bluuebunny/crossref_metadata_2025_split huggingface dataset:
Change in neutrophil to lymphocyte ratio as a prognostic and predictive marker in response to targeted therapy for metastatic renal cell carcinoma.
Authors: Alimohamed Nimira S. , Templeton Arnoud J. , Knox Jennifer J. , Lin Xun , Simantov Ronit , Xie Wanling , Lawrence Nicola Jane , Broom Reuben James , Fay Andre Poisl , Rini Brian I. , Bjarnason Georg A. , Smoragiewicz Martin , Kollmannsberger Christian K. , Kanesvaran Ravindran , Wells Connor , Amir Eitan , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2017

404 Background: The neutrophil to lymphocyte ratio (NLR) is a marker of inflammation. We evaluated whether NLR is independently prognostic when adjusted for the International mRCC Database Consortium (IMDC) model and evaluated change in NLR ("NLR conversion") as a predictive marker of response to targeted therapy. Methods: A total of 5,227 metastatic renal cell carcinoma (mRCC) patients treated with targeted therapy were included; 1,199 patients in the training cohort from the IMDC and 4028 patients as the validation cohort from pooled prospective randomized controlled trials involving targeted therapy. NLR was examined at initiation of first-line targeted therapy and at 6 weeks after. The prognostic role of NLR and NLR conversion on overall survival (OS) and progression free survival (PFS) was assessed using Cox regression models adjusting for IMDC prognostic score. Results: Median baseline NLR was 3.4 and 2.9 in the training and validation cohorts, respectively. NLR >3.0 at baseline was independently associated with OS and PFS in both the training and validation cohorts (Table). A decrease in NLR by week 6 was associated with longer OS (21.1 vs. 9.7 months; HR 0.57, p<0.001), PFS (8.8 vs. 4.6 months; HR 0.54, p<0.001), and higher objective response rates (35% vs. 13%, p<0.001) compared to patients without a decrease. A rise in NLR showed opposite effects for all three endpoints. These findings were also confirmed in the validation set. Conclusions: NLR is an independent prognostic factor after controlling for IMDC criteria. NLR conversion can be an early biomarker of benefit to targeted therapy. [Table: see text]
The impact of BMI on outcomes of patients with metastatic renal cell carcinoma treated with targeted therapy: An external validation data set and analysis of underlying biology from The Cancer Genome Atlas.
Authors: Albiges Laurence , Hakimi A. Ari , Lin Xun , Simantov Ronit , Zabor Emily C. , Jacobsen Anders , Furberg Helena , Fay Andre Poisl , Heng Daniel Yick Chin , Signoretti Sabina , McKay Rana R. , Choueiri Toni K. 
Published: February 2017

405 Background: Obesity is a risk factor for renal cell carcinoma (RCC) and a poor prognostic factor across many tumor types. However, reports have suggested that RCC developing in an obesogenic environment may be more indolent. We recently reported on the favorable impact of body mass index (BMI) on survival in the International mRCC Database Consortium (IMDC). The current work aims to externally validate this finding and characterize the underlying biology. Methods: We conducted an analysis of 4,657 metastatic RCC (mRCC) patients (pts) treated on phase II-III clinical trials sponsored by Pfizer from 2003-2013. We assessed the impact of BMI on overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Additionally, we analysed metastatic pts from the clear cell RCC (ccRCC) cohort of TCGA dataset to correlate the expression of Fatty Acid Synthase (FASN) with BMI and OS. Results: At targeted therapy (TT) initiation, 1,829 (39%) pts were normal or underweight (BMI <25 kg/m2) and 2,828 (61%) were overweight or obese (BMI ≥25 kg/m2). Overall, the high BMI group had a longer median OS (23.4 months) than the low BMI group (14.5 months) (hazard ratio (HR) = 0.830, p= 0.0008, 95% CI 0.743-0.925) after adjusting for the IMDC prognostic risk group and other risks factors. In addition, pts with high BMI had improved PFS (HR=0.821, 95% CI 0.746-0.903, p<0.0001) and ORR (odds ratio =1.527, 95% CI 1.258-1.855, p<0.001). These results remain valid when stratified by line of therapy. When stratified by histological subtype, the favorable outcome associated with high BMI was only observed in ccRCC. Toxicity patterns did not differ between BMI groups. In the the Cancer Genome Atlas (TCGA) dataset (n=61), there was a trend towards improved OS in the high BMI group (p=0.07). FASN gene expression inversely correlated with both OS (p=0.002) and BMI (p=0.034). Conclusions: In an external cohort,we validate BMI as an independent prognostic factor for improved survival in mRCC. Given that this finding was observed in ccRCC only, we hypothesize that lipid metabolism may be modulated by the fat laden tumors cells. FASN staining in the IMDC cohort is ongoing to better investigate the obesity paradox in mRCC.
Proteomic stratification of clear cell renal cell carcinoma utilizing The Cancer Genome Atlas (TCGA) with external validation.
Authors: Kaffenberger Samuel D. , Ciriello Giovanni , Winer Andrew G. , Voss Martin Henner , Maranchie Jodi Kathleen , Tamboli Pheroze , Rathmell Kimryn , Choueiri Toni K. , Motzer Robert J. , Coleman Jonathan A. , Russo Paul , Hsieh James , Hakimi A. Ari 
Published: February 2017

