bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single CTC characterization to identify phenotypic and genomic heterogeneity as a mechanism of resistance to AR signaling directed therapies (AR Tx) in mCRPC patients.
Authors: Scher Howard I. , Graf Ryon , Louw Jessica , Jendrisak Adam , Johnson Ann , Greene Stephanie , Rodriguez Angel , Schreiber Nicole A. , McLaughlin Brigit , Dugan Lyndsey , Fleisher Martin , Lee Jerry , Wang Yipeng , Marrinucci Dena C. , Landers Mark , Dittamore Ryan Vance 
Published: February 2017

163 Background: AR directed Tx, including Abiraterone (A) and Enzalutamide (E), prolong survival in patients with mCRPC and are FDA approved. After primary Tx with either A or E, the response to E or A is decreased as is the duration of response. NGS tissue sequencing of mCRPC shows a range of disease phenotypes and genotypes which are associated with increased tumor heterogeneity. Single site biopsy, may not represent the diversity of disease. Our objective is to develop biomarkers of heterogeneity from the analysis of single cells from patients with mCRPC. Methods: 221 blood samples from 179 unique patients (pts) were collected from pts about to begin AR Tx (n = 150) or Taxanes (n = 71). Samples were analyzed with the Epic Sciences platform. Analysis included digital pathology of 20 discrete phenotypic cell features inclusive of AR, CK, size and shape measures. 9225 single CTCs were characterized, data standardized, features clustered and categorized into 15 phenotypically distinct CTC subtypes. Individual pt samples were then analyzed for the frequency and heterogeneity (Shannon Index) of CTC subtypes and monitored for clinical endpoints. A subset of CTCs (n = 350) were individually sequenced and analyzed for clonality and CNV to assess genomic heterogeneity. Results: A diversity of CTC phenotypes were observed at each line of therapy. In AR Tx pts, high heterogeneity predicts 6mo PFS (OR = 2.57, p = 0.01) and shorter OS (HR = 4.5, p < 0.001). Separately, specific CTC phenotypes also predict 6mo PFS (OR = 5, p < 0.001) and shorter OS (HR = 5.8, p < 0.001). Heterogeneity scores were not associated with taxane resistance. NGS analysis identified subclonal drivers of disease progression including multiple private and/or clustered genomic drivers. Conclusions: Single CTC characterization of phenotype and genotype supports the concept of tumor heterogeneity as a driver of disease resistance. The heterogeneity observed supports the potential value of single cell characterization to identify rare somatic sub-clonal alterations and can aid in the development of rational therapeutic trials.
Treatment patterns after abiraterone acetate in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Post hoc analysis of COU-AA-302.
Authors: Flaig Thomas W. , Smith Matthew R. , Saad Fred , Rathkopf Dana E. , Mulders Peter F.A. , Small Eric Jay , Shore Neal D. , Fizazi Karim , De Porre Peter , Kheoh Thian , Li Jinhui , Todd Mary Beth , Griffin Thomas W. , Ryan Charles J. , De Bono Johann S. 
Published: February 2017

168 Background: Treatment patterns of mCRPC have changed substantially in the last few years. In COU-AA-302 (chemotherapy-naïve men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival vs placebo plus prednisone (P). There is limited information about treatment patterns after AA. In this post hoc analysis of pts in the AA treatment arm who progressed, we characterized subsequent therapy after pts discontinued study drug. Methods: In COU-AA-302, 546 pts were randomized and received AA. Treatment patterns of pts receiving ≥ 1 subsequent therapy for mCRPC after progressing on AA were collected retrospectively and source verified. Results: As of March 2014, 8% (44/546) of pts continued on AA; 67% (365/546) received ≥ 1 subsequent therapy for mCRPC. 36% (194/546) and 15% (83/546) of pts had ≥ 2 and ≥ 3 subsequent therapies, respectively. 80% (435/543) of pts in the P arm had ≥ 1 subsequent therapy. Most frequent subsequent therapy in AA pts was taxane chemotherapy (docetaxel [DOC], cabazitaxel [CBZ]), androgen signaling–directed therapy (AA, enzalutamide [ENZ], ketoconazole [KETO]), and immunotherapy (sipuleucel-T [SIP-T]) (Table). Among AA pts who received DOC as first subsequent therapy, median age was 69 years; median duration of DOC post-AA (n = 261) was 3 months (IQR: 0.95-5.7); and PSA progression was the most common reason for discontinuation. Among AA pts with baseline PSA and ≥ 1 post-baseline PSA value, 40% (40/100) had ≥ 50% PSA decline (27/100 confirmed responses) with first subsequent DOC chemotherapy. Conclusions: This post hoc analysis indicates that treatment with subsequent therapy was common (67% and 80%) in pts with chemotherapy-naïve mCRPC who progressed with AA or P, respectively. PSA decline suggests antitumor activity in pts who progressed with AA and received subsequent DOC. Despite limitations of a retrospective analysis, these data support further assessment of subsequent therapy following AA treatment for mCRPC. Clinical trial information: NCT00887198. [Table: see text]
Long-term indwelling double-J stent for malignant ureteric obstruction: Tolerance and complications.
Authors: Irani Jacques , Biscans Clément , Hugues Guillaume , Bernardeau Simon , Delpech Pierre-Olivier 
Published: February 2017

