bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do margin details matter? The prognostic significance of capsule invasion at the site of involved margin in prostatectomy specimens.
Authors: Watkins John Morgan , Russo James Kyle , Laszewski Michael , Rodacker Mark , Watkins Patricia L. , Dufan Tarek A. , Koleilat Nadim 
Published: February 2017

131 Background: An involved surgical margin at prostatectomy has long been associated with elevated risk of prostate cancer recurrence; however, not all patients with an involved margin will relapse, and thus details of the involved margin may provide an opportunity for risk subset stratification. The present investigation seeks to determine whether a difference exists in recurrence rates when the margin involvement is at a site of prostate capsule invasion versus within the prostate parenchyma proper. Methods: Patients were retrospectively identified for inclusion by clinically localized disease and PSA <30 at diagnosis, managed with prostatectomy alone and identified to have involvement of surgical margin(s). Exclusion criteria were: pT3b or pN1 disease, immediate/non-salvage post-operative radiation or hormone therapy, or insufficient follow-up (<12 months). Pathology slides were reviewed by a pathologist blinded to outcome, for determination of capsule invasion at a site of margin involvement. Disease recurrence was defined as PSA >0.2 and rising, per contemporary guidelines. Kaplan-Meier method was employed for disease control estimates. Results: Between 2003 and 2010, 155 patients were identified for inclusion in the present study. The median age was 61 years, and all had cT1-2 disease (75% T1c). At diagnosis, the Gleason score was 6, 7, and 8-9 for 103 (66%), 42 (27%), and 10 (6%) patients, respectively, with median PSA 5.6 (85% <10). For 149 patients with reviewable margin site data, 51 (34%) demonstrated involvement within or beyond the capsule. At a median follow-up of 68 months (range 13-137), 62 patients had experienced PSA relapse. The estimated 5-year PSA relapse rates for patients with an involved margin at the site of capsule invasion versus prostate parenchyma were 49% versus 34%, respectively (p=0.015). Conclusions: Early PSA relapse rates for all patients with involved surgical margin(s) but negative seminal vesicles and nodes at prostatectomy are high; however, for patients who are followed without immediate adjuvant therapy, presence of tumor cells at the margin in a site of capsule invasion or penetration confers a higher risk of recurrence.
The association between statin use and outcomes in patients initiating androgen deprivation therapy.
Authors: Hamilton Robert James , Ding Keyue , Crook Juanita M. , O'Callaghan Christopher J. , Higano Celestia S. , Dearnaley David , Horwitz Eric , Goldenberg Larry , Gospodarowicz Mary K. , Klotz Laurence 
Published: February 2017

145 Background: Studies are conflicting regarding the association between statin use and biochemical recurrence after surgery or radiotherapy for localized prostate cancer. A handful of studies have observed favorable associations between statins and prostate cancer-specific (PCSM) and overall mortality (OS), however, this has not been studied in an advanced disease cohort nor has the combination of statins and androgen deprivation therapy (ADT) been specifically studied. Methods: Patients with PSA >3 ng/mL after >1 year following primary or salvage radiotherapy (RT) were enrolled in a randomized trial of intermittent (IAD) vs. continuous (CAD) ADT (NCT00003653). Statin use at baseline and during the study was captured and modeled as a time-dependent covariate. The primary end-point was OS. Models were adjusted for age, time from RT to ADT and PSA at baseline. As results were nearly identical between the IAD and CAD arms they are reported as aggregates unless otherwise indicated. Results: Of 1,364 patients enrolled, 585 (43%) reported statin use during the study. Statin users were younger (72.7 vs. 73.8, p=0.001) and less likely to have PSA >15 (20 vs. 25%, p=0.04). Median follow-up was 6.9 years and 524 deaths occurred. Statin use was associated with a reduced risk of overall death (HR: 0.64; 95% C.I. 0.53 – 0.78, p<0.001) and PCSM (HR: 0.64, 95% C.I. 0.48 – 0.86, p=0.003). Statin users had 14% longer time to castration resistance but this did not reach statistical significance (p=0.15). In the IAD arm, statin users had more off-treatment intervals (p=0.04) and longer time off-treatment (median: 0.85 vs. 0.64 years, p=0.06). Across 6 functional domains, statin users reported better quality of life scores. Conclusions: In men treated with ADT following primary or salvage RT, statin use was associated with improved overall and prostate cancer-specific survival and improved quality of life. In patients treated with IAD, statin use was associated with more off-treatment intervals and longer time off-treatment. A prospective trial of statins in men commencing ADT is warranted to confirm this observation.
