宮原 良二

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, persistent, and intractable enteritis; however, an effective treatment strategy is yet to be established. Mesenchymal stem cells (MSCs) and their paracrine factors exhibit anti-inflammatory actions and have been proposed as a new therapeutic candidate for IBD treatment, although the efficacy of MSC lysate on enteritis is unclear. AIMS: Here, we examined the efficacy and appropriate regimen of filtrated murine adipose-derived mesenchymal stem cell lysate (FADSTL) in an acute colitis mouse model as a novel cell-free MSC therapy. METHODS: To confirm the clinical effects of FADSTL, survival rate, body weight, and disease activity index (DAI) were investigated in the DSS-induced colitis mouse model. Further, differences in efficacy with dosing frequency were assessed to optimize the proper regimen. Colon length, histological findings, gene expression of inflammatory mediators and tight junction proteins in colon tissues, and anti-apoptotic effects were also compared in 3-day continuous FADSTL administration and PBS groups. RESULTS: Three-day continuous FADSTL administration significantly improved weight loss and DAI score compared to those in the PBS-treated group, whereas the effect was not observed with single administration. Additionally, colon shortening and histological inflammation were suppressed in the FADSTL-treated group. Further, this treatment decreased gene expression of inflammatory mediators, maintained expression of tight junction proteins in the colon, and showed anti-apoptotic effects. CONCLUSIONS: FADSTL effects were dependent on its administration frequency, suggesting the requirement of continuous FADSTL administration. FADSTL improved colitis by maintaining the intestinal barrier function through its anti-inflammatory and anti-apoptotic actions.

BACKGROUND: Bacteria of oral origin (BO) in the gut are associated with prognosis in patients with cirrhosis. The Greengenes database (gg_13_8) is widely used in microbiome analysis, but the expanded Human Oral Microbiome Database (eHOMD), a specialized database for BO, can add more detailed information. We used each database to evaluate the relationship between the albumin-bilirubin grade (ALBI) and the microbiome in patients with hepatitis C. METHODS: Eighty patients were classified into the low ALBI group (LA; n = 34) or high ALBI group (HA; n = 46). Isolated DNA from stool was amplified to target the V3-4 regions of 16S rRNA. The microbiomes of the two groups were compared using gg_13_8 or eHOMD. We evaluated the associations between microbiomes and prognoses using Cox proportional hazards models. RESULTS: At the genus level, the two groups differed significantly regarding 6 (gg_13_8) and 7 (eHOMD) types of bacteria. All types except Akkermansia are classified as BO. Both databases showed an increase in Streptococcus and Veillonella. eHOMD showed a decrease in Fusobacterium and an increase in Fretibacterium; both produce various types of short-chain fatty acids. At the species level, the two groups demonstrated significant differences in 2 (gg_13_8) and 6 (eHOMD) bacterial types. Selenomonas noxia and Streptococcus salivarius were related to poor prognosis in univariate analysis. CONCLUSION: The HA group demonstrated increased BO, most of which produce lactic acid or acetic acid. The correlation between the microbiome and metabolism might be related to prognosis. eHOMD was a useful database for analyzing BO.

世界ではじめて早期慢性膵炎を取り入れた診断基準「慢性膵炎臨床診断基準2009」が本邦から提唱されてから10年間が経過した。この間、慢性膵炎の病態形成メカニズムに着目したmechanistic definitionとよばれる概念が海外から提唱され、早期慢性膵炎もこの定義に取り入れられた。この概念から考えると、早期慢性膵炎は機能不全に至っておらずまた可逆性の病態を想定している。2019年日本で発表された、慢性膵炎の新基準「慢性膵炎臨床診断基準2019」もこの概念を取り入れ、早期慢性膵炎の診断項目は危険因子の観点から改訂された。現在、早期慢性膵炎は国際的にその概念が確立されつつあるが、いまだ確立された定義や診断基準はなく、画像診断のみならず、遺伝や環境因子、その他さまざまなバイオマーカーを踏まえ、鑑別診断を明確に否定し適切に診断することで、慢性膵炎の進行を防ぎ後期合併症を回避することが重要である。今後新たなバイオマーカーや診断方法の開発が期待される。(著者抄録)

BACKGROUND/AIM: The aim of this study was to investigate the outcomes of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC), including those with disease refractory to lenvatinib, in clinical practice. PATIENTS AND METHODS: Of 34 patients treated with atezolizumab plus bevacizumab, a total of 23, including 16 with lenvatinib failure, were enrolled in this retrospective study. The adverse events, changes in liver function and antitumor responses at 6 weeks after starting therapy were evaluated. RESULTS: The incidence of grade 3 adverse events was low, at 13.0%. Albumin-bilirubin scores did not worsen at 3 and 6 weeks compared to baseline. The objective response rate and disease control rate at 6 weeks were 17.4% and 78.3% according to Response Evaluation Criteria in Solid Tumors (RECIST), and 30.4% and 78.3% according to modified RECIST, respectively. CONCLUSION: Our results suggest that atezolizumab plus bevacizumab might have potential therapeutic safety and efficacy in patients with advanced HCC, including those with disease refractory to lenvatinib. Further studies are needed to confirm the outcomes of atezolizumab plus bevacizumab after lenvatinib failure.

