Docking Proteins Upregulate IL-1ß Expression in Lower Esophageal Sphincter Muscle in Esophageal Achalasia.

Background/Objectives: Esophageal achalasia is an archetypal esophageal motility disorder characterized by abnormal peristalsis of the esophageal body and impaired lower esophageal sphincter (LES) relaxation. Methods: In this study, the mRNA expression of docking proteins 1 and 2 (DOK1 and DOK2, respectively) were analyzed and the mechanisms underlying achalasia onset were investigated. Results:DOK1 and DOK2 mRNA levels significantly increased in the LES of patients with achalasia. Moreover, significant correlations were observed between IL-1ß and DOK1, IL-1ß and DOK2, ATG16L1 and DOK1, and HSV1-miR-H1-3p and DOK2 expression levels. However, a correlation between ATG16L1 and DOK2 or between HSV-miR-H1-3p and DOK1 expression was not observed. In addition, a positive correlation was observed between patient age and DOK1 expression. Microarray analysis revealed a significant decrease in the expression of hsa-miR-377-3p and miR-376a-3p in the LES muscle of patients with achalasia. Conclusions: These miRNAs possessed sequences targeting DOK. The upregulation of DOK1 and DOK2 expression induces IL-1ß expression in the LES of achalasia patients, which may contribute to the development of esophageal motility disorder.

The Potential of Narrow-Band Imaging as a Novel Light Source for Photodynamic Therapy for Superficial Cancers via Endoscopes.

Background: Photodynamic therapy (PDT) has advanced through the utilization of photosensitizers and specific-wavelength light (≥ 600 nm). However, the widespread adoption of PDT is still impeded by high equipment costs and stringent laser safety requirements. Porphyrins, crucial in PDT, have another absorbance peak of blue light (λ = 380 - 500 nm). This peak corresponds to the wavelength of narrow-band imaging (NBI) (λ = 390 - 445 nm), an image-enhancement technology integrated into endoscopes by Olympus Medical Systems. The study aimed to investigate the potential of widely adopted NBI as a PDT light source for superficial cancers via endoscopes. Methods: Esophageal and biliary cancers were selected for investigation. Human esophageal cancer cell lines (KYSE30, KYSE70, KYSE170) and cholangiocarcinoma cell lines (HuCCT-1, KKU-213) were subjected to verteporfin-mediated PDT under NBI light (λ = 390 - 445 nm). Assessments included spectrometry, crystal violet staining, and fluorescein imaging of singlet oxygen generation and apoptosis. Results: Verteporfin exhibited a peak (λ = 436 nm) consistent with the NBI spectrum, suggesting compatibility with NBI light. NBI light significantly inhibited the growth of esophageal and biliary cancer cells. The half-maximum effective concentration (EC50) values (5 J/cm2) for KYSE30, KYSE70, KYSE170, HuCCT-1, and KKU-213 were calculated as 2.78 ± 0.37µM, 1.76 ± 1.20 µM, 0.77 ± 0.16 µM, 0.65 ± 0.18 µM, and 0.32 ± 0.04 µM, respectively. Verteporfin accumulation in mitochondria, coupled with singlet oxygen generation and observed apoptotic changes, suggests effective PDT under NBI light. Conclusions: NBI is a promising PDT light source for superficial cancers via endoscopes.

Characteristics and Risk Factors of Delayed Perforation in Endoscopic Submucosal Dissection for Early Gastric Cancer.

(1) Background: Delayed perforation after gastric endoscopic submucosal dissection (ESD) for early gastric cancer is a relatively uncommon and serious complication that sometimes requires emergency surgery. This study aimed to determine the clinicopathological features, risk factors, and appropriate management strategies for delayed perforation. (2) Methods: This study included 735 patients with 791 lesions who underwent ESD for early gastric cancer at a single institution between July 2009 and June 2019. We retrospectively compared the clinical features of patients with and without delayed perforations. (3) Results: The incidence of delayed perforations was 0.91%. The identified risk factors included a postoperative stomach condition and histopathological ulceration. A comparison between delayed and intraoperative perforations revealed a postoperative stomach condition as a characteristic risk factor for delayed perforation. Patients with delayed perforation who avoided emergency surgery tended to exhibit an earlier onset of symptoms such as abdominal pain and fever. No peritoneal seeding following delayed perforation was observed for any patient. (4) Conclusions: A postoperative stomach condition and histopathological ulceration were risk factors for delayed perforation. Delayed perforation is a significant complication that requires careful monitoring after gastric ESD for early gastric cancer, particularly in patients with postoperative gastric conditions.

