Clinical outcomes of endoscopic resection for the treatment of intermediate- or high-risk gastric small gastrointestinal stromal tumors: a multicenter retrospective study.

BACKGROUND AND AIMS: Many studies of gastric gastrointestinal stromal tumors (g-GISTs) following endoscopic resection (ER) have typically focused on tumor size, with most tumors at low risk of aggressiveness after risk stratification. There have been few systematic studies on the oncologic outcomes of intermediate- or high-risk g-GISTs after ER. METHODS: From January 2014 to January 2020, we retrospectively collected patients considered at intermediate- or high-risk of g-GISTs according to the modified NIH consensus classification system. The primary outcome was overall survival (OS). RESULTS: Six hundred and seventy nine (679) consecutive patients were diagnosed with g-GISTs and treated by ER between January 2014 and January 2020 in three hospitals in Shanghai, China. 43 patients (20 males and 23 females) were confirmed at intermediate-or high-risk. The mean size of tumors was 2.23 ± 1.01 cm. The median follow-up period was 62.02 ± 15.34 months, with a range of 28 to 105 months. There were no recurrences or metastases, even among patients having R1 resections. The 5-year OS rate was 97.4% (42/43). CONCLUSION: ER for intermediate- or high-risk gastric small GISTs is a feasible and safe method, which allows for a wait-and-see approach before determining the necessity for imatinib adjuvant or surgical treatment. This approach to g-GISTs does require that patients undergo close follow-up.

Automatically optimized radiomics modeling system for small gastric submucosal tumor (<2 cm) discrimination based on EUS images.

BACKGROUND AND AIMS: The clinical management of small gastric submucosal tumors (SMTs) (<2 cm) faces a non-negligible challenge because of the lack of guideline consensus and effective diagnostic tools. This article develops an automatically optimized radiomics modeling system (AORMS) based on EUS images to diagnose and evaluate SMTs. METHODS: A total of 205 patients with EUS images of small gastric SMTs (<2 cm) were retrospectively enrolled in the development phase of AORMS for the diagnosis and the risk stratification of GI stromal tumor (GIST). A total of 178 patients with images from different centers were prospectively enrolled in the independent testing phase. The performance of AORMS was compared to that of endoscopists in the development set and evaluated in the independent testing set. RESULTS: AORMS demonstrated an area under the curve (AUC) of 0.762 for the diagnosis of GIST and 0.734 for the risk stratification of GIST, respectively. In the independent testing set, AORMS achieved an AUC of 0.770 and 0.750 for the diagnosis and risk stratification of small GISTs, respectively. In comparison, the AUCs of 5 experienced endoscopists ranged from 0.501 to 0.608 for diagnosing GIST and from 0.562 to 0.748 for risk stratification. AORMS outperformed experienced endoscopists by more than 20% in diagnosing GIST. CONCLUSIONS: AORMS implements automatic parameter selection, which enhances its robustness and clinical applicability. It has demonstrated good performance in the diagnosis and risk stratification of GISTs, which could aid endoscopists in the diagnosis of small gastric SMTs (<2 cm).

Efficacy of image-enhanced endoscopy for colorectal adenoma detection: A multicenter, randomized trial.

