Cohort Of Renal Cell Carcinoma Patients Research Articles

Semaphorin 3A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells

Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8+ T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4+ and CD8+ T cells enhance CD8+ T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8+ T-cell infiltration. We further show that SEMA3A affects CD8+ T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8+ T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours.

Hsa_circ_0057105 modulates a balance of epithelial-mesenchymal transition and ferroptosis vulnerability in renal cell carcinoma.

The incidence of renal cell carcinoma (RCC) has increased in recent years. Metastatic RCC is common and remains a major cause of mortality. A regulatory role for circular RNAs (circRNAs) in the occurrence and progression of RCC has been identified, but their function, molecular mechanisms, and potential clinical applications remain poorly understood. High-throughput RNA sequencing was used to explore the differential expression of circRNAs and their related pathways in RCC patients. Transwell and CCK-8 assays were used to assess the function of hsa_circ_0057105 in RCC cells. The clinical relevance of hsa_circ_0057105 was evaluated in a cohort of RCC patients. The hsa_circ_0057105 regulatory axis was defined using RNA pull-down, luciferase reporter assays, and fluorescence in situ hybridization assays, and the in vivo effect of hsa_circ_0057105 was validated using animal experiments. Single-sample gene set enrichment analysis and correlation analysis of RNA-seq data showed that hsa_circ_0057105 was potentially oncogenic and may serve to regulate epithelial-mesenchymal transition (EMT) activation in RCC. Hsa_circ_0057105 expression was associated with advanced TNM stages and was an independent prognostic factor for poor RCC patient survival. Phenotypic studies show that hsa_circ_0057105 can enhance the migration and invasion abilities of RCC cells. Further, hsa_circ_0057105 was shown to inhibit the expression of miR-577, a miRNA that regulated the expression of both COL1A1, which induced EMT activation, and VDAC2, which modulated ferroptosis sensitivity. The dual regulatory roles of hsa_circ_0057105 on EMT and ferroptosis sensitivity were verified using rescue experiments. Animal studies confirmed that hsa_circ_0057105 increased the metastatic ability and ferroptosis sensitivity of RCC cells in vivo. In RCC, hsa_circ_0057105 regulates COL1A1 and VDAC2 expression through its sponge effect on miR-577, acting like a 'double-edged sword'. These findings provide new insight into the relationship between EMT and ferroptosis in RCC and provide potential biomarkers for RCC surveillance and treatment.

The prognostic value of galactosylceramide-sulfotransferase (Gal3ST1) in human renal cell carcinoma

Renal cell carcinoma (RCC) is the deadliest primary genitourinary malignancy typically associated with asymptomatic initial presentation and poorly predictable survival. Next to established risk factors, tumor microenvironment may alter metastatic capacity and immune landscape. Due to their high concentrations, sulfoglycolipids (sulfatides) were among the first well-described antigens in RCC that are associated with worse prognosis. As sulfatide detection in routine diagnostics is not possible, we aimed to test the prognostic value of its protein counterpart, sulfatide-producing enzyme Gal3ST1. We performed retrospective long-term follow up analysis of Gal3ST1 expression as prognostic risk factor in a representative RCC patient cohort. We observed differentially regulated Gal3ST1 expression in all RCC types, being significantly more associated with clear cell RCC than to chromophobe RCC (p = 0.001). Surprisingly, in contrast to published observations from in vitro models, we could not confirm an association between Gal3ST1 expression and a malignant clinical behaviour of the RCC. In our cohort, Gal3ST1 did not significantly influence progression-free survival (Hazard Ratio (HR): 1.7 95% CI (0.6–4.9), p = 0.327). Particularly after adjusting for histology, T-stage, N-status and M-status at baseline, we observed no independent prognostic effect (HR = 1.0 95% CI (0.3–3.3), p = 0.96). The analysis of Gal3ST1 mRNA expression in a TCGA dataset supported the results of our cohort. Thus, Gal3ST1 might help to differentiate between chromophobe RCC and other frequent RCC entities but—despite previously published data from cell culture models—does not qualify as a prognostic marker for RCC. Further investigation of regulatory mechanisms of sulfatide metabolism in human RCC microenvironment is necessary to understand the role of this quantitatively prominent glycosphingolipid in RCC progression.

