A Convoy of Magnetic Millirobots Transports Endoscopic Instruments for Minimally-Invasive Surgery.

Small-scale robots offer significant potential in minimally invasive medical procedures. Due to the nature of soft biological tissues, however, robots are exposed to complex environments with various challenges in locomotion, which is essential to overcome for useful medical tasks. A single mini-robot often provides insufficient force on slippery biological surfaces to carry medical instruments, such as a fluid catheter or an electrical wire. Here, for the first time, a team of millirobots (TrainBot) is reported to generate around two times higher actuating force than a TrainBot unit by forming a convoy to collaboratively carry long and heavy cargos. The feet of each unit are optimized to increase the propulsive force around three times so that it can effectively crawl on slippery biological surfaces. A human-scale permanent magnetic set-up is developed to wirelessly actuate and control the TrainBot to transport heavy and lengthy loads through narrow biological lumens, such as the intestine and the bile duct. The first electrocauterization performed by the TrainBot is demonstrated to relieve a biliary obstruction and open a tunnel for fluid drainage and drug delivery. The developed technology sheds light on the collaborative strategy of small-scale robots for future minimally invasive surgical procedures.

A Magnetic Millirobot Walks on Slippery Biological Surfaces for Targeted Cargo Delivery.

Small-scale robots hold great potential for targeted cargo delivery in minimally invasive medicine. However, current robots often face challenges in locomoting efficiently on slippery biological tissue surfaces, especially when loaded with heavy cargo. Here, we report a magnetic millirobot that can walk on rough and slippery biological tissues by anchoring itself on the soft tissue surface alternatingly with two feet and reciprocally rotating the body to move forward. We experimentally studied the locomotion, validated it with numerical simulations, and optimized the actuation parameters to fit various terrains and loading conditions. Furthermore, we developed a permanent magnet set-up to enable wireless actuation within a human-scale volume that allows precise control of the millirobot to follow complex trajectories, climb vertical walls, and carry cargo up to four times its own weight. Upon reaching the target location, it performs a deployment sequence to release the liquid drug into tissues. The robust gait of our millirobot on rough biological terrains, combined with its heavy load capacity, makes it a versatile and effective miniaturized vehicle for targeted cargo delivery.

A High-Fidelity Artificial Urological System for the Quantitative Assessment of Endoscopic Skills.

Minimally-invasive surgery is rapidly growing and has become a standard approach for many operations. However, it requires intensive practice to achieve competency. The current training often relies on animal organ models or physical organ phantoms, which do not offer realistic surgical scenes or useful real-time feedback for surgeons to improve their skills. Furthermore, the objective quantitative assessment of endoscopic skills is also lacking. Here, we report a high-fidelity artificial urological system that allows realistic simulation of endourological procedures and offers a quantitative assessment of the surgical performance. The physical organ model was fabricated by 3D printing and two-step polymer molding with the use of human CT data. The system resembles the human upper urinary tract with a high-resolution anatomical shape and vascular patterns. During surgical simulation, endoscopic videos are acquired and analyzed to quantitatively evaluate performance skills by a customized computer algorithm. Experimental results show significant differences in the performance between professional surgeons and trainees. The surgical simulator offers a unique chance to train endourological procedures in a realistic and safe environment, and it may also lead to a quantitative standard to evaluate endoscopic skills.

A Hybrid Surgical Simulator for Interactive Endoscopic Training.

Endoscopy serves as an indispensable minimally-invasive surgical procedure. Due to the limited view and non-intuitive operation of the instrument, the mastery of endoscopic manipulation requires deep medical knowledge as well as complex perception and motor skills of the surgeon. Intensive surgical training is required, and simulation-based training is of more and more importance over traditional animal- or cadaver-based approaches. Here, we developed a hybrid surgical simulator that consists of a realistic physical organ model and an artificial intelligence (AI)-driven cyber model. We built a physical model of the full urinary tract with soft materials and detailed blood vessel structures. Endourological procedures were performed to localize and treat renal calculi by a flexible endoscope. An AI algorithm detects the lesions automatically with high accuracy and provides quantitative feedback about an operator's endoscopic skills. The hybrid simulator system shows great potential as an interactive and personalized learning environment for endoscopic skills. Clinical Relevance- This work establishes a preliminary approach for realistic endoscopic training. The developed hybrid surgical simulator - with high-fidelity physical organ models and quantitative feedback - can deliver effective hands-on learning to surgeons to improve their endoscopic skills.

Impact of Salvage Surgery following Colonic Endoscopic Polypectomy for Patients with Invasive Neoplasia.

