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Background: Left gastric artery (LGA) pseudoaneurysm presenting with upper gastrointestinal (UGI) bleeding is rare but fatal, unless treated., Aims: We aimed to describe the clinical and endoscopic features of patients with UGI bleeding due to LGA pseudoaneurysms., Methods: We performed a computerized search of our hospital's de-identified clinical data warehouse to identify patients with UGI bleeding due to an LGA pseudoaneurysm between 2000 and 2020. Patients' electronic medical records and data on esophagogastroduodenoscopy and digital subtraction angiography were reviewed retrospectively., Results: Of 26 patients with an LGA pseudoaneurysm, six patients had UGI bleeding related to an LGA pseudoaneurysm. No patients had previous vascular diseases or pancreatitis. One patient had liver cirrhosis and a history of radiofrequency ablation for hepatocellular carcinoma, one had colon cancer, two had undergone abdominal surgeries, one had received chemoradiotherapy for renal cell carcinoma, and one had no intraabdominal diseases. Symptoms were hematemesis in two, hematochezia in the other two, and melena in the remaining two patients. Esophagogastroduodenoscopy showed a pulsating bulge in the ulcer in two and a large Dieulafoy's lesion-like structure in four patients. All patients achieved hemostasis by angioembolization., Conclusion: LGA pseudoaneurysm should be suspected in UGI bleeding if a large Dieulafoy's lesion-like structure or a pulsating bulge in the ulcer is found at the lesser curvature of the gastric body on endoscopy and if the patient has any intra-abdominal inflammatory disease., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/aims: Diverticular peroral endoscopic myotomy (D-POEM) is known to be a safe and feasible technique for managing diverticular diseases of the esophagus. In this study, we aim to report our experience with D-POEM and to investigate the usefulness of endoscopic functional luminal imaging probe (EndoFLIP) in determining the need for cardiomyotomy with septotomy for symptomatic epiphrenic diverticulum., Methods: Consecutive patients who underwent D-POEM for symptomatic epiphrenic diverticulum between September 2019 and September 2021 were eligible for this study. EndoFLIP and high-resolution manometry results and endoscopic treatment outcomes were retrospectively investigated., Results: A total of 9 patients with symptomatic epiphrenic diverticulum were included. The median size of the diverticulum and septum was 50 (interquartile range [IQR], 48-80) mm and 20 (IQR, 20-30) mm, respectively. The overall technical success rate was 100%, with a median procedure time of 60 (IQR, 46-100) minutes. The 5 patients (high-resolution manometry results; 3 normal, 1 ineffective esophageal motility, and 1 Jackhammer esophagus) who had decreased esophagogastric junction distensibility index on pre-procedure EndoFLIP underwent cardiomyotomy with septotomy regardless of the presence of esophageal motility disorders, and the distensibility index increased and normalized after procedure. The mean dysphagia score decreased from 2.0 ± 1.0 pre-procedure to 0.4 ± 0.7 during a median follow-up of 11 (IQR, 4-21) months post-procedure. No serious adverse events that required surgical intervention or delayed discharge were noted., Conclusions: EndoFLIP may help decide whether to perform combined cardiomyotomy and septotomy for the treatment of an epiphrenic diverticulum. Further large-scale studies are needed to confirm these results.

Background: Currently, there are no high-resolution impedance manometry (HRIM)-based diagnostic criteria for non-obstructive dysphagia (NOD). New impedance parameters, such as the esophageal impedance integral (EII) and volume of inverted impedance (VII) ratios, have shown strong correlations with bolus transit. This study compared the EII and VII ratios as diagnostic tools for NOD., Methods: We analyzed 36 participants (12 patients with achalasia, 12 patients with NOD [7 with normal motility and 5 with ineffective esophageal motility], and 12 asymptomatic controls) who underwent HRIM with a maximum of 5 swallows per participant. The EII and VII ratios were calculated as Z2 (post-swallow)/Z1 (pre-swallow). Bolus transit was retrospectively evaluated using transluminal impedance analysis., Key Results: Both EII and VII ratios could effectively distinguish the achalasia group from the non-achalasia groups (area under the receiver operating characteristic curve [AUROC]: 0.83 for VII vs. 0.80 for EII; p = 0.73). However, the VII ratio was significantly better in discriminating asymptomatic controls from patients with dysphagia (NOD + achalasia) (AUROC: 0.81 vs. 0.68; p = 0.01). Moreover, the VII ratio was better in discriminating asymptomatic controls from patients with NOD (AUROC: 0.68 vs. 0.51; p = 0.06). In repeated swallows, the VII ratio was consistently the lowest in controls and the highest in patients with achalasia, whereas the EII ratio did not show a consistent pattern., Conclusions & Inferences: The VII ratio was more reliable than the EII ratio for describing bolus transit and distinguishing patients with NOD from asymptomatic controls, even during repeated measures of subsequent swallows., (© 2022 John Wiley & Sons Ltd.)

Background and Aims: In the efforts toward reducing bleeding-related mortality, it is crucial to determine the risk factors for rebleeding after endoscopic hemostasis in benign peptic ulcer (BPU)., Methods: Between 2013 and 2017, the medical records of 864 BPU patients were selected from 5076 who had undergone emergency endoscopy for suspected upper gastrointestinal bleeding. Patients who visited the emergency room or were hospitalized for other illnesses were selected. The primary end point was rebleeding within 30 days after initial endoscopy. The risk factors of rebleeding and subgroup analyses according to patient location were evaluated., Results: Among 864 BPU bleeding patients, rebleeding after completion of BPU bleeding occurred in 140 (16.2%). Initial indicators of hypotension (OR 1.878, p = 0.005) and Forrest classes Ia (OR 25.53, p < 0.001), Ib (OR 27.91, p = 0.005), IIa (OR 21.41, p < 0.001), and IIb (OR 23.74, p < 0.001) were independent risk factors of rebleeding compared to Forrest class III, and being inpatients (OR 1.75, p = 0.01). Compared to the outpatients, the inpatients showed significantly higher rebleeding rates (25.6% vs 13.8%, p < 0.001), predictive bleeding scores, red blood transfusion counts, proportion of Forrest classes Ia, Ib, and IIb (p < 0.001), and overall mortality rates (68.8% vs 34.0%, p < 0.001)., Conclusions: Patient location was a novel predictive factor of BPU rebleeding. Particularly, being an inpatient correlated with increased rebleeding. Furthermore, Forrest classes Ia, Ib, IIa, and IIb were predictive of rebleeding not only the included BPUs, but also in the inpatient or outpatient groups., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Subepithelial tumor (SET) size is important in determining the treatment plan; however, size estimation for gastric SETs has not been well investigated. We aimed to investigate which method predicts SET size most accurately by retrospectively analyzing surgically removed SETs., Methods: From January 2015 through June 2020, patients who underwent surgical gastric SET removal at Asan Medical Center, Seoul, Korea, were enrolled. SET sizes measured by pathologists and endoscopists were retrospectively reviewed. The reliability of SET size measurement by endoscopic ultrasonography (EUS) and endoscopy was calculated using intraclass correlation coefficient (ICC), with pathologic size as the gold standard., Results: Overall, EUS was highly reliable (ICC 0.86, P < 0.001), and endoscopy was moderately reliable (ICC 0.75, P < 0.001). When analyzed according to SET location, endoscopy was highly reliable in the lesser curvature's lower third (ICC 0.86, P = 0.014), middle third (ICC 0.88, P < 0.001), and upper third (ICC 0.90, P < 0.001); as well as the anterior wall's middle third (0.84, P < 0.001) and the posterior wall's upper third (ICC 0.80, P < 0.001). EUS (ICC 0.96, P = 0.005) and endoscopy (ICC 0.95, P = 0.008) both were most reliable for lower-third posterior wall lesions, whereas endoscopy was unreliable for middle-third greater curvature lesions (ICC 0.41, P = 0.05)., Conclusions: Both EUS and endoscopy were reliable methods for measuring gastric SET size, and overall, EUS was more reliable than endoscopy. In terms of SET location, EUS was consistently reliable, whereas endoscopy showed variable reliability. When measuring SET size by endoscopy, additional size measurements with EUS should be considered in certain locations., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Exogenous contrast agents in photoacoustic imaging help improve spatial resolution and penetration depth and enable targeted molecular imaging. To screen efficient photoacoustic signaling materials as contrast agents, we propose a light absorption-weighted figure of merit (FOM) that can be calculated using material data from the literature and numerically simulated light absorption cross-sections. The calculated light absorption-weighted FOM shows that a Ti nanodisc has a photoacoustic conversion performance similar to that of an Au nanodisc and better than that of a Pt nanodisc. The photoacoustic imaging results of Ti, Au, and Pt nanodiscs, which are physically synthesized with identical shapes and dimensions, experimentally demonstrated that the Ti nanodisc could be a highly efficient contrast agent., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Concomitant amyloid pathology contributes to the clinical heterogeneity of Lewy body diseases (LBDs)., Objective: The objective of this study was to investigate the pattern and effect of amyloid accumulation on cognitive dysfunction in Parkinson's disease (PD) and dementia with Lewy bodies (DLB)., Methods: We retrospectively assessed 205 patients with LBD (91 with DLB and 114 with PD) who underwent 18 F-florbetaben positron emission tomography and divided them into amyloid-positive and amyloid-negative groups depending on global standardized uptake value ratios (SUVRs). We investigated the effect of group on the regional and global SUVRs using general linear models (GLMs) after controlling for age, sex, cognitive status, and score on the Korean version of the Mini-Mental State Examination. Moreover, the effect of amyloid on cognitive function, depending on the type of LBD, was evaluated using GLMs with interaction analysis., Results: In all evaluated regions including the striatum, the DLB group showed a higher SUVR than the PD group. Among amyloid-positive patients, the DLB group had a higher regional SUVR than the PD group in the frontal and parietal cortices. There was a significant interaction effect between amyloid and disease groups in language and memory function. In patients with PD, global amyloid load was negatively associated with language (B = -2.03; P = 0.010) and memory functions (B = -1.96; P < 0.001). However, amyloid load was not significantly associated with cognitive performance in the DLB group., Conclusions: Although the burden of amyloid was higher in the DLB group, amyloid accumulation was negatively associated with the memory and language functions in the PD group only. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Background/aims: Epstein-Barr virus (EBV) and Helicobacter pylori (HP) coinfection may synergistically induce severe inflammatory responses in the stomach tissue, increasing the risk of developing gastric cancer. We aimed to analyze the effect of EBV and HP coinfection on the clinicopathologic features and prognosis of gastric cancer, as well as to evaluate the role of EBV infection in non-gastric carcinoma with lymphoid stroma (non-GCLS)., Methods: Overall, 956 patients who underwent surgery for gastric cancer between September 2014 and August 2015 were eligible and divided into groups, according to GCLS morphology, EBV infection, and HP infection. Clinicopathologic characteristics and oncologic outcomes were analyzed retrospectively., Results: EBV and HP coinfection was significantly associated with male sex, proximal location, GCLS morphology, and equivocal p53 expression (p<0.001). Multivariate analysis revealed that EBV infection alone (hazard ratio [HR], 0.362; 95% CI, 0.131 to 0.996; p=0.049) and lower third location (HR, 0.624; 95% CI, 0.413 to 0.943; p=0.025) were inversely correlated with overall survival. During median follow-up period of 72 months, overall survival rate was not significantly different between the EBV and HP coinfection group and others (97.6% vs 86.8%; log-rank p=0.144). In non-GCLS patients (n=920), overall survival rate was not significantly different between the EBV infection group and others (96.9% vs 86.4%; log-rank p=0.126)., Conclusions: EBV and HP coinfection is not an independent prognostic factor for gastric cancer. EBV infection status, regardless of HP infection, affects the clinicopathologic features of all types of gastric cancer. However, it does not lead to a significant difference in overall survival of non-GCLS patients.

