bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolonged survival with personalized immunotherapy (AGS-003) in combination with sunitinib in unfavorable risk metastatic RCC (mRCC).
Authors: Amin Asim , Dudek Arkadiusz , Logan Theodore , Lance Raymond S. , Holzbeierlein Jeffrey M. , Master Viraj A. , Pal Sumanta Kumar , Knox Jennifer J. , Karsh Lawrence Ivan , Plessinger Doug , Nicolette Charles A. , Figlin Robert A. 
Published: February 2017

357 Background: During the past decade, VEGF targeted therapies have become standard treatment for advanced RCC. While targeted therapies have yielded improved efficacy, durable remissions are rare, particularly in unfavorable risk subjects. In a pivotal trial, treatment with sunitinib yielded a median OS of 5.3 months for poor risk and 20.7 months for intermediate risk subjects. Similarly, the validation dataset for the Heng risk model (ASCO 2011) revealed a median OS of 8 months for poor risk and 21 months for intermediate risk patients treated with VEGF targeted therapies. Durable responses have been elicited by immunotherapy in RCC. We report an update on patients with mRCC treated with combined VEGF TKI (sunitinib) plus autologous immunotherapy (AGS-003). Methods: In this phase II study, subjects with unfavorable prognosis mRCC (poor and intermediate risk) were treated with sunitinib plus autologous dendritic cell immunotherapy (AGS-003). Treatment consisted of standard 6-week cycles of sunitinib plus AGS-003 (once every 3 weeks x5 doses, then every 12 weeks until PD). Tumor response was assessed per RECIST and subjects were followed for PFS and OS. Immune monitoring samples were taken at screening, baseline and after the third and fifth doses of AGS-003 and analyzed by multiparametric flow cytometry. Results: 21 subjects were treated. As previously reported, the median overall PFS was 11.2 months and the final median OS was 30.2 months. When analyzed by baseline Heng risk status, the median PFS was 19.4 months for intermediate (n=11) and 5.8 months for subjects with poor risk features (n=10) at baseline. The median OS is 39.5+ months for intermediate and 9.1 months for subjects with poor risk. Conclusions: The results from this single-arm phase II study represent a near doubling of expected PFS and OS for unfavorable risk subjects treated with AGS-003 plus sunitinib. Updated survival and immunologic findings will be presented, as 8 of 21 subjects are still alive and continue to be followed. These results support the ongoing phase III ADAPT study, which is designed to validate these encouraging clinical and immunologic findings. Clinical trial information: NCT00678119.
MicroRNA as novel blood-based biomarkers in clear cell renal cell carcinoma.
Authors: Hakimi A. Ari , Jacobsen Anders , Mikkilineni Nina , Fiegoli Brandon , Blass Sara , Grigoryev Yevgeniy , Viale Agnes , Socci Nicholas D. , Voss Martin Henner , Motzer Robert John , Reuter Victor E. , Coleman Jonathan A. , Russo Paul , Hsieh James 
Published: February 2017

375 Background: MicroRNAs (miRNA) are short, non-coding RNAs involved in post-transcriptional gene regulation. Several reports have assessed their role as blood based biomarkers given their tissue and cancer-specific expression. Using an integrative approach we sequenced the miRNA transcriptome of the plasma of several clear cell renal cell carcinoma (ccRCC) patients both before and after surgery as well as several controls. Methods: We performed next generation miRNA sequencing (miRNAseq) on eight pairs (pre- and post-operative plasma samples) and four non-cancer controls to identify potential biomarker candidates. We further integrated our data with the miRNAseq tumor data from the Cancer Genome Atlas (TCGA) study to determine whether plasma miRNA levels are representative of tumor miRNA expression in ccRCC. Results: Overall, 930 unique miRNAs were detected, including 272 at greater than or equal to 10 read counts. There was a global shift of miRNA expression toward the non-cancer controls in the postoperative samples compared to preoperative. We further identified several stably expressed miRNAs across all samples and controls including miR-16, miR-191, and miR-103. We also identified several potential biomarker candidates by looking at differential expression both in terms of preoperative and postoperative status, as well as tumor vs. control including miR-378 and miR-660. Intriguingly, the plasma miRNA expression patterns showed no relationship to the tumor expression patterns using the TCGA samples. Conclusions: Plasma miRNA expression patterns are consistently altered in ccRCC and, following surgery, globally revert to the non-cancerous levels of the controls. Several biomarker candidates have been identified and a panel is undergoing validation in larger cohorts. Plasma miRNA levels do not appear to reflect tumor levels in ccRCC.
Randomized phase II trial of docetaxel (Doc) and prednisone (Pred) with or without AZD2171 (cediranib), in chemotherapy-naive, metastatic castrate-resistant prostate cancer (mCRPC) (NCI 7451).
Authors: Heath Elisabeth I. , Mannuel Heather Dorothy , Liu Glenn , Lara Primo , Monk J. P. , Flaig Thomas W. , Zurita Amado J. , Vaishampayan Ulka N. , Stella Philip J. , Smith Daryn W. , Dobson Kimberlee , Hussain Arif , Al-Janadi Anas , Ivy S. Percy , Heilbrun Lance K. 
Published: February 2017

