Corilagin alleviates liver fibrosis in zebrafish and mice by repressing IDO1-mediated M2 macrophage repolarization.

BACKGROUND: Liver fibrosis caused by chronic liver injury, eventually develops into liver cirrhosis and hepatocellular carcinoma. Currently, there are no effective drugs to relieve liver fibrosis due to the lack of molecular pathogenesis characteristics. Former research demonstrates that the hepatic immune microenvironment plays a key role in the pathogenesis of liver fibrosis, thus macrophages are important immune cells in the liver. Our previous study has found that IDO1 plays an important role in the liver immune microenvironment. CRG is a gallic acid tannin found in medicinal plants of many ethnicities that protects against inflammation, tumors and chronic liver disease. However, the mechanism of by which CRG mediates the interaction of IDO1 with macrophages during hepatic immune maturation is not clear. PURPOSE: To investigate the regulatory mechanism of CRG in liver fibrosis and the intrinsic relationship between IDO1 and macrophage differentiation. METHODS: Zebrafish, RAW264.7 cells and mice were used in the study. IDO1 overexpression and knockdown cell lines were constructed using lentiviral techniques. RESULTS: We discovered that CRG remarkably reduced the AST and ALT serum levels. Histological examination revealed that CRG ameliorates CCL4-induced liver fibrosis and depressed the expression of α-SMA, Lamimin, Collagen-Ι and fibronectin. Besides, we found that CRG promoted increased MerTK expression on partly macrophages. Interestingly, in vitro, we found that CRG suppressed IDO1 expression and regulated macrophage differentiation by upregulating CD86, CD80 and iNOS, while downregulating CD206, CD163, IL-4 and IL-10 expression. Additionally, we found that CRG could inhibit hepatic stellate cell activation by direct or indirect action. CONCLUSION: Our findings suggest that CRG alleviates liver fibrosis by mediating IDO1-mediated M2 macrophage repolarization.

A serum metabolomics study based on LC-MS: Chemosensitization effects of Rauvolfia vomitoria Afzel. combined with 5- fluorouracil on colorectal cancer mice.

Colorectal cancer (CRC) is one of the malignant tumors with high incidence, and is mainly treated by chemotherapy at present. However, during CRC treatment, long-term use of traditional chemotherapeutic drugs will reduce the sensitivity of chemotherapy. Our previous studies have shown that Rauvolfia vomitoria total alkaloids (RVA) played an important role in 5-fluorouracil (5-FU) chemosensitization in CRC therapy, but its intervention mechanism has not been clarified completely in the metabolic level. Therefore, in this study, LC-MS based metabolomics was employed to explore the mechanism of 5-FU chemosensitization in CRC induced by the combination of RVA and conventional chemotherapeutic with 5-FU. The results showed that the final tumor weight of the high-dose combined group was significantly different from that of the 5-FU alone group. To evaluate the chemosensitization effects of RVA, serum samples collected from six groups (six mice in each group) with different administration methods were analyzed by HPLC-Q-Exactive Orbitrap/MS. After multivariate statistical analysis and metabolites identification, 25 different metabolites were identified between the 5-FU treatment group and combined high-dose treatment group, among which lipid and fatty acid metabolism pathways were mostly affected. These results suggest that RVA may sensitize traditional chemotherapeutic drug 5-FU and exert anti-tumor activity through influencing lipid metabolism and cell energy metabolism. Metabolomics provided a new insight into estimate of the therapeutic effect and dissection of the potential mechanisms of traditional Chinese medicine in treating colorectal cancer.

Expression of PBRM1 as a prognostic predictor in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitor.

