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BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

DOI： 10.1007/s00535-024-02099-7

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INTRODUCTION: A remission induction therapy of granulocyte and monocyte adsorptive apheresis (GMA) was given to patients with Crohn's disease (CD). However, establishing an appropriate treatment strategy for GMA in patients with CD remains unclear. METHODS: This study evaluated the clinical efficacy and subsequent clinical progression after GMA in patients with CD who underwent GMA in seven independent institutions in Japan from 2010 to 2023. RESULTS: Sixteen patients were enrolled. The overall remission and response rates were 25.0% and 68.8%, respectively. All patients responding to GMA received biologics that were continuously used and 36.4% of patients remained on the same biologics 52 weeks after GMA. Notably, all patients who continued the same biologics had previously experienced a loss of response to biologics. CONCLUSION: GMA may exhibit effectiveness even in cases with refractory CD. Moreover, it represents a potential novel therapeutic option for refractory CD with loss of response to biologics.

DOI： 10.1111/1744-9987.14103

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Background and study aims Gastric adenocarcinoma of the fundic gland type (GA-FG) is characterized by an elevated lesion with vessel dilation exhibiting branching architecture (DVBA). However, this feature is also found in fundic gland polyps (FGPs), posing a challenge in their differentiation. In this study, we aimed to investigate the clinicopathological features of gastric elevated lesions with DVBA and assess the efficacy of the white ring sign (WRS) as a novel marker for distinguishing between FGPs and GA-FGs. Methods We analyzed 159 gastric elevated lesions without DVBA and 51 gastric elevated lesions with DVBA, further dividing the latter into 39 in the WRS-positive group and 12 in the WRS-negative group. The clinicopathological features, diagnostic accuracy, and inter-rater reliability were analyzed. Results Univariate and multivariate analyses for gastric elevated lesions with DVBA identified the histological type consistent with FGPs and GA-FGs, along with the presence of round pits in the background gastric mucosa, as independent predictors. FGPs were present in 92.3% (36/39) of the WRS-positive group and GA-FGs were observed in 50.0% (6/12) of the WRS-negative group. WRS positivity and negativity exhibited high diagnostic accuracy, with 100% sensitivity, 80.0% specificity, and 94.1% accuracy for FGPs, and 100% sensitivity, 86.7% specificity, and 88.2% accuracy for GA-FGs. Kappa values for WRS between experts and nonexperts were 0.891 and 0.841, respectively, indicating excellent agreement. Conclusions WRS positivity and negativity demonstrate high diagnostic accuracy and inter-rater reliability for FGPs and GA-FGs, respectively, suggesting that WRS is a useful novel marker for distinguishing between FGPs and GA-FGs.

DOI： 10.1055/a-2301-6248

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Language：Japanese   Publisher：日本大腸検査学会  

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INTRODUCTION: Carbazochrome sodium sulfonate (CSS) is a hemostatic agent that reduces capillary permeability and enhances capillary resistance. However, its specific effects on colorectal endoscopic submucosal dissection (ESD) outcomes remain uncertain. This study aimed to assess the risk factors for post-ESD bleeding and the effect of CSS on colorectal ESD outcomes. METHODS: First, we retrospectively analyzed the risk factors for post-ESD bleeding using data from 1,315 lesions in 1,223 patients who underwent ESD for superficial colorectal neoplasms at eight institutions. Second, patients were divided into CSS and non-CSS groups using propensity score matching, and their outcomes from colorectal ESD were analyzed. RESULTS: The risk factors for post-colorectal ESD bleeding were identified as age of ≥70 years, tumor located in the rectum, tumor size of ≥40 mm, and post-ESD defect unclosure in both univariate and multivariate analyses. The CSS and non-CSS groups each consisted of 423 lesions after propensity score matching. The post-colorectal ESD bleeding rate was 3.5% (15/423) and 3.3% (14/423) in the CSS and non-CSS groups, respectively, indicating no significant differences. Among patients with the high-risk factors for post-ESD bleeding, the administration of CSS also did not demonstrate a significant reduction in the post-ESD bleeding rate compared to the non-CSS group. CONCLUSION: CSS administration is ineffective in preventing post-colorectal ESD bleeding in both the general population and individuals at a high risk for such bleeding. Our results indicate the necessity to reconsider the application of CSS for preventing post-colorectal ESD bleeding.

DOI： 10.1159/000539367

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BACKGROUND AND AIM: Image enhancement endoscopy techniques, such as linked color imaging (LCI) and autofluorescence imaging (AFI), have shown promise in diagnosing mucosal inflammation in ulcerative colitis (UC). However, no studies have directly compared the diagnostic efficacy of LCI and AFI. This prospective observational study aimed to compare their diagnostic accuracy for histological healing in UC. METHODS: This study included 81 UC patients, resulting in a total of 204 endoscopic images captured using LCI and AFI, respectively. Spearman's rank correlation coefficients assessed the correlation between LCI and AFI coloration and Geboes histopathology score (GHS). Six endoscopists, who were blinded to clinicopathological features, evaluated these images, and subsequently, the diagnostic accuracy was evaluated. RESULTS: Spearman's rank correlation coefficients between LCI index, AFI index (reverse gamma value), and GHS were 0.324 and -0.428, respectively (P < 0.001), indicating a significant correlation between LCI and AFI coloration and histological healing. In LCI and AFI classifications, mean values for diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 76.3 ± 2.2 versus 77.8 ± 2.7, 91.8 ± 4.0 versus 83.2 ± 7.6, 53.4 ± 10.0 versus 70.0 ± 5.3, 74.0 ± 3.5 versus 80.0 ± 1.6, and 82.9 ± 5.2 versus 75.5 ± 7.5, respectively. No significant difference in diagnostic accuracy existed between LCI and AFI classifications. However, LCI displayed higher sensitivity than AFI while AFI showed higher specificity compared with LCI (P < 0.05). CONCLUSIONS: LCI and AFI offer comparable diagnostic accuracy for histological healing. Clinically, it is necessary to recognize diagnostic features characterized by higher sensitivity in LCI and greater specificity in AFI.

DOI： 10.1111/jgh.16586

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BACKGROUND: Real-world data regarding ustekinumab (UST) for ulcerative colitis (UC) particularly in biologics-naïve patients is currently limited. This study aimed to elucidate the real-world effectiveness and safety of UST for UC. METHODS: Overall, 150 patients with UC treated with UST from March 2020 to January 2023 were enrolled across 7 referral hospitals. To assess the clinical efficacy and persistence of UST, retrospective analyses were conducted from weeks 8 to 56. Predictive factors concerning the response and persistence of UST were examined through univariate and multivariate analyses. RESULTS: Of the 150 patients, 125 received UST for remission induction, including 36% biologics-naïve. The response and remission rates were 72.8% and 56.0% at week 8 and 73.2% and 63.4% at week 56, respectively. Biologics-naïve patients represented higher response and remission rates at week 8 (84.4% and 73.3%) than those with biologics exposure (66.2% and 46.2%). Patients with prior antitumor necrosis factor (anti-TNF) and vedolizumab (VDZ) exposure had relatively lower response and remission rates (34.5% and 24.1%, respectively). The 1-year cumulative persistence rate was 84.0%. Multivariate analysis revealed that the chronic continuous type and prior anti-TNF and VDZ exposure were negative predictive factors for week 8 responsiveness. Clinical response at week 8 was a predictor of 1-year persistence. Adverse event incidence remained notably low at 6.4%. CONCLUSIONS: This study highlights the safety and effectiveness of UST as an induction and maintenance therapy for UC. Chronic continuous type and previous anti-TNF and VDZ exposure negatively contributed to short-term effectiveness, whereas short-term effectiveness provided good persistency.

DOI： 10.1093/crocol/otae024

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Esophageal cancer, which is common among the elderly, has the poorest prognosis among gastrointestinal cancers. Previously, we demonstrated that ferrichrome, produced by the probiotic Lactobacillus casei, exhibited anti-tumor effects in various gastrointestinal cancers, including colorectal and gastric cancers, with minimal effects on non-cancerous intestinal cells. However, it remains unclear whether ferrichrome exerts anti-tumor effects in esophageal cancer. A sulforhodamine B assay revealed that ferrichrome suppressed esophageal adenocarcinoma (OE33, OE19) and squamous cell carcinoma (KYSE70) cells. Ki-67 staining indicated that ferrichrome inhibited the proliferation of esophageal cancer cells. Cell cycle analysis showed that ferrichrome inhibited the DNA synthesis. TUNEL staining revealed that ferrichrome-induced DNA fragmentation. We also confirmed the cleavage of caspase-9 and PARP in ferrichrome-treated cells. Reverse transcription polymerase chain reaction demonstrated an increase in the mRNA of DNA damage-inducible transcript 3 (DDIT-3), a key regulator of programmed cell death, in ferrichrome-treated OE33 cells. In an in vivo OE33 xenograft model, intraperitoneal administration of 5-mg/kg ferrichrome for 14 days resulted in an almost complete inhibition of tumor growth. However, 14 days of intraperitoneal administration of 20-mg/kg 5-fluorouracil (5-FU), but not 20-mg/kg ferrichrome, induced weight loss and myelosuppression in both young and aged mice. Our findings indicate that ferrichrome induces DNA damage-inducible transcript-3, thereby producing anti-tumor effects, including cell cycle arrest and apoptosis, with minimal adverse effects in esophageal cancer cells. This illustrates the high potential of ferrichrome as an anti-tumor drug against esophageal carcinoma.

DOI： 10.1016/j.heliyon.2024.e28070

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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RATIONALE: Both ulcerative colitis (UC) and sarcoidosis are chronic inflammatory diseases with unknown etiologies and are rare. However, the odds ratio in UC patients has been reported to range from 1.7 to 2.1, suggesting a potential etiology between sarcoidosis and UC. Furthermore, the underlying etiologies of UC and sarcoidosis remain unidentified. Sharing the experience of a UC patient with cardiac sarcoidosis could provide valuable insights to prevent sudden death in UC patients. PATIENT CONCERNS: A 71-year-old Japanese woman was diagnosed with UC at 58-year-old and maintained remission on mesalazine treatment. She complained of just palpitation; therefore, she consulted a cardiologist. DIAGNOSES: The patient received a diagnosis of cardiac sarcoidosis with complicating ulcerative colitis based on the results of N-terminal prohormone of the brain natriuretic peptide (NT-proBNP), imaging examinations, and histology. INTERVENTION: The patient was treated with prednisolone and methotrexate. The prednisolone was then tapered, and the methotrexate dose was adjusted based on her symptoms, imaging results, and laboratory findings. OUTCOME: She no longer had any symptoms, and the abnormal FDG uptake had disappeared after 2 years. LESSON: In UC patients, periodic or additional (in case of symptomatic) electrocardiography and NT-proBNP are recommended for the early detection of cardiac sarcoidosis, a life-threatening complication.

DOI： 10.1097/MD.0000000000036207

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BACKGROUND: Granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn has been used as a remission induction therapy for patients with active ulcerative colitis (UC). Herein, we investigated the influence of concomitant medications in the remission induction of GMA in patients with active UC. METHODS: This multicenter retrospective cohort study included patients with UC underwent GMA in five independent institutions in Japan from January 2011 to July 2021. Factors including concomitant medications associated with clinical remission (CR) were analyzed statistically. RESULT: A total of 133 patients were included. Seventy-four patients achieved a CR after GMA. The multivariable analysis revealed that concomitant medication with 5-aminosalicylic acid, Mayo endoscopic subscore (MES), and concomitant medication with immunosuppressors (IMs) remained as predictors of CR after GMA. In the subgroup analysis in patients with MES of 2, concomitant medication with IMs was demonstrated as a significant negative factor of CR after GMA (P = .042, OR 0.354). Seventy-four patients who achieved CR after GMA were followed up for 52 weeks. In the multivariable analysis, the maintenance therapy with IMs was demonstrated as a significant positive factor of sustained CR up to 52 weeks (P = .038, OR 2.214). Furthermore, the rate of sustained CR in patients with biologics and IMs was significantly higher than that in patients with biologics only (P = .002). CONCLUSION: GMA was more effective for patients with active UC that relapsed under treatment without IMs. Furthermore, the addition of IMs should be considered in patients on maintenance therapy with biologics after GMA.

DOI： 10.1002/jca.22040

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RATIONALE: Latent tuberculosis (TB) infection screening before inducing anti-tumor necrosis factor (anti-TNF) alpha agents is important to prevent TB reactivation. However, latent TB infection reactivation may still occur, and the ideal therapeutic strategy for patients with inflammatory bowel disease (IBD) who develop active TB infection has not been established. Vedolizumab (VDZ) has a good safety profile, with low incidence rates of serious infections. However, its safety in patients with latent TB infection reactivation associated with anti-TNF-alpha agents remains unknown. PATIENT CONCERNS: A 21-year-old Vietnamese male patient presented to our hospital with hemorrhagic stool. He had no personal or family history of IBD or TB. DIAGNOSES: Colonoscopy revealed multiple longitudinal ulcers and a cobblestone appearance in the terminal ileum, as well as multiple small erosions and aphtha throughout the colon. Computed tomography revealed a right lung nodular lesion. Serological interferon-gamma release assay and several culture tests were all negative. Thus, he was diagnosed with ileocolonic Crohn's disease (CD) without TB. INTERVENTIONS: The intravenous anti-TNF-alpha agent administration with an immunomodulator was initiated. OUTCOMES: Computed tomography revealed nodular lesion expansion at the right lung, and serological interferon-gamma release assay was positive. He was diagnosed with latent TB infection reactivation. Anti-TNF-alpha agent with an immunomodulator was immediately discontinued, and anti-TB therapy was initiated. His endoscopic findings were still active, and VDZ was selected for maintenance therapy because VDZ has a favorable safety profile with low incidence rates of serious infections. Consequently, mucosal healing was achieved without active TB relapse. LESSONS: This case report presented a patient in whom VDZ was continued as maintenance therapy without inducing TB relapse in a patient with CD who developed latent TB infection reactivation associated with anti-TNF-alpha agents and summarized the safety profile of VDZ for patients with IBD with active or latent TB infection. VDZ may be a safe option for induction and maintenance therapy in patients with CD, even in cases with latent TB infection reactivation.

DOI： 10.1097/MD.0000000000034331

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BACKGROUND : Transnasal endoscopy presents a technical difficulty when inserting the flexible endoscope. It is unclear whether a particular breathing method is useful for transnasal endoscopy. Therefore, we conducted a prospective randomized controlled trial to compare endoscopic operability and patient tolerance between patients assigned to nasal breathing or oral breathing groups. METHODS : 198 eligible patients were randomly assigned to undergo transnasal endoscopy with nasal breathing or with oral breathing. Endoscopists and patients answered questionnaires on the endoscopic operability and patient tolerance using a 100-mm visual analog scale ranging from 0 (non-existent) to 100 (most difficult/unbearable). The visibility of the upper-middle pharynx was recorded. RESULTS : Patient characteristics did not differ significantly between the groups. Nasal breathing showed a higher rate of good visibility of the upper-middle pharynx than oral breathing (91.9 % vs. 27.6 %; P < 0.001). Nasal breathing showed lower mean [SD] scores than oral breathing in terms of overall technical difficulty (21.0 [11.4] vs. 35.4 [15.0]; P < 0.001). Regarding patient tolerance, nasal breathing showed lower scores than oral breathing for overall discomfort (22.1 [18.8] vs. 30.5 [20.9]; P = 0.004) and other symptoms, including nasal and throat pain, choking, suffocating, gagging, belching, and bloating (all P < 0.05). The pharyngeal bleeding rate was lower in the nasal breathing group than in the oral breathing group (0 % vs. 9.2 %; P = 0.002). CONCLUSIONS : Nasal breathing is superior to oral breathing for those performing and undergoing transnasal endoscopy. Nasal breathing led to good visibility of the upper-middle pharynx, improved endoscopic operability, and better patient tolerance, and was safer owing to decreased pharyngeal bleeding.

