Quantification of fibrinogen-to-pre-albumin ratio provides an integrating parameter for differential diagnosis and risk stratification of early-stage colorectal cancer.

BACKGROUND: Circulating fibrinogen to pre-albumin ratio (FPR) and albumin to fibrinogen ratio (AFR) are effective factors for predicting the prognosis of colorectal cancer (CRC). However, the role of these two ratios in diagnosing early-stage CRC and identifying the stage II CRC subgroup with high relapse risk remains unknown. This study aimed to assess the potential of FPR and AFR in differential diagnosis and risk stratification of early-stage CRC. METHODS: A discovery (694 and 512 patients with benign colorectal polyps and stage I-II CRC, respectively) and validation (201 benign colorectal polyps cases and 202 stage I-II CRC individuals) cohorts were enrolled in this study. Receiver operating characteristic curve (ROC), Kaplan-Meier curve, and time-dependent ROC were used to evaluate the diagnostic efficacy of AFR and FPR in the two cohorts and overall population, and the discriminating role of FPR in identifying clinical high-relapse risk patients in comparison with common clinical characteristics in stage II CRC patients. RESULTS: The area under the curve (AUC) of the preoperative circulating FPR was higher than that of AFR in the diagnosis of stage I-II CRC from colorectal adenomas and benign colorectal polyps in the discovery and validation cohorts and overall population. Carcinoembryonic antigen (CEA) combined with FPR could effectively discriminate early-stage CRC from colorectal adenomas or benign polyps. Preoperative FPR could effectively distinguish stage II subgroups with high and low relapse risk. It was superior to common clinical characteristics in identifying high-risk surgical patients who could benefit from adjuvant chemotherapy (CT) [time-dependent AUC: 0.637 vs. 0.511, p < 0.001 for predicting recurrence-free survival (RFS); 0.719 vs. 0.501, p < 0.001 for predicting overall survival (OS)]. Furthermore, CT treated stage II patients with FPR > 20 had the highest recurrence (31.16%) and death rates (21.88%), with similar highest recurrence (30.70%) and death (26.82%) rates found in non-CT-treated patients with FPR > 20. Stage II CRC patients with 20 ≥ FPR > 15 could significantly benefit from postoperative CT, as the recurrence (33.30%) and death (35.71%) rates within non-CT treated patients were approximately five times higher than those of the CT-treated cases (6.77% and 7.41% for the recurrence and death rates, respectively). No significant difference in recurrence rate was observed between L-FPR (≤ 15) patients with (10.00%) or without CT (9.76%), indicating that these patients might not require to receive adjuvant CT after curative resection. CONCLUSIONS: Preoperative FPR combined with CEA is superior to common tumor biomarkers, FPR, or AFR in distinguishing early-stage CRC from benign colorectal polyps. Circulating FPR can be an effective biomarker for identifying high-risk patients and choosing suitable therapeutics for early-stage CRC.

Cancer-elicited inflammation attenuates response and outcome in tyrosine kinase inhibitor naive patients with advanced NSCLC.

OBJECTIVE: Cancer elicited inflammation is the main environmental cause leading to carcinogenesis and metastasis of non-small cell lung cancer (NSCLC). Roles of the inflammatory biomarker in predicting the clinical efficacy of tyrosine kinase inhibitor (TKI) and prognosis of naive patients with advanced NSCLC need to be determined, and the best inflammatory predicted biomarker remains unknown. METHODS: A total of 178 eligible advanced NSCLC patients (124 and 54 cases within discovery and validation cohorts, respectively) who received first-line EGFR-TKI between July of 2014 and October of 2020 were enrolled in the present study. We detected circulating immune cell counting, albumin (Alb), pre-albumin (pAlb), ALP, AST, LDH, GGT, HDL-c, and fibrinogen (Fib) concentrations, and calculated 22 inflammatory ratios and scores. Logistic regression and Cox proportional hazards models were used to assess the impact of these ratios and scores on objective response and disease control rate (ORR and DCR) as well as progression-free survival (PFS) in these patients. RESULTS: Twenty-five percentage and 24.07% of NSCLC patients were observed objective response to the treatment of first-line EGFR-TKI in discovery and validation cohort, respectively. Univariate and multivariate Cox regression showed that high PLR, NPS, SII, SIS, mSIS, GLR and FPR as well as low PNI were significantly associated with poor PFS in discovery cohort. However, only high SII and FPR were found to be associated with unsatisfactory outcome in validation cohort. Time-dependent areas under ROC of FPR were 0.702 (0.517-0.888) in discovery cohort, and 0.767 (0.613-0.921) in validation cohort, which were extremely higher than the other biomarkers. The patients with FPR-SII combined score 2 harbored worse prognosis compared to the combined score 0 in discovery (plog-rank = 0.003, adjusted HR = 2.888, 95%CI = 1.500-5.560) and validation cohort (plog-rank = 0.001, adjusted HR = 3.769, 95%CI = 1.676-8.478) as well as overall population (plog-rank < 0.001, adjusted HR = 3.109, 95%CI = 1.878-5.147), and its time-dependent AUCs were 0.747 (0.594-0.900) and 0.815 (0.688-0.942) in the two cohorts, respectively, which were significantly higher than the single biomarker in the two cohorts. The patients with high FPR and FPR-SII score harbored worse DCR than the low patients in the two cohorts and overall population, respectively. Moreover, the similar poor survival was observed in advanced high-FPR NSCLC patients with different treatment options, however, the survival of low-FPR patients with treatment of single TKI, radiotherapy or chemotherapy or radio-chemotherapy combined TKI was good compared to the high-FPR patients with radio-chemotherapy combined TKI, and the survival differences were observed between TKI (plog-rank < 0.001) or radiotherapy combined TKI (plog-rank = 0.014) treated low-FPR patients and the high FPR patients. Additionally, FPR-SII combined score could monitor the progression of the disease in real-time, and the median month of the positive score appearance was significantly earlier than CT/MRI detection (p < 0.001 for 3 months vs. 13 months). CONCLUSIONS: High-grade cancer elicited inflammation could attenuates response and outcome in tyrosine kinase inhibitor naive patients with advanced NSCLC. FPR-SII combined score was the best inflammatory biomarker to monitor and predict the progression of advanced NSCLC patients with treatment of TKI.

