bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase Ib clinical trial of the multitargeted kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC).
Authors: Molina Ana M. , Hutson Thomas E. , Larkin James M. G. , Gold Anne , Andresen Corina , Wood Karen , Motzer Robert John , Michaelson M. Dror
Published: February 2017

358

Background: Lenvatinib (L) is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR 1-4, RET, KIT, and PDGFβ. Everolimus (E) is an oral mTOR inhibitor approved for RCC. This Phase (Ph) 1b/2 study investigates the combination of L plus E in RCC patients (pts) (NCT01136733). The Ph 1b component reported here assessed safety, tolerability, and maximum tolerated dose (MTD). Methods: Pts with advanced unresectable or metastatic RCC, ECOG PS 0-1, age ≥18 y, were eligible for Ph 1b. Pts received L plus E, daily, in 28-day cycles. A standard 3+3 dose-escalation design with expansion cohort was used to identify the MTD. Results: 20 pts (M/F: 14/6; median age: 59 y [range 46-72]; median of 2 prior therapeutic regimens [range 0-5]; 17/20 pts [85%] had received prior anti-VEGF treatment (tx); 7/20 pts [35%] had also received prior mTOR-targeted tx) were treated at 3 dose levels of L (12 mg [n=7]; 18 mg [n=11]; 24 mg [n=2]) in combination with E 5 mg. DLTs were observed in 4 pts: G3 nausea and vomiting (1 pt) and G2 mucositis (1 pt) with 24 mg; G3 elevated creatinine phosphokinase, G2 fatigue, and G1 reflux with 18 mg; G3 abdominal pain with 12 mg. The MTD was L 18 mg plus E 5 mg. Median duration of tx was 19 wk (range 1-68, 6/20 (30%) pts ongoing). The most common tx-related adverse events (AEs), all grades, were fatigue 50% (G3, 5%); diarrhea 40% (G3, 10%); mucosal inflammation 40%; proteinuria 40% (G3, 10%); decreased appetite 35%; nausea, vomiting each 35% (each G3 5%); hypertension 35%; rash 30%; dry skin, epistaxis, weight decreased, constipation, edema peripheral (G3 5%), each 20%. There was 1 G4 tx-related AE of hypercholesterolemia. In the MTD and lower-dose cohorts, partial response (PR) was observed in 6/18 (33%) pts; durable stable disease (SD) (≥23 wk) or PR were achieved in 11/18 (61%) pts. Median PFS was 442 days (approx. 15 mos) in MTD and lower-dose cohorts. Conclusions: Lenvatinib 18 mg in combination with everolimus 5 mg appeared to be well tolerated when administered to multiply pretreated patients with advanced RCC in this Ph1b study. The PRs observed and SD durability warrant further evaluation in this refractory population during the ongoing Ph 2 part of the study. Clinical trial information: NCT01136733.
Association of adverse health outcomes with partial and radical nephrectomy: Is it time to reassess the “gold standard” for the small renal mass?
Authors: Shuch Brian , Hanley Janet , Lai Julie , Setodji Claude Messan , Vourganti Srinivas , Chow Wong Ho , Saigal Christopher
Published: February 2017

363

Background: Partial (PN) and radical (RN) nephrectomy are treatments for the small renal mass. PN is considered the gold standard, as it may protect against renal dysfunction compared to RN. As active surveillance is emerging as a possible strategy, it is essential to understand the adverse health outcomes associated with both interventions. Methods: A retrospective, case-controlled series was performed using the Surveillance, Epidemiology, and End Results-Medicare dataset. Individuals treated with PN or RN for ≤4 cm non-metastatic, renal cell carcinoma (RCC) were compared to two control groups (non-muscle invasive bladder cancer [BCC] and non-cancer patients [NCC]). A Greedy Algorithm matched surgical groups (1:1) to controls by demographics and comorbidity. Medical claims >30 days after treatment were examined for renal, cardiovascular, and secondary cancer events. Results: Patients undergoing PN (1,436) and RN (4,247) were matched to controls and no significant differences were noted in key variables. All cancer groups had 10-year cancer-specific survival >95%. The time to event model demonstrated an increased risk of renal events for both treatments. Compared to BCC and NCC, RN hazard ratios were 2.415 (p < 0.0001) and 6.211 (p < 0.0001), respectively, while PN hazard ratios were 1.513 (p < 0.0001) and 4.926 (p < 0.0001), respectively. Secondary cancers were increased for both PN and RN compared to both control groups (p < 0.0001). Cardiovascular events were increased for both PN and RN compared to NCC (p < 0.0001), but this failed to reach significance when either group was compared to BCC controls. Conclusions: RCC patients treated with PN and RN are at significant risk of subsequent adverse health outcomes. When compared to RN, PN may have better renal outcome; however, when compared to controls, both options significantly increase renal events. The increase in secondary cancers and cardiovascular events with PN and RN is concerning and requires further investigation. As active surveillance is an emerging strategy, it may be time to rethink our current treatment paradigm for the small renal mass.
SGN-75 in the treatment of patients with CD70-positive malignancies including metastatic renal cell carcinoma.
Authors: Thompson John A. , Forero Andres , Heath Elisabeth I. , Pal Sumanta Kumar , Ansell Stephen Maxted , Infante Jeffrey R. , De Vos Sven , Hamlin Paul A. , Whiting Nancy Cherry , Zhao Baiteng , Tannir Nizar M.
Published: February 2017