DOI： 10.1055/a-1900-6004

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BACKGROUND: Given the increasing health concerns for patients with inflammatory bowel disease (IBD), amidst the COVID-19 pandemic, we investigated the impact of the pandemic on the anxiety and behavioral changes in Japanese patients with IBD. METHODS: We analyzed 3032 questionnaires from patients with IBD, aged 16 years or older visiting 30 hospitals and 1 clinic between March 2020 and June 2021. The primary outcome was the score of the anxiety experienced by patients with IBD during the pandemic. RESULTS: Participants reported a median age of 44 years; 43.3% of the patients were women. Moreover, 60.6% and 39.4% were diagnosed with ulcerative colitis and Crohn's disease, respectively, with a median disease duration of 10 years. Participants indicated an average of disease-related anxiety score of 5.1 ± 2.5 on a ten-point scale, with a tendency to increase, 1 month after the number of infected persons per population increased. The top three causes for anxiety were the risk of contracting COVID-19 during hospital visits, SARS-CoV-2 infection due to IBD, and infection by IBD medication. Factors associated with anxiety were gender (women), being a homemaker, hospital visit timings, mode of transportation (train), use of immunosuppressive drugs, and nutritional therapy. Most patients continued attending their scheduled hospital visits, taking their medications, experienced the need for a family doctor, and sought guidance and information regarding COVID-19 from primary doctors, television, and Internet news. CONCLUSIONS: Patients with IBD experienced moderate disease-related anxiety due to the pandemic and should be proactively informed about infectious diseases to relieve their anxiety.

DOI： 10.1007/s00535-022-01949-6

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BACKGROUND: Mucinous adenocarcinoma of the colorectum is a rare histological subtype characterized by an abundant mucinous component. Mucinous tumors are frequently diagnosed at an advanced stage, which indicates an aggressive subtype. However, few case reports have been published, and little information is available concerning genetic alterations in mucinous adenocarcinoma. CASE SUMMARY: A 76-year-old man underwent en bloc endoscopic submucosal dissection (ESD) for the management of a type 0-Is+IIa lesion. Histological examination revealed an intramucosal mucinous adenocarcinoma with signet-ring cell carcinoma and well-to-moderately differentiated tubular adenocarcinoma. Three years after the ESD, local recurrence was detected by an endoscopic examination, revealing a new 0-Is+IIa lesion with a phenotype similar to the previously resected lesion. Re-ESD was chosen for the management of the recurrent tumor, and the histological examination showed positive tumor infiltration at the vertical margin. Additional surgical resection was performed for the curative treatment. Genetic analysis showed pathogenic alterations in RNF43 and TP53 in the adenoma and an additional SMAD4 alteration in the carcinoma. CONCLUSION: This mucinous mucosal adenocarcinoma case was suggested to have an aggressive phenotype and a careful and close follow-up are required.

DOI： 10.4251/wjgo.v15.i1.186

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A 24-year-old woman was admitted to our hospital due to abdominal pain and a high fever. She was diagnosed with ileocolonic Crohn's disease (CD), complicated with a gastro-colic fistula and splenomegaly. After initial treatment with an infliximab-biosimilar, all blood cell line counts markedly decreased. Three-dimensional reconstructed computed tomography revealed splenic vein narrowing. Thus, her pancytopenia was deemed to have likely been caused by hypersplenism. Surgery was performed, and clinical remission was maintained without pancytopenia. This is the first report of a CD patient with pancytopenia caused by hypersplenism that was triggered by gastro-colic fistula-associated splenic vein obstruction.

DOI： 10.2169/internalmedicine.9590-22

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In Japan, establishing a medical cooperation system for patients with inflammatory bowel disease (IBD) between IBD flagship and local care hospitals is a crucial task. Thus, this retrospective multicenter cohort study aims to examine the actual state of medical treatment in patients with IBD via a questionnaire survey administered to eight dependent institutes in Hokkaido, Japan. The present results clarified the clinical disparities of IBD treatment and hospital function between IBD flagship hospitals and local care hospitals. Moreover, the understanding level of IBD treatment in medical staff was significantly lower in local care than in IBD flagship hospitals. Furthermore, an abounding experience of IBD treatment affected the understanding level of IBD treatment of both medical doctors and staff. These findings indicate that selecting patients with IBD corresponding to disease activity, educational system for the current IBD treatment, and promotion of team medicine with multimedical staff can resolve clinical discrepancies between IBD flagship and local care hospitals. The IBD treatment inequities in Japan will be eliminated with the development of an appropriate medical cooperation system between IBD flagship and local care hospitals.

DOI： 10.11405/nisshoshi.120.590

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BACKGROUND: Infliximab (IFX) effectively treats patients with inflammatory bowel disease (IBD). IFX-biosimilar (IFX-BS) has the same amino acid sequence as that of the IFX originator, and its increasing use is expected to reduce national healthcare costs. Long-term efficacy and safety of IFX-BS in patients with Crohn's disease (CD) and ulcerative colitis (UC) have not been completely investigated. METHODS: We conducted a retrospective, multicenter observational study of patients with IBD who received IFX-BS treatment at three hospitals between October 2016 and April 2022. Clinical data were collected from electronic medical records and evaluated for achieving clinical remission (CR) using Crohn's disease activity index (CDAI) and partial Mayo (pMayo) score, persistency of long-term IFX-BS administration, and clinical response rate in the bio-naïve and bio-failure groups. RESULTS: A total of 117 patients with IBD (90 CD and 27 UC) were included. The study findings indicated that both bio-naïve and bio-failure groups of patients with UC showed similar effectiveness of IFX-BS. The treatment persistence rate in patients with CD was significantly higher in the bio-naïve (P = 0.042) and switch (P = 0.010) groups than in the bio-failure group. In the former two groups, the treatment persistence rate was high at two years after administration (more than 80%). In patients with UC, the findings indicated higher treatment persistence rate in the switch group than in the bio-naïve group. Univariable and multivariable analyses for treatment persistence rate showed that the albumin level at the initial IFX-BS administration and groups (bio-naïve, bio-failure and switch) were effective factors for patients with CD. Adverse events were reported in 18 patients (15.4%). CONCLUSION: The present study demonstrates the long-term effectiveness and safety of IFX-BS. In addition to the favorable remission induction in the bio-naïve and bio-failure groups, we demonstrated remission maintenance and treatment persistence rates beyond two years. Albumin level and groups were associated with better treatment persistence in patients with CD.

DOI： 10.1371/journal.pone.0288393

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Various heterogeneous nuclear ribonucleoproteins (hnRNPs) have been reported to be associated with cancer cell growth. However, it remains unclear whether hnRNP G-T, which is specifically expressed in the testis, is expressed in tumor cells, and whether hnRNP G-T expressed in colorectal cancer (CRC) cells is associated with tumor progression. We herein report that hnRNP G-T promoted cancer cell growth and stabilized mRNA of ZDHHC11 in CRC. The cell growth was inhibited by transfection of siRNA of hnRNP G-T in cancer cells, but not in non-cancerous epithelial cells. The tumor promotive effect of hnRNP G-T was confirmed in an HCT116 transplanted mouse model. RT-PCR and western blotting indicated the augmentation of hnRNP G-T in CRC in comparison to non-cancerous cells. The downregulation of hnRNP G-T inhibited cancer cell growth and promoted apoptosis in CRC. A transcriptome analysis combined with immunoprecipitation revealed that hnRNP G-T stabilized 174 mRNAs, including ZDHHC11 mRNA. The cell growth was also suppressed by the transfection of siRNA of ZDHHC11 and the mRNA and the protein expression were decreased by the transfection of siRNA of hnRNP G-T. These results suggested that hnRNP G-T promotes the cell growth of CRC by regulating the mRNA of ZDHHC11. Therefore, hnRNP G-T will be highlighted as an effective therapeutic target with less adverse effects in CRC therapy.

DOI： 10.1002/cam4.4738

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BACKGROUND: Carbazochrome sodium sulfonate (CSS) is conventionally administered to prevent post-endoscopic submucosal dissection (ESD) bleeding in many institutions, but research on its preventive efficacy is lacking. Therefore, we investigated the risk of post-ESD bleeding and the preventive efficacy of CSS administration. METHODS: We retrospectively reviewed 304 lesions in 259 patients with gastric neoplasms who underwent ESD at Asahikawa Medical University Hospital from 2014 to 2021. In the CSS group, CSS 100 mg/day was intravenously infused with maintenance fluid replacement on postoperative days 0-2. The risk factors of post-ESD bleeding, including CSS administration, were investigated. RESULTS: The overall rate of post-ESD bleeding was 4.6% (14/304). The univariate analysis showed that atrial fibrillation (Af), warfarin intake, heparin replacement, and tumor location in the lower third were significant risk factors for increasing the likelihood of postoperative bleeding. In the multivariate analysis, Af (odds ratio [OR] 3.83, 95% CI 1.02-14.30; p &lt; 0.05), heparin replacement (OR 4.60, 95% CI 1.02-20.70; p &lt; 0.05), and tumor location in the lower third of the stomach (OR 6.67, 95% CI 1.43-31.00; p &lt; 0.05) were independent factors for post-ESD bleeding. Post-ESD bleeding was observed in 5.2% (9/174) of the CSS group and 3.8% (5/130) of the non-CSS group, with no significant difference between the two groups (p = 0.783). Additionally, CSS was not shown to have preventive effects in groups with higher-risk factors, such as Af diagnosis, warfarin use, heparin replacement, and tumor location in the lower third of the stomach. CONCLUSION: CSS administration was not effective for the prevention of the post-ESD bleeding in the overall patient population as well as in higher-risk patients. This suggests that the administration of CSS for post-ESD bleeding prevention may need to be reconsidered.

DOI： 10.1007/s00464-022-09171-4

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Language：English   Publisher：(一社)日本癌治療学会  

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Background and study aims  Recent advances in cancer treatment have involved the clinical application of immune checkpoint inhibitors (ICIs) for various type of cancers. The adverse events associated with ICIs are generally referred to as immune-related adverse events (irAEs). Gastrointestinal irAEs are a major disorder, but gastritis is not frequently observed. The aims of this study were to elucidate the clinical, endoscopic, and histological characteristics of irAE gastritis. Patients and methods  Information on patients treated with ICIs were collected from a single institute over 3 years. IrAE gastritis was identified based on the clinical course and endoscopic and histopathological findings. Of the 359 patients treated with ICIs, four cases of irAE gastritis were identified in clinical records from the endoscopy unit. The endoscopic and histopathological findings were analyzed, and further immunohistochemical studies with immune subtype markers and programmed cell death ligand-1 (PD-L1) antibody were conducted. Results  Among four patients with irAE gastritis, the remarkable endoscopic characteristics were network-pattern erosion, erythematous and edematous mucosa with thick purulent discharge, and fragile mucosa. Corresponding histological features were fibrinopurulent exudate, severe inflammatory cell infiltration, and epithalaxia, respectively. The PD-L1 expression rate was ≥ 1 % in the gastric tissue of all patients with gastritis. These patients were treated with prednisolone (PSL) and their symptoms improved within a few days to 2 weeks. Conclusions  IrAE gastritis were characterized by specific endoscopic findings. The appropriate endoscopic diagnosis may lead to effective treatment with PSL.

DOI： 10.1055/a-1839-4303

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DOI： 10.1055/a-1550-1913

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BACKGROUND: Reconstruction surgery-associated stricture frequently occurs in patients with long-gap esophageal atresia (LGEA). While several endoscopic dilatation methods have been applied and would be desirable, endoscopic recanalization is very difficult in cases with complete esophageal closure. Surgical treatment has been performed for a severe stricture, which causes extensive damage to the infant. No reports have described successful endoscopic recanalization for complete closure due to scarring after surgery for LGEA. We herein report the case of successful endoscopic recanalization by single endoscopist in an LGEA patient with complete closure after reconstruction surgery. CASE PRESENTATION: A seven-month-old boy with LGEA who received reconstruction surgery and gastrostomy immediately after birth presented to our unit due to vomiting and malnutrition. Contrast radiography and peroral endoscopy detected complete closure of the esophagus at the anastomotic site. After confirming the length of stricture as several millimeters, we punctured the center of the lumen with a 25-G puncture needle under fluoroscopy. An endoscope was then inserted via the gastrostomy and the puncture hole was detected at the center of the lumen. After passing the guidewire, endoscopic balloon dilation was performed three times, and the hole was sufficiently dilatated. Oral ingestion was feasible, and his nutritional condition was improved. CONCLUSIONS: To our knowledge, this is the first report to propose a less invasive endoscopic approach to recanalize a site of complete esophageal closure in a LGEA patient after reconstruction surgery by single endoscopist. Our endoscopic procedure using an ultrathin endoscope and puncture needle may be a therapeutic option for the treatment of patients with complete esophageal closure in a LGEA patient after reconstruction surgery.

DOI： 10.1186/s12876-022-02207-y

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BACKGROUND: Chemotherapy for advanced gastric cancer is recommended in the guidelines; however, later-line treatment remains controversial. Since immune checkpoint inhibitors have been used for the treatment of various malignancies, trials have been performed for gastric cancer. A phase 3 trial indicated the survival benefit of nivolumab monotherapy for gastric cancer patients treated with prior chemotherapy regimens. PATIENTS AND METHODS: A regional cohort study was undertaken to determine the real-world data of nivolumab treatment for patients with advanced or recurrent gastric cancer. The patients were enrolled for 2 years from October 2017 to October 2019 and were prospectively followed for 1 year to examine the overall survival (OS). The patient characteristics were analyzed in a multivariate analysis and a nomogram to predict the probability of survival was generated. RESULTS: In total, 70 patients who received nivolumab as ≥third-line chemotherapy were included in the Asahikawa Gastric Cancer Cohort. The median OS was 7.5 (95% CI, 4.8-10.2) months and the response rate was 18.6%. Diffuse type classification, bone metastasis, high neutrophil/lymphocyte ratio, and high CRP were associated with poor OS/prognosis in the multivariate analysis. A nomogram was developed based on these clinical parameters and the concordance index was 0.80 (95% CI, 0.68-0.91). The responders were aged and were frequently diagnosed with intestinal type gastric cancer, including patients with a HER2-positive status (27.3%) or microsatellite instability-high (27.3%) status. CONCLUSIONS: The regional cohort study of nivolumab monotherapy for gastric cancer patients revealed prognostic factors and a nomogram was developed that could predict the probability of survival.

DOI： 10.1002/cam4.4461

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BACKGROUND: The impact of the body composition on the pathophysiology and clinical course of Crohn's disease (CD) has not been fully elucidated. AIMS: To reveal the correlations among body composition and long-term outcomes in CD after anti-TNF therapy. METHODS: Ninety-one patients who received anti-TNF therapy as their first biologic treatment were enrolled. The skeletal muscle index (SMI), visceral and subcutaneous fat area (VFA, SFA), and the ratio of the VFA to SFA (mesenteric fat index; MFI) at the 3rd lumbar level were measured using computed tomography (CT) imaging before the induction. The correlation among the body composition and outcomes were retrospectively analyzed. RESULTS: The 5-year cumulative secondary failure- and resection-free rates in patients with a low SMI (39.1% and 64.8%) were significantly lower than those with a high SMI (67.5% and 92.7%; p = 0.0071 and 0.0022, respectively). The 5-year cumulative secondary failure-free rate in the patients with low VF (45.0%) was significantly lower than that in those with high VF (77.6%; p = 0.016), and the 5-year cumulative resection-free rate in patients with a high MFI (68.9%) was significantly lower than that in those with a low MFI (83.0%; p = 0.031). Additionally, patients with low age and BMI had significantly lower cumulative secondary failure- and resection-free rates than those with high age and BMI (low age: 37.4% and 71.2%; high age: 70.7% and 88.9%; p = 0.0083 and 0.027, respectively) (low BMI: 27.2% and 64.8%; high BMI: 68.3% and 87.9%; p = 0.014 and 0.030, respectively), respectively. In the multivariate analyses, a low SMI was the only independent risk factor for secondary failure (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.04-4.44), while low age (HR 4.06, 95% CI 1.07-15.4), a low SMI (HR 4.19, 95% CI 1.01-17.3) and high MFI were risk factors for bowel resection (HR 4.31, 95% CI 1.36-13.7). CONCLUSION: The skeletal muscle mass and ratio of visceral to subcutaneous fat were suggested to reflect the long-term clinical outcome and may be helpful as prognostic markers after anti-TNF therapy in CD.

DOI： 10.3389/fnut.2022.765209

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BACKGROUND: We previously showed that Lactobacillus brevis-derived polyphosphate (poly P) exerts a curative effect on intestinal inflammation. However, whether or not poly P improves the inflammation and injury of distant organs remains unclear. AIMS: We aimed to investigate the change in the intestinal microbiome and to evaluate the protective effect of poly P on injuries in a cerulein-induced acute pancreatitis (AP) mouse. METHODS: Poly P was orally administered to BALB/C mice every day for 24 days, and then mice were intraperitoneally injected with cerulein. Before cerulein injection, stool samples were collected and analyzed by 16S rRNA gene sequencing. Mice were sacrificed at 24 h after the last cerulein injection; subsequently, the serum, pancreas, and colon were collected. RESULTS: The microbial profile differed markedly between poly P and control group. Notably, the levels of beneficial bacteria, including Alistipes and Candidatus_Saccharimonas, were significantly increased, while those of the virulent bacteria Desulfovibrio were decreased in the poly P group. The elevations of the serum amylase and lipase levels by cerulein treatment were suppressed by the pre-administration of poly P for 24 days, but not for 7 days. The numbers of cells MPO-positive by immunohistology were decreased and the levels of MCP-1 significantly reduced in the AP + Poly P group. An immunofluorescence analysis showed that the ZO-1 and occludin in the colon was strongly augmented in the epithelial cell membrane layer in the AP + Poly P group. CONCLUSIONS: Poly P attenuates AP through both modification of the intestinal microbiome and enhancement of the intestinal barrier integrity.