Aims: Aberrant overactivation/overexpression of NRF2 is implicated as a driving event in tumor progression, which has been attributed to its mutation or inactivation of the inhibitory protein, KEAP1. However, alternative mechanisms responsible for sustained activation of NRF2 are less understood., Main Methods: Human colon cancer cell lines and tissues obtained from colorectal cancer (CRC) patients were used. To examine the expression levels of ARD1 and NRF2, Western blot and immunofluorescence analyses were performed. To investigate the potential relevance of NRF2 and ARD1 to human CRC, NRF2 and ARD1 were individually silenced in human colon cancer cells (HCT-116) by transfection with their specific small interfering RNA (siRNA). To determine the functional role of ARD1 in NRF2 regulation, in situ proximate ligation, co-immunoprecipitation, nano-LC-ESI MS/MS, and in vitro acetylation assays were performed., Key Findings: ARD1 knockdown in human colon cancer cell lines significantly reduced the protein levels of NRF2 without affecting its mRNA expression; however, silencing of NRF2 did not alter ARD1 protein expression. In addition, these two proteins were co-localized and physically interacted with each other both in human colon cancer cells (HCT-116) and human colon tumor tissues. Mechanistically, ARD1 overexpression increased the acetylation levels of NRF2. Moreover, an in vitro acetylation assay and mass spectrometric analysis demonstrated that ARD1 could directly acetylate NRF2. Ectopic expression of mutant forms of ARD1 with defective acetyltransferase activity reduced the stability of NRF2., Significance: In conclusion, ARD1 may potentiate the oncogenic function of NRF2 in human colon cancer by stabilizing this transcription factor., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

African swine fever virus (ASFV) causes a highly contagious and fatal disease affecting both domesticated and wild pigs. Substandard therapies and inadequate vaccinations cause severe economic damages from pig culling and removal of infected carcasses. Therefore, there is an urgent need to develop a rapid point-of-use approach that assists in avoiding the spread of ASFV and reducing economic loss. In this study, we developed a colorimetric sensing platform based on dual enzymatic amplification that combined the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 12a (Cas12a) system and the enzyme urease for accurate and sensitive detection of ASFV. The mechanism of the sensing platform involves a magnetic bead-anchored urease-conjugated single-stranded oligodeoxynucleotide (MB@urODN), which in the presence of ASFV dsDNA is cleaved by activated CRISPR/Cas12a. After magnetically separating the free urease, the presence of virus can be confirmed by measuring the colorimetric change in the solution. The advantage of this method is that it can detect the presence of virus without undergoing a complex target gene duplication process. The established method detected ASFV from three clinical specimens collected from porcine clinical tissue samples. The proposed platform is designed to provide an adequate, simple, robust, highly sensitive and selective analytical technique for rapid zoonotic disease diagnosis while eliminating the need for vast or specialized tools.

Few studies have focused on assessing the usefulness of scoring systems such as the Rockall score (RS), Glasgow-Blatchford score (GBS), and AIMS65 score for risk stratification and prognosis prediction in peptic ulcer bleeding patients. This study aimed to assess scoring systems in predicting clinical outcomes of patients with peptic ulcer bleeding. A total of 682 peptic ulcer bleeding patients who underwent esophagogastroduodenoscopy between January 2013 and December 2017 were found eligible for this study. The area under the receiver-operating characteristic curve (AUROC) of each score was calculated for predicting rebleeding, hospitalization, blood transfusion, and mortality. The median age of patients was 64 (interquartile range, 56-75) years. Of the patients, 74.9% were men, and 373 underwent endoscopic intervention. The median RS, GBS, and AIMS65 scores were significantly higher in patients who underwent endoscopic intervention than in those who did not. The AUROC of RS for predicting rebleeding was significantly higher than that of GBS (P = .022) or AIMS65 (P < .001). GBS best predicted the need for blood transfusion than either pre-RS (P = .013) or AIMS65 (P = .001). AIMS65 score showed the highest AUROC for mortality (0.652 vs. 0.622 vs. 0.691). RS was significantly associated with rebleeding (odds ratio, 1.430; P < .001) and overall survival (hazard ratio, 1.217; P < .001). The RS, GBS, and AIMS65 scoring systems are acceptable tools for predicting clinical outcomes in peptic ulcer bleeding. RS is an independent prognostic factor of rebleeding and overall survival., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background/aims: We aimed to develop an endoscopic scoring system to evaluate gastric atrophy and intestinal metaplasia using narrow-band imaging (NBI) and near focus mode (NFM) to compare endoscopic scores with the Operative link for gastritis assessment (OLGA) and the Operative link for gastric intestinal metaplasia assessment (OLGIM)., Methods: A total of 51 patients who underwent diagnostic esophagogastroduodenoscopy were prospectively enrolled and endoscopic scoring using NBI and NFM was performed. Four areas (the lesser and greater curvatures of the antrum and the lesser and greater curvature side of the corpus) were observed and biopsies were taken. The degree of atrophy was scored from 0 to 2 according to the Kimura-Takemoto classification. The degree of intestinal metaplasia was scored from 0 to 4 according to the location and the extent of the intestinal metaplasia., Results: The correlation coefficient for atrophy between the endoscopic and histologic scores was 0.70 (95% CI: 0.52-0.81 p  < .001) and for intestinal metaplasia, it was 0.75 (95% CI: 0.60-0.85; p  < .001). For atrophic gastritis, an endoscopic score >1 correlated with OLGA stage III and IV with a sensitivity, specificity, positive predictive value, negative predictive value, and agreement of 88, 74, 75, 87, and 80.4%, respectively, and for intestinal metaplasia, an endoscopic score >1 correlated with high OLGIM stage III and IV with 100, 59, 69, 100, and 78.4%, respectively., Conclusions: Endoscopic scoring for gastric atrophy and intestinal metaplasia using NBI-NFM likely correlates with histologic staging in Korea, a high-risk region for gastric cancer.

