Infrapyloric (No. 206) and greater curvature (No. 204) lymph node metastasis in adenocarcinoma located in the right half of the transverse colon (InCLART Study): protocol for a multicentre prospective observational study.

INTRODUCTION: In the case of right-sided transverse colon cancer (RTCC) and hepatic flexure colon cancer (HFCC), there is a potential connection of lymph drainage between mesentery and greater omentum. However, most previous reports have been limited case series with No. 206 and No. 204 lymph node (LN) dissection for RTCC and HFCC. METHODS AND ANALYSIS: The InCLART Study is a prospective observational study aiming to enrol 427 patients with RTCC and HFCC treated at 21 high-volume institutions in China. The prevalence of infrapyloric (No. 206) and greater curvature (No. 204) LN metastasis and short-term outcomes will be investigated in a consecutive series of patients with T2 or deeper invasion RTCC or HFCC, following the principle of complete mesocolic excision with central vascular ligation. Primary endpoints were performed to identify the prevalence of No. 206 and No. 204 LN metastasis. Secondary analyses will be used to estimate prognostic outcomes, intraoperative and postoperative complications, the consistency of preoperative evaluation and postoperative pathological results of LN metastasis. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the Ruijin Hospital Ethics Committee (approval number: 2019-081) and has been or will be approved successively by each participating centre's Research Ethics Board. The findings will be disseminated in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03936530; https://clinicaltrials.gov/ct2/show/NCT03936530).

PKCδ promotes the invasion and migration of colorectal cancer through c-myc/NDRG1 pathway.

Objective: Colorectal cancer (CRC) is the third cause of expected cancer deaths both in men and women in the U.S. and the third most commonly diagnosed cancer in China Targeted therapy has been proven to improve overall survival for unresectable metastatic CRC. But the location of the primary tumor or the presence of various core driver gene mutations that confer resistance may limit the utility of targeted therapy. Therefore, it is of great significance to further elucidate novel mechanisms of invasion and metastasis of CRC and find potential novel therapeutic targets. Protein Kinase C Delta (PKCδ) plays an important role in various diseases, including tumors. In CRC, the function of PKCδ on proliferation and differentiation is mostly studied but various research results were reported. Therefore, the role of PKCδ in CRC needs to be further studied, especially in tumor invasion and metastasis in CRC which few studies have looked into. Methods: The expression of PRKCD was analyzed by the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases and Immunohistochemical (IHC). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) enrichment analysis were used to explore the biological functions and pathways related to PRKCD. Lentivirus transfection was used to construct CRC cell lines with overexpression and knock-down of PKCδ or N-myc Downstream Regulated Gene 1 (NDRG1). Cell invasion and migration assay, wound healing assay were used to detect the function of PKCδ and NDRG1 in the invasion and migration of cells. Flow cytometry analysis was used to detect the influence of PKCδ on the CRC cell cycles .Immunofluorescence histochemistry ,Immunoprecipitation Assay and qPCR were used to detect the relationship of PKCδ and NDRG1. Xenograft model was used to verify the role of PKCδ in vivo. Results: PKCδ is overexpressed in CRC and could promote Epithelial-Mesenchymal Transition (EMT) and the invasion and migration of CRC in vitro. We confirmed that PKCδ and the tumor suppressor factor NDRG1 had a co-localization relationship in CRC. PKCδ inhibited NDRG1 transcription and protein expression. Overexpressing NDRG1 could inhibit the function of PKCδ in promoting tumor invasion and migration. PKCδ could regulate c-Myc, one transcription factor of NDRG1, to down-regulate NDRG1. In vivo, overexpressing PKCδ could promote xenograft growth and volume. Thus, our results showed that PKCδ reduced the expression of NDRG1 through c-Myc, promoting the invasion and migration of CRC through promoting EMT. Conclusion: The increased expression of PKCδ in CRC tumor tissue could promote the invasion and migration of tumor cells, and one of the mechanisms may be regulating c-Myc to inhibit the expression of NDRG1 and promote EMT.

ACACB is a novel metabolism-related biomarker in the prediction of response to cetuximab therapy inmetastatic colorectal cancer.

Cetuximab is one of the most valuable targeted therapy monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC). However, the mechanisms affecting cetuximab resistance in CRC treatment remain unclear. Metabolism, especially fatty acid metabolism, has been reported to play an important role in tumor treatment. The correlation between cetuximab resistance and metabolism and whether it can be a new biomarker to evaluate the sensitivity of cetuximab in CRC treatment still need to be further explored. In this study, we perform a comprehensive analysis to confirm the relationship between fatty acid metabolism and cetuximab resistance, and the differentially expressed genes (DEGs) related to cetuximab drug resistance in CRC are screened by bioinformatics technology. We find that acetyl-CoA carboxylase beta (ACACB), ADH1C, CES1, MGLL, FMO5, and GPT are the hub DEGs, and ACACB is the most important biomarker among them. In addition, we systematically analyze the role of ACACB in the tumorigenesis of CRC, including tissue expression, CRC cell growth, cetuximab sensitivity, and potential downstream pathways, by using bioinformatics techniques, in vitro experiments and clinical cohort validation. Our results confirm that cetuximab resistance is correlated with metabolism. ACACB can lead to decreased sensitivity to cetuximab in CRC, and its mechanism may be related to EGFR phosphorylation, which could affect the activation of the mTOR/Akt signaling pathway and regulation of CDT1-, cyclin D1-, and p21-related cell cycle modulation.