DOI： 10.1007/s10620-020-06747-9

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BACKGROUND: Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract, although its etiology has largely been unclear. Tumor necrosis factor inhibitors (TNF-I) are effective for the treatment. Recently, biosimilars of TNF-I, such as CT-P13, have been developed and are thought to possess equal efficacy and safety to the original TNF-I. Sarcoidosis is also a systemic granulomatous disease of unknown etiology. In steroid-resistant cases of sarcoidosis, TNF-I have been reported effective for achieving resolution. However, the progression of sarcoidosis due to the TNF-I also has been reported. We herein report a case of pulmonary sarcoidosis with a Crohn's disease (CD) patient developed after a long period administration (15 years) of TNF-I. CASE PRESENTATIONS: A 37-year-old woman with CD who had been diagnosed at 22 years old had been treated with the TNF-I (original infliximab; O-IFX and infliximab biosimilar; IFX-BS). Fifteen years after starting the TNF-I, she developed a fever and right chest pain. Chest computed tomography (CT) revealed clustered small nodules in both lungs and multiple enlarged hilar lymph nodes. Infectious diseases including tuberculosis were negative. Bronchoscopic examination was performed and the biopsy specimens were obtained. A pathological examination demonstrated noncaseating granulomatous lesions and no malignant findings. TNF-I were discontinued because of the possibility of TNF-I-related sarcoidosis. After having discontinued for four months, her symptoms and the lesions had disappeared completely. Fortunately, despite the discontinuation of TNF-I, she has maintained remission. CONCLUSIONS: To our knowledge, this is the first case in which sarcoidosis developed after switching from O-IFX to IFX-BS. To clarify the characteristics of the cases with development of sarcoidosis during administration of TNF-I, we searched PubMed and identified 106 cases. When developing an unexplained fever, asthenia, uveitis and skin lesions in patients with TNF-I treatment, sarcoidosis should be suspected. Once the diagnosis of sarcoidosis due to TNF-I was made, the discontinuation of TNF-I and administration of steroid therapy should be executed promptly. When re-starting TNF-I, another TNF-I should be used for disease control. Clinicians should be aware of the possibility of sarcoidosis in patients under anti-TNF therapy.

DOI： 10.1186/s12876-021-01948-6

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Purpose Despite the established activity of regorafenib in metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC), its toxicity profile has limited clinical use. We aimed to evaluate the pharmacokinetics of regorafenib and its active metabolites M-2/M-5, and to clarify the relationships between total drug-related exposure and clinical outcomes in real-world practice. Methods Blood samples at steady state were obtained during Cycle 1 from patients treated with regorafenib. Plasma concentrations of regorafenib and its metabolites were measured by liquid chromatography-tandem mass spectrometry. The efficacy and safety endpoints were progression-free survival (PFS) and dose-limiting toxicities (DLTs), respectively. The exposure-response relationships were assessed. Results Thirty-four Japanese patients with advanced cancers were enrolled (CRC, n = 26; GIST and HCC, each n = 4). Nine patients started regorafenib treatment at the recommended dose of 160 mg once daily (3 weeks on / 1 week off), while the other patients received a reduced starting dose to minimize toxicities. The median PFS was significantly longer in patients achieving total trough concentrations (Ctrough) of regorafenib and M-2/M-5 ≥2.9 µg/mL than those who did not (112 vs. 57 days; p = 0.044). Furthermore, the cumulative incidence of DLTs during the first 2 cycles was significantly higher in patients with summed Ctrough levels ≥4.3 µg/mL than in others (p = 0.0003). Conclusions Dose titration of regorafenib to achieve drug-related Ctrough levels between 2.9 and 4.3 µg/mL in Cycle 1 may improve efficacy and safety, warranting further investigation in a larger patient population.Clinical trial registry: Not applicable.

DOI： 10.1007/s10637-021-01115-4

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BACKGROUND: Endoscopic submucosal dissection (ESD) is currently a common procedure although it requires a long procedural time. We conducted a prospective study to determine the efficacy and safety of lidocaine injection for shortening the procedural time and relieving bowel peristalsis during ESD. METHODS: A multicenter randomized controlled study was conducted in three hospitals. Ninety-one patients who underwent colorectal ESD were enrolled. Patients were randomly divided into two groups using the envelope method: the lidocaine group and saline group. The primary endpoint was the procedural time, and the secondary endpoints were the procedural time in each part of the colon and the grade of bowel peristalsis and the incidence and amounts of antispasmodic drugs use and adverse events. RESULTS: The patients' demographics were not markedly different between the two groups. The mean procedural time in the lidocaine group was not markedly different from that in the saline group. In contrast, at the proximal site, the procedural time in the lidocaine group (57 min) was significantly shorter in the saline group (80 min). The grade of bowel peristalsis in the lidocaine group (0.67) was significantly lower than in the saline group (1.17). Antispasmodic drug use was significantly rarer in the lidocaine group than in the saline group. The incidence of adverse events was not markedly different between the two groups. CONCLUSIONS: Local lidocaine injection is a feasible option for preventing bowel peristalsis, particularly in the proximal colon, leading to a reduced procedural time for ESD and decreased antispasmodic drug use. University Hospital Medical Information Network Center (UMIN number: 000022843).

DOI： 10.1007/s00464-020-08017-1

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BACKGROUND: Granulocyte and monocyte adsorptive apheresis (GMA) is widely used as a remission induction therapy for active ulcerative colitis (UC) patients. However, there are no available biomarkers for predicting the clinical outcome of GMA. We investigated the utility of Fecal calprotectin (FC) as a biomarker for predicting the clinical outcome during GMA therapy in active UC patients. METHODS: In this multicenter prospective observation study, all patients received 10 sessions of GMA, twice a week, for 5 consecutive weeks. FC was measured at entry, one week, two weeks, and at the end of GMA. Colonoscopy was performed at entry and after GMA. The clinical activity was assessed based on the partial Mayo score when FC was measured. Clinical remission (CR) was defined as a partial Mayo score of ≤ 2 and endoscopic remission (ER) was defined as Mayo endoscopic subscore of either 0 or 1. We analyzed the relationships between the clinical outcome (CR and ER) and the change in FC concentration. RESULT: Twenty-six patients were included in this study. The overall CR and ER rates were 50.0% and 19.2%, respectively. After GMA, the median FC concentration in patients with ER was significantly lower than that in patients without ER (469 mg/kg vs. 3107 mg/kg, p = 0.03). When the cut-off value of FC concentration was set at 1150 mg/kg for assessing ER after GMA, the sensitivity and specificity were 0.8 and 0.81, respectively. The FC concentration had significantly decreased by one week. An ROC analysis demonstrated that the reduction rate of FC (ΔFC) at 1 week was the most accurate predictor of CR at the end of GMA (AUC = 0.852, P = 0.002). When the cut-off value of ΔFC was set at ≤ 40% at 1 week for predicting CR at the end of GMA, the sensitivity and specificity were 76.9% and 84.6%, respectively. CONCLUSION: We evaluated the utility of FC as a biomarker for assessing ER after GMA and predicting CR in the early phase during GMA in patients with active UC. Our findings will benefit patients with active UC by allowing them to avoid unnecessary invasive procedures and will help establish new strategies for GMA.

DOI： 10.1186/s12876-021-01889-0

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Gastric cancer is a heterogenous disease with different phenotypes, genotypes, and clinical outcomes, including sensitivity to treatments and prognoses. Recent medical advances have enabled the classification of this heterogenous disease into several groups and the consequent analysis of their clinicopathological characteristics. Gastric cancer associated with Epstein-Barr virus (EBV) and microsatellite-unstable tumors are considered to be the two major subtypes as they are clearly defined by well-established methodologies, such as in situ hybridization and polymerase chain reaction-based analyses, respectively. However, discrepancies in the histological diagnosis of gastric neoplasms remain problematic, and international harmonization should be performed to improve our understanding of gastric carcinogenesis. We re-evaluated Japanese cases of early gastric cancer according to the current World Health Organization (WHO) criteria and classified them into genomic subtypes based on microsatellite instability (MSI) and EBV positivity to determine the initial genetic events in gastric carcinogenesis. A total of 113 Japanese early gastric cancers (including low- and high-grade dysplasias) treated with endoscopic resection over 5 years were archived in our hospital. A histological re-evaluation according to the WHO criteria revealed 54 adenocarcinomas, which were divided into 6 EBV-positive (11.1%), 7 MSI-high (MSI-H, 13.0%), and 41 microsatellite stable cases (75.9%). MSI-H adenocarcinoma was confirmed by an immunohistochemistry assay of mismatch repair proteins. Programmed death-ligand 1 immunostaining with two antibodies (E1L3N and SP263) was positive in tumor cells of one MSI-H adenocarcinoma case (1/7, 14.3%). The proportion of stained cells was higher with clone SP263 than with E1L3N. Histologically, EBV-positive carcinomas were poorly differentiated (83.8%), and MSI-H cancers were frequent in well to moderately differentiated adenocarcinoma (85.7%), indicating that the EBV-positive subtype presented with high-grade morphology even when an early lesion. Our study indicates that the WHO criteria are useful for subdividing Japanese early gastric cancers, and this subdivision may be useful for comparative analysis of precursor lesions and early carcinoma.

DOI： 10.1002/cjp2.209

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Previous investigations have indicated that RNA-binding proteins (RBPs) are key molecules for the development of organs, differentiation, cell growth and apoptosis in cancer cells as well as normal cells. A bioinformatics analysis based on the mRNA expression and a somatic mutational database revealed the association between aberrant expression/mutations of RBPs and cancer progression. However, this method failed to detect functional alterations in RBPs without changes in the expression, thus leading to false negatives. To identify major tumor-associated RBPs, we constructed an siRNA library based on the database of RBPs and assessed the influence on the growth of colorectal, pancreatic and esophageal cancer cells. A comprehensive analysis of siRNA functional screening findings using 1198 siRNAs targeting 416 RBPs identified 41 RBPs in which 50% inhibition of cell growth was observed in cancer cells. Among these RBPs, 12 showed no change in the mRNA expression and no growth suppression in non-cancerous cells when downregulated by specific siRNAs. We herein report for the first time cancer-promotive RBPs identified by a novel functional assessment using an siRNA library of RBPs combined with expressional and mutational analyses.

DOI： 10.3390/cancers13133165

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Intake of probiotics or fermented food produced by some probiotic bacteria is believed to exert anti-tumor functions in various cancers, including pancreatic cancer, because several studies have demonstrated the anti-tumor effects of probiotic bacteria in vitro and in vivo in animal carcinogenesis models. However, the mechanisms underlying the anticancer effects of probiotics on pancreatic cancer have not been clarified. In this study, we assessed the anti-tumor effects of probiotic bacteria against pancreatic cancer cells. Among the known probiotic bacteria, Aspergillus oryzae exhibited a strong pancreatic tumor suppression effect. The culture supernatant of A. oryzae was separated by HPLC. Heptelidic acid was identified as an anti-tumor molecule derived from A. oryzae by LC-MS and NMR analysis. The anti-tumor effect of heptelidic acid was exhibited in vitro and in vivo in a xenograft model of pancreatic cancer cells. The anti-tumor effect of heptelidic acid was exerted by the p38 MAPK signaling pathway. Heptelidic acid traverses the intestinal mucosa and exerts anti-tumor effects on pancreatic cancer cells. This is a novel anti-tumor mechanism induced by beneficial bacteria against pancreatic cancer in which bacterial molecules pass through the intestinal tract, reach the extra-intestinal organs, and then induce apoptosis via an inducible signaling pathway.

DOI： 10.1038/s41598-021-90707-4

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Gastric adenocarcinoma of the fundic gland mucosa type (GA-FGM) was proposed as a new variant of gastric adenocarcinoma of the fundic gland type (GA-FG). However, at present, the influence of Helicobacter pylori and the speed of progression and degree of malignancy in GA-FGM remain unclear. Herein, we report the first case of intramucosal GA-FGM that was endoscopically observed before and after H. pylori eradication over 15 years. The lesion showed the same tumor size with no submucosal invasion and a low MIB-1 labeling index 15 years after its detection using endoscopy. The endoscopic morphology changed from 0-IIa before H. pylori eradication to 0-IIa+IIc and then 0-I after H. pylori eradication. These findings suggest that the unaltered tumor size reflects low-grade malignancy and slow growth, and that the endoscopic morphology is influenced by H. pylori eradication.

DOI： 10.5230/jgc.2021.21.e11

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BACKGROUND: Colorectal cancers develop through several pathways, including the adenoma-carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. METHODS: SRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo. RESULTS: Ferrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway. CONCLUSIONS: Ferrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.

DOI： 10.1186/s12935-020-01723-9

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Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), is an intractable intestinal inflammation associated with the disruption of the intestinal mucosa. We previously demonstrated that Lactobacillus brevis-derived long-chain polyphosphate (poly P) improved the intestinal barrier function by the upregulation of cell adhesion and relieved intestinal inflammation, thereby exerting a curing effect on colitis in vitro, in vivo, and in an investigator-initiated clinical study of UC. However, how poly P improves mucosal defects induced by intestinal inflammation has not been elucidated. In this study, we detected the accumulation of platelets in inflamed tissues induced by poly P in a dextran sulfate sodium- (DSS-) induced colitis mouse model. A light transmission aggregometry analysis and scanning electron microscopy showed that poly P promoted the platelet aggregation. An SRB assay and ki-67 staining showed that the supernatant of poly P-treated platelet-rich plasma (PRP) increased intestinal epithelial cell growth. A wound healing assay showed that the supernatant of poly P-treated PRP, but not poly P itself, accelerated wound healing. A Western blotting analysis indicated that mitogen-activated protein kinase activation was induced by the supernatant of poly P-treated human PRP in the epithelial cells and its wound healing effect was significantly decreased by the inhibition of ERK signaling. These data suggested that platelet-derived mediators induced by poly P improved intestinal inflammation through the promotion of epithelial cell growth by the activation of the ERK signaling pathway. The mechanism is a novel host-microbe interaction through mammalian platelet-derived mediators induced by bacterial molecules.

DOI： 10.1155/2021/5582943

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An attempt to use combination therapy with anti-tumor necrosis factor α (TNFα) antibodies and tacrolimus (TAC) has been tried to induce remission in ulcerative colitis (UC). However, the optimal dose of TAC in combination therapy with anti-TNFα antibodies (TAC + anti-TNFα therapy) remains unclear. We examined the efficacy of various doses of TAC + anti-TNFα therapy in a mouse colitis model. Dextran sulfate sodium induced colitis model mice were divided into an anti-TNFα antibody monotherapy group and the groups that received various doses of TAC + anti-TNFα therapy. The nuclear factor expression of activated T-cells, cytoplasmic 1 (NFATc1) in the nuclei and the mRNA expression of inflammatory cytokines were assessed by immunohistochemistry and RT-PCR, respectively. The serum anti-TNFα antibody concentration was measured with an enzyme-linked immunosorbent assay. The colon length and histological severity were significantly improved in the groups that received any dose of TAC + anti-TNFα therapy. The nuclear expression of NFATc1 was inversely proportional to the administered doses of TAC. The expression levels of inflammatory cytokines tended to decrease in proportion to the dose of TAC. The serum concentration of anti-TNFα antibodies in the high-dose TAC + anti-TNFα therapy was significantly higher than those in the other groups. Low-dose TAC exerted its immunosuppressive effect on T-cells, and additionally, high-dose TAC maintained the serum anti-TNFα antibody concentration. When administered in combination with anti-TNFα antibodies, the dose of TAC should be adjusted according to the disease severity.

