RASAL2 promotes tumor progression through LATS2/YAP1 axis of hippo signaling pathway in colorectal cancer.

BACKGROUND: Patients with colorectal cancer (CRC) have a high incidence of regional and distant metastases. Although metastasis is the main cause of CRC-related death, its molecular mechanisms remain largely unknown. METHODS: Using array-CGH and expression microarray analyses, changes in DNA copy number and mRNA expression levels were investigated in human CRC samples. The mRNA expression level of RASAL2 was validated by qRT-PCR, and the protein expression was evaluated by western blot as well as immunohistochemistry in CRC cell lines and primary tumors. The functional role of RASAL2 in CRC was determined by MTT proliferation assay, monolayer and soft agar colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through siRNA/shRNA mediated knockdown and overexpression assays. Identification of RASAL2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. RESULTS: Integrated genomic analysis identified copy number gains and upregulation of RASAL2 in metastatic CRC. RASAL2 encodes a RAS-GTPase-activating protein (RAS-GAP) and showed increased expression in CRC cell lines and clinical specimens. Higher RASAL2 expression was significantly correlated with lymph node involvement and distant metastasis in CRC patients. Moreover, we found that RASAL2 serves as an independent prognostic marker of overall survival in CRC patients. In vitro and in vivo functional studies revealed that RASAL2 promoted tumor progression in both KRAS/NRAS mutant and wild-type CRC cells. Knockdown of RASAL2 promoted YAP1 phosphorylation, cytoplasm retention and ubiquitination, therefore activating the hippo pathway through the LATS2/YAP1 axis. CONCLUSIONS: Our findings demonstrated the roles of RASAL2 in CRC tumorigenesis as well as metastasis, and RASAL2 exerts its oncogenic property through LATS2/YAP1 axis of hippo signaling pathway in CRC.

Granulin epithelin precursor promotes colorectal carcinogenesis by activating MARK/ERK pathway.

BACKGROUND: Granulin epithelin precursor (GEP) is reported to function as a growth factor stimulating proliferation and migration, and conferring chemoresistance in many cancer types. However, the expression and functional roles of GEP in colorectal cancer (CRC) remain elusive. The aim of this study was thus to investigate the clinical significance of GEP in CRC and reveal the molecular mechanism of GEP in CRC initiation and progression. METHODS: The mRNA expression of GEP in CRC cell lines were detected by qRT-PCR. The GEP protein expression was validated by immunohistochemistry in tissue microarray (TMA) including 190 CRC patient samples. The clinicopathological correlation analysis were achieved by GEP expression on TMA. Functional roles of GEP were determined by MTT proliferation, monolayer colony formation, cell invasion and migration and in vivo studies through siRNA/shRNA mediated knockdown assays. The cancer signaling pathway identification was acquired by flow cytometry, western blot and luciferase activity assays. RESULTS: The mRNA expression of GEP in CRC was significantly higher than it in normal colon tissues. GEP protein was predominantly localized in the cytoplasm and most of the CRC cases demonstrated abundant GEP protein compared with non-tumorous tissues. GEP overexpression was associated with non-rectal location, advanced AJCC stage, regional lymph node and distant metastasis. By Kaplan-Meier survival analysis, GEP abundance served as a prognostic marker for worse survival in CRC patients. GEP knockdown exhibited anti-cancer effect such as inhibiting cell proliferation, monolayer colony formation, cell invasion and migration in DLD-1 and HCT 116 cells and decelerating xenograft formation in nude mice. siGEP also induced G1 cell cycle arrest and apoptosis. Luciferase activity assays further demonstrated GEP activation was involved in MAPK/ERK signaling pathway. CONCLUSION: In summary, we compressively delineate the oncogenic role of GEP in colorectal tumorigenesis by activating MAPK/ERK signaling pathway. GEP might serve as a useful prognostic biomarker and therapeutic target for CRC.

