OBJECTIVE: To determine whether monotropein has an anticancer effect and explore its potential mechanisms against colorectal cancer (CRC) through network pharmacology and molecular docking combined with experimental verification. METHODS: Network pharmacology and molecular docking were used to predict potential targets of monotropein against CRC. Cell counting kit assay, plate monoclonal assay and microscopic observation were used to investigate the antiproliferative effects of monotropein on CRC cells HCT116, HT29 and LoVo. Flow cytometry and scratch assay were used to analyze apoptosis and cell cycle, as well as cell migration, respectively in HCT116, HT29, and LoVo cells. Western blotting was used to detect the expression of proteins related to apoptosis, cell cycle, and cell migration, and the expression of proteins key to the Akt pathway. RESULTS: The Gene Ontology and Reactome enrichment analyses indicated that the anticancer potential of monotropein against CRC might be involved in multiple cancer-related signaling pathways. Among these pathways, RAC-beta serine/threonine-protein kinase (Akt1, Akt2), cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-9 (MMP9), epidermal growth factor receptor (EGFR), cell division control protein 42 homolog (CDC42) were shown as the potential anticancer targets of monotropein against CRC. Molecular docking suggested that monotropein may interact with the 6 targets (Akt1, Akt2, CDK6, MMP9, EGFR, CDC42). Subsequently, cell activity of HCT116, HT29 and LoVo cell lines were significantly suppressed by monotropein (P<0.05). Furthermore, our research revealed that monotropein induced cell apoptosis by inhibiting Bcl-2 and increasing Bax, induced G₁-S cycle arrest in colorectal cancer by decreasing the expressions of CyclinD1, CDK4 and CDK6, inhibited cell migration by suppressing the expressions of CDC42 and MMP9 (P<0.05), and might play an anticancer role through Akt signaling pathway. CONCLUSION Monotropein exerts its antitumor effects primarily by arresting the cell cycle, causing cell apoptosis, and inhibiting cell migration. This indicates a high potential for developing novel medication for treating CRC.
Humans ; Proto-Oncogene Proteins c-akt/metabolism* ; Cell Proliferation ; Matrix Metalloproteinase 9 ; Molecular Docking Simulation ; Cell Cycle ; ErbB Receptors ; Apoptosis ; Colorectal Neoplasms/pathology* ; Cell Line, Tumor