38 Background: Cediranib + Doc were shown in a phase I trial to be feasible, with early evidence for efficacy in mCRPC patients (pts). A multi-center randomized Phase II screening trial of Cediranib+Doc+Pred (Arm A) vs. Doc+Pred (Arm B) was initiated in mCRPC pts. Methods: mCRPC pts with no prior chemotherapy were eligible. All received Doc at 75 mg/m2IV q 3 weeks and Pred 5 mg po bid. Cycle length was 21 days. Arm A pts also received Cediranib at 30 mg po daily. The primary endpoint was 6-month progression-free survival (PFS). We hypothesized 6-month PFS rates of 0.70 on Arm A and 0.50 on Arm B. Secondary endpoints included toxicity, PSA response, and RECIST response. Here we report the toxicity and PSA response data. Results: Of 58 pts enrolled, 57 were treated (29 Arm A, 28 Arm B). Median age = 68 years (range 51-84); 33% African-American, 63% Caucasian; median baseline PSA136 ng/mL (range 0.12 – 3,650); 57% had Gleason grade 8-10; and 40% had both bone/ visceral disease. Median nadir PSA was 10.5 ng/mL (range 0.10 – 1,484) in Arm A, and 25.9 ng/mL (range 0.00 – 2,076) in Arm B. Median number of cycles (range): Arm A = 9 (0 - 31); Arm B = 6.5 (1-39 ). 68% pts in Arm A required a dose reduction of at least one Cediranib dose level. Doc dose was reduced in 45% pts on Arm A and in 18% pts on Arm B. Primary grade 4 toxicity was neutropenia (11 [38%] pts A; 5 [18%] pts B), which prompted Cediranib dose reduction. Grade 3 toxicities included fatigue (9 (31%) A, 1 (4%) B); hypertension (8 (28%) A, 1 (4%) B); anemia (6 (21%) A, 2 (7%) B); neutropenia (4 (14%) A; 6 (21%) B); diarrhea (3 (10%) A, 1 (4%) B); deep vein thrombosis (2 (7%) A, 1 (4%) B); and pulmonary embolism (1 (3%) A). An amendment reduced Cediranib to 20 mg daily dose. PSA decrease ≥ 90% at nadir occurred for 13/29 = 45% on Arm A, and 6/28 = 21% on Arm B. PSA decrease ≥ 50% at nadir occurred for 19/29 = 66% on Arm A, and 17/28 = 61% on Arm B. Clinical partial response rates were 8/15 = 53% on Arm A and 3/9 = 33% on Arm B. Conclusions: The addition of Cediranib to Doc/Pred has increased toxicity but may be associated with higher rates of PSA response and clinical response in mCRPC patients. PFS results will be reported. Clinical trial information: NCT00527124.
Clinical evaluation of 2-(18F) fluoro-2 deoxy-D-glucose PET/ CT in hereditary leiomyomatosis and renal cell carcinoma.
Authors: Shuch Brian , Asher Kevin P. , Chen Clara , Lin Kelly , Bratslavsky Gennady , Linehan W. Marston , Srinivasan Ramaprasad 
Published: February 2017

