bluuebunny/crossref_metadata_2025 huggingface dataset:
Src pathway activation in RCC and the correlation with grade and survival and the development of a rational new target in RCC.
Authors: Lee Chung-Han , Voss Martin Henner , Mano Roy , Motzer Robert John , Hsieh James
Published: February 2017

453

Background: Loss of the VHL tumor suppressor in clear cell renal cell carcinoma (ccRCC) leads to the accumulation of Hypoxia Inducible Factor (HIF) and aberrant transcription of downstream targets such as VEGF. Inhibition of VEGF is the underlying therapeutic principle of several approved targeted agents; however, other HIF transcriptional targets remain to be explored. Increased expression of the HIF transcriptional target CUB domain-containing protein 1 (CDCP1) is associated with poor survival in ccRCC. CDCP1 is a substrate and binding partner for Src-family tyrosine kinases (SFKs) and dictates substrate specificity. Crosstalk between the SFK signaling cascade and the HIF pathway may result in feed forward signal amplification. Upregulation of Src signaling increases HIF-dependent transcription by both VHL-dependent and -independent mechanisms. Reciprocally, HIF accumulation can activate Src through PDGFRα, focal adhesion kinase, and CDCP1. Methods: Data from The Cancer Genome Atlas (TCGA) was used to assess mRNA expression and protein phosphorylation as well as clinical parameters and outcome in patients with ccRCC. Correlations were analyzed via Mann-Whitney U-test. Survival data was obtained using the TCGA portal, and analyzed by logrank test. To investigate the therapeutic potential of Src inhibition, the IC50 of Dasatinib in primary tumors derived cell lines were determined by an AlamarBlue Assay. Results: Increased Src and CDCP1 mRNA expression and decreased phosphorylation on the Src inhibitory site Y527 correlated with increased Fuhrman grade. Decreased phosphorylation on the inhibitory site Y527 correlated with worse median overall survival (78.4 vs. 19.7 months, p< 0.00001). Similarly, increased Src and CDCP1 mRNA expression correlated with worse overall survival (78.4 vs. 26.9 months, p < 0.00001, 78.4 vs. 37.2 months, p = 0.005). In vitro inhibition of Src with Dasatinib induces growth inhibition of primary cell lines with sarcomatoid or rhabdoid features, histomorphologic criteria associated with higher grade disease and worse prognosis. Conclusions: The Src pathway might be biologically relevant for ccRCC, and Src inhibition may have therapeutic potential.
Conditional survival (CS) of metastatic renal cell carcinoma (mRCC) patients treated with high dose interleukin-2 (HD IL-2).
Authors: Parikh Kinjal , Stenehjem David D. , Sendilnathan Arun , Crispin Hilda , Van Atta Joan , Batten Julia Anne , Sageser Daniel , Grossmann Kenneth F. , Wang Junfeng , Samlowski Wolfram E. , Tantravahi Srinivas Kiran , Agarwal Neeraj
Published: February 2017

460

Background: CS is a clinically useful prediction measure that adjusts prognosis of patients on the basis of survival since treatment initiation or therapy duration. CS was recently reported in mRCC patients treated with VEGF targeted therapy in patients stratified by Heng’s criteria. CS has not been reported in mRCC in the context of treatment with HD IL-2. Methods: Patients with histologically confirmed clear cell mRCC treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 were evaluated. Performance status and prognostic risk groups were included. Two-year CS was defined as the probability of surviving an additional 2 years from initiation of HD IL-2 to 18 months after the start of HD IL-2 at 3-month intervals estimated by Kaplan-Meier methodology. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) were male. The median overall survival from HD IL-2 administration was 817 days. Stratification by Heng’s criteria at therapyinitiation resulted in survival estimates for the favorable (n = 13; 15%), intermediate (n = 56; 66%) and poor (n = 16; 19%) prognostic groups of 1616 (p = 0.1993 vs intermediate), 817 (p = 0.0041 vs poor), and 365 (p < 0.0001 vs favorable) days, respectively. Two-year overall CS increased from 56.2% at therapy initiation to 89.5% at 18 months (Table). Two-year CS stratified by Heng’s favorable, intermediate, and poor prognostic risk groups is presented in the Table. Conclusions: CS is a relevant prediction measure in the context of mRCC treated with HD IL-2.A longer survival interval from HD IL-2 treatment was associated with an increased survival probability. CS in this cohort was especially relevant in adjusting prognosis for patients with Heng’s intermediate risk. [Table: see text]
Long-term responders to everolimus: A subgroup analysis of the sector study.
Authors: Barthelemy Philippe , Escudier Bernard , Joly Florence , Geoffrois Lionnel , Laguerre Brigitte , Houede Nadine , Gross-Goupil Marine , Yann-Alexandre Vano , Lucidarme Olivier , Bidault François , Kelkouli Nadia , Oudard Stephane
Published: February 2017

