Disease-free Survival In Colorectal Cancer Patients Research Articles

Predictive value of red blood cell distribution width and hematocrit for short-term outcomes and prognosis in colorectal cancer patients undergoing radical surgery.

Previous studies have reported that low hematocrit levels indicate poor survival in patients with ovarian cancer and cervical cancer, the prognostic value of hematocrit for colorectal cancer (CRC) patients has not been determined. The prognostic value of red blood cell distribution width (RDW) for CRC patients was controversial. To investigate the impact of RDW and hematocrit on the short-term outcomes and long-term prognosis of CRC patients who underwent radical surgery. Patients who were diagnosed with CRC and underwent radical CRC resection between January 2011 and January 2020 at a single clinical center were included. The short-term outcomes, overall survival (OS) and disease-free survival (DFS) were compared among the different groups. Cox analysis was also conducted to identify independent risk factors for OS and DFS. There were 4258 CRC patients who underwent radical surgery included in our study. A total of 1573 patients were in the lower RDW group and 2685 patients were in the higher RDW group. There were 2166 and 2092 patients in the higher hematocrit group and lower hematocrit group, respectively. Patients in the higher RDW group had more intraoperative blood loss (P < 0.01) and more overall complications (P < 0.01) than did those in the lower RDW group. Similarly, patients in the lower hematocrit group had more intraoperative blood loss (P = 0.012), longer hospital stay (P = 0.016) and overall complications (P < 0.01) than did those in the higher hematocrit group. The higher RDW group had a worse OS and DFS than did the lower RDW group for tumor node metastasis (TNM) stage I (OS, P < 0.05; DFS, P = 0.001) and stage II (OS, P = 0.004; DFS, P = 0.01) than the lower RDW group; the lower hematocrit group had worse OS and DFS for TNM stage II (OS, P < 0.05; DFS, P = 0.001) and stage III (OS, P = 0.001; DFS, P = 0.001) than did the higher hematocrit group. Preoperative hematocrit was an independent risk factor for OS [P = 0.017, hazard ratio (HR) = 1.256, 95% confidence interval (CI): 1.041-1.515] and DFS (P = 0.035, HR = 1.194, 95%CI: 1.013-1.408). A higher preoperative RDW and lower hematocrit were associated with more postoperative complications. However, only hematocrit was an independent risk factor for OS and DFS in CRC patients who underwent radical surgery, while RDW was not.

Prognostic value of preoperative white blood cell to hemoglobin ratio and fibrinogen to albumin ratio in patients with colorectal cancer.

The prognostic value of preoperative white blood cell to hemoglobin ratio (WHR) and fibrinogen to albumin ratio (FAR) in colorectal cancer (CRC) is unknown. The purpose of this study was to analyze the correlation between preoperative WHR and FAR and the prognosis of CRC patients. The retrospective study analyzed the medical records of 207 patients with colorectal cancer who were admitted to Linyi People's Hospital between June 1, 2017 and June 1, 2021. The receiver operator curve was used to determine the cutoff value of 4.604 for WHR and 0.086 for FAR, and the patients were divided into high and low groups for comparative analysis of clinical data. Cox proportional hazards regression models were used to assess independent risk factors for disease-free survival (DFS) and overall survival (OS) in univariate and multifactorial analyses. Kaplan-Meier methods were used for survival analysis and logrank tests were used to assess survival differences. Multifactorial Cox analysis showed that tumor pathological stage (HR = 6.224, 95% CI:3.063-12.647, P < .001), and WHR (HR = 3.681, 95% CI:1.768-7.401, P < .001) were the independent risk factors for DFS in CRC patients. Tumor pathological stage (HR = 4.080, 95% CI:1.992-8.360, P < .001), and WHR (HR = 3.397, 95% CI:1.662-6.940, P = .001) were independent risk factors for OS. High levels of WHR and high levels of FAR were associated with lower DFS (P < .001) and OS (P < .001).CRC patients with both higher WHR and FAR had significantly lower DFS (P < .001) and OS (P < .001). DFS and OS may be shorter in CRC patients with high WHR and high FAR, perhaps associated with poor prognosis in CRC patients, and WHR and FAR may be potential CRC prognostic markers.

