Mitochondrial DNA Copy Number as a Biomarker for Guiding Adjuvant Chemotherapy in Stages II and III Colorectal Cancer Patients with Mismatch Repair Deficiency: Seeking Benefits and Avoiding Harms.

BACKGROUND: Colorectal cancer (CRC) patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) status are conventionally perceived as unresponsive to adjuvant chemotherapy (ACT). The mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA copy number (mtDNA-CN) expression. In light of previous findings indicating that the frequent truncating-mutation of TFAM affects the chemotherapy resistance of MSI CRC cells, this study aimed to explore the potential of mtDNA-CN as a predictive biomarker for ACT efficacy in dMMR CRC patients. METHODS: Levels of MtDNA-CN were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) in a cohort of 308 CRC patients with dMMR comprising 180 stage II and 128 stage III patients. Clinicopathologic and therapeutic data were collected. The study examined the association between mtDNA-CN levels and prognosis, as well as the impact of ACT benefit on dMMR CRC patients. Subgroup analyses were performed based mainly on tumor stage and mtDNA-CN level. Kaplan-Meier and Cox regression models were used to evaluate the effect of mtDNA-CN on disease-free survival (DFS) and overall survival (OS). RESULTS: A substantial reduction in mtDNA-CN expression was observed in tumor tissue, and higher mtDNA-CN levels were correlated with improved DFS (73.4% vs 85.7%; P = 0.0055) and OS (82.5% vs 90.3%; P = 0.0366) in dMMR CRC patients. Cox regression analysis identified high mtDNA-CN as an independent protective factor for DFS (hazard ratio [HR] 0.547; 95% confidence interval [CI] 0.321-0.934; P = 0.0270) and OS (HR 0.520; 95% CI 0.272-0.998; P = 0.0492). Notably, for dMMR CRC patients with elevated mtDNA-CN, ACT significantly improved DFS (74.6% vs 93.4%; P = 0.0015) and OS (81.0% vs 96.7%; P = 0.0017), including those with stage II or III disease. CONCLUSIONS: The mtDNA-CN levels exhibited a correlation with the prognosis of stage II or III CRC patients with dMMR. Elevated mtDNA-CN emerges as a robust prognostic factor, indicating improved ACT outcomes for stages II and III CRC patients with dMMR. These findings suggest the potential utility of mtDNA-CN as a biomarker for guiding personalized ACT treatment in this population.

Perineural invasion affects prognosis of patients undergoing colorectal cancer surgery: a propensity score matching analysis.

BACKGROUND: Tumour perineural invasion (PNI) is a predictor of poor prognosis, but its effect on the prognosis of patients with colorectal cancer (CRC) has not yet been elucidated. METHODS: This retrospective study used propensity score matching (PSM). The clinical case data of 1470 patients with surgically treated stage I-IV CRC at Wuhan Union Hospital were collected. PSM was used to analyse and compare the clinicopathological characteristics, perioperative outcomes, and long-term prognostic outcomes of the PNI(+) and PNI(-) groups. The factors influencing prognosis were screened using Cox univariate and multivariate analyses. RESULTS: After PSM, 548 patients were included in the study (n = 274 in each group). Multifactorial analysis showed that neurological invasion was an independent prognostic factor affecting patients' OS and DFS (hazard ratio [HR], 1.881; 95% confidence interval [CI], 1.35-2.62; P = 0.0001; HR, 1.809; 95% CI, 1.353-2.419; P < 0.001). Compared to PNI(+) patients without chemotherapy, those who received chemotherapy had a significant improvement in OS (P < 0.01). The AUROC curve of OS in the PNI(+) subgroup (0.802) was higher than that after PSM (0.743), while that of DFS in the PNI(+) subgroup (0.746) was higher than that after PSM (0.706). The independent predictors of PNI(+) could better predict the prognosis and survival of patients with PNI(+). CONCLUSIONS: PNI significantly affects the long-term survival and prognosis of patients with CRC undergoing surgery and is an independent risk factor for OS and DFS in patients with CRC undergoing surgery. Postoperative chemotherapy significantly improved the OS of PNI(+) patients.

Modified Naples prognostic score for evaluating the prognosis of patients with obstructive colorectal cancer.

