46.8 months. The recurrence rate for all patients was 6.7% (2/30). The clinical complete resection rates of adenocarcinoma were 89.2% (25/28); rates for Tis, T1a(M), and T1a(OD) were 89.4% (17/19), 100% (4/4), and 80% (4/5), respectively. CONCLUSIONS: EP may potentially achieve clinical complete resection of early stage (Tis and T1a) duodenal ampullary adenocarcinomas.

DOI： 10.1002/jhbp.1398

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status. METHODS: Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC). RESULTS: We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model. CONCLUSIONS: Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.

DOI： 10.1097/HC9.0000000000000285

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: FOLFIRINOX (FFX) is a standard treatment for patients with advanced pancreatic cancer. However, it often causes serious hematological adverse events. This study aimed to identify the risk factors for febrile neutropenia (FN) and grade 4 (G4) neutropenia during treatment with FFX in the real world. PATIENTS AND METHODS: We analyzed data obtained from a nationwide multicenter observational study (JASPAC 06) that included 399 patients with unresectable or recurrent pancreatic cancer who received FFX at 27 institutions in Japan. RESULTS: Nadir neutrophil counts occurred from day 8 to day 22 of cycle 1, and granulocyte colony-stimulating factor was administered to over a quarter of the patients in the first cycle. Of 399 patients, FN and G4 neutropenia occurred in 51 (13%) and 108 (27%) patients, respectively. Most FN (83%) and G4 neutropenia (75%) occurred in the first or second cycles. Multivariate logistic regression analyses showed that total bilirubin (TB) > the upper limit of normal range (ULN) and no dose modification from the original regimen were significantly associated with FN, and that TB > ULN, no dose modification from the original regimen, low platelet count (<15×104/μl), and recurrent disease after pancreatectomy were independent risk factors for G4 neutropenia. CONCLUSION: No dose modification from the original regimen and TB > ULN were risk factors for FN and G4 neutropenia.

DOI： 10.21873/anticanres.16601

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Since the popularization of cancer screening and an improvement in treatment over the last two decades, multiple primary malignant neoplasms (MPMNs) have been increasingly reported. We report a patient who developed metachronous MPMNs in the breast, the endometrium, and the pancreas over a period of 13 years. A 42-year-old woman was first diagnosed with breast cancer and underwent breast-conserving surgery with adjuvant radiation therapy and endocrine therapy. Four years after breast surgery, she was diagnosed with endometrial cancer and underwent a laparoscopic modified radical hysterectomy with bilateral oophorectomy with pelvic lymph node dissection followed by adjuvant chemotherapy. However, there was peritoneal dissemination of endometrial cancer 1 year after surgery, which could be removed laparoscopically followed by adjuvant chemotherapy. Ten years after breast cancer surgery, pleural metastasis of breast cancer was diagnosed and treated by endocrine therapy. Thirteen years after breast cancer surgery, a pancreatic tumor with multiple liver masses emerged. It was difficult to diagnose whether primary or metastasis cancer by the results of the pathological analysis. Finally, we diagnosed primary pancreatic cancer with liver metastasis by clinical examination with the BRCA2-pathogenic variant. These tumors were well responded to chemotherapy and the patient survived during a follow-up period of 8 months. According to MPMNs, breast cancer patients should be followed-up carefully for the possibility of BRCA pathogenic variant and development of different primary malignant neoplasms.

DOI： 10.14740/wjon1658

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記述言語：日本語   出版者・発行元：(一社)日本膵臓学会  

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

J-GLOBAL

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aberrant glycosylation is a prominent feature of cancer, that can be used as targets to improve the existing cancer biomarkers, and help to assess metastasis risks, and therapeutic effects. We developed a targeted O-glycoproteomics method using serum specimens, and evaluated its utility in identifying advanced colorectal cancer (CRC) markers. To this end, we combined consecutive lectin affinity purification using Maclura pomifera lectin (MPL), jacalin, and Sambucus nigra lectin, which have affinities for the following O-glycans, that have received attention as cancer-related antigens, Tn (GalNAc-Ser/Thr), Sialyl Tn (Siaα2-6GalNAc-Ser/Thr), T (Galβ1-3GalNAc-Ser/Thr), Sialyl T (Siaα2-3Galβ1-GalNAc-Ser/Thr), and di-Sialyl T (Siaα2-3Galβ1-3[Siaα2-6] GalNAc-Ser/Thr), with a unique O-glycoproteomics approach. A total of 2,068 O-glycoforms derived from 265 proteins were identified in healthy individuals and patients with advanced CRC, of which 44 CRC-specific O-glycoforms were extracted. Particularly, five glycoproteins with T, Sialyl T, and di-Sialyl T antigens in specific peptide regions were evaluated quantitatively and statistically. We found that fibulin-2 (FBLN2) (aa330-349)/T antigen (area under the curve [AUC] = 0.92); macrophage colony-stimulating factor 1 (CSF1) (aa370-395)/(T + di-Sialyl T) (AUC = 0.94); macrophage mannose receptor 1 (MRC1) (aa1083-1101 and aa1215-1229)/T (AUC = 0.96 and 0.99); fibrinogen alpha chain (FGA) (aa354-367, aa511-527 and aa559-573)/Sialyl T (AUC = 0.98, 0.90 and 0.94); and complement component C7 (C7) (aa692-701)/di-Sialyl T (AUC = 1.00), can have high diagnostic efficacy to strategically predict advanced CRC groups. Hence, they could be promising markers for detection of advanced CRC, and provide new clinical test indicators along with lectins, such as MPL and jacalin. Our O-glycoproteomics platform provides a novel tool and resource, for researchers and clinicians seeking to better understand and treat advanced CRC.

DOI： 10.3389/fonc.2023.1104936

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The clinical outcomes of everolimus rechallenge in patients with pancreatic neuroendocrine neoplasms (PNENs) are unknown. This study aimed to investigate the treatment outcomes and safety of everolimus rechallenge treatment with PNENs. METHODS: Clinical data of everolimus-treated patients with PNENs at two institutions were collected. Patients who underwent everolimus rechallenge were included in the study. We analyzed the progression-free survival (PFS) and treatment response associated with everolimus rechallenge and the adverse events. RESULTS: Between 2008 and 2020, 117 patients received initial treatment with everolimus, of which 14 patients received everolimus rechallenge. With regard to the grade of PNENs, there were 2 cases of G1, 11 cases of G2, and 1 case of G3. The median rechallenge PFS was 5.7 months. The objective response rate was 21.4%. the disease control rate was 71.4%. The only major grade 3 or 4 adverse event was neutropenia (n = 1, 7.1%). No other severe adverse event was observed. CONCLUSION: The outcomes and safety of everolimus rechallenge were verified, and it was deemed an acceptable treatment. Everolimus rechallenge may provide a new drug therapy for patients with advanced PNENs for whom no other drug treatment option is available.

DOI： 10.3390/cancers14225669

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/PURPOSE: This study aimed to investigate the efficacy of intensive fluid-loading therapy post-endoscopic retrograde cholangiopancreatography (ERCP) for the prevention of post-ERCP pancreatitis (PEP) in at-risk patients. METHODS: In this retrospective study, data of 1200 patients at risk for PEP were investigated. After propensity score matching, 404 patients were included in the normal (n = 202) and hydration (n = 202) groups. On the day of ERCP, patients in both groups were infused with 2000 ml/24 h of fluid before ERCP. Meanwhile, the hydration group received an additional 1000 ml/10 h of lactated Ringer's solution postoperatively. RESULTS: The incidence of PEP was lower in the hydration group (12.4%) than in the normal group (24.3%) (odds ratio [OR]: 0.44; 95% CI: 0.26-0.75, p = .003). The incidence of severe PEP was 2.0% and 6.9% in the hydration and normal groups (OR: 0.27; 95% CI: 0.09-0.84, p = .027), respectively. The incidence of fatal PEP was 0% and 2.0% in the hydration and normal groups (OR: N.A.: p = .123), respectively. CONCLUSIONS: Post-ERCP hydration may be an effective method of preventing PEP, including severe PEP, in at-risk patients.

DOI： 10.1002/jhbp.1267

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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）  

BACKGROUND AND PURPOSE: During endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS), tract dilation is one of the most important steps, and the placement of conventional metal stents with 8.5 Fr delivery devices is difficult due to the large outer shape of the device. Fine-gauge balloon catheters have become popular because of their stricture penetration ability and ease of dilation. This study aimed to evaluate the utility of fine-gauge balloon catheters. PATIENTS AND METHODS: This retrospective study involved 38 patients who underwent conventional metal stent placement. The patients were classified into two groups: those who underwent dilation with a fine-gauge balloon catheter before initial metal stenting (balloon dilation group) and those who underwent bougie dilation only (non-balloon dilation group). We evaluated the stenting success rate after initial dilation and adverse events. RESULTS: Seventeen and twenty-one patients were included in the balloon dilation and non-balloon dilation groups, respectively. The stenting success rate after initial dilation was 100% (17/17) in the balloon dilation group and 71.4% (15/21) in the non-balloon dilation group (p = 0.024). As adverse events, peritonitis was observed in one case (4.8%) in the balloon dilation group, and in three cases (14.3%) in the non-balloon dilation group (p = 0.613). CONCLUSIONS: Dilation using a fine-gauge balloon catheter before conventional metal stent with 8.5 Fr delivery device placement is considered effective in EUS-HGS.

DOI： 10.3390/jcm11195681

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In IgG4-related sclerosing cholangitis (IgG4-SC), the necessity of biliary drainage (BD) is unclear. In this study, we aimed to retrospectively investigate the improvement of liver damage and jaundice in cases of IgG4-SC with and without BD, before starting steroids. METHODS: Fifty-two patients with IgG4-SC were investigated in the study. The study endpoints were the normalization rate of alkaline phosphatase (ALP)/total bilirubin (T-Bil) after 8 weeks of steroids, with and without BD. RESULTS: Propensity score matching was performed based on ALP and T-Bil, and 28 patients were included. There were 14 patients each in the BD and non-BD groups. Before initiation of steroids, the mean ALP in the BD group and the non-BD group was 378/461 (p = 0.541); the mean T-Bil was 2.5/1.8 (p = 0.401). Eight weeks after initiation of steroids, ALP improvement rate in BD group/non-BD group was 69.2%/61.5% (p = 1.000), and T-Bil improvement rate was 100%/100% (p = Ns). CONCLUSIONS: Steroids for IgG4-SC could prove effective in improving liver damage and jaundice, regardless of the presence or absence of BD. BD for IgG4-SC aimed to improve jaundice may not be necessary.

DOI： 10.1002/jhbp.1230

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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：Wiley  

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) can progress in non-obese patients as in obese patients. Reports on long-term prognosis in non-obese NAFLD patients are controversial. Therefore, we aimed to examine the long-term prognosis of non-obese patients with NAFLD. METHODS: This single-center, retrospective cohort study enrolled biopsy-proven non-obese and obese NAFLD patients between January 2002 and December 2011 and followed them up until 31 March 2021, for death and clinical events (cardiovascular and liver-related events and extrahepatic cancers). RESULTS: Of the 223 NAFLD patients, 58 (26.0%) were non-obese. Compared with obese patients, they had a lower fibrosis stage (0.8 ± 0.80 vs 1.2 ± 0.91; P = 0.004), milder lobular inflammation (0.9 ± 0.7 vs 1.1 ± 0.7; P = 0.02), and significantly lower serum creatinine, total bilirubin, ferritin, and type IV collagen 7S and higher high-density lipoprotein levels. After a median follow-up of 8.9 years, no significant difference was noted in mortality between the two groups (2 [3.4%] non-obese vs 5 [3.0%] obese; log-rank test, P = 0.63). Twelve patients (20.7%) in the non-obese group and 32 (19.4%) in the obese group had clinical events. Although the obese group had a higher incidence of clinical events during the first 10 years of follow-up, the non-obese group had a higher incidence after that (log-rank test, P = 0.67). The non-obese group had a high incidence of malignancy (9 [15.5%] non-obese vs 14 [8.3%] obese; P = 0.13). CONCLUSION: Non-obese NAFLD does not necessarily have a good prognosis, and some cases have a poor prognosis such as extrahepatic cancers. Further validation is required in the future.

DOI： 10.1002/jgh3.12808

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jgh3.12808

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Approximately 60% of patients with chronic constipation (CC) have a significantly higher rate of loss of defecation desire (LODD). Bile acids are expected to have a restorative effect on defecation desire (DD) because they lower the rectal sensory threshold, which is an objective index of DD. Elobixibat (EXB) specifically inhibits the ileal bile acid transporter/apical sodium-dependent bile acid transporter, which is a transporter involved in the reabsorption of bile acids in the terminal ileum. This study aims to investigate the LODD improvement rate in patients with CC after 4 weeks of EXB treatment. Methods: A total of 40 adult patients with CC who meet the eligibility criteria will be enrolled. Patients will receive oral EXB (10 mg/day) for 4 weeks. A patient diary will be provided daily at 4 weeks after treatment. The primary endpoint will be the percentage LODD improvement at week 4 of the treatment period from week 2 of the observation period using questionnaires. Ethics and dissemination: Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board prior to participant enrolment (approval number: CRB21-008). The results of this study will be submitted for publication in international peer-reviewed journals, and key findings will be presented at international scientific conferences. Participants desiring the results of this study will be directly contacted for data dissemination. Trial registration: This trial was registered at ClinicalTrials.gov (NCT05165199). Protocol version: 1.0, September 21, 2021.

DOI： 10.1016/j.conctc.2022.100958

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neuroendocrine carcinoma (NEC) is a rare subtype of malignant gallbladder tumor. Although surgical resection is the only potentially curative therapy for gallbladder NEC, most cases are surgically unresectable because of advanced stage disease and/or biologically aggressive behavior. The standard palliative treatment for malignant gallbladder tumors is chemotherapy; however, the efficacy of chemoradiotherapy in the treatment of gallbladder tumors is controversial. Here, we report a case of gallbladder NEC that showed a durable response to chemoradiotherapy. A 68-year-old Japanese man presented with a huge gallbladder tumor with liver and duodenal invasion. Pathological findings revealed poorly differentiated NEC of the gallbladder. After seven cycles of chemotherapy comprising cisplatin and irinotecan, computed tomography (CT) revealed remarkable tumor shrinkage, but an enlarged portal lymph node. The patient was treated with 50.4 Gy in 28 fractions with two cycles of cisplatin and etoposide. After chemoradiotherapy, the enlarged lymph node also decreased in size. Maximum standardized uptake value of fluorodeoxyglucose-positron emission tomography/CT(FDG-PET/CT) changed from 8.2 to physiological accumulation. We defined this condition as a complete response on both enhanced CT and FDG-PET/CT; therefore, we did not perform systemic treatment and only observed his condition. This patient remained healthy with no recurrence at 3 years after chemoradiotherapy.

DOI： 10.1007/s12328-022-01645-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is useful in diagnosing subepithelial lesions (SELs), and adequate tissue sampling is necessary to differentiate between benign and malignant diseases to determine therapeutic strategies. This study aimed to evaluate sampling adequacy and diagnostic performance of EUS-FNA for SELs with Franseen needles. This retrospective study enrolled 130 patients who underwent EUS-FNA with a 22-gauge needle for SELs from January 2010 to March 2021. We compared sampling adequacy and predictive factors influencing the sampling adequacy of EUS-FNA for SELs between Franseen and conventional needles. The sampling adequacy rates were 95.0% (38/40) with Franseen needles and 76.7% (69/90) with conventional needles (p = 0.011). The mean number of punctures with Franseen needles (2.80) was significantly less than that with conventional needles (3.42) (p &lt; 0.001). In the multivariate analysis, the use of Franseen needles (p = 0.029; odds ratio [OR], 5.37; 95% confidence interval [CI], 1.18-23.36) was an independent factor influencing the sampling adequacy. Compared to conventional needles, the Franseen needle could play a vital role in accurately diagnosing SELs by yielding better sampling adequacy and reducing the number of passes.

DOI： 10.3390/diagnostics12071667

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Peptide receptor activation therapy (PRRT) is a promising treatment option for metastatic neuroendocrine tumors (NETs). However, predicting tumor shrinkage before treatment is challenging. We analyzed the shrinkage rate of each metastatic tumor lesion to identify predictive factors related to shrinkage. Patients with metastatic NET who underwent PRRT were included in this retrospective study. For each patient, between one to five metastatic lesions were selected in descending order of size, and the change in the maximum tumor diameter after treatment was defined as the shrinkage rate per lesion (L-SR). We analyzed the relationship between pretreatment clinicopathological factors and L-SR. The median L-SR of all 75 lesions in 20 patients was 20% (95% CI: 4.8-26.1%). While previous treatment with cytotoxic agents (34.4%, p &lt; 0.05) and primary tumor of the pancreas (27.8%, p &lt; 0.05) were significantly favorable factors, a primary tumor of the rectum was significantly more resistant to shrinkage (-20.5%, p &lt; 0.001). Therefore, lesion-based analysis of PRRT for NETs showed that pancreatic NET and previous treatment with cytotoxic agents were favorable factors for tumor shrinkage; however, rectal NET was a factor associated with resistance to shrinkage.

DOI： 10.3390/cancers14143317

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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：BMJ  

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome phenotype in the liver and thus obviously associated with metabolic abnormalities, including insulin resistance-related to hyperglycaemic and hyperlipidaemia. The prevalence of NAFLD is increasing worldwide. However, currently, there is no consensus regarding the efficacy and safety of drugs used to treat patients with NAFLD/non-alcoholic steatohepatitis (NASH). Guanabenz acetate, a selective α2-adrenoceptor stimulator used in the treatment of hypertension, binds at a high-affinity constant to a nuclear transcriptional coregulator, helicase with zinc finger 2 (Helz2) and inhibits Helz2-medaited steatosis in the liver; chronic oral administration of guanabenz acetate produces a dose-dependent inhibition of lipid accumulation by inhibiting lipogenesis and activating fatty acid Β-oxidation in the liver of obese mice, resulting in improvement of insulin resistance and hyperlipidaemia. Taken all together, guanabenz acetate has a potentially effective in improving the development of NAFLD/NASH and metabolic abnormalities. In this randomised, open label, parallel-group, phase IIa study, we made attempts to conduct a proof-of-concept assessment by evaluating the efficacy and safety of guanabenz acetate treatment in patients with NAFLD/NASH.

Methods and analysis

A total of 28 adult patients with NAFLD or NASH and hypertension complications meeting the inclusion/exclusion criteria will be enrolled. Patients will be randomised to receive either 4 or 8 mg guanabenz acetate (n=14 per group). Blood tests and MRI will be performed 16 weeks after commencement of treatment. The primary endpoint will be the percentage reduction in hepatic fat content (%) measured using MRI-proton density fat fraction from baseline by at least 3.46% at week 16 after treatment initiation.

Ethics and dissemination

Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment (YCU021001). The results of this study will be submitted for publication in international peer-reviewed journals, and the key findings will be presented at international scientific conferences. Participants wishing to know the results of this study will be contacted directly on data publication.

Trial registration number

This trial is registered with ClinicalTrials.gov (number: NCT05084404).

Protocol version

V.1.1, 19 August 2021.

DOI： 10.1136/bmjopen-2021-060335

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The diagnosis of gallbladder lesions remains challenging. The efficacy of computed diffusion-weighted imaging (DWI) with high b-values and apparent diffusion coefficient (ADC) for the diagnosis of gallbladder cancer remains unknown. We aimed to investigate the usefulness of computed DWI with high b-values and the combination of computed DWI and ADC in differentiating malignant and benign gallbladder lesions. METHODS: Sixty patients (comprising 30 malignant and 30 benign lesions) who underwent magnetic resonance imaging for gallbladder lesions were included in this retrospective study. Qualitative evaluations were performed using conventional DWI with b1000, computed DWI with b1500, b1000 DWI/ADC, and computed b1500 DWI/ADC, and their diagnostic performances were compared. RESULTS: The sensitivity, specificity, and accuracy of computed b1500 DWI/ADC were 90% (27/30), 80% (24/30), and 85% (51/60), respectively. The accuracy of computed b1500 DWI/ADC was higher than that of conventional b1000 DWI (52%, 31/60, p < 0.001), computed b1500 DWI (72%, 43/60, p = 0.008), and b1000 DWI/ADC (78%, 47/60, p = 0.125). The specificity of computed b1500 DWI/ADC was also higher than that of conventional b1000 DWI (7%, 2/30, p < 0.001), computed b1500 DWI (47%, 14/30, p = 0.002), and b1000 DWI/ADC (67%, 20/30, p = 0.125). No significant difference was observed in the sensitivity between the groups. CONCLUSION: This study shows that computed DWI with high b-values combined with ADC can improve diagnostic performance when differentiating malignant and benign gallbladder lesions. Computed diffusion-weighted magnetic resonance imaging with high b-values in the diagnosis of gallbladder lesions. *Computed DWI with b1500 combined with ADC can improve diagnostic performance when differentiating gallbladder lesions compared with conventional methods (b1000 DWI).

DOI： 10.1007/s00261-022-03586-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective The effectiveness of everolimus for the management of pancreatic neuroendocrine neoplasms (PNENs), including the G3/NEC types, remains unclear. We therefore investigated the effectiveness of the drug for the management of PNENs. Methods We analyzed the progression-free survival (PFS) and overall survival (OS) associated with everolimus and factors influencing the PFS and OS. Results One hundred patients were evaluated. The PFS associated with the G1/G2 types tended to be significantly longer than that associated with the G3/NEC types (hazard ratio [HR], 0.45; p =0.005). A multivariate analysis showed that the significant factors influencing the PFS were age (<65 years old; HR, 0.44; p =0.002), grade (G1/G2; HR, 0.42; p =0.006), everolimus treatment line (≤2nd; HR, 0.55; p =0.031), and presence of treatment with metformin (yes; HR, 0.29; p =0.044). The median OS was 63.8 months. In the multivariate analysis, the significant factors influencing the OS were grade (G1/G2; HR, 0.21; p <0.001), volume of liver metastasis (≤25%; HR, 0.27; p <0.001), everolimus treatment line (≤2nd; HR, 0.27; p <0.001), and presence of primary tumor resection (yes; HR, 0.33; p =0.005). Conclusions The effectiveness of everolimus in the management of G3/NEC types and prognoses tended to be poorer than those associated with the G1/G2 types. Everolimus combined with metformin and early-line treatment with everolimus may be effective for managing advanced PNENs.

