Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway in TP53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC. Our findings suggest that targeting the JAK2-STAT3-UCHL3-ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.

Colorectal cancer is the third leading cause of cancer-related mortality worldwide.Hepatic resection is the standard treatment for colorectal cancer liver metastasis.Microwave ablation(MWA),as a minimally invasive therapeutic approach,offers an alternative treatment option for these patients.But the clinical efficacy of hepatic resection and MWA in treating colorectal cancer liver metastasis patients is still inconclusive.Literatures were retrieved on comparative studies about the treatment of colorectal cancer liver metastasis with hepatic resection and MWA from multiple databases,including sinoMed,PubMed,Web of Science,EMBASE,CNKI,Wanfang,etc.The cutoffdate of retrieval was September 2024.Finally,a total of 13 studies comprising 2 057 patients,were included in this study.The papers were assessed using the Newcastle-Ottawa Scale and Jadad Scale.All included studies were of high quality.Data extraction focused on postoperative complications,length of hospital stay,surgical duration,hospitalization costs,and patient survival outcomes,including overall survival(OS)and disease-free survival(DFS).A meta-analysis was performed using Review Manager 5.4 software.There were no significant differences in OS(HR=1.03,95%CI:0.85-1.25,P=0.77)and DFS(HR=1.27,95%CI:0.94-1.71,P=0.13)between the MWA group and the hepatic resection group.In the subgroup analysis of patients with≤5 liver metastases and size of metastases≤3 cm,there were no statistically significant differences in OS and DFS between the MWA group and the hepatic resection group.The MWA group exhibited shorter hospital stay,reduced hospitalization costs,decreased surgical duration,less intraoperative blood loss,and lower incidence of complications compared to the hepatic resection group(P＜0.05).Therefore,for patients with colorectal liver metastases characterized by a number of liver metastases≤5 and size of metastases≤3 cm,MWA serves as an effective alternative to hepatic resection,with a lower morbidity associated with treatment.Further validation of these findings is warranted through additional randomized controlled trials and cohort studies.The registration number of this Meta-analysis on the PROSPERO platform is CRD42024610278.

Protective ileostomy is an important bridging procedure in low anterior resection for rectal cancer, aimed at preventing severe anastomotic complications. It has been shown to significantly reduce the risk of pelvic infections resulting from anastomotic leakage. However, whether ileostomy plays a positive clinical role in preventing anastomotic leaks remains a subject of considerable debate. The procedure for creating a protective ileostomy is relatively simple and convenient, making it a commonly used approach in clinical practice. Nevertheless, as a traumatic surgical procedure, ileostomy itself may lead to a range of complications. Therefore, it is crucial to comprehensively understand the potential complications associated with ileostomy, develop optimized management strategies, and carefully select appropriate patients for preventive ileostomy, as these steps hold significant clinical value. This article provides a systematic review of the types, development, and application of preventive ileostomy, as well as the management and prevention strategies for common complications. The aim is to offer valuable guidance to clinical surgeons in optimizing stoma management and minimizing complications in rectal cancer sphincter-preserving surgery.

Colorectal cancer is the third leading cause of cancer-related mortality worldwide.Hepatic resection is the standard treatment for colorectal cancer liver metastasis.Microwave ablation(MWA),as a minimally invasive therapeutic approach,offers an alternative treatment option for these patients.But the clinical efficacy of hepatic resection and MWA in treating colorectal cancer liver metastasis patients is still inconclusive.Literatures were retrieved on comparative studies about the treatment of colorectal cancer liver metastasis with hepatic resection and MWA from multiple databases,including sinoMed,PubMed,Web of Science,EMBASE,CNKI,Wanfang,etc.The cutoffdate of retrieval was September 2024.Finally,a total of 13 studies comprising 2 057 patients,were included in this study.The papers were assessed using the Newcastle-Ottawa Scale and Jadad Scale.All included studies were of high quality.Data extraction focused on postoperative complications,length of hospital stay,surgical duration,hospitalization costs,and patient survival outcomes,including overall survival(OS)and disease-free survival(DFS).A meta-analysis was performed using Review Manager 5.4 software.There were no significant differences in OS(HR=1.03,95%CI:0.85-1.25,P=0.77)and DFS(HR=1.27,95%CI:0.94-1.71,P=0.13)between the MWA group and the hepatic resection group.In the subgroup analysis of patients with≤5 liver metastases and size of metastases≤3 cm,there were no statistically significant differences in OS and DFS between the MWA group and the hepatic resection group.The MWA group exhibited shorter hospital stay,reduced hospitalization costs,decreased surgical duration,less intraoperative blood loss,and lower incidence of complications compared to the hepatic resection group(P＜0.05).Therefore,for patients with colorectal liver metastases characterized by a number of liver metastases≤5 and size of metastases≤3 cm,MWA serves as an effective alternative to hepatic resection,with a lower morbidity associated with treatment.Further validation of these findings is warranted through additional randomized controlled trials and cohort studies.The registration number of this Meta-analysis on the PROSPERO platform is CRD42024610278.

