bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of comorbidity and PSA doubling time on the risk of death in men experiencing PSA failure following radiation therapy with or without androgen deprivation therapy for unfavorable-risk prostate cancer.
Authors: Patel Sagar Anil , Chen Ming-Hui , Loffredo Marian , Renshaw Andrew A. , Kantoff Philip W. , D'Amico Anthony Victor
Published: March 2017

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Background: The optimal management of men with PSA failure following initial prostate cancer therapy based on comorbidity is unknown. We investigated the impact that PSA doubling time (DT) and comorbidity had on the risk of all cause (AC), prostate cancer-specific (PCS) and other cause mortality (OCM) following PSA failure. Methods: Between 1995 and 2001, 206 men with unfavorable-risk PC were randomized to receive radiation therapy alone or in combination with 6 months of androgen deprivation therapy (ADT). After a median follow up of 16.2 years, 108 men experienced PSA failure (85, no or minimal; 23, moderate to severe comorbidity) and formed the study cohort. Cox and Fine-Gray regression analysis was used to determine whether PSA DT was associated with the risk of ACM and PCSM/OCM respectively, stratified by ACE-27 comorbidity score. Results: After a median follow up of 13.71 years following PSA failure, 81 of the 108 men (75%) died. Longer PSA DT was associated with a decreased risk of PCSM in men with no/minimal (AHR 0.33, 95% CI 0.17-0.65, p= 0.001) and moderate/severe comorbidity (AHR 0.014, 95% CI 0.002-0.129, p= 0.0002) with a trend toward an increased risk of OCM in men with no/minimal (AHR 1.42, 95% CI 0.94-2.16, p= 0.10) and moderate/severe comorbidity (AHR 1.68, 95% CI 0.85-3.35, p= 0.14). However, increasing PSA DT was only associated with a decreased risk of ACM in men with no/minimal (AHR 0.69, 95% CI 0.50-0.96, p = 0.03) but not moderate/severe comorbidity (AHR 0.95, 95% CI 0.51-1.78, p= 0.87). Conclusions: The extent and natural history of comorbidity as well as PSA DT should be taken into consideration when deciding on appropriate management and/or clinical trial eligibility at the time of PSA failure. Specifically, randomized studies are needed to determine whether survival is prolonged in men with life-shortening comorbidity with salvage ADT at the time of PSA failure versus surveillance and reserving ADT use for symptomatic progression. For all other men, trials comparing ADT with or without novel agents shown to prolong survival in men with metastatic castrate resistant PC is warranted.
Twitter mentions and academic citations in the urologic oncology literature.
Authors: Hayon Solomon , Stormont Ian , Dunne Meagan M , Siddiqui Mohummad Minhaj
Published: March 2017

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Background: Social media use has dramatically increased in academic medicine with over 70% of journals now using twitter accounts. This calls into question if there is a measurable association between academic impact and Twitter use. We sought to quantify the relationship between the number of Twitter mentions and the number of academic citations a urologic oncology publication receives. Methods: 210 papers from 7 prominent urology journals were examined 18 months after publication from December 2014-January 2015. Articles were evaluated with 2 citation based “bibliometrics” (Scopus, Google Scholar) and 1 social media based metric (Altmetric). Altmetric software allowed for individual tweets regarding an article to be examined. Scores and Twitter mentions for oncology and non-oncology publications were compared using ANOVA and contingency analysis. Results: 79 articles were oncology related while 131 pertained to other topics. The mean number of Twitter mentions for oncology articles was 4.1, compared to 2.4 for non-oncology articles (p=0.004). Articles with at least one twitter mention had 2.0 fold more Scopus citations (p<0.01), 2.1 fold more Google Scholar citations (p<0.01), and 27.8 fold higher Altmetric scores (p<0.001). Oncology authors tended to be more active on Twitter, with 13.9% of oncology authors self-tweeting their own articles versus 5.3% of non-oncology authors (p=0.04). Authors self-tweeting oncology articles was associated with an increased number of citations, with a 10.3 and 7.9 mean citation increase in Google Scholar and Scopus scores (p=0.04 and p=0.01) compared to non-self-tweeted oncology articles. (See table.) Conclusions: Social media appears to be more prominent in the urologic oncology community. The number of citations a urologic oncology publication receives is associated with the number of mentions it has on Twitter. Authors self-tweeting articles may be a factor that increases paper visibility and academic impact. [Table: see text]
Prediction of pathological outcome at radical prostatectomy for MRI-ultrasound fusion prostate biopsy versus standard transrectal ultrasound guided prostate biopsy.
Authors: Arora Hans , Nyame Yaw A. , El-Shafei Ahmed , Kara Onder , Purysko Andrei , Stephenson Andrew J. , Jones J. Stephen , Klein Eric A.
Published: March 2017

