Gain of Chromosome 5q Predicts a Favorable Prognosis in Localized Renal Cell Carcinoma.

Approximately 65% of renal cell carcinomas (RCC) are diagnosed at a localized stage. We investigated the chromosome 5q gain impact on disease-free survival (DFS) in RCC patients. Overall, 676 patients with stages 1-2 RCC and having cytogenetic analysis were included. Gain of 5q was observed in 108 patients, more frequently in clear cell (ccRCC) than non-clear cell tumors. Gain of 5q is likely an independent prognostic factor since the concerned patients had a decreased recurrence risk in stages 1-2 RCC, confirmed in multivariable analysis. Detecting 5q gain could enhance recurrence risk assessment, allowing tailored post-surgery surveillance, and reducing unnecessary treatments.

CD70 is Consistently Expressed in Primary and Metastatic Clear Cell Renal Cell Carcinoma.

BACKGROUND: CD70 is commonly overexpressed in renal cell carcinoma and is minimally expressed in normal human tissue, making it a potential therapeutic target for patients with advanced renal cell carcinoma. The expression frequency of CD70 in metastatic renal cell carcinoma is not well established. MATERIALS AND METHODS: We assessed CD70 immunohistochemistry in 391 primary renal tumors and 72 metastatic renal cell carcinomas on a tissue microarray including 26 sets of paired primary and metastatic tumors. RESULTS: CD70 was frequently overexpressed in clear cell carcinoma, with a significantly lower expression rate in papillary renal cell carcinoma (P < .0001). No expression of CD70 was detected in other types of renal tumors and normal renal parenchyma. In clear cell renal cell carcinoma, CD70 expression was significantly correlated with hypoxia pathway proteins, corroborating with a recent study suggesting that CD70 is a downstream target gene of hypoxia-inducible factor. While higher expression levels were observed in males and non-Caucasians, CD70 expression was not associated with tumor grade, sarcomatoid differentiation, stage, or cancer-specific survival. Further, analysis of 26 paired primary and metastatic tumors from same individuals revealed a concordance rate of 85%. CONCLUSION: Our findings validated CD70 as a promising therapeutic target for patients with metastatic clear cell renal cell carcinoma. The utility of primary tumor tissue as surrogate samples for metastatic clear cell carcinoma awaits future CD70-targeted clinical trials.

Pathological and genetic markers improve recurrence prognostication with the University of California Los Angeles Integrated Staging System for patients with clear cell renal cell carcinoma.

PURPOSE: To elucidate which patients with clear cell renal cell carcinoma have the highest risk for disease relapse after curative nephrectomy is challenging but is acutely relevant in the era of approved adjuvant therapies. Pathological and genetic markers were used to improve the University of California Los Angeles Integrated Staging System (UISS) for the risk stratification and prognostication of recurrence free survival (RFS). PATIENTS AND METHODS: Necrosis, sarcomatoid features, Rhabdoid features, chromosomal loss 9p, combined chromosomal loss 3p14q and microvascular invasion (MVI) were tested in univariable and multivariable analyses for their ability to improve the discriminatory ability of the UISS. RESULTS: In the development cohort, during the median follow-up time of 43.4 months (±SD 54.1 months), 50/240 (21%) patients developed disease recurrence. MVI (HR: 2.22; p = 0.013) and the combined loss of chromosome 3p/14q (HR: 2.89; p = 0.004) demonstrated independent association with RFS and were used to improve the assignment to the UISS risk category. In the current UISS high-risk group, only 7/50 (14%) recurrence cases were correctly identified; while in the improved system, 23/50 (45%) were correctly prognosticated. The concordance index meaningfully improved from 0.55 to 0.68 to distinguish patients at intermediate risk versus high risk. Internal validation demonstrated a robust prognostication of RFS. In the external validation cohort, there was no case with disease recurrence in the low-risk group, and the mean RFS times were 13.2 (±1.8) and 8.2 (±0.8) years in the intermediate and high-risk groups, respectively. CONCLUSIONS: Adding MVI and combined chromosomal loss3p/14q to the UISS improves the ability to define the patient group with clear cell renal cell carcinomawho are at the highest risk for disease relapse after surgical treatment.

Thioredoxin 1 (Trx1) is associated with poor prognosis in clear cell renal cell carcinoma (ccRCC): an example for the crucial role of redox signaling in ccRCC.