Background/aims: We evaluated the clinical significance and prognostic power of functional luminal imaging probe (FLIP) panometry in patients with achalasia treated with peroral endoscopic myotomy (POEM), and examined the clinical parameters associated with symptomatic improvement and the presence of contractility (POC) following POEM., Methods: We reviewed the electronic medical records of patients with achalasia treated with FLIP panometry and POEM at a tertiary teaching hospital in Seoul, Republic of Korea. Follow-up examination was composed of esophageal manometry and questionnaires on symptoms. We analyzed the FLIP data by interpolating using the cubic spline method in MATLAB., Results: We retrospectively analyzed 33 men and 35 women (mean age: 52 ± 17 years), of whom 14, 39, and 15 patients were diagnosed with achalasia types I, II, and III, respectively. The FLIP panometry diagnoses were reduced esophagogastric junction opening (REO) with a retrograde contractile response (n = 43); REO with an absent contractile response (n = 5); REO with a normal contractile response (n = 11); and a retrograde contractile response (n = 9). Overall, the patients showed improvements in Eckardt scores following POEM from 6.48 ± 2.20 to 1.16 ± 1.15 ( P < 0.01). Post-POEM symptomatic improvement was not significantly associated with any of the clinical parameters, including panometry diagnosis. Conversely, post-POEM POC was significantly associated with the presence of repetitive antegrade contractions and achalasia subtypes (both P < 0.01)., Conclusion: While FLIP panometry was not significantly associated with the clinical course of achalasia, FLIP panometry was associated with POC following POEM and may complement manometry in the functional evaluation of esophageal motility disorders.

The importance of multi-omic-based approaches to better understand diverse pathological mechanisms including neurodegenerative diseases has emerged. Spatial information can be of great help in understanding how biomolecules interact pathologically and in elucidating target biomarkers for developing therapeutics. While various analytical methods have been attempted for imaging-based biomolecule analysis, a multi-omic approach to imaging remains challenging due to the different characteristics of biomolecules. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a powerful tool due to its sensitivity, chemical specificity, and high spatial resolution in visualizing chemical information in cells and tissues. In this paper, we suggest a new strategy to simultaneously obtain the spatial information of various kinds of biomolecules that includes both labeled and label-free approaches using ToF-SIMS. The enzyme-assisted labeling strategy for the targets of interest enables the sensitive and specific imaging of large molecules such as peptides, proteins, and mRNA, a task that has been, to date, difficult for any MS analysis. Together with the strength of the analytical performance of ToF-SIMS in the label-free tissue imaging of small biomolecules, the proposed strategy allows one to simultaneously obtain integrated information of spatial distribution of metabolites, lipids, peptides, proteins, and mRNA at a high resolution in a single measurement. As part of the suggested strategy, we present a sample preparation method suitable for MS imaging. Because a comprehensive method to examine the spatial distribution of multiple biomolecules in tissues has remained elusive, our strategy can be a useful tool to support the understanding of the interactions of biomolecules in tissues as well as pathological mechanisms.

Background: No definite guidelines for the management of small esophageal subepithelial tumors (SETs) have been established, because there are limited data and studies on their natural history. We aimed to assess the natural history and propose optimal management strategies for small esophageal SETs., Methods: Patients diagnosed as esophageal SETs ≤ 30 mm in size between 2003 and 2017 using endoscopic ultrasound (EUS) with a minimal follow-up of 3 months were enrolled, and their esophagogastroduodenoscopy (EGD) and EUS were retrospectively reviewed., Results: Of 275 esophageal SETs in 262 patients, the initial size was < 10 mm, 10-20 mm, and 20-30 mm in 104 (37.8%), 105 (38.2%), and 66 (24.0%) lesions, respectively. Only 22 (8.0%) SETs showed significant changes in size and/or echogenicity and/or morphology at a median of 40 months (range, 4-120 months). Tissues of 6 SETs showing interval changes were obtained using EUS-guided fine needle aspiration biopsy; 1 was identified as a gastrointestinal stromal tumor (GIST) and was surgically resected, while the other 5 were leiomyomas and were regularly observed. Eight SETs showing interval changes were resected surgically or endoscopically without pathological confirmation; 1 was a GIST, 2 were granular cell tumors, and the other 5 were leiomyomas., Conclusion: Regular follow-up with EGD or EUS may be necessary for esophageal SETs ≤ 30 mm in size considering that small portion of them has a possibility of malignant potential. When esophageal SETs ≤ 30 mm show significant interval changes, pathological confirmation may precede treatment to avoid unnecessary resection., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Biomolecule detection based on the localized surface plasmon resonance (LSPR) phenomenon has advantages in label-free detection, good sensitivity, and measurement simplicity and reproducibility. However, in order to ultimately be used for actual diagnosis, the ability to detect trace amounts of biomarkers is necessary, which requires the development of signal enhancement strategies that enable ultrasensitive detection. In this paper, we provide a straightforward and efficient route to boost LSPR sensitivity based on multiple sample washings. We found that repeated washing and drying cycles lead to a shift in the LSPR peak in a concentration-dependent manner, where this process drives the accumulation of a precipitate, formed by an enzyme reaction with target specificity, in the sample's LSPR active plasmonic nano-valley structure. Results show that the washing and drying process leads to a signal enhancement of more 200 times compared to a sensor with only enzyme-based amplification. To maximize this effect, optimization of the plasmonic nanostructure was also carried out to finally achieve atto-molar detection of miRNA with a distinguishable LSPR peak shift., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

Despite recent studies suggesting a declining incidence and prevalence of dementia on a global scale, epidemiologic results with respect to Alzheimer's disease (AD) are lacking due to the methodological limitations inherent to conducting large-scale cohort investigations of this topic. The aim of the current study was to investigate the incidence and prevalence of AD in Korea. We conducted a secondary analysis within the National Health Insurance System (NHIS) database, a unique resource that reports medical information for the entire Korean population. AD diagnoses as well as evaluations of vascular risks were defined based on International Statistical Classification of Diseases (ICD-10) codes along with prescription records. The cut-off age for diagnosing AD was defined as the age of the patient's highest Youden index. In this study, the incidence and prevalence of AD in the Korean population aged 40 years or older showed an overall increase between 2006 and 2015. Although both older and younger age groups showed an increase in the incidence and prevalence of AD, the highest increase was observed in older age groups. Based on the highest Youden's index value (sensitivity + specificity - 1), the cut-off value for the diagnosis of AD was 69 years with an area under the curve (AUC) of 0.92. We found that the incidence of AD was higher in individuals with underlying vascular risks. However, in recent years, the prevalence of AD was conversely found to be lower in individuals with hypertension or dyslipidemia. Despite efforts toward reducing the number of AD cases through educational, policy, and various public health and preventive medicine interventions, the incidence and prevalence of AD continues to grow in Korea. Efforts aimed at early diagnosis and the modification of underlying risks may be critical to reducing the socioeconomic burden of AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Baek, Kim, Han, Kwon, Na, Lyoo and Cho.)

Background/aims: The treatment of superficial esophageal neoplasms (SENs) in cirrhotic patients is challenging and rarely investigated. We evaluated the outcomes of endoscopic submucosal dissection (ESD) to determine the efficacy and safety of treating SENs in patients with liver cirrhosis., Methods: The baseline characteristics and treatment outcomes of patients who underwent ESD for SENs between November 2005 and December 2017 were retrospectively reviewed., Results: ESD was performed in 437 patients with 481 SENs, including 15 cirrhotic patients with 17 SENs. En bloc resection (88.2% vs. 97.0%) and curative resection (64.7% vs. 78.9%) rates were not different between the cirrhosis and non-cirrhosis groups (p=0.105 and p=0.224, respectively). Bleeding was more common in cirrhotic patients (p=0.054), and all cases were successfully controlled endoscopically. The median procedure and hospitalization duration did not differ between the groups. Overall survival was lower in cirrhotic patients (p=0.003), while disease-specific survival did not differ between the groups (p=0.85)., Conclusion: ESD could be a safe and effective treatment option for SENs in patients with cirrhosis. Detailed preprocedural assessments are needed, including determination of liver function, esophageal varix status, and remaining life expectancy, to identify patients who will obtain the greatest benefit.