Preoperative fibrinogen to prealbumin ratio as a novel predictor for clinical outcome of hepatocellular carcinoma.

AIM: To investigate prognostic value of preoperative inflammatory biomarkers in hepatocellular carcinoma (HCC). PATIENTS & METHODS: Preoperative circulating fibrinogen, prealbumin, fibrinogen to prealbumin ratio (FPR), neutrophil to lymphocyte ratio, derived neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio, platelet to lymphocyte ratio were detected and calculated in 230 HCC patients. X-tile software, Kaplan-Meier curve, Cox regression, time-dependent receiver-operating characteristic were used to explored prognostic roles of them in HCC. RESULTS: Multivariate Cox regression showed that high FPR was significantly associated with decreased recurrence-free survival (p = 0.034) and overall survival (p < 0.001) within HCC patients. FPR generated the largest area under curve of time-dependent receiver-operating characteristic comparing to the other biomarkers. Overall survival of HCC patients receiving chemotherapy was superior to the cases without receiving chemotherapy only in high FPR subgroup (p = 0.028). CONCLUSION: Preoperative FPR was superior to other biomarkers to independently predict survival of HCC patients, and it could identify the patients who could benefit from adjuvant chemotherapy.

Circulating fibrinogen to pre-albumin ratio is a promising biomarker for diagnosis of colorectal cancer.

BACKGROUND: Inflammation and nutrition are closely associated with initiation and progression of colorectal cancer (CRC). This study aimed to investigate the diagnostic value of the FAR (FAR = 100*Fibrinogen/Albumin) and FPR (FPR = Fibrinogen/pre-Albumin) in CRC. METHODS: Neutrophil-to-lymphocyte ratio (NLR), FPR, and FAR were calculated in 455 newly diagnosed CRC patients, 455 healthy individuals, and 455 benign controls with colorectal polyp. The diagnostic value of biomarker for CRC was evaluated by receiver operating characteristic curve (ROC). Logistic regression analysis was adopted to assess the risk factors for telling CRC apart from benign disease. Moreover, the combined biomarkers were used for discriminating between CRC and benign disease. RESULTS: Neutrophil-to-lymphocyte ratio, FAR, and FPR were significantly higher in CRC patients compared with the benign or healthy controls (P < 0.05). ROC analysis showed that the diagnostic efficacy of FAR and FPR were better than NLR for CRC. Besides, FPR, NLR, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA199) were markedly associated with differentiation of benign disease and CRC in the logistic regression analysis. And the combination of FPR, CEA, and CA199 had the maximum area under the ROC curve (AUC) in separating CRC from benign disease (AUC = 0.845, Sensitivity = 67.9%, Specificity = 85.3%, Positive Predictive Value = 83.5%, Negative Predictive Value = 70.9%). CONCLUSIONS: Fibrinogen/pre-Albumin could be a useful CRC diagnostic biomarker, and the combination of FPR, CEA, and CA199 could significantly improve the diagnostic efficacy in discriminating CRC from the benign colorectal disease.

The predictive and prognostic role of a novel ADS score in esophageal squamous cell carcinoma patients undergoing esophagectomy.