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Background: Magnetic resonance imaging (MRI)-ultrasound (US) fusion prostate biopsy has been shown to be able to detect prostate cancer, with the goal of targeting specific lesions. Our objective was to evaluate the ability of this technique to accurately determine the final pathological outcome at the time of radical prostatectomy as compared to standard template 12-core transrectal ultrasound (TRUS) guided prostate biopsy. Methods: We performed a retrospective analysis of patients who underwent both prostate biopsy and prostatectomy at the Cleveland Clinic. Patients who underwent standard template 12-core TRUS biopsies between January 2005 through December 2013, and MRI-US fusion biopsies from January 2014 through June 2015 were included. Patients who had more than 12 cores taken during TRUS biopsy were excluded. Relevant covariates included patient demographics as well as pre-biopsy PSA and prostate size, which were collected from the electronic medical record. Continuous variables were compared using Wilcoxon rank-sum tests and categorical variables were assessed with χ2 test. Results: In total 543 patients were included. Of these, 491 underwent 12-core standard template TRUS biopsy whereas 54 underwent MRI-US fusion biopsy. Between the two groups there were no significant differences in age (median 62 years versus 63 years, p = 0.21), race (17.5% versus 12.3 % African American, p = 0.32), family history (31.5% versus 29.3% positive, p = 0.74), prostate size (47.75g, IQR 39.5-59 versus 42.7g, IQR 37-56, p = 0.08), pre-biopsy PSA (5.2 ng/mL, IQR 4.1-7.6 versus 4.97, IQR 3.24-6.95, p = 0.14). Of the fusion biopsy patients, 14 of 54 (25.9%) were upgraded from biopsy to prostatectomy, whereas 214 of 491 (43.6%) of TRUS biopsy patients were upgraded (p = 0.02). Conclusions: Of men undergoing transrectal biopsy for the diagnosis of prostate cancer, MRI-US fusion techniques have a lower rate of upgrading at final pathology at prostatectomy as compared to standard 12-core TRUS-guided biopsy.
Medications for urologic malignancies in the open payments data: Financial relationships between industry and urologists.
Authors: Maruf Mahir , Sidana Abhinav , Purnell Stephanie , Fleischman William , Brancato Sam Joseph , Agrawal Shantanu , Agarwal Piyush K.
Published: March 2017

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Background: The Open Payments program was enacted to increase transparency of the financial relationships between physicians and the pharmaceutical industry. We examined the non-research related financial relationships between urologists and industry in the US using the 2014 Open Payments data as it pertains to payments associated with drugs used in the treatment of urologic cancers. Methods: A descriptive analysis of the Open Payments data released by the Centers for Medicare & Medicaid Services for 2014 was performed. The total payment amount associated with medications prescribed by urologists to treat urologic malignancies was calculated. Results: For drugs associated with all urologic cancers, 44,200 payments, totaling $4,693,561, were made to 5666 urologists. Approximately 82% of payments (76% of the financial value) associated with urologic cancers were for prostate cancer. Of these, payments were primarily associated with anti-androgen therapy ($2,803,435, 79%), followed by hormonal therapy ($672,342, 19%) and chemotherapy ($63,693, 2%). Payments were most commonly in the form of food and beverage (90%), but were only 18% (0.8M) of the total payment amount. Janssen Scientific Affairs reported the largest proportional value of financial ties (24% or 1.1M) but this only accounted for 3% of the number of payments. Conclusions: Nearly 66% of urologists have received a non-research related payment associated with a urologic cancer drug from industry in 2014. Payments associated with prostate cancer drugs were largest in sum and frequency, and consisted largely of payments associated with anti-androgen therapy. This likely coincides with the fact that urologists predominantly prescribe anti-androgens and the recent FDA approval of newer anti-androgens within the last decade.
Can focal therapy impact perioperative, oncological, and functional outcomes in men who underwent focal therapy salvage robotic-assisted radical prostatectomy? A retrospective matched-pair comparative study.
Authors: Nunes-Silva Igor , Barret Eric , Srougi Victor , Baghdadi Mohammed , Barreras Silvia Garcia , Capogrosso Paolo , Rembeyo Gregory , Carneiro Arie , Sanchez-Salas Rafael , Rozet François , Galiano Marc , Cathelineau Xavier
Published: March 2017

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Background: Salvage surgery is an option for recurrent prostate cancer(PCa) after focal therapy(FT). This is the first study to assess the impact of FT on surgical outcomes comparing salvage robotic-assisted radical prostatectomy(S-RARP) versus primary-RARP(P-RARP). We aimed to compare the impact of FT on perioperative, oncological and functional outcomes in men underwent S-RARP versus P-RARP. Methods: Prospective data of 2775 men underwent RARP for localized PCa from 2000 to 2016 were reviewed. Twenty-five men underwent S-RARP after FT failure(S-RARP group). Total 2750 underwent RARP as primary treatment. Matched-pair 1:2 selection of 44 out of 2750 patients by age, IPSS and IIEF5 defined P-RARP group. Primary endpoint was between-groups differences on functional outcomes. Secondary endpoint was oncological data. p < 0.05 was significant. Results: Surgical time, transfusion and complication rates were comparable(p > 0.05). Rates of continence probability[49.5%(SE 0.13) versus 62.4%(SE 0.08), p = 0.8 and 73%(SE 0.14) versus 76.5%(SE 0.07), p = 0.8, at 1 and 2 years, respectively] and the chance for achieving continence[HR 1.062, 95%CI 0.54-2.08, p = 0.861] were comparable between-groups. Potency recovery was significant lower on S-RARP[3±2 versus 9.22±6.55, p = 0.008]. S-RARP showed significant lower rates of cumulative BCR-free survival probability[67.6%(SE 0.12) versus 95.1%(SE 0.03), p = 0.001 and 56.3%(SE 0.15) versus 92.4%(SE 0.04), p = 0.001, at 1 and 2 years, respectively]. S-RARP presented significant increased risk of BCR[HR 4.8, 95%CI 1.67-13.76, p = 0.004]. Upstaging was an independent predictor factor for BCR on S-RARP[HR 14.65, 95%CI 1.46-146.37, p = 0.022] (Table 1). Conclusions: Salvage-RARP following FT failure is feasible and safe with acceptable complications rates. Patients assigned to FT should be previously advised about lower erectile recovery rates in case of a salvage surgery. Urologists may be warned about the risk of undertreatment in patients presenting failure along FT follow-up.
The IMPACT of 68GA-PSMA-PET in definitive radiotherapy planning for prostate cancer patients.
Authors: Onal Cem , Torun Nese , Akkus Yildrim Berna
Published: March 2017