The clinical outcome of renal cell carcinoma with rhabdoid and sarcomatoid differentiation.

e16083 Background: Renal cell carcinoma (RCC) with rhabdoid (RD) or sarcomatoid differentiation (SD) represents high-grade RCC with an aggressive clinical behavior. Little success has been reported in treating these patients. No standard management has been established and there is a lack of insight in these entities because of their relatively low incidences. We reviewed a cohort of RCC patients with RD and SD and correlated the pathologic features with their clinical outcomes. Methods: A retrospective study of RCC patients with RD or SD feature at a single center from 2008 to 2016 was conducted. Patient characteristics, pathology findings, clinical management, and survival data were collected. Results: A total of 36 RCC patients, with median age of 65 [47-88] years old, were included. The male-to-female ratio was 2.6:1. Among them, 24 were with pure SD and 12 with RD (7 pure and 5 mixed features). At diagnosis, 14 patients (38.9%) presented with stage IV disease. The median follow-up was 21 [2-53] months. Of the 36 patients, 24 developed metastasis, including 16/24 (67%) with SD, 4/7 patients (57%) with pure RD, and 4/5(80%) with mixed features. Mortality rate was 79% for SD, 75% for RD and 100% for those with mixed features. The overall survival was 23, 22, and 13 months for SD, pure RD and those with mixed features, respectively. 12 patients were treated with tyrosine kinase inhibitors (TKI) in first-line and 7 with immune checkpoint inhibitors (ICI) in the second or third line setting. Longer duration of treatment was seen with ICI than TKI, 12.8 [5-25] vs 5.9 [1-18] months (p = 0.03). Partial response was seen in 6/7 (86%) and stable disease in 1/7 (14%) patients treated with ICI. No survival benefit was seen in patients treated with TKI alone (p = 0.60). Patients received ICI had significantly prolonged overall survival compared to those received TKI alone, 31.4 vs 17.8 months (p < 0.001). Conclusions: The presence of RD or SD portends poor outcome in RCC with conventional management, especially in those with mix of both features. However, these patients had exceptionally high response and improved survival if treated with ICI. A prospective study using ICI focusing on RCC patients with these pathologic features is warranted and could provide hope for such dismal entities.

Association of elevated C-reactive protein with oncologic outcomes in renal CELL carcinoma: A multicenter analysis.

596 Background: C-reactive protein (CRP) is a systemic inflammatory marker which has been associated with overall survival (OS) in Renal Cell Carcinoma (RCC) patients in Asia. Data supporting utility of CRP as a predictive marker in non-Asian populations are sparse and controversial. We analyzed utility of pre-treatment CRP as a predictor of survival and oncological outcomes in a multicenter cohort of RCC patients. Methods: Retrospective international 3 center analysis of patients of patients with RCC with pretreatment CRP values from 2006-2017. CRP > 0.5mg/dl was used as threshold for elevation and the cohort was subdivided into two groups for descriptive analysis (normal-CRP ≤0.5 and elevated-CRP > 0.5). Primary outcome was recurrence-free survival (RFS). Secondary outcome was overall survival (OS). Kaplan-Meier (KMA) and multivariable analyses (MVA) were utilized to delineate survival outcomes and their predictors. Results: Overall 2695 patients were analyzed (1791 Male/904 female, CRP≤0.5 1198/CRP > 0.5 1496; mean follow-up 36 months). Patients with elevated CRP had higher incidence of hypertension (p = 0.001), BMI (p < 0.001), and tumor size (3.91 cm vs. 6.05 cm, p < 0.001). MVA for RFS demonstrated elevated CRP (OR = 0.542, p = 0.005), increasing tumor size (OR = 0.915, p < 0.001), and high tumor grade (OR = 0.322 p < 0.001) to be independent risk factors. MVA for all-cause mortality demonstrated elevated CRP (OR = 12.396, p = 0.005), increasing tumor size (OR = 1.126, p < 0.001), high tumor grade (OR = 2.474, p < 0.001), and receipt of PN (OR = 1.826, p = 0.001) to be independent risk factors. For normal vs. elevated CRP, KMA revealed 5-year RFS of 90% vs. 85% (p = 0.001), 95% vs 85% (p = 0.163), 85% vs 62% (p = 0.001), 50% vs 60% (p = 0.513) for Stages 1, 2, 3, and 4, respectively. KMA revealed 5-year OS of 98% vs 80% (p = 0.001), 95% vs 80% (p = 0.103), 95% vs 65% (p = 0.001), 99% vs 40% (p < 0.001) for Stages 1, 2, 3, and 4, respectively. Conclusions: Pre-treatment CRP was an independent predictor of recurrence free survival and overall survival in a multicenter cohort of RCC patients. While further confirmation is requisite, our findings suggest incorporation of CRP into nomographic and risk stratification protocols.