INTRODUCTION: Patients with esophageal squamous cell carcinoma (ESCC) have various comorbidities. Thus, it is necessary to determine the appropriateness of performing treatment based on the patient's general condition. AIM: This study aimed to clarify the prognostic predictors of ESCC indicated for endoscopic submucosal dissection (ESD). METHODS: This retrospective study enrolled 241 patients with superficial ESCC endoscopically diagnosed as ESD-indicated lesions at the Nagoya University Hospital between January 2007 and December 2017. We evaluated the 3- and 5-year overall survival (OS) rates and prognostic predictors, such as the Prognostic Nutritional Index (PNI), Charlson Comorbidity Index (CCI), Psoas Muscle Index, and Controlling Nutritional Status score. Furthermore, we created a score-based classification using the prognostic predictors identified by multivariate analysis, and the 3- and 5-year OS rates were compared among the calculated scores. RESULTS: In the multivariate analysis, PNI < 45 (hazard ratio [HR]: 2.39; 95% confidence interval [CI]: 1.28-4.46; p = 0.006) and CCI ≥ 3 (HR: 4.42; 95% CI: 2.40-8.12; p < 0.001) were significantly associated with the OS. Based on the HR, 0 and 1 were assigned to PNI and 0, 2, and 4 were assigned to CCI, and the score classification of 0-5 points was created. The 3- and 5-year OS rates in patients with a score 3 were significantly higher than in those with scores 4 and 5. As a result of scoring, the prognosis was stratified; the 3- and 5-year OS rates in patients with scores 4 and 5, that is, CCI ≥ 6, were clearly low, at approximately 10%. CONCLUSIONS: CCI and PNI can be prognostic predictors of patients with superficial ESCC indicated for ESD. Observation without ESD might be an acceptable strategy among patients with CCI ≥ 6.

INTRODUCTION: Dysphagia is a common symptom that occurs in patients with diabetes mellitus (DM). There have been few prospective observational studies on esophageal motility disorders in DM using high-resolution manometry (HRM). This study aimed to clarify the characteristics of esophageal motility disorders using HRM in patients with dysphagia and compare them between DM and non-DM patients. METHODS: Patients with dysphagia were prospectively recruited between October 2018 and July 2019. Patients (n = 89) underwent esophagogastroduodenoscopy and HRM and completed the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. Manometry parameters and motility disorder classifications were compared between DM and non-DM patients. We also investigated the differences in clinical backgrounds and questionnaire scores among DM patients with normal and abnormal manometry results. RESULTS: A higher prevalence of esophageal motility disorder was observed in DM patients (60%, 21/35) compared to non-DM patients (29.6%, 16/54) (p = 0.001). The prevalence of minor disorders such as ineffective esophageal motor disorder and fragmented peristalsis was significantly higher (45 vs. 11%), and the distal contractile integral, integrated relaxation pressure, and contractile front velocity values were lower in the DM group. Among DM patients, those with abnormal esophageal motility had a significantly higher prevalence of neuropathy, retinopathy, and nephropathy, as well as higher reflux or constipation scores on the GSRS, than those with normal results. CONCLUSIONS: Among patients with dysphagia, the frequency of minor esophageal motility disorders was higher in DM patients than in non-DM patients. Abnormal esophageal motility related to poor esophageal clearance was associated with higher prevalence of diabetic complications.

Sedation in gastroenterological endoscopy has become an important medical option in routine clinical care. Here, the Japan Gastroenterological Endoscopy Society and the Japanese Society of Anesthesiologists together provide the revised "Guidelines for sedation in gastroenterological endoscopy" as a second edition to address on-site clinical questions and issues raised for safe examination and treatment using sedated endoscopy. Twenty clinical questions were determined and the strength of recommendation and evidence quality (strength) were expressed according to the "MINDS Manual for Guideline Development 2017." We were able to release up-to-date statements related to clinical questions and current issues relevant to sedation in gastroenterological endoscopy (henceforth, "endoscopy"). There are few reports from Japan in this field (e.g., meta-analyses), and many aspects have been based only on a specialist consensus. In the current scenario, benzodiazepine drugs primarily used for sedation during gastroenterological endoscopy are not approved by national health insurance in Japan, and investigations regarding expense-related disadvantages have not been conducted. Furthermore, including the perspective of beneficiaries (i.e., patients and citizens) during the creation of clinical guidelines should be considered. These guidelines are standardized based on up-to-date evidence quality (strength) and supports on-site clinical decision-making by patients and medical staff. Therefore, these guidelines need to be flexible with regard to the wishes, age, complications, and social conditions of the patient, as well as the conditions of the facility and discretion of the physician.

A 65-year-old woman with a history of treatment for splenic marginal zone B-cell lymphoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma underwent esophagogastroduodenoscopy. A reddish elevated lesion was found in the fundus of the stomach. On image-enhanced endoscopy, several findings, such as glandular structures of varying sizes suggesting well-differentiated adenocarcinoma, pruned blood vessels, and dilated blood vessels in deeper mucosa suggesting MALT lymphoma, were observed. The final pathological diagnosis after surgical resection was collision tumors of well-differentiated adenocarcinoma and MALT lymphoma. The features of both tumors could be observed simultaneously with image-enhanced endoscopy.

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) is useful for pathologically diagnosing gastrointestinal stromal tumor (GIST) before surgery. However, its role in mutation analysis remains unclear. To examine the feasibility of analyzing GIST mutations using mRNA obtained with EUS-FNA, we prospectively enrolled 41 patients with subepithelial lesion from which EUS-FNA was successfully acquired tissue sample. Thirty-two, 5, and 4 subepithelial lesions were diagnosed as GISTs, schwannomas, and leiomyomas, respectively. After RNA was extracted from FNA sample, RNA was converted to cDNA. Full-length sequence of the KIT cDNA amplified via the polymerase chain reaction (PCR) was successful in 31 (96.9%) out of 32 GIST and three out of 9 non-GIST (33.3%). The KIT mutation statuses of 31 GISTs in which KIT cDNA was amplified were successfully determined through directional sequencing. Furthermore, 15 of 16 surgically excised GISTs exhibited the same mutation status in both the EUS-FNA and resected samples. In vitro experiment, the minimum number of cells required to amplify full-length of KIT cDNA from RNA was one-tenth of that required to amplify KIT exon11 gene from DNA. This study clarifies that mutation analysis using RNA obtained with EUS-FNA is feasible and reliable. Moreover, our data would support that RNA-based mutation is superior to DNA-based mutation analysis in GIST.