Protective ileostomy is an important bridging procedure in low anterior resection for rectal cancer, aimed at preventing severe anastomotic complications. It has been shown to significantly reduce the risk of pelvic infections resulting from anastomotic leakage. However, whether ileostomy plays a positive clinical role in preventing anastomotic leaks remains a subject of considerable debate. The procedure for creating a protective ileostomy is relatively simple and convenient, making it a commonly used approach in clinical practice. Nevertheless, as a traumatic surgical procedure, ileostomy itself may lead to a range of complications. Therefore, it is crucial to comprehensively understand the potential complications associated with ileostomy, develop optimized management strategies, and carefully select appropriate patients for preventive ileostomy, as these steps hold significant clinical value. This article provides a systematic review of the types, development, and application of preventive ileostomy, as well as the management and prevention strategies for common complications. The aim is to offer valuable guidance to clinical surgeons in optimizing stoma management and minimizing complications in rectal cancer sphincter-preserving surgery.

Objective:To develop a prognostic prediction model for patients with colorectal cancer based on a peripheral blood cell composite score (PBCS) system.Methods:This retrospective observational study included patients who had primary colorectal cancer without distant metastasis, who did not undergo radiotherapy or chemotherapy before surgery, who did not receive leukocyte or platelet-raising therapy within 1 month before surgery, and whose postoperative pathology confirmed colorectal adenocarcinoma with complete tumor resection. Patients with severe anemia, infection, or hematologic diseases before surgery, as well as those with severe heart, lung, or other important organ diseases or concurrent malignant tumors, were excluded. In total, 1021 patients with colorectal cancer who underwent surgical treatment in the Department of Gastrointestinal Surgery of the Fourth Hospital of Hebei Medical University from April 2018 to April 2020 were retrospectively included as the training set (766 patients) and the internal validation set (255 patients). Additionally, using the same criteria, 215 patients with colorectal cancer who underwent surgical treatment in another treatment group from March 2015 to December 2020 were selected as the external validation set. The "surv_cutpoint" function in R software was used to analyze the optimal cut-off values of neutrophils, lymphocytes, and platelets, and a PBCS system was established based on the optimal cut-off values. The scoring rules of the PBCS system were as follows: Neutrophils and platelets below the optimal cut-off value = 1 point, otherwise 0 points; Lymphocytes above the optimal cut-off value = 1 point, otherwise 0 points. The scores of the three cell types were added together to obtain the PBCS. Univariate and multivariate Cox regression analyses were performed to explore the correlation between patients' clinicopathological features and prognosis, and a nomogram was constructed based on the Cox regression analysis to predict patients' prognosis. The accuracy of the nomogram prediction model was validated using the C-index, calibration curve, and decision curve analysis.Results:The optimal cut-off values for neutrophils, lymphocytes, and platelets were 4.40×10 9/L, 1.41×10 9/L, and 355×10 9/L, respectively. The patients were divided into high and low groups according to the optimal cut-off values of these cells. Survival curve analysis showed that a high lymphocyte count (training set: P=0.042, internal validation: P=0.010, external validation: P=0.029), low neutrophil count (training set: P=0.035, internal validation: P=0.001, external validation: P=0.024), and low platelet count (training set: P=0.041, internal validation: P=0.030, external validation: P=0.024) were associated with prolonged overall survival (OS), with statistically significant differences in all cases. Survival analysis of different PBCS groups showed that patients with a high PBCS had longer OS than those with a low PBCS ( P<0.05). Univariate and multivariate Cox regression analysis results showed that aspirin use history, vascular thrombus, neural invasion, CA19-9, N stage, operation time, M stage, and PBCS were independent factors affecting OS (all P<0.05). The PBCS was also an independent factor affecting disease-specific survival ( P<0.05), but not progression-free survival ( P>0.05). The above independent risk or protective factors were included in R software to construct a nomogram for predicting OS. The C-index (0.873), calibration curve, and decision curve analysis (threshold probability: 0.0%–75.2%) all indicated that the nomogram prediction model had good predictive performance for OS. Conclusion:This study demonstrates that the PBCS constructed based on preoperative peripheral blood levels of neutrophils, lymphocytes, and platelets is an independent factor associated with the prognosis of patients with colorectal cancer. The nomogram model constructed based on this score system exhibits good predictive efficacy for the prognosis of these patients.