BACKGROUND: Invasive neoplasia (Tis-T1) are increasingly being encountered in the daily routine of endoscopic polypectomy. However, the need for salvage surgery following endoscopic therapy for invasive neoplasia is controversially discussed. PATIENTS AND METHODS: Patients with endoscopic removal of invasive neoplasia were identified from the national Surveillance Epidemiology and End Results (SEER) Database 2005 to 2015. Survival analysis and Cox proportional hazard regression analysis in cancer-specific mortality and overall survival rate was used, which were stratified by T stage and polyp size. RESULTS: A total of 5805 patients with endoscopic removal of invasive neoplasia were included in the analysis, of whom 1214 (20.9%) underwent endoscopic treatment alone and 4591 (79.1%) underwent endoscopic resection plus surgery. The survival analysis revealed that patients undergoing salvage surgery had a significantly better cancer-specific survival (97.4% vs. 95.8%, p-value = 0.017). In patients with T1 stage, additional salvage surgery led to a significantly higher cancer-specific survival (92.1% vs. 95.0%, p value = 0.047). CONCLUSION: Salvage surgery following endoscopic polypectomy may improve the oncological survival of patients with invasive neoplasia, especially in patients with T1 stage. Furthermore, the T stage, size, and localization of polyps, as well as the level of CEA, could be identified as significant predictors for lymphonodal and distant metastases.

Systematic review and meta-analysis of clinical outcomes of COVID-19 patients undergoing gastrointestinal endoscopy.

BACKGROUND: The impact of gastrointestinal endoscopy on COVID-19 infection remains poorly investigated. We herein performed a systematic review and meta-analysis to evaluate the outcomes of COVID-19 in patients undergoing gastrointestinal endoscopy. METHOD: Ovid Medline, Ovid EMBASE, Ovid the Cochrane Library, and other electronic databases were searched until 30 November 2020 to identify publications with confirmed COVID-19 infection in patients undergoing gastrointestinal endoscopy. The primary outcomes were SARS-CoV-2 transmission, personal protective equipment use, rates of case fatality, complications, and procedural success. RESULTS: A total of 18 articles involving 329 patients were included in this systematic review and meta-analysis. The overall basic reproduction rate is 0.37, while the subgroup results from Asia, Europe, and North America are 0.13, 0.44, and 0.33, respectively. The differences in personal protective equipment use between the positive transmission and non-transmission group are mainly in isolation gowns, N95 or equivalent masks, and goggles or face-shields. The rate of case fatality, complication, and procedural success are 0.17 (95% confidence interval = 0.02-0.38), 0.00 (95% confidence interval = 0.00-0.02), and 0.89 (95% confidence interval = 0.50-1.00), respectively. The fatality rate in Europe was the highest (0.23, 95% confidence interval = 0.04-0.50), which is significantly different from other continents (p = 0.034). CONCLUSION: The risk of SARS-CoV-2 transmission within gastrointestinal endoscopy units is considerably low if proper use of personal protective equipment is applied. Similarly, a low fatality and complication rate, as well as a high procedural success rate, indicated that a full recovery of endoscopic units should be considered.

Comprehensive analysis of lncRNA-miRNA-mRNA regulatory networks for microbiota-mediated colorectal cancer associated with immune cell infiltration.

Recent findings have identified microbiota as crucial participants in many disease conditions, including cancers. Competing endogenous RNA (ceRNA) is regarded as a candidate mechanism involving relevant biological processes. We therefore constructed a ceRNA network using the TCGA and GEO database, to determine the potential mechanisms of microbiota-mediated colorectal carcinogenesis and progression. We found a total of 75 lncRNAs, 8 miRNAs, and 9 mRNAs in the probiotics-mediated ceRNA network and a total of 49 lncRNAs, 4 miRNAs, and 3 mRNA in the pathobiont-mediated ceRNA network, which could induce the microbiota-mediated carcinogenesis and progression. The GO and KEGG analysis indicated that the ceRNA network is mainly enriched in the metabolic process, and two unique pathways (the p53 signaling pathway and microRNA in cancer), respectively. A four-gene signature (FRMD6-AS2, DIRC3, LIFR-AS1, and MRPL23-AS1) was suggested as an independent prognostic factor. Four lncRNAs (LINC00355, KCNQ1OT1, LINC00491, and HOTAIR) were associated with poor survival. Three small molecule candidate anticancer drugs (Pentoxyverine, Rimexolone, and Doxylamine) were identified. A four-gene signature (FAM129A, BCL2, PMAIP1, and RPS6) is significantly correlated with immune infiltration level. This study provides a promising biomarker reservoir to explore the mechanism by which microbiota regulate the ceRNA network involving the immune response, and further participate in colorectal carcinogenesis and progression.

Nuclear IGF1R interacts with NuMA and regulates 53BP1­dependent DNA double­strand break repair in colorectal cancer.