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Background: The implementation of 68Ga-PSMA-PET-imaging for staging and the impact on stage adaption during treatment radiotherapy (RT) planning is not well studied yet. The present work is to evaluate the integration of 68Ga-PSMA-PET into standard RT planning and to determine the influence on staging and on changes in the initially planned treatment concept for definitive RT in prostate cancer patients. Methods: A total of 66 prostate cancer patients with PSMA-PET delivered before treatment were retrospectively analyzed. All patients had bone scintigraphy and magnetic resonance imaging (MRI) of abdomen (52 patients; 79%) or thoraco-abdominal computed tomography (CT) (14 patients; 21%). After PSMA-imaging, all information was reviewed and re-classification was performed with the additional information taken into account. Thereafter, patients were evaluated with the information obtained by PSMA-PET imaging led to a change in staging and subsequently resulted in a change of the RT concept and treatment fields. Results: Median age of patients was 66 years (range 46 – 84 years). Median pretreatment PSA level was 25.2 ng/mL (range 4.4 – 130.8 ng/mL). The initial stage was changed in 27 patients (41%); 8 patients (12%) under-staged, 11 patients (17%) over-staged and 8 patents (12%) had distant metastasis. RT fields changed in 9 patients (14%) and RT cancelled because of distant metastasis detected with PSMA-PET in 6 patients (9%). The mean pretreatment PSA values were significantly higher in over-staged patients or patient with distant metastasis compared to under-staged patients (55.0±38.8 ng/mL vs. 28.1±19.1 ng/mL; p = 0.02). Also upstaging was observed more frequently in patients with ≥ T3a disease compared to patients with < T3 disease (15 patients [56%] vs. 4 patients [15%]; p = 0.04). However, Gleason score and primary tumor SUV had no significant impact on stage change and particularly on RT decision and treatment plan changes. Conclusions: The performance of a PSMA-PET frequently leads to changes in the stage, altering the RT treatment regimen especially in patients with extensive stage disease and higher pretreatment PSA values.
EZH2 expression and clinical outcome in African-American men with prostate cancer.
Authors: Narayan Vivek , Lal Priti , Zeigler-Johnson Charnita , Malkowicz S. Bruce , Rebbeck Timothy
Published: March 2017

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Background: Despite increasing recognition of molecular differences in prostate cancers from African-American men (AAM) and European-American men (EAM), the prognostic utility of novel tissue biomarkers in AAM remains poorly defined. Overexpression of the oncogenic transcriptional regulator EZH2 has been associated with clinical outcome in localized prostate cancer, but it has not been adequately evaluated in AAM. We sought to define the prognostic significance of EZH2 overexpression in a racially-balanced cohort of men with localized prostate cancer and to explore potential race-specific differences. Methods: This was a retrospective analysis of men who underwent radical prostatectomy at the University of Pennsylvania between 1991 and 2010. Subjects with formalin fixed paraffin embedded tissue available for EZH2 immunohistochemistry were included. Slides were graded in a semi-quantitative manner for both the volume and the intensity of EZH2 staining. Multivariate Cox regression models were used to evaluate the independent association of clinicopathologic parameters, including EZH2 staining index, and biochemical recurrence (BCR)-free survival. Results: 121 patients (62 AAM, 59 EAM) were eligible for analysis. 56 patients (46.3%) demonstrated EZH2 overexpression, which was balanced between AAM and EAM subgroups (43.6% vs 49.2%, respectively). Extracapsular extension, positive surgical margins, and EZH2 overexpression were independently associated with BCR-free survival (HR of 2.02 for EZH2 overexpression, 95% CI 1.05 – 3.86, p = 0.035). Potential effect modification by race was identified (p for interaction = 0.056). While EZH2 overexpression was independently associated with BCR-free survival in AAM (HR 2.78, 95% CI 1.06 – 7.32, p = 0.038), no significant association was identified in the EAM subset (HR 0.89, 95% CI 0.35 – 2.29, p = 0.812). Conclusions: EZH2 overexpression is a valid prognostic marker in AAM treated with prostatectomy. The potential for enhanced prognostic significance of EZH2 overexpression in AAM may lend insight into observed racial disparities. These results highlight the need for adequate representation of AAM in clinical trials evaluating novel EZH2-directed therapies.
Risk prediction-modeling approach to identify best predictive parameters for urethral strictures after prostate brachytherapy.
Authors: Singhal Sandeep , Parliament Matthew , Jamaluddin Muhammad Faisal , Lee Emma , Sloboda Ron , Usmani Nawaid
Published: March 2017

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Background: Urethral strictures (US) are a rare complication of prostate brachytherapy (BXT), with prior studies showing radiation dose to the bulbomembranous urethra is associated with stricture formation. This retrospective case-control study explored clinical and dosimetric parameters associated with the development of BXT-related urethral strictures. Methods: A cohort of 34 patients developed urethral strictures after BXT at our institution for the period of 2008-2014. Each case was matched with two controls (68 controls) that had not developed a US according to similar baseline International Prostate Symptom Score (IPSS), planned prostate volume, post-implant prostate V150, and post-implant prostate D90 dosimetry parameters. US development was compared with clinical (i.e. age, IPSS, etc) and dosimetric (i.e. prostate, urethra, urethra segments) variables. Statistical modeling for risk prediction was applied, which included adjusted R2, Mallows’ C Selection (Cp), Schwartz’s information criterion (BIC), forward selection (FS), and backward selection (BS) to identify the parameters with prediction ability of toxicity. CV analysis was performed to select the best subset selection on the full data set in order to obtain the most predictive parameter selection. Results: The results show that the R2statistic increases from 6% (only one) to 33 %, (all of the parameters included). The table demonstrates minimum best-fit parameters in the different models. (See table.) CV with minimum standard error (MSE) identified a model with 5 parameters that included age, baseline IPSS, UD30, UD5, and U5mm V200Apex shows best prediction ability for US. Conclusions: This modeling approach, which is novel in BXT, helped to identify a combination of parameters with some predictive ability of radiation toxicity. Further evaluation is required to validation. [Table: see text]
Genome-wide alterations in gene expression of prostate cancer (PC) cells surviving neoadjuvant androgen deprivation therapy (ADT).
Authors: Ferrari Anna C. , Chen Ying , Sabaawy Hatem E. , Stein Mark N. , Foran David , Yegnasubramanian Srinivasan T.
Published: March 2017

