bluuebunny/crossref_metadata_2025_split huggingface dataset:
S-TRAC trial: Sensitivity analyses of disease-free survival (DFS).
Authors: George Daniel J. , Pantuck Allan J. , Motzer Robert J. , Ravaud Alain , Escudier Bernard , Staehler Michael D. , Serfass Lucile , Krishnaswami Sriram , Casey Michelle , Lechuga Mariajose , Koch Gary , Figlin Robert A. 
Published: February 2018

633 Background: DFS has been frequently used as endpoint in the adjuvant setting and was the primary basis of approval for adjuvant cancer therapies. In S-TRAC, adjuvant sunitinib demonstrated a significant improvement of DFS vs. placebo in patients with locoregional renal cell carcinoma (RCC) based on blinded independent central review. DFS was defined as time from randomization until recurrence or death from any cause or second cancer. In the absence of a standard definition of DFS in RCC, multiple sensitivity analyses were performed to confirm the robustness of the DFS results from S-TRAC. Methods: Two analyses considered the time to recurrence including and excluding RCC specific deaths and contralateral kidney recurrence. Additional analyses used the same event and censoring rules as the primary analysis but considered earliest dates of relapse for equivocal new lesions later determined to be unequivocal -to align with RECIST 1.1 criteria for new lesions- and some alternative dates for secondary malignancies. Other sensitivity analyses evaluating alternative event and censoring rules as well as the imbalance in censoring in the first year in the primary analysis will also be presented. Results: The HR from select sensitivity analyses are presented in the Table. Conclusions: Results of sensitivity analyses with alternative definitions of DFS in S-TRAC demonstrated the robustness of the primary DFS analysis, with consistent HRs (0.76-0.81) favoring sunitinib. Clinical trial information: NCT00375674. [Table: see text]
Comparison of tumor mutational burden (TMB) in PBRM1/BAP1-based subsets of advanced renal cell carcinoma (aRCC).
Authors: Pal Sumanta K. , Madison Russell , Chung Jon , Agarwal Neeraj , Bergerot Paulo Gustavo , Bosse Dominick , Sokol Ethan , Hartmaier Ryan James , Miller Vincent A. , Ross Jeffrey S. , Choueiri Toni K. , Ali Siraj Mahamed 
Published: February 2018

634 Background: Using IHC, Joseph et al (J Urol 2016) propose that 40.1%, 48.6%, 8.7% and 1.8% of patients (pts) can be characterized as PBRM1+BAP1+, PRBM1-BAP1+, PBRM1+BAP1- and PBRM1-BAP1-, respectively. We sought to confirm consistency of the frequency of genomic alterations (GAs) and IHC data and to compare TMB across subsets. Methods: DNA was extracted from 40 microns of FFPE sections from pts with aRCC. Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 688X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. TMB was determined on 1.2 million Mb of sequenced DNA; results are reported in subsets segregated by presence or absence of PBRM1 and BAP1 alteration. Results: 648 consecutive pts (459:189 M:F) with clear cell RCC (ccRCC) were assessed with a median age of 58, and 368 consecutive pts (254:114 M:F) with non-clear cell RCC (nccRCC) were assessed with a median age of 57. Mutations in BAP1 and PBRM1 were found more frequently in ccRCC vs nccRCC (P < 0.05 for both). In pts with ccRCC, average TMB was highest in pts with co-occurring PBRM1 and BAP1 GAs (4.87 muts/Mb), and lowest in pts lacking both GAs (2.77 muts/Mb) (P < 0.05). TMB was similar across PBRM1/BAP1-based subsets amongst pts with nccRCC. Conclusions: As anticipated, the frequency of PBRM1/BAP1-mutated subsets by CGP is inversely related to the frequency of subsets with PBRM1/BAP1 loss by IHC from previous reports. In addition to these confirmatory findings, this large series identifies that pts with dual PBRM1/ BAP1 GAs (associated with the worst prognosis) had the highest TMB. [Table: see text]
Comprehensive genetic characterization of TFE3-positive renal cell carcinoma.
Authors: Jeong Chang Wook , Cho Jae So , Lee Moses , Choi Murim , Song Cheryn , Lee Sangchul , Ku Ja Hyeon , Kwak Cheol , Kim Hyeon Hoe 
Published: February 2018

