Combined detection of preoperative neutrophil to lymphocyte ratio and interleukin-6 as an independent prognostic factor for patients with non-metastatic colorectal cancer

BackgroundThis study sought to explore the value of the neutrophil to lymphocyte ratio (NLR) and interleukin-6 (IL-6) in predicting the prognosis of patients with non-metastatic colorectal cancer (CRC).MethodsThe data of 88 surgical CRC patients were retrospectively analyzed. A receiver operating characteristic (ROC) curve analysis was conducted to determine the patients’ thresholds for the NLR and IL-6. Kaplan-Meier curve and Cox regression models were used to assess the prognostic values.ResultsA ROC analysis was conducted to calculate the NLR cut-off value. The area under the curve (AUC) of the NLR was 0.739 [95% confidence interval (CI): 0.634 to 0.844] for overall survival (OS), and 0.799 (95% CI: 0.705 to 0.892) for disease-free survival (DFS). The AUC of IL-6 was 0.773 (95% CI: 0.670 to 0.876) for OS, and 0.817 (95% CI: 0.728 to 0.906) for DFS. The AUC of NLR + IL-6 was 0.805 (95% CI: 0.710 to 0.899) for OS and 0.853 (95% CI: 0.774 to 0.933) for DFS, which were higher than the NLR or IL-6 alone AUCs for OS and DFS. In addition, a high NLR and IL-6 value was significantly correlated with tumor differentiation and tumor-node-metastasis staging. The NLR was positively correlated with IL-6 level (r=0.481). The results of the Kaplan-Meier analysis showed that a high NLR + IL-6 value was correlated with worse OS and DFS.ConclusionsA high NLR and IL-6 value is a better independent prognostic biomarker of CRC than the NLR or IL-6 level alone, and may be applied in clinical practice to identify high-risk patients.     

The prognostic role of neutrophil-to-lymphocyte ratio and C-reactive protein in metastatic colorectal cancer using regorafenib: a systematic review and meta-analysis

BackgroundThe application of regorafenib has changed the landscape of subsequent-line treatment in metastatic colorectal cancer (mCRC). Baseline neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP), as two of the most common inflammatory factors, are suggested to be potential prognostic factors for mCRC patients treated with regorafenib, but the results are conflicting. In this study, we conducted a meta-analysis to evaluate the prognostic role of NLR and CRP in mCRC patients treated with regorafenib.MethodsWe searched online databases such as Embase, PubMed, and the Cochrane library up to April 2022, without language limitation, to identify clinical studies evaluating the prognostic role of NLR or CRP in regorafenib treated mCRC patients. The main endpoints were hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS). The associations between NLR, CRP, and the above endpoints were extracted. Review Manager 5.4 was used to conduct the combined analysis. The Newcastle-Ottawa Scale (NOS) was applied for assessing the quality of included studies. Heterogeneity was detected by chi-square-based Q test and I² statistic, and publication bias was evaluated by funnel plot asymmetry and Egger’s test.ResultsEight studies involving 1,287 cases were included, with 5 reporting survival outcomes based on NLR level and 4 reporting survival according to CRP level. The results of meta-analysis showed that the calculated HR of OS for subsequent-line regorafenib in mCRC patients with high versus low NLR was 2.52 [I²=52%, 95% confidence interval (CI): 1.75–3.64; P<0.00001]. The combined HR of PFS with high versus low baseline NLR was 2.11 (I²=12%, 95% CI: 1.80–2.48; P<0.00001). For patients with a high level of CRP, the OS was significantly shorter when compared with patients with a low level of CRP (I²=0%, HR =1.88; 95% CI: 1.55–2.29; P<0.00001).ConclusionsHigh level of NLR could be associated with OS in mCRC patients treated with regorafenib. It is suggested that the impact of regorafenib on OS may vary according to the baseline NLR.     