BACKGROUND: Inflammatory, immune, and nutritional status are key factors in obstructive colorectal cancer (OCRC). This study aims to investigate the value of modified Naples prognostic score (M-NPS) in evaluating OCRC prognosis. METHODS: A total of 196 OCRC patients were retrospectively analyzed to construct M-NPS based on serum albumin (ALB), total cholesterol (CHOL), neutrophil:lymphocyte ratio (NLR), and lymphocyte:monocyte ratio (LMR), and then they were divided into three groups. The Kaplan-Meier (KM) method and Cox proportional hazard regression analysis were performed for overall survival (OS) and disease-free survival (DFS) of OCRC patients. RESULTS: Patients with high M-NPS had worse OS and DFS (P = 0.0001, P = 0.0011). Multivariate COX analysis showed that M-NPS was an independent prognostic factor for OCRC patients. Patients in the M-NPS 2 group had significantly worse OS (hazard ratio [HR] = 4.930 (95% confidence interval [95% CI], 2.217-10.964), P < 0.001) and DFS (HR = 3.508 (95% CI, 1.691-7.277), P < 0.001) than those in the 0 group. CONCLUSION: M-NPS was an independent prognostic factor for OCRC patients; it might provide a potential reference for immunonutritional intervention in patients with obstruction.

Endoscopic fully covered self-expandable metal stent and vacuum-assisted drainage to treat postoperative colorectal cancer anastomotic stenosis with fistula.

BACKGROUND: Digestive tract reconstruction is required after the surgical resection of a colorectal malignant tumor. Some patients may have concomitant anastomotic complications, such as anastomotic stenosis with fistula (ASF), postoperatively. Therefore, we evaluated the efficacy and safety of endoscopic fully covered self-expandable metal stent and homemade vacuum sponge-assisted drainage (FSEM-HVSD) for the treatment of ASF following the radical resection of colorectal cancer. METHODS: Patients treated with FESM-HVSD were prospectively analyzed and followed up for ASF following colorectal cancer treatment in our medical center from 2017 to 2021 for the observation and evaluation of its safety and efficacy. RESULTS: Fifteen patients with a mean age of 55.80 ± 11.08 years were included. Nine patients (60%) underwent protective ileostomy. All 15 patients were treated with endoscopic FSEM-HVSD. The median time from the index operation to the initiation of FSEM-HVSD was 80 ± 20.34 days in patients who underwent protective ileostomy versus 11.4 ± 4.4 days in those who did not. The average number of endoscopic treatments per patient was 5.70 ± 1.25 times. The mean length of hospital stay was 27.60 ± 4.43 days. FSEM-HVSD treatment was successful in 13 patients, and no patients had any complications. The follow-up time was 1 year. Twelve of 15 (80%) patients achieved prolonged clinical success after FSEM-HVSD treatment, 1 experienced anastomotic tumor recurrence and underwent surgery again, and 1 patient required balloon dilation for anastomotic stenosis recurrence. CONCLUSIONS: FSEM-HVSD is an effective, safe, and minimally invasive treatment for ASF following colorectal cancer treatment. This technique could be the preferred treatment strategy for patients with ASF.

Development and validation of a prognostic scoring system for patients with colorectal cancer hepato-pulmonary metastasis: a retrospective study.

BACKGROUND: Hepato-pulmonary metastasis of colorectal cancer (CRC) is a rare disease with poor prognosis. This study aims to establish a highly efficient nomogram model to predict overall survival (OS) and cancer-specific survival (CSS) in patients with colorectal cancer hepato-pulmonary metastasis (CRCHPM). METHODS: We retrospectively analyzed the data of patients with CRCHPM from SEER database and Wuhan Union Hospital Cancer Center (WUHCC). A total of 1250 CRCHPM patients were randomly assigned to the training, internal validation, and external validation cohorts from 2010 to 2016.Univariate and multivariate cox analysis were performed to identify independent clinicopathological predictors of OS and CSS, and a nomogram was constructed to predict OS and CSS in CRCHPM patients. RESULTS: A nomogram of OS was constructed based on seven independent predictors of age, degree of differentiation, T stage, chemotherapy, number of lsampled lymph nodes, number of positive lymph nodes, and tumor size. Nomogram showed favorable sensitivity in predicting OS at 1, 3 and 5 years, with area under the receiver operating characteristic curve (AUROC) values of 0.802, 0.759 and 0.752 in the training cohort;0.814, 0.769 and 0.716 in the internal validation cohort;0.778, 0.756 and 0.753 in the external validation cohort, respectively. A nomogram of CSS was constructed based on three independent predictors of T stage, chemotherapy, and tumor size. The AUROC values of 1, 3 and 5 years were 0.709,0.588,0.686 in the training cohort; 0.751, 0.648,0.666 in the internal validation cohort;0.781,0.588,0.645 in the external validation cohort, respectively. Calibration curves, Concordance index (C-index), and decision curve analysis (DCA) results revealed that using our model to predict OS and CSS is more efficient than other single clinicopathological characteristics. CONCLUSION: A nomogram of OS and CSS based on clinicopathological characteristics can be conveniently used to predict the prognosis of CRCHPM patients.