DOI： 10.1248/bpb.b20-00916

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A 60-year-old man had received octreotide for a metastatic neuroendocrine tumor (NET) in the rectum. Computed tomography and ultrasonography revealed a cardiac tumor, diffuse thickness of the ventricular wall and pericardial effusion, which was diagnosed as cardiac metastasis. The metastatic lesions continued to grow despite the alteration of chemotherapy, and the patient complained of repeated syncope and was admitted to our hospital at 11 months after the diagnosis of cardiac metastasis. An electrocardiogram during syncope showed sustained ventricular tachycardia, which was considered to be caused by the cardiac metastasis. We herein report a case of NET with cardiac metastasis which caused lethal arrhythmia along with a review of the pertinent literature.

DOI： 10.2169/internalmedicine.5208-20

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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BACKGROUND: This study clarifies the long-term effectiveness of ustekinumab based on real-life data from Japanese Crohn's disease (CD) patients. METHODS: A total of 137 patients were included, and 124 patients (90.5%) were exposed to anti-tumor necrosis factor-α agents. RESULTS: The clinical remission rate at week 52 was 32.4% in moderate to severely active CD patients. The achievement of clinical remission for 8 weeks after ustekinumab therapy induction was associated with clinical remission at week 52. Ustekinumab persistence rate at week 104 was 81.4%. CONCLUSION: Ustekinumab is effective and persistent in CD patients with the previous treatment history of several biologics.

DOI： 10.1093/crocol/otaa061

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INTRODUCTION: Familial adenomatous polyposis (FAP) is typically characterized by more than hundred adenomatous polyps in the colorectum, caused by germline APC mutation. A small proportion of the polyps progress to colorectal adenocarcinoma via adenoma-carcinoma sequence. Serrated lesions and polyps, characterized by a serrated architecture of the epithelium, are noted for two types of genetic pathways in colorectal carcinogenesis. BRAF and KRAS mutations are observed in the serrated pathway. CASE REPORT: We report a young FAP patient with rectal serrated adenomas that were removed by colonoscopic procedures. The histological features with villiform projections and slit-like serration indicated traditional serrated adenoma. A genetic examination with next-generation sequencing showed a somatic BRAF mutation in the serrated adenoma and APC mutations in the tubular adenomas. His germline mutation was found at APC p.Q1928fs*. CONCLUSION: Serrated adenomas with dual genetic alterations in a FAP patient may be associated with colorectal carcinogenesis and should be considered a target lesion for treatment. The present study demonstrated the malignant potential of serrated adenoma in a FAP patient.

DOI： 10.1007/s00384-020-03657-0

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RATIONALE: Gastric mixed adenoneuroendocrine carcinoma (gMANEC) is a rare malignant tumor. Most gMANECs are diagnosed at an advanced stage and have a worse prognosis than gastric adenocarcinoma. In order to improve the prognosis, it is necessary to diagnose gMANEC at an early stage. However, the endoscopic features of early gMANECs are unclear. We, herein, report a case of early gMANEC that showed characteristic magnifying endoscopic findings. PATIENT CONCERNS: A 78-year-old man was referred to our institution for endoscopic resection of a gastric lesion. He had a medical history of distal gastrectomy due to early gastric cancer with negative surgical margins 9 years previously. DIAGNOSIS: Esophagogastroduodenoscopy showed a reddish depressed lesion on the suture line of the gastric remnant, which was classified as type 0-IIc according to the Paris classification. ME-NBI at the oral side of the lesion revealed the absence of the microsurface pattern (MSP) and scattered microvessels with dilation and caliber variation, while ME-NBI at the anal side showed an irregularly tubular MSP. An endoscopic forceps biopsy showed a well- to moderately differentiated adenocarcinoma. INTERVENTIONS: We performed endoscopic submucosal dissection, and en bloc resection of the tumor was successfully achieved. OUTCOMES: The histological findings showed two distinct components: neuroendocrine carcinoma (NEC) and well-differentiated adenocarcinoma, which comprised ∼60% and 40% of the tumor, respectively. The NEC component corresponded to the site with the absence of an MSP and scattered microvessels on ME-NBI, while the well-differentiated adenocarcinoma component corresponded to the site with an irregularly tubular MSP. The pathological diagnosis was mixed adenoneuroendocrine carcinoma, infiltrating into the deep submucosal layer. LESSONS: We propose that the absence of an MSP plus an irregular MSP is characteristics of gMANEC, which was useful for the diagnosis of gMANEC before treatment.

DOI： 10.1097/MD.0000000000022306

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BACKGROUND: Familial adenomatous polyposis (FAP) is characterized by colorectal polyposis and adenocarcinoma that is frequently accompanied by extracolonic neoplasm. The risk of gastric carcinoma is increasing in Western FAP patients as well as Asian patients. METHODS: We report the case of an FAP patient with fundic gland polyposis who developed gastric adenocarcinoma and metachronous pyloric gland adenomas. These tumors were endoscopically resected, and immunohistochemistry with gastric mucin (i.e., MUC6, MUC5AC) showed that the tumors belonged to the gastric subtype. Somatic mutation profiles were determined by target amplicon sequencing using a next-generation sequencer. RESULTS: Germline APC variant c.5782delC was found by direct sequencing and somatic KRAS mutations in these tumors were identified by next-generation sequencing. Different KRAS mutation alleles (KRAS p.Gly12Ala, p.Gly12Arg, and p.Gly12Asp) indicated these dysplastic lesions developed from a distinct origin in fundic gland polyposis. Sequential mutations of the APC and KRAS were judged-based on a database search-to be characteristic of the adenoma-carcinoma sequence in colorectal carcinogenesis. CONCLUSION: The colonic adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions was indicated in FAP-associated gastric carcinogenesis.

DOI： 10.1002/mgg3.1348

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Pancreatic cancer is associated with a poor prognosis due to challenges in early detection, severe progression of the primary tumor, metastatic lesions, and resistance to antitumor agents. However, previous studies have indicated a relationship between the microbiome and pancreatic cancer outcomes. Our previous study demonstrated that ferrichrome derived from Lactobacillus casei, a probiotic bacteria, exhibited tumor‑suppressive effects in colorectal and gastric cancer, and that the suppressive effects were stronger than conventional antitumor agents, such as 5‑fluorouracil (5‑FU) and cisplatin, suggesting that certain probiotics exert antitumorigenic effects. However, whether or not probiotic‑derived molecules, including ferrichrome, exert a tumor‑suppressive effect in other gastrointestinal tumors, such as pancreatic cancer, remains unclear. In the present study, it was demonstrated that probiotic‑derived ferrichrome inhibited the growth of pancreatic cancer cells, and its tumor‑suppressive effects were further revealed in 5‑FU‑resistant pancreatic cancer cells in vitro and in vivo in a mouse xenograft model. Ferrichrome inhibited the progression of cancer cells via dysregulation of the cell cycle by activating p53. DNA fragmentation and cleavage of poly (ADP‑ribose) polymerase were induced by ferrichrome treatment, suggesting that ferrichrome induced apoptosis in pancreatic cancer cells. A transcriptome analysis revealed that the expression p53‑associated mRNAs was significantly altered by ferrichrome treatment. Thus, the tumor‑suppressive effects of probiotics may mediated by probiotic‑derived molecules, such as ferrichrome, which may have applications as an antitumor drug, even in refractory and 5‑FU‑resistant pancreatic cancer.

DOI： 10.3892/ijo.2020.5096

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The oncogenic properties of heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) have been reported, although the tumor-promoting mechanism remains unclear. We herein report the mechanism underlying colorectal cancer cell progression mediated by hnRNP H1. The growth of colorectal cancer cells was suppressed by hnRNP H1 downregulation. A terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed the anti-apoptotic effect of hnRNP H1 in colorectal cancer cells. An RNA immunoprecipitation assay revealed that hnRNP H1 bound to sphingosine-1-phosphate lyase 1 (SGPL1). Reverse transcription-polymerase chain reaction revealed the high expression of hnRNP H1 mRNA in colorectal cancer cells and Spearman's rank correlation coefficient showed a strong positive correlation between hnRNP H1 mRNA and SGPL1 mRNA. An siRNA of hnRNP H1 decreased SGPL1 mRNA expression in colorectal cancer cells, but not in non-tumorous cells. These findings suggested that hnRNP H1 increased SGPL1 mRNA expression specifically in cancer cells through direct binding. Targeted knockdown of hnRNP H1 or SGPL1 with siRNAs upregulated p53 phosphorylation and p53-associated molecules, resulting in cell growth inhibition, while hnRNP H1 upregulated the mRNA of SGPL1 and inhibited p53 activation, thereby promoting tumor cell growth. This is a novel mechanism underlying colorectal cancer cell progression mediated by hnRNP H1-SGPL1 mRNA stabilization.

DOI： 10.3390/ijms21124514

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BACKGROUND & AIMS: We compared the diagnostic accuracy of the fecal calprotectin (FCP) test vs the fecal immunochemical blood test (FIT) in determining the endoscopic severity and predicting outcomes of patients with ulcerative colitis (UC). METHODS: We performed a nationwide study of 879 patients with UC, enrolled at medical centers across Japan, from March 2015 to March 2017. We collected data on fecal biomarkers, endoscopic severities, and other clinical indices from Cohort 1 (n = 427) and assessed the diagnostic accuracy of FCP measurement and FIT results in determining clinical severity, based on Mayo score, and endoscopic remission, based on Mayo endoscopic sub-score (MES) or UC endoscopic index of severity. We also followed 452 patients in clinical remission from UC (Cohort 2) for 12 months and evaluated the associations of FCP levels and FIT results with clinical recurrence. RESULTS: The levels of FCP and FIT each correlated with the MES and UC endoscopic index of severity. There were no significant differences in the areas under the curve of FCP vs FIT in distinguishing patients with MES≤1 from those with MES≥2 (P = .394) or in distinguishing patients with MES=0 from those with MES≥1 (P = .178). Among 405 patients in clinical remission at baseline, 38 (9.4%) had UC recurrences within 3 months and 90 (22.2%) had recurrences within 12 months. FCP≥146 mg/kg (hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.80-8.33) and FIT≥77 ng/mL (HR, 2.92; 95% CI, 1.76-4.83) were independently associated with clinical recurrence within 12 months. UC recurred within 12 months in 69% of patients with levels of FCP≥146 mg/kg and FIT ≥77 ng/mL; this value was significantly higher than the rate of recurrence in patients with levels of FCP≥146 mg/kg and FIT <77 ng/mL (31.5%, P < .001) or patients with levels of FCP<146 mg/kg and FIT ≥77 ng/mL (30.0%, P < .001). CONCLUSION: In a nationwide study of patients with UC in Japan, we found that the level of FCP and FIT could each identify patients with endoscopic markers of disease severity (MES≥2). The combination of FCP and FIT results can identify patients in remission who are at risk for disease recurrence. Clinical Trials Registry no: UMIN000017650 (http://www.umin.ac.jp/ctr/).

DOI： 10.1016/j.cgh.2019.07.054

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RNA regulation mediating RNA-binding proteins (RBPs) have been shown to be related to the maintenance of homeostasis as well as cancer progression. However, the tumor-associated functions as well as the detailed mechanisms underlying the anti-tumor effects of most RBPs have yet to be explored. We herein report that the phosphorylated heterogeneous ribonucleoprotein (hnRNP) A0 promotes mitosis through the RAS-associated protein 3 GTPase-activating protein catalytic subunit 1 (RAB3GAP1)-Zeste white 10 interactor (ZWINT1) cascade. The downregulation assay of 20 representative hnRNPs, a major family of RNA-binding proteins, in colorectal cancer cells revealed that hnRNPA0 is a strong regulator of cancer cell growth. The tumor promotive function of hnRNPA0 was confirmed in gastrointestinal cancer cells, including pancreatic, esophageal, and gastric cancer cells, but not in non-cancerous cells. Flow cytometry and Western blotting analyses revealed that hnRNPA0 inhibited the apoptosis through the maintenance of G2/M phase promotion in colorectal cancer cells. A comprehensive analysis of mRNAs regulated by hnRNP A0 and immunostaining revealed that mitotic events were regulated by the hnRNPA0-RAB3GAP1 mRNA-mediated ZWINT-1 stabilization in colorectal cancer cells, but not in non-tumorous cells. The interaction of hnRNP A0 with mRNAs was dramatically changed by the deactivation of its phosphorylation site in cancer cells, but not in non-tumorous cells. Therefore, the tumor-specific biological functions characterized by the abnormal phosphorylation of RBPs are considered to be an attractive target for tumor treatment.

DOI： 10.1038/s41419-020-2439-7

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The goal of ulcerative colitis (UC) treatment has recently been shown to be "mucosal healing," as no drug directly induces mucosal healing. Probiotics possess sufficient safety, but their efficacy in the treatment of UC remains controversial because of the influence of intestinal conditions. It is believed that the identification of bioactive molecules produced by probiotics and their application will help to solve this issue. We therefore identified a probiotic-derived long-chain polyphosphate as a molecule enhancing the intestinal barrier function. This study demonstrated that long-chain polyphosphate exhibited antiinflammatory effects in a human macrophage and interleukin-10 knockout transfusion mouse model. The first-in-human trial showed that 7 of the 10 enrolled patients acquired clinical remission, 4 of whom achieved endoscopic remission despite a history of treatment with anti-tumor necrosis factor (TNF)-α agents. No adverse reactions were observed. Long-chain polyphosphate might be useful for the treatment of refractory UC, even in patients with failure or intolerance to anti-TNF-α therapy.

DOI： 10.1002/cpt.1628

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BACKGROUND: Epstein-Barr virus (EBV)-associated carcinoma is a gastric cancer subtype with a morphology characterized by gastric carcinoma with lymphoid stroma (GCLS). Clinicopathological studies have indicated a better prognosis for GCLS than for common gastric carcinomas. Some previous cases of early gastric cancer associated with EBV had been diagnosed by endoscopic resection. CASE SUMMARY: We present two GCLS cases subjected to endoscopic submucosal dissection (ESD) for a definitive diagnosis. A protruded gastric lesion was identified by routine endoscopic examination, but forceps biopsy showed no atypical cells before ESD. The resected specimen showed a poorly differentiated adenocarcinoma with lymphoid cells involving the mucosa and submucosa. The final diagnosis was submucosa-invasive poorly differentiated gastric adenocarcinoma. Accordingly, additional gastrectomy was recommended to obtain a complete cure. One patient underwent additional distal gastrectomy with lymph node dissection, but the other was refused because of cardiovascular complications. Both patients remained in remission for more than half a year. EBV positivity was determined by EBV-encoded RNA in situ hybridization. We also conducted a literature review of cases of early gastric cancer associated with EBV that had been diagnosed by ESD. CONCLUSION: Submucosa-invasive GCLS could be dissected using ESD, and EBV positivity should be subsequently assessed to determine whether or not any additional curative surgery is required. Further prospective investigations on the prevalence of lymph node metastasis in EBV-associated carcinoma should be performed to expand the indications for endoscopic resection.

DOI： 10.4251/wjgo.v11.i10.925

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DOI： 10.1007/s12029-018-0078-3

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BACKGROUND: Steroid therapy is primarily used to prevent esophageal stricture after endoscopic submucosal dissection (ESD). However, esophageal stricture can still occur after preventive therapy, and the effect of preventive steroid therapy cannot be predicted before stricture formation. This study aimed to clarify the risk factors for esophageal stricture after preventive steroid therapy. METHODS: This was a retrospective study conducted at three institutions. From January 2011 to February 2018, 28 large-sized SENs in 26 patients who had a mucosal defect that involved more than three-quarters of the esophageal circumference were enrolled. We classified white coats on artificial ulcers after esophageal ESD into three groups (thin, moderately thick, thick) based on endoscopic images obtained on postoperative day 7. RESULTS: The white coat status on the artificial ulcer after ESD was a significant risk factor for post-ESD stricture (p < 0.05). The stricture rates in patients with thin, moderately thick and thick white coats were 10.0, 36.4 and 85.7%, respectively. When thin and moderately thick white coats were combined, the stricture rate was 23.8%. The rate of stricture in lesions with thick white coats was significantly higher than that in patients with thin white coats or thin to moderately thick white coats (p < 0.05). The multivariate analysis revealed that the white coat status was an independent factor related to esophageal stricture (odds ratio 13.70, 95% confidence interval 1.22-154.0; p = 0.034). CONCLUSIONS: The thickness of the white coat is a useful marker for predicting the risk of post-ESD stricture and the effectiveness of preventive steroid therapy.