Elevated kinesin family member 26B is a prognostic biomarker and a potential therapeutic target for colorectal cancer

Background

Kinesins play a key role in the development and progression of many human cancers. The present study investigated the expression and clinical significance of kinesin family member 26B (KIF26B) in colorectal cancer (CRC).

Methods

Using quantitative real-time PCR and Western blot analyses as well as immunohistochemical staining of a tissue microarray we examined KIF26B mRNA and protein levels in CRC tumor tissues and paired adjacent normal mucosa. Moreover, the effect of KIF26B knockdown on CRC cell proliferation was investigated using Cell Counting Kit-8 assays.

Results

Expression of KIF26B was found to be elevated in CRC. Suppression of KIF26B inhibited CRC cell proliferation. Furthermore, upregulated expression of KIF26B was significantly correlated with tumor size (P = 0.020), American Joint Committee on Cancer (AJCC) stage (P = 0.018), T stage (P = 0.026), N stage (P = 0.013), and differentiation histology (P = 0.047). KIF26B was also shown to be an independent prognostic indicator of overall survival for CRC patients (HR 5.621; 95% CI 2.302–13.730; P < 0.001).

Conclusion

Our data indicate that KIF26B plays an important role in colorectal carcinogenesis and functions as a novel prognostic indicator and a potential therapeutic target for CRC.     

Comprehensive analysis of immune related lncRNAs in the tumor microenvironment of stage II–III colorectal cancer

BackgroundLong non-coding RNAs (lncRNAs) associated with immunological function have increasingly been found to act as effective prognostic biomarkers of the overall survival (OS) of colorectal cancer (CRC) patients. We sought to identify a signature of immune-related lncRNAs that offered value as a tool for the prospective prognostic evaluation of patients with stage II–III CRC.MethodsThe clinical and gene expression data of CRC patients in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases was obtained and separated into a training cohort composed of 202 samples, a test cohort of 124 samples from the {"type":"entrez-geo","attrs":{"text":"GSE72970","term_id":"72970"}}GSE72970 dataset, and a validation cohort of 91 samples from the {"type":"entrez-geo","attrs":{"text":"GSE143985","term_id":"143985"}}GSE143985 dataset.ResultsWe firstly evaluated intratumoral immune cell infiltration by conducting a Single-sample gene set enrichment analyses (ssGSEA) analysis to separate patient tumors into those with low immune cell infiltration and those with high immune cell infiltration. We then compared lncRNA and mRNA expression profiles between these two tumor types, leading us to focus on eight lncRNAs identified within the resultant mRNA-lncRNA co-expression network. Multivariate Cox regression models were then utilized to detect an immune-associated lncRNA signature that offered value for prognostic model construction. Functional analyses revealed this lncRNA signature to be associated with key immunological pathways including the JAK-STAT signaling, T cell receptor signaling, and Rap1 signaling pathways.ConclusionsTogether, our results suggest that our immune-related 4 lncRNA signature can reliably predict stage II–III CRC patient prognosis, thereby guiding efforts to better understand this disease and to effectively treat it.     

Comprehensive bioinformatics analyses identified Homeobox B9 as a potential prognostic biomarker and therapeutic target for gastric cancer

BackgroundThe Homeobox B (HOXB) family promotes tumor progression, but the mechanism of its action in gastric cancer (GC) is unclear. We sought to identify the HOXB family members that are critical to the prognosis of GC patients.MethodsThe Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal, UALCAN, Kaplan-Meier plotter, and the GeneMANIA databases were used to analyze the messenger RNA (mRNA) expression levels, prognostic value, and gene-gene interaction network of the HOXB9 family members in GC. The expression of HOXB9 in GC and its relationship with various clinicopathological parameters and the prognosis of patients were verified by immunohistochemistry.ResultsThe expression of HOXB3, HOXB5, HOXB6, HOXB7, HOXB9, and HOXB13 mRNA was significantly upregulated in GC. There was a significant correlation between the upregulation of HOXB3, HOXB5, and HOXB9 mRNA and a low overall survival (OS) rate. The high expression of HOXB7, HOXB9, and HOXB13 mRNA was closely correlated to tumor grade and stage. HOXB9 was the HOXB family member most closely related to the occurrence and development of GC. A further analysis showed that HOXB9 might be involved in deoxyribonucleic acid repair and division regulation. A validation study showed that the advanced cancer group had a higher level of HOXB9 expression than the early cancer group. The high expression of HOXB9 in gastric tissue plays an important role in the survival and prognosis of GC patients.ConclusionsHOXB family members have different degrees of abnormal expression in GC. High HOXB9 expression in GC tissues was significantly correlated with a worse prognosis. Thus, HOXB9 is a potential novel biomarker and therapeutic target for GC.     