Angiopoietin-like protein 3 blocks nuclear import of FAK and contributes to sorafenib response

BackgroundPoor drug response of sorafenib is a major challenge which reduces clinical benefit of renal cell carcinoma (RCC) patients. It is therefore of great clinical significance to elucidate the underlying mechanism to restore the therapeutic response to sorafenib.MethodsAngiopoietin-like protein 3 (ANGPTL3) protein levels were measured by western blot and immunohistochemistry in two cohorts of RCC patients. Loss-of-function and gain-of-function experiments were performed to investigate the biological roles of ANGPTL3 in response to sorafenib treatment in RCC cells. Human proteome microarray and immunoprecipitation analysis were performed to explore the molecular mechanisms underlying the functions of ANGPTL3.ResultsANGPTL3 was upregulated in sorafenib-responsive RCC, which correlated with clinically good sorafenib response. Knockdown of ANGPTL3 conferred sorafenib-tolerance traits to RCC cells, whereas overexpression of ANGPTL3 restored sorafenib sensitivity in RCC cells. Mechanistically, ANGPTL3 bound to Focal Adhesion Kinase(FAK) and restained sorafenib induced nuclear translocation of FAK, leading to attenuate the ubiquitination of p53, which contributed to cellular apoptosis and enhanced sorafenib response.ConclusionsANGPTL3 may be a novel predictor for the response of sorafenib therapy in RCC patients, and a potential target in improving its therapeutic effect.

Highly expressed lncRNA CRNDE promotes cell proliferation through Wnt/β-catenin signaling in renal cell carcinoma.

Recently, numerous studies revealed that long non-coding RNAs (lncRNAs) play complex roles in the field of tumor biology, while the functions of lncRNA in renal cell carcinoma (RCC) remain largely unknown. In the current study, we retrieved Oncomine database and found a lncRNA colorectal neoplasia differentially expressed (CRNDE) which is highly expressed in different cohorts of RCC patients; this clue reminds us that CRNDE might exert its functions in RCC tumorigenesis. We then detected the level of CRNDE in fresh RCC tissues and found that CRNDE is significantly up-regulated compared with adjacent tissues. Furthermore, both loss and gain function assays revealed that CRNDE promotes RCC cell proliferation and growth both in vitro and in vivo.In addition, we found that CRNDE regulates the cell cycle transition from G0/G1 stage to S stage and modulates the expression of CCND1 and CCNE1. Moreover, we further illustrated that CRNDE activates Wnt/β-catenin signaling in RCC cell lines. Taken together, in the current study, we found that lncRNA CRNDE is highly expressed in RCC malignant tissues and the heightened CRNDE robustly promotes RCC cell proliferation through activating Wnt/β-catenin signaling; our findings enlarge our knowledge in the molecular pathology of RCC tumorigenesis.

