Learning Curve of Intracorporeal Anastomosis in Laparoscopic Colectomy for Right Side Colon Cancer: A Cumulative Sum Analysis.

BACKGROUND/AIM: Recently, laparoscopic colectomy with intracorporeal anastomosis for colon cancer gained popularity due to the evolution of the laparoscopic linear stapler device and improved techniques from laparoscopic surgeons. However, there are technical difficulties associated with intracorporeal anastomosis. The aim of the study was to clarify the number of cases that are required for laparoscopic surgeons to master the technique of intracorporeal anastomosis in right side colon cancer. PATIENTS AND METHODS: In this retrospective single-center study, 51 consecutive patients who underwent intracorporeal overlap anastomosis, between July 2018 and March 2020, by one laparoscopic surgeon were selected. Clinicopathological and perioperative data were obtained from our database. The learning curves of intracorporeal anastomosis time (IAT) were created using the cumulative sum (CUSUM) method. RESULTS: The CUSUM score for IAT increased as the number of operative cases progressed, up to the 20th case (Phase 1), after which it started to decrease (Phase 2). Compared to the initial learning phase (Phase 1), the master phase (Phase 2) had a significantly faster IAT (p<0.001), significantly decreased incidence of organ/space surgical site infection (p=0.009), and significantly decreased postoperative hospital stay (p=0.021). CONCLUSION: Twenty cases were required for a laparoscopic surgeon to achieve expertise when conducting intracorporeal anastomosis in laparoscopic colectomy for right side colon cancer. It was suggested that proficiency in intracorporeal anastomosis may contribute to a reduction in the incidence of organ/space surgical site infections and postoperative hospital stay.

Differential Expression and Prognostic Correlation of Immune Related Factors Between Right and Left Side Colorectal Cancer.

Background: Growing evidence suggests that colorectal cancer (CRC) should be considered a heterogeneous disease. The right side (RCC) and left side (LCC) colorectal cancer have different clinical characteristics and immune landscapes. The aim of this study was to analyze differential expression and prognostic correlation of immune-related factors between RCC and LCC. Methods: The gene expression profile and clinical characteristics of CRC patients were retrieved from The Cancer Genome Atlas data portal (n=525). Using a deconvolution algorithm, immune cell infiltration in RCC and LCC based on the RNA-seq data was analyzed. Differentially expressed genes (DEGs) were obtained by performing differential gene expression analysis. Immune-related DEGs were derived by the intersection with immune-related factors downloaded from the IMMPORT database. To further validate the findings, we applied immunohistochemical (IHC) staining of a CRC tissue microarray (TMA). The distribution of immune cells in RCC and LCC and changes in the expression of immune molecules on their membranes were verified. The expression levels of circulating cytokines were measured by flow cytometry to detect the cytokines secreted by immune cells in RCC and LCC. Furthermore, to reveal the prognostic value of differential immune factors on RCC and LCC patients, survival analysis based on mRNA levels using TCGA cohort and survival analysis using protein levels was performed using our CRC patients. Results: The infiltration of immune cells differed between RCC and LCC, the infiltration degree of macrophages M0 was significantly higher in LCC, while the infiltration degree of differentiated macrophages M1 and M2, CD4+ T and CD8+ T cells was significantly higher in RCC. The expression of related molecules by immune cells also differed between RCC and LCC. The expression of 7 genes in RCC was higher than that in LCC, which were CCR5, CD209, CD8A, HCK, HLA-DPB1, HLA-DQA1, HLA-DRA, respectively. Meanwhile, the expression of 2 genes in LCC was higher than in RCC, which were IL-34 and PROCR. Patients with RCC having high expression of HLA-DQA1 mRNA or proteins had better survival and LCC patients with high expression of IL 34 mRNA or protein had better survival. Conclusions: In this study, we comprehensively compared differences in immune cells and regulating factors between left and right colorectal cancer. Different expression patterns and their effects on survival were identified. The analysis of immune-related factors may provide a theoretical basis for precise immunotherapy of RCC and LCC.

Interactions of occult tumor spread and surgical technique on overall and disease-free survival in patients operated for stage I and II right-sided colon cancer.