BACKGROUND: Improved adenoma detection at colonoscopy has decreased the risk of developing colorectal cancer. However, whether image-enhanced endoscopy (IEE) further improves the adenoma detection rate (ADR) is controversial. AIM: To compare IEE with white-light imaging (WLI) endoscopy for the detection and identification of colorectal adenoma. METHODS: This was a multicenter, randomized, controlled trial. Participants were enrolled between September 2019 to April 2021 from 4 hospital in China. Patients were randomly assigned to an IEE group with WLI on entry and IEE on withdrawal (n = 2113) or a WLI group with WLI on both entry and withdrawal (n = 2098). The primary outcome was the ADR. The secondary endpoints were the polyp detection rate (PDR), adenomas per colonoscopy, adenomas per positive colonoscopy, and factors related to adenoma detection. RESULTS: A total of 4211 patients (966 adenomas) were included in the analysis (mean age, 56.7 years, 47.1% male). There were 2113 patients (508 adenomas) in the IEE group and 2098 patients (458 adenomas) in the WLI group. The ADR in two group were not significantly different [24.0% vs 21.8%, 1.10, 95% confidence interval (CI): 0.99-1.23, P = 0.09]. The PDR was higher with IEE group (41.7%) than with WLI group (36.1%, 1.16, 95%CI: 1.07-1.25, P = 0.01). Differences in mean withdrawal time (7.90 ± 3.42 min vs 7.85 ± 3.47 min, P = 0.30) and adenomas per colonoscopy (0.33 ± 0.68 vs 0.28 ± 0.62, P = 0.06) were not significant. Subgroup analysis found that with narrow-band imaging (NBI), between-group differences in the ADR, were not significant (23.7% vs 21.8%, 1.09, 95%CI: 0.97-1.22, P = 0.15), but were greater with linked color imaging (30.9% vs 21.8%, 1.42, 95%CI: 1.04-1.93, P = 0.04). the second-generation NBI (2G-NBI) had an advantage of ADR than both WLI and the first-generation NBI (27.0% vs 21.8%, P = 0.01; 27.0% vs 21.2.0%, P = 0.01). CONCLUSION: This prospective study confirmed that, among Chinese, IEE didn't increase the ADR compared with WLI, but 2G-NBI increase the ADR.

Long-term clinical outcomes of endoscopic submucosal dissection in rectal neuroendocrine tumors based on resection margin status: a real-world study.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been widely adopted in treating rectal neuroendocrine tumors (NETs). However, clinical outcomes in rectal NETs after ESD with different resection margin status remain scanty, particularly in patients with positive resection margins. This study aimed to evaluate the long-term clinical outcomes of ESD in rectal NET based on the resection margin status. METHODS: This retrospective study included 436 patients diagnosed with rectal NET who had undergone ESD. Clinical data, including age, sex, tumor size, stage, invasion, and the resection margin status, were collected. Further, the patients were assessed for complications, recurrence, distant metastasis, and long-term outcomes. RESULTS: Among all 436 patients, 395 patients had their primary ESD in our hospital. Complete resection was achieved in 319 patients. Patients who did not achieve complete resection opted for follow-up (n = 73), salvage surgery (n = 1) and salvage ESD (n = 2). Another 41 had their primary ESD in other hospital with incomplete resection and had salvage ESD in our hospital. All 436 patients had a median follow-up period of 61.4 months (range 33.4-125.3 months). During the follow-up period, two patients developed recurrences, while three patients developed metastasis. There were no significant differences in the 5-year progression-free survival and overall survival between patients with incomplete resection opting for follow-up compared to the other two groups (P = 0.5/0.8). However, the complication rates were significantly higher in patients who received salvage ESD. CONCLUSION: This study demonstrated that positive resection margins have no influence on survival in patients with rectal NET treated using ESD.

The efficacy of full-thickness endoscopic resection of subepithelial tumors in the gastric cardia.

BACKGROUND: Gastric subepithelial tumors (SETs) may harbor potential malignancy. Although it is well recognized that large SETs should be resected, the precise treatment strategy remains controversial. Compared to surgical resection, endoscopic resection (ER) has many advantages; however, ER of SETs in the cardia is challenging. AIM: To evaluate the safety and efficacy of endoscopic full-thickness resection (EFTR) for the treatment of gastric cardia SETs. METHODS: We retrospectively reviewed data from all patients with SETs originating from the muscularis propria layer in the gastric cardia that were treated by EFTR or submucosal tunneling ER (STER) at Zhongshan Hospital Fudan University between November 2014 and May 2022. Baseline characteristics and clinical outcomes, including procedure times and complications rates, were compared between groups of patients receiving EFTR and STER. RESULTS: A total of 171 tumors were successfully removed [71 (41.5%) tumors in the EFTR and 100 (58.5%) tumors in the STER group]. Gastrointestinal stromal tumors (GISTs) were the most common SET. The en bloc resection rate was 100% in the EFTR group vs 97.0% in STER group (P > 0.05). Overall, the EFTR group had a higher complete resection rate than the STER group (98.6% vs 91.0%, P < 0.05). The procedure time was also shorter in the EFTR group (44.63 ± 28.66 min vs 53.36 ± 27.34, P < 0.05). The most common major complication in both groups was electrocoagulation syndrome. There was no significant difference in total complications between the two groups (21.1% vs 22.0%, P = 0.89). CONCLUSION: EFTR of gastric cardia SETs is a very promising method to facilitate complete resection with similar complications and reduced operative times compared to STER. In cases of suspected GISTs or an unclear diagnosis, EFTR should be recommended to ensure complete resection.