Background: Although the criteria for the indication of endoscopic submucosal dissection (ESD) for undifferentiated early gastric cancer (UD-EGC) have been recently proposed, accumulating reports on the non-negligible rate of lymph node metastasis (LNM) after indicated ESD raise questions on the reliability of the current criteria., Aim: To investigate the prevalence and risk factors of LNM in UD-EGC cases meeting the expanded indication for ESD., Methods: We retrospectively reviewed 4780 UD-EGC cases that underwent surgical resection between January 2008 and February 2019 at Asan Medical Center, a tertiary university hospital in Korea. To identify the risk factors of LNM of UD-EGC meeting the expanded criteria for ESD, we performed a case-control study by matching the cases with LNM to those without at a ratio of 1:4. We reviewed the clinical, endoscopic, and histologic features of the cases to identify features with a significant difference according to the presence of LNM. Univariate and multivariate logistic regression analyses were performed to estimate the odds ratios (ORs)., Results: Of the 4780 UD-EGC cases, 1240 (25.9%) were identified to meet the expanded indication for ESD. Of the 1240 cases, 14 (1.1%) cases had LNM. Among the various clinical, endoscopic, and histopathological features that were evaluated, mixed histology (tumors consisting of 10%-90% of signet ring cells) had a marginally significant association ( P = 0.059) with the risk of LNM. Moreover, diffuse blurring of the muscularis mucosae (MM) underneath the tumorous epithelium, a previously unrecognized histologic feature, had a significant association with the absence of LNM ( P = 0.028). Multivariate logistic regression analysis showed that the blurring of MM was the only explanatory variable significantly associated with a reduced risk of LNM (OR: 0.12, 95%CI: 0.02-0.95; P = 0.045)., Conclusion: The risk of LNM is higher than expected when using the current expanded indication for UD-EGC. Histological evaluation could provide useful clues for reducing the risk of LNM., Competing Interests: Conflict-of-interest statement: All authors have no conflict of interest related to the study., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Bariatric surgery is the most effective treatment for weight recidivism, and endoscopic bariatric treatment has been developed for a similar effect without anatomical modification. An intragastric satiety-inducing device (ISD) is a minimally invasive approach to induce satiety by continuously pressing the stomach and stimulating ghrelin-producing cells. To enhance the therapeutic effects of ISD, photodynamic therapy (PDT) can be combined by generating singlet oxygen under laser irradiation. Methylene blue (MB), as a photosensitizer (PS), was coated on the ISD surface for singlet oxygen production to stimulate or destroy cells. Ghrelin-producing cells effectively inhibited ghrelin secretion and induced gastrointestinal satiety signals compared with the MB-uncoated device via PDT. Herein, MB-embedded ISDs were developed, and their photoresponsive abilities were demonstrated in the device itself and in vitro. PDT with an MB-embedded ISD was successfully performed in a porcine model, which had 2-fold reduced body weight gain (12% in PDT vs 24% in control) and 2-fold reduced ghrelin levels (21.2 pg/mL in PDT vs 45.1 pg/mL in control) at the first week postprocedure. The simple and unique operation extends the point of view in PDT and is expected to be a novel endoscopic bariatric therapy.

Sirtuin 1 (SIRT1), an NAD + -dependent histone/protein deacetylase, has multifaceted functions in various biological events such as inflammation, aging, and energy metabolism. The role of SIRT1 in carcinogenesis, however, is still under debate. Recent studies have indicated that aberrant overexpression of SIRT1 is correlated with metastasis and poor prognosis in several types of malignancy, including colorectal cancer. In the present study, we found that both SIRT1 and SIRT1 phosphorylated on serine 27 were coordinately upregulated in colon cancer patients' tissues and human colon cancer cell lines. This prompted us to investigate a role of phospho-SIRT1 in the context of colon cancer progression. A phosphorylation-defective mutant form of SIRT1, in which serine 27 was substituted by alanine (SIRT1-S27A), exhibited lower protein stability compared to that of wild-type SIRT1. Notably, human colon cancer (HCT-116) cells harboring the SIRT1-S27A mutation showed decreased cell proliferation and reduced capability to form xenograft tumor in athymic nude mice, which was accompanied by diminished transcriptional activity of Snail. HCT-116 cells carrying SIRT1-S27A were less capable of deacetylating the Snail protein, with a concomitant decrease in the levels of interleukin (IL)-6 and IL-8 mRNA transcripts. Taken together, these observations suggest that SIRT1 stabilized through phosphorylation on serine 27 exerts oncogenic effects at least partly through deacetylation-dependent activation of Snail and subsequent transcription of IL-6 and IL-8 in human colon cancer cells., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: This study aimed to evaluate the real-world efficacy of immune checkpoint inhibitors (ICIs), and to identify clinicolaboratory factors to predict treatment outcomes in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving ICIs., Materials and Methods: Sixty patients with metastatic or unresectable ESCC treated with nivolumab (n=48) or pembrolizumab (n=12) as ≥ second-line treatment between 2016 and 2019 at Asan Medical Center were included., Results: The median age of the patients was 68 years (range, 52 to 76 years), and 93.3% were male. Most patients had metastatic disease (81.7%) and had been previously treated with fluoropyrimidines, platinum, and taxane. In 53 patients with measurable disease, the overall response rate and disease control rate were 15.1% and 35.8%, respectively. With a median follow-up duration of 16.0 months, the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval [CI], 1.54 to 2.19) and 6.4 months (95% CI, 4.77 to 8.11), respectively. After multivariate analysis, recent use of antibiotics, low prognostic nutrition index (< 35.93), high Glasgow Prognosis Score (≥ 1) at baseline, and ≥ 1.4-fold increase in neutrophil-to-lymphocyte ratio after one cycle from baseline were significantly unfavorable factors for both PFS and OS. Younger age (< 65 years) was a significant factor for unfavorable PFS and hyponatremia (< 135 mmol/L) for unfavorable OS., Conclusion: The use of ICIs after the failure of chemotherapy showed comparable efficacy in patients with advanced ESCC in real practice; this may be associated with host immune-nutritional status, which could be predicted by clinical and routine laboratory factors.

Background/aims: Heme oxygenase-1 (HO-1) plays a central role in cellular defense against inflammatory insults, and its induction in macrophages potentiates their efferocytic activity. In this study, we explored the potential role of macrophage HO-1 in the resolution of experimentally induced colitis., Methods: To induce colitis, male C57BL/6 mice were treated with 2% dextran sulfate sodium (DSS) in the drinking water for 7 days. To investigate efferocytosis, apoptotic colon epithelial CCD 841 CoN cells were coincubated with bone marrow-derived macrophages (BMDMs)., Results: Administration of the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blunted the resolution of DSS-induced intestinal inflammation and expression of the proresolving M2 macrophage marker CD206. BMDMs treated with apoptotic colonic epithelial cells showed significantly elevated expression of HO-1 and its regulator Nrf2. Under the same experimental conditions, the proportion of CD206-expressing macrophages was also enhanced. ZnPP treatment abrogated the upregulation of CD206 expression in BMDMs engulfing apoptotic colonic epithelial cells. This result was verified with BMDMs isolated from HO-1-knockout mice. BMDMs, when stimulated with lipopolysaccharide, exhibited increased expression of CD86, a marker of M1 macrophages. Coculture of lipopolysaccharide-stimulated BMDMs with apoptotic colonic epithelial cell debris dampened the expression of CD86 as well as the pro-inflammatory cytokines in an HO-1-dependent manner. Genetic ablation as well as pharmacologic inhibition of HO-1 significantly reduced the proportion of efferocytic BMDMs expressing the scavenger receptor CD36., Conclusions: HO-1 plays a key role in the resolution of experimentally induced colitis by modulating the polarization of macrophages.