Redefining postprostatectomy biochemical progression: The significance of a PSA cutoff below 0.2 ng/ml—Results from two retrospective series with and without salvage radiotherapy.
Authors: Budäus Lars , Schiffmann Jonas , Tennstedt Pierre , Bottke Dirk , Heinzer Hans , Graefen Markus , Moser Lutz , Bartkowiak Detlef , Wiegel Thomas 
Published: February 2017

153 Background: Biochemical recurrence (BCR) after radical prostatectomy (RP) is usually defined at a PSA >0.2 ng/ml. BCR may precede clinical progression by years. Though salvage radiotherapy (SRT) is recommend to be initiated at PSA <0.5 ng/ml, its efficiency at PSA <0.2 ng/ml is not well documented. Methods: We relied on two independent post-RP cohorts. Cohort 1 (n=311, Hamburg) comprised men whose post-RP PSA levels had risen to 0.1-0.2 ng/ml. Further biochemical and clinical progression were recorded during follow-up. Cohort 2 (n=198, Berlin) were patients with BCR who received SRT (66/72 Gy) at a PSA <0.5 ng/ml. The median follow-up was 6.9 years. Post-SRT progression and overall survival were addressed by Kaplan-Meier analysis and Cox regression modelling. Results: In cohort 1, 299 (96%) men experienced further PSA progression (>0.2 ng/ml) within a median time of 7 months. Subsequent PSA rise to >0.3, >0.4, and >0.6 ng/ml was recorded in 174 (58%), 123 (41%), and 24 (8%) men, respectively. Twenty-four (8%) men developed metastases. In cohort 2, 112 men received SRT at PSA between 0.03 and 0.2 ng/ml, and 86 at 0.2-0.499 ng/ml. The latter group, had a poorer 10-years BCR-free Kaplan-Meier rate, 43% vs. 66% (p=0.051). Together with pT<3, Gleason Score <7, and post-RP PSA <0.03 ng/ml, SRT at PSA <0.2 ng/ml was an independent favorable predictor of freedom from BCR (OR=0.60, p<0.05). Ultimately, 14 patients died. However, overall survival did not significantly correlate with the pre-SRT PSA. Conclusions: The vast majority of patients with a PSA >0.1 ng/ml after RP will subsequently progress to PSA >0.2 ng/ml. Improved progression free survival can be achieved, if SRT is administered at a PSA <0.2 ng/ml. Therefore the contemporary PSA threshold for defining BCR after RP needs to be reconsidered and early sRT should be contemplated on a individual basis for optimizing oncological outcomes.
Genomic analysis of circulating cell-free DNA (cfDNA) to investigate mechanisms of resistance to enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Azad Arun , Wyatt Alexander , Volik Stanislav , Haegert Anne , Le Bihan Stephane , Bell Robert H , Anderson Shawn A , McConeghy Brian , Shukin Robert , Gleave Martin Edwin , Collins Colin , Chi Kim N. 