635 Background: MiT family translocation renal cell carcinoma (RCC) is very rare variant which has translocation of Xp11.2/TFE3 gene or t(6;11)/TFEB gene. Xp11.2 translocation RCC is predominantly reported in younger age and has aggressive features. However, its pathophysiology or genetic characteristics are rarely understood. The aim of the study is to describe the comprehensive genetic characteristics of TFE3-positive RCC diagnosed by immunohistochemistry. Methods: We identified patients who were clinically diagnosed as Xp11.2 translocation RCC by immunostaining positive of TFE3 from two tertiary referral hospitals. Among them, a total of 19 patients whose fresh frozen tissue and normal DNA were achieved were included in the analysis. Whole exome sequencing (WES) was performed to evaluate somatic mutations and copy-number variation (CNV). We also performed RNAseq on the TFE3-positive RCC, 7 clear cell RCC, and 4 normal kidney tissue for comparison. Fusion partners were identified and clustering analysis was done by RNAseq. Results: Mutational landscape of TFE3-positive RCC is unique by low somatic mutation rate and very rare COSMIC variants. High prevalence of CNV with loss of 3p, 6q, 9, gain of 5, 7, and 12 were most frequent. We identified NONO, RBM10, SFPQ, ASPSCR1 and PRCC as fusion partner as previously described. We could not find TFE3 fusion in 6 out of 19 patients by RNAseq, and they were older and had more mutations than the others. They were also genetically clustered with clear cell RCC. Oxidative reducatase pathway was upregulated and immune response and cell adhesion were downregulated by gene ontology results from heatmap clusters. These may promote metastasis, resistant to immunity and cell survival in poorer condition which could be potential mechanism of Xp11.2 translocation RCC aggressiveness. Conclusions: TFE3-positive RCC showed distinctive mutation pattern with low somatic mutation and rare common driver gene. One-third clinically diagnosed Xp11.2 translocation RCC (6/19) did not have real gene fusion even in TFE3 overexpression. They were older and had more somatic mutations than the others. Furthermore, they were clustered with clear cell RCC.
Effects of cabozantinib on bone turnover markers in patients with metastatic renal cell carcinoma.
Authors: Ratta Raffaele , Verzoni Elena , Pantano Francesco , Grassi Paolo , Martinetti Antonia , Morelli Daniele , Sottotetti Elisa , Mennitto Roberta , Fucà Giovanni , Prisciandaro Michele , De Braud Filippo G. , Santini Daniele , Procopio Giuseppe 
Published: February 2018

638 Background: In-vitro studies have shown that cabozantinib has a strong inhibitory action on osteoclast differentiation and bone-resorption activity. The aim of this analysis was to investigate the effects of cabozantinib on bone turnover markers in patients (pts) with metastatic renal cell carcinoma (mRCC). Methods: We included mRCC pts treated with cabozantinib within the Italian Managed Access Program (MAP) at the Istituto Nazionale Tumori of Milan (Italy). Plasma samples from every patient were collected at baseline and after 3 and 6 months of treatment. The bone resorption markers C-terminal telopeptide of type I collagen (CTx) and tartrate-resistant acid phosphatase isoenzyme 5b (TRACP 5b), the osteoclastogenesis markers osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL), vitamin D and parathormone (PTH) were measured by immunometric assay techniques. Data were analyzed using the RM One-Way ANOVA test with Greenhouse-Geisser correction followed by uncorrected Fisher’s LSD multiple comparison tests with individual variances computed for each comparison. Statistical tests were performed using the program GraphPad Prism (San Diego, CA). Results: Twenty-two pts have been treated with cabozantinib. Mature data were available for 11 pts. Analysis of TRACP 5b, OPG, RANKL and vitamin D did not show any significant variations during treatment with cabozantinib. CTx showed a significant reduction after 6 months of treatment (MV 171.5 pg/mL, STD 208.4) from baseline (mean value [MV] 352.2 pg/mL, standard deviation [STD] 210.1) (p = 0.0439) in the whole study population. PTH levels significantly increased after 3 months of treatment (MV 86.79 pg/mL, STD 34.99) from baseline (MV 30.77 pg/mL, STD 12.64) (p = 0.0003), while significantly decreased after 6 months (MV 75.01 pg/mL, STD 53.1) (p = 0.0174). Conclusions: Our data suggested that cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx; it was also associated with an asymptomatic transient secondary increase of parathormone. This is the first clinical evidence on effects of cabozantinib on bone metabolism in a small population of mRCC pts.
Evaluation of prostate cancer risk in men with PSA < 1.5.
Authors: Stanton Whitney N. , Crawford E. David , Arangua Paul , Hoenemeyer John , La Rosa Francisco G. , van Bokhoven Adrie , Lucia M. Scott , Poage Wendy , Werahera Priya N. 
Published: February 2018