A partial epithelial-mesenchymal transition signature for highly aggressive colorectal cancer cells that survive under nutrient restriction.

Partial epithelial-mesenchymal transition (p-EMT) has recently been identified as a hybrid state consisting of cells with both epithelial and mesenchymal characteristics and is associated with the migration, metastasis, and chemoresistance of cancer cells. Here, we describe the induction of p-EMT in starved colorectal cancer (CRC) cells and identify a p-EMT gene signature that can predict prognosis. Functional characterisation of starvation-induced p-EMT in HCT116, DLD1, and HT29 cells showed changes in proliferation, morphology, and drug sensitivity, supported by in vivo studies using the chorioallantoic membrane model. An EMT-specific quantitative polymerase chain reaction (qPCR) array was used to screen for deregulated genes, leading to the establishment of an in silico gene signature that was correlated with poor disease-free survival in CRC patients along with the CRC consensus molecular subtype CMS4. Among the significantly deregulated p-EMT genes, a triple-gene signature consisting of SERPINE1, SOX10, and epidermal growth factor receptor (EGFR) was identified. Starvation-induced p-EMT was characterised by increased migratory potential and chemoresistance, as well as E-cadherin processing and internalisation. Both gene signature and E-cadherin alterations could be reversed by the proteasomal inhibitor MG132. Spatially resolving EGFR expression with high-resolution immunofluorescence imaging identified a proliferation stop in starved CRC cells caused by EGFR internalisation. In conclusion, we have gained insight into a previously undiscovered EMT mechanism that may become relevant when tumour cells are under nutrient stress, as seen in early stages of metastasis. Targeting this process of tumour cell dissemination might help to prevent EMT and overcome drug resistance. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

YAP1 expression in colorectal cancer confers the aggressive phenotypes via its target genes

ABSTRACT Yes-associated protein1 (YAP1), a downstream effector of the Hippo pathway, is over-expressed in several types of malignancies. We analyzed retrospectively the TCGA database using 447 colorectal cancer (CRC) samples to determine the correlation between YAP1 expression level and CRC patient prognosis. YAP1-enforced expressed CRC cell lines were constructed using the lentivirus particles containing a YAP1 insert. YAP1 was highly expressed in CRC cancerous tissues and is associated with distant metastasis of CRC patients. Kaplan – Meier analysis indicated that CRC patients with a higher YAP1 expression group (n = 104) had worse disease-free survival (DFS) and overall survival (OS) than lower YAP1 expression group (n = 343) (p = 0.008 and p = 0.022). Univariate and multivariate analysis indicated that the elevated YAP1 expression predicted the aggressive phenotype and was an independent indicator for OS and DFS of CRC patients. YAP1 over-expression in CRC cells enhanced their migration and invasion significantly which can be reversed by AXL, CTGF, or CYR61 interference. The study suggested that YAP1 affected the prognosis of CRC patients and controlled the abilities of invasion and migration of CRC cells via its target genes AXL, CTGF, and CYR61.

The Antineoplastic Effect of Heparin on Colorectal Cancer: A Review of the Literature.

Heparin and derivatives are commonly used for thrombophylaxis in surgical colorectal cancer (CRC) patients. Recent studies have suggested that, besides its protective effect on the incidence of venous thromboembolism, heparin has an anti-cancer effect. The aim of this review was to explore the literature and report the antineoplastic effect of heparin and derivatives on CRC. MEDLINE and EMBASE databases were searched for relevant articles. Nineteen studies were included (n = 19). Fifteen were lab studies conducted in vivo or in vitro on CRC cell lines and/or mice (n = 15). Four were in vivo clinical studies (n = 4). CRC tumor growth was reduced by 78% in one study, (p < 0.01), while tumorigenesis was suppressed in heparin-treated mice in seven studies. A high dose of low molecular weight heparin for extended duration significantly reduced post-operative VEGF, suggesting that such a regime may inhibit tumor angiogenesis and distant metastasis. A randomized trial demonstrated the antineoplastic effect of nadroparin as the 6 month survival in palliative patients increased. Another study has reported that disease-free survival of CRC patients was not affected by a similar tinzaparin regime. The anti-cancer properties of heparin and derivatives are promising, especially in lab studies. Further clinical trials are needed to investigate the anti-cancer benefit of heparin on CRC.