BACKGROUND: Chronic inflammation is deemed to play a significant effect on initiation and progression of esophageal squamous cell carcinoma (ESCC). In current study, we investigated the prognostic and predictive role of albumin (Alb) to fibrinogen (Fib) ratio (AFR) and a novel AFR-Alb-derived neutrophil/lymphocyte ratio (dNLR) score (ADS) in ESCC patients undergoing esophagectomy and compared them with Fib, Alb, neutrophil to lymphocyte ratio (NLR), dNLR, platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR). MATERIALS AND METHODS: A total of 153 clinical confirmed ESCC patients undergoing esophagectomy between January 2011 and December 2013 were included in present study. We detected preoperative Alb, Fib and neutrophil, monocyte, lymphocyte and platelet count, and obtained overall survival (OS) by 3 years' follow-up in the cases. X-tile software, Kaplan-Meier curve, Cox regression and predicted nomogram were used to evaluate the predictive and prognostic role of them in ESCC patients. RESULTS: The optimal cut-off values of Fib, Alb, AFR, NLR, dNLR, PLR and LMR were 3.2 mg/dL, 38.2 g/L, 9.3, 2.1, 4.3, 145.9 and 2.3, respectively. High levels of Fib [(adjusted hazard ratio (HR) = 2.148, 95% confidential interval (CI) (1.229-3.753)], dNLR (adjusted HR = 2.338, 95% CI 1.626-5.308) and PLR (adjusted HR = 1.964, 95% CI 1.129-3.415) as well as low AFR (adjusted HR = 2.381, 95% CI 1.152-4.926) and Alb (adjusted HR = 2.398, 95% CI 1.342-4.273) were significantly associated with decreased OS in ESCC patients. The survival predictive areas under the time-dependent receiver operating characteristics curve of AFR, dNLR and Alb were higher than Fib and PLR, respectively. High ADS score was significantly associated with short 3 years' OS of ESCC patients (adjusted HR = 2.94, 95% CI 1.70-5.08). Moreover, OS of ESCC patients receiving adjuvant radio-chemotherapy was longer than those without the treatment in high ADS score subgroup (p = 0.001), however, no significant survival difference was observed in the patients with or without treatment radio-chemotherapy (p = 0.297). Additionally, a significant difference was observed in c-index values of the nomograms including or without ADS (0.720 vs. 0.670, p < 0.05). CONCLUSIONS: Preoperative ADS was a prospective biomarker to predict clinical efficacy of adjuvant radio-chemotherapy and clinical prognosis of ESCC patients undergoing esophagectomy, and the score could apparently improve predicted efficacy of the nomogram.

Significance of combined preoperative serum Alb and dNLR for diagnosis of pancreatic cancer.

AIM: To investigate diagnostic value of preoperative inflammatory biomarkers in pancreatic cancer (PCC). MATERIALS & METHODS: Preoperative circulating Alb/Fib ratio, neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), platelet/lymphocyte ratio and lymphocyte/monocyte ratio were detected and calculated in 226 PCC individuals, 232 healthy controls and 142 additional cancer controls. Receiver-operating characteristic curve and area under the curve (AUC) were used to evaluate the diagnostic efficacy of PCC. RESULTS: Combined circulating dNLR and Alb could effectively improve the diagnosis of PCC (AUC = 0.931), single dNLR could distinguish early-stage PCC and the disease from healthy controls (AUC = 0.895) and additional cancer controls (AUC = 0.794). CONCLUSION: Circulating dNLR was an effective biomarker for diagnosis and identification of early-stage PCC. Combined dNLR and Alb could improve the diagnostic efficacy of the disease.

Combination of preoperative NLR, PLR and CEA could increase the diagnostic efficacy for I-III stage CRC.

BACKGROUND: Inflammation plays an important role in the development and progression of CRC. The members of inflammatory biomarkers, preoperative NLR and PLR, have been proved by numerous studies to be promising prognostic biomarkers for CRC. However, the diagnostic value of the two biomarkers in CRC remains unknown, and no study reported the combined diagnostic efficacy of NLR, PLR and CEA. METHODS: Five hundred and fifty-nine patients with I-III stage CRC undergoing surgical resection and 559 gender- and age-matched healthy controls were enrolled in this retrospective study. NLR and PLR were calculated from preoperative peripheral blood cell count detected using white blood cell five classification by Sysmex XT-1800i Automated Hematology System and serum CEA were measured by electrochemiluminescence by ELECSYS 2010. The diagnostic performance of NLR, PLR and CEA for CRC was evaluated by ROC curve. RESULTS: Levels of NLR and PLR in the cases were significantly higher than them in the healthy controls. ROC curves comparison analyses showed that the diagnostic efficacy of NLR (AUC=.755, 95%CI=.728-.780) alone for CRC was significantly higher than PLR (AUC=.723, 95%CI=.696-.749, P=.037) and CEA (AUC=.690, 95%CI=.662-.717, P=.002) alone. In addition, the diagnostic efficacy of the combination of NLR, PLR and CEA(AUC=.831, 95%CI=.807-.852)for CRC was not only significantly higher than NLR alone but also higher than any combinations of the two of these three biomarkers (P<.05). Moreover, the NLR and PLR in the patients with TNM stage I/II was higher than that in the healthy controls, and patients with stage III had a higher NLR and PLR than those with stage I/II, but no significant difference was observed. CONCLUSION: Our study indicated that preoperative NLR could be a CRC diagnostic biomarker, even for early stage CRC, and the combination of NLR, PLR and CEA could significantly improve the diagnostic efficacy.

