Blood Volume as a new functional image-based biomarker of progression in metastatic renal cell carcinoma.
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SUBMITTER: Drljevic-Nielsen A
PROVIDER: S-EPMC8490379 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPreliminary data showed prognostic impact of contrast-enhanced computed tomography (DCE-CT) identified Blood Volume (BV) in patients with metastatic renal cell carcinoma (mRCC). BV as an independent prognostic factor remains to be assessed.Materials and methodsDCE-CT identified BV was prospectively quantified in patients with mRCC receiving first line therapies, adjusted for International mRCC Database Consortium (IMDC) individual features and treatments, and associated with overall survival (OS), progression-free survival (PFS) and objective response (ORR), using Cox and logistic regression, respectively.Results105 patients with mRCC were included. Median baseline BV was 32.87 mL × 100 g-1 (range 9.52 to 92.87 mL × 100 g-1). BV above median was associated with IMDC favorable risk category (P = 0.004), metastasis free interval ≥ 1 year (P = 0.007), male gender (P = 0.032), normal hemoglobin (P = 0.040) and normal neutrophils (P = 0.007), whereas low BV was associated with poor risk IMDC features (P < 0.05). Patients with high vs. low baseline BV had longer PFS (12.5 vs. 5.6 months, P = 0.015) and longer OS (42.2 vs. 22.4 months, P = 0.001), respectively. In multivariate analysis high baseline BV remained independent favorable for OS (HR 0.49, 95% CI 0.30-0.78, P = 0.003) and PFS (HR 0.64; 95% CI 0.42-0.97, P = 0.036). BV as a continuous variable was also associated with OS in the multivariate analysis (HR 0.98, 95% CI 0.96-1.00, P = 0.017). The estimated concordance index (c-index) was 0.688 using IMDC score and 0.701 when BV was added.ConclusionsDCE-CT identified Blood Volume is a new, independent prognostic factor in mRCC, which may improve the prognostic accuracy of IMDC.
| S-EPMC7350156 | biostudies-literature
Project description:The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR) of 0.14, p < 0.0001, 95% confidence interval (CI) 0.04-0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05-0.34) were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only (p < 0.0001). Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.
| S-EPMC5713295 | biostudies-literature
Project description:: Clear cell renal cell carcinoma (ccRCC) is the main type of RCC, which is the most common type of malignant kidney tumor in adults. A subpopulation (>30%) of ccRCC patients develop metastasis; however, the molecular mechanism remains largely unknown. Here, we found that LTF, the gene encoding lactotransferrin, is dramatically downregulated in primary tumors compared to normal tissues derived from ccRCC patients deposited in The Cancer Genome Atlas (TCGA) database and is a favorable prognostic marker. Moreover, LTF downregulation appears to be more dominant in metastatic ccRCC. LTF overexpression suppresses migration ability in A498 ccRCC cells with high metastatic potential, whereas LTF knockdown fosters cellular migration in poorly metastatic ccRCC cells. Gene set enrichment analysis demonstrated that LTF expression inversely correlates with the progression of epithelial-mesenchymal transition (EMT) in ccRCC, which was further confirmed by RT-PCR experiments. Therapeutically, the administration of recombinant LTF protein significantly suppresses the cell migration ability and lung metastatic potential of ACHN cells, as well as LTF-silenced A498 cells. The gene knockdown of lipoprotein receptor-related protein 1 (LRP1) robustly blocked recombinant LTF protein-induced inhibition of cellular migration and gene expression of EMT markers in ACHN cells. LTF downregulation and LRP1 upregulation combined predicted a poor overall survival rate in ccRCC patients compared to that with either factor alone. Our findings uncover a new mechanism by which LTF may interact with LRP1 to inhibit metastatic progression in ccRCC and also reveal the therapeutic value of recombinant LTF protein in treating metastatic ccRCC.