Background/aims: Postprocedural bleeding is known to be relatively low after argon plasma coagulation (APC) for gastric neoplasms; however, there are few studies proving the effect of antithrombotic agents. This study aimed to analyze the incidence of delayed bleeding (DB) based on antithrombotic agents administered and to identify the risk factors for DB in APC for gastric tumors., Methods: A total of 785 patients with 824 lesions underwent APC for single gastric neoplasm between January 2011 and January 2018. After exclusion, 719 and 102 lesions were classified as belonging to the non-antithrombotics (non-AT) and AT groups, respectively. The clinical outcomes were compared between the two groups, and we determined the risk factors for DB in gastric APC., Results: Of the total 821 cases, DB occurred in 20 cases (2.4%): 17 cases in the non-AT group and three cases in the AT group (2.4% vs 2.9%, p=0.728). Multivariate analysis of the risk factors for DB confirmed the following significant, independent risk factors: male sex (odds ratio, 7.66; 95% confidence interval, 1.02 to 57.69; p=0.048) and chronic kidney disease (odds ratio, 4.51; 95% confidence interval, 1.57 to 13.02; p=0.005). Thromboembolic events and perforation were not observed in all patients regardless of whether they took AT agents., Conclusions: AT therapy is acceptably safe in gastric APC because it does not significantly increase the incidence of DB. However, patients with chronic kidney disease or male sex need to receive careful follow-up on the incidence of post-APC bleeding.

Background: Although upper gastrointestinal (GI) neoplasms are not rare in patients with familial adenomatous polyposis (FAP), few studies have focused on them and the long-term outcomes of their treatment by endoscopy. Therefore, we aimed to investigate the prevalence and endoscopic treatment outcomes of upper GI neoplasms in patients with FAP., Methods: Among 215 patients diagnosed with FAP between January 1991 and December 2019, 208 who underwent esophagogastroduodenoscopy were eligible. The clinical features and endoscopic treatment outcomes of upper GI neoplasms were retrospectively investigated and analyzed., Results: Among the enrolled patients, 113 (54.3%) had one or more upper GI neoplasms: gastric adenoma (n = 34), gastric cancer (n = 7), nonampullary duodenal adenoma (n = 86), and ampullary adenoma (n = 53). Among patients with gastric neoplasms (n = 37), 24 (64.9%) underwent treatment (endoscopic treatment: 22, surgery: 2). No tumor-related mortality occurred during median follow-up of 106 months (interquartile range [IQR] 63-174). Endoscopic treatment was performed in 47 (54.7%) of 86 patients with nonampullary duodenal adenoma and in 32 (60.4%) of 53 patients with ampullary adenoma. No patient underwent surgery for duodenal neoplasms, and no tumor-related mortality occurred during median follow-up of 88 months (IQR 42-145). The proportion of patients with increased Spigelman stage at 2 years after the initial diagnosis or treatment was significantly higher in untreated group than in the group treated for duodenal neoplasms (27.3% vs. 0.0%, p = 0.001)., Conclusion: Endoscopic surveillance in FAP patients is important for the detection and treatment of upper GI neoplasms in early stage. In particular, endoscopic therapy for duodenal neoplasms can reduce the severity of duodenal polyposis., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Few studies have focused on preoperative nutritional status of esophageal cancer patients eligible for upfront surgery. We aimed to investigate the association of preoperative nutritional status with prognosis of patients who undergo upfront surgery for esophageal cancer. A total of 274 patients who underwent upfront surgery for esophageal squamous cell carcinoma between January 2012 and December 2016 were eligible. Preoperative nutritional status was evaluated using prognostic nutritional index (PNI) scoring system, nutritional risk screening 2002 (NRS 2002), and controlling nutritional status. The median age was 63 years (interquartile range, 58-70) and 94.7% of patients were male. The pathological stages were Stage I-74.5% (204/274), Stage II-20.4% (56/274), and Stage III-5.1% (14/274). Multivariate analysis revealed that advanced stage, a low PNI, and a high NRS 2002 were independent predictors of overall survival. During median follow-up period of 55 mo, overall survival rates were lower in the high NRS 2002 group ( P  < 0.001). A high NRS 2002 score was associated with frequent postoperative complications, especially pneumonia and anastomosis site leakage ( P  = 0.003). The poor preoperative nutritional status with a high NRS 2002 is associated with postoperative complications as well as poor overall survival in patients with upfront surgery for esophageal cancer.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2022.2042573.

MicroRNAs (miRNAs), found in blood and body fluids, have emerged as potential non-invasive biomarkers for disease and injury. miRNAs are quantitatively evaluated using typical RNA analysis methods such as the quantitative reverse transcription polymerase chain reaction, microarrays, and Northern blot, all of which require complex procedures and expensive reagents. To utilize miRNAs as practical biomarkers, it will be helpful to develop simple and user-friendly sensors. In this study, a paper-based miRNA sensor was developed by combining two methods: (1) target-recycled DNAzyme (Dz) amplification and (2) graphene oxide-assisted Dz blotting on paper. The Dz spots on paper caused a miRNA-dependent color change in presence of colorimetric reagents and facilitated the quantification of absolute amount of the target miRNA, irrespective of the volume, with high reproducibility. This approach is technologically straightforward and enables quantification of as low as 7.75 fmol miRNA using a portable smartphone., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Biomolecule detection based on surface-enhanced Raman scattering (SERS) for application to biosensors and bio-imaging requires the fabrication of SERS nanoprobes that can generate strong Raman signals as well as surface modifications for analyte-specific recognition and binding. Such requirements lead to disadvantages in terms of reproducibility and practicality, and thus, it has been difficult to apply biomolecule detection utilizing the advantages of the SERS phenomenon to actual clinically relevant analysis. To achieve reproducible and practical SERS signal generation in a biomolecule-specific manner without requiring the synthesis of nanostructures and their related surface modification to introduce molecules for specific recognition, we developed a new type of SERS probe formed by enzyme reactions in the presence of Raman reporters. By forming unique plasmonic structures, our method achieves the detection of biomolecules on chips with uniform and stable signals over long periods. To test the proposed approach, we applied it to a SERS-based immunohistochemistry assay and found successful multiplexed protein detection in brain tissue from transgenic mice.

Background: Ingested foreign objects frequently require emergency removal. This study aimed to investigate the clinical outcomes of endoscopic removal of foreign bodies from the upper gastrointestinal tract and the risk factors for adverse events., Methods: Adults (> 18 years) who underwent endoscopic management of ingested foreign bodies at two centers, one inland and one on the coast, between January 2008 and December 2017 were eligible. Clinical characteristics and procedure-related outcomes were retrospectively reviewed. Patients were divided into two groups, based on whether the foreign bodies were sharp or blunt in shape., Results: A total of 853 patients aged 19-96 years were analyzed. Ingestion of fish bones was more common in the coastal area, whereas ingestion of food boluses was more common in the inland area. The duration of impaction ranged from 1 h to over 1 month and was significantly longer in patients who ingested blunt than sharp foreign bodies (15 vs. 5 h, p < 0.001). Most (98.9%) foreign bodies were successfully removed. Adverse events occurred in 31.2 % of patients, including ulcers (4.0%) and perforations (3.3 %). Multivariate analysis showed that age (odds ratio [OR] 1.015, p = 0.012), sharp foreign bodies (OR 5.133, p < 0.001), location in the esophagus (OR 2.723, p = 0.018), and duration of impaction (OR 1.431, p < 0.001) were factors associated with adverse events., Conclusions: Early recognition and timely endoscopic removal of ingested foreign bodies, particularly in elderly patients and those with sharp foreign bodies, may improve clinical outcomes., (© 2021. The Author(s).)