DOI： 10.2169/internalmedicine.9416-22

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記述言語：日本語   出版者・発行元：(公社)日本アイソトープ協会  

ペプチド受容体放射性核種療法(PRRT)の薬剤であるルテチウムオキソドトレオチド([177Lu]Lu-oxodotreotide)を投与した際の,患者が滞在している室内の空気中の放射能濃度を測定した。処置室および待機室においては検出限界未満であったが,特別措置病室において一部の症例でルテチウム(177Lu)が検出された。しかし検出された空気中濃度は,医療法施行規則別表第3第2欄で示されている空気中濃度限度を大きく下回っていた。(著者抄録)

DOI： 10.3769/radioisotopes.71.135

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J01507&link_issn=&doc_id=20220727080005&doc_link_id=10.3769%2Fradioisotopes.71.135&url=https%3A%2F%2Fdoi.org%2F10.3769%2Fradioisotopes.71.135&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Chronic constipation (CC) is a functional disorder that negatively impacts the quality of life of patients. This is a protocol for a multicentre, 12-week, randomised, double-blind, placebo-controlled study to test the efficacy and safety of elobixibat (EXB) versus placebo in patients with CC. METHODS AND ANALYSIS: This will be a multicentre, double-blind, placebo-control, randomised controlled trial. A total of 100 adult patients with CC, diagnosed based on Rome IV criteria, who fulfil the inclusion/exclusion criteria will be enrolled. The patients will be randomly assigned to receive EXB (10 mg) or placebo treatment (n=50 per group). Blood tests and stool sampling will be performed 12 weeks following initiation of treatment and questionnaires will be issued to participants. The primary outcome will be the change in complete spontaneous bowel movements after 12 weeks of administration. The secondary outcomes will include the change in Japanese Patient Assessment of Constipation Quality of Life and absolute serum and faecal bile acid. ETHICS AND DISSEMINATION: Ethics approval has been obtained from Yokohama City University Certified Institutional Review Board before participant enrolment. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. PROTOCOL VERSION: V.3.0, 15 June 2021. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (number NCT04784780).

DOI： 10.1136/bmjopen-2021-060704

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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：Ovid Technologies (Wolters Kluwer Health)  

INTRODUCTION: No reports on both blood and fecal bile acids (BAs) in patients with nonalcoholic fatty liver disease (NAFLD) exist. We simultaneously assessed the serum and fecal BA patterns in healthy participants and those with NAFLD. METHODS: We collected stool samples from 287 participants from 5 hospitals in Japan (healthy control [HC]: n = 88; mild fibrosis: n = 104; and advanced fibrosis group: n = 95). Blood samples were collected and analyzed for serum BAs and 7α-hydroxy-4-cholesten-3-one (C4)-a surrogate marker for BA synthesis ability-from 141 patients. Concentrations of BAs, including cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid, ursodeoxycholic acid, and lithocholic acid (LCA), were measured using liquid chromatography-mass spectrometry. RESULTS: The total fecal BA concentration was significantly higher in the NAFLD group with worsening of fibrosis than in the HC group. Most of the fecal BAs were secondary and unconjugated. In the fecal BA fraction, CA, DCA, chenodeoxycholic acid, ursodeoxycholic acid, and LCA were significantly higher in the NAFLD than in the HC group. The total serum BA concentration was higher in the NAFLD group with worsening of fibrosis than in the HC group. In the serum BA fraction, CA, LCA, and C4 concentrations were significantly higher in the NAFLD than in the HC group. DISCUSSION: Fecal and serum BA and C4 concentrations were high in patients with NAFLD with worsening of fibrosis, suggesting involvement of abnormal BA metabolism in NAFLD with fibrosis progression. Abnormalities in BA metabolism may be a therapeutic target in NAFLD with fibrosis.

DOI： 10.14309/ctg.0000000000000503

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Opioid-induced constipation (OIC) may occur in patients receiving opioid treatment, decreasing their quality of life (QOL). We compared the effectiveness of magnesium oxide (MgO) with that of naldemedine (NAL) in preventing OIC. This proof-of-concept, randomized controlled trial (registration number UMIN000031891) involved 120 patients with cancer scheduled to receive opioid therapy. The patients were randomly assigned and stratified by age and sex to receive MgO (500 mg, thrice daily) or NAL (0.2 mg, once daily) for 12 weeks. The change in the average Japanese version of Patient Assessment of Constipation QOL (JPAC-QOL) from baseline to 2 weeks was assessed as the primary endpoint. The other endpoints were spontaneous bowel movements (SBMs) and complete SBMs (CSBMs). Deterioration in the mean JPAC-QOL was significantly lower in the NAL group than in the MgO group after 2 weeks. There were fewer adverse events in the NAL group than in the MgO group. Neither significant differences in the change in SBMs between the groups nor serious adverse events/deaths were observed. The CSBM rate was higher in the NAL group than in the MgO group at 2 and 12 weeks. In conclusion, NAL significantly prevented deterioration in constipation-specific QOL and CSBM rate compared with MgO.

DOI： 10.3390/cancers14092112

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/PURPOSE: The detection ability and role of different imaging modalities to detect pancreatic neuroendocrine neoplasms (PNENs) including small lesions is unclear. This study aimed to compare the ability of endoscopic ultrasound (EUS) and computed tomography (CT) to detect PNENs. METHODS: Data of patients who underwent EUS and contrast-enhanced CT and were diagnosed with PNENs were analyzed. The detection rates of pancreatic lesions with EUS and CT based on tumor size and influencing factors were investigated. RESULTS: For 256 PNEN lesions, the detection rate of EUS was better than that of CT (94.5% vs. 86.3%; p < 0.001). EUS was significantly superior to CT for PNENs ≤ 5 mm (58.3% vs 16.7%; p = 0.006) and 5-10 mm (97.7% vs 79.5%; p = 0.008). There was no significant difference in the detection rate between EUS and CT for PNENs > 10 mm (98.4% vs 96.4%; p = 0.375). Size (≤ 5 mm) and insulinoma were independent factors associated with poor EUS and CT detection rates. CONCLUSIONS: EUS exhibited better detection ability than CT, with an excellent detection rate for PNENs > 5 mm, except for insulinomas. CT could detect PNENs > 10 mm, which are amenable to treatment.

DOI： 10.1002/jhbp.1144

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：英語  

Theranostics is a term coined by combining the words "therapeutics" and "diagnostics," referring to single chemical entities developed to deliver therapy and diagnosis simultaneously. Neuroendocrine tumors are rare cancers that occur in various organs of the body; and they express neuroendocrine factors such as chromogranin A and somatostatin receptor. Somatostatin analogs bind to somatostatin receptor, and when combined with diagnostic radionuclides, such as gamma-emitters, are utilized for diagnosis of neuroendocrine tumor. Somatostatin receptor scintigraphy when combined with therapeutic radionuclides, such as beta-emitters, are effective in treating neuroendocrine tumor as peptide receptor radionuclide therapy. Somatostatin receptor scintigraphy and peptide receptor radionuclide therapy are some of the most frequently used and successful theranostics for neuroendocrine tumor. In Japan, radiopharmaceuticals are regulated under a complex law system, creating a significant drug lag, which is a major public concern. It took nearly 10 years to obtain the approval for somatostatin receptor scintigraphy and peptide receptor radionuclide therapy use by the Japanese government. In 2021, 111 Lu-DOTATATE (Lutathera®), a drug for peptide receptor radionuclide therapy, was covered by insurance in Japan. In this review, we summarize the history of the development of neuroendocrine tumor theranostics and theranostics in general, as therapeutic treatment for cancer in the future. Furthermore, we briefly addressed the Japanese point of view regarding the development of new radiopharmaceuticals.

DOI： 10.1111/cas.15327

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The appropriate delivery of death pronouncements potentially affects bereaved families' wellbeing positively. Although younger physicians need to learn the competencies and entrustable professional activities (EPAs) to conduct death pronouncement independently, both of which have not been clarified. Therefore, this study aimed to develop a list of competencies and EPAs necessary for death pronouncement practice, which resident physicians need to acquire by the end of their residency training (postgraduate year 2). METHODS: An anonymous modified Delphi study was conducted with a panel of 31 experts. The experts were invited online from general wards in hospitals with resident physicians across Japan to participate in the study using the purposive and snowball sampling method. A non-anonymous web conference was held with three additional external evaluators to finalize the item list. The consensus criterion was defined as a mean response of at least 4 points on a 5-point Likert scale for each competency and EPA item and a rating of 4 or 5 points by at least 80% of the participants. RESULTS: Consensus was achieved, with consistently high levels of agreement across panel members, on 11 competencies and 9 EPA items. Additionally, a correspondence matrix table between competencies and EPAs was developed. CONCLUSIONS: This study clarified the standardized educational outcomes as competencies in death pronouncement practice and the unit of professional practice of physicians who can perform this independently (EPAs), serving as a blueprint to aid the development of an educational model and evaluation method for clinical educational institutions and developers of medical school curriculums.

DOI： 10.1186/s12909-022-03149-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The present prospective phase 1/2 study aimed to elucidate the efficacy and safety of 177 Lu-DOTATATE (four cycles of 7.4 GBq) in Japanese patients with unresectable, progressive neuroendocrine tumors (NETs). METHODS: From April 2018 to October 2020, 15 patients with advanced NETs (five midgut, eight pancreatic, and two lung NETs) were enrolled. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were evaluated. Pharmacokinetics and dosimetry were also evaluated in three midgut patients. RESULTS: The mean absorbed doses of 177 Lu-DOTATATE to the kidneys (20.7 Gy/29.6 GBq) and the bone marrow (0.631 Gy/29.6 GBq) were within the radiation tolerance doses. The ORR of the whole population was 53% (90% CI, 30%-76%). ORRs of the midgut and non-midgut NETs were 60% (90% CI, 19%-92%) and 50% (90% CI, 22%-78%), respectively. There was no difference in the maximum reduction rate of the sum of the target lesion diameters between patients with midgut and non-midgut NET. The median PFS was not reached; the PFS rate at 52 weeks was 80% (90% CI, 56.1%-91.7%). AEs of Grade 3 or higher were lymphopenia (47%) and leukopenia (7%). CONCLUSION: 177 Lu-DOTATATE demonstrated remarkable tumor shrinkage and tolerability in Japanese patients with advanced NETs.

DOI： 10.1002/jhbp.1101

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters-diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel-Lindau (VHL) disease-and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of "neuroendocrine tumor" (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published.

DOI： 10.1007/s00535-021-01827-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The incidence and risk factors of severe anaphylaxis by intravenous anti-cancer drugs are unclear, whereas those of milder reactions have been reported. STUDY DESIGN: Electronic medical charts of cancer patients who have undergone intravenous chemotherapy between January 2013 and October 2020 in a university hospital were retrospectively reviewed. Non-epithelial malignancies were also included in the analysis. "Severe anaphylaxis" was judged using Brown's criteria: typical presentation of anaphylaxis and one or more of hypoxia, shock, and neurologic compromise. (UMIN000042887). RESULTS: Among 5584 patients (2964 males [53.1%], 2620 females [46.9%], median age 66 years), 88,200 person-day anti-cancer drug administrations were performed intravenously, and 27 severe anaphylaxes were observed. The causative drugs included carboplatin (14 cases), paclitaxel (9 cases), and cisplatin, docetaxel, trastuzumab, and cetuximab (1 case each). The person-based lifetime incidence of severe anaphylaxis for patients who received at least one intravenous chemotherapy was 0.48% (27/5584, 95% confidence interval (CI) 0.30%-0.67%) and the administration-based incidence was 0.031% (27/88,200, 95% CI 0.019%-0.043%). Among 124 patients who received at least 10 carboplatin administrations, 10 patients experienced carboplatin-induced severe anaphylaxis (10/124, 8.1%, 95% CI 3.0%-13.1%). Carboplatin caused severe anaphylaxis after at least 9-min interval since the drip started. Thirteen out of 14 patients experienced carboplatin-induced severe anaphylaxis within a 75-day interval from the previous treatment. Paclitaxel infusion caused severe anaphylaxis after a median of 5 min after the first drip of the day at a life-long incidence of 0.93% (9/968, 95% CI 0.27%-1.59%). CONCLUSION: We elucidated the high-risk settings of chemotherapy-induced severe anaphylaxis.

DOI： 10.1002/cam4.4252

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記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE) is one of the most reliable treatments for unresectable, progressive neuroendocrine tumors (NETs) with somatostatin receptor expression. We have, for the first time, reported the results of the tolerability, safety, pharmacokinetics, dosimetry, and efficacy of this treatment for Japanese patients with NET. METHODS: Patients with unresectable, somatostatin receptor scintigraphy (SRS)-positive NETs were enrolled in this phase I clinical trial. They were treated with 29.6 GBq of 177Lu-DOTATATE (four doses of 7.4 GBq) combined with amino acid solution infusion plus octreotide long-acting release (LAR) 30 mg. The primary objective of this study was to evaluate the tolerability, safety, pharmacokinetics, and dosimetry of a single administration of this treatment in patients with SRS-positive NETs. RESULTS: Six Japanese patients (three men and three women; mean age 61.5 years; range 50-70 years) with SRS-positive unresectable NETs were recruited. 177Lu-DOTATATE was eliminated from the blood in a two-phase manner. Cumulative urinary excretion of radioactivity was 60.1% (range 49.0%-69.8%) within the initial 6 h. The cumulative renal absorbed dose for 29.6 GBq of 177Lu-DOTATATE was 16.8 Gy (range 12.0-21.2 Gy), and the biological effective dose was 17.0 Gy (range 12.2-21.5 Gy). Administration of 177Lu-DOTATATE was well tolerated, with no dose-limiting toxicities. Grade 3 lymphopenia occurred in two (33.3%) cases, but there were no other severe toxicities. Four patients achieved partial response (objective response rate, 66.7%), one patient had stable disease, and one patient had progressive disease. CONCLUSION: PRRT with 177Lu-DOTATATE was well-tolerated and showed good outcomes in Japanese patients with unresectable NETs. Peptide receptor radionuclide therapy, 177Lu-DOTA0-Tyr3-octreotate .

DOI： 10.1007/s12149-021-01674-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is an innovative treatment for advanced somatostatin-positive neuroendocrine tumors (NETs). PRRT cannot be performed in Japan because there is no approval or insurance cover so far. METHODS: We relied on foreign institutions to perform PRRT for Japanese patients with NETs. We retrospectively evaluated the safety and efficacy of PRRT. The inclusion criteria were pathologically confirmed well-differentiated NET and visible tumor uptake on pre-therapeutic somatostatin receptor scintigraphy. 177 Lu-DOTA-TOC was used as the standard treatment, and patients received three infusions every 8 weeks. Until the end of 2017, combination treatment with 90 Y and 177 Lu-DOTA-TOC was performed using the same protocol. RESULTS: Thirty-five patients were evaluated, and the primary lesions were pancreas, rectum, small intestine, stomach, and other locations. The partial response rate was 42.9%. Progression-free survival (PFS) was 12.8 months and overall survival was 42.8 months. There was no significant difference in PFS between front-line and late-line PRRT (11.0 months vs 28.0 months; P = .383). Severe adverse events included lymphocytopenia (20.0%) and thrombocytopenia (5.7%). Myelodysplastic syndrome occurred in one case. CONCLUSION: PRRT was effective and safe for Japanese patients with advanced NETs. PRRT was equally effective as front-line and late-line treatment.

DOI： 10.1002/jhbp.1014

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記述言語：日本語   出版者・発行元：(一社)日本膵臓学会  

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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: Gut microbiota composition is associated with the pathogenesis of non-alcoholic fatty liver disease. However, the association between gut microbiota composition and non-alcoholic fatty liver disease in non-obese patients remains unclear. We compared clinical parameters and gut microbiota profiles of healthy controls and non-obese and obese patients with non-alcoholic fatty liver disease. METHODS: We examined the clinical parameters and gut microbiota profiles by 16S rRNA sequences and short-chain fatty acid levels in fecal samples from 51 non-obese patients with non-alcoholic fatty liver disease (body mass index <25 kg/m2 ) and 51 obese patients with non-alcoholic fatty liver disease (body mass index ≥30 kg/m2 ) who underwent pathological examination and 87 controls at five hospitals in Japan. RESULTS: Although no significant differences between the non-obese and other groups were observed in alpha diversity, a significant difference was found in beta diversity. We observed a significant decrease in serum alanine aminotransferase levels, Eubacterium population, and butyric acid levels in non-obese patients with non-alcoholic fatty liver disease compared with those in obese patients with non-alcoholic fatty liver disease. A significant negative correlation was found between the stage of hepatic fibrosis and Eubacterium abundance in non-obese patients with non-alcoholic fatty liver disease. CONCLUSIONS: The decrease in the abundance of Eubacterium that produces butyric acid may play an important role in the development of non-alcoholic fatty liver disease in non-obese individuals. This study was registered at the University Hospital Medical Information Network clinical trial registration system (UMIN000020917).

DOI： 10.1111/jgh.15487

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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：Wiley  

BACKGROUND: Constipation is a common, distressing complication in patients with cancer receiving palliative care. Elobixibat is a novel inhibitor of the ileal bile acid transporter that is used to treat chronic constipation by stimulating bowel function. However, its efficacy in patients with cancer has not been examined. This study investigated the drug's effectiveness in patients with cancer with chronic constipation. PATIENTS AND METHODS: This prospective-sampling, single-center, observational study included hospitalized patients with cancer diagnosed, using the Rome IV criteria, with chronic constipation. Within 2 weeks of hospitalization, each participant was administered elobixibat (5-15 mg) daily until discharge. Spontaneous bowel movements (SBMs), complete spontaneous bowel movements (CSBMs), Bristol stool form scale (BSFS) scores, and the Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL) scores were assessed before and after elobixibat administration. We also evaluated the relationship between the amount of food consumed and the SBM frequency. RESULTS: Among the 83 participants, the mean pre- and post-treatment frequencies of daily SBMs were 0.3 and 1.2 (p < .0001) and those of CSBMs were 0.1 and 0.6 (p < .0001), respectively. The mean pretreatment BSFS score was 1.6, whereas the post-treatment value was 3.5 (p < .0001); the mean PAC-QOL score (overall) improved from 1.01 to 0.74 (p = .01). There was no significant change in the daily SBM frequency between fasting and feeding states (1.2 vs. 1.3; p = .8), and there was no correlation between the amount of food intake and the SBM frequency after elobixibat administration (r = .03). Serious adverse events were not observed. CONCLUSION: This study showed that elobixibat is safe and effective for patients with cancer with chronic constipation, regardless of the food intake amount. IMPLICATIONS FOR PRACTICE: Elobixibat was effective at relieving chronic constipation in patients with various cancers. Serious adverse events were not observed, and the relief of constipation was independent of variation in food intake.

DOI： 10.1002/onco.13879

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/onco.13879

記述言語：日本語   出版者・発行元：(NPO)日本高齢消化器病学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extrapulmonary neuroendocrine carcinoma (EPNEC) is a lethal disease with a poor prognosis. Platinum-based chemotherapy is used as the standard first-line treatment for unresectable EPNEC. Several retrospective studies have reported the results of the utilization of temozolomide (TMZ) as a drug for the second-line treatment for EPNEC. Patients with unresectable EPNEC that were resistant to platinum-based combination chemotherapy were recruited for a prospective phase II study of TMZ monotherapy. A 200 mg/m2 dose of TMZ was given from day 1 to day 5, every 4 weeks. Response rate (RR) was evaluated as the primary end-point. The presence of O6 -methylguanine DNA methyltransferase (MGMT) in EPNEC patients was also evaluated as exploratory research. Thirteen patients were enrolled in this study. Primary lesions were pancreas (n = 3), stomach (n = 3), duodenum (n = 1), colon (n = 1), gallbladder (n = 1), liver (n = 1), uterus (n = 1), bladder (n = 1), and primary unknown (n = 1). Each case was defined as pathological poorly differentiated neuroendocrine carcinoma from surgically resected and/or biopsied specimens. The median Ki-67 labeling index was 60% (range, 22%-90%). The RR was 15.4%, progression-free survival was 1.8 months (95% confidence interval [CI], 1.0-2.7), overall survival (OS) was 7.8 months (95% CI, 6.0-9.5), and OS from first-line treatment was 19.2 months (95% CI, 15.1-23.3). No grade 3 or 4 hematological toxicity had occurred and there was one case of grade 3 nausea. One case presented MGMT deficiency and this case showed partial response. Temozolomide monotherapy is a feasible, modestly effective, and safe treatment for patients with unresectable EPNEC following platinum-based chemotherapy, especially those with MGMT deficiency.

DOI： 10.1111/cas.14811

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/PURPOSE: The relationship between autoimmune pancreatitis (AIP) and malignancy has been reported. However, the potential risk for cancer in patients with immunoglobulin 4 (IgG4)-related sclerosing cholangitis (IgG4-SC) is unclear. The present study aimed to evaluate the incidence of cancer in IgG4-SC patients. METHODS: We retrospectively collected clinical data for 121 patients diagnosed with IgG4-SC from 7 hospitals. We calculated the standardized incidence ratio (SIR) of cancer in IgG4-SC patients based on the national cancer rates. The SIR of the period after the diagnosis of IgG4-SC were calculated. RESULTS: The mean follow-up period was 6.4 years, with 121 IgG4-SC patients. During the follow-up period, 26 patients had cancer, and 29 cancers were diagnosed. The SIR of cancer after the diagnosis of IgG4-SC was 1.90 (95% confidence interval [CI] 1.67-2.21). The SIR of pancreatic and bile duct cancer was 10.30 and 8.88, respectively. The SIR of cancer in <1 year, 1-5 years, and >5 years after diagnosis of IgG4-SC were 2.58, 1.01, and 2.44, respectively. CONCLUSIONS: IgG4-SC patients have a high risk of cancer including pancreatic and bile duct cancer. The risk of cancer was high less <1 year and >5 years after diagnosis of IgG4-SC. Therefore, IgG4-SC patients may require careful long-term follow-up.

DOI： 10.1002/jhbp.957

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective Neuroendocrine neoplasms (NENs) are rare and indolent diseases, but the efficacy of treatment without surgical resection is temporary and limited. Targeted immunotherapy is an important treatment strategy in several cancers. However, the tumor and host immune reactions in the NEN microenvironment are poorly understood. Therefore, we investigated the immune checkpoint system and host immune response in pathological NEN specimens. Methods The expression of the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1 was immunohistochemically detected in archival tissue samples obtained from 20 patients with gastroenteropancreatic NENs. We additionally assessed the expression of programmed death (PD)-1, PD-L1, and the tumor-infiltrating lymphocyte (TIL) markers CD8 and family of transcription factor P3 (FOXP3). Results All 20 NENs expressed the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1. The PD-L1 and/or PD-1 expression in the tumor cells and/or TILs was confirmed in 75% of the cases. PD-1-, CD8-, and FOXP3-positive TILs were more frequently associated with PD-L1-positive tumors than with PD-L1 negative tumors (PD-1: 19.5 vs. 7.3, CD8: 18.1 vs. 7.1, FOXP3: 13.2 vs. 3.2, p=0.438, p=0.419, P=0.603, respectively). The number of cells positive for PD-1 tended to gradually increase in increasing grade of NENs but did not reach significance (Grade 1: 5.8, Grade 2: 10.2, NEC: 18.1, p=0.903). Conclusion NENs consistently express mismatch repair proteins but have a high expression of PD-L1 and/or PD-1 in the tumor microenvironment. NEC and PD-L1-positive NENs may be immunologically "hot" tumors, so an immunological approach may be an appropriate treatment strategy for these tumors.

