Glycosylation and Its Role in Immune Checkpoint Proteins: From Molecular Mechanisms to Clinical Implications.

Immune checkpoint proteins have become recent research hotspots for their vital role in maintaining peripheral immune tolerance and suppressing immune response function in a wide range of tumors. Therefore, investigating the immunomodulatory functions of immune checkpoints and their therapeutic potential for clinical use is of paramount importance. The immune checkpoint blockade (ICB) is an important component of cancer immunotherapy, as it targets inhibitory immune signaling transduction with antagonistic antibodies to restore the host immune response. Anti-programmed cell death-1 (PD-1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies are two main types of widely used ICBs that drastically improve the survival and prognosis of many patients with cancer. Nevertheless, the response rate of most cancer types remains relatively low due to the drug resistance of ICBs, which calls for an in-depth exploration to improve their efficacy. Accumulating evidence suggests that immune checkpoint proteins are glycosylated in forms of N-glycosylation, core fucosylation, or sialylation, which affect multiple biological functions of proteins such as protein biosynthesis, stability, and interaction. In this review, we give a brief introduction to several immune checkpoints and summarize primary molecular mechanisms that modulate protein stability and immunosuppressive function. In addition, newly developed methods targeting glycosylation on immune checkpoints for detection used to stratify patients, as well as small-molecule agents disrupting receptor-ligand interactions to circumvent drug resistance of traditional ICBs, in order to increase the clinical efficacy of immunotherapy strategies of patients with cancer, are also included to provide new insights into scientific research and clinical treatments.

Revolutionizing sphincter preservation in ultra-low rectal cancer: exploring the potential of transanal endoscopic intersphincteric resection (taE-ISR): a propensity score-matched cohort study.

BACKGROUND: With the optimization of neoadjuvant treatment regimens, the indications for intersphincteric resection (ISR) have expanded. However, limitations such as unclear surgical field, impaired anal function, and failure of anal preservation still exist. Transanal total mesorectal excision can complement the drawbacks of ISR. Therefore, this study combined these two techniques and proposed transanal endoscopic intersphincteric resection (taE-ISR), aiming to explore the value of this novel technique in anal preservation for ultra-low rectal cancer. MATERIAL AND METHODS: Four high-volume centres were involved. After 1:1 propensity score-matching, patients with ultra-low rectal cancer underwent taE-ISR ( n =90) or ISR ( n =90) were included. Baseline characteristics, perioperative outcomes, pathological results, and follow-up were compared between the two groups. A nomogram model was established to assess the potential risks of anal preservation. RESULTS: The incidence of adjacent organ injury (0.0% vs. 5.6%, P =0.059), positive distal resection margin (1.1% vs. 8.9%, P =0.034), and incomplete specimen (2.2% vs. 13.3%, P =0.012) were lower in taE-ISR group. Moreover, the anal preservation rate was significantly higher in taE-ISR group (97.8% vs. 82.2%, P =0.001). Patients in the taE-ISR group showed a better disease-free survival ( P =0.044) and lower cumulative recurrence ( P =0.022) compared to the ISR group. Surgery procedure, tumour distance, and adjacent organ injury were factors influencing anal preservation in patients with ultra-low rectal cancer. CONCLUSION: taE-ISR technique was safe, feasible, and improved surgical quality, anal preservation rate and survival outcomes in ultra-low rectal cancer patients. It held significant clinical value and showed promising application prospects for anal preservation.

Natural orifice specimen extraction surgery versus small-incision assisted laparoscopic radical right hemicolectomy.

Conventional laparoscopic-assisted right hemicolectomy requires a small abdominal incision to extract the specimen, which becomes an important source of postoperative complications and impairs perioperative experience. Transvaginal natural orifice specimen extraction surgery (NOSES VIIIA) avoids this small incision by extracting the specimen through the vagina. Here we describe the design of a multicenter, open-label, parallel, noninferior, phase III randomized controlled trial (NCT05495048). The aim of this study is to confirm that the NOSES VIIIA procedure is not inferior to small-incision assisted right hemicolectomy in long-term oncological efficacy. A total of 352 female patients with right colon adenocarcinoma/high-grade intraepithelial neoplasia will be randomly assigned to the NOSES VIIIA arm and the small-incision arm in a 1:1 ratio. The primary end point of this trial is 3 year disease-free survival. Clinical Trial Registration: NCT05495048 (ClinicalTrials.gov).

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.

Safety and feasibility of laparoscopic surgery for colorectal and gastric cancer under the Chinese multi-site practice policy: admittance standards of competence are needed.

Background: The multi-site practice (MSP) policy has been practiced in China over 10 years. This study aimed to investigate the safety and feasibility of performing laparoscopic surgery for colorectal cancer (LSCRC) and gastric cancer (LSGC) under the Chinese MSP policy. Methods: We collected and analysed the data from 1,081 patients who underwent LSCRC or LSGC performed by one gastrointestinal surgeon in his original hospital (n = 573) and his MSP institutions (n = 508) between January 2017 and December 2020. Baseline demographics, intraoperative outcomes, post-operative recovery, and pathological results were compared between the original hospital and MSP institutions, as well as between MSP institutions with and without specific competence (surgical skill, operative instrument, perioperative multi-discipline team). Results: In our study, 690 patients underwent LSCRC and 391 patients underwent LSGC. The prevalence of post-operative complications was comparable for LSCRC (11.5% vs 11.1%, P = 0.89) or LSGC (15.2% vs 12.6%, P = 0.46) between the original hospital and MSP institutions. However, patients in MSP institutions without qualified surgical assistant(s) and adequate instruments experienced longer operative time and greater intraoperative blood loss. The proportion of patients with inadequate lymph-node yield was significantly higher in MSP institutions than in the original hospital for both LSCRC (11.5% vs 21.2%, P < 0.01) and LSGC (9.8% vs 20.5%, P < 0.01). Conclusion: For an experienced gastrointestinal surgeon, performing LSCRC and LSGC outside his original hospital under the MSP policy is safe and feasible, but relies on the precondition that the MSP institutions are equipped with qualified surgical skills, adequate operative instruments, and complete perioperative management.

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.