462

Background: Everolimus is considered as a standard of care for the second line treatment of metastatic renal cell carcinoma (mRCC). Currently no clinical or biological predictive factors are available to help physicians to choose the best second line option between everolimus or TKI. Whether correlation exists between response to first line and response to second line remains debatable. Methods: We performed a subgroup analysis of the SECTOR study, a retrospective survey of patients (pts) receiving everolimus after TKI in 26 french centers to analyse long responders to everolimus. Long-term response to everolimus was defined as progression-free >9 months. Recorded variables included: patients characteristics of first line TKI (duration, response), duration of everolimus, efficacy and toxicity as well as overall survival. Results: 164 patients in 26 french cancer centres were included in the SECTOR study between october 2008 and october 2012. All patients received everolimus as second line treatment. Median age was 64.6 y.o, main histological subtype was clear-cell carcinoma (92.3%). Among the whole study cohort, we identified 30 patients (21%) as long-term responders (ranging from 9 to 33 months). Analysis of this patient population is ongoing and will be presented at the meeting. Correlation between long response and prognostic factors, as well as response to first TKI will be determined. Conclusions: Everolimus achieves long-term response in more than 20% of mRCC treated in second line. Prolonged treatment was relatively well tolerated without any unexpected late toxicity. Further investigations, especially biological studies, are warranted to identify predictive factors which will help physicians to identify long-term responder and choose the best second line option for mRCC patients.
A study of real-time CLIA-enabled whole genome tumor sequencing: Results for testicular cancer and sarcomatoid RCC.
Authors: Bryce Alan Haruo , Borad Mitesh J. , Condjella Rachel M. , Egan Jan B. , Champion Mia D. , Hunt Katherine S , McWilliams Robert R. , McCullough Ann E. , Kurdoglu Ahmet , Aldrich Jessica , Izatt Tyler , Nasser Sara , Christoforides Alexis , Phillips Lori , Liang Winnie S. , Barrett Michael T. , Craig David W. , Carpten John D. , Stewart A. Keith
Published: February 2017

463

Background: The genomic assessment of cancer has been revolutionized by next-generation sequencing and is increasingly being applied in the clinic to guide therapeutic decision-making. Time to reporting of results, specimen quantity, and analyte quality have constrained initial clinical applications to gene panels and whole exome based strategies. Methods: Patients underwent surgical resection, excisional or core biopsies, or bone marrow biopsy. Samples were analyzed by whole genome or exome sequencing and RNA sequencing, bioinformatics analysis, and therapeutic target prioritization by a multi-disciplinary Clinical Genomics Board. All prioritized targets were CLIA validated using Sanger sequencing, RT-qPCR, FISH, or IHC as appropriate. Treatment was delivered using off-label FDA approved drugs, clinical trials, or single patient INDs. Results: We have enrolled 40 patients with advanced, treatment-refractory cancers of whom sequencing data is available on 33. The initial 6 patients were evaluated in a non-CLIA pilot phase and 27 in the CLIA enabled phase. Upon availability of the initial report, identified targets of putative therapeutic relevance were then prioritized by the CGB in 22/27 patients (81%) for subsequent CLIA validation. Eleven patients have been treated with genomically selected therapy with partial response in 3/10 assessed patients. A testicular cancer patient had aberrations in two testes specific genes, a copy number gain in TSSK6 and a novel gene fusion between thyroid hormone receptor associated protein 3 (THRAP3) and Tektin 2 (TEKT2). Additionally, a case of papillary renal cell carcinoma had an amplification of YAP1 and a previously unreported P287T mutation in CCND1, suggesting potential benefit with a CDK4/6 inhibitor. Treatment is ongoing and results will be reported. Conclusions: Integrated whole genome analysis in a CLIA setting is feasible. Integration of SNV, copy number and transcriptional data may allow for selection of putative driver genes to enhance targeted therapy decisions. Barriers for future broader implementation include the need for reduced time from biopsy to report and availability of therapies.
Impact of altered Wnt1/ß-catenin expression on clinicopathology and prognosis in renal cell carcinoma.
Authors: Kruck Stephan , Eyrich Christian , Scharpf Marcus , Fend Falko , Stenzl Arnulf , Bedke Jens
Published: February 2017

465

Background: Members of the Wnt/ß-catenin signaling pathway are abnormally expressed in renal cell carcinoma (RCC). This study analyzed the role of Wnt1/ß-catenin alterations in clear cell RCC (ccRCC) with regard to clinicopathology, overall survival (OS) and cancer specific survival (CSS) to prove the options of a Wnt targeted therapy. Methods: Corresponding ccRCCs and benign renal tissue were analyzed in 278 patients for Wnt1 and ß-catenin by immunohistochemistry in tissue microarrays. Expression scores including intensity and percentage of stained cells were compared between normal kidney and ccRCCs. Data was categorized according to the mean expressions core and correlated to tumor and patients’ characteristics and analyzed for OS and CSS according to the Kaplan-Meier and log-rank test. To identify prognostics value of wnt1 and ß-catenin, univariable and multivariable Cox proportional hazard regression models were used. Results: High Wnt1 tumor expression was associated with increased tumor diameter (p=0.01), stage (p=0.004) and vascular invasion (p=0.02). Positive membranous ß-catenin was associated with advanced stage (p=0.003), vascular invasion (p=0.01) and tumor necrosis (p=0.004). Increased tumor diameter (p=0.01), stage (p=0.003), node involvement (0.04), grade (p=0.001), vascular invasion (p=0.002), and sarcomatoid differentiation (p=0.01) were found in patients with high cytoplasmic ß-catenin. Furthermore, this patient subgroup showed reduced OS (p=0.03) and CSS (p=0.009). Conclusions: Significant clinicopathological associations underline the oncogenic potential of Wnt1/ß-catenin pathway parameters. Whereas, cytoplasmic ß-catenin was identified as the most valuable parameter with regard to clinico-prognostic implications for future targeted therapies.
In vitro and in vivo effects of the mTOR inhibitors everolimus (EVE) and temsirolimus (TEM).
Authors: Chen David , O'Reilly Michael Terence , McSheehy Paul M.J.
Published: February 2017