Abstract A09: PDXovo: Ultra-fast in vivo drug sensitivity matrices for renal cell carcinoma patients prior to administration of targeted therapy

Abstract Our next generation PDX model of renal cell carcinoma (RCC) offers the ability to pre-determine de novo drug resistance in fresh patient tumor samples prior to targeted therapy. Implantation of tumor specimens into the chorioallantoic membrane (CAM) of the chicken embryo results in high engraftment efficiencies within two days permitting large-scale “tumor avatar” studies due to its angiogenic microenvironment. Functional tumor heterogeneity studies can be performed in context of drug resistance within two weeks, an approach that could guide the selection of drugs and anticipate outcomes for RCC patients. This ultrafast PDX model is mirrored by high-frequency ultrasound imaging that permits quantitation of tumor volume and tumor vascularity in a high-throughput manner. Using this “tumor avatar” model paired with a prospective RCC patient cohort, we observe intratumoral functional heterogeneity in the context of Sunitinib treatment as determined by high-frequency ultrasound imaging, highlighting its interventional potential in the clinic. Citation Format: Matt Lowerison, Hon S. Leong, Yaroslav Fedyshyn, Ann F. Chambers, James Lacefield, Nicholas E. Power. PDXovo: Ultra-fast in vivo drug sensitivity matrices for renal cell carcinoma patients prior to administration of targeted therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A09.

Combined cell surface carbonic anhydrase 9 and CD147 antigens enable high-efficiency capture of circulating tumor cells in clear cell renal cell carcinoma patients.

Circulating tumor cells (CTCs) have emerged as promising tools for noninvasive cancer detection and prognosis. Most conventional approaches for capturing CTCs use an EpCAM-based enrichment strategy, which does not work well in cancers that show low or no expression of EpCAM, such as renal cell carcinoma (RCC). In this study, we developed a new set of cell surface markers including CA9 and CD147 as alternative CTC-capture antigens specifically designed for RCC patients. We showed that the expression of both CA9 and CD147 was prevalent in a RCC patient cohort (n=70) by immunohistochemical analysis, with both molecules in combination covering 97.1% of cases. The NanoVelcro platform combined with CA9-/CD147-capture antibodies demonstrated significantly higher efficiency for capturing both CTC-mimicking renal cancer cells and RCC CTCs in peripheral blood, compared to the conventional EpCAM-based method. Using immunofluorescence cytological validation at the single-cell level, we were able to identify bona fide CTCs in RCC patient blood following the well-accepted criteria in our CTC-capture system. We further demonstrated a significant association of CTC numbers as well as the CTC expression status of Vimentin, a mesenchymal marker, with disease progression, including pathologic features and clinical staging. These results provide new insights into developing novel, effective targets/approaches for capturing CTCs, making CTCs a valuable tool for improved cancer detection, prognosis and treatment in RCC.

MP63-18 SURGICAL TREATMENT IN 1,084 CONSECUTIVE RENAL LESIONS IN A SINGLE TERTIARY REFERRAL UNITED KINGDOM CENTER – TARGETED OUTCOME MEASURES USING A NOVEL DECISION TREE PLATFORM