OBJECTIVE: PBRM1, located on 3p21, functions as a tumor suppressor and somatic mutation of PBRM1 is frequent in clear cell renal cell carcinoma (ccRCC). This study aims to determine the influence of PBRM1 expression on the prognosis of patients with mRCC receiving tyrosine kinase inhibitor (TKI) treatment. METHODS: We identified 116 mRCC patients who were administered sunitinib or sorafenib as first-line therapy, between January 2006 and December 2016 at our institution. PBRM1 expression was assessed by immunohistochemistry. The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS), log-rank test was used to compare the survival outcomes between patients with low and high PBRM1 expression levels, and the Cox proportional hazard regression model was used to estimate the prognostic value. Prognostic accuracy was determined using Harrell concordance index, and nomograms were built to evaluate the prognosis of mRCC. RESULTS: Patients with low PBRM1 expression had significantly shorter median PFS (9 vs 26 months, P < 0.001) and OS (21 vs 44 months, P < 0.001) than those with high expression. Multivariate analysis showed that PBRM1 expression was an independent predictor of PFS (HR 1.975, P = 0.013) and OS (HR 2.282, P = 0.007). The model built by the addition of PBRM1 improved the C-index of PFS and OS to 0.72 and 0.82, respectively. CONCLUSIONS: The expression of PBRM1 could be a significant prognostic factor for mRCC patients treated with targeted therapy, and it increases the prognostic accuracy of the established prognostic model.

Sunitinib or Sorafenib as Neoadjuvant Therapy May not Improve the Survival Outcomes of Renal Cell Carcinoma with Tumor Thrombus.

OBJECTIVES: The purpose of this work was to investigate the effect of sorafenib or sunitinib as neoadjuvant therapy on the survival outcomes of renal cell carcinoma (RCC) with tumor thrombus. METHODS: A total of 92 RCC patients with tumor thrombus were included in this 2-center retrospective research from January 2007 to December 2014. Sorafenib and sunitinib were administered as neoadjuvant therapy in 9 patients and 14 patients, respectively, and 69 patients constituted non-neoadjuvant therapy groups. The Kaplan-Meier method was used to estimate the recurrence-free survival (RFS) and overall survival (OS). Log-rank test was used to compare the survival outcomes of patients with or without neoadjuvant therapy. RESULTS: The overall median RFS and OS time for all 92 patients were 28 months (95% CI 17-39 months) and 42 months (95% CI 30-54 months). Patients with neoadjuvant therapy had no significantly longer median RFS (30 vs. 28 months, p = 0.376) and OS (45 vs. 42 months, p = 0.702) than those without neoadjuvant therapy. CONCLUSIONS: Neoadjuvant therapy of sorafenib or sunitinib might not improve survival outcomes for high risk RCC patients with tumor thrombus. Thus, neoadjuvant therapy for RCC with tumor thrombus should be considered cautiously.

Significance of preoperative prognostic nutrition index as prognostic predictors in patients with metastatic renal cell carcinoma with tyrosine kinase inhibitors as first-line target therapy.

OBJECTIVE: Prognostic nutritional index (PNI) is a recognized indicator of both immune and nutritional status. It was firstly used as a preoperative prognostic indicator, and its role in the prognosis of patients with metastatic renal cell carcinoma (mRCC) has not yet been investigated in large-scale study. The purpose of this work was to investigate the prognostic role of pretreatment PNI in patients with mRCC with sorafenib or sunitinib as first-line targeted therapy. METHOD: In this retrospective single-center research, the Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS) of 178 mRCC patients who received first-line therapy of sorafenib or sunitinib. Log-rank test was used to compare the survival outcomes of patients with low pretreatment PNI (PNI < 51.62) and high pretreatment PNI (PNI ≥ 51.62), and Cox proportional hazard regression model was used to compare PFS and OS between these two groups. Prognostic accuracy was determined using Harrell concordance index. RESULTS: The overall median PFS and OS time for all 178 patients were 11 months (95% CI 9-12 months) and 24 months (95% CI 19-33 months), respectively. Patients with low pretreatment PNI both had significantly shorter median PFS (7 vs 19 months, P < 0.001) and OS (14 vs 50 months, P < 0.001) than those with high PNI. Multivariate analysis showed that pretreatment PNI was an independent predictor of OS (HR 1.658, 95% CI 1.040-2.614, P = 0.033) and an independent predictor of PFS as well (HR 1.842, 95% CI 1.226-2.766, P = 0.003). The model built by the addition of pretreatment PNI improved predictive accuracy of PFS and OS compared with the International Metastatic Renal Cell Carcinoma Database Consortium Model (Heng model) (c-index: 0.68 and 0.70). Comparing to NLR (neutrophil-to-lymphocyte ratio) (0.69 and 0.72), PNI might be a preciser factor to predict PFS and OS (0.71 and 0.73). CONCLUSIONS: Low pretreatment PNI could be a significant risk factor for mRCC patients who received tyrosine kinase inhibitors as first-line target therapy and increase the accuracy of established prognostic model.

