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Background Single-incision plus one-port laparoscopic surgery (SILS + 1) has been demonstrated to be minimally invasive while possessing better cosmesis and less pain compared with conventional laparoscopic surgery (CLS). However, SILS + 1 as an alternative to CLS for colorectal cancer is still controversial. Methods A total of 1071 patients who underwent curative laparoscopic surgery for colon cancer between 2015 and 2018 were included. Of these patients, 258 SILS + 1 cases and 516 CLS cases were analyzed using propensity score matching. The baseline characteristics, surgical outcomes, pathologic findings and recovery course, morbidity and mortality within postoperative 30 days and 3-year disease-free and overall survival were compared. Results Baseline characteristics were balanced between the groups. The mean operating time was significantly shorter in SILS + 1 group, with less estimated blood loss. Tumor size, tumor differentiation, number of harvested lymph nodes, resection margin and pathologic T, N, TNM stage was similar between the groups. There was no significant difference in overall perioperative complications. Uni- and multivariate analyses revealed that SILS + 1 was not a risk factor for complications. Postoperatively, SILS + 1 group showed faster recovery than CLS group in terms of ambulation, bowel function, oral intake and discharge. The 3-year disease-free survival rates of SILS + 1 and CLS groups were 90.1% and 87.3%(p = 0.59), respectively and the 3-year overall survival rates were 93.3% vs. 89.8%(p = 0.172). Discussion Our study revealed that SILS + 1 is safe, feasible, oncologically efficient, and may be considered as a surgical option for selected patients with colorectal cancer.

The abnormal expression of glutathione S-transferase P1 (GSTP1) is associated with the progression of several tumor types. However, its role and molecular mechanism in the progression of colorectal cancer (CRC) are largely unknown.To examine the effect of GSTP1 in CRC and determine its possible mechanisms.In the present study, immunohistochemistry (IHC) and the quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis were used to detect the expression of GSTP1 and signal transducer and activator of transcription 3 (STAT3) in CRC tissues. Western blotting was applied to detect the expression of GSTP1 and proteins of the Janus kinase (JAK)-STAT3 pathway in different CRC cell lines. The interaction and co-localization of GSTP1 and STAT3 were detected using co-immunoprecipitation (co-IP) and immunofluorescence (IF) in the SW620 cell line.A positive correlation was identified between the expression of GSTP1 and STAT3 in human CRC tissues. The overexpression of GSTP1 promoted the proliferation, invasion and metastasis of CRC cells by upregulating STAT3. The GSTP1 and STAT3 can directly bind to and regulate each other. The interaction between them is regulated by the upstream gene called F-box only protein 8 (FBX8).The present study demonstrated that GSTP1 could enhance the expression of STAT3 to promote the proliferation, invasion and metastasis of CRC cells, which provides a potential therapeutic target for the clinical treatment of CRC.

Background Studies have proved that the enhanced recovery after surgery (ERAS) protocol can significantly improve the recovery course of patients during the perioperative period. The application of minimally invasive surgery is a critical component of ERAS protocol. Single-incision plus one port laparoscopic surgery (SILS plus one) could achieve further minimally invasive surgical results than conventional laparoscopic surgery (CLS). The objective of this trial is to evaluate the safety and feasibility of SILS plus one with ERAS protocol in colorectal cancer. Methods This is a prospective, single-center, open-label, single-arm trial. A total of 120 eligible patients with colorectal cancer will receive SILS plus one followed by the ERAS management during the perioperative period. The primary endpoint is postoperative hospital stay. The secondary endpoints include rehabilitative rate of the fourth postoperative day, postoperative medical cost, postoperative pain score, postoperative recovery indexes, inflammatory immune response indexes, compliance with ERAS measures, 6 min postoperative walking test (6MWT), hospital readmissions, and early postoperative complications. Discussion This trial will be the first to evaluate the short-term outcomes of SILS plus one assisted with ERAS protocol for patients with colorectal cancer and will provide valuable clinical evidence on the benefit of the combination of these two techniques, hopefully, to provide patients with more safe, economic, feasible, and rapid surgery and perioperative strategies. Trial Registration Clinical Trial Registry, NCT0426829. Registered February 15, 2020 (https://clinicaltrials.gov/ct2/show/NCT04268290).

