Discovery of a novel small-molecule activator of SIRT3 that inhibits cell proliferation and migration by apoptosis and autophagy-dependent cell death pathways in colorectal cancer.

Colorectal cancer (CRC) is well known as a prevalent malignancy affecting the digestive tract, yet its precise etiological determinants remain to be elusive. Accordingly, identifying specific molecular targets for colorectal cancer and predicting potential malignant tumor behavior are potential strategies for therapeutic interventions. Of note, apoptosis (type I programmed cell death) has been widely reported to play a pivotal role in tumorigenesis by exerting a suppressive effect on cancer development. Moreover, autophagy-dependent cell death (type II programmed cell death) has been implicated in different types of human cancers. Thus, investigating the molecular mechanisms underlying apoptosis and autophagy-dependent cell death is paramount in treatment modalities of colorectal cancer. In this study, we uncovered that a new small-molecule activator of SIRT3, named MY-13, triggered both autophagy-dependent cell death and apoptosis by modulating the SIRT3/Hsp90/AKT signaling pathway. Consequently, this compound inhibited tumor cell proliferation and migration in RKO and HCT-116 cell lines. Moreover, we further demonstrated that the small-molecule activator significantly suppressed tumor growth in vivo. In conclusion, these findings demonstrate that the novel small-molecule activator of SIRT3 may hold a therapeutic potential as a drug candidate in colorectal cancer.

Correlation between tumor budding and the long-term follow-up outcomes after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

BACKGROUND: The effect of tumor budding (TB) on the prognosis of patients with esophageal squamous cell carcinoma (ESCC) after endoscopic submucosal dissection (ESD) remains unclear. We evaluated the long-term outcomes of patients with superficial ESCC after ESD and the risk factors of TB for the long-term prognosis. METHODS: We conducted a retrospective study in a Chinese hospital. All patients with ESCC treated by ESD and reported TB were included consecutively. Comparative analyses were conducted in three parts: specimen analysis, follow-up analyses of unmatched patients, and propensity score-matched (PSM) patients. Cox proportional hazard regression models were constructed to identify risk factors for overall survival and recurrence-free survival (RFS). RESULTS: A total of 437 patients were enrolled [154 TB and 283 no tumor budding (NTB)], and 258 patients (52 TB and 206 NTB) were included in the follow-up analysis. Results showed that the invasion depth, differentiation type, and positive vascular invasion (all p < 0.001) of the TB group were significantly different from the NTB group. The all-cause mortality and the median RFS time between the two groups were comparable. RFS rate at 5 years were 84.6% and 80.6%, respectively (p = 0.43). Cox analyses identified that having other cancers but not TB, as a risk factor independently associated with overall survival and RFS after ESD. CONCLUSION: TB tends to be associated with invasion depth, differentiation type, and positive vascular invasion. However, it might not affect the long-term outcomes of patients with superficial ESCC after ESD when other high-risk factors are negative.

Impact of Submucosal Saline Injection During Cold Snare Polypectomy for Colorectal Polyps Sized 3-9 mm: A Multicenter Randomized Controlled Trial.

INTRODUCTION: The role of submucosal injection during cold snare polypectomy (CSP) remains uncertain. In this study, we investigated the impact of submucosal saline injection during CSP for colorectal polyps sized 3-9 mm. METHODS: This was a multicenter randomized controlled trial conducted in 6 Chinese centers between July and September 2020 (ChiCTR2000034423). Patients with nonpedunculated colorectal polyps sized 3-9 mm were randomized in a 1:1 ratio to either CSP with submucosal injection (SI-CSP) or conventional CSP (C-CSP). The primary outcome was the incomplete resection rate (IRR). Secondary outcomes included procedure time, intraprocedural bleeding, delayed bleeding, and perforation. RESULTS: One hundred fifty patients with 234 polyps in the SI-CSP group and 150 patients with 216 polyps in the C-CSP group were included in the analysis. The IRR was not decreased in the SI-CSP group compared with that in the C-CSP group (1.7% vs 1.4%, P = 1.000). The median procedure time in the SI-CSP group was significantly longer than that in the C-CSP group (108 seconds vs 48 seconds, P < 0.001). The incidences of intraprocedural bleeding and delayed bleeding were not significantly different between the 2 groups ( P = 0.531 and P = 0.250, respectively). There was no perforation in either group. DISCUSSION: Submucosal saline injection during CSP for colorectal polyps sized 3-9 mm did not decrease the IRR or reduce adverse events but prolonged the procedure time.