Application of nanotechnology in the early diagnosis and comprehensive treatment of gastrointestinal cancer.

Gastrointestinal cancer (GIC) is a common malignant tumour of the digestive system that seriously threatens human health. Due to the unique organ structure of the gastrointestinal tract, endoscopic and MRI diagnoses of GIC in the clinic share the problem of low sensitivity. The ineffectiveness of drugs and high recurrence rates in surgical and drug therapies are the main factors that impact the curative effect in GIC patients. Therefore, there is an urgent need to improve diagnostic accuracies and treatment efficiencies. Nanotechnology is widely used in the diagnosis and treatment of GIC by virtue of its unique size advantages and extensive modifiability. In the diagnosis and treatment of clinical GIC, surface-enhanced Raman scattering (SERS) nanoparticles, electrochemical nanobiosensors and magnetic nanoparticles, intraoperative imaging nanoparticles, drug delivery systems and other multifunctional nanoparticles have successfully improved the diagnosis and treatment of GIC. It is important to further improve the coordinated development of nanotechnology and GIC diagnosis and treatment. Herein, starting from the clinical diagnosis and treatment of GIC, this review summarizes which nanotechnologies have been applied in clinical diagnosis and treatment of GIC in recent years, and which cannot be applied in clinical practice. We also point out which challenges must be overcome by nanotechnology in the development of the clinical diagnosis and treatment of GIC and discuss how to quickly and safely combine the latest nanotechnology developed in the laboratory with clinical applications. Finally, we hope that this review can provide valuable reference information for researchers who are conducting cross-research on GIC and nanotechnology.

A nomogram based on pretreatment levels of serum bilirubin and total bile acid levels predicts survival in colorectal cancer patients.

BACKGROUND: Serum bilirubin and total bile acid (TBA) levels have been reported to be strongly associated with the risk and prognosis of certain cancers. Here, we aimed to investigate the effects of pretreatment levels of serum bilirubin and bile acids on the prognosis of patients with colorectal cancer (CRC). METHODS: A retrospective cohort of 1474 patients with CRC who underwent surgical resection between January 2015 and December 2017 was included in the study. Survival analysis was used to evaluate the predictive value of pretreatment levels of bilirubin and bile acids. X-Tile software was used to identify optimal cut-off values for total bilirubin (TBIL), direct bilirubin (DBIL) and TBA in terms of overall survival (OS) and disease-free survival (DFS). RESULTS: DBIL, TBIL, and TBA were validated as significant prognostic factors by univariate Cox regression analysis for both 3-year OS and DFS. Multivariate Cox regression analyses confirmed that high DBIL, TBIL and TBA levels were independent prognostic factors for both OS (HR: 0.435, 95% CI: 0.299-0.637, P < 0.001; HR: 0.436, 95% CI: 0.329-0.578, P < 0.001; HR: 0.206, 95% CI: 0.124-0.341, P < 0.001, respectively) and DFS (HR: 0.583, 95% CI: 0.391-0.871, P = 0.008; HR:0.437,95% CI: 0.292-0.655, P <0.001; HR: 0.634, 95% CI: 0.465-0.865, P = 0.004, respectively). In addition, nomograms for OS and DFS were established according to all significant factors, and the c-indexes were 0.819 (95% CI: 0.806-0.832) and 0.835 (95% CI: 0.822-0.849), respectively. CONCLUSIONS: TBIL, DBIL and TBA levels are independent prognostic factors in colorectal cancer patients. The nomograms based on OS and DFS can be used as a practical model for evaluating the prognosis of CRC patients.