DOI： 10.2169/internalmedicine.5648-20

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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 Science and Business Media LLC  

<title>Abstract</title>Genetically engineered mice (GEM) are the gold standard for cancer modeling. However, strict recapitulation of stepwise carcinogenesis from a single tumor-initiating epithelial cell among genetically intact cells in adults is not feasible with the currently available techniques using GEM. In previous studies, we partially overcame this challenge by physically isolating organs from adult animals, followed by genetic engineering in organoids and subcutaneous inoculation in nude mice. Despite the establishment of suitable ex vivo carcinogenesis models for diverse tissues, tumor development remained ectopic and occurred under immunodeficient conditions. Further refinement was, therefore, necessary to establish ideal models. Given the poor prognosis and few models owing to the lack of gall bladder (GB)-specific <italic>Cre</italic> strain, we assumed that the development of authentic models would considerably benefit GB cancer research. Here, we established a novel model using GB organoids with mutant <italic>Kras</italic> and <italic>Trp53</italic> loss generated in vitro by lentiviral <italic>Cre</italic> transduction and CRISPR/Cas9 gene editing, respectively. Organoid-derived subcutaneous tumor fragments were sutured to the outer surface of the GB in syngeneic mice, which developed orthotopic tumors that resembled human GB cancer in histological and transcriptional features. This model revealed the infiltration of similar subsets of immune cells in both subcutaneous and orthotopic tumors, confirming the appropriate immune environment during carcinogenesis. In addition, we accurately validated the in vivo efficacy of gemcitabine, a common therapeutic agent for GB cancer, in large cohorts. Taken together, this model may serve as a promising avatar of patients with GB cancer in drug discovery and precision medicine.

DOI： 10.1038/s41389-021-00322-1

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その他リンク： http://www.nature.com/articles/s41389-021-00322-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/PURPOSE: The role of endoscopic preoperative biliary drainage for pancreatic head cancer is controversial because of the high incidence of stent occlusion before surgery. We sought to validate a suitable stent for biliary drainage in patients with pancreatic cancer undergoing neoadjuvant chemotherapy (NAC)/neoadjuvant chemoradiotherapy (NAC-RT). METHODS: We evaluated patients who received preoperative neoadjuvant therapy for pancreatic head cancer between January 2013 and December 2019. A covered metal (CMS) or plastic stent (PS) was inserted in symptomatic patients for biliary drainage. Recurrent biliary obstruction (RBO), success rate of endoscopic drainage, adverse events, and surgical outcomes were compared between the CMS and PS groups. RESULTS: Occurrence rate of RBO was significantly higher with PS (97%) vs CMS (15%, P < .001), and time to RBO was significantly longer with CMS vs PS (not reached vs 40.5 days, P < .001). Delayed schedule associated with RBO for neoadjuvant chemotherapy was significantly lower in CMS vs PS (14% vs 50%, P < .05). There was no difference in postoperative bleeding, operation time, complications, and rate of a microscopically margin-negative resection between groups. CONCLUSIONS: Use of CMS during NAC/NAC-RT allows for safe chemotherapy without causing cholangitis or biliary obstruction and for surgery to be performed.

DOI： 10.1002/jhbp.958

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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 Japan  

Background: Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics. Methods: Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients. Results: A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years
p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression). Conclusions: FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.

DOI： 10.1007/s00535-020-01735-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics. METHODS: Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients. RESULTS: A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression). CONCLUSIONS: FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.

DOI： 10.1007/s00535-020-01755-y

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記述言語：日本語   出版者・発行元：(一社)日本消化管学会  

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記述言語：英語  

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It occurs with a prevalence of up to 25%, of which 10-20% cases progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. The histopathology of NASH is characterized by neutrophilic infiltration, and endotoxins from gram-negative rods have been postulated as a contributing factor. Elevations in endotoxin levels in the blood can be classified as intestinal and hepatic factors. In recent years, leaky gut syndrome, which is characterized by impaired intestinal barrier function, has become a significant issue. A leaky gut may prompt intestinal bacteria dysbiosis and increase the amount of endotoxin that enters the liver from the portal vein. These contribute to persistent chronic inflammation and progressive liver damage. In addition, hepatic factors suggest that liver damage can be induced by low-dose endotoxins, which does not occur in healthy individuals. In particular, increased expression of CD14, an endotoxin co-receptor in the liver, may result in leptin-induced endotoxin hyper-responsiveness in obese individuals. Thus, elevated blood endotoxin levels contribute to the progression of NASH. The current therapeutic targets for NASH treat steatosis and liver inflammation and fibrosis. While many clinical trials are underway, no studies have been performed on therapeutic agents that target the intestinal barrier. Recently, a randomized placebo-controlled trial examined the role of the intestinal barrier in patients with NAFLD. To our knowledge, this study was the first of its kind and study suggested that the intestinal barrier may be a novel target in the future treatment of NAFLD.

DOI： 10.3389/fendo.2021.770986

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Data on FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer are limited. In the JASPAC06 study-a nationwide, multicenter, observational study-FOLFIRINOX for patients with unresectable or recurrent pancreatic cancer as any line of treatment showed favorable efficacy and safety in Japanese clinical practice. METHODS: We performed exploratory analyses of patients with unresectable or recurrent pancreatic cancer who received FOLFIRINOX as the second-line chemotherapy in Japanese clinical settings. RESULTS: Of the 399 evaluable patients, 44 were eligible for inclusion in the analysis. The patients' characteristics were as follows: median age, 62 years; men, 26 (59%); Eastern Cooperative Oncology Group-Performance status 0/1, 30 (68%)/14 (32%); disease status, recurrent/local/metastatic: 4 (9%)/8 (18%)/32 (73%). The initial dose was reduced in 28 (64%) patients. The median time to treatment failure and number of cycles were 4.5 (range, 0.2-19.1) months and 6 cycles (range, 1-13 or more), respectively. The major grade 3/4 adverse events were neutropenia in 29 (66%), leucopenia in 17 (39%), anorexia in 7 (16%), febrile neutropenia in 5 (11%), and anemia in 5 (11%) patients. The median overall survival, progression-free survival, and 1-year survival rates were 10.3 (95% confidence interval [CI], 7.2-13.3), 4.1 (95% CI, 2.6-5.5) months, and 30%, respectively. CONCLUSION: Our findings suggest that FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer was effective in patients with a good performance status. It displayed toxicity similar to that observed with its use as a first-line treatment.

DOI： 10.1016/j.pan.2020.07.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/OBJECTIVES: Pancreatic neuroendocrine carcinoma (PanNEC)-G3 often presents along with genetic abnormalities such as KRAS, RB1, and TP53 mutations. However, the association between these genetic findings and response to chemotherapy and prognosis has not been clarified. This study aimed to clarify the clinicopathological features of PanNEC-G3. METHODS: We performed a subgroup analysis of the Japanese PanNEN-G3 study (multicenter, retrospective study), which revealed that Rb loss and KRAS mutation were predictors of the response to platinum-based regimen in PanNEN-G3. We re-classified WHO grades of PanNENs using the 2017 WHO classification and then analyzed the clinicopathological features and prognostic factors in 49 patients with PanNEC-G3. RESULTS: The rates of Rb loss and KRAS mutation in PanNEC-G3 were 54.5% and 48.7%, respectively. Patients with Rb loss and/or KRAS mutation showed a higher response rate to first-line platinum-based regimen than those without Rb loss or KRAS mutation (object response rate 70.0% vs 33.3%, odds ratio 9.22; 95% CI 1.26-67.3, P = 0.029), but tended to have shorter overall survival rates than those without Rb loss or KRAS mutation (median 239 vs 473 days, hazard ratio 2.11; 95% CI 0.92-4.86, P = 0.077). CONCLUSIONS: Patients with PanNEC-G3 have varied clinical outcomes for platinum-based regimen. When grouped based on Rb loss and KRAS mutation, there seemed to be two groups with distinct prognoses and responses to the platinum-based regimen. PanNEC-G3 could, therefore, be classified into two distinct groups based on immunohistochemical and genetic findings.

DOI： 10.1016/j.pan.2020.07.400

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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：Frontiers Media SA  

Background: Neuroendocrine tumors (NETs) are rare, but their worldwide incidence is gradually increasing. NETs are generally heterogeneous; however, in rare cases, they have been shown to change their phenotype (i.e., nonfunctional to functional or one functional phenotype to the addition of another functional phenotype). Here, we present two cases of liver metastatic NETs with phenotype transformation at the advanced stage that led to life-threatening events. Case presentation: A 73-year-old woman had a small intestinal nonfunctional NET with liver metastasis. After uncontrollable liver metastasis at the advanced stage, she developed duodenal perforation with hypergastremia. The patient was treated with octreotide and proton pump inhibitors and underwent endoscopic closure for duodenal perforation, but her general condition gradually deteriorated, and she died 2 weeks after duodenal perforation. Another patient, a 50-year-old man, had a functional NET (gastrinoma) with liver metastasis and duodenal ulcer. After uncontrollable liver metastasis at the advanced stage, he developed hypoglycemia. Although octoreotide and diazoxide were administrated for hyperalimentation, his hypoglycemia was uncontrollable, and he died after 4 months owing to general deterioration. Conclusion: The present cases show that advanced NETs with treatment-uncontrollable liver metastasis can transform their phenotype, specifically from a nonfunctional NET into a functional NET, and from one functional NET into the addition of another functional NET. These experiences suggest that the presence of treatment-resistant liver metastasis might be a hallmark of the potential to gain novel functions.

DOI： 10.3389/fonc.2020.555963

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) pathogenesis involves abnormal metabolism of cholesterol and hepatic accumulation of toxic free-cholesterol. Elobixibat (EXB) inhibits the ileal bile acid (BA) transporter. EXB and cholestyramine (CTM) facilitate the removal of free cholesterol from the liver by decreasing BA recirculation to the liver, thereby stimulating novel BA synthesis from cholesterol. In this randomised, double-blind, placebo-controlled, parallel-group, phase IIa study, we aim to provide a proof-of-concept assessment by evaluating the efficacy and safety of EXB in combination with CTM in patients with NAFLD. METHODS AND ANALYSIS: A total of 100 adult patients with NAFLD, diagnosed based on low-density lipoprotein cholesterol (LDL-C) level of >120 mg/dL and liver fat content of ≥8% by MRI-based proton density fat fraction (MRI-PDFF), who meet the inclusion/exclusion criteria will be enrolled. The patients will be randomly assigned to receive the combination therapy of 10 mg EXB and 9 g CTM powder (4 g CTM), 10 mg EXB monotherapy, 9 g CTM powder monotherapy or a placebo treatment (n=25 per group). Blood tests and MRIs will be performed 16 weeks following treatment initiation. The primary study endpoint will be the absolute LDL-C level change at week 16 after treatment initiation. The exploratory endpoint will include absolute changes in the liver fat fraction as measured by MRI-PDFF. This proof-of-concept study will determine whether the combination therapy of EXB and CTM is effective and safe for patients with NAFLD. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. TRIAL REGISTRATION NUMBER: NCT04235205.

DOI： 10.1136/bmjopen-2020-037961

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記述言語：日本語   出版者・発行元：(NPO)日本緩和医療学会  

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記述言語：日本語   出版者・発行元：(一社)日本膵臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本膵臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Patients taking opioids are known to develop opioid-induced constipation (OIC), which reduces their quality of life. The aim of this study is to compare magnesium oxide with naldemedine and determine which is more effective in preventing OIC. METHODS: This proof-of-concept, prospective, randomized controlled trial commenced in Japan in March 2018. Initially, a questionnaire-based survey will be conducted targeting adult patients with cancer who concomitantly commenced opioid treatment and OIC prevention treatment. Patients will then be randomly allocated to a magnesium oxide group (500 mg thrice daily) or a naldemedine group (0.2 mg once daily). Each drug will be orally administered for 12 weeks. The primary endpoint is defined as any improvement in scores on the Japanese version of Patient Assessment of Constipation Quality of Life questionnaire (JPAC-QOL) from baseline to 2 weeks of treatment. DISCUSSION: The primary endpoint is change in JPAC-QOL score from baseline to 2 weeks of intervention. The key secondary endpoint will be change in spontaneous bowel movements at 2 and 12 weeks of intervention. This study will determine whether magnesium oxide or naldemedine is more effective for the prevention of OIC. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000031891. Registered March 25, 2018.

DOI： 10.1186/s13063-020-04385-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is performed safely and effectively in elderly patients; however, whether ESD for EGC in elderly patients with frailty is safe and improves prognosis remains unclear. METHODS: In total, 142 patients aged ≥80 years who underwent ESD for EGC between September 2008 and September 2014 were included. We compared outcomes between patients with frailty and those without frailty. Frailty was assessed using the Clinical Frailty Scale (CFS) based on a patient's status before admission. Study endpoints were short- and long-term clinical outcomes after ESD. RESULTS: Patients were allocated into two groups: no frailty (CFS 1-3, n = 101) versus frailty (CFS 4-7, n = 41). Short-term clinical outcomes, specifically, adverse events and curability, did not differ between the two groups. For the long-term clinical outcomes, patients with frailty had significantly worse outcomes after ESD than those without frailty (the 3-year overall survival rates were 73.2% vs. 93.1%; P < 0.001 with log-rank test). The Cox proportional hazards model showed that frailty was only an independent risk factor for poor prognosis. CONCLUSIONS: ESD for EGC is safe for elderly patients with or without frailty. However, elderly patients with frailty have a significantly poorer prognosis than those without frailty after ESD. Our results indicate that the frailty evaluation may be helpful to determine whether ESD for EGC should be performed. Geriatr Gerontol Int 2020; 20: 461-466.

DOI： 10.1111/ggi.13905

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Neuroendocrine tumors (NETs) are rare, but their worldwide incidence is gradually increasing. NETs are generally heterogeneous; however, in rare cases, they have been shown to change their phenotype (i.e., nonfunctional to functional or one functional phenotype to the addition of another functional phenotype). Here, we present two cases of liver metastatic NETs with phenotype transformation at the advanced stage that led to life-threatening events. Case presentation: A 73-year-old woman had a small intestinal nonfunctional NET with liver metastasis. After uncontrollable liver metastasis at the advanced stage, she developed duodenal perforation with hypergastremia. The patient was treated with octreotide and proton pump inhibitors and underwent endoscopic closure for duodenal perforation, but her general condition gradually deteriorated, and she died 2 weeks after duodenal perforation. Another patient, a 50-year-old man, had a functional NET (gastrinoma) with liver metastasis and duodenal ulcer. After uncontrollable liver metastasis at the advanced stage, he developed hypoglycemia. Although octoreotide and diazoxide were administrated for hyperalimentation, his hypoglycemia was uncontrollable, and he died after 4 months owing to general deterioration. Conclusion: The present cases show that advanced NETs with treatment-uncontrollable liver metastasis can transform their phenotype, specifically from a nonfunctional NET into a functional NET, and from one functional NET into the addition of another functional NET. These experiences suggest that the presence of treatment-resistant liver metastasis might be a hallmark of the potential to gain novel functions.

DOI： 10.3389/fonc.2020.555963

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S2468-1253(20)30216-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Since pancreatic steatosis is reported as a possible risk factor for pancreatic cancer, the development of a non-invasive method to quantify pancreatic steatosis is needed. Proton density fat fraction (PDFF) measurement is a magnetic resonance imaging (MRI) based method for quantitatively assessing the steatosis of a region of interest (ROI). Although it is commonly used for quantification of hepatic steatosis, pancreatic PDFF can greatly vary depending on the ROI's location because of the patchy nature of pancreatic fat accumulation. In this study, we attempted to quantify pancreatic steatosis by fat-water MRI with improved reproducibility. METHODS: Using the MRI images of 159 patients with nonalcoholic fatty liver disease, we attempted to calculate the average PDFF of whole pancreas. We set ROIs covering the entire area of the pancreas appearing in every slice and calculated the average PDFF from all the voxels included in the pancreas. We named this average value as whole-pancreatic PDFF and evaluated the reproducibility of the measured values. In addition to whole-pancreatic PDFF, we measured the average PDFF of the pancreatic head (head-PDFF) and that of the pancreatic body plus tail separately and analyzed their correlation with the clinical characteristics of the patients. RESULTS: The mean inter-examiner coefficient of variation of the whole-pancreatic PDFF was 11.39%. The whole-pancreatic PDFF was correlated with age (p = 0.039), body mass index (p = 0.0093) and presence/absence of diabetes (p = 0.0055). The serum level of low-density lipoprotein cholesterol was inversely correlated with the head-PDFF. CONCLUSION: We developed a new measurement method of the pancreatic PDFF with greater reproducibility. Using this method, we characterized pancreatic steatosis in detail. This novel measurement method allows accurate estimation of the severity of pancreatic steatosis and is therefore useful for the detailed characterization of pancreatic steatosis.

DOI： 10.1371/journal.pone.0224921

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記述言語：英語  

DOI： 10.2169/internalmedicine.2894-19

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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：S. Karger AG  

INTRODUCTION: Chronic constipation (CC) is a highly prevalent functional bowel disorder with low treatment satisfaction and impaired quality of life (QOL). However, physicians tend to emphasize only "stool frequency," and relationship between "stool form" and QOL remains unclear. In this study, we aimed to investigate the actual situation of CC treatment in Japan and elucidate the relationship between stool form and QOL in patients with CC. METHODS: We conducted an online questionnaire survey in September 2018 targeting Japanese adult patients already diagnosed with CC and taking prescribed drugs. Assessments included the type of drug treatment, treatment duration, frequency of drug use, frequency of bowel movements (BMs), Bristol Stool Form Scale (BSFS), and Japanese version of the Patient Assessment of Constipation QOL (PAC-QOL) scores. Relationship between BSFS and Japanese PAC-QOL scores was analyzed, and most important factor that influences QOL was investigated. RESULTS: A total of 614 subjects were enrolled. Of these, 398 (64.8%) regularly used magnesium oxide and 162 (26.4%) used stimulant laxative, especially 81 (50.0%) used stimulant laxative "everyday." Mean score of the PAC-QOL was 1.29 ± 0.74, and the lowest score (highest QOL) of 0.94 ± 0.61 was observed in BSFS type 4. Significant difference was seen between BSFS type 4 and all the other types except type 7. Multivariate analysis revealed that normal stool form (BSFS type 4) and BMs ≥3/week are strongly related to decreases of PAC-COL score. In BSFS types 6 and 7, 36% of individuals experienced self-discontinuation of prescribed drugs and 53% self-reduced drug intake because of excessive effects. CONCLUSIONS: Stool form and frequency of BMs are relevant to QOL, especially normal stool form (BSFS type 4) is important for improving the QOL in patients with constipation. Physicians should focus on "stool form" and reconsider the prescription especially in BSFS types 6-7 patients.

DOI： 10.1159/000502815

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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/hepr.13382

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記述言語：日本語  

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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）  

Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m2 , irinotecan 180 mg/m2 , leucovorin 200 mg/m2 , bolus 5-fluorouracil [5-FU] 400 mg/m2 , and continuous 5-FU 2400 mg/m2 ) or a modified FOLFIRINOX (oxaliplatin 85 mg/m2 , irinotecan 150 mg/m2 , leucovorin 200 mg/m2 , and continuous 5-FU 2400 mg/m2 ) as first-line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (-/*6, 12 patients; -/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (-/*6, 33 patients; -/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 -/*6 than among those with UGT1A1 -/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 -/*6, tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. However, for patients who received the modified FOLFIRINOX, there was no difference in the frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with WT UGT1A1.

DOI： 10.1111/cas.13883

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.pan.2018.11.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

© 2019, Society of Surgical Oncology. Background: The role of surgery in pancreatic neuroendocrine neoplasm grade 3 (pNEN-G3) treatment remains unclear. We aimed to clarify the role of surgery for pNEN-G3, which has recently been reclassified as pancreatic neuroendocrine tumor-G3 (pNET-G3) and pancreatic neuroendocrine carcinoma-G3 (pNEC-G3), with and without metastases, respectively. Methods: We analyzed a subgroup of patients from the Japanese pancreatic NEC study, a Japanese multicenter case-series study of pNEN-G3. Pathologists subclassified 67 patients as having pNET-G3 or pNEC-G3 based on morphological features. We compared the overall survival (OS) rates among patients who were grouped according to whether they had undergone tumor-targeted surgery for tumors without (SwoM) or with (SwM) metastases, or non-surgical procedures (NS). Results: Data from 21 patients with pNET-G3 (SwoM, n = 6; SwM, n = 5; NS, n = 10) and 46 patients with pNEC-G3 (SwoM, n = 8; SwM, n = 5; NS, n = 33) were analyzed. OS of patients with pNET-G3 was significantly longer after SwoM and SwM than with NS (p = 0.018 and p = 0.022). In contrast, OS did not significantly differ between either SwoM or SwM and NS (p = 0.093 and p = 0.489) among patients with pNEC-G3. Conclusion: The role of surgery should be considered separately for pNET-G3 and pNEC-G3. Although SwoM and SwM can be considered for pNET-G3, caution is advised before considering SwM and SwoM for pNEC-G3.

DOI： 10.1245/s10434-019-07252-8

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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：Ovid Technologies (Wolters Kluwer Health)  

OBJECTIVES: FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin) is the standard therapy worldwide for unresectable pancreatic cancer; however, clinical data for Japanese patients are limited. Therefore, the observational study of FOLFIRINOX for patients with pancreatic cancer was conducted. METHODS: The study included 399 patients with unresectable or recurrent pancreatic cancer, from 27 institutions in Japan, treated with FOLFIRINOX and surveyed until December 2015. RESULTS: The median age was 63 years; in most patients, the Eastern Cooperative Oncology Group performance status was 1 or lower. The initial dose was reduced in 270 patients (68%). The main grade 3/4 toxicities were neutropenia (64%), anorexia (14%), and febrile neutropenia (13%). Fatal adverse events occurred in 5 patients, 4 of whom did not satisfy the main inclusion criteria of a previous Japanese phase II FOLFIRINOX study. The median overall survival and progression-free survival times were 10.8, and 4.5 months, respectively. The objective response rate was 21%, and the disease control rate was 61%. The median overall survival times were 11.1, 18.5, and 4.9 months in chemotherapy-naïve patients with metastatic, locally advanced, and recurrent disease, respectively. CONCLUSION: When carefully managed, FOLFIRINOX is acceptably safe and efficacious in Japanese patients with unresectable pancreatic cancer.

