BACKGROUND AND AIMS:An increasing number of patients with rectal cancer who respond well to neoadjuvant chemoradiotherapy (nCRT) are being considered for organ preservation programs. However, due to the lack of high-level evidence, the survival outcomes of the organ preservation programs are still full of controversy and uncertainty. METHODS:To assess the effects of total mesorectal excision (TME) surgery, watch-and-wait (W&W), and local excision (LE) on long-term outcomes after nCRT, we searched PubMed, Embase, and Web of Science for articles published between 1 January 2010, and 31 December 2023. RESULTS:We found 7029 pieces of literature, of which 26 studies met the inclusion criteria, and recruited 2778 participants in the network meta-analysis. Risk of bias assessment showed that most included studies had a low risk of bias. Low-certainty evidence suggests that the TME group was significantly superior to all other interventions for the 2-year local regrowth rate. (W&W group [OR, 0.20; 95% CI, 0.12-0.35], LE group compared with TME group [3.00; 1.60-5.80]). There was no significant difference in the 2-year local regrowth rate between W&W and LE group (OR, 0.60; 95% CI, 0.32-1.20). There was high to moderate certainty evidence that at 3 years, the W&W group had a significant advantage in overall survival compared with the TME group (OR, 0.37; 95% CI, 0.09-0.95). After 5 years, no significant difference in overall survival was found between the 3 treatment modalities. CONCLUSIONS:We concluded that TME achieved the most significant reduction in 2-year local regrowth rates. However, the W&W strategy and LE demonstrated noninferiority to TME in long-term survival outcomes.

Colorectal cancer has the highest mortality rate of all digestive system diseases. Considering the debate about cytokines and biases that exist in traditional observational study designs, we performed a two-sample Mendelian randomization (MR) analysis to explore the association of circulating cytokines with CRC risk. In this study, we used cytokine genetic variants from a recently published genome-wide association study (GWAS) including 14,824 European-ancestry participants. Summary-level data for colorectal cancer were obtained from genome-wide association analyses of the FinnGen consortium. In addition, we conducted independent supplementary analyses using genetic variation data of colorectal cancer and cytokines from a large public GWAS in 2021. Among 91 circulating factors, we only found IL-12B to be significantly associated with CRC risk (odds ratio [OR]: 1.19; 95% confidence interval [CI]: 1.00-1.42; p = .046). We used 2021 data for analysis and found that higher Interleukin-12p70 levels (IL-12p70) were revealed to have a significant positive association with CRC risk (OR: 1.27; 95% CI: 1.13-1.43; p < 1.22 × 10-3). Moreover, CRC was suggestively correlated with an elevated level of vascular endothelial growth factor (VEGF) (OR: 1.17; 95% CI: 1.02-1.35; p = .026), macrophage colony-stimulating factor (M-CSF) (OR: 0.85; 95% CI: 0.76-0.96; p = .005), IL-13 (OR: 1.15; 95% CI: 1.02-1.30; p = .028), IL-10 (OR: 1.23; 95% CI: 1.01-1.49; p = .037), and IL-7 (OR: 1.19; 95% CI: 1.02-1.39; p = .024). Our MR studies support that one cytokine IL-12 is significantly associated with CRC risk and that five cytokines VEGF, M-CSF, IL-13, IL-10, and IL-7 are associated with CRC risk.

