bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of prostate-specific membrane antigen (PSMA) radioimmunotherapy on circulating tumor cell (CTC) count.
Authors: Karir Beerinder S , Batra Jaspreet S , Date Pravin R. , Hodes Gillian , Christos Paul J. , Beltran Himisha , Nanus David M. , Bander Neil Harrison , Tagawa Scott T. 
Published: February 2017

199 Background: CTC counts with CellSearch methodology are prognostic; changes following therapy may be associated with improved outcomes. Since FDA clearance, baseline and follow up CTC counts were included in studies of radiolabeled J591. The effect of J591 alone (without an effector molecule) is unknown. Methods: Our phase II single-dose 177Lu-J591 (Cohort 3), phase I fractionated dose 177Lu-J591 (expansion cohorts), and phase I fractionated 177Lu-J591 + docetaxel (all pts) trials were analyzed. Any pt with baseline and at least 1 follow-up CTC count (CellSearch) was included in the analysis. A retrospective subset of patients undergoing J591-based imaging without an effector molecule attached was also analyzed. Results: 48 pts received 177Lu-J591 with prospectively measured CTC counts with median age of 73.7 years. 26 of 48 (54.2%) had unfavorable (≥5 CTCs/7.5 mL blood) baseline CTCs (median 29, range 5-449 CTCs/7.5 mL). Of the 23 with ≥5 baseline CTCs and available 4-6 wk post-treatment counts, 22 (95.6%) had declines of 15-100%, with 12 (52.2%) converting to favorable counts. Of the 18 with ≥5 baseline CTCs and available 12-14 wk post-treatment counts, 10 (55.5%) had declines of 8-100%, with 7 (38.9%) converting to favorable counts. Of the 22 of 48 (45.8%) with baseline CTC counts <5, 1 became unfavorable at 4-6 wks, later re-converting to favorable (early control rate of 95.5%) and 1 became unfavorable at 12-14 wks (sustained control rate of 95.5%). 7 men with unfavorable counts underwent imaging with 20 mg of J591 without an attached effector molecule; 4 (57%) demonstrated decline in CTCs following the imaging dose, with 1 stable and 2 continued to increase prior to subsequent therapy. Conclusions: In addition to the favorable PSA declines previously reported, radiolabeled J591 results in frequent favorable changes in CTC counts, with >90% of men with baseline unfavorable counts receiving 177Lu-J591 demonstrating CTC count decline or control in pts with baseline favorable counts. A small retrospective subset suggests that CTC counts may also be controlled with naked (unlabeled) anti-PSMA monoclonal antibody and a prospective study investigating this phenomenon will begin enrollment. Clinical trial information: NCT00195039 , NCT00538668 , NCT00916123 .
Project data sphere (PDS) in prostate cancer: A first look including concomitant medication use.
Authors: Gill Bethany , Khoja Leila , Li Zhu Juan , Hamilton Robert James , Koritzinsky Marianne , Penn Linda , Abdallah Kald , Pintilie Melania , Joshua Anthony M. 
Published: February 2017

204 Background: PDS enables patient-level analyses of control arms of cancer trials. The interface (www.projectdatasphere.org) allows for both web-based and download-based analyses. We aimed to validate established prostate cancer prognostic models and explore the effect of concomitant medications on survival in mCRPC. Methods: Data was obtained for 2,747 control subjects with mCRPC from 7 Phase III clinical trials with 1962 subjects available for OS analyses from 5 studies. Overall survival was estimated using the Kaplan-Meier Method. Cox-proportional hazards models, stratified by trial, were used to estimate hazard ratios. Results: Metastatic site was significant for overall survival (Median: Node only 23.69m, Bone 18.17m, Lung 14.72m, Liver 9.43m; p < 0.001). Of the 23 types of medication examined, after adjusting for metastatic site, patients taking proton pump inhibitors (HR: 1.155, p=0.017) and Erythropoietin (HR: 1.49, p-value<.001) had worse overall survival whilst patients taking fish oil (HR:0.68, p-value=0.033) and non-lipophilic statins (HR:0.69, p=.00277) had improved overall survival. Within the limits of available data, we validated the prognostic models for overall survival proposed by Templeton et al. and Sonpavde et al individually and after inclusion of concomitant medication where patients taking metformin (HR=0.729, p=.0082) and Cox 2 inhibitors (HR=0.708, p=.015) had improved OS whilst those taking low molecular weight heparin (HR=1.352, p=.004) had worse OS. Conclusions: As a first project utilizing open-source PDS data in prostate cancer, we validated two prostate cancer prognostic models and illuminated the ability to undertake novel analyses such as the association of concomitant medications with outcome. Limitations of the data relate to incomplete and inconsistent data entry. Future expansion of patient trials and numbers will help to facilitate future analyses.
Effect of cabazitaxel on the growth of human castration-refractory prostate cancer cells in vitro compared to docetaxel and on the anti-tumor properties of the angio-inhibitor PEDF in vivo.
Authors: Nelius Thomas , Jarvis Courtney , Martinez-Marin Dalia , Filleur Stephanie 
Published: February 2017