INTRODUCTION AND OBJECTIVES: Renal cell carcinoma (RCC) patients treated with radical (RN) or partial nephrectomy (PN) are at risk of postoperative acute kidney injury (AKI). We sought to investigate the incidence, trends and predictors of postoperative AKI in a large cohort of RCC patients treated with RN or PN. METHODS: Between January 1998 and December 2010, patients who underwent RN or PN for RCC were identified within the Nationwide Inpatient Sample. Incidence and temporal trends of AKI were analyzed. Association between AKI and in-hospital complications, mortality, length of stay and charges were evaluated using logistic regression models adjusted for clustering. Finally, predictors of AKI were identified using multivariable logistic regression analysis. RESULTS: Overall, 253,222 (78.1%) and 71,176 (21.9%) patients respectively underwent RN and PN. Of these, 17,828 (5.5%) experienced AKI. Incidence of AKI following RN/PN significantly increased over the period (estimated annual percentage change [EAPC]1⁄416.6% [17.7-18.8], p<0.001). Although higher overall incidence of AKI was observed after RN compared to PN (RN: 0.38/ 100,000 vs. PN: 0.09/100,000), the rate of increase in AKI over time was greater following PN compared to RN (RN: EAPC1⁄415.5% [16.817.9]; PN: EAPC1⁄419.0% [22.2-25.5], p<0.001) following PN. Incidence of any complication, mortality, prolonged hospital stay and excessive hospital costs were significantly greater in patients who experienced AKI, irrespective of the procedure (RN or PN) [all p<0.001]. Predictors of AKI after RN/PN included older age, higher comorbid status, higher chronic kidney disease stage and surgery at urban hospitals (all p<0.05). CONCLUSIONS: There is rising incidence of AKI after RN and PN. Increasing awareness of AKI incidence, identification of patients at risk prior to surgery, early postoperative AKI diagnosis, collaboration with nephrologists, implementation of renoprotective strategies, and long-term renal functional follow-up are warranted in these patients to provide improved outcomes and reduce costs.

Multiplatform molecular analysis of biomarkers in renal cell carcinoma.

501 Background: Predictive biomarkers of response to targeted therapy are lacking in renal cell carcinoma (RCC). We evaluated a cohort of RCC patients referred for molecular profiling to identify potentially actionable recurrent molecular aberrations. Methods: 166 consecutive renal cases referred to Caris Life Sciences over 2 yrs were evaluated with central pathology review. Cases were subtyped into clear cell (ccRCC), n=100, papillary (PRCC), n=20, sarcomatoid, n=10, translocation, n=6, medullary, n=4 or unclassified, n=26. 63% of cases were metastatic. Testing included a combination of sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and/or gene amplification (CISH or FISH). Results: ccRCC had a 52% loss of PTEN, while PRCC had a 21% loss (p value=0.02). 100% of ccRCC with sarcomatoid features (4) showed aberrant expression of PD-L1 and were infiltrated with PD-1+ tumor infiltrating lymphocytes; 100% of 10 non-ccRCC sarcomatoids also had aberrant expression of PD-L1. Loss of PBRM1 expression was observed in 60% of ccRCC. Loss of histone 3 lysine 36 trimethylation (H3K36me3), which is associated with SETD2 mutations, was observed in 30% of ccRCC. TOP2A was overexpressed in ccRCC at 30% and in non-ccRCC at 50%. 100% of ccRCC and PRCC overexpressed EGFR; a single unclassified renal cell carcinoma did not overexpress EGFR. 50% of cases had cMET overexpression, amplification, or mutation. HER2 was not amplified or overexpressed in any RCC; a single rare HER2 mutation (R816H) was found in a collecting duct carcinoma. VHL mutations were identified in 50% of ccRCC tumors. We observed lower rates of TP53 (14%), ATM (6%), and PIK3CA(4% ccRCC, 7% PRCC) mutations compared to other cancers. Conclusions: Multiplatform molecular profiling of renal cell carcinoma identifies potential predictive biomarkers in ccRCC. The documented activity of everolimus in ccRCC (RECORD-1 trial) may be attributable to PIK3CA pathway alterations. RCC with sarcomatoid features may respond to PD1/PD-L1 targeted immunotherapies. The impact of molecular profiling in ccRCC to predict responses to currently available targeted therapy has important implications for trial design and patient selection.