466

Background: Two mTOR inhibitors are approved for treating mRCC: EVE following the failure of VEGF-targeted therapy and TEM as first-line therapy in poor-risk patients. Both agents exert their clinical effect by binding to FKBP-12, which then interacts with mTOR to inhibit its kinase activity. We compared the activity of EVE and TEM in in vitro and in vivo models. Methods: EVE and TEM binding to mTOR was assessed using time-resolved fluorescence resonance energy transfer. Inhibition of cell proliferation in A549, NCI-H460, and MCF7 human tumor cell lines was assessed by methylene blue protein staining. Phosphorylation of the downstream mTOR target pS6 was assessed via immunohistochemistry in A549 cells. Antitumor activity of EVE (oral) and TEM (intraperitoneal) at doses between 0.1 and 2.5 mg/kg once daily was assessed in vivo in A549, KB-31, KB-8511, and HCT-116 human tumor xenograft models. Results: The binding efficiency of TEM for mTOR was reduced 10-fold compared with that of EVE (EC50, 56 nM vs 6 nM; p < 0.01). EVE demonstrated 6- to 7-fold greater inhibition of cell proliferation than TEM (IC50, 1.0 nM vs 6.5 nM in A549 [p < 0.001], 0.7 nM vs 4.7 nM in NCI-H460 [p < 0.01], and 19.4 nM vs 150 nM in MCF7 [p < 0.001]). Complete inhibition of pS6 phosphorylation in A549 cells at 24 hours was achieved with 6.7 nM EVE, but required 20 nM TEM. In all xenograft models, EVE and TEM showed a dose-response relationship over the range of 0.1-2.5 mg/kg/day. EVE was significantly more potent than TEM in the A549 model (EC50, 0.11 mg/kg vs 0.51 mg/kg; p = 0.002); no appreciable differences between EVE and TEM were observed in the KB-31, KB-8511, and HCT-116 xenograft models. However, correcting for drug exposure suggests increased potency of EVE over TEM. Conclusions: Compared with TEM, EVE had a higher affinity for the molecular target of FKBP-12. This was consistent with more potent antitumor activity in vitro and in vivo. Whether these data would translate into a better therapeutic index for EVE is unknown. However, the results suggest that these mTOR inhibitors may not be clinically interchangeable.
PD-L1 expression in primary clear cell renal cell carcinomas (ccRCCs) and their metastases.
Authors: Callea Marcella , Genega Elizabeth M , Gupta Mamta , Fay André P , Song Jiaxi , Carvo Ingrid , Bhatt Rupal Satish , McDermott David F. , Atkins Michael B. , Choueiri Toni K. , Freeman Gordon J , Signoretti Sabina
Published: February 2017

467

Background: Clinical trials evaluating anti-PD-1 and anti-PD-L1 antibodies (Abs) in ccRCC have shown promising efficacy in a subset of patients. Preliminary studies have demonstrated that tumor PD-L1 expression increases the likelihood of benefit with anti-PD-1 Ab, but fails to identify all responders. One potential explanation for these results is that predictive biomarkers are usually evaluated in the primary tumors, which are more readily available; however, biomarker expression in nephrectomy samples may not accurately reflect expression in the metastases that are being targeted by therapy. In this study, we compared PD-L1 expression in a series of ccRCCs and their metastases. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue blocks from 34 primary ccRCCs and corresponding metastases were retrieved. Multiple areas of the primary tumors, including areas of predominant and highest Fuhrman nuclear grade (FNG), were selected for analysis. Slides were immunostained with a mouse monoclonal anti-PD-L1 antibody (405.9A11). The assay was validated using FFPE cell line controls known to be positive or negative for PD-L1 expression by flow cytometry. The presence of tumor cells with membranous staining was assessed. A case was considered positive when any tumor cell positivity was detected. Results: Positive membranous PD-L1 expression in tumor cells was observed in 10/34 (29%) primary ccRCCs. In 3 of these 10 cases (30%), the metastases were negative. In 2 cases the primary tumor was negative but the metastases were positive. In twenty-two cases, both the primary tumor and the corresponding metastasis were negative. The pattern of PD-L1 staining was highly heterogeneous in the primary tumors and was restricted to areas of highest FNG. The staining was more homogeneous in the metastases. PD-L1 expression by the tumor infiltrating immune cells is currently being evaluated. Conclusions: Discordant expression of PD-L1 between the primary tumor and the corresponding metastases was detected in 5/34 (15%) cases, suggesting that accurate assessment of predictive biomarkers for PD-1 blockade in ccRCC might require analysis of metastatic lesions. Analysis of a larger patient cohort is ongoing to confirm these findings.
Correlation of distinctive angiogenetic profiles with clinical outcome for different treatment sequences in mRCC.
Authors: Bianconi Maristella , Scartozzi Mario , Faloppi Luca , Loretelli Cristian , Zizzi Antonio , Giampieri Riccardo , Bittoni Alessandro , Del Prete Michela , Burattini Luciano , Montironi Rodolfo , Cascinu Stefano
Published: February 2017