The prognostic role of fasting plasma glucose levels on survival in advanced colorectal cancer patients with type II diabetes mellitus: a retrospective cohort study

BackgroundPrevious studies have shown that type II diabetes mellitus (T2DM) has a significant effect on the occurrence and development of colorectal cancer (CRC). The associations between fasting plasma glucose (FPG) and overall survival (OS) of CRC patients with T2DM are still controversial. The present study sought to examine the association between FPG control and OS in advanced CRC patients with T2DM.MethodsThe data of advanced CRC patients with T2DM who were admitted to Harbin Medical University Cancer Hospital from May 2010 to May 2019 were retrospectively collected and examined. Record patient clinical data including age, sex, blood pressure, body mass index (BMI), primary tumor site, T stage, N stage, histological grade, number of metastatic sites, primary tumor surgery, etc. The baseline FPG which was measured before the first-line treatment and the FPG measured before each admission treatment during advanced chemotherapy were collected. OS was determined as the end point of the study. All the patients were followed-up for at least 3 years. The Kaplan-Meier log-rank method and the Cox proportional hazards regression analyses were used for the analysis of OS and hazard factors.ResultsA total of 210 patients met the inclusion criteria for the study, who had a median age of 66.5 years; 94 patients had baseline FPG levels ≤7 mmol/L, and 116 patients had baseline FPG levels >7 mmol/L. Compared to the baseline FPG >7 mmol/L group, the OS of patients in the baseline FPG ≤7 mmol/L group was not significantly prolonged (P=0.88). There were 52 patients in the FPG-A group and 61 in the FPG-B group. Similarly, there was no significant difference in OS between the FPG-A and FPG-B groups (P=0.96). The N0 stage subgroup analysis showed that glycemic control ≤7 mmol/L resulted in longer OS.ConclusionsThe results of the present study showed that FPG levels may not affect the survival of advanced CRC patients with T2DM. However, this needs multicenter prospective studies to confirm.     

Circulating lncRNA EGFR-AS1 as a diagnostic biomarker of colorectal cancer and an indicator of tumor burden

BackgroundColorectal cancer (CRC) is one of the most common malignancies. Although CRC treatment has been significantly improved, patient survival remains low because most patients already have advanced disease at diagnosis. Early screening and diagnosis of tumors is critical; however, the current tissue biopsy and radiological evaluation methods have very limited effectiveness. Therefore, establishing new convenient and non-invasive biomarkers is urgently needed for timely detection, therapeutic assessment, and prognostic prediction. At present, non-coding RNAs (ncRNAs) have attracted research attention owing to their potential oncological applications.MethodsThe long ncRNA epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) is overexpressed in multiple malignancies including CRC. The present study examined the circulating EGFR-AS1 level in CRC, and the results showed that EGFR-AS1 could be considered an indicator of tumor burden.ResultsElevated circulating EGFR-AS1 levels were detected in CRC cases (n=128) compared with control cases comprising endoscopy confirmed CRC-free individuals [n=64, median expression normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 1.578 vs. 0.780, P<0.001]. Individuals with larger tumors (≥5 cm) had elevated circulating EGFR-AS1 levels compared to those with smaller tumors (<5 cm, 1.739 vs. 1.290, P<0.001). The expression of serum EGFR-AS1 in stage III/IV CRC was higher than that in stage I/II CRC (1.691 vs. 1.412, P<0.05). Plasma EGFR-AS1 levels were markedly reduced following surgical resection of colorectal lesions in a subset of patients [n=32, 1.192 (pre-surgery) vs. 0.692, P<0.001]. Furthermore, the expression of EGFR-AS1 in resected CRC tissues was significantly higher than that in paracancerous tissues (n=32, 1.336 vs. 0.487, P<0.001).ConclusionsThese results highlight the potential of EGFR-AS1 as a diagnostic biomarker in CRC.     