BACKGROUND AND AIMS: The therapeutic efficacy and safety of ustekinumab for Crohn's disease (CD) have been reported from randomized controlled trials and real-world data. However, there are few studies describing the identification of patients most suitable for ustekinumab therapy. The aim of this study was to prospectively evaluate the patients receiving ustekinumab and identify predictors of the treatment efficacy. METHODS: Patients with moderate to severe active CD scheduled to receive ustekinumab were enrolled. The responders and nonresponders were compared at weeks 0, 8, 24, and 48 by evaluating patient demographics, simple endoscopic scores (SES-CD), ustekinumab and cytokine concentrations, and cellular fractions. RESULTS: The clinical response and clinical remission rates in the 22 enrolled patients were 59.1% and 31. 8% at week 8, 68.2% and 45.5% at week 24, and 54.4% and 40.9% at week 48, respectively. There were no significant differences in patients' demographic and disease characteristics at baseline between responders and nonresponders. A combination of low SES-CD and high serum TNF-α concentration at baseline showed a good correlation with the clinical response. Serum TNF-α concentration was decreased because of the therapy. The ratio of CD4+TNF-α cells at baseline was significantly higher in responders than in nonresponders; however, the ratios of CD45+CD11b+TNF-α and CD45+CD11c+TNF-α cells were not different. The ratio of CD4+ TNF-α cells decreased with the treatment in the responders but not in the nonresponders. CONCLUSIONS: The combination of 2 factors, namely higher serum TNF-α concentration and lower SES-CD at baseline, may assist clinicians in selecting the appropriate therapy for patients with moderate to severe CD.

PURPOSE: Shear wave elastography (SWE) using transabdominal ultrasonography (US) is widely used for diagnosis of tissue stiffness. Ultrasound shear wave dispersion (SWD) enables evaluation of tissue viscosity using SWE. The objective of this study was to investigate the reliability and clinical significance of SWD in pancreatic screening. METHODS: SWE and SWD were measured in 76 patients examined by US in pancreatic screenings performed between November 2017 and November 2018. The median pancreatic elastic modulus (PEM) and dispersion slope were obtained from at least five measurements. The reproducibility of these values and their correlations with patient characteristics, pancreatic echogenicity, and the pancreas-to-spleen attenuation ratio (P/S) on plain CT, which is associated with fatty change in pancreatic parenchyma, were investigated retrospectively. RESULTS: The median PEM and dispersion slope were 7.4 kPa and 15.7 (m/sec)/kHz, respectively, and both values had high intraclass correlation coefficients, showing high reproducibility (ρ = 0.869 and ρ = 0.867, respectively). The interquartile range/median value of PEM and dispersion slope were 0.36 and 0.28, respectively. PEM had a positive correlation with age (rs = 0.348, p = 0.002), and dispersion slope was positively correlated with age (rs = 0.278, p = 0.016) and BMI (rs = 0.397, p < 0.001). The hyperechoic pancreas had significantly higher PEM (6.6 vs. 7.8 kPa, p = 0.037) and dispersion slope (13.2 vs. 16.3 (m/sec)/kHz, p < 0.001). On plain CT performed in 50 patients, the P/S was not correlated with PEM (rs = - 0.180, p = 0.221), but was inversely correlated with dispersion slope (rs = - 0.338, p = 0.019). CONCLUSION: Measurement of SWD in pancreatic screening was highly reproducible and may permit objective evaluation of fatty change of the pancreas.

Although the majority of gastrointestinal stromal tumors (GISTs) possess KIT mutations that induce constitutive signal transduction, the clinical outcomes are variable. The ETS translocation variant 1 (ETV1) gene encodes a transcription factor that is reported to cooperate with KIT in GISTs. However, the clinical role of ETV1 is largely unknown. The aim of this study was to examine ETV1 expression and its associations with clinical features in GISTs. We conducted a cohort study involving 64 patients with GISTs who underwent surgical resection between October 2008 and February 2015. ETV1 mRNA expression was compared with that in non-GISTs and was analyzed among risk classifications or clinical outcomes. The GIST samples exhibited significantly higher ETV1 mRNA expression than the non-GIST samples (P < 0.0001). Sixty-four GISTs were stratified into high or low ETV1 mRNA expression groups based on the median relative abundance of ETV1 mRNA. The multivariate analysis showed that low ETV1 expression, as well as tumor size and mitotic index, was an independent factor of recurrence (hazard ratio: 8.1). Patients with high ETV1 expression achieved significantly longer recurrence-free survival (RFS) times than those with low ETV1 expression (P = 0.025). Our study revealed that low ETV1 expression is an independent factor of recurrence after surgery in patients with GISTs, and thus, low ETV1 expression might be a marker of more aggressive malignant GISTs.