Analysis of Diagnostic Value of YKL-40 in Ovarian Cancer.

OBJECTIVE: Early diagnosis of ovarian cancer is crucial in clinical practice but is difficult. Accumulating studies have investigated the utility of YKL-40 in early detection of ovarian cancer. The aim of this study was to evaluate the overall accuracy of YKL-40 in diagnosis of ovarian cancer through a meta-analysis of published studies. METHODS: A comprehensive search of related literature was performed in PubMed, Web of Science, and China National Knowledge Infrastructure databases. Meta-DiSc 1.4 and STATA 11.0 were selected for data analysis, and Quality Assessment of Diagnostic Accuracy Studies tool version 2 was used to assess the quality of included studies. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and summary receiver operating characteristic curve. RESULTS: A total of 13 studies dating up to May 2015 with 1623 individuals were enrolled in the present study. The pooled characteristics of these studies were as follows: sensitivity 0.71 (95% confidence interval [CI], 0.68-0.75), specificity 0.90 (95% CI, 0.88-0.92), positive likelihood ratio 7.24 (95% CI, 4.22-12.43), negative likelihood ratio 0.34 (95% CI, 0.27-0.42), and diagnostic odds ratio 24.93 (95% CI, 12.61-49.27), respectively. The area under the curve was 0.8471. CONCLUSIONS: The results indicated that YKL-40 could be regarded as an effective biomarker for diagnosis of ovarian cancer.

Null genotype of GSTM1 and GSTT1 may contribute to susceptibility to male infertility with impaired spermatogenesis in Chinese population.

Glutathione-S-transferases (GSTs) play a protective role during spermatogenesis and GST genes may be involved in impaired spermatogenesis. A case-control study was performed to explore the association of genes GSTM1 and GSTT1, two members of GST gene family, with spermatogenesis impairment. The deletion polymorphism distribution of genes GSTM1 and GSTT1 was investigated in 353 patients with azoospermia or oligospermia and 201 fertile controls in Chinese population using multiplex PCR. As a result, the frequencies of null genotype of genes GSTM1 (67.4% versus 57.7%, p = 0.022, OR = 1.516, 95% CI = 1.001-2.168) and GSTT1 (61.8% versus 46.8%, p = 0.001, OR = 1.838, 95% CI = 1.295-2.610) in patients were significantly higher than those in controls. After stratifying patients, the frequencies of null genotype of gene GSTM1 in oligospermia (68.3% versus 57.7%, p = 0.027, OR = 1.580, 95% CI = 1.051-2.375) and GSTT1 in azoospermia (66.9% versus 46.8%, p < 0.001, OR = 2.299, 95% CI = 1.484-3.562) as well as oligospermia (57.9% versus 46.8%, p = 0.025, OR = 1.567, 95% CI = 1.057-2.322) were still significantly higher compared with controls. The results suggested that null genotypes of GSTM1 and GSTT1 are associated with spermatogenesis impairment and may contribute to susceptibility to spermatogenesis impairment and male infertility in Chinese population.

Genetic variants of eNOS gene may modify the susceptibility to idiopathic male infertility.

In testis, eNOS is responsible for synthesis of nitric oxide (NO) which is an essential gas message regulator in spermatogenesis, suggesting that eNOS gene plays a role in normal spermatogenesis and the genetic variants of eNOS gene may be potential genetic risk factors of spermatogenesis impairment. In this study, the polymorphic distributions of three common polymorphism loci including T-786C, 4A4B and G894T in eNOS gene were investigated in 355 Chinese infertile patients with azoospermia or oligozoospermia and 246 healthy fertile men and a meta-analysis was carried in order to explore the possible relationship between the three loci of eNOS gene and male infertility with spermatogenesis impairment. As a result, allele -786C of T-786C (11.4% versus 6.5%, p = 0.004) and 4A of 4A4B (11.0% versus 6.3%, p = 0.005) as well as genotype TC of T-786C (22.8% versus 13.0%, p = 0.002) and AB of 4A4B (18% versus 11%, p = 0.015) were significantly associated with idiopathic male infertility. The haplotypes T-4A-G (7.4% versus 4.1%, p = 0.015) and C-4B-G (7.6% versus 4.4%, p = 0.028) could increase the susceptibility to male infertility, whereas haplotype T-4B-G (67.0% versus 75.2%, p = 0.002) might be a protective factor for male infertility. The results of meta-analysis revealed that the polymorphism of T-786C was associated with male infertility. These findings suggested that the variants of eNOS gene may modify the susceptibility to male infertility with impaired spermatogenesis.

