bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative total bone imaging (QTBI) in patients with metastatic castration-resistant prostate cancer (CRPC) using NaF PET/CT.
Authors: Liu Glenn , Perlman Scott , Perk Tim , Harmon Stephanie , Simmons Kelly , Staab Mary Jane , Jeraj Robert 
Published: February 2017

180 Background: CRPC is frequently associated with the development of osseous metastases. While imaging allows treatment response determination in soft tissue metastasis, its application in bony metastasis is limited to staging. Methods: QTBI is an innovative tool that allows extraction of comprehensive functional information in all osseous metastases, as well as treatment response in individual lesions, using 18F-Sodium Fluoride (NaF) PET/CT. We completed a multi-center trial assessing the performance characteristics (test-retest) and responsiveness of QTBI as an imaging biomarker of treatment response in men with metastatic CRPC to bone treated with either a taxane-based or androgen-signaling pathway directed therapy. Results: 54 patients have been enrolled from three academic centers. Potential imaging biomarkers of treatment response have been identified. Here we present initial data regarding the inter-lesional response heterogeneity and implications. Conclusions: Changes in SUVmax, SUVtotal, and SUVmean reflect quantifiable PET measurements that are complementary, but may have different meaning depending on the treatment administered (cytotoxic vs cytostatic). Relying on one measure alone can be misleading, particularly when assessing treatment response. For example, some lesions may experience a decrease in SUVmax, while simultaneously having an increase in SUVtotal. This implies that the therapy decreased the max functional activity of the lesion, but the overall functional burden of the lesion increased analogous to “slowing down” progression. This is in contrast with lesions that decrease (increase) in both SUVmax and SUVtotal, which would imply decreased activity and burden (increased activity and burden). We will show data representative of the above along with clinical outcomes in support of this conclusion, as well as the implications of treatment response heterogeneity in the clinical outcome. In summary, QTBI provides a unique tool in understanding the dynamics of treatment response, allowing newer trial designs that can explore combination, sequence, and the issue of continuing treatment beyond progression with existing therapies. Clinical trial information: NCT01516866.
Response to taxane chemotherapy as first subsequent therapy after abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Post-hoc analysis of COU-AA-302.
Authors: De Bono Johann Sebastian , Smith Matthew Raymond , Saad Fred , Rathkopf Dana E. , Mulders Peter F.A. , Small Eric Jay , Shore Neal D. , Fizazi Karim , De Porre Peter , Kheoh Thian San , Li Jinhui , Todd Mary Beth , Griffin Thomas W. , Ryan Charles J. 
Published: February 2017

184 Background: In study COU-AA-302 of chemotherapy-naïve men with mCRPC, AA plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival vs placebo plus prednisone (P). There is limited information about response to subsequent therapy after AA. In this post hoc analysis of pts in the AA treatment arm who progressed, we evaluated the clinical outcome to chemotherapy as first subsequent therapy. Methods: In COU-AA-302, 546 pts were randomized and received AA. Clinical outcome and discontinuation data from pts receiving chemotherapy as first subsequent therapy after progressing on AA were collected retrospectively and source verified. Median time to prostate-specific antigen (PSA) progression was estimated using the Kaplan-Meier method. Results: 73% (365/502; 44 still continuing on AA) of pts in the AA treatment arm received ≥ 1 subsequent therapy. Chemotherapy, docetaxel (DOC) or cabazitaxel (CBZ), was the most common first subsequent therapy. As of March 2014, following AA on study 53% (265/502) of pts received taxane chemotherapy (261 DOC, 4 CBZ) as first subsequent therapy. Median duration of first subsequent chemotherapy, mainly DOC, was 3 months (IQR, 1.0-5.0). Results are summarized (Table). Conclusions: This post hoc analysis describes antitumor activity in pts who progressed with AA and received taxane chemotherapy as first subsequent therapy. Despite the limitations of a retrospective analysis, these data support further assessment of subsequent therapies following AA treatment for mCRPC. Clinical trial information: NCT00887198. [Table: see text]
The oral CYP17-Lyase (L) inhibitor VT-464 in patients with CRPC.
Authors: De Bono Johann Sebastian , Pezaro Carmel Jo , Gillessen Silke , Shore Neal D. , Nordquist Luke T. , Efstathiou Eleni , Araujo John C. , Berry William R. , Liu Glenn , Vogelzang Nicholas J. , Omlin Aurelius Gabriel , Schotzinger Robert J. , Eisner Joel Robert , Moore William R. 
Published: February 2017