368

Background: SGN-75 is an antibody-drug conjugate composed of a humanized anti-CD70 mAb conjugated to the microtubule-disrupting agent MMAF via a plasma-stable linker. Upon binding to CD70, SGN-75 internalizes and releases cys‑mcMMAF which binds tubulin and induces G2/M arrest and apoptosis. Methods: A phase 1, dose-escalation, multicenter study was initiated to investigate the safety, tolerability, PK, and antitumor activity of SGN-75 monotherapy in pts with CD70-positive metastatic RCC or relapsed/refractory NHL (ClinicalTrials.gov #NCT01015911). SGN-75 was administered IV in cohort-specific doses using 2 schedules [every 3 weeks (q3wk) or weekly (days 1, 8, 15 q28 days)] at doses of 0.3-4.5 mg/kg. Pts were eligible to receive treatment until PD. Results: A total of 58 pts (39 RCC/19 NHL) with a median age of 60.5 yrs (range 30-82) were treated. The MTD was 3 mg/kg q3wk; 2 pts had DLTs at 4.5 mg/kg q3wk (NHL pt had neutropenia and RCC pt had proteinuria). Weekly dosing (N=11) was terminated at the 0.6 mg/kg dose level after 2 pts with NHL developed idiopathic thrombocytopenic purpura. At the MTD, adverse events (AEs) in ≥30% of RCC pts (N=21) were fatigue (52%), dry eye (48%), nausea (38%), constipation (33%), and corneal epithelium defect (33%). AEs ≥ Grade 3 in >10% of RCC pts treated at the MTD were corneal epithelium defect (19%) and thrombocytopenia (14%). PK analysis suggested that SGN-75 exposure was approximately dose-proportional with a mean terminal half-life of 6-11 days. Among the 32 pts with RCC treated in the q3wk schedule, all had prior nephrectomy and a median of 3 prior therapies (range 1-6). All pts had clear cell RCC, with the exception of 2 pts who had papillary RCC. Most pts had high CD70 expression by central IHC analysis (2 or 3+, 80-100% of cells). The best clinical responses of RCC pts treated q3wk were 2 PR, 12 SD, 12 PD, and 6 were not evaluable. Durations of response for the 2 responding pts were 23 and 41 weeks. The median duration of disease control (PR and SD) was 46.4 weeks [95% CI (12, 46)]. Conclusions: SGN-75 monotherapy was generally well tolerated in pts with metastatic RCC. Evidence of antitumor activity was observed in heavily pretreated RCC pts and further studies of SGN-75 in RCC are warranted. Clinical trial information: NCT01015911.
Prognostic significance of indeterminate lung nodules in renal cell carcinoma.
Authors: Xu Rena , Horick Nora , McGovern Francis J. , Dahl Douglas M. , Feldman Adam S. , Blute Michael L. , Olumi Aria F. , Michaelson M. Dror
Published: February 2017

377

Background: Many patients with newly diagnosed renal cell carcinoma (RCC) are found to have indeterminate lung nodules at the time of diagnosis. Current guidelines are vague about the necessity and frequency of additional chest imaging. We sought to determine whether the presence of indeterminate lung nodules at the time of diagnosis affects long-term survival for patients with early stage RCC. Methods: A retrospective review was performed of all patients at our institution who underwent nephrectomy for stage I-III RCC between 2001 and 2006 and had baseline chest imaging available for review. Presence of indeterminate lung nodule(s) on preoperative chest imaging was determined, along with tumor stage, grade, and histology; patient age, gender, body mass index, and smoking status; and Charlson comorbidity score. The time from diagnosis to last documented follow-up, and to first detected metastasis and/or death if applicable, was determined. Univariate and multivariate analyses were performed. The primary outcome of interest was disease-free survival; the secondary outcome was overall survival. The study follow-up period extended to July 2012. Results: In a multivariate analysis of 240 patients, disease-free survival was significantly associated with the presence of indeterminate lung nodules (HR 1.900, 95% CI: [1.042, 3.463]; p = 0.036). The number and size of the nodules did not add statistical significance. Disease-free survival was also associated with tumor stage (stage II: HR 5.611, p < 0.001; stage III: HR 2.488, p = 0.0129) and grade (HR 2.433 for grade 3 or 4, p = 0.005). Overall survival was only associated with Charlson comorbidity score (HR 1.294, p < 0.0001) and primary tumor size (HR 1.287, p < 0.0001). Conclusions: The presence of indeterminate lung nodules at the time of diagnosis of RCC had a negative impact on disease-specific survival. Tumor stage and grade were also significant prognostic factors. These findings underscore the importance of baseline chest imaging as well as vigilant surveillance of patients in whom lung nodules are identified.
Contrasting the vascular response to sunitinib as measured by DCE-CT, DCE-MRI, and DCE-US.
Authors: Hudson John M. , Williams Ross , Bailey Colleen , Kiss Alex , Milot Laurent M. , Atri Mostafa , Stanisz Greg J. , Burns Peter N. , Bjarnason Georg A.
Published: February 2017