Application of endoscopic technique in completely occluded anastomosis with anastomotic separation after radical resection of colon cancer: a case report and literature review.

BACKGROUND: Anastomosis-related complications are common after the radical resection of colon cancer. Among such complications, severe stenosis or completely occluded anastomosis (COA) are uncommon in clinical practice, and the separation of the anastomosis is even rarer. For such difficult problems as COA or anastomotic separation, clinicians tend to adopt surgical interventions, and few clinicians try to solve them through endoscopic operations. CASE PRESENTATION: In this article, we present a case of endoscopic treatment of anastomotic closure and separation after radical resection for sigmoid carcinoma. After imaging examination and endoscopic evaluation, we found that the patient had a COA accompanied by a 3-4 cm anastomotic separation. With the aid of fluoroscopy, we attempted to use the titanium clip marker as a guide to perform an endoscopic incision and successfully achieved recanalization. We used a self-expanding covered metal stent to bridge the intestinal canal to resolve the anastomotic separation. Finally, the patient underwent ileostomy takedown, and the postoperative recovery was smooth. The follow-up evaluation results showed that the anastomotic stoma was unobstructed. CONCLUSIONS: We reported the successful application of endoscopic technique in a rare case of COA and separation after colon cancer surgery, which is worth exploring and verifying through more clinical studies in the future.

The value of haematological parameters and serum tumour markers for predicting KRAS mutations in 784 Chinese colorectal cancer patients: a retrospective analysis.

BACKGROUND: Identifying the mutation status of KRAS is important for optimizing treatment in patients with colorectal cancer (CRC). The aim of this study was to investigate the predictive value of haematological parameters and serum tumour markers (STMs) for KRAS gene mutations. METHODS: The clinical data of patients with colorectal cancer from January 2014 to December 2018 were retrospectively collected, and the associations between KRAS mutations and other indicators were analysed. Receiver operating characteristic (ROC) curve analysis was performed to quantify the predictive value of these factors. Univariate and multivariate logistic regression models were applied to identify predictors of KRAS mutations by calculating the odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). RESULTS: KRAS mutations were identified in 276 patients (35.2%). ROC analysis revealed that age, CA12-5, AFP, SCC, CA72-4, CA15-3, FERR, CYFRA21-1, MCHC, and tumor location could not predict KRAS mutations (P = 0.154, 0.177, 0.277, 0.350, 0.864, 0.941, 0.066, 0.279, 0.293, and 0.053 respectively), although CEA, CA19-9, NSE and haematological parameter values showed significant predictive value (P = 0.001, < 0.001, 0.043 and P = 0.003, < 0.001, 0.001, 0.031, 0.030, 0.016, 0.015, 0.019, and 0.006, respectively) but without large areas under the curve. Multivariate logistic regression analysis showed that CA19-9 was significantly associated with KRAS mutations and was the only independent predictor of KRAS positivity (P = 0.016). CONCLUSIONS: Haematological parameters and STMs were related to KRAS mutation status, and CA19-9 was an independent predictive factor for KRAS gene mutations. The combination of these clinical factors can improve the ability to identify KRAS mutations in CRC patients.

Perineural invasion is associated with poor prognosis of colorectal cancer: a retrospective cohort study.

PURPOSE: Perineural invasion (PNI) is associated with poor prognosis in a variety of cancers. Our aim was to determine the clinicopathological factors associated with PNI in colorectal cancer (CRC) and its impact on patient survival. MATERIAL AND METHODS: The clinical data of 1412 patients diagnosed with CRC from July 2013 to July 2016 were retrospectively collected. PNI was determined based on hematoxylin-eosin staining. The relationships of PNI with various clinicopathological factors and prognosis were analyzed. RESULTS: The incidence of PNI in the entire cohort was 21.5%. PNI was significantly more common in patients with lower tumor differentiation, higher tumor stage, vascular invasion, TNM stage, tumor diameter, MMR/KRAS/NRAS/BRAF mutation, and more positive lymph nodes. Logistic regression analysis showed that T stage, vascular invasion, tumor diameter, and MMR were the main influencing factors of PNI. Cox regression analysis showed that poor tumor differentiation, N stage, TNM stage, PNI, and BRAF status were independent prognostic factors for OS. The OS, CSS, and PFS rate of the PNI (-) group was higher than that of the PNI (+) group, and the difference was statistically significant (P < 0.001). CONCLUSION: PNI in patients with colorectal cancer is significantly associated with T stage, TNM stage, vessel invasion, tumor diameter, MMR status, and BRAF mutation. PNI status is an independent prognostic factor for CRC. Assessing the postoperative PNI status may help predict prognosis and determine further treatment options for these patients.