本稿では,Spherical K-means(SpK)により抽出された複数スケールの特徴量と位置特徴量を用いた胃壁μCT画像からの粘膜層,粘膜下層,筋層及び腫瘍の抽出手法について報告する.胃壁のμCT画像から解剖学的構造を抽出することで腫瘍の立体構造把握が可能である.従来手法では複数スケールの特徴抽出フィルタをSpKによって学習し,パッチから特徴抽出を行った.その後得られた特徴量に基づいてSVMによって分類を行っていた.しかし,SpKにより生成された特徴抽出フィルタは濃度値に基づく特徴量を抽出するため,粘膜層と筋層のように濃度値が類似した領域同士の特徴量が近しい値になる.本手法ではSpKにより得られる複数スケールの特徴量にパッチの位置特徴量を追加して分類する事によって,濃度値に基づく特徴量では分類できない領域の分類を可能にする.パッチの位置特徴量としてパッチの中心座標を用いる.本手法を胃壁μCT像に適用した結果,粘膜層,粘膜下層,筋層及び腫瘍の抽出に対するDICE係数は68.3%,63.2%,82.2%,69.1%であった.特に従来手法と比べ,腫瘍の抽出に対するDICE係数は26.1%向上した.(著者抄録)

BACKGROUND: The prevalence of Barrett's esophageal adenocarcinoma (BEA) is increasing in Japan. Accurate assessment of lymphovascular invasion (LVI) after endoscopic resection or surgery is essential in evaluating treatment response. This study aimed to assess the usefulness of immunostaining in determining the extent of LVI in superficial BEA. METHODS: We retrospectively included 41 patients who underwent endoscopic resection or surgery between January 2007 and July 2018. In all cases, 3-μm serial sections from paraffin-embedded resected specimens were used for hematoxylin and eosin (H-E) staining and immunostaining for D2-40 and CD31. Two specialized gastrointestinal pathologists (T.Y. and T.T.), blinded to clinical information, independently evaluated the extent of LVI from these specimens. The LVI-positivity rate was evaluated with respect to the depth of invasion, changes in the positivity rate on immunostaining, pathological characteristics of patients with LVI, lymph node metastasis or relapse, and course after treatment. RESULTS: H-E staining alone identified LVI in 7 patients (positivity rate: 17.1%). Depths of invasion were categorized based on extension to the submucosa (SM) or deeper. On immunostaining for D2-40 and CD31, additional positivity was detected in 2 patients with SM1 and 1 SM3, respectively; LVI was detected in 10 patients (positivity rate: 24.4%). LVI-positivity rates with invasion of the superficial muscularis mucosa (SMM)/lamina propria mucosa (LPM)/deep muscularis mucosa (DMM), SM 1, 2, and 3 were 0, 75, 28.6, and 55.6%, respectively. CONCLUSIONS: Combined H-E staining and immunostaining is useful in diagnosing LVI in superficial BEA, particularly in endoscopically resected specimens.

INTRODUCTION: In laparoscopic gastrectomy, a method to locate the margin of an early-stage cancerous lesion that is invisible from the serosal surface and impalpable during laparoscopic procedures is needed to determine an appropriate transection line. We conducted a prospective study to develop a new marking method using preoperative submucosal injection of indocyanine green (ICG). METHODS: Patients undergoing laparoscopic gastrectomy for T1 gastric cancer were recruited. The first 11 patients comprised the learning set and the subsequent 18 patients the validation set. ICG was endoscopically injected in the submucosal layer of the stomach approximately 1 cm away from the tumor edge 1 or 3 days before surgery. The diameters of the visualized ICG were compared with those of a conventional marking method using India ink in 10 historical controls. RESULTS: In the learning set, the optimal amount of ICG was determined to be 0.1 mL at a concentration of 0.5 mg/mL. In the validation set, the same procedure was repeated. No technical problems or adverse reactions related to ICG injection were observed. In all cases, ICG was successfully detected, and negative surgical margins were pathologically confirmed. The mean long diameter of the visualized ICG fluorescence measured at the mucosal surface of the stomach was significantly smaller in the current study than in the historical controls in whom India ink was used (21 vs 52 mm, P < 0.0001). CONCLUSIONS: The preoperative submucosal ICG marking was safely performed and successfully detected without excessive blurring during laparoscopic gastrectomy.

BACKGROUND: Vascular invasion is an important criterion for resectability and deciding the therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC), but imaging diagnosis is currently difficult. Endoscopic ultrasound (EUS) elastography (EG) images have band-like artifacts on the border between tumor and vessel due to different movement if the tumor is not connected to the vessel, i.e., no invasion. Based on this phenomenon, we assessed the usefulness of EUS-EG in the diagnosis of vascular invasion in PDAC. METHODS: The subjects were 44 out of 313 patients with PDAC who underwent EUS between January 2015 and November 2018, followed by surgery, no chemotherapy or radiotherapy, and pathological evaluation. Diagnostic accuracies of vascular invasion using dynamic computed tomography (CT), EUS B-mode and EUS-EG were compared with histopathological diagnosis. RESULTS: In 44 subjects (48 sites) who underwent both dynamic CT and EUS-B mode, the sensitivity, specificity and accuracy were 0.733, 0.697 and 0.708 on dynamic CT (48 sites); 0.733, 0.606 and 0.646 in EUS B-mode (48 sites); and 0.917, 0.900 and 0.906 in EUS-EG (32 sites). In 27 subjects (29 sites) with a tumor contacting a vessel with no vascular obstruction or stenosis on dynamic CT, the sensitivity, specificity and accuracy were 0.556, 0.750 and 0.690 on dynamic CT; 0.667, 0.700 and 0.690 in EUS B-mode; and 0.889, 0.850 and 0.862 in EUS-EG. CONCLUSIONS: These results suggest that EUS combined with EG improves diagnostic performance of vascular invasion in PDAC, especially in cases of which vascular invasion cannot be clearly assessed by dynamic CT.

