bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary anti-VEGF-refractory metastatic renal cell carcinoma (mRCC): Clinical characteristics, risk factors, and subsequent therapy.
Authors: Heng D. Y. , MacKenzie M. J. , Vaishampayan U. N. , Knox J. J. , Bjarnason G. A. , Tan M. , Wood L. , Donskov F. , Rini B. I. , Choueiri T. K. ,   International mRCC Database Consortium
Published: February 2017

305 Background: A proportion of patients treated with anti-VEGF therapy first line exhibit progressive disease (PD) as best response (per RECIST). The characteristics and outcome of this population are poorly understood. Methods: Data from patients with mRCC treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Results: One thousand fifty-six evaluable patients were treated with VEGF-inhibitors as their first-line antiangiogenic therapy. Of those, 272 (26%) patients had PD as best response. Their initial treatment was sunitinib (n=203), sorafenib (n=51), or bevacizumab (n=18). Six percent of patients were favorable risk, 55% intermediate risk, and 39% poor risk as per Heng et al JCO 2009 prognostic factors. On multivariable analysis, predictors of PD at first restaging were KPS < 80% (OR 2.3, p < 0.0001), diagnosis to treatment < 1 year (OR 2.1, p < 0.0001), neutrophilia (OR 1.9, p = 0.0021), thrombocytosis (OR 1.7, p = 0.0068), and anemia (OR 1.6, p = 0.0058). The median progression-free survival (PFS) and overall survival (OS) in patients with primary refractory disease vs. patients without (i.e., partial response or stable disease) was 2.4 vs. 11 months (p<0.0001) and 6.8 vs. 29 months (p<0.0001), respectively. Only 108 (40%) VEGF-refractory patients proceeded to receive 2nd line VEGF inhibitors (sunitinib (n=32), sorafenib (n=44), axitinib (n=2), bevacizumab (n=4)), mTOR inhibitors (temsirolimus (n=14), everolimus (n=11)), or interferon (n=1). The response rate, PFS and OS of this second-line therapy was 9%, 2.5 months and 7.4 months, respectively. The response rate, PFS and OS of those receiving second-line VEGF vs. mTOR inhibitors was 10% vs. 6% (p=NS), 2.8 vs. 2.0 months (p=0.069) and 7.9 vs. 4.7 months (p=0.40), respectively. Conclusions: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR agents may not be better than alternate anti-VEGF agents after primary anti-VEGF failure. Investigation into the mechanism of primary resistance and alternative therapeutic strategies are needed. [Table: see text]
A phase I trial of combined tivozanib (AV-951) and temsirolimus therapy in patients (pts) with renal cell carcinoma (RCC).
Authors: Kabbinavar F. F. , Srinivas S. , Hauke R. J. , Amato R. J. , Esteves B. , Dhillon R. , Cotreau M. M. , Al-Adhami M. , Bhargava P. , Fishman M. N. 
Published: February 2017

330 Background: Tivozanib, a potent and selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, has demonstrated antitumor activity in a phase II study in RCC (Proceedings of ASCO 2009, Abstract 5032). Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for treatment of advanced RCC. This phase Ib open-label study examined combination tivozanib and temsirolimus therapy in pts with advanced RCC to determine the safety and tolerability, maximum tolerated dose (MTD), and clinical activity of this drug regimen. Methods: Pts with advanced RCC (with clear cell component) who had failed up to 1 prior VEGF-targeted therapy received daily oral tivozanib (3 wks on, 1 wk off = 1 cycle) and intravenous temsirolimus (once weekly). A standard 3+3 dose escalation design was used at four levels: 0.5 mg/d tivozanib and 15 mg/wk temsirolimus; 1.0 mg/d and 15 mg/wk; 1.5 mg/d and 15 mg/wk; and 1.5 mg/d and 25 mg/wk. Results: As of 9/15/10, 28 pts had been treated and accrual was closed. Demographic features were: 26 male/2 female; 89% Caucasian; median age 62 years (range, 43–71); Karnofsky Performance Status of 100/90/80 for 16, 7, and 4 pts respectively (1 pt missing data). Twenty of 28 pts (71%) had received prior VEGF-targeted therapy. Median duration of treatment was 21.1 wks (range, 0.3–94.0). Treatment-related adverse events seen in ≥10% of pts were (number of pts with all grades/grade 3 toxicity): fatigue (14/3), decreased appetite (9/0), stomatitis (7/1), thrombocytopenia (6/1), diarrhea (6/0), nausea (6/1), vomiting (3/0), and decreased weight (3/0). There were no grade 4 events. The MTD of this combination was tivozanib 1.5 mg/d and temsirolimus 25 mg/wk, and no dose limiting toxicities were encountered. Clinical activity was observed, including tumor responses in pts who had failed VEGF targeted therapies. Conclusions: The combination of tivozanib with temsirolimus was well tolerated and showed clinical activity in patients with advanced RCC. Tivozanib is the first VEGFR TKI that can be combined with temsirolimus at the full dose and schedule of both agents. [Table: see text]
Phase I study of high-dose interleukin (HD-IL2) and sorafenib in patients with metastatic clear cell renal cell carcinoma (RCC) and melanoma.
Authors: Lam E. T. , Lesinski G. , Mortazavi A. , Kendra K. L. , Carson W. E. , Tahiri S. , Liersemann R. , Clinton S. K. , Olencki T. , Monk J. P. 
Published: February 2017

