Novel cut-off values of time from diagnosis to systematic therapy predict the overall survival and the efficacy of targeted therapy in renal cell carcinoma: A long-term, follow-up, retrospective study.

OBJECTIVES: Metastatic renal cell carcinoma can occur synchronously or metachronously. We characterized the time from diagnosis to systematic therapy as a categorical variable to analyze its effect on the overall survival and first-line treatment efficacy of metastatic renal cell carcinoma patients. METHODS: We initially enrolled 949 consecutive metastatic renal cell carcinoma patients treated with targeted therapies retrospectively from December 2005 to December 2019. X-tile analysis was used to determine cut-off values of time from diagnosis to systematic therapy referring to overall survival. Patients were divided into different groups based on the time from diagnosis to systematic therapy and then analyzed for survival. RESULTS: Of 358 eligible patients with metastatic renal cell carcinoma, 125 (34.9%) had synchronous metastases followed by cytoreductive nephrectomy, and 233 (65.1%) had metachronous metastases. A total of 28 patients received complete metastasectomy. Three optimal cut-off values for the time from diagnosis to systematic therapy (months) - 1.1, 7.0 and 35.9 - were applied to divide the population into four groups: the synchro group (time from diagnosis to systematic therapy ≤1.0), early group (1.0 < time from diagnosis to systematic therapy ≤ 7.0), intermediate group (7.0 < time from diagnosis to systematic therapy < 36.0) and late group (time from diagnosis to systematic therapy ≥36.0). The targeted therapy-related overall survival (P < 0.001) and progression-free survival (P < 0.001) values were significantly different among the four groups. Patients with longer time from diagnosis to systematic therapy had better prognoses and promising efficacy of targeted therapy. With the prolongation of time from diagnosis to systematic therapy, complete metastasectomy was more likely to achieve and bring a better prognosis. CONCLUSIONS: The time from diagnosis to systematic therapy impacts the survival of metastatic renal cell carcinoma patients treated with targeted therapy. The cutoff points of 1, 7 and 36 months were statistically significant. The statistical boundaries might be valuable in future model establishment.

A novel nomogram can predict pathological T3a upstaged from clinical T1a in localized renal cell carcinoma.

HYPOTHESIS: Nomogram can be built to predict the pathological T3a upstaging from clinical T1a in patients with localized renal cell carcinoma before surgery. PURPOSE: Renal cell carcinoma (RCC) patients with clinical T1a (cT1a) disease who are upstaged to pathological T3a (pT3a) have reduced survivals after partial nephrectomy. We aimed to develop a nomogram-based model predicting pT3a upstaging in RCC patients with preoperative cT1a based on multiple preoperative blood indexes and oncological characteristics. MATERIALS AND METHODS: Between 2010 and 2019, 510 patients with cT1a RCC were individually matched according to pT3a upstaging and pathological T1a (pT1a) at a 1:4 ratio using clinicopathologic features. Least absolute shrinkage and selection operator regression analysis was used to identify the most important risk factor from 40 peripheral blood indicators, and a predictive model was established. Multivariate logistic regression analysis was performed with the screened blood parameters and clinical data to identify significant variables. Harrell's concordance index (C-index) was applied to evaluate the accuracy of the model for predicting pT3a upstaging in patients with cT1a RCC. RESULTS: Out of 40 blood indexes, the top ranked predictor was fibrinogen (FIB). Age, the ratio of the tumor maximum and minimum diameter (ROD), FIB, and tumor size were all independent risk factors for pT3a upstaging in multivariate analysis. A predictive ARFS model (Age, ROD, FIB, tumor Size) was established, and the C-index was 0.756 (95% CI, 0.681-0.831) and 0.712 (95% CI, 0.638-0.785) in the training and validation cohorts, respectively. CONCLUSIONS: Older age, higher ROD, increased FIB level, and larger tumor size were independent risk factors for upstaging. The ARFS model has a high prediction efficiency for pT3a upstaging in patients with cT1a RCC.

Combination of Hematology Indicators and Oncological Characteristics as a New Promising Prognostic Factor in Localized Clear Cell Renal Cell Carcinoma.