64 Background: Prostate Specific Antigen (PSA) screening remains controversial primarily because of over detection and treatment. There is an unmet clinical need to identify patients at increased risk for high-grade (HG – Gleason Score ≥7) prostate cancer (PCa) since PSA has low sensitivity. Combining PSA with well-validated prostate cancer biomarkers (PCM) can improve risk assessment. We investigated the performance of three PCMs (phi – prostate health index, 4KScore, and SelectMDx) on patients with PSA levels < 1.5 ng/mL that represent a “safe zone” where risk of any PCa is rare Methods: 652 men were screened for PCa during the annual Prostate Cancer Awareness Week at the University of Colorado Hospital. This study was supported by Prostate Condition Education Council and the Schramm Foundation. phi is evaluated using p2PSA, total PSA, and free PSA in serum. Phi < 52.7 suggests absence of HG PCa. 4KScore incorporates four kallikrein protein biomarkers: total PSA, free PSA, intact PSA, human kallikrein protein, and clinical information. A 4KScore < 20% suggests absence of HG PCa. The SelectMDx post-DRE urine test measures mRNA levels of the homeobox C6 and distal-less homeobox 1 biomarkers. SelectMDx score of 0% indicates absence of HG PCa. Results: No patients with a PSA < 1.5 had SelectMDx > 0% and/or phi > 52.7. One patient had a 4KScore of 27%, indicating a risk for HG PCa. For patients with PSA between 1.5-3.99, 2.9% (4/135), 7.4% (4/54), and 2.3% (2/85) had positive phi, 4KScore, and SelectMDx results, respectively. Conclusions: Men with PSA <1.5 ng/mL are at very low risk for HG PCa. Men with PSA between 1.5-3.99 with positive PCM results may be referred for further evaluation. [Table: see text]
Treatment trends of localized renal cell carcinoma by hospital type: A NCDB analysis.
Authors: Cahn David B. , Handorf Elizabeth , Edwards Daniel C. , Kidd Laura , Geynisman Daniel M. , Kadow Brian T. , Greenberg Richard E. , Viterbo Rosalia , Chen David , Kutikov Alexander , Uzzo Robert , Smaldone Marc C. 
Published: February 2018

641 Background: Weighing operative, oncologic and comorbid risks guide treatment recommendations for localized kidney cancers. We hypothesize that individualized surgical decision making may also be influenced by surgical center and volume. Methods: The National Cancer Database (NCDB) was queried for patients 18-80 years old with pT1a-T2bN0M0 RCC, treated by partial (PN) or radical nephrectomy (RN), or ablation (ABL) from 2004-2014. After adjusting for clinicopathologic characteristics, we evaluated the association of hospital volume (vol) and center classification with receipt of PN. High vol was defined as the top 10% in treatment volume. Results: 142,090 patients met inclusion criteria, where 58% (n = 82,498) and 41% (n = 58,873) were treated by RN and PN, respectively, and 1% (n = 719) by ABL. The utilization of PN increased over time (2004: 24% vs 2014: 53%; p < 0.001). Stratified by tumor stage, 60% (n = 47,484) of pT1a and 24% (n = 9,906) of pT1b tumors were treated by PN. On multivariate analysis, patients treated at a high-vol center (OR 1.89, 95% CI 1.57-2.28) had a greater likelihood of receiving a PN when compared to treatment elsewhere. Additionally, compared to a community cancer program, treatment at a comprehensive community cancer center (OR 1.39, 95%CI 1.23-1.57), academic/research (OR 1.67, 95%CI 1.47-1.90), or integrated network cancer program (OR 1.48, 95%CI 1.24-1.77) had a higher likelihood of receiving a PN. The median distance travelled was 9.8 and 18.1 miles, for treatment at non high vol and high vol centers, respectively. An inverse correlation was noted between increasing tumor stage and receipt of PN, compared to pT1a tumors (pT1b [OR 0.22, 95%CI 0.20-0.23], pT2a [OR 0.06, 95%CI 0.05-0.06], pT2b [OR 0.03, 95%CI 0.02-0.03]). Conclusions: In the NCDB, despite increased utilization of PN at higher vol centers, the majority of localized renal tumors are still treated with RN. Smaller tumor size, treatment at a higher vol centers, comprehensive community cancer centers, academic/research programs, or integrated network cancer programs increase the likelihood of receipt of PN. Evaluation of population based trends aid in understanding localized RCC surgical management and may help quality improvement efforts.
Association of dividing pathologically upstaged T3a renal cell carcinoma with improved alignment of outcomes: A call for TMN revision.
Authors: Hamilton Zachary , Capitanio Umberto , Pruthi Deepak K. , Bindayi Ahmet , Larcher Alessandro , Ryan Stephen , Reddy Madhumitha , Yim Kendrick , Bloch Aaron , Field Charles , Berquist Sean , Ballon-Landa Eric , Liss Michael , McGregor Thomas B , Montorsi Francesco , Derweesh Ithaar 
Published: February 2018