Colonic intussusception after endoscopic mucosal resection successfully managed by endoscopic procedure.

Adult-onset intussusception, particularly associated with colonoscopy, is extremely rare. A 78-year-old man, referred to our hospital for colonic endoscopic mucosal resection (EMR), experienced subsequent dull abdominal pain, as well as elevated peripheral blood leukocytosis and C-reactive protein levels. Abdominal computed tomography (CT) revealed a colocolonic intussusception at the hepatic flexure. Emergency colonoscopy revealed ball-like swollen mucosa distal to the EMR site of the ascending colon. The mucosa was intact without necrosis. The endoscopic approach was able to temporarily release the intussusception. A transanal drainage tube was inserted through the endoscope to prevent relapse. Both CT and colonoscopy showed release of the intussusception. Our case underscores the importance of considering colocolonic intussusception in post-colonoscopy abdominal pain, advocating for endoscopic management after excluding mucosal necrosis.

Fusion Imaging Objectively Demonstrates Improved Pancreas Visualization through Manipulation Techniques: A Prospective Interventional Study.

Objective Abdominal ultrasonography (AUS) is used to screen for abdominal diseases owing to its low cost, safety, and accessibility. However, the detection rate of pancreatic disease using AUS is unsatisfactory. We evaluated the visualization area of the pancreas and the efficacy of manipulation techniques for AUS with fusion imaging. Methods Magnetic resonance imaging (MRI) volume data were obtained from 20 healthy volunteers in supine and right lateral positions. The MRI volume data were transferred to an ultrasound machine equipped with a fusion imaging software program. We evaluated the visualization area of the pancreas before and after postural changes using AUS with fusion imaging and assessed the liquid-filled stomach method using 500 ml of de-aerated water in 10 randomly selected volunteers. Patients This study included 20 healthy volunteers (19 men and 1 woman) with a mean age of 33.0 (21-37.5) years old. Results Fusion imaging revealed that the visualization area of the entire pancreas using AUS was 55%, which significantly improved to 75% with a postural change and 90% when using the liquid-filled stomach method (p=0.043). Gastrointestinal gas is the main obstacle for visualization of the pancreas. Conclusion Fusion imaging objectively demonstrated that manipulation techniques can improve pancreatic visualization.

Partial Stent-in-Stent Method with an Uncovered Self-Expandable Metallic Stent for Unresectable Malignant Hilar Bile Duct Obstruction.

(1) Background: There is controversy regarding stent placement for unresectable malignant hilar biliary obstruction (UMHBO). We mainly use the partial stent-in-stent (PSIS) method with an uncovered self-expandable metallic stent (UCSEMS) based on the drainage area and patency period. In this study, we investigated the usefulness and safety of the PSIS method. (2) Methods: In total, 59 patients who underwent the PSIS method for UMHBO at our hospital were included in the study. The technical success rate, clinical success rate, time to recurrent biliary obstruction (TRBO) and overall survival (OS) from the first placement, factors affecting TRBO and OS, and early complications within 30 days after the procedure were evaluated retrospectively. (3) Results: The technical and clinical success rates were 100% and 96.6%, respectively, with a TRBO of 121 days [95% confidence interval: 82-231] and an OS of 194 days [95% confidence interval: 113-305] after the first placement. Early complications occurred in nine patients (15.3%), including five cases of cholangitis, three cases of pancreatitis, and one case of cholecystitis. (4) Conclusions: The PSIS method for UMHBO is safe and useful with high technical and clinical success rates.

Autophagy-Related Gene ATG7 Polymorphism Could Potentially Serve as a Biomarker of the Progression of Atrophic Gastritis.