406 Background: Proteomics represents the ultimate convergence of DNA and expression alterations. We therefore sought to leverage TCGA reverse phase protein array (RPPA) data with an independent proteomic platform to identify druggable targets and pathways associated with prognosis in clear cell renal cell carcinoma (ccRCC). Methods: Unsupervised hierarchical consensus clustering was performed and differentially expressed proteins were identified for pathway analysis. Associations with clinicogenomic factors were assessed and Cox proportional hazards models were performed for disease-specific survival (DSS). Results: RPPA clustering of 324 patients from the ccRCC TCGA revealed 5 robust clusters characterized by alterations in specific pathways and divergent prognoses. Cluster 1 was characterized by poor DSS, decreased expression of receptor tyrosine kinases (RTK) and upregulation of the mTOR pathway. It was also associated with mTOR pathway genomic alterations, sarcomatoid histology and the ccb prognostic mRNA signature (all p<0.001). Cluster 2 was characterized by increased expression of RTKs and interestingly, had upregulation of the mTOR pathway with excellent DSS. After accounting for stage and grade, cluster designation remained independently associated with DSS (HR 0.23 for cluster 2, 95% CI 0.08-0.68; p=0.008). External validation was performed on a separate cohort of 189 patients with a different quantitative proteomics platform. A panel of phosphoproteins (pHER1, pHER2, pHER3, pSHC, pMEK, pAKT), highly discriminant between the most divergent RPPA clusters (1 and 2) was evaluated. Those at the highest quartile of activation in > 3 proteins were associated with improved DSS (HR 0.19, 95% CI 0.05-0.082; p=0.03). Patients with mTOR pathway activation segregated to those with coincident RTK activation (n=83) and those without (n=13). Conclusions: We have identified and validated proteomic signatures which cluster ccRCC patients into 5 prognostic groups. Furthermore, two distinct mTOR-activated clusters—one with high RTK activity and one with increased mTOR pathway genomic alterations were revealed, which may have prognostic and therapeutic implications.
Phase Ib evaluation of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Sznol Mario , McDermott David F. , Jones Suzanne Fields , Mier James Walter , Waterkamp Daniel , Rossi Cheryl , Wallin Jeffrey , Funke Roel Peter , Bendell Johanna C. 
Published: February 2017