378

Background: Medical imaging (DCE-MRI, DCE-CT, DCE-US) provides localized information about the integrity and hemodynamics of the tumor microvasculature. Methods: 34 treatment (Rx) naive pts with mRCC and an abdominal tumor suitable for imaging received Sunitinib 50 mg on a 4wk-on/2wk-off schedule. DCE-US, DCE-CT, and DCE-MRI were done at baseline, during the first course of Rx and after 2wks off Rx. Imaging parameters obtained included vessel permeability (Ktrans), extracellular volume fraction (ve) and Ktrans/ve=Kep (by DCE-MRI), permeability surface product (PS, by DCE-CT), blood volume (BV, by DCE-CT and DCE-US), and blood flow (by DCE-US). We also developed a morphology parameter (MP) that relates the flow kinetics of an intravascular microbubble contrast agent to tumor vascular morphology using DCE-US. Results: A range of imaging parameters that predicted for progression free survival (PFS) were identified in responding pts (N = 26). Baseline imaging parameters correlated with PFS: Ktrans by DCE-MR (r = 0.53, p = 0.01, N = 24), BV by DCE-CT (r = 0.48, p = 0.02, N = 25) and disorganized vessel morphology (large MP) by DCE-US (Spearman r = 0.-0.45, p = 0.02, N = 24). Changes from baseline imaging parameters correlated with PFS: BV by DCE-US at 2 wks (r = -0.46, p = 0.02, N = 24), Kep by DCE-MR at 2 wks (r = -0.45, p = 0.03, N = 24) and MP at 1wk (r = 0.67, p = 0.02, N = 12). There was a correlation between imaging methods: BV measured by DCE-CT correlated with BV by DCE-US (r = 0.46, p = 0.03, N = 23) and Kep by DCE-MR (r = 0.59, p = 0.003, N = 22); Permeability measured by DCE-MR (Ktrans) and DCE-CT (PS) correlated at 2wks (r = 0.56, p = 0.01, N = 21). Conclusions: This is the first study to contrast DCE-US, DCE-CT, and DCE-MRI imaging in pts receiving antiangiogenic therapy. Baseline parameters for all three methods can predict for PFS. Changes from baseline in DCE-US and DCE-MRI parameters also predict for PFS. There is a correlation between imaging methods in parameters that measure BV and permeability. A novel DCE-US parameter was developed (MP) that quantifies the degree of tumor vascular disorganization. Baseline values in MP and changes during Rx correlate with PFS. Clinical trial information: OCT1205, SU Timing RCC.
Effect of VEGF and VEGFR polymorphisms on clinical outcome and response in patients with advanced renal cell carcinoma receiving first-line treatment.
Authors: Bianconi Maristella , Scartozzi Mario , Faloppi Luca , Loretelli Cristian , Zizzi Antonio , Giampieri Riccardo , Bittoni Alessandro , Del Prete Michela , Burattini Luciano , Montironi Rodolfo , Cascinu Stefano
Published: February 2017

388

Background: For the last few years, sunitinib has been considered the standard treatment for first-line metastatic renal cell carcinoma, but in 2010 a new drug pazopanib had been approved for treatment in this setting. Recent data from the COMPARZ and PISCES study seem to suggest a non-inferiority of pazopanib confronted with sunitinib in PFS and OS and a patients’ preference for pazopanib if we consider quality of life parameters. The aim of our study is to investigate whether polymorphisms of VEGF and VEGFR can influence PFS and OS when patients are treated either with sunitinib or pazopanib as first-line treatment. Methods: 97 histologic samples of mRCC patients were tested for VEGF-A, VEGF-C, and VEGFR-1, 2, 3 single nucleotide polymorphisms (SNPs). Patients’ progression free survival (PFS) and overall survival (OS) were analyzed for first-line treatment. Results: In patients treated with sunitinib VEGF-A rs833061 resulted significant in PFS (CC+CT vs TT, p < 0.0001) and OS (p < 0.0001). VEGF-A rs699947 was significant for PFS (AA+AC vs. CC) p = 0.0001) and OS (p < 0.0001). VEGF-A rs2010963 was significant in PFS (CC vs. CG vs. GG, p = 0.0001) and in OS (p = 0.0045). VEGR3 rs6877011 was significant in PFS (CC vs. CG, p = 0.0075) and OS (p = 0.0001). At multivariate analysis rs833061, rs2010963, and rs68877011 were significant in PFS. rs833061 and rs68877011 were independent factors in OS. In the pazopanib treated groups of patients VEGF-A rs833061 resulted significant in PFS (TT+CT vs. CC p = 0.027) Conclusions: In our analysis patients with CC or CT polymorphism of rc833061 had a favourable PFS and OS if treated with sunitinib instead patients treated with pazopanib seems to have benefit if CT+TT polymorphism, A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line with sunitinib. Patients with C polymorphism of rs6877011 and G polymorphism of rs307822 seem equally to have a favourable impact in first-line therapy with sunitinib. Our data seem to suggest that biology could have a role in the choice of first-line treatment for mRCC patients. Further data will be presented at the Symposium.
Association of a 2-weeks-on and 1-week-off schedule of sunitinib with decreased toxicity in metastatic renal cell carcinoma.
Authors: Najjar Yana George , Elson Paul , Wood Laura S. , Garcia Jorge A. , Dreicer Robert , Rini Brian I.
Published: February 2017

406

Background: Treatment of metastatic renal cell carcinoma (mRCC) with sunitinib can be associated with toxicity leading to dose reduction. Maintaining adequate sunitinib dosing and avoiding dose interruptions that lower drug levels are essential for optimizing clinical efficacy. Standard sunitinib schedule is 4 weeks of treatment and 2 weeks of rest (schedule 4/2). Empirically in clinical practice, several metastatic RCC patients at The Cleveland Clinic (CCF) have been changed from a 4/2 schedule to a 2 weeks on /1 week off (2/1) schedule after experiencing toxicity in an attempt to maintain daily dose but reduce toxicity. Methods: The medical records of mRCC patients who were changed to a 2/1 schedule of sunitinib at CCF were retrospectively reviewed. Patient toxicity on each schedule was recorded during routine clinic visits and graded according to the Common Toxicity Criteria, version 4.0. Results: 21 patients were identified: 71% male, 78% clear cell histology, and 29% prior systemic therapy. All but one had prior nephrectomy. 95% of patients on the 4/2 schedule had grade 3 or 4 toxicity which led to the schedule change to 2/1. No grade 4 toxicities were observed on the 2/1 schedule, and 33% of patients experienced grade 3 toxicity (p = 0.0001 for comparison of worst grade toxicity on 4/2 versus 2/1). Two of the most common toxicities, fatigue and hand-foot syndrome (HFS), were significantly less frequent on the 2/1 schedule than on the 4/2 schedule (fatigue 52% all grade/33% grade 3 on 4/2 versus 33%/14% on 2/1; HFS 33%/29% on 4/2 versus 14%/0% on 2/1; p =.04 for both). Median overall treatment duration on the 4/2 schedule was 13.5 months (range 1.1-60.6 months) and median overall treatment duration on the 2/1 schedule was 24.4 months (range 1.3 to 67.6+ months). Conclusions: Treatment with sunitinib on a 2/1 schedule is associated with significantly decreased toxicity in patients who initially experience grade 3 or greater toxicity on the 4/2 schedule and can extend treatment duration considerably. Prospective clinical trials are required to define the optimal schedule of sunitinib to balance efficacy and toxicity.
Relative quantification of protein expression in metastatic renal cell carcinoma using iTRAQ LC-MS/MS analysis reveals galectin-1 as a potential prognostic marker and therapeutic target.
Authors: White Nicole M.A. , Masui Olena , DeSouza Leroi , Krakovska Olga , Matta Ajay , Bjarnason Georg A. , Siu K.W. Michael , Yousef George M.
Published: February 2017