PURPOSE: To determine if "medial to lateral" (ML) dissection with devascularization first is superior to "lateral to medial" (LM) dissection regarding numbers of lymph node micro metastases (MM) and isolated tumor cells (ITC) as well as 5-year disease-free (5YDFS) and 5-year overall survival (5YOS) in stage I/II right-sided colon cancer. METHODS: Two datasets are used. ML group consists of consecutive stage I/II patients from a prospective trial. LM group is the original dataset from a previous publication. All harvested lymph nodes are examined with monoclonal antibody CAM 5.2 (immunohistochemically). Lymph node harvest and 5YOS/5YDFS were compared between ML/LM groups, stage I/II tumors and MM/ITC presence/absence. RESULTS: 117 patients included ML:51, LM:66. MM/ITC positive in ML 37.3% (19/51), LM 31.8% (21/66) p = 0.54. The 5YDFS for patients in ML 70.6% and LM 69.7%, p = 0.99, 5YOS: 74.5% ML and 71.2% LM (p = 0.73). No difference in 5YDFS/5YOS between groups for Stage I/II tumors; however, LM group had an excess of early tumors (16) when compared to ML group, while lymph node harvest was significantly higher in ML group (p < 0.01) 15.1 vs 26.7. 5YDFS and 5YOS stratified by MM/ITC presence/absence was 67.5%/71.4%, p = 0.63, and 75.0%/71.4%, p = 0.72, respectively. Death due to recurrence in MM/ITC positive was significantly higher than MM/ITC negative (p = 0.012). CONCLUSION: Surgical technique does not influence numbers of MM/ITC or 5YDFS/5YOS. Presence of MM/ITC does not affect 5YOS/5YDFS but can be a potential prognostic factor for death due to recurrence. CLINICAL TRIAL: Safe Radical D3 Right Hemicolectomy for Cancer through Preoperative Biphasic Multi-Detector Computed Tomography (MDCT) Angiography" registered at http://clinicaltrials.gov/ct2/show/NCT01351714 .

Analysis of multi-omics differences in left-side and right-side colon cancer.

BACKGROUND: Colon cancer is one of the most common tumors in the digestive tract. Studies of left-side colon cancer (LCC) and right-side colon cancer (RCC) show that these two subtypes have different prognoses, outcomes, and clinical responses to chemotherapy. Therefore, a better understanding of the importance of the clinical classifications of the anatomic subtypes of colon cancer is needed. METHODS: We collected colon cancer patients' transcriptome data, clinical information, and somatic mutation data from the Cancer Genome Atlas (TCGA) database portal. The transcriptome data were taken from 390 colon cancer patients (172 LCC samples and 218 RCC samples); the somatic mutation data included 142 LCC samples and 187 RCC samples. We compared the expression and prognostic differences of LCC and RCC by conducting a multi-omics analysis of each using the clinical characteristics, immune microenvironment, transcriptomic differences, and mutation differences. The prognostic signatures was validated using the internal testing set, complete set, and external testing set (GSE39582). We also verified the independent prognostic value of the signature. RESULTS: The results of our clinical characteristic analysis showed that RCC had a significantly worse prognosis than LCC. The analysis of the immune microenvironment showed that immune infiltration was more common in RCC than LCC. The results of differential gene analysis showed that there were 360 differentially expressed genes, with 142 upregulated genes in LCC and 218 upregulated genes in RCC. The mutation frequency of RCC was generally higher than that of LCC. BRAF and KRAS gene mutations were the dominant genes mutations in RCC, and they had a strong mutual exclusion with APC, while APC gene mutation was the dominant gene mutation in LCC. This suggests that the molecular mechanisms of RCC and LCC differed. The 4-mRNA and 6-mRNA in the prognostic signatures of LCC and RCC, respectively, were highly predictive and may be used as independent prognostic factors. CONCLUSION: The clinical classification of the anatomic subtypes of colon cancer is of great significance for early diagnosis and prognostic risk assessment. Our study provides directions for individualized treatment of left and right colon cancer.

Construction of a long noncoding RNA-based competing endogenous RNA network and prognostic signatures of left- and right-side colon cancer.

BACKGROUND: Cancers located on the right and left sides of the colon have distinct clinical and molecular characteristics. This study aimed to explore the regulatory mechanisms of location-specific long noncoding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) in colon cancer and identify potential prognostic biomarkers. METHOD: Differentially expressed lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs) between right- and left-side colon cancers were identified by comparing RNA sequencing profiles. Functional enrichment analysis was performed for the DEGs, and a ceRNA network was constructed. Associations between DELs and patient survival were examined, and a DEL-based signature was constructed to examine the prognostic value of these differences. Clinical colon cancer tissues and Gene Expression Omnibus (GEO) datasets were used to validate the results. RESULTS: We identified 376 DELs, 35 DEMs, and 805 DEGs between right- and left-side colon cancers. The functional enrichment analysis revealed the functions and pathway involvement of DEGs. A ceRNA network was constructed based on 95 DEL-DEM-DEG interactions. Three DELs (LINC01555, AC015712, and FZD10-AS1) were associated with the overall survival of patients with colon cancer, and a prognostic signature was established based on these three DELs. High risk scores for this signature indicated poor survival, suggesting that the signature has prognostic value for colon cancer. Examination of clinical colon cancer tissues and GEO dataset analysis confirmed the results. CONCLUSION: The ceRNA regulatory network suggests roles for location-specific lncRNAs in colon cancer and allowed the development of an lncRNA-based prognostic signature, which could be used to assess prognosis and determine treatment strategies in patients with colon cancer.

