Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer.

Background: Cuprotosis is a novel form of programmed cell death that involves direct targeting of key enzymes in the tricarboxylic acid (TCA) cycle by excess copper and may result in mitochondrial metabolic dysfunction. However, whether cuprotosis may mediate the tumor microenvironment (TME) and immune regulation in colorectal cancer (CRC) remains unclear. Methods: Ten cuprotosis-related genes were selected and unsupervised consensus clustering was performed to identify the cuprotosis patterns and the correlated TME characteristics. Using principal component analysis, a COPsig score was established to quantify cuprotosis patterns in individual patients. The top 9 most important cuprotosis signature genes were analyzed using single-cell transcriptome data. Results: Three distinct cuprotosis patterns were identified. The TME cell infiltration characteristics of three patterns were associated with immune-excluded, immune-desert, and immune-inflamed phenotype, respectively. Based on individual cuprotosis patterns, patients were assigned into high and low COPsig score groups. Patients with a higher COPsig score were characterized by longer overall survival time, lower immune cell as well as stromal infiltration, and greater tumor mutational burden. Moreover, further analysis demonstrated that CRC patients with a higher COPsig score were more likely to respond to immune checkpoint inhibitors and 5-fluorouracil chemotherapy. Single-cell transcriptome analysis indicated that cuprotosis signature genes recruited tumor-associated macrophages to TME through the regulation of TCA and the metabolism of glutamine and fatty acid, thus influencing the prognosis of CRC patients. Conclusion: This study indicated that distinct cuprotosis patterns laid a solid foundation to the explanation of heterogeneity and complexity of individual TME, thus guiding more effective immunotherapy as well as adjuvant chemotherapy strategies.

Structured training curricula for robotic colorectal surgery in China: does laparoscopic experience affect training effects?

Background: Robotic surgery has been widely adopted for colorectal cancer (CRC). Many surgeons in China have completed structured training programs and have performed robotic colorectal surgeries. This multicenter study aimed to evaluate the training effects of structured training curricula in China for surgeons with different laparoscopic experiences during their initial implementation of robotic colorectal surgery. Methods: Ten surgeons from five high-volume centers participated in this retrospective study. The baseline characteristics, perioperative data, and pathological outcomes were compared between the first 15 robotic surgeries performed by five surgeons with extensive laparoscopic experience (group A) and the first 15 robotic surgeries performed by five surgeons with limited laparoscopic experience (group B) at each center. Results: Compared with group B, group A showed shorter operation time (200.9 vs. 254.2 min, P<0.001), less blood loss (100.0 vs. 150.0 mL, P=0.025), and a lower incidence of intraoperative complications (2.7% vs. 21.4%, P=0.015). The reoperation rate (1.3% vs. 5.3%, P=0.036) and postoperative complication rate (6.7% vs. 22.7%, P=0.025) were significantly lower in group A than in group B. There were no statistically significant differences in baseline characteristics (e.g., age, sex, and tumor location) and pathological information (e.g., tumor stage, lymph node count, and tumor size) between the two groups. Radical resection (R0) was performed in all cases. Conclusions: In China, structured training curricula can help surgeons with extensive laparoscopic experience make a smooth transition from laparoscopic to robotic surgery. However, the higher intraoperative and postoperative complication rates indicate that structured training curricula still require further refinement for surgeons with limited laparoscopic experience.

Structured training curriculums for transanal total mesorectal excision in China: refinement is needed.

Background: Transanal total mesorectal excision (TaTME) is an alternative for mid-low rectal cancer. In China, this procedure has been performed in high-volume centers with structured training curriculums. The efficacy of the TaTME structured training curriculums in China is still unclear. This multicenter study aimed to explore the effectiveness of the structured training curriculums in China. Methods: Seven high-volume centers in China participated in this study. The first 25 patients who underwent TaTME in each center were enrolled. In the cohort, patients were divided into 3 groups. The first 5 procedures (group 1) were performed under proctoring according to the requirement of structured training curriculums. The latter 20 cases without proctoring were split into 2 groups (10 cases in each group, groups 2 and 3) according to the order of operation date. The baseline characteristics, perioperative complications, and pathological outcomes were compared between groups 1 and 2, as well as between groups 2 and 3. Results: Symptomatic anastomotic leakage (AL) occurred in 18.6% of the patients in group 2 compared with 5.7% in group 1 (P1=0.08) and 5.0% in group 3 (P2=0.04). Seven (11.3%) patients in group 2 developed defecation disorders whereas no patients had this complication in group 3 (P2=0.02). Compared with group 2, the operative time was shorter (235 vs. 223 min, P2=0.40), while the rates of intraoperative complications (15.7% vs. 5.7%, P2=0.10), postoperative complications (31.3% vs. 25.7%, P2=0.06), AL (20.0% vs. 8.6%, P2=0.04), and positive distal resection margin (DRM) (7.5% vs. 2.9%, P2=0.27) were lower in group 3. Conclusions: The effect of the structured training curriculums was acceptable but needed further improvement. The prevalence of anastomosis-related complications and the quality control of specimens are still not optimal, and measures for refinement (for example, more cases under proctoring) are needed in the curriculums.

Risk factors of chylous ascites and its relationship with long-term prognosis in laparoscopic D3 lymphadenectomy for right colon cancer.

BACKGROUND: Chylous ascites (CA) after laparoscopic D3 lymphadenectomy for right colon cancer is not rare. However, the risk factors for CA have not been fully explored. Few studies have investigated the effect of CA on long-term prognosis. METHODS: The clinical data of patients with right colon cancer who underwent laparoscopic D3 lymphadenectomy in five centers from January 2013 to December 2018 were retrospectively collected. Univariate and multivariate analyses were performed to determine the clinicopathological factors associated with CA. Then, the long-term prognosis of patients with and without CA was compared by propensity score matching and Kaplan-Meier survival analysis. RESULTS: The incidence of CA was 4.4% (48/1090). Pathological T stage (p = 0.025), dissection along the left side of the superior mesenteric artery (p < 0.001) and the number of retrieved lymph nodes (p < 0.001) were independent risk factors for CA. After propensity score matching, 48 patients in the CA group and 353 patients in the non-CA group were enrolled. Kaplan-Meier survival analysis indicated that CA was not associated with overall survival (p = 0.454) and disease-free survival (p = 0.163). In patients with stage III right colon cancer, there were no significant differences in overall survival (p = 0.501) and disease-free survival (p = 0.254). CONCLUSIONS: Pathological T stage, number of retrieved lymph nodes, and left side dissection along the superior mesenteric artery were independent risk factors for CA after laparoscopic D3 lymphadenectomy. CA does not impair the oncological outcomes of patients.