Visceral Adiposity as a Significant Predictor of Sunitinib-Induced Dose-Limiting Toxicities and Survival in Patients with Metastatic Clear Cell Renal Cell Carcinoma

Sunitinib is a first-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about the predictive factors of sunitinib-induced dose-limiting toxicity (DLT) in Asian populations. We investigated whether body composition predicts sunitinib-induced DLT. We retrospectively reviewed sunitinib-treated Korean patients with clear cell mRCC from eight institutions. Body composition was measured using computed tomography. DLT was defined as any adverse event leading to dose reduction or treatment discontinuation. Univariate analysis was used to compare body composition indices, and logistic regression analyses were performed for factors predicting early DLT. Overall, 111/311 (32.5%) of patients experienced DLT. Significant differences were observed in the subcutaneous adipose tissue index (SATI; p = 0.001) and visceral adipose tissue index (VATI; p < 0.001) between patients with and without DLT. Multivariate analyses revealed that VATI (odds ratio: 1.013; p = 0.029) was significantly associated with early DLT. Additionally, 20% of patients who had a body mass index (BMI) greater than 23 kg/m2 and a low VATI experienced DLT, whereas 34.3% of the remaining groups had DLT (p = 0.034). Significant differences were observed for median progression-free survival (13.0 vs. 26.0 months, respectively; p = 0.006) between patients with low and high VATI. Visceral adiposity was a significant predictor of sunitinib-associated DLT and survival. Patients with a low VATI and a BMI greater than 23 kg/m2 experienced lower DLTs.

Download Full-text

NOVEL PLASMA GLYCOPROTEIN BIOMARKERS PREDICT PROGRESSION-FREE SURVIVAL IN SURGICALLY RESECTED CLEAR CELL RENAL CELL CARCINOMA

10.1101/2022.01.11.21268517 ◽

2022 ◽

Author(s):

Daniel Serie ◽

Amanda A Myers ◽

Daniela A Haehn ◽

Alexander Parker ◽

Essa Bajalia ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Differential Expression ◽

Renal Cell ◽

Clear Cell ◽

Progression Free Survival ◽

P Value ◽

Cell Renal Cell Carcinoma ◽

Free Survival ◽

Kaplan Meier

Introduction: Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS). Methods: Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrells c-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves. Results: The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate p ≤0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR=6.47, P=9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR=10.69, P=0.001), clusterin A2G2 motif (HR=7.38, P=0.002), complement component C8A A2G2S2 motif (HR=11.59, P=0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR=6.30, P=0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9-10.7, all with p-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (p <0.0001). Conclusion: Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.

Download Full-text

Increased visceral adipose tissue in male patients with clear cell renal cell carcinoma

Clinical Cancer Investigation Journal ◽

10.4103/ccij.ccij_62_18 ◽

2018 ◽

Vol 7 (4) ◽

pp. 132 ◽

Cited By ~ 4

Author(s):

Federico Greco ◽

Vincenzo Cirimele ◽

CarloAugusto Mallio ◽

BrunoBeomonte Zobel ◽

RosarioFrancesco Grasso

Keyword(s):

Renal Cell Carcinoma ◽

Adipose Tissue ◽

Cell Carcinoma ◽

Visceral Adipose Tissue ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Male Patients ◽

Visceral Adipose

Download Full-text

The association between renal sinus fat area and the progression-free survival in Chinese non-metastatic clear-cell renal cell carcinoma patients

Oncotarget ◽

10.18632/oncotarget.19012 ◽

2017 ◽

Vol 8 (39) ◽

pp. 65481-65491

Author(s):

Haichao Huang ◽

Shi Chen ◽

Wei Yu ◽

Zirong Ye ◽

Wei Li ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Progression Free Survival ◽

Cell Renal Cell Carcinoma ◽

Renal Sinus ◽

Free Survival ◽

Renal Sinus Fat

Download Full-text

ASPEN: A randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps4590 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS4590-TPS4590