Nuclear insulin­like growth factor 1 receptor (nIGF1R) has been associated with poor overall survival and chemotherapy resistance in various types of cancer; however, the underlying mechanism remains unclear. In the present study, immunoprecipitation­coupled mass spectrometry was performed in an IGF1R­overexpressing SW480­OE colorectal cancer cell line to identify the nIGF1R interactome. Network analysis revealed 197 proteins of interest which were involved in several biological pathways, including RNA processing, DNA double­strand break (DSB) repair and SUMOylation pathways. Nuclear mitotic apparatus protein (NuMA) was identified as one of nIGF1R's colocalizing partners. Proximity ligation assay (PLA) revealed different levels of p53­binding protein 1 (53BP1)­NuMA colocalization between IGF1R­positive (R+) and IGF1R­negative (R­) mouse embryonic fibroblasts following exposure to ionizing radiation (IR). 53BP1 was retained by NuMA in the R­ cells during IR­induced DNA damage. By contrast, the level of NuMA­53BP1 was markedly lower in R+ cells compared with R­ cells. The present data suggested a regulatory role of nIGF1R in 53BP1­dependent DSB repair through its interaction with NuMA. Bright­field PLA analysis on a paraffin­embedded tissue microarray from patients with colorectal cancer revealed a significant association between increased nuclear colocalizing signals of NuMA­53BP1 and a shorter overall survival. These results indicate that nIGF1R plays a role in facilitating 53BP1­dependent DDR by regulating the NuMA­53BP1 interaction, which in turn might affect the clinical outcome of patients with colorectal cancer.

Soft Liver Phantom with a Hollow Biliary System.

Hepatobiliary interventions are regarded as difficult minimally-invasive procedures that require experience and skills of physicians. To facilitate the surgical training, we develop a soft, high-fidelity and durable liver phantom with detailed morphology. The phantom is anatomically accurate and feasible for the multi-modality medical imaging, including computer tomography (CT), ultrasound, and endoscopy. The CT results show that the phantom resembles the detailed anatomy of real livers including the biliary ducts, with a spatial root mean square error (RMSE) of 1.7 ± 0.7 mm and 0.9 ± 0.2 mm for the biliary duct and the liver outer shape, respectively. The sonographic signals and the endoscopic appearance highly mimic those of the real organ. An electric sensing system was developed for the real-time quantitative tracking of the transhepatic puncturing needle. The fabrication method herein is accurate and reproducible, and the needle tracking system offers a robust and general approach to evaluate the centesis outcome.

Magnetic endoscopic imaging as a rational investment for specific colonoscopies: a systematic review and meta-analysis.

BACKGROUND: Magnetic endoscopic imaging (MEI) was regarded as an adjuvant device to improve procedural efficacy and patients' comfort during colonoscopy. METHODS: Several electronic databases were searched to identify eligible studies. Based on the heterogeneity of included studies, random-effects or fixed-effects models were used to calculate pooled risk ratios (RR), risk difference (RD) or mean difference (MD) along with 95% confidence intervals (CIs). RESULTS: Twenty-one randomized controlled trials (RCTs) were selected for meta-analysis, with a total of 7,060 patients. Although there is a slightly lower risk of cecal intubation failure with the adjuvant of MEI (RD 3%; P < 0.00001) compared to the control group, the updated studies show no significant benefits. Similarly, the cecal intubation time, pain scores, and loop formation with the adjuvant of MEI did not show any advantages. However, considerable significant benefits were found in the subgroup of technically difficult colonoscopy and inexperienced colonoscopists. Moreover, MEI was associated with lower loop intubation time, lower abdominal compression times, and better lesion localization. CONCLUSION: The clinical benefits of MEI could be exaggerated. However, MEI has considerable advantages in technically difficult colonoscopies, the assistance for inexperienced colonoscopists, loop resolving, and lesion localization.

Prognostic relevance of neuroendocrine differentiation in colorectal cancer: a population-based, propensity score matching study.

PURPOSE: Neuroendocrine differentiation (NED) may serve as a prognostic factor in colorectal cancer; however, the prognostic relevance of NED remains controversial. The aim of the present study was to determine whether NED influenced the survival of patients in colorectal cancer while exploring its potential interactions with other clinicopathological features. METHODS: Patients with primary stage I to IV colorectal adenocarcinoma ranging between 2010 and 2015 were identified using the Surveillance, Epidemiology, and End Results database. The Kaplan-Meier technique, Cox proportional hazards model, propensity score matching, and stratification analyses were employed in this study. RESULTS: A total of 94,291 patients (including 101 patients with NED and 94,190 patients without NED) were included. In the univariable analyses, NED was found to be correlated with a significantly poorer overall survival (hazard ratio (HR) of death = 3.09, 95% CI 2.42-3.95, P < 0.001) and cancer-specific survival (HR of death = 3.77, 95% CI 2.94-4.83, P < 0.001). Moreover, NED remained independently correlated with overall survival (HR of death = 1.84, 95% CI 1.34-2.51, P < 0.001) and cancer-specific survival (HR of death = 2.01, 95% CI 1.45-2.79, P < 0.001) after adjusting in multivariable and propensity score analyses. Furthermore, further stratification analyses indicated that the influence of NED on survival was not affected by tumor location, differentiation, T stage, and distant metastasis status; however, it was found to be associated with lymph node metastasis. CONCLUSIONS: NED is associated with poor survival outcomes among colorectal cancer patients, especially in those with positive lymph nodes.