383 Background: 2-(18F) fluoro-2 deoxy-D-glucose (FDG) PET/CT is a useful tool in the staging of malignancies. In patients with kidney cancer, the role of FDG is limited in those with clear-cell histology and remains to be evaluated with other subtypes. Kidney cancer associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is characterized by a defect in the Krebs cycle rendering these tumors highly dependent on aerobic glycolysis (the ‘Warburg effect’) with high glucose uptake to fulfill their energy requirements; we hypothesized that FDG PET/CT may have excellent sensitivity for staging in this condition. Methods: We retrospectively reviewed patients with HLRCC kidney cancer that underwent FDG PET/CT in conjunction with anatomic imaging at our institution. The ability of FDG PET/CT to detect malignant lesions (defined using pathologic or radiologic criteria) was evaluated. Results: A total of 30 patients underwent 42 PET /CTs. Conventional imaging identified a total of 107 lesions. Both patient and lesion-based analyses were performed. A total of 90 lesions, including ten renal lesions, were classified as malignant. 76 of 80 extra-renal lesions were correctly identified as malignant by PET/CT (sensitivity, 95%, CI 88-98%). In contrast, only 4 of 10 renal lesions were correctly identified as malignant (sensitivity, 40%, CI 17-69%). 11 of 12 histologically confirmed extra-renal lesions were PET avid (sensitivity, 92%, CI-64-98%). 10 of 12 (83%) benign lesions associated with HLRCC including uterine/cutaneous leiomyomas and adrenal nodules were PET avid. In a patient based analysis, all 18 patients with extra-renal spread of kidney cancer were correctly identified (sensitivity 100%, CI 82-100%). Conclusions: FDG PET/CT is a highly sensitive diagnostic modality for identifying metastatic kidney cancer associated with HLRCC. Prospective studies evaluating the utility of PET/CT imaging to characterize response to systemic therapy are currently underway.
Investigating the association of cytoplasmic and nuclear HIF-2 expression with cancer specific survival (CSS) in clear cell renal cell carcinoma.
Authors: Kroeger Nils , Seligson David B. , Signoretti Sabina , Yu Hong , Birkhaeuser Frederic D. , Magyar Clara , Huang Jiaoti , Riss Joseph , Kabbinavar Fairooz F. , Belldegrun Arie S. , Pantuck Allan J. 
Published: February 2017

387 Background: Studies support the prognostic importance of HIF-2α for ccRCC. Interestingly, a recent study has implicated HIF-2α as part of a protein translational initiation complex, a cytoplasmic function that goes far beyond its role as a nuclear transcription factor. We hypothesized that both the absolute expression as well as the subcellular localization of HIF-2α would predict clinicopathological features and CSS in ccRCC. Methods: A tissue microarray (TMA) study was conducted on 308 ccRCC patients. Survival differences were investigated with the log rank test and associations with CSS with uni- and multivariate Cox regression analyses. Recursive partition tree analysis was used to identify relevant cutoff values. Results: The median follow-up was 2.29 years (IQR 11.82). The mean percentage of positive cells was 22.45±18.00 and 0.12 ± 0.29 for HIF-2α nuclear (N) and cytoplasmic (C), respectively. High HIF-2α N (cutoff>32%) expression was associated with smaller tumor sizes (p = 0.002) and less advanced Fuhrman grades (p = 0.044). To the contrary, tumors with high HIF-2α C (>0%) more often had lymph node (p = 0.004), distant metastases (p = 0.021), and higher Fuhrman grades (p<0.0001). Univariate analyses showed an association of high HIF-2α N (p = 0.035) with better CSS. This was not found when HIF-2α N was used as a continuous variable (p = 0.067). In contrast, HIF-2α C demonstrated an association with CSS when examined as both a continuous (p < 0.0001) and as a dichotomized variable (p < 0.0001). After adjustment for TNM stage, ECOG PS, and Fuhrman grade, both continuous (p < 0.0001) and dichotomized (p < 0.0001) HIF-2α C variables remained significant predictors of CSS, while neither HIF-2α N variable was retained. The ratio of HIF-2α C/N was the strongest predictor of CSS in multivariate analysis (p = 0.001; HR 4.83 [95% CI: 1.99 – 11.76]). Conclusions: Our investigation suggests an important role for HIF-2α as a cytoplasmic protein translational initiation complex in ccRCC. This novel observation warrants further molecular and genetic studies examining biological pathways that are involved in the tumor promotive properties of HIF-2α in the cytoplasm.
Everolimus for patients with metastatic renal cell carcinoma (mRCC) refractory to anti-VEGF therapy: Preliminary results of a pooled analysis of noninterventional studies.
Authors: Albiges Laurence , Bergmann Lothar , Eymard Jean-Christophe , Schmidinger Manuela , Bamias Aristotelis , Ktiouet Meryem , Fischer Gregor , Xanthaki Despoina , Guderian Gernot 
Published: February 2017