642 Background: Incidental pathological upstaging to pT3a disease can occur after surgical treatment of clinical T1 and T2 Renal Cell Carcinoma (RCC), and upstaged pT3a disease is associated with worsened outcomes. Oncologic and survival outcomes within the pT3a category are heterogeneous. We investigated recurrence and survival outcomes in pT3a disease, and aimed to better categorize this cohort for improvement on current TMN staging. Methods: Multi-center retrospective analysis of patients with renal cell carcinoma (cT1-3aN0M0) from 1987-2016. After initial comparison of outcomes between pT1, pT2 and pT3a, patients were substratified within the pT3a category based on presenting clinical stage. Comparison was drawn between pT1, pT2 and the subdivided pT3a group (cT1 → pT3a, cT2 → pT3a, and cT3a → pT3a). Primary outcome was recurrence free survival (RFS). Secondary outcome was overall survival (OS). Kaplan−Meier (KM) analysis was utilized. Results: 2640 patients were analyzed (2125 cT1, 448 cT2, 67 cT3a, mean follow up 67.8 months). Rate of incidental T3a upstaging from cT1-2 was 14.7%. Compared to pT1-2 disease, patients with incidental pT3a upstaging had higher rate of recurrence (7.5% vs. 29.6%, p < 0.001) and all-cause mortality at last follow up (15.9% vs. 25.4%, p < 0.001). With regards to RFS, when pT3a was subdivided based on presenting clinical stage, significant differences in RFS emerged which aligned differently. Compared to 5 year RFS of pT1 (94.4%), cT1 → pT3a aligned with pT2 (76.6% and 81.2%, p = 0.346) while cT2 → pT3a aligned with cT3a → pT3a 47.4% and 44.0%, p = 0.815). With regards to OS, a similar alignment was noted for 5 year OS after subdivision, where pT1 was 89.9%, while cT1 → pT3a correlated with pT2 (79.8% and 83.1%, p = 0.640) and cT2 → pT3a correlated with cT3a → pT3a 67.0% and 64.2%; p = 0.893). Conclusions: Patients with cT1 → pT3a have outcomes more similar to pT2, than patients with cT2 → pT3a which align more closely to cT3a → pT3a. Future refinements of the TNM staging system for RCC should consider re-grouping cT1 → pT3a into the pT2 group. Further confirmation is requisite.
Cabozantinib (C) exposure-response (ER) modeling of efficacy and safety endpoints as a function of clearance in patients (pts) with renal cell carcinoma (RCC).
Authors: Jonasch Eric , Motzer Robert J. , Escudier Bernard , Powles Thomas , Markby David W , Nielsen Jace , Lacy Steven , Choueiri Toni K. 
Published: February 2018

645 Background: C is approved for the treatment of advanced RCC after prior antiangiogenic therapy at 60 mg qd with dose reductions to 40 mg and 20 mg used to manage adverse events (AEs). In this study, ER analyses were used to evaluate the effect of C dose on progression-free survival (PFS) and safety endpoints at different apparent clearance (CL/F) values for pts in the phase 3 METEOR study (NCT01865747). Methods: Predicted steady-state C exposures were calculated for doses of 60, 40, and 20 mg in pts with CL/F values of 1.3, 2.23, and 3.3 L/hr; these values were based on population PK models and represent pts with low, average, and high CL/F, respectively. Time-to-event Cox proportional hazard ER models were used to characterize the relationship between predicted C exposure and the probability of PFS and 4 common C AEs: fatigue/asthenia (grade ≥3), palmar-plantar erythrodysesthesia (PPE; grade ≥1), diarrhea (grade ≥3), and hypertension (systolic BP > 160 mmHg or diastolic BP > 100 mmHg). Results: Among the 282 pts evaluated, predicted C CL/F values ranged from 0.51 to 7.24 L/hr. Predicted C exposure at the 60 mg dose ranged from 758 to 1923 ng/mL for representative pts with high and low CL/F (3.3 and 1.3 L/hr). A 60 mg dose for a high CL/F pt is predicted to yield C exposure similar to that of an average CL/F pt dosed at 40 mg (758 vs 748 ng/mL). At the 3 CL/F values evaluated, the hazard ratio (HR) for PFS modestly favored the 60 mg vs 40 mg dose, with the greatest impact on high CL/F pts (HR 1.13, 95% CI 1.10-1.16). 4 common C AEs are predicted to occur at lower rates at the 40 mg vs 60 mg dose; HRs ranged from 0.51-0.82 with the greatest effect in pts with low CL/F. Conclusions: Predicted C CL/F values and C exposures varied among pts with RCC in the METEOR study. ER models suggest that pts with high CL/F may have less favorable PFS outcomes at a starting dose of 40 mg vs the recommended 60 mg dose. Patients with low CL/F are predicted to have decreased rates of AEs at lower doses. Clinical trial information: NCT01865747. [Table: see text]
The importance of the need for better systemic therapy in the definitive treatment of high-risk prostate cancer regardless of whether the initial treatment modality was external beam radiation, I-125 brachytherapy, or radical prostatectomy.
Authors: Ciezki Jay P. , Reddy Chandana A. , Mian Omar Y. , Garcia Jorge A. , Klein Eric A. , Ulchaker James , Angermeier Kenneth , Campbell Steven C. , Stephenson Andrew J. 
Published: February 2018