Background: Although the rate of early detection and endoscopic treatment of gastric neuroendocrine tumors (NETs) is steadily increasing, there are insufficient studies on the long-term outcomes of endoscopic treatment. Therefore, we aimed to investigate the clinical features and long-term outcomes of endoscopic treatment for type 1 gastric NETs., Methods: Subjects who underwent endoscopic treatment for gastric NETs between March 1997 and December 2015 were included. Clinical features and endoscopic treatment outcomes were retrospectively investigated by reviewing medical records., Results: In total, 125 subjects underwent endoscopic treatment including forceps biopsy (n = 21), argon plasma coagulation (n = 1), endoscopic mucosal resection (EMR, n = 62), and endoscopic submucosal dissection (ESD, n = 41). In total, 103 patients with 114 lesions, who underwent EMR or ESD, were analyzed to evaluate endoscopic and oncologic outcomes. The rates of en bloc resection in the EMR and ESD groups were 91.5% and 97.7%, respectively. Complete resection rates were significantly higher in the ESD group than in the EMR group; it was also higher in < 1-cm small-sized lesions than in 1-2-cm large-sized lesions. Adverse events were similar between the two groups. During a median follow-up period of 63 months, local recurrence rates were 6.5% and 2.4% in the EMR and ESD groups, respectively, and the disease-free survival rate did not differ significantly between the groups., Conclusion: Endoscopic treatment for type 1 gastric NETs less than 2 cm in diameter and confined to mucosal and submucosal layers could be an effective and safe treatment strategy based on the favorable long-term outcome., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background and Aims: The prognosis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is favorable, especially in the absence of lymph node metastasis (LNM). We investigated LNM incidence and location in superficial type gastric MALT lymphoma., Methods: We performed a retrospective analysis of 450 patients newly diagnosed with gastric MALT lymphoma with tumor infiltration confined to the mucosa or submucosa as evidenced by endoscopic ultrasonography. LNM incidence and location were evaluated., Results: Of the 450 patients, most patients (434, 96.4%) were initially LNM negative as confirmed by computed tomography (CT) scanning. Sixteen patients (3.6%) were LNM positive. There was no difference in clinical characteristics between the 2 groups except for the extent of lymphoma involvement and endoscopic findings. Among 41 patients undergoing abdominal/pelvic CT (APCT) only, LNM was detected in 1 (2.4%). There were 8 LNM cases among 238 patients undergoing both APCT and chest CT (3.4%). Among 171 patients undergoing APCT, chest CT, and neck CT, 7 cases of LNM were detected (4.1%). The detection rates for each CT were as follows: abdominal CT, 13/450 (2.9%); chest CT, 6/408 (1.5%); and neck CT, 1/171 (0.6%). Among 6 patients with chest CT-positive findings, 3 showed no evidence of LNM on APCT., Conclusion: LNM was an infrequent finding in gastric MALT lymphoma patients with tumor infiltration confined to the mucosa or submucosa. Besides endoscopy and endoscopic ultrasonography, APCT and chest CT are considered as optimal initial workup modalities in patients with assumed primary superficial gastric MALT lymphoma., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aims: Data regarding the prognosis of early esophageal cancer are lacking. This study investigated the long-term outcomes and factors affecting the survival of patients with mucosal esophageal squamous cell carcinoma (T1aESCC)., Methods: We analyzed the clinical and tumor-specific parameters of 263 patients who received surgical resection (SR; n=63) or endoscopic resection (ER; n=200) for T1aESCC. Underlying comorbidities were scored using the Charlson comorbidity index (CCI). Overall survival (OS) was the primary outcome, and multivariate regression analysis was performed to predict factors for OS., Results: Of the study patients (age, 64.5±8.0 years), the CCI was 1.0±1.4 in the ER group and 0.6±0.9 in the SR group (p=0.107). The 5-year OS rate during follow-up (54.4±20.4 months) was 85.7% (ER group, 86.8%; SR group, 82.4%; p=0.631). The cumulative 5-year incidence of esophageal cancer recurrence was 10.5% in the ER group (vs 0% in the SR group). The overall mortality rate was 12.9% (ER group, 12.0%; SR group, 15.9%; p=0.399). The most common cause of mortality was second primary cancers in the ER group (75%) and organ dysfunction or postoperative complications in the SR group (70%). According to multivariate analysis, only CCI was significantly associated with OS (p<0.001). The 5-year OS rate in patients with a CCI >2 and in those with a CCI ≤2 was 60.2% and 88.2%, respectively (p<0.001). The treatment method (ER vs SR) was not a significant affecting factor (p=0.238)., Conclusions: The long-term prognosis of patients with T1aESCC was significantly associated with underlying comorbidities.

Background/aim: We investigated the oncologic outcomes in elderly patients who underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) by focusing on the impact of comorbidities, sarcopenia, and nutritional status., Methods: Between 2005 and 2016, 280 patients aged ≥ 80 years with 289 EGCs underwent ESD at a tertiary care center. The short- and long-term survival outcomes were assessed. Cox regression analysis was used to identify factors associated with survival, including clinicopathologic factors and abdominal muscle area measured by computed tomography., Results: The rates of en bloc , R0, and, curative resection were 99.3%, 90.0%, and 69.2%, respectively. The rates of post-ESD bleeding and perforation rates were 2.1% and 3.1%, respectively, and no cases showed significant life-threatening adverse events. Over a median follow-up period of 70.5 months, the 3- and 5-year overall survival (OS) rates were 89.5% and 77.1%, respectively; of the114 patients who died, only four (3.5%) were due to gastric cancer. A total of 173 (61.8%) had sarcopenia, and they had lower rates of 3-year (88.4% vs. 91.4%) and 5-year (73.1% vs. 84.0%; p = 0.046) OS than did those without sarcopenia. In multivariable analyses, prognostic nutritional index (hazard ratio [HR], 0.93; 95% confidence interval [CI]: 0.90-0.98; p = 0.002) and Charlson comorbidity index (HR 1.19; 95% CI: 1.03-1.37; p = 0.018) were significant factors associated with overall survival., Conclusions: ESD was a feasible and safe therapeutic method to use in elderly patients, whose long-term survival was significantly associated with nutritional status and comorbidities. These results suggest the need for a possible extension of the curative criteria for ESD in elderly patients with EGC.

Background: Benign esophageal anastomotic strictures have typically been treated using endoscopic methods, often with balloon dilatation (BD). However, recurrent esophageal strictures after BD have been reported. We evaluated the efficacy and safety of endoscopic incisional therapy (EIT) and BD for treating an anastomotic stricture after a total gastrectomy., Methods: Subjects who underwent EIT or BD as a first treatment for esophagojejunostomy anastomotic stricture after a total gastrectomy between January 2010 and December 2018 were eligible. The medical records of these cases were retrospectively reviewed. Stricture was defined as an inability to pass a normal diameter endoscope (10.2 mm). The stricture area was incised under direct vision with the nano-insulated-tip knife in a radial fashion parallel to the longitudinal axis of the esophagus., Results: Twenty-one patients in our database presented with benign anastomotic stricture after a total gastrectomy for advanced gastric cancer. The BD group included 12 patients. The remaining nine patients underwent EIT, and three of these cases received an immediate additional BD. The re-stricture rate was significantly different between the BD and EIT groups (41.7% vs. 0%, respectively; P = 0.045). There were no significant differences in procedure time, interval from surgery to first stricture, hospitalization period, or complication rates between the groups. One patient developed a microperforation during BD and was treated without surgical intervention., Conclusions: EIT is a safe and effective primary treatment modality compared with BD for esophagojejunostomy anastomotic stricture after a total gastrectomy as it shows a significantly lower re-stricture rate., (© 2020. The Society for Surgery of the Alimentary Tract.)

More than half of the world's populations are considered to be infected by Helicobacter pylori . It causes a chronic inflammation of the stomach, which is implicated in the pathogenesis of gastric ulcer and cancer. Silibinin, a polyphenolic flavonoid derived from milk thistle, has been known for its hepatoprotective effects, and recent studies have revealed its chemopreventive potential. In the present study, we examined the anti-inflammatory effects of silibinin in human gastric cancer MKN-1 cells and in the stomach of C57BL/6 mice infected by H. pylori . Pretreatment with silibinin attenuated the up-regulation of COX-2 and inducible nitric oxide synthase (iNOS) in H. pylori -infected MKN-1 cells and mouse stomach. In addition, the elevated translocation and DNA binding of NF-κB and STAT3 induced by H. pylori infection were inhibited by silibinin treatment. Moreover, H. pylori infection in combination with high salt diet resulted in dysplasia and hyperplasia in mouse stomach, and these pathological manifestations were substantially mitigated by silibinin administration. Taken together, these findings suggest that silibinin exerts anti-inflammatory effects against H. pylori infection through suppression of NF-κB and STAT3 and subsequently, expression of COX-2 and iNOS., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed., (Copyright © 2021 Korean Society of Cancer Prevention.)