PURPOSE: Thioredoxins are major regulatory proteins of oxidative signaling. Trx1 is the most prominent thioredoxin and, therefore, the current study sought to evaluate the prognostic role of Trx1 in ccRCC. METHODS AND PATIENTS: A tissue micro-array (TMA) study was carried out to evaluate the association of Trx1 with clinicopathological features and survival outcome. Data from the Cancer Genome Atlas (TCGA) were evaluated for the association of characteristics in the Trx1 gene with clinicopathological features and survival outcome. RESULTS: In the TMA, patients with ccRCC that had high Trx1 levels had lower T stages (p < 0.001), less often distant metastases (p = 0.018), lower nuclear grades (p < 0.001), and less often tumor necrosis (p = 0.037) or sarcomatoid features (p = 0.008). Patients with a combined score of ≥ 10 had better DSS than patients with a low combined score of < 10 (HR 95% CI 0.62 (0.39-0.98)). Interestingly, the survival outcome is compartment specific: ccRCC patients whose tumors had exclusively Trx1 expression in the cytoplasm had the worst survival outcome (HR 3.1; 95% CI 1.2-8.0). Genomic data from the TCGA demonstrated that patients with ccRCCs that had Trx1 losses had more advanced clinicopathological features and worse survival outcome in disease specific (p < 0.001), overall (p = 0.001), and progression free survival (p = 0.001) when compared to patients with ccRCCs without copy number variations (CNV) or gains. CONCLUSION: The current study suggests a possible role of Trx1 in the tumor biology of ccRCC and thus, the current study strongly advises in depth investigations of redox signaling pathways in ccRCC.

p53 is functionally inhibited in clear cell renal cell carcinoma (ccRCC): a mechanistic and correlative investigation into genetic and molecular characteristics.

PURPOSE: Although p53 is rarely mutated in ccRCC, its overexpression has been linked to poor prognosis. The current study sought to elucidate the unique role of p53 in ccRCC with genomic, proteomic, and functional analyses. MATERIALS AND METHODS: Data from the Cancer Genome Atlas (TCGA) were evaluated for genomic and proteomic characteristics of p53; a tissue micro array (TMA) study was carried out to evaluate the association of p53 and phosphorylated p53 (pp53) with clinical outcome. Mechanistic in vitro experiments were performed to confirm a pro-apoptotic loss of p53 in ccRCC and p53 isoforms as well as posttranslational modifications of p53 where assessed to provide possible reasons for a functional inhibition of p53 in ccRCC. RESULTS: A low somatic mutation rate of p53 could be confirmed. Although mRNA levels were correlated with poor prognosis and clinicopathological features, there was no monotonous association of mRNA levels with survival outcome. Higher p53 protein levels could be confirmed as poor prognostic features. In vitro, irradiation of ccRCC cell lines markedly induced levels of p53 and of activated (phosphorylated) p53. However, irradiated ccRCC cells demonstrated similar proliferation, migration, and p53 transcriptional activity like non-irradiated controls indicating a functional inhibition of p53. p53 isoforms and could not be correlated with clinical outcome of ccRCC patients. CONCLUSIONS: p53 is rarely mutated but the wildtype p53 is functionally inhibited in ccRCC. To investigate mechanisms that underlie functional inhibition of p53 may provide attractive therapeutic targets in ccRCC.

Prognostic Impact of Membranous/Nuclear Epidermal Growth Factor Receptor Localization in Clear Cell Renal Cell Carcinoma.

EGFR is overexpressed in the majority of clear cell renal cell carcinomas (CCRCCs). Although EGFR deregulation was found to be of great significance in CCRCC biology, the EGFR overexpression is not associated with EGFR-targeted therapy responsiveness. Moreover, the prognostic role of EGFR expression remains controversial. In the present study, we evaluated the role played by EGFR overexpression in CCRCC and its prognostic significance associated with different immunohistochemical localization patterns. In our study, the Total Score (TS) related to membranous-cytoplasmic EGFR expression showed a significant correlation with grade, pathologic stage (pT), and Stage, Size, Grade, and Necrosis (SSIGN) score, and a negative correlation with nuclear EGFR expression. No significant correlations were shown between nuclear EGFR and clinic-pathological features. Additionally, a correlation between SGLT1 expression levels and pT was described. Multivariate analysis identifies pT and SSIGN score as independent prognostic factors for CCRCC. A significantly increased survival rate was found in the case of positive expression of nuclear EGFR and SGLT1. Based on our findings, SGLT1 and nuclear EGFR overexpression defines a subgroup of CCRCC patients with good prognosis. Membranous-cytoplasmic EGFR expression was shown to be a poor prognostic factor and could define a CCRCC subgroup with poor prognosis that should be responsive to anti-EGFR therapies.