Some patients may develop adverse events during neoadjuvant chemoradiotherapy combined with immunotherapy, influencing response rates. The roles of intestinal microbiome and its metabolites in therapeutic adverse events remain unclear. We collected baseline fecal samples from 21 patients with adverse events (AE group) and 11 patients without adverse events (Non-AE group). Their microbiota and metabolome were characterized using metagenomic shotgun sequencing and untargeted metabolomics. At the species level, the gut microbiota in the Non-AE group exhibits significantly higher abundance of Clostridium sp. Alistipes sp. and lower abundance of Lachnoclostridium sp. Weissella cibaria, Weissella confusa, compared to the AE group (p < .05). A total of 58 discriminative metabolites were identified between groups. Beta-alanine metabolism was scattered. Boc-beta-cyano-L-alanine and CoQ9 were significantly increased in patients without adverse events, while linoleic acid increased in patients with adverse events. The increased Alistipes sp. in the Non-AE group was positively correlated with Boc-beta-cyano-L-alanine and negatively correlated with linoleic acid (p < .05). We constructed a combined microbiome-metabolite model to distinguish Non-AE and AE patients with an AUC of 0.963 via the random forest algorithm. Our findings provided a novel insight into the interplay of multispecies microbial cluster and metabolites of rectal patients with adverse events in neoadjuvant chemoradiotherapy combined with immunotherapy. These microbiota and metabolites deserve further investigations to reveal their roles in adverse events, providing clues for better treatment scenarios.Trial registration number: ClinicalTrials.gov identifier: NCT05368051

The treatment of diabetic wounds is a major challenge faced by the medical system, and there is a growing interest in developing innovative therapies to accelerate wound healing. Regenerative medicine with cells has shown promising potential in skin repair, with the regenerative properties primarily attributed to the paracrine effects of secreted products, including exosomes. Compared to cell-based approaches, using exosomes as a cell-free therapy for chronic wounds has several advantages. Exosomes can regulate intercellular communication by releasing their contents, including mRNA, miRNA, lipids, and proteins, which further promote wound healing. Exosomes are well explored in biomedical application owing to their advantages such as their biocompatibility and low immunogenicity. However, the common method of exosome administration is through injection, but due to their rapid clearance rate in the body, maintaining the necessary therapeutic concentration around the wound is challenging. Therefore, it is necessary to develop a new biocompatible scaffold as a carrier for extracellular vesicles, allowing them to sustain the therapeutic concentration at chronic non-healing wound sites and continuously promote wound healing. Engineered exosomes are kinds of exosomes modified with internal treated molecules, surface decoration or delivered through engineered platform. In addition, some researchers have further processed and modified exosomes, known as engineered exosomes, with internal treated molecules, surface decoration, or delivery through engineered platforms. Compared to regular exosomes, engineered exosomes have greater advantages in promoting wound healing. In this review, we summarize the molecular mechanisms of exosomes from different sources with varying modifications in wound healing. Advantages and limitations of different engineered exosomes for chronic wound repair were also discussed. Finally, we highlight the challenges and future development directions for translating our knowledge of engineered exosomes into clinical practice.

The morbidity and mortality of gastrointestinal tumours remain high worldwide. Surgical resection is currently the most critical radical therapeutic schedule, while postoperative complications and sentinel lymph node (SLN) identification are closely related to the outcome. Indocyanine green (ICG)-mediated fluorescence imaging is increasingly being used in gastrointestinal surgery. It has been embraced by various surgical disciplines as a potential method to improve lymph node detection and enhance surgical field visualization. ICG can passively concentrate in SLN because of enhanced permeation and retention effects. After excitation by near-infrared light devices, SLN can display higher intensity fluorescence, helping visualization for better lymph node dissection. In addition, visual assessment of intestinal blood flow through ICG may reduce the incidence of anastomotic leakage. Although it has good clinical application, ICG-imaging still faces some problems, such as a higher false-negative rate, poorly targeted biodistribution, and lower fluorescence contrast, due to the lack of active tumour targeting. Thus, different ICG-coupled nanoparticles with inherent characteristics or functional modification-enhanced SLN identification features for gastrointestinal cancers bring benefit through active tumour targeting, superior tumour-background ratio, and high resolution. Nano-ICG combined with potential substances, including enhanced imaging contrast and/or combination therapy (chemotherapy, targeted therapy, immunotherapy, etc.), have been packaged and accumulated in the tumour area through active targeting for multimodal imaging and treatment. In this review, we outline the intraoperative application and possible future nanodirections of ICG in gastrointestinal cancer. The prospects and challenges of nano-ICG diagnostic and therapeutic methods in clinical applications are also discussed.