DOI： 10.1097/mpa.0000000000001049

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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：AMER ASSOC CANCER RESEARCH  

Purpose: Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinumbased chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.
Experimental Design: A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed.
Results: Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P &lt; 0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS, 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (P = 0.035).
Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. (C) 2017 AACR.

DOI： 10.1158/1078-0432.CCR-16-3135

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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：LIPPINCOTT WILLIAMS & WILKINS  

Background: This study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicity, and efficacy of second-line chemotherapy with FOLFIRINOX after gemcitabine (GEM)-based chemotherapy failure in metastatic pancreatic cancer (MPC).
Methods: We studied 18 histopathologically proven MPC patients. The schedule was 85 mg/m(2) oxaliplatin, irinotecan, and 400 mg/m2 leucovorin, followed by 400 mg/m(2) 5-fluorouracil (5-FU) as a bolus on day 1 and 2400 mg/m(2) 5-FU as a 46-hour continuous infusion biweekly. The dose of irinotecan was defined as follows: level 0: 100 mg/m(2), level 1: 125 mg/m(2), level 2: 150 mg/m(2), and level 3: 180 mg/m(2). The doses of other drugs were fixed. The primary endpoint of phase II study was the response rate (RR).
Results: We initially evaluated 6 patients in a phase I study. One patient developed neutropenia and 1 patient developed hyperglycemia and severe infection. Accordingly, level 1 was chosen as the MTD. According to a phase II study, the RR was 22.2% and the disease control rate was 61.1%. The progression-free survival and overall survival were 2.8 (range, 0.7-19.1) and 9.8 (2.4-19.8) months, respectively. The most common severe adverse event was neutropenia (66.7%). Febrile neutropenia occurred in 1 (5.6%) case.
Conclusion: The recommended dose was 85 mg/m(2) oxaliplatin, 100 mg/m(2) irinotecan, and 400 mg/m(2) leucovorin, followed by 400 mg/m(2) 5-FU as a bolus on day 1 and 2400 mg/m(2) 5-FU as a 46-hour continuous infusion. These results indicate that second-line FOLFIRINOX is a marginally effective treatment for GEM-based chemotherapy failure cases.

DOI： 10.1097/MD.0000000000006769

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記述言語：英語   出版者・発行元：SPRINGER JAPAN KK  

Several new developments have occurred in the field of pancreatic neuroendocrine neoplasm (PNEN) recently in Japan. First, the utility of chromogranin A (CgA), useful for the diagnosis and monitoring of the treatment response of neuroendocrine neoplasm (NEN), has been demonstrated in Japan. For PNEN diagnosis and treatment, grading and correct histological diagnosis according to the WHO 2010 classification is important. Regarding the histological diagnosis, the advent of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has enabled correct pathological diagnosis and suitable treatment for the affected tissue. Furthermore, EUS-FNA has also facilitates the assessment of the presence or absence of gene mutations. In addition, patients who have a well-differentiated neuroendocrine tumor (NET) showing a Ki-67 index of higher than 20 % according to the WHO 2010 classification, have also been identified, and their responses to treatment were found to be different from those of patients with poorly differentiated neuroendocrine carcinoma (NEC). Therefore, the concept of NET G3 was proposed. Additionally, somatostatin receptor type 2 is expressed in several cases of NET, and somatostatin receptor scintigraphy (In-111-octreoscan) has also been approved in Japan. This advancement will undoubtedly contribute to the localization diagnosis, the identification of remote metastasis, and assessments of the treatment responses of PNEN. Finally, regarding the treatment strategy for PNEN, the management of liver metastasis is important. The advent of novel molecular-targeted agents has dramatically improved the prognosis of advanced PNEN. Multimodality therapy that accounts for the tumor stage, degree of tumor differentiation, tumor volume, and speed of tumor growth is required.

DOI： 10.1007/s00535-016-1250-9

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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：KARGER  

Background/Aims: Somatostatin receptor (SSTR) scintigraphy (SRS) is the standard imaging modality for evaluation of gastroenteropancreatic neuroendocrine tumor (GEP-NET) in Western countries. However, this modality was not approved in Japan until recently. The purpose of this study was to evaluate the clinical efficacy of SRS for detecting GEP-NET in Japanese patients. Methods: Japanese patients with advanced GEP-NET were enrolled and evaluated by the SRS and CT. We also compared SRS and immunohistochemical expression of SSTRtype 2a (SSTR2a). Results:We enrolled 16 patients and the primary sites were the pancreas in 9, the stomach in 1, the small intestine in 2, the colon in 3, and unknown in 1. SRS showed positive findings in 3 (100%) of grade 1 (G1) and in 12 (92.3%) of grade 2 (G2) lesions. In the liver, SRS and CT detected lesions in 13 and 14 cases, respectively. The concordance rate of SSTR2a expression with SRS findings was 93.8% in the whole body and 92.9% in the liver. Conclusions: SRS could detect almost all of G1 and G2. SRS could be useful to detect lesions, with a high concordance rate with CT and pathological findings. We confirmed that SRS is a useful and reliable modality for Japanese patients. (C) 2017 S. Karger AG, Basel

DOI： 10.1159/000470838

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記述言語：日本語   出版者・発行元：一般社団法人 日本消化器外科学会  

症例は69歳の女性で，上顎洞癌に対する化学放射線療法後に行ったPET-CTで肝腫瘍を指摘され当科紹介受診となった．血管造影下CTでは肝S6に35 mm大の腫瘤を認め，動脈相で辺縁に造影効果を認め門脈相で低濃度であった．直腸癌の既往があり，画像所見と合わせ直腸癌異時性肝転移の術前診断のもと，腹腔鏡下肝S6部分切除術を施行した．病理組織学的には既往の直腸癌，上顎洞癌のいずれの組織型とも異なっていた．免疫組織学的検査でsynaptophysin，chromogranin A，CD56が陽性であり，神経内分泌癌と診断した．術後早期に肺・肝再発し，5th lineまで薬物療法を行ったが，術後1年7か月で死亡した．肝原発神経内分泌癌は非常にまれな疾患で，その治療対策を講じるためにはさらなる症例の蓄積が必要である．

DOI： 10.5833/jjgs.2015.0182

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その他リンク： https://search.jamas.or.jp/link/ui/2017216596

DOI： 10.1200/jco.2016.34.4_suppl.297

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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：S. Karger AG  

A 49-year-old Japanese man had multiple huge masses (max. size 60 mm diameter) in his liver. These tumors were pathologically diagnosed by tumor biopsy as epithelioid hemangioendotheliomas of the liver. In this case, multiple liver tumors existed in both lobes. Also this patient did not agree to receive surgical resection including liver transplantation. Chemotherapy with sorafenib at a dose of 400 mg/body twice a day was started. About 6 months later, CT findings revealed that these tumors were shrinking slightly
33 months later, the tumors obviously showed a partial response in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST). Also 60 months later, the partial response continued with sorafenib monotherapy.

DOI： 10.1159/000443986

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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：BIOMED CENTRAL LTD  

Background: Endoscopic biliary stenting (EBS) is one of the most important palliative treatments for biliary tract cancer. However, reflux cholangitis arising from bacterial adherence to the inner wall of the stent must be avoided. We evaluated the use of EBS above the sphincter of Oddi to determine whether reflux cholangitis could be prevented in preoperative cases.
Methods: Fifty-seven patients with primary biliary tract cancer were retrospectively recruited for the evaluation of stent placement either above (n = 25; inside stent group) or across (n = 32; conventional stent group) the sphincter of Oddi. We compared the stent patency periods prior to the time of surgical resection.
Results: The preoperative periods were 96.3 days in the conventional stent group and 96.8 days in the inside stent group (P = 0.979). Obstructive jaundice and/or acute cholangitis occurred in 7 patients (28.0%) in the inside stent group and in 15 patients (46.9%) in the conventional stent group during the preoperative period (P = 0.150). The average patency periods of the stents were 85.2 days (range, 13-387 days) for the inside stent group and 49.1 days (range, 9-136 days) for the conventional stent group (log-rank test: P = 0.009). The mean numbers of re-interventions because of stent occlusion were 0.32 for the inside stent group and 1.03 for the conventional stent group (P = 0.026). Post-endoscopic retrograde cholangiopancreatography complications occurred in 2 patients in the inside stent group and 4 patients in the conventional stent group (P = 0.516). Postoperative liver abscess occurred in 1 patient in the inside stent group and 5 patients in the conventional stent group (P = 0.968). Inside stent placement was the only significant preventative factor associated with stent obstruction based on univariate (hazard ratio [HR], 0.286; 95% confidence interval [CI], 0.114-0.719; P = 0.008) and multivariate (HR, 0.292; 95% CI, 0.114-0.750; P = 0.011) analyses.
Conclusion: Temporary plastic stent placement above the sphincter of Oddi is a better bridging treatment than conventional stent placement in preoperative primary biliary tract cancer.

DOI： 10.1186/s12876-015-0233-2

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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：WILEY-BLACKWELL  

Background and AimSelf-expandable metallic stents have mainly been used for the palliation of malignant gastric outlet obstruction (GOO). However, their use in long-term survivors and the feasibility, safety and benefit of additional intervention for stent dysfunction remain controversial. The present study examined the long-term benefits of endoscopic gastroduodenal stenting.
MethodsWe reviewed 61 patients treated with Niti-S stents at several hospitals and estimated the efficacy of stent intervention, stent patency, eating period and factors related to poor effectiveness.
ResultsAll 61 first stent interventions and 14 additional stent interventions (11second interventions and 3 third interventions) were successfully carried out. Clinical success rates were 83.6% and 85.7%, and median stent patency was 214 days and 146 days (P=0.47), respectively. Fifty patients could be treated with a first stent only, and 11 patients received additional stents. At the time of study termination or death, 70.0% of the former group and 63.6% of the latter group maintained oral intake (P=0.71), and each 86% and 100% among the group could maintain oral intake for a period exceeding half of their remaining lives after first stent intervention. Karnofsky performance status 50 (P=0.03), ascites (P=0.009), and peritoneal dissemination (P=0.001) appeared to be factors related to poor effectiveness.
ConclusionsDespite the presence of factors related to poor effectiveness, endoscopic gastroduodenal stenting would be the first treatment of choice for GOO and provide long-term benefits. If stent dysfunction occurs, additional stent intervention enables continued oral intake safely.

DOI： 10.1111/den.12300

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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 JAPAN KK  

BackgroundAutoimmune pancreatitis (AIP) with cyst formation (ACF) is often refractory to corticosteroid treatment (CST).
AimTo determine the characteristic features for the development of ACF.
MethodsWe studied characteristics in AIP patients (n = 116) whether any factors might be related to ACF. Additionally, an individual database of 24 patients was compiled to investigate factors included CST effectiveness.
ResultThe results of univariate analysis for type 1 AIP patients revealed significant association of ACF with the elevation of pancreatic enzymes, peripancreas vascular involvement (PVI) and varix formation at disease onset (P &lt; 0.05), while multivariate analysis revealed only the absence of varix formation (odds ratio = 0.033, P = 0.0015) as a significant independent predictor of the development of ACF. The comparison of the characteristic features in ACF grouped by the diameter of the cysts revealed that only the effectiveness of the CST was significantly recognized in ACF measuring less than 55mm in diameter than that with patients in the group with smaller cysts (P &lt; 0.05).
ConclusionThe varix formation is an independent predictor of the development of ACF. A pooled analysis indicated that the disease process might be irreversible in AIP patients with large cystic lesions exceeding 55mm in diameter and those patients tended to show a refractory course even if CST were conducted.

DOI： 10.1002/jhbp.160

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DOI： 10.1158/1538-7445.AM2014-CT318

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/ol.2014.2271

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Endoscopic treatment for postoperative benign bile duct stricture (BBS) is a therapeutic challenge. No previous studies have compared endoscopic treatments for BBS and malignant bile duct stricture (MBS). The aim of this study was to compare endoscopic treatments for postoperative BBS and MBS. Methodology: This study enrolled 22 consecutive patients with a diagnosis of postoperative BBS and 110 patients diagnosed with MBS. Cases involving digestive tract reconstruction were excluded. We compared the length of the bile duct strictures, the success rate of endoscopic treatment, and the incidence of complications. Results: The following results were obtained for the postoperative BBS and MBS groups, respectively: length of bile duct stricture, 6.50 mm vs. 24.3 mm (P&lt;0.0001).; success rate of endoscopic treatment, 90.9% vs. 93.6% (P=0.6551). Post-ERCP pancreatitis occurred after 11 sessions (10.7%) vs. 7 sessions (1.83%) (P=0.0002) and post-ERCP cholangitis occurred after 7 sessions (6.80%) vs. 4 sessions (1.04%) (P=0.0021). BBS was a significant risk factor for post-ERCP pancreatitis and cholangitis based on a multivariate analysis (OR 10.732; P=0.0,022; OR, 6.443; P=0.0260). Conclusion. Post-ERCP-related complications were more frequent after postoperative BBS than after MBS. The need for careful endoscopic treatment may be greater for postoperative BBS cases than for MBS cases.

DOI： 10.5754/hge13136

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

症例は65歳、女性。2010年12月6日膵体部癌に対して、他院にて膵頭十二指腸切除術を施行。2011年4月より術後補助療法としてゲムシタビンによる単独化学療法を施行。2011年7月より、ゲムシタビン+S-1による化学療法を施行。2012年3月のCTにて残膵に明らかな再発が認められたため、当院に転院。患者本人・家人に十分な説明の上、FOLFIRINOXによる化学療法を施行した。治療6コースでPR、9コースで画像上CRが得られたため残膵全摘を施行した。二次治療としてのFOLFIRINOXが有用な症例もあることより、症例ごとにその治療の可否を検討する必要があるものと考えられ報告を行った。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2014&ichushi_jid=J00296&link_issn=&doc_id=20140730260021&doc_link_id=%2Fab8gtkrc%2F2014%2F004107%2F023%2F0901-0904%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2014%2F004107%2F023%2F0901-0904%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.1200/jco.2014.32.15_suppl.e20695

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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：WILEY-BLACKWELL  

BackgroundPatients with borderline resectable pancreatic head cancer (BRPHC) have been treated with neoadjuvant chemoradiation therapy (NACRT) using metallic stents. The aim of the present study was to evaluate the efficacy and complications of covered self-expanding metallic stents (CSEMS) during the NACRT and surgical period.
Patients and MethodsWe reviewed the outcomes of patients with BRPHC, then divided them chronologically into three groups as follows. Group A: upfront surgery with plastic stent (PS) deployment; group B: PS deployment plus neoadjuvant chemotherapy (NAC) and/or NACRT; group C: CSEMS deployment plus NAC/NACRT. Patients were categorized as borderline resectable based on National Comprehensive Cancer Network Guidelines, 2010. Days to reintervention (DR), reintervention rate, and the rate of R0 and complications were studied. Safe margin-negative resection (R0) surgery was defined as R0 surgery without reintervention during the NACRT period and no postoperative complications.
ResultsDR were as follows. Groups A, B and C were 32, 55 and 97 days, respectively (P&lt;0.05). R0 surgery obtained in groups A, B and C was 53% (9/17), 100% (17/17) and 93% (14/15), respectively. CSEMS did not interfere with surgery. Safe R0 surgery obtained in groups B and C was 11% (2/19) and 67% (10/15), respectively (P&lt;0.05). Multivariate analysis showed that the odds ratio for safe R0 surgery was 16.210 (95% CI 2.457-106.962, P=0.003) for CSEMS placement.
ConclusionCSEMS should be considered to relieve symptomatic biliary obstruction in patients with BRPHC receiving NACRT in view of the high attainability rate of safe R0 surgery compared to that with PS deployment.

DOI： 10.1111/den.12049

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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  

Background. Pancreatic cancer is an aggressive malignancy with one of the worst mortality rates of all cancers. Recently, collapsin response mediator proteins (CRMPs) were reported to be associated with proliferation, apoptosis, differentiation, and invasion in several cancers. However, CRMP expression and their role in pancreatic cancer have not been investigated. This study aimed to clarify the clinical significance of CRMPs in pancreatic cancer.
Methods. Expression of crmp genes in 11 pairs of pancreatic cancer and corresponding noncancerous pancreas tissues were examined by real-time RT-PCR. Knockdown of CRMP4 expression using siRNA was examined in pancreatic cancer cell lines to determine whether CRMP4 regulates cell proliferation and invasion in vitro. Furthermore, CRMP4 protein levels in primary tumors of pancreatic cancer (n = 53) were examined by immunohistochemistry and compared with the clinicopathological features of the tumors.
Results. Of all the CRMPs, only CRMP4 was differentially expressed in pancreatic cancer tissues (p = 0.008). CRMP4 knockdown using siRNA reduced cellular invasion, but did not affect proliferation. The expression of CRMP4 was detected immunohistochemically in 34 (64.2 %) of the 53 pancreatic cancer samples, and CRMP4 expression was correlated with severe venous invasion (p = 0.044), stage (p = 0.019), and liver metastasis (p = 0.021). Multivariate analyses suggested that venous invasion and CRMP4 overexpression were prognostic factors for survival.
Conclusions. Our results suggested that CRMP4 is significantly associated with poor prognosis by promoting liver metastasis and can serve as a novel therapeutic target for pancreatic cancer.

DOI： 10.1245/s10434-012-2491-3

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The aims of the current retrospective cohort study were to compare OS of the primary resection (R-g) and the non-resection group (NR-g) after 2005. Methodology: Ninety-five patients with stage IV colorectal cancer with unresectable distant metastases were divided into 2 groups; R-g; 37 and NR-g; 58. Results: The only significant difference in clinical factors between the 2 was R0 resection rate (p = 0.007). The MST in R-g was superior to that in NR-g, 30.7 vs. 21.9 months (p = 0.031). After excluding the patients that underwent R0 resection, there was no difference in OS between the 2; however, the MST was 28.6 months in R-g and 17.1 months in NR-g. Conclusions: The advantage of resection of the primary is still unclear and a well-designed randomized Phase III study is expected. However, the current results suggest that resection of the primary lesion before intensive chemotherapy had some benefit for prognosis.

DOI： 10.5754/hge.13459

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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：GEORG THIEME VERLAG KG  

Background and study aims: In endoscopic nasobiliary drainage (ENBD), repositioning the catheter from the mouth to the nose is complicated. We devised a method using catheters with magnets and verified its utility and safety. Patients and methods: We prospectively enrolled 20 patients undergoing ENBD at Yokohama City University Hospital. Results: The procedures were successful in all 20 cases and no case required a change of operators to a senior doctor. The mean time for the procedure was 36.6 seconds. The emetic reflex was induced 0.5 times on average using the magnet method. The mean X-ray exposure time was 29.6 seconds. No complications occurred. Conclusions: The magnet-loaded catheter method for positioning the ENBD catheter before finally leading it through the nose took little time and was performed successfully and safely. Therefore, the magnet method could become the first choice among techniques for ENBD catheter placement.

DOI： 10.1055/s-0033-1344330

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.pan.2013.05.006

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: To clarify the surgical outcome and propose an appropriate strategy for biliary stricture (BS) treatment after living donor liver trans, plantation (LDLT). Methodology: Among 53 patients who underwent LDLT at our institute, 45 patients had duct-to-duct anastomosis. Of these, 33 who survived for at least 12 months after LDLT comprised the study group. Clinical parameters, BS treatment outcomes, and predictive factors for long-term patency were investigated. Results: Eleven patients developed BS. Binary leakage occurred significantly more frequently, and the number of external biliary tubes Was significantly lower than the number of graft bile-duct Openings, in the BS group compared with the non-BS group (p=0.001 and 0.004). Multivariate analysis showed that the number of external biliary tubes was the only risk factor. Long-term patency was achieved in two patients in whom stents were retained for more than 20 months, which was significantly longer than in other patients (p=0.01). Identical stent-retention for more than 6 months was a risk factor for cholangitis. Conclusions : The number of external biliary tubes should match the number of graft bile-duct openings. When BS occurs, the duration of stent retention should be more than 20 months, and stents should be exchanged at least every 6 months.

DOI： 10.5754/hge12285

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aims: The gastrointestinal motility effects of endogenous incretin hormones enhanced by dipeptidyl peptidase-IV (DPP-IV) inhibitors have not yet been sufficiently investigated. The aim of this study was to determine whether single pre-prandial sitagliptin, the DPP-IV inhibitor, administration might have an effect on the rate of liquid gastric emptying using the 13C-acetic acid breath test. Methods Ten healthy male volunteers participated in this randomized, two-way crossover study. The subjects fasted for overnight and were randomly assigned to receive 50 mg sitagliptin 2 hours before ingestion of the liquid test meal (200 kcal per 200 mL, containing 100 mg 13C-acetate) or the test meal alone. Under both conditions, breath samples were collected for 150 minutes following the meal. Liquid gastric emptying was estimated by the values of the following parameters: the time required for 50% emptying of the labeled meal (T1/2), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (Tlag), the gastric emptying coefficient and the regression-estimated constants (β and κ), calculated by using the 13CO2 breath excretion curve using the conventional formulae. The parameters between the 2 test conditions were compared statistically. Results No significant differences in the calculated parameters, including T1/2, Tlag, gastric emptying coefficient or ß and κ, were observed between the 2 test conditions. Conclusions The present study revealed that single-dose sitagliptin intake had no significant influence on the rate of liquid gastric emptying in asymptomatic volunteers. © 2013 The Korean Society of Neurogastroenterology and Motility.