Cytotoxin-associated gene A (CagA) is an oncoprotein that H. pylori injects into the host's gastric epithelial cells and that induces proinflammatory cytokines, such as interleukin (IL)-18 and IL-1ß. As a result, it leads to atrophic gastritis (AG), a precancerous lesion of gastric cancer. On the other hand, host cells degrade CagA using autophagy systems. However, few studies exist about the single nucleotide polymorphisms (SNPs) in MAP1LC3A, MAP1LC3B, ATG4A, ATG4B, ATG4C, ATG7, and ATG13, which belong to the autophagy-related genes concerning AG. This study aimed to detect biomarkers associated with AG. Herein, H. pylori-positive subjects (n = 200) were divided into the AG (n = 94) and non-AG (n = 106) groups. Thirty tag SNPs were selected from the above seven candidate genes. The SNP frequency between the two groups was analyzed. The frequency of the C/T or T/T genotype at rs4683787 of ATG7 was significantly lower in the AG group than in the non-AG group (p = 0.034, odds ratio = 0.535). Based on multivariate analysis, the C/C genotype of rs4684787 and age were independently associated with gastric mucosal atrophy. This finding helps stratify the patients needing timely endoscopic screening or early eradication of H. pylori.

An Analysis of Delayed Bleeding in Cases of Colorectal Endoscopic Submucosal Dissection Due to Types of Direct Oral Anticoagulants in Japan.

BACKGROUND & AIMS: Reported rates of delayed bleeding (DB) after endoscopic resection using direct oral anticoagulants (DOACs) are high and heterogeneous. This large-scale multicenter study analyzed cases of DB after colorectal endoscopic submucosal dissection related to various types of DOACs in Japan (the ABCD-J study) with those associated with warfarin. METHODS: We retrospectively reviewed 1019 lesions in patients treated with DOACs and 459 lesions in patients treated with warfarin among 34,455 endoscopic submucosal dissection cases from 47 Japanese institutions between 2012 and 2021. The DB rate (DBR) with each DOAC was compared with that with warfarin. Risk factors for DB in patients treated with DOACs or warfarin were also investigated. RESULTS: The mean tumor sizes in the DOAC and warfarin groups were 29.6 ± 14.0 and 30.3 ± 16.4 mm, respectively. In the DOAC group, the DBR with dabigatran (18.26%) was significantly higher than that with apixaban (10.08%, P = .029), edoxaban (7.73%, P = .001), and rivaroxaban (7.21%, P < .001). Only rivaroxaban showed a significantly lower DBR than warfarin (11.76%, P = .033). In the multivariate analysis, heparin bridging therapy (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.27-3.73, P = .005), rectal location (2.01, 1.28-3.16, P = .002), and procedure time ≥55 minutes (2.43, 1.49-3.95, P < .001) were significant risk factors for DB in the DOAC group. The DB risk in the DOAC group (OR, (95% CI)) was 2.13 (1.30-3.50) and 4.53 (2.52-8.15) for 1 and 2 significant risk factors, respectively. CONCLUSIONS: Dabigatran was associated with a higher DBR than other DOACs, and only rivaroxaban was associated with a significantly lower DBR than warfarin.

Impact of low pharyngeal/esophageal pressure associated with sarcopenia on postendoscopic submucosal dissection pneumonia in patients with superficial esophageal cancer.

OBJECTIVES: The aging population, including patients with superficial esophageal cancer, encounters critical dysphagia- and postoperative pneumonia-related issues. Although endoscopic submucosal dissection (ESD) provides advantages over other modalities, older patients are at higher risk of postoperative pneumonia. Furthermore, the etiologies of pneumonia are complex and include patient- (such as sarcopenia) and treatment- (including ESD) related factors. Therefore, this study evaluated swallowing function in patients with superficial esophageal cancer and identified post-ESD pneumonia-associated factors. METHODS: Comprehensive swallowing function and sarcopenia were evaluated in patients pre-ESD and 2 months post-ESD using high-resolution manometry and several swallowing studies by multiple experts. The effects of mucosal resection and sarcopenia on swallowing function changes post-ESD, the relationship between preoperative swallowing function and sarcopenia, and the factors influencing postoperative pneumonia were investigated. RESULTS: Twenty patients were included in the study. Patients with preoperative sarcopenia had significantly lower pharyngeal/upper esophageal sphincter and tongue pressures than those without sarcopenia. However, ESD did not worsen pharyngeal or upper esophageal pressure. Post-ESD pneumonia incidence tended to be higher in patients with sarcopenia than in those without sarcopenia. The lower upper esophageal sphincter-integrated relaxation pressure (UES-IRP) was a significant factor in pneumonia development. Furthermore, the receiver operating characteristic curve for UES-IRP in pneumonia yielded an area under the curve of 0.82. CONCLUSIONS: Sarcopenia is associated with preoperative dysphagia, which increases post-ESD pneumonia risk. Therefore, postoperative pneumonia incidence is expected to increase with an aging population, making preoperative sarcopenia and swallowing function evaluation crucial.