392 Background: In RECORD-1, the oral mTOR inhibitoreverolimus significantly improved PFS compared with placebo in patients with mRCC refractory to 1 or 2 prior VEGFr-TKIs. Here, we provide prospective data from European countries on everolimus use in patients with mRCC after failure of anti-VEGF therapy. Methods: To evaluate the safety and efficacy of everolimus in routine clinical practice, data were pooled from 4 prospective, noninterventional studies conducted in Germany, France, Greece, and Austria. Results: Data from the first 6 months of treatment are available for 534 patients. At baseline, median time since diagnosis of first metastasis from RCC was 1.8 years, and 91% of patients were of favorable or intermediate MSKCC risk prognosis. Predominantly clear cell mRCC was evident in 90% of patients, and most patients had prior nephrectomy (89%). Best overall response by investigator assessment was partial response in 13%, stable disease in 56%, and progressive disease in 32%. Overall, 77% of patients experienced ≥1 adverse event (AE) and 22% experienced ≥1 serious AE. AEs occurring in >5% of patients included stomatitis (25%), anemia (13%), asthenia (9%), fatigue (8%), pneumonitis (8%), rash (8%), diarrhea (7%), decreased appetite (7%), hypertriglyceridemia (6%), dyspnea (6%), nausea (6%), and peripheral edema (5%). Serious AEs occurring in >2% of patients included stomatitis (3.4%), general health deterioration (2.2%), anemia (2.1%), dyspnea (2.1%), and pneumonitis (2.1%). Median everolimus duration was 4.8 months. Treatment was discontinued due to disease progression in 50% of patients and AEs in 24% of patients. A similar proportion of patients had Karnofsky performance status ≥70 at baseline (86%) and at end of analysis (80%). Updated data will be available in February 2012. Conclusions: Preliminary results of this pooled analysis of 4 European studies substantiate the safety of everolimus reported in the pivotal RECORD-1 trial and provide evidence for the effectiveness of everolimus in routine use. The results support the use of everolimus as a standard of care for VEGF-refractory patients with mRCC.
Characteristics and clinical outcomes of patients with renal cell carcinoma with sarcomatoid dedifferentiation (sRCC).
Authors: Merrill Megan M. , Wood Christopher G. , Tannir Nizar M. , Slack Rebecca , Babaian Kara , Jonasch Eric , Pagliaro Lance C. , Compton Zachary , Tamboli Pheroze , Sircar Kanishka , Pisters Louis L. , Matin Surena F. , Karam Jose A. 
Published: February 2017

401 Background: sRCC is an aggressive subset of renal cell carcinomas that is associated with poor prognosis. We describe clinical and pathological characteristics and outcomes of the largest single-institutional cohort of patients with sRCC who underwent nephrectomy. Methods: Data were collected from 1986 to 2011 for patients identified as having sRCC. 221 patients with complete data who underwent a radical or partial nephrectomy and had a sarcomatoid component in the primary kidney tumor were included in the analysis. Clinical and pathologic variables were reviewed and Kaplan-Meier curves were used to compare differences in overall survival. Results: Mean age at diagnosis was 57 years and median tumor size was 11 cm (range 1.5-27.0 cm). 93% of patients were symptomatic at presentation and 96% had an ECOG performance status of 0 or 1. 12 patients had a preoperative biopsy that showed sRCC. 75% of patients were pT3 or higher at time of nephrectomy and 69% presented with metastatic disease. Of these, 11.8% had radiographic evidence of regional nodal involvement alone and 88.2% had distant metastatic disease. The associated epithelial component was clear cell in 72% of the patients, papillary in 12.7% and chromophobe in 3.1%. 29 patients received presurgical systemic therapy, while 161 patients received postoperative systemic therapy. During a median follow-up of 20.5 months, 187 patients (84%) died. Overall survival for the entire cohort at 1 year was 48%. Overall 1-, 2-, and 3-year survival rates for patients with metastatic disease at presentation versus no metastatic disease were 36, 20, and 16% versus 74, 51, and 44% respectively (p < 0.001). Patients with clear cell RCC epithelial component had a survival advantage over those with non-clear cell components with 1-, 2-, and 3-year survival rates of 52, 34, and 31% versus 38, 19, and 12% (p = 0.0057). Conclusions: The majority of patients with sRCC who underwent nephrectomy present with metastatic disease and outcomes are dismal despite surgical intervention and multimodal therapy. Overall survival is better for patients who present without metastatic disease and have clear cell histology at time of nephrectomy.
ER stress protein GRP78 as a therapeutic target combined with antiangiogenic therapy in renal cell carcinoma.
Authors: Han Kyung Seok , Li Na , Raven Peter A. , Li Estelle , Fazli Ladan , Gleave Martin E. , So Alan I. 
Published: February 2017