DOI： 10.5056/jnm.2013.19.2.227

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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 JAPAN KK  

Successful precut sphincterotomy (PS) in difficult biliary cannulation (DBC) requires a large incision for deroofing the papilla. However, the high complication rate poses a substantial problem, in addition to the need for expert skills. Pancreatic stent placement could facilitate this procedure. Needle-knife precut papillotomy with a small incision using a layer-by-layer method over a pancreatic stent (NKPP-SIPS) could potentially improve the success rate and reduce the complication rate of PS.
To validate the efficacy, feasibility and safety of NKPP-SIPS in DBC.
Therapeutic endoscopic retrograde cholangiopancreatography with a na &lt; ve papilla was performed in 1619 cases between May 2004 and July 2011. We prospectively divided the patients chronologically, in terms of the period during which the procedure was performed, into two groups: group A; needle-knife precut papillotomy (NKPP) performed between April 2004 and October 2006; group B; NKPP-SIPS performed between November 2006 and July 2011. The success rates and complication rates were evaluated. NKPP was performed without pancreatic stent placement and the cut was made starting at the papillary orifice, extended upward over a length of more than 5-10 mm for deroofing the papilla. On the other hand, in NKPP-SIPS, a pancreatic stent was placed initially as a guide, and to prevent post-ERCP pancreatitis, the incision was begun at the papillary orifice in a layer-by-layer fashion and extended upward in 1-2 mm increments, not going beyond the oral protrusion, finally measuring less than 5 mm in length.
PS was performed in 8.3 % of the patients (134/1619). The cannulation success rate of PS in the entire group was 94.0 % (126/134). NKPP and NKPP-SIPS were performed in 36 and 98 of the patients, respectively. There was one case of major bleeding in group A, and no severe complications in group B. The success rates of bile duct cannulation increased from 86.1 % (31/36) in group A to 96.9 % (95/98) in group B (p = 0.0189). The overall complication rate of PS was YC 33 % (12/36) in group A (major bleeding 8.3 %; mild to moderate pancreatitis 19.4 %; perforation requiring surgery 2.8 %), and 7.1 % (7/98) in group B (mild to moderate pancreatitis 6.1 %; minor perforation 1 %) (p &lt; 0.001).
NKPP-SIPS has significantly improved the success rate and reduced the complication rate of DBC, proving that a small incision starting at the orifice of the PS is sufficient, feasible and safe in DBC, when a pancreatic stent is inserted at the outset.

DOI： 10.1007/s00534-012-0552-4

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）   出版者・発行元：Elsevier B.V.  

Background/objectives: The absence of major-vessel involvement is a crucial factor in the resectability and prognosis of pancreatic cancer. However, arterial invasion cannot be evaluated adequately using imaging findings alone. We therefore developed a scoring system to assess arterial invasion by pancreatic adenocarcinoma using multidetector row computed tomography (MDCT) and serum tumor markers. Methods: Twenty patients who underwent distal pancreatectomy and splenectomy for pancreatic adenocarcinoma were examined retrospectively using 4-, 16- or 64-row MDCT and serum tumor markers. Splenic arterial invasion was evaluated in terms of length of tumor contact, circumferential involvement (&lt
180° or ≥180°) and deformity of vascular diameter. Preoperative expression of carbohydrate antigen 19-9 (CA19-9), DUPAN-2 and S-Pancreas-1 antigen (SPan-1) were also evaluated. The presence or absence of arterial invasion was confirmed histopathologically in all 20 cases. Results: In 11 of 20 cases invasion into splenic arteries was observed histopathologically, mostly involving the external elastic lamina and periarterial nerves. Sensitivity, specificity and accuracy were 100%, 88.9% and 95%, respectively, for length of tumor contact (&lt
16 mm or ≥16 mm), 90.9%, 77.8% and 85% for circumferential involvement (&lt
180° or ≥180°), and 100%, 66.7% and 85% for deformity of vascular diameter. Furthermore, the sensitivity, specificity and accuracy were all increased to 100% when tumor markers were included in the score. Conclusions: MDCT is a useful technique for diagnosing arterial invasion of pancreatic body and tail cancer, even in comparison with pathological examination
however, this new scoring system can be further complemented and made more reliable by measurements of serous tumor markers. Copyright © 2012, IAP and EPC.

DOI： 10.1016/j.pan.2012.12.364

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記述言語：英語   出版者・発行元：SPRINGER  

As laparoscopic cholecystectomy and liver transplantation (LT) have become more common, so has biliary stricture. Fortunately, endoscopic treatment has almost simultaneously been developed. This article reviews the recent reports concerning the management of benign biliary strictures (BBS).
The literature regarding the diagnosis and treatment of BBS is reviewed after an electronic search of PubMed from 1982 to 2009 was performed.
Despite the existence of diagnostic tools including tumor markers, brush cytology, intraductal ultrasonography and other imaging modalities, differentiating BBS from malignant stricture remains challenging, as does differentiating IgG4-related sclerosing cholangitis from other benign strictures. Endoscopic treatment with balloon dilation of the stricture and serial insertions of stents is the preferred initial treatment for BBS. However, the outcomes of endoscopic treatments for primary sclerosing cholangitis or chronic pancreatitis are poorer than those for post-surgical biliary stricture. When endoscopic treatments fail to repair complicated biliary strictures such as Bismuth types III, IV, and V, surgical repair is recommended. Among the non-anastomotic BBS, intrahepatic bilateral type strictures after LT may require repeat transplantation.
Early referral to tertiary centers with an alliance among hepatobiliary surgeons, interventional radiologists, and endoscopists is necessary to assure optimal results.

DOI： 10.1007/s00595-012-0333-3

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1111/j.1443-1661.2011.01230.x

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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：BAISHIDENG PUBL GRP CO LTD  

AIM: To evaluate the effectiveness of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) resistant to transarterial chemoembolization (TACE).
METHODS: This study was conducted on 42 patients who received HAIC for advanced HCC between 2001 and 2010 at our hospital. 5-fluorouracil (5-FU) was administered continuously for 24 h from day 1 to day 5 every 2-4 wk via an injection reservoir. Intra-arterial cisplatin or subcutaneous interferon was administered in combination with the 5-FU. The patients enrolled in this retrospective study were divided into two groups according to whether or not they fulfilled the criteria for resistance to TACE proposed by the Japan Society of Hepatology in 2010 (written in Japanese); one group of patients who did not fulfill the criteria for TACE resistance (group A, n = 23), and another group who fulfilled the criteria for TACE resistance (group B, n = 19). We compared the outcomes in terms of the response and survival rates between the two groups.
RESULTS: Both the response rate and tumor suppression rate following HAIC were significantly superior in group A than in group B (response rate: 48% vs 16%, P = 0.028, tumor suppression rate: 87% vs 53%, P = 0.014). Furthermore, both the progression-free survival rate and survival time were significantly superior in group A than in group B (3-, 6-, 12-, and 24-mo = 83%, 70%, 29% and 20% vs 63%, 42%, 16% and 0%, respectively, P = 0.040, and 9.8 nno vs 6.2 mo, P = 0.040). A multivariate analysis (Cox proportional hazards regression model) showed that resistance to TACE was an independent predictor of poor survival (P = 0.007).
CONCLUSION: HAIC administrating 5-FU was not effective against advanced HCC resistant to TACE. Other tools for treatment, i.e., molecular-targeting agents may be considered for these cases. (C) 2012 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v18.i16.1933

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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：BIOMED CENTRAL LTD  

Background: The ideal medication for acid-related diseases should have a rapid onset of action to promote hemostasis and cause efficient resolution of symptoms. The aim of our study was to comparatively investigate the inhibitory effect on gastric acid secretion of a single oral administration of omeprazole plus mosapride with that of omeprazole alone.
Methods: Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 hours after a single oral administration of omeprazole 20 mg or that of omeprazole 20 mg plus mosapride 5 mg (the omeprazole being administered one hour after the mosapride). Each administration was separated by a 7-days washout period.
Results: The average pH during the 6-hour period after administration of omeprazole 20 mg plus mosapride 5 mg was higher than that after administration of omeprazole 20 mg alone (median: 3.22 versus 4.21, respectively; p = 0.0247).
Conclusions: In H. pylori -negative healthy male subjects, an oral dose of omeprazole 20 mg plus mosapride 5 mg increased the intragastric pH more rapidly than omeprazole 20 mg alone.

DOI： 10.1186/1471-230X-12-25

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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：KARGER  

Background: The preoperative diagnosis of branch duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas can be very difficult, since low-risk and high-risk lesions can be difficult to differentiate even after cytological analysis. The purpose of this study was to evaluate the preoperative diagnostic value of endoscopic ultrasonography (EUS) in differentiating low-risk and high-risk IPMNs.
Methods: We retrospectively identified 36 patients who underwent preoperative EUS for branch duct IPMNs. The pathological diagnosis after surgical resection was low-grade dysplasia (n = 26), moderate dysplasia = 1), high-grade dysplasia or carcinoma in situ (n = 5), and invasive carcinoma (n = 4). We divided the patients into two groups: low risk (low-grade dysplasia or moderate dysplasia) and high risk (high-grade dysplasia or carcinoma). We focused on the diameter of the cystic dilated branch duct, the main pancreatic duct, and the mural nodule as measured using the EUS findings.
Results: The cystic dilated branch duct diameter (31.5 mm vs. 41.9 mm, P = 0.0225) was significantly correlated with low-risk and high-risk IPMNs, but the main pancreatic duct diameter (5.37 mm vs. 5.44 mm, P = 0.9418) was not significantly correlated with the low-risk and high-risk IPMNs. The mural nodule diameter of the papillary protrusions (4.3 mm vs. 16.4 mm, P &lt; 0.0001) and the width diameter of the mural nodule (5.7 mm vs. 23.2 mm, P &lt; 0.0001) were significantly correlated with low-risk and high-risk IPMNs.
Conclusions: The mural nodule of papillary protrusions diameter and width diameter observed using EUS was a reliable preoperative diagnostic finding capable of distinguishing low-risk and high-risk IPMNs. Copyright (C) 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

DOI： 10.1016/j.pan.2011.12.008

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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  

A 50-year-old man with primary biliary cirrhosis underwent living-donor liver transplantation (LDLT) using a graft of a left hemiliver with a left caudate lobe and duct-to-duct hepaticocholedochostomy. Postoperative bile leakage necessitated percutaneous drainage 22 days after LDLT. The patient presented to our hospital 205 days after the LDLT with abdominal distension and fever. Computed tomography showed ascites and a diffusely mottled pattern in the graft. The caudate lobe was swollen, and its bile ducts were dilated. The inferior vena cava was forced to the right by the swollen caudate lobe, and the root of the hepatic vein was stretched. The hepatic vein was not contrasted. Endoscopic retrograde cholangiography showed a biliary anastomotic stricture. Based on these findings, we diagnosed a severe outflow block of the hepatic vein and biliary anastomotic stricture. We performed balloon dilation of the biliary anastomosis and implanted a metallic stent in the hepatic vein. Thereafter, his clinical symptoms improved dramatically.

DOI： 10.1007/s00595-011-0037-0

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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：ZHEJIANG UNIV  

Objective: The ideal medication for the treatment of acid-related diseases, e.g., peptic ulcers, stress-related gastric bleeding, functional dyspepsia, and gastroesophageal reflux disease, should have a rapid onset of action to promote hemostasis and relieve the symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of a proton pump inhibitor, omeprazole 20 mg, and an H-2-receptor antagonist, roxatidine 75 mg. Methods: Ten Helicobacterpylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 h after single oral administration of omeprazole 20 mg and roxatidine 75 mg. Each administration was separated by a 7-d washout period. Results: During the 6-h study period, the average pH after administration of roxatidine was higher than that after administration of omeprazole (median: 4.45 vs. 2.65; P=0.0367). Also during the 6-h study period, a longer duration of maintenance at pH above 2, 5, and 6 was observed after administration of roxatidine 75 mg than after administration of omeprazole 20 mg (median: 90.6% vs. 55.2%, P=0.0284; 43.7% vs. 10.6%, P=0.0125; 40.3% vs. 3.3%, P=0.0125; respectively). Conclusions: In Helicobacter pylori-negative healthy male subjects, oral administration of roxatidine 75 mg increased the intragastric pH more rapidly than that of omeprazole 20 mg.

DOI： 10.1631/jzus.B1100078

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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：JAPAN SOC INTERNAL MEDICINE  

Objectives The aim of this study was to characterize the pancreatic cystic lesions in von Hippel-Lindau (VHL) disease and to document the changes that occur in the pancreas.
Methods We retrospectively analyzed the medical records and the computed tomography (CT) and magnetic resonance imaging (MRI) findings of 20 VHL patients who were diagnosed between 1996 and 2010 at our hospital. The clinical findings, family history and type of tumors and/or cysts were reviewed for each patient. We also analyzed the imaging findings for the pancreas in detail.
Results Pancreatic involvement was noted in 16 of the 20 patients (80%). Eleven patients had multiple cysts diffusely distributed in the pancreas, and one patient had a single cyst in the pancreas head. Two patients had serous cystic neoplasms (SCNs) with multiple cysts, and another two patients had neuroendocrine tumors (NETs) which were conventional radiological findings. The largest cysts of four patients (26.7%) increased in size and that of three patients (20%) decreased in size during the follow-up period. We performed surgical resections for the pancreatic tumors (one NET and one SCN) and also performed endoscopic treatment for a pancreatic cyst in one VHL patient with obstructive jaundice. None of the patients died as a result of pancreatic disease.
Conclusion The most common type of pancreatic lesions was multiple cysts. SCNs were present in only 10% of the VHL patients. Pancreatic cysts showed positive and/or negative growth according to the CT and MRI findings. The pancreatic cystic lesions did not influence the outcome of the VHL patients.

DOI： 10.2169/internalmedicine.51.7194

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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：WILEY-BLACKWELL  

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, for which the development of new biomarkers and therapeutic targets has become critical. The main cause of poor prognosis in PDAC patients is the high invasive and metastatic potential of the cancer. In the present study, we report a new signaling pathway that was found to mediate the enhanced tumor cell motility in pancreatic cancer. Semaphorin 4D (Sema4D) is a ligand known to be expressed on different cell types, and has been reported to be involved in the regulation of immune functions, epithelial morphogenesis, and tumor growth and metastasis. In this study, we revealed for the first time that the cancer tissue cells expressing Sema4D in PDAC are tumor-infiltrating lymphocytes. The overexpression of Sema4D and of its receptor, plexinB1, was found to be significantly correlated with clinical factors, such as lymph node metastasis, distant metastasis, and poor prognosis in patients with PDAC. Through in vitro analysis, we demonstrated that Sema4D can potentiate the invasiveness of pancreatic cancer cells and we identified the downstream molecules. The binding of Sema4D to plexinB1 induced small GTPase Ras homolog gene family, member A activation and resulted in the phosphorylation of MAPK and Akt. In addition, in terms of potential therapeutic application, we clearly demonstrated that the enhanced-cell invasiveness induced by Sema4D could be inhibited by knockdown of plexinB1, suggesting that blockade of plexinB1 might diminish the invasive potential of pancreatic cancer cells. Our findings provide new insight into possible prognostic biomarkers and therapeutic targets in PDAC patients. (Cancer Sci 2011; 102: 2029-2037)

DOI： 10.1111/j.1349-7006.2011.02053.x

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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：ELSEVIER SCIENCE INC  

DOI： 10.1016/j.cgh.2011.03.030

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In July 2003, a 63-year-old man received a low anterior resection for rectal cancer. In February 2006, he underwent a right hepatectomy for a solitary metastatic liver tumor
the liver tumor had not invaded the bile duct, and a curative resection was performed. In August 2008, an enhanced computed tomography examination revealed a massive focal lesion at the point of the common bile duct. Endoscopic ultrasonography clearly revealed a hyperechoic polypoid lesion that had spread laterally on the surface of the slightly dilated bile duct and had a smooth outer hyperechoic layer. No lymph nodes were present in this region. Endoscopic retrograde cholangiopancreatography revealed an irregular stricture, and a biopsy was performed through the scope. Microscopic examination revealed a tumor characterized as a moderately differentiated adenocarcinoma resembling the liver tumor. We diagnosed the intrabiliary tumor as a metachronous metastatic bile duct tumor from rectal cancer without involvement of the liver parenchyma. This is a very rare case, with recurrence only in an extrahepatic bile duct after the complete resection of a metastatic liver tumor. This is the first clinical, pathological, and radiological description of this rare condition. © Springer 2011.

DOI： 10.1007/s12328-011-0240-y

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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  

Background Relapse and spontaneous remission (SR) are characteristic features of autoimmune pancreatitis (AIP).
Aim and methods We conducted a study to determine if the predictive factors might be potentially related to the relapse in 70 consecutive AIP patients. Regarding SR, we studied the data of patients without corticosteroid treatment (CST).
Results CST was administered to 60% (42/70) of the patients; however, relapse was noted in 45.2% (19/42) of these patients. In 95% (18/19) of the AIP patients developing relapse, the relapse occurred within 3 years. The relapse rate was 80% (12/15) in the AIP patients administered CST for less than 12 months and 25.9% (7/27) in those administered CST for over 12 months (p &lt; 0.01). The results of univariate analysis revealed significant association of relapse with the presence of jaundice, IgG4 seropositivity, presence of diffuse pancreas swelling, duodenal papillitis (DP), history of initial CST, and history of supportive treatment (p &lt; 0.05), whereas multivariate analysis revealed that IgG4 seropositivity (OR 10.506, p = 0.0422) and the presence of jaundice (OR 6.945, p = 0.0174) are significant independent factors predictive of relapse in AIP patients. SR was recognized in 65.0% (13/20) of AIP patients without CST. The results of univariate analysis revealed that SR was associated with IgG4 seropositivity (p &lt; 0.05), and multivariate analysis identified IgG4 seropositivity (OR 0.032, p = 0.0092) as a significant independent factor predictive of SR in these cases.
Conclusion AIP patients with IgG4 seropositivity and jaundice are at a higher risk of relapse and they could therefore be candidates for over 3 years of maintenance CST. AIP patients with IgG4 seronegativity have a high likelihood of SR.

DOI： 10.1007/s00535-011-0393-y

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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  

Expression of the forkhead/winged helix family of transcription factor P3+ regulatory T cells (FOXP3(+) Treg), a master gene of regulatory T cells (Treg) is observed in patients with autoimmune pancreatitis (AIP). We investigated the usefulness of detection of FOXP3(+) Treg in the main duodenal papilla for differential diagnosis between AIP and pancreatic cancer (Pca).
Firstly, we determined the cut-off value of FOXP3 expression in duodenal papilla taken from the patients with AIP (n = 22) and chronic pancreatitis (n = 21). Data from 32 patients with AIP and 30 patients with Pca who had undergone endoscopic biopsy were then studied. The numbers of FOXP3(+) Treg-positive lymphocytes and IgG4-positive plasma cells per high-power field (HPF) were counted in all the histopathological specimens.
The areas under the receiver-operating characteristic (AUROC) curves for FOXP3(+) and IgG4 expression were 0.934 and 0.953, respectively. Cut-off values calculated based on AUROC data were 14/HPF in FOXP3 and 10/HPF in IgG4. Seropositivity for IgG4 was observed in 22 out of the 31 patients with AIP (sensitivity 71.0%, specificity 84.6%, accuracy 75.0%). Significant infiltration of the major duodenal papilla by FOXP3(+) lymphocytes (a parts per thousand yen14/HPF) was recognized in 18 of the 32 patients with AIP (sensitivity 56.3%, specificity 100%, accuracy 77.4%). Significant infiltration of the major duodenal papilla by IgG4-positive plasma cells (a parts per thousand yen10/HPF) was recognized in 27 of the 32 patients with AIP (sensitivity 84.4%, specificity 80.0%, accuracy 82.3%).
Observation of FOXP3(+) cells in the main duodenal papilla may be useful in the differential diagnosis between AIP and Pca.

DOI： 10.1007/s00534-010-0359-0

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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：KOREAN SOC NEUROGASTERONTEROL & MOTILITY  

Background/Aims
There are few reports on the correlation between chewing gum and the gastrointestinal functions. But previous report showed use of chewing gum to be an effective method for controlling gastrointestinal symptoms. The aim of this study was to determine the correlation between chewing gum and gastric emptying using the continuous real time C-13 breath test (BreathID system).
Methods
Ten healthy male volunteers participated in this randomized, 2-way crossover study. The subjects fasted overnight and were randomly assigned to chewing gum (Xylish, 2-3/1 tablet) for an hour following intake of a test meal (200 kcal/200 mL) or intake of the test meal alone. Gastric emptying was monitored for 4 hours after administration of the test meal by the C-13-acetic acid breath test performed continually using the BreathID system.
Results
No significant differences in the calculated parameters, namely, T-1/2 (median, 111.82 vs 109.26 minutes; P = 0.575), T-lag (median, 53.28 vs 56.53 minutes; P = 0.333), gastric emptying coefficient (median, 3.58 vs 3.65; P = 0.285), regression-estimated constant beta (median, 1.85 vs 1.80; P = 0.575) and regression-estimated constant kappa (median, 0.61 vs 0.62; P = 0.959) were observed between the test meal alone group and the test meal and chewing gum group.
Conclusions
This study showed that chewing gum had no effect on the rate of gastric emptying. Therefore, since chewing gum did not enhance the speed of gastric emptying, it may ameliorate gastrointestinal symptoms through other mechanisms, such as saliva and autonomic nervous system.

DOI： 10.5056/jnm.2011.17.2.174

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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：INT SCIENTIFIC LITERATURE, INC  

Background: A visceral fat area of more than 100 cm(2) as measured by computed tomography (CT) at the umbilical level has been included as a criterion for obesity in all the proposed criteria for metabolic syndrome. However, CT cannot be used frequently because of radiation exposure. We evaluated the usefulness of measurement of the serum levels of nitric oxide (NO), instead of CT and the waist circumference, as a marker of abdominal visceral fat accumulation.
Material/Methods: The study was carried out in 80 subjects. The serum levels of NO metabolites (nitrate/nitrite) were measured using the Griess reagent.
Results: Simple and multiple regression analysis revealed that the serum levels of NO metabolites showed the greatest degree of correlation with the visceral fat area (r = 0.743, p &lt; 0.0001), and corresponded to a visceral fat area of 100 cm(2), as determined using the ROC curve, was 21.0 mu mol/ml (sensitivity 88%, specificity 82%); this method was more sensitive than the waist circumference for evaluation of the visceral fat accumulation.
Conclusions: Measurement of the serum levels of NO metabolites may be a simple, safe, convenient and reliable method for the evaluation of visceral fat accumulation in clinical diagnostic screening.

DOI： 10.12659/msm.881445

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: To determine the correlation between domperidone and gastric emptying using the continuous real time C-13 breath-test (BreathID system), a novel non-invasive technique for measuring gastric emptying.
Methodology: Six healthy male volunteers participated in this randomized, two-way crossover study. Subjects fasted overnight and were randomly assigned to receive a test meal (400kcal per 400mL) 30 minutes after intake of domperidone (10mg) with 50mL of water or intake of 50mL of water alone. Gastric emptying was monitored for 4h after administration of the test meal by C-13-acetic acid breath test continually performed using the BreathID system. The time taken for emptying of 50% of the labeled meals (T1/2), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (T lag), the gastric emptying coefficient (GEC), and the regression-estimated constants (6 and K) were calculated. Differences in the parameters measured at two time-points were analyzed using the Wilcoxon&apos;s signed-rank test.
Results: No significant differences in calculated parameters (T lag, T1/2, GEC, beta or kappa) were observed between the treated and non-treated groups.
Conclusions: This study showed that domperidone had no effect on gastric emptying. The drug ameliorates nausea and vomiting via its antagonic activity against dopamine receptor. Therefore, domperidone probably ameliorates nausea through other mechanisms.