Colon metal stents as a bridge to surgery had no significant effects on the perineural invasion: a retrospective study.

PURPOSE: The long-term oncological effects of self-expandable metallic stent (SEMS) as a "bridge to surgery" are contradictory, and perineural invasion was supposed to be enhanced by the stenting. In this retrospective study, we compared the perineural invasion and the oncological outcomes between the stent as a bridge to surgery (SBTS)- and emergency surgery (ES)-treated patients to evaluate the results of stenting on the perineural invasion. METHODS: The clinical data of patients with acute intestinal obstruction caused by colorectal cancer from January 2013 to January 2017 were retrospectively collected. Forty-three patients underwent semi-elective curative resection after endoscopic SEMS insertion, and sixty-three underwent ES. The adverse events and long-term follow-up outcomes were assessed. The clinicopathological characteristics, perineural invasion rates, and survival rates were compared between the two patient groups. RESULTS: Stent insertion resulted in significantly lower stoma rate (32.6% vs 46%; P = 0.03), post-operative overall complication rate (11.6% vs 28.6%, P = 0.038), and total hospital stay (17.07 ± 5.544 days vs 20.48 ± 7.372 days, P = 0.042). Compared with the ES group, there was no significant increase in the incidence of peripheral invasion in the SBTS group (39.5% vs 47.6%, P = 0.411). No significant difference was noted in the survival rate and long-term prognosis between the SEMS and ES groups (P = 0.964). The technical success rate was 95.6%, and the clinical success rate was 97.7%. CONCLUSIONS: Preoperative colon stenting was an effective transitional method for colorectal cancer patients with complete obstruction. Short-term stent implantation had no significant effect on perineural invasion in patients with CRC.

Long-term tumour outcomes of self-expanding metal stents as 'bridge to surgery' for the treatment of colorectal cancer with malignant obstruction: a systematic review and meta-analysis.

PURPOSE: To explore the long-term oncological results of self-expanding metal stents (SEMS) as a surgical transition compared with those of simple emergency surgery. METHODS: A systematic review of studies involving long-term tumour outcomes comparing SEMS with emergency surgery was conducted. All studies included information on 3-year and 5-year survival rates, 3-year and 5-year disease-free survival (DFS) rates, and local and overall recurrence rates; the results were expressed as odds ratios. RESULTS: Overall, 24 articles and 2508 patients were included, including 5 randomised controlled trials, 3 prospective studies, and 16 retrospective studies. The 3-year survival rate (odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.69-1.12, P = 0.05), 5-year survival rate (OR = 0.91, 95% CI 0.70-1.17, P = 0.67), 3-year DFS rate (OR = 1.14, 95% CI 0.91-1.42, P = 0.65), 5-year DFS rate (OR = 1.35, 95% CI 0.91-2.02, P = 0.17), overall recurrence rate (OR 1.04, 95% CI 0.77-1.41, P = 0.14), and local recurrence rate (OR 1.37, 95% CI 0.84-2.23, P = 0.92) were determined. There was no significant difference between the randomised and observational studies in the subgroup analysis, and the 5-year survival rate was higher in studies with a stent placement success rate of ≥ 95%. CONCLUSION: SEMS implantation was a viable alternative in malignant left colon obstruction as a transition to surgery; its long-term survival results, including 5-year DFS and overall survival, were equivalent to those of emergent surgery.

Oncological consequence of emergent resection of perforated colon cancer with complete obstruction after stent insertion as a bridge to surgery.