| S-EPMC7226440 | biostudies-literature
Project description:BackgroundAngiogenesis is prominent in metastatic renal cell carcinoma (mRCC). We compared two angiogenesis assessment methods: dynamic contrast-enhanced computed tomography (DCE-CT)-derived blood volume (BV) and blood flow (BF) and core biopsy microvessel density (MVD).MethodsAs planned in DaRenCa Study-1 study, DCE-CT and core biopsy were performed from the same tumour/metastasis at baseline. MVD was assessed by CD34 immunostaining in tumour (CD34-indexT) or tumour including necrosis (CD34-indexTN). BV and BF were assessed using the DCE-CT software. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier analysis. Spearman coefficient (rho) tested the correlation between MVD and BV, BF, or CT density (HU).ResultsAt baseline, 25 patients had analysable scans and tissue. BVdeconv, BVPatlak, and BFdeconv > median were associated with favourable OS (43.2 versus 14.6 months, p = 0.002; 31.6 versus 20.2 months, p = 0.015; and 31.6 versus 24.5 months, p = 0.019). CD34-indexT and CD34-indexTN did not correlate with age (p = 0.543), sex (p = 0.225), treatment (p = 0.848), International mRCC Database Consortium category (p = 0.152), synchronous versus metachronous metastatic disease (p = 0.378), or tumour volume (p = 0.848). CD34-indexT or CD34-indexTN > median was not associated with PFS (p = 0.441 and p = 0.854, respectively) or OS (p = 0.987 and p =0.528, respectively). CD34-indexT or CD34-indexTN was not correlated with BV, BF, or HU (rho 0.20-0.26).ConclusionsDifferently from MVD, DCE-CT-derived BV and BF had prognostic impact and may better reflect angiogenesis in mRCC.Trial registrationNCT01274273.
| S-EPMC8322257 | biostudies-literature
Project description:A method that relies on subtractive tissue-directed shot-gun proteomics to identify tumor proteins in the blood of a patient newly diagnosed with cancer is described. To avoid analytical and statistical biases caused by physiologic variability of protein expression in the human population, this method was applied on clinical specimens obtained from a single patient diagnosed with nonmetastatic renal cell carcinoma (RCC). The proteomes extracted from tumor, normal adjacent tissue and preoperative plasma were analyzed using 2D-liquid chromatography-mass spectrometry (LC-MS). The lists of identified proteins were filtered to discover proteins that (i) were found in the tumor but not normal tissue, (ii) were identified in matching plasma, and (iii) whose spectral count was higher in tumor tissue than plasma. These filtering criteria resulted in identification of eight tumor proteins in the blood. Subsequent Western-blot analysis confirmed the presence of cadherin-5, cadherin-11, DEAD-box protein-23, and pyruvate kinase in the blood of the patient in the study as well as in the blood of four other patients diagnosed with RCC. These results demonstrate the utility of a combined blood/tissue analysis strategy that permits the detection of tumor proteins in the blood of a patient diagnosed with RCC.
| S-EPMC3251958 | biostudies-literature
Project description:BackgroundSunitinib is a protein tyrosine kinase (PTK) inhibitor that has immune-modulating properties. In this context, peripheral blood mononuclear cells (PBMC), mainly constituted by lymphocytes, could be a perfect surrogate tissue for identifying and assaying pharmacodynamic biomarkers of sunitinib. In this study, we investigated the changes in lymphocytes count as pharmacodynamic biomarker in metastatic renal cell carcinoma (mRCC) patients under sunitinib therapy. Thereafter, we studied the ex vivo effect of sunitinib and SU12262 (active metabolite) on PBMC from naïve mRCC patients using a high throughput kinomic profiling method.MethodsThe prognostic value of total lymphocytes count between Day 0 and Day 21 (expressed as a ratio D21/D0) was retrospectively investigated in 88 mRCC patients under sunitinib therapy. PTK PamChip® microarrays were used to explore prospectivelythe ex vivo effect of sunitinib and SU12662 on PTK activity in PBMC from 21 naïve mRCC patients.ResultsIn this retrospective study, D21/D0 lymphocytes ratio (Hazard Ratio, 1.83; CI95%, 1.24-2.71; p=0.0023) was independently associated with PFS. Interestingly, kinomic analysis showed that D21/D0 lymphocytes ratio and Heng prognostic model was statistically associated with the ex vivo sunitinib and SU12662 effect in PBMC.ConclusionThe present study highlights that D21/D0 total lymphocytes ratio could be a promising pharmacodynamic biomarker in mRCC patients treated with sunitinib. Additionally, it paves the way to investigate the kinomic profile in PBMC as a prognostic factor in a larger cohort of mRCC patients under sunitinib therapy.