Low expression of ZHX3 is associated with progression and poor prognosis in colorectal cancer

Accumulating studies suggest that ZHX3, the member of ZHX family, is involved in a variety of biological functions such as development and differentiation. Recently, ZHX3 may also be involved in the progression of several cancer types including renal cancer, gastric cancer, liver cancer and breast cancer. However, the potential role of ZHX3 in colorectal cancer (CRC) is still unknown. In this study, we analyzed the protein levels of ZHX3 by immunohistochemistry and evaluated its relationship with the clinicopathological features and prognosis in 286 CRC patients. In vitro cell proliferation assay, plate colony formation assay and xenograft model in nude mice were applied to evaluate CRC cell proliferative ability. Our results showed that the expression of ZHX3 was significantly downregulated in CRC tissues compared with paired adjacent nontumor tissues. Furthermore, the ZHX3 expression was found to have a strong correlation with tumor size, tumor invasion depth and TNM stage. Kaplan-Meier analysis demonstrated that low ZHX3 expression was related to a poorer overall survival and disease-free survival in CRC patients. In addition, cox's proportional hazards analysis indicated that low ZHX3 expression was an independent prognostic indicator of poor prognosis. Functionally, reduced expression of ZHX3 promotes the proliferation of CRC cells both in vitro and in vivo. Conversely, overexpression of ZHX3 inhibited the growth of CRC cells, indicated that ZHX3 was significantly correlated with CRC progression. Our results indicate for the first time that ZHX3 may be a potential marker of cancer prognosis and CRC recurrence.

Application of preoperative serum CYFRA 21-1 level in the prognosis of colorectal cancer

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.

The predictive value of advanced lung cancer inflammation index for short-term outcomes and prognosis of colorectal cancer patients who underwent radical surgery.

The purpose of this study was to investigate the predictive value of advanced lung cancer inflammation index (ALI) for short-term outcomes and prognosis of colorectal cancer (CRC) patients who underwent radical surgery. CRC patients who underwent radical resection were included from Jan 2011 to Jan 2020 in our single clinical centre. Short-term outcomes, overall survival (OS), and disease-free survival (DFS) were compared in different groups. Cox analysis was conducted to identify independent risk factors for OS and DFS. A total of 4010 patients who underwent radical CRC surgery were enrolled in the current study. As a result, the low ALI group had longer operation time (p = 0.02), more intra-operative blood loss (p < 0.01), longer postoperative hospital stay (p < 0.01), and more overall complications (p < 0.01). Moreover, ALI (p < 0.01, OR = 0.679, 95% CI = 0.578-0.798) was an independent risk factor for overall complications. As for survival, the low ALI group had worse OS in all TNM stages (p < 0.01), stage II (p < 0.01) and stage III (p < 0.01). Similarly, the low ALI group had worse DFS in all TNM stages (p < 0.01), stage II (p < 0.01), and stage III (p < 0.01). In Cox analysis, ALI was an independent risk factors for OS (p < 0.01, HR = 0.707, 95% CI = 0.589-0.849) and DFS (p < 0.01, HR = 0.732, 95% CI = 0.622-0.861). Lower ALI was associated with more postoperative complications, worse OS, and DFS for CRC patients who underwent radical surgery. Furthermore, ALI was an independent risk factor for overall complications, OS, and DFS. Surgeons should pay close attention to patients with low ALI before surgery and make clinical strategies cautiously.