PURPOSE: Colonic perforation is a life-threatening complication after colonic stent insertion as a bridge to surgery for acute obstruction caused by colorectal cancer. The oncological consequence of colonic perforation after emergent surgical intervention was unknown. The aim of this short communication was to investigate whether or not the perforation and emergent surgery had obviously impact on the peritoneal recurrence and long-term survival of patients. METHODS: Data of the patients who underwent colorectal stenting as a bridge to surgery in 5 years from 2012 to 2017 was collected by the Endoscopical Surgery Group of Hubei. The perforated cases treated by emergent operation were retrospectively analyzed. RESULTS: During 5 years from 2012 to 2017, 116 cases of colorectal stenting as a bridge to surgery had been performed, and 7 patients had perforation after stent placement and treated by emergent surgery, including 1 case of synchronic liver metastasis treated by one-stage metastasectomy. One of the 7 patients died of septic shock after operation, and the remaining patients were followed up for 6-60 months. There was no evidence of abdominal implantation or extra-abdominal metastasis. CONCLUSION: This small case series implicated that colonic perforation after stent insertion for malignant colorectal obstruction treated by emergent surgery might not obviously increase the peritoneal implantation and metastasis.

Clinical Effectiveness of Endoscopic Stent Placement in Treatment of Acute Intestinal Obstruction Caused by Colorectal Cancer.

BACKGROUND Emergency endoscopic intestinal stenting has been applied with increasing frequency in colorectal cancer patients with acute intestinal obstruction. However, its clinical effectiveness as compared to emergency surgery remains controversial. MATERIAL AND METHODS The clinical data of 96 patients with acute intestinal obstruction caused by colorectal cancer from April 2012 to April 2018 were retrospectively collected. Statistical technique success rate, clinical success rate, operative time, average indwelling time of stent, complications, transition time to second-stage surgery, postoperative hospital stay, sputum rate, and postoperative infection rate were studied. RESULTS Endoscopic colonoscopy was successfully performed in 94 patients. The success rate of stent placement was 97.9%, and the average operative time was 35 minutes (range, 25-85 minutes). Forty-two patients underwent stage I colectomy after relief of the obstruction. The average stent retention time was 7 days (range, 5-15 days). Two patients suffered from anastomotic infection. Their intestinal preparation time, hospital stay, fistula rate, and infection rate were lower than those of patients undergoing emergency operation for colon cancer intestinal obstruction. A total of 52 patients with colon cancer underwent palliative stent placement. Three patients had complications, including 1 case of stent displacement in the palliative care group and 2 cases with perforation in the bridge surgery group. CONCLUSIONS Emergency endoscopic placement of an intestinal stent is safe and effective in the treatment of patients with acute intestinal obstruction caused by colorectal cancer. It is also a safe and simple procedure for patients receiving advanced palliative treatment, which greatly improves their quality of life and is easy for patients' families to accept.

ZBP1-mediated apoptosis and inflammation exacerbate steatotic liver ischemia/reperfusion injury.

Steatotic donor livers are becoming more and more common in liver transplantation. However, the current use of steatotic grafts is less acceptable than normal grafts due to their higher susceptibility to ischemia/reperfusion (I/R) injury. To investigate the mechanism underlying the susceptibility of steatotic liver to I/R injury, we detected cell death markers and inflammation in clinical donor livers and animal models. We found that caspase-8-mediated hepatic apoptosis is activated in steatotic liver I/R injury. However, ablation of caspase-8 only slightly mitigated steatotic liver I/R injury without affecting inflammation. We further demonstrated that RIPK1 kinase induces both caspase-8-mediated apoptosis and cell death-independent inflammation. Inhibition of RIPK1 kinase significantly protects against steatotic liver I/R injury by alleviating both hepatic apoptosis and inflammation. Additionally, we found that RIPK1 activation is induced by Z-DNA binding protein 1 (ZBP1) but not the canonical TNF-α pathway during steatotic liver I/R injury. Deletion of ZBP1 substantially decreases the steatotic liver I/R injury. Mechanistically, ZBP1 is amplified by palmitic acid-activated JNK pathway in steatotic livers. Upon I/R injury, excessive reactive oxygen species trigger ZBP1 activation by inducing its aggregation independent of the Z-nucleic acids sensing action in steatotic livers, leading to the kinase activation of RIPK1 and the subsequent aggravation of liver injury. Thus, ZBP1-mediated RIPK1-driven apoptosis and inflammation exacerbate steatotic liver I/R injury, which could be targeted to protect steatotic donor livers during transplantation.

