bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world outcomes in second-line treatment of metastatic castration-resistant prostate cancer (mCRPC): The Prostate Cancer Registry.
Authors: Chowdhury Simon , Birtle Alison J. , Bjartell Anders , Costa Luis , Feyerabend Susan , Galli Luca , Kalinka-Warzocha Ewa , Kramer Gero , Lumen Nicolaas , Maroto Pablo , Matveev Vsevolod B , Paiss Thomas , Pisconti Salvatore , Spaeth Dominique , Veiga Francisco Gomez , Antoni Laurent , Klumper Edwin , Wapenaar Robert , van den Berg Erik , Lee Emma 
Published: September 2018

5028 Background: The Prostate Cancer Registry is a prospective, international observational study that began in June 2013 and will assess the characteristics and management of > 3000 mCRPC patients (pts) in routine clinical practice for ≤ 3 years. Methods: Data were collected from men with mCRPC irrespective of treatment (tx). This interim analysis reports baseline characteristics, txs and outcomes in pts with ≥ 12-month follow-up receiving second-line mCRPC tx following docetaxel as the only prior mCRPC tx. Results: The most commonly initiated second-line mCPRC txs (n ≥ 50) were abiraterone acetate + prednisone (AAP, n = 177), enzalutamide (ENZ, n = 94), or cabazitaxel (CAB, n = 70). Characteristics and outcomes are shown in the table below. TTP was not significantly different for AAP vs ENZ, AAP vs CAB or ENZ vs CAB (propensity score adjusted p = 0.5954, p = 0.5888 and p= 0.4808, respectively). Conclusions: In this real-world study, clinical outcomes reveal that, in pts receiving second-line mCRPC tx after docetaxel, TTP was similar across tx groups; QoL improved most in AAP and ENZ groups and no deterioration was observed most in AAP and CAB groups. Clinical trial information: NCT02236637. [Table: see text]
Sipuleucel-T (sip-T) to induce cytolytic T lymphocyte (CTL) activity against target antigens in men with hormone-sensitive and castration-resistant prostate cancer (CRPC).
Authors: Drake Charles G. , Antonarakis Emmanuel S. , Petrylak Daniel Peter , Quinn David I. , Kibel Adam S. , Chang Nancy N. , Dearstyne Erica , Campogan Dwayne , Haynes Heather , Vu Tuyen , Sheikh Nadeem Anwar , Small Eric Jay 
Published: September 2018

5046 Background: Sip-T is an FDA-approved autologous cellular immunotherapy for patients with asymptomatic or minimally symptomatic metastatic CRPC (mCRPC), manufactured from peripheral blood mononuclear cells (PBMCs) cultured with the immunogen PA2024 (prostatic acid phosphatase [PAP] conjugated to granulocyte macrophage colony-stimulating factor). Treatment with sip-T induces cellular and humoral immune responses to both PA2024 and PAP (Antonarakis, ASCO 2015; Petrylak, ECC 2015; Small Clin Cancer Res 2015). To further elucidate the mechanism of sip-T–induced immune responses, we evaluated proliferative and cytolytic characteristics of PA2024- and PAP-specific T cells. Methods: Antigen-specific proliferation of CD4 (T helper [TH]) and CD8 (CTL) T cells was quantified using flow cytometry. To assess CTL lytic activity, cell-surface CD107a expression, indicating lysosomal fusion with the cell membrane and expulsion of lytic enzymes, was measured after stimulation with PAP or PA2024. CTL lytic activity was assessed in 13 patients (from 3 sip-T trials [NCT01431391, NCT01981122, and NCT01487863] in hormone-sensitive PC and mCRPC patients) and 1 healthy donor (control). Results: In sip-T–treated patients, a significant increase in proliferation of both CTLs and TH cells was detected in response to PA2024 (p < 0.05) and PAP (p < 0.10) at week 6 compared with baseline. Increased PA2024-specific proliferation was maintained in TH cells through week 26 (p < 0.05). CTL CD107a expression increased in sip-T patient samples stimulated with PAP and PA2024 but not in the healthy donor control. Preliminary analyses suggest that patients with longer overall survival (OS) may have greater CTL CD107a activity. Conclusions: Sip-T treatment was associated with well-maintained antigen-specific cellular responses, including robust CTL responses, demonstrating sip-T induces antigen-specific tumor lysis and providing a biologic basis for OS benefit in mCRPC patients. Ongoing work will examine whether patients with longer OS display greater CTL activity. Clinical trial information: NCT01431391; NCT01981122; NCT01487863.