Ex vivo comparative study using the Endolifter® as a traction device for enhancing submucosal visualization during endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a technically demanding procedure, and exposure of the submucosa depends on the action of gravity and submucosal injection. The aim of the study was to investigate the effectiveness of the Endolifter(®) as a traction device for enhancing submucosal visualization during ESD. METHODS: This was a prospective ex vivo comparative study conducted between September 2010 and March 2011 in the Prince of Wales Hospital. Consecutive ESDs were performed by four experienced endoscopists in an ex vivo ESD model with or without the Endolifter(®). The Endolifter(®) allows simultaneous grasping, retracting and lifting of the mucosa during ESD, resulting in exposure of the submucosa. Each of the procedures were recorded and reviewed later by two independent assessors. The outcome measures included the proportion of time that the submucosa was visualized during the procedures (SM ratio), procedural times, perforation rates, amount of submucosal injections, and the difficulty of the procedure. RESULTS: Forty-eight gastric ESD procedures were performed on the model. The SM ratio was higher in the Endolifter(®) group (P = 0.007), particularly for lesions located at the antrum (P < 0.001). The time required for submucosal dissection and the total procedural time were also less in the Endolifter(®) group. The endoscopists rated the ESD procedures in the Endolifter(®) group as less difficult (P = 0.033). CONCLUSIONS: The Endolifter(®) improved submucosal visualization during gastric ESD and reduces the difficulty of performing the procedures. The device may improve the ease of performing ESD in low-volume centers or large mucosal lesions.

Personalized laparoscopic resection of colon cancer with the use of indocyanine green lymph node mapping: Technical and clinical outcomes.

INTRODUCTION: To describe the experience of utilization of real time indocyanide green (ICG) fluorescent imaging for mapping out drainage lymph node and hence personalized lymphadenectomy in colorectal resection. METHODS: Perioperative injection of ICG before or during colon cancer resection by either intraluminal submucosal injection or laparoscopic peritumoural injection. The drainage lymph nodes were mapped out, and hence lymphadenectomy was performed enbloc with the main tumor. The effectiveness of mapping of drainage lymphatics and the procedure performed were recorded. RESULTS: A total of 21 patients (M:F = 14: 7) had perioperative ICG injection to map out the drainage lymphatics. The overall success rate was 86%. Seven patients (33%) had endoscopic submucosal injection, while 14 patients (67%) had intraoperative peritumoural injection. Three patients who had endoscopic submucosal injection had ICG extravasation, and hence failed lymph node mapping. Four patients (19%) had a change in extent of resection according to the lymph node mapping results. CONCLUSIONS: Personalized oncological colorectal resection and lymphadenectomy can be performed with the aid of ICG technology. Laparoscopic subserosal ICG injection may be the preferred route, as it minimize extravasation and aids to identify drainage lymph nodes without prolonging minimally invasive surgery. Further studies are required to determine the best route, strength, and timing of ICG injection and concordance with pathology to tailor the extent of resection for individual patients.

Perioperative changes in haemoglobin and ferritin concentrations from preoperative intravenous iron isomaltoside for iron deficiency anaemia in patients with colorectal cancer: A pilot randomised controlled trial.

BACKGROUND: Patients with colorectal cancer have a high risk of iron deficiency anaemia (IDA) due to chronic tumour induced blood loss, a reduced dietary iron intake from poor nutrition or gastrointestinal malabsorption. This pilot, double blinded, randomised controlled trial (RCT) examined the effect and feasibility of using preoperative iron isomaltoside for treating iron deficiency anaemia. METHODS: Forty eligible adults with IDA were randomised to receive either intravenous iron isomaltoside (20 mg.kg-1 up to 1000 mg over 30 minutes) or usual preoperative care (control) three weeks before scheduled colorectal surgery. The primary outcomes were perioperative changes in haemoglobin and ferritin concentrations. RESULTS: The recruitment rate was 78% of all eligible referred patients (1.9 patients/month). The haemoglobin and ferritin concentrations were higher in the iron isomaltoside group than the control group over the perioperative period (group*time interaction P = 0.042 and P < 0.001 respectively). Mean haemoglobin change from baseline to before surgery was higher in the iron isomaltoside group (7.8, 95% CI: 3.2 to 12.3 g.l-1) than the control group (1.7, 95% CI: -1.9 to 5.3 g.l-1) [mean difference 6.1, 95% CI: 0.3 to 11.8 g.l-1; P = 0.040]. The ferritin change from baseline to before surgery between groups was large in favour of the iron isomaltoside group (mean difference 296.9, 95% CI: 200.6 to 393.2 µg.l-1; P < 0.001]. There were no differences between groups in packed red blood cell transfusions needed, surgical complications, quality of recovery and days (alive and) at home within 30 days after surgery. CONCLUSION: Iron isomaltoside therapy was safe and had a minimal effect on perioperative changes in haemoglobin concentration. Given the slow recruitment and new evidence emerging during the conduct of this study, conducting a multi-centre RCT based on the current pilot trial protocol is unlikely to be feasible. TRIAL REGISTRATION: ClinicalTrials.gov NCT03565354.