Evaluation of Clear Cell, Papillary, and Chromophobe Renal Cell Carcinoma Metastasis Sites and Association With Survival.

Importance: There exists considerable biological and clinical variability between histologic variants of metastatic renal cell carcinoma (mRCC). Data reporting on patterns of metastasis in histologic variants of mRCC are sparse. Objective: To characterize sites of metastasis and their association with survival across the 3 most common histologic variants of mRCC: clear cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC). Design, Setting, and Participants: In this multicenter, international cohort study, the International mRCC Database Consortium (IMDC) database was used to identify consecutive patients starting systemic therapy for mRCC between 2002 and 2019. Patients with mixed histologic subtype were excluded. Statistical analysis was performed from February to June 2020. Exposures: Data regarding histologic subtype and sites of metastatic involvement at the time of first systemic therapy initiation were collected. Main Outcomes and Measures: The primary outcomes were prevalence of metastatic site involvement and overall survival (OS) from time of systemic therapy initiation. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases. Results: A total of 10 105 patients were eligible for analysis. Median (interquartile range) age at diagnosis was 60 (53-67) years, 7310 (72.4%) were men and 8526 (84.5%) underwent nephrectomy. Of these, 9252 (92%) had ccRCC, 667 (7%) had pRCC, and 186 (2%) had chrRCC. The median number of sites of metastasis was 2 (range, 0-7). In ccRCC, the most common sites of metastasis were lung (70%; 6189 of 8804 patients [448 missing]), lymph nodes (45%; 3874 of 8655 patients [597 missing]), bone (32%; 2847 of 8817 patients [435 missing]), liver (18%; 1560 of 8804 [448 missing]), and adrenal gland (10%; 678 of 6673 patients [2579 missing]). Sites of metastasis varied between subtypes. Lung, adrenal, brain, and pancreatic metastases were more frequent in ccRCC, lymph node involvement was more common in pRCC, and liver metastases were more frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (95% CI, 13.7-18.8 months) for the pleura and 50 months (95% CI, 41.1-55.5 months) for the pancreas. Compared with ccRCC, patients with pRCC tended to have lower OS, regardless of metastatic site. Conclusions and Relevance: Sites of metastatic involvement differ according to histologic subtype in mRCC and are associated with OS. These data highlight the clinical and biological variability between histologic subtypes of mRCC. Patterns of metastatic spread may reflect differences in underlying disease biology. Further work to investigate differences in immune, molecular, and genetic profiles between metastatic sites and histologic subtypes is encouraged.

Systemic treatment of advanced/metastatic renal cell carcinoma in the context of SARS-CoV-2 pandemic: recommendations from the interdisciplinary working group for renal tumors (IAG-N).

This letter summarizes recommendations from the interdisciplinary working group of renal tumors (IAGN) of the German Cancer Society for the systemic treatment of advanced/metastatic renal cell carcinoma in the context of the current SARS-CoV-2 pandemic.

The cytosolic isoform of glutaredoxin 2 promotes cell migration and invasion.

BACKROUND: Cytosolic glutaredoxin 2 (Grx2c) controls axonal outgrowth and is specifically induced in many cancer cell lines. We thus hypothesized that Grx2c promotes cell motility and invasiveness. METHODS: We characterized the impact of Grx2c expression in cell culture models. We combined stable isotope labeling, phosphopeptide enrichment, and high-accuracy mass spectrometry to characterize the underlying mechanisms. RESULTS: The most prominent associations were found with actin dynamics, cellular adhesion, and receptor-mediated signal transduction, processes that are crucial for cell motility. For instance, collapsin response mediator protein 2, a protein involved in the regulation of cytoskeletal dynamics, is regulated by Grx2c through a redox switch that controls the phosphorylation state of the protein as well. Cell lines expressing Grx2c showed dramatic alterations in morphology. These cells migrated two-fold faster and gained the ability to infiltrate a collagen matrix. CONCLUSIONS: The expression of Grx2c promotes cell migration, and may negatively correlate with cancer-specific survival. GENERAL SIGNIFICANCE: Our results imply critical roles of Grx2c in cytoskeletal dynamics, cell adhesion, and cancer cell invasiveness.