Abstract A36: Unveiling biomarker and mechanism of drug resistance to molecular targeted therapeutics in renal cell carcinoma

Abstract Introduction and Objective: Renal cell carcinoma (RCC) is the most lethal of the urologic malignancies and it is largely incurable when it becomes metastatic. Recent development of molecular targeted agents such as tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors have provided some survival benefit for a subset of RCC patients. Overall, only 30% patients exhibit a response to these agents, however, almost all patients eventually develop drug resistance. Currently, there is no reliable biomarker(s) for predicting drug response for individual patients and the mechanism(s) of drug resistance is largely unknown. It is known that DAB2IP, a novel member of the Ras GTPase-activating protein gene family, is associated with cell proliferation, apoptosis, metastasis and chemo- or radio-resistance in several cancer types. In the present study, we decided to investigate the association between DAB2IP expression and therapeutic response to molecular targeted agents in RCC patients and explored the possible mechanism of DAB2IP in regulating drug response of RCC cells. Methods: DAB2IP expression was evaluated by immunohistochemistry (IHC) in a cohort of RCC patients who had received targeted therapies. Correlation between DAB2IP expression and patients' survival was analyzed. The effect of DAB2IP on RCC cells was examined using a panel of knockdown (KD) or overexpression cells generated by gene transfection and also determined for their in vitro and in vivo (xenograft model) responses to targeted agents treatment. The mechanism of drug resistance was delineated by signaling cascade profiling with a variety of molecular biologic techniques such as cDNA array, ChIP, reporter gene assay, real-time PCR and Western blot. Results: The levels of DAB2IP expression in RCC specimens determined by IHC positively correlate with the survival of patients receiving targeted therapies. DAB2IP KD RCC cells exhibit drug resistance to mTOR inhibitor Temsirolimus (Tem) treatment compared with the control from both in vitro and in vivo experiments. In contrast, increased DAB2IP in RCC cells by gene transfection can sensitize their response to Tem. Mechanistically, loss of DAB2IP was able to activate both the PI3K/mTOR pathway and the ERK/RSK1 pathway that further led to increased expression of hypoxia-inducible factor (HIF)-2α protein. Inhibitor(s) of either the mTOR pathway or the ERK pathway only partially suppressed growth of DAB2IP KD cells. However, the combination of both inhibitors achieved a synergistic growth inhibition in resistant cells. In this event, HIF-2α, but not HIF-1α, appeared to be a key converging factor and we further demonstrated that silencing of HIF-2α expression with specific shRNA was able to reverse the resistant phenotype in DAB2IP KD cells. Conclusions: DAB2IP represents a new predictive biomarker for the therapeutic response of RCC patients to targeted therapy. Most importantly, its functional role in RCC provides new therapeutic strategies in combating this lethal disease. Citation Format: Jiancheng Zhou, Kaijie Wu, Eunjin Yun, Payal Kapur, Rey-Chen Pong, Dalin He, Jer-Tsong Hsieh. Unveiling biomarker and mechanism of drug resistance to molecular targeted therapeutics in renal cell carcinoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A36.

Validation of the pretreatment neutrophil-lymphocyte ratio as prognostic factor regarding cancer-specific, metastasis-free, and overall survival in a European cohort of patients with renal cell carcinoma.

410 Background: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammation response and data from previous studies report controversial results about its independent prognostic role in non-metastatic renal cell carcinoma (RCC). Thus, we decided to evaluate the prognostic significance of NLR in a large cohort of RCC patients. Methods: Data from 843 consecutive non-metastatic RCC patients, operated with radical nephrectomy or nephron sparing surgery between 2000 and 2010 at a single tertiary academic center, were evaluated retrospectively. Pre-treatment NLR was calculated one day before surgical intervention. Patients were categorized according to a NLR cut-off value of 3.2. Cancer-specific–, metastasis-free–, as well as overall survival were assessed using the Kaplan-Meier method. To evaluate NLR’s independent prognostic significance, a multivariate Cox regression model was performed for all three endpoints. Results: An increased NLR was associated with several well established prognostic factors including tumor size, tumor grade, and histologic tumor necrosis (all p&lt;0.05). Although an increased NLR was statistically significantly associated with poor outcome for all clinical endpoints (p&lt;0.001), multivariate analysis identified an increased NLR as an independent prognostic factor for overall (HR=1.58, 95% CI=1.12-2.20, p=0.008), but not for cancer-specific (HR=1.55, 95% CI=0.89-2.70, p=0.116), nor for metastasis-free survival (HR=1.37, 95% CI=0.88-2.14, p=0.160). Conclusions: Risk prediction for cancer-related endpoints using NLR does not seem to add independent prognostic information to other well established prognostic factors in patients with non-metastatic RCC. Regarding patients’ overall survival, an increased NLR represented an independent risk factor, which might reflect a higher risk for cardiovascular, infectious, as well as for gastrointestinal morbidities and mortalities.

