金子 達哉

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2lowH3K27me3high cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.

Background/Aims: Esophageal motility disorders (EMDs) contribute to the pathophysiology of gastroesophageal reflux disease. However, the causes of EMDs and their impact on gastroesophageal reflux disease-associated symptoms remain unknown. This study aims to elucidate clinical features associated with various types of EMDs in patients with heartburn symptoms. Methods: Of the 511 patients who underwent high-resolution manometry, 394 who were evaluated for heartburn symptoms were examined. Patients subjected to high-resolution manometry were classified into 4 groups: outflow obstruction group, hypermotility group, hypomotility group, and normal motility group. Symptoms were evaluated using 3 questionnaires. Patient characteristics and symptoms for each EMD type were compared with those of the normal motility group. Results: Of the 394 patients, 193 (48.9%) were diagnosed with EMDs, including 71 with outflow obstruction, 15 with hypermotility, and 107 with hypomotility. The mean dysphagia score was significantly higher in each of the 3 EMD groups compared with those with normal motility. The mean acid reflux and dyspepsia scores were significantly lower in the outflow obstruction group (P < 0.05). The mean body mass index and median Brinkman index were significantly higher in the hypermotility group (P = 0.001 and P = 0.018, respectively), whereas the mean diarrhea and constipation scores were significantly lower in the hypomotility group (P < 0.05). Conclusions: The results of our study indicate that different EMDs have distinct characteristics. Cigarette smoking and high body mass index were associated with esophageal hypermotility. Assessment of the dysphagia symptom scores may help identify patients with EMDs.

BACKGROUND: This study aimed to prevent missing gastric cancer and point out low-quality images by developing a double-check support system (DCSS) for esophagogastroduodenoscopy (EGD) still images using artificial intelligence. METHODS: We extracted 12,977 still EGD images from 855 cases with cancer [821 with early gastric carcinoma (EGC) and 34 malignant lymphoma (ML)] and developed a lesion detection system using 10,994 images. The remaining images were used as a test dataset. Additional validation was performed using a new dataset containing 50 EGC and 1,200 non-GC images by comparing the interpretation of ten endoscopists (five trainees and five experts). Furthermore, we developed another system to detect low-quality images, which are not suitable for diagnosis, using 2198 images. RESULTS: In the validation of 1983 images from the 124 cancer cases, the DCSS diagnosed cancer with a sensitivity of 89.2%, positive predictive value (PPV) of 93.3%, and an accuracy of 83.3%. EGC was detected in 93.2% and ML in 92.5% of cases. Comparing with the endoscopists, sensitivity was significantly higher in the DCSS, and the average diagnostic time was significantly shorter using the DCSS than that by the trainees. The sensitivity, specificity, PPV, and accuracy in detecting low-quality images were 65.8%, 93.1%, 79.6%, and 85.2% for "Blur" and 57.8%, 91.7%, 82.2%, and 78.1% for "Mucus adhesion," respectively. CONCLUSIONS: The DCSS showed excellent capability in detecting lesions and pointing out low-quality images.

The genetic characteristics of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) in the Japanese population is unclear. This study aims to investigate the genetic characteristics from nondysplastic BE (NDBE) to early EAC in Japan. Clinical information was collected. Moreover, the genetic profile of NDBE without concurrent dysplasia, early EAC, and surrounding BE were also investigated using endoscopic biopsy samples and formalin-fixed, paraffin-embedded specimens from Japanese patients by targeted next-generation sequencing. Immunohistochemical staining for p53 was also performed for EAC lesions. Targeted NGS was performed for 33 cases with 77 specimens. No significant difference exists in the NDBE group between the number of putative drivers per lesion in the short-segment Barrett's esophagus (SSBE) and long-segment Barrett's esophagus (LSBE) [0 (range, 0-1) vs. 0 (range, 0-1). p = 1.00]. TP53 putative drivers were found in two patients (16.7%) with nondysplastic SSBE. TP53 was the majority of putative drivers in both BE adjacent to EAC and EAC, accounting for 66.7% and 66.7%, respectively. More putative drivers per lesion were found in the EAC than in the NDBE group [1 (range, 0-3) vs. 0 (range, 0-1). p < 0.01]. The genetic variants of TP53 in the Japanese early EAC were similar to those in western countries. However, TP53 putative drivers were detected even in Japanese patients with nondysplastic SSBE. This is significant because such nondysplastic SSBE might have higher risk of progressing to high-grade dysplasia or EAC. The risks of progression may not be underestimated and appropriate follow-ups may be necessary even in patients with SSBE.Trial registration: This study was registered at the University Hospital Medical Information Network (UMIN000034247).