65 Background: While androgen deprivation therapy (ADT) is a common form of systemic therapy for treating high-risk prostate cancer (HRCaP), distant metastases development remains the predominate form of failure. We present a description of the sites of failure after treatment of HRCaP with External Beam Radiation (EBRT), I-125 Brachytherapy (PB), or Radical Prostatectomy (RP). This is accompanied by an analysis of prostate cancer-specific mortality (PCSM) after clinical failure. Methods: The study includes 2186 patients with HRCaP according to NCCN guidelines (684 EBRT, 409 PB, and 1093 RP). The association of PCSM with clinical and pathologic variables was assessed with Fine and Gray regression with non-PCSM mortality treated as a competing event. Results: The median f/u is 52 months. Overall, there were 323 clinical failures (sites of first failures: 287 distant (DM), 34 local (LF), 2 DM + LF). The median time to the diagnosis of DM was 44 months. ADT was used in 93% of EBRT, 53% of PB and 19% of RP patients. Further details regarding the development of DM is shown in Table 1. The type of initial treatment was not associated with PCSM after DM (Table 1). The only factor significantly associated with PCSM was Gleason Score (p = 0.0372). Conclusions: DM is the primary mode of failure after definitive treatment of HRCaP. The type of initial definitive treatment did not affect PCSM after DM. The cure rates of all forms of definitive treatment of HRCaP would benefit from better systemic therapy. [Table: see text]
A phase I, open-label, dose-escalation and cohort expansion study evaluating the safety and immune response to autologous dendritic cells transduced with AdGMCA9 in patients with metastatic renal cell carcinoma.
Authors: Faiena Izak , Zomorodian Nazy , Comin-Anduix Begonya , Sachadeva Ankush , Bot Adrian , Kabinnivar Fariouz , Said Jonathan W. , Cheung-Lau Gardenia , Pang Jia , Macabali Mignonette , Cabrera Paula , Kaplan-Lefko Paula , Berent-Maoz Beata , Liu Sandy , Pantuck Allan J. , Belldegrun Arie S. , Chamie Karim , Drakaki Alexandra 
Published: February 2018

653 Background: We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with metastatic RCC (mRCC) in this phase 1 study targeting CAIX overexpressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) manufactured per GMP in collaboration with the NCI Rapid Access to Intervention Development (RAID) program. The final product was produced using DCs produced ex-vivo from patients’ peripheral blood mononuclear cells (PBMC), by culturing with GM-CSF & IL-4, then engineered with AdGMCAIX prior to intradermal injection. The injected transduced DCs were expected to stimulate an antigen specific immune response against CAIX expressing RCC. Three dose escalation cohorts (5, 15, and 50 X 106 cells/administration) were injected based on 3+3 design. DC-AdGMCAIX was given intradermally q2wkX3 doses. The primary aim is safety. Secondary aims are to evaluate immune responses & antitumor effects per RECIST 1.1. Eligibility criteria included patients with clear cell mRCC with ECOG 0-1, measurable disease, and adequate organ function. Results: Fifteen patients with clear cell mRCC were enrolled. Nine patients received all 3 planned vaccine doses, comprising DC expressing CAIX, CD11c and other relevant markers. No serious adverse events (SAEs) were seen. Grade 1/2 AEs include fatigue (3/1), leukopenia (1/1) and flu-like symptoms (0/1). Of the 9 patients who received treatment, 1 expired of progressive disease (PD), 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have PD and are currently receiving standard-of-care therapies, and 1 has completed treatment with stable disease at 6 mon follow up and is being evaluated for retreatment. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any SAEs noted at the doses tested. These data support further development of Ad-GMCAIX vaccine strategies, either alone, or in combination with approved therapies. Clinical trial information: NCT01826877.