Objective:To develop a prognostic prediction model for patients with colorectal cancer based on a peripheral blood cell composite score (PBCS) system.Methods:This retrospective observational study included patients who had primary colorectal cancer without distant metastasis, who did not undergo radiotherapy or chemotherapy before surgery, who did not receive leukocyte or platelet-raising therapy within 1 month before surgery, and whose postoperative pathology confirmed colorectal adenocarcinoma with complete tumor resection. Patients with severe anemia, infection, or hematologic diseases before surgery, as well as those with severe heart, lung, or other important organ diseases or concurrent malignant tumors, were excluded. In total, 1021 patients with colorectal cancer who underwent surgical treatment in the Department of Gastrointestinal Surgery of the Fourth Hospital of Hebei Medical University from April 2018 to April 2020 were retrospectively included as the training set (766 patients) and the internal validation set (255 patients). Additionally, using the same criteria, 215 patients with colorectal cancer who underwent surgical treatment in another treatment group from March 2015 to December 2020 were selected as the external validation set. The "surv_cutpoint" function in R software was used to analyze the optimal cut-off values of neutrophils, lymphocytes, and platelets, and a PBCS system was established based on the optimal cut-off values. The scoring rules of the PBCS system were as follows: Neutrophils and platelets below the optimal cut-off value = 1 point, otherwise 0 points; Lymphocytes above the optimal cut-off value = 1 point, otherwise 0 points. The scores of the three cell types were added together to obtain the PBCS. Univariate and multivariate Cox regression analyses were performed to explore the correlation between patients' clinicopathological features and prognosis, and a nomogram was constructed based on the Cox regression analysis to predict patients' prognosis. The accuracy of the nomogram prediction model was validated using the C-index, calibration curve, and decision curve analysis.Results:The optimal cut-off values for neutrophils, lymphocytes, and platelets were 4.40×10 9/L, 1.41×10 9/L, and 355×10 9/L, respectively. The patients were divided into high and low groups according to the optimal cut-off values of these cells. Survival curve analysis showed that a high lymphocyte count (training set: P=0.042, internal validation: P=0.010, external validation: P=0.029), low neutrophil count (training set: P=0.035, internal validation: P=0.001, external validation: P=0.024), and low platelet count (training set: P=0.041, internal validation: P=0.030, external validation: P=0.024) were associated with prolonged overall survival (OS), with statistically significant differences in all cases. Survival analysis of different PBCS groups showed that patients with a high PBCS had longer OS than those with a low PBCS ( P<0.05). Univariate and multivariate Cox regression analysis results showed that aspirin use history, vascular thrombus, neural invasion, CA19-9, N stage, operation time, M stage, and PBCS were independent factors affecting OS (all P<0.05). The PBCS was also an independent factor affecting disease-specific survival ( P<0.05), but not progression-free survival ( P>0.05). The above independent risk or protective factors were included in R software to construct a nomogram for predicting OS. The C-index (0.873), calibration curve, and decision curve analysis (threshold probability: 0.0%–75.2%) all indicated that the nomogram prediction model had good predictive performance for OS. Conclusion:This study demonstrates that the PBCS constructed based on preoperative peripheral blood levels of neutrophils, lymphocytes, and platelets is an independent factor associated with the prognosis of patients with colorectal cancer. The nomogram model constructed based on this score system exhibits good predictive efficacy for the prognosis of these patients.

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced cytokine storms constitute the primary cause of coronavirus disease 19(COVID-19)progression,severity,criticality,and death.Gluco-corticoid and anti-cytokine therapies are frequently administered to treat COVID-19,but have limited clinical efficacy in severe and critical cases.Nevertheless,the weaknesses of these treatment modalities have prompted the development of anti-inflammatory therapy against this infection.We found that the broad-spectrum anti-inflammatory agent inosine downregulated proinflammatory interleukin(IL)-6,upregulated anti-inflammatory IL-10,and ameliorated acute inflammatory lung injury caused by mul-tiple infectious agents.Inosine significantly improved survival in mice infected with SARS-CoV-2.It indirectly impeded TANK-binding kinase 1(TBK1)phosphorylation by binding stimulator of interferon genes(STING)and glycogen synthase kinase-3β(GSK3β),inhibited the activation and nuclear trans-location of the downstream transcription factors interferon regulatory factor(IRF3)and nuclear factor kappa B(NF-κB),and downregulated IL-6 in the sera and lung tissues of mice infected with lipopoly-saccharide(LPS),H1N1,or SARS-CoV-2.Thus,inosine administration is feasible for clinical anti-inflammatory therapy against severe and critical COVID-19.Moreover,targeting TBK1 is a promising strategy for inhibiting cytokine storms and mitigating acute inflammatory lung injury induced by SARS-CoV-2 and other infectious agents.