DOI： 10.1007/s10388-019-00659-y

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BACKGROUND: Autofluorescence imaging (AFI) is useful for diagnosing colon neoplasms, but what affects the AFI intensity remains unclear. This study investigated the association between AFI and the histological characteristics, aberrant methylation status, and aberrant expression in colon neoplasms. METHODS: Fifty-three patients with colorectal neoplasms who underwent AFI were enrolled. The AFI intensity (F index) was compared with the pathological findings and gene alterations. The F index was calculated using an image analysis software program. The pathological findings were assessed by the tumor crypt density, cell densities, and N/C ratio. The aberrant methylation of p16, E-cadherin, Apc, Runx3, and hMLH1 genes was determined by a methylation-specific polymerase chain reaction. The aberrant expression of p53 and Ki-67 was evaluated by immunohistochemical staining. RESULTS: An increased N/C ratio, the aberrant expression of p53, Ki-67, and the altered methylation of p16 went together with a lower F index. The other pathological findings and the methylation status showed no association with the F index. CONCLUSIONS: AFI reflects the nuclear enlargement of tumor cells, the cell proliferation ability, and the altered status of cell proliferation-related genes, indicating that AFI is a useful and practical method for predicting the dysplastic grade of tumor cells and cell proliferation.

DOI： 10.3390/molecules24061106

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DOI： 10.14309/ajg.0000000000000069

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Background: Immuno-oncology is a novel target of cancer therapy. Nivolumab is a monoclonal anti-programed death-1 antibody recently used to treat patients with chemotherapy-resistant gastric and gastroesophageal cancer. Although the disease control rate is reported to be very high, few cases demonstrate a complete response. Case Presentation: A 25-year-old man diagnosed with gastroesophageal cancer was treated with chemotherapy followed by surgical resection. Pathological diagnosis was poorly differentiated adenocarcinoma with distant lymph node metastasis. Residual lymph node metastasis was treated with nivolumab monotherapy, resulting in complete disappearance. No recurrence has been observed for 2 years since discontinuation of nivolumab. This rare case was additionally subjected to pathological and genetic analysis, suggesting that a high tumor mutation burden (10.7 mutations/Mb) might be associated with sensitivity to nivolumab. Summary: We reported a case of advanced gastroesophageal junction cancer with distal lymph node metastasis that was successfully treated with chemotherapy, surgical resection, and nivolumab therapy. An aggressive search for biomarkers implying benefit effects of nivolumab should be performed.

DOI： 10.3389/fonc.2019.01375

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BACKGROUND: Venous thromboembolism (VTE) has been shown to be more frequent in inflammatory bowel disease (IBD) than in the general population in Western studies. However, the actual state of VTE in Asian IBD remains poorly understood. AIMS: To reveal the incidence of VTE in IBD patients in Japan. METHODS: Eighty-five patients admitted to 3 gastroenterology centers were registered from 2013 to 2018. The incidence of VTE in patients with IBD (n = 42) was prospectively compared to that among patients with other digestive diseases (n = 43). The presence of VTE was surveyed using contrast-enhanced computed tomography and/or ultrasonography at admission and at 1-2 weeks after admission. The patient characteristics and laboratory data of IBD patients with or without VTE were compared to determine the risk factors for VTE. RESULTS: The incidence of VTE with IBD was 16.7%, which was significantly more frequent than with other digestive diseases (2.3%; p = 0.0296). In IBD patients, VTE was detected in 6 of 22 patients with ulcerative colitis (27.2%) but in only 1 of 20 patients with Crohn's disease (5.0%). VTE was diagnosed at admission in 4 IBD patients and 2 weeks after admission in 3 IBD patients. The risk factors of VTE in IBD were the presence of an indwelling central venous catheter, a low level of total protein, a low activated partial thromboplastin time, and a high level of fibrinogen degradation products. CONCLUSION: VTE was frequently detected in Japanese IBD patients both at and after admission. Adequate screening and prophylaxis for VTE is deemed necessary in IBD.

DOI： 10.1159/000495289

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Background and study aims  Symptomatic capsule retention is a very rare adverse event following patency capsule, and the vast majority of cases are resolved without either surgical or endoscopic intervention. We herein describe a rare case of small bowel perforation after swallowing a patency capsule in a 37-year-old man suspected of having Crohn's disease.

DOI： 10.1055/a-0752-9903

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BACKGROUND/AIMS: Venous thromboembolism (VTE) is a major extraintestinal manifestation in inflammatory bowel disease (IBD), regarded as an independent risk factor for VTE according to reports from Western countries. However, the incidence and risk factors of VTE in Asian IBD patients are not fully understood. We aimed to reveal the incidence and risk factors of VTE in Japanese IBD inpatients. METHODS: The incidence of VTE in inpatients with IBD (n=340), gastrointestinal cancers (n=557), and other gastrointestinal diseases (n=569) treated at our hospital from 2009 to 2013 was retrospectively investigated. The characteristics and laboratory data of IBD inpatients with and without VTE were compared in univariate and multivariate analyses. Clinical courses of VTE in IBD were surveyed. RESULTS: VTE was detected in 7.1% of IBD inpatients, significantly higher than in gastrointestinal cancer inpatients (2.5%) and inpatients with other gastrointestinal diseases (0.88%). The incidence of VTE in ulcerative colitis (UC) patients (16.7%) was much higher than that in those with Crohn's disease (3.6%). In the univariate analysis, the risk factors were an older age, central venous catheter, prednisolone, surgery, low serum albumin, high serum C-reactive protein and D-dimer. According to a multivariate analysis, >50 years of age and surgery were the only risk factors. The in-hospital mortality rate of IBD inpatients with VTE was 4.2%. CONCLUSIONS: The incidence of VTE with IBD, especially UC, was found to be high compared with other digestive disease, which was almost equivalent to that of Western countries. The efficacy of prophylaxis needs to be investigated in Asian IBD patients.

DOI： 10.5217/ir.2018.16.3.416

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BACKGROUND: Pancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers. METHODS: The ExmiRs from patients with pancreatic cancer (n = 32) or IPMN (n = 29), and patients without neoplasms (controls; n = 22) were enriched using ExoQuick-TC™. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction. RESULTS: The expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls (p < 0.05). A receiver operating characteristic curve analysis showed that the area under the curve and the diagnostic accuracy of ExmiRs were 5-20% superior to those of three serum bulky circulating miRs (e.g.; ExmiR-21: AUC 0.826, accuracy 80.8%. Circulating miR-21: AUC 0.653, accuracy 62.3%). In addition, high ExmiR-451a was associated with mural nodules in IPMN (p = 0.010), and high ExmiR-21 was identified as a candidate prognostic factor for the overall survival (p = 0.011, HR 4.071, median OS of high-ExmiR-21: 344 days, median OS of low-ExmiR-21: 846 days) and chemo-resistant markers (p = 0.022). CONCLUSIONS: The level of three ExmiRs can thus serve as early diagnostic and progression markers of pancreatic cancer and IPMN, and considered more useful markers than the circulating miRs (limited to these three miRs).

DOI： 10.1186/s12885-018-4006-5

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BACKGROUND: Takayasu's arteritis (TA) is a large-vessel vasculitis pathologically characterized by granulomatous necrotizing vasculitis with giant cells. Although the cause of TA is still unclear, genetic factors as well as immunological abnormalities, particularly the overactivation of Th1 and Th-17, are considered to play important roles in the pathogenesis of this disease. Eosinophilic gastroenteritis (EGE) is a type of refractory inflammation in which numerous eosinophils infiltrate the inflammatory area. It is known that the overactivation of Th2 is associated with the pathogenesis of EGE, although the cause of EGE is still unclear. The immunological abnormalities in TA are therefore thought to be different from those in EGE. To date, no cases of complication of TA and EGE have been reported. CASE PRESENTATIONS: An 18 year-old female was diagnosed with EGE and treated with prednisolone. At 6 months after completion of the treatment, the patient experienced chest pain, and was diagnosed with TA. TH1 and TH17 immunity are thought to be involved with TA, while TH2 are considered to be involved with EGE. In this case, the expression of IL-17 mRNA in the colon mucosa greatly decreased after prednisolone treatment for EGE. CONCLUSIONS: This is the first report of TA complicated with EGE, and the overactivation of TH17 is considered to be associated with the pathogenesis of these two diseases.

DOI： 10.1186/s13099-018-0251-z

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BACKGROUND: Eradication therapies for Helicobacter pylori infection are advancing as new acid inhibitory reagents approved. The aim of this study was to assess the efficacy and safety of vonoprazan-based triple treatment. MATERIALS AND METHODS: Triple therapy with vonoprazan and two antibiotics (amoxicillin and clarithromycin or metronidazole) received focus in this analysis. We performed a multicenter retrospective study of patients who received vonoprazan-based eradication therapy between February 2015 and February 2016 and conducted a review of the literature. RESULTS: The eradication rate among the 799 patients in our multicenter study was 94.4% (95% confidence interval [CI] 92.6-96.2%) in the per-protocol analysis for first-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg, twice a day for 7 days) and 97.1% (95% CI 93.0-101.1%) for second-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and metronidazole 250 mg, twice a day for 7 days). The overall incidence of adverse events was 4.4% in an intention-to-treat analysis with no patients hospitalized. In a literature review, six reports, in which 1380 patients received vonoprazan-based first-line eradication therapy, were included and were all reported by Japanese researchers. The eradication success rates in per-protocol analysis were between 85 and 93%, which was roughly the same among the studies. CONCLUSIONS: Vonoprazan-based triple therapy was effective and safe for Helicobacter pylori eradication in real-world experience, confirmed by a multicenter study and a review of the pertinent literature.

DOI： 10.1007/s10620-017-4664-1

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OBJECTIVE: Helicobacter pylori (H. pylori) eradication rarely develops into antibiotic-associated hemorrhagic colitis (AAHC), in which the etiology of colitis remains unclear. We herein report a rare case of AAHC caused by second-line therapy for H. pylori eradication. RESULTS: A 65-year-old female was administered second-line therapy for H. pylori composed of 1500 mg of amoxicillin, 500 mg of metronidazole and 40 mg of vonoprazan for 7 days because of first-line therapy failure. A day after completing second-line therapy, she complained of abdominal pain and hematochezia. Colonoscopy revealed a hemorrhage and edematous mucosa with no transparent vascular pattern in the transverse colon. A bacterial culture detected Klebsiella oxytoca (K. oxytoca), but no other pathogenic bacteria. A drug-induced lymphocyte stimulation test (DLST) showed positive reactions for both amoxicillin and metronidazole. According to these findings, the patient was diagnosed with AAHC. Bowel rest for 6 days relieved her abdominal pain and hematochezia. CONCLUSIONS: The present case developed AAHC caused by second-line therapy for H. pylori eradication. The pathogenesis is considered to be associated with microbial substitution as well as a delayed-type allergy to antibiotics, suggesting that AAHC is a potential adverse event of second-line therapy for H. pylori eradication.

DOI： 10.1186/s12941-017-0230-0

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Ferrichrome is known to be a siderophore, but it was recently identified as a tumor-suppressive molecule derived from Lactobacillus casei ATCC334 ( L. casei). In the present study, we investigated the effects of ferrichrome in gastric cancer cells. Cell lines and xenograft models treated with ferrichrome demonstrated growth suppression. The expression levels of cleaved poly (adenosine diphosphate-ribose) polymerase, and cleaved caspase-9 were increased by ferrichrome treatment. Although the tumor-suppressive effects of ferrichrome were almost completely diminished by the iron chelation, the reduction in the intracellular iron by ferrichrome did not correlate with its tumor-suppressive effects. An exhaustive docking simulation indicated that iron-free ferrichrome can make stable conformations with various mammalian molecules, including transporters and receptors. In conclusion, probiotic-derived ferrichrome induced apoptosis in gastric cancer cells. The iron binding site of ferrichrome is the structure responsible for its tumor suppressive function.

DOI： 10.1177/1010428317711311

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PURPOSE: Endoscopic retrograde ileography (ERIG) is developed in our institute and applied clinically for the diagnosis and assessment of the Crohn's disease activity. We have further improved the technique using 3-dimensional - computed tomography enteroclysis (3D-CTE) and conducted a retrospective study to determine the feasibility and the diagnostic value of endoscopic retrograde 3D-CTE (ER 3D-CTE) in Crohn's disease patients in a state of remission. METHODS: Thirteen Crohn's patients were included in this pilot study. CTE was performed after the infusion of air or CO2 through the balloon tube following conventional colonoscopy. The primary endpoint of this study was to assess the safety of this method. Secondarily, the specific findings of Crohn's disease and length of the visualized small intestine were assessed. RESULTS: The procedures were completed without any adverse events. Gas passed through the small intestine and enterographic images were obtained in 10 out of 13 cases, but, in the remaining patients, insertion of the balloon tubes into the terminal ileum failed. Various features specific to Crohn's disease were visualized using ER 3D-CTE. A cobble stone appearance or hammock-like malformation was specific and effective for diagnosing Crohn's disease and the features of anastomosis after the surgical operations were also well described. Therefore, this technique may be useful after surgery. CONCLUSION: In this study, ER 3D-CTE was performed safely in Crohn's disease patients and may be used for the diagnosis and follow-up of this disease.

DOI： 10.1016/j.ejro.2017.04.003

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Bifidobacterium breve and other Gram-positive gut commensal microbes protect the gastrointestinal epithelium against inflammation-induced stress. However, the mechanisms whereby these bacteria accomplish this protection are poorly understood. In this study, we examined soluble factors derived from Bifidobacterium breve and their impact on the two major protein degradation systems within intestinal epithelial cells, proteasomes and autophagy. Conditioned media from gastrointestinal Gram-positive, but not Gram-negative, bacteria activated autophagy and increased expression of the autophagy proteins Atg5 and Atg7 along with the stress response protein heat shock protein 27. Specific examination of media conditioned by the Gram-positive bacterium Bifidobacterium breve (Bb-CM) showed that this microbe produces small molecules (<3 kDa) that increase expression of the autophagy proteins Atg5 and Atg7, activate autophagy, and inhibit proteasomal enzyme activity. Upregulation of autophagy by Bb-CM was mediated through MAP kinase signaling. In vitro studies using C2BBe1 cells silenced for Atg7 and in vivo studies using mice conditionally deficient in intestinal epithelial cell Atg7 showed that Bb-CM-induced cytoprotection is dependent on autophagy. Therefore, this work demonstrates that Gram-positive bacteria modify protein degradation programs within intestinal epithelial cells to promote their survival during stress. It also reveals the therapeutic potential of soluble molecules produced by these microbes for prevention and treatment of gastrointestinal disease.

DOI： 10.1152/ajpgi.00092.2016

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Previous reports have suggested that some probiotics inhibit tumorigenesis and cancer progression. However, the molecules involved have not yet been identified. Here, we show that the culture supernatant of Lactobacillus casei ATCC334 has a strong tumour-suppressive effect on colon cancer cells. Using mass spectrometry, we identify ferrichrome as a tumour-suppressive molecule produced by L. casei ATCC334. The tumour-suppressive effect of ferrichrome is greater than that of cisplatin and 5-fluorouracil, and ferrichrome has less of an effect on non-cancerous intestinal cells than either of those agents. A transcriptome analysis reveals that ferrichrome treatment induces apoptosis, which is mediated by the activation of c-jun N-terminal kinase (JNK). Western blotting indicates that the induction of apoptosis by ferrichrome is reduced by the inhibition of the JNK signalling pathway. This we demonstrate that probiotic-derived ferrichrome exerts a tumour-suppressive effect via the JNK signalling pathway.

DOI： 10.1038/ncomms12365

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全消化管に病変が出現するクローン病では、上部消化管病変が高頻度に見られる。竹の節状外観は、胃噴門部から胃体部の小彎にかけて襞を横切る亀裂状の陥凹とされている。クローン病診断における竹の節状外観の有用性を検討するために、上部消化管内視鏡画像を用いて3名の観察者に臨床情報をブラインドにして研究を行った。観察者それぞれのクローン病診断における竹の節状外観の感度は30.5%、56.9%、51.4%で、特異度は99.6%、98.5%、99.3%であった。したがって竹の節状外観はクローン病患者の拾い上げには十分に貢献しないが、本所見を認めたときはクローン病の可能性を考えて検査を進める必要がある。(著者抄録)

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Upper gastrointestinal (GI) lesions are frequently reported in Crohn's disease, in which the entire GI tract is affected. In these cases, erosive fissures regularly transversing folds that are longitudinally aligned along the lesser curvature of the gastric body and cardia are described as having a "bamboo joint-like appearance". We designed a blinded experiment in which upper GI imaging without a final diagnosis was checked by three observers to determine the usefulness of the bamboo joint-like appearance in the diagnosis of Crohn's disease. For the three observers, sensitivities of appearance were 30.5%, 56.9%, and 51.4%, while specificities were 99.6%, 98.5%, and 99.3%. Thus, the bamboo joint-like appearance was not useful for the identification of Crohn's disease patients. Nevertheless, patients exhibiting the bamboo joint-like appearance in upper GI imaging should undergo further examination due to the high probability of Crohn's disease.