474

Background: Renal cell carcinoma treatment has radically changed in recent years, revolutioning patients’ outcome. Treatment strategies comprises TKIs, mainly directed against the angiogenic pathway, and mTOR inhibitors. Patients’ response to these treatments is widely variable and the optimal sequence is still matter of debate. In our previous report VEGF and VEGFR polymorphisms showed a predictive and prognostic role in the first-line treatment with sunitinib or pazopanib. The aim of our study was to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms in defining a tailored sequence for RCC patients. Methods: 97 formalin-fixed paraffin-embedded tissue blocks from mRCC patients were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients were divided into two groups of sequences TKI-mTOR and TKI-TKI. SNPs results were correlated with progression free survival (PFS) and overall survival (OS). Results: 68 patients received second line treatment, either TKI or mTOR inhibitor. Patients expressing a TT polymorphism of VEGF A rs833061 had a better PFS compared to CC+CT polymorphism patients if receiving a mTOR inhibitor; while patients receiving a TKI had a better PFS if with a CC+CT polymorphism instead of a TT polymorphism of the same SNP (p<0,0001). OS analysis showed a similar correlation between polymorphism and treatment (p=0,0002). Conclusions: Our findings suggest that angiogenetic profile according to VEGF A rs833061 polymorphism may have a relevant role in selecting the most appropriate treatment sequence in mRCC patients. This selection tool would allow clinicians to improve efficacy and avoid unnecessary toxicity thus resulting in a better patients’ outcome and global quality of life.
Association of clinical parameters and overall survival (OS) in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with high-dose interleukin-2 (HD IL-2).
Authors: Stenehjem David D. , Parikh Kinjal , Batten Julia Anne , Van Atta Joan , Crispin Hilda , Sageser Daniel S. , Grossmann Kenneth F. , Wang Junfeng , Tantravahi Srinivas Kiran , Samlowski Wolfram E. , Agarwal Neeraj
Published: February 2017

476

Background: HD IL-2 immunotherapy can provide durable responses in mRCC, but has a high incidence of severe adverse events (AEs). Therefore, determining pts most likely to achieve response before and during HD-IL2 treatment will help clinicians and pts best utilize HD IL-2 for the treatment of mRCC. Methods: Sequential clear cell mRCC pts treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 were included. The following clinical parameters were assessed: AE incidence, type and severity; total dose of IL-2 received and use of a 40 MIU dose cap; baseline weight, age, gender and MSKCC prognostic risk; and systemic therapy pre- or post-HD IL-2. Univariate and multivariate analyses were constructed using COX Proportional Hazard model. Results: 85 pts with clear cell mRCC treated with HD IL-2 were included with a median age of 56 years (range 32-76). Pts belonged to the following MSKCC categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. The median OS was 817 days. Multivariate analysis identified 6 factors associated with OS including: MSKCC prognostic group (intermediate vs good HR = 4.31, CI 1.41-16.04), grade 3 rigors (no vs yes HR = 3.07, CI 1.49-6.47), baseline weight (<80 vs >80 kg HR = 2.18, CI 1.08-4.39), total dose of IL-2 administered (quartile 1 vs 2 HR 2.90, CI 1.06-8.57; quartile 1 vs 3 HR 7.37, CI 2.63-21.54; quartile 1 vs 4 HR 25.17, CI 7.34-102.01), composite of the number and severity of AEs (continuous, HR 5.11, CI 1.01-27.56), and gender (female vs male HR 2.84, CI 1.06-7.20). Factors not associated with an OS benefit in this model include age at metastatic disease, use of a 40 MIU IL-2 dose cap and systemic therapy pre- or post-HD IL2. Conclusions: The following parameters predicted an OS benefit with HD IL-2 when controlled for MSKCC prognostic risk and systemic therapy pre or post HD IL-2: fewer and less severe AEs; higher baseline weight; male gender; and the ability to tolerate a higher cumulative dose of IL-2. Notably increased age did not portend poor outcome, and should not be considered a contraindication to treatment with HD IL-2 in otherwise eligible patients.
Neutrophil to lymphocyte ratio and response to tyrosine kinase inhibitor therapy in metastatic renal cell carcinoma.
Authors: Templeton Arnoud J. , Amir Eitan , Aneja Priya , Vera-Badillo Francisco Emilio , Hermanns Thomas , McNamara Mairead Geraldine , Heng Daniel Yick Chin , Knox Jennifer J.
Published: February 2017

477

Background: Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are markers of host inflammation and have prognostic value in many solid tumors. Here we aimed to explore the association of NLR and PLR with response to tyrosine kinase inhibitor (TKI) treatment in metastatic renal cell carcinoma (mRCC). Methods: Data from patients with mRCC treated at the Princess Margaret Cancer Centrein Toronto with a TKI as first-line treatment were retrospectively collected. The association of several variables with response to treatment (complete response [CR] or partial response [PR] vs. stable disease > 3 months [SD] or progressive disease [PD]) was assessed by binary logistic regression. Significant variables were dichotomized and cut-offs selected by the area under the receiver operating characteristic (AUC) curve. Results: Data from 157 patients treated between 11/2004 and 09/2012 were analyzed. Median age at start of TKI treatment was 61 years and first-line treatment was sunitinib, sorafenib, and other in 49%, 43%, and 8% of patients, respectively. Best response was CR/PR, SD, and PD in 27%, 55%, and 18% patients. On multivariable analysis NLR > 2.5 and Karnofsky Performance Status (KPS) < 90% were associated with a lower likelihood of response and each allocated a score of 1 unit. Response rates for a score of 0, 1, or 2 were 45% (29-61%), 28% (17-38%), 10% (1-19%), respectively. PLR did not retain association with response in multivariable analysis. Conclusions: NLR and KPS are associated with response to TKI treatment in mRCC. Data from an external validation set will also be presented.
Suitability of clear cell renal cell carcinoma to heat shock proteins-inhibitors.
Authors: Brunelli Matteo , Massari Francesco , Ciccarese Chiara , Ferrero Stefano , Gazzano Giacomo , Modena Alessandra , Bria Emilio , Tortora Giampaolo , Bosari Silvano , Martignoni Guido
Published: February 2017