410 Background: MPDL3280A, a human anti-PD-L1 IgG1 mAb engineered to remove Fc-effector function, prevents PD-L1 binding to the inhibitory receptors PD-1 and B7.1 on activated T cells. Single-agent MPDL3280A has demonstrated clinical activity in various cancers, including RCC. Bev was postulated to enhance the antitumor effects of MPDL3280A by blocking VEGF-related suppressive effects on immune function and lymphocyte traffic. Therefore, a multicenter Phase Ib study was conducted to determine the safety and activity of MPDL3280A + bev, including in a cohort of mRCC pts. Methods: mRCC pts with clear cell histology and available pre-treatment tumor specimens were enrolled. In addition to the safety and activity endpoints, an exploratory objective was to assess treatment effects on the tumor microenvironment and peripheral biomarkers. Bev 15 mg/kg was given alone on Cycle 1 Day 1 and concurrently with MPDL3280A 20 mg/kg q3w thereafter. On-treatment tumor biopsy was performed during Cycle 1 and 4-6 weeks after the start of Cycle 2. Objective responses were assessed by RECIST v1.1. The clinical data cutoff was July 7, 2014. Results: 12 pts were evaluable for safety. The median age was 64 y, 58% were male and 83% had no prior systemic therapy. The median duration of exposure was 232.5 days. Grade 3-4 AEs included postoperative wound infection, hypercalcemia, tumor pain, acute respiratory failure in a patient with influenza (1 pt each) and hypertension (3 pts). No Grade 3-4 AEs were assessed as related to MPDL3280A. Among first-line mRCC pts with ≥ 1 tumor assessment (n = 10), the ORR was 40% (3 of 4 responses confirmed at the time of the data cutoff). Minimum follow-up was 2.1 mo. Increases in tumor-infiltrating CD8+ T cells were observed on-treatment. Updated data, including biomarkers, will be presented. Conclusions: The combination of MPDL3280A + bev waswell tolerated in clear cell mRCC pts. Promising preliminary clinical activity and immune modulation of the tumor microenvironment were observed. A Phase II trial of MPLD3280A ± bevacizumab vs sunitinib in pts with previously untreated mRCC is currently ongoing. Clinical trial information: NCT01633970.
A phase II trial of everolimus and bevacizumab in advanced non-clear cell renal cell cancer.
Authors: Voss Martin Henner , Chen Yingbei , Chaim Joshua , Coskey Devyn Taylor , Woo Kaitlin , Patil Sujata , Molina Ana M. , Hsieh James , Motzer Robert J. , Feldman Darren Richard 
Published: February 2017

411 Background: VEGF- and mTOR-directed therapies achieve inferior outcomes in patients (pts) with advanced non-clear cell renal cell cancer (ncRCC) as compared to clear cell RCC. Limited effectiveness of monotherapy supports the study of combination regimens, and a phase II trial of everolimus (E) + bevacizumab (B) was conducted in pts with metastatic ncRCC. Methods: Treatment-naïve pts received E + B at standard doses until progression or intolerance to therapy. The primary endpoint was progression free survival (PFS) with the goal to see 22 of 34 pts progression-free on treatment >6 months (mo). Correlative analyses include next generation sequencing (NGS) from tumor and germline across 341 genes of interest, as well as immunohistochemistry (IHC) for markers of mTOR activation and vessel density. Results: 34 pts were enrolled, all are evaluable (median follow up 11.2 mo). The most common histologic subtype was unclassified RCC (URCC, n=23), the majority of which had papillary growth as a major component (URCC with papillary features, n=14). Other variants included chromophobe (n=5), papillary (n=4), and medullary RCC (n=2). 19 pts achieved PFS >6 mo; 8 continue on treatment. PFS varied by histology (p<0.001), and objective response rates (ORR) were higher in pts with significant papillary (7 of 18) or chromophobe (2 of 5) elements, than for the remaining pts (1 of 11). Presence of a major papillary component was associated with treatment benefit across the entire cohort (Table), particularly in the subgroup of URCC, where this feature correlated with ORR (43 vs. 11%), median PFS (12.9 vs. 1.9mo) and OS (18.5 vs. 9.3 mo) (p<0.001). IHC markers did not correlate with treatment effect. NGS was performed on 33 cases. Conclusions: ncRCC represent a heterogeneous group of malignancies. This study did not reach its primary endpoint, yet it suggests efficacy for E+B in patients with ncRCC characterized by papillary features. Genomic tumor and germline analysis is being performed to help define the underlying biology. Clinical trial information: NCT01399918. [Table: see text]
Role of ITPR1/HIF-2α axis in protecting renal cancer cells against natural killer cells.
Authors: Messai Yosra , Noman Zaeem , Hasmim Meriem , Janji Bassam , Albiges Laurence , Escudier Bernard , Chouaib Salem 
Published: February 2017