412

Background: Metastatic renal cell carcinoma (RCC) is one of the most treatment-resistant cancers. Identification of proteins involved in tumor progression will help gain a better understanding of the disease and will form the basis for the identification of novel therapeutic targets. Methods: Using six fresh-frozen primary and six unmatched metastatic RCC tumors, we used iTRAQ labeling and LC-MS/MS analysis to identify proteins differentially expressed in metastatic versus primary RCC. We verified protein expression by western blot and immunohistochemical analyses and the measured the effect of dysregulated protein expression on biological processes with RCC cell line models. Results: After analysis, we identified 29 proteins differentially expressed in metastatic versus primary RCC. We verified expressions of profilin-1, 14-3-3 zeta/delta, and galectin-1 (Gal-1) on two independent tissue sets by western blot (10 primary and 10 metastatic RCC tissues) and immunohistochemistry (22 primary and 23 metastatic tissues). Overexpression of Gal-1 in CAKI-1 cells lead to decreased actin, increased vimentin expression, and increased cellular migration. Additionally, when Gal-1 was decreased via siRNA, cells showed decreased cellular migration. Protein array analysis showed expression of cell motility-related proteins HSP27, JNK, and RSK, were altered after siRNA transfection. We also showed that Gal-1 expression was increased in response to HIF-1alpha. Furthermore, we analyzed the expression of Gal-1 mRNA in 404 RCC patients using the Cancer Genome Anatomy Project, and found that patients who had higher Gal-1 expression in the primary RCC had significantly decreased overall survival (41 vs. 78 months; p < 0.01). Conclusions: Gal-1 is increased in metastatic RCC and can effect cell migration by targeting proteins involved in cell motility. This may be a downstream effect of HIF-1α dysregulation. Decreased Gal-1 significantly decreased cellular migration suggesting Gal-1 may serve as a potential therapeutic target. Additionally, we showed that increased Gal-1 expression was associated with decreased overall survival.
Prognostic impact of baseline serum C-reactive protein in metastatic renal cell carcinoma treated with sunitinib.
Authors: Yann-Alexandre Vano , Beuselinck Benoit , Wolter Pascal , Teghom Corine , Philip Debruyne , Karadimou Alexandra , Lerut Evelyne , Robert Paridaens , Schöffski Patrick , Oudard Stephane
Published: February 2017

425

Background: The aim of our study was to determine whether baseline serum C-reactive protein (CRP) level could predict outcome of patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib in first-line setting. Methods: We reviewed the charts of 187 consecutive patients in three hospitals in Belgium and France who started sunitinib as first targeted treatment between 2005 and 2012. Data were collected from each individual patient file on known prognostic factors for mRCC and anatomical location of metastatic sites, response rate, progression free survival (PFS), and overall survival (OS). Results: 187 eligible patients were identified by retrospective chart review. Median PFS was 26 months in the group with baseline CRP within normal limits (≤5 mg/l) versus 8 months in the group with elevated baseline CRP (>5 mg/l) (p < 0.0001). Median OS was 50 versus 12 months respectively (p < 0.0001). In the group with normal baseline CRP, 69% of patients experienced a partial response (PR) compared to 31% of patients in the group with elevated baseline CRP (p < 0.0001). On multivariate analysis, taking into account baseline neutrophil count, platelet count, ECOG PS, serum lactate dehydrogenase (LDH) activity, hemoglobin levels, corrected serum calcium levels, interval between initial diagnosis of RCC and start of systemic therapy </≥12 months, presence/absence of liver metastases or bone metastases and prior nephrectomy, baseline serum CRP-level was found to be an independent variable associated with poor PFS (p = 0.01) and OS (p < 0.0001). Conclusions: Baseline serum CRP level is an independent parameter correlated with ORR, PFS and OS in mRCC patients treated with sunitinib in first-line. [Table: see text]
Prostate-specific mRNA detection in whole blood as an analytically validated prognostic biomarker for patients with castration-resistant prostate cancer (CRPC).
Authors: Danila Daniel Costin , Anand Aseem , Heller Glenn , Wan Mingliang , Herkal Amrita , Patel Chintan , Khanin Raya , Schultz Nikolaus , Lilja Hans , Fleisher Martin , Scher Howard I.
Published: February 2017