480

Background: Heat shock proteins (HSP) HSP27 and HSP90 are expressed in response to a wide variety of insults, thus allowing the cell to adapt to stress. In cancer cells, both HSP27 and HSP90 may participate to carcinogenesis, suggesting these chaperones as an appealing target for cancer therapeutics. The role of HSP in the development and progression of renal-cell carcinomas (RCCs) remains to be defined. We sought to evaluate a series of clear cell RCCs. Methods: 388 RCCs with clear cell histology available on 10 tissue microarrays were recruited. Each case was represented by 3 neoplastic cores. All these cases were stratified according to the Mayo Clinic SSIGN (Size, Staging, Grading, Necrosis) score into five prognostic groups with increasing worse prognosis (1 to 5). Immunostainings for HSP27 and 90 were performed. A mean score number from the three cores was set per case (percentage x intensity). Results were detailed per number of scorable cases per SSIGN category (1 to 5). Results: 117 and 122 RCCs were respectively available for HSP90 and HSP27 scoring. The remaining samples were lost due to the lack of tissue sections or to the absence of adequate neoplastic cells scorable. HSP90 scored 4,9 in 32 with SSIGN1, 3,5 in 41 SSIGN2, 4,8 in 11 SSIGN3, 4,2 in 22 SSIGN4 and 5 in 3 SSIGN5 patients. HSP27 scored 4,6 in 33 with SSIGN1, 3,1 in 43 SSIGN2, 2,6 in 11 SSIGN3, 3,6 in 24 SSIGN4 and 2,7 in 3 SSIGN5 patients. A significant trend of increasing value for HSP90 has been observed when comparing cases tabled SSIGN1-2 versus SSIGN3-5 (4,2 to 4,6 mean values) (p=0.05); a minor stratification has been observed for HSP27 (3,8 to 3,9) (p=0.08). Conclusions: In conclusion, HSP90 and HSP27 are variable immunoexpressed in a subset of clear cell RCCs, with a trend to higher prognostic SSIGN score. At light of new emerging targeted-therapies in kidney cancer, we report an increasing suitability of these patients to therapies that target the pathways of heat shock protein molecules. Additional learning of the HSP role in clear cell RCCs carcinogenesis is required to guide future therapeutic developments.
Immunohistochemical evaluation of aldose reductase expression in collecting duct carcinoma for differential diagnosis from other renal malignancy.
Authors: Hashimoto Yasuhiro , Yamamoto Hayato , Okamoto Akiko , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Koie Takuya , Ohyama Chikara , Mimata Hiromitsu
Published: February 2017

483

Background: Collecting duct carcinoma (CDC) is a rare tumor but its recognition is important for the prediction of prognosis and decision making of the treatment. However, its diagnosis is challenging because of versatility of pathological features. We explored the possibility whether aldose reductase (AR), osmoregulatory protein and abundant in renal medulla, can be used as a marker for the pathologic diagnosis of CDC. Methods: We prepared anti-AR monoclonal antibodies, examined expression of AR protein in the human normal kidney. Immunohistochemical expressions of AR, 34bE12, a-methyl CoA racemase (AMACR) and expressions of lectins (Ulex europaeus agglutinin 1; UEA-1 and peanut agglutinin; PNA) were examined on normal kidney, 12 cases of CDC, 10 cases of papillary renal cell carcinoma (pRCC), and 10 cases of invasive urothelial carcinoma (iUC). Results: AR expression distributed preferentially in the renal medulla and not in the cortex, reflected by its high concentration in medulla (2.12 ±1.35 μg/mg) compared with cortex (0.13 ± 0.03 μg/mg). Immunohistochemically, AR was strongly positive in 9 of 12 CDC cases. AR was negative in cases of either iUC or pRCC. In contrast, although lectins were positive in all cases of CDC, they were also found in all types of malignancy. iUC was positive for 34bE12 in all cases but also so in some cases of CDC and pRCC. AMACR was positive for all the cases of pRCC but also positive for other tumors. Conclusions: Compared with other markers, AR may be a more specific and potentially useful marker for CDC. [Table: see text]
Association of partial nephrectomy and presence of robotic surgery for kidney cancer in the United States.
Authors: Kardos Steven V. , Shuch Brian , Schulam Peter , Trinh Quoc-Dien , Sun Maxine , Shippee Nathan D. , Sammon Jesse D. , Kim Simon P.
Published: February 2017

484

Background: While hospital and surgeon characteristics are associated with the type of nephrectomy performed for renal cell carcinoma (RCC), it is unknown whether hospital presence of robotic surgery increases the likelihood of patients receiving partial nephrectomy (PN). Therefore, we evaluate the relationship of PN and hospital presence of robotic surgery from a population-based cohort in the U.S. Methods: After merging the Nationwide Inpatient Sample (NIS) and the American Hospital Association (AHA) survey from 2006 to 2008, we identified 21,999 patients who underwent either PN or radical nephrectomy (RN) for RCC. The primary outcome of this study was the type of nephrectomy performed. Multivariable logistic regression was used to identify hospital characteristics associated with receipt of PN, after adjusting for patient case mix. Results: Overall, we identified 4,832 (22.0%) and 16,347 (88.0%) patients who were surgically treated for RCC with PN and RN, respectively. On multivariable analysis, patients undergoing surgery were more likely to receive PN at academic (OR: 2.77;p<0.001), urban (OR: 3.66; p<0.001), and American College of Surgeon (ACOS) designated cancer centers (OR: 1.10; p<0.05) compared to non-academic, rural, and non-designated hospitals, respectively. After adjusting for patient and hospital characteristics, patients undergoing surgery at hospitals with presence of robotic surgery were also associated with higher adjusted odds ratios for receipt of PN compared to those treated at hospitals without the presence of this advanced treatment technology (OR: 1.28; p<0.001). Conclusions: While academic status and urban locations are established characteristics influencing the type of nephrectomy performed for RCC, ACOS cancer center designation and hospital presence of robotic surgery were also associated with higher use of PN. Our results are informative in identifying key hospital characteristics which may facilitate greater adoption of PN.
Potential impact of prior high-dose IL-2 on the outcomes of sunitinib (Su) treatment (tx) in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Rosenbaum Eli , Gottfried Maya , Hammers Hans J. , Eisenberger Mario A. , Carducci Michael Anthony , Sinibaldi Victoria J. , Neiman Victoria , Sarid David , Gez Eliahu , Hayat Henry , Peer Avivit , Sella Avishay , Mermershtain Wilmosh , Rouvinov Keren , Berger Raanan , Kejzman Daniel
Published: February 2017