BACKGROUND AND AIM: The effectiveness of cold snare polypectomy (CSP) for superficial non-ampullary duodenal epithelial tumors (SNADETs) regarding long-term outcomes is not fully clarified. This study aimed to investigate long-term outcomes of CSP for SNADETs. METHODS: Patients diagnosed with sporadic SNADETs and treated with CSP at Chiba University Hospital between March 2015 and May 2018 were retrospectively analyzed. Long-term outcomes, short-term outcomes, and adverse events were investigated. RESULTS: In total, 35 patients with 46 lesions were included. The en-bloc resection rate was 97.8%. Thirty-seven lesions (80.4%) were diagnosed as adenomatous. The R0 resection rate for adenomatous lesions was 70.3%. Follow-up investigations more than 12 months after CSP were completed for 35 adenomatous lesions (94.6%). The median observation period after CSP was 48 months. One patient whose observation period was only 3 months died from chronic heart failure with cardiac sarcoidosis 6 months after CSP. No patient died from SNADETs. The relapse-free survival rate at 12 months after CSP was 97.1%. One recurrence (2.7%) was observed 12 months after CSP. We removed the recurrence lesion with CSP and cold forceps polypectomy. No new recurrence occurred within the observation period. No perforation or post-operative bleeding occurred for CSP. CONCLUSIONS: Cold snare polypectomy for diminutive and small SNADETs is a safe and useful procedure with a high en-bloc resection rate and long-term local control capability.

Somatic mutations including the background mucosa in patients with Lugol-voiding lesions (LVLs) are still not well known. The aim of this study was to evaluate the somatic mutations of the background mucosa in patients with LVLs (Squamous cell carcinoma (SCC), intraepithelial neoplasia (IN), and hyperplasia). Twenty-five patients with LVLs (9 with SCC, 6 with IN, and 10 with hyperplasia) were included. A targeted sequence was performed for LVLs and background mucosa using an esophageal cancer panel. Each mutation was checked whether it was oncogenic or not concerning OncoKB. In LVLs, TP53 was the most dominant mutation (80%). Furthermore, 72% of TP53 mutations was putative drivers. In background mucosa, NOTCH1 was the most dominant mutation (88%) and TP53 was the second most dominant mutation (48%). Furthermore, 73% of TP53 mutations and 8% of NOTCH1 mutations were putative drivers. Putative driver mutations of TP53 had significantly higher allele frequency (AF) in SCC than in IN and hyperplasia. Conversely, putative driver mutations of NOTCH1 did not have a significant accumulation of AF in the progression of carcinogenesis. Furthermore, in SCC, AF of TP53 mutations was significantly higher in LVLs than in background mucosa, but not in IN and hyperplasia. Regarding NOTCH1, a significant difference was not observed between LVLs and background mucosa in each group. The background mucosa in patients with LVLs already had putative driver mutations such as TP53 and NOTCH1. Of these two genes, TP53 mutation could be the main target gene of carcinogenesis in esophageal SCC. Clinical Trials registry: UMIN000034247.

In 2020, Olympus Medical Systems Corporation introduced the Texture and Color Enhancement Imaging (TXI) as a new image-enhanced endoscopy. This study aimed to evaluate the visibility of neoplasms and mucosal atrophy in the upper gastrointestinal tract through TXI. We evaluated 72 and 60 images of 12 gastric neoplasms and 20 gastric atrophic/nonatrophic mucosa, respectively. The visibility of gastric mucosal atrophy and gastric neoplasm was assessed by six endoscopists using a previously reported visibility scale (1 = poor to 4 = excellent). Color differences between gastric mucosal atrophy and nonatrophic mucosa and between gastric neoplasm and adjacent areas were assessed using the International Commission on Illumination L*a*b* color space system. The visibility of mucosal atrophy and gastric neoplasm was significantly improved in TXI mode 1 compared with that in white-light imaging (WLI) (visibility score: 3.8 ± 0.5 vs. 2.8 ± 0.9, p < 0.01 for mucosal atrophy; visibility score: 2.8 ± 1.0 vs. 2.0 ± 0.9, p < 0.01 for gastric neoplasm). Regarding gastric atrophic and nonatrophic mucosae, TXI mode 1 had a significantly greater color difference than WLI (color differences: 14.2 ± 8.0 vs. 8.7 ± 4.2, respectively, p < 0.01). TXI may be a useful observation modality in the endoscopic screening of the upper gastrointestinal tract.