Circulating tumour cells and survival in abiraterone- and enzalutamide-treated patients with castration-resistant prostate cancer.
Authors: De Laere Bram , Van Oyen Peter , Ghysel Christophe , Ost Piet , Demey Wim , Hoekx Lucien , Schrijvers Dirk L. , Brouwers Barbara Anna Henk , Lybaert Willem , Everaert Els Grieta , Ampe Jozef , Van Kerckhove Piet , De Maeseneer Daan Joost , Strijbos Michiel Hendrik , Bols Alain , Fransis Karen , Van den Eynden Gert , Vandebroek Jean , Van Laere Steven J , Dirix Luc Yves 
Published: September 2018

5049 Background: A heterogeneous landscape of patients with metastatic castration-resistant prostate cancer (mCRPC) exists in current clinical practice. We investigated the prognostic value of CTC enumeration and dynamics, in the context of second-line endocrine therapies (i.e. abiraterone or enzalutamide). Methods: In a prospective, multicentre study blood samples were collected from patients with mCRPC at baseline (n = 147) and follow-up (n = 95/147(64.6%)). At baseline, patients were stratified in favourable ( < 5 CTCs/7.5mL) and unfavourable (≥5 CTCs/7.5mL) groups, whereas at follow-up, in those demonstrating a stable, in- or decreasing CTC count. PFS and OS were compared between groups. PSA changes at 10-12 weeks were evaluable in 83 patients. Results: Patients with ≥5 CTCs/7.5 mL (n = 59) at baseline had a shorter PFS (3.9 vs. 11.3 months, p< 0.0001) and OS (9.34 months vs. not reached, p< 0.0001). Patients demonstrating increasing CTCs (n = 21) on therapy had a shorter PFS (4.03 vs. 10.36 vs. 13.08 months, p < 0.0001) and OS (11.2 months vs. not reached, p < 0.0001), compared to patients with decreasing (n = 41) and stable (n = 33) CTCs, respectively. Multivariate Cox regression showed that the number of CTCs (HR (95%CI): 1.0054 (1.0006–1.010), p= 0.0260) and an increasing follow-up CTC count (HR (95%CI): 2.8987 (1.2856–6.536), p= 0.0103) were independent predictors of PFS. CTC increase was the sole independent predictor for OS (HR (95%CI): 7.3512 (1.7953–30.101), p= 0.0055). At 10-12 weeks, a PSA response of ≥30% and ≥50% was achieved in 46/83 (55.4%) and 33/83 (39.8%) patients, respectively, which was statistically different between chemo-naive or -pretreated patients (≥30%: p= 0.0395), patients with increasing, stable or decreasing CTC counts (≥30%: p= 0.0019; ≥50%: p= 0.0032), and patients with increasing or stable/decreasing CTC counts (≥30%: p= 0.0006; ≥50%: p= 0.0014). Conclusions: CTC levels are associated with PFS and OS in mCRPC patients, starting a new line of endocrine therapy. Follow-up CTC enumeration is associated with PSA response and its dynamics is an independent predictor of PFS and OS, thereby demonstrating the pharmacodynamic properties of CTCs.
Incidence of intrathoracic (IT) metastases detected by 68Ga-PSMA-11 PET in early stage prostate cancer (PC).