Relationship of SNP of H2BFWT gene to male infertility in a Chinese population with idiopathic spermatogenesis impairment.

The H2B family, member W, testis specific (H2BFWT) gene encodes a testis specific histone that plays a crucial role in reorganization and remodeling of chromatin and epigenetic regulation during spermatogenesis, suggesting that the gene may be involved in spermatogenesis impairment. To test the speculation, the allele and haplotype frequencies of two single-nucleotide polymorphism loci in this gene, -9C>T and 368A>G, were investigated in 409 infertile patients with idiopathic azoospermia or oligozoospermia and 209 fertile men as controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. As the results, the frequencies of -9T (52.8% vs. 41.6%, p = 0.009) and 368G (43.0% vs. 32.5%, p = 0.012) were significantly higher in patients than those in controls; after stratifying patients, the significant higher frequencies were still detected in allele -9T for azoospermia (57.4% vs. 41.6%, p = 0.001) and allele 368G for oligozoospermia (45.4% vs. 32.5%, p = 0.007). The haplotype CA was significantly decreased (22.8% vs. 33.0%, p = 0.006) whereas TG was significantly increased (18.3% vs. 7.2%, p < 0.001) in infertile patients compared with controls. These results indicated that the polymorphism -9C>T and 368A>G in H2BFWT gene are associated with male infertility with idiopathic azoospermia or oligozoospermia, suggesting that H2BFWT gene might be contribute to susceptibility to spermatogenesis impairment in Chinese population.

[Single nucleotide polymorphisms of the genes related with spermatogenesis impairment].

Male infertility is a complex disease affecting the reproduction of childbearing couples, for which genetic polymorphism of spermatogenesis genes is an important genetic pathogenic factor. Lots of genes closely related with spermatogenesis have been successfully identified through the gene knockout technology. Spermatogenesis impairment related genes include those associated with expression enzymes, receptors, cell apoptosis, transcription regulation, and so on. The genetic susceptibility of these genes, infection, and environment jointly contribute to non-obstructive azoospermia and oligozoospermia in males. The analysis of the single nucleotide polymorphism (SNP) of spermatogenesis impairment related genes helps explain the possible mechanism of pathogenesis at the molecular level, and provides theoretical evidence for the clinical diagnosis and treatment of male infertility. The article focuses on the correlation of the SNPs of spermatogenesis impairment related genes with azoospermia and oligozoospermia.

The value of circulating fibrinogen-to-pre-albumin ratio in predicting survival and benefit from chemotherapy in colorectal cancer.

BACKGROUND: To evaluate the prognostic role of circulating fibrinogen-to-pre-albumin (FPR) in colorectal cancer (CRC) with different tumor locations, and its involvement in chemosensitivity and chemoresistance. PATIENTS AND METHODS: A total of 2917 eligible CRC patients from multiple centers were enrolled in this prospective study, and 3 years follow-up was carried out to obtain the outcome of these patients. Circulating fibrinogen (Fib), pre-albumin (pAlb), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were detected, and we calculated FPR according to the detected results. Kaplan-Meier curves, Cox proportional regression, time-dependent receiver operating characteristic curves, Harrell's concordance index, calibration, and decision curves were used to investigate the role of FPR in predicting chemotherapy efficacy and prognosis of CRC patients. RESULTS: Our results showed that cancer bulk, its infiltrating depth, and the distal metastasis status of CRC determined circulating FPR levels. A high FPR was associated with a significantly inferior prognosis, while the outcomes of right-sided patients with stage III and IV CRC were worse than left-sided cases. Only FPR was found to be a reliable and independent prognostic factor for each stage of CRC. In addition, the prognostic FPR-contained nomograms were superior to the non-FPR nomograms and FPR in predicting the outcomes in both localized and metastatic CRC patients. The circulating FPR was significantly associated with chemotherapeutic efficacy in stage III and IV CRC patients. In particular, low-grade (FPR < 15) and medium-grade (15 ⩽ FPR < 20) FPR patients exhibited a complete response to chemotherapy and attenuated chemosensitivity, respectively; in contrast, high-grade inflammation (FPR ⩾ 20) conferred resistance to the treatment. CONCLUSION: Circulating FPR is a robust and independent prognostic factor, a simple and economically-friendly predictor of chemotherapy efficacy within cases of localized and metastatic CRC. FPR-contained nomograms are more effective in predicting the prognosis of these patients. FPR and the nomogram can be recommended for the evaluation of chemotherapy efficacy and to aid decision-making associated with the management of these patients.

High-Grade Inflammation Attenuates Chemosensitivity and Confers to Poor Survival of Surgical Stage III CRC Patients.