187 Background: VT-464 is an oral, non-steroidal inhibitor of CYP17-L and an antagonist of androgen receptor (AR) variants F876L and T877A which are associated with resistance to enzalutamide (ENZ) and abiraterone/prednisone (AA), respectively. INO-VT-464-CL-001 is a Phase (Ph) 1/2 study of VT-464 in treatment-naïve (TN) and treatment-failure (TF) patients with CRPC. Results are reported for Ph 1 (TN patients) and early results from Ph 2 patients. Methods: Phase 1: safety, tolerability, PK and initial efficacy (PSA and steroid concentrations) in M0 and M1 TN patients in escalated dose-cohorts from 50 to 600 mg bid in 28-day continuous dosing cycles. Phase 2: preliminary efficacy in M0 and M1 TN and TF (post-AA, -ENZ, and/or CHEMO) patients at 450 mg bid. Results: In Ph 1, 26 TN patients received VT-464 at 50 mg bid (n=1), 100 mg bid (n=1), 200 mg bid (n=4), 300 mg bid (n=8), 450 mg bid (n=9) and 600 mg bid (n=3) with 2 patients currently on study (15 and 29 months). Another 10 TN patients received VT-464 in Ph 2 at 450 mg bid. Most Ph 1 adverse events (AEs) were grade 1 or 2 and not considered drug related. There were 18 grade 3 AEs and 1 grade 5 AE considered not related to study drug, plus 4 grade 3 AEs (vasovagal/syncope) considered at least possibly related. For a single oral 450 mg dose, t½ was 6.8±0.8h (mean±SEM), Cmax was 8.6±1.2uM and Tmax was 3.4±0.7h. 19 of 26 Ph 1 and Ph 2 TN patients who received from 300 to 600 mg bid had PSA responses (6 PSA30%, 2 PSA50% and 1 PSA90% response). Preliminary PSA responses in Ph 2 TF patients included a PSA90% response in a prior-ENZ pre-chemo patient and a PSA50% response in a prior-ENZ and -chemo patient. No mineralocorticoid excess syndrome (MES) or changes in ACTH response or LFTs were observed. Plasma testosterone concentrations were reduced to near or below the limit of quantification in most patients at ≥ 450 mg bid, with normal progesterone and cortisol concentrations. No supplemental steroids were used. Conclusions: Clinical results at the doses evaluated support VT-464 CYP17 L-selectivity. The PSA50% and PSA90% responses in 2 of 7 prior Xtandi patients, combined with a lack of MES despite no supplemental steroids, warrants further investigation in the ongoing Ph 2 study, particularly in prior ENZ and AA patients. Clinical trial information: NCT02012920.
Association of changes in biomarkers with treatment with cabozantinib (Cabo) in metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the 100mg nonrandomized expansion cohort of a randomized discontinuation trial.
Authors: Leibowitz-Amit Raya , Pintilie Melania , Laird A. Douglas , Aftab Dana T. , Berger Raanan , Chi Kim N. , Joshua Anthony M. 
Published: February 2017

196 Background: Cabo, an oral inhibitor of receptor tyrosine kinases (RTK) including MET and VEGFR2, showed activity in early clinical studies in mCRPC, and is being investigated in phase 3 trials. Our primary aim was to retrospectively study the potential association between plasma concentrations of known markers of hypoxia, RTK cell signaling, inflammation, bone metabolism, chemo-attraction and epithelial-mesenchymal transition with response to Cabo in patients (pts) who received 100mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). Methods: Our cohort of mCRPC pts with available plasma samples comprised of 81 pts with bone lesions assessed for bone scan response (BSR, defined as ≥30% decrease in lesion area compared to baseline). Thirty three pts also had measurable disease and were assessed for RECIST response. Plasma samples were available for all pts at baseline, at 6 weeks and at time of best response. Levels of 27 plasma biomarkers were measured in duplicate using ELISA. Spearman correlation coefficients were calculated for the association between response and biomarker levels at each time point. Results: Sixty six of 81 pts (81%) had a BSR, and 6 of 33 pts (18%) had a partial response by RECIST. No significant associations were found between the levels of any of the biomarkers at baseline or subsequent time points and either BSR or response by RECIST. Over time, the plasma concentrations of soluble VEGFR2 were significantly decreased during treatment with Cabo, consistent with the known effects of VEGFR inhibition on soluble VEGFR2. The plasma concentrations of nine markers (VEGFA, CA9, clusterin, FLT3L, Gas6A, Bone Alkaline phosphatase, and the soluble forms of the RTKs MET, IGF1R and AXL) were significantly increased during treatment with Cabo irrespective of response. Conclusions: These results demonstrate that metabolic alterations occur following treatment with Cabo in pts with mCRPC. Changes in certain biomarkers during treatment with Cabo could suggest potential co-targeting approaches with Cabo or other RTK inhibitors in mCRPC.
Phenotypic characterization of circulating tumor cells (CTCs) from neuroendocrine prostate cancer (NEPC) and metastatic castration-resistant prostate cancer (mCRPC) patients to identify a novel diagnostic algorithm for the presence of NEPC.
Authors: Beltran Himisha , Jendrisak Adam , Landers Mark , Mosquera Juan Miguel , Kossai Myriam , Louw Jessica , Krupa Rachel , Nanus David M. , Tagawa Scott T. , Marrinucci Dena , Rubin Mark A. , Dittamore Ryan Vance 
Published: February 2017