Fumarate Hydratase Enhances the Therapeutic Effect of PD-1 Antibody in Colorectal Cancer by Regulating PCSK9.

Despite the notable achievements of programmed death 1 (PD-1) antibodies in treating various cancers, the overall efficacy remains limited in the majority of colorectal cancer (CRC) cases. Metabolism reprogramming of tumors inhibits the tricarboxylic acid (TCA) cycle, leading to down-regulation of fumarate hydratase (FH), which is related to poor prognosis in CRC patients. By establishing a tumor-bearing mouse model of CRC with Fh1 expression deficiency, we confirmed that the therapeutic effect of PD-1 antibodies alone was suboptimal in mice with low Fh1 expression, which was improved by combination with a protein invertase subtilisin/kexin 9 (PCSK9) inhibitor. Mechanistically, FH binds to Ras-related nucleoprotein (RAN), which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. On the contrary, the expression of PCSK9 increased in CRC cells with low FH expression, which antagonized the effects of immunotherapy. Overall, CRC patients with low FH expression may benefit from combinatorial therapy with PD-1 antibodies and PCSK9 inhibitors to enhance the curative effect.

MYL9 expressed in cancer-associated fibroblasts regulate the immune microenvironment of colorectal cancer and promotes tumor progression in an autocrine manner.

BACKGROUND: The tumor microenvironment (TME) is an important factor that regulates the progression of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) are the main mesenchymal cells in the TME and play a vital role in tumor progression; however, the specific underlying mechanisms require further study. METHODS: Multiple single-cell and transcriptome data were analyzed and validated. Primary CAFs isolation, CCK8 assay, co-culture assay, western blotting, multiple immunofluorescence, qRT-PCR, ELISA, immunoprecipitation, ChIP, double luciferase, and animal experiments were used to explore the potential mechanism of MYL9 regulation in CRC. RESULTS: Our findings revealed that MYL9 was predominantly localized and expressed in CAFs rather than in CRC cells, and bioinformatics analysis revealed that high MYL9 expression was strongly associated with poor overall and disease-free survival in various tumors. In addition, high MYL9 expression is closely associated with M2 macrophage infiltration, which can lead to an immunosuppressive microenvironment in CRC, making it insensitive to immunotherapy. Mechanically, MYL9 can regulate the secretion of CAFs on CCL2 and TGF-ß1, thus affecting the immune microenvironment and progression of CRC. In addition, MYL9 bounded with IQGAP1 to regulate CCL2 and TGF-ß1 secretion through the ERK 1/2 pathway, and CCL2 and TGF-ß1 synergistically promoted CRC cells progression through the PI3K-AKT pathway. Furthermore, MYL9 promotes epithelial-mesenchymal transition (EMT) in CRC. During the upstream regulation of MYL9 in CAFs, we found that the EMT transcription factor ZEB1 could bind to the MYL9 promoter in CAFs, enhancing the activity and function of MYL9. Therefore, MYL9 is predominantly expressed in CAFs and can indirectly influence tumor biology and EMT by affecting CAFs protein expression in CRC. CONCLUSIONS: MYL9 regulates the secretion of cytokines and chemokines in CAFs, which can affect the immune microenvironment of CRC and promote CRC progression. The relationship between MYL9 expression and CRC clinical staging and immunotherapy is closer in CAFs than in tumor cells; therefore, studies using CAFs as a model deserve more attention when exploring tumor molecular targets in clinical research.

Development and Interpretation of a Clinicopathological-Based Model for the Identification of Microsatellite Instability in Colorectal Cancer.