Clinicopathologic and epidemiological characteristics of prognostic factors in post-surgical survival of colorectal cancer patients in Jiangsu Province, China.

Poor survival among colorectal cancer (CRC) patients has been widely associated with clinico-epidemiological features and treatment regimen. In Jiangsu (China), however, it is not known which one of the prognostic factors explains the survival disparities among patients with CRC. This prospective study using 1078 patients (stages I-IV) that underwent surgery at Jiangsu Hospital, explored the relevant factors affecting the prognoses of right-side colon cancer (RCC), left-side colon cancer (LCC) and rectal cancer (ReC) patients. Of these cases, 234 (21.7%), 241 (22.4%) and 603 (55.9%) were found to have RCC, LCC and ReC respectively. Compared to LCC, RCC exhibited a greater proportion of older patients, poorly differentiated carcinomas, higher T-stage and higher TNM-stage. The overall survival (OS) for RCC was 60 vs.78 or 77 months for LCC or ReC respectively (P = 0.030). There were no significant differences in OS between LCC and ReC across the subgroups (P = 0.633). In multivariate analysis, RCC patients had age (>60 vs. ≤60 years, HR = 1.529, P = 0.019), N-stage (N1 vs. N0, HR = 4.056, P = 0.012) and M-stage (M1 vs. M0, HR = 3.442, P < 0.0001) as independent prognostic factors, whereas smoking status was found to be a predictor of mortality (smoker vs. nonsmoker, HR = 2.343, P = 0.017) for LCC. In addition, age (>60 vs. ≤60 years, HR = 2.199, P < 0.0001), alcohol consumption (drinker vs. nondrinker, HR = 0.510, P = 0.034), tumor grade (Poor vs. well/moderate, HR = 2.759, P = 0.031) and T-stage (T3-4 vs. T1-2, HR = 1.742, P < 0.0001) were found to be predictors of mortality for ReC. There were significant pairwise interactions across subgroups. Furthermore, significant differences were observed for LCC vs. RCC (OS, HR = 0.783, P = 0.039), but no statistically significant differences for ReC vs. RCC (P = 0.149) and LCC vs. ReC (P = 0.355). Nevertheless, significant differences remained between ReC vs. RCC for male (HR = 0.591, P = 0.009), drinker (HR = 0.396, P = 0.005), rural resident (HR = 0.437,P = 0.022), tumor grade (well/moderate, HR = 0.475, P = 0.022), T-stage (T1-2, HR = 0.362, P = 0.001), N-stage (N0, HR = 0.604, P = 0.011), M-stage(M0, HR = 0.401, P = 0.006) and TNM-stage (I-II, HR = 0.567, P = 0.005). Statistically significant differences were observed for LCC vs. RCC for gender (female, HR = 0.495, P = 0.003) and T-stage (T1-2, HR = 0.417, P = 0.010) as well as for LCC vs. ReC in patients with smoking habits (HR = 1.951, P = 0.002) and M-stage (M0, HR = 2.291, P = 0.003). These findings suggest that the variations in CRC post-surgical survival in China may be primarily explained with the clinicopathologic features and epidemiological characteristic of the patients. Patients with RCC had significantly worse OS compared to both LCC and ReC in several subgroups.

Colon Cancer Tumor Location Defined by Gene Expression May Disagree With Anatomic Tumor Location.

