Ferroptosis-related molecular patterns reveal immune escape, inflammatory development and lipid metabolism characteristics of the tumor microenvironment in acute myeloid leukemia.

Background: An increasing number of studies have revealed the influencing factors of ferroptosis. The influence of immune cell infiltration, inflammation development and lipid metabolism in the tumor microenvironment (TME) on the ferroptosis of tumor cells requires further research and discussion. Methods: We explored the relationship between ferroptosis-related genes and acute myeloid leukemia (AML) from the perspective of large sample analysis and multiomics, used multiple groups to identify and verify ferroptosis-related molecular patterns, and analyzed the sensitivity to ferroptosis and the state of immune escape between different molecular pattern groups. The single-sample gene set enrichment analysis (ssGSEA) algorithm was used to quantify the phenotypes of ferroptosis-related molecular patterns in individual patients. HL-60 and THP-1 cells were treated with ferroptosis inducer RSL3 to verify the therapeutic value of targeted inhibition of GPX4. Results: Three ferroptosis-related molecular patterns and progressively worsening phenotypes including immune activation, immune exclusion and immunosuppression were found with the two different sequencing approaches. The FSscore we constructed can quantify the development of ferroptosis-related phenotypes in individual patients. The higher the FSscore is, the worse the patient's prognosis. The FSscore is also highly positively correlated with pathological conditions such as inflammation development, immune escape, lipid metabolism, immunotherapy resistance, and chemotherapy resistance and is negatively correlated with tumor mutation burden. Moreover, RSL3 can induce ferroptosis of AML cells by reducing the protein level of GPX4. Conclusions: This study revealed the characteristics of immunity, inflammation, and lipid metabolism in the TME of different AML patients and differences in the sensitivity of tumor cells to ferroptosis. The FSscore can be used as a biomarker to provide a reference for the clinical evaluation of the pathological characteristics of AML patients and the design of personalized treatment plans. And GPX4 is a potential target for AML treatment.

A novel fatty acid metabolism-related signature identifies features of the tumor microenvironment and predicts clinical outcome in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is the most common malignancy of the hematological system, and there are currently a number of studies regarding abnormal alterations in energy metabolism, but fewer reports related to fatty acid metabolism (FAM) in AML. We therefore analyze the association of FAM and AML tumor development to explore targets for clinical prognosis prediction and identify those with potential therapeutic value. METHODS: The identification of AML patients with different fatty acid metabolism characteristics was based on a consensus clustering algorithm. The CIBERSORT algorithm was used to calculate the proportion of infiltrating immune cells. We used Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis to construct a signature for predicting the prognosis of AML patients. The Genomics of Drug Sensitivity in Cancer database was used to predict the sensitivity of patient samples in high- and low-risk score groups to different chemotherapy drugs. RESULTS: The consensus clustering approach identified three molecular subtypes of FAM that exhibited significant differences in genomic features such as immunity, metabolism, and inflammation, as well as patient prognosis. The risk-score model we constructed accurately predicted patient outcomes, with area under the receiver operating characteristic curve values of 0.870, 0.878, and 0.950 at 1, 3, and 5 years, respectively. The validation cohort also confirmed the prognostic evaluation performance of the risk score. In addition, higher risk scores were associated with stronger fatty acid metabolisms, significantly higher expression levels of immune checkpoints, and significantly increased infiltration of immunosuppressive cells. Immune functions, such as inflammation promotion, para-inflammation, and type I/II interferon responses, were also significantly activated. These results demonstrated that immunotherapy targeting immune checkpoints and immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages, are more suitable for patients with high-risk scores. Finally, the prediction results of chemotherapeutic drugs showed that samples in the high-risk score group had greater treatment sensitivity to four chemotherapy drugs in vitro. CONCLUSIONS: The analysis of the molecular patterns of FAM effectively predicted patient prognosis and revealed various tumor microenvironment (TME) characteristics.

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.

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.

Corrigendum: Seven Glycolysis-Related Genes Predict the Prognosis of Patients With Pancreatic Cancer.

[This corrects the article DOI: 10.3389/fcell.2021.647106.].