Effects of preoperative bicarbonate and lactate levels on short-term outcomes and prognosis in elderly patients with colorectal cancer

PurposeThe aim of this study was to analyze the effect of preoperative bicarbonate and lactate levels (LL) on the short-term outcomes and prognosis in elderly (≥ 65 years) patients with colorectal cancer (CRC).MethodsWe collected the information of CRC patients from Jan 2011 to Jan 2020 in a single clinical center. According to the results of preoperative blood gas analysis, we divided patients into the higher/lower bicarbonate group and the higher/lower lactate group, and compared their baseline information, surgery-related information, overall survival (OS) and disease-free survival (DFS).ResultsA total of 1473 patients were included in this study. Comparing the clinical data of the higher/lower bicarbonate group and the higher/lower lactate group, the lower group were older (p < 0.01), had higher rates of coronary heart disease (CHD) (p = 0.025), a higher proportion of colon tumors (p < 0.01), larger tumor size (p < 0.01), higher rates of open surgery (p < 0.01), more intraoperative blood loss (p < 0.01), higher overall complications (p < 0.01) and 30-day deaths (p < 0.01). The higher LL patients had more male patients (p < 0.01), higher body mass index (BMI) (p < 0.01) and drinking rates (p = 0.049), higher rates of type 2 diabetes mellitus (T2DM) (p < 0.01) and lower rates of open surgery (p < 0.01). In multivariate analysis, age (p < 0.01), BMI (p = 0.036), T2DM (p = 0.023), and surgical methods (p < 0.01) were independent risk factors of overall complications. The independent risk factors for OS included age (p < 0.01), tumor site (p = 0.014), tumor stage (p < 0.01), tumor size (p = 0.036), LL (p < 0.01), and overall complications (p < 0.01). The independent risk factors of DFS included age (p = 0.012), tumor site (p = 0.019), tumor stage (p < 0.01), LL (p < 0.01), and overall complications (p < 0.01).ConclusionPreoperative LL significantly affected postoperative OS and DFS of CRC patients, but bicarbonate might not affect the prognosis of CRC patients. Therefore, surgeons should actively focus on and adjust the LL of patients before surgery.

The Impact of Serum Parameters Associated with Kidney Function on the Short-Term Outcomes and Prognosis of Colorectal Cancer Patients Undergoing Radical Surgery.

The current study was designed to investigate the impact of blood urea nitrogen (BUN), serum uric acid (UA), and cystatin (CysC) on the short-term outcomes and prognosis of colorectal cancer (CRC) patients undergoing radical surgery. CRC patients who underwent radical resection were included from Jan 2011 to Jan 2020 in a single clinical centre. The short-term outcomes, overall survival (OS), and disease-free survival (DFS) were compared in different groups. A Cox regression analysis was conducted to identify independent risk factors for OS and DFS. A total of 2047 CRC patients who underwent radical resection were included in the current study. Patients in the abnormal BUN group had a longer hospital stay (p=0.002) and more overall complications (p=0.001) than that of the normal BUN group. The abnormal CysC group had longer hospital stay (p < 0.01), more overall complications (p=p < 0.01), and more major complications (p=0.001) than the normal CysC group. Abnormal CysC was associated with worse OS and DFS for CRC patients in tumor stage I (p < 0.01). In Cox regression analysis, age (p < 0.01, HR = 1.041, 95% CI = 1.029-1.053), tumor stage (p < 0.01, HR = 2.134, 95% CI = 1.828-2.491), and overall complications (p=0.002, HR = 1.499, 95% CI = 1.166-1.928) were independent risk factors for OS. Similarly, age (p < 0.01, HR = 1.026, 95% CI = 1.016-1.037), tumor stage (p < 0.01, HR = 2.053, 95% CI = 1.788-2.357), and overall complications (p=0.002, HR = 1.440, 95% CI = 1.144-1.814) were independent risk factors for DFS. In conclusion, abnormal CysC was significantly associated with worse OS and DFS at TNM stage I, and abnormal CysC and BUN were related to more postoperative complications. However, preoperative BUN and UA in the serum might not affect OS and DFS for CRC patients who underwent radical resection.