337 Background: HD-IL2 has demonstrated activity for immune therapy of RCC and melanoma. Sorafenib is a multitargeted kinase inhibitor with antiangiogenic activity and may also modulate antitumor immunity. This ongoing phase I study assesses the safety, tolerability, dose-limiting toxicity (DLT), and maximum tolerated dose of the combination of HD-IL2 and sorafenib in patients with unresectable or metastatic clear cell RCC and melanoma. Methods: Eligible patients with ECOG PS 0-1, adequate organ function, and favorable or intermediate Motzer status (RCC patients) received up to two series of therapy. Each 82-day series consisted of two cycles of bolus HD-IL2 and 8 weeks of sorafenib. HD-IL2 (600,000 IU/kg IV q8h x 8-12 doses) was given on days 1-5 (cycle 1) and 15-20 (cycle 2). Sorafenib was given on days 29-82 and discontinued 48-72 hours prior to the next series. Dosing levels for sorafenib were (1) 200mg daily, (2) 200mg BID, (3) 200mg qAM and 400mg qPM, and (4) 400mg BID. Patients who achieved stable disease (SD), partial response (PR), or complete response (CR) after Series 1 proceeded to Series 2. Results: Fourteen patients (8 RCC, 6 melanoma) have been treated. Nine patients completed Series 1 (5 patients came off study due to poor tolerance of HD-IL2, prior to receiving sorafenib). Six patients had SD or better (3 PR, 3 SD) after Series 1. Of these, five have completed Series 2 and one patient progressed during sorafenib treatment in the second series. No DLTs were observed at the first 3 dose levels. All observed grade 3 and 4 AEs were transient and attributable to the known toxicities of HD-IL2 or sorafenib, and were not considered DLT. Adverse events occurring more frequently in Series 2 (HD-IL2 after sorafenib) included proteinuria and dry skin. One death occurred in a patient with melanoma who received only the first cycle of HD- IL2 (never received sorafenib) and one week later experienced sudden death at home, an event reported as possibly related to the HD-IL2. Conclusions: No DLT was seen in this study of HD-IL2 and sorafenib and the toxicity was predictable and manageable. Both RCC and melanoma patients experienced PR and SD, but not CR. Enrollment to cohort 4 is ongoing. [Table: see text]
Chromosome 14q imbalances and pathways associated with resistance to antiangiogenic therapy in clear cell renal cell carcinoma.
Authors: Jonasch E. , Alvarez K. , Peterson L. , Tannir N. M. , Sircar K. , Tamboli P. , Monzon F. A. 
Published: February 2017