Evaluation of the prognostic role of co-morbidities on disease outcome in renal cell carcinoma patients.

BACKGROUND: Co-morbidities may induce local and systemic tumor progression of renal cell carcinoma (RCC); however, the prognostic impact of co-morbidities has not yet been well characterized. PATIENTS AND METHODS: RCC patients (n = 2206) surgically treated at three academic institutions in the US and Europe were included in the analysis. Presence of diabetes mellitus, hypertension, chronic kidney disease, chronic obstructive pulmonary disease, coronary heart disease, and hypothyroidism were investigated for their association with clinicopathological features and cancer-specific survival. RESULTS: Hypertension was associated with less advanced T stages (p = 0.025), a lower risk of lymph-node (p = 0.026) and distant metastases (p = 0.001), and improved cancer specific survival in univariable analysis (HR 0.81 95% CI 0.69-0.96, p = 0.013). However, hypertension was not an independent prognostic factor after adjustment for TNM stages, grading, and ECOG performance status (HR 0.95, 95% CI 0.80-1.12; p = 0.530). A correlation between the use of concomitant anti-hypertensive medications and improved survival outcome was not identified. All other investigated co-morbidities did not show significant associations with clinicopathological features or cancer-specific survival. CONCLUSION: Although the investigated co-morbidities are capable or inducing pathophysiological changes that are predisposing factors for tumor progression, none is an independent prognostic factor in patients with RCC.

The VENUSS prognostic model to predict disease recurrence following surgery for non-metastatic papillary renal cell carcinoma: development and evaluation using the ASSURE prospective clinical trial cohort.

BACKGROUND: The current World Health Organization classification recognises 12 major subtypes of renal cell carcinoma (RCC). Although these subtypes differ on molecular and clinical levels, they are generally managed as the same disease, simply because they occur in the same organ. Specifically, there is a paucity of tools to risk-stratify patients with papillary RCC (PRCC). The purpose of this study was to develop and evaluate a tool to risk-stratify patients with clinically non-metastatic PRCC following curative surgery. METHODS: We studied clinicopathological variables and outcomes of 556 patients, who underwent full resection of sporadic, unilateral, non-metastatic (T1-4, N0-1, M0) PRCC at five institutions. Based on multivariable Fine-Gray competing risks regression models, we developed a prognostic scoring system to predict disease recurrence. This was further evaluated in the 150 PRCC patients recruited to the ASSURE trial. We compared the discrimination, calibration and decision-curve clinical net benefit against the Tumour, Node, Metastasis (TNM) stage group, University of California Integrated Staging System (UISS) and the 2018 Leibovich prognostic groups. RESULTS: We developed the VENUSS score from significant variables on multivariable analysis, which were the presence of VEnous tumour thrombus, NUclear grade, Size, T and N Stage. We created three risk groups based on the VENUSS score, with a 5-year cumulative incidence of recurrence equalling 2.9% in low-risk, 15.4% in intermediate-risk and 54.5% in high-risk patients. 91.7% of low-risk patients had oligometastatic recurrent disease, compared to 16.7% of intermediate-risk and 40.0% of high-risk patients. Discrimination, calibration and clinical net benefit from VENUSS appeared to be superior to UISS, TNM and Leibovich prognostic groups. CONCLUSIONS: We developed and tested a prognostic model for patients with clinically non-metastatic PRCC, which is based on routine pathological variables. This model may be superior to standard models and could be used for tailoring postoperative surveillance and defining inclusion for prospective adjuvant clinical trials.

Active Smoking Is Associated With Worse Prognosis in Metastatic Renal Cell Carcinoma Patients Treated With Targeted Therapies.