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記述言語：英語   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

The factors involved in the progression of non-alcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) are not fully understood and thus it is urgently needed to elucidate these factors. Steatosis is not causal in the development of NASH, but rather it sensitizes the liver to the damaging effects of second hits such that stressors innocuous to a healthy liver lead to the development of NASH in the steatotic liver. In the previous study, most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, very-low-density lipoprotein (VLDL) synthesis, especially hepatic microsomal triglyceride transfer protein (MTP) mRNA expression, was impaired in the NASH group. Moreover, NASH showed significantly higher incidence of minor alley appearance compared with NAFL, indicating the possibility of association between NASH pathogenesis and decreased congenital MTP activity. MTP is one of the enzymes that transfer triglycerides to nascent apolipoprotein B, producing VLDL and removing lipid from the hepatocyte. A growing body of literature suggests that the measurement of hepatic MTP expression may be helpful for diagnosis; and moreover, hepatic MTP activator may be a possible therapeutic agent for the treatment of NASH.

DOI： 10.1254/jphs.10R14FM

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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  

Bile duct strictures remain a major source of morbidity after orthotopic liver transplantation (OLT). Endoscopic management by the conventional methods of biliary dilatation and/or stent placement has been successful, but sometimes severe complications occur, necessitating prolonged therapy. The aim of this study is to clarify the complications of the endoscopic approach for endoscopic dilatation and/or stent placement.
Of 46 patients who underwent living-donor liver transplantation, 10 were diagnosed as having anatomic biliary strictures by endoscopic retrograde cholangiopancreatography (ERCP). Two patients developing biliary strictures after deceased-donor liver transplantation were also enrolled in the study. For the purpose of comparison, 302 patients with a total of 550 consecutive ERCP cases (including 115 patients with 250 malignant bile duct strictures) were recruited in this study. Success rate, number of endoscopy sessions, the median procedure time for ERCP, and incidence of complications including post-ERCP pancreatitis were compared in the OLT cases and other cases.
The following results were obtained in the OLT cases, malignant stricture cases, and all cases, respectively: mean number of endoscopy sessions was 3.62, 2.17, and 1.94 (P = 0.0216, P &lt; 0.0001); post-ERCP pancreatitis occurred in 5 (12.5%), 10 (4.0%), and 19 cases (3.5%) (P = 0.0327, P = 0.0093); and severe pancreatitis occurred in 2 cases of OLT. In a univariate analysis for post-ERCP pancreatitis, OLT was extracted as the only significant risk factor.
Endoscopic maneuvering for biliary dilatation and/or stent placement following OLT was associated with a higher risk of post-ERCP pancreatitis than the use of the same technique for the treatment of malignant biliary stricture. Endoscopic treatment after OLT was a significant risk factor for post-ERCP pancreatitis.

DOI： 10.1007/s00534-010-0330-0

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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：WILEY-BLACKWELL  

Liver abscess is recognized as a life-threatening disease. However, even in recent years, approximately 50% of liver abscess cases are considered to be cryptogenic. Here, we report a case of liver abscess associated with periodontal bacterial infection by Fusobacterium necrophorum, which is commonly found in the oropharyngeal flora. A 36-year-old man presented with fever and contrast-enhanced abdominal computed tomography revealed multiple liver abscesses. F.necrophorum was isolated from oral smears, liver aspirates and blood samples. Liver abscesses caused by periodontal bacterial infection are rare, however, the incidence is expected to increase in the future, as periodontitis is extremely common and is on the rise as one of the most common chronic infections in the world. A systemic survey including periodontitis may be required for the exact diagnosis of the source of infection.

DOI： 10.1111/j.1872-034X.2010.00748.x

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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：WILEY-BLACKWELL PUBLISHING, INC  

Background and Aim:
Differentiation of sclerosing cholangitis-associated autoimmune pancreatitis (SC-AIP), primary sclerosing cholangitis (PSC) and cancer of the hilar part of the bile duct (CHB) has been challenging. The aim of the present study was to evaluate characteristic intraductal ultrasonography (IDUS) features that could be used to discriminate SC-AIP from PSC and CHB.
Methods:
Six patients with SC-AIP, 10 patients with PSC and 12 patients with CHB were identified. We reviewed the following bile duct features observed using IDUS to determine their usefulness for differentiating SC-AIP from PSC and CHB: presence of symmetrical wall thickness, wall thickness, presence of homogeneous internal foci and presence of lateral mucosal lesions continuous to the hilar.
Results:
IDUS results (SC-AIP, PSC, CHB) were as follows: wall thickness (mm), 3.7 +/- 0.9, 2.6 +/- 0.9, 2.8 +/- 0.0.6; presence of symmetrical wall thickness, 100% (6/6), 20% (2/10), 8.3% (1/12); presence of homogeneous internal foci, 100% (6/6), 10% (1/10), 8.3% (1/12); and presence of lateral mucosal lesions continuous to the hilar, 83.3% (5/6), 40%(4/10), 25% (3/12). Symmetrical wall thickness of the bile duct, homogeneous internal foci and lateral mucosal lesions continuous to the hilar were detected significantly more often among the patients with SC-PSC than among the patients with PSC or CHB (P &lt; 0.05).
Conclusions:
IDUS findings, such as symmetrical wall thickness, presence of homogeneous internal foci and presence of lateral mucosal lesions continuous to the hilar can facilitate the differential diagnosis of SC-AIP from PSC and CHB.

DOI： 10.1111/j.1443-1661.2010.01039.x

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: ideally, medications for the treatment of acid-related diseases should have a rapid onset of action to promote hemostasis and the resolution of symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of lafutidine alone or combined with peppermint oil.
Methodology: Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 4 hours after a single oral administration of lafutidine (10mg) or the administration of lafutidine (10mg) with peppermint oil (0.64mL). Each administration was separated by a 7-day washout period.
Results: No significant difference in the average pH was observed during the 4-hour period after the combined administration of lafutidine and peppermint oil and after the administration of lafutidine alone (median gastric pH: 5.09 versus 5.29; p=0.3122).
Conclusions: In H. pylori-negative healthy male subjects, an oral dose of lafutidine combined with peppermint oil did not increase the intragastric pH faster than lafutidine alone.

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000313695

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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：KARGER  

Aim: Capsule endoscopy is limited by the poor image quality of the distal bowel and incomplete small bowel transit. The aim of this study was to establish an optimal medication protocol for capsule endoscopy performed using a real-time viewer. Methods: A total of 80 patients were prospectively recruited. The patients were randomized into two groups: the &apos;conventional group&apos; (without any preparation) and the &apos;real-time group&apos; (in which a real-time viewer was attached). At 60 min after swallowing the capsule, if the capsule had reached the small bowel, 500 ml of polyethylene glycol was administered; if the capsule was still located in the stomach, 10 mg of metoclopramide was given intramuscularly, followed by 500 ml of polyethylene glycol solution. Results: The completion rate was significantly higher in the real-time group as compared with that in the conventional group (72.5 vs. 90.0%). Our protocol yielded a significantly improved image quality of the distal small bowel [image quality score = 1.6 vs. 3.0 (max 4.0)]. The detection rate of lesions in the distal small bowel was higher in the real-time group than in the conventional group. Conclusions: The present study clearly showed that our protocol yielded an improved completion rate and also improved image quality. Copyright (C) 2011 S. Karger AG, Basel

DOI： 10.1159/000323225

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掲載種別：研究論文（学術雑誌）   出版者・発行元：12  

DOI： 10.1111/j.1365-2893.2009.01253.x

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The aim of this study was to evaluate the correlation between gastrointestinal symptoms and diet therapy.
Methodology: The subjects comprised of 8 patients who attended the diabetes division at Fujisawa City Hospital between April and June 2007. The subjects were diagnosed as having diabetes mellitus based on the results of a blood analysis. The body weight of the subjects was measured, and the subjects were asked to score their gastrointestinal symptoms according to the Frequency Scale for the Symptoms of GERD (FSSG) before and after diet therapy for 9 to 14 days.
Results: Diet therapy for diabetic subjects was effective for weight reduction. The total FSSG score was decreased, and the reduction in dysmotility-like symptoms was greater than the reduction in acid-reflux-related symptoms.
Conclusions: Diet therapy for mild diabetic patients also improves gastrointestinal symptoms.

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Percutaneous endoscopic gastrostomy is the standard method for enteral feeding in patients predicted to require long-term enteral nutrition because of dysphagia. A direct techinique with gastropexy is available, in which oropharyngeal passage of the internal bumper can be avoided. The aim of this study was to assess the early complications of percutaneous endoscopic gastrostomy performed using the new direct technique.
Methodology: Between August 2005 and July 2009, 231 patients underwent percutaneous endoscopic gastrostomy at our hospital. We analyzed the clinical characteristics of the patients related to the development of early complications such as bleeding or local infection. Early complications were defined as complications occurring within 7 days of the percutaneous endoscopic gastrostomy.
Results: The study population comprised 231 patients: 157 men and 74 women (median age, 73 years; range, 28-92 years). The percutaneous endoscopic gastrostomy was performed using the pull-through technique in 134 of these patients (58%), whereas the direct technique with gastropexy was employed in the remaining 97 patients (42%). In the multiple logistic regression analyses, only the use/non-use of the direct technique was identified as a variable significantly associated with the incidence of bleeding (odds ratio 5.236, 95% confidence interval 1.040 - 26.316; p=0.0447) and the incidence of local infection (odds ratio 0.283, 95% confidence interval 0.100 - 0.802; p=0.0175).
Conclusions: Use of the direct technique for performing percutaneous endoscopic gastrostomy was associated with the increased incidence of the early complication of bleeding, but the decreased incidence of local infection.

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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：WILEY-BLACKWELL  

Aim: Although non-alcoholic fatty liver disease (NAFLD) is now a common cause of chronic liver disease, discriminating between simple steatosis and non-alcoholic steatohepatitis (NASH), especially early-stage NASH, remains difficult. We investigated the clinical usefulness of measuring the spleen volume as a marker of early-stage NASH.
Methods: We evaluated computed tomography (CT) images obtained in 84 patients with histologically diagnosed NAFLD (22 with simple steatosis, 62 with NASH with mild fibrosis [stages 1-2]). We defined the data obtained by the following formula as a spleen-body index (SBI): SBI = maximal CT axial section area of the spleen (cm(2))/body surface area (BSA) (cm(2)) x 10(4). We compared the SBI between patients with simple steatosis and those with NASH with mild fibrosis.
Results: The mean SBI of the simple steatosis group was 15.8 +/- 3.9, while that of the NASH with mild fibrosis group was 18.7 +/- 5.7. This difference between the two groups was significant (P = 0.0314). A multiple logistic regression analysis showed that the SBI was significantly correlated with the discrimination of simple steatosis and NASH with mild fibrosis. The area under the receiver-operator curve was 0.661 for distinguishing between simple steatosis and NASH with mild fibrosis (P = 0.026, 95% confidence interval = 0.532-0.789).
Conclusion: Spleen enlargement may be a distinct feature of NASH, especially early-stage NASH. SBI might be a non-invasive and simple method of differentiating NASH and simple steatosis.

DOI： 10.1111/j.1872-034X.2010.00643.x

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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：MOSBY-ELSEVIER  

DOI： 10.1016/j.gie.2010.01.033

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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：WILEY-BLACKWELL  

Aim:
Congenital extrahepatic portosystemic shunt (CEPS) is a rare anomaly in which the enteric blood bypasses the liver and drains into the systemic veins through various venous shunts. Patients with CEPS often have liver tumors and complications such as cardiac or other anomalies, but portosystemic encephalopathy and gastrointestinal bleeding occur only occasionally. The clinical problems differ for each individual with CEPS, and establishing a prognosis can be very difficult.
Methods:
We reviewed the clinical features of 136 reported cases of CEPS and classified these cases according to their portosystemic shunts.
Results:
We classified portal blood flow directly into the inferior vena cava (IVC) as type A (88 cases), portal blood flow into the renal vein as type B (36 cases), and portal blood flow into the iliac vein via an inferior mesenteric vein as type C (12 cases). Type A patients were complicated with cardiac anomalies at a higher rate than other types. Type C patients had lower prevalences of cardiac anomalies and portosystemic encephalopathy than the other types, but the prevalence of gastrointestinal bleeding was significantly higher (P &lt; 0.0001). The prognosis of CEPS has improved, and only six deaths have been previously reported, all of which occurred in type A patients.
Conclusions:
We reviewed the previously reported cases of CEPS. Classification according to the portosystemic shunt system might be useful for investigating the clinical features of CEPS.

DOI： 10.1111/j.1872-034X.2010.00667.x

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掲載種別：研究論文（学術雑誌）   出版者・発行元：4  

DOI： 10.1111/j.1365-2893.2009.01179.x

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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：WILEY-BLACKWELL PUBLISHING, INC  

Paraganglioma, a sporadically occurring rare tumor should be included in the differential diagnosis of retroperitoneal tumors, such as malignant lymphomas, gastrointestinal stromal tumors, sarcoma and carcinoma of unknown primary site. A 58-year-old Japanese woman presented with a large retroperitoneal tumor detected by ultrasonography (US). She had no medical history of hypertension. Computed tomography showed a mass, 7 cm in diameter, located between the pancreas and the inferior vena cava. It was unclear whether the mass originated from the duodenum or the mesentery. Endoscopic ultrasonography (EUS) demonstrated a large solid paraduodenal mass. Doppler US revealed sparse vascularity in the tumor. With the differential diagnosis of retroperitoneal tumor, we carried out EUS-FNA. At the time of the third needle puncture, transient severe hypertension was noted, with a blood pressure measurement of 269/130 mmHg. Data obtained from urine and blood examinations after EUS-fine-needle aspiration indicated a diagnosis of paraganglioma.

DOI： 10.1111/j.1443-1661.2010.00939.x

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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：TAYLOR & FRANCIS AS  

Objective. The role of gastric acid reflux is difficult to separate from that of pancreatic-biliary reflux in the pathogenesis of erosive esophagitis (EE) and Barrett&apos;s esophagus (BE). Gastric surgery patients provide a good mode. for both significant pancreatic-biliary reflux and marked gastric acid inhibition. We assessed the risk of EE and BE after distal gastrectomy in a case-controlled study. Material and methods. One hundred and sixty patients (121 men, 39 women; median age 68 years; range 32-86 years) with distal gastrectomies (Billroth-I) and 160 sex- and age-matched controls with intact stomachs were enrolled. The presence of EE and BE were diagnosed based on the Los Angeles Classification and the Prague C & M Criteria, respectively. A conditional logistic regression model with adjustments for potential confounding factors was used to assess the associations. Results. According to the multivariate analyses, patients with distal gastrectomies tended to have inverse associations with the risks of EE and BE, and the inverse association with the risk of BE reached a significant level. Conclusions. Distal gastrectomy is not a risk factor for the development of BE and BE. This lack of a. positive association between distal gastrectomy and BE and BE may suggest that pancreatic-biliary reflux with a limited amount of acid is not sufficient to damage the esophageal mucosa.

DOI： 10.3109/00365520903536507

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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  

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. The spectrum of NAFLD is broad, extending from simple steatosis through nonalcoholic steatohepatitis (NASH). Iron is regarded as a putative element that interacts with oxygen radicals, and high rates of hyperferritinemia and increased hepatic iron stores have been demonstrated in NASH. We investigated serum ferritin concentrations, HFE gene mutations, and insulin resistance in Japanese NASH patients and the diagnostic utility of serum ferritin concentrations as a means of distinguishing NASH. Serum ferritin concentrations were measured in 86 patients with histopathologically verified NAFLD (24 with steatosis and 62 with NASH) and 20 control subjects, they were tested for HFE gene mutations and their insulin resistance was measured. The serum ferritin concentration was significantly higher in the NASH patients than in the patients with simple steatosis (P = 0.006). There was no significant difference between the groups in HFE gene mutation (C282Y, H63D, and S65C), and the serum ferritin level was related with insulin resistance. The area under the ROC curve was 0.732 for distinguishing NASH from simple steatosis (P = 0.005; 95% CI, 0.596-0.856). In conclusion high serum ferritin concentrations are a distinguishing feature of Japanese NASH patients independent of HFE gene mutations.

DOI： 10.1007/s10620-009-0771-y

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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：LIPPINCOTT WILLIAMS & WILKINS  

Objective: Patients with autoimmune pancreatitis (AIP) sometimes present with Mikulicz disease (MD); however, the clinical features regarding these AIP patients with MD have not yet been fully elucidated. Our aim is to study the clinical differences between AIP with and without MD.
Methods: Twenty-eight AIP patients were divided into 2 groups, one with MD and one without it. The following factors having a possible association with the presence or absence of MD were investigated: sex; serum IgG and IgG4 levels; the presence or absence of antinuclear auto-antibodies, jaundice, diabetes mellitus, swollen duodenal papilla, diffuse pancreatic swelling, spontaneous remission, and relapse.
Results: The MD and non-MD groups consisted of 5 AIP and 23 AIP patients, respectively. The results of univariate analysis revealed that AIP patients presenting with MD were significantly associated with a younger onset, female predominance, high serum IgG4 titer, and diffuse pancreatic swelling (P &lt; 0.05). In 4 of the MD patients, onset preceded pancreatitis.
Conclusions: Autoimmune pancreatitis patients presenting with MD tended to have different clinical features from the non-MD AIP patients, such as having an earlier onset, female tendency, and diffuse pancreatic swelling with a high titer of serum IgG4. Autoimmune pancreatitis with MD tended to precede gastroenterological events.

DOI： 10.1097/MPA.0b013e3181bc119d

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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：BAISHIDENG PUBLISHING GROUP INC  

AIM: To test the hypothesis that the shape and length of Barrett's epithelium are associated with prevalence of erosive esophagitis.
METHODS: A total study population comprised 869 patients who underwent endoscopy during a health checkup at our hospital. The presence and extent of Barrett's epithelium were diagnosed based on the Prague C & M Criteria. We originally classified cases of Barrett's epithelium into two types based on its shape, namely, flamelike and lotus-like Barrett's epithelium, and into two groups based on its length, its C extent &lt; 2 cm, and &gt;= 2 cm. Correlation of shape and length of Barrett's epithelium with erosive esophagitis was examined.
RESULTS: Barrett's epithelium was diagnosed in 374 cases (43%). Most of these were diagnosed as short-segment Barrett's epithelium. The prevalence of erosive esophagitis was significantly higher in subjects with flame-like than lotus-like Barrett's epithelium, and in those with a C extent of &gt;= 2 cm than &lt; 2 cm.
CONCLUSION: Flame-like rather than lotus-like Barrett's epithelium, and Barrett's epithelium with a longer segment were more strongly associated with erosive esophagitis. (C) 2010 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v16.i4.484

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-0030-1255772

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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：KARGER  

Background and Aims: FOXP3+ regulatory T cells (Tregs) play a central role in self-tolerance and suppress the effective antitumor immune response. A recent study revealed that indoleamine 2,3-dioxygenase (IDO)-mediated tryptophan depletion was able to affect local tumor-infiltrating lymphocytes. The aim of this study was to investigate the clinical significance of the tumor-infiltrating Tregs and tumoral IDO expression during the progression of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Methods: We investigated the prevalence and localization of FOXP3+ Tregs, CD8+ lymphocytes, and IDO expression in IPMNs by immunohistochemistry. We recruited 39 cases with IPMNs (IPMA: adenoma, n = 11; IPMB: borderline malignancy, n = 9; IPMC: noninvasive carcinoma, n = 7; I-IPMC: invasive IPMC, n = 12). Results: The prevalence of Tregs increased step by step during the carcinogenesis of IPMNs (Kruskal-Wallis test: p &lt; 0.0001). IDO expression in the tumor was observed in 5 cases with IPMNs (IPMC, n = 1; I-IPMC, n = 4). IDO expression in the tumor was positively correlated with the prevalence of Tregs in IPMNs. Conclusions: FOXP3+ Tregs play a role in controlling the immune surveillance against IPMNs at the premalignant stage. IDO expression in the tumor is one of the late-stage phenomena of multistage carcinogenesis of IPMNs. Copyright (C) 2010 S. Karger AG, Basel and IAP

DOI： 10.1159/000308966

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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：BioMed Central Ltd.  

Introduction: Gastrointestinal stromal tumor is the most frequent nonepithelial tumor found in the gastrointestinal tract. One important clinical problem is that gastrointestinal stromal tumors, especially the extramural growth type, can be difficult to distinguish from other organ tumors. The case of a patient with an extramural gastrointestinal stromal tumor of the duodenum that mimicked a pancreatic head tumor has previously been reported. Here, we report a rare case of a patient with a duodenal gastrointestinal stromal tumor with extramural growth that mimicked a pancreatic neuroendocrine tumor. In this case, the gastrointestinal stromal tumor was also associated with neurofibromatosis type 1 (also known as von Recklinghausen's disease). To the best of our knowledge, this is the first report to describe the case of a patient with a duodenal gastrointestinal stromal tumor with neurofibromatosis type 1 in which the radiological findings resembled those of a pancreatic neuroendocrine tumor. Case presentation: A 60-year-old Japanese woman with a history of neurofibromatosis type 1 was admitted to our hospital for the treatment of a tumor of her pancreas. She had no symptoms, but an abdominal ultrasonography screening examination had revealed a hypoechoic mass in the head of her pancreas. Laboratory data, including tumor markers, were within the normal ranges, and her insulin and glucagon levels were also within the normal ranges. However, her plasma gastrin level was elevated at 580 pg/mL (30 to 150 pg/mL). A computed tomography examination revealed a hypervascular tumor measuring 14 mm in diameter in the head of her pancreas. We diagnosed the patient as having a pancreatic neuroendocrine tumor and performed a tumor resection with a duodenal wedge resection. Microscopic analysis revealed spindle cell tumors in a trabecular pattern. The patient was finally diagnosed as having a duodenal gastrointestinal stromal tumor of the uncommitted type. Conclusion: Extramural growth-type gastrointestinal stromal tumors can be difficult to distinguish from other organ tumors. In our case, a duodenal gastrointestinal stromal tumor was difficult to distinguish from a pancreatic neuroendocrine tumor based on radiological findings. When patients are identified as having hypervascular lesions that have adhered to the gastrointestinal tract, the possibility of an extramural growth-type gastrointestinal stromal tumor as a differential diagnosis should be considered in patients with neurofibromatosis type 1.