The value of endoscopically-placed metal clips for transcatheter arterial embolization in the treatment of recurrent acute non-variceal upper gastrointestinal bleeding.

OBJECTIVE: Acute nonvariceal upper gastrointestinal bleeding (ANVUGIB) is a common clinical emergency. Transcatheter arterial embolization (TAE) is usually used to locate the bleeding site and provide interventional embolization. During TAE, there is a low positive rate of angiography, and localization of the culprit vessel is difficult. The purpose of this study was to demonstrate the role of preplaced metal clips in TAE for ANVUGIB patients. MATERIALS AND METHODS: Patients with ANVUGIB in whom bleeding sites were identified endoscopically and treated with TAE from January 1st, 2005 to July 1st, 2021 were retrospectively included. According to the presence or absence of preplaced metal clips, they were divided into two groups. The main outcome measurements included the clinical success rate and rebleeding rate. Secondary outcome measurements included the mortality rate and the need for surgery. Predictors of the clinical success rate were assessed with univariate analysis and multivariate analysis. RESULTS: A total of 102 patients were included in this study, and all of them had undergone arterial embolization. There were 73 cases in the group with metal clips and 29 cases in the group without metal clips with consistent baseline information. The group with metal clips had a higher clinical success rate (82.2% vs. 45.0%, P < 0.001), lower rebleeding rate (8.2% vs 27.6%, P = 0.039) and additional surgery rate (11.0% vs 20.7%, P < 0.001) than the group without metal clips. In univariate analysis, ROCKALL score and preplaced metal clip marking were shown to affect clinical success rate. In multivariate analysis, metal clip marking was found to facilitate clinical success (OR = 3.750, 95CI = 1.456-9.659, P = 0.004). CONCLUSION: In ANVUGIB patients, preplaced metal clips could improve the clinical success rate of TAE and reduce the mortality rate and the risk of rebleeding.

Endoscopic transcecal appendectomy: a new endotherapy for appendiceal orifice lesions.

BACKGROUND: Endoscopic transcecal appendectomy (ETA) has been reported as a minimally invasive alternative procedure for lesions involving the appendiceal orifice. The aim of this case series study was to evaluate the feasibility, safety, and effectiveness of ETA for lesions at the appendiceal orifice. METHODS: This retrospective study included consecutive patients with appendiceal orifice lesions who underwent ETA between December 2018 and March 2021. The primary outcome was technical success. The secondary outcomes included postoperative adverse events, postoperative hospital stay, and recurrence. RESULTS: 13 patients with appendiceal orifice lesions underwent ETA during the study period. The median lesion size was 20 mm (range 8-50). Lesions morphologies were polypoid lesions (n = 5), laterally spreading tumors (n = 4), and submucosal lesions (n = 4). Technical success with complete resection was achieved in all 13 cases. There were no postoperative bleeding, perforation, or intra-abdominal abscess. The median length of hospital stay after ETA was 8 days (range 6-18). There was no tumor recurrence during a median follow-up of 17 months (range 1-28). CONCLUSIONS: ETA is feasible, safe, and effective for complete resection of appendiceal orifice lesions. Larger, multicenter, prospective studies are needed to further assess this technique.

Comparison of effectiveness and safety between endoscopic and surgical resection for 2-5 cm gastric stromal tumors.