Published: February 2017

157 Background: Factors driving clinical resistance to ENZ are poorly understood. Genomic analysis of cfDNA is a promising and minimally invasive approach for investigating mechanisms of therapeutic resistance in mCRPC. Methods: Baseline plasma samples were collected from 53 mCRPC pts commencing ENZ. In 31 of these pts, 12-week and treatment cessation samples were also obtained. DNA was extracted and subjected to array Comparative Genomic Hybridization (aCGH) for chromosome copy number (CN) analysis and androgen receptor (AR) gene sequencing (MiSeq) for mutation analysis. Endpoints were i) PSA50 or PSA30 response rates (RR) (PSA decline ≥ 50% or 30% for ≥ 3 weeks); and ii) radiographic/clinical progression-free survival (PFS). Results: CN changes on baseline aCGH included 8p loss (26%), 8q gain (32%), MYC gain (28%), CCND1 gain/amplification (amp) (11%), MET gain (13%), RB1 loss (21%) and AR gain/amp (30%). Correlation of clinical and genomic data showed multiple links between AR CN status and outcomes on ENZ. Firstly, compared to no AR gain/amp, pts with pre-treatment AR gain/amp had lower PSA50 (41% vs. 19%, P=0.12; Χ2) and PSA30 RR (54% vs. 25%, P=0.051; Χ2) and shorter median PFS (4.6 vs. 2.3 months, P<0.001; log-rank). Secondly, on multivariate analysis, pre-treatment AR gain/amp (HR 3.42, P=0.002) together with prior abiraterone (HR 4.72, P=0.001) was confirmed as an independent prognostic factor for PFS. Thirdly, in pts with serial plasma samples, 16% (5/31) had a change in AR CN status from baseline with 3 pts converting from no AR gain to AR gain and 2 pts from AR gain to AR amp. Of note, median PFS in these 5 pts was only 2.8 months. Finally, AR gain/amp at baseline or emergence of AR gain/amp on-treatment was associated with decreased median PFS compared with no AR CN increase at any timepoint (2.3 months vs. 6.5 months, P<0.001; log-rank). Conclusions: Detection of AR gain/amp in pre- or on-treatment cfDNA samples correlated with adverse outcomes on ENZ. These data indicate that AR gain/amp may be a biomarker of primary and acquired resistance to ENZ in mCRPC pts. Updated data including AR gene sequencing will be presented.
A genome-wide linkage study of lethal prostate cancer predisposition gene in a set of high-risk pedigrees.
Authors: Cannon-Albright Lisa A , Teerlink Craig , Alex Anitha , Albright Frederick S. , Stephenson Robert A , Agarwal Neeraj 
Published: February 2017

159 Background: Using the unique Utah genealogical resource that links 12 generations of genealogy data to a statewide cancer registry from 1966 and statewide death certificates from 1904 we have identified a set of high-risk prostate cancer pedigrees with multiple cases having died from prostate cancer. Methods: Clusters of prostate cancer cases descended from a common ancestor, among whose descendants is observed a statistical excess of prostate cancer (high-risk prostate cancer pedigrees) were recruited and sampled. Pedigrees with 4 or more cases dying from prostate cancer (as evidenced by inclusion as a cause of death on a Utah death certificate) were genotyped with 720k high-density SNPs across the genome. Linkage analysis with markers not in linkage disequilibrium was performed to identify regions hypothesized to contain a prostate cancer predisposition gene. Results: A single extended Utah high-risk prostate cancer pedigree including 6 distantly related sampled prostate cancer cases who went on to die as a result of their cancer showed significant evidence for linkage at chromosome arm 4q24 (LOD score = +3.28), with 5 of the 6 cases having inherited the same region of chromosome 4 from a common ancestor. Conclusions: The inability of association studies to identify prostate cancer predisposition genes has returned focus to linkage studies of highly informative high-risk pedigrees, which provide power for identifying and localizing regions of interest for predisposition genes. A focus on only those cases who are members of high-risk prostate cancer pedigrees, who also went on to die as a result of their prostate cancer, has resulted in the identification of evidence for a prostate cancer predisposition gene on chromosome arm 4q24, confirming a previous GWAS that reported association with prostate-cancer-specific-survival (Pomerantz MM et al., 2011) in this region harboring TET2 (a tumor suppressor gene involved in pathogenesis of acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms), and PP2A (implicated in androgen receptor regulation in prostate cancer cell lines).
Prostate-specific antigen velocity as a predictive biomarker in a prospective prostate cancer screening study (IMPACT study).
