Yoichi Akazawa

Procedure Time for Gastric Endoscopic Submucosal Dissection according to Location, considering Both Mucosal Circumferential Incision and Submucosal Dissection

Background. Previous assessments of technical difficulty and procedure time for endoscopic submucosal dissection (ESD) of gastric neoplasms did not take into account several critical determinants of these parameters. However, two key phases of ESD determine the total procedure time: the mucosal circumference incision speed (CIS) and submucosal dissection speed (SDS). Methods. We included 302 cases of en bloc and R0 resection of gastric neoplasms performed by 10 operators who had completed the training program at our hospital. Twelve locations were classified based on multiple criteria, such as condition of surrounding mucosa, lesion vascularity, presence of submucosal fat, ulcers, scars, fibrosis, and scope and device maneuverability. Lesions in different locations were classified into three groups based on the length of the procedure: fast, moderate, or late. Results. A significant difference was found in CIS and SDS for each location (p < 0.01), which demonstrates the validity of this classification system. In several locations, CIS and SDS were not consistent with each other. Conclusion. CIS and SDS did not correspond to each other even for lesions in the same location. Consideration of ESD procedure time for gastric neoplasms requires a more elaborate classification system than that previously reported.

Clinicopathological features of alpha-fetoprotein producing early gastric cancer with enteroblastic differentiation

AIM To investigate clinicopathological features of early stage gastric cancer with enteroblastic differentiation (GCED). METHODS We retrospectively investigated data on 6 cases of early stage GCED and 186 cases of early stage conventional gastric cancer (CGC: well or moderately differentiated adenocarcinoma) who underwent endoscopic submucosal dissection or endoscopic mucosal resection from September 2011 to February 2015 in our hospital. GCED was defined as a tumor having a primitive intestine-like structure composed of cuboidal or columnar cells with clear cytoplasm and immunohistochemical positivity for either alpha-fetoprotein, Glypican 3 or SALL4. The following were compared between GCED and CGC: age, gender, location and size of tumor, macroscopic type, ulceration, depth of invasion, lymphatic and venous invasion, positive horizontal and vertical margin, curative resection rate. RESULTS Six cases (5 males, 1 female; mean age 75.7 years; 6 lesions) of early gastric cancer with a GCED component and 186 cases (139 males, 47 females; mean age 72.7 years; 209 lesions) of early stage CGC were investigated. Mean tumor diameters were similar but rates of submucosal invasion, lymphatic invasion, venous invasion, and non-curative resection were higher in GCED than CGC (66.6% vs 11.4%, 33.3% vs 2.3%, 66.6% vs 0.4%, 83.3% vs 11% respectively, P < 0.01). Deep submucosal invasion was not revealed endoscopically or by preoperative biopsy. Histologically, in GCED the superficial mucosal layer was covered with a CGC component. The GCED component tended to exist in the deeper part of the mucosa to the submucosa by lymphatic and/or venous invasion, without severe stromal reaction. In addition, Glypican 3 was the most sensitive marker for GCED (positivity, 83.3%), immunohistochemically. CONCLUSION Even in the early stage GCED has high malignant potential, and preoperative diagnosis is considered difficult. Endoscopists and pathologists should know the clinicopathological features of this highly malignant type of cancer.

Efficacy of a potassium‑competitive acid blocker for improving symptoms in patients with reflux esophagitis, non‑erosive reflux disease, and functional dyspepsia