DOI： 10.1186/1752-1947-4-302

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000297160

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000288508

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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：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.49.3233

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-0029-1244147

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DOI： 10.1055/s-0029-1215414

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-0029-1214857

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1055/s-0029-1215119

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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：WILEY-BLACKWELL PUBLISHING, INC  

Aim:
Genetic factors as well as environmental factors play an important role in the development of non-alcoholic fatty liver disease (NAFLD). Recently, inducible nitric oxide synthase (iNOS) was significantly higher in the severest form of non-alcoholic steatohepatitis (NASH), and nitric oxide (NO) has been determined to play an important role in the process of fibrosis in NASH. In this study, we investigated iNOS gene polymorphisms for associations with NAFLD.
Methods:
A total of 115 NAFLD patients, consisting of 65 patients with NASH and 50 patients with simple steatosis, in whom a positive diagnosis had been made by liver biopsy, and 435 healthy control subjects, were recruited into this study.
Results:
We investigated 10 single nucleotide polymorphisms (SNP) of the iNOS gene, one of which, rs1060822, had the lowest P-value in the allele frequency model (P = 0.00078) with an odds ratio (95% confidence interval) of 0.49 (0.32-0.75). Four SNP, rs2297510, rs2297511, rs2797512 and rs1060822, were significantly associated with NAFLD, even when the most conservative Bonferroni&apos;s correction was applied. Linkage disequilibrium analysis revealed that SNP rs1060822 and three other SNP, rs2297510, rs2297511 and rs2797512, were in the same block. We also investigated associations between rs1060822 genotypes and the fibrosis index, and the results of the analysis revealed an additive increase in the fibrosis index and intrahepatic iNOS mRNA expression in the patients with the T allele of rs1060822.
Conclusion:
This is the first study to identify genetic variations in iNOS that may influence the risk of NAFLD and liver fibrosis in NAFLD.

DOI： 10.1111/j.1872-034X.2009.00539.x

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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：JOHN WILEY & SONS INC  

The specific mechanisms of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) pathogenesis remain unknown. In the present study we investigated the differences between NAFL and NASH in terms of liver lipid metabolites and serum lipoprotein. In all, 104 Japanese subjects (50 men and 54 postmenopausal women) with histologically verified NAFL disease (NAFLD) (51 with NAFL, 53 with NASH) were evaluated; all diagnoses were based on liver biopsy findings and the proposed diagnostic criteria. To investigate the differences between NAFL and NASH in humans, we carefully examined (1) lipid inflow in the liver, (2) lipid outflow from the liver, (3) very-low-density lipoprotein (VLDL) synthesis in the liver, (4) triglyceride (TG) metabolites in the liver, and (5) lipid changes and oxidative DNA damage. Most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, VLDL synthesis and lipid outflow from the liver were impaired, and surplus TGs might have been produced as a result of lipid oxidation and oxidative DNA damage in the NASH group. Conclusion: A growing body of literature suggests that a deterioration in fatty acid oxidation and VLDL secretion from the liver, caused by the impediment of VLDL synthesis, might induce serious lipid oxidation and DNA oxidative damage, impacting the degree of liver injury and thereby contributing to the progression of NASH. Therefore, dysfunctional VLDL synthesis and release may be a key factor in progression to NASH. (HEPATOLOGY 2009;50:772-780.)

DOI： 10.1002/hep.23094

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Hepatic mitochondrial beta-oxidation is considered to play a pivotal role in the pathogenesis of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine whether there were differences between patients with NASH and healthy controls in a breath test with C-13-octanoate, a medium-chain fatty acid.
Methodology: The subjects were 8 patients (5 men, 3 women, median age 46.5 years) with histologically proven NASH and 6 healthy controls (5 men, 1 women, and median age 27.8 years). The C-13 breath test was performed for 4 hours using the BreathID system with a 100mL of water, containing 100mg C-13-octanoate.
Results: There were no significant differences between NASH patients and controls about all breath test; parameters.
Conclusions: NASH-mediated changes in breath test parameters after ingestion of C-13-octanoate were not observed in our study. The present study findings suggest the possible preservation of C-13-octanoate metabolism (mitochondrial beta-oxidation) in patients with NASH.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.cgh.2009.01.007

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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：WILEY-BLACKWELL PUBLISHING, INC  

Background
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver injury in many countries. Genetic factors are important for the development of NAFLD, as well as environmental factors. Recently an angiotensin II type 1 receptor (AGTR1) has been recognized as important in the aetiology of fibrosis in the liver.
Objective
In this study we investigated the association between angiotensin II type 1 receptor gene polymorphism (ATGR1) and NAFLD.
Methods
One hundred and sixty-seven NAFLD patients [106 with nonalcoholic steatohepatitis (NASH) and 61 with simple steatosis] with a positive diagnosis by liver biopsy and 435 healthy control subjects were recruited in this study.
Results:
We investigated 12 single nucleotide polymorphisms (SNPs) of the ATGR1 gene, among which rs3772622 showed the lowest P-value of allele frequency model (P=0.0000012) with an odds ratio (95% confidence interval) of 1.95 (1.49-2.55). Five SNPs (rs3772622, rs3772633, rs2276736, rs3772630 and rs3772627) were significantly associated with NAFLD, even when the most conservative Bonferroni&apos;s correction was applied. Linkage disequilibrium analysis revealed that SNP rs3772622 and another four SNPs (rs3772633, rs2276736, rs3772630 and rs3772627) were in the same block. We investigated the association between rs3772622 genotypes and the fibrosis index. The results of the analysis revealed an additive increase of the fibrosis index in the patients with the A allele of rs3772622.
Conclusions
This is the first report to demonstrate the genetic variations in ATGR1 that may influence the risk of NAFLD and liver fibrosis in NAFLD.

DOI： 10.1111/j.1478-3231.2009.01988.x

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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：BIOMED CENTRAL LTD  

Background: The association between obesity and the risk of Barrett&apos;s esophagus (BE) is unclear. Furthermore, the association between visceral obesity and the risk of BE is entirely unknown.
Methods: We conducted a retrospective study in 163 patients with non-alcoholic fatty liver disease (NAFLD) who underwent both endoscopy and abdominal CT at an interval of less than a year at our institution. BE was endoscopically diagnosed based on the Prague C & M Criteria. The surface areas of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were calculated from CT images at the level of the umbilicus. The correlations between the BMI, VAT, and SAT and the risk of BE were examined by univariate and multivariate analyses.
Results: Sixty-nine of the 163 study participants (42.3%) were diagnosed to have endoscopic BE, which was classified as short-segment BE (SSBE) in almost all of the cases. There were no significant differences in the age or gender distribution between the groups with and without BE. According to the results of the univariate analysis, VAT was significantly associated with the risk of BE; the BMI tended to be higher in the group with BE than in the group without BE, but this relation did not reach statistical significance. VAT was independently associated with the risk of BE even after adjustment for the BMI.
Conclusion: In Japanese patients with NAFLD, obesity tended to be associated with the risk of BE, and this risk appeared to be mediated for the most part by abdominal visceral adiposity.

DOI： 10.1186/1471-230X-9-56

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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：WILEY-BLACKWELL PUBLISHING, INC  

Aim:
We evaluated the characteristic endoscopic ultrasonography (EUS) findings of early autoimmune pancreatitis (AIP).
Methods:
Nineteen patients with AIP were identified from our database. We reviewed the following features of EUS as being potentially characteristic of early AIP: hyperechoic foci, hyperechoic strands, lobularity, hyperechoic pancreatic duct margins and reduced echogenicity. According to the Cambridge classification for chronic pancreatitis, we classified AIP into early AIP (Grades 0-2) and advanced AIP (Grades 3-5) and examined the histopathological findings in each stage of AIP.
Results:
There were nine cases of early AIP and 10 cases of advanced AIP. Five of the nine early cases of AIP showed spontaneous remission without corticosteroid therapy (P &lt; 0.05). The EUS findings were as follows (early vs advanced): hyperechoic foci, 100% (9/9) vs 100% (10/10); hyperechoic strands, 66.7% (6/9) vs 70% (7/10); lobularity, 77.8% (7/9) vs 20% (2/10); hyperechoic pancreatic duct margin, 88.9% (8/9) vs 30% (3/10); reduced echogenicity, 88.9% (8/9) vs 90% (9/10). Lobularity and hyperechoic pancreatic duct margin were detected at a significantly higher frequency in early AIP than in the advanced AIP patients (P &lt; 0.05). Regarding the histopathological findings, acinar cells were better preserved in the cases of early AIP, whereas acinar cells were reduced in number and replaced by massive fibrosis in the patients with advanced AIP.
Conclusions:
Lobularity and hyperechoic pancreatic duct margin are characteristic EUS features of early AIP, which has a more favorable prognosis, and shows a higher frequency of spontaneous remission and preservation of acinar cells, than advanced AIP.

DOI： 10.1111/j.1443-1661.2009.00879.x

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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：WILEY-BLACKWELL PUBLISHING, INC  

Hepatocellular carcinoma (HCC) is one of the most commonly occurring malignances worldwide. Curative therapies such as resection, percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) have been applied to patients with early-stage HCC. Patients with more advanced cancers require local or systemic therapies. We present the results of our retrospective review conducted to evaluate whether transarterial chemoembolization (TACE) alone and combined TACE with percutaneous ablation for HCC exhibited superior efficacy to palliative treatment.
The effects of TACE and of the combined therapies (TACE + PEI or TACE + RFA) on the long-term survival rates were evaluated in 268 untreated HCC patients by various statistical analyses.
The cumulative survival rates in the TACE alone group were significantly superior to those in the palliative treatment group. Further, the cumulative survival rates in the combined TACE + PEI/RFA group were significantly superior to those in the TACE alone group. When the comparison among the groups was restricted to patients with two or three tumors fulfilling the Milan criteria, significantly greater prolongation of survival was observed in the combined TACE + PEI/RFA group than in the PEI/RFA alone group.
The aforementioned treatment modalities yielded greater improvements of the survival rate and survival duration as compared to palliative treatment in HCC patients. Furthermore, in terms of the effect on the survival period, combined TACE + PEI/RFA therapy was more effective than TACE monotherapy, and also more effective than PEI or RFA monotherapy in cases with multiple tumors fulfilling the Milan criteria.

DOI： 10.1111/j.1872-034X.2009.00490.x

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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：MOSBY-ELSEVIER  

DOI： 10.1016/j.gie.2009.02.020

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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  

The antithrombotic effects of low-dose aspirin (LDA) are well established, and it is used for primary and secondary prevention of cardiovascular events. However, the small intestinal toxicity of LDA remains unclear. The aim of this study was to review the characteristics of small bowel injury in long-term LDA users with capsule endoscopy (CE).
We retrospectively reviewed all chronic LDA users (&gt; 3 months) who underwent CE for suspected small bowel diseases from May 2004 to May 2008 at two medical centers.
At our institutions, a total of 22 patients (13 males and 9 females, mean age 66.3 years) taking LDA underwent a CE examination. The indications for CE were obscure gastrointestinal bleeding in 21 patients and 1 patient who had abdominal pain. Twenty-one patients (95.5%) had some small bowel mucosal injury. Small bowel erosions were identified in 14 patients (63.6%). This enteropathy was characterized by multiple petechiae, loss of villi, erosions, and ulcers with round, irregular, and punched-out shapes. Two patients had circumferential ulcers with stricture. In most patients, small bowel lesions were multifocal and were evenly distributed in the small bowel. No patients failed to pass the capsule.
This is the first CE report that has studied the characteristics of small bowel injury in chronic LDA users. CE is useful to diagnose small bowel enteropathy associated with LDA.

DOI： 10.1007/s00535-009-0040-z

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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：BIOMED CENTRAL LTD  

Background: We aimed to estimate whether the macroscopic extent of gastric mucosal atrophy is associated with a risk for esophageal squamous cell carcinoma using a case-control study in Japanese subjects, a population known to have a high prevalence of CagA-positive H. pylori infection.
Methods: Two hundred and fifty-three patients who were diagnosed as having esophageal squamous cell carcinoma, and 253 sex-and age-matched controls were enrolled in the present study. The macroscopic extent of gastric mucosal atrophy was evaluated based on the Kimura and Takemoto Classification. A conditional logistic regression model with adjustment for potential confounding factors was used to assess the associations.
Results: Body gastritis, defined endoscopically, was independently associated with an increased risk for esophageal squamous cell carcinoma.
Conclusion: Our findings suggest that macroscopic body gastritis may be a risk factor for esophageal squamous cell carcinoma in Japan. Further studies are needed to confirm these findings.

DOI： 10.1186/1471-230X-9-34

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The aim of this study was to evaluate the risk factors of perforation during endoscopic submucosal dissection (ESD).
Methodology: ESD was performed using a Flex knife in 64 patients with a total of 67 gastric tumors. Perforation occurred at the sites of a total of 4 lesions (5.9% [4/67]) for which conservative treatment had been effective. We evaluated several possible risk factors for perforation following ESD, such as tumor size, the location of the lesion, the operation time, and other clinical factors.
Results: All the perforations occurred in the posterior wall of the gastric upper or middle body. In an analysis adjusted for age and sex, the tumor size (odds ratio (OR), 1.017; 95% confidence interval (CI), 1.004-1.030), the location of the lesion in an upper region (OR, 10.64; 95%CI, 1.160-10.00) and the operation time (OR, 1.017; 95%CI, 1.013-1.295) were significantly associated with the incidence of perforation. All perforations were transient, resolving within 7 days, and did not require surgical treatment.
Conclusions: A large tumor size, the location of the lesion in an upper region, and a long operation time are risk factors for perforation following ESD.

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Coffee is one of the most popular beverages worldwide, however, few studies have examined the effects of coffee on the gastrointestinal system. The aim of this study was to determine whether there was a correlation between coffee intake and gastric emptying using a novel non-invasive technique for measuring gastric emptying with a continuous real time C-13 breath test (BreathID system: Oridion, Israel).
Methodology: Six healthy male volunteers participated in this randomized, two-way crossover study. The subjects were randomly assigned to receive a test meal (200kcal per 200mL) plus postprandial 190mL black coffee or the test meal alone after fasting overnight. A C-13-acetic acid breath test was continuously performed using the BreathID system, which monitors gastric emptying, for 4 hours after the administration of the test meal. Using Oridion Research Software (13 version), the time for emptying of 50% of the labeled meals (T 1/2) and the analog to the scintigraphy lag time for 10% emptying of the labeled meal (T lag) were calculated. The parameters between two occasions were compared using the Wilcoxon signed-rank test.
Results: After coffee intake the T 1/2 and T lag constant were significantly decreased.
Conclusions: The decrease in the T 1/2 and T lag suggests the acceleration of gastric emptying. This study showed that postprandial coffee intake enhances gastric emptying, suggesting the potential use of coffee in clinical settings for patients with functional gastrointestinal disorders.

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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：SPANDIDOS PUBL LTD  

In human subjects, aberrant crypt foci (ACF) can be classified as dysplastic or non-dysplastic using magnifying colonoscopy. Dysplastic ACF are thought to be a biomarker for the risk of colorectal cancer (CRC). Hyperinsulinemia and insulin-like growth factor-1 (IGF-1) have also been reported to be associated with an increased risk of CRC. To clarify this association, we investigated the relationship between diabetes risk, IGF-1 and the number of dysplastic ACF. Assessment of the number of dysplastic ACF in the entire colorectum is technically difficult, and we imaged the lower rectum only. Blood collections were taken in the morning on the day of colonoscopy. A total of 512 ACF were counted in 84 male participants, and a correlation was demonstrated to exist between age, body mass index (BMI), fasting blood sugar (FBS), insulin, homeostasis model assessment-insulin resistance (HOMA-IR), plasma leptin levels, plasmal IGF-1 levels and the number of dysplastic ACF. A significant association between plasma IGF-1 levels and the number of dysplastic ACF was still demonstrable after adjustment for age, BMI, FBS, insulin, HOMA-IR and plasma leptin levels. Our findings suggest that increased plasma leptin and IGF-1 levels, hyperinsulinemia and insulin resistance may promote the growth of dysplastic ACF. The results of multiple regression analysis revealed that increased plasma IGF-1 levels are associated with the number of dysplastic ACF present, and may be an independent risk factor for CRC. In conclusion, elevated plasma IGF-1 may promote the growth of dysplastic ACF and play a key role in colon carcinogenesis in male individuals.

DOI： 10.3892/mmr_00000105

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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  

The aim of the study was to evaluate bowel dysmotility in patients with a history of abdominal surgery by measuring both gastric transit time and small bowel transit time during capsule endoscopy and assessing the completeness of the examination. The study included 26 patients who had undergone abdominal surgery (postoperative group) and 52 patients who had not (control group). The capsule reached the cecum in 50.0% of the postoperative group and 80.8% of the control group (P = 0.005). While there was no significant difference in gastric transit time between the two groups (P = 0.882), small bowel transit time was significantly longer in the postoperative group (338.3 +/- A 119.2 min) than in the control group (266.4 +/- A 110.8 min, P = 0.010). This is the first study to report that the small bowel transit time during capsule endoscopy is prolonged in patients who had a history of abdominal surgery, resulting in a lower frequency of complete examination.

DOI： 10.1007/s10620-008-0467-8

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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：BIOMED CENTRAL LTD  

Background: Spontaneous rupture is rare complication of hepatocellular carcinoma (HCC) with high mortality rate in cirrhotic cases. The aim of this study was to determine the factors influencing prognosis in cases of spontaneously ruptured HCC and to investigate the outcomes of the treatments employed, especially transcatheter arterial embolization (TAE).
Methods: A retrospective multicenter study was conducted in 48 cirrhotic patients with spontaneous rupture of HCC. Conservative treatment was employed in 32 patients (ConT group) and TAE was performed in 16 patients (TAE group).
Results: The median survival time (MST) in the ConT group was only 13.1 days and the survival rate was extremely poor: 59.4% at 7 days, 37.5% at 14 days, and 6.3% at 30 days. On the other hand, the MST in the TAE group was 244.8 days and the survival rate was 87.5% at 1 month, 56.3% at 3 months, 23.4% at 12 months, and 15.6% at 24 months. According to the results of univariate analyses, factors associated with poor hepatic function and poor suitability for TAE was important determinants of short-term death (less than 3 weeks) among the patients (p &lt; 0.05). On the other hand, among the patients in whom initial TAE was successfully performed (n = 15), a multivariate analysis showed that a maximum tumor size not exceeding 7 cm was the only independent factor determining long-term survival (p = 0.0130).
Conclusion: Despite the inherent limitations of this retrospective study, TAE appears to be a useful treatment strategy for cirrhotic patients with spontaneous HCC rupture, as it yielded a longer survival period compared with conservative treatment in patients with ruptured HCC. Among the patients with ruptured HCC in whom initial TAE was successfully performed, the maximum tumor size was an important factor influencing survival.

DOI： 10.1186/1471-230X-9-29

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The ideal medication for treatment of acid related diseases should have a rapid onset of action to promote hemostasis. The aim of our study was to investigate the inhibitory effects on gastric acid secretion after single intravenous administrations of lansoprazole 30 mg and famotidine 20 mg.
Methodology: Twelve Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 4 hours after single intravenous administration of lansoprazole 30 mg or famotidine 20 mg.
Results: The average pH during the 4-hour period after administration of famotidine was higher than after lansoprazole (median: 5.15 versus 3.55, respectively; p = 0.0376). During the 4-hour study period, famotidine 20 mg provided a longer duration of pH &gt; 3, 3.5, 4, 5, 6 and 7, compared to lansoprazole 30 mg (median: 73.6% versus 57.0%; p = 0.0414, 66.8% versus 47.8%; p = 0.0281, 60.8% versus 38.8%; p = 0.0150, 55.7% versus 29.7%; p = 0.0281, 45.0% versus 23.1%; p = 0.0414 and 23.9% versus 3.65%; p = 0.0076).
Conclusions: In Helicobacter pylori-negative healthy male subjects, an intravenous dose of famotidine 20 mg more rapidly increases intragastric pH than lansoprazole 30 mg.

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: In contrast to Western countries where erosive esophagitis (EE) is more prevalent in males, there is a high incidence of EE in elderly females in Japan. We aimed to examine the gender differences in the age-stratified prevalence of EE and Barrett&apos;s epithelium.
Methodology: The study population comprised 869 cases (463 men and 406 women) who had undergone an upper endoscopy at the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. EE was graded according to the Los Angeles Classification. Barrett&apos;s epithelium was diagnosed based on the Prague C & M Criteria.
Results: In contrast to the decrease of the proportion of EE with aging in males, that in females remained constant. The results suggest that the suppressive effect of the increased gastric mucosal atrophy associated with aging was wiped out by the age-related effect of the increased incidence of hiatal hernia. The proportions of Barrett&apos;s epithelium in both males and females increased with aging.
Conclusions: In Japan, the prevalence of elderly females complicated with hiatal hernia, which was partly due to osteoporosis and kyphosis, may affect the proportion of EE and probably Barrett&apos;s epithelium.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction. Penetration of the colon to the posterior uterine wall secondary to diverticulitis is unusual, with diagnostic methods not yet established. Non-invasive imaging, such as computed tomography and magnetic resonance imaging may help to establish a proper diagnosis, but confirmation may be reached only after surgical exploration. Case presentation. We report the case of a 78-year-old Japanese woman who presented with a low grade fever and mild diarrhea which occurred two or three times a week. Computed tomography and magnetic resonance imaging demonstrated a capsular lesion including an air structure with a diameter of 5 cm, between the posterior aspect of the uterine body and the sigmoid colon. A gastrograffin enema and colonoscopy demonstrated a giant diverticulum of the sigmoid colon with no evidence of malignancy. These data confirmed the diagnosis of diverticulitis complicated by a giant diverticulum. Because of a relapsing fever after therapy with antibiotics, the patient had en bloc surgical treatment of the uterus, fallopian tubes, ovaries and sigmoid colon, the organs involved in the diverticulitis, followed by an uneventful recovery. Conclusion. This is a rare case report of penetration of the sigmoid colon to the posterior uterine wall secondary to diverticulitis. © 2009 Akiyama et al.
licensee Cases Network Ltd.