Comparison of efficacy, safety, and quality of life between sorafenib and sunitinib as first-line therapy for Chinese patients with metastatic renal cell carcinoma.

BACKGROUND: Sorafenib and sunitinib are widely used as first-line targeted therapy for metastatic renal cell carcinoma (mRCC) in China. This study aimed to compare the efficacy, safety, and quality of life (QoL) in Chinese mRCC patients treated with sorafenib and sunitinib as first-line therapy. METHODS: Clinical data of patients with mRCC who received sorafenib (400 mg twice daily; 4 weeks) or sunitinib (50 mg twice daily; on a schedule of 4 weeks on treatment followed by 2 weeks off) were retrieved. Primary outcomes were overall survival (OS), progression-free survival (PFS), adverse events (AEs), and QoL (SF-36 scores), and secondary outcomes were associations of clinical characteristics with QoL. RESULTS: Medical records of 184 patients (110 in the sorafenib group and 74 in the sunitinib group) were reviewed. PFS and OS were comparable between the sorafenib and sunitinib groups (both P > 0.05). The occurrence rates of leukocytopenia, thrombocytopenia, and hypothyroidism were higher in the sunitinib group (36.5% vs. 10.9%, P < 0.001; 40.5% vs. 10.9%, P < 0.001; 17.6% vs. 3.6%, P = 0.001), and that of diarrhea was higher in the sorafenib group (62.7% vs. 35.2%, P < 0.001). There was no significant difference in SF-36 scores between the two groups. Multivariate analysis indicated that role-physical and bodily pain scores were associated with the occurrence rate of grade 3 or 4 AEs (P = 0.017 and 0.005). CONCLUSIONS: Sorafenib has comparable efficacy and lower toxicity profile than sunitinib as first-line therapy for mRCC. Both agents showed no significant impact on QoL of patients.

Association of post-treatment hypoalbuminemia and survival in Chinese patients with metastatic renal cell carcinoma.

BACKGROUND: Hypoalbuminemia adversely affects the clinical outcomes of various cancers. The purpose of this study was to estimate the prognostic value of hypoalbuminemia 3-5 weeks after treatment in patients with metastatic renal cell carcinoma (mRCC) who received sorafenib or sunitinib as first-line treatment. METHODS: In this single-center, retrospective study, we assessed the progression-free survival (PFS) and overall survival (OS) of 184 mRCC patients who received first-line sorafenib or sunitinib treatment. PFS and OS were compared between patients with post-treatment hypoalbuminemia (post-treatment albumin level <36.4 g/L) and those with normal post-treatment albumin level (albumin level ≥36.4 g/L). The Memorial Sloan Kettering Cancer Center (MSKCC) risk model stratified mRCC patients into three risk categories. Prognostic values of all patient characteristics including MSKCC risk category were determined by using univariate and multivariate Cox regression models. Prognostic value was further determined using the Harrell concordance index and receiver operating characteristic curve analysis. RESULTS: The median PFS and OS of the 184 patients were 11 months (95% confidence interval [CI] 9-12 months) and 23 months (95% CI 19-33 months), respectively. Patients with post-treatment hypoalbuminemia had significantly shorter median PFS (6 months [95% CI 5-7 months]) and OS (11 months [95% CI 9-15 months]) than patients who had normal post-treatment albumin levels (PFS: 12 months [95% CI 11-16 months], P < 0.001; OS: 31 months [95% CI 24-42 months], P < 0.001), respectively. Multivariate analysis showed that post-treatment hypoalbuminemia was an independent predictor of PFS (hazard ratio [HR], 2.113; 95% CI 1.390-3.212; P < 0.001) and OS (HR, 2.388; 95% CI 1.591-3.585; P < 0.001). Post-treatment hypoalbuminemia could also be combined with the MSKCC risk category for better prediction about OS. The model that included post-treatment hypoalbuminemia and MSKCC risk category improved the predictive accuracy for PFS and OS (c-index: 0.68 and 0.73, respectively) compared with the basic MSKCC risk model (c-index: 0.67 and 0.70, respectively). The prognostic values for PFS and OS of the integrated MSKCC risk model involving post-treatment hypoalbuminemia were significantly more accurate than the basic MSKCC risk model using likelihood ratio analysis (both P < 0.001). CONCLUSIONS: Post-treatment hypoalbuminemia can be considered an independent prognostic factor for patients with mRCC who undergo first-line treatment with tyrosine kinase inhibitors. Additionally, integrating post-treatment serum albumin level into the basic MSKCC risk model can improve the accuracy of this model in predicting patient overall survival and progression-free survival.