NLRP7 deubiquitination by USP10 promotes tumor progression and tumor-associated macrophage polarization in colorectal cancer.

BACKGROUND: NOD-like receptors affect multiple stages of cancer progression in many malignancies. NACHT, LRR, and PYD domain-containing protein 7 (NLRP7) is a member of the NOD-like receptor family, although its role in tumorigenesis remains unclear. By analyzing clinical samples, we found that NLRP7 protein levels were upregulated in colorectal cancer (CRC). We proposed the hypothesis that a high level of NLRP7 in CRC may promote tumor progression. Here, we further investigated the role of NLRP7 in CRC and the underlying mechanism. METHODS: NLRP7 expression in human CRC and adjacent non-tumorous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effect of NLRP7 in CRC progression was investigated in vitro and in vivo. Proteins interacting with NLRP7 were identified by immunoprecipitation and mass spectrometry analysis while immunofluorescence staining revealed the cellular location of the proteins. Cellular ubiquitination and protein stability assays were applied to demonstrate the ubiquitination effect on NLRP7. Cloning and mutagenesis were used to identify a lysine acceptor site that mediates NLRP7 ubiquitination. Cytokines/chemokines affected by NLRP7 were identified by RNA sequencing, qRT-PCR, and enzyme-linked immunosorbent assay. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and immunohistochemistry. RESULTS: NLRP7 protein levels, but not mRNA levels, were upregulated in CRC, and increased NLRP7 protein expression was associated with poor survival. NLRP7 promoted tumor cell proliferation and metastasis in vivo and in vitro and interacted with ubiquitin-specific protease 10, which catalyzed its deubiquitination in CRC cells. NLRP7 stability and protein levels in CRC cells were modulated by ubiquitination and deubiquitination, and NLRP7 was involved in the ubiquitin-specific protease 10 promotion of tumor progression and metastasis in CRC. K379 was an important lysine acceptor site that mediates NLRP7 ubiquitination in CRC cells. In CRC, NLRP7 promoted the polarization of pro-tumor M2-like macrophages by inducing the secretion of C-C motif chemokine ligand 2. Furthermore, NLRP7 promoted NF-κB nuclear translocation and activation of C-C motif chemokine ligand 2 transcription. CONCLUSIONS: We showed that NLRP7 promotes CRC progression and revealed an as-yet-unidentified mechanism by which NLRP7 induces the polarization of pro-tumor M2-like macrophages. These results suggest that NLRP7 could serve as a biomarker and novel therapeutic target for the treatment of CRC.

RNA binding protein CUGBP1 mediates the liver metastasis of colorectal cancer by regulating the ErbB signal pathway.

BACKGROUND: The CUGBP1 (CELF1) is differentially expressed in liver metastasis and no liver metastasis colorectal cancers (CRC) tissues and the function of CUGBP1 in CRC is still unclear. METHODS: Five cases of colorectal adenocarcinoma and 6 cases of liver metastatic CRC lesions were collected and subjected to cDNA microarray and bioinformatical analyses. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to confirm the result. Cell function assays were used to study the function of CUGBP1, and the western blot was used to discover the change of the downstream molecules. RESULTS: CUGBP1 was significantly elevated in liver metastatic CRC lesions. Besides, the CUGBP1 can promote proliferation, colony formation, invasion, metastasis abilities as well as increase the apoptosis rates of CRC cells. ERBB2 was positively related to the CUGBP1. Western blot results found that silence of CUGBP1 decreased the protein level of p-AKT and p-ERK without influence the expression level of total protein of AKT and ERK. CONCLUSIONS: CUGBP1 can promote liver metastasis of CRC by promoting the phosphorylation of AKT and ERK through the ErbB signaling pathway. CUGBP1 is a potential biomarker for early detection of CRC and maybe a novel therapeutic target of CRC treatment, especially in liver metastasis.