DOI： 10.4076/1752-1947-3-8957

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000235922

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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：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.48.2229

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000209218

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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：KARGER  

Background and Aims: Small intestinal toxicity of low-dose aspirin remains unclear. The purpose of this capsule endoscopy study was to assess the incidence of small bowel injury in healthy volunteers treated with short-term low-dose aspirin. Methods: Healthy subjects were randomly assigned to receive low-dose aspirin for 14 days (Aspirin group) or no drugs for 14 days (Control group). The two treatment occasions were separated by a washout period of at least 4 weeks. All subjects underwent capsule endoscopy at the end of each treatment period. Results: After 2 weeks of treatment, the percentages of subjects with small bowel pathology were 80% in the Aspirin group compared with 20% in the Control group (p = 0.023). The incidence of small bowel mucosal breaks in the Aspirin group was higher than that in the Control group, although the difference was not significant (30 vs. 0%; p = 0.210). Conclusions: This is the first pilot study using capsule endoscopy to report on the relation between small bowel injury and low-dose aspirin. Among the healthy subjects, the short-term administration of low-dose aspirin was associated with a mild mucosal inflammation of the small bowel. Copyright (c) 2009 S. Karger AG, Basel

DOI： 10.1159/000204465

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: The granulocyte-colony stimulating factor-producing tumor was first reported in 1977, however, anaplastic pleomorphic type carcinoma of the pancreas producing granulocyte-colony stimulating factor is still rare. Case presentation: A 63-year-old man was admitted to our hospital with body weight loss (-10 kg during months) and upper abdominal pain from 3 weeks. Abdominal computed tomography demonstrated a pancreatic tumor 10 cm in size and multiple low-density areas in the liver. On admission, the peripheral leukocyte count was elevated to 91,500/mm3 and the serum concentration of granulocyte-colony stimulating factor was 134 pg/mL (normal, &lt
18.1 pg/mL). Based on liver biopsy findings, the tumor was classified as an anaplastic pleomorphic-type carcinoma. Immunohistochemical staining showed that pancreatic carcinoma cells were positive for granulocyte-colony stimulating factor. The patient developed interstitial pneumonia, probably caused by granulocyte-colony stimulating factor, and died 11 days after admission. Conclusion: This is a rare case report of anaplastic pleomorphic-type carcinoma of the pancreas producing granulocyte-colony stimulating factor and confirmed by immunohistochemistry. © 2008 Nakajima et al
licensee BioMed Central Ltd.

DOI： 10.1186/1752-1947-2-391

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記述言語：英語   出版者・発行元：SPRINGER  

DOI： 10.1007/s10620-008-0272-4

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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：BIOMED CENTRAL LTD  

Background: Evidence regarding the association between alcohol consumption and the gastro-esophageal reflux disease (GERD) spectrum has been conflicting. We examined the association between alcohol consumption and erosive esophagitis and Barrett&apos;s epithelium in Japanese men.
Methods: The study population comprised 463 men subjects who had undergone an upper endoscopy at the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. The presence of erosive esophagitis and Barrett&apos;s epithelium was diagnosed based on the Los Angeles Classification and the Prague C and M Criteria, respectively. We divided the study population into four groups: never drinkers, light drinkers ( less than 25.0 g of ethanol per day), moderate drinkers ( 25.0 to 50.0 g of ethanol per day), and heavy drinkers ( more than 50.0 g of ethanol per day). A linear regression of the logistic regression analysis was used to analyze the dose-response trends.
Results: Compared with never drinkers, light drinkers ( less than 25.0 g ethanol per day), moderate drinkers ( 25.0 to 50.0 g per day), and heavy drinkers ( more than 50.0 g per day) had ORs for erosive esophagitis of 1.110 (95% CI: 0.553 - 2.228, p = 0.7688), 1.880 ( 95% CI: 1.015 - 3.484, p = 0.0445) and 1.988 ( 95% CI: 1.120 - 3.534, p = 0.0190), respectively. These groups had ORs for Barrett&apos;s epithelium of 1.278 ( 95% CI: 0.752 - 2.170, p = 0.3643), 1.458 ( 95% CI: 0.873 - 2.433, p = 0.1500), and 1.912 ( 95% CI: 1.185 - 3.086, p = 0.0079), respectively. The odds ratios/grams ( alcohol)/day of dose response trends for erosive esophagitis and Barrett&apos;s epithelium were 1.015 ( 95% CI: 1.004 - 1.026, p = 0.0066) and 1.012 ( 95% CI: 1.003 - 1.021, p = 0.0079), respectively.
Conclusion: These findings suggest that alcohol consumption in Japanese men tends to be associated with an increased risk of erosive esophagitis and Barrett&apos;s epithelium.

DOI： 10.1186/1471-230X-8-58

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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：MOSBY-ELSEVIER  

Background: Differentiating primary sclerosing cholangitis (PSC) and sclerosing cholangids caused by autoimmune pancreatitis (SC-AIP) is often challenging. Recently, endoscopic findings of the duodenal papilla in cases with AIP or PSC were reported by Unno and Parlak, although the endoscopic differentiation of these 2 conditions has not yet been fully clarified.
Objective: Our purpose was to clarify, the endoscopic findings of the duodenal papilla in patients with SC-AIP and those with PSC and to determine criteria for the differentiation of these conditions.
Design: Case series.
Setting: Restrospective.
Patients: Twenty-seven,en patients With SC-AIP and 12 patients with PSC who had undergone ERCP were identified from out database. We reviewed these records to determine whether the duodenal papillary findings (swollen papilla/normal papilla/small papilla) might be potentially useful for differentiating SC-AIP and PSC. Immunohistopathological findings for the duodenal papilla were also examined by using immunoglobulin G4 (IgG4) among the infiltrating plasma cells.
Interventions: ERCP, biopsy specimen taken from duodenal papilla.
Main Outcome Measurements: The presence of a swollen duodenal papilla with IgG4-positive plasma cells was useful for discriminating SC-AIP from with PSC.
Results: A swollen duodenal papilla was observed in 63% (17/27) of the patients with SC-AIP, whereas there was no swelling of the duodenal papilla of the patients with PSC. A small papilla was recognized in 50% (6/12) of the patients with PSC. IgG4-positive plasma cells in the duodenal papilla were significantly detected in the patients with SC-AIP but not in the patients with PSC.
Limitation: Single-center study.
Conclusions: Characteristic duodenal endoscopic papillary features in patients with SC-AIP, such as a swollen duodenal papilla and positive immunostaining for IgG4, might be helpful for discriminating this condition from PSC.

DOI： 10.1016/j.gie.2008.08.013

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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：WILEY-BLACKWELL  

Aim: Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. In this study we analyzed the expression profile of genes and biological pathways involved in NASH in comparison with non-NASH by gene set enrichment analysis (GSEA) employing a DNA microarray technique.
Methods: mRNA from liver biopsy specimens was collected from a group of NASH patients and a group of non-NASH patients. We analyzed the relative abundance of mRNA using high-density oligonucleotide microarrays containing probes for 54 675 known genes, and investigated the pathogenetic mechanisms of NASH by means of a powerful technique for analyzing molecular profiling data, GSEA.
Results: The results showed that the level of expression of 27 gene sets was significantly higher and the level of expression of 25 gene sets was significantly lower in the NASH samples than in the non-NASH samples. Based on these results we created an online, publicly available, searchable database containing the data for the gene expression profiles of the NASH patients (http://www2.genome.rcast.u-tokyo.ac.jp/__/NASH/NASH_GSEA2/).
Conclusion: Our data revealed differences in expression of many gene sets that are involved in the pathogenesis of NASH.

DOI： 10.1111/j.1872-034X.2008.00399.x

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記述言語：英語   出版者・発行元：SPRINGER  

DOI： 10.1007/s10620-008-0273-3

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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：WILEY-BLACKWELL  

DOI： 10.1111/j.1440-1746.2008.05662.x

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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：BIOMED CENTRAL LTD  

Background: The changes in the liver in nonalcoholic fatty liver disease (NAFLD) range over a wide spectrum, extending from steatosis to steatohepatitis (NASH). However it has remained difficult to differentiate between NASH and non-progressive NAFLD on the basis of the clinical findings alone.
Aims: In this study we investigated the clinical usefulness of plasma Pentraxin3 (PTX3) levels to predict NASH. Plasma PTX3 was measured in 70 patients with histologically verified NAFLD (28 with non-NASH and 42 with NASH) and 10 healthy control subjects.
Results: The plasma PTX3 level was significantly higher in the NASH cases than in the non-NASH cases (p = 0.0021) and control subjects (p = 0.045). And the plasma PTX3 level was significantly higher in the stages 3-4 NAFLD cases than in the stages 0-2 NAFLD cases (p&lt;0.0001). The PTX3 values were closely correlated with the stages of liver fibrosis (p&lt;0.0001, Kruskal-Wallis test). To detect NASH compared with non-NASH, the area under the curve for plasma PTX3 were 0.755, and to detect stages 3-4 NAFLD compared with stages 0-2 NAFLD, the area under the curve for plasma PTX3 were 0.850.
Conclusion: This is the first study to demonstrate consistent and profound elevation of plasma PTX3 levels in NASH in comparison with non-NASH. The results suggest that plasma PTX3 levels may not only be laboratory values that differentiate NASH from non-NASH, but marker of the severity of hepatic fibrosis in NASH.

DOI： 10.1186/1471-230X-8-53

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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：MOSBY-ELSEVIER  

DOI： 10.1016/j.gie.2008.04.023

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記述言語：英語   出版者・発行元：SPRINGER  

DOI： 10.1007/s10620-008-0219-9

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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  

We report a rare case of adenosquamous carcinoma of the pancreas associated with humoral hypercalcemia of malignancy (HHM) in which parathyroid hormone-related protein (PTH-rP) was identified as the causative factor of hypercalcemia. A 72-year-old Japanese man was admitted to our institution complaining of fever and abdominal pain. Abdominal computed tomography demonstrated a large tumor in the body of the pancreas, with multiple liver metastases. Both serum calcium and PTH-rP levels were elevated. No accumulation was observed on bone scan with technetium-99. The patient died of pneumonia 3 months after admission. Autopsy demonstrated that the neoplasm in the pancreas showed an abrupt histological transition from adenocarcinoma to squamous cell carcinoma. PTH-rP was identified in the primary pancreatic tumor cells by immunohistochemical examination and a reverse-transcription polymerase chain reaction (RTPCR) method. We concluded that PTH-rP was the causative factor of the HHM, based on the laboratory data, immunohistochemical examination, and messenger RNA (mRNA) expression. This is a very rare report of adenosquamous cell carcinoma of the pancreas associated with HHM.

DOI： 10.1007/s00534-007-1258-x

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The aim of this study was to determine whether there was a correlation between body positions and gastric emptying, using a novel non-invasive technique for measuring gastric emptying with a continuous real time (13)C breath test (BreathID system).
Methodology: Ten healthy male volunteers participated in this randomized, two-way crossover study. On both occasions. the (13)C breath test was performed for 4 hours using the BreathID system with a liquid meal (200kcal per 200mL) containing 100mg (13)C-acetic acid. Subjects were randomly assigned to sit comfortable (the sitting position) or to lie supine (the lying position).
Results: In the lying position, T 1/2 and T lag were significantly delayed. The gastric emptying coefficient was also decreased in lying position.
Conclusions: This study showed that gastric emptying following a liquid meal was significantly delayed in the lying position compared to the sitting position, suggesting the potential use of these findings in the clinical setting for patients receiving enteral nutrition via the stomach.

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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：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Barrett&apos;s epithelium is currently believed to be related to acid gastroesophageal reflux. The aim was to determine the role of pancreatic-biliary reflux in the genesis of Barrett&apos;s epithelium.
Methodology: The study population comprised 1055 cases (606 men and 449 women; median age, 67years) who had undergone an upper endoscopy at 67 the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. The study population was composed of 869 cases with intact stomachs and 186 cases with distal-gastrectomies. The presence and the progression of Barrett&apos;s epithelium were diagnosed based on the Prague C & M Criteria. The correlations of clinical factors, including distal-gastrectomy, with the presence and the progression of Barrett&apos;s epithelium were examined.
Results: The study demonstrated that 42.2% of the total population was diagnosed to have Barrett&apos;s epithelium and, in 12.6% of the cases with Barrett&apos;s epithelium, the progression of Barrett&apos;s epithelium was observed during the median 72 month follow-up. A distal gastrectomy was not significantly correlated with either the incidence or progression of Barrett&apos;s epithelium.
Conclusions: This lack of association between gastric surgery and Barrett&apos;s epithelium suggests that pancreatic-biliary reflux with limited acid is not sufficient for the genesis of Barrett&apos;s epithelium.

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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：BIOMED CENTRAL LTD  

Background: Genetic factors as well as environmental factors are important in the development of NAFLD and in this study we investigated associations between polymorphisms of peroxisome proliferators-activated receptor gamma coactivator 1 alpha polymorphism (PPARGC1A) and NAFLD.
Aims: We recruited 115 patients with biopsy-proven NAFLD, 65 with NASH and 50 with simple steatosis, and 441 healthy control subjects and investigated 15 SNPs of PPARGC1A.
Results: SNP rs2290602 had the lowest p value in the dominant mode (p = 0.00095), and the odds ratio for NAFLD (95% CI) was 2.73 (1.48-5.06). rs2290602 was significantly associated with NAFLD even when the most conservative Bonferroni&apos;s correction was applied (p = 0.0143). The frequency of the T allele of rs2290602 was significantly higher in the NASH patients than in the control subjects (p = 0.00093, allele frequency mode), and its frequency in the NASH patients tended to be higher than in the simple steatosis patients (p = 0.09). The results of the real-time RT-PCR study showed that intrahepatic mRNA expression of PPARGC1A was lower in the TT group than in the GG or GT group at SNP rs2290602 (p = 0.0454).
Conclusion: This is the first study to demonstrate a significant association between genetic variations in PPARGC1A and NAFLD. This finding suggested that PPARGC1A polymorphism and lower expression of PPARGC1A mRNA in the liver are an important genetic contribution to etiology of NAFLD.

DOI： 10.1186/1471-230X-8-27

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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  

Background/Purpose. Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas have a favorable prognosis. However, invasive ductal carcinomas of the pancreas show a rapid progression. The aim of this study was to investigate gene mutations in pure pancreatic juice from IPMN patients and to define these genetic mutations in relation to the histopathological and clinical features of IPMNs.
Methods. Twenty-two patients with IPMN, 21 patients with ductal carcinoma, and 20 patients with normal pancreas or chronic pancreatitis were recruited for this study. We measured the main pancreatic duct's largest diameter and the maximum size of a dilated branch was assessed by ultrasonography or endoscopic ultrasonography. Pure pancreatic juice was collected and was investigated for K-ras, p16, and p53 mutations.
Results. Mutant K-ras gene was detected in 13 of the 22 patients (59.1%) with IPMNs. Different kinds of mutations were detected in the same patient in 4 cases. In the 13 patients with mutant K-ras gene, the diameter of the most dilated part of the main pancreatic duct was 2-8 mm ( average, 4.5 mm) and in 7 patients with wild-type K-ras gene, the diameter was 2 5 mm ( average, 2.7 mm). There was a significant difference in the diameter of the main pancreatic duct between patients with and without the mutant K-ras gene ( P = 0.0323).
Conclusions. The incidence of K-ras mutation may be associated with the hypersecretion of mucin.

DOI： 10.1007/s00534-007-1223-8

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記述言語：日本語  

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000127417

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000140976

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記述言語：英語  

DOI： 10.1159/000151298

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000140975

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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：AMER ASSOC CANCER RESEARCH  

Purpose: Tumor-infiltrating lymphocytes represent the host immune response to cancer. CD4(+) CD25(+) FOXP3(+) regulatory T cells (Tregs) suppress the immune reaction. The aim of the present study was to investigate the clinicopathologic significance and roles of Tregs and CD8(+) T cells during hepatocarcinogenesis.
Experimental Design: We examined the infiltration of FOXP3(+) Tregs and CD8(+) Tcells in the tumor stroma and nontumorous liver parenchyma using 323 hepatic nodules including precursor lesions, early hepatocellular carcinoma (HCC), and advanced HCC, along with 39 intrahepatic cholangiocarcinomas and 59 metastatic liver adenocarcinomas. We did immunohistochemical comparative studies.
Results: The prevalence of Tregs was significantly higher in HCC than in the nontumorous liver (P &lt; 0.001). The patient group with a high prevalence of Tregs infiltrating HCC showed a significantly lower survival rate (P = 0.007). Multivariate analysis revealed that the prevalence of Tregs infiltrating HCC was an independent prognostic factor. The prevalence of Tregs increased in a stepwise manner (P &lt; 0.001) and that of CD8(+) T cells decreased during the progression of hepatocarcinogenesis (P &lt; 0.001). Regardless of the presence of hepatitis virus infection or histopathologic evidence of hepatitis, the prevalence of Tregs was significantly increased in nontumorous liver bearing primary hepatic tumors.
Conclusions: Tregs play a role in controlling the immune response to HCC during the progression of hepatocarcinogenesis. It has been suggested that primary hepatic cancers develop in liver that is immunosuppressed by a marked infiltration of Tregs. A high prevalence of Tregs infiltrating HCC is thought to be an unfavorable prognostic indicator.

DOI： 10.1158/1078-0432.CCR-06-2363

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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：AMER ASSOC CANCER RESEARCH  

Purpose: It is difficult to predict the biological behavior of pancreatic endocrine tumors (PETs). Our aim was to evaluate the prognostic significance of certain variables in PETs.
Experimental Design: The following variables were examined in 37 patients with PETs and then compared with other clinicopathologic characteristics: histologic tumor structure; microvessel density (MVD) measured by three different methods, including a unique method involving calculation of solid area MVD; endothelial proliferation; and the immunohistochemical expression of vascular endothelial growth factor-A and CXC chemokine CXCL-12. Intratumoral vascular structures were analyzed by double immunofluorescence using 30-mu m-thick sections.
Results: The presence of focal and intensive solid growth of tumor cells (large solid nests; P=0.003), low solid area MVD (P=0.002), a high endothelial cell proliferation index (EPI; P=0.005), and high expression of CXCL-12 in PET cells (P=0.018) were significant unfavorable prognostic indicators. The predominant structure of the overall tumor histology and the expression of vascular endothelial growth factor-A did not separate aggressive PETs. In areas of focal solid growth, tumor-associated blood vessels had obviously low MVD and high EPI, and their structures were poorly formed with highly abnormal features, in comparison with other areas. High expression of CXCL-12 in tumor cells was significantly associated with variables representing tumor growth, hematogenous tumor spread, low MVD, high EPI, and the presence of large solid nests.
Conclusions: This study has provided novel findings on the prognostic features of tumor architecture and tumor-associated angiogenesis in PETs. CXCL-12 is the first candidate molecule in association with neoangiogenesis in PETs.

DOI： 10.1158/1078-0432.CCR-06-1408

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000106753

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000108627

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000107937

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000106976

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000106754

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1440-1746.2006.04557.x

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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  

A case of undifferentiated spindle-cell carcinoma of the gallbladder is described. A 72-year-old man presented with right hypochondralgia and fever. Imaging studies revealed a well-demarcated solid tumor (with a necrotic center) in the gallbladder that invaded the liver and transverse colon. On gross examination of the surgical specimen, the cut surface of the polypoid tumor showed nodular invasive growth. Microscopically, the tumor was composed of atypical spindle-shaped tumor cells that proliferated in a whirling or interlacing pattern. The tumor also showed foci with a malignant epithelial component that simulated a carcinosarcoma. Immunohistochemically, the biphasic differentiation of the tumor was highlighted by the different immunoreactivity to antibodies against cytokeratins, epithelial membrane antigen (EMA), and vimentin shown by the malignant epithelial components and the spindle-cell components. However the latter showed faint positivity for cytokeratin antibody. These results suggested that the spindle-cell carcinoma of the gallbladder originated from cholecystic mucosa and showed sarcomatous reaction or dedifferentiation, as indicated by the presence of vimentin-positive cells. The proliferation index, as detected by ki-67, in the spindle-cell component was higher than that in the epithelial component, which may account for the more aggressive biological behavior of the spindle-cell component.

DOI： 10.1007/s00534-006-1100-x

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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 JAPAN KK  

Background. We examined contrast-enhanced harmonic gray-scale sonographic findings of pancreatic carcinoma in relation to the pathological findings in resected specimens to evaluate correlations between observations made by this modality and the pathological findings. Methods. The pathological findings of surgical specimens obtained from 16 patients were examined in relation to the contrast-enhanced harmonic gray-scale sonography findings. Lesion vascularity was examined by contrast-enhanced harmonic gray-scale sonography from 20 to 50s after the injection of Levovist (Schering, Berlin, Germany) (early phase), and lesion enhancement was also monitored at approximately 90s after injection (delayed phase). Results. Contrast-enhanced harmonic gray-scale sonography showed positive enhancement in 12 of the 16 lesions (peripheral tumor region alone, n = 9; entire tumor, n = 3), while the other 4 lesions showed no contrast enhancement in any region. Twelve enhanced regions (9 peripheral tumor region and 3 entire tumor regions) detected by contrast-enhanced harmonic gray-scale sonography showed: (1) mild fibrosis with inflammation, in 10 regions (83%); (2) the presence of both carcinoma cells and residual acinar cells in 8 (67%); and (3) presence of relatively large arteries in 2 (17%). In contrast, 13 non-enhanced regions (4 entire tumor regions and 9 central regions) showed: (1) severe fibrosis in 10 regions (77%); (2) necrosis in 7 (54%); and (3) mucin in 4 (31%). Conclusions. Contrast-enhanced harmonic gray-scale sonographic findings of pancreatic carcinoma are influenced by interstitial histological features associated with tumor growth.

DOI： 10.1007/s00535-005-1598-8

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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  

Background Medication for the relief of heartburn should have the rapid onset of action required for on-demand use. We studied the inhibition of gastric acid secretion by lafutidine and rabeprazole, given in single doses to fasting and postprandial subjects. Methods. A total of 22 healthy male, Helicobacter pylori-negative volunteers participated in this randomized, two-way crossover study. They were randomly assigned to receive a single oral dose of 10mg lafutidine or 20mg rabeprazole after fasting overnight (12 subjects, fasting study) or after eating a test meal (noodles, 364kcal; protein, 10.1g; fat, 16g; carbohydrates, 44.9g; NaCl, 1.1g; 10 subjects, postprandial study). Intragastric pH was monitored continuously for 6h after treatment. The other drug was given after a washout period of at least 7 days, and intragastric pH was similarly monitored. Results. In the fasting study, lafutidine sustained pH at &gt; 3 and &gt; 4 during the second, third, fourth, fifth, and sixth hours of the study for significantly longer than rabeprazole. During the first 6h after treatment, lafutidine sustained pH at more than 2, 3, 3.5, 4, 5, 6, and 7 longer than rabeprazole. In the postprandial study, lafutidine sustained pH &gt; 3 and &gt; 4 for longer periods than rabeprazole during the third, fourth, fifth, and sixth hours of the study. During the first 6h after treatment, lafutidine sustained pH at more than 2, 3, 3.5, 4, 5, 6, and 7 longer than rabeprazole. Conclusions. Lafutidine 10mg produces a prompter rise in intragastric pH than rabeprazole 20mg in fasting and postprandial Helicobacter pylori-negative male subjects.

DOI： 10.1007/s00535-005-1569-0

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