170 Background: JJ stent is designed to be placed for short periods. In rare cases, long-term JJ can be considered particularly in malignant ureteric obstruction. The objective of this study was to assess tolerance and complications in patients with indwelling JJ. Methods: Data from consecutive patients who had a JJ stent placed for more than 6 months between 1992 and 2013 were analyzed. Patients were all followed in a single center where JJ stents were changed every 6 months or earlier in case of complications. Results: The study included 36 patients (22 female and 14 male). Mean age was 69.4 yrs. Median ASA 3 (IQ = 1). Mean creatinine before the 1st JJ 204 micromol/L (SD 232). Most frequent causes of obstruction were colorectal (30%), gynecological (25%) and prostate cancer (14%). In 7 cases, a bilateral JJ stent was placed. Median FU was 26.4 months. Median number of JJ changed per patient was 5.5 (IQ 6.0). Median duration for each JJ was 6 months (IQ 2.1). There was one case of broken stent and 5 cases of stent encrustation, all being managed endoscopically in a single procedure.Grade III-IV complications following theClavien-Dindo classification are reported in the table. All 17 deaths (47.2%) were related to cancer progression. Conclusions: Long-term complications related to indwelling JJ stents are not uncommon. However, we found that when changing the stent systematically every 6 months (or earlier in case of complications), and when taking into account the patient's situation (status/disease) that led to the indwelling JJ indication, tolerance and rate of complications were acceptable. [Table: see text]
Dehydroepiandrosterone in metastatic castration-resistant prostate cancer: Preliminary results from the SU2C-PCF West Coast Dream Team (WCDT).
Authors: Kim Won , Ryan Charles J. , Zhang Li , Youngren Jack , Wilton John , Alumkal Joshi J. , Beer Tomasz M. , Baertsch Robert , Stuart Josh , Chi Kim N. , Gleave Martin , Rettig Matthew , Reiter Robert Evan , Lara Primo , Evans Christopher P. , Small Eric Jay 
Published: February 2017

179 Background: Aberrant androgen receptor (AR) phenotypes (e.g. splice variants, amplification) are strongly correlated with abiraterone (Abi) and enzalutamide (Enz) resistance. Low serum dehydroepiandrosterone (DHEA) is also associated with poor outcomes to AR-targeted therapy. Here, we investigate the relationship between serum DHEA, AR phenotype, and treatment efficacy in the WCDT. Methods: Patients (pts) with progressive mCRPC enrolled to the WCDT from UCSF, OHSU, UCLA, UBC, and UCD were included in this analysis. Serum DHEA was analyzed via high-pressure liquid chromatography and tandem mass spectrometry. Limit of quantitation (LQ) of DHEA was 0.2ng/mL. Full-length AR (AR-FL) and AR-v7 expression, obtained via RNAseq of metastatic tumor biopsies, was expressed as total reads mapped to gene. PSA response (PSAr) was defined as ≥ 50% PSA decline. Results: 35 pts were included in this analysis: 15 had treatment-naïve mCRPC, and 20 had prior AR-targeted therapy (14 Abi, 6 Enz). All pts were docetaxel-naïve. 11 pts had DHEA < LQ; of these, 10 had received prior AR-targeted therapy. 12 pts received subsequent chemotherapy, and 23 received subsequent Abi/Enz (7 Abi, 16 Enz). In pts with DHEA < LQ, 4/5 (80%) chemotherapy-treated pts had PSAr, while 1/6 (17%) Abi/Enz-treated pts had PSAr. In pts with DHEA ≥ LQ, 2/7 (27%) chemotherapy-treated pts had PSAr, while 9/16 (56%) Abi/Enz-treated pts had PSAr. The relationship between DHEA and PSAr was significantly different between the treatment groups (p = 0.0285). DHEA was higher in patients with PSAr to Abi/Enz versus those without PSAr (median, 0.871 versus 0.275ng/mL, p = 0.006). In an analysis of 27 pts with RNAseq data, the AR-v7/AR-FL ratio was significantly higher in those with DHEA < LQ (median ratio 8.91, versus 3.38 in DHEA ≥ LQ, p = 0.032). Conclusions: In this exploratory analysis, there is a significant difference in the relationship between DHEA and PSAr in chemotherapy- versus Abi/Enz-treated patients. DHEA < LQ was also associated with a higher AR-v7/AR-FL ratio, a potential avenue for further exploration of tumor biology. These results support a larger study to evaluate DHEA as a potential biomarker in mCRPC. Clinical trial information: NCT02432001.
BPS-001, a complex biologic agent extracted from the medicinal leech (Huridinaria manillensis) for treatment of metastatic castration-resistant prostate cancer.
Authors: Stratton M. Suzanne , Ammar Amr , Wang Yuzhuo , Hessein Mohamed , Guns Emma , Kucuk Omer , Merzouk Ahmed , Kwok David 
Published: February 2017