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Background: Although androgen deprivation therapy initially decreases PC tumor burden, resistance to further androgen receptor (AR)-directed treatments or chemotherapy is inevitable once CRPC is established. We postulated that the stress of ADT triggers widespread alterations in expression that renders a metastable physiologic state conditioned by epigenetic changes that might be initially reversible by targeting non-androgen pathways. We conducted a pilot study to explore genome-wide expression alterations in PC foci surviving 3 months ADT (eADT). Methods: mRNA from 7 frozen microdissected PC foci and normal counterparts (NC) were processed for RNA-seq. RNA-seq changes in eADT specimens were compared first with NC and the untreated PC in the TCGA PRAD (TCGA) database to castrate resistant (mCRPC) specimens in the dbGAP study phs000915.v1.p1database. The raw data (fastq files) was quantified using kallisto, normalized by TMM using R package edgeR, batch effects corrected using R package SVA. Analysis of differential gene expression by R package sleuth. Pathway and gene set by GSEA, GAGE/pathview packages for Gene Ontology (GO) and KEGG. Results: TMPRSS2-ERG+, 5/7. Highest DEG in eADT vs. TCGA vs mCRPC were non-coding RNA’s. Among 17431 differentially regulated paths; GSEA of eADT vs TCGA or mCRPC: 341 (1.95%) and 1366 (7.84%) up- vs 46 (0.26%) and 59 (0.34%) down-regulated. KEGG paths, eADT vs. TCGA or mCRPC, 11 and 53 up vs. 2 and 3 down- respectively. Highly down- path in eADT vs TCGA (log q < 10-17) was ribosomal vs. cell cycle and DNA replication in mCRPC. Six paths significantly up- in eADT vs TCGA or mCRPC: Wnt, adherence junction, steroid biosynthesis, unsaturated fatty acids, citrate cycle, ErbB. Calcium, MAPK, insulin, GnRH and Hedgehog were also up- in eADT vs mCRPC. AR full-length was marginally higher in eADT than TCGA and lower than mCRPC, no differences in gene targets. Conclusions: This pilot data shows that ADT triggers a wide range of gene expression alterations that support PC cell survival and may be vulnerable to therapeutic targeting in addition to the androgen pathway. Validation of these findings is planned in a larger set of samples from the same bank.
Prostate cancer specific mortality and overall survival outcomes for salvage radiation therapy after radical prostatectomy.
Authors: Agrawal Shree , Efstathiou Jason A. , Michalski Jeff M. , Pisansky Thomas Michael , Koontz Bridget F. , Liauw Stanley L. , Abramowitz Matthew , Pollack Alan , Anscher Mitchell Steven , Moghanaki Drew , Den Robert B. , Zietman Anthony L. , Lee W. Robert , Stephans Kevin L. , Hearn Jason W.D. , Spratt Daniel Eidelberg , Gao Tianming , Kattan Michael W. , Stephenson Andrew J. , Tendulkar Rahul D.
Published: March 2017

9

Background: Early salvage radiation therapy (SRT) following radical prostatectomy (RP) has been shown to reduce biochemical recurrence and distant metastases. We aim to identify factors predictive of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) from a consortium database from 10 academic institutions. Methods: 2,454 node-negative patients (pts) with detectable post-prostatectomy PSA ( ≥ 0.01 ng/mL) treated with SRT ± neoadjuvant/concurrent androgen deprivation therapy (N/C ADT) were included. Cumulative incidence and Kaplan-Meier methods were used to estimate rates of PCSM and ACM, respectively. Univariate and multivariable analyses (MVA) were performed by competing risks regression and Cox proportional hazards methods for PCSM and ACM. Results: Median follow-up was 5 years from SRT completion and 8 years from date of RP; 24% had pathologic Gleason score (GS) of ≤ 6, 56% GS 7, and 19% GS ≥ 8; 56% extraprostatic extension (EPE), 18% seminal vesicle invasion (SVI), 58% positive surgical margins, and 16% received N/C ADT. Median age at RP and SRT were 62 years (IQR 56-66) and 64 years (59-69), respectively. Median SRT dose was 66 Gy (IQR 65-68) and median pre-SRT PSA was 0.5 ng/mL (IQR 0.3-1.1). MVA performed from SRT completion date demonstrated higher pre-SRT PSA (HR = 2.1), higher GS (GS 7 vs. ≤ 6: HR 2.0; GS ≥ 8 vs. 6: HR 3.3) , SVI (HR 2.5), year of SRT (2000-2004, 1995-1999, 1985-1994 vs. 2005-2012; HR 2.9, HR 2.5, HR 3.6, respectively) were significantly associated with higher PCSM. These same variables were all significantly associated with higher PCSM and ACM rates calculated from both SRT completion date and date of RP. Conclusions: Initiation of early SRT at lower post-operative PSA levels following RP is associated with reduced risk of PCSM and ACM, even when calculated from RP date to account for lead time bias. Other factors significantly associated with PCSM include higher GS, SVI, and earlier year of SRT. [Table: see text]
Prospective comparative analysis of oncologic and functional outcomes between focal therapy and robotic radical prostatectomy.
Authors: Barreras Silvia Garcia , Sanchez-Salas Rafael , Sivaraman Arjun , Barret Eric , Secin Fernando P. , Redondo Cristina , Velilla Guillermo , Nunes-Silva Igor , Srougi Victor , Rembeyo Gregory , Baghdadi Mohammed , Rozet François , Galiano Marc , Cathala Nathalie , Mombet Annick , Prapotnich Dominic , Cathelineau Xavier
Published: March 2017