Authors: Aggarwal Rahul Raj , Cooperberg Matthew R. , Nguyen Hao Gia , Small Eric Jay , Ryan Charles J. , Feng Felix Yi-Chung , Chang Albert , Greene Kirsten L , Carroll Peter , Hope Tom 
Published: September 2018

5056 Background: Standard imaging in early stage PC has focused on detecting metastases (mets) within the abdomen and pelvis. The incidence of IT mets (lung, mediastinal, or supraclavicular) mets is unknown, but presumed to be negligible. Whole body 68Ga-PSMA PET has greater sensitivity compared to conventional imaging, affording the opportunity to estimate the incidence of IT mets. Methods: Newly diagnosed or biochemically recurrent (BCR) PC patients (pts) with apparent localized disease on standard imaging were enrolled on a prospective study of 68Ga-PSMA PET imaging between June 2015 and January 2017 and were analyzed for incidence of IT mets. Positive lesions were defined as uptake higher than blood pool. When appropriate, patients underwent confirmatory biopsy of the PSMA-avid IT lesions. Results: 364 pts underwent 68Ga-PSMA PET imaging, including 121 (33%) pts with newly diagnosed PC and 243 (67%) pts with BCR. 145 pts (40%) had at least 1 PSMA-avid metastasis. PSMA-avid IT mets were detected in 20 pts (5.5% of overall cohort; 13.8% of those with ≥ 1 PET-positive mets), including 3 newly diagnosed (2.5%) pts and 17 (7.0%) pts with BCR. 9 of 20 pts (45%) had IT mets as the only detectable site of metastasis on PET. Biopsy of the PSMA-avid IT lesion was found to harbor PC in 5/5 patients (100%). Sites of detection included: supraclavicular node, n = 9 (2.5%); mediastinal node(s), n = 10 (3.6%), and visceral lung, n = 4 (1.0%). In the entire study cohort of 364 pts, 43% of pts had a Gleason Score ≥ 8 at diagnosis, median PSA was 4.87 ng/mL (range: 0.04 – 83.7), and the median PSA doubling time was 6.2 months (range: 0.4 – 78.3) in patients with BCR. There were no significant differences in PSA, PSA doubling time, Gleason grade, or stage between patients harboring IT metastases vs. those who did not. Conclusions: IT mets are detected by 68Ga-PSMA PET imaging at an appreciable frequency in early stage PC with apparent localized disease by conventional imaging, which may significantly impact management in these cases. Further studies are warranted to validate these findings and determine the optimal strategy for the detection and treatment of supradiaphragmatic metastases in newly diagnosed and biochemically recurrent PC. Clinical trial information: NCT02918357.
Whole blood androgen receptor (AR) variant (ARV12, ARV14) expression and overall survival (OS) in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Giridhar Karthik , Sosa Carlos , Hillman David W. , Sanhueza Cristobal T. , Wang Liguo , Cheville John C. , Dehm Scott , Kohli Manish 
Published: September 2018

5058 Background: The detection of full length AR (AR-FL) or AR variants (AR-Vs) in blood and association with outcomes in mCRPC is unknown. We compared whole blood mRNA expression of AR-FL and AR-Vs to circulating tumor cells (CTCs) for predicting OS and time to treatment failure (TTF). Methods: We isolated RNA from whole blood collected in PAXgene RNA tubes and concurrent metastatic tissue biopsy from 51 men with mCRPC prior to initiation of abiraterone acetate in a prospective clinical trial (NCT#01953640). Whole transcriptome sequencing (RNAseq) was performed on blood samples and paired biopsies to detect AR-FL, ARV1, ARV3, ARV7, ARV8, AR12, ARV14, and ARV45. Reads were aligned to the GRCh38 reference genome with the spliced-alignment TopHat2 package. The Pearson correlation coefficient was calculated between AR-FL in blood and matched bone biopsy. CTCs were determined using the CELLSEARCH assay. Cox proportional hazard regression analysis