Oncological outcome of surgical treatment in 336 patients with renal cell carcinoma

The most effective therapy against renal cell carcinoma (RCC) is surgical treatment; however, there have been few large-scale studies that focused on the oncological outcome of this disease in China. The aim of the current study was to report the clinicopathological results and cancer-specific survival (CSS) rate in RCC patients after surgical treatment in our center. We retrospectively analyzed the clinicopathological data of 336 RCC patients who underwent radical or partial nephrectomy between 1999 and 2006. Of the 336 patients, 226 were male and 110 were female; the median age was 51 years. Univariate and multivariate analyses were conducted to identify the independent prognostic predictors for this cohort of RCC patients. During follow-up, the overall 5-year CSS rate was 81.4%. The 5-year CSS rates for patients with stage-I, -II, -III, and -IV RCC were 94.7%, 88.9%, 68.8%, and 19.3%, respectively. The patients with T1N0M0 (T1) and T2N0M0 (T2) tumors had similar survival curves. For patients with T1 category tumor, the survival rate did not differ significantly between the radical nephrectomy and nephron-sparing surgery groups. For the 21 patients with metastasis confined to the local lymph nodes, the 5-year survival rate was 31.6% after radical nephrectomy and lymph node dissection. For the 15 patients with vena caval tumor thrombus, the 5-year survival rate was 52.5% after radical nephrectomy and tumor thrombus extirpation. Multivariate Cox regression showed that stage was an independent predictor for CSS (hazard ratio, 3.359; P < 0.001). For localized RCC, the oncological outcome of this cohort is comparable to that reported in the Western literature. For some patients with locally advanced RCC, aggressive surgical treatment can lead to better long-term survival. However, the prognosis of the patients with metastasis still needs to be improved.

Phase I study of PTK787/ZK222584 (PTK/ZK) and RAD001 for patients with advanced solid tumors and dose expansion in renal cell carcinoma patients

5039 Background: PTK/ZK is an orally active tyrosine kinase inhibitor that blocks all known VEGF receptors. RAD001 is an orally active macrolide which selectively inhibits mTOR. Combination therapy with VEGFR and mTOR inhibition may have additive efficacy in several tumor types, particularly renal cell carcinoma (RCC). Materials and Methods: A phase I/II study of PTK/ZK and RAD001 was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety and tolerability. Patients were given escalating daily doses of PTK/ZK in combination with RAD001 (see table ) in 28-day cycles. Patients were assessed for adverse events every 2 weeks and tumor response every 2 cycles. A dose expansion cohort of 20 patients with metastatic RCC is ongoing to further evaluate safety and preliminary efficacy. Results: To date, 27 patients have received a total of 136 cycles. The dose escalation phase included 14 patients and 3 dose levels; dose-limiting toxicities included grade 3 diarrhea and hypertriglyceridemia (14%); asthenia, fatigue and mucositis (7%). Pharmacokinetic studies are pending. A MTD of PTK/ZK 1,000 mg and RAD001 5 mg daily was determined and studied in an expanded cohort of RCC patients. Prior therapy with a VEGF inhibitor was allowed. To date, 13 evaluable RCC patients demonstrate 2 (15%) partial responses and 8 (62%) with stable disease &gt; 3 months; median TTP is 6 months. Conclusions: PTK/ZK and RAD001 combination is well-tolerated and demonstrates clinical activity in patients with RCC despite prior exposure to VEGF inhibition. An MTD of 1,000 mg daily of PTK/ZK and 5 mg daily of RAD001 is the recommended dose for Phase II/III testing. [Table: see text] No significant financial relationships to disclose.