205 Background: Docetaxel/DTX and cabazitaxel/CBZ have shown promise in the treatment of metastatic Castration-Refractory Prostate Cancer/mCPRC however, comparative studies are missing. Toxicities of these drugs are significant, urging the need to modify taxane regimens. Recently, low-dose metronomic/LDM treatments using conventional chemotherapeutic drugs have shown benefits in CPRC in improving the effect of anti-angiogenic agents. Previously, we have demonstrated that LDM-DTX in combination with PEDF curbs significantly CRPC growth, limits metastases formation and prolongs survival in vivo. In this study, we intended to compare the cytotoxic effect of CBZ and DTX on CRPC cells in vitro and CL1 tumors in vivo. Methods: PC3, DU145 cell lines were from ATCC.CL1 cells were obtained from androgen-deprived LNCaP cells. Cell proliferation was assessed by crystal violet staining and cell cycle analyses. In vitro cytotoxicity assays were performed on CL1 cells/RAW264.7 macrophages co-cultures treated with PEDF and increasing doses of taxanes. For the in vivo studies, CL1 cells were engineered to stably express the DsRed Express protein +/- PEDF. PEDF anti-tumor effects were assessed on s.c. xenografts treated with DTX (5mg/kg ip ev. 4 day) as reference, CBZ (5mg/kg ip ev. 4 days, 1mg/kg for 10 days, 0.5mg/kg q.a.d. and 0.1mg/kg daily) or placebo. Results: CBZ limits cell proliferation with a greater efficacy than DTX in all CRPC cell lines tested. DU145 presented the largest difference. High doses of taxane blocked tumor cells in mitosis, whereas LDM increased the SubG1 population. This effect was significantly higher in DU145 cells treated with CBZ. In vivo, 5mg/kg CBZ delayed tumor growth more efficiently than 5mg/kg DTX. PEDF/5mg/kg CBZ markedly delayed tumor growth compared to all treatments. Finally, engulfment of tumor cells by macrophages was higher in combined treatments suggesting an inflammation-related process. Conclusions: CBZ is more efficient than DTX both in vitro and in vivo.The data also reinforce PEDF as a promising anti-neoplasic agent in combination with LDM taxane chemotherapies.
Primary resistance to abiraterone acetate (AA) after docetaxel treatment in metastatic castration-resistant prostate cancer (mCRPC): A multicenter retrospective analysis.
Authors: Maruzzo Marco , Basso Umberto , Diminutto Alberto , De Giorgi Ugo , Fratino Lucia , Lo Re Giovanni , D'Angelo Alessandro , Donini Maddalena , Verderame Francesco , Ratta Raffaele , Procopio Giuseppe , Campadelli Enrico , Massari Francesco , Gasparro Donatello , Macrini Sveva , Messina Caterina , Giordano Monica , Maines Francesca , Zagonel Vittorina , Caffo Orazio 
Published: February 2017

206 Background: AA improves survival in mCRPC patients pre-treated with docetaxel. All patients eventually become resistant at different interval times, but some of them show an early progression and should be considered as primary resistant (PRES). To date, no factors have been identified as predictive of primary resistance. Methods: The clinical outcomes of a consecutive series of patients treated with AA after docetaxel failure in 19 Italian Hospitals within a Named Patient Program (NPP) was previously reported (BJU 2014). In the present analysis, we focus on patients who achieved an investigator-assessed PFS ≤ 3 months (PRES) and those with PFS ≥ 12 months (long term responders, LR). The main aim is to determine clinical characteristics associated with primary resistance. Results: Among the 265 patients enrolled in the NPP, we identified 97 PRES (37%) and 71 LP (27%). Poor performance status, visceral metastases, presence of pain, low baseline haemoglobin level, increased LDH and ALP levels, and short time from diagnosis to AA therapy were significantly associated with early progression (Table). Conclusions: Several clinical parameters appear to correlate with early progression under AA. Their role as potential predictive factors of resistance deserve further exploration in order to develop alternative treatment strategies. [Table: see text]
Exploring the effects of abiraterone/enzalutamide failure prior to the initiation of radium-223 dichloride in men with metastatic castrate-resistant prostate cancer.
Authors: Cotogno Patrick , Ledet Elisa M. , Steinberger Allie E. , Chowdry Rajasree Pia , Stolten Michael , Sartor Oliver 
Published: February 2017