BACKGROUND: Smoking increases the risk of developing renal cell carcinoma (RCC) but the effect of tobacco consumption on survival outcome of patients with metastatic RCC (mRCC) treated with targeted therapies has not been well characterized. PATIENTS AND METHODS: The primary outcome was overall survival (OS) and secondary outcome was progression-free survival (PFS). Patients with mRCC were categorized as current, former, and nonsmokers at the time of starting targeted therapy. Smoking data from 1980 patients with mRCC treated with targeted therapy were collected through the International mRCC Database Consortium (IMDC) from 12 international cancer centers. RESULTS: Although former and nonsmokers had comparable OS times (23.8 vs. 23.4 months; P = .898), current smokers had significantly shorter OS (16.1 months; P < .001) than nonsmokers. Current but not former smoking status was an independent poor prognosis factor (hazard ratio [HR], 1.3; P = .002) when adjusted for the IMDC risk criteria. Each pack-year increased the risk of death by 1% (HR, 1.01; P = .036). The duration of first-line therapy response was not different and was 7.7 months versus 7.5 months versus 6.4 months in never, former (P = .609), and current smokers (P = .839), respectively. CONCLUSION: Active smoking is associated with diminished OS in mRCC patients treated with targeted therapy agents. However, patients who quit smoking returned to a similar risk of death from RCC compared with patients who never smoked. Smoking cessation should be a counseling priority among mRCC patients receiving targeted agents and smoking should be considered as a confounding factor in major clinical trials.

Receptor activator of NF-κB (RANK)-mediated induction of metastatic spread and association with poor prognosis in renal cell carcinoma.

BACKGROUND: Inhibition of the receptor activator of NF-κB ligand (RANKL) has become a standard of care supportive treatment to prevent skeletal related events in cancer patients. Moreover, RANKL inhibition has been implicated with better survival outcome in lung cancer, while RANKL expression induces tumor progression and metastatic spread in vivo in breast cancer. Whether RANK/RANKL may have an impact on the pathogenesis of clear cell renal cell carcinoma (ccRCC) is currently unknown. PATIENTS AND METHODS: A retrospective tissue micro array (TMA)-study was carried out determining the expression of RANK/RANKL in primary tumors of 306 ccRCC patients. Additionally, 24 ccRCC cell lines were employed for in vitro analyses of the RANK/RANKL axis including cell proliferation, migration and anchorage independent growth. RESULTS: RANK (+) vs. RANK (-) tumors had both worse cancer specific survival (CSS) (6.3 vs. 1.3 years; p < 0.001) and recurrence free survival (RFS) (9.9 vs. 5.8 years; p < 0.001). RANK (+) (HR 2.21; p < 0.001) was an independent prognostic factor for CSS and RFS (HR 4.98; p < 0.001). RANKL treatment resulted in increased proliferation, soft agar growth, and colony formation of RANK (+) RCC cell lines, which could be reversed by treatment with an NF-κB inhibitor and with a combination of osteoprotegrin and RANKL in vitro. CONCLUSIONS: RANK is expressed in ccRCC tissue, correlates with clinicopathological features, survival outcome, and when stimulated with RANKL can induce ccRCC progression in vitro. Consequently, RANKL inhibition combined with standard of care treatment may be a promising approach to improve ccRCC patient's survival.

Microvascular and lymphovascular tumour invasion are associated with poor prognosis and metastatic spread in renal cell carcinoma: a validation study in clinical practice.

OBJECTIVE: To validate microvascular (MVI) and lymphovascular (LVI) invasion as prognostic factors in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Data of patients with RCC who underwent radical or nephron-sparing surgery were prospectively collected from three academic centres. The occurrence of MVI and LVI was determined with standard staining protocols by experienced pathologists at the time of diagnosis. The association of MVI and LVI with clinicopathological data, metastatic spread, and cancer-specific survival (CSS) were evaluated with Fisher's exact tests, binary logistic regression analyses, and univariable and multivariable Cox proportional hazard regression models. RESULTS: MVI was present in 201 of 747 patients (26.9%) and was associated with advanced Tumour-Node-Metastasis (TNM) stages, high Fuhrman grades, and sarcomatoid features (all P < 0.001). MVI was associated with a higher rate of metastatic spread. LVI was present in 32 of 573 patients (5.5%) and was associated with advanced TNM stages, high Fuhrman grade, and sarcomatoid features (all P < 0.001). Two-thirds of LVI-positive patients died (P < 0.001). Both LVI and MVI were significantly associated with CSS in all patients, clear cell RCC (ccRCC), and localised RCC in univariable analysis (all P < 0.001). On multivariable analysis, presence of MVI was identified as an independent prognostic factor (hazard ratio 2.09; P = 0.001). Moreover, MVI [odds ratio (OR) 2.7; P = 0.001] and not macrovascular invasion (P = 0.895) was an independent predictor of sychronuous metastatic spread. LVI was the strongest factor associated with sychronous metastatic spread (OR 4.73, 95% confidence interval 1.84-12.14; P = 0.001) in all patients and in the subgroup of patients with ccRCC (P = 0.001). CONCLUSIONS: The present study validated LVI and MVI as prognostic factors for poor outcome in RCC. These findings endorse an evaluation of both variables in the clinical routine setting to facilitate survival prognostication in follow-up protocols and for assignment to adjuvant treatment trials.