Long non-coding RNA CCL14-AS suppresses invasiveness and lymph node metastasis of colorectal cancer cells by regulating MEP1A

BackgroundLong non-coding RNAs (lncRNAs) play important roles in the biology of colorectal cancer (CRC). There are several lncRNAs associated with invasion and metastasis have been characterized in CRC. However, studies focusing on the precise molecular mechanisms by which lncRNAs function in lymph node (LN) metastasis in CRC are still limited.MethodsIn this study, by analyzing TCGA dataset, we identified that AC244100.2 (termed CCL14-AS), a novel lncRNA enriched in the cytoplasm, was negatively correlated with LN metastasis and unfavorable prognosis of CRC. In situ hybridization was used to examine CCL14-AS expression in clinical CRC tissues. Various functional experiments including migration assay and wound-healing assay were used to investigate the effects of CCL14-AS on CRC cells migration. The nude mice popliteal lymph node metastasis model assay further confirmed the effects of CCL14-AS in vivo.ResultsCCL14-AS expression was significantly downregulated in CRC tissues compared to adjacent normal tissues. In addition, low CCL14-AS expression was correlated with advanced T classification, LN metastasis, distant metastasis, and shorter disease-free survival of CRC patients. Functionally, CCL14-AS overexpression inhibited the invasiveness of CRC cells in vitro and LN metastasis in nude mice. On the contrary, knockdown of CCL14-AS promoted the invasiveness and LN metastasis abilities of CRC cells. Mechanistically, CCL14-AS downregulated the expression of MEP1A via interacting with MEP1A mRNA and reduced its stability. Overexpression of MEP1A rescued the invasiveness and LN metastasis abilities in CCL14-AS-overexpressing CRC cells. Moreover, the expression levels of CCL14-AS was negatively correlated with that of MEP1A in CRC tissues.ConclusionsWe identified a novel lncRNA, CCL14-AS, as a potential tumor suppressor in CRC. Our findings supported a model in which the CCL14-AS/MEP1A axis serves as critical regulator in CRC progression, suggesting a novel biomarker and therapeutic target in advanced CRC.

Identification of potential biomarkers for colorectal cancer by clinical database analysis and Kaplan-Meier curves analysis.

This study aimed to explore critical genes as potential biomarkers for the diagnosis and prognosis of colorectal cancer (CRC) for clinical utility. To identify and screen candidate genes involved in CRC carcinogenesis and disease progression, we downloaded microarray datasets GSE89076, GSE73360, and GSE32323 from the GEO database identified differentially expressed genes (DEGs), and performed a functional enrichment analysis. A protein-protein interaction network was constructed, and correlated module analysis was performed using STRING and Cytoscape. The Kaplan-Meier survival curve shows the survival of the hub genes. The expression of cyclin-dependent kinase (CDK1), cyclin B1 (CCNB1), and PCNA in tissues and changes in tumor grade were analyzed. A total of 329 DEGs were identified, including 264 upregulated and 65 downregulated genes. The functions and pathways of DEGs include the mitotic cell cycle, poly(A) RNA binding replication, ATP binding, DNA replication, ribosome biogenesis in eukaryotes, and RNA transport. Forty-seven Hub genes were identified, and biological process analysis showed that these genes were mainly enriched in cell cycle and DNA replication. Patients with mutations in CDK1, PCNA, and CCNB1 had poorer survival rates. CDK1, PCNA, and CCNB1 were significantly overexpressed in the tumor tissues. The expression of CDK1 and CCNB1 gradually decreased with increasing tumor grade. CDK1, CCNB1, and PCNA can be used as potential markers for the diagnosis and prognosis of CRC. These genes are overexpressed in colon cancer tissues and are associated with low survival rates in CRC patients.