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

Humans ; Colonoscopy ; Colorectal Neoplasms/pathology*

Objective: To explore the concordance and causes of different mismatch repair (MMR) and microsatellite instability (MSI) detection results in endometrial carcinoma (EC) molecular typing. Methods: A total of 214 EC patients diagnosed from January 2021 to April 2023 were selected at the Department of Pathology, Peking University Third Hospital. The immunohistochemistry (IHC) results of MMR protein were reviewed. Tumor specific somatic mutations, MMR germline mutations, microsatellite scores and tumor mutation burden (TMB) were detected by next-generation sequencing (NGS) with multi-gene panel. Methylation-specific PCR was used to detect the methylation status of MLH1 gene promoter in cases with deficient MLH1 protein expression. In cases with discrepant results between MMR-IHC and MSI-NGS, the MSI status was detected again by PCR (MSI-PCR), and the molecular typing was determined by combining the results of TMB and MLH1 gene promoter methylation. Results: (1) In this study, there were 22 cases of POLE gene mutation subtype, 55 cases of mismatch repair deficient (MMR-d) subtype, 29 cases of p53 abnormal subtype, and 108 cases of no specific molecular profile (NSMP). The median age at diagnosis of MMR-d subtype (54 years old) and the proportion of aggressive histological types (40.0%, 22/55) were higher than those of NSMP subtype [50 years old and 12.0% (13/108) respectively; all P<0.05]. (2) Among 214 patients, MMR-IHC test showed that 153 patients were mismatch repair proficient (MMR-p), 49 patients were MMR-d, and 12 patients were difficult to evaluate directly. MSI-NGS showed that 164 patients were microsatellite stable (MSS; equal to MMR-p), 48 patients were high microsatellite instability (MSI-H; equal to MMR-d), and 2 patients had no MSI-NGS results because the effective sequencing depth did not meet the quality control. The overall concordance between MMR-IHC and MSI-NGS was 94.3% (200/212). All the 12 discrepant cases were MMR-d or subclonal loss of MMR protein by IHC, but MSS by NGS. Among them, 10 cases were loss or subclonal loss of MLH1 and (or) PMS2 protein. Three discrepant cases were classified as POLE gene mutation subtype. In the remaining 9 cases, 5 cases and 3 cases were confirmed as MSI-H and low microsatellite instability (MSI-L) respectively by MSI-PCR, 6 cases were detected as MLH1 gene promoter methylation and 7 cases demonstrated high TMB (>10 mutations/Mb). These 9 cases were classified as MMR-d EC. (3) Lynch syndrome was diagnosed in 27.3% (15/55) of all 55 MMR-d EC cases, and the TMB of EC with MSH2 and (or) MSH6 protein loss or associated with Lynch syndrome [(71.0±26.2) and (71.5±20.1) mutations/Mb respectively] were significantly higher than those of EC with MLH1 and (or) PMS2 loss or sporadic MMR-d EC [(38.2±19.1) and (41.9±24.3) mutations/Mb respectively, all P<0.01]. The top 10 most frequently mutated genes in MMR-d EC were PTEN (85.5%, 47/55), ARID1A (80.0%, 44/55), PIK3CA (69.1%, 38/55), KMT2B (60.0%, 33/55), CTCF (45.5%, 25/55), RNF43 (40.0%, 22/55), KRAS (36.4%, 20/55), CREBBP (34.5%, 19/55), LRP1B (32.7%, 18/55) and BRCA2 (32.7%, 18/55). Concurrent PTEN, ARID1A and PIK3CA gene mutations were found in 50.9% (28/55) of MMR-d EC patients. Conclusions: The concordance of MMR-IHC and MSI-NGS in EC is relatively high.The discordance in a few MMR-d EC are mostly found in cases with MLH1 and (or) PMS2 protein loss or MMR protein subclonal staining caused by MLH1 gene promoter hypermethylation. In order to provide accurate molecular typing for EC patients, MLH1 gene methylation, MSI-PCR, MMR gene germline mutation and TMB should be combined to comprehensively evaluate MMR and MSI status.
Female ; Humans ; Middle Aged ; Class I Phosphatidylinositol 3-Kinases/metabolism* ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis* ; DNA Mismatch Repair/genetics* ; Endometrial Neoplasms/pathology* ; Microsatellite Instability ; Mismatch Repair Endonuclease PMS2/genetics* ; Molecular Typing

Screening and early diagnosis and treatment have been proven effective in reducing the incidence and mortality of colorectal cancer. Colonoscopy combined with pathological examination is the gold standard for colorectal cancer screening. However, due to the invasiveness, high cost and the need for professional endoscopists of colonoscopy, it is not feasible to directly use this method for mass population screening. Fecal immunochemical test (FIT) is one of the screening techniques recommended by authoritative international guidelines for colorectal cancer screening, and has been widely used in population-based colorectal cancer screening programs in countries around the world. This paper elaborates on the value of FIT in colorectal cancer screening from different aspects, such as the technical principles, the screening efficiency, the screening strategies, and the population effects and benefits. Additionally, it describes the current situation of colorectal cancer screening in China and summarizes the challenges faced in colorectal cancer screening in order to optimize the FIT-based colorectal cancer screening strategies in the population and provide theoretical reference for effective colorectal cancer screening.
Humans ; Early Detection of Cancer/methods* ; Colonoscopy ; Mass Screening ; Colorectal Neoplasms/pathology* ; Occult Blood

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.
Humans ; Irinotecan/therapeutic use* ; Oxaliplatin/therapeutic use* ; Colorectal Neoplasms/pathology* ; Retrospective Studies ; Fluorouracil ; Colonic Neoplasms/chemically induced* ; Rectal Neoplasms/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/adverse effects* ; Camptothecin/adverse effects*