Authors: Mikropoulos Christos , Selkirk Christina , Saya Sibel , Bancroft Elizabeth , Dadaev Tokhir , Brendler Charles , Saunders Edward , Leongamornlert Daniel , Page Elizabeth , Borrella Clara Cieza , study Collaborators And Steering Group The IMPACT , Moss Sue , Kote-Jarai Zsofia , Helfand Brian , Eeles Ros A. 
Published: February 2017

16 Background: We retrospectively assessed the clinical application of Prostate Specific Antigen Velocity (PSA V) in the IMPACT study (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in men at higher genetic risk and controls). This is a case-control prostate cancer (PrCa) screening study for men with a known genetic predisposition to PrCa; participants with a single PSA reading above 3ng/ml are offered diagnostic TRUS prostate biopsies (PB). Methods: We calculated PSA velocity (PSA V) using all three validated methods, including the arithmetic mean, the linear regression and the first and last readings equations. Pearson chi-square test was used to compare PSA V between four genetic groups: BRCA1 carriers and BRCA1 negative controls and BRCA2 carriers and BRCA2 negative controls. Results: PSA V data were evaluated in 191 men who underwent a PB with a total of 57 PrCas diagnosed. PSA V using both a threshold of 0ng/ml/year and 0.75ng/ml/year in any of the three methods was not predictive of PrCa diagnosis in BRCA1/2 controls and BRCA1 carriers. Conversely, BRCA2 carriers with a PSA V over 0.75ng/ml/year (by linear regression) were 5 times more likely to be diagnosed with PrCa [95%CI=1.5-14; p=0.003]. Interestingly PSA V using linear regression was predictive of clinically significant tumours as defined by Gleason Score (GS) >= 7. Regardless of their genetic status, men with a PSA V over 0.75/ng/ml/year were 3 times more likely to have a clinically significant PrCa [95% CI: 1.006-11.107; p=0.045] whereas men with a BRCA2 mutation were 12 times more likely [95%CI: 1.1-98; p=0.039]. Conclusions: PSA V is an important tool for identifying which men with a BRCA2 mutation would benefit from a prostatic biopsy and could be incorporated into a predictive model, along with the total PSA value. PSA V also predicts for tumour aggressiveness regardless of genetic predisposition, but more so for those with a known high risk gene mutation. Clinical trial information: NCT00261456.
Germ line predictors of response to androgen deprivation therapy in men with advanced prostate cancer.
Authors: Agarwal Neeraj , Buckley Tyler Howard , Farnham Jim M. , Patel Shiven B. , Alex Anitha , Teerlink Craig , Albright Frederick S. , Stephenson Robert A , Cannon-Albright Lisa A 
Published: February 2017

162 Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict time to response to androgen deprivation therapy (ADT) in advanced prostate cancer, serve as prognostic and predictive biomarkers, and guide towards more individualized upfront therapy. Methods: 47 polymorphisms (PMs) in 22 genes involved in the androgen metabolic pathway were investigated using tagging SNPs for association with time to onset of castration resistance in 144 Caucasian men diagnosed with advanced prostate cancer undergoing ADT. Linear regression was employed using Gleason score as a covariate and assessing each SNP under one of three genetic models: 1) an additive model in which the number of minor alleles contributes increasing risk (or protection), 2) a dominant model in which the presence of 1 or 2 minor alleles have the same effect, and 3) a recessive model in which the presence of 2 minor alleles are necessary. Results: PMs in 3 genes (CYP1A1, HSD17B3, and HSD17B12) were significantly associated with time to prostate cancer recurrence after medical castration while controlling for Gleason Score. Table summarizes the genes found to be significantly associated with time to recurrence and the modes of inheritance considered. (Only SNPs found to be nominally significant (p < .05) either with or without controlling for Gleason score in at least one model are shown.) Conclusions: In this preliminary report of ongoing work, germ line variations in multiple genes in the sex steroid hormone metabolic pathway predicted time to response to ADT, and warrant further validation to define their role as prognostic and predictive markers in this setting. [Table: see text]
Tumor-directed PET imaging of metastases in metastatic castration-resistant prostate cancer (mCRPC) using Zr-89 labeled antiprostate-specific membrane antigen (PSMA) antibody J591.