Predictive value of tumor-infiltrating lymphocytes detected by flow cytometry in colorectal cancer

The high heterogeneity of tumor cells and the surrounding immune microenvironment affects the response to treatment in colorectal cancer (CRC) patients. Therefore, there is a need to identify new immune biomarkers to predict the treatment efficacy of CRC. This study aimed to explore the predictive value of tumor-infiltrating lymphocytes (TIL) for survival in CRC patients. Flow cytometry and gated analysis were performed to measure the TILs in tissue samples obtained from 536 CRC patients. The COX regression analysis showed that the CD8 + CD279+ cells had the highest impact of all evaluated TILs on postoperative disease-free survival (DFS) (P < 0.05). The optimal CD8 + CD279+ cutoff point for the prediction of survival was 12.2%. The Kaplan-Meier analysis showed significantly higher DFS in the high CD8 + CD279+ group compared with the low CD8 + CD279+ group (P < 0.05). CD8 + CD279+ cells were associated with DFS in CRC patients with the KARS mutation, MSI/MMR, perineural invasion, and those treated with neoadjuvant chemotherapy and other chemotherapeutic treatments (P < 0.05). After the multivariate adjustment, the expression of CD8 + CD279+ remained an independent risk factor for DFS. Overall, the CD8 + CD279+ cells were identified as an independent prognostic factor in CRC patients and could be used as a potential marker for postoperative DFS.

Molecular Subtypes Based on Cuproptosis-Related Genes and Tumor Microenvironment Infiltration Characterization in Colorectal Cancer.

Recent studies have demonstrated the biological significance of cuproptosis modification, a newly discovered programmed cell death, in tumor progression. Nonetheless, the potential role of cuproptosis-related genes (CRGs) in the immune landscape and tumor microenvironment (TME) formation of colorectal cancer (CRC) remains unknown. We comprehensively assessed cuproptosis modification patterns of 1339 CRC samples based on 27 CRGs and systematically analyzed the correlation of these patterns with TME. The CRG-score was constructed to quantify cuproptosis characteristics by LASSO and multivariate Cox regression methods, and its predictive capability was validated in an independent cohort. We identified three distinct cuproptosis modification patterns in CRC. The TME immune cell infiltration demonstrated immune heterogeneity among these three subtypes. Enrichment for multiple metabolism signatures was pronounced in cluster A. Cluster C was significantly correlated with the signaling pathways of immune activation-related, resulting in poor prognoses. Cluster B with mixed features possibly represents a transition phenotype or intratumoral heterogeneity. Then, based on constructed eight-gene CRG-score, we found that the signature could predict the disease-free survival of CRC patients, and the low CRG-score was related to increased neoantigen load, immunity activation, and microsatellite instability-high (MSI-H). Additionally, we observed significant correlations of the CRG-score with the cancer stem cell index and chemotherapeutic drug susceptibility. This study demonstrated that cuproptosis was correlated with tumor progression, prognosis, and TME. Our findings may improve the understanding of CRGs in TME infiltration characterization of CRC patients and contribute to guiding more effective clinical therapeutic strategies.

IGFBP5 is Upregulated and Associated with Poor Prognosis in Colorectal Cancer.

PurposeThis study aimed to investigate the role of IGFBP5 in colorectal cancer (CRC) and the relationship between the expression of IGFBP5 and clinicopathological parameters in CRC patients.Patients and MethodsImmunohistochemical analysis was used to detect the expression of IGFBP5 and its correlation with clinicopathological parameters of CRC patients. Prognosis analysis, gene set enrichment analysis, and protein interaction network analysis were performed using bioinformatics analysis. The Genomics of Drug Sensitivity in Cancer (GDSC) dataset was used to analyze the correlation between the expression of IGFBP5 and drug resistance.ResultsImmunohistochemical analysis revealed that the expression of IGFBP5 was significantly higher in CRC tissues than in para-cancerous tissues (P < 0.05). High expression of IGFBP5 was associated with tumor differentiation and the N stage of CRC (P < 0.05). Moreover, high expression of IGFBP5 predicted worse overall survival and disease-free survival in CRC patients (P < 0.05). The expression of IGFBP5 was associated with cell–matrix adhesion, extracellular matrix binding, and collagen binding (P < 0.05). Furthermore, IGFBP5 was involved in the Hedgehog signaling pathway and PI3K-Akt signaling pathway (P < 0.05). IGF1, IGF2, SPP1, LTBP1, and FAM20C were most closely related to IGFBP5.ConclusionThe expression of IGFBP5 is upregulated and associated with tumor differentiation, lymph node metastasis, drug resistance, and prognosis in CRC patients.