BACKGROUND: As endoscopic resection remains controversial, this study aims to compare the effectiveness and safety between endoscopic and surgical resection for 2-5 cm gastric stromal tumors (GSTs). METHODS: Patients with 2-5 cm GST resected at West China Hospital from March 2008 to April 2019 were enrolled. Propensity score matching (PSM) (1:1) was performed to achieve baseline data consistency. RESULTS: 112 patients were matched between the endoscopic resection group (ER) and the open surgery group. There were no significant differences in the complete resection rate (94.6% vs. 100%), the incidence of complications (25.0% vs. 14.3%), the recurrence rate (0% vs. 1.8%) and the 5-year relapse-free survival (100% vs. 97.9%) (P > 0.05). The ER had a shorter fasting time (3.5 days vs. 5 days), a shorter postoperative hospital stay (7 days vs. 8 days) and a lower hospitalization cost (3,589.16 USD vs. 5,931.24 USD) (P < 0.05). 54 cases were matched between the ER and the laparoscopic surgery group (LS). There were no significant differences in the complete resection rate (92.6% vs. 96.3%), the incidence of complications (22.2% vs. 11.1%), the fasting time (4 days vs. 3 days), the recurrence rate (0% vs. 3.7%) and the 5-year relapse-free survival (100% vs. 96.3%) (P > 0.05). The hospitalization cost (3,589.25 USD vs. 4,715.16 USD) was lower in the ER, and the postoperative hospital stay was shorter in the LS (6 days vs. 7 days) (P < 0.05). CONCLUSIONS: Although slightly higher incidences of incomplete resection and perforation were shown in the endoscopic resection group, there was insignificant difference between groups (P > 0.05). Endoscopic resection might be an alternative surgical method for 2-5 cm GSTs.

Artificial intelligence for diagnosing microvessels of precancerous lesions and superficial esophageal squamous cell carcinomas: a multicenter study.

BACKGROUND: Intrapapillary capillary loop (IPCL) is an important factor for predicting invasion depth of esophageal squamous cell carcinoma (ESCC). The invasion depth is closely related to the selection of treatment strategy. However, diagnosis of IPCLs is complicated and subject to interobserver variability. This study aimed to develop an artificial intelligence (AI) system to predict IPCLs subtypes of precancerous lesions and superficial ESCC. METHODS: Images of magnifying endoscopy with narrow band imaging from three hospitals were collected retrospectively. IPCLs subtypes were annotated on images by expert endoscopists according to Japanese Endoscopic Society classification. The performance of the AI system was evaluated using internal and external validation datasets (IVD and EVD) and compared with that of the 11 endoscopists. RESULTS: A total of 7094 images from 685 patients were used to train and validate the AI system. The combined accuracy of the AI system for diagnosing IPCLs subtypes in IVD and EVD was 91.3% and 89.8%, respectively. The AI system achieved better performance than endoscopists in predicting IPCLs subtypes and invasion depth. The ability of junior endoscopists to diagnose IPCLs subtypes (combined accuracy: 84.7% vs 78.2%, P < 0.0001) and invasion depth (combined accuracy: 74.4% vs 67.9%, P < 0.0001) were significantly improved with AI system assistance. Although there was no significant differences, the performance of senior endoscopists was slightly elevated. CONCLUSIONS: The proposed AI system could improve the diagnostic ability of endoscopists to predict IPCLs classification of precancerous lesions and superficial ESCC.

Value of the diving method for capsule endoscopy in the examination of small-intestinal disease: a prospective randomized controlled trial.

BACKGROUND AND AIMS: Video capsule endoscopy (VCE) is limited by poor image quality and incomplete small-bowel transit. This study was designed to evaluate the diving method for VCE in the examination of small-intestinal disease. METHODS: From July 2017 to September 2017, eligible patients were randomly assigned to 2 groups, the diving group and the control group. For the diving group, 500 mL of water was administered every hour when the capsule reached the small bowel. The primary outcomes were image quality and positive findings. Secondary outcomes were the completion rate of examination, gastric transit time (GTT), small-bowel transit time (SBTT), lesion detection rate, adverse events, and patient satisfaction. RESULTS: One hundred forty patients were included. The scores of endoscopic images in the proximal third and middle third of the small bowel in the diving group were significantly higher than that in the control group (3.47 ± .60 vs 3.11 ± .63 [P = .007] and 3.24 ± .59 vs 2.78 ± .74 [P = .002], respectively). The positive findings in the distal third of the small bowel were significantly different between the 2 groups (P = .005). The completion rate in the diving group was significantly higher (92.19% vs 76.32%, respectively; P = .012). The GTT, SBTT, and lesion detection rate were similar in 2 groups (P = .282, .067, and .577, respectively). No discomfort or adverse events were reported except for a few cases of frequent urination. CONCLUSIONS: The diving method for VCE examination effectively improves the endoscopic view in the proximal and middle thirds of the small bowel and the positive findings in the distal small intestine and increases the completion rate. (Clinical trial registration number: ChiCTR-RDR-17011823.).