494

Background: Targeted txs are the tx of choice in most mRCC pts. However, HDIL2 which may produce durable responses in a small percentage of cases, is still an option in carefully selected pts. While the effect of prior HDIL2 on the outcome of targeted txs in mRCC pts is poorly defined, a recent single center report (Birkhäuser FD, Cancer J 2013) revealed an improved disease-specific survival in pts treated with prior HDIL2. We aimed to study the effect of prior HDIL2 tx on outcome of mRCC pts treated with sunitinib. Methods: Records from 302 mRCC pts treated with Su from 2004 to 2013 in 9 centers across 2 countries were retrospectively reviewed. We compared the response rate, progression free survival (PFS), and overall survival (OS), between post HDIL2 pts (n=27) and individually matched tx naïve pts (n=27). Progression free survival and overall survival were determined by Cox regression. Results: All pts had prior nephrectomy and clear cell histology. The groups were matched by age (median 61), gender (male 74%), Heng risk (favorable 37%, intermediate 59%, poor 4%), sunitinib induced hypertension (67%), sunitinib dose reduction/treatment interruption (41%), smoking status (active 7%), use of angiotensin system inhibitors (41%), the presence of more than one metastases site (96%), and pre-tx neutrophil to lymphocyte ratio (> 3 in 22%). Furthermore, they were balanced regarding the presence of lung (68%), liver (31%), and bone (43%) metastases, and the use of bisphosphonates (32%). In prior HDIL2 versus tx naïve pts, objective response was partial response/stable disease 89% (n=24) versus 74% (n=20), and progressive disease at first imaging evaluation within the first 3 months (mos) 11% (n=3) versus 26% (n=7) (p=0.29, OR 2.4). Median progression free survival was 21 versus 12 mos (HR 2.3, p=0.005), and median overall survival 25 versus 20 mos (HR 2.2, p=0.013). Conclusions: In metastatic renal cell carcinoma patients treated with sunitinib, prior high dose IL-2 therapy may improve the outcome.
Safety and efficacy of targeted therapy for renal cell carcinoma (RCC) with brain metastasis.
Authors: Bastos Diogo Assed , Molina Ana M. , Jia Xiaoyu , Velasco Susanne , Patil Sujata , Voss Martin Henner , Feldman Darren Richard , Motzer Robert John
Published: February 2017

497

Background: Brain metastases (Bm) in RCC are associated with poor prognosis. The safety and efficacy of TT in this setting is not well established since patients (pts) with Bm were excluded from pivotal clinical trials. The primary objective was to assess safety and efficacy of TT in pts with Bm. Methods: Pts with mRCC treated with ≥ 28 days of TT after Bm diagnoses were retrospectively identified. Kaplan-Meier method and Cox proportional hazards model were used to analyze the association between clinical features and OS. Results: 65 pts were identified, including 52 (80%) treated with anti-angiogenic agents and 13 (20%) treated with mTOR inhibitors. Most pts had extracranial metastasis (98%) and 54% had ≥ 2 brain lesions. Fifty seven pts (88%) had local therapy for Bm before TT including surgery in 3 (5%), radiation therapy (RT) in 36 (55%) and both surgery and RT in 18 (28%). Median follow-up was 12.3 months (1.1 – 58.8). Median treatment duration was 3.4 months (0.3 – 31.9) for 1st line and 1.9 months (0.2 – 23.6) for 2nd line. Median OS was 12.2 months (95% CI 8.0 to 15.5). On univariate analysis using various clinical and treatment variables, MSKCC risk group (p = 0.001), histology subtype (clear vs other) (p < 0.0001), and number of Bm at diagnosis (p = 0.004) correlated with OS and retained statistical significance on multivariate analysis (Table). CNS complications were identified in only 5 pts (8%), including 2 with radiation necrosis and 3 with Bm hemorrhage. Conclusions: The use of targeted agents for pts with RCC and Bm appears safe with OS that compares favorably to historical results in the pre-TT era. Clear cell RCC, favorable MSKCC risk status, and solitary Bm are associated with better outcome. [Table: see text]
Overcoming mTOR resistance: Results of a phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat.
Authors: Plimack Elizabeth R. , Wong Yu-Ning , Malizzia Lois , Corrigan Alycia , Olszanski Anthony J. , Denlinger Crystal Shereen , Roethke Susan , Tetzlaff Colleen H. , Hudes Gary R.
Published: February 2017