was performed on AR-FL, each AR-V, and CTCs for association with OS and TTF. We compared the area under the curve (AUC) using CTCs alone to a multivariable model that included AR-Vs for predicting OS. Results: The median follow up was 3.0 years, (range 0.3-3.5); the median CTC count was 3 (range 0-372); 34/53 men were deceased. Blood based AR-FL or AR-Vs were detected in 50/53 patients with following distribution: AR-FL (41/53), ARV3 (9/53), ARV45 (8/53), ARV12 (4/53), ARV14 (4/53), ARV7 (2/53), and ARV8 (2/53). Whole blood AR-FL transcripts were highly correlated to paired bone biopsy (r2= 0.76). Elevated transcripts of either ARV12 or ARV14 were associated with decreased OS [hazard ratio (HR) 3.46, p = 0.006]. CTC count ≥5 was associated with poorer OS [HR 3.42, p = 0.02] and shorter TTF [HR 3.52, p = < 0.001]. Adjusting for CTC counts, in a multivariate model, blood AR12 expression was associated with poor OS [HR = 6.33, p = 0.009]. AR12 and CTCs trended toward improved AUC compared to CTC alone (0.78 vs 0.71, p = 0.07). Conclusions: AR-FL and AR-Vs are detectable in whole blood and are highly correlated with metastatic bone AR-FL expression. AR-Vs may add to prognostication in mCRPC and further validation is needed. Clinical trial information: NCT#01953640.
Ten-year overall and prostate cancer (PCa)-specific mortality in high-risk patients after high-dose-rate brachytherapy combined with external beam radiation therapy (HDR-BT/EBRT) compared with EBRT alone.
Authors: Wedde Trude Baastad , Fosså Sophie , Brabrand Sigmund , Kaasa Stein , Russnes Kjell Magne , Hellebust Taran Poulsen , Tafjord Gunnar , Lilleby Wolfgang 
Published: September 2018

5059 Background: The effect of dose-escalation with HDR-BT boost for high-risk PCa is not known. The objective is to compare 10-year PCa-specific mortality (PCSM) and overall mortality (OM) in non-metastatic patients treated with HDR-BT/EBRT (2004-2010) to EBRT alone (historical RCT, SPCG-7, 1996-2003). Methods: HDR-BT boosts (10 Gy x 2) were given 2 weeks apart followed by 50 Gy conformal EBRT (2 Gy x 25) to the prostate and seminal vesicles (assuming alpha/beta ratio of 3, EQD2 = 102 Gy). The HDR-BT/EBRT group (N:325) received Androgen Deprivation Therapy (ADT) for a total of 2 years. Patients in the control group (N:296) received 70 Gy (2Gy x 35) to the prostate and seminal vesicles with lifelong Anti-Androgen Treatment (AA). cT1-cT2 vs cT3 tumours and Gleason score 6-7 vs 8-10 were analysed. For each treatment group PCSM and OM were established by Kaplan-Meier (KM) analyses, and inter-treatment differences were tested by the logrank tests. Cox regression analysis evaluated the significance of available pre-treatment variables. Significance level p < 0.05. Results: In both groups the median age was 66 years. Median follow-up was 104 (range 13-120) and 120 (range 3-120) months for the HDR-BT/EBRT and EBRT groups respectively. KM plots revealed an 1.8% risk of PCSM in the HDR-BT/EBRT patient group and an 8.4% risk in the EBRT cohort (p = 0.001). For OM, the figures were 12.3% in the HDR-BT/EBRT group compared to 23.3% in the EBRT group (p = 0.014). In the Cox regression analysis, treatment (HR = 3.9, CI95% 1.8-8.3) and Gleason score (HR = 3.2, CI95% 1.8-5.9) were significantly associated with PCSM whilst T-stage, age and PSA levels were not. Treatment (HR = 1.7, CI95% = 1.1-2.6) was the only factor significantly associated with OM. Conclusions: In men with high-risk PCa dose-escalation with HDR-BT/EBRT compared to EBRT alone resulted in a significantly decreased risk of 10-year PCSM and OM despite shorter length of hormonal therapy. PCSM was significantly influenced by both Gleason score and type of treatment, whereas treatment remained the only significant covariate for OM.