PURPOSE: This study aimed to construct a predictive model for recurrence and metastasis in patients with localized clear cell renal cell carcinoma (ccRCC) based on multiple preoperative blood indexes and oncological characteristics. PATIENTS AND METHODS: Overall, 442 patients with localized ccRCC between 2013 and 2015 were included. Using least absolute shrinkage and selection operator (LASSO) Cox regression analysis, the top three risk factors from the peripheral blood indicators were screened to construct a risk score, and a prognostic model was established. Harrell's concordance index (C-index) was applied to evaluate the predictive accuracy of the model for predicting disease-free survival (DFS) in ccRCC. RESULTS: Out of 38 blood indexes, the top three predictors were fibrinogen (FIB), C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR). The FIB-CRP-NLR (FCN) score (hazard ratio [HR]: 1.86, 95% confidence interval [CI]: 1.21-2.9, P = 0.005) was an independent prognostic factor in multivariate analysis. Furthermore, the FIB-CRP-NLR-T-Grade (FCNTG) risk model combining FCN score, T stage and Furhman grade achieved a higher prognostic accuracy (mean C-index, 0.728) than both the FCN score alone (mean C-index, 0.675) and the stage, size, grade, and necrosis (SSIGN) score (mean C-index, 0.686) in the validation cohort. CONCLUSION: The FCN score combining peripheral blood indicators of inflammation and coagulation is an independent prognostic marker of ccRCC. The FCNTG model, which systemically incorporates preoperative blood indexes to oncological characteristics, shows its advantages of convenience and high prediction efficiency.

A novel nomogram can predict pathological T3a upstaged from clinical T1a in localized renal cell carcinoma

ABSTRACT Hypothesis: Nomogram can be built to predict the pathological T3a upstaging from clinical T1a in patients with localized renal cell carcinoma before surgery. Purpose: Renal cell carcinoma (RCC) patients with clinical T1a (cT1a) disease who are upstaged to pathological T3a (pT3a) have reduced survivals after partial nephrectomy. We aimed to develop a nomogram-based model predicting pT3a upstaging in RCC patients with preoperative cT1a based on multiple preoperative blood indexes and oncological characteristics. Materials and Methods: Between 2010 and 2019, 510 patients with cT1a RCC were individually matched according to pT3a upstaging and pathological T1a (pT1a) at a 1:4 ratio using clinicopathologic features. Least absolute shrinkage and selection operator regression analysis was used to identify the most important risk factor from 40 peripheral blood indicators, and a predictive model was established. Multivariate logistic regression analysis was performed with the screened blood parameters and clinical data to identify significant variables. Harrell's concordance index (C-index) was applied to evaluate the accuracy of the model for predicting pT3a upstaging in patients with cT1a RCC. Results: Out of 40 blood indexes, the top ranked predictor was fibrinogen (FIB). Age, the ratio of the tumor maximum and minimum diameter (ROD), FIB, and tumor size were all independent risk factors for pT3a upstaging in multivariate analysis. A predictive ARFS model (Age, ROD, FIB, tumor Size) was established, and the C-index was 0.756 (95% CI, 0.681-0.831) and 0.712 (95% CI, 0.638-0.785) in the training and validation cohorts, respectively. Conclusions: Older age, higher ROD, increased FIB level, and larger tumor size were independent risk factors for upstaging. The ARFS model has a high prediction efficiency for pT3a upstaging in patients with cT1a RCC.

EGF reverses multi-drug resistance via the p-ERK pathway in HepG2/ADM and SMMC7721/ADM hepatocellular carcinoma models.

AIM: To investigate signaling pathways for reversal of EGF-mediated multi-drug resistance (MDR) in hepatocellular carcinoma (HCC) models. MATERIALS AND METHODS: HCC MDR cell strain HepG2/adriamycin (ADM) and SMMC7721/ADM models were established using a method of exposure to medium with ADM between low and high concentration with gradually increasing concentration. Drug sensitivity and reversal of multi-drug resistance by EGF were determined and the cell cycle distribution and apoptosis were analyzed by flow cytometry. Phosphorylation of ERK1, ERK2, ERK5 and expression of Bim were detected by Western blotting. RESULTS: The results showed that HepG2/ADM and SMMC7721/ADM cells were resistant not only to ADM, but also to multiple anticancer drugs. When used alone, EGF had no anti-tumor activity in HepG2/ADM and SMMC7721/ADM cells in vitro, while it increased the cytotoxicity of ADM. EGF induced cell apoptosis and G0/G1 phase cell cycle arrest in HepG2/ADM And SMMC7721/ADM cells, while enhancing activity of p-ERKs and up-regulated expression of BimEL. CONCLUSIONS: EGF might enhance the chemosensitivity of HepG2/ADM and SMMC7721/ADM cells via up-regulating p-ERKs and BimEL protein.