Authors: Feldman Jarett L. , Morris Michael J. , Tagawa Scott T. , Nanus David M. , Solomon Stephen Barnett , Carrasquillo Jorge A. , Reuter Victor E. , Lewis Jason Stuart , O' Donoghue Joseph A. , Martinez Danny F. , Slovin Susan F. , Rathkopf Dana E. , Gonen Mithat , Beylergil Volkan , Durack Jeremy C. , Cheal Sarah M. , Bander Neil Harrison , Scher Howard I. , Larson Steven M. , Pandit-Taskar Neeta 
Published: February 2017

164 Background: There is no standard imaging (SI) modality that specifically and accurately images prostate cancer (PC) metastases, hampering prognostication and response assessment. J591 is a humanized antibody that targets the external domain of PSMA. We have previously reported on the feasibility, PK and biodistribution properties of 89Zr-J591 in 10 patients (pts) (Pandit-Taskar et al, Eur J Nuc Med Img 2014). We now report on the targeting/accuracy in 50 pts with mCRPC. Methods: Following standard CT/MRI, bone scan (BS), and FDG PET imaging, 5 mCi of 89Zr-J591 was administered IV. 89Zr-J591 was imaged 6-8 days after injection. Positive (pos) scan findings were confirmed, where possible, with biopsies (bxs) in the following preference: concordant 89Zr-J591 and FDG pos, 89Zr-J591 and FDG mismatch, and a mismatch between SI and any PET. Results: Imaging: A total of 703 lesions in 50 pts were identified using all imaging modalities. Bone:538 total bone lesions were detected. 491(91%) lesions were present on J591 of which 99 were only evident by J591. BS identified 339 (63%), CT 301 (56%), and FDG 207 (38%). Soft Tissue: 165 total soft tissue lesions were detected. 90 (55%) were seen on J591 of which 17 were only evident by J591. CT identified 124 (75%) and FDG 88 (53%). Pathology:46 bx’s were evaluable (21 bone, 25 soft tissue) in 34 pts. Of the unique J591 lesions biopsied (bx’d), 5/7 were pos for PC. Bone: We bx’d 19 J591 pos lesions and 2 J591 neg sites. Overall, path concordance with J591 was: 89% true pos, 100% true neg, 11% false pos, and 0% false neg. Soft tissue: We bx’d 16 J591 pos lesions and 9 J591 neg sites. Of these, we found 88% true pos, 11% true neg, 13% false pos, and 89% false neg. Conclusions: J591 PET identifies additional disease in bone not seen using other imaging modalities. These lesions are highly likely to correspond to disease by bx. However, the tracer performed less well in soft tissue, with a high false neg rate. Clinical trial information: NCT01543659.
Effect of metastatic site biopsy on circulating tumor cell (CTC) count in castrate resistant prostate cancer (CRPC) stage.
Authors: Kohli Manish , Eiken Patrick W , McMenomy Brendan P , Atwell Thomas D , Tan Winston , Qin Rui , Carlson Rachel , Campion Michael B , Wang Liewei , Costello Brian Addis , Pitot Henry Clement , Quevedo Fernando , Scheel Elizabeth A , Ho Thai Huu , Bryce Alan Haruo , Paz-Fumagalli Ricardo , Moynihan Timothy J. , Dronca Roxana Stefania , Liu Minetta C. 