Purpose: To develop a circulating tumor DNA (ctDNA) methylation signature for early detection of metastatic relapse and surveillance of therapeutic efficacy in stage III CRC. Perimental design: The deferentially methylated locations (DMLs) between 52 normal intestinal mucosa and 134 stage III CRC tissue and between plasma from 96 stage I/II CRC patients and 73 stage IV CRC patients were detected by high-throughput targeted methylation sequencing. CtDNA methylation signature was established by random forest with DMLs shared by plasma and tissue samples. This signature was then applied to predict the risk of metastatic disease recurrence in blood samples from 50 stage III CRC patients and dynamic monitor the recurrence risk in serial blood samples from 4 CRC patients. Results: 2237 and 1185 hypermethylation markers were identified in CRC tissue and plasma from stage IV CRC patients, respectively. Our signature achieved the sensitivity of 84.21% and specificity of 81.81% in distinguishing late CRC from early CRC in the validation cohort. Moreover, this signature yielded high sensitivity (87.5%) and specificity (94.12%) for predicting metastatic disease relapse in a cohort of 50 stage III CRC patients, and could be an independent risk factor for relapse in those patients (HR, 18.7; 95% CI, 5.3-66.2; P = 9.86e-6). The analyses of serial blood samples of CRC showed that this model was more sensitive to monitor treatment response than imaging examination and serum carcinoembryonic antigen (CEA). Conclusions: We identify a ctDNA methylation signature for stratifying risk of recurrence in stage III CRC and non-invasively monitoring treatment response.Statement of translational relevanceWe successfully developed a ctDNA methylation signature for risk assessment of metastatic disease recurrence in stage III CRC patients and surveillance of therapeutic efficacy of CRC. Funding: This work was supported by the National Key R&D program of China (2017YFC1309002), National Natural Science Foundation of China (81672821, 81872041, 81773101, 81802306, 81903002), Natural Science Foundation Key program of Guangdong Province of China (2018B0303110017), Natural Science Foundation of Guangdong Province of China (2018A030310457, 2019A1515011436), Science and Technology Planning Project of Guangdong Province, China (2017B020226005). Declaration of Interest: The authors Jianbing Fan, Xia Li are employees of AnchorDx Medical Co., Ltd., a company that focuses on the development of next generation sequencing diagnostic products for cancer detection using liquid biopsy. All other authors declare no competing financial interest. Ethical Approval: It was approved by the Human Research Ethical Review Board in Southern Hospital of Southern Medical University and Southern Theater General Hospital of Chinese people's Liberation Army.

Background CMTM6 is a novel key regulator of PD-L1. High expression of both CMTM6 and PD-L1 may predict the benefit of PD-1 axis blockade in lung cancer. We aimed to investigate the expression pattern of CMTM6 between mismatch repair-defective (dMMR) and mismatch repair-proficient (pMMR) colorectal cancer (CRC) tissues and assess its correlation with the response to PD-1/PD-L1 pathway blockade. Methods Immunohistochemistry (IHC) was used to analyze CMTM6 and PD-L1 expression and immune cell density in dMMR/pMMR CRC. Quantitative multiplex immunofluorescence (IF) was performed to detect CMTM6, PD-L1, CD4, CD8, CD68 and CD163 expression in CRC patients treated with PD-1/PD-L1 inhibitors. Result IHC analysis showed that CMTM6 and PD-L1 were both expressed in tumor cells (TCs) and invasion front immune cells (ICs). CMTM6 and PD-L1 expression and CD4+, CD8+, CD68+ or CD163+ cell density were significantly higher in dMMR CRC patients than in pMMR CRC patients. CMTM6 expression was positively correlated with PD-L1 expression and CD163+ M2 macrophage density in dMMR CRC. IF analysis showed that the coexpression rate of CMTM6/PD-L1 and the expression rate of CMTM6 in CD8+ T cells and CD163+ M2 macrophages were significantly increased in the group that exhibited clinical benefit. CMTM6 expression in M2 macrophages was identified as the best biomarker for predicting the responsiveness to PD-1/PD-L1 inhibitors. Conclusions CMTM6 expression in M2 macrophages may predict the PD-1/PD-L1 inhibitor response rate in CRC patients more accurately than dMMR/microsatellite instability-high (MSI-H) status. It can also identify pMMR CRC patients who could benefit from PD-1/PD-L1 inhibitors.

Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis., The mechanisms underlying pre-metastatic niche formation by cancer derived exosomes is unclear. Here they show that colorectal cancer (CRC) derived exosomal miR-25-3p promotes vascular leakiness and angiogenesis, CRC metastasis, and is upregulated in CRC pateints with metastasis, and suggest miR-25-3p as a biomarker for CRC metastasis.

Radioresistance hampers success in the treatment of patients with advanced colorectal cancer (CRC). Improving our understanding of the underlying mechanisms of radioresistance could increase patients’ response to irradiation (IR). MicroRNAs are a class of small RNAs involved in tumor therapy response to radiation. Here we found that miR-214 was markedly decreased in CRC cell lines and blood of CRC patients after IR exposure. Meanwhile, autophagy was enhanced in irradiated CRC cells. Mechanically, ATG12 was predicted and identified as a direct target of miR-214 by dual luciferase assay, qPCR, and Western blot. In vitro and in vivo experiments showed that miR-214 promoted radiosensitivity by inhibiting IR-induced autophagy. Restoration of ATG12 attenuated miR-214-mediated inhibition of cell growth and survival in response to IR. Importantly, miR-214 was highly expressed in radiosensitive CRC specimens and negatively correlated with plasma level of CEA. Moreover, ATG12 and LC3 expressions were increased in radioresistant CRC specimens. Our study elucidates that miR-214 promotes radiosensitivity by inhibition of ATG12-mediated autophagy in CRC. Importantly, miR-214 is a determinant of CRC irradiation response and may serve as a potential therapeutic target in CRC treatment.

Background Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) metastasis and chemoresistance have not been fully characterized. Methods CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1. Results CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients. Conclusions CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC. Electronic supplementary material The online version of this article (10.1186/s12943-019-1019-x) contains supplementary material, which is available to authorized users.

// Huijun Xie 1, 2, 3, * , Xiaoli Ren 1, 2, 3, * , Sainan Xin 1, 2, 3, * , Xiaoliang Lan 4 , Guifeng Lu 1, 2, 3 , Yuan Lin 1, 2, 3 , Shaoshan Yang 1, 2, 3 , Zhicheng Zeng 1, 2, 3 , Wenting Liao 1, 2, 3 , Yan-Qing Ding 1, 2, 3 , Li Liang 1, 2, 3 1 Department of Pathology, Nanfang Hospital, Guangzhou, Guangdong, China 2 Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China 3 Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China 4 Department of General Surgery, Nanfang Hospital, Guangzhou, Guangdong, China * These authors contributed equally to this work Correspondence to: Li Liang, email: redsnow007@hotmail.com Yan-Qing Ding, email: dyq@fimmu.com Keywords: hsa_circ_001569, miR-145, colorectal cancer, FMNL2, BAG4 Received: December 08, 2015 Accepted: March 07, 2016 Published: April 05, 2016 ABSTRACT Circular RNAs (circRNAs), a large class of RNAs, have recently shown huge capabilities as gene regulators in mammals. Some of them bind with microRNAs (miRNAs) and act as natural miRNA sponges to inhibit related miRNAs’ activities. Here we showed that hsa_circ_001569 acted as a positive regulator in cell proliferation and invasion of colorectal cancer (CRC). Moreover, hsa_circ_001569 was identified as a sponge of miR-145 and up-regulated miR-145 functional targets E2F5, BAG4 and FMNL2. In CRC tissues, circ_001569 negatively correlated with miR-145, and miR-145 correlated negatively with E2F5, BAG4 and FMNL2 expressions. Our study reveals a novel regulatory mechanism of circ_001569 in cell proliferation and invasion in CRC, provides a comprehensive landscape of circ_001569 that will facilitate further biomarker discoveries in the progression of CRC.