A Novel Monochromatic Light to Detect Target Specimens Within Endoscopic Ultrasonography-guided Fine-needle Aspiration Biopsy Samples.

BACKGROUND/AIM: Endoscopic ultrasonography (EUS)-guided fine-needle aspiration biopsy (EUS-FNB) enhances the diagnostic capabilities of EUS by providing additional pathological samples. However, detecting the target specimens within the collected samples can be challenging. The aim of this study was to determine the optimal wavelength of light for detection of target specimens within EUS-FNB samples in an animal experiment. MATERIALS AND METHODS: EUS-FNB pancreatic tissue samples were collected from a male beagle (weight, 10 kg), and the samples were illuminated with monochromatic light ranging from 430 to 700 nm in 5-nm intervals. The intensities of the target specimen and blood samples were analyzed using the densitometry of the images obtained through irradiation. RESULTS: We found that transmitted monochromatic light of 605 nm most vividly enhanced the contrast between the target specimens and blood in the samples in the impression of appearance. CONCLUSION: Thus, microscopical observations under transmitted light of 605 nm are optimal for target tissue identification within EUS-FNB samples.

Safety and Diagnostic Yield of Endoscopic Ultrasound-Guided Fine-Needle Biopsy for Hypervascular Pancreatic Lesions.

Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) is a common technique for diagnosing pancreatic lesions with high accuracy and a low incidence of procedural adverse events. However, occasional adverse events, particularly bleeding, may occur. Procedures for hypervascular lesions are considered important, but their risks are unknown. We aimed to evaluate the safety and diagnostic yield of EUS-FNB for hypervascular pancreatic solid lesions. This study included 301 patients with 308 solid pancreatic lesions who underwent EUS-FNB between May 2011 and December 2018. We performed propensity-score matching to balance clinical differences between hypervascular and hypovascular lesions and analyzed 52 lesions. We compared the safety and diagnostic performance of propensity score-matched cohorts. The sensitivity, specificity, and accuracy rates of EUS-FNB for hypervascular lesions were 94.7%, 100%, and 96.2%, and those for hypovascular lesions were 80.0%, 100%, and 84.6%, respectively. There was no difference in diagnostic performance between hypervascular and hypovascular lesions. Furthermore, adverse events occurred in only one patient (pancreatitis) in the hypovascular group. There were no significant differences in the occurrence of adverse events between hypervascular and hypovascular lesions (0% vs. 3.8%, p = 1.000). Therefore, EUS-FNB may be safe with a high diagnostic yield, even for hypervascular solid pancreatic lesions.

ATG16L1 and ATG12 Gene Polymorphisms Are Involved in the Progression of Atrophic Gastritis.

Helicobacter pylori (H. pylori) infection causes a progression to atrophic gastritis and results in gastric cancer. Cytotoxin-associated gene A (CagA), a major virulence factor of H. pylori, is injected into gastric epithelial cells using the type IV secretion system. On the other hand, gastric epithelial cells degrade CagA using an autophagy system, which is strictly regulated by the autophagy-related (ATG) genes. This study aimed to identify SNPs in ATG5, ATG10, ATG12, and ATG16L1 associated with gastric mucosal atrophy (GMA). Here, two-hundred H. pylori-positive participants without gastric cancer were included. The degree of GMA was evaluated via the pepsinogen method. Twenty-five SNPs located in the four candidate genes were selected as tag SNPs. The frequency of each SNP between the GMA and the non-GMA group was evaluated. The rs6431655, rs6431659, and rs4663136 in ATG16L1 and rs26537 in ATG12 were independently associated with GMA. Of these four SNPs, the G/G genotype of rs6431659 in ATG16L1 has the highest odd ratio (Odds ratio = 3.835, 95% confidence intervals = 1.337-1.005, p = 0.008). Further functional analyses and prospective analyses with a larger sample size are required.