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Background: Focal therapy (FT) is an emerging treatment alternative for organ-confined Prostate cancer (PCa). The aim is to perform a non-randomized prospective analysis to compare oncological, functional and morbidity outcomes after FT and robotic radical prostatectomy (RARP). Methods: From July 2009 to September 2015, 1883 patients underwent RARP and 373 FT. Of those, we selected 1410 men (1222 RARP and 236 FT) according to the NCCN PCa risk classification: 402(27.5%),388(26.6%) and 668(45.8%) patients were very low risk, low risk and intermediate risk, respectively. Within FT, 188 men underwent focal high-intensity focused ultrasound (HIFU) and 48 cryotherapy. Oncologic outcomes were analyzed in terms of biochemical recurrence (BCR) free survival (Phoenix definition for FT, and PSA >0.2 ng/dl in RARP), and the need for further treatment. FT failure was defined as any positive control biopsy after treatment. Overall suvival and metastasis free survival were estimated using Cox regression and Kaplan-Meier methods. Complications were graded as Clavien-Dindo classification. Functional outcomes were assessed with validated questionnaries for genitourinary symptoms and sexual function. Results: Median follow-up was 45.4 mo (IQR: 25.3-65.5). BCR-free survival was comparable among RARP and FT ( 10.6% RARP vs 9% FT, p 0.69). Patients with intermediate risk PCa were significantly associated with BCR in both groups (HR 8.47;95% CI 4.57-15.71; p< 0.001). In FT group positive biopsy in the treated lobe was seen in 42(17.7%) men. No differences were found in overall survival, neither mestastases free survival between treatments; (p 0.85 and p 0.142 respectively). FT was associated with higher risk of further treatments (HR 5.21; 95% CI 3.7-7.35; p <0.001). FT had higher rates of complications (15.3% vs 9% for RARP, p 0.004). RARP was associated with less continence recovery vs FT at 3, 6 and 12 mo (p <0.001). Potency is higher between FT men at 3,6 and 12 mo (<p 0.001). Conclusions: For selected patients with organ confined PCa, RARP and FT offered comparable oncological control with FT requiring higher additional treatments. Potency and continency appears to be better preserved in FT patients.
Influence of common comorbid conditions on a 17-gene assay for prediction of adverse pathology in clinically low-risk prostate cancer.
Authors: Cullen Jennifer , Sesterhenn Isabell , Lawrence H. Jeffrey , Kuo Huai-Ching , Srivastava Shiv , Rosner Inger L. , Zhang Nan , Brand Timothy C. , Shindel Alan W
Published: March 2017

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Background: Well-validated molecular biomarkers can improve risk stratification in newly diagnosed PCa. It is important to demonstrate that biomarkers are not influenced by common clinical conditions. A 17-gene biopsy-based RT-PCR assay (Oncotype Genomic Prostate Score, GPS) has been validated as an independent predictor of adverse pathology and biochemical recurrence after surgery. We sought to explore the association between comorbid conditions and GPS. Methods: We examined the association between GPS and obesity (OB), diabetes mellitus (DM), hypertension (HTN), hypercholesterolemia (HC), coronary artery disease (CAD) and Low Testosterone (Low T) in a cohort of surgically treated men with clinically low-risk PCa. All men were seen and treated at Madigan Army Medical Center or Walter Reed National Military Medical Center. Diagnoses were abstracted from the electronic medical record. OB was defined as body mass index (BMI) > 30 kg/m2. Low T was defined as total T < 300 ng/mL. Student’s T test and ANOVA were used to assess differences in GPS between the groups of men with or without relevant diagnoses. Results: GPS results were available in 402 patients; 389 (97%) had BMI data. Pre-treatment serum testosterone (T) levels were available for 120 patients. There were no significant differences in mean GPS between men with or without OB, HTN, HCL, DM, and low T (p > 0.05). This relationship persisted when men with no vascular risk factors were compared to men with any vascular risk factor (DM/HTN/HCL) and/or with diagnosed coronary artery disease. There was a modest but statistically significant inverse correlation between GPS and continuous serum T (r = -0.18; p = 0.049). Conclusions: Comorbidities that are common in older men with prostate cancer do not appear to influence GPS results. Although Low T was not associated with GPS, there was a weakly negative association between GPS and continuous T. This may reflect the more aggressive PCa phenotype that has been reported in patients with progressively lower serum T.
OncotypeDx genomic scores independent of disease volume in men with favorable-risk prostate cancer.
Authors: Grimberg Dominic C. , Nyame Yaw A. , Greene Daniel J. , Gupta Karishma , Berglund Ryan Kent , Gong Michael C. , Stephenson Andrew J. , Klein Eric A.
Published: March 2017