The aim of the present study was to investigate the efficacy of a potassium-competitive acid blocker (PCAB) named vonoprazan (VPZ) for improving symptoms in patients with reflux esophagitis (RE), non-erosive reflux disease (NERD), and functional dyspepsia (FD). A hospital-based, retrospective study of outpatients in our department (Department of Gastroenterology, University of Juntendo, Tokyo, Japan) between March 2015 and August 2016 was performed. The patients who were experiencing heartburn, acid regurgitation, gastric pain, and/or a heavy feeling in the stomach of at least moderate severity at baseline were treated with 20 mg VPZ once daily for 4 weeks. The patients completed the global overall symptom (GOS) scale to determine their symptom severity at baseline and after the 4 week treatment period. The proportions of patients with RE, NERD, and FD achieving improvement of their symptoms, defined as a GOS scale score of 1 (‘no problem’) or 2 (‘minimal problem’), were evaluated. During 4 weeks of VPZ therapy, changes in the gastroesophageal reflux disease (GERD) score, which was defined as the total points for heartburn and acid regurgitation on the GOS scale in patients with RE and NERD, and in the FD score, which was defined as the total points for gastric pain and a heavy feeling in the stomach on the GOS scale in patients with FD, were also evaluated. A total of 88 eligible cases were included in the present study, comprising 20 patients with RE, 25 patients with NERD, and 43 patients with FD. The rates of symptomatic improvement in patients with RE, NERD, and FD were 75.0, 60.0, and 48.8%, respectively. For the patients who were first administered VPZ, the rates of symptomatic improvement were 90.9, 66.7, and 58.8% in patients with RE, NERD, and FD, respectively. For those patients who were resistant to 8 weeks of proton pump inhibitor therapy, the rates of symptomatic improvement were 55.6, 53.8, and 42.3% in patients with RE, NERD, and FD, respectively. The GERD score in patients with RE and NERD, and the FD score in FD patients, were decreased after 4 weeks of VPZ therapy (P<0.01). In patients with RE, NERD and FD, the possibility that PCAB may be used as a novel therapeutic drug was suggested. However, the number of study subjects was small; therefore, further, larger and prospective studies are required.

Association of medications for lifestyle-related diseases with reflux esophagitis.

Background Because of a change in lifestyle, especially adoption of westernized eating habits, lifestyle-related diseases have become increasingly prevalent. The aim of this study was to investigate the association of medications for lifestyle-related diseases with reflux esophagitis (RE). Methods We conducted a hospital-based, cross-sectional retrospective study of consecutive outpatients who received an upper gastrointestinal endoscopy in our department from February 2008 to November 2014, which was performed by one specialist who was a member of the Japan Gastroenterological Endoscopy Society. We investigated the patient profile, Helicobacter pylori (H. pylori) infection status, medications for lifestyle-related diseases (including calcium channel blockers, statins, and bisphosphonates), and upper gastrointestinal endoscopic findings (RE, hiatal hernia, Barrett’s mucosa, and endoscopic gastric mucosal atrophy [EGA]). Patients with gastrectomy, peptic ulcer disease, gastric or esophageal malignant disease, and those who used proton pump inhibitors or histamine-2 receptor antagonists were excluded. We divided the subjects into a group without RE (RE(−)) and a RE (RE(+)) group as judged by endoscopy, and investigated the risk factors for RE. Results Of 1,744 consecutive cases, 590 cases (300 males and 290 females; mean age 60.5±13.2 years) were eligible. RE(−) and RE(+) cases numbered 507 and 83, respectively. Bivariate analysis showed significant positive associations of RE with male sex, body mass index (BMI), calcium channel blockers, Barrett’s mucosa, hiatal hernia and negative associations of RE with H. pylori positivity, EGA. Multivariate analysis showed significant positive associations of RE with BMI (odds ratio [OR]: 1.20, 95% confidence interval [95% CI]: 1.10–1.29), use of calcium channel blockers (OR: 2.12, 95% CI: 1.16–3.87), Barrett’s mucosa (OR: 2.97, 95% CI: 01.64–5.38), hiatal hernia (OR: 3.13, 95% CI: 1.79–5.47) and negative associations of RE with H. pylori positivity (OR: 0.20, 95% CI: 0.07–0.57), use of statins (OR: 0.42, 95% CI: 0.18–0.96), and EGA (OR: 0.83, 95% CI: 0.70–0.98). Conclusion Calcium channel blockers were positively associated with RE and statins were negatively associated with RE, while bisphosphonates were not associated with RE.