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.

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.

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.

Seven Glycolysis-Related Genes Predict the Prognosis of Patients With Pancreatic Cancer.

Objectives: To identify the key glycolysis-related genes (GRGs) in the occurrence and development of pancreatic ductal carcinoma (PDAC), and to construct a glycolysis-related gene model for predicting the prognosis of PDAC patients. Methodology: Pancreatic ductal carcinoma (PDAC) data and that of normal individuals were downloaded from the TCGA database and Genotype-Tissue Expression database, respectively. GSEA analysis of glycolysis-related pathways was then performed on PDAC data to identify significantly enriched GRGs. The genes were combined with other patient's clinical information and used to construct a glycolysis-related gene model using cox regression analysis. The model was further evaluated using data from the validation group. Mutations in the model genes were subsequently identified using the cBioPortal. In the same line, the expression levels of glycolysis related model genes in PDAC were analyzed and verified using immunohistochemical images. Model prediction for PDAC patients with different clinical characteristics was then done and the relationship between gene expression level, clinical stage and prognosis further discussed. Finally, a nomogram map of the predictive model was constructed to evaluate the prognosis of patients with PDAC. Results: GSEA results of the training set revealed that genes in the training set were significantly related to glycolysis pathway and iconic glycolysis pathway. There were 108 differentially expressed GRGs. Among them, 29 GRGs were closely related to prognosis based on clinical survival time. Risk regression analysis further revealed that there were seven significantly expressed glycolysis related genes. The genes were subsequently used to construct a predictive model. The model had an AUC value of more than 0.85. It was also significantly correlated with survival time. Further expression analysis revealed that CDK1, DSC2, ERO1A, MET, PYGL, and SLC35A3 were highly expressed in PDAC and CHST12 was highly expressed in normal pancreatic tissues. These results were confirmed using immunohistochemistry images of normal and diseases cells. The model could effectively evaluate the prognosis of PDAC patients with different clinical characteristics. Conclusion: The constructed glycolysis-related gene model effectively predicts the occurrence and development of PDAC. As such, it can be used as a prognostic marker to diagnose patients with PDAC.

Combined fibrinogen-to-pre-albumin ratio and carbohydrate antigen 19-9 score is a promising metric to predict progression of metastatic colorectal mucinous adenocarcinoma.

BACKGROUND: Chronic inflammation is a hallmark of colorectal mucinous adenocarcinoma (CMA). Albumin-to-fibrinogen ratio (AFR) and fibrinogen-to-pre-albumin ratio (FPR) were independent prognostic factors for many kinds of solid malignancies. However, the association between the inflammatory scores and progression of metastatic CMA remains unknown. METHODS: Peripheral blood neutrophil count and circulating fibrinogen, albumin, and pre-albumin levels were detected, and neutrophil-to-albumin ratio (NAR), neutrophil-to-pre-albumin ratio(NPAR), AFR, and FPR were calculated in 42 metastatic MCA patients. Kaplan-Meier curve, Cox regression, time-dependent receiver operating characteristic curve (tdROC) were selected to investigate the prognostic utility of them in the patients. RESULTS: Metastatic CMA patients commonly occurred in middle-younger patients (80.95%). NPAR (adjusted hazard ratio (HR)=2.405, 95% confidence interval (CI)=1.195-4.842) and FPR (plog-rank =0.007, adjusted HR=2.364, 95% CI=1.203-4.645) were significantly associated with poor progression-free survival in these patients. The prognostic prediction area under tdROC (AUROC) of FPR was significantly higher than that of NPAR(0.703 versus 0.537). Moreover, the patients with a high CA19-9-FPR score showed worse outcomes than those with the low score (plog-rank <0.001, adjusted HR=7.273, 95% CI=2.721-19.435 for the score 1 versus 0). The prediction AUROC, sensitivity, and specificity of the score were 0.892 (0.788-0.996), 76.32%, and 100.00%, respectively, and its predicted efficacy was better than that of the single biomarkers. CONCLUSION: The combined CA19-9-FPR score is an economical, simple, effective, and independent prognostic factor for metastatic MCA.

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.