197 Background: NEPC is an aggressive variant of prostate cancer that most commonly arises in later stages of mCRPC, especially with visceral metastases in the setting of a low PSA. There are no reliable serum markers to identify patients that are transforming to NEPC and incidence of CTCs in these patients is unknown. Detection of NEPC has clinical implications as these patients are often treated with platinum chemotherapy rather than with androgen receptor (AR) targeted therapies such as abiraterone or enzalutamide. We sought to determine if phenotypic characterization of CTCs could differentiate NEPC from mCRPC. Methods: 24 pts (16 pts with tissue confirmed NEPC and 8 pts with mCRPC) had blood collection for CTC analysis utilizing the Epic Sciences platform. Epic analysis included identification of traditional CTCs (CK+, CD45- cells, with intact nuclei, morph distinct), CK- CTCs (CK-, CD45-, intact nuclei, morph distinct), small CTCs (CK+, CD45-, intact nuclei, small cell size), and CTC clusters. We examined CTCs at the single cell level for CTC size, shape, epithelial and AR expression. Advanced digital pathology algorithms measured size and shape measurements of CTCs. Results: CTCs from NEPC patients demonstrated strong statistical differentiation from mCRPC patients, with unique CTC morphology and protein chemistry that was not seen in mCRPC CTCs. NEPC CTCs had increase prevalence of unique CTC phenotypes including: small size, AR negativity, and presence of nucleoli. Unique cell types enabled a multivariate biomarker that is strongly associated with CTCs exclusive to tissue confirmed NEPC. Conclusions: CTCs from NEPC have unique phenotypes compared with those from mCRPC. If confirmed, the utilization of a liquid biopsy to diagnose NEPC may enable earlier identification of patients prone to visceral metastasis, and intervention to cytotoxic therapeutics. Additionally, identification of patients with NEPC could help for patient selection for AR vs. NEPC targeted therapeutics. [Table: see text]
Ferumoxytol enhanced MRI for lymph node staging in prostate cancer.
Authors: Brown Anna Mary , Sankineni Sandeep , Bernardo Marcelino , Daar Dagane , Weaver Juanita , McKinney Yolanda , Couvillon Anna , Gulley James L. , Pinto Peter A. , Dahut William L. , Madan Ravi Amrit , Choyke Peter L. , Turkbey Baris 
Published: February 2017

208 Background: Conventional imaging methods of lymph node staging in prostate cancer are limited. The goal of this study is to determine the utility of ferumoxytol enhanced MRI in lymph node (LN) staging. Methods: This ongoing IRB-approved clinical trial enrolls prostate cancer patients at high risk for LN metastases. Patients first undergo baseline T2 and T2* weighted MRI scans followed by 7.5mg/Kg ferumoxytol injection. Repeat scans are acquired at 24 hr and 48 hr post-injection. The criterion for positive LNs was hyperintense signal indicating failure to take up ferumoxytol. Validation was determined on clinical grounds or by histopathology when available. Results: To date, 11 patients have completed the study. One patient was examined pre-operatively while the other 10 had suspected therapy failure. Median age and PSA were 65 yrs (36-75) and 5.6ng/dL (0.3-201). Of 16 LNs with median size 1.6 x 1.1cm, 10 were true positives, one was false positive and one was false negative with 4 nodes pending validation. The LN status was correctly identified in 8 of 11 patients [Table]. Conclusions: Ferumoxytol enhanced MRI shows promise in detecting malignant LNs with diameter >6mm in prostate cancer paients. This method is performed in a conventional MRI unit with off-label use of an FDA-approved agent and thus could be widely available. However, further validation is necessary before routine use. Clinical trial information: NCT02141490. [Table: see text]
Presence of myeloid-derived suppressor cells (MDSC) in patients with metastatic castration-sensitive and castration-resistant prostate cancer.
Authors: Autio Karen A. , Wong Phillip , Rabinowitz Angel , Yuan Jianda , Slavin Lauryn Michelle , Brennan Ryan , DerSarkissian Melineh , Mu Zhenyu , Scher Howard I. , Lesokhin Alexander M. 
Published: February 2017