BACKGROUND AND AIMS: Endoscopic treatment is recommended for low-grade dysplasia (LGD), high-grade dysplasia (HGD), and colorectal cancer (CRC) with submucosal (SM) invasion <1000 μm. However, diagnosis of invasion depth requires experience and is often difficult. This study developed and evaluated a novel computer-aided diagnosis (CAD) system to determine whether endoscopic treatment is appropriate for colorectal lesions using only white-light endoscopy (WLE). METHODS: We extracted 3442 images from 1035 consecutive colorectal lesions (105 LGDs, 377 HGDs, 107 CRCs with SM <1000 μm, 146 CRCs with SM ≥1000 μm, and 300 advanced CRCs). All images were WLE, nonmagnified, and nonstained. We developed a novel CAD system using 2751 images; the remaining 691 images were evaluated by the CAD system as a test set. The capability of the CAD system to distinguish endoscopically treatable lesions and untreatable lesions was assessed and compared with the results from 2 trainees and 2 experts. RESULTS: The CAD system distinguished endoscopically treatable from untreatable lesions with 96.7% sensitivity, 75.0% specificity, and 90.3% accuracy. These values were significantly higher than those from trainees (92.1%, 67.6%, and 84.9%; P < .01, <.01, and <.01, respectively) and were comparable with those from experts (96.5%, 72.5%, and 89.4%, respectively). Trainees assisted by the CAD system demonstrated a diagnostic capability comparable with that of experts. CONCLUSIONS: The CAD system had good diagnostic capability for making treatment decisions for colorectal lesions. This system may enable a more convenient and accurate diagnosis using only WLE.

The current study aimed to evaluate the efficacy of linked color imaging (LCI) in improving the visibility of superficial non-ampullary duodenal epithelial tumors (SNADETs). We prospectively evaluated 44 consecutive patients diagnosed with SNADETs. Three trainees and three experts assessed the visibility scores of white light imaging (WLI), LCI, and blue laser imaging-bright (BLI-b) for SNADETs, which ranged from 1 (not detectable without repeated cautious examination) to 4 (excellent visibility). In addition, the L* a* b* color values and color differences (ΔE*) were evaluated using the CIELAB color space system. For SNADETs, the visibility scores of LCI (3.53 ± 0.59) were significantly higher than those of WLI and BLI-b (2.66 ± 0.79 and 3.41 ± 0.64, respectively). The color differences (ΔE*) between SNADETs and the adjacent normal duodenal mucosa in LCI mode (19.09 ± 8.33) were significantly higher than those in WLI and BLI-b modes (8.67 ± 4.81 and 12.92 ± 7.95, respectively). In addition, the visibility score of SNADETs and the color differences in LCI mode were significantly higher than those in WLI and BLI-b modes regardless of the presence of milk white mucosa (MWM). LCI has potential benefits, and it is considered a promising clinical modality that can increase the visibility of SNADETs regardless of the presence of MWM.This study was registered at the University Hospital Medical Information Network (UMIN000028840).