Background: Heterogeneous clinical and molecular characteristics are reported in colorectal cancer (CRC) with different tumor laterality. However, the outcome of left- and right-sided patients with stage I-III CRC and the role of chronic inflammation in survival differences between them remain unclear. Method: A prospective study including 1,181 surgical patients with stage I-III CRC was carried out to investigate the involvement of circulating fibrinogen-to-pre-albumin (Alb) ratio (FPR) and primary tumor sidedness in the clinical outcome of those patients. We further investigated the effect of FPR on adjuvant chemotherapy response and recurrence in stage III patients. Results: Our study showed that the right tumor location was significantly associated with poor recurrence-free survival (RFS) (p = 0.04, adjusted HR = 1.41, 95% CI = 1.02-1.94) and overall survival (OS) (p = 0.04, adjusted HR = 1.55, 95% CI = 1.01-2.38) only in the stage III disease. In these patients, T4 stage distribution (83.39 vs. 70.94%, p < 0.01) within right-sided cases was significantly higher than left-sided patients. Moreover, preoperative FPR within right-sidedness (p < 0.01), T4 stage (p < 0.05), and large cancer bulk (≥5 cm) (p < 0.05) subgroups was significantly elevated compared to their counterparts, and it was gradually rising following the increased cancer bulk (p trend < 0.01). High-FPR distribution (52.30 vs. 27.00%, p < 0.01) within right-sided patients with the stage III disease was significantly higher than that in the left-sided cases. RFS (p log-rank < 0.01) and OS (p log-rank < 0.01) of the high-FPR patients were extremely inferior to the low-FPR cases, and the significant associations were observed when they were adjusted by other confounders including primary tumor location (p < 0.01, adjusted HR = 1.96, 95% CI = 1.42-2.70 for RFS; p < 0.01, adjusted HR = 2.44, 95% CI = 1.59-3.75 for OS). Additionally, RFS of adjuvant chemotherapy-treated high-FPR patients was superior to the patients without chemotherapy (p log-rank = 0.01) but was inferior to the low-FPR patients undergoing the treatment, especially in the 5-FU- and XELOX-treated subgroup. Conclusion: These findings indicate that chronic high-grade inflammation weakens chemotherapy efficacy and contributes to the poor prognosis of stage III surgical CRC patients.

The Role of Cancer-Elicited Inflammatory Biomarkers in Predicting Early Recurrence Within Stage II-III Colorectal Cancer Patients After Curable Resection.

BACKGROUND: Smoldering cancer-related inflammation attenuates chemotherapy efficacy and contributes to unsatisfactory outcome for patients of colorectal cancer (CRC). Various inflammation-based biomarkers were reported to predict the survival of the disease, however, it remains unclear which is the best inflammation-based biomarker. The aim of present study was to compare the prognostic role of those biomarkers and to establish superior survival score for post-recurrence survival in radically operative patients with stage II-III CRC. PATIENTS AND METHODS: Preoperative peripheral neutrophil, lymphocyte, monocyte, platelet, serum albumin (Alb), pre-Alb, and plasma fibrinogen (Fib) were detected in the discovery and validation cohort which included a total of 1533 stage II-III surgical CRC patients. We calculated and compared fourteen inflammation-based biomarkers for predicting recurrence-free survival (RFS) of the patients with stage II-III CRC. RESULTS: In this study, the platelet to lymphocyte ratio (PLR), lymphocyte to monocyte (LMR), systemic inflammation response index (SIRI), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), modified systemic inflammation score (mSIS), fibrinogen and neutrophil to lymphocyte ratio score (F-NLR), ratio of Alb to Fib (AFR), and ratio of Fib to pre-Alb (FPR) were all related to the RFS of the patients in both discovery and validation cohorts, however, only the LMR, SIRI, PNI, mSIS, F-NLR, AFR and FPR remained independent predictors for RFS in multivariate analysis. Both the C-index of the FPR (0.629 for 36 months) and the areas under the time-dependent receiver operating characteristic (ROC) curves (0.625 for 12 months, 0.641 for both 24 and 0.637 months) showed that it was superior to the other inflammation-based prognostic scores for predicting the RFS of stage II-III surgical CRC patients. Moreover, elevated FPR was significantly associated with unsatisfactory RFS regardless of TNM stage and primary tumor location. Stage II low FPR patients showed the best RFS regardless of chemotherapy. The better RFS was observed in chemotherapy-treated stage II high FPR patients than those without the treatment, and the outcomes of patients with treatment of XELOX, capecitabine and XELOX were superior to the other regimens to treat patients in stage III low- and high-FPR populations, respectively. Additionally, the carcinoembryonic antigen (CEA)-FPR combined score one (adjusted HR=2.764, 95% CI=2.129-3.589) and two (adjusted HR=3.543, 95% CI=2.317-5.420) were extremely associated with RFS of these patients, and the predicted AUC of the combined score for 12, 24 and 36 months were 0.657, 0.657 and 0.653 in stage II-III patients, which were superior to the single CEA and FPR, respectively. CONCLUSION: In conclusion, FPR is superior to the other inflammatory biomarkers as a useful recurrence indicator in stage II-III surgical CRC patients in terms of prognostic ability; it helps to choose the effective chemotherapy regimen and to increase the predicted efficacy of CEA and the combined CEA and FPR score could effectively predict recurrence of the patients.