BACKGROUND: Double-balloon endoscopic retrograde cholangiography (DB-ERC) is widely performed for biliary diseases after reconstruction in gastrointestinal surgery, but there are few reports on DB-ERC after hepatectomy or living donor liver transplantation (LDLT). AIM: To examine the success rates and safety of DB-ERC after hepatectomy or LDLT. METHODS: The study was performed retrospectively in 26 patients (45 procedures) who underwent hepatectomy or LDLT (liver operation: LO group) and 40 control patients (59 procedures) who underwent pancreatoduodenectomy (control group). The technical success (endoscope reaching the choledochojejunostomy site), diagnostic success (performance of cholangiography), therapeutic success (completed interventions) and overall success rates, insertion and procedure (completion of DB-ERC) time, and adverse events were compared between these groups. RESULTS: There were no significant differences between LO and control groups in the technical [93.3% (42/45) vs 96.6% (57/59), P = 0.439], diagnostic [83.3% (35/42) vs 83.6% (46/55), P = 0.968], therapeutic [97.0% (32/33) vs 97.7% (43/44), P = 0.836], and overall [75.6% (34/45) vs 79.7% (47/59), P = 0.617] success rates. The median insertion time (22 vs 14 min, P < 0.001) and procedure time (43.5 vs 30 min, P = 0.033) were significantly longer in the LO group. The incidence of adverse events showed no significant difference [11.1% (5/45) vs 6.8% (4/59), P = 0.670]. CONCLUSION: DB-ERC after liver operation is safe and useful but longer time is required, so should be performed with particular care.

BACKGROUND: The feasibility of magnetic anchor-guided endoscopic submucosal dissection (MAG-ESD) using a neodymium magnet for colorectal tumors has not been evaluated. The aim of this study was to clarify the feasibility of MAG-ESD for colorectal tumors. METHODS: This prospective trial was conducted at Yamashita Hospital. MAG-ESD was performed for 49 colorectal tumors. The magnetic anchor comprised an internal magnet attached to an endoclip with 3-0 silk. Both external and internal magnets were made using neodymium magnets. The feasibility of traction achieved using MAG-ESD, en bloc resection rate, complete en bloc resection rate, time required for preparation and attachment of the magnetic anchor, procedure time, rate of retrieval of magnetic anchors, and adverse events were evaluated. RESULTS: MAG-ESDs were successfully performed for 48 colorectal tumors except for a rectal case in which the internal magnet stuck to the endoscope. En bloc resections and complete en bloc resections were achieved in all cases. Attaching the magnetic anchor required a median of 8 min (range 3-37 min). Median procedure time was 76 min (range 28-283 min) and the magnetic anchors were retrieved in all cases without adverse events. CONCLUSION: MAG-ESD is feasible and safe in the colon and may facilitate the treatment of all difficult lesions. (UMIN000024100).

BACKGROUND/AIM: Sorafenib results in several adverse events, the mechanism and predictors of which are unknown. Recently, it was reported that metabolism by microbiome changes the structure and effects of drugs. The blood levels of sorafenib may be affected by enterohepatic recycling of sorafenib due to microbial enzymes in the gut. We evaluated the relationship between adverse events caused by sorafenib treatment and microbiome in patients with advanced hepatocellular carcinoma. MATERIALS AND METHODS: Twenty-five patients were classified into two groups based on the presence of hand-foot syndrome (HFS) or diarrhea within 12 weeks post-sorafenib treatment. Before sorafenib treatment, the fecal samples were analyzed targeting the V3-V4 region of 16s ribosomal RNA. Microbiome and predicted functional gene were compared between two groups. RESULTS: The non-HFS group had a richer abundance of Veillonella, Bacillus, Enterobacter, Faecalibacterium, Lachnospira, Dialister, and Anaerostipes than the HFS group at genus level. Carotenoid biosynthesis and bacterial invasion of epithelial cells were enriched in the HFS group. The former three bacteria are classified as oral-origin bacteria, and the two predicted functions are associated with dysbiosis. The non-diarrhea group had a higher abundance of Butyricimonas and a lower abundance of Citrobacter, Peptostreptococcus, and Staphylococcaceae than the diarrhea group. Eight categories of predicted functional genes were detected with differences between the two groups. CONCLUSION: The non-HFS group had a higher relative abundance of oral-origin bacteria, which likely led to more robust dysbiosis in the gut. This dysbiosis may affect enterohepatic recycling. Additionally, the metabolism of these short-chain fatty acids in the gut may be different between the diarrhea and non-diarrhea groups.

BACKGROUND: There are a number of reports that demonstrate the high diagnostic accuracy of colon capsule endoscopy (CCE) for polyp detection. However, some colorectal polyps are missed on CCE, and the clinical factors influencing those missed polyps are still unknown. OBJECTIVE: The aim of this study was to elucidate the clinical factors related to missing colorectal polyp on CCE by using per-polyp analysis. METHODS: We performed a retrospective multi-center study of 53 consecutive patients who underwent both CCE and colonoscopy (CS) within 3 months from January 2014 to -December 2017. Of those patients, we analyzed 151 polyps detected on CCE, and 149 polyps detected on CS diagnosed as neoplasm according to histopathological result. RESULTS: The capsule excretion rate was 81%. One hundred three polyps were detected on both CS and CCE, 46 polyps (31%) were missed on CCE, and 48 polyps were considered false positive on CCE when CS result was considered as the gold standard. Per-polyp sensitivity and positive predictive value on CCE were 69.1 and 68%. On multiple logistic analysis, only the segmental transit time on CCE was identified as the independent factor influencing missed polyp on CCE. CONCLUSIONS: The clinical factor related to missing colorectal polyp on CCE was the segmental transit time.