P53 status in primary tumor predicts efficacy of first-line abiraterone and enzalutamide in castration-resistant prostate cancer patients.
Authors: Maughan Benjamin Louis , Guedes Liana , Boucher Kenneth M. , Rajoria Gaurav , Liu Zach , Klimek Szczepan , Zoino Roberto , Antonarakis Emmanuel S. , Lotan Tamara L. 
Published: September 2018

5064 Background: We tested whether tissue-based analysis of p53 and PTEN genomic status, measured predominantly in primary tumor samples, may be predictive for sensitivity to abiraterone and enzalutamide in castration resistant prostate cancer (CRPC). Methods: We performed a retrospective analysis of 309 consecutive patients with CRPC treated with first-line abiraterone or enzalutamide. Of these, 116 men (38%) had available tumor tissue for analysis, and formed the basis of this study. Deleterious TP53 missense mutations and PTEN deletions were interrogated using genetically validated immunohistochemical assays for p53 protein nuclear accumulation and PTEN protein loss. OS and PFS were compared between patients with and without p53 and/or PTEN alterations. Results: 46% of evaluable cases had PTEN loss and 27% had p53 nuclear accumulation. 45% (53/118) of cases underwent targeted next generation sequencing and p53 nuclear accumulation was 91% sensitive and 90% specific for underlying TP53 missense mutation. OS and PFS did not differ significantly according to PTEN status but were associated with p53 status. Median OS was 15.8 months (95% CI, 15.8–23.9) and 28.7 months (95% CI, 28.7–42.7) for men with and without p53 nuclear accumulation, respectively (HR 1.98; P = 0.007). Median PFS was 5.5 months (95% CI, 3.53–10.5 months) and 10.2 months (95% CI, 7.37–13.3 months) in men with and without p53 nuclear accumulation, respectively (HR 1.73; P = 0.013). In multivariable analyses, p53 status was independently associated with both OS (HR 2.13; P = 0.016) and PFS (HR 1.83; P = 0.034). This effect was also seen in the subset of patients with prostatectomy tissue only. In patients with p53 nuclear accumulation median PFS (p < 0.001) and median OS (p < 0.001) were decreased compared to wild-type patients. No effect was seen with PTEN loss in either PFS (p = 0.12) or OS (p = 0.50). Conclusions: p53 status may be a biomarker of sensitivity to novel hormonal therapies in CRPC. PTEN was not a biomarker of sensitivity in our study. These results require prospective validation.
History of PSA screening on prostate cancer aggressiveness.
