Validation and update of a clinical score model to predict technical difficulty of colorectal endoscopic submucosal dissection: a multicenter prospective cohort study.

BACKGROUND AND AIMS: The Zhongshan colorectal endoscopic submucosal dissection (CR-ESD) score model was proposed to grade the technical difficulty of CR-ESD. The objective of this study was to prospectively validate and update the score model. METHODS: A multicenter prospective cohort analysis of CR-ESD was conducted. Individual data on patients, lesions, and outcomes of CR-ESD were used to validate the original model and further refine the difficulty of the prediction model. Data were randomly divided into discovery and internal validation cohorts. A multivariate Cox regression analysis was conducted on the discovery cohort to develop an updated risk-scoring system, which was then validated. RESULTS: Five hundred forty-eight patients with 565 colorectal lesions treated by ESD from 4 hospitals were included. In the prospective validation cohort, the area under the receiver-operating characteristic (ROC) curve for the original model was .707. Six risk factors were identified and assigned point values: tumor size (2 points for 30-50 mm, 3 points for ≥50 mm), at least two-thirds circumference of the lesion (3 points), tumor location in the cecum (2 points) or flexure (2 points), laterally spreading tumor-nongranular lesions (1 point), preceding biopsy sampling (1 point), and NBI International Colorectal Endoscopic type 3 (3 points). The updated model had an area under the ROC curve of .738 in the discovery cohort and of .782 in the validation cohort. Cases were categorized into easy (score = 0-1), intermediate (score = 2-3), difficult (score = 4-6), and very difficult (score ≥7) groups. Satisfactory discrimination and calibration were observed. CONCLUSIONS: The original model achieved an acceptable level of prediction in the prospective cohort. The updated model exhibited superior performance and can be used in place of the previous version. (Clinical trial registration number: ChiCTR2100047087.).

Porphyromonas gingivalis predicts local recurrence after endoscopic submucosal dissection of early esophageal squamous cell carcinoma or precancerous lesion.

BACKGROUND: Porphyromonas gingivalis plays an oncogenic role in development and progression of esophageal squamous cell carcinoma (ESCC). However, the impact of P. gingivalis on local recurrence of early ESCC or precancerous lesion after ESD treatment remains unknown. The present study aimed to evaluate the impact of P. gingivalis on local recurrence after ESD treatment of early ESCC or high-grade dysplasia (HGD). METHODS: The amount of P. gingivalis was assessed by immunohistochemistry in 205 patients with early ESCC or HGD. Univariate and multivariate Cox regression analyses were performed to determine the effect of P. gingivalis on local recurrence. Propensity score matching analysis was performed to reduce the imbalance of baseline characteristics. A nomogram integrating significant prognostic factors was built for local recurrence prediction. RESULTS: The amount of P. gingivalis increased significantly in neoplasms that invaded up to muscularis mucosa and submucosa compared with lesions confined to epithelium or lamina propria. Overabundance of P. gingivalis was positively associated with invasion depth, post-ESD stricture and local recurrence. Univariate and multivariate Cox regression analyses revealed that P. gingivalis, longitudinal length of lesion and lymphovascular invasion were independent predictors for post-ESD recurrence. A nomogram comprising P. gingivalis, lymphovascular involvement, and lesion length performed well for prediction of post-ESD local recurrence with the concordance indices of 0.72 (95%CI, 0.62 to 0.80), 0.72 (95%CI, 0.63 to 0.80), and 0.74 (95%CI, 0.65 to 0.83) in the validation cohort, the entire cohort, and the subcohort after PSM, respectively. CONCLUSION: P. gingivalis overabundance is a risk factor and a potential predictor for local recurrence of early ESCC or HGD after ESD treatment. Thus, clearance of P. gingivalis represents an attractive strategy for prognosis improvement and for prevention of ESCC.

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.

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.

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.

Using a deep learning system in endoscopy for screening of early esophageal squamous cell carcinoma (with video).