Survival analysis and prognostic factors of palliative radiotherapy in patients with metastatic colorectal cancer: a propensity score analysis

BackgroundRadiation therapy (RT) is known to have beneficial effects on the palliative treatment of patients with advanced cancer. However, valid data on this treatment method are limited, especially for patients with metastatic colorectal cancer (mCRC). This study aimed to identify prognostic factors and investigate the outcomes of mCRC patients who received palliative RT.MethodsA total of 488 mCRC patients who underwent systemic therapy with or without palliative RT between 2014 and 2019 were included in the study. Of the 488 patients, 155 received systemic treatment combined with palliative RT (RT group), while 333 were only administered systemic treatment (non-RT group). Propensity score matching (PSM) was conducted to eliminate possible bias, and overall survival (OS) was calculated using the Kaplan-Meier (KM) method. A log-rank test was used to compare the survival outcomes of each group, and a multivariate analysis was conducted using a Cox proportional hazards model.ResultsThe RT group had a higher OS than that of the non-RT group (P=0.001). After PSM, the median OS of the RT group was 50.8 months, and for the non-RT group it was 32.2 months (P=0.003). Subgroup analysis revealed that RT had a better effect on the OS of patients who had synchronous metastasis, or who didn’t receive targeted therapy or local treatment (including surgery, ablation, and intervention). Multivariate analysis of the whole cohort showed that palliative RT was associated with improved OS. Moreover, multivariate analysis of the RT group showed that systemic therapy before RT, and the site of RT was in the liver and lung, were independent prognostic factors affecting survival time.ConclusionsWe demonstrated that systemic treatment followed by palliative RT led to a better OS for mCRC patients. This combination method can therefore be seen as a suitable treatment approach for patients with mCRC.     

Expression characteristics of long non-coding RNA in colon adenocarcinoma and its potential value for judging the survival and prognosis of patients: bioinformatics analysis based on The Cancer Genome Atlas database