Introduction Anastomotic leakage (AL) is defined as the failure of complete healing or disruption of the anastomosis subsequent to rectal cancer surgery, resulting in the extravasation of intestinal contents into the intra-abdominal or pelvic cavity. It is a serious complication of rectal cancer surgery, accounting for a considerable increase in morbidity and mortality. The use of fluorescence imaging technology in surgery allows surgeons to better evaluate blood perfusion. However, the conclusions of some existing studies are not consistent, so a consensus on whether the near-infrared indocyanine green (NIR–ICG) imaging system can reduce the incidence of AL is needed.Methods This POSTER trial is designed as a multicentre, prospective, randomised controlled clinical study adhering to the “population, interventions, comparisons, outcomes (PICO)” principles. It is scheduled to take place from August 2019 to December 2024 across eight esteemed hospitals in China. The target population consists of patients diagnosed with rectal cancer through pathological confirmation, with tumours located≤10 cm from the anal verge, eligible for laparoscopic surgery. Enrolled patients will be randomly assigned to either the intervention group or the control group. The intervention group will receive intravenous injections of ICG twice, with intraoperative assessment of anastomotic blood flow using the near-infrared NIR–ICG system during total mesorectal excision (TME) surgery. Conversely, the control group will undergo conventional TME surgery without the use of the NIR-ICG system. A 30-day follow-up period postoperation will be conducted to monitor and evaluate occurrences of AL. The primary endpoint of this study is the incidence of AL within 30 days postsurgery in both groups. The primary outcome investigators will be blinded to the application of ICG angiography. Based on prior literature, we hypothesise an AL rate of 10.3% in the control group and 3% in the experimental group for this study. With a planned ratio of 2:1 between the number of cases in the experimental and control groups, and an expected 20% lost-to-follow-up rate, the initial estimated sample size for this study is 712, comprising 474 in the experimental group and 238 in the control group.Ethics and dissemination This study has been approved by Ethics committee of Beijing Friendship Hospital, Capital Medical University (approval number: 2019-P2-055-02). The results will be disseminated in major international conferences and peer-reviewed journals.Trial registration number NCT04012645.

Immune checkpoint therapy, such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade, has achieved remarkable results in treating various tumors. However, most cancer patients show a low response rate to PD-1/PD-L1 blockade, especially those with microsatellite stable/mismatch repair-proficient colorectal cancer subtypes, which indicates an urgent need for new approaches to augment the efficacy of PD-1/PD-L1 blockade. Cholesterol metabolism, which involves generating multifunctional metabolites and essential membrane components, is also instrumental in tumor development. In recent years, inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine proteinase that regulates cholesterol metabolism, has been demonstrated to be a method enhancing the antitumor effect of PD-1/PD-L1 blockade to some extent. Mechanistically, PCSK9 inhibition can maintain the recycling of major histocompatibility protein class I, promote low-density lipoprotein receptor-mediated T-cell receptor recycling and signaling, and modulate the tumor microenvironment (TME) by affecting the infiltration and exclusion of immune cells. These mechanisms increase the quantity and enhance the antineoplastic effect of cytotoxic T lymphocyte, the main functional immune cells involved in anti-PD-1/PD-L1 immunotherapy, in the TME. Therefore, combining PCSK9 inhibition therapy with anti-PD-1/PD-L1 immunotherapy may provide a novel option for improving antitumor effects and may constitute a promising research direction. This review concentrates on the relationship between PCSK9 and cholesterol metabolism, systematically discusses how PCSK9 inhibition potentiates PD-1/PD-L1 blockade for cancer treatment, and highlights the research directions in this field.