501

Background: Elevation of pAKT levels has been shown to result from mTOR inhibition. We hypothesized that the HDAC inhibitor Vorinostat (Vori) would abrogate Ridaforolimus (Rida) resistance due to downregulation pAKT when used in combination in renal cell carcinoma (RCC). Methods: The primary objective was to determine the MTD most applicable to RCC patients (pts), thus while all solid tumors were allowed, prior cytotoxic chemotherapy was limited to 1 regimen. There was no limit to the number of prior targeted or immunotherapies. ECOG PS 0-1 and adequate organ and marrow function were required. A modified 3+3 dose escalation design tested 2 dose levels concurrently by escalating each drug in separate cohorts. Rida was dosed days 1-5 weekly, Vori days 1-3 weekly. Results: 15 pts (10 clear cell RCC, 3 papillary RCC, 1 esophageal, 1 carcinoid) were treated at one of 3 dose levels: 1) Rida 20mg QD + Vori 100mg BID, 2) Rida 20 mg QD + Vori 200 mg BID, 3) Rida 40 mg QD + Vori 100 mg BID. Inability to complete 80% of doses during cycle 1 due to thrombocytopenia resulted in DLTs in 2/6 pts in dose level 2. There were no other DLTs and no grade 4-5 toxicities. Related grade 3 toxicities were: hyperglycemia (1), anemia (2), fatigue (1), and mucositis (1). Grade 2 pneumonitis was seen in 2 pts. The MTD was Rida 20mg QD + Vori 100mg BID, however all 7 pts who received >2 cycles ultimately required dose reduction to Rida 10-20 mg QD + Vori 100 mg QD, for thrombocytopenia in 6/7 cases. Thus the recommended phase II dose to allow for chronic dosing is Rida 20mg QD + Vori 100mg QD. Four pts, all with RCC, maintained stable disease for 19, 21, 31+ and 59+ weeks. Of these, 3 had progressed on prior temsirolimus or everolimus including the 2 pts with ongoing disease control at the time of data cutoff (31+ and 59+ weeks), both of whom have papillary RCC. Conclusions: Rida 20mg QD + Vori 100 mg QD is the recommended phase II dose for this combination. Prolonged disease control was seen in 4/13 RCC pts, 3 of whom progressed on prior a prior mTOR inhibitor. Further study of combined mTOR and HDAC inhibition in RCC with tumor sampling to assess for pharmacodynamics and proof of concept is warranted to further define the toxicity, efficacy and mechanism of this combination. Clinical trial information: NCT01169532.
Utilizing percentage of sarcomatoid differentiation as a prognostic factor in renal cell carcinoma.
Authors: Kim Timothy , Lin Hui-Yi , Yue Binglin , Dhillon Jasreman , Fishman Mayer N. , Sverrisson Einar Freyr , Spiess Philippe E. , Gupta Shilpa , Pow-Sang Julio M. , Poch Michael Adam , Sexton Wade Jeffers
Published: February 2017

507

Background: Sarcomatoid renal cell carcinoma (sRCC) is a histologic feature that denotes an aggressive variant of kidney cancer and worse overall outcomes. Our aim was to determine if the percentage of sarcomatoid differentiation (% Sarc) could be used for prognostic risk stratification. Methods: We performed a retrospective analysis of patients who underwent surgery at our center and found to have sRCC. A single genitourinary pathologist reviewed each specimen for %Sarc and other pathologic variables of interest. %Sarc was analyzed as a continuous variable and as a binary variable using cut-points of 5%, 10%, and 25%. Potential prognostic factors associated with overall survival (OS) were determined using the Cox regression model. OS curves were generated with Kaplan-Meier methods and survival differences compared using the log-rank test. Results: Between 1998 and 2012, 1,307 consecutive cases of RCC were identified, of which 59 patients were confirmed to have sRCC (4.5%). As a continuous variable %Sarc was associated with OS (p=0.023). Predictors of survival on multivariable analysis included pT stage, tumor size, cM stage and % Sarc at the 25% binary level. OS was most dependent on the presence or absence of metastatic disease (4 months vs. 21.2 months, p=0.001). However, in a subgroup analysis of cM0 patients with locally advanced (≥ pT3) tumors, OS was significantly diminished in patients with >25% Sarc compared to ≤25% Sarc (p=0.045). OS relative to %Sarc was no different in subgroup analyses of patients with early stage disease (pT1-T2, M0) or in patients with clinical metastatic disease. Conclusions: Patients with sRCC have a poor overall outcome as evidenced by high rates of recurrence and death. Patients without clinical metastatic disease and >25% Sarc have a higher risk of relapse and worse OS. More effective understanding of the biological basis for the aggressive behavior of sarcomatoid RCC is needed, and nomograms to predict recurrence or survival following nephrectomy could incorporate this pathologic feature for added risk stratification.
Clinicopathologic factors associated with the development of sunitinib induced hypertension (HTN) in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Neiman Victoria , Gottfried Maya , Hammers Hans J. , Eisenberger Mario A. , Carducci Michael Anthony , Sinibaldi Victoria J. , Rosenbaum Eli , Sarid David , Gez Eliahu , Peer Avivit , Neumann Avivit , Kovel Svetlana , Sella Avishay , Mermershtain Wilmosh , Rouvinov Keren , Berger Raanan , Kejzman Daniel
Published: February 2017