BackgroundTo investigate the expression characteristics of long non-coding RNA (lncRNA) in colon adenocarcinoma (COAD) and its potential value in predicting the prognosis of patient survival.MethodsWe downloaded COAD-related RNA sequencing (RNA-seq) data and patient survival data from The Cancer Genome Atlas (TCGA). The data were analyzed for lncRNA expression differences, subjected to Cox regression analysis for survival rate, and Kaplan-Meier (KM) survival curves were plotted to analyze the role of the key genes related to prognostic survival by pathway enrichment analysis.ResultsThe data of 494 COAD clinical samples from TCGA were analyzed; 204 lncRNAs were differentially expressed, 156 were up-regulated, and 48 were down-regulated. The 10 genes with the most significant expression differences were Linc02418, Blacat1, ELFN1-AS1, CRNDE, {"type":"entrez-nucleotide","attrs":{"text":"AC002384.1","term_id":"2275183","term_text":"AC002384.1"}}AC002384.1, {"type":"entrez-nucleotide","attrs":{"text":"AL353801.1","term_id":"7635432","term_text":"AL353801.1"}}AL353801.1, LINC01645, {"type":"entrez-nucleotide","attrs":{"text":"AC073283.2","term_id":"8571848","term_text":"AC073283.2"}}AC073283.2, {"type":"entrez-nucleotide","attrs":{"text":"AC087379.1","term_id":"11994025","term_text":"AC087379.1"}}AC087379.1, and LINC00484. Cox regression analysis of 204 lncRNA genes showed that 23 lncRNA genes with significant effects on the prognosis and survival rate of COAD patients were obtained when P<0.05 was used as the threshold. With P≤0.001 as the threshold, the KM curves of 4 genes (Linc02257, Linc02474, {"type":"entrez-nucleotide","attrs":{"text":"Ac010789.1","term_id":"5917964","term_text":"AC010789.1"}}Ac010789.1, {"type":"entrez-nucleotide","attrs":{"text":"Ac083967.1","term_id":"10717234","term_text":"AC083967.1"}}Ac083967.1) were statistically significant (P<0.05). The gene Linc02257 was selected for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and it was revealed that the inheritance of Linc02257-regulated gene expression was closely related to tumor development, such as collagen-containing extracellular matrix, organogenesis, activity of membrane protein receptors, and ion channel activity. The signaling pathways regulated by Linc02257 were also closely related to tumors, such as neuroactive ligand-receptor interaction, the PI3K-AKT signaling pathway, calcium signaling pathway, and protein digestion and absorption.ConclusionsIn COAD, lncRNA is differentially expressed and plays an important role in the disease regulation. It has potential application value in the diagnosis, targeted therapy, and prognosis of COAD patients.     

ANTXR1 as a potential prognostic biomarker for hepatitis B virus-related hepatocellular carcinoma identified by a weighted gene correlation network analysis

BackgroundWith high incidence and mortality rates, hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. Chronic hepatitis B virus (HBV) infection is a leading cause of HCC, especially for Asians and blacks. However, the molecular mechanisms underlying HBV-related HCC are unclear. This study sought to identify novel prognostic biomarkers and explore the potential pathogenesis of HBV-related HCC.MethodsThe gene expression profiles and corresponding clinical information of HCC from The Cancer Genome Atlas Liver Hepatocellular Carcinoma data set were analyzed by a weighted gene co-expression network analysis. Correlations between the co-expression modules and clinical traits were calculated. Next, key modules associated with HBV infection were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted for the genes in the key modules. The hub genes were identified based on the protein-protein interaction (PPI) network via the Cytoscape. Finally, an overall survival (OS) analysis was performed.ResultsThe two modules (i.e., the brown and yellow modules) most relevant to HBV infection were constructed. A functional enrichment analysis revealed that the genes in the two modules were mainly enriched in HCC-related pathways, such as the phosphatidylinositol-3-kinase and protein kinase B signaling pathway, focal adhesion, human papillomavirus infection, the Rap1 signaling pathway, and the cyclic guanosine monophosphate-dependent protein kinase (cGMP-PKG) signaling pathway. Ten hub genes [i.e., COL3A1, ANTXR1, COL14A1, THBS2, ADAMTS2, AEBP1, PRELP, EMILIN1, DCN and PODN] in the brown module, and 10 hub genes [i.e., USP34, SEC24C, ZNF770, STAG1, TSTD2, PKD1P6, CCNK, GFT2I, NT5C2 and SMG6] in the yellow module were identified. Among the hub genes, ANTXR1 (Anthrax-toxin receptor 1) was significantly correlated with HBV-related HCC patients’ OS.ConclusionsANTXR1 represents a potential therapeutic target for HBV-related HCC. This study offers novel insights into the molecular mechanisms of HBV-induced tumorigenesis, which needs to be further validated by basic experiments and large-scale cohort studies.     