Background: Accurate evaluation of the response to preoperative treatment enables the provision of a more appropriate personalized therapeutic schedule for locally advanced rectal cancer (LARC), which remains an enormous challenge, especially neoadjuvant immunotherapy plus chemoradiotherapy (nICRT). Methods: This prospective, multicenter cohort study enrolled patients with LARC from 6 centers who received nICRT. The dynamic variation in the gut microbiome during nICRT was evaluated. A species-level gut microbiome prediction (SPEED) model was developed and validated to predict the pathological complete response (pCR) to nICRT. Findings: A total of 50 patients were enrolled, 75 fecal samples were collected from 33 patients at different time points, and the pCR rate reached 42.4% (14/33). Lactobacillus and Eubacterium were observed to increase after nICRT. Additionally, significant differences in the gut microbiome were observed between responders and non-responders at baseline. Significantly higher abundances of Lachnospiraceae bacterium and Blautia wexlerae were found in responders, while Bacteroides, Prevotella, and Porphyromonas were found in non-responders. The SPEED model showcased a superior predictive performance with areas under the curve of 98.80% (95% confidence interval [CI]: 95.67%-100%) in the training cohort and 77.78% (95% CI: 65.42%-88.29%) in the validation cohort. Conclusions: Programmed death 1 (PD-1) blockade plus concurrent long-course CRT showed a favorable pCR rate and is well tolerated in microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) patients with LARC. The SPEED model can be used to predict the pCR to nICRT based on the baseline gut microbiome with high robustness and accuracy, thereby assisting clinical physicians in providing individualized management for patients with LARC. Funding: This research was funded by the China National Natural Science Foundation (82202884).

e15612 Background: Thymalfasin, as an immunomodulator, can enhance the anti-tumor effects of T cells, NK cells, and macrophages. This study explored the efficacy and safety of a new adjuvant treatment regimen for rectal cancer, combining thymalfasin with chemoradiotherapy and the PD-1 inhibitor tislelizumab, and its impact on the immune microenvironment. Methods: This retrospective study enrolled 26 patients with locally advanced rectal cancer from March 2021 to December 2022. Thirteen patients received long-course concurrent chemoradiotherapy combined with concurrent tislelizumab treatment, and thirteen received thymalfasin combined with long-course chemoradiotherapy and concurrent tislelizumab treatment (radiotherapy: 50 Gy/25 f; capecitabine, 1000mg/m2, bid; tislelizumab: 200mg, every 21 days, 3 cycles; Thymalfasin: 1.6mg, biw). The postoperative pathological complete response rate (ypT0N0M0), tumor regression grade (AJCC 8th Version), and adverse event (CTCAE 4.0) incidence were assessed, along with changes in the immune microenvironment before and after treatment using multiplex immunofluorescence staining. Results: The pathological complete response rates observed postoperatively were 61.5% in the treatment group, compared to 38.5% in the control group. The distribution of tumor regression grades 0, 1, 2, and 3 was 69.2%, 15.4%, 15.4%, 0% in the treatment group respectively, and 38.5%, 38.5%, 7.7%, 15.4%, in the control group respectively. The adverse event rates reached 84.6% in the treatment group and 76.9% in the control group, with all events classified as either grade 1 or 2 according to the CTCAE 4.0. Significant reductions in CD4+PD1+ cell density (p < 0.001), CD8+PD1+ cell density (p = 0.024), CD68+ cell density (p = 0.007), the CD4/CD8 ratio (p < 0.001), and the CD68+CD86+/CD68+CD163+ ratio (p = 0.012) were demonstrated through multiplex immunofluorescence following neoadjuvant treatment. The treatment group exhibited significant decreases in CD8+PD1+ cell density (p = 0.025) and CD68+CD163+ cell density (p = 0.021) when compared to the control group. Conclusions: Thymalfasin combined with chemoradiotherapy and tislelizumab as a neoadjuvant treatment regimen for patients with locally advanced lower rectal cancer has shown favorable efficacy and safety. Neoadjuvant chemoradiotherapy combined with immunotherapy restored T cell function and reduced the proportion of tumor-associated macrophages, but macrophages polarized towards an M2-like phenotype. Thymalfasin may play a role by synergizing with the PD-1 inhibitor to restore cytotoxic T cell function and block macrophage polarization towards M2 cells. Clinical trial information: NCT06024356 .