LXRα Promotes the Differentiation of Human Gastric Cancer Cells through Inactivation of Wnt/ß-catenin Signaling.

LXRα is a subtype of the liver X receptors (LXRs). There is accumulating evidence to support the involvement of LXRα in a variety of malignancies. However, the function and specific mechanism of LXRα in gastric cancer (GC) remain unclear. In this study, the expression of LXRα was significantly lower in poorly differentiated and undifferentiated GC tissues compared with well- and moderately differentiated GC tissues by immunohistochemistry analysis. The activation of LXRα leads to the decreased expression of ß-catenin, CD44, and Cyclin D1, whereas the inhibition of LXRα has opposite effect. The same results were obtained in animal experiments. Furthermore, results showed that CD44 and Cyclin D1 expression significantly decreased when Wnt/ß-catenin signaling was blocked in LXRα silent GC cells, whereas it was significantly increased when Wnt/ß-catenin signaling was activated in LXRα over-expressed GC cells. CD44 and Cyclin D1, downstream targets of Wnt/ß-catenin signaling, are specific markers for cell differentiation. Therefore, we conclude that LXRα may promote the differentiation of human GC cells through inactivation of Wnt/ß-catenin signaling.

Chemotherapy-induced neutropenia and the prognosis of colorectal cancer: a meta-analysis of cohort studies.

INTRODUCTION: Recently, there has been a controversial discussion about the prognostic value of chemotherapy-induced neutropenia (CIN) in colorectal cancer patients. Thus, a meta-analysis was conducted to determine the relationship between CIN and the prognosis of colorectal cancer patients. METHODS: We searched the PubMed, EMBASE, and Cochrane library databases to identify studies evaluating the association between CIN and colorectal cancer prognosis. Pooled random/fixed effect models were used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the association. RESULTS: Eight studies were selected for the meta-analysis, for a total of 2,745 patients. There was significant improved survival among colorectal cancer patients with CIN (HR = 0.62, 95% CI = 0.47-0.76). However, significant heterogeneity was found (p = 0.000, Ι2 = 75.0%). Through subgroup analysis, we could greatly eliminate the heterogeneity and found that neutropenia was associated with better survival in stage IV colorectal cancer patients, no matter the HR calculated by overall survival (OS) or progression-free survival (PFS). Meanwhile, the prognostic value of neutropenia in stage II/III colorectal cancer can be found when the HR is calculated by disease-free survival (DFS). Additionally, we observed significant differences after stratification according to various tumor stages, endpoints, and the use of G-CSF. CONCLUSIONS: Our results which, based on a cohort study, indicate that CIN is associated with improved survival in patients with colorectal cancer. However, further randomized controlled trials are warranted.

[Expression of LXR-ß in human gastric cancer tissue and the effect of GW3965 on the proliferation of gastric cancer cell line SGC-7901].

OBJECTIVE: To examine the expression of liver X receptor-ß (LXR-ß) in human gastric cancer tissue, and to explore the effect of GW3965, an agonist of LXRs, on proliferation of gastric cancer cell line SGC-7901.
 METHODS: The immunohistochemical assay was used to detect the expression of LXR-ß, activating transcription factor 4 (ATF4) in gastric cancer tissues and the corresponding pericarcinoma tissues in 114 patients. Real-time quantitative PCR and Western blot were used to determine mRNA and protein levels of ATF4 and ATP-binding cassette 1 (ABCA1), one of the downstream target genes of LXRs, in SGC-7901 cells with or without GW3965 treatment. Cell counting kit-8 (CCK-8) assay was performed to detect cell proliferation. The expression of ATF4 was silenced by short hairpin RNA (shRNA).
 RESULTS: The expressions of LXR-ß and ATF-4 were obviously down-regulated in the gastric cancer tissues than that in the corresponding pericarcinoma tissues (both P<0.05). Compared with the control cells, GW3965 treatment inhibited proliferation of SGC-7901 cells and up-regulated ATF4 and ABCA1 expressions (both P<0.05). Knockdown of ATF4 can reverse the antiproliferative effect of GW3965 on SGC-7901 cells.
 CONCLUSION: The expression of LXR-ß is decreased in human gastric cancer tissues, and activation of LXRs by GW3965 could inhibit the proliferation of SGC-7901 cells via ATF4.