Author(s):

Andrew J. Armstrong ◽

Susan Halabi ◽

Tim Eisen ◽

Walter Michael Stadler ◽

Robert R Jones ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Case Series ◽

Progression Free Survival ◽

Clinical Activity ◽

Cell Renal Cell Carcinoma ◽

Therapeutic Decisions ◽

Undifferentiated Histology

TPS4590 Background: Currently no level 1 evidence exists to guide therapeutic decisions in patients with metastatic non-clear cell renal cell carcinoma. Case series and retrospective analyses suggest that strategies targeting either the VEGF or mTOR/TORC1 pathways have clinical activity in papillary, chromophobe, or poorly differentiated histologic subtypes. Methods: We are conducting an international, randomized phase 2 trial of patients with metastatic non-clear cell RCC; either papillary, chromophobe, or undifferentiated histology; any Motzer risk group; and who have had no prior systemic therapy. All patients contribute tissue to an international biorepository for correlative genomic, genetic, and protein biomarker studies, along with companion longitudinal plasma and urine angiome studies. Patients are randomized to either everolimus or sunitinib (1:1) at FDA approved dosing until progression. The primary endpoint is progression free survival. Trial status: Seventy-three out of a planned 108 subjects have been enrolled at the time of abstract submission: median age 64, 59 white, 10 black, 4 unknown race, and includes 42 papillary and 31 chromophobe/undifferentiated histologies, 49 men and 22 women. Accrual is anticipated to be completed by December 2013. Accrual distribution by country is currently 43 (USA), 27 (UK), and 3 (Canada). The first DSMB meeting was conducted after 40 subjects completed at least 6 months of therapy and concluded that there were no unexpected safety signals and that the study should proceed. Tissue (primary, some metastatic, urine, plasma, whole blood) has been collected on all patients to date through the Duke Center for Human Genetics Biorepository. Clinical trial information: NCT01108445.

Download Full-text

Synchronous Brain Metastases as a Poor Prognosis Factor in Clear Cell Renal Carcinoma: A Strong Argument for Systematic Brain Screening

10.21203/rs.3.rs-196626/v1 ◽

2021 ◽

Author(s):

Valentine Ruste ◽

Marie-Pierre Sunyach ◽

Ronan Tanguy ◽

Emmanuel Jouanneau ◽

Camille Schiffler ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Whole Brain Radiotherapy ◽

Progression Free Survival ◽

Cell Renal Cell Carcinoma ◽

Strong Argument ◽

Poor Prognostic Factor ◽

Fuhrman Grade

Abstract PurposeBrain metastases (BM) usually represent a poor prognostic factor in solid tumors. About 10% of patients with renal cancer (RCC) will present BM. Local therapies such as stereotactic radiotherapy (SRT), whole brain radiotherapy (WBRT), and surgery are used to achieve brain control. We compared survival between patients with synchronous BM (SynBM group) and metachronous BM (MetaBM group). MethodsIt is a retrospective study of patients with clear cell renal cell carcinoma (ccRCC) and BM treated with TKI between 2005 and 2019 at the Centre Léon Bérard in Lyon. We collected prognostic factors: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, the TNM stage, the histological subtypes and the Fuhrman grade. Overall survival (OS) was defined from diagnosis of metastatic ccRCC to death. Brain progression-free survival (B-PFS) was defined from focal brain therapy to brain progression or death.Results99 patients were analyzed, 44 in the SynBM group and 55 in the MetaBM group. OS in the MetaBM group was 49.4 months versus 19.6 months in the SynBM group, p=0.0002. The median time from diagnosis of metastasic disease to apparition of BM in the MetaBM group was 22.9 months (4.3; 125.7). SRT was used for 101 lesions (66.4%), WBRT for 25 patients (16.4%), surgery for 21 lesions (13.8%), surgery followed by radiation for 5 lesions (3.3%). B-PFS for all patients was 7 months (IC95% [5.0-10.5]). ConclusionsSurvival of patients with synchronous BM is inferior to that of patients with metachronous BM. Outcome is poor in both cases after diagnosis of BM. Brain screening should be encouraged at time of diagnosis of metastatis in ccRCC.