Authors: Cullen Jennifer , Gerald Thomas , Burke Allen , Kuo Huai-Ching , Rosner Inger L. , Srivastava Shiv , Sesterhenn Isabell 
Published: September 2018

5066 Background: In 2012, PSA screening for prostate cancer (CaP) detection was given a “Grade D” recommendation for all men by the USPSTF. Recent U.S. studies report declines in PSA screening with concomitant increases in advanced CaP at diagnosis. This study examined the association between PSA screening history and CaP aggressiveness in a racially diverse, military cohort with equal health care access. Methods: This retrospective cohort study evaluated CaP patients undergoing radical prostatectomy (RP) from 1994-2015 at Walter Reed National Military Medical Center. Whole-mounted prostatectomy specimens were classified using 2014 ISUP Gleason grading system. Excluding the diagnostic PSA, screening history was categorized as: ≥ 6 PSA’s prior to CaP diagnosis (uppermost quartile), 1-5 (lower 3 quartiles), vs. no screening history. Multivariable logistic regression (MLR) was used to examine NCCN risk stratum (intermediate-high vs. low) and Gleason upgrade (GU) from biopsy to RP. Multivariable Cox proportional hazards (Cox PH) analyses were used to model time to biochemical recurrence (BCR). Multivariable models controlled for age at RP, race, family history and obesity (BMI > 30 vs. ≤ 30 kg/m2). The GU and BCR models also controlled for NCCN risk classification. Results: There were 1,772 eligible patients with a median follow-up and age at RP of 7.0 and 59.8 years, respectively. Prior to CaP diagnosis, 42% and 19% of men had 1-5 and ≥ 6 PSA’s screenings, respectively. MLR showed greater odds of intermediate or high vs. low risk disease for PSA screening history of none vs. 1-5 (OR = 1.33, CI = 1.03-1.70, p = 0.028) but not for none vs. ≥ 6 (p = 0.44). MLR showed increased odds of GU for none vs. ≥ 6 (OR = 1.81, CI = 1.23-2.7, p < 0.001). Multivariable Cox PH models showed incrementally poorer BCR-free survival as screening history decreased (HRNone vs. ≥6 = 2.27, CI = 1.54-3.33, p < 0.001; HRNone vs. 1-5= 1.49, CI = 1.15-1.92, p = 0.002). Conclusions: In this RP cohort, higher risk stratum, increased GU, and poorer BCR-free survival were associated with no PSA screening history. BCR-free survival was incrementally worsened by less PSA screening. A complete absence of PSA screening may lead to more aggressive disease at presentation and poorer clinical outcomes.
Validation of cAMP phosphodiesterase-4D7 (PDE4D7) for its independent contribution to risk stratification in a prostate cancer patient cohort with longitudinal biological outcomes.
Authors: Rijntjes Jos , Alves de Inda Marcia , van Strijp Dianne , den Biezen-Timmermans Eveline , van Brussel Anne , Wrobel Janneke , van Zon Hans , Vos Pieter , Baillie George S , Tennstedt Pierre , Schlomm Thorsten , Houslay Miles , Bangma Chris H. , Heinzer Hans , Hoffmann Ralf 
Published: September 2018

5069 Background: In this study we present the retrospective validation of the prognostic prostate cancer biomarker PDE4D7 in predicting longitudinal biological outcomes in a historical cohort of radical prostatectomy patients. Methods: Biopsy punches from 550 patients were collected from a representative tumor area of FFPE surgical resections. RNA was extracted and PDE4D7 quantified by one-step RT-qPCR. PDE4D7 scores were calculated by normalization of PDE4D7 to the averaged expression of four reference genes. The independent prognostic value of the PDE4D7 scores were evaluated using uni- and multivariate Cox proportional hazard regression. Multivariate analyses were adjusted for clinical prognostic variables. Post-surgical outcomes tested were: PSA relapse, start of salvage treatment, progression to metastases, overall and prostate cancer specific mortality. Logistic regression was used to create a combined prognostic model of PDE4D7 with clinical risk and tested in outcome prediction. Results: The PDE4D7 score was significantly associated with time to PSA failure after prostatectomy (HR 0.53; 95% CI 0.41-0.67 for each unit increase; p < 1.0E-04). After adjustment for pathology Gleason, pT stage, surgical margin status, and seminal vesicle invasion the HR was 0.55 (95% CI 0.43-0.72; p < 1.0E-04). Patients with a high PDE4D7 score that were clinically classified as intermediate to high risk of progression were re-classified into a group with an average progression risk less than the average cohort risk of clinically very low risk patients. The maximum benefit, compared to Gleason score, was observed in the clinically intermediate favorable risk group. Combining clinical risk with PDE4D7 scores improved the overall risk stratification. Conclusions: The PDE4D7 score has potential to provide independent risk information and, in particular, to re-stratify patients with clinical intermediate to high risk characteristics to a very low risk profile.