The effect of metformin on the survival of colorectal cancer patients with type 2 diabetes mellitus

Evidence from previous studies suggests a protective effect of metformin in patients with colorectal cancer (CRC). The aim of this study was to examine the associations between metformin use and overall survival (OS) and disease-free survival (DFS) in CRC patients with type 2 diabetes mellitus (DM). We retrospectively included patients who underwent surgery for CRC at Limoges’ University Hospital between 2005 and 2019 and diagnosed with type 2 DM. Data on the characteristics of patients, CRC, comorbidities and drug exposure were collected from the electronic medical records. The exposure was the use of metformin and the outcomes were OS and DFS. We identified 290 CRC patients with type 2 DM. A total of 144 (49.7%) of them were treated with metformin. Metformin users were significantly younger, with higher body mass index and less diabetes-related complications compared to non-users. The 2-year OS was significantly higher in metformin users than in non-users (86.9 ± 2.9% vs. 71.0 ± 4.0%, p = 0.001). In multivariate analysis, metformin use was associated with better OS (adjusted hazard ratios [aHR] = 0.45 95% confidence interval [95% CI]: 0.21–0.96) and better DFS (aHR = 0.31; 95% CI: 0.18–0.54). In conclusion, the use of metformin may improve OS and DFS in CRC patients with type 2 DM.

TOX3 regulates the proliferation and apoptosis of colorectal cancer by downregulating RhoB via the activation of the MAPK pathway.

TOX high mobility group box family member 3 (TOX3) can function as tumor suppressor or oncogene in different tumors, while ras homolog family member B (RhoB) is a well-known tumor suppressor. The expression and role of TOX3 in colorectal cancer (CRC) are unknown. This study aimed to investigate the expression of TOX3 in CRC and the role of TOX3/mitogen-activated protein kinase (MAPK)/RhoB signaling in the proliferation and apoptosis of CRC cells. We showed that TOX3messenger RNA (mRNA) and protein expression levels were significantly upregulated in CRC tissues and cell lines. High TOX3 expression was associated with high T stage, nodal invasion, and advanced tumor stage. Disease-free survival (DFS) was shortened for CRC patients with high expression of TOX3, while overall survival showed no significant difference. TOX3 promoted proliferation, inhibited apoptosis, and decreased the sensitivity to oxaliplatin of CRC cells. In addition, the inhibition of TOX3 led to the upregulation of RhoB, and RhoB overexpression suppressed the proliferation and promoted apoptosis of CRC cells. Moreover, TOX3 overexpression upregulated MAPK signaling, while MAPK signaling inhibitor U0126 induced CRC cell proliferation arrest or apoptosis, and attenuated the inhibition of RhoB in TOX3 overexpression cells. In addition, the overexpression of TOX3 increased tumor volume in nude mice. In conclusion, TOX3 may be an oncogene in CRCand can predict DFS inCRC patients. TOX3/MAPK/RhoB signaling plays an important role in the modulation of proliferation and apoptosis of CRC cells.

Salivary Fusobacterium nucleatum serves as a potential biomarker for colorectal cancer

SummaryFusobacterium nucleatum (Fn) is primarily colonized in the oral cavity. Recently, Fn has been closely associated with the tumorigenesis of colorectal cancer (CRC). Here, we showed that the relative level of Fn DNA was increased in the saliva of the CRC group compared with the normal colonoscopy, hyperplastic polyp, and adenoma groups. Receiver operating characteristic curve analysis illustrated that Fn DNA was superior to carcinoembryonic antigen and carbohydrate antigen 19-9 in CRC diagnosis. Moreover, levels of Fn DNA were associated with the overall survival and disease-free survival of CRC patients, which was an independent factor for prognostic prediction. Transcriptome sequencing identified 1,287 differentially expressed mRNAs in tumor tissues between CRC patients with high-Fn and low-Fn infection. Kyoto encyclopedia of genes and genomes analysis showed that ECM-receptor interaction and focal adhesion were the top two significant pathways. Overall, salivary Fn DNA may be a noninvasive diagnostic and prognostic biomarker for CRC patients.