Pancreatic Juice Cytology Evaluations Using Synthetic Secretin and Serial Pancreatic Juice Aspiration Cytological Examination for the Diagnosis of Pancreatic Ductal Adenocarcinoma.

Pathological examination by endoscopic ultrasound-fine needle aspiration is not possible in approximately 10% of pancreatic tumor cases. Pancreatic juice cytology (PJC) is considered an alternative diagnostic method. However, its diagnostic capability is insufficient, and PJC has been repeatedly redevised. Serial pancreatic juice aspiration cytological examination (SPACE) and secretin-loaded PJC (S-PJC) have been recently introduced as alternative diagnostic methods. This study aimed to determine the diagnostic capacity and safety of SPACE and S-PJC using a propensity score-matched analysis. The sensitivity, specificity, and accuracy were 75.0%, 100%, and 92.3% for S-PJC, respectively, and 71.4%, 100%, and 92.3% for SPACE, respectively, meaning that there was no significant difference between the groups. Four patients (15.4%) each in the S-PJC and SPACE groups experienced complications, including postendoscopic retrograde cholangiopancreatography, pancreatitis, and cholangitis. Overall, there was no difference in efficacy and safety between the SPACE and S-PJC groups.

Polymorphism in autophagy-related genes LRP1 and CAPZA1 may promote gastric mucosal atrophy.

BACKGROUND: Helicobacter pylori secretes cytotoxin-associated gene A (CagA) into the gastric epithelium, causing gastric mucosal atrophy (GMA) and gastric cancer. In contrast, host cells degrade CagA via autophagy. However, the association between polymorphisms in autophagy-related genes and GMA must be fully elucidated. RESULTS: We evaluated the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (low-density lipoprotein receptor-related protein 1, LRP1; capping actin protein of muscle Z-line alpha subunit 1, CAPAZ1; and lysosomal-associated membrane protein 1, LAMP1) and GMA in 200 H. pylori-positive individuals. The frequency of the T/T genotype at rs1800137 in LRP1 was significantly lower in the GMA group than in the non-GMA group (p = 0.018, odds ratio [OR] = 0.188). The frequencies of the G/A or A/A genotype at rs4423118 and T/A or A/A genotype at rs58618380 of CAPAZ1 in the GMA group were significantly higher than those in the non-GMA group (p = 0.029 and p = 0.027, respectively). Multivariate analysis revealed that C/C or C/T genotype at rs1800137, T/A or A/A genotype at rs58618380, and age were independent risk factors for GMA (p = 0.038, p = 0.023, and p = 0.006, respectively). Furthermore, individuals with the rs1800137 C/C or C/T genotype of LRP1 had a 5.3-fold higher susceptibility to GMA. These genetic tests may provide future directions for precision medicine for individuals more likely to develop GMA. CONCLUSION: LRP1 and CAPZA1 polymorphisms may be associated with the development of GMA.

Comparison between Target Sample Check Illuminator and White Light Observation in Discriminating the Presence of Target Specimen for Endoscopic Ultrasound-Guided Fine Needle Aspiration Sample.

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an essential endoscopic tissue sampling method for diagnosing pancreatobiliary diseases; however, determining the presence of target specimens mixed in the blood by conventional observation is challenging due to the small size of the obtained sample. This study investigated the usefulness of a target sample check illuminator (TSCI) that emits a specific wavelength of light to determine the presence of target specimens. Twenty-seven patients who underwent EUS-FNA at our hospital were included. Conventional white light observation was performed for the collected samples, followed by TSCI; six people evaluated the presence of the target specimen on a 5-point scale. The target specimen discrimination score using TSCI (median: 5) was significantly higher than that using conventional white light observation (median: 1) (p < 0.001). No significant difference was observed in the discrimination score between the evaluator (novice vs. expert, p = 0.162) and puncture needle (22G vs. 25G, p = 0.196). The discriminability of TSCI in the samples obtained using EUS-FNA was significantly higher than that of conventional observation. TSCI does not depend on the evaluator or puncture needle for the identification of the target specimen; hence, it can provide a good pathological specimen and may contribute to the improvement of the diagnostic ability.