45

Background: To estimate the association between molecular biomarkers and outcomes, robust assays are needed before qualification in prospective trials. Although tumor specific transcripts detected in blood by PCR have been associated with outcome, an analytically validated PCR platform enabling detection of CTC-associated transcripts in clinical settings remains to be identified. Here we explore detecting a panel of prostate specific transcripts in conjunction with conventional markers in CRPC. Methods: Blood was collected from 97 patients with progressive CRPC in PAXgene tubes (2.5 ml) for total RNA extraction. Five genes expressed in prostate but not in nucleated blood cells were analyzed by primer-specific RT-PCR. Fluidigm Dynamic Array platform was analytically validated for KLK3, KLK2, HOXB13, GHRL2 and FOXA1 assays. Each PCR-reaction was run in 6 replicates, detection thresholds for each gene were chosen by ROC analysis of an independent set of 56 CRPC patients versus 51 healthy volunteers, and results were reported as transcripts present or absent. CellSearch reported CTC number/7.5 ml of blood drawn into CellSave tube. Results: Prostate specific transcripts for KLK3, KLK2, HOXB13, GHRL2 and FOXA1were detected in 50 (52%), 39 (40%), 53 (55%), 28 (29%) and 47 (48%) of patients, respectively.Two or more genes were detected in 53/97 patients (55%, 95% CI 45-65%) of patients with progressive CRPC studied with a median survival time of 17 months (95% CI: 13.8, 23.5). 40/45 CRPC-patients with ≥5 CTC and 13/52 CRPC patients with <5 CTC had transcripts present in blood. CTC and the gene panel had a substantial level of agreement, kappa of 0.631 (95% CI: 0.479, 0.783). Transcript detection predicted overall survival in proportional hazards models that included LDH dichotomized at 250. The predictive accuracy (CPE) of PCR detection + LDH was 0.759 (SE 0.035), comparable to CTC-enumeration + LDH (0.771, SE 0.033). Conclusions: Detecting prostate specific mRNA in whole blood using validated RT-PCR assays, applicable to larger CRPC cohorts, provides prognostic value. The clinical utility in monitoring treatment will be prospectively explored.
Postoperative modified Glasgow prognostic score as an independent predictor of overall survival in clinically localized clear cell renal cell carcinoma.
Authors: Herrel Lindsey Allison , Tai Caroline Gar-Ling , Westby Ruth , Ogan Ken , Canter Daniel , Pattaras John , Nieh Peter , Master Viraj A.
Published: February 2017

456

Background: Renal cell carcinoma (RCC) demonstrates heterogeneous behavior. Approximately 30% to 40% of patients with clinically localized RCC will later metastasize. Current tools are imperfect for predicting who will have distant spread of disease. The utility of the modified Glasgow Prognostic Score (mGPS) calculated from C-reactive protein (CRP) and albumin levels, has been well-studied as a pre-operative predictive tool in patients with various solid organ malignancies, including clear cell renal cell carcinoma. This score has not been used in the post-operative setting, and we hypothesized that mGPS can be a powerful tool to predicting overall survival. Methods: Patients undergoing nephrectomy for clinically localized RCC from 2005 to 2010 were studied. Inclusion criteria required clear cell histology and no nodal or metastatic disease at the time of surgery. Additionally, only patients with post-operative C-reactive protein and albumin recorded were included in the analyses. Demographic and clinico-pathological variables were analyzed as categorical variables with the exception of age and tumor size, which were analyzed as continuous variables. Patients were assigned an mGPS score of 0, 1, or 2 based on post-operative data (0 = CRP ≤ 10 mg/l, 1 = CRP>10 mg/l and 2 = CRP>10 mg/l and albumin<3.5 g/dL). Survival analyses utilized Kaplan-Meier and multivariate Cox regression models. Results: Study criteria were met in 142 patients. Mean age was 59 years and 61% were men. No patients had T4 disease while 25% had T3, 9% had T2, and 66% had T1 disease. A post-operative mGPS of 0, 1, and 2 was assigned to 69%, 13% and 18% of the study population, respectively. Multivariate analysis identified post-operative high mGPS (mGPS = 2) as an independent predictor of overall survival (HR 5.591; CI 95% 1.508, 20.734; p = 0.010). Conclusions: In patients with clinically localized clear cell renal cell carcinoma, post-operative mGPS score is an independent predictor of overall survival. Accordingly, mGPS may be a useful tool to monitor disease progression in this patient population.
Renal cell carcinoma: A prognostic target for spectral pathology.
Authors: Hughes Caryn S. , Brown Mick D. , Gardner Peter , Shanks Johnathan H. , Clarke Noel W. , Jimenez-Hernandez Melody
Published: February 2017

459

Background: In contrast to standard pathology, where stained cells and tissues are examined visually under a microscope, spectral pathology is the study of changes in cellular composition of unstained tissue using molecular fingerprint techniques, such as infrared and Raman spectroscopy. Hyperspectral images are collected which provide not only spatial information but also data of high dimensionality, probing the global biochemistry of the biological specimen in the mid-infrared range. Methods: 9 paraffin-embedded, formalin-fixed clear cell renal carcinoma tissue sections (8μm thick) of different grade, stage and with respective matched pairs, were floated onto infrared-transmitting substrates. After dewaxing, Fourier transform infrared imaging spectroscopy was performed on a Varian 670-IR spectrometer coupled with a Varian 620-IR imaging microscope (Agilent Technologies, CA) equipped with a 128×128 pixel Mercury-Cadmium-Telluride focal planar array detector. A hyperspectral image is obtained whereby each pixel records an infrared spectrum at a pixel resolution of ~5.5x5.5μm. Mosaic images were captured of full tissue specimens (one imaging tile equates to a tissue sampling area of ~700×700μm). Results: We have been able to detect the phenotype of ccRCC and observed a diminishing glycogen-rich signal during tumour progression towards high grade tissue. The spectral characteristics of ccRCC have been correlated with H and E, PAS, and CA-IX staining. Conclusions: Cancer metabolism can be tracked by lipid and glycogen infrared bands that carry a unique spectral signature, depending on tumour aggressiveness. The future focus is to generate a prognostic model for small renal masses.
Effect of novel growth hormone-releasing hormone antagonists on growth of experimental renal cell carcinomas.
Authors: Rick Ferenc , Szalontay Luca , Abi-Chaker Andrew , Block Norman L. , Halmos Gabor , Schally Andrew V.
Published: February 2017