Ineffective esophageal motility (IEM) is the most common manometric abnormality in gastroesophageal reflux disease (GERD). However, the impact of IEM on esophageal chemical clearance has not been fully investigated. This study aimed to determine the impact of IEM on esophageal chemical clearance in patients with GERD. A total of 369 patients with GERD symptoms who underwent upper endoscopy and high-resolution manometry (HRM) test were retrospectively analyzed. The relationship between IEM and erosive esophagitis was examined. In addition, the impact of IEM on chemical clearance was examined in patients who underwent an additional combined multichannel intraluminal impedance-pH (MII-pH) test. Esophageal chemical clearance capability was evaluated via postreflux swallow-induced peristaltic wave (PSPW) index and acid clearance time (ACT). Of 369 patients, 181 (49.1%) had esophageal motility disorders, of which 78 (21.1%) had IEM. The proportion of IEM patients in those with erosive esophagitis and those without were 16.2% and 21.7%, respectively, and no significant difference was observed (P = 0.53). After excluding patients other than those with IEM and normal esophageal motility, 64 subsequently underwent MII-pH test. The median values of the PSPW index in the IEM and normal esophageal motility group were 11.1% (4.2%-20.0%) and 17.1% (9.8%-30.6%), respectively. The PSPW index was significantly lower in the IEM group than in the normal esophageal motility group (P < 0.05). The median ACT values in the IEM group and normal esophageal motility group were 125.5 (54.0-183.5) seconds and 60.0 (27.2-105.7) seconds, respectively. The ACT was significantly longer in the IEM group than in the normal esophageal motility group (P < 0.05). In conclusion, IEM was found to be associated with chemical clearance dysfunction as measured against the PSPW index and ACT. As this condition could be a risk factor for GERD, future treatments should be developed with a focus on chemical clearance.

Objective: Long-term administration of proton pump inhibitors (PPIs) after eradication of Helicobacter pylori infection has been reported to increase the risk for development of gastric cancer (GC). We investigated whether long-term administration of PPI affects ectopic and metachronous recurrence of GC after endoscopic treatment.Methods: Participants were 687 patients who underwent endoscopic treatment for GC from January 2005 to March 2018. Questionnaire surveys and medical record reviews of medications, including PPIs, H2 receptor antagonists and low-dose aspirin (LDA) were conducted for all patients. The influence of PPI in ectopic and metachronous recurrence of GC was evaluated with Cox's proportional hazard analysis.Results: Patients who did not respond to the questionnaire and those who underwent additional treatment after endoscopic treatment were excluded from analyses; 418 patients were included. During an average observation period of 1608 days (range, 375-4993 days), 136 patients (32.5%) took PPIs for more than 1 year and 94 took PPIs for more than 3 years; of those, 40 had ectopic and metachronous recurrences. Cox's proportional hazards analysis revealed that long-term use of PPIs (for both 1 year and 3 years) was not a risk factor for recurrence. In addition, age, severity of gastric atrophy, long-term use of LDA, current infection with H. pylori, and cure achieved with the first endoscopic treatment were also not risk factors for recurrence.Conclusions: Long-term use of PPIs does not affect ectopic and metachronous recurrence of GC after endoscopic treatment.

Background: The present study aimed to evaluate the efficacy of linked color imaging (LCI) in diagnosing Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Methods: A total of 112 and 12 consecutive patients with BE and EAC were analyzed. The visibility scores of BE and EAC ranging from 4 (excellent visibility) to 0 (not detectable) were evaluated by three trainees and three experts using white light imaging (WLI), LCI mode, and blue laser imaging bright (BLI-b) mode. In addition, L∗a∗b∗ color values and color differences (ΔE∗) were evaluated using the CIELAB color space system. Results: The visibility score of the BE in LCI mode (2.94 ± 1.32) was significantly higher than those in WLI (2.46 ± 1.48) and BLI-b mode (2.35 ± 1.46) (p < 0.01). The color difference (ΔE∗) from the adjacent gastric mucosa in LCI mode (17.11 ± 8.53) was significantly higher than those in other modes (12.52 ± 9.37 in WLI and 11.96 ± 6.59 in BLI-b mode, p < 0.01). The visibility scores of EAC in LCI mode (2.56 ± 1.47) and BLI-b mode (2.51 ± 1.28) were significantly higher than that in WLI (1.64 ± 1.46) (p < 0.01). The color difference (ΔE∗) from the adjacent normal Barrett's mucosa in LCI mode (19.96 ± 7.97) was significantly higher than that in WLI (12.95 ± 11.86) (p = 0.03). Conclusion: The present findings suggest that LCI increases the visibility of BE and EAC and contributes to the improvement of the detection of these lesions.