Objective: To evaluate the participation rate and detection of colorectal neoplasms based on annual fecal immunochemical testing (FIT) for three consecutive years in a population-based colorectal cancer screening program in China. Methods: Based on a population-based colorectal cancer screening program conducted from May 2018 to May 2021 in 6 centers in China, 7 793 eligible participants aged 50-74 were included and offered free FIT and colonoscopy (for those who were FIT-positive on initial screening). At baseline, all participants were invited to receive FIT. In subsequent screening rounds, only FIT-positive participants who did not undergo colonoscopy or FIT-negative participants were invited to have repeated FIT screening. FIT-positive participants were recommended to undertake colonoscopy and pathological examination (if abnormalities were found during colonoscopy). An overall of three rounds of annual FIT screening were conducted. The primary outcomes of the study were the participation rate of FIT screening, the compliance rate of colonoscopy for FIT-positive participants, and the detection rate of colorectal neoplasms. Results: Among the 7 793 participants included in this study, 3 310 (42.5%) were male, with age of (60.50±6.49) years. The overall participation rates for the first, second and third round of FIT screening were 94.0%(7 327/7 793), 86.8% (6 048/6 968) and 91.3% (6 113/6 693), respectively. Overall, 7 742 out of 7 793 participants (99.3%) attended at least one round of screening, and 5 163 out of 7 793 participants (66.3%) attended all three rounds of screening. The positivity rate was significantly higher in the first (14.6%, 1 071/7 327) round compared with the second (5.6%, 3 41/6 048) and third (5.5%, 3 39/6 113) screening rounds (P<0.001). The overall compliance rates of colonoscopy examination among FIT-positive subjects were over 70% in three rounds, which were 76.3% (817/1 071), 75.7% (258/341) and 71.7% (243/339), respectively. In a multivariate logistic regression model considering factors including sex, education background, smoking, alcohol drinking, previous colonoscopy examination, colonic polyp history and family history of colorectal cancer among first-degree relatives, gender and smoking status were related factors affecting the participation rate of FIT screening, with higher rate in males and non-smokers. In addition, logistic regression analysis also found that age was negatively correlated with the compliance rate of colonoscopy in FIT positive patients. The detection rate of advanced tumors (colorectal cancer + advanced adenoma) declined from the first round to subsequent rounds [1st round: 1.15% (90/7 793); 2nd round: 0.57% (40/6 968); and 3rd round: 0.58% (39/6 693)], however, the positive predictive value for advanced neoplasms increased round by round, and was 11.02% in the first screening round, 15.50% in the second screening round, and 16.05 % in the third screening round. In each screening round, the detection rate for advanced neoplasms was higher in men than that in women, and increased with age. Conclusions: Annual repeated FIT screening has high acceptance and satisfying detection rates in the Chinese population. To optimize and improve the effectiveness of colorectal cancer screening, multi-round repeated FIT screening should be implemented while ensuring high participation rates.
Humans ; Male ; Female ; Early Detection of Cancer ; Predictive Value of Tests ; Colonoscopy ; Mass Screening ; Adenoma/diagnosis* ; Colorectal Neoplasms/pathology*

To explore the predictive value of preoperative serum CYFRA 21-1 in colorectal cancer (CRC) resection patients. In this retrospective study, 456 patients with CRC who received surgical treatment in the Department of General Surgery, Affiliated Hospital of Nantong University from January 2016 to February 2018 were analyzed. Preoperative CYFRA 21-1, CEA, CA19-9 and pathological data of the study subjects were collected. Determine the cut-off value of CYFRA 21-1 based on the X-tile. Chi-square test or Fisher exact probability test were used to compare clinicopathological features in different CYFRA 21-1 level groups. Univariate and multivariate regression analysis of factors affecting 5-year overall survival (OS) and disease-free survival (DFS). Kaplan-Meier survival curves were used to analyze 5-year differences in OS and DFS in CRC patients with different levels of CYFRA 21-1, CEA and CA19-9. Receiver operating characteristic(ROC) was adopted. ROC curves were used to analyze the prognostic efficacy of CYFRA21-1 for CRC, and nomogram maps were used to predict 1, 3, and 5-year survival rates. The results showed that the optimal cut-off values of serum CYFRA 21-1, CEA and CA19-9 were 4.9 ng/ml, 29.2 ng/ml and 72.8 U/ml, respectively. Different gender, tumor size, location, degree of differentiation, depth of invasion, lymph node metastasis and tumor node metastasis (TNM) classification stage were significantly different between the two groups with high and low CYFRA 21-1, the P-values were 0.018,<0.001,<0.001,<0.001, 0.002, 0.001, 0.003, respectively. CYFRA 21-1 (≥4.9 ng/ml) was an independent risk factor for 5-year OS (HR: 4.008, 95%CI: 2.309-6.958, P<0.001) and DFS (HR: 3.75, 95%CI: 2.227-6.314, P<0.001) in CRC patients. CYFRA 21-1 predicts a 5-year AUC of 0.725 and 0.720 for OS and DFS, respectively, and 0.804 and 0.827 for the combination of CEA and CA19-9. Based on the results of multivariate Cox regression analysis, nomogram graphs of OS and DFS were established, the C-indexes were 0.799 and 0.803, respectively. In conclusion, preoperative serum CYFRA 21-1 level may be an independent risk factor affecting the prognosis of patients with colorectal cancer. The prognostic model established by CYFRA 21-1 combined with CEA, CA19-9 and TNM stages may provide references for the prevention of CRC recurrence and clinical decision-making.
Humans ; Colorectal Neoplasms/pathology* ; CA-19-9 Antigen ; Retrospective Studies ; Neoplasm Staging ; Neoplasm Recurrence, Local/pathology* ; Biomarkers, Tumor