339 Background: Antiangiogenic agents are used to treat metastatic clear cell renal cell carcinoma (ccRCC). Currently there are no biomarkers of therapeutic efficacy for these agents. Hypoxia inducible factor (HIF) alpha ratios have been linked to phenotypically distinct ccRCC subpopulations. The HIF1 alpha gene is located on chromosome 14q. In this study, the goal was to determine whether chromosomal imbalances identified with SNP arrays are linked to HIF ratios, and to clinical outcome. Methods: We obtained archival FFPE tumor specimens from 56 patients with mRCC treated with sorafenib or bevacizumab. DNA from the FFPE blocks was analyzed with Affymetrix 250K Nsp SNP microarrays. We identified the presence of genomic imbalances and loss of heterozygosity (LOH) to obtain virtual karyotypes. We then evaluated candidate genes in gain/lost chromosomal regions by qPCR and immunohistochemistry (IHC) in the bevacizumab treated specimens. Results: In the bevacizumab cohort, HIF1-alpha containing14q loss showed a significant association with worse response to treatment (CR/ PR vs. SD/PD, Fisher exact test, p = 0.0473). In addition, HIF1A mRNA expression was significantly reduced in all samples with 14q loss and was associated with PFS (HR = 2.29, 95% CI = 1.01-5.16, p = 0.045). HIF-1alpha protein expression was also reduced in samples with 14q loss. Conclusions: Chromosomal imbalances are associated with outcomes in ccRCC patients treated with antiangiogenic agents, and can lead to changes in gene expression. Low HIF1A expression was strongly correlated with shorter PFS. We hypothesize that loss of 14q could lead to an imbalance in HIF-1alpha/HIF-2alpha activity, leading to increased HIF-2alpha and enhanced c-Myc expression, which improves tumor cell viability and engenders resistance to cellular stress induced by antiangiogenic therapy. No significant financial relationships to disclose.
Relationship between the loss of the retinoblastoma tumor suppressor and radiosensitivity.
Authors: Den R. B. , Ciment S. , Sharma A. , Mellert H. , Mc-Mahon S. , Dicker A. , Knudsen K. E. 
Published: February 2017

34 Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation. Loss of RB has been observed in 25–30% of prostate cancers and is correlated with increasing tumor stage and grade. The clinical consequences of RB loss are unknown. We have previously shown that RB loss results in a castrate resistant phenotype. We hypothesized that RB loss would downregulate the G1-S cell cycle arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to mitotic catastrophe. Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts. Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in all cell lines (p<0.05). Cell death was not mediated through increased apoptosis, however, there was increased cell cycling despite the presence of DNA damage in the RB knockdown cells. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05). Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. RB status is integral to determining which therapeutic modality should be employed in the management of prostate cancer. No significant financial relationships to disclose.
Lipid profiles and the risk of kidney cancer in the Swedish AMORIS study.
Authors: Van Hemelrijck M. , Garmo H. , Hammar N. , Walldius G. , Lambe M. , Jungner I. , Holmberg L. 
Published: February 2017

342 Background: Since multiple epidemiologic studies showed a link between obesity and kidney cancer (KCa), the lipid metabolism is thought to play a role in development of KCa. With the exception of cholesterol and total fat intake, the association between changes in lipid biomarkers and KCa has not often been researched. We assessed the link between lipid profiles and KCa risk in a large prospective cohort study. Methods: A cohort based on 85,261 persons (> 20 years old) with baseline measurements of glucose, triglycerides (TG), total cholesterol, HDL, LDL, apolipoprotein A-I and apoB was selected from the Swedish Apolipoprotein Mortality Risk (AMORIS) study. Multivariate Cox proportional hazards models were used to analyze associations between quartiles and dichotomized values of these lipid components and KCa risk. All models were adjusted for age, gender, socioeconomic status, fasting status, history of kidney disease prior to baseline (ICD9: 580-93), and glucose, cholesterol, and TG levels (depending on the covariate of interest). Results: During a mean follow-up of 12 years, 161 persons developed KCa (58% men). The mean age at baseline was 46 years. TG were the only lipid component for which a statistically significant association was found with risk of KCa (Hazard Ratio (HR): 1.05 (95%CI: 0.59-1.87), 1.77 (1.05-2.98), and 1.77 (1.04-3.02) for the second, third, and fourth quartile, compared to the first, with p-value for trend: 0.008). The lipid ratio of TG and HDL also showed a statistically significant positive association with risk of KCa (HR: 1.21 (0.71-2.08), 1.56 (0.94-2.58), and 1.92 (1.17-3.17) for the second, third, and fourth quartile, compared to the first, with p-value for trend: 0.004). No other associations were found between lipid components and KCa risk. Conclusions: This detailed analysis of lipid components and risk of KCa found a relation between levels of TG and KCa risk. In contrast to previous studies, we did not find an association between cholesterol levels and KCa risk. Lipid profiles based on the markers used in this study do not seem to reflect the etiological pathway that has previously been shown between obesity and KCa. Further mechanistic studies are required to assess the link between lipid deregulation and KCa. No significant financial relationships to disclose.
An evaluation of the role of Src in renal cancer.
Authors: Qayyum T. , McArdle P. A. , Seywright M. , Mcmillan D. C. , Aitchison M. , Edwards J. E. 
Published: February 2017