OBJECTIVES: Accurate diagnosis of invasion depth is important for reliable treatment of esophageal squamous cell carcinoma (ESCC), but it is limited to the muscularis mucosae to slight submucosal invasion (MM/SM1). The diagnostic accuracy of invasion depth is unsatisfactory and remains to be improved. We aimed to investigate the association between the color of the superficial ESCC and invasion depth using linked color imaging (LCI) under light-emitting diode (LED) light sources. METHODS: Lesions diagnosed as superficial ESCC were observed using white light imaging and then by LCI. The color values were calculated using Commission Internationale de l'Eclariage - L*a*b* color space, and the color difference was calculated according to invasion depth. The vascular diameters and vascular angles of the intrapapillary capillary loops were pathologically analyzed. Their correlation with mucosal color was also investigated by LCI. RESULTS: In all, 52 lesions from 48 patients were analyzed. On the basis of invasion depth, the color difference between the normal mucosa and the lesion was larger in the MM/SM1 or deeper group than in the epithelium and the lamina propria mucosa (EP/LPM) group using LCI (P = 0.025). The vascular diameter was positively correlated with the b* color value (correlation coefficient = 0.302, P = 0.033). CONCLUSION: Observation using LCI under LED light sources may improve the endoscopic diagnosis of the invasion depth of superficial ESCC. Further research is needed to validate its usefulness. (UMIN000024615).

BACKGROUND AND AIM: Magnifying endoscopy is useful for diagnosis of early gastrointestinal neoplasms by visualizing microvascular (MV) and microsurface (MS) structures of the mucosa when combined with image-enhanced endoscopy. However, precise control of the endoscope is needed because the depth of focus is narrow and the target may move. These problems may be overcome by the all-in-focus (AIF) technique, which was developed in the engineering field. The aim of the study was to evaluate magnifying endoscopic image with AIF algorithm. METHODS: Twenty gastric neoplasms were examined. Images were acquired at 80× magnification and converted to endoscopic images with an AIF algorithm (EI-AIF). The focus area and MV and MS patterns in the original image and the EI-AIF were compared on a 5-point Likert scale, where 5 indicates that the EI-AIF was superior. Intraclass correlation coefficients (ICCs) were used to assess the inter-evaluator reliability. An image quality measurement value was calculated for each image as an indicator of the degree of focus. RESULTS: The scores for focus area, MV, and MS were 4.78 ± 0.45 (ICC = 0.63), 4.12 ± 0.76 (ICC = 0.70), and 4.72 ± 0.52 (ICC = 0.45), respectively, with the EI-AIF significantly superior for all three items (P < 0.05 by Student's t-test). ICCs for the focus area and MV were > 0.60, indicating strong inter-evaluator reliability. Image quality measurement was higher for the EI-AIF compared with the original image in every case. CONCLUSIONS: Endoscopic observation with AIF algorithm gives a better image quality that allows easier evaluation of MV and MS patterns. This technique may resolve the difficulties with magnifying endoscopic observation.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and the most common gastrointestinal lymphoma. The prognostic/predictive indicators among patients with gastric and intestinal DLBCL (giDLBCL) are controversial beyond their anatomical sites. We compared giDLBCL cases and investigated the clinical utility of newly emerging indicators with an emphasis on programmed cell death ligand 1 (PD-L1) expression. METHODS: This retrospective study included 174 patients with primary gastric (n = 129) or intestinal (n = 45) DLBCL treated with rituximab-containing chemotherapy between 1995 and 2018. RESULTS: Compared with gastric DLBCL (gDLBCL) cases, patients with intestinal DLBCL (iDLBCL) had a significantly higher rate of advanced Lugano stage (71% vs 37%, P < 0.001), perforation (13% vs. 0.8%, P = 0.001), PD-L1 expression on microenvironment immune cells (miPD-L1, 70% vs 46%, P = 0.008), CD10 positivity (47% vs 28%, P = 0.027), and CD5 positivity (9% vs 1.6%, P = 0.040). The iDLBCL patients showed significantly worse progression-free survival (PFS) and overall survival (OS) than gDLBCL cases (P = 0.0338 and P = 0.0077, respectively). PD-L1 expression on tumor cells was detected in only 3 (2%) of 174 cases with early relapse and/or an aggressive clinical course; whereas, miPD-L1-positive cases had significantly better OS than the miPD-L1-negative gDLBCL and iDLBCL cases (P = 0.0281 and P = 0.0061, respectively). Multivariate analysis revealed that miPD-L1 negativity (P = 0.030) was an independent adverse prognostic factor for OS in giDLBCL. CONCLUSIONS: The anatomical site of disease did not influence outcome in giDLBCL cases treated with rituximab-containing chemotherapy; while, miPD-L1 expression had a favorable impact on the outcome.

PURPOSE: The aim of this study was to evaluate the impact of cervical lymph node dissection on acid reflux and duodenogastroesophageal reflux (DGER) in patients undergoing transthoracic esophagectomy with gastric tube reconstruction and intrathoracic esophagogastrostomy. METHODS: Thirty-one patients receiving transthoracic esophagectomy with gastric tube reconstruction by intrathoracic esophagogastrostomy were divided into the following two groups: a two-field lymph node dissection group (2F group) and a three-field lymph node dissection group (3F group). All patients underwent 24-h pH and bilirubin monitoring and gastrointestinal endoscopy at 1 year after surgery. The 24-h pH and bilirubin monitoring results, endoscopic findings, and reflux symptoms were compared between the 2 groups. RESULTS: No acid reflux was observed in the 2F group, whereas it was observed in 6 (40%) patients in the 3F group (p = 0.007). DGER was found in 2 patients (13%) in the 2F group and in 8 (53%) in the 3F group (p = 0.023). Four patients (25%) in the 2F group and 9 (60%) in the 3F group (p = 0.048) had reflux esophagitis. CONCLUSION: Cervical lymph node dissection increases acid reflux and DGER and can lead to an increase in the incidence of reflux esophagitis in patients undergoing intrathoracic esophagogastrostomy.