Creation and Validation of a Survival Nomogram Based on Immune-Nutritional Indexes for Colorectal Cancer Patients.

Nutritional and inflammatory status was associated with prognosis in various types of malignant cancer, including colorectal cancer (CRC). This clinical research was performed to estimate the prognostic role of immune-nutritional indexes CRC in patients and to set up a survival nomogram based on the significant immune-nutritional indexes. 1024 CRC patients underwent surgical resection from Wuhan Union Hospital were enrolled and divided into the test cohort (n = 717) and validation cohort (n = 307). A total of 19 immune-nutritional indexes were included into our analysis. The Cox regression analysis was utilized to identify the informative immune-nutritional indexes which were closely associated with overall survival (OS) and disease-free survival (DFS). Survival nomograms were created in the test set and further verified in the validation set. Td-ROC was curved to estimate the predictive performance of survival nomograms for CRC patients. Body mass index (BMI), chemotherapy, TNM stage, T stage, lactate dehydrogenase (LDH)/prealbumin (PA), monocytes (MON)/albumin (ALB), and prognostic nutritional index (PNI) were seven potent prognostic biomarkers of CRC patients. We created an OS-nomogram based on the seven risk indexes, and the predictive accuracy expressed with area under curve (AUC) was 0.826 for 1-year, 0.809 for 3-year, and 0.80 for 5-year OS rates in the test set and 0.795 for 1-year, 0.749 for 3-year, and 0.647 for 5-year OS rates in the validation set. TNM stage, T stage, LDH/ALB, and MON/ALB were risk factors for unfavorable DFS in CRC patients. We further built a DFS-nomogram based on the four risk factors, and the predictive performance presented with AUC was 0.806 for 1-year, 0.763 for 3-year, and 0.82 for 5-year DFS rates in the test set, and 0.704 for 1-year, 0.692 for 3-year, and 0.692 for 5-year DFS rates in the validation set. Our survival nomogram based on immune-nutritional indexes is a useful and potential prognostic tool in CRC patients.

A novel inflammation-related prognostic biomarker for predicting the disease-free survival of patients with colorectal cancer

BackgroundTo develop and evaluate the prognostic value of a comprehensive inflammatory biomarker for postoperative colorectal cancer (CRC) patients.MethodsA total of 646 CRC patients were recruited between August 2017 and December 2019 from Fujian Medical University Union Hospital, with follow-up data up to 2021. The least absolute shrinkage and selection operator method (LASSO) was used to select inflammation indicators in order to construct a comprehensive biomarker (named NSAP). The Cox regression model was utilized to analyze the association between the NSAP and the disease-free survival (DFS) of CRC. Predictive performance and clinical utility of prognostic models were evaluated by area under the curve (AUC) and decision curve analyses (DCAs).ResultsDuring a median follow-up of 23 months, 95 clinical outcomes were observed, with a 1-year survival rate is 89.47%. A comprehensive inflammatory biomarker (NSAP) was established based on four blood indicators (including neutrophil-to-lymphocyte ratio (NLR), neutrophil×monocyte-to-lymphocyte ratio (SIRI), albumin-to-globulin ratio (AGR), and platelet-to-lymphocytes ratio (PLR)). Patients with a lower NSAP had significantly associated with better DFS of CRC (HR=0.53, 95%CI 0.32–0.89). Moreover, compared to a previously established model, the traditional TNM staging system or/and tumor markers, the nomogram based on NSAP displayed more excellent predictive ability (0.752 vs 0.597, 0.711 and 0.735, P < 0.05). DCAs also demonstrated that the established nomogram had better utility for decision making.ConclusionsOur study suggests that NSAP may be a useful comprehensive prognostic biomarker for predicting the DFS of CRC patients. The nomogram based on NSAP can be considered a valuable tool to estimate the prognosis of patients with CRC.