222 Background: MDSC contribute to an immune suppressive environment and have been implicated in cancer progression. Measurement (identification and enumeration) is challenged by the lack of analytically valid assays limiting data interpretation between groups. This impacts our understanding of rationale immune targets and design of clinical trials. We employed a novel biomarker based assay in whole blood to enumerate MDSC from patients with metastatic castration sensitive (CSPC) and castration resistant prostate cancer (CRPC). Methods: Whole blood was collected in Cyto-Chex (Streck) tubes. A published computational algorithm-based approach (developed by Memorial Sloan Kettering Cancer Center and commercialized by Serametrix) was employed to determine the %MDSC-monocytic and coefficient of variance (CV=ratio of SD and geometric mean fluorescence intensity) to assess HLA-DR spread on CD14+CD11b cells. Samples were performed in duplicate. Clinical variables including clinical state, past and current treatment, metastatic sites, PSA, and standard prognostic markers were collected. Results: 36 pts with metastatic prostate cancer (29 CRPC; 7 CSPC) were included. Median (SD) %MDSC in 29 CRPC pts was 21.15 (5.33) and median (SD) CV was1.29 (0.25); 7 CSPC demonstrated a median (SD) %MDSC 19.15 (4.86) and median (SD) CV 1.22 (0.25). MDSC did not differ between chemotherapy exposed (n=13) and chemotherapy naive (n=16) CRPC (23.3 vs 19.5, p=ns). MDSC were not significantly higher in those with visceral mets, though a trend existed (20.3 vs 24.0, p=0.076). PSA did not appear to correlate with MDSC or CV. Conclusions: Understanding the distribution and characterization of MDSC in various clinical states in prostate cancer is relevant to the development of immune targets in this disease. MDSC were quantifiable in both CSPC and CRPC. There was a trend for higher MDSC values in patients with visceral metastases, which historically are associated with worse prognoses. Presence of MDSC in metastatic CSPC and CRPC has important therapeutic and trial implications. Further discovery in larger cohorts and earlier disease states is underway.
Previous enzalutamide therapy and response to subsequent taxane therapy in metastatic castration-resistant prostate cancer.
Authors: Gizzi Marco , Baciarello Giulia , Flechon Aude , Beuzeboc Philippe , Angelergues Antoine , Roubaud Guilhem , Bompas Emmanuelle , Le Moulec Sylvestre , Latorzeff Igor , Delva Remy , Voog Eric , Priou Frank , Duclos Brigitte , Laguerre Brigitte , Vassal Cecile , Gross Goupil Marine , Patrikidou Anna , Fizazi Karim , Loriot Yohann 
Published: February 2017

227 Background: Cross-resistance between taxanes and androgen receptor axis targeted agents is a matter of debate in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data about response to taxanes after prior enzalutamide suggest some level of cross-resistance (van Soest et al, Eur J Cancer 2013) though this was not confirmed in other models (Al Nakouzi N, Eur Urol 2014). The first objective of this study was to assess the impact of previous enzalutamide therapy on the efficacy of subsequent taxane-based chemotherapy. The second objective was to investigate the prognosis of patients when chemotherapy was initiated in enzalutamide-pretreated patients. Methods: Data from 96 enzalutamide- and placebo-treated patients enrolled in the Prevail phase III trial were retrospectively collected from 14 centers in France. Changes in prostate specific antigen (PSA) levels, progression free survival (PFS) and RECIST criteria v 1.1 were used to determine the activity of docetaxel (n=89) or cabazitaxel (n=7) treatment. The Halabi model was used to predict survival probabilities for the enzalutamide- or placebo-pretreated patients when chemotherapy was initiated (Halabi et al, J Clin Oncol 2014). Results: Overall, 96 patients were included in this analysis (58 in the placebo arm vs. 38 in enzalutamide arm). PSA response to taxanes (defined as a decline of ≥50% from baseline) was marginally lower in enzalutamide-vs. placebo-pretreated patients (34% vs. 53%, p=0.10). PSA response in enzalutamide-pretreated patients was not different from that observed with docetaxel given every 3 weeks in TAX 327 trial (Tannock et al, NEJM 2004) (45%, p=0.20, binomial test). Median PFS and objective response rates were similar between the two groups (4.8m vs 6.7 m;p=0.14 and 45% vs 43%;p=0.83 respectively). Halabi score was well-balanced between the two groups (p=0.30). Conclusions: Taxanes retain efficacy in enzalutamide-pretreated mCRPC. At the time of first-line taxane-based chemotherapy initiation, the prognosis of enzalutamide-treated patients according to the Halabi score was not different from that of enzalutamide-naïve patients.
Radium-223 dichloride (Ra-223) in U.S. expanded access program (EAP).
Authors: Vogelzang Nicholas J. , Fernandez Daniel Celestino , Morris Michael J. , Iagaru Andrei , Brown Alan , Almeida Fabio , Sweeney Christopher , Smith Matthew Raymond , Dicker Adam , Wong Yu-Ning , Shore Neal D. , Bangerter Keith , Petrenciuc Oana , Sartor A. Oliver 
Published: February 2017