508

Background: The VEGFR inhibitor sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). HTN, an on-target class effect of VEGF signaling-pathway inhibitors, has been shown to correlate with clinical outcome. Studies have shown the association between genetic polymorphisms in several genes, and the development of HTN in patients treated with targeted therapies. We aimed to study the association between readily available clinicopathologic factors and the development of sunitinib induced HTN in mRCC patients. Methods: Records from mRCC patients treated with sunitinib in 9 centers across 2 countries were retrospectively reviewed. Sunitinib induced HTN was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg. Analysis of the association between clinicopathologic factors and the development of HTN was performed using logistic regression. Results: Between 2004-2013, 302 patients with mRCC were treated with sunitinib. The incidence of sunitinib induced HTN was 50% (n=152). Clinicopathologic factors included in the analysis were age (median 63), gender (67% male), HENG risk (good 22%, intermediate 59%, poor 19%), smoking status (active 21%), BMI (obese=BMI ≥30, 28%; overweight=BMI 25-29.9, 37%; normal weight= BMI <25, 35%), pre-treatment HTN (58%), past nephrectomy (83%), histology (73% clear cell), > 1 metastatic site (82%), metastatic site (lung 72%, liver 25%, bones 40%), pre-treatment neutrophil to lymphocyte ratio (>3 in 45%), treatment line (first vs advanced), sunitinib dose reduction/treatment interruption (45%). Absence of liver metastases (OR 3.5, p=0.02), pre-treatment neutrophil to lymphocyte ratio ≤ 3 (OR 5.5, p=0.001), and BMI (overweight and normal weight vs obese, OR 2.2 and 2.3 respectively, p=0.01 both) were independently associated with the development of HTN. Conclusions: In metastatic renal cell carcinoma patients treated with sunitinib, readily available clinicopathologic factors may be used to identify patients who are prone to the development of HTN.
Survival of patients with papillary type II renal cell carcinoma treated with tyrosine-kinase inhibitors: A comparison with clear cell histologies.
Authors: Casuscelli Jozefina , Buchner Alexander , Szabados Bernadett , Stief Christian G. , Staehler Michael D.
Published: February 2017

511

Background: The sequential use of Tyrosine-kinase inhibitors leads to a longer survival in patients with clear-cell renal cell carcinoma (ccRCC). However to-date there is little data available on the survival of patients with non-clear-cell RCC treated with TKI. We focused on papillary type II renal cell carcinoma (papIIRCC) and assessed the outcome of our patients with metastatic disease on systemic treatment. The outcome was compared with our patients with clear cell histology. Methods: Patients with histologic evidence of papillary type II renal cell carcinoma or clear cell renal cell carcinoma were treated with single agent sunitinib or sorafenib. Progression free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier curves. Patients were identified from an institutional database and had to have a follow up of ≥2 years. Subgroup analyses were performed to determine the influence of primary tumor stage and cell differentiation on PFS and OS. Results: 18 patients with papIIRCC received sunitinib (16) or sorafenib (2) while 166 patients with ccRCC were treated with sunitinib (78%) or sorafenib (22%). Median PFS for papIIRCC is 8.9 mos, for ccRCC it is 11 mos. OS for papIIRCC is 15 mos, while ccRCC show an OS of 32 mos. The same tendency for longer PFS and OS is seen in ccRCC patients with low primary tumor grade and highly differentiated carcinomas, whereas large tumors and low differentiation determine a poor prognosis in both groups. Conclusions: Most papIIRCC patients have a poor outcome and shorter PFS than ccRCC on the same therapy. They benefit from the TKI therapy, but the survival is clearly reduced compared with ccRCC patients. This may be due to the poor prognosis of the papillary type II histology, but the assumption is that the administered therapy is not conceived for this type of RCC. Future studies are required to determine the optimal therapy for papillary type II renal cell cancer.
The evolution of debulking nephrectomy and patient characteristics in metastatic renal cell cancer patients enrolled into first-line tyrosine kinase inhibitors clinical trials.
Authors: Sella Avishay , Wang Kongming , Sella Tal
Published: February 2017

513

Background: The introduction of tyrosine kinase inhibitors (TKIs) revolutionized treatment of metastatic renal cell cancer (mRCC). The role of debulking nephrectomy (DN) still remains unresolved. We reviewed the rate of DN and characteristics of patients enrolled in prospective clinical trials with TKIs through and after 2007 (Motzer, N Engl J Med, 2007). Methods: PubMed, Cochrane library, ASCO and ESMO web sites were searched for phase I-III clinical trials with at least 15 patients of first line TKIs administered alone/combination for mRCC. Expanded access/randomized discontinuation trials were excluded. We used PRISMA guidelines for data collection. All trials included histology, DN, prior cytokine therapy and efficacy data. Trials missing either performance status (PS) or MSKCC criteria data were included. We reviewed 72 trials; 42 trials are included: Group 1: 22 (phase I/II-19, phase III-3) trials completed through 2007 with 2,355 patients, Group 2: 20 trials (phase I/II-17, phase III-3) completed after 2007 with 3,719 patients. Thirty trials with 1,055 patients, all phase I/II, were excluded. Group characteristics were compared using a Pearson Chi-square test at a 2-sided significance level of 0.05, median progression free survival (PFS) with available 95% CI were compared using weighted T-Test. Results: Group 2 had statistically significantly (p<0.001) less DN (85.7% vs 93.7%), less prior cytokine therapy (11.7% vs 46.8%), more poor prognosis (9.8% vs 4.0%), and intermediate prognosis characteristics (56.0% vs 51.9%), more PS 2 (2.8% vs 0.8%), and a similar rate of clear cell histology (97.9% vs 97.2%, p=0.097). Clinical objective response per intent to treat analysis was higher in Group 2 (28.6% vs 23.1%, p<0.001) with similar clinical benefit (73.2% vs 75.3%, p=0.074) and comparable PFS (median 9 vs 8.2 months, p = 0.2528). Conclusions: The use of debulking nephrectomy in patients participating in clinical trials has declined in the TKIs era. More patients with worse prognostic parameters participated in TKI trials after 2007. The reduction in prior cytokine therapy prevents estimation of these changes on TKI efficacy.