214 Background: FDA approval of three life-prolonging agents for metastatic castrate resistant prostate cancer (mCRPC) has occurred since April 2011. Two agents, abiraterone (abi) and enzalutamide (enza), disrupt androgen signaling. The third, radium-223 dichloride (Ra-223), targets bone metastases via alpha radiation. We sought to explore associations between prior abi/enza progression, number of Ra-223 cycles, prognostic factors, and overall survival (OS). Methods: Forty-two mCRPC patients (pts) treated with Ra-223 were identified. The sample was stratified based on progression (or not) on abi or enza prior to starting Ra-223. Number of Ra-223 doses administered, prognostic variables before Ra-223 treatment, and Kaplan-Meier estimates of overall survival (OS) were compared. Results: A strong association (p = 0.016) was demonstrated between prior abi/enza failure and number of Ra-223 doses administered. Patients without prior abi/enza failure were more likely to receive ≥ 4 doses of Ra-223 (94.12% vs 60.0%; odds ratio [OR] = 10.667; 95% CI, 1.214 – 93.699; p = 0.033). In comparison, those not receiving at least 4 doses of Ra-223 had a negative predictor in OS (p = .001) with a median survival of 89 days (n = 10; 95% CI, 44.064 – 133.936) compared to 303 days (n=15; 95% CI, 170.452 – 435.548). Patients initiating Ra-223 treatment after abi/enza progression had a higher median PSA (207.5 vs 49.2 ng/mL, p = 0.001), LDH (315 vs 253.5 U/L, p = 0.007) and alkaline phosphatase (ALP) (191 vs 106 U/L, p = 0.004). Conclusions: Our retrospective single institution analysis indicates that mCPRC patients who previously failed abi/enza are significantly less likely to complete 4 or more Ra-223 doses. These patients had significantly worse prostate cancer by a variety of standard prognostic variables. More information is needed from larger data sets to better understand this patient population and to best determine the optimal timing of Ra-223 administration.
Association between PSA declines at 4 weeks and OS in patients treated with abiraterone acetate (AA) for metastatic castration resistant prostate cancer (mCRPC) after docetaxel.
Authors: Rescigno Pasquale , Lorente David , Ferraldeschi Roberta , Bianchini Diletta , Sideris Spyridon , Zafeiriou Zafeiris , Smith Alan David , Mehra Niven , Grist Emily , Jayaram Anuradha , Kolinsky Michael Paul , Perez Lopez Raquel , Mateo Joaquin , Parker Chris , Dearnaley David Paul , Hall Emma , Tunariu Nina , Attard Gerhardt , De Bono Johann Sebastian 
Published: February 2017

215 Background: Falls in prostate specific antigen (PSA) levels by 50% from the baseline at 12 weeks are currently used to assess response to treatment for mCRPC (Scher et al, 2008). However PSA decline algorithms do not provide robust intermediate endpoints of overall survival (OS) benefit in mCRPC. We evaluated the association between PSA decline at 4 weeks and OS. Methods: We identified mCRPC patients who had received treatment with abiraterone acetate (AA) plus prednisolone post-docetaxel at the Royal Marsden (London, UK) between 01.01.2006 and 30.04.14. Patients were eligible for this analysis if they had PSA levels assessed at baseline, after 4 weeks and 12 weeks of treatment. PSA response at 4 weeks was defined as a ≥30% (PSA4w30) and ≥50% (PSA4w50) decline from baseline (PSABL). Association with outcome was analyzed using multivariate Cox regression and log-rank analyses. A significant p-value of 0.0167 was pre-specified to account for multiple testing. Demographics and clinical data were retrospectively collected from the hospital electronic patient record system (EPR). Results: We identified 124 patients who had received AA post-docetaxel and were eligible for this analysis. PSA4w30 was associated with longer OS (median OS 11.1 vs. 6.8 months; HR 0.50; 95% CI 0.32-0.80; p=.004). PSA4w50 was not associated with OS. A ≥50% PSA decline at 12 weeks (PSA12w50), the standard response measure, was also associated with OS (median OS 9.3 vs. 8.2; HR 0.49; 95% CI 0.29-0.80; p=.005). PSA4w30 was significantly associated with PSA12w50 (p<.001). Lack of a PSA response at 4 weeks correlated with a lack of response at 12 weeks (p=0.000), with a sensitivity of 84.9% [95% CI 75-91.4] and a specificity of 86.5% [95%CI 72–94.1]). PSA4w30 remained significantly correlated with OS (P<.001) in multivariate analyses including other established prognostic factors in mCRPC (ECOG PS, albumin, PSABL, ALP, LDH, Hemoglobin). Conclusions: Further studies to identify mCRPC patients not responding to treatment as early as possible are warranted; PSA4w30 may be useful to help identify patients unlikely to benefit from AA.
ODM-204: A novel dual inhibitor of CYP17A1 and androgen receptor for the treatment of castration-resistant prostate cancer—Preclinical data.
Authors: Oksala Riikka , Moilanen Anu , Riikonen Reetta , Rummakko Petteri , Huhtaniemi Riikka , Kallio Pekka 
Published: February 2017