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Background: To determine if disease volume at biopsy correlates with GPS among men with favorable risk prostate cancer. Methods: All men with NCCN very low (VLR) and low risk (LR) and GPS from 2013-2016 were identified. Disease volume was characterized by percent of positive cores, number of cores with >50% involvement, and largest involvement of any single core. Nonparametric equality of medians was performed to compare the median likelihood of favorable pathology between quartiles. Results: 112 (37.8%) with VLR and 184 (62.2%) with LR disease were identified. The likelihood of favorably pathology by quartile are listed in Table 1. 7/105 (6.3%) with VLR were reclassified as LR, and 13/181 (7.2%) with LR were reclassified as intermediate risk (IR). Patients reclassified to IR by GPS had a median likelihood favorable pathology of 63.0% (IQR 62.0-63.0), 20.0% positive cores (IQR 13.0-29.0), 0 cores with > 50% involved (IQR 0-1), largest core involvement of 20.0% (IQR 10.0-20.0), and PSA density of 0.12 ng/ml/cc (IQR 0.10-0.14). Conclusions: Differences in the likelihood of favorable pathology by disease volume were not clinically significant in men with favorable risk disease. [Table: see text]
Genomic mechanisms of resistance to neoadjuvant leuprolide plus abiraterone in locally advanced prostate cancer.
Authors: Sowalsky Adam G. , Ye Huihui , Schaefer Rachel J. , Voznesensky Olga S. , Zhang Zhenwei , Lis Rosina , Bubley Glenn J. , Taplin Mary-Ellen , Balk Steven P.
Published: March 2017

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Background: Blocking both gonadal and extragonadal androgens with leuprolide and abiraterone acetate (AA) is approved by the FDA to treat mCRPC. Applying this treatment in the neoadjuvant setting reduced intratumoral testosterone levels in our Phase 2 trial, but pathologic CR's were rare and minimal residual disease was observed in some patients. Methods: We performed laser capture microdissection to isolate pure foci of residual tumor cells from 19 patients who underwent RP following 24 weeks of leuprolide plus AA. We also isolated 19 foci of matched benign glands as germline controls. In 15 of the 19 cases, we dissected 2 spatially-distinct foci of residual tumor. We then performed whole exome sequencing to assess somatic mutations and copy number variations (CNVs). Results: A diversity of genomic resistance mechanisms were observed. Resistance to AA as predicted by mutation of the ligand binding domain of AR was observed in only one case. In contrast, the majority residual tumor foci harbored CNVs coinciding with gain of oncogenes or loss of tumor suppressor genes. Importantly, only a limited number of alterations were shared between foci from the same case, as most mutations were unshared. Shared CNVs frequently included arm-level single copy losses of 10q ( PTEN), 13q ( BRCA2), 5q ( CHD1), 17p ( TP53), 16q ( ZFHX3) and 8p ( NKX3-1), and gain of 8q ( MYC). Mutations not shared by foci in the same case included further biallelic inactivation of PTEN, BRCA2 and TP53, as well as point mutations and single copy losses of BRCA1 and RB1. Distinct, focal gains included AR, PIK3CA and BRAF, and mutations also accumulated in KMT2B, KMT2C and KMT2D. Conclusions: By sampling multiple foci of residual tumor, we identified mutations that likely emerged by subclonal selection by ADT, which cooperated with the shared, clonal mutations that contributed to de novo development of the index lesion. Strikingly, the spectrum of alterations mimics mCRPC with enrichment for alterations affecting cell cycle, DNA damage repair and chromatin modifier pathways. If these alterations permit the tumor to evade AR directed therapy and subsequently mediate relapse, adjuvant therapies targeted to these mutations may increase survival. Clinical trial information: NCT00924469.
Outcomes of men who underwent treatment for prostate cancer from a prospective follow up of a racially diverse, multi-institutional active surveillance cohort.
Authors: Haney Nora M. , Feibus Allison H. , Liu James , Leinwand Gabriel , Ledet Elisa M. , Moparty Krishnarao , Lewis Brian E. , Thomas Raju , Sartor Oliver , Silberstein Jonathan L.
Published: March 2017

e536

Background: Active surveillance (AS) is an increasingly accepted alternative to treatment for low-grade prostate cancer (PCa). However, it remains unclear what factors may predict which patients will upgrade to a higher grade cancer. We sought to analyze the characteristics at time of diagnosis and outcomes of those men in our racially diverse AS cohort who underwent treatment for PCa. Methods: Men from our AS database were analyzed. Inclusion criteria was PSA < 20 ng/mL, Gleason Score ≤ 7, and clinical stage ≤ T2a. Men who elected active treatment for their PCa at diagnosis or refused subsequent imaging and biopsy were excluded from this cohort. Univariate analysis was done to compare the clinical variables of the treatment group with the entire cohort. Results: We identified 56 men who were treated for PCa from the 308 men currently enrolled in our AS cohort. All 56 men in the treatment group had low risk PCa at diagnosis and initiation of AS. At diagnosis, the treatment group was not significantly different in comparison with our entire cohort with respect to age, BMI, family history of PCa, PSA at diagnosis, prior negative biopsy, TRUS volume, PSAD, smoking status and clinical staging. However the eventual treatment group did differ at diagnosis with respect to greater linear length of cancer per core (p < 0.01), greater % involvement of disease (p = 0.03), and greater number of total cores at time of diagnosis (p = 0.04). The men in this group underwent treatment for PCa for the following reasons: 36 for Gleason Score upgrading, 5 due to increased volume of disease, 6 due to rising PSA, 1 due to MRI findings, 1 due to rising PSA on Avodart and 7 elected treatment despite no significant changes in disease. 31 of the men had RARPs, 17 XRT, 4 had XRT + ADT, 3 had Brachytherapy, and 1 with XRT + salvage RP. Conclusions: Within our prospectively enrolled racially diverse AS cohort, the patients who underwent treatment for PCa had clinical factors that differed in comparison to the whole cohort. Further prospective study is needed to determine how these factors may ultimately impact long term outcomes.
The impact of race on perceptions of anxiety after radical prostatectomy.
Authors: Kundu Shilajit , Wong Vincent , Victorson David , Burns James , Guitierrez Sandra , McVary Kevin , Schaeffer Edward M. , Psutka Sarah P , Meeks Joshua , Schaeffer Anthony J , Murphy Adam , Cella David
Published: March 2017