BACKGROUND AND AIMS: Few artificial intelligence-based technologies have been developed to improve the efficiency of screening for esophageal squamous cell carcinoma (ESCC). Here, we developed and validated a novel system of computer-aided detection (CAD) using a deep neural network (DNN) to localize and identify early ESCC under conventional endoscopic white-light imaging. METHODS: We collected 2428 (1332 abnormal, 1096 normal) esophagoscopic images from 746 patients to set up a novel DNN-CAD system in 2 centers and prepared a validation dataset containing 187 images from 52 patients. Sixteen endoscopists (senior, mid-level, and junior) were asked to review the images of the validation set. The diagnostic results, including accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were compared between the DNN-CAD system and endoscopists. RESULTS: The receiver operating characteristic curve for DNN-CAD showed that the area under the curve was >96%. For the validation dataset, DNN-CAD had a sensitivity, specificity, accuracy, PPV, and NPV of 97.8%, 85.4%, 91.4%, 86.4%, and 97.6%, respectively. The senior group achieved an average diagnostic accuracy of 88.8%, whereas the junior group had a lower value of 77.2%. After referring to the results of DNN-CAD, the average diagnostic ability of the endoscopists improved, especially in terms of sensitivity (74.2% vs 89.2%), accuracy (81.7% vs 91.1%), and NPV (79.3% vs 90.4%). CONCLUSIONS: The novel DNN-CAD system used for screening of early ESCC has high accuracy and sensitivity, and can help endoscopists to detect lesions previously ignored under white-light imaging.

Endoscopic full-thickness resection (EFTR) without laparoscopic assistance for nonampullary duodenal subepithelial lesions: our clinical experience of 32 cases.

BACKGROUND: Standard treatment for nonampullary duodenal tumors has not yet been established. In case of tumors originated from the muscularis propria (MP) layer and adherent to the serosa layer, the lesions can not be completely removed by ESD. However, with the development of the endoscopic suture technique, endoscopic full-thickness resection (EFTR) of duodenal subepithelial lesions has become possible. METHODS: We retrospectively analyzed 32 patients with nonampullary duodenal subepithelial lesions who underwent EFTR between February 2012 and January 2017. The suturing method, complications that occurred during and after the operations, perioperative management, tumor characteristics, and pathological findings were analyzed in all patients. RESULTS: The complete resection rate was 100%; all patients successfully received EFTR except for one patient who required conversion to open surgery. Severe abdominal pain was observed after the operation in one patient who then received laparoscopic exploration, and the possibility of delayed perforation was considered. Another patient showed a decline in blood oxygen saturation (SO2) and was transferred to the intensive care unit (ICU) for further management. Delayed bleeding and fistula were not observed. All patients achieved complete remission. CONCLUSION: EFTR is a safe, minimally invasive treatment modality that ensures complete eradication of the duodenal subepithelial lesions.

Efficacy and safety of endoscopic resection for small submucosal tumors originating from the muscularis propria layer in the gastric fundus.

BACKGROUND: Gastric small submucosal tumors (SMTs) are becoming increasingly common. However, the fundus of stomach is regarded as a difficult area for endoscopic resection (ER). In this study, we investigated the efficacy, safety, and long-term outcomes of ER for small SMTs of the gastric fundus in a large series of patients, research that was previously lacking. METHODS: 537 consecutive patients with SMTs no more than 20 mm in diameter, occurring in the gastric fundus and originating from the muscularis propria layer, which were treated with endoscopic submucosal excavation or endoscopic full-thickness resection (EFTR) were included in this retrospective study at Zhongshan Hospital of Fudan University from January 2013 to September 2016. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. RESULTS: En bloc resection was achieved in 100% of patients, and complete resection was achieved for 530 (98.7%) lesions. Although the total rate of complications was 9.3%, few serious adverse events occurred in only three (0.6%) patients, including major pneumoperitoneum, major hydrothorax, and bleeding. Unlike lager tumor sizes and longer procedure times, endoscopist experience had a positive impact on decreasing the likelihood of complications. Based on statistical analysis, tumors with greater size near the cardia, which were treated by EFTR, were the significant contributors to longer operative times. A median follow-up of 32 months was available, and all patients were free from local recurrence or distant metastasis during the study period. CONCLUSIONS: Although the gastric fundus presents technical difficulties, ER is effective for the resection of small gastric SMTs with a high complete resection rate and rare serious adverse events.