358 Background: The aim of the current study was to assess the expression levels of c-Src, phosphorylated Src, dephosphorylated c-Src at 530 and the downstream marker Fak 861 in renal cancer. Methods: In all, 60 patients undergoing potentially curative nephrectomy for localised renal cancer were included. Imunohistochemical staining was utilised to assess expression of c-Src, dephosphorlated c-Src at 530, phosphorylated Src at the Y416 site, and Fak 861. Expression was assessed using the weighted histoscore method. Results: High membrane c-Src was associated with increased cancer specific survival (p=0.032). In addition, increased cancer-specific survival was associated with high levels of cytoplasm and membrane expression of c-Src (p=0.039). When assessed individually, membrane, cytoplasm and nuclear expression of phosphorylated Src was not significantly associated with cancer specific survival. However when membrane and cytoplasm expression was combined, high expression was associated with decreased cancer specific survival (p=0.001). Low cytoplasm Fak expression was associated with increased cancer specific survival (p=0.029). When expression of Fak was combined with phosphorylated Src, high expression was associated with decreased cancer specific survival (p=0.003). When taking together high membrane c-Src and phosphorylated Src expression, this was associated with increased cancer specific survival (p=0.029). On multivariate analysis, combined expression of membrane c-Src and phosphorylated Src (HR 0.49, 95% CI 0.24-0.99, p=0.047) and combined Fak and phosphorylated Src expression (HR 1.88, 95% CI 1.06-3.34, p=0.030) were significant independent predictors of cancer specific survival. Conclusions: The results suggest that activated c-Src is associated with improved survival and activated Src family members are associated with decreased survival. This would suggest that another member of the Src family maybe associated with decreased survival. Further work is required to identify which of the Src family members are expressed in renal cancer and would therefore allow specific inhibitors for these Src family members to be developed. No significant financial relationships to disclose.
Use of CXCR4 expression to predict the efficacy of sorafenib treatment in patients with metastatic renal cell carcinoma.
Authors: Guo J. , Tang B. , Sheng X. N. , Cui C. L. 
Published: February 2017

359 Background: CXCR4, a chemokine receptor, is implicated in the metastastic process. Higher expression of CXCR4 in renal cell carcinoma predicts shorter disease-free survival and poorer prognosis. This study aims to investigate the relationship of CXCR4 expression with the efficacy of target drugs in treatment of metastatic renal cell carcinoma (mRCC). Methods: A total of 58 patients with mRCC treated with target drugs (26 with sorafenib, 23 with sunitinib, 5 with pazopanib, 2 with CCI-779, and 2 with axitinib) as the first-line therapy in Beijing Cancer Hospital between 2006 and 2010 were investigated. CXCR4 expression in tissue was detected by immunohistochemistry. Survival curves were estimated according to the Kaplan-Meier method and evaluated with the Log-rank test. The correlation of CXCR4 expression with Memorial Sloan-Kettering Cancer Center criteria (MSKCC) was assessed with χ2 test. p < 0.05 was considered statistically significant. Results: CXCR4 expression was negative in 6.9% (4/58) of patients, low in 19.0% (11/58) of patients, intermediate in 56.9% (33/58) of patients and high in 17.2% (10/58) of patients, which was not correlated with MSKCC (p = 0.143). The PFS of patients with negative or low CXCR4 expression (20.0 ± 5.9 months) was longer than those with intermediate or high expression (8.5 ± 1.3 months), which, however, was not statistically different (p = 0.131). The PFS of sorafenib-treated patients with negative or low CXCR4 expression was 20.0±8.0 months while the patients with intermediate or high CXCR4 expression was 6.0 ± 0.8 months (p = 0.038). No such correlation existed in the group of patients treated with sunitinib (p = 0.947). And median OS had not been achieved yet. Conclusions: CXCR4 can predict the efficacy of sorafenib treatment in mRCC patients. Patients with negtive or low CXCR4 expression are more likely to obtain longer PFS than those with intermediate or high CXCR4 expression. [Table: see text]
Use of TMPRSS2-ERG gene rearrangement and quantitative ERG expression to predict clinical recurrence after radical prostatectomy.
Authors: Klein E. A. , Falzarano S. M. , Maddala T. , Cherbavaz D. , Novotny W. F. , Millward C. , Magi-Galluzzi C. 
Published: February 2017