DOI： 10.11405/nisshoshi.113.1208

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AIM: To compare previously reported randomized controlled studies (RCTs) of cold and hot polypectomy, we systematically reviewed and clarify the utility of cold polypectomy over hot with respect to efficacy and adverse events. METHODS: A meta-analysis was conducted to evaluate the predominance of cold and hot polypectomy for removing colon polyps. Published articles and abstracts from worldwide conferences were searched using the keywords "cold polypectomy". RCTs that compared either or both the effects or adverse events of cold polypectomy with those of hot polypectomy were collected. The patients' demographics, endoscopic procedures, No. of examined lesions, lesion size, macroscopic and histologic findings, rates of incomplete resection, bleeding amount, perforation, and length of procedure were extracted from each study. A forest plot analysis was used to verify the relative strength of the effects and adverse events of each procedure. A funnel plot was generated to assess the possibility of publication bias. RESULTS: Ultimately, six RCTs were selected. No significant differences were noted in the average lesion size (less than 10 mm) between the cold and hot polypectomy groups in each study. Further, the rates of complete resection and adverse events, including delayed bleeding, did not differ markedly between cold and hot polypectomy. The average procedural time in the cold polypectomy group was significantly shorter than in the hot polypectomy group. CONCLUSION: Cold polypectomy is a time-saving procedure for removing small polyps with markedly similar curability and safety to hot polypectomy.

DOI： 10.3748/wjg.v22.i23.5436

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Although probiotics are known to have antitumor activity, few bacteria-derived antitumor molecules have been identified. The present study explored an antitumor molecule derived from Lactobacillus brevis SBL8803 (L. brevis 8803) and the mechanisms that underlie its effects. Cell viability and apoptosis were assessed by a sulforhodamine B assay and terminal deoxynucleotidyl transferase dUTP staining, respectively. Phosphorylated extracellular signal-regulated kinase (ERK) and cleaved poly ADP-ribose polymerase (PARP) expression were detected by western blotting. The conditioned medium of L. brevis 8803 inhibited SW620 cells viability and the effect was reduced by the degradation of polyphosphate (poly P) in the conditioned medium. A xenograft model showed that poly P inhibited the growth of SW620 cells. Poly P induced the apoptosis of SW620 cells through activation of the ERK pathway. In contrast, in primary cultured cells derived from normal mouse, poly P did not affect cell viability. Probiotic-derived poly P is expected to be an antitumor drug with fewer adverse effects than conventional drugs.

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Many pharmaceutical agents not only require microbial metabolism for increased bioavailability and bioactivity, but also have direct effects on gut microbial assemblage and function. We examined the possibility that these actions are not mutually exclusive and may be mutually reinforcing in ways that enhance long-term of these agents. Daikenchuto, TU-100, is a traditional Japanese medicine containing ginseng. Conversion of the ginsenoside Rb1 (Rb1) to bioactive compound K (CK) requires bacterial metabolism. Diet-incorporated TU-100 was administered to mice over a period of several weeks. T-RFLP and 454 pyrosequencing were performed to analyze the time-dependent effects on fecal microbial membership. Fecal microbial capacity to metabolize Rb1 to CK was measured by adding TU-100 or ginseng to stool samples to assess the generation of bioactive metabolites. Levels of metabolized TU-100 components in plasma and in stool samples were measured by LC-MS/MS. Cecal and stool short-chain fatty acids were measured by GC-MS. Dietary administration of TU-100 for 28 days altered the gut microbiota, increasing several bacteria genera including members of Clostridia and Lactococcus lactis. Progressive capacity of microbiota to convert Rb1 to CK was observed over the 28 days administration of dietary TU-100. Concomitantly with these changes, increases in all SCFA were observed in cecal contents and in acetate and butyrate content of the stool. Chronic consumption of dietary TU-100 promotes changes in gut microbiota enhancing metabolic capacity of TU-100 and increased bioavailability. We believe these findings have broad implications in optimizing the efficacy of natural compounds that depend on microbial bioconversion in general.

DOI： 10.1002/prp2.215

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METHODS: Pneumocystis carinii pneumonia occasionally appears in immunodeficient patients. While several reports have shown that Pneumocystis carinii pneumonia occurred in the early phase of starting infliximab treatment in patients with Crohn's disease (CD), the present case suggests for the first time that an increased dosage of infliximab may also lead to pneumonia. RESULTS: A 51-year-old male had been taking 5 mg of infliximab for the treatment of CD for 10 years with no adverse events. Beginning in September 2013, the dose of infliximab had to be increased to 10 mg/kg because his status worsened. Thereafter, he complained of a fever and cough, and a CT scan revealed ground-glass opacities in the lower lobes of the bilateral lung with a crazy-paving pattern. Bronchoscopy detected swelling of the tracheal mucosa with obvious dilations of the vessels. A polymerase chain reaction using a bronchoalveolar lavage fluid sample detected specific sequences for Pneumocystis jirovecii; thus he was diagnosed with Pneumocystis carinii (jirovecii) pneumonia. After discontinuing infliximab and starting antibiotic treatment, his symptoms and CT findings were dramatically improved. CONCLUSIONS: The administration of an increased dosage of infliximab can cause Pneumocystis carinii pneumonia in CD patients.

DOI： 10.1186/s13099-016-0086-4

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BACKGROUND AND AIMS: No endoscopic examination has been able to evaluate severity of ulcerative colitis (UC) by quantification. This prospective study investigated the efficacy of quantifying autofluorescence imaging (AFI) to assess the severity of UC, which captures the fluorescence emitted from intestinal tissue and then quantifies the intensity using an image-analytical software program. MATERIALS AND METHODS: Eleven endoscopists separately evaluated 135 images of conventional endoscopy (CE) and AFI from a same lesion. A CE image corresponding to Mayo endoscopic subscore 0 or 1 was defined as being inactive. The fluorescence intensities of AFI were quantified using an image-analytical software program (F index; FI). Active inflammation was defined when Matts' histological grade was 2 or more. A cut-off value of the FI for active inflammation was determined using a receiver operating characteristic (ROC) analysis. The inter-observer consistency was calculated by unweighted kappa statistics. RESULTS: The correlation coefficient for the FI was inversely related to the histological severity (r = -0.558, p < 0.0001). The ROC analysis showed that the optimal cut-off value for the FI for active inflammation was 0.906. The average diagnostic accuracy of the FI was significantly higher than those of the CE (84.7 vs 78.5 %, p < 0.01). The kappa values for the inter-observer consistency of CE and the FI were 0.60 and 0.95 in all participants, 0.53 and 0.97 in the less-experienced endoscopists group and 0.67 and 0.93 in the expert group, respectively. CONCLUSIONS: The quantified AFI is considered to be an accurate and objective indicator that can be used to assess the activity of ulcerative colitis, particularly for less-experienced endoscopists.

DOI： 10.1007/s00384-015-2332-5

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While the progress of chemotherapy and molecular targeted therapy has improved the outcome of colorectal cancer patients, the mortality of colon cancer remains high, indicating the need to develop novel therapeutic targets for improving the outcome of colon cancer. Heterogeneous ribonucleoprotein A1 (hnRNP A1) is highly expressed in colorectal cancer and its expression correlates with malignant transformation. In this study, we performed a microarray analysis with the RNA immunoprecipitation (RNA-IP) method and identified hnRNP A1-interacting miRs, including miR-26a and -584, in a colorectal cancer cell line, SW620. A SRB assay revealed the tumor suppressive effect of miR-26a and -584, and the tumor suppressive effect of these miRs was diminished by the downregulation of hnRNP A1. The combined method of a transcriptome analysis and RNA-IP revealed hnRNP A1-interacting mRNAs, including cyclin dependent kinase 6 (CDK6). A Western blot analysis revealed the downregulation of CDK6 in miR-26a and -584 overexpression cells, as well as hnRNP A1 knockdown cells. The binding assay indicated that the binding of hnRNP A1-CDK6 mRNA was reduced by transfection of miR-26a and -584. The expression of cleaved caspase-3 was induced in miR-26a and -584 overexpression cells. These data indicate that miR-26a and -584 inhibit the binding of hnRNP A1-CDK6 mRNA and induce colorectal cancer cell apoptosis.

DOI： 10.1016/j.bbrc.2015.10.055

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Probiotics exhibit beneficial functions for host homeostasis maintenance. We herein investigated the mechanism by which Lactobacillus brevis-derived poly P exhibited a beneficial function. Immunostaining indicated that poly P was captured in the plasma membrane via integrin β1 in Caco2/bbe cells. The uptake of poly P was reduced by the inhibition of integrin β1 as well as caveolin-1, a major component of lipid rafts. The function of poly P, including the induction of HSP27 and enhancement of the intestinal barrier function, was suppressed by the inhibition of caveolin-1, illustrating that the function of poly P was mediated by the endocytic pathway. High-throughput sequencing revealed that poly P induced tumor necrosis factor alpha-induced protein 3, which contributes to cytoprotection, including upregulation of the intestinal barrier function. The present study demonstrates a novel host-probiotic interaction through the uptake of bacterial substance into host cells, which is distinct from pattern recognition receptor pathways.

DOI： 10.1016/j.bbrc.2015.09.159

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The clinical importance of Crohn's disease (CD)-specific lesions in the upper gastrointestinal tract (upper GIT) has not been sufficiently established. The aim of this case-control study is to investigate the characteristic findings of CD in the upper GIT. In 2740 patients who underwent gastroduodenoscopy at Asahikawa Medical University between April 2011 and December 2012, 81 CD patients, 81 gender- and age-matched non-IBD patients, and 66 ulcerative colitis (UC) patients were investigated in the present study. (1) The diagnostic ability and odds ratio of each endoscopic finding (a bamboo joint-like appearance in the cardia, erosions, and/or ulcers in the antrum, notched signs, and erosions and/or ulcers in the duodenum) were compared between the CD and non-IBD patients or UC patients. (2) The interobserver agreement of the diagnosis based on the endoscopic findings was evaluated by 3 experienced and 3 less-experienced endoscopists. The incidence of detecting a bamboo joint-like appearance, notched signs, and erosions and/or ulcers in the duodenum was significantly higher in the CD patients than in the non-IBD and UC patients. In addition, the diagnostic ability and odds ratio of a bamboo joint-like appearance for CD were higher than those for the other findings. Kendall's coefficients of concordance in the group of experienced and less-experienced endoscopists were relatively high for a bamboo joint-like appearance (0.748 and 0.692, respectively). A cardiac bamboo joint-like appearance is a useful finding for identifying high-risk groups of CD patients using only gastroduodenoscopy.

DOI： 10.1097/MD.0000000000001500

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Inflammatory bowel disease frequently causes intestinal obstruction because of extensive fibrosis. This study investigated whether polyphosphate (poly P), an active molecule derived from Lactobacillus brevis, could improve the fibrosis in a model of chronic colitis. In this study, dextran sodium sulfate (DSS)-induced chronic colitis models and trinitrobenzene sulfonic acid (TNBS)-induced colitis models were used as models of fibrosis. To clarify the mechanism responsible for the observed effects, Caco-2/brush border epithelial (BBE) and naive T helper lymphocyte (THP)-1 cells were treated with lipopolysaccharide (LPS) to induce inflammation. Non-cancer human colon fibroblast (CCD-18) cells were treated with transforming growth factor beta 1 (TGF-β1) to induce fibrosis. The expression levels of fibrosis- and inflammation-associated molecules were evaluated by both a Western blotting analysis and reverse transcriptase-polymerase chain reaction (RT-PCR). The histologic inflammation and fibrosis were significantly improved in the group administered poly P in both the DSS and TNBS colitis models. The levels of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were significantly decreased by poly P treatment. The expression levels of TGF-β1 and collagens in the colitis mice were decreased by poly P. The LPS-induced expressions of IL-1β and TGF-β1 in Caco-2/BBE cells and of TNF-α in THP-1 cells were reduced by poly P treatment. Poly P did not affect the expression of collagens and connective tissue growth factor in the CCD-18 cells. In conclusion, poly P suppresses intestinal inflammation and fibrosis by downregulating the expression of inflammation- and fibrosis-associated molecules in the intestinal epithelium. The administration of poly P is therefore a novel option to treat fibrosis because of chronic intestinal inflammation.

DOI： 10.1016/j.trsl.2015.02.002

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BACKGROUND: The role of hnRNP A1 in the onset of intestinal inflammation remains unclear. This study investigated the function of hnRNP A1 in mice enteritis models. METHODS: C57Bl6/J mice were intraperitoneally injected with anti-CD3 antibodies to develop enteritis. In the DSS-induced colitis group, the mice were allowed free access to 3% DSS solution in their drinking water for 5 days. 3H-mannitol flux and complementary DNA array tests were used to assess the intestinal barrier function and messenger RNA (mRNA) expression, respectively. Real-time PCR was performed after immunoprecipitation with anti-hnRNP antibodies to determine the specific mRNA binding of hnRNP A1. RESULTS: The hnRNP A1 expression was increased in the intestine of the mouse at 24 hours after treatment with anti-CD3 antibodies and 5 days after starting DSS administration. Small interfering RNA (siRNA) against hnRNP A1 exacerbated the intestinal injuries in both models. According to the microarray analysis, trefoil factor 2 (TFF2) was identified as a candidate molecule targeted by hnRNP A1 in the anti-CD3 antibody-induced enteritis group. Moreover, the binding between hnRNP A1 and TFF2 mRNA significantly increased in the enteritis mice, and the administration of siRNA against either hnRNP A1 or TFF2 exacerbated the degree of intestinal injury. In the DSS-induced colitis group, treatment with the siRNA of hnRNP A1 worsened the intestinal injury, while the expression of TFF3 did not change. CONCLUSIONS: hnRNP A1 improves intestinal injury in anti-CD3 antibody-induced enteritis mice through the upregulation of TFF2, which regulates apoptosis and enhances epithelial restoration, whereas this molecule ameliorates DSS-induced colitis through a different pathway.

DOI： 10.1097/MIB.0000000000000401

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Multiple myeloma is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal protein. However, the involvement of pancreas is a rare event. We herein report a rare case of pancreatic plasmacytoma, which was detected before the diagnosis of multiple myeloma.An 83-year-old male was referred to our hospital for further evaluation of obstructive jaundice and a pancreatic mass. A contrast-enhanced computed tomography (CT) scan revealed solid masses with homogenous enhancement in the pancreatic head and retroperitoneum. The histological findings of the retroperitoneal mass obtained by CT-guided biopsy showed multiple sheets of atypical plasma cells, which were positively immunostained for CD79a, CD138, and the κ light chain. Serum immunoelectrophoresis detected M-component of immunoglobulin A-κ, and the histological findings of the bone marrow revealed an abnormally increased number of atypical plasma cells with irregular nuclei and cytoplasmic vacuolation. The patient was therefore diagnosed to have multiple myeloma involving the pancreas and retroperitoneum. Although chemotherapy was performed, the patient died 6 months after the diagnosis.The pancreatic plasmacytoma was detected before the multiple myeloma in the present case. It is difficult to diagnose a pancreatic plasmacytoma without a history of multiple myeloma and related disease.

DOI： 10.1097/MD.0000000000000914

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BACKGROUND: EMR and endoscopic submucosal dissection (ESD) are used frequently to remove colon neoplasms. However, the predominance of these procedures has not yet been thoroughly explored. OBJECTIVE: To compare the efficacy and adverse events related to EMR with those related to ESD for colon neoplasms. DESIGN: A meta-analysis of 8 studies published between 2005 and 2013. SETTING: Multicenter review. PATIENTS: Patients from 8 studies yielding 2299 lesions. INTERVENTIONS: EMR or ESD. MAIN OUTCOME MEASUREMENTS: En bloc resection, curative resection, recurrence, and adverse events. RESULTS: The pooled odds ratios (OR) (OR [95% confidence interval]) for the tumor size, length of the procedure, en bloc resection, curative resection, recurrence, additional surgery, delayed bleeding, and perforation by ESD versus EMR were 7.38 (6.42-8.34), 58.07 (36.27-79.88), 6.84 (3.30-14.18), 4.26 (3.77-6.57), 0.08 (0.04-0.17), 2.16 (1.16-4.03), 0.85 (0.45-1.60), and 4.96 (2.79-8.85), respectively. LIMITATIONS: This analysis included only nonrandomized studies. CONCLUSION: The size of the tumor and rate of en bloc resection and curative resection were higher, and the rate of recurrence was lower in the ESD group versus the EMR group. However, in the ESD group, the procedure was longer, and the rate of additional surgery and perforation was higher, suggesting that the indications for ESD should therefore be rigorously determined in order to avoid such problems.