469

Background: Although targeted therapy has improved the clinical outcome for patients with metastatic renal cell carcinoma (RCC), a complete response is rare and therapy has adverse effects. Early antagonists of growth hormone-releasing hormone (GHRH) were shown to inhibit experimental RCC cell line, Caki-1, in vitro and in vivo. Herein, we investigate the effects of novel and highly potent antagonists of GHRH of MIA class on the growth of three RCC cell lines. Methods: The expression of GHRH receptor in all three cell lines was evaluated by ligand competition studies. The influence of GHRH antagonists MIA-602, MIA-604, MIA-606, and MIA-690 on cell viability was assessed by MTS assay in ACHN, A498, and 786-0 human RCC cells. GHRH antagonists were given at dose of 5µg daily in these three nude-mice xenograft models. Cell cycle parameters were analyzed by laser flow cytometry. Results: Ligand competition studies revealed specific, high affinity binding sites for GHRH receptor in all three RCC cell lines. GHRH antagonists inhibited the proliferation of all three RCC cells in a dose dependent manner. GHRH antagonists caused significant inhibition of tumor growth of ACHN, A498, and 786-0 RCCs ranged from 53-75% after 35 days of treatment (p<0.001). Treatment of ACHN cells with MIA-690 (10µM) led to a significant increase in number of cells with subG1DNA content, suggesting apoptosis. Conclusions: The effectiveness of the novel GHRH antagonists in inhibiting growth of experimental RCC models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists is mainly due to direct inhibitory effects exerted through GHRH receptors. Biochemical and histological evaluation is needed to explore the mechanisms of action of GHRH antagonists in RCC.
Prognostic utility of CCP score in men with prostate cancer after primary external beam radiation therapy.
Authors: Freedland Stephen J. , Gerber Leah , Reid Julia E. , Welbourn William , Tikishvili Eliso , Park Jimmy , Younus Adib , Gutin Alexander , Sangale Zaina , Lanchbury Jerry S. , Salama Joseph Kamel , Stone Steven
Published: February 2017

47

Background: Accurate risk stratification improves decision making in localized prostate cancer. The CCP score, a prognostic RNA signature based on the average expression level of 31 cell cycle progression (CCP) genes, was developed to aid in this task. Previously, the CCP score was shown to be predictive of biochemical recurrence (BCR) after prostatectomy, and prostate cancer specific mortality in men undergoing observation. However, the value of CCP score in men undergoing primary electron beam radiation therapy (EBRT) was untested. Methods: The CCP score was derived retrospectively from the diagnostic biopsy of 141 patients treated with EBRT at the Durham VA medical Center. Inclusion criteria were disease diagnosis from 1991 to 2006 and available biopsy tissue. Approximately half of the cohort was African-American. Outcome was time from EBRT to BCR using Phoenix definition, and median follow-up for patients without BCR was 4.8 years. Association with outcome was evaluated by CoxPH survival analysis and likelihood ratio tests. Results: Patient data were censored at 5-years of follow-up and 19 patients (13%) had BCR. The median CCP score was 0.12(IQR -0.43 to 0.66). In univariable analysis, CCP score was a significant prognostic variable (p-value = 0.0017). The hazard ratio (HR) for BCR was 2.55 (95% CI (1.43, 4.55)) for a one-unit increase in CCP score (equivalent to a doubling of gene expression). In a predefined multivariable analysis that included Gleason score, PSA, and percent positive cores, the HR for CCP changed only marginally and remained significant (HR per CCP unit 2.09 (95% CI (1.05, 4.18), p-value = 0.035), indicating that CCP provides prognostic information that is not provided by standard clinical parameters. Further adjustment for hormonal therapy or radiation dose did not materially alter this association. The score was also associated with prostate cancer specific mortality. There was no evidence for interaction between CCP and any clinical variable, including ethnicity. Conclusions: In a cohort of men treated with EBRT, the CCP score was significantly associated with outcome and provided prognostic information beyond what was available from clinical parameters. If validated in a larger cohort, CCP score could be used to select high-risk men undergoing EBRT who may need combination therapy for their clinically localized prostate cancer.
Sarcomatoid renal cell carcinoma (SRCC): University of Nebraska Medical Center experience.
Authors: Tandra Pavankumar , Wang Jue , Loberiza Fausto R. , Hemstreet George P. , Krishnamurthy Jairam , Bhatt Vijaya Raj
Published: February 2017

472

Background: Sarcomatoid differentiation is not a distinct histological entity and it can present in any of the subtypes of renal cell carcinoma (RCC). Although many studies were published in the literature about its aggressive clinical course, limited clinical data was available about its management and especially about the role of newer targeted therapies. At our institution, we looked at the prognostic factors in SRCC and the role of systemic therapy in its management. Methods: During the years of 1997 to 2012, we studied the records of over 400 patients diagnosed with RCC. Out of them, 43 were identified as having SRCC. Cox proportional hazards risk analysis was used to analyze the factors associated with the risk of mortality. Survival probability was estimated using Kaplan Meier method. Results: Median age at diagnosis was 58. Median tumor size was 9.75 cm. High Furhmans grades (III & IV) were seen in 67.44%. 68.29% patients presented with stage IV disease. 74.42 % patients had upfront nephrectomy. Of the systemic therapies given, 20.9% received cytokines, 16.2% received chemotherapy and 34.8% received target therapy. Probability of survival at 1 year was 50% (95% CI 33-65) and at 5 years was 24% (95% CI 10-41). Median time to progression was 13 months (95% CI 7 -23). Factors associated with risk of mortality were mainly the stage at diagnosis [HR 2.174, p = 0.0123, CI (1.184-3.992)], Nephrectomy [HR0.243, p = 0.0012, CI (0.104- 0.571)] and the use of target therapy [HR 0.313, p = 0.0070, CI (0.134-0.728)]. Conclusions: Our study confirmed that the SRCC is more aggressive than conventional RCC in its presentation and in its median time to progression. It responds poorly and unpredictably to systemic therapies. In our study, upfront nephrectomy and target therapy appeared to be independent predictors of survival. SRCC needs to be considered as a different disease entity and new treatment options need to be explored for this unfortunate subset of patients with kidney cancer.
Mortality following hip fractures in men with prostate cancer.
Authors: Van Hemelrijck Mieke , Garmo Hans , Michaelsson Karl , Thorstenson Andreas , Stattin Pär , Akre Olof , Holmberg Lars , Adolfsson Jan
Published: February 2017