e538

Background: Despite the potential side effects associated with treating prostate cancer, many men choose treatment over observation. The relative treatment benefits and harms to heath related quality of life outcomes (HRQOL) remain poorly understood. In particular, there is a paucity of data detailing the differences in perceived treatment outcomes in African American (AA) and Hispanic men. We prospectively evaluated the functional and psychosocial effects of prostate cancer treatment in men and hypothesize that there may be differences in outcomes in Caucasian men vs. AA/Hispanic men. Methods: We enrolled 105 men with recently diagnosed prostate cancer at our institution in an internet-based study which used validated questionnaires to longitudinally assess HRQOL domains such as sexual and urinary function, bowel function, anxiety, and depression, at 1, 3, 6, and 12 months following treatment. Linear mixed models were used to examine changes in self-reported measures at enrollment (pre-treatment) and at each post-treatment follow-up assessment. We focused our analysis on the 62 patients who chose radical prostatectomy as treatment: 49 of these men were non-Hispanic white; 13 were AA or Hispanic. Results: Despite significant declines in functional outcomes such as erectile function (P < .001 for both groups), anxiety was significantly lowered post-treatment in both groups as well. Significant reductions in anxiety were noted for Caucasian men (4.6 points , P < 0.001) and were even greater for AA/Hispanic men (7.9 points, P < .001). When controlling for differences in income, marital status, education, and improvements in urinary score, the impact on anxiety remained significant (P < 0.05) at 3, 6, and 12 months . Based on previous analysis, these improvements are both statistically and clinically significant improvements. Conclusions: We found significant reductions in anxiety after prostate cancer surgery. While these reductions were found in all men, AA and Hispanic men reported a greater reduction in anxiety compared to the Caucasian cohort. This suggests that AA/Hispanic men may have a different perspective regarding prostate cancer and treatment outcomes. Further work is necessary to elucidate this difference in perspective.
Training and skills assessment for MRI/TRUS fusion-guided prostate biopsy: End-fire vs. side-fire ultrasound probes.
Authors: Jain Amit L , Sidana Abhinav , Stanik Zachary , Maruf Mahir , Calio Brian P. , Sugano Dordaneh , Hammerich Kai Hans , Wright Collier , Ball Mark Wayne , Valera Vladimir , Turkbey Baris , Choyke Peter L. , Wood Bradford J. , Pinto Peter A.
Published: March 2017

e540

Background: Magnetic resonance imaging (MRI)/transrectal ultrasound (TRUS) fusion-guided prostate biopsy (FBx) has rapidly proliferated in prostate cancer evaluation. FBx success may be dependent on multiple factors, including skills learned with user experience and the type of ultrasound (US) probe used. Our objective of this study was to compare the accuracy of the MRI/TRUS FBx technique utilizing an end fire versus a side fire US probe on an FBx platform. Methods: The participants of the study consisted of three different experience levels (expert ( > 1000 FBx), Urology fellows with none to minimal FBx experience, Urology residents with no FBx experience). Each participant performed three trials of the FBx with the UroNav System in separate phantom models of the prostate. Each trial involved targeting the same set of fiducials through FBx platform and then using US only; first using an end fire US probe, and then using a side fire US probe. Fusion registration error (FRE) was defined as the distance between MR target and transformed core location from the US only biopsy. Results: Six users with 3 different experience levels performed the FBx. Mean FRE with the end fire probe for the residents, fellows, expert was 7.42(±0.11), 5.10(±0.73) & 3.75(±0.75) respectively. Mean FRE with the side fire probe for the residents, fellows, expert was 6.08(±0.09), 4.76(±0.68) & 3.46(±0.08) respectively. There was no significant difference between the FRE averages for end fire vs. side fire. There was an inverse relationship of mean FRE with user experience level (corr. coefficient (r) = -0.79, p = 0.011 for end fire; r = -0.84, p = 0.004 for side-fire). Conclusions: We report the results of a pilot study comparing the efficacy of side fire and end fire US probes in MRI/TRUS FBx. Our preliminary results suggest the type of US probe used does not significantly affect FRE and FBx performance. As expected, FRE decreases with increased user experience. A larger study with more participants will be needed to compare these probes with adequately powered analysis and will dictate the practice in clinical settings as minimization of FRE will improve diagnostic accuracy of this technique in detecting clinically significant cancer.
The effect of androgen deprivation therapy on prostate cancer-specific mortality in high-risk prostate cancer: Patients treated with low dose-rate brachytherapy without supplementary external beam radiotherapy.
Authors: Ciezki Jay P. , Reddy Chandana A. , Weller Michael A. , Tendulkar Rahul D. , Stephans Kevin L. , Ulchaker James , Angermeier Kenneth , Campbell Steven C. , Stephenson Andrew J. , Klein Eric A.
Published: March 2017