Role of Chronic Inflammatory Ratios in Predicting Recurrence of Resected Patients with Stage I-III Mucinous Colorectal Adenocarcinoma.

BACKGROUND: Cancer-related inflammation is the main cause of the progression of mucinous colorectal adenocarcinoma (MCA). Circulating fibrinogen-to-pre-albumin ratio (FPR) is associated with the clinical outcome in colorectal cancer (CRC). However, the prognostic role of FPR and which is the best inflammatory prognostic biomarker within MCA remain unknown. METHODS: We enrolled 157 patients with stage I-III MCA in this study. Kaplan-Meier curve, Cox regression, and time-dependent receiver operation characteristic curve analysis were performed to assess the prognostic value and efficacy of the neutrophil-to-albumin ratio (NAR), neutrophil-to-pre-albumin ratio (NPAR), albumin-to-alkaline phosphatase ratio (AAPR), albumin-to-globulin ratio (AGR), albumin-to-fibrinogen ratio (AFR), and FPR in these patients. RESULTS: We found that NAR, NPAR, and FPR were significantly associated with unsatisfactory recurrence-free survival (RFS) in patients with stage I-III MCA, and the predicted efficacy of FPR was superior to that of the other two inflammatory biomarkers. Moreover, patients with a high combined TNM-CA199-FPR score had worse outcomes, with a high predicted efficacy of up to 0.779 (0.703-0.856). Using FPR, the patient was monitored for the recurrence up to two months earlier than that achieved using the common imaging techniques (4 vs 6 median months) in stage I-III MCA patients undergoing radical resection. CONCLUSION: FPR is the preferred inflammatory biomarker and commonly used for predicting and monitoring recurrence in stage I-III MCA patients. The combined TNM-CA199-FPR score is an economical, simple, effective, and independent prognostic factor for localized disease.

A Novel Prognostic Score Based on ZG16 for Predicting CRC Survival.

BACKGROUND: Colorectal cancer (CRC) is one of the lethal malignant tumors worldwide. However, the underlying mechanism of CRC and its biomarkers remain unclear. The aim of this study was to identify the key genes associated with CRC and to further explore their prognostic significance. METHODS: Four expression profile datasets (GSE41657, GSE74602, GSE113513, and GSE40967) downloaded from Gene Expression Omnibus (GEO) and one RNAseq dataset of CRC from The Cancer Genome Atlas (TCGA) database were included in our study. The Cox model was utilized for univariate or multivariate survival analysis. GEPIA and HAP database were adopted for verification of DEGs (ZG16). The decision curve analysis (DCA) and time-dependent ROC were chosen for evaluating the prognostic effectiveness of biomarkers. RESULTS: In total, 88 differentially expressed genes (DEGs) were identified, and the GO and KEGG enrichment analyses of DEGs were processed. After, the protein-protein interaction (PPI) network was constructed and 15 hub genes including ZG16 were identified. The differential expression of ZG16 between tumor and normal colorectal tissues were further verified in GEPIA and HAP database. Subsequent survival indicated that expression of ZG16 is negatively correlated with overall survival of OS and is an independent prognostic factor for CRC patients. Furthermore, the construction of a prognostic score containing ZG16, TNM stage and age exhibited superior effectiveness for predicting long-term survival of CRC patients. Additionally, our results were verified using the GSE40967 dataset, which indicated an improved performance of combined risk score based on ZG16 for predicting OS of CRC patients. CONCLUSION: ZG16 is a potential parameter for predicting prognosis in CRC. Furthermore, a combination of ZG16, TNM stage, and age allows improved prognosis of CRC.

Chemotherapy plus bevacizumab as an optimal first-line therapeutic treatment for patients with right-sided metastatic colon cancer: a meta-analysis of first-line clinical trials.