Pretreatment Serum Prealbumin as an Independent Prognostic Indicator in Patients With Metastatic Renal Cell Carcinoma Using Tyrosine Kinase Inhibitors as First-Line Target Therapy.

BACKGROUND: Although serum prealbumin is a sensitive marker to assess malnutrition, its prognostic impact in patients with metastatic renal cell carcinoma (mRCC) remains elusive. METHODS: Patients' data were retrospectively retrieved from the medical records of Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine from March 2006 to July 2015 to access overall survival (OS) and progression-free survival (PFS). The survival outcomes of patients with low pretreatment prealbumin (< 200 mg/L) and high pretreatment prealbumin (≥ 200 mg/L) were compared using a log-rank test and Cox proportional hazard regression model. Prognostic accuracy was determined using the Harrell concordance index (c-index). RESULTS: The median PFS and OS for 143 patients were 11 months (95% confidence interval [CI], 9-14 months) and 27 months (95% CI, 22-39 months), respectively. The low pretreatment prealbumin group had significantly shorter median PFS (6 vs. 14 months, P < .001) and OS (10 vs. 34 months, P < .001) than the normal pretreatment prealbumin group. Multivariate analysis showed that pretreatment prealbumin was an independent predictor of OS (hazard ratio [HR] 1.963; 95% CI, 1.140-3.381; P = .015) and also an independent predictor of PFS (HR 2.021; 95% CI, 1.227-3.329; P = .006). Further, addition of pretreatment prealbumin to the Heng model enhanced the predictive accuracy of PFS and OS (c-index: 0.70 and 0.74) compared with the Heng model alone (c-index: 0.69 and 0.72). CONCLUSION: Low pretreatment serum prealbumin is an independent prognosticator of risk and survival outcomes in patients with mRCC receiving tyrosine kinase inhibitors as first-line treatment and also increases the accuracy of established prognostic models.

Assessment of response to anti-angiogenic targeted therapy in pulmonary metastatic renal cell carcinoma: R2* value as a predictive biomarker.

PURPOSE: To evaluate the utility of MR R2*-mapping and the optimal time-point for assessing the response of pulmonary metastatic renal cell carcinoma (mRCC) to anti-angiogenic targeted therapy (aATT). MATERIALS AND METHODS: The exploration-sample group and the validation-sample group consisted of 22 and 16 patients. The parameters of MR R2*-mapping, including the R2* value at each time-point (R2*base, R2*1cyc and R2*2cyc) and change between different time-points (R2*(1cyc-base)/base, R2*(2cyc-base)/base and R2*(2cyc-1cyc)/1cyc), were evaluated with a receiver-operating-characteristic analysis, and a cut-off value derived from the clinical outcome was applied to the Kaplan-Meier method to assess the value of R2* mapping and Response-Evaluation-Criteria in Solid Tumours (RECIST) during treatment evaluation. RESULTS: The inter-, intra-observer agreements and inter-scan consistency were excellent (p > 0.80). For the exploration-sample group, the areas under the curve for the parameters of MR R2* mapping were 0.55, 0.60, 0.83, 0.64, 0.88 and 0.83 for R2*base, R2*1cyc, R2*2cyc, R2*(1cyc-base)/base, R2*(2cyc-base)/base and R2*(2cyc-1cyc)/1cyc. For the validation-sample, R2*(2cyc-base)/base better predicted progression-free survival (p = 0.03) than RECIST and other R2* mapping parameters with a lower p value. CONCLUSION: Assessing aATT outcome based on changes in the R2* value between baseline and second treatment is more accurate than assessment at other time-points and assessment based on the RECIST. KEY POINTS: • The inter-scan consistency of R2*-mapping in pulmonary mRCC are excellent. • The intra-/inter-observer agreement of R2* mapping in pulmonary mRCC are excellent. • Using changes in R2* value between baseline/after second-treatment is better than RECIST. • The choice of baseline/after second treatment is better than other time-points.