Five cases of endoscopically noted esophageal stenosis due to abnormal aortic angiogenesis.

Right aortic arch is caused by a malformation of the aorta while Kommerell's diverticulum is a saccular aneurysm arising at the origin of the subclavian artery. Both diseases are caused by malformations during embryonic development and can subsequently cause compression of the esophagus and trachea due to abnormal arterial migration. Here, we report five cases of esophageal stenosis due to aortic angiogenesis anomalies. Three of the five cases had aortic running abnormalities, noted on computed tomography (CT). However, until it was observed for the first time, esophageal stricture was not recognized as an esophagogastroduodenoscopy (EGD) finding due to the lack of knowledge of diseases such as Kommerell's diverticulum even when EGD was performed during regular follow-up after treatment for esophageal cancer or other conditions. Symptoms include dysphagia and dyspnea due to stenosis of the esophagus and trachea, however, regardless of symptomatic presentation, the presence of esophageal stenosis on EGD should be considered as an effect of aortic travel abnormality or Kommerell's diverticulum. Although there have been no reports of Kommerell's diverticulum rupture due to endoscopic manipulation, gastroenterologists should consider the possibility of Kommerell's diverticulum during clinical decision making.

Long­term prognosis and comprehensive endoscopic treatment strategy for esophageal cancer, including salvage endoscopic treatment after chemoradiation therapy.

Endoscopic submucosal dissection (ESD) is the first treatment option for superficial squamous cell carcinoma of the esophagus (SSCE). Salvage endoscopic treatment for recurrent advanced esophageal cancer after chemoradiotherapy (CRT) has been reported. However, there are few reports on long-term prognosis after salvage endoscopic treatment in Japan. The present study investigated long-term treatment results after conventional ESD for SSCE and after salvage endoscopic treatment for locally recurrent lesions after CRT. Outcomes of esophageal ESD were retrospectively investigated at Nagasaki University Hospital and long-term prognosis after salvage endoscopic treatment for locally recurrence lesions after CRT was examined. The en-bloc curative resection rate was 89.5% (606/676) for conventional ESD. The 5-year cause-specific survival rate (CSS) was 98.5%. A total of 77 patients underwent salvage endoscopic treatment [ESD or photodynamic therapy (PDT)] for locally recurrent lesions after CRT. The 3-year CSS was 81.3 and 77.1% for salvage ESD and salvage PDT, respectively. SSCE management using ESD yielded high en-bloc curative resection and survival rates. Overall, establishing salvage endoscopic treatment made long-term control of the underlying disease possible, while also maintaining the quality of life for patients with recurrent advanced esophageal cancer deeper than patients with T1b who underwent CRT and patients with recurrence after additional CRT following ESD.

'Underwater endoscopic mucosal resection with submucosal injection and marking' for superficial non-ampullary duodenal epithelial tumors to achieve R0 resection: a single-center case series.

OBJECTIVES: To describe an endoscopic technique named 'underwater endoscopic mucosal resection (UEMR) with submucosal injection and marking (UEMR-SIM)' and to evaluate the therapeutic characteristics of superficial non-ampullary duodenal epithelial tumors (SNADETs) < 20 mm vis-a-vis classical EMR (CEMR) and UEMR techniques. MATERIALS AND METHODS: This retrospective study included 103 consecutive SNADET patients (103 lesions) who underwent CEMR, UEMR, or UEMR-SIM. The UEMR-SIM procedure included (1) marking and submucosal injection, (2) filling of the duodenal lumen with 0.9% saline, (3) snaring of the lesion, and (4) electrosurgical removal. The procedural outcomes were compared between the UEMR-SIM and other-procedure groups. RESULTS: The en bloc resection rate was significantly higher in the UEMR-SIM group (100%) than in the CEMR group (76.8%) (p = 0.015) but was not statistically different between the UEMR-SIM and UEMR groups (88.0%) (p = 0.236). The R0 resection rate was significantly higher in the UEMR-SIM group (90.9%) than in the UEMR group (48.0%) (p = 0.001) but was not statistically different between the UEMR-SIM and CEMR groups (76.8%) (p = 0.209). CONCLUSIONS: Our study indicates that the proposed method, UEMR-SIM for SNADETs, is feasible to achieve a high R0 resection rate and a potentially low local recurrence rate.