247 Background: The ALSYMPCA study (Parker, NEJM, 2013) was the basis for regulatory approval of Ra-223 for the treatment of castrate-resistant prostate cancer (CRPC) patients (pts) with symptomatic bone metastases. The aim of this prospective EAP was to monitor acute and long-term safety of Ra-223. Pt profiles and findings in the EAP setting are presented. Methods: In the EAP, CRPC pts with symptomatic bone metastases who either received or were not eligible for docetaxel received Ra-223 50 kBq/kg by injection q4wks for 6 cycles. Primary endpts: ECOG PS, symptomatic skeletal-related events (SSE), treatment-emergent adverse events [TEAEs], routine laboratory tests including PSA. Exploratory endpts: overall survival (OS), SSE rates, changes in total ALP (tALP)/PSA responses, time to tALP normalization, and to tALP and PSA progression. Descriptive statistics were used. Results: 184 pts entered treatment; baseline characteristics were similar as seen in ALSYMPCA (N=600) (exceptions in table); 67% had total ALP <220 U/L and 47% mild/moderate pain. 81/184 (44%) received all 6 injections; 26 (14%) had a dose interruption/delay, 18 due to AEs. Median OS was 17m (50/184; 27% pts). TEAEs occurring at ≥10% were anemia, fatigue, diarrhea, and nausea. The most common Grade 3/4 hematologic TEAE was anemia (11%). Majority of pts had no change in ECOG PS within each trt cycle. 19 (10%) pts had an SSE, 13 received EBRT for bone pain. 33% of pts had a ≥30% confirmed ALP decline from baseline and 16% had a ≥50% decline. Median time to ALP progression was not reached. Median time to PSA progression was 4m and 6% had a confirmed PSA response. Conclusions: In heavily pretreated patients with CRPC and bone metastases and in an EAP setting, Ra-223 was well tolerated with no new safety concerns and a positive effect on efficacy parameters. Clinical trial information: NCT01516762. [Table: see text]
Creation of a standardized set of patient-centered outcomes for advanced prostate cancer: An international effort.
Authors: Morgans Alicia Katherine , van Bommel Annelotte , Stowell Caleb , Penson David F. ,   Advanced Prostate Cancer Working Group of ICHOM
Published: February 2017

282 Background: Clinical trials and international registries assess outcomes considered relevant to men with advanced prostate cancer (CaP). However, we lack a single standardized set of outcomes, making direct comparisons between populations and quality of care assessments challenging. We sought to create a minimum standardized set of outcomes relevant to men with advanced CaP. Methods: The International Consortium for Health Outcomes Measurement assembled a multi-disciplinary working group to create a minimum set of measures to collect for men with advanced CaP. We used a modified Delphi method to establish pertinent measures and case-mix characteristics. Results: Approximately 24 experts, including clinicians and patient advocates, from North America, Europe, and Australia participated. We defined the included population as men with metastatic prostate cancer or biochemical recurrence who failed or were ineligible for salvage therapy. Outcomes important to all men with advanced CaP, such as overall survival, and measures specific to subgroups, such as time to metastasis, were identified. Measures gathered from clinical data include risk-stratification characteristics and measures of disease control. Patient-reported outcome measures, like pain control, depression, and erectile, urinary, and bowel dysfunction, were also identified. Conclusions: Standardized outcome measures are necessary to assess quality of care across different populations, and are critical to ensure value in health care. Our international, multi-disciplinary team identified clinical data and patient-reported outcomes to provide a basis for international health outcome comparisons and future assessments of quality of care for men with advanced CaP.