Programmed cell death protein (PD-1) is an important immunosuppressive molecule, which can inhibit interaction between PD-1 and its ligand PD-L1, further enhancing the T cell response and anti-tumor activity, which is called immune checkpoint blockade. Immunotherapy, represented by immune checkpoint inhibitors, has opened up a new era of tumor treatment and is gradually being applied to colorectal cancer recently. Immunotherapy was reported could achieve a high objective response rate (ORR) for colorectal cancer with high microsatellite instability (MSI), thus opening up a new era of colorectal cancer immunotherapy. Along with the increasing use of PD1 drugs in colorectal cancer, we should pay more attention to the adverse effects of these immune drugs while seeing the hope. Immune-related adverse events (irAEs) caused by immune activation and immune homeostasis during anti-PD-1/PD-L1 therapy can affect multi-organ and even be fatal in serious cases. Therefore, understanding irAEs is essential for their early detection and appropriate management. In this article, we review the irAEs that occur during the treatment of colorectal cancer patients with PD-1/PD-L1 drugs, analyze the current controversies and challenges, and point out future directions that should be explored, including exploring efficacy predictive markers and optimizing the paradigm of individualized immunotherapy.

Background: This study aimed to assess the Caprini score in predicting venous thromboembolism (VTE) events and develop a risk assessment model to predict the occurrence of short-term VTE after colorectal cancer surgery. Methods: The study included 181 patients who underwent colorectal cancer surgery at Beijing Friendship Hospital, from October 2020 to May 2022. The results of the Caprini score 24 h after surgery were recorded to evaluate its predictive value. Multifactorial staging was used to determine independent risk factors for VTE, and nomogram models were constructed based on these factors. Sixty-one patients at Beijing Chaoyang Hospital were used for external validation. Results: The incidence of VTE after colorectal cancer was 17.6% in 32 patients. Age (odds ratio [OR] 1.106, 95% confidence interval [CI] 1.049–1.167, P < 0.001), sex (female) (OR 2.981, 95% CI 1.176–7.557, P = 0.021), and cardiovascular disease [CVD] (OR 5.611, 95% CI 2.043–15.413, P = 0.001) were independent risk factors for postoperative VTE. The nomogram model showed good predictive performance (area under the curve [AUC], 0.837 [95% CI, 0.762–0.917]; Nagelkerke R 2 , 0.347; Brier score, 0.106) compared with the Caprini score (AUC, 0.760 [95% CI, 0.674–0.847]; Nagelkerke R 2 , 0.104; Brier score, 0.131). The decision curve analysis showed that the nomogram model had a better net clinical benefit. Conclusions: The Caprini score is moderately efficient in predicting the occurrence of VTE after colorectal cancer surgery, and the 3-item nomogram model can be used as a predictive tool in VTE prevention decisions after colorectal cancer surgery.

Transanal total mesorectal excision (taTME) is a promising surgical procedure for middle and low rectal cancer; however, it is linked to significant morbidity. This study aimed to determine the incidence of postoperative surgical complications and anastomotic leakage following taTME and to identify their associated risk factors. The prospective clinical data of 114 patients, who underwent taTME and primary anastomosis for mid-low rectal cancer between November 2016 and June 2022, were retrospectively analyzed. Univariate and multivariate analyses were performed to identify clinical characteristics and risk factors for predicting surgical complications and anastomotic leakage. Surgical complications occurred in 40 (35.1%) patients within the first 30 days following surgery. Based on the Clavien–Dindo classification, minor complications (Clavien–Dindo grades I + II) accounted for 30.7%, while major complications (Clavien–Dindo grades III + IV) accounted for only 4.4%. None of the patients died within 30 days. The incidence of anastomotic leakage was 15.8%: 4.4% as grade A (5 cases), 9.6% as grade B (11 cases), and 1.8% as grade C (2 cases). Preoperative T3-4 was identified as an independent risk factor for surgical complications (p = 0.031) by multivariate analysis. American Society of Anesthesiology score ≥ 3 (P = 0.021) and incomplete total mesorectal excision specimens (P = 0.030) were significantly associated with the risk of anastomotic leakage. In this study, the incidence of surgical complications and anastomotic leakage in taTME aligned with previously reported rates. Preoperative T3-4 was significantly associated with surgical complications. American Society of Anesthesiology score ≥ 3 and incomplete TME specimens independently increased the risk of anastomotic leakage.