e550

Background: Androgen deprivation therapy (ADT) is a mainstay accompaniment of external beam radiotherapy (EBRT) for treating high-risk prostate cancer (HPCaP). Both low dose-rate brachytherapy (LDR) as the sole method of radiotherapy and the need for ADT in conjunction with it are relatively unexplored with HRCaP. We present an inception cohort study of HRCaP patients treated with LDR alone with or without ADT. Methods: The study includes 515 patients with HRCaP according to NCCN guidelines. They were treated with I-125 LDR alone to a dose of 144 Gy with lateral, superior, and inferior margins of at least 5 mm (medin D90 = 149.39 Gy). The association of prostate cancer-specific mortality (PCSM) with pre-treatment variables was assessed with Fine and Gray regression with non-PCSM mortality treated as a competing event. PCSM rates were calculated using the cumulative incidence method. Results: The median age is 70 years. The median f/u is 48.9 months. Fifty-four percent were Gleason 7, 28% were Gleason 8, and 11% were Gleason 9. Fifty-three percent received ADT for a median duration of 6 months (range = 1-32 months). At 5 years, the PCSM rate was 1.2 % for LDR and 4.2% for LDR + ADT, and at 10 years, the PCSM rate for LDR was 3.3% and 4.2% for LDR + ADT (p = 0.34). Table 1 shows the association of pre-treatment factors with PCSM. Conclusions: ADT does not affect PCSM for HRCaP patients. Further studies should be done to explore if ADT is necessary with LDR for HRCaP. [Table: see text]
Is multiparametric MRI able to characterize margin for focal brachytherapy in low-grade prostate cancer?
Authors: Ken Soleakhena , Graff-Cailleaud Pierre , Bachaud Jean-Marc , Aziza Richard , Arnault Sandra , Lusque Amellie , Arnaud Francois-Xavier , Brun Thomas , Portalez Daniel , Malavaud Bernard
Published: March 2017

e555

Background: Focal brachytherapy is proposed in our institute as an alternative treatment to active surveillance for low-grade prostate cancer (PCa). This study aims at characterizing the tumor focus and its margin with multiparametric Magnetic Resonance Imaging (mpMRI). Methods: Patients pre-qualified for this study were positive for PCa (Gleason 3+3) on a previous standard biopsy series. New series of mp-MRI-guided and ultrasound-targeted biopsies were performed and in total, 17 patients with confirmed tumor and diameter < 20mm were included in this phase II clinical trial (NCT01902680). mpMRI were acquired on a 1.5T Magnetom Aera Siemens scan. Anatomic imaging consists in Fast Spin Echo T2-weighted MRI (T2-MRI) and functional Diffusion Weighted MRI (DWI-MRI) and Dynamic Contrast Enhanced MRI (DCE-MRI) were also performed. After mpMRI registration, tumor volumes of interest (VOI) were drawn on anatomic T2-MRI. VOI and VOI+2mm were reported on functional DWI-MRI and DCE-MRI. Extracted parameters were Apparent Diffusion Coefficient (ADC) and KTrans. All parameters distributions were analyzed with Olea Sphere v3.0 and compared to contralateral normal appearing tissue. Focal brachytherapy was then delivered to all patients with linked 125I seeds with a dose prescription of 152 Gy on the Planning Target Volume (PTV = VOI+2mm). Results: ADC parameters (mean, meadian, 25th and 75th percentiles) are found to be significantly lower in tumor volume (VOI) compared to contralateral normal tissue (p < 0.012 for all ADC parameters), confirming diffusion tumor mass restriction. Different distributions of ADC and KTrans were observed among patients: majority (66.66%) of low ADC and abnormal KTrans values were included in the VOI but interestingly, the 2mm margin allows us to treat additional abnormal ADC and KTrans volumes on 1/3 of the patients. Conclusions: This study confirms that mpMRI is a non-invasive technique able to characterize tumor margin for focal brachytherapy in low-grade PCa. Target volume margin definition is a hot topic when focal treatments (e.g. cryotherapy or HIFU) are considered and mpMRI can bring quantitative answers. Clinical trial information: NCT01902680.
Assessment of discomfort and pain in patients undergoing fusion-MRI-guided versus TRUS-guided prostate biopsy.
Authors: Robins Dennis , Lipsky Michael , Wenske Sven
Published: March 2017

e556

Background: The addition of MRI fusion guided prostate biopsy (FusionBx) to transrectal ultrasound guided template biopsy (TRUSBx) has increased sensitivity in detecting clinically relevant prostate cancer (PCa) over TRUSBx alone. FusionBx in conjunction with TRUSBx requires more biopsies in less accessible locations and takes more time than TRUSBx, suggesting that FusionBx+TRUSBx may be less tolerable to patients than TRUSBx alone. Objective of our study was to investigate patient pain associated with FusionBx+TRUSBx versus TRUSBx. Methods: Patients undergoing FusionBx+TRUSBx or TRUSBx alone from April through September 2016 at Columbia University Medical Center for PCa detection or surveillance were asked to complete a validated pain survey immediately after biopsy. Responses were graded from 0-10 (0: no pain/willing to return for repeat procedure; 10: excruciating pain/not willing to return for repeat procedure). Procedures were performed by a single urologist with a 1% Lidocaine periprostatic nerve block. Pain scores between groups were compared via Mann-Whitney U test. Results: A total of 94 patients were included, with 50 FusionBx+TRUSBx and 44 TRUSBx. For each group, median age was 66.5 (range 47-84) and 68 years (range 44-86), and median number of cores was 14 (range 12-22) and 12 (range 6-14), respectively. Prostate biopsy pain questionnaire scores did not differ significantly for any of the questions. Patients in both groups had mild discomfort overall with the procedure (3 out of 10), the probe insertion (2 out of 10) and the biopsy portion of the exam (3 out of 10). If medically necessary, both groups were very willing to come back for the same procedure again (1 out of 10). Conclusions: Patients reported no difference in pain or discomfort with added FusionBx relative to TRUSBx alone. Both procedures were mildly painful with patients very willing to return for repeat biopsy. Patients tolerate the addition of FusionBx to TRUSBx alone. Patients’ pain experience or discomfort does not seem to hinder whether FusionBx of the prostate should be performed, or not.