Partial nephrectomy versus radical nephrectomy for clinical localised renal masses.

BACKGROUND: Partial nephrectomy and radical nephrectomy are the relevant surgical therapy options for localised renal cell carcinoma. However, debate regarding the effects of these surgical approaches continues and it is important to identify and summarise high-quality studies to make surgical treatment recommendations. OBJECTIVES: To assess the effects of partial nephrectomy compared with radical nephrectomy for clinically localised renal cell carcinoma. SEARCH METHODS: We searched CENTRAL, MEDLINE, PubMed, Embase, Web of Science, BIOSIS, LILACS, Scopus, two trial registries and abstracts from three major conferences to 24 February 2017, together with reference lists; and contacted selected experts in the field. SELECTION CRITERIA: We included a randomised controlled trial comparing partial and radical nephrectomy for participants with small renal masses. DATA COLLECTION AND ANALYSIS: One review author screened all of the titles and abstracts; only citations that were clearly irrelevant were excluded at this stage. Next, two review authors independently assessed full-text reports, identified relevant studies, evaluated the eligibility of the studies for inclusion, assessed trial quality and extracted data. The update of the literature search was performed by two independent review authors. We used Review Manager 5 for data synthesis and data analyses. MAIN RESULTS: We identified one randomised controlled trial including 541 participants that compared partial nephrectomy to radical nephrectomy. The median follow-up was 9.3 years.Based on low quality evidence, we found that time-to-death of any cause was decreased using partial nephrectomy (HR 1.50, 95% CI 1.03 to 2.18). This corresponds to 79 more deaths (5 more to 173 more) per 1000. Also based on low quality evidence, we found no difference in serious adverse events (RR 2.04, 95% CI 0.19 to 22.34). Findings are consistent with 4 more surgery-related deaths (3 fewer to 78 more) per 1000.Based on low quality evidence, we found no difference in time-to-recurrence (HR 1.37, 95% CI 0.58 to 3.24). This corresponds to 12 more recurrences (14 fewer to 70 more) per 1000. Due to the nature of reporting, we were unable to analyse overall rates for immediate and long-term adverse events. We found no evidence on haemodialysis or quality of life.Reasons for downgrading related to study limitations (lack of blinding, cross-over), imprecision and indirectness (a substantial proportion of patients were ultimately found not to have a malignant tumour). Based on the finding of a single trial, we were unable to conduct any subgroup or sensitivity analyses. AUTHORS' CONCLUSIONS: Partial nephrectomy may be associated with a decreased time-to-death of any cause. With regards to surgery-related mortality, cancer-specific survival and time-to-recurrence, partial nephrectomy appears to result in little to no difference.

Adjuvant Treatment of High-risk Renal Cell Carcinoma: Leaving the Desert?

In a recent trial, adjuvant treatment with sunitinib significantly prolonged disease-free survival compared to placebo. This positive result is muted by the rate of side effects and overtreatment, raising the question of proper patient and agent selection in the adjuvant setting.

Risk factors and model for predicting toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted therapies are standard treatment for metastatic renal cell carcinoma (mRCC); however, toxicities can lead to drug discontinuation, which can affect patient outcomes. This study was aimed at identifying risk factors for toxicity and constructing the first model to predict toxicity-related treatment discontinuation (TrTD) in mRCC patients treated with VEGF-targeted therapies. METHODS: The baseline characteristics, treatment outcomes, and toxicity data were collected for 936 mRCC patients receiving first-line VEGF-targeted therapy from the International Metastatic Renal Cell Carcinoma Database Consortium. A competing risk regression model was used to identify risk factors for TrTD, and it accounted for other causes as competing risks. RESULTS: Overall, 198 (23.8%) experienced TrTD. Sunitinib was the most common VEGF-targeted therapy (77%), and it was followed by sorafenib (18.4%). The median time on therapy was 7.1 months for all patients and 4.4 months for patients with TrTD. The most common toxicities leading to TrTD included fatigue, diarrhea, and mucositis. In a multivariate analysis, significant predictors for TrTD were a baseline age ≥60 years, a glomerular filtration rate (GFR) <30 mL/min/1.73 m(2) , a single metastatic site, and a sodium level <135 mmol/L. A risk group model was developed that used the number of patient risk factors to predict the risk of TrTD. CONCLUSIONS: In the largest series to date, age, GFR, number of metastatic sites, and baseline sodium level were found to be independent risk factors for TrTD in mRCC patients receiving VEGF-targeted therapy. Based on the number of risk factors present, a model for predicting TrTD was built to be used as a tool for toxicity monitoring in clinical practice.