Effect of a patient education video and prehabilitation on the quality of preoperative person-centred coordinated care experience: protocol for a randomised controlled trial.

INTRODUCTION: Multimodal prehabilitation, an emerging field within the Perioperative Medicine specialty, requires close multidisciplinary team coordination. The goal is to optimise the patient's health status in the 4-8 weeks before elective surgery to withstand surgical stress. Most patients are unfamiliar with the concept of prehabilitation but are interested in participating in such a programme after explanation. The objective of this randomised controlled trial is to evaluate the effect of prehabilitation (patient education video and multimodal prehabilitation) on the preoperative patient-centred coordinated care experience. METHOD AND ANALYSIS: One hundred patients undergoing major elective surgery (cardiac, colorectal, hepatobiliary-pancreatic and urology) will be recruited into a two-group, parallel, superiority, single-blinded randomised controlled trial. Patients will be randomised to receive either preoperative patient education comprising of a video and prehabilitation programme with standard care (intervention) or standard care (control). The primary outcome measure will be the quality of preoperative patient care experience using the 11-item Chinese version of the Person-Centred Coordinated Care Experience Questionnaire (P3CEQ) before surgery. Secondary outcomes will include the change in Hospital Anxiety and Depression Scale (HADS) score from trial enrolment to before surgery, Quality of Recovery Score (QoR-15) on third day after surgery and Days Alive and At Home within 30 days after surgery (DAH30). Intention-to-treat and per-protocol analyses will be performed. ETHICS AND DISSEMINATION: The Joint CUHK-NTEC Clinical Research Ethics Committee approved the study protocol (CREC Ref. No. 2021.518-T). The findings will be presented at scientific meetings, in peer-reviewed journals and to study participants. TRIAL REGISTRATION NUMBER: ChiCTR2100053637.

Automatic Detection and Classification of Colorectal Polyps by Transferring Low-Level CNN Features From Nonmedical Domain.

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Although polypectomy at early stage reduces CRC incidence, 90% of the polyps are small and diminutive, where removal of them poses risks to patients that may outweigh the benefits. Correctly detecting and predicting polyp type during colonoscopy allows endoscopists to resect and discard the tissue without submitting it for histology, saving time, and costs. Nevertheless, human visual observation of early stage polyps varies. Therefore, this paper aims at developing a fully automatic algorithm to detect and classify hyperplastic and adenomatous colorectal polyps. Adenomatous polyps should be removed, whereas distal diminutive hyperplastic polyps are considered clinically insignificant and may be left in situ . A novel transfer learning application is proposed utilizing features learned from big nonmedical datasets with 1.4-2.5 million images using deep convolutional neural network. The endoscopic images we collected for experiment were taken under random lighting conditions, zooming and optical magnification, including 1104 endoscopic nonpolyp images taken under both white-light and narrowband imaging (NBI) endoscopy and 826 NBI endoscopic polyp images, of which 263 images were hyperplasia and 563 were adenoma as confirmed by histology. The proposed method identified polyp images from nonpolyp images in the beginning followed by predicting the polyp histology. When compared with visual inspection by endoscopists, the results of this study show that the proposed method has similar precision (87.3% versus 86.4%) but a higher recall rate (87.6% versus 77.0%) and a higher accuracy (85.9% versus 74.3%). In conclusion, automatic algorithms can assist endoscopists in identifying polyps that are adenomatous but have been incorrectly judged as hyperplasia and, therefore, enable timely resection of these polyps at an early stage before they develop into invasive cancer.