221 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression and persistent activation of AR signaling axis by residual tissue/tumor androgens. Targeting AR and androgen biosynthesis together may be more effective than either alone. ODM-204 is a novel, non-steroidal dual inhibitor of CYP17A1 and AR, which has shown promising results in preclinical studies. Methods: The binding affinity of ODM-204 to wild type AR was determined in rat prostate cytosolic lysates. The potency and functional activity of ODM-204 to human AR were demonstrated in cells stably transfected with the full-length AR and androgen-responsive reporter gene constructs. In addition, assays for AR nuclear translocation and the transactivation of human AR mutants T877A, W741L, and F876L were conducted. The effects of ODM-204 on the growth of androgen-dependent VCaP and LNCaP cells in vitro and subcutaneously grafted VCaP cells in vivo with the oral dose of 50 mg/kg/day were studied. The inhibition of CYP17A1 by ODM-204 was studied in vitro by using human and rat testicular microsomes and a human adrenal cortex cell line, and in vivo in male rats coadministered with luteinizing hormone releasing hormone agonist leuprolide acetate to mimic clinical situation. Results: ODM-204 is a potent inhibitor of both AR and CYP17A1. It binds to AR with a high affinity (Ki=47 nM) and selectivity and has a high potency towards CYP17A1 (IC50=22 nM). In addition, ODM-204 inhibited testosterone-mediated nuclear translocation of AR and the mutant ARs (IC50 values for AR(T877A), AR(W741L), and AR(F876L) were 95, 277, and 6 nM, respectively), and suppressed androgen-induced cell proliferation of LNCaP (IC50=170 nM) and VCaP (IC50=280 nM) cells. In a VCaP xenograft model, ODM-204 showed significant antitumor activity (tumor growth inhibition=66%). In rats, inhibitory effects of leuprolide acetate on testosterone production and androgen-sensitive organ weights were potentiated by ODM-204. Conclusions: ODM-204 is a promising new dual CYP17A1 and AR inhibitor for the treatment of CRPC. Clinical trials in patients with mCRPC will be started in early 2015.
Multivariable analysis of predictors of side effects of cabazitaxel in the Italian Expanded Access Program.
Authors: di Lorenzo Giuseppe , Buonerba Carlo , Bracarda Sergio , Gasparro Donatello , Gernone Angela , Messina Caterina , Zagonel Vittorina , Puglia Livio , Bosso Davide , De Placido Sabino 
Published: February 2017

225 Background: Cabazitaxel-based chemotherapy provides a survival benefit after docetaxel failure in patients with prostate cancer. Grade 3-4 neutropenia and febrile neutropenia were relatively frequent in the registrative trial, but their incidence in clinical practice is likely to be lower, as shown by data collected in the Expanded Access Program (EAP). While cumulative doses of docetaxel are associated to neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this study, we assessed 'per cycle' incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel. Methods: The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant side effects identified was assessed using a Generalised Estimating Equations (GEE) model at univariate and multivariate analysis. Multivariate logistic regression analysis was performed using a backward selection procedure. Variables with a p value ⩽0.1 were kept in the final model. Results: Per cycle incidence of grade 3-4 neutropenia was 8.7%, while febrile neutropenia occurred only in 0.9% of cycles and was an early event, occurring during the first three cycles only. Multivariate logistic regression analysis showed that the odds of having grade 3 – 4 neutropenia, febrile neutropenia and anemia were statistically significantly reduced by 10, 48 and 7%, respectively, every 10 mg/m2 increase of total prior dose of cabazitaxel. Interestingly, a body surface area > 2 m2 was associated to increased odds of having grade 3-4 neutropenia. In this regard, it must be noted that all patients with body surface area > 2 m2 had their total dose capped to 50 mg, with a mean (95% CI) and median (IQR) dose reduction of 7.1 (7.58-6.69) and 5.9 (2.76-10.27) % with respect to planned dose. Conclusions: Cumulative doses of cabazitaxel are associated to decreased risk of bone marrow toxicity. Patients with body surface area >2 m2 are at increased risk of bone marrow toxicity and dose capping should be considered. These data indicate that cabazitaxel should not be arbitrarily suspended because of concerns of cumulative toxicity.
Phase 1/2a, open-label, dose-escalation and safety study of APC-100 in men with advanced prostate cancer.
Authors: Kyriakopoulos Christos , Heath Elisabeth I. , Eickhoff Jens C. , Kolesar Jill , Yayehyirad Mulusew , Moll Thomas , Liu Glenn 
Published: February 2017