The efficacy of dental floss and a hemoclip as a traction method for the endoscopic full-thickness resection of submucosal tumors in the gastric fundus.

BACKGROUND: Endoscopic full-thickness resection (EFTR) provides a significant advancement to the treatment of gastrointestinal submucosal tumors (SMTs). However, technological challenges, particularly in the gastric fundus, hinder its wider application. Here, we investigated the efficacy of a simple traction method that used dental floss and a hemoclip (DFC) to facilitate EFTR. METHODS: Between July 2014 and December 2016, we retrospectively reviewed data from all patients with SMTs in the gastric fundus originating from the muscularis propria layer that were treated by EFTR at Zhongshan Hospital of Fudan University. Baseline characteristics and clinical outcomes, including procedure time and complications rate, were compared between groups of patients receiving DFC-EFTR and conventional EFTR. RESULTS: A total of 192 patients were included in our analysis (64 in the DFC-EFTR group and 128 in the conventional EFTR group). Baseline characteristics for the two groups were similar. The mean time for DFC-EFTR and conventional EFTR was 44.2 ± 24.4 and 54.2 ± 33.2 min, respectively (P = 0.034). Although no serious adverse events presented in any of our cases, post-EFTR electrocoagulation syndrome (PEECS), as a minor complication, was less frequent in the DFC-EFTR group (3.1% vs. 12.5%, P = 0.036). Univariate and multivariate analysis identified that DFC, when used in EFTR, played a significant role in reducing procedure time and the rate of PEECS. The mean procedure time was significantly shorter in the DFC-EFTR group for lesions over 1.0 cm (P = 0.005), when the lesions were located in the greater curvature of the gastric fundus (P = 0.025) or when the lesions presented with intraluminal growth (P = 0.032). Moreover, when EFTR was carried out by experts, the mean procedure time was 20.4% shorter in the DFC-EFTR group (P = 0.038). CONCLUSIONS: This study indicated that DFC-EFTR for SMTs in the gastric fundus resulted in a shorter procedure time and reduced the risk of PEECS, a minor complication.

Efficacy and safety of endoscopic submucosal dissection for submucosal tumors of the colon and rectum.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) of colorectal submucosal tumors (SMTs) is becoming increasingly common; however, there have been few large consecutive studies analyzing its therapeutic efficacy and safety. The aim of this study was to evaluate the efficacy, safety, and long-term outcomes of ESD for colorectal SMTs. METHODS: This retrospective study included 412 consecutive patients with colorectal SMTs who underwent ESD at the Zhongshan Hospital of Fudan University from January 2008 to July 2014. Tumor histopathology, completeness of resection, adverse events, tumor recurrence, and distant metastasis were analyzed. RESULTS: Complete resection was achieved for 358 lesions (86.9%). Thirteen patients had serious adverse events (3.2%) including bleeding and perforation, and 28 patients (6.8%) had post-ESD electrocoagulation syndrome (PEECS). Because more ESDs for colorectal SMTs were performed by endoscopists, the rate of complete resection increased (78.5% vs 88.5%), and the rate of serious adverse events decreased (9.2% vs 2.0%). SMTs in the colon increased the risk of incomplete resection (19.6% vs 11.3%), serious adverse events (8.7% vs 1.6%), and PEECS (16.3% vs 4.1%). SMTs originating from the muscularis propria and sized ≥20 mm increased the rate of PEECS (22.7% vs 5.9% and 31.3% vs 5.8%, respectively). CONCLUSION: ESD is effective for resection of colorectal SMTs and rarely causes serious adverse events. Tumor location and the experience of endoscopists influence the complete resection rate and the development of serious adverse events. ESD is feasible for large tumors and tumors in the muscularis propria, but this is associated with relatively high risks of adverse events.