Microwave coagulation/ablation in combination with sorafenib suppresses the overgrowth of residual tumor in VX2 liver tumor model.

OBJECTIVES: Our study is to evaluate the effect of thermal ablation on residual VX2 tumor tissue and the efficiency of sorafenib as an adjuvant therapy after insufficient microwave coagulation (MWC) on a rabbit VX2 liver tumor model. METHODS: Thirty-seven rabbits with orthotic VX2 liver tumors were randomly divided into MWC group (n=11), combination treatment group (n=14), and control group (n=12). The therapeutic efficacy was evaluated by contrast enhanced ultrasound (CEUS), magnetic resonance imaging (MRI), pathological and immunohistochemical examinations. Analysis of enhancement characteristics included enhancement level, pattern, and location. The necrotic degree of tumor was analyzed by semi-quantitative classification. The apparent diffusion coefficiency (ADC) was calculated using diffused weighted image (DWI). RESULTS: The tumor growth was accelerated in MWC group compared with control group and combination treatment group. A low metastasis rate was shown in combination treatment group compared with other two groups. The degree of necrosis in combination treatment group was greater than that in MWC group. The ADC value on DWI was higher compared with that of the control and MWC group, with statistical significance (P<0.05). With adjuvant therapy of sorafenib after insufficient ablation, the microvessel density (MVD) was lower than that of control group, whereas in MWC group the MVD was higher than that of control group, with statistical significance (P<0.05). CONCLUSION: Insufficient thermal ablation promotes residual tumor progression. While the adjuvant therapy of sorafenib serves as an effective way to suppress the overgrowth and neovascularization of residual tumor after insufficient thermal ablation.

Early treatment response to sorafenib for rabbit VX2 orthotic liver tumors: evaluation by quantitative contrast-enhanced ultrasound.

The aim of our study was to investigate the application of contrast-enhanced ultrasound (CEUS) and its quantification analysis for the prediction of early treatment response of sorafenib on rabbit VX2 liver tumor model. Rabbits were implanted VX2 tumor mass to establish a liver tumor model. Fourteen days after tumor implantation, rabbits presented with single liver tumor were randomly divided into two groups. Rabbits in treatment group were given by gavage once a day for 14 days with sorafenib suspension at a dose of 30 mg/kg, whereas rabbits in control group were given saline by gavage of the same volume. CEUS was performed before treatment and 3, 7, 14 days after treatment for the analysis of tumor size, enhancement pattern, and necrosis range. The time intensity curve (TIC) was used to obtain quantitative parameters of enhancement patterns. Before sorafenib administration, tumor volumes ranged from 0.24 to 0.75 cm(3) (mean 0.49 ± 0.18 cm(3)) in treatment group and 0.24 to 0.44 cm(3) (mean 0.30 ± 0.12 cm(3)) in control group. The dynamic enhancement patterns of tumors were homogeneous hyper-enhancement (n = 8), heterogeneous hyper-enhancement (n = 4), and peripheral rim-like enhancement (n = 2). All tumors of the treatment group presented with peripheral rim-like enhancement with large necrotic area after sorafenib administration, whereas tumors of the control group showed heterogeneous hyper-enhancement (n = 5) and peripheral rim-like enhancement (n = 2). There was a significant difference in area under the curve (AUC) before and after sorafenib treatment (P = 0.045). CEUS may be of value in the evaluation of early therapeutic response after sorafenib administration.