36 Background: The association of TMPRSS2-ERG fusions and ERG expression in prostate cancer (PC) with adverse clinical outcomes has been controversial, with mixed results in the literature. We conducted a study to test whether tumor-derived gene expression profiles, including the presence of TMPRSS2-ERG fusions and ERG gene expression, are associated with clinical recurrence (cR) after radical prostatectomy (RP). Methods: All patients with clinical stage T1/T2 prostate cancer treated with RP at CC from 1987 to 2004 were identified (n∼f2,600). A cohort sampling design was used to select 127 patients with cR and 374 patients without cR after RP. For each patient a primary Gleason pattern (GP) sample, secondary (or highest) GP sample, and an adjacent nontumor tissue sample were evaluated. Surgical Gleason Score (GS) and clinical data were centrally reviewed. RNA was extracted from 6 manually dissected 10 μ m formalin-fixed paraffin-embedded sections obtained from RP specimens and expression of TMPRSS2-ERGa, TMPRSS2-ERGb, ERG and reference genes were quantified using RT-PCR. Times to cR, PSA recurrence, and PC death were analyzed using Cox PH regression. Results: Blocks from 441 patients were evaluable. Median F/U was 5.8 years. Patients were mostly Caucasian (83%), clinical stage T1 (66%), had baseline PSA <10 ng/mL (82%), and had surgical Gleason score ≤7 (87%). 848 tumor samples and 410 non-tumor samples were assessed. TMPRSS2-ERGa and/or TMPRSS2-ERGb fusions were present in 51.8% of tumor samples and 7.5% of non-tumor samples. There was 89% concordance (95% CI: 86%, 92%) for TMPRSS2-ERG fusion status between the 2 tumor samples for each patient. High ERG expression was strongly associated with the presence of TMPRSS2-ERG fusions (p <0.01). We did not find an association between TMPRSS2-ERG a/b gene rearrangement or ERG expression with cR, PSA recurrence, PC death, or surgical GS (p > 0.2). Conclusions: This study was notable for the large number of cR events, use of a standardized quantitative assay, and rigorous central review of pathology and clinical data. We did not find an association of TMPRSS2-ERG gene rearrangements or ERG expression with aggressiveness of prostate cancer post RP. [Table: see text]
Real-life treatment of patients with advanced or metastatic renal cell carcinoma in German oncology and urology outpatient centers (RCC-Registry).
Authors: Mueller L. , Goebell P. , Blumenstengel K. , Lueck A. , Koska M. , Marschner N. 
Published: February 2017

367 Background: Until 2006, advanced or metastatic renal cell carcinoma (mRCC) patients were treated with immunomodulators such as interleukins and interferons. Multiple new targeted therapeutics, mainly signal transduction inhibitors, have been developed resulting in fundamental changes of therapeutic standards for patients with mRCC. In 2007, recruitment into the registry started in order to survey the treatment of mRCC patients, the course of disease and treatment as well as the therapeutic decision-making processes. Methods: It is intended to enroll 1,000 mRCC patients and collect data for each case for a maximum of 3 years. Over 100 oncology and urology outpatient centers in Germany are participating. Inclusion Criteria: (1) patients with metastatic or locally advanced RCC requiring antineoplastic therapy, (2) start of first palliative therapy within 1 year before enrolment, (3) age at least 18 years, and (4) Informed written consent. Results: By May 2010, 509 patients were enrolled. At the start of systemic therapy mean age were 66.2 years for male and 69.0 years for female patients, respectively. Patients have a Charlson Comorbidity Index of 1.0. More than 94% of patients had metastases at inclusion. 62.8% of the patients received sunitinib as first-line treatment, 12.0% received temsirolimus, 9.6% were treated with bevacizumab/interferon alpha, and 9.1% received sorafenib. Median duration determined using Kaplan-Meier analyses of first-line treatment with: sunitinib: 8.5 months (n=319), temsirolimus: 2.6 months (n=60), bevacizumab/interferon alpha: 4.6 months (n=49), and sorafenib: 6.7 months (n=45) whereby the duration of ongoing therapies was censored as the date of last documentation; thus the final duration might exceed the given values. After first-line treatment with sunitinib most of the patients received either sorafenib (12.4%, n=63) or temsirolimus (7.7%, n=39) in the second line. Conclusions: The registry provides an overview of the current treatment of mRCC patients in German outpatient cancer centers and shows how fast the insights of clinical studies concerning treatment of mRCC patients are transferred into current medical practice. [Table: see text]