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Background: Rapid loss of bone-mineral density is a known side-effect of androgen deprivation therapy (ADT) for prostate cancer (PCa). Hip fractures are also independently associated with risk of mortality. To our knowledge few population-based observational studies have yet investigated the risk of dying following fractures among men with PCa. We aimed to assess skeletal-related events and mortality in more detail by specifically studying the link between hip fractures in PCa men and risk of death. Methods: PCBaSe Sweden 2.0 is based on the National Prostate Cancer Register and contains age and county matched men free of PCa. We selected all men (n=14,205) who had been hospitalized with a hip fracture, as registered in the National Patient Register, between 2006 and 2010. A total of 2300 were diagnosed with PCa before the hip fracture and 66% of them were treated with ADT. The main outcome was death as registered in the National Cause of Death Register. The risk of death was estimated using multivariate Cox Proportional Hazards regression analyses and standardized mortality ratios (SMRs) taking into account PCa risk category, history of fractures, civil status, Charlson Comorbidity Index, and treatment with bisphosphonates. Results: In the analysis for risk of death >90 days after a hip fracture, there was an increased risk of death among PCa men on ADT, especially those aged <84 years (e.g., HR at 3-6 months after hip fracture: 2.47 (95%CI: 1.85-3.30) compared to men free of PCa with a hip fracture). The SMRs showed that PCa men on ADT who got a hip fracture were seven times more likely to die than expected in the reference population of all men with PCa, whereas PCa men who were not on ADT and had a hip fracture were 13 times more likely to die than expected in this reference population. However, the absolute risk difference between men with and without a hip fracture was 30 per 1,000 person-years when evaluating the effect of a hip fracturing among men on ADT, whereas a hip fracture would cause an additional 20 per 1,000 person-years to die among PCa men without ADT as well as among men free of PCa. Conclusions: Our SMRs and absolute risk calculations show that hip fractures are more dangerous in PCa men treated with ADT than in PCa men without ADT or in men free of PCa.
Nomograms to predict late urinary toxicity after prostate cancer radiotherapy.
Authors: Mathieu Romain , Ospina Arango Juan David , Beckendorf Veronique , Delobel Jean Bernard , Messai Taha , Bossi Alberto , Le Prise Elisabeth , Guerif Stephane , Simon Jean-Marc , Dubray Bernard M. , Zhu Jian , Lagrange Jean-Leon , Pommier Pascal , Gnep Khemara , Acosta Oscar , de Crevoisier Renaud
Published: February 2017

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Background: Tools are needed to predict toxicity after prostate cancer treatment. The objective of the study was to analyze late urinary toxicity after prostate cancer radiotherapy (RT) by symptom description and identification of patient characteristics or treatment parameters allowing for the generation of nomograms. Methods: 965 patient received a median total dose of 70 Gy (range, 65-80 Gy) for localized prostate cancer, using different fractionations (2 or 2.5 Gy/day) and RT techniques. Medical history was recorded. Late urinary toxicity was assessed, prospectively in half of the patients, using the CTCAE v3 classification: urinary frequency, incontinence, bleeding and retention (dysuria). Patients or treatment related predictors of late urinary toxicity (> grade 2) were identified by Univariate and multivariate Cox regression models. Nomograms were built up and their performance were assessed. Results: The median follow-up was 61 months. The 5-year (≥grade 2) global urinary toxicity, urinary frequency, hematuria, urinary retention and urinary incontinence rates were: 15%, 10%, 5%, 3% and 1%, respectively. The 5-year (≥ grade 3) urinary toxicity rate was 3%. The following parameters significantly increased the 5 year risk of global urinary toxicity (≥ grade 2): anticoagulant treatment (RR=2.35), total dose (RR=1.09), age (RR=1.06), bladder D25 (RR=1.03) and maximum dose (RR=1.1). Urinary frequency was increased by the total dose (RR=1.07) and diabetes (RR=4). Hematuria was increased by anticoagulant treatment (RR=2.9). Urinary retention (dysuria) was increased by the total dose (RR=1.1). Corresponding nomograms and their calibration plots were generated. Conclusions: The first nomograms to predict late urinary toxicity but also specific urinary symptoms after prostate RT were generated, contributing to prostate cancer treatment decision.
Multidisciplinary care and management of very low-risk prostate cancer.
Authors: Aizer Ayal A. , Paly Jonathan J. , Zietman Anthony L. , Nguyen Paul Linh , Beard Clair , Rao Sandhya K. , Kaplan Irving D. , Niemierko Andrzej , Hirsch Michelle S. , Wu Chin-Lee , Olumi Aria F. , Michaelson M. Dror , D'Amico Anthony Victor , Efstathiou Jason Alexander
Published: February 2017