The current study sought to clarify the role of phosphodiesterase type 5 inhibitors (PDE-5i) and a vacuum erection device (VED) in penile rehabilitation after laparoscopic nerve-preserving radical proctectomy (LNRP) for rectal cancer. Participants were assigned to one of the following arms—no-intervention, nightly use of sildenafil 25 mg for 3 months after surgery, or concurrent use of nightly sildenafil 25 mg/day for 3 months and a vacuum erection device (VED) 10 to 15 minutes/day for 3 months—in a nonrandomized fashion. All participants had a follow-up of over 12 months prospectively, and patients had baseline, 3-, 6-, and 12-month assessment based on the International Index of Erectile Function–5 (IIEF-5). Seventy-one cases were included in final analyses. In the no-intervention group, the mean baseline IIEF-5 score of 21.9 decreased rapidly to 5.0 at 3 months ( p < .001), 9.2 at 6 months ( p < .001), and stayed at 10.9 at 12 months ( p < .001). In the single therapy group, the mean baseline IIEF-5 score of 22.4 decreased dramatically to 9.0 at 3 months ( p < .001), 14.9 at 6 months ( p = .005), and stayed at 15.1 at 12 months ( p = .005). In the combined therapy group, the mean baseline IIEF-5 score of 23.0 decreased slightly to 15.0 at 3 months ( p = .005), 18.0 at 6 months ( p = .038), and maintained at 18.7 at 12 months ( p = .163). Findings suggested an over 50% decline in the quality of erection function of the patients after LNRP. The early use of PDE-5i alone or combined use of PDE-5i and VED after LNRP maintained erectile function at 12 months.

Incomplete total mesorectal excision (TME) may lead to local recurrence. Factors predicting suboptimal quality of laparoscopic TME have not been well documented. The aim of the prospective observational study was to evaluate factors influencing the quality of laparoscopic TME.Patients undergoing laparoscopic TME for rectal cancer between October 2012 and March 2013 were included. Uni- and multivariate logistic analysis were performed to identify factors independently predicting the suboptimal quality of laparoscopic TME.A total of 52 patients undergoing laparoscopic TME for rectal cancer were included for analysis. Mesorectal resection was complete in 71.2%, nearly complete in 17.3%, and incomplete in 11.5%. Factors found to be significantly related to suboptimal TME in univariate analysis were as follows: BMI ≥ 25 kg/ cm2 (OR = 11.79, 95% CI: 2.88-48.25; p = 0.003) and advanced tumor stage (pT3/4) (OR = 1.90, 95% CI: 1.41-100.00; p = 0.023). Multivariate analysis identified BMI ≥ 25 kg/m2 (OR = 21.05, 95%CI: 3.26-136.06; p = 0.010), advanced tumor stage (pT3/4) (OR = 19.03, 95% CI: 1.55-233.88; p = 0.021) and neoadjuvant radiochemotherapy (OR = 29.76, 95% CI: 1.65-537.93; p = 0.022) as factors that were independently related to suboptimal TME.Laparoscopic TME is feasible with the quality of mesorectal excision which was influenced by patient-, tumor-, and treat- ment-related factors.

e13003 Background: Recurrent somatic mutations and methylation patterns have previously been identified as biomarkers for non-invasive screening of colorectal cancer (CRC). However, most clinical screening assays have focused on a limited number of genomic loci, potentially reducing sensitivity and specificity. Here, we examined the potential utility of using an expanded set of mutation and methylation markers to improve screening accuracy of CRC. Methods: Pairs of colorectal tumor and tumor-adjacent tissues were resected from 41 CRC patients in Nanfang Hospital (NFH), China. The DNA was extracted, processed, and sequenced with Singlera Genomics’ OncoAim assay, which detects mutations across 59 genes implicated in cancer and quantifies the methylation level for key CRC genes. Matched pre- or post-surgery plasma samples were also collected and processed in parallel. Results: Thirty-eight tumor samples (93%) contained somatic mutations with greater than 5% allele frequency, while twenty-nine tumor samples (71%) contained aberrant methylation patterns. Among the tumor-adjacent samples, six contained somatic mutations and eight contained epigenetic abnormalities. Out of three tumor samples without any detectable somatic mutations, one showed an aberrant methylation pattern. Importantly, aberrant methylation patterns in tumor samples were also detected in matched plasma samples. Conclusions: Parallel mutation screening and methylation analysis not only improves the diagnostic yield, but also paves the way for non-invasive monitoring on patients with no common mutations.