428 Background: Antiangiogenic therapy deprives oxygen and nutrition from the tumor. These stresses cause unfolded proteins in tumor cells. Glucose regulated protein 78 (GRP78) binds to unfolded proteins and its subsequent activation suppresses global mRNA translation to protect cells from excessive unfolded proteins. We investigated a potential role of GRP78 as a combined therapeutic target in renal cell carcinoma treated with antiangiogenic therapy. Methods: Renal cell carcinoma cells (Caki-1, Caki-2, UMRC-3, and UMRC-6) were used to investigate the effect of GRP78 knockdown, which was performed by small interfering RNA. Caki-1 xenografts were developed and treated with sunitinib 40mg/kg/day to evaluate in vivo expression of GRP78 during antiangiogenic therapy. Caki-1 cells stably overexpressing GRP78 were developed to investigate the role of GRP78 in cancer cell. Hypoxic stress was induced by 1% hypoxia chamber and hypoglycaemic stress was induced by glucose-free media. Downstream signalling pathways of GRP78 were evaluated by Western blots. Results: In vitro hypoxia and/or glucose deprivation induced GRP78 upregulation in Caki-1 cells. GRP78 was also induced in Caki-1 xenografts treated by sunitinib. Overexpression of GRP78 increased tumor proliferation in hypoxic and/or hypoglycemic stresses by activating PERK/eIF2α pathway and protected tumor cells from stress-induced apoptosis. Knockdown of GRP78 using small interference RNA inhibited cancer cell survival and induced apoptosis in renal cell carcinoma cells in vitro. GRP78 knockdown also sensitized renal cell carcinoma cells to ER stress-induced apoptosis and hypoxic and hypoplycemic stress-induces apoptosis. Conclusions: Antiangiogenic therapy induces ER stress by depriving oxygen and glucose from renal cell carcinoma. ER protein GRP78 has a critical role in protecting renal cell carcinoma cells from hypoxic and hypoglycemic stress induced by antiangiogenic therapy. Knockdown of GRP78 sensitizes RCC cells to apoptotic cell death from anti-angiogenic stresses. Our results suggest that GRP78 is a novel therapeutic target in renal cell carcinoma management.
Nanoscale proteomic profiling to define diagnostic signatures and biomarkers of therapeutic activity in patients with RCC.
Authors: Fan Alice C. , Leppert John , Liliental Joanna E. , Xu Liwen , Thong Alan E. , Yost Christine , Yaghi Alia , Brooks James D. , Harshman Lauren Christine , Sabatti Chiara , Srinivas Sandy , Felsher Dean W. 
Published: February 2017

432 Background: Novel agents that inhibit kinases in the hypoxia and MTOR pathways can achieve response rates of 30-60% in renal cell carcinoma (RCC); however, protein biomarkers to diagnose RCC and guide treatment have not been identified. Methods: We developed the use of two high-throughput, nanoscale immunoassays to profile hypoxia and downstream signaling in clinical specimens from patients with RCC. These automated technologies minimize errors due to manual variability, and make 96 independent measurements per overnight experiment. We used size-based protein separation (Sally Instrument, Protein Simple) to quantify proteins using antibody-specific detection, normalized to loading control. Next, we used a nano-immunoassay with charge-based separation (NIA, Nanopro1000 Instrument, Protein Simple) to distinguish multiple charged modifications of individual proteins, and measure relative ratios of individual unphosphorylated and phosphorylated isoforms. Results: We first optimized assays for proteins in MAPK, PI3K and STAT pathways, and loading controls, to analyze frozen surgical specimens and ex-vivo fine needle aspirates (FNA’s) performed immediately following nephrectomy. We analyzed more than 200 FNA’s from solid tumors, comparing RCC with paired adjacent non-tumor tissue, and other epithelial malignancies. Basal MAPK signaling of tumors varied across 3 logs of expression. Unique to NIA, we analyzed percent phosphorylation and resolved differences in single phosphorylations. Subtle differences in basal MAPK signaling between tumor calls and adjacent non-tumor tissue can distinguish RCC from other malignancies. Lastly, we prospectively collected and analyzed blood peripheral mononuclear cells from 20 RCC patients before and during treatment with standard targeted therapies. Kinase inhibitors can preferentially inhibit or activate specific protein phospho-isoforms. Conclusions: Our studies demonstrate that rapid and quantitative nanoproteomic profiling in very small amounts of clinical specimen may accelerate translational studies for novel diagnostic and predictive biomarkers.