Peroral endoscopic myotomy for the treatment of esophageal diverticulum: an experience in China.

BACKGROUND: With the development of minimally invasive endoscopic approaches for the esophagus in recent years, peroral endoscopic myotomy (POEM) in the treatment of esophageal diverticulum has been described recently in some reports due to its successful outcomes. The aim of this study is to report our experience with the use of diverticular POEM (D-POEM) technique in the management of esophageal diverticulum. METHODS: This retrospective study included consecutive patients with symptomatic esophageal diverticulum who visited our endoscopy center between April 2014 and January 2019. D-POEM was performed based on the principles of submucosal endoscopy. A new symptomatic scoring system was introduced to evaluate the severity of diverticular symptoms. RESULTS: A total of 10 patients with esophageal diverticulum (Zenker's 2, mid-esophagus 5, and epiphrenic 3) were included. The overall technical success rate of D-POEM was 100%, with a mean procedure time of 38.9 ± 20.5 (range 16-70) min. No serious complications occurred. Clinical improvement was achieved in 90% (9/10) of patients. The symptomatic score was significantly decreased from 2.5 (IQR 2.00-3.25) to 1.0 (IQR 0-1.25) (P = 0.007) during a median follow-up period of 11.0 (IQR 10.25-17.25) months. CONCLUSION: These findings suggested complete septotomy by D-POEM. Our preliminary data and experience put forwarded D-POEM as a safe and effective technique for esophageal diverticulum.

Per-oral endoscopic dual myotomy for the treatment of achalasia.

BACKGROUND: Repeat per-oral endoscopic myotomy is occasionally performed for persistent/recurrent symptoms in patients with achalasia, and yields favorable outcomes. We investigated a novel technique, per-oral endoscopic dual myotomy (dual-POEM), where a second myotomy was performed during a single session to augment the efficacy and avoid repeat interventions. The aim of this study was to evaluate its feasibility, safety and efficacy. METHODS: Consecutive patients diagnosed with achalasia who underwent dual-POEM (1/2018-5/2019) were prospectively collected and retrospectively analyzed. Patients with baseline Eckardt score ≥ 9, ≥ 10 years of symptoms, and/or having prior interventions other than myotomy received dual-POEM. The primary outcome was clinical success (Eckardt score ≤ 3). Secondary outcomes were procedure-related adverse events, change in lower esophageal sphincter (LES) pressure, and reflux complications. RESULTS: Seventeen patients received dual-POEM. Procedure-related adverse events were observed in 2 (11.8%) patients (mucosal injury and pneumonitis). Both were minor in severity. During a median follow-up of 33 months (interquartile range, IQR [31,35]; range, 19-36), clinical success was achieved in 16 (94.1%) patients. The median Eckardt score decreased from 9 (IQR [8, 11.5]; range 7-12) to 1 (IQR [1, 2]; range 0-4) (P < 0.001), and LES pressure decreased from 25.8 mmHg (IQR [21.7, 33.5]; range 17.7-46.3) to 7.4 mmHg (IQR [6.3, 10.4]; range 2.2-12.6) (P < 0.001). Seven (41.2%) patients developed postprocedural reflux either by gastroesophageal reflux disease questionnaire or esophagitis endoscopically, all successfully treated with proton pump inhibitors. CONCLUSION: Dual-POEM preliminarily demonstrated high efficacy with a favorable safety profile in patients with achalasia with predictors of treatment failure.

Endoscopic submucosal dissection with additional radiotherapy in the treatment of T1a esophageal squamous cell cancer: randomized controlled Trial.