Endoscopic submucosal dissection for early esophageal cancer in elderly patients with relative indications for endoscopic treatment.

BACKGROUND: According to the Japanese Esophageal Society (JES) guidelines, early esophageal squamous cell carcinoma (SCC) involving the muscularis mucosae (M3) or upper submucosal (SM1) layers are relative indications for endoscopic submucosal dissection (ESD). Additional esophagectomy or chemoradiotherapy is recommended for patients with relative indications after evaluation. However, elderly patients (≥ 60 years) with relative indications in China often refuse additional treatment because of the debilitating side effects. The aim of this study was to evaluate the long-term outcomes of elderly patients with relative indications who did not undergo additional treatment after ESD. METHODS: Data from elderly patients with relative indications who underwent ESD for early esophageal SCC between January 2008 and December 2013 were reviewed retrospectively. Stricture and recurrence, and 5-year progression-free survival (PFS) and overall survival rates were compared with patients with absolute indications for ESD. RESULTS: 158 elderly patients were included and analyzed (89 in the absolute indications group and 69 in the relative indications group). The baseline characteristics were balanced between the two groups. During 56 months (range 1 - 108) of follow-up, the postoperative stricture rates were similar in the absolute and relative indications groups (21.3 % vs. 31.9 %; P  = 0.13). The hazard ratio (HR) for PFS in the absolute vs. the relative indications groups was 1.025 (95 % confidence interval [CI] 0.36 - 2.95; P = 0.96). The 5-year PFS rates were 90.5 % (95 %CI 83.44 - 97.56) and 90.8 % (95 %CI 83.74 - 97.86) for the absolute and relative indications groups, respectively. The HR for overall survival in the absolute vs. the relative indications groups was 0.564 (95 %CI 0.13 - 2.52; P = 0.45). The 5-year overall survival rates were 96.6 % (95 %CI 92.88 - 100) and 95.6 % (95 %CI 90.70 - 100) for the absolute and relative indications groups, respectively. CONCLUSIONS: Based on this study, regular follow-up without additional treatment may be considered as another choice for elderly patients with early esophageal SCC and relative indications after ESD.

Efficacy and Safety of Endoscopic Submucosal Dissection for Colorectal Carcinoids.

BACKGROUND & AIMS: Although endoscopic submucosal dissection (ESD) of colorectal carcinoids is increasing, little is known about long-term outcomes of patients. We investigated the efficacy and safety of ESD of colorectal carcinoids and evaluated long-term outcomes, including local recurrence and metastasis. METHODS: We performed a retrospective analysis of data collected from 239 consecutive patients with colorectal carcinoids <20 mm who underwent endoscopic ultrasonography (to evaluate the size of tumor and the depth of invasion), followed by ESD from January 2007 through October 2012 at the Zhongshan Hospital of Fudan University. Histology and patient data were collected during a median follow-up period of 52 months (range, 25-94 months) to determine tumor stage and type, completeness of resection, complications, tumor recurrence, and distant metastasis. RESULTS: En bloc resection was achieved for all of the 239 treated lesions; tumor tissues were completely resected for 216 of the lesions (90.38%). Eight patients had ESD-related complications (3.35%). As more ESDs were performed by endoscopists, the rate of complete tumor resection increased, and the rate of complications decreased. ESD of carcinoids in colon increased the risk of non-R0 resection and the rate of complications. During the follow-up period, all patients remained free from local recurrence. However, distant metastases were detected in 6 patients (2.51%); lymphovascular invasion was a risk factor for metastasis. CONCLUSIONS: ESD is effective for the resection of rectal carcinoids <20 mm and causes complications in less than 4% of patients. ESD for colonic carcinoids is feasible but associated with a higher non-R0 resection rate and a trend toward higher complications risk. Tumor features and stage determine risk for distant metastasis, so long-term follow-up is essential.

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.

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.