In recent years, transnasal endoscopy had been more widely accepted for its safety and convenience, and although it can lead to a weaker pharyngeal reflex, compared with the effects of transoral endoscopy, examinees often suffer intolerable pain and discomfort during passage of the endoscope through the nasal cavity. The aim of this study was to estimate the relationship between the uncomfortable factors during transnasal endoscopy and nasal patency. The subjects comprised 23 consecutive patients who underwent transnasal endoscopy from October 2007 to April 2009 at our Gastroenterology and Otorhinolaryngology Departments. Immediately prior to endoscopy, the left and right nasal resistance was measured with an active anterior rhinomanometer; a value of 100 Pa was determined as nasal resistance. The transnasal endoscope was inserted in the subjectively preferred side by the examinee. Thereafter, the subjects were asked to fill in a questionnaire on physical tolerance during the procedure, to quantify the sensations of nasal pain, nausea, and choking on a 10-point visual analogue scale. The mean scores were 3.0 ± 2.7 for nasal pain, 1.7 ± 2.0 for choking, and 1.6 ± 1.9 for nausea. The most intolerable factor among the complaints was pain (45%), which was followed by nausea (18%) and choking (9%). Unilateral nasal resistance was significantly related with nasal pain only (P = 0.0135). In conclusion, the most difficult problem during transnasal endoscopy was pain, which was related to nasal patency. We successfully demonstrated the clinical significance of nasal patency in determining the side of insertion for transnasal endoscopy.

Evaluation of the pancreatic elastic modulus (PEM) using shear wave elastography (SWE) requires at least 5 measurements to ensure reproducibility. The aim of this study was to evaluate improvement in reproducibility of SWE, using the propagation display method in normal pancreas ([NP] phase 1) and to examine the differences in PEM between NP and chronic pancreatitis (CP), intraductal papillary mucinous neoplasm (IPMN) and autoimmune pancreatitis ([AIP] phase 2). In phase 1, the measurement success rate, median PEM in repeated measurements and appropriate number of SWE measurements were determined in 109 cases with NP. In phase 2, PEM was measured in CP (n = 10), IPMN (n = 31) and AIP (n = 5), using the required number of SWE measurements determined in phase 1. In phase 1, the measurement success rate was 93.9% (92/109 cases). The median PEM for NP was 14.6 kPa and the appropriate number of SWE measurements was at least 3. In phase 2, the median PEMs in CP, IPMN and AIP were 19.6, 18.1 and 17.2 kPa, respectively, with significant differences between NP and CP (p = 0.0133) and between NP and IPMN (p = 0.0436). Use of the propagation display method in SWE improves the reproducibility of measurement of PEM.

OBJECTIVES: The time to recurrent biliary obstruction (TRBO) of unresectable distal malignant biliary obstruction is generally thought to be longer when a self-expandable metal stent (SEMS) with a thicker inner diameter is used for drainage, but the dependence on the inner diameter using a fully covered SEMS (FCSEMS) is uncertain. The objective of this multicenter prospective study was to compare TRBO and adverse events, such as cholecystitis and pancreatitis, in treatment of patients with unresectable malignant biliary obstruction using 8- and 10-mm diameter FCSEMS. METHODS: Eighteen tertiary-care centers participated in the study. Patients were allocated to the 8- and 10-mm diameter groups. TRBO, non-inferiority of the 8-mm FCSEMS, overall survival time, frequency and type of adverse events, and non-recurrent biliary obstruction (RBO) rate at the time of death were compared between the two groups. RESULTS: Median TRBO did not differ significantly between the 8-mm (n = 102) and 10-mm (n = 100) groups (275 vs 293 days, P = 0.971). The hazard ratio of the 8- to 10-mm groups was 0.90 (80% confidence interval, 0.77-1.04; upper limit lower than the acceptable hazard ratio [1.33] of the null hypothesis). Based on these findings, the 8-mm diameter stent was determined to be non-inferior to the 10-mm diameter stent. Survival time, incidence of adverse events and non-RBO rate at the time of death did not differ significantly between the two groups. CONCLUSIONS: Time to RBO with an 8-mm diameter FCSEMS was non-inferior to that with a 10-mm diameter FCSEMS. This finding is important for development of future SEMS.