BACKGROUND: Endoscopic submucosal dissection (ESD) is effective for treating T1a early esophageal squamous cell carcinoma (ESCC). However, occasional recurrences are inevitable. This trial was designed to clarify the efficacy of combining ESD with additional radiotherapy in the treatment of T1a ESCC. METHODS: Between January 2015 and September 2018, patients with early ESCC (T1aN0M0) following ESD were randomly assigned (1:1) to the radiotherapy group or non-radiotherapy group. Patients in the radiotherapy group received a median radiation dose of 59.4 Gy within 2 months after ESD. In the non-radiotherapy group, patients underwent regular follow-up only. Recurrence-free survival, cancer-specific survival, overall survival, and complications were evaluated. RESULTS: 70 patients completed the per-protocol treatment. Three patients in the non-radiotherapy group experienced intraluminal mucosal recurrence compared with none in the radiotherapy group. No local lymph node or distant metastases occurred in either group. The 3-year cumulative recurrence-free survival was 100 % in the radiotherapy group and 85.3 % in the non-radiotherapy group (P = 0.04; hazard ratio 0.08, 95 % confidence interval [CI] 0.01 - 0.86). However, there was no significant difference in RFS between the treatments within the T1a invasion subgroups (P > 0.05). No patient died in either group. Mucosal defects of more than three-quarters of the esophageal circumference were positively correlated with stenosis (P < 0.01; odds ratio 23.26, 95 %CI 4.04 - 133.86). No severe radiation toxicities were recorded. CONCLUSIONS: Radiotherapy after ESD might be a safe and effective optional therapeutic strategy to prevent recurrence of T1a ESCC.

Risk factors for distal migration of biliary plastic stents and related duodenal injury.

BACKGROUND: The risk factors of duodenal injury from distal migrated biliary plastic stents remain uncertain. The aim of this study was to determine the risk factors of distal migration and its related duodenal injury in patients who underwent placement of a single biliary plastic stent for biliary strictures. METHODS: We retrospectively reviewed all patients with biliary strictures who underwent endoscopic placement of a single biliary plastic stent from January 2006 to October 2017. RESULTS: Two hundred forty-eight patients with 402 endoscopic retrograde cholangiopancreatography procedures were included. The incidence of distal migration was 6.2%. The frequency of duodenal injury was 2.2% in all cases and 36% in cases with distal migration. Benign biliary strictures (BBS), length of the stent above the proximal end of the stricture (> 2 cm), and duration of stent retention (< 3 months) were independently associated with distal migration (p = 0.018, p = 0.009, and p = 0.016, respectively). Duodenal injury occurred more commonly in cases with larger angle (≥ 30°) between the distal end of the stent and the centerline of the patient's body (p = 0.018) or in cases with stent retention < 3 months (p = 0.031). CONCLUSIONS: The risk factors of distal migration are BBS and the length of the stent above the proximal end of the stricture. The risk factor of duodenal injury due to distal migration is large angle (≥ 30°) between the distal end of the stent and the centerline of the patient's body. Distal migration and related duodenal injury are more likely to present during the early period after biliary stenting.

Magnetic bead-assisted endoscopic submucosal dissection: a gravity-based traction method for treating large superficial colorectal tumors.

BACKGROUND: Colorectal endoscopic submucosal dissection (ESD) has always been challenging for endoscopists, but the procedure can be facilitated after adequate exposure of submucosal layer and cutting line. We developed a traction method based on gravity for facilitating colorectal ESD, referred as magnetic bead-assisted ESD (MBA-ESD). This study aimed to compare the safety and effectiveness of MBA-ESD and conventional ESD for treating large superficial colorectal tumors. METHODS: This retrospective study included consecutive patients with large (≥ 20 mm in their maximal diameter) superficial colorectal tumors who underwent MBA-ESD or conventional ESD at our endoscopy center between June 2017 to January 2018. Each patient in the MBA-ESD group was matched to a patient in the conventional ESD group using propensity scores. RESULTS: Thirteen patients in each group were matched for the analyses. The baseline characteristics were balanced after propensity matching. The incidence of overall complications was significantly lower in the matched MBA-ESD group (0% vs. 38.5%, P = 0.039), while similar rates of en bloc resection, R0 resection, curative resection, and tumor recurrence were noted. Although without statistic difference, dissection time and speed were improved when using MBA-ESD (33 min vs. 40 min, P = 0.111; and 21 mm2/min vs. 16 mm2/min, P = 0.143, respectively). CONCLUSIONS: MBA-ESD is a feasible, safe, and effective method for treating large superficial colorectal tumors. Further large, prospective and controlled studies are needed to fully assess this method.