Chemotherapy is not recommended for patients with deficient mismatch repair (dMMR) in colorectal cancer (CRC); therefore, assessing the status of MMR is crucial for the selection of subsequent treatment. This study is aimed at building predictive models to accurately and rapidly identify dMMR. A retrospective analysis was performed at Wuhan Union Hospital between May 2017 and December 2019 based on the clinicopathological data of patients with CRC. The variables were subjected to collinearity, least absolute shrinkage and selection operator (LASSO) regression, and random forest (RF) feature screening analyses. Four sets of machine learning models (extreme gradient boosting (XGBoost), support vector machine (SVM), naive Bayes (NB), and RF) and a conventional logistic regression (LR) model were built for model training and testing. Receiver operating characteristic (ROC) curves were plotted to evaluate the predictive performance of the developed models. In total, 2279 patients were included in the study and were randomly divided into either the training or test group. Twelve clinicopathological features were incorporated into the development of the predictive models. The area under curve (AUC) values of the five predictive models were 0.8055 for XGBoost, 0.8174 for SVM, 0.7424 for NB, 8584 for RF, and 0.7835 for LR (Delong test, P value < 0.05). The results showed that the RF model exhibited the best recognition ability and outperformed the conventional LR method in identifying dMMR and proficient MMR (pMMR). Our predictive models based on routine clinicopathological data can significantly improve the diagnostic performance of dMMR and pMMR. The four machine learning models outperformed the conventional LR model.

Changes in Bacteroides and the microbiota in patients with obstructed colorectal cancer: retrospective cohort study.

BACKGROUND: The relationship between intestinal obstruction due to colorectal cancer (CRC) and the gut microbiota remains largely unknown. The aim of this study was to investigate the potential association between alterations in gut microbiota and CRC in the presence of intestinal obstruction. METHODS: Patients with CRC with or without obstruction were recruited and compared using 1:1 propensity score matching (PSM). Total DNA from tumours and adjacent normal tissues of 84 patients and 36 frozen tumour tissues was extracted and amplified. 16S RNA sequencing was used to uncover differences in microbiota composition between the two groups. RESULTS: A total of 313 patients with CRC were recruited. Survival analysis demonstrated that patients in the obstruction group had shorter overall survival time and disease-free survival (DFS) time than those in the non-obstruction group. Microbial richness and diversity in tumour tissues of patients with obstruction were significantly higher than those of patients with no obstruction. The alpha diversity indices and beta diversity exhibited were different between the two groups (P < 0.05). At the phylum and genus levels, Bacteroidetes were significantly enriched in the tumour tissues of patients with obstruction. Alpha diversity in tumour tissues was closely related to specific microbiota. These findings were replicated in the 16S rRNA analyses from frozen samples. There were more Bacteroidetes in CRC patients with obstruction. CONCLUSIONS: Patients with obstructed CRC have worse prognosis and have differences in their microbiota. Higher levels of Bacteroides were observed in patients with obstructed CRC.

Gut microbiota distinct between colorectal cancers with deficient and proficient mismatch repair: A study of 230 CRC patients.

Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) and proficient DNA mismatch repair (pMMR) exhibit heterogeneous tumor characteristics, distinct responses to immunotherapy, and different survival outcomes. However, it is unclear whether gut microbiota is distinct between CRCs with different MMR status. In this study, we used immunohistochemistry for four major MMR proteins to determine the MMR status in 230 CRC patients. The gut microbiota was profiled in cancerous and adjacent normal tissues by using bacterial 16S rRNA sequencing. The differences in microbiota diversity, composition and related metabolic pathways between patients with dMMR and pMMR CRCs were explored. Linear discriminant analysis effect size (LEfSe) analysis was further applied to validate the significant taxonomic differences at the genus level. In our study cohort, dMMR status was identified in 29 of 230 (12.61%) tumors. The richness (alpha-diversity) of gut microbiome in dMMR tumor tissue was higher compared with pMMR tumor tissues. The microbial community composition (beta-diversity) between the two groups was significantly different. The dMMR group was enriched considerably for some microbiota, including Fusobacteria, Firmicutes, Verrucomicrobia, and Actinobacteria at the phylum level and Fusobacterium, Akkermansia, Bifidobacterium, Faecalibacterium, Streptococcus, and Prevotella bacteria at the genus level. However, the pMMR group was dominated by Proteobacteria at the phylum level and Serratia, Cupriavidus and Sphingobium at the genus level. Moreover, a wide variety of microbiota associated functional pathways were observed with different MMR status. KEGG pathway analysis indicated a higher abundance of the biosynthesis and metabolic pathways of glycan and nucleotide, cell growth and death pathways, genetic replication and repair pathways in dMMR samples compared with the pMMR group. These findings demonstrate that CRC patients with different MMR status have distinct gut bacterial community richness, compositions and related metabolic pathways, suggesting basis that may explain the effectiveness of immunotherapy in dMMR tumors.