Next-generation sequencing analysis for gastric adenocarcinoma with enteroblastic differentiation: emphasis on the relationship with hepatoid adenocarcinoma

Histologically tubulopapillary structures with glycogen-rich clear cytoplasm in gastric adenocarcinoma with enteroblastic differentiation (GAED) are well known, but a solid growth pattern can also be observed as a minor component. In contrast, hepatoid adenocarcinoma (HAC) of the stomach shows many overlapping features, including solid pattern and α-fetoprotein expression. In this study, we employed next-generation sequencing (NGS) to establish a molecular/clinicopathological concept of GAED and clarify whether these two tumors should be grouped together in one category. Among 2273 primary gastric cancers treated in our hospital between 2008 and 2017, we defined 51 cases as GAEDs showing tubulopapillary or solid patterns that express at least one of the following markers: α-fetoprotein, glypican-3, or spalt-like transcription factor 4. All cases previously diagnosed as HAC in our hospital had clear cytoplasm and were included as GAEDs by histological re-evaluation and immunohistochemical findings. We performed NGS for 24 histologically typical GAEDs and Sanger sequencing for the remaining cases. The most frequently mutated gene was TP53, and almost all cases with missense mutation showed p53 overexpression. An analysis of copy number variation revealed that ERBB2 amplification was the most frequent in GAED. Additionally, HER2 immunohistochemistry and fluorescence in situ hybridization confirmed that 22% of informative cases were HER2 positive. There was no correlation between molecular/clinicopathological parameters and α-fetoprotein expression or growth patterns in GAED. Our analysis showed that GAED frequently harbors TP53 mutations and ERBB2 amplification. As with conventional gastric adenocarcinoma, trastuzumab may be effective for GAED. Furthermore, HAC may be subcategorized as a solid-type GAED.

Efficacy of alfacalcidol and alendronate on lumbar bone mineral density in osteoporotic patients using proton pump inhibitors

It has been indicated that proton pump inhibitor (PPI) use is associated with a loss of the anti-fracture efficacy of alendronate (AD). However, there are few prospective studies that have investigated the efficacy of AD on lumbar bone mineral density (BMD) in osteoporotic patients who are using PPIs. Thus, the aim of the present study was to investigate the efficacy of alfacalcidol (AC) and AD on lumbar BMD in osteoporotic patients using PPIs. A prospective, randomized, active control study enrolled such osteoporotic patients (age, ≥50 years). The patients were randomly assigned to receive AC (1 µg/day) or AD (35 mg/week) and were followed up for one year. Patient profiles were maintained, and lumbar BMD, bone-specific alkaline-phosphatase (BAP) and collagen type-I cross-linked N-telopeptide (NTX), upper gastrointestinal endoscopy results, and the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) were evaluated. Percentage changes in lumbar BMD, NTX, BAP, and change in FSSG score from baseline to the end of one year of treatment were investigated. Sixteen patients were eligible for analysis (eight assigned to receive AC, eight assigned to receive AD). The percentage change in lumbar BMD from baseline to the end of treatment was −0.4±4.0% for the AC group vs. 6.8±6.3% for the AD group (P=0.015). No significant percentage change of BAP and NTX between the two groups was observed. Subsequent to one year of treatment, the FSSG score did not change from the baseline values for either study group, and no new bone fractures or esophagitis were observed in either group of patients. The findings demonstrated that in osteoporotic patients using concomitant PPIs, there was a greater increase in lumbar BMD after one year of treatment with AD compared with AC. However, the number of study subjects was small; thus, further, large prospective studies are required to determine the effect of AD in osteoporotic patients using concomitant PPIs.

Immunohistochemical and genetic characteristics of a colorectal mucin-rich variant of traditional serrated adenoma

Recently, several morphological variants of traditional serrated adenoma (TSA) of the colorectum have been recognised, and mucin‐rich TSA (MR‐TSA) and serrated tubulovillous adenoma (S‐TVA) were introduced as distinct morphological variants separate from conventional TSA (C‐TSA). This aim of this study was to elucidate the immunohistochemical and genetic characteristics of MR‐TSAs.