| S-EPMC5341893 | biostudies-literature
Project description:BackgroundHigher treatment facility (TF) volume has been linked with improved oncologic treatment outcomes.ObjectiveTo determine the association between TF volume and overall survival in patients with metastatic renal cell carcinoma (mRCC).Design, setting, and participantsThe National Cancer Database (NCDB) was queried for all patients with mRCC with survival data available (2004-2013, cohort A). Overall survival was assessed based on TF volumes, and increasingly narrow inclusion criteria were used to confirm the cohort A association: cohort B=mRCC patients with active treatment; cohort C=mRCC patients with systemic therapy; cohort D=mRCC patients with systemic therapy at the reporting institution; and cohort E=mRCC patients with systemic therapy at the reporting institution with known liver and lung metastatic status. Sensitivity analyses were also performed on subcohorts of mRCC who never underwent a nephrectomy (C1, D1, and E1).Outcome measurements and statistical analysisThe effect of volume on time to death (from any cause) was determined using Cox regression models, adjusting for multiple clinical pathologic factors. Volume effects (assessed continuously) were modeled using flexible cubic splines, and adjusted 1-yr survivals were obtained from the model.Results and limitationsA total of 41 836 mRCC patients were treated at 1222 TFs. The median age was 65 yr. Of the patients, 66% were men and 79% had clear cell mRCC. Median TF volume was 2.2 patients per year (pts/yr). Across all cohorts, higher TF volume was associated with improved outcomes. Adjusted 1-yr survival in cohort A was 0.36 at 2 pts/yr, 0.39 at 5 pts/yr, 0.42 at 10 pts/yr, and 0.46 at 20 pts/yr, with similar magnitudes of effect in cohorts B-E. Limitations include the retrospective nature of NCDB analysis and the lack of information on treatment regimens used at specific facilities, which may explain mechanisms of effects.ConclusionsHigher facility volume is associated with improvements in survival for patients being treated for mRCC. Steps should be taken to standardize management of mRCC patients, such as evidence-based pathway development, clinical trial access, and multidisciplinary resource availability at lower-volume TFs.Patient summaryIn this report, we analyzed a large cancer database and found that patients with metastatic kidney cancer survived longer if they were managed at facilities that treated a higher volume of such patients. This information can help find the best treatment environment for patients with metastatic kidney cancer.
| S-EPMC7548437 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is one of the most common urological malignancies. Identifying novel biomarkers and investigating the underlying mechanism of ccRCC development will be crucial to the management and treatment of ccRCC in patients. Thymosin b10 (TMSB10), a member of the thymosin family, is involved in various physiological processes, including tissue regeneration and inflammatory regulation. Moreover, it has been found to be upregulated in many types of carcinoma. However, its roles in ccRCC remain to be elucidated. The present study aimed to explore the expression of TMSB10 in ccRCC through mining The Cancer Genome Atlas (TCGA) and Oncomine databases, and to investigate the association between TMSB10 expression and clinicopathological factors. Furthermore, immunohistochemistry assays and western blotting were conducted to verify TMSB10 expression levels in human ccRCC tissues and cell lines. Functional analyses were also performed to identify the roles of TMSB10 in vitro. The results revealed that TMSB10 was significantly upregulated in RCC tissues and cell lines. The expression of TMSB10 was closely associated with various clinicopathological parameters. In addition, high expression of TMSB10 predicted poor clinical outcome. The receiver operating characteristic curve revealed that TMSB10 could sufficiently distinguish the tumor from normal kidney (area under the curve = 0.9543, P<0.0001). Furthermore, knockdown of TMSB10 impaired the proliferation of ccRCC cells, and attenuated cell and invasion in vitro. In addition, TMSB10 knockdown downregulated reduced the phosphorylation of PI3K and the expression of vascular endothelial growth factor. In conclusion, the present study demonstrated that high expression of TMSB10 could serve as a useful diagnostic and prognostic biomarker and a potential therapeutic target for ccRCC.