234 Background: Normal human prostate epithelium and prostate carcinoma exhibit high levels of oxidative stress, which is thought to play a role in the pathogenesis of prostate cancer. APC-100 (2,2,5,7,8-Pentamethyl-6-chromanol) is an oxidative stress modulator that reduces reactive oxygen species (ROS) in prostate cancer cells and inhibits growth of cultured androgen-dependent and independent human prostate cancer cells. We aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of APC-100 in men with castrate-resistant prostate cancer (CRPC). Methods: This open label phase 1/2a study utilizes a time-to-event reassessment method (TITE-CRM) design. Patients (pts) in cohorts of 3 were treated with escalating doses of APC-100 (900mg-2400mg) orally once daily continuously in 150 mg capsules. Cycles were 28 days. All patients were evaluable with PSAs and imaging studies. Results: Twenty pts (median age 72 [range 54-87]) with metastatic and non-metastatic CRPC were enrolled in the dose escalation cohort. Pts remained on study for a median of 12 weeks (range 4-36) and received therapy for a median of 3 cycles (range 1-9). One possible DLT (elevated ALT) was seen at dose level 1 and the patient was taken off study. No other DLTs at least possibly related to therapy were seen and no dose reductions were required. Most frequent AEs at least possibly related to therapy included nausea (grade 1 in 6 pts) and elevated transaminases (grade 1-3 in 5 patients). After enrolment of 20 pts the MTD was not reached, however the maximal feasible dose was exceeded due to the number of capsules required. Five of the 20 patients had stable disease per PSA and/or RECIST 1.1 as their best response. The median progression free survival (PFS) for the cohort was 2.8 months (range 1-8). Conclusions: APC-100 appears to be well tolerated with the MTD not reached. Limited PK assessment supports the need for alternative formulation to allow dose escalation to doses necessary to achieve exposures required for response. Once MTD is established, future studies will explore the activity of APC-100 as a therapeutic and chemopreventive intervention. Clinical trial information: NCT01436214.
A multicenter phase I study of cabazitaxel (Cbz), mitoxantrone (Mito), and prednisone (Pred) (CAMP) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Aggarwal Rahul Raj , Bryce Alan H. , Weinberg Vivian K. , Ryan Charles J. , Derleth Christina Louise , Harzstark Andrea , Lee Mina , Small Eric Jay 
Published: February 2017

238 Background: Cbz/pred extends survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase 1 trial was initiated through the DOD PCCTC to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred (CAMP). Methods: Chemotherapy (chemo)-naïve pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m2 were each evaluated in combination with escalating doses of Mito (starting dose 4 mg/m2), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 20 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3.0-791.2). There were 2 DLTs observed at the dose level of Cbz 25 mg/m2 + Mito 10 mg/m2 (sepsis and febrile neutropenia). No DLTs were observed with Cbz 20 mg/m2 (N = 10), establishing Cbz 20 mg/m2 + Mito 12 mg/m2 as the MTD and RP2D. The most common grade ≥ 3 related adverse events were hematologic (neutropenia, n = 8; thrombocytopenia, n = 3; febrile neutropenia, n = 2). No cardiac adverse events were observed. The median number of treatment cycles was 9 (range 2-16), and 5 pts remain on study. Greater than 50% maximal PSA declines from baseline were observed in 8 of 18 evaluable pts (44%). Objective tumor responses have been observed in 2 of 4 pts (50%) with measurable disease, with evaluation ongoing. The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m2) was safely combined with Cbz 20 mg/m2, a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m2. Preliminary efficacy data are encouraging with durable responses observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.