PurposeSurgical complications following laparoscopic rectal cancer surgery remain a major clinical problem. The prognostic nutritional index (PNI) is reportedly associated with postoperative outcomes. We aimed to evaluate the correlation between PNI and short-term surgical complications in patients with rectal cancer after laparoscopic surgery.MethodsThe prospective clinical data of 225 patients with rectal cancer receiving laparoscopic surgery between January 2021 and April 2022 were retrospectively analyzed. The cut-off values and diagnostic accuracy of PNI preoperatively and on postoperative day (POD) 1 were determined using receiver operating characteristic (ROC) curves. Univariate and multivariate analyses were performed to identify clinical characteristics and risk factors for surgical complications.ResultsIn total, 81 (36.0%) patients developed surgical complications. The optimal cut-off value for preoperative PNI was 40.15, and that for PNI on POD 1 was 35.28. The DeLong test found no statistically between–group difference in the area under the ROC curve (P = 0.598). Multivariate analysis identified that a preoperative PNI ≤40.15 [odds ratio (OR): 2.856, 95% confidence interval (CI): 1.287–6.341, P = 0.010] and PNI on POD 1 ≤35.28 (OR: 2.773, 95% CI: 1.533–5.016, P = 0.001) were independent risk factors for surgical complications. Patients with a preoperative PNI ≤40.15 or PNI on POD 1 ≤35.28 were more likely to have surgical complications after laparoscopic surgery for rectal cancer (61.1% vs. 31.2%, P = 0.001; 53.0% vs. 28.9%, P = 0.001).ConclusionPreoperative and POD 1 PNI were independent predictors of short-term surgical complications after laparoscopic surgery for rectal cancer.

Immunotherapies, especially the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, have revolutionized the therapeutic strategies of various cancers. As for colorectal cancer (CRC), the current clinical application of PD-1/PD-L1 inhibitors are mainly used according to the mutation pattern, which is categorized into deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H) and proficient mismatch repair (pMMR), or non-high levels of microsatellite instability (non-MSI-H). PD-1/PD-L1 inhibitors have been proven to have favorable outcomes against dMMR/MSI-H CRC because of more T-cell infiltration into tumor tissues. Nevertheless, the effectiveness of PD-1/PD-L1 inhibitors in pMMR/non-MSI-H CRC is still uncertain. Because of the quite-lower proportion of dMMR/MSI-H in CRC, PD-1/PD-L1 inhibitors have been reported to combine with other antitumor treatments including chemotherapy, radiotherapy, and targeted therapy for better therapeutic effect in recent clinical trials. Neoadjuvant therapy, mainly including chemotherapy and radiotherapy, not only can reduce clinical stage but also benefit from local control, which can improve clinical symptoms and the quality of life. Adding immunotherapy into neoadjuvant therapy may change the treatment strategy of primary resectable or some metastatic CRC. In this review, we focus on the development of neoadjuvant anti-PD-1/PD-L1 therapy and discuss the future perspectives in CRC.

Background Prediction and management of short-term postoperative complications in patients with colorectal cancer are essential in postoperative rehabilitation. Through CT scan images, we can easily measure some parameters of abdomen anatomic characteristics. This study aimed to assess whether there is a relationship between the abdomen anatomic characteristics and short-term postoperative complications. Materials and methods We conducted a retrospective study. Eighty patients in each complication group and non-complication group were recruited with propensity score match. Demographics, perioperative laboratory results and surgical information were collected and compared between groups with univariate analysis. Significant elements were brought into subsequent logistic regression analysis and ROC analysis for further identification. Results Univariate analysis showed that preoperative white blood cells, preoperative neutrophil counts, rectus abdominis thickness (RAT), subcutaneous fat thickness (SFT), and abdomen depth (AD) were significantly different between the complication group and non-complication group. Logistic regression analysis demonstrated that higher RAT ( p = 0.002), SFT ( p < 0.001) and AD ( p < 0.001) independently predicted the incidence of short-term postoperative complications. Conclusions In this study on patients undergoing radical resection of colorectal cancer, abdomen anatomic characteristics including higher RAT, SFT and AD are associated with an increased risk of short-term postoperative complications.