209 Background: We established that subcutaneous BPS-001 reduced tumor size and inhibited tumor growth in PC3, LNCaP and 22RV-1 mouse xenografts; and, tumor lHC demonstrated an increase in caspase-3 and decreases in expression of P21, Ki-67 and PCNA. We also showed that BPS-001 reduced PSA expression in both In vitro and in In vivo xenografts (LNCaP and 22RV1). We now demonstrate that BPS-001 inhibits angiogenesis in the xenografts; and, In vitro studies demonstrate that BPS-001 affects expression of adhesion molecules and the androgen receptor. In addition, BPS-001 inhibited tumor growth in a TRAMP allograft model. Methods: CD31 expression was measured using IHC of the previous mouse xenografts. In vitro androgen receptor and adhesion molecule expression were assessed by Western blot. Transplantable TRAMP-C2 mouse prostate cancer in B57CL allografts were grown to 5 mm prior to initiation of treatment. Immune markers in TRAMP allograft tumors were measured by IHC. Results: Mechanistic studies show BPS-001 acts by blocking angiogenesis demonstrated by a > 50% decrease in expression of CD31 in the LNCaP and 22RV-1 xenografts. Furthermore, preliminary toxicology studies show similar efficacy to docetaxel with no weight loss in the longer-term PC3 xenograft study as was observed with docetaxel. Preliminary toxicology studies of BPS-001 also support a favorable toxicity profile, and the therapeutic dose (1-5 mg/Kg, QW or BIW) is well within the margin of safety. Dose limiting toxicity (bleeding) was observed at doses of 20mg/Kg daily. In vitro studies showed BPS-001 decreased expression of both N- and P- cadherins and the androgen receptor. BPS-001 inhibited tumor growth in the TRAMP allograft models. IHC analyses of the TRAMP allograft tumors suggest immunomodulation. Conclusions: BPS-001 exhibits anticancer activity with no observed toxicity in the therapeutic range. Effects of BPS-001 include inhibition of angiogenesis, downregulation of adhesion molecules associated with advanced prostate cancer and inhibition of androgen receptor signaling. Elucidation of the mechanism of action is ongoing.
The prevalence of objectively measurable disease in phase III trials of metastatic castration-resistant prostate cancer (mCRPC).
Authors: Madan Ankit , Baker Mary K , May Jori E , Naik Gurudatta , Bae Sejong , Sonpavde Guru 
Published: February 2017

215 Background: Given the historical low prevalence of measurable disease in mCRPC, phase II trials have employed suboptimal endpoints accounting for prostate specific antigen (PSA) and bone scan changes. Changes in bone scan and PSA have not always translated to survival improvement. Improved computerized tomography technology may be increasing the proportion of men with measurable disease, suggesting that measurable changes need to be reconsidered. We analyzed phase III trials of mCRPC to systematically quantitate the proportion of mCRPC with measurable disease. Methods: Data from the both arms of published phase III trials of mCRPC were eligible for analysis. Baseline characteristics were required including the number enrolled, setting (pre-docetaxel [D], D-based, post-D), proportion of patients with measurable disease and the year of completion of trial accrual. General Linear Model was used to evaluate the difference in measurable disease rate based on setting and year of completion of accrual. Results: Seventeen phase III trials totaling 17,609 men with mCRPC were evaluable; 5160 were pre-D, 7573 were D-based and 4876 were post-D. The trials completed accrual between 2002 and 2012. Ten trials used RECIST 1.0, 5 trials used RECIST 1.1 and 2 trials used other criteria. The overall proportion of men with measurable disease was 47.8%. The measurable disease rate (range) in trials in the pre-D setting was 40.5% (30.5-57), in the D-based setting was 51.9% (29.1-87.5), and in the post-D setting was 48.9% (38.8-56.6). There was no statistical difference in the proportion of men with measurable disease based on setting or year of completion of accrual. Conclusions: The proportion of men with measurable disease in phase III trials of mCRPC completing accrual between 2002 and 2012 was 47.8%% with no significant difference based on setting or year of completing accrual. Given these higher measurable disease rates compared to historical rates and recent demonstration of strong association of RECIST changes with OS in mCRPC, RECIST changes need to be considered as a co-primary endpoint in phase II trials to obtain a firm signal of efficacy before launching phase III trials.
How many patients could have a salvage local treatment after radiotherapy/brachytherapy for prostate cancer?
Authors: Hennequin Christophe , Mongiat-Artus Pierre , De Kerviler Eric , Vercellino Laetitia , Ravery Vincent , Meria Paul , Culine Stephane , Desgrandchamps Francois , Quero Laurent 
Published: February 2017