Robotic surgery for rectal cancer: A systematic review of current practice.

AIM: To give a comprehensive review of current literature on robotic rectal cancer surgery. METHODS: A systematic review of current literature via PubMed and Embase search engines was performed to identify relevant articles from january 2007 to november 2013. The keywords used were: "robotic surgery", "surgical robotics", "laparoscopic computer-assisted surgery", "colectomy" and "rectal resection". RESULTS: After the initial screen of 380 articles, 20 papers were selected for review. A total of 1062 patients (male 64.0%) with a mean age of 61.1 years and body mass index of 24.9 kg/m(2) were included in the review. Out of 1062 robotic-assisted operations, 831 (78.2%) anterior and low anterior resections, 132 (12.4%) intersphincteric resection with coloanal anastomosis, 98 (9.3%) abdominoperineal resections and 1 (0.1%) Hartmann's operation were included in the review. Robotic rectal surgery was associated with longer operative time but with comparable oncological results and anastomotic leak rate when compared with laparoscopic rectal surgery. CONCLUSION: Robotic colorectal surgery has continued to evolve to its current state with promising results; feasible surgical option with low conversion rate and comparable short-term oncological results. The challenges faced with robotic surgery are for more high quality studies to justify its cost.

Quality of life after laparoscopic vs open sphincter-preserving resection for rectal cancer.

AIM: To compare quality of life (QoL) outcomes in Chinese patients after curative laparoscopic vs open surgery for rectal cancer. METHODS: Eligible Chinese patients with rectal cancer undergoing curative laparoscopic or open sphincter-preserving resection between July 2006 and July 2008 were enrolled in this prospective study. The QoL outcomes were assessed longitudinally using the validated Chinese versions of the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires before surgery and at 4, 8, and 12 mo after surgery. The QoL scores at the different time points were compared between the laparoscopic and open groups. A higher score on a functional scale indicated better functioning, whereas a higher score on a symptom scale indicated a higher degree of symptoms. RESULTS: Seventy-four patients (49 laparoscopic and 25 open) were enrolled. The two groups of patients were comparable in terms of sociodemographic data, types of surgery, tumor staging, and baseline mean QoL scores. There was no significant decrease from baseline in global QoL for the laparoscopic group at different time points, whereas the global QoL was worse compared to baseline beginning at 4 mo but returned to baseline by 12 mo for the open group (P = 0.019, Friedman test). Compared to the open group, the laparoscopic group had significantly better physical (89.9 ± 1.4 vs 79.2 ± 3.7, P = 0.016), role (85.0 ± 3.4 vs 63.3 ± 6.9, P = 0.005), and cognitive (73.5 ± 3.4 vs 50.7 ± 6.2, P = 0.002) functioning at 8 mo, fewer micturition problems at 4-8 mo (4 mo: 32.3 ± 4.7 vs 54.7 ± 7.1, P = 0.011; 8 mo: 22.8 ± 4.0 vs 40.7 ± 6.9, P = 0.020), and fewer male sexual problems from 8 mo onward (20.0 ± 8.5 vs 76.7 ± 14.5, P = 0.013). At 12 mo after surgery, no significant differences were observed in any functional or symptom scale between the two groups, with the exception of male sexual problems, which remained worse in the open group (29.2 ± 11.3 vs 80.0 ± 9.7, P = 0.026). CONCLUSION: Laparoscopic sphincter-preserving resection for rectal cancer is associated with better preservation of QoL and fewer male sexual problems when compared with open surgery in Chinese patients. These findings, however, should be interpreted with caution because of the small sample size of the study.