For organ transplantation patients, the therapeutic drug monitoring (TDM) of immunosuppressive drugs is essential to prevent the toxicity or rejection of the organ. Currently, TDM is done by immunoassays or liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods; however, these methods lack specificity or are expensive, require high levels of skill, and offer limited sample throughput. Although matrix-assisted (MA) laser desorption ionization (LDI) mass spectrometry (MS) can provide enhanced throughput and cost-effectiveness, its application in TDM is limited due to the limitations of the matrixes such as a lack of sensitivity and reproducibility. Here, we present an alternative quantification method for the TDM of the immunosuppressive drugs in the blood of organ transplant patients by utilizing laser desorption ionization mass spectrometry (LDI-MS) based on a tungsten disulfide nanosheet, which is well-known for its excellent physicochemical properties such as a strong UV absorbance and high electron mobility. By adopting a microliquid inkjet printing system, a high-throughput analysis of the blood samples with enhanced sensitivity and reproducibility was achieved. Furthermore, up to 80 cases of patient samples were analyzed and the results were compared with those of LC-MS/MS by using Passing-Bablok regression and Bland-Altman analysis to demonstrate that our LDI-MS platform is suitable to replace current TDM techniques. Our approach will facilitate the rapid and accurate analysis of blood samples from a large number of patients for immunosuppressive drug prescriptions.

Abstract: Peroral endoscopic myotomy (POEM) is an endoscopic alternative to surgical myotomy in patients with achalasia. This study aimed to evaluate the efficacy and clinical outcomes of POEM.A total of 20 patients with achalasia who underwent POEM between October 2016 and November 2017 were prospectively recruited. The intraoperative esophagogastric junction distensibility index (mm2/mm Hg) was measured pre- and post-myotomy using an endoluminal functional lumen imaging probe. Clinical response was defined as Eckardt score ≤3. Health-related quality of life was measured by the 36-item short-form health survey score.POEM was successfully completed in all cases. The median procedure time was 68.5 minutes (range 50.0-120.0), and the median myotomy length was 13 cm (range 11-18). Major adverse events were encountered in 2 cases. Overall, clinical responses were observed in all patients during a median follow-up of 11.9 months (range 1.2-26.2). Postoperative esophagogastric junction distensibility index was significantly higher than baseline (from 1.3 [range 0.8-6.9] to 6.3 [range 25-19.2], P < .001). The median Eckardt scores were decreased after POEM (5 [range 2-11] to 1 [range 0-3], P < .001), and the 36-item short-form health survey score was also improved significantly after POEM (67.5 [range 34.5-93.9] to 85.7 [range 53.4-93.3], P = .004).POEM is an effective treatment for achalasia, based on the improvement of both symptoms and objective measures.Clinicaltrial.gov NCT02989883., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

SIRT1 is a mammalian NAD + -dependent deacetylase, which is known to be involved in various physiological events, such as adaptive response to environmental stresses including caloric restriction, as well as in aging and cellular senescence. However, recent studies have revealed overexpression of SIRT1 in many different types of human malignancies, particularly colon cancer. Interleukin-1β (IL-1β) is a proinflammatory cytokine that plays a major role in invasiveness, stemness and progression of colon cancer. However, the interaction between IL-1β and SIRT1 in the tumor development and progression remains elusive. In this study, we found that IL-1β induces SIRT1 protein expression in human colon cancer HCT-116 cells. IL-1β-induced SIRT1 upregulation led to enhanced expression of mRNA transcripts of pro-inflammatory cytokines, IL-6 and IL-8 as well as that of IL-1β. Knockdown of SIRT1 prevented IL-1β-induced phosphorylation and nuclear accumulation of c-Jun. Furthermore, pharmacologic inhibition of SIRT1 abrogated clonogenicity and migrative capability of human colon cancer cells stimulated with IL-1β. In summary, IL-1β-induced SIRT1 upregulation stimulates production of proinflammatory cytokines via a nuclear accumulation of c-Jun, leadng to colon cancer growth and progression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Circumferential endoscopic submucosal dissection (ESD) for large lesions induces severe stricture, requiring subsequent treatment. We aimed to evaluate the efficacy of allogeneic epithelial cell sheet transplantation in preventing esophageal stricture after circumferential ESD in a porcine model., Materials and Methods: A total of 15 conventional pigs underwent a 4 cm long circumferential ESD in the mid-esophagus. Out of these animals, 11 were immediately subjected to allogeneic oral mucosal cell sheet transplantation at the resection site, whereas four pigs underwent circumferential ESD only. We performed upper endoscopy 1 and 2 weeks after ESD and assessed the degree of esophageal stricture and histologic characteristics., Results: Dysphagia scores and weight change ratios recorded 1 and 2 weeks after ESD did not differ between the two groups. The stricture rate 2 weeks after ESD was 100% in the control group and 90.9% in the cell sheet group ( p  = 1.000). The median mucosal constriction rates of the control and cell sheet groups were 73.5% (range 63.0-80.0%) and 53.8% (37.5-73.3%, p  = .018), respectively. With regard to microscopic measurements, the length of re-epithelialization was greater in the cell sheet group than in the control group (2,495 µm vs. 369 µm, p  = .008). Median fibrosis thickness and degree of muscle damage were not significantly different between groups., Conclusions: Although allogeneic epithelial cell sheet transplantation showed greater re-epithelialization and less mucosal constriction of post-ESD ulcers, it was not sufficiently effective in preventing post-ESD stricture.

While failure in resolution of inflammation is considered to increase the risk of tumorigenesis, there is paucity of experimental as well as clinical evidence supporting this association. Resolvin D1 (RvD1) is a representative pro-resolving lipid mediator that is endogenously generated from docosahexaenoic acid for the resolution of inflammation. Here, we report a decreased level of RvD1 in the blood from colorectal cancer patients and mice having inflammation-induced colon cancer, suggesting plasma RvD1 as a potential biomarker for monitoring colorectal cancer. Administration of RvD1 attenuated dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colorectal carcinogenesis by suppressing the production of interleukin-6 (IL-6) and IL-6-mediated chromosomal instability. The protective effect of RvD1 against chromosomal instability is associated with downregulation of IL-6-induced Cyclin D1 expression, which appears to be mediated by blocking the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) axis. RvD1 inhibited the STAT3 signaling pathway by interfering with the binding of IL-6 to its receptor (IL-6R), suggesting the novel function of RvD1 as a putative IL-6R antagonist. Together, our findings suggest that RvD1-mediated blockade of IL-6 signal transmission may contribute to inhibition of chromosomal instability and tumorigenesis., (© 2021 Federation of American Societies for Experimental Biology.)

Background: Endoscopic surveillance after total gastrectomy (TG) for gastric cancer is routinely performed to detect tumor recurrence and postoperative adverse events. However, the reports on the clinical benefits of endoscopic surveillance are ambiguous. We investigated the clinical benefit of endoscopic surveillance after TG for gastric cancer., Methods: We analyzed 848 patients who underwent TG with R0 resection for gastric cancer between 2011 and 2012 (380 early gastric cancer and 468 advanced gastric cancer) and underwent regular postoperative surveillance with endoscopy and abdominopelvic computed tomography (CT) with contrast., Results: Median follow-up periods were 58 months for both endoscopy (range, 3-96) and abdominopelvic CT (range, 1-96). Tumor recurrence occurred in 167 patients (19.7%), of whom seven (4.2%) were locoregional recurrences in the peri-anastomotic area (n = 5) or regional gastric lymph nodes (n = 2). Whereas the peri-anastomotic recurrences were detected by both endoscopy and abdominopelvic CT, regional lymph node recurrences were only detected by abdominopelvic CT. Out of the 23 events of postoperative adverse events, the majority (87%) were detected by radiologic examinations; three events of benign strictures in the anastomotic site were detected only by endoscopy., Conclusion: Endoscopic surveillance did not have a significant role in detecting locoregional tumor recurrence and postoperative adverse events after TG with R0 resection for gastric cancer. Routine endoscopic surveillance after TG may be considered optional and performed according to the capacities of each clinical setting., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Purpose: The association of serum lipids with gastric cancer is controversial. We clarified the role of serum lipids in the development, progression, and prognosis of gastric cancer., Materials and Methods: In total, 412 patients diagnosed with gastric cancer were prospectively recruited, and 2,934 control subjects who underwent screening endoscopy were enrolled from December 2013 to March 2017 to conduct a case-control study in a tertiary center. Serum lipid profiles, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (apoA-I), and apolipoprotein B, and clinicopathologic characteristics were analyzed., Results: The gastric cancer group showed significantly lower HDL-C, higher LDL-C, and lower apoA-I level than the control group. In multivariate analysis, old age (odds ratio [OR], 1.051; p < 0.001), smoking (OR, 1.337; p < 0.001), a family history of gastric cancer (OR, 2.038; p < 0.001), Helicobacter pylori seropositivity (OR, 4.240; p < 0.001), lower HDL-C (OR, 0.712; p=0.020), and higher LDL-C (p=0.002) were significant risk factors for gastric cancer. Lower HDL-C and higher LDL-C remained significant after adjustments for covariates, including age and sex. In a subgroup analysis of the gastric cancer group, lower TG levels were associated with undifferentiated histology. No serum lipids were associated with overall survival., Conclusion: Lower HDL-C and higher LDL-C were associated with the risk of gastric cancer, even after adjusting for age, sex, and other factors. In the gastric cancer group, undifferentiated histology was associated with lower TG levels.