PI3K/AKT/mTOR pathway plays a major pathogenetic role in glycogen accumulation and tumor development in renal distal tubules of rats and men.

Activation of the PI3K/AKT/mTOR pathway is a crucial molecular event in human clear cell renal cell carcinoma (ccRCC), and is also upregulated in diabetic nephropathy. In diabetic rats metabolic changes affect the renal distal tubular epithelium and lead to glycogen-storing Armanni-Ebstein lesions (AEL), precursor lesions of RCC in the diabetes induced nephrocarcinogenesis model. These lesions resemble human sporadic clear cell tubules (CCT) and tumor cells of human ccRCC.Human sporadic CCT were examined in a collection of 324 nephrectomy specimen, in terms of morphologic, metabolic and molecular alterations, and compared to preneoplastic CCT and RCC developed in the rat following streptozotocin-induced diabetes or N-Nitrosomorpholine administration. Diabetic and non-diabetic rats were subjected to the dual PI3K/mTOR inhibitor, NVP/BEZ235.Human sporadic CCT could be detected in 17.3% of kidney specimens. Human and rat renal CCT display a strong induction of the PI3K/AKT/mTOR pathway and related metabolic alterations. Proteins involved in glycolysis and de novo lipogenesis were upregulated. In in vivo experiments, dual inhibition of PI3K and mTOR resulted in a reduction of proliferation of rat diabetes related CCT and increased autophagic activity.The present data indicate that human sporadic CCT exhibit a pattern of morphologic and metabolic alterations similar to preneoplastic lesions in the rat model. Activation of the PI3K/AKT/mTOR pathway in glycogenotic tubuli is a remarkable molecular event and suggests a preneoplastic character of these lesions also in humans.

The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study.

BACKGROUND: Previous prognostic models for second-line systemic therapy in patients with metastatic renal cell carcinoma have not been studied in the setting of targeted therapy. We sought to validate the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in patients with metastatic renal cell carcinoma receiving next-line targeted therapy after progression on first-line targeted therapy. METHODS: In this population-based study, we analysed patients who received second-line targeted therapy for metastatic renal cell carcinoma at 19 centres in Canada, USA, Greece, Japan, Singapore, South Korea, and Denmark. The primary endpoint was overall survival since the initiation of second-line therapy. We compared the prognostic performance of the IMDC model with the three-factor MSKCC model used for previously treated patients for overall survival since the start of second-line targeted therapy. FINDINGS: Between Jan 1, 2005, and Nov 30, 2012, we included 1021 patients treated with second-line targeted therapy. Median overall survival since the start of second-line targeted therapy was 12·5 months (95% CI 11·3-14·3). Five of six predefined factors in the IMDC model (anaemia, thrombocytosis, neutrophilia, Karnofsky performance status [KPS] <80, and <1 year from diagnosis to first-line targeted therapy) were independent predictors of poor overall survival on multivariable analysis. The concordance index using all six prognostic factors (ie, also including hypercalcaemia) was 0·70 (95% CI 0·67-0·72) with the IMDC model and was 0·66 (95% CI 0·64-0·68) with the three-factor MSKCC model. When patients were divided into three risk categories using IMDC criteria, median overall survival was 35·3 months (95% CI 28·3-47·8) in the favourable risk group (n=76), 16·6 months (14·9-17·9) in the intermediate risk group (n=529), and 5·4 months (4·7-6·8) in the poor risk group (n=261). INTERPRETATION: The IMDC prognostic model can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in first-line targeted therapy. The IMDC prognostic model in the second-line targeted therapy setting has an improved prognostic performance and is applicable to a more contemporary patient cohort than that of the three-factor MSKCC model. FUNDING: DF/HCC Kidney Cancer SPORE P50 CA101942-01, Kidney Cancer Research Network of Canada, Canadian Institute for Health Research, Trust Family, Loker Pinard, Michael Brigham, and Gerald DeWulf.