Published: February 2017

190 Background: It is not known if biopsy of CRPC stage metastases alters CTC results. We evaluated pre & post biopsy CTC counts in a prospective cohort undergoing pre-chemotherapy abiraterone acetate/prednisone (AA/P). Methods: CTC enumeration was performed on 7.5mL blood using the FDA cleared immunomagnetic/immunofluorescence assay (CellSearch). Time of blood draw for CTC counts pre/post biopsy was recorded for each biopsy. Biopsies were performed using 11/13 gauge core biopsy device for bone lesions and 18 gauge core needle biopsy device for soft tissue/nodal metastases. All patients (pts) underwent two serial biopsies 3 months apart. Change in CTC counts pre/post biopsy for visits 1 and 2 were evaluated using Wilcoxon signed rank test (significance at p<0.05). Differences in CTC count change (visit1) pre/post biopsy based on metastatic site (skeletal vs. non-skeletal) was compared using Wilcoxon rank-sum test. Results: Median age of the cohort was 74 years (IQR: 68-78); median PSA at V1 was 16.4 ng/ml (IQR: 6.4-87.6); at V2 was 11.5 ng/ml (IQR: 1.8-23.7). Of 59 pts undergoing biopsies 42 were in bone and 17 in nodal/soft tissue masses. At V1, pre/post biopsy CTC counts were measured on 50 and 49 pts, respectively; at V2, pre/post CTC counts were measured on 43 and 36 pts. High volume metastatic disease at V1 was observed in 67.8 % of all pts. Table lists CTC counts and time of collection pre/post biopsy for both visits. Mean change in pre/post biopsy CTC counts for skeletal sites was 0.7 (range: -12 to 64) compared to 12.1 (range: -21 to 13) for non-skeletal sites (p=0.23). Conclusions: An increase in mean CTC counts after biopsy of CRPC metastases was observed. No significant differences in change of CTC counts based on site biopsied (skeletal versus non-skeletal) was noted. Correlation with clinical outcomes is on-going. Clinical trial information: NCT# 01953640. [Table: see text]
Testosterone levels in metastatic castration-resistant prostate cancer (mCRPC).
Authors: von Klot Christoph A. J. , Boeker Alena , Herrmann Thomas R. W. , Kramer Mario W. , Kuczyk Markus A. , Merseburger Axel S. 
Published: February 2017

191 Background: It is common practice to continue anti-androgen therapy in terms of androgendeprivation when performing chemotherapy or androgendeprivation with new second generation therapeutic agents such as enzalutamide or abiraterone acetate. Clinical Studies aiming at the question whether continuation of conventional ADT is necessary in this setting are currently recruiting. In this study we analyzed androgen deprivation in patients with mCRPC under chemotherapy and second generation androgen suppression. Methods: Out of 620 screened patients a total of 36 patients with continuous testosterone monitoring and mCRPC underwent therapy with docetaxel, abiraterone acetate, enzalutamide, carboplatin, carbozantinib or cabazitaxel and were evaluated. Data were gathered from our center over a median follow up period of 27.8 (0.6 - 65.1) month. A cutoff of 0.5 ng/dL was used to discriminate patients according to testosterone castration levels. Statistical evaluation was performed applying Kaplan Meier survival estimates, Cox regression and log rank test. Results: Median follow up was 26.2 month (range 1.4 - 64.8 month). Mean patient age was 70.9 years (range 51 - 86 years). The mean testosterone concentration in our cohort was 0.5 ng/dL. Serum testosterone levels varied greatly: ranging from 0 to 16 ng/dL. A total of 18 patients died during follow up. Median survival over all patients according to Kaplan-Meier survival estimation was 38.7 month (95% CI: 31 - NA month). Median survival for patients with testosterone levels below and above 0.5 ng/dL were 48.67 and 18.13 month respectively (log rank test: p = 0.0029). In Cox regression analysis, the hazard ratio for risk of death for patients with testosterone concentrations > 0.5ng/dL was 6.03 (95% CI: 1.5 - 25, p - 0.0132). For the covariates PSA velocity, patient age and primary Gleason score there was no significant effect on risk of death (p = 0.0597, 0.5006, 0.7354). Conclusions: In patients with mCRPC i.e rising PSA or progression under androgen deprivation, conventional suppression of testosterone levels still represents a vital factor for overall survival even at the mCRPC stage and under therapy with second line anti hormonal therapeutic medication and chemotherapy.