| S-EPMC7115359 | biostudies-literature
Project description:BackgroundRenal Cell Carcinoma (RCC) is difficult to treat with 5-year survival rate of 10% in metastatic patients. Main reasons of therapy failure are lack of validated biomarkers and scarce knowledge of the biological processes occurring during RCC progression. Thus, the investigation of mechanisms regulating RCC progression is fundamental to improve RCC therapy.MethodsIn order to identify molecular markers and gene processes involved in the steps of RCC progression, we generated several cell lines of higher aggressiveness by serially passaging mouse renal cancer RENCA cells in mice and, concomitantly, performed functional genomics analysis of the cells. Multiple cell lines depicting the major steps of tumor progression (including primary tumor growth, survival in the blood circulation and metastatic spread) were generated and analyzed by large-scale transcriptome, genome and methylome analyses. Furthermore, we performed clinical correlations of our datasets. Finally we conducted a computational analysis for predicting the time to relapse based on our molecular data.ResultsThrough in vivo passaging, RENCA cells showed increased aggressiveness by reducing mice survival, enhancing primary tumor growth and lung metastases formation. In addition, transcriptome and methylome analyses showed distinct clustering of the cell lines without genomic variation. Distinct signatures of tumor aggressiveness were revealed and validated in different patient cohorts. In particular, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. Machine learning and mathematical modeling confirmed the importance of CFB and SAA2 together, which had the highest impact on distant metastasis-free survival. From these data sets, a computational model predicting tumor progression and relapse was developed and validated. These results are of great translational significance.ConclusionA combination of experimental and mathematical modeling was able to generate meaningful data for the prediction of the clinical evolution of RCC.
| S-EPMC8527701 | biostudies-literature
Project description:Multiple blood parameters are used to determine the prognosis of renal cell carcinoma (RCC). Mean platelet volume/platelet count (MPV/PC) ratio is related to disease progression in various cancers. Our study tried to evaluate the prognostic value of the MPV/PC ratio in RCC patients who underwent surgery. We retrospectively reviewed 89 patients who underwent radical or partial nephrectomy for RCC in a single institution. Baseline characteristics and MPV/PC ratios were analyzed. The optimal cut-off value of the MPV/PC ratio was determined by a receiver operating characteristic (ROC) curve, and our patients were divided into low and high MPV/PC ratio groups. The Kaplan-Meier survival curve and Cox proportional hazards model were applied for progression-free survival (PFS) and overall survival (OS) analyses. Harell's C-index was used to compare the prognostic values of the MPV/PC ratio, MPV and PC. Lower MPV/PC ratios were correlated with more advanced tumor stages and worse outcomes. The optimal cut-off value of the preoperative MPV/PC ratio was 0.034 (sensitivity 84.6%, specificity 56.6%). The Kaplan-Meier survival curve revealed that low MPV/PC ratios were associated with worse PFS (p = 0.007) and OS (p = 0.017). Multivariate analysis showed that low MPV/PC ratios were an independent unfavorable factor for PFS (p = 0.044) and OS (p = 0.015). Harell's C-indexes showed that the prognostic value of the MPV/PC ratio was significantly better than MPV and PC (p < 0.001). Low MPV/PC ratios are an independent, unfavorable risk factor for disease progression and overall survival in patients undergoing surgery for RCC.
| S-EPMC8396988 | biostudies-literature