Strategy for Scanning Peptide-Coding Circular RNAs in Colorectal Cancer Based on Bioinformatics Analysis and Experimental Assays.

Background: Colorectal cancer (CRC) is the third most common cause of cancer deaths worldwide. Numerous studies have reported that circular RNAs (circRNAs) have important functions in CRC. It was first thought that circRNAs were non-coding RNA; however, more recently they were discovered to encode peptides and play a pivotal role in cancer development and progression. It was shown that most circRNAs possess coding potential; however, not all of them can truly encode peptides. Therefore, a practical strategy to scan for coding circRNAs is needed. Method: Sequence analyses included open reading frame (ORF) prediction, coding peptide prediction, and the identification of unique sequences. Then, experimental assays were used to verify the coded peptides, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was introduced to detect sequences of circRNAs with coding potential, and Western blot was used to identify the encoded peptides. Finally, the functions of the circRNAs were primarily explored. Result: An efficient strategy for searching circRNAs with coding potential was created. We verified this schedule using public databases and LC-MS/MS, then two of these circRNAs were selected for further verification. We used commercial antibodies that can also identify the predicted peptides to test the coded peptides. The functions of the circRNAs were explored primarily, and the results showed that they were mainly involved in the promotion of proliferation and invasion ability. Discussion: We have constructed an efficient strategy of scanning circRNAs with coding potential. Our strategy helped to provide a more convenient pathway for identifying circRNA-derived peptides, which can be a potential therapeutic target or a diagnostic biomarker.

Prediction of technically difficult endoscopic submucosal dissection for large superficial colorectal tumors: a novel clinical score model.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is a promising technique for removing superficial GI tumors, but ESD is technically difficult. The aim of this study was to establish a clinical score model for grading technically difficult colorectal ESD. METHODS: Data on patients, lesions, and outcomes of colorectal ESD at 2 centers were analyzed. The objective parameter of successful ESD within 60 minutes was set as an endpoint to evaluate the difficulty. Independent predictors of difficulty in the derivation cohort were identified by multiple logistic regression analysis and used to develop a clinical score. We validated the score model in the validation cohort. RESULTS: The clinical score comprised tumor size of 30 to 50 mm (1 point) or ≥50 mm (2 points), at least two-thirds circumference of the lesion (2 points), location in the cecum (1 point), flexure (2 points) or dentate line (1 point), and laterally spreading tumor nongranular lesions (1 point). Areas under the receiver operator characteristic curves for the score model were comparable (derivation [.70] vs internal validation [.69] vs external validation [.69]). The probability of successful ESD within 60 minutes in easy (score = 0), intermediate (score = 1), difficult (score = 2-3), and very difficult (score ≥4) categories were 75.0%, 51.3%, 35.6%, and 3.4% in the derivation cohort; 73.3%, 47.9%, 31.8%, and 16.7% in the internal validation cohort; and 79.5%, 66.7%, 43.3%, and 20.0% in the external validation cohort, respectively. CONCLUSIONS: This clinical score model accurately predicts the probability of successful ESD within 60 minutes and can be applied to grade the technical difficulty before the procedure.

HDAC2 promotes the EMT of colorectal cancer cells and via the modular scaffold function of ENSG00000274093.1.

Histone deacetylase 2 (HDAC2), a member of the Histone deacetylase family, plays a vital role in various carcinomas. In this study, we identified that HDAC2 expression levels are associated with liver metastasis, higher T stages and poor prognosis in colorectal cancer. HDAC2 down-regulation via lentivirus-mediated expression of HDAC2-targeting shRNA reduced the in vitro migration and invasion ability of HCT116 cell as well as their liver metastasis in nude mouse xenografts. Mechanistically, HDAC2 promotes epithelial-mesenchymal transition (EMT) in colorectal cancer cells by combining HDAC1 with EZH2 (a key histone methyltransferase), possibly through the modular scaffold function of a new lncRNA, ENSG00000274093.1. HDAC2 thus appears to promote CRC cell migration and invasion through binding HDAC1 and EZH2 via ENSG00000274093.1.