DOI： 10.1016/j.gie.2014.07.034

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BACKGROUNDS: The efficacy of clipping for preventing the delayed bleeding after the removal of colon polyps is still controversial. In order to clarify this efficacy, a randomized controlled study was performed. METHODS: One hundred and fifty-six patients with colon neoplasms (288 lesions) were enrolled in the study. The patients were randomly divided into two groups: clipping or nonclipping groups using a sealed envelope method before the endoscopic resections. Eight specialists and nine residents were invited to perform this procedure. The risk factors and the rates of delayed bleeding after the endoscopic resections in each group were investigated. RESULTS: There were no significant differences in the bleeding rate between the clipping and nonclipping groups, while the length of the procedure was significantly longer and the cost was higher in the clipping group than in the nonclipping group. The rate of bleeding was significantly higher in cases with polyps 2 cm or larger and with a longer procedure time, while none of the other factors affected the bleeding rate. CONCLUSIONS: This randomized controlled study revealed no significant effect of prophylactic clipping for preventing delayed bleeding after the endoscopic resection of colon polyps.

DOI： 10.1155/2015/490272

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DOI： 10.1016/j.gie.2014.12.014

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BACKGROUND: No method for sufficiently making the differential diagnosis of intestinal lymphoma resembling lymphoid hyperplasia (LH) on endoscopy has yet been established. OBJECTIVE: The aim of this study was to evaluate the usefulness of narrow-band imaging (NBI) in diagnosing intestinal lymphoma. DESIGN: Prospective study. SETTING: Single-center study. PATIENTS: Sixty-one patients with primary or systemic lymphoma were enrolled in this study. INTERVENTIONS: The terminal ileum and entire colon were observed by using conventional endoscopy. NBI was subsequently performed when small polypoid lesions were detected. A decrease in the number of vascular networks (DVNs) and the presence of irregular vessels on the surface of the epithelia were defined as characteristic findings of intestinal lymphoma. The diagnostic accuracy of these 2 findings in distinguishing intestinal lymphoma from LH was examined. MAIN OUTCOME MEASUREMENTS: The ability to use NBI to distinguish intestinal lymphoma from LH. RESULTS: Two hundred ninety-four small polypoid lesions, including 59 lymphomas and 235 LH lesions, were detected. The rates of detecting DVNs and the presence of irregular vessels were significantly higher in the lymphoma samples (81.4% and 62.7%) than in the LH samples (25.5% and 4.7%). Based on these findings, the diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values for differentiating intestinal lymphoma from LH were 88.8%, 62.7%, 95.3%, 77.1%, and 91.1%, respectively, which are significantly higher than those of conventional endoscopy. LIMITATIONS: Single-center study. CONCLUSION: DVNs and the presence of irregular vessels on NBI are thus considered to be useful findings for differentiating intestinal lymphoma from benign LH.

DOI： 10.1016/j.gie.2014.03.030

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Probiotics have been used for the treatment of inflammatory bowel diseases (IBD). However, the effects of probiotics on the induction and maintenance of remission in ulcerative colitis (UC) or Crohn's disease (CD) still remain controversial. This systematic review verified the findings of high-quality randomized controlled trials (RCTs) which investigated the therapeutic effects of probiotics on IBD. After the quality assessment, 20 RCTs which investigated the effects of probiotics on the induction or maintenance of remission in IBD were identified. From the results of the validation of these RCTs, beneficial effects of probiotic treatments to improve the response rate and remission rate on the remission induction therapies [risk ratio (RR) 1.81; 95 % confidence interval (CI) 1.40-2.35 and RR 1.56; 95 % CI 0.95-2.56, respectively] were verified. Furthermore, probiotic treatments exhibited effects equal to mesalazine on the maintenance of remission in UC (RR 1.00; 95 % CI 0.79-1.26). In contrast, no significant effect of probiotic treatments was shown in either the induction or maintenance of remission in CD. Because there were many variations in the conditions among these studies, a further analysis evaluating the effects of probiotic treatments in IBD is needed to clarify the optimal probiotics and treatment regimens for each condition or population in IBD patients.

DOI： 10.1007/s12328-013-0440-8

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DOI： 10.1007/s12328-014-0456-8

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The Japanese traditional medicine daikenchuto (TU-100) has anti-inflammatory activities, but the mechanisms remain incompletely understood. TU-100 includes ginger, ginseng, and Japanese pepper, each component possessing bioactive properties. The effects of TU-100 and individual components were investigated in a model of intestinal T lymphocyte activation using anti-CD3 antibody. To determine contribution of intestinal bacteria, specific pathogen free (SPF) and germ free (GF) mice were used. TU-100 or its components were delivered by diet or by gavage. Anti-CD3 antibody increased jejunal accumulation of fluid, increased TNFα, and induced intestinal epithelial apoptosis in both SPF and GF mice, which was blocked by either TU-100 or ginger, but not by ginseng or Japanese pepper. TU-100 and ginger also blocked anti-CD3-stimulated Akt and NF-κB activation. A co-culture system of colonic Caco2BBE and Jurkat-1 cells was used to examine T-lymphocyte/epithelial cells interactions. Jurkat-1 cells were stimulated with anti-CD3 to produce TNFα that activates epithelial cell NF-κB. TU-100 and ginger blocked anti-CD3 antibody activation of Akt in Jurkat cells, decreasing their TNFα production. Additionally, TU-100 and ginger alone blocked direct TNFα stimulation of Caco2BBE cells and decreased activation of caspase-3 and polyADP ribose. The present studies demonstrate a new anti-inflammatory action of TU-100 that is microbe-independent and due to its ginger component.

DOI： 10.1371/journal.pone.0097456

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It is well known that microRNAs (miRs) are abnormally expressed in various cancers and target the messenger RNAs (mRNAs) of cancer-associated genes. While (miRs) are abnormally expressed in various cancers, whether miRs directly target oncogenic proteins is unknown. The present study investigated the inhibitory effects of miR-18a on colon cancer progression, which was considered to be mediated through its direct binding and degradation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1). An MTT assay and xenograft model demonstrated that the transfection of miR-18a induced apoptosis in SW620 cells. A binding assay revealed direct binding between miR-18a and hnRNP A1 in the cytoplasm of SW620 cells, which inhibited the oncogenic functions of hnRNP A1. A competitor RNA, which included the complementary sequence of the region of the miR-18a-hnRNP A1 binding site, repressed the effects of miR-18a on the induction of cancer cell apoptosis. In vitro single and in vivo double isotope assays demonstrated that miR-18a induced the degradation of hnRNP A1. An immunocytochemical study of hnRNP A1 and LC3-II and the inhibition of autophagy by 3-methyladenine and ATG7, p62 and BAG3 siRNA showed that miR-18a and hnRNP A1 formed a complex that was degraded through the autophagolysosomal pathway. This is the first report showing a novel function of a miR in the autophagolysosomal degradation of an oncogenic protein resulting from the creation of a complex consisting of the miR and a RNA-binding protein, which suppressed cancer progression. © 2014 Macmillan Publishers Limited.

DOI： 10.1038/onc.2013.429

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BACKGROUND: Acute lower gastrointestinal hemorrhage originating from the appendix is rare and often intractable, because it is almost impossible to approach the bleeding point by endoscopy. We herein describe the first case of bleeding from the appendix, which was successively controlled by a therapeutic barium enema administered into the appendix. CASE PRESENTATION: A 71-year-old male visited our hospital because of melena. He has been receiving an anti-coagulation drug, ticlopidine hydrochloride, for 10 years. By an emergency colonoscopy, a hemorrhage was detected in the appendix, and the lesion responsible for the bleeding was regarded to exist in the appendix. Two hundred milliliters of 50 W/V% barium was sprayed into the orifice of the appendix using a spraying tube. The bleeding could thus be immediately stopped, and a radiological examination revealed the accumulation of barium at the cecum and the orifice of the appendix. The barium accumulation disappeared by the next day, and no obvious anal bleeding was observed. Two weeks after stopping the bleeding from the appendix, an appendectomy was performed to prevent any further refractory hemorrhaging. The patient has had no complaints of any abdominal symptoms or anal bleeding for 10 months. CONCLUSIONS: A therapeutic barium enema is a useful procedure to control bleeding from the appendix and to avoid emergency surgery, such as partial cecectomy and hemicolectomy.

DOI： 10.1186/1471-230X-13-152

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Barrett's esophagus (BE) is metaplastic columnar epithelium converted from normal squamous epithelia in the distal esophagus that is thought to be a precancerous lesion of esophageal adenocarcinoma. BE is attributed to gastroesophageal reflux disease (GERD), and therefore gastric acid or bile acids are thought to be factors that cause epithelial cell damage and inflammation in the gastro-esophageal junction. The decrease of adherent junction molecules, E-cadherin has been reported to be associated with the progression of the Barrett's carcinoma, but the initiation of BE is not sufficiently understood. BE is characterized by the presence of goblet cells and occasionally Paneth cells are observed at the base of the crypts. The Paneth cells possess dense granules, in which human antimicrobial peptide human defensin-5 (HD-5) are stored and secreted out of the cells. This study determined the roles of HD-5 produced from metaplastic Paneth cells against adjacent to squamous cells in the gastro-esophageal junction. A human squamous cell line Het-1A, was incubated with the synthetic HD-5 peptide as a model of squamous cell in the gastro-esophageal junctions, and alterations of E-cadherin were investigated. Immunocytochemistry, flowcytometry, and Western blotting showed that the expression of E-cadherin protein was decreased. And a partial recovery from the decrease was observed by treatment with a CD10/neprilysin inhibitor (thiorphan). In conclusion, E-cadherin expression in squamous cells was reduced by HD-5 using in vitro experiments. In gastro-esophageal junction, HD-5 produced from metaplastic Paneth cells may therefore accelerate the initiation of BE.

DOI： 10.1016/j.bbrc.2013.08.026

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70歳代女。黒色便が出現し、その後排便時に暗赤色の下血があり、ふらつきも認めたため救急搬送された。下部消化管内視鏡では出血源を認めなかったが、回腸末端より血液流出があり、小腸出血が疑われた。入院時には活動性出血は認めず、経過観察としたが徐々に貧血が進行し、大量の下血と血圧低下、Hbも減少したため、中等症以上の消化管出血と診断し、RCC(濃厚赤血球)輸血を行った。Dynamic CTでは、近位空腸に造影剤の血管外漏出を認め、空腸出血が示唆された。緊急血管造影を行ったところ、上腸間膜動脈根部より3・4番目の空腸枝より造影剤の血管外漏出を認めたため、スポンゼルにて塞栓術を行った。下血は持続し開腹術を考慮したが、経口的DBE(ダブルバルーン内視鏡)を行った。空腸に多数の大小様々な憩室を認め、口側から3個目の憩室内に露出血管を認め、クリッピングを行った。経過良好で完全止血と判断し、第9病日に退院した。

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Background: The precise role of microRNAs in inflammatory disease is not clear. The present study investigated the effect of microRNA (miR-146b) with respect to improving intestinal inflammation. Methods: The microRNA profile in interleukin-10 deficient mice was examined using microRNA arrays and miR-146b was selected for the subsequent experiments. The expression vectors containing either the whole sequence of miR-146b or small interfering RNA for miR-146b were intraperitoneally administered to the dextran sodium sulfate (DSS)-induced colitis mouse. The expression levels of inflammation-related mediators were examined by the reverse transcriptase-polymerase chain reaction and western blotting analysis. Intestinal barrier function was evaluated by an ex vivo mannitol flux study. Results: The overexpression of miR-146b activated the NF-κB pathway, improved epithelial barrier function, relieved intestinal inflammation in the DSS-induced colitis mice, and improved the survival rate of mice with lethal colitis. Furthermore, this amelioration of intestinal inflammation by miR-146b was negated by the inhibitor for the NF-κB pathway. The overexpression of miR-146b decreased the expression of siah2, which has a target sequence for miR-146b, and promoted the ubiquitination of TRAF proteins. This suggests that the up-regulation of NF-κB by miR-146b was mediated by inhibition of the ubiquitination of TRAF proteins upstream of NF-κB. Conclusions: miR-146b improves intestinal inflammation by up-regulating NF-κB as a result of the decreased expression of siah2, which ubiquitinates TRAF proteins. Modulation of the miR-146b expression is a potentially useful therapy for the treatment of intestinal inflammation via activation of the NF-κB pathway. © 2013 John Wiley & Sons, Ltd.

DOI： 10.1002/jgm.2717

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BACKGROUND/AIMS: While biological drugs are useful for relieving the disease activity and preventing abdominal surgery in patients with Crohn's disease (CD), it is unclear whether the use of biological drugs in CD patients with no history of abdominal surgery is appropriate. We evaluated the effects of infliximab and other factors on extending the duration until the first surgery in CD patients on a long-term basis. METHODS: The clinical records of 104 CD patients were retrospectively investigated. The cumulative nonoperation rate until the first surgery was examined with regard to demographic factors and treatments. RESULTS: The 50% nonoperative interval in the 104 CD patients was 107 months. The results of a univariate analysis revealed that a female gender, the colitis type of CD, and the administration of corticosteroids, immunomodulators, or infliximab were factors estimated to improve the cumulative nonoperative rate. A multivariate analysis showed that the colitis type and administration of infliximab were independent factors associated with a prolonged interval until the first surgery in the CD patients with no history of abdominal surgery. CONCLUSIONS: This study suggests that infliximab treatment extends the duration until the first surgery in CD patients with no history of abdominal surgery. The early use of infliximab before a patient undergoes abdominal surgery is therefore appropriate.

DOI： 10.1155/2013/879491

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INTRODUCTION: Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. These probiotic effects are considered to be displayed through the mediation of effective molecules derived from these bacteria because live bacteria as well as their conditioned media exhibit beneficial effects in many cases. However, many of the probiotic-derived molecules which mediate such benefits have so far been poorly characterized. We previously found that competence and sporulation factor (CSF) activates the Akt and p38 MAPK pathways and protects epithelial cells from oxidant stress in the mammalian intestine. The purpose of this study is to determine the CSF effect on reducing intestinal inflammation. METHODS AND RESULTS: A protein array demonstrated that CSF induced the anti-inflammatory cytokine, IL-10, and decreased the release of pro-inflammatory mediators, IL-4, IL-6 and CXCL-1, induced by TNF-α in Caco2/bbe cells. CSF also induced the cytoprotective protein Hsp 27 in Caco2/bbe cells. The histological score of intestinal inflammation in 2% dextran sodium sulfate (DSS)-treated mice with the administration of 10 nM CSF was significantly lower than that of control mice. CSF also improved the survival rate of mice treated with a lethal concentration of DSS. CONCLUSION: Therefore, CSF is a potentially effective treatment for intestinal inflammation.

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BACKGROUND: Some patients under close colonoscopic surveillance still develop colorectal cancer, thus suggesting the overlook of colorectal adenoma by endoscopists. AFI detects colorectal adenoma as a clear magenta, therefore the efficacy of AFI is expected to improve the detection ability of colorectal adenoma. The aim of this study is to determine the efficacy of AFI in detecting colorectal adenoma. METHODS: This study enrolled 88 patients who underwent colonoscopy at Asahikawa Medical University and Kushiro Medical Association Hospital. A randomly selected colonoscopist first observed the sigmoid colon and rectum with conventional high resolution endosopy (HRE). Then the colonoscopist changed the mode to AFI and handed to the scope to another colonoscopist who knew no information about the HRE. Then the second colonoscopist observed the sigmoid colon and rectum. Each colonoscopist separately recorded the findings. The detection rate, miss rate and procedural time were assessed in prospective manner. RESULTS: The detection rate of flat and depressed adenoma, but not elevated adenoma, by AFI is significantly higher than that by HRE. In less-experienced endoscopists, AFI dramatically increased the detection rate (30.3%) and reduced miss rate (0%) of colorectal adenoma in comparison to those of HRE (7.7%, 50.0%), but not for experienced endoscopists. The procedural time of HRE was significantly shorter than that of AFI. CONCLUSIONS: AFI increased the detection rate and reduced the miss rate of flat and depressed adenomas. These advantages of AFI were limited to less-experienced endoscopists because experienced endoscopists exhibited a substantially high detection rate for colorectal adenoma with HRE.