Download Full-text

Predictors of Progression-Free Survival and Overall Survival in Metastatic Non-Clear Cell Renal Cell Carcinoma: A Single-Center Experience

World Journal of Oncology ◽

10.14740/wjon1188 ◽

2019 ◽

Vol 10 (2) ◽

pp. 101-111 ◽

Cited By ~ 3

Author(s):

Sasanka Kumar Barua ◽

Yashasvi Singh ◽

Saumar Jyoti Baruah ◽

Rajeev T.P. ◽

Puskal K. Bagchi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Progression Free Survival ◽

Single Center ◽

Cell Renal Cell Carcinoma ◽

Free Survival ◽

Single Center Experience

Download Full-text

Predicting Clear Cell Renal Cell Carcinoma Survival Using Kurtosis of Cytoplasm in the Hematoxylin Channel from Histology Slides

Journal of Oncology ◽

10.1155/2022/7693993 ◽

2022 ◽

Vol 2022 ◽

pp. 1-9

Author(s):

Jun Wang ◽

Jianhui Chen ◽

Liren Jiang ◽

Qi Wu ◽

Dawei Wang

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Survival Analysis ◽

Cell Carcinoma ◽

Survival Time ◽

Renal Cell ◽

Clear Cell ◽

Progression Free Survival ◽

Cell Renal Cell Carcinoma ◽

Free Survival

Purpose. Grade-dependent decrease of lipid storage in clear cell renal cell carcinoma (ccRCC) leads to morphology changes in HE sections. This study investigated the role of cytoplasmic features in frozen sections of ccRCC on prognosis using the digital pathology approach. Methods. We established an automatic pipeline that performed tumor region selection, stain vector normalization, nuclei segmentation, and feature extraction based on the pathologic data from Shanghai General Hospital and The Cancer Genome Atlas database. Extracted features were subjected to survival analysis. Results. Kurtosis of the cytoplasm in the hematoxylin channel was correlated with progression-free survival (HR 0.10, 95% CI: 0.04–0.24, p = 6.52 ∗ 10 − 7 ) and overall survival (HR 0.11, 95% CI: 0.05–0.31, p = 1.72 ∗ 10 − 5 ) in ccRCC, which outperformed other texture features in this analysis. Multivariate Cox regression analysis revealed that low kurtosis of cytoplasm in the hematoxylin channel was an independent predictor for a shorter progression-free survival time ( p = 0.044 ) and overall survival time (p = 0.01). Kaplan–Meier survival analysis of progression-free survival and overall survival also showed a significantly worse prognosis in patients with low kurtosis of the cytoplasm in the hematoxylin channel (both p < 0.0001 ). Lower kurtosis of cytoplasm in the hematoxylin channel was associated with higher pathologic grade, less cholesterol ester, and more mitochondrial DNA content. Conclusion. Kurtosis of the cytoplasm in the hematoxylin channel predicts survival in clear cell renal cell carcinoma.

Download Full-text

Prognostic and predictive role of intra-tumoral CXCR1 expression in patients receiving tyrosine kinase inhibitors for metastatic clear-cell renal cell carcinoma

Journal of Clinical Urology ◽

10.1177/20514158211012270 ◽

2021 ◽

pp. 205141582110122

Author(s):

Sridhar Panaiyadiyan ◽

Brusabhanu Nayak ◽

Prabhjot Singh ◽

Seema Kaushal ◽

Subhradip Karmakar ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tyrosine Kinase ◽