A Triptolide Loaded HER2-Targeted Nano-Drug Delivery System Significantly Suppressed the Proliferation of HER2-Positive and BRAF Mutant Colon Cancer.

BACKGROUND: Colon cancer (CRC) was a malignant tumor and there were about 25% of patients with tumor metastasis at diagnosis stage. Chemotherapeutic agents for metastatic CRC patients were with great side effects and the clinical treatment results of advanced CRC were still not satisfactory. Human epidermal growth factor receptor 2 (HER2) is overexpressed in some CRC patients and is an effective target for CRC patient treatment. Anti-HER2 therapy had a beneficial role in the treatment of HER2-positive metastatic CRC with fewer side effects. CRC patients with BRAF mutations were resistant to HER2 antibodies treatment. Therefore, there was an urgent need to develop new therapeutic agents. METHODS: HER2 targeted nanoparticles (TPLNP) drug delivery system loading triptolide (TPL) were prepared and identified. The effects of TPLNP and free TPL on cell viability, targeting and cell cycle progression on HT29 (BRAF mutation) with HER2 overexpression, were evaluated by Cell Counting Kit-8 (CCK8), Fluorescence Activating Cell Sorter (FACS) and immunofluorescence methods, respectively. The anti-tumor efficacies of TPLNP were evaluated in subcutaneous xenograft model of colon cancer and the survival rate, tumor volume, liver and kidney indexes of tumor-bearing mice were measured. RESULTS: TPLNP was small in nanosize (73.4±5.2nm) with narrow size distribution (PDI=0.15±0.02) and favorable zeta potential (pH=9.6, zeta potential: -57.3±6.69mV; pH=7.0, zeta potential: -28.7±5.1mV; pH=5.6, zeta potential: -21.1±4.73mV). Comparing with free TPL treatment group, TPLNP developed stranger colon cancer-killing efficiency in a dose- and time-dependent manner detected with CCK8 method; achieved good in vitro colon cancer targeting detected with flow cytometry and immunofluorescence experiments; enhanced more HT29-HER2 apoptosis and induced more cell cycle arrested in G1-S phase detected with FACS in vitro. As for in vivo antitumor response, TPLNP remarkably inhibited the growth of colon cancer in the colon cancer xenograft model, significantly improved the survival rate and did not exhibit significant liver and kidney toxicity in contrast with free TPL in vivo. CONCLUSION: TPLNP was effectively against colon cancer with HER2 overexpression and BRAF mutation in pre-clinical models. In summary, the TPLNP appeared to be a promising treatment option for CRC in clinical application based on improved efficacy and the favorable safety profile.

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.

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.

Comparative study on artificial intelligence systems for detecting early esophageal squamous cell carcinoma between narrow-band and white-light imaging.

BACKGROUND: Non-magnifying endoscopy with narrow-band imaging (NM-NBI) has been frequently used in routine screening of esophagus squamous cell carcinoma (ESCC). The performance of NBI for screening of early ESCC is, however, significantly affected by operator experience. Artificial intelligence may be a unique approach to compensate for the lack of operator experience. AIM: To construct a computer-aided detection (CAD) system for application in NM-NBI to identify early ESCC and to compare it with our previously reported CAD system with endoscopic white-light imaging (WLI). METHODS: A total of 2167 abnormal NM-NBI images of early ESCC and 2568 normal images were collected from three institutions (Zhongshan Hospital of Fudan University, Xuhui Hospital, and Kiang Wu Hospital) as the training dataset, and 316 pairs of images, each pair including images obtained by WLI and NBI (same part), were collected for validation. Twenty endoscopists participated in this study to review the validation images with or without the assistance of the CAD systems. The diagnostic results of the two CAD systems and improvement in diagnostic efficacy of endoscopists were compared in terms of sensitivity, specificity, accuracy, positive predictive value, and negative predictive value. RESULTS: The area under receiver operating characteristic curve for CAD-NBI was 0.9761. For the validation dataset, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CAD-NBI were 91.0%, 96.7%, 94.3%, 95.3%, and 93.6%, respectively, while those of CAD-WLI were 98.5%, 83.1%, 89.5%, 80.8%, and 98.7%, respectively. CAD-NBI showed superior accuracy and specificity than CAD-WLI (P = 0.028 and P ≤ 0.001, respectively), while CAD-WLI had higher sensitivity than CAD-NBI (P = 0.006). By using both CAD-WLI and CAD-NBI, the endoscopists could improve their diagnostic efficacy to the highest level, with accuracy, sensitivity, and specificity of 94.9%, 92.4%, and 96.7%, respectively. CONCLUSION: The CAD-NBI system for screening early ESCC has higher accuracy and specificity than CAD-WLI. Endoscopists can achieve the best diagnostic efficacy using both CAD-WLI and CAD-NBI.