23 Background: In our institution, as soon as biochemical relapse (BR; nadir PSA + 2 ng/ml) occurred after external beam radiotherapy (EBRT) or brachytherapy (BT), 18-fluorocholine-PET-CT (18-FCH-PET) with or without multiparametric prostate MRI are performed. The aim is to select patients for a salvage local treatment (SLT) with a curative intent. We presented here the results of this approach. Methods: Records of patients with BR, without clinical evidence of relapsing disease and with at least a18-FCH-PET performed, were retrospectively reviewed. Patients were considered eligible for SLT if the relapse was only local or in case of nodal relapse reasonably encompass in a RT field. Results: Between 2010 and 2014, 89 pts were included, 23 initially treated with BT and 66 with EBRT. Prognostic group at diagnosis were: favourable: 25 (28%), intermediate: 35 (39%), unfavourable: 29 (33%). At the time of relapse, mean age was 72 yrs and mean PSA level: 6.2 ng/ml. After 18-FCH-PET ± MRI, patients were classified as: no target lesion identified: 20 (22.5%); local relapse: 35 (39%); nodal relapse: 22 (25%); distant metastases: 12 (13%.5%). Among 35 pts with a local relapse, 14 had SLT (cryotherapy:13; cyberknife:1). Reasons to not performed SLT were: advanced age or poor performance status: 10; Gleason 8-10: 2; T3 on MRI: 2; Patient refusal (fear of incontinence): 7. Among 22 pts with a nodal relapse, only 3 could have salvage EBRT. Reasons to not performed SLT were: old age or poor PS: 5; extensive nodal relapse: 8; local and nodal relapse: 6. At the end, 57 pts (64%) are potentially eligible for SLT and 17 (19%) could have it. Conclusions: In routine practice, in a population of 89 pts with a BR, 64% are eligible for SLT but 19% could have it. Main reasons for not having SLT were absence of target lesions, extensive disease, or advanced age. This result justified the realisation of an extensive staging at the time of BR after EBRT or brachytherapy.
A Phase 3, randomized, double-blind, placebo-controlled study of tasquinimod (TASQ) in men with metastatic castration-resistant prostate cancer (mCRPC), secondary endpoints.
Authors: Sternberg Cora N. , Armstrong Andrew J. , Pili Roberto , Nederman Tore , Carducci Michael Anthony 
Published: February 2017

239 Background: TASQ is an oral agent with immunomodulatory, anti-angiogenic and anti-metastatic properties that targets the tumor microenvironment. It was recently reported from this study that in chemotherapy-naïve men with mCRPC, single-agent TASQ statistically significantly improved rPFS, by both central (HR (95% CI) 0.64 (0.54-0.75)) and local review, as compared to PBO but no OS benefit was demonstrated (HR (95% CI) 1.10 (0.94-1.28)). In this abstract the results of secondary efficacy endpoint analyses are presented. Methods: Men with asymptomatic to mildly symptomatic chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive TASQ or PBO once daily until progression or toxicity. Randomization was stratified by KPS ( ≥ 90% vs < 90%), presence/absence of visceral disease, and geographic region. The secondary efficacy endpoints discussed here include a panel of radiological, PSA based and symptomatically assessed measures. Results: 1245 pts were randomized (TASQ, n = 832; PBO, n = 413) between 29 Mar 2011 and 7 Dec 2012 at 240 sites in 37 countries. Baseline characteristics were balanced between the 2 groups. In general, all radiology-based and PSA-based secondary endpoints showed statistically significant differences between TASQ and PBO in favor of TASQ. E.g. median time to radiological progression was 8.4 m for TASQ vs. 5.5 m for PBO, p < 0.001, HR (95% CI) 0.628 (0.534-0.739) by central assessment. However, symptomatically assessed endpoints in general showed statistically significant differences in favor of PBO. E.g. median time to symptomatic progression was 9.5 m for TASQ vs. 11.9 m for PBO, p = 0.031, HR (95% CI) 1.171 (1.014-1.353). Grade ≥ 3 TEAEs were more common with TASQ than PBO (42.8 vs 33.6%). Conclusions: Outcome of the radiological and PSA-based endpoints favor TASQ in contrast to the symptomatically assessed endpoints, which favor placebo. Overall survival was not improved, which may be due to limited efficacy of TASQ in the studied population, toxicity, or the differential use of effective life-prolonging agents post-TASQ/placebo. Clinical trial information: NCT01234311.
Incidence of testosterone escape with LHRH agonists in patients receiving radiotherapy for prostate cancer.
Authors: Wilke Derek R , Patil Nikhilesh Gajanan , Hollenhorst Helmut , Bowes David , Rutledge Robert 
Published: February 2017