417 Background: Clear cell renal cell carcinomas frequently display inactivation of VHL gene leading to increased level of hypoxia inducible factors (HIFs). The specific role of VHL mutations and selective activation of HIF-2 alpha in modulating RCC susceptibility to cytotoxic immune response remains largely unknown. Methods: In this study, we used 786-0 RCC VHL-mutated cell line selectively induces HIF-2 alpha stabilization.Chromium release cytotoxicity assay was regularly used to evaluate tumor target cells sensitivity to NK-mediated lysis. Confocal microscopy was aso used to analyse immunologic synapse formation and for autophagy studies. Immunochemistry staining using RCC tissue microarrays was performed to evaluate HIF-2 alpha and ITPR1 expression in RCC patients. Results: We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared to the VHL-corrected cell line (WT7). This resistance was found to require HIF-2α stabilization. Based on global gene expression profiling and ChIP assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF-2α and targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Interestingly, using a large group (235) of RCC patients,we demonstrated the existence of a significant correlation between HIF-2α and ITPR1 expression Mechanistically, HIF-2α in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK mediated killing through the activation of autophagy in target cells by NK derived signal. Both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased Granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Conclusions: Our data provide insights into the link between HIF-2α, the ITPR1-related pathway and natural immunity and strongly suggest a role for the HIF-2α /ITPR1 axis in regulating RCC cell survival. Futur NK cell-based immunotherapy should integrate HIF-2/ITPR1 axis as intrinsic feature of resistance tumor cells to improve NK cell response in RCC patients.
Association of resistance to antiangiogenic therapy with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma.
Authors: Liu Xiande , Hoang Anh , Zhou Lijun , Kalra Sarathi , Yetil Alper , Sun Mianen , Ding Zhiyong , Tamboli Pheroze , Rao Priya , Karam Jose A. , Wood Christopher G. , Matin Surena F. , Zurita Amado J. , Bex Axel , Griffioen Arjan W. , Gao Jianjun , Sharma Padmanee , Tannir Nizar M. , Sircar Kanishka , Jonasch Eric 
Published: February 2017

419 Background: Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and anti-angiogenic therapy is the current mainstay of treatment. RCC patients develop innate or adaptive resistance to anti-angiogenic therapy. There is a need to identify biomarkers which predict therapeutic resistance and guide combination therapy. Methods: Tissue microarrays with triplicate cores for each case were generated from 33 unaffected kidneys, 41 untreated primary RCC, and 42 bevacizumab and 39 sunitinib pretreated primary RCC from patients with metastatic RCC. Immunohistochemistry was used to visualize immune cell infiltration. Staining quantitation was performed using a Vectra multispectral system. Statistical analysis was performed using unpaired Student´s t-test. Results: We assessed the interaction between anti-angiogenic therapy and tumor immune microenvironment, and determined their impact on clinical outcome. Here we found that anti-angiogenic therapy treated RCC primary tumors demonstrated increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient survival. Furthermore, anti-angiogenic therapy treated specimens showed higher infiltration of CD4+FOXP3+regulatory T cells (Tregs) and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T lymphocyte infiltration and were negatively related to patient overall survival (OS) and/or progression free survival (PFS). Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Conclusions: This study indicates that anti-angiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy, and will guide the development of combination therapy with PD-1/PD-L1 blocking agents.
Comparison of stereotactic body radiotherapy and conventional external beam radiotherapy in renal cell carcinoma.
Authors: Tinkle Christopher L. , Shiao Stephen Lawrence , Weinberg Vivian K. , Lin Amy M. , Gottschalk Alexander R. 
Published: February 2017