Detection and Clinical Value of Circulating Tumor Cells as an Assisted Prognostic Marker in Colorectal Cancer Patients.

BACKGROUND: Circulating tumor cells (CTCs) are cells that have been shed into the vasculature from a primary tumor and circulate in the bloodstream. It has been suggested that detecting CTCs could help the clinician to detect early metastasis or recurrence more effectively. This trial sets out to assess the detection and clinical value of CTCs as an assisted prognostic marker in patients with colon cancer and rectal cancer. METHODS: A prospective cohort of patients with colorectal cancer (CRC) was enrolled from July 2015 to February 2018 in Shanghai Minimally Invasive Surgery Center, Shanghai, China. In this study, 149 patients with CRC were enrolled and underwent surgical treatment. There were 79 cases of colon cancer and 70 cases of rectal cancer, including 93 males and 56 females. To investigate the correlativity and clinical value of CTCs, the patients were statistically analyzed in different subgroups: colon cancer group vs rectal cancer group, and left hemicolon cancer group vs right hemicolon cancer group. RESULTS: The results of analysis comparing CTC counts and clinical pathological features in colon and rectal cancer indicated that with increased tumor stage, the number of CTCs also increased, with significant statistical differences. CTC counts in patients with colon and rectal cancer showed positive correlations with TNM staging (P=0.001, 0.013, respectively), T staging (P=0.021, 0.001), N staging (P=0.014, 0.035) and M staging (P=0.018, 0.203). Detection of serum biomarkers in CTC-positive and CTC-negative groups indicated a significantly increasing expression in the CTC-positive group. To confirm the correlations between CTCs and histoembryological differences, analysis was conducted with the patients in two subgroups: left hemicolon cancer group and right hemicolon cancer group. The results showed that the positive rate of CTCs increased in both groups with the increase in tumor stage. The survival analysis indicated that there was a steep gradient in survival in the follow-up period, particularly in the CTC-positive group (P=0.000). Risk assessment curves showed that the change escalated more rapidly in the CTC-positive group. Furthermore, with the increase in T stage, changes in the survival curve and risk curve escalated more rapidly in the CTC-positive group. CONCLUSION: It was confirmed that in the left hemicolon cancer group, a much higher coincidence rate could be found on CTC-positive rate and clinicopathological features, than in the right hemicolon cancer group. The sensitivity of CTCs may be related to the histoembryological location of the tumor, lymphatic metastasis and the depth of infiltration. Monitoring CTCs may have value in evaluating clinical staging and estimating clinical prognosis.

Staged laparoscopic management of locally advanced gastric cancer with outlet obstruction.

BACKGROUND: The prognosis of patients with locally advanced gastric cancer with outlet obstruction is poor. Gastrectomy with curative intent is often initially impossible or difficult. OBJECTIVE: We report our experience of curative distal gastrectomy after laparoscopic gastrojejunostomy and fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy to examine the feasibility and safety of this modified strategy for locally advanced gastric cancer with outlet obstruction, initially deemed unresectable. METHODS: Between October 2017 and June 2019, 15 patients diagnosed with locally advanced gastric cancer with outlet obstruction sequentially underwent gastrojejunostomy, received four cycles of FLOT chemotherapy, and underwent laparoscopic distal gastrectomy with curative intent (R0 resection + D2 lymphadenectomy). Clinical data were retrospectively collected and analyzed. RESULTS: R0 resection was possible in 12/15 patients, laparoscopically in 11, and one conversion to laparotomy was necessary. There was no perioperative mortality in the 12 patients. Pathologic evaluation of the resected specimens revealed that complete tumor grade regression 1a (TRG1a), TRG1b, TRG2, and TRG3 occurred in 3, 2, 4, and 3 patients, respectively. CONCLUSION: This case series showed that curative surgical resection was feasible as a staged approach for patients with locally advanced gastric cancer with outlet obstruction, after initial staged gastrojejunostomy and chemotherapy.

Comparative study of oncologic efficacy of cephalomedial to lateral dissection versus medial to lateral dissection in laparoscopic total mesorectal excision for rectal cancer: An RCT study.

BACKGROUND AND OBJECTIVES: We compared the 3-year overall survival between cephalomedial-to-lateral approach proctectomy (CEMP) and medial-to-lateral approach proctectomy (MAP) in patients undergoing laparoscopic total mesorectal excision for rectal cancer. The advantages of CEMP and the clinical value of No. 253 lymph nodes resection have not been objectively analyzed in literature. METHODS: This was a prospective, two-arm, multicenter, single-blinded, randomized trial. The primary endpoint was 3-year overall survival, and secondary endpoints included safety, feasibility, oncological radicality (including number of No. 253 lymph nodes harvested), short-term outcome, 3-year disease-free survival, rate of postoperative complications, mortality, and rate of recurrence. RESULTS: From May 2016 to July 2020, 506 patients were enrolled-256 in the CEMP group and 250 in the MAP group. Comparison of overall survival and disease-free survival showed that there was treatment benefit in the CEMP group (28.22 ± 12.12 vs. 27.44 ± 13.06, p = 0.485; 27.24 ± 12.01 vs. 26.42 ± 12.81; p = 0.457). More No. 253 lymph nodes were harvested in the CEMP group, and cases with positive No. 253 lymph nodes had worse prognosis in stage III. Surgical safety was equal for both approaches. CONCLUSIONS: Dissection of No. 253 lymph nodes may be important to improve clinical prognosis, but further studies with larger samples are needed to confirm this finding.