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Background: The National Comprehensive Cancer Network (NCCN) recommends active surveillance (AS) as the primary management option for patients with very low-risk prostate cancer (VLRPC) and an expected survival of <20 years. Factors associated with selection of AS are therefore of clinical importance. We hypothesized that care at a multidisciplinary clinic (MC), where multiple physicians simultaneously review each case, will be associated with increased rates of AS in men with VLRPC, including those with limited life expectancy. Methods: Of 630 patients with low-risk prostate cancer managed at one of three tertiary care centers in Boston, MA in 2009, 274 (43.5%) had VLRPC. Patients were either seen by one or more individual providers in sequential visits (N=178) or at an MC (N=96), in which concurrent consultation with two or more of the following specialties was obtained: urology, medical oncology, and radiation oncology. Results: Patients seen at an MC were more likely to select AS than those seen by individual providers (64% vs 30%, p<.001), an association which remained significant on multivariable logistic regression (OR=4.16, p<.001), see Table. When the analysis was limited to patients with an expected survival of <20 years based on the 2007 Social Security Life Table, this association remained highly significant (OR=5.19, p<.001). Conclusions: Multidisciplinary care is strongly associated with selection of AS, adherence to NCCN guidelines, and minimization of over-treatment in patients with VLRPC. [Table: see text]
Evaluation of PTEN status in circulating tumor cells (CTCs) and matched tumor tissue from patients with castrate-resistant prostate cancer (CRPC).
Authors: Punnoose Elizabeth , Tucker Eric , Marrinucci Dena , Amler Lukas C. , Koeppen Hartmut , Patel Premal H. , Yan Yibing , Riisnaes Ruth , Attard Gerhardt , De Bono Johann Sebastian
Published: February 2017

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Background: PTEN loss occurs frequently in prostate cancer and may trigger progression to CRPC through activation of the PI3K/AKT pathway. A blood-based assay that determines PTEN status in CRPC patients could enable informed treatment decisions such as the use of a PI3K-targeted therapy. We evaluated PTEN status in archived tissue, metastatic bone biopsies, and CTCs from CRPC patients. Here we report the results of PTEN evaluation in CTCs from 42 CRPC patients and matched tissue from 6 patients with more underway. Methods: Nucleated cells from CRPC patient blood were plated onto glass slides and subjected to IF staining and CTC identification by high-speed fluorescent scanners at Epic Sciences. CTCs were identified as CK+/CD45- cells with intact DAPI nuclei, and samples with ≥5 CTCs per 2 slides (74%) were then tested for PTEN by FISH. Partial loss was defined as a decrease in PTEN copies (PTEN < CEP10) and total loss as zero PTEN copies. PTEN IHC in tissue was stained using CST clone 138G6 and H-scores ≤ 200 counted as loss. Results: Partial or total loss of PTEN by FISH was observed in 15 of 31 patients (48%) by CTC analysis. Changes in ploidy were frequently observed and broad heterogeneity seen both within and between patients. Weighted across patients, the most frequently observed abnormal genotypes in CTCs were 2 CEP10/0 PTEN (total loss, diploid, 5.8%), 3 CEP10/0 PTEN (total loss, triploid, 4.5%), and 3 CEP10/3 PTEN (PTEN-normal, triploid, 4.2%). These genotypes were not observed in over 1,000 white blood cells evaluated evenly across 31 patients, demonstrating that cells identified as CTCs on the Epic platform show malignant features not observed in normal cells. PTEN loss was detected by IHC in 6 of 8 (75%) archived patient samples and 7 of 8 (87%) of matched bone biopsies. Where CTCs were available (6 cases), PTEN status was correctly determined as lost in 4 cases, normal in 1 case and borderline in one case. Conclusions: Our results illustrate the high percentage of PTEN loss in CRPC patients and the potential for using CTCs as a non-invasive, real-time biopsy to determine a patient’s PTEN status. PTEN status will be determined using these assays in an upcoming AKT inhibitor Phase II trial.
Sentinel lymph node in prostate carcinoma: Methodology, feasibility, surgical, and oncological consequences: A prospective study about 93 patients.
Authors: Soler Claude , Perraud Yves , Gremillet Eric , Armand Corine , Geissler Benjamin , Steiner Aline , Levigne Frederic
Published: February 2017

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Background: There are few studies in the field of prostatic sentinel lymph node (SLN) procedure: in the literature at the most 10 publications are found. However the interest of urological surgeons is growing fast. We want to evaluate the rate of SLN SPECT-CT detection, the rate of SLN involvement, and the incidence of the SLN biopsy on the surgical and oncological management of patients. Methods: 93 patients with prostate cancer were included (gleason 6-9). All patients were elected for a radical laparoscopic prostatectomy. Nanocis* was intratumorally injected, guided by transrectal ultrosonography. 2 injections 0.6 ml in each lobe of the prostate were performed. Patient underwent planar imaging and SPECT-CT 2 hours after injections. Surgery was performed 18 hours after. Results: A lymphatic pelvic drainage was seen in 95,6 % (89/93) by SPECT-CT (external or internal iliac arteries areas). For 27 patients lymphatic drainage was on the right side, for 24 patients it was on the left side, for the 37 remaining patients migration was bilateral. The radioguided lymphadenectomy was assisted by a laparoscopic gamma-probe (Clerad, France), the SLN detection rate was 97.7% (87/89); the average number of resected radioactive nodes was 1.6 (range 1 to 5). By all the ways, a limited pelvic lymph node dissection was performed (including external iliac to common iliac arteries areas) in all 93 cases. An SLN involvement was found in 6 cases (5/87= 5.75%); in these 6 cases and in the 81 cases without SLN involvement, no metastatic involvement was found in the other lymph nodes, as well as in the 6 patients for which no SLN could be selectively resected (4 with no drainage seen and 2 not detected intra-operatively although visualized on lymphoscintigraphy). Conclusions: The low rate of lymphatic involvement is not surprising considering the Gleason score range 6 to 9 (low metastatic risk). So, the preliminary results are very attractive, especially for these patients that could have been falsely considered as N0. Our study is still in progress, and if these results are confirmed on a larger scale, then SLN procedure could be considered in the routine management of low risk prostatic carcinomas.