BACKGROUND: Cancers of the right colon have been shown to differ from left-side colon cancers in prognosis, response to epithelial growth factor receptor inhibitors, microsatellite instability and BRAF mutation status, and other molecular characteristics. Clinical application of these differences will benefit from a deeper understanding of how tumor location defines and is defined by gene expression. MATERIALS AND METHODS: This study was carried out using Affymetrix microarray datasets (Cohort A: training set, n = 352; validation set, n = 519) and samples from The Cancer Genome Atlas Colon Adenocarcinoma database (Cohort B: n = 408), in which tumor location was reported. Gene expression patterns characteristic of tumor side were identified in a manner unbiased by statistical classification method. RESULTS: In the Cohort A validation set, the anatomic locations of 75% of tumors agree with the locations predicted by gene expression (so-called genomic location), whereas 8% of tumors had genomic locations discordant with their anatomic locations, and 17% of tumors had ambiguous genomic locations. Genomic location was a better predictor of microsatellite instability, CpG island methylator phenotype status, and BRAF mutation status than anatomic location. Tumors with ambiguous genomic location were significantly (P = 1.3 × 10-7) more likely to have the mesenchymal consensus molecular subtype (40%) than those with a specific genomic location (18%). A genomic signature to predict genomic location was defined. CONCLUSION: Tumor location is increasingly considered in deciding treatment of a colon tumor. We showed that genomic location was superior to anatomic location as a predictor of molecular characteristics, suggesting that it may be a more accurate predictor of response.

Immune Landscape of Colorectal Cancer Tumor Microenvironment from Different Primary Tumor Location.

To define differences in tumor microenvironment (TME) immune phenotypes between right and left colorectal cancers (CRCs) and explore their therapeutic implications. Gene expression profiling and clinical characteristics of patients with CRC were retrieved from The Cancer Genome Atlas data portal. Immune cell infiltration was estimated based on single-sample gene set enrichment analysis. CRCs tissue microarrays (TMAs) containing 90 consecutive cases of surgical samples were used for validation. Expression of CD8A and VEGFA was confirmed by immunohistochemistry (IHC) analysis with TMAs, and overall survival (OS) was analyzed. Expression profiling data demonstrated that CRC immune microenvironment from right side tumor was characterized as increased infiltration of immune cells with enhanced cytotoxic function, based on higher cytotoxic activity scores (CYT) and interferon-γ signatures. Expression of VEGFA, which could be neutralized by bevacizumab, was associated with decreased levels of activated CD8+ T-cells, Th1 cells, and PRF1 expression on the right side, but not on the left side. IHC analysis of TMAs further confirmed an inverse correlation between CD8A and VEGFA expression, and revealed a favorable OS for patients with CD8AHiVEGFALo disease among right-side CRCs. For the left side, higher CD56bright natural killer cell infiltration and active 4-1BB/IFN-ɑ signaling, which could providing a favorable condition for cetuximab-mediated antibody-dependent cell-mediated cytotoxicity effect, was present in a cohort with extended OS. In the TME, features of immune phenotype sidedness were identified, providing an implication for differential responses to bevacizumab/cetuximab treatment. In addition, a new avenue for innovative experimental design and combinational immunotherapy to treat CRC patients was suggested.

Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials.

The aim of the present study was to determine whether or not the overall survival (OS) and disease-free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right-side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left-side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni- and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020-1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.

Safety and Feasibility of Self-Expandable Metallic Stent Insertion for the Right-Side Colonic Malignant Obstruction and Its Clinical Benefits

PURPOSE: The efficacy of stenting for the right-side colonic malignant obstruction is unknown. The purpose of this study was to evaluate the safety and feasibility of self-expandable metallic stent insertion for the right-side colonic malignant obstruction and its clinical benefits. METHODS: We retrospectively reviewed clinical data from 460 patients who underwent right hemicolectomy for right-side colon cancer from January 2006 to January 2014 at Korea University Anam Hospital. Twenty four patients who developed malignant obstruction in the right -side colon were identified and analyzed. RESULTS: Self-expandable metallic stent insertion was attempted in 14 patients, and initial technical success was achieved in 13 patients (92.9%). No immediate stent-related complications were reported. Complete relief of obstruction was achieved in all of the 13 patients. Eleven patients who failed stenting underwent emergency operation. All of the 13 patients with stent underwent laparoscopic surgery and only one case was converted to open. Only three patients in the emergency group underwent laparoscopic surgery but one was converted. Operative time and number of retrieved lymph nodes did not differ between the two groups. Postoperative hospital stay (9.8+/-3.2 in stent group vs. 16.3+/-10.9 days in emergency group, p=0.082) tended to be shorter in the stent group. Estimated blood loss (38.5+/-138.7 in stent group vs. 381.8+/-411.9 in emergency group, p=0.010) and duration for resuming diet (3.2+/-2.2 in stent group vs. 6.6+/-7.0 days in emergency group, p=0.017) were significantly better in the stent group. CONCLUSION: Self-expandable metallic stent appears to be safe and feasible in the right-side colonic malignant obstruction. It facilitates minimally invasive surgery and may result in better short-term surgical outcome.