MicroRNAs (miRNAs) are important post-transcriptional gene regulators and can serve as potential biomarkers for many diseases. Most of the current miRNA detection techniques require purification from biological samples, amplification, labeling, or tagging, which makes quantitative analysis of clinically relevant samples challenging. Here we present a new strategy for the detection of miRNAs with uniformity over a large area based on signal amplification using enzymatic reactions and measurements using time-of-flight secondary ion mass spectrometry (ToF-SIMS), a sensitive surface analysis tool. This technique has high sequence specificity through hybridization with a hairpin DNA probe and allows the identification of single-base mismatches that are difficult to distinguish by conventional mass spectrometry. We successfully detected target miRNAs in biological samples without purification, amplification, or labeling of target molecules. In addition, by adopting a well-known chromogenic enzymatic reaction from the field of biotechnology, we extended the use of enzyme-amplified signal enhancement ToF (EASE-ToF) to protein detection. Our strategy has advantages with respect to scope, quantification, and throughput over the currently available methods, and is amenable to multiplexing based on the outstanding molecular specificity of mass spectrometry (MS). Therefore, our technique not only has the potential for use in clinical diagnosis, but also provides evidence that MS can serve as a useful readout for biosensing to perform multiplexed analysis extending beyond the limitations of existing technology., Competing Interests: There are no competing interests to declare.

Heregulin-β1, a ligand of ErbB-2 and ErbB-3/4 receptors, has been reported to potentiate oncogenicity and metastatic potential of breast cancer cells. In the present work, treatment of human mammary cancer (MCF-7) cells with heregulin-β1 resulted in enhanced cell migration and expression of manganese superoxide dismutase (MnSOD) and its mRNA transcript. Silencing of MnSOD abrogated clonogenicity and migrative ability of MCF-7 cells. Heregulin-β1 treatment also increased nuclear translocation, antioxidant response element binding and transcriptional activity of NF-E2-related factor 2 (Nrf2). A dominant-negative mutant of Nrf2 abrogated heregulin-β1-induced MnSOD expression. Treatment with heregulin-β1 caused activation of protein kinase B (Akt) and extracellular signal-regulated protein kinase (ERK). The pharmacological inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase 1/2, which are upstream of Akt and ERK, respectively, attenuated heregulin-β1-induced MnSOD expression and nuclear localization of Nrf2. In conclusion, heregulin-1 induces upregulation of MnSOD and activation of Nrf2 via the Akt and ERK signaling in MCF-7 cells, which may confer metastatic potential and invasiveness of these cells., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed., (Copyright © 2021 Korean Society of Cancer Prevention.)

Tumor-associated macrophages (TAMs) represent one of the most abundant components of the tumor microenvironment and play important roles in tumor development and progression. TAMs display plasticity and functional heterogeneity as reflected by distinct phenotypic subsets. TAMs with an M1 phenotype have proinflammatory and anti-tumoral properties whereas M2-like TAMs exert anti-inflammatory and pro-tumoral functions. Tumor cell debris generated during chemotherapy can stimulate primary tumor growth and recurrence. According to our previous study, phagocytic engulfment of breast tumor cell debris by TAMs attenuated chemotherapeutic efficacy through the upregulation of heme oxygenase-1 (HO-1). To verify the impact of HO-1 upregulation on the profile of macrophage polarization during cytotoxic therapy, we utilized a syngeneic murine breast cancer (4T1) model in which tumor bearing mice were treated with paclitaxel (PTX). PTX treatment markedly downregulated the surface expression of the M1 marker CD86 in infiltrated TAMs. Notably, there were significantly more cytotoxic CD8 + T cells in tumors of mice treated with PTX plus the HO-1 inhibitor, zinc protophorphyrin IX (ZnPP) than in mice treated with PTX alone. Interestingly, the tumor-inhibiting efficacy of PTX and ZnPP co-treatment was abrogated when macrophages were depleted by clodronate liposomes. Macrophage depletion also decreased the intratumoral CD8 + T cell population and downregulated the expression of Cxcl9 and Cxcl10. The expression of the M1 phenotype marker, CD86 was higher in mice injected with PTX plus ZnPP than that in mice treated with PTX alone. Conversely, the PTX-induced upregulation of the M2 marker gene, Il10 in CD11b + myeloid cells from 4T1 tumor-bearing mice treated was dramatically reduced by the administration of the HO-1 inhibitor. Genetic ablation of HO-1 abolished the inhibitory effect of 4T1 tumor cell debris on expression of M1 marker genes, Tnf and Il12b , in LPS-stimulated BMDMs. HO-1-deficient BMDMs exposed to tumor cell debris also exhibited a diminished expression of the M2 macrophage marker, CD206. These findings, taken all together, provide strong evidence that HO-1 plays a pivotal role in the transition of tumor-inhibiting M1-like TAMs to tumor-promoting M2-like ones during chemotherapy.

There is a plethora of evidence to support that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately overexpressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains largely undefined. In this study, we found that 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), one of the final products of COX-2, induced upregulation of vascular endothelial growth factor (VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in breast cancer patients. Moreover, human tissue analysis showed that the levels of 15d-PGJ 2 as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human breast cancer tissues. In conclusion, the elevated levels of 15d-PGJ 2 during inflammatory response activate VEGF expression through NRF2-driven induction of HO-1 in human breast cancer cells, proposing a novel mechanism underlying the oncogenic function of 15d-PGJ 2 .

Background: Duodenal gastrointestinal stromal tumors (GISTs) are rare, and reports on duodenal GIST bleeding are few. We analyzed the risk factors and clinical outcomes of hemorrhagic duodenal GISTs and compared them with those of gastric GISTs., Methods: Primary duodenal GISTs surgically diagnosed between January 1998 and December 2017 were retrospectively reviewed. Furthermore, patients with duodenal GIST were compared with those with primary gastric GIST histopathologically diagnosed between January 1998 and May 2015 using previously published data., Results: Of the 170 total patients with duodenal GISTs, 48 (28.2%) exhibited tumor bleeding. Endoscopic intervention, embolization, and non-interventional conservative treatment were performed for initial hemostasis in 17, 1, and 30 patients, respectively. The 5-year survival rate was 81.9% in the bleeding group and 89.4% in the non-bleeding group (P = 0.495). Multivariate analysis showed that p53 positivity was a significant risk factor for duodenal GIST bleeding (hazard ratio [HR] 2.781, P = 0.012), and age ≥ 60 years (HR 3.163, P = 0.027), a large maximum diameter (comparing four groups: < 2, 2-5, 5-10, and ≥ 10 cm), and mitotic count ≥ 5/high-power field (HPF) (HR 3.265, P = 0.032) were risk factors for overall survival. The incidence of bleeding was significantly higher in duodenal GISTs than in gastric GISTs (28.2% vs. 6.6%, P < 0.001), and the re-bleeding rate after endoscopic hemostasis was also higher in duodenal GISTs than in gastric GISTs (41.2% vs. 13.3%, P = 0.118)., Conclusion: In patients with duodenal GIST with old age, large tumor diameter, and mitotic count ≥ 5/HPF, a treatment plan should be established in consideration of the poor prognosis, although tumor bleeding does not adversely affect the prognosis. Duodenal GISTs have a higher incidence of tumor bleeding and re-bleeding rate after endoscopic hemostasis than gastric GISTs.

Signal transducer and activator of transcription 3 (STAT3) has been considered as a potential target for development of anticancer therapeutics. Here, we report a novel mechanism by which the cyclopentenone prostaglandin, 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) functions as an allosteric inhibitor of STAT3. 15d-PGJ 2 inhibits phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3 in H-Ras-transformed human mammary epithelial cells (MCF10A-Ras) through the Michael addition reaction at cysteine 259 of STAT3. Comparative studies with 15d-PGJ 2 analogues reveal that both C12-C13 and C9-C10 double bonds conjugated to the carbonyl group in the cyclopentenone ring of 15d-PGJ 2 are essential for STAT3 binding. Antiproliferative and pro-apoptotic activities of 15d-PGJ 2 in MCF10A-Ras cells are attributable to covalent modification of STAT3 on Cys259, and mimic the effects induced by mutation of this amino acid., (© 2021 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)