Arsenic trioxide combined with co-stimulatory molecule blockade prolongs survival of cardiac allografts in alloantigen-primed mice.

Various memory cell populations existing before organ transplantation are believed to be important barriers to extending the graft survival time. Here, we report that arsenic trioxide (As(2)O(3)), a common component of some Chinese traditional preparations, could obviously reduce the proliferation of splenic T cells in alloantigen-primed mice in vitro. Furthermore, we evaluated As(2)O(3) treatment alone or in combination with blocking monoclonal antibodies (mAb) against co-stimulatory molecules (LFA-1 and CD154) in the prevention of heart transplant rejection in alloantigen-primed mice. Alloantigen-primed mice were randomly divided into 4 groups of 6 animals each. The control group was given normal saline; the As(2)O(3) group received As(2)O(3) (5 mg/kg/d) (i.p.) on days 0-10 post-transplantation; the Ab group received 100 µg anti-LFA-1 mAb+250 µg anti-CD154 mAb (i.p.) on the day of transplantation and 3 more times every alternate day and the As(2)O(3)+Ab group received a combined As(2)O(3) and Ab treatment protocol. The survival of the allografts was almost doubled among the As(2)O(3) group and Ab group compared with the control group (5, 5.6 vs 3.3 days). A marked prolongation (16 days) of graft survival was achieved by the combination protocol compared with the control group (3.3 days; P<0.05). None of the treatment group showed side effects. Five days after transplantation, cardiac allografts, splenic T cells and serum were harvested for analysis. Compared with the control group, most of the treatment groups showed: (i) alleviation of allograft rejection in different levels; (ii) IFN-γ expression was reduced and TGF-ß expression increased in both peripheral blood and within the grafts; (iii) the proportions of CD4(+) or CD8(+) memory T cells in the spleen of the recipients were significantly reduced while the expression of regulatory T cells (Tregs) was enhanced; (iv) the alloresponses of memory T cells were inhibited, and levels of alloantibodies in recipients' sera were also decreased. Among all these changes, the As(2)O(3)+Ab group showed the most significant changes. Our study highlights an obvious synergistic action of As(2)O(3) when combined with co-stimulatory molecules blockade in prolonging the survival of cardiac allografts in alloantigen-primed mice.

Isatis tinctoria L. combined with co-stimulatory molecules blockade prolongs survival of cardiac allografts in alloantigen-primed mice.

Memory T cells present a unique challenge in transplantation. Although memory T cells express robust immune responses to invading pathogens, they may be resistant to the effects of immunosuppressive therapies used to prolong graft survival. In previous studies, we found that compound K, the synthesized analogue of highly unsaturated fatty acids from Isatis tinctoria L., reduced acute cardiac allograft rejection in mice (Wang et al., 2009 [1]). Here, we further investigated the effect of compound K on cardiac allograft rejection in alloantigen-primed mice. We found that compound K significantly inhibited CD4(+) and CD8(+) memory T cells proliferation in a mixed lymphocyte reaction (MLR). In vivo, compound K combined with anti-CD154 and anti-LFA-1 monoclonal antibodies (mAbs) significantly extended the survival time of heart grafts in alloantigen-primed mice with no obvious toxic side effects. Furthermore, our data suggests that compound K works by reducing the expression of both IL-2 and IFN-gamma within the graft rather than enhancing expression of regulatory T cells (Tregs). Compound K can also inhibit the alloresponses of memory T cells, while increasing the proportion of CD4(+) memory T cells in the spleen of the recipients and significantly reducing the level of alloantibodies in the serum. Our study highlights the unique immune effects of compound K that may be further explored for clinical use in extending the survival of transplant grafts.