BACKGROUND: Monoclonal antibodies of anti-epidermal growth factor receptor (EGFR) have been recommended as first-line therapy for patients with left-sided metastatic colorectal cancer (mCRC) with wild-type RAS. The effect of tumour laterality on antivascular endothelial growth factor antibody and how to optimise targeted therapies for the right-sided cases remain controversial. PATIENTS AND METHODS: A comprehensive meta-analysis enrolling 16 first-line clinical trials was performed to evaluate the efficacy of chemotherapy alone and chemotherapy plus targeted therapies for patients with mCRC with right primary tumour site, and we validated the results in metastatic setting (14 trials containing 4306 patients with unresectable mCRC). RESULTS: Here, we found that progression-free survival (PFS) (combined HR 1.30, 95% CI 1.17 to 1.44) and overall survival (OS) (combined HR 1.46, 95% CI 1.32 to 1.62) of the right-sided patients were significantly inferior to the left-sided individuals receiving chemotherapy alone in overall population, regardless of race. Similar results were also observed in metastatic setting. OS of patients with left-sided mCRC receiving chemotherapy plus bevacizumab was superior to the right-sided individuals (combined median survival ratio (MSR)=1.23, 95% CI 1.08 to 1.39 for overall population; combined MSR=1.23, 95% CI 1.05 to 1.45 for metastatic setting), especially for wild-type RAS and mixed population. Moreover, the right-sided patients benefited more from chemotherapy plus bevacizumab comparing with chemotherapy alone in both overall population and metastatic setting. Importantly, the RAS-wild right-sided patients achieved longer PFS (combined HR 0.67, 95% CI 0.52 to 0.88) and OS (combined HR 0.74, 95% CI 0.56 to 0.98) from chemotherapy plus bevacizumab comparing with chemotherapy associated with anti-EGFR agents. CONCLUSIONS: Patients with right-sided mCRC show impaired chemosensitivity, and chemotherapy plus bevacizumab can be an optimal first-line therapeutic regimen for the RAS-wild patients with right-sided mCRC.

Elevated FPR confers to radiochemoresistance and predicts clinical efficacy and outcome of metastatic colorectal cancer patients.

Association of chronic inflammation, primary tumor sidedness, adjuvant therapy and survival of metastatic colorectal cancer (mCRC) remains unclear. Circulating inflammatory cell, fibrinogen (Fib), albumin (Alb), pre-albumin (pAlb), Alb/Fib (AFR) and Fib/pAlb (FPR) were detected, and clinical outcome was obtained to determine the predictive, prognostic and monitoring roles of them in discovery and validation cohort. We found that elevated FPR, low AFR and poor survival was observed in right-sided mCRC comparing to the left-sided disease, elevated FPR harbored the highest areas under curve to independently predict poor progression-free survival and overall survival in overall and left-sided mCRC case in two cohorts. No survival difference was examined between the two-sided patients in subgroups stratified by FPR. Radiochemoresistance was observed in high FPR case. However, the patient could benefit from bevacizumab plus radiochemotherapy. Low FPR patient showed the best survival with treatment of palliative resection plus radiochemotherapy. Moreover, circulating FPR was significantly increased ahead imaging confirmed progression and it reached up to the highest value within three months before death. Additionally, c-indexes of the prognostic nomograms including FPR were significantly higher than those without it. These findings indicated that FPR was an effective and independent factor to predict progression, prognosis and to precisely identify the patient to receive optimal therapeutic regimen.

Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients.

The emerging debate between primary tumor location and clinical outcome of bevacizumab treated metastatic colorectal cancer (mCRC) continues. The aim of the present study is to investigate the association between the primary tumor location and clinical outcome of 115 mCRC patients receiving bevacizumab based treatment. A meta-analysis including 21 studies was carried out to confirm the conclusion. In our prospective study, we found that right-sided mCRC commonly occurred in older cases (p = 0.03) with multiple-site metastasis (p = 0.03). Progression-free survival (PFS) of the left-sided patients undergoing bevacizumab plus a FOLFIRI regimen was superior to the right-sided cases (p = 0.03, crude HR = 0.31, 95%CI = 0.11-0.87; adjusted HR = 0.21, 95%CI = 0.06-0.66). The meta-analysis confirmed that efficacy of bevacizumab-based treatment in left-sided mCRC patients was better than the right-sided cases in the overall population (P h = 0.24, combined OR = 1.36, 95%CI = 1.07-1.72), RAS/BRAF wild-type (P h = 0.19, combined OR = 1.66, 95%CI = 1.17-2.34), clinical trial (P h = 0.23, combined OR = 1.42, 95%CI = 1.07-1.88), Caucasian population (P h = 0.18, combined OR = 1.37, 95%CI = 1.02-1.85) and first-line (P h = 0.19, combined OR = 1.48, 95%CI = 1.13-1.96) subgroups. Improved survival of bevacizumab plus chemotherapy treated left-sided mCRC patients was observed in the overall population [P h < 0.01, combined MSR = 1.09, 95%CI = 1.00-1.18 for PFS; P h < 0.01, combined MSR = 1.24, 95%CI = 1.13-1.36 for overall survival (OS)], especially in the RAS/BRAF wild-type (P h = 0.09, combined MSR = 1.10, 95%CI = 1.03-1.19 for PFS; P h = 0.02, combined MSR = 1.34, 95%CI = 1.21-1.49 for OS). These findings indicate that primary tumor sidedness can predict clinical outcome of bevacizumab-treated RAS/BRAF wild-type mCRC patients and the left-sided patients may benefit more from bevacizumab plus FOLFIRI.