BACKGROUND: The effect of intra-operative chemotherapy (IOC) on the long-term survival of patients with colorectal cancer (CRC) remains unclear. In this study, we evaluated the independent effect of intra-operative infusion of 5-fluorouracil in combination with calcium folinate on the survival of CRC patients following radical resection. METHODS: 1820 patients were recruited, and 1263 received IOC and 557 did not. Clinical and demographic data were collected, including overall survival (OS), clinicopathological features, and treatment strategies. Risk factors for IOC-related deaths were identified using multivariate Cox proportional hazards models. A regression model was developed to analyze the independent effects of IOC. RESULTS: Proportional hazard regression analysis showed that IOC (hazard ratio [HR]=0.53, 95% confidence intervals [CI] [0.43, 0.65], P  < 0.001) was a protective factor for the survival of patients. The mean overall survival time in IOC group was 82.50 (95% CI [80.52, 84.49]) months, and 71.21 (95% CI [67.92, 74.50]) months in non-IOC group. The OS in IOC-treated patients were significantly higher than non-IOC-treated patients ( P  < 0.001, log-rank test). Further analysis revealed that IOC decreased the risk of death in patients with CRC in a non-adjusted model (HR=0.53, 95% CI [0.43, 0.65], P  < 0.001), model 2 (adjusted for age and gender, HR=0.52, 95% CI [0.43, 0.64], P  < 0.001), and model 3 (adjusted for all factors, 95% CI 0.71 [0.55, 0.90], P  = 0.006). The subgroup analysis showed that the HR for the effect of IOC on survival was lower in patients with stage II (HR = 0.46, 95% CI [0.31, 0.67]) or III disease (HR=0.59, 95% CI [0.45, 0.76]), regardless of pre-operative radiotherapy (HR=0.55, 95% CI [0.45, 0.68]) or pre-operative chemotherapy (HR=0.54, 95% CI [0.44, 0.66]). CONCLUSIONS: IOC is an independent factor that influences the survival of CRC patients. It improved the OS of patients with stages II and III CRC after radical surgery. TRIAL REGISTRATION chictr.org.cn, ChiCTR 2100043775.
Humans ; Fluorouracil/therapeutic use* ; Leucovorin/therapeutic use* ; Colorectal Neoplasms/pathology* ; Retrospective Studies ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Proportional Hazards Models ; Prognosis

Objective:To investigate the application value of domestic robotic surgical system in radical resection of hilar cholangiocarcinoma (hCCA).Methods:The retrospective and descriptive study was constructed. The clinicopathological data of a 66-year-old male patient with hCCA who was admitted to the Second Hospital of Shandong University in November 2022 were collected. Radical resection of hCCA was performed using the Toumai? laparoscopic surgical robot system. Observation indicators: (1) intraoperative conditions; (2) postoperative conditions; (3) follow-up. Count data were represented as absolute numbers and (or) percentages.Results:(1) Intraoperative conditions. The patient underwent radical resection of hCCA successfully using robotic surgical system, including tumor resection, lymph node dissection, and gastrointestinal reconstruc-tion. The operation time and volume of intraoperative blood loss were 400 minutes and 100 mL, respectively, and no intraoperative blood transfusion was required. (2) Postoperative conditions. The patient began ambulation on postoperative day 1 and began taking liquid food on postoperative day 4. Liver function examination and abdominal computed tomograph (CT) on postoperative day 5 showed a decrease in serum bilirubin, no biliary or intestinal leakage, and no edema or necrosis at the anastomotic site. The abdominal pre-anastomotic and post-anastomotic drainage tubes were removed on the 7th and 9th day after the surgery respectively, and the patient was discharged on the 10th day after surgery. Results of postoperative pathological examination showed moderately to poorly differentiated adenocarcinoma of the bile duct. Immunostaining was positive for CK7 and CK19. The Ki-67 proliferation index was 35%. The proximal and distal resection margin of bile duct were negative. The tumor diameter was 30 mm. Perineural invasion was positive. The surgical specimen margin was negative. Two lymph nodes were identified containing tumor cells positive for malignancy. No tumor cell metastasis was detected in the No.8, No.12 or gastric lesser curvature lymph nodes submitted for pathological examination. (3) Follow-up. The patient was followed up at postoperative 1-, 3-, 5-month after discharge. During follow-up period, results of liver function examination and abdominal CT showed liver function restore to normal levels, no complication such as biliary fistula, intestinal fistula, gastroparesis or tumor metastasis.Conclusion:The Domestic Toumai ? laparoscopic surgical robot system can be applied to radical resection of hCCA.