Cell Carcinoma ◽

Tyrosine Kinase Inhibitors ◽

Renal Cell ◽

Kinase Inhibitors ◽

Clear Cell ◽

Progression Free Survival ◽

Cell Renal Cell Carcinoma ◽

Free Survival

Objective: We aimed to evaluate the role of intra-tumoral CXCR1 expression in predicting prognosis and treatment response in metastatic clear-cell renal cell carcinoma patients receiving tyrosine kinase inhibitors. Materials and methods: Patients with metastatic clear-cell renal cell carcinoma presented between February 2018–December 2019 were studied for the CXCR1 expression in tumor tissues before starting tyrosine kinase inhibitors. Primary outcome measure was progression-free survival. Secondary outcome measures included overall survival and prediction of treatment response. Results: The study included 35 patients with a mean age of 53.6±9.6 years. At a mean follow-up of 12.2±4.1 months, 17 (48.6%) patients had disease progression including eight (22.9%) deaths. Patients with high CXCR1 expression, compared to those with low CXCR1 expression, had a significantly shorter 12-month progression-free survival (35.4% vs 77.9%, p=0.01) and an insignificant impact on 12-month overall survival. The CXCR1 expression scores significantly differed between patients with progressive and nonprogressive disease (20.1 vs 15.1, p=0.01) and patients with high CXCR1 expression had a reduced benefit from tyrosine kinase inhibitors. The multivariate Cox regression analysis showed CXCR1 expression as a significant predictor of progression-free survival. Conclusion: High intra-tumoral CXCR1 expression before tyrosine kinase inhibitors can be an independent prognostic factor for progression-free survival and predictor of reduced benefit in patients with metastatic clear-cell renal cell carcinoma. Level of evidence: Level 2b.

Download Full-text

Prognostic significance and tumor-immune infiltration of mTOR in clear cell renal cell carcinoma

PeerJ ◽

10.7717/peerj.11901 ◽

2021 ◽

Vol 9 ◽

pp. e11901

Author(s):

Na Li ◽

Jie Chen ◽

Qiang Liu ◽

Hongyi Qu ◽

Xiaoqing Yang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Univariate Analysis ◽

Prognostic Significance ◽

Clinical Role ◽

Cell Renal Cell Carcinoma ◽

Cancer Specific Survival ◽

Immune Infiltration

Mammalian target of rapamycin (mTOR), a serine/threonine kinase involved in cell proliferation, survival, metabolism and immunity, was reportedly activated in various cancers. However, the clinical role of mTOR in renal cell carcinoma (RCC) is controversial. Here we detected the expression and prognosis of total mTOR and phosphorylated mTOR (p-mTOR) in clear cell RCC (ccRCC) patients, and explored the interactions between mTOR and immune infiltrates in ccRCC. The protein level of mTOR and p-mTOR was determined by western blotting (WB), and their expression was evaluated in 145 ccRCC and 13 non-tumor specimens by immunohistochemistry (IHC). The relationship to immune infiltration of mTOR was further investigated using TIMER and TISIDB databases, respectively. WB demonstrated the ratio of p-mTOR to mTOR was higher in ccRCC than adjacent specimens (n = 3), and IHC analysis elucidated that p-mTOR expression was positively correlated with tumor size, stage and metastasis status, and negatively correlated with cancer-specific survival (CSS). In univariate analysis, high grade, large tumor, advanced stage, metastasis, and high p-mTOR expression were recognized as prognostic factors of poorer CSS, and multivariate survival analysis elucidated that tumor stage, p-mTOR and metastasis were of prognostic value for CSS in ccRCC patients. Further TIMER and TISIDB analyses uncovered that mTOR gene expression was significantly associated with numerous immune cells and immunoinhibitors in patients with ccRCC. Collectively, these findings revealed p-mTOR was identified as an independent predictor of poor survival, and mTOR was associated with tumor immune infiltrates in ccRCC patients, which validated mTOR could be implicated in the initiation and progression of ccRCC.

Download Full-text