Resistance to anticancer drugs is a critical issue in cancer treatment. Alterations in gene expression and DNA methylation profiles that accompany the acquisition of drug resistance are associated with resistance mechanisms. To analyze chemotherapy-associated alterations in gene expression and DNA methylation in gastric cancer cells obtained from ascites, ascitic fluids were collected from a patient with gastric cancer before chemotherapy with capecitabine and oxaliplatin (CapeOX), and after the disease had progressed. The fluids were cultured for 10 days, passaged into new flasks, and cultured for an additional 2 weeks. Normal cells, including white blood cells and mesothelial cells, were removed. The expression and DNA methylation profiles of 18,185 genes were analyzed using microarray, and compared between cells in ascitic fluids collected before and after the chemotherapy with CapeOX. In addition, fluorouracil- and oxaliplatin-resistant AGS cells were established and analyzed. Pathways having genes with expression profiles altered by CapeOX included those associated with 'signaling by G-protein-coupled receptor' and the 'immune system'. Genes that were commonly expressed at higher levels in CapeOX-resistant ascitic cells, fluorouracil-resistant AGS cells. and oxaliplatin-resistant AGS cells compared with those in untreated cells included telomerase reverse transcriptase (TERT), apolipoprotein C1 (APOC1) and serine/threonine/tyrosine kinase 1 (STYK1), whereas genes commonly expressed at lower levels in the three drug-resistant cell types compared with the untreated cells included defensin β4A (DEFB4A). A comparatively large number of genes exhibited altered methylation levels in drug-resistant AGS cells compared with the CapeOX-resistant cells. In addition, among the genes expressed at higher levels in decitabine-treated AGS cells, the majority were expressed at higher levels in fluorouracil-resistant AGS cells, and exhibited lower methylation levels. Taken together, the present study has demonstrated that comparing the expression profiles of gastric cancer cells obtained from ascitic fluids before and after chemotherapy with the expression profiles of drug-resistant cultured cells is a useful method for analyzing the molecular mechanisms underlying chemotherapy resistance.

Many researchers suggested that ultrathin endoscopy improves patient acceptance of endoscopic examinations. However, ultrathin endoscopy provides less image resolution and luminous intensity. Therefore, we focused on the visibility of early gastric cancer on ultrathin endoscopy with Flexible spectral imaging color enhancement (FICE) in this study. Thirty-six patients with early gastric cancer were prospectively enrolled. One endoscopist performed the endoscopic examinations by white light conventional endoscopy (W-CE), white light ultrathin endoscopy (W-UE), FICE ultrathin endoscopy (F-UE) and white light plus FICE ultrathin endoscopy (WF-UE) in the patients. Four other endoscopists were asked to evaluate the visibility of gastric cancer on the W-CE, W-UE, F-UE and WF-UE images with a 5-point Likert scale. The lesions were classified as uncolored, normocolored or reddish. We examined the color difference between early gastric cancer and the surrounding mucosa. To examine the relationship between the color difference and the vessel density, we also measured the difference in vessel density using pathologic specimens stained with hematoxylin and eosin. The Likert score of WF-UE was significantly higher than those of the other three methods (p<0.001). The color difference of F-UE was higher than that of W-CE in the reddish group (p=0.049). The difference in vessel density was higher in the reddish group than in the normocolored group (p=0.048). In conclusion, the visibility of early gastric cancer from the surrounding mucosa using ultrathin endoscopy with FICE was better than that using white light conventional endoscopy, especially for reddish lesions.

Plummer-Vinson syndrome is a rare entity, characterized by dysphagia, esophageal web formation, and iron deficiency anemia. The patient was a 63-year-old woman with a clinical history of iron deficiency anemia and glossitis in her 20s to 40s and who had experienced swallowing difficulties for the past 20 years. A membranous stricture was found in the cervical esophagus during a fluoroscopic examination. An endoscopic examination conducted under general anesthesia revealed an oblique linear scar on the proximal surface of the stricture. Sequential balloon dilation was performed successfully. We suggest that the esophageal web formation might have been related to the healing of an esophageal ulcer.

BACKGROUND: Linked color imaging (LCI) is a method of endoscopic imaging that emphasizes slight differences in red mucosal color. AIM: To evaluate LCI in diagnostic endoscopy of early gastric cancer and to compare LCI and pathological findings. METHODS: Endoscopic images were obtained for 39 patients (43 lesions) with early gastric cancer. Three endoscopists evaluated lesion recognition with white light imaging (WLI) and LCI. Color values in Commission Internationale de l'Eclairage (CIE) 1976 L*a*b* color space were used to calculate the color difference (ΔE) between cancer lesions and non-cancer areas. After endoscopic submucosal dissection, blood vessel density in the surface layer of the gastric epithelium was evaluated pathologically. The identical region of interest was selected for analyses of endoscopic images (WLI and LCI) and pathological analyses. RESULTS: LCI was superior for lesion recognition (P < 0.0001), and ΔE between cancer and non-cancer areas was significantly greater with LCI than WLI (29.4 vs 18.6, P < 0.0001). Blood vessel density was significantly higher in cancer lesions (5.96% vs 4.15%, P = 0.0004). An a* cut-off of ≥ 24 in CIE 1976 L*a*b* color space identified a cancer lesion using LCI with sensitivity of 76.7%, specificity of 93.0%, and accuracy of 84.9%. CONCLUSION: LCI is more effective for recognition of early gastric cancer compared to WLI as a result of improved visualization of changes in redness. Surface blood vessel density was significantly higher in cancer lesions, and this result is consistent with LCI image analysis.

Pancreatic cancer is one of the most aggressive human cancers and is associated with a poor prognosis. To develop a novel strategy for pancreatic cancer treatment, it is essential to elucidate the molecular mechanisms underlying the invasion and proliferation of cancer cells. ATPase family AAA domain containing protein 2 (ATAD2) is a highly conserved protein with an AAA+ domain and a bromodomain. Accumulating studies have demonstrated that ATAD2 is associated with the progression of multiple cancers. The present study demonstrated that ATAD2 depletion suppressed cell invasion and migration. In addition, ATAD2 knockdown suppressed anchorage-independent growth of pancreatic cancer cells. Finally, ATAD2 depletion was demonstrated to sensitize pancreatic cancer cells to gemcitabine. The results of the present study indicate that ATAD2 is involved in the malignant characteristics of pancreatic cancer.