DOI： 10.1186/1471-230X-12-75

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DOI： 10.1111/j.1443-1661.2011.01188.x

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BACKGROUND AND AIMS: Autofluorescence imaging (AFI) is a novel technology which can capture fluorescence emitted from intestinal tissues. While AFI is useful for detecting colorectal neoplasms, it is unclear whether AFI can facilitate the diagnosis by differentiating the extent of dysplasia of colorectal neoplasms. This study investigated the efficacy of AFI in discriminating high-grade from low-grade adenoma. MATERIALS AND METHODS: Sixty-seven patients who underwent colonoscopy with AFI were enrolled in this study. The AFI images obtained from 158 lesions in these patients were visually classified into four categories, namely, green (G), green with magenta spots (GM), magenta with green spots (MG), and magenta (M), according to their color intensities, immediately after the examination. The AFI images of the lesions were quantified using an image-analytical software program (F index). Either the F index or the visual assessment was prospectively compared with the dysplastic grade. RESULTS: The F index of the high-grade adenomas was significantly lower than that of the low-grade adenomas, hyperplasia, and normal mucosa (p < 0.05). The incidence of the lesions classified into the M classification for high-grade adenomas (55.6%) was significantly higher than that of either low-grade adenomas (20.8%) or hyperplasia (0%). No correlation was observed between the F index or the visual classification and the tumor shape. The F index was not influenced by the size of the lesion, while the size was significantly associated with the visual classification of AFI. CONCLUSIONS: AFI, particularly the F index, is considered to be a useful procedure for estimating the dysplastic grade of colonic adenomas.

DOI： 10.1007/s00384-011-1311-8

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

【背景・目的】DSS慢性腸炎モデルマウスに対する麦芽乳酸菌L.brevis SBC8803死菌体の治療効果を明らかにする。【結果】DSS慢性腸炎モデルマウスにL.brevis SBC8803死菌体を注腸投与したところ、1)腸管短縮を有意に抑制し、病理学的所見を有意に改善する。2)HSP25・70の発現を回復させる。3)TNF-α、IL-1βの発現を有意に抑制する。【まとめ】L.brevis SBC8803死菌体はHSPの発現誘導や炎症関連サイトカインの発現調節により慢性炎症に伴う腸管障害を軽減させる。炎症性腸疾患に対する新規治療薬としての臨床応用が期待される。(著者抄録)

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DOI： 10.1055/s-0031-1291502

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BACKGROUND: Probiotics have been clinically administered to improve intestinal damage in some intestinal inflammations. However, probiotic treatments are not always effective for these intestinal disorders because live bacteria must colonize and maintain their activity under unfavorable conditions in the intestinal lumen when displaying their functions. This study investigated the physiological functions of a heat-killed body of a novel probiotic, Lactobacillus brevis SBC8803, on the protection of intestinal tissues, the regulation of cytokine production, the improvement of intestinal injury, and the survival rate of mice with dextran sodium sulfate (DSS)-induced colitis. METHODS: Heat shock protein (Hsp) induction and mitogen-activated protein kinase (MAPK) phosphorylation in intestinal epithelia by heat-killed L. brevis SBC8803 were examined by Western blotting. The barrier function of intestinal epithelia was measured with [(3) H]-mannitol flux in the small intestine under oxidant stress. The effects of the bacteria on improving epithelial injury and cumulative survival rate were investigated with a DSS colitis model. RESULTS: Heat-killed L. brevis SBC8803 induced Hsps, phosphorylated p38 MAPK, regulated the expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β and IL-12, and improved the barrier function of intestinal epithelia under oxidant stress. The induction of Hsp and the protective effect were negated by p38 MAPK inhibitor. These functions relieve intestinal impairments and improve the survival rate in mice with lethal colitis. CONCLUSIONS: The administration of heat-killed L. brevis SBC8803 helps to successfully maintain intestinal homeostasis, while also curing intestinal inflammation. A therapeutic strategy using heat-killed bacteria is expected to be beneficial for human health even in conditions unsuitable for live probiotics because the heat-killed body is able to exhibit its effects without the requirement of colonization.

DOI： 10.1002/ibd.21597

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DOI： 10.1136/gut.2009.205526

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BACKGROUND: A method for the differential diagnosis of intestinal lymphomas resembling lymphoid hyperplasia (LH) by endoscopy remains to be clearly established. OBJECTIVE: To evaluate the usefulness of autofluorescence imaging (AFI) in diagnosing intestinal lymphoma. SETTING: Single-center study. DESIGN: Prospective study. PATIENTS: One hundred forty-three samples obtained from the intestinal tissues of 21 patients with malignant lymphoma were included in the study. INTERVENTIONS: The terminal ileum and entire colon were observed using conventional endoscopy equipped with AFI. The AFI images were taken by 3 endoscopists and then were evaluated by 3 predominant color intensities; green, magenta, and blended. To quantify the strength of fluorescence captured by AFI, the area of the obtained biopsy specimens on images was manually traced, the signal density of either magenta or green was measured, and then the ratio of the reverse gamma value of green divided by that of magenta was defined as the Fluorescence index (F index). MAIN OUTCOME MEASUREMENTS: The ability to use AFI to distinguish intestinal lymphoma from normal or LH. RESULTS: The cell density is inversely proportional to the F index. The F index of lymphoma was significantly lower than that of normal mucosa or LH. The visual classification of AFI showed the overall accuracy in diagnosing lymphoma was 91.5%, and was well correlated with the F index. LIMITATIONS: Single-center study. CONCLUSIONS: AFI-embossed lymphoma lesions seemed as magenta and could be discriminated from LH or normal mucosa with a high overall accuracy through perception of the cell density of the lesion. Therefore, AFI is considered to be an effective procedure for determining the accurate stage and appropriate therapy in intestinal lymphoma.

DOI： 10.1097/MCG.0b013e3181fbe22a

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Henoch-Schönlein purpura (HSP) is a type of systemic vasculitis of the small vessels, which frequently involves the skin, kidney and gastrointestinal tract. While the typical intestinal features of HSP include diffuse mucosal redness, small ring-like petechiae and haemorrhagic erosions, tumour-like lesions are rarely observed. The current study presents a rare case of HSP with an intestinal tumour-like lesion in the caecum. The intestinal lesion caused fresh melaena, and was completely resolved with the administration of factor XIII as described in previously reported cases. It is important to immediately undergo proper treatment for improving tumour-like lesions which may cause severe complications, such as excessive haemorrhage and stricture.

DOI： 10.1136/bcr.08.2010.3251

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Amyloidosis occurs as a result of the extracellular deposition of protein fibrils in organs and tissues, thus causing mild to severe pathophysiological changes. The gastrointestinal tract is a common site of amyloid deposition. While intestinal amyloidosis frequently results in polypoid lesions, ulcerations, nodules and petechial mucosal haemorrhage, tumour-like lesions are rarely developed and infrequently diagnosed before the resection because of the difficulty in differentiating them from colon cancer. The authors herein reported a case of intestinal amyloid A amyloidosis with a complication of a tumour-like lesion endoscopically resembling a malignant lesion, which was completely diminished after 1 month of observation with bowel rest. Such conservative treatment is a feasible option to cure intestinal tumour-like lesions in patients with intestinal amyloidosis when no neoplastic change is histologically detected, possibly decreasing the need for surgery of the fragile mucosa.

DOI： 10.1136/bcr.01.2011.3775

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Percutaneous endoscopic jejunostomy (PEJ) has been developed and is considered to be a better method than percutaneous endoscopic gastrostomy for preventing the occurrence of aspiration pneumonia. However, the incidence of other complications associated with this procedure is less clear. We herein report a rare case with a small intestinal intussusception due to a PEJ placement. In this case, a radiologic examination with gastrografin was useful to detect the typical findings of a small intestinal intussusception, a beak-like filling defect, and identify the location of the lesion. An endoscopic examination that was carefully performed with a thin scope was effective to observe the ischaemic change of the small intestine and immediately determine the indication for surgical treatment. This case highlights the necessity to carefully manage patients with a PEJ placement, considering the risk of small intestinal intussusceptions when the patient complains of symptoms that are suspicious for an intestinal obstruction.

DOI： 10.1136/bcr.07.2010.3169

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

背景・目的;新規プロバイオティクスである麦芽乳酸菌(Lactobacillus brevis)SBC8803死菌の生理活性を解明するためにDSS腸炎モデルマウスを用いて検討をした。結果;麦芽乳酸菌SBC8803は急性炎症に伴う腸管の短縮を有意に抑制し、病理学的所見を改善させ、炎症性サイトカインである、TNF-α、IL-1β、IL-12を有意に抑制し、累積生存率を延長させた。総括;麦芽乳酸菌SBC8803死菌は抗炎症作用を有しており炎症性腸疾患などの消化器疾患への臨床応用の可能性がある。(著者抄録)

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DOI： 10.1016/j.gie.2010.07.011

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Probiotics exhibit beneficial effects on human health, particularly in the maintenance of intestinal homeostasis in a complex manner notwithstanding the diversity of an intestinal flora between individuals. Thus, it is highly probable that some common molecules secreted by probiotic and/or commensal bacteria contribute to the maintenance of intestinal homeostasis and protect the intestinal epithelium from injurious stimuli. To address this question, we aimed to isolate the cytoprotective compound from a lactobacillus strain, Lactobacillus brevis SBC8803 which possess the ability to induce cytoprotective heat shock proteins in mouse small intestine. L. brevis was incubated in MRS broth and the supernatant was passed through with a 0.2-µm filter. Caco2/bbe cells were treated with the culture supernatant, and HSP27 expression was evaluated by Western blotting. HSP27-inducible components were separated by ammonium sulfate precipitation, DEAE anion exchange chromatography, gel filtration, and HPLC. Finally, we identified that the HSP27-inducible fraction was polyphosphate (poly P), a simple repeated structure of phosphates, which is a common product of lactobacilli and other bacteria associated with intestinal microflora without any definitive physiological functions. Then, poly P was synthesized by poly P-synthesizing enzyme polyphosphate kinase. The synthesized poly P significantly induced HSP27 from Caco2/BBE cells. In addition, Poly P suppressed the oxidant-induced intestinal permeability in the mouse small intestine and pharmacological inhibitors of p38 MAPK and integrins counteract its protective effect. Daily intrarectal administration of poly P (10 µg) improved the inflammation grade and survival rate in 4% sodium dextran sulfate-administered mice. This study, for the first time, demonstrated that poly P is the molecule responsible for maintaining intestinal barrier actions which are mediated through the intestinal integrin β1-p38 MAPK.

DOI： 10.1371/journal.pone.0023278

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Diphyllobothrium is a member of Cestoda family, which is the largest parasite of humans. The diagnosis of diphyllobothriasis is based on the detection of eggs in the stool. Because the remainder of the scolex causes a relapse in diphyllobothriasis, the scolex must be completely discharged to cure the parasite infection. However, the scolex or forefront of the Diphyllobothrium is difficult to detect with gastroduodenoscopy and colonoscopy, because most Diphyllobothrium attach to the jejunal wall. In the present case, capsule endoscopy detected proglottids as well as forefront of the parasite at jejunum. Based on the results of capsule endoscopy, the patient underwent additional vermifuge (anthelminthic) treatment to cure the diphyllobothriasis and discharged a worm measuring 3 m in length with a scolex. Capsule endoscopy is a practical option to determine whether additional vermifuge treatment is required through the detection of the proglottids as well as a scolex or forefront of the parasite.

DOI： 10.1136/bcr.05.2010.3023

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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Collagenous colitis (CC) is one of the causes of undefined watery diarrhea, which is histologically accompanied by thickening of the subepithelial collagen layer. CC associated with lansoprazole normally occurs within several weeks after initial administration, but no case presenting after long-term administration of lansoprazole has yet been reported. A 77-year-old male with 6-year history of administration of lansoprazole complained of watery diarrhea and weight loss. Colonoscopy revealed disappearance of vascular networks and red spots in the sigmoid colon. Biopsy specimen showed erosion and collagen bands thickened, so the patient was diagnosed as CC. After lansoprazole discontinuation, the watery diarrhea disappeared and histological abnormalities improved.

DOI： 10.1007/s12328-009-0126-4

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We herein present a quite atypical case of primary gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma in the transverse colon. Computed tomography and endoscopic ultrasonography revealed diffuse thickening of the wall, and colonoscopy showed a white-colored mucosa with reduced superficial vessels in the entire transverse colon. The lesion was diagnosed as MALT lymphoma by pathological examination of the biopsied specimen. Secondary macroglobulinemia of IgM-kappa type was also found in the present case. After chemotherapy and radiation, the lesions in the transverse colon improved and the patient has been in good condition without any evidence of recurrence for more than 1 year.

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Small cell carcinoma of the oesophagus (SCCE) is an infrequent tumour associated with a poor prognosis. We herein propose the first case of SCCE treated by endoscopic mucosal resection (EMR) and its endoscopic images with narrow band imaging (NBI) and autofluorescence imaging (AFI). A 63-year-old man complained of a loss of appetite. An upper endoscopic examination revealed a 7 mm nodule located 33 cm from the incisors. A weakly stained area was shown by iodine staining. NBI detected brownish amorphous dots with irregular vessels on the surface of the nodule and AFI distinctly embossed the lesion magenta. A biopsy specimen obtained from the lesions revealed typical SCCE. The patient underwent EMR to remove the SCCE and thereafter remained in a state of clinical remission for 18 months. In summary, NBI and AFI may be useful for detecting and differentially diagnosing SCCE from the squamous cell carcinoma of the oesophagus. EMR is therefore considered to be a potentially useful therapeutic option for removing SCCE instead of performing an oesophagotomy.

DOI： 10.1136/bcr.06.2009.2048

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

An 83-year-old woman who was admitted to other hospital, was consulted us because of continuous tarry stool and abdominal fullness. On upper endoscopy, the submucosal tumor from greater curvature of gastric fornix invaginated into the duodenal bulbus, showing so-called "ball valve syndrome (BVS)". As the tumor incarcerted again on the following endoscoopy, she underwent laparoscopic partial gastrectomy. The submucosal tumor was diagnosed histologically as gastrointestinal stromal tumor (GIST) arising from the muscularis mucosae. This is the first report that GIST arising from the muscularis mucosae in gastric fornix showed a BVS.

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BACKGROUND: The technical difficulties related to the insertion of a long intestinal tube into the jejunum under fluoroscopy present a considerable problem in patients with an intestinal obstruction. OBJECTIVE: To evaluate the usefulness of endoscopic long intestinal-tube placement with the ultrathin esophagogastroduodenoscope (UT-EGD). DESIGN: A prospective randomized clinical trial was conducted. PATIENTS: Twenty-eight consecutive patients who presented with an intestinal obstruction were included in the study. INTERVENTION: The UT-EGD was inserted nasally into at least the second portion of the duodenum or beyond. After a guidewire was introduced through the working channel, with fluoroscopic guidance, the UT-EGD itself was carefully removed with the guidewire left in place. Next, a hydrophilic intestinal tube was advanced over the guidewire into the jejunum, and then the guidewire was removed. MAIN OUTCOME MEASUREMENTS: Primary end points are the total procedure time, the radiation exposure time, and the rate of complications, all compared with the conventional method. RESULTS: The mean (+/-SD) total procedure time was 18.7 +/- 8.4 minutes for the UT-EGD method and 39.5 +/- 15.0 minutes for the conventional method, with a significant time difference between the 2 methods (P < .0005). The mean (+/-SD) radiation exposure time was also shorter with the UT-EGD method (11.1 +/- 6.0 minutes) than with the conventional method (30.3 +/- 13.7 minutes) (P < .0005). There were no complications, except for mild nasal bleeding with each method. CONCLUSIONS: The UT-EGD method has definite advantages in the placement of a long intestinal tube for patients with an intestinal obstruction in comparison with the conventional method.

DOI： 10.1016/j.gie.2008.01.043

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：自然科学社  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Event date： 2010.10

Language：Japanese   Presentation type：Poster presentation  

Venue：横浜  

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Event date： 2010.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：旭川  

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Event date： 2010.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大津  

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Event date： 2010.6

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：東京  

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Event date： 2010.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京  

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Event date： 2010.5

Language：English   Presentation type：Poster presentation  

Venue：New Orleans  

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Event date： 2010.5

Language：English   Presentation type：Poster presentation  

Venue：New Orleans  

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Event date： 2010.4

Language：English   Presentation type：Oral presentation (general)  

Venue：新潟  

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Event date： 2010.1

Language：English   Presentation type：Poster presentation  

Venue：東京  

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Event date： 2009.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都  

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Event date： 2009.10 - 2010.10

Language：English   Presentation type：Poster presentation  

Venue：札幌  

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Event date： 2009.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松山  

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Event date： 2009.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌  

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Event date： 2008.5

Language：English   Presentation type：Poster presentation  

Venue：San Diego, USA  

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Event date： 2006.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌  

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