PD-L1和PD-1作为治疗结直肠癌的免疫检查新靶点的研究进展

免疫抗癌疗法是一种新的治疗实体肿瘤的方法。在这个新的领域,免疫系统里作为负向调节因子的免疫检查位点,在抗肿瘤免疫反应领域中起着重要的作用。因此,诸如抗细胞毒性T淋巴细胞相关抗原4(CTLA-4)、程序性细胞死亡蛋白（PD-1）、程序性细胞死亡蛋白配体1（PD-L1）,现在已经研发出了针对前述这三者免疫检查位点的阻断因子,用于抗肿瘤的药物,在临床前期研究和临床研究中有着可喜的成果。本文综述关于在结直肠癌中免疫检查位点阻断剂的生物背景和临床研发最新进展。关于阻断PD-1和PD-L1的临床前期试验结果的前景令人充满希望,尤其是在带有微卫星不稳定性（MSI）的结直肠癌患者中更加明显。接下来进一步深入开展的临床试验将证实这些初步结果,并且评估这二者联合治疗方法的可行性和确认这两个生物标记物作为免疫检查位点阻断剂的效应在哪些人群中更有可能受益或更加抵抗。     

术前白蛋白与纤维蛋白原比值对三阴性乳腺癌患者的预后影响和临床意义

目的:探讨术前白蛋白与纤维蛋白原比值（albumin to fibrinogen,AFR）对三阴性乳腺癌患者的预后影响和临床意义。方法:回顾性分析我院自2010年1月至2013年12月间就诊的195例三阴性乳腺癌患者。用受试者工作特性曲线（ROC）确定AFR的最佳临界值。采用卡方检验或Fisher精确检验分析比较计数资料。Kaplan-Meier方法和Log rank方法用于分析生存曲线。单因素和多因素分析（Cox比例风险回归模型）用于评估独立的预后因素。结果:ROC曲线确定AFR最佳临界值为15.00,依此分两组,即低AFR组（AFR＜15.00）和高AFR组（AFR≥15.00）。单因素和多因素分析显示AFR是三阴性乳腺癌DFS（P=0.045,HR:0.627,95%CI:0.397~0.990;P=0.026,HR:0.595,95%CI:0.377~0.940）和OS（P=0.039,HR:0.238,95%CI:0.061~0.927;P=0.001,HR:0.385,95%CI:0.221~0.670）的独立预后因素。高AFR组患者术后中位DFS和OS显著高于低AFR组患者,差异具有显著统计学意义（χ2=8.190,P=0.004;χ2=8.720,P=0.003）。散点图分析显示,AFR与ALB呈显著正相关（R2=0.028,P=0.020）,AFR与FIB呈显著负相关（R2=0.516,P＜0.000 1）。此外,对伴有淋巴管侵犯的患者,高AFR组患者比低AFR组患者术后生存时间长,预后更好。结论:术前AFR是影响患者预后的独立因素。AFR具有操作简单、易于推广、成本低、可重复性好等优点,具有潜在的临床应用价值。     

Enrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist,gremlin-1

The cancer invasion front (CIF), a spatially-recognized area due to the frequent presence of peritumoral desmoplastic reaction, represents a cancer site where many hallmarks of cancer metastasis occur. It is now strongly suggested that the desmoplastic microenvironment holds crucial information for determining tumor development and progression. Despite extensive research on tumor-host cell interactions at CIFs, the exact paracrine molecular network that is hardwired into the proteome of the stromal and cancer subpopulations remains partially understood. Here, we interrogated the signaling pathways and the molecular functional signatures across the proteome of a desmoplastic coculture model system of colorectal cancer progression. We discovered a group of bone morphogenetic protein (BMP) antagonists that coordinates major biological programs in CIFs, including cell proliferation, invasion, migration and differentiation processes. Using a mathematical model of cancer cell progression, coupled to in vitro cell migration assays, we demonstrated that the prominent BMP antagonist gremlin-1 (GREM1) may trigger motility of cancer cell cohorts. Our data collectively demonstrate that the desmoplastic CIFs deploy a microenvironmental signature, based on BMP antagonism, in order to regulate the motogenic fates of cancer cell cohorts invading the adjacent stroma.