Effect of Esophageal Endoscopic Submucosal Dissection on Motility and Symptoms: A Prospective Study

Background Endoscopic submucosal dissection (ESD) of esophageal tumors can cause stenosis, yet the effect of esophageal ESD on motility remains unclarified. This study aimed to compare esophageal motility and symptoms, before and after ESD, using high-resolution manometry (HRM) and symptom scoring. Methods Twenty-eight patients with 35 cT1a cancers were prospectively enrolled between December 2014 and February 2016. Pre- and post-ESD symptom score and HRM were recorded. Based on circumferential resection (CR), patients were divided into group A (n = 17, <2/3 CR) or B (n = 11, 2/3 CR or greater). HRM parameters evaluated were distal contractile integral (DCI), contractile front velocity (CFV), intrabolus pressure, integrated relaxation pressure, distal latency, and peristaltic breaks. Results Symptom scores worsened after ESD in 8/11 patients in group B, and 0/17 patients in group A. There was no significant difference in any HRM parameter after ESD in the whole study group but mean DCI tended to increase (p = 0.07). In group B, DCI increased significantly after ESD (p = 0.04), and CFV tended to decrease after ESD (p = 0.08). Conclusions DCI tended to increase after esophageal ESD. ESD affected the symptom score and esophageal motility in cases with 2/3 CR or greater. This trial is registered with UMIN000015829.

Improved Visibility of Barrett’s Esophagus with Linked Color Imaging: Inter- and Intra-Rater Reliability and Quantitative Analysis

Background/Aims: To evaluate the usefulness of linked color imaging (LCI) and blue LASER imaging (BLI) in Barrett’s esophagus (BE) compared with white light imaging (WLI). Methods: Five expert and trainee endoscopists compared WLI, LCI, and BLI images obtained from 63 patients with short-segment BE. Physicians assessed visibility as follows: 5 (improved), 4 (somewhat improved), 3 (equivalent), 2 (somewhat decreased), and one (decreased). Scores were evaluated to assess visibility. The inter- and intra-rater reliability (intra-class correlation coefficient) of image assessments were also evaluated. Images were objectively evaluated based on L* a* b* color values and color differences (ΔE*) in a CIELAB color space system. Results: Improved visibility compared with WLI was achieved for LCI: 44.4%, BLI: 0% for all endoscopists; LCI: 55.6%, BLI: 1.6% for trainees; and LCI: 47.6%, BLI: 0% for experts. The visibility score of trainees compared with experts was significantly higher for LCI (p = 0.02). Intra- and inter-rater reliability ratings for LCI compared with WLI were “moderate” for trainees, and “moderate-substantial” for experts. The ΔE* revealed statistically significant differences between WLI and LCI. Conclusion: LCI improved the visibility of short-segment BE compared with WLI, especially for trainees, when evaluated both subjectively and objectively.

Usefulness of Demarcation of Differentiated-Type Early Gastric Cancers after Helicobacter pylori Eradication by Magnifying Endoscopy with Narrow-Band Imaging

Background/Aims: Early gastric cancer after Helicobacter pylori (Hp) eradication is difficult to demarcate. We used the vessel plus surface classification system (VSCS) to determine whether magnifying endoscopy with narrow-band imaging (ME-NBI) could demarcate differentiated-type early gastric cancers after Hp eradication, and to identify causes of an unclear demarcation line (DL). Methods: Among 100 lesions of differentiated-type early gastric cancer resected endoscopically, 34 lesions in the Hp-eradicated group and 66 in the Hp-infected group were retrospectively compared. Clinicopathological factors and ME-NBI findings, including the presence or absence of the DL, were examined. Histopathologically, histological gastritis, the surface structure at the tumor border, well-differentiated adenocarcinoma with low-grade atypia (tub1-low), and non-neoplastic epithelium (NE) coverage rate on the tumor surface and at the tumor border were evaluated. Results: DL (–) cases were more frequent in the Hp-eradicated group (11.8%, 4/34) than in the Hp-infected group (1.5%, 1/66; p < 0.05). The Hp-eradicated group had a higher NE coverage rate than the Hp-infected group (p < 0.05). All DL (–) cases had tub1-low or NE at the tumor border. Conclusion: ME-NBI with VSCS can identify the DL in most patients (88.2%) with differentiated-type early gastric cancer after Hp eradication.