24 Background: LHRH agonists (LHRHa) are commonly combined with radiotherapy in the neoadjuvant, concurrent, and adjuvant setting. Testosterone escape (TTE) (>1.74 nmol/L or >50 ng/dL) during therapy with LHRHa has been described, but the incidence and impact of TTE on outcome in this patient group needs to be characterized further. Methods: We performed a retrospective review of a database used for clinical outcomes and research ethics board approved studies, including chart audit of select patients (pts) where information was missing. To be included in the study, there had to be information on: 1) type of LHRHa, date of initiation, date of cessation, or duration of therapy and 2) radiotherapy information, with at least 6 months of follow-up after radiotherapy, 3) had to have radiotherapy to the prostate or prostate bed, and 4) had to have a least one testosterone- (TT) and prostatic-specific antigen (PSA) measurement. Results: 670 pts had a start date for androgen deprivation therapy (ADT) in the database. 630 pts had received an LHRHa, 560 pts had a start date for radiotherapy. 375 pts had sufficient information on ADT, radiotherapy, TT, and PSA levels, and 361 of these patients had information regarding their LHRHa. Median follow-up of patients still alive is 4.7 years. The median duration of LHRHa was 2.02 years. The median number of testosterone measurements per patient was 6. The incidence of TTE per patient course of treatment was: buserelin 9.3%; goserelin 10.5%; leuprolide IM 11.5%; leuprolide sc 23.9%; triptorelin 6.7% (p=0.02). Biochemical failure was defined as per the "nadir +2" definition, or at a value > 0.2 in those patients having had previous radical prostatectomy. There was no significant difference in either biochemical failure-free survival or overall survival in patients who experienced TTE versus those who did not. The most common PSA level during a TTE was an undetectable PSA. Conclusions: Even though there appears to be no impact of TTE on either biochemical relapse-free survival or overall survival, this study demonstrates that a rising PSA does not rule out TTE. Longer-term follow-up is planned.
The role of salvage extended lymph node dissection (LND) in patients with rising PSA and PET/CT scan detected nodal recurrence of prostate cancer.
Authors: Porres Daniel , Osmonov Daniar , Aksenov Alexey , Thissen Andrea Katharina , Kuru Timur H. , Pfister David J. K. P. , Junemann Klaus-Peter , Heidenreich Axel 
Published: February 2017

242 Background: According to the risk constellation recurrence rate of prostate cancer following local therapy is up to 60%. Early salvage radiotherapy already showed a benefit in progression-free survival. We analyzed the impact of salvage extended lymph node dissection on cancer control in patients with rising PSA and nodal recurrence in PET/CT scan. Methods: Between 2003 and 2015 we performed a salvage extended lymph node dissection in 95 patients with rising PSA and nodal recurrence in PET/CT scan after previous local therapy for prostate cancer. The extent of resection field was adjusted to the pre-operative imaging. Results: We identified 95 patients with rising PSA and nodal recurrence in PET/CT scan with a mean age of 66 years (55-76 years). There were no significant intraoperative complications. Postoperatively, 12% had Clavien/Dindo grade 3 complications. Complete PSA response, defined as a postoperative PSA level < 0.2 ng/ml, was diagnosed in 36% of patients. With a median follow-up of 19 months (1-101 months) cancer-specific mortality rate was less than 1%. Median progression-free survival was 7 months (1-43 months). The interval until the initiation of systemic treatment was 12 months (1-43 months). Conclusions: Salvage LND can be performed without significant complications. Immediate complete PSA response can be achieved in one third of patients and systemic therapy can be delayed by one year. For a general treatment recommendation individual predictive markers are currently still missing.