434 Background: Renal cell carcinoma (RCC) is considered a radiation-resistant histology, often with poor response to conventionally fractionated external beam radiotherapy (EBRT). We compared outcomes for patients treated with EBRT versus stereotactic body radiotherapy (SBRT) for RCC. Methods: From 2004 and 2012, a total of 89 patients were treated with either EBRT or SBRT and retrospectively reviewed. Patients with locally recurrent RCC, bone or soft tissue RCC metastases, or primary RCC in a solitary kidney were included. 51 patients received EBRT, while 38 patients received SBRT. The median biologically effective dose (BED), assuming an α/β ratio of 10, was 32.6 Gy10 for the EBRT group and 48.0 Gy10 for the SBRT group. Local failure (LC) was defined pathologically or by imaging according to RECIST 1.1 and toxicity reported according to CTCAE v4.0 guidelines. Univariable and multivariable analyses using Cox’s regression model was performed to determine predictors of local control. Results: Median follow up from RT was 9.8 mo (range: <1-73 mo) with EBRT and 19.7 mo (range: <1-61 mo) with SBRT (p=0.26). EBRT patients were younger (p=0.02) and more were M1 (p=0.04), yet other baseline features did not differ significantly. Total RT dose, dose/fraction, and BED10 were significantly higher in the SBRT group (p≤0.002 for each), while number of fractions was significantly fewer (p<0.001). The 1-year LC estimate was 88% (95% CI, 72-96%) with SBRT and 50% (95% CI, 32-65%) with EBRT (p=0.001), with no significant difference in rate of distant recurrences (p=0.37). The 1-year progression free survival (PFS) and overall survival (OS) between the EBRT and SBRT groups were 17% (95% CI, 8-29%) vs. 39% (95% CI, 24-54%) (p=0.06) and 39% (95% CI, 25-52%) vs. 82% (95% CI, 65-91%) (p=0.002), respectively. The use of SBRT was the most important independent factor significantly predictive of local control on multivariable analysis (p=0.001, LLR test; HR=0.29, 95% CI, 0.13-0.61), while neither age nor metastasis at diagnosis was predictive. No drade 3-4 toxicity was observed in either RT group. Conclusions: The data support that SBRT improves local control over standard fractionation schemes. Higher dose per fraction, with a BED in the range of 48 Gy10, is a safe and effective local treatment modality for RCC.
Thermal ablation for the treatment of bone metastases (BM) in patients (pts) with metastatic renal cell carcinoma (mRCC): Experience from IGR.
Authors: Matias Margarida , Deschamps Frederic , Albiges Laurence , Loriot Yohann , Massard Christophe , Fizazi Karim , De Baere Thierry , Escudier Bernard J. 
Published: February 2017

437 Background: Local treatment of BM in mRCC pts comprises different approaches including thermal ablation techniques as well as radiofrequency ablation (RFA) and cryotherapy. We report our experience for the treatment of BM of mRCC pts using thermal ablation. Methods: The medical records of all pts with mRCC submitted to thermal ablation of BM from Feb 2008 to Oct 2013 were retrospectively analyzed. Intention of treatment was recorded in 3 categories: complete treatment of all BM in pts with oligometastatic disease or prevention of skeletal related events (SRE) risk and/or pain relief in pts with multimetastatic disease. The local control rate and prognostic factors for local failure (LF) were analyzed including patient characteristics, extension of disease, BM characteristics and type of treatment. Results: 22 pts with BM of mRCC were treated by thermal ablation techniques, with 32 procedures (3 pts had >=3 BM treated). Histology of primary tumor was clear cell in 20 and chromophobe carcinoma in 2 pts. At time of BM treatment, Heng prognostic score was good, intermediate and poor in 36, 59 and 5% of pts. Median age was 67 yrs (48-85). A majority of men were treated (16/22=73%). In 34%, pts had BM synchronous with the primary. BM presented cortical bone erosion in 69% and neurological structures in the vicinity in 50%. Intention of treatment was complete control of BM in 43% and prevention of risk of SRE and/or pain relief in 57% of pts. Cryotherapy was performed in 72% and RF in 28% of cases. Concomitant cimentoplasty and arterial embolization was performed in 70% and 30% respectively. Pain relief was achieved in 81% of pts. LF occurred in 19% of pts (n=6) (95% CI: 4-33%). The median follow-up was 13.4 months (95% CI: 11-21). Median OS was not reached. 86% of pts are still alive at 12 months. The unfavorable prognostic factors for LF were BM size >50 mm (p=0.035) and neurological structures in the vicinity (p=0.0083). Conclusions: Thermal ablation techniques are treatment options that should be considered in the curative and palliative treatment of BM in pts with mRCC. When indications are carefully discussed, these techniques have the potential to achieve good local control and acceptable survival.