Self-expandable metallic stenting as a bridge to elective surgery versus emergency surgery for acute malignant right-sided colorectal obstruction.

BACKGROUND: The use of a self-expandable metallic stent (SEMS) as a bridge to surgery has increased for patients with obstructing colorectal cancer. However, relatively few reports have compared SEMS as a bridge to elective surgery for acute malignant obstruction of the right-sided colon (MORC) vs. emergency surgery (ES). This study aimed to evaluate the benefits of elective surgery after SEMS placement vs. ES for patients (including stage IV cases) with acute MORC. METHODS: Patients with acute MORC who underwent radical resection for a primary tumour from July 2008 to November 2016 at Zhongshan Hospital of Fudan University were retrospectively enrolled. Postoperative short-term outcomes, progression-free survival (PFS), and overall survival (OS) were compared between the SEMS and ES groups. RESULTS: In total, 107 patients with acute MORC (35 in the SEMS group and 72 in the ES group) were included for analysis. The Intensive Care Unit admission rate was lower (11.4% vs. 34.7%, P = 0.011), the incidence of complications was reduced (11.4% vs. 29.2%, P = 0.042), and the postoperative length of hospitalisation was significantly shorter (8.23 ± 6.50 vs. 11.18 ± 6.71 days, P = 0.033) for the SEMS group. Survival curves showed no significant difference in PFS (P = 0.506) or OS (P = 0.989) between groups. Also, there was no significant difference in PFS and OS rates between patients with stage II and III colon cancer. After colectomy for synchronous liver metastases among stage IV patients, the hepatectomy rates for the SEMS and ES groups were 85.7% and 14.3%, respectively (P = 0.029). The hazard ratio for colectomy alone vs. combined resection was 3.258 (95% CI 0.858-12.370; P = 0.041). CONCLUSION: Stent placement offers significant advantages in terms of short-term outcomes and comparable prognoses for acute MORC patients. For synchronous liver metastases, SEMS placement better prepares the patient for resection of the primary tumour and liver metastasis, which contribute to improved survival.

[Effect of three-dimensional acellular fibrotic lung matrices on fibroblast-to-myofibroblast differentiation].

OBJECTIVE: To explore the effect of three-dimensional (3D) and two-dimensional (2D) acellular fibrotic lung matrices on fibroblast-to-myofibroblast differentiation. METHODS: Twenty adult SD rats were randomly divided into control group and idiopathic pulmonary fibrosis (IPF) group. The pulmonary fibrosis was induced by Bleomycin. Normal and fibrotic decellularized lungs were made, then sections with 500 µm (3D) and 10 µm (2D) thick were cut by a standard Vibratome. The lung fibroblasts were isolated from the lungs of SD rats at postnatal day 1, which were seeded dropwise into different slices (2D/3D normal and fibrotic scaffolds), then cultured for 72 hours in vitro. The protein expression of alpha smooth muscle actin (α-SMA) was measured by immunofluorescence staining and western blot. RESULTS: There was no spatial structure both in 2D normal scaffold and fibrotic scaffold. The spatial structure was different between 3D normal scaffold and fibrotic scaffold. The relative expression amount of α-SMA in 2D normal and fibrotic scaffold group and none scaffold group were (4.64 ± 0.36, 4.86 ± 0.37, 4.67 ± 0.35, respectively), there were no difference among them (P>0.05). In 3D fibrotic scaffold group, the relative expression amount of α-SMA was significantly increased compared with those in 3D normal scaffold group and 2D fibrotic scaffold group (6.29 ± 0.85 vs 4.85 ± 0.56, 4.86 ± 0.37, both P<0.05). CONCLUSION: 3D acellular fibrotic lung scaffold can promote fibroblast-to-myofibroblast differentiation.