Circulating tumor cell (CTC), as a novel tumor marker, has the characteristics of non-invasive, dynamic monitoring and high accuracy, and provides precise molecular characteristics of tumors and helps understand the changes in tumor development. Therefore, CTC has important clinical value in the dynamic monitoring of tumor progression. In order to standardize and guide the application of CTC detection in the diagnosis and treatment of gastrointestinal neoplasms, Gastric Cancer Group of Oncology Branch of Chinese Medical Association, Colorectal Cancer Professional Committee of Chinese Medical Doctor Association, Colorectal Cancer Professional Committee of Chinese Anti-Cancer Association, Gastric Cancer Professional Committee of Chinese Anti-Cancer Association, Digestive Tract Polyp and Precancerous Lesion Professional Committee of Chinese Anti-Cancer Association, jointly convened some domestic experts to discuss and formulate the Chinese expert consensus on the application of circulating tumor cell detection in the diagnosis and treatment of gastrointestinal neoplasms (2023 edition). The consensus provides opinions on the detection technology and clinical application of CTC detection in the diagnosis and treatment of gastrointestinal neoplasms, including the prediction of tumor prognosis, the monitoring of tumor recurrence and metastasis, the evaluation of treatment response, and the additional diagnostic value, providing guidance for clinical application.
Humans ; Stomach Neoplasms/therapy* ; Neoplastic Cells, Circulating/pathology* ; Consensus ; Neoplasm Recurrence, Local ; Colorectal Neoplasms/therapy*

INTRODUCTION: Acute malignant large bowel obstruction (MBO) occurs in 8%-15% of colorectal cancer patients. Self-expandable metal stents (SEMS) have progressed from a palliative modality to use as bridge to surgery (BTS). We aimed to assess the safety and efficacy of SEMS for MBO in our institution. METHODS: The data of patients undergoing SEMS insertion for MBO were reviewed. Technical success was defined as successful SEMS deployment across tumour without complications. Clinical success was defined as colonic decompression without requiring further surgical intervention. Rates of complications, median time to surgery, types of surgery and rates of recurrence were studied. RESULTS: Seventy-nine patients underwent emergent SEMS placement from September 2013 to February 2020. Their mean age was 68.8 ± 13.8 years and 43 (54%) patients were male. Mean tumour length was 4.2 cm ± 2.2 cm; 89.9% of malignant strictures were located distal to the splenic flexure. Technical and clinical success was 94.9% and 98.7%, respectively. Perforation occurred in 5.1% of patients, with none having stent migration or bleeding. Fifty (63.3%) patients underwent SEMS insertion as BTS. Median time to surgery was 20 (range 6-57) days. Most (82%) patients underwent minimally invasive surgery. Primary anastomosis rate was 98%. Thirty-nine patients had follow-up beyond 1-year posttreatment (median 34 months). Local recurrence and distant metastasis were observed in 4 (10.3%) and 5 (12.8%) patients, respectively. CONCLUSION Insertion of SEMS for acute MBO has high success rates and a good safety profile. Most patients in this audit underwent minimally invasive surgery and primary anastomosis after successful BTS.
Humans ; Male ; Middle Aged ; Aged ; Aged, 80 and over ; Female ; Colorectal Neoplasms/pathology* ; Singapore ; Tertiary Care Centers ; Stents/adverse effects* ; Intestinal Obstruction/etiology* ; Treatment Outcome ; Retrospective Studies ; Palliative Care