Experience in Simultaneous Endoscopic Submucosal Dissection Treating Synchronous Multiple Primary Early Esophageal Cancers.

Objective: Synchronous multiple primary early esophageal cancers (SMPEEC) are rare and aggressive. Early detection of esophageal cancer can improve survival rate. Endoscopic submucosal dissection (ESD) is a minimally invasive endoscopic treatment of early esophageal cancers. However, ESD for SMPEEC is little known. We aimed to clarify the clinical outcomes of simultaneous ESD treating SMPEEC. Methods: We retrospectively reviewed the medical data of 34 patients, who underwent ESD for SMPEEC at Endoscopy Center of Zhongshan Hospital, Fudan University, between May 2013 and December 2014. The data of lesion size, histopathology, en bloc resection, curative resection, complication, and tumor local recurrence were analyzed. Results: Among 34 patients, 67 lesions were removed simultaneously in 33 cases; 2 lesions were removed in 2 operations for 1 case. For the simultaneous resection, the en bloc rate was 97.01% (65/67) and the curative resection rate was 92.54% (62/67). Postoperative stricture occurred in two cases and delayed bleeding occurred in one case. There was one local recurrence, no metastasis or procedure-related death. Conclusions: Simultaneous ESD as a treatment for SMPEEC is technically feasible, benefited from reducing hospitalization time and medical expenses. For the cases with risk factors of complications, simultaneous ESD needs to be avoided.

Clinical Values of Dental Floss Traction Assistance in Endoscopic Full-Thickness Resection for Submucosal Tumors Originating from the Muscularis Propria Layer in the Gastric Fundus.

BACKGROUND: Endoscopic full-thickness resection (EFTR) derived from endoscopic submucosal dissection has gradually been accepted and even promoted for the treatment of submucosal tumors (SMTs) originating from the muscularis propria (MP) layer. However, there are some difficulties when EFTR is used to treat MP lesions in the gastric fundus. This study intends to explore whether EFTR can be made simpler, safer, and more effective with the traction assistance of dental floss. METHODS: The clinical data of patients (trial group) with lesions in the MP layer in the gastric fundus undergoing EFTR with traction assistance of dental floss at Zhongshan Hospital, in 2016, were reviewed retrospectively. The control group was matched with the trial group according to tumor size. The differences in tumor resection time, patient hospitalization time, and complication rate were evaluated. RESULTS: There was no significant difference in the average age of the two groups, each of which comprised 24 cases (58.7 ± 11.8 years versus 56.6 ± 7.9 years, t = 0.663, P = .511). However, there was a statistically significant difference in the operative time between the two groups (10.8 ± 2.8 minutes versus 19.0 ± 4.7 minutes, t = 7.298, P < .05). There was no statistically significant difference in the length of the postoperative hospital stay (3.2 ± 0.5 days versus 3.2 ± 0.5 days, t = 0.291, P = .772). In the trial group, there were 19 cases of gastrointestinal stromal tumors (group 1) and 5 cases of leiomyoma. The control group had similar results. Neither group experienced postoperative delayed bleeding, perforation, or other complications. CONCLUSIONS: When EFTR is used to treat SMTs originating from the MP in the gastric fundus, dental floss traction assistance can relieve the tumor boundary to simplify the surgical procedure and save the operation time.