bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

98 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.
Integrated somatic subtypes of localized intermediate-risk prostate cancer.
Authors: Fox Natalie S , Lalonde Emilie , Livingstone Julie , Hopkins Julia , Shiah Yu-Jia , Huang Vincent , Yamaguchi Takafumi , Sabelnykova Veronica , Heisler Lawrence , Fraser Michael , van der Kwast Theodorus , Bristow Robert G. , Boutros Paul Christopher 
Published: March 2017

e560 Background: Approximately two thirds of intermediate risk prostate cancer patients are over- or under- treated because we cannot correctly prognose this risk group; therefore we require novel biomarkers to better direct patient therapies and avoid subjecting patients to side effects without benefit. One reason genomic biomarkers are not currently used in clinical settings is because they are notoriously difficult to validate in follow-up studies. Furthermore, the lack of clear prostate cancer subtypes prevents the development of subtype specific biomarkers as is standard practice in breast cancer. We aim to improve biomarker validation rates by defining prostate cancer subtypes that can be used to create subtype specific biomarkers. Methods: First, we assess large scale genomic patterns using whole genome sequencing and methylation data and create integrative subtypes for intermediate risk prostate cancer. Second, we assess associations between specific aberrations and subtypes, and determine whether certain types of molecular aberrations are more important background aberrations for subtype specific biomarker development. Finally, we assess biases in prognostic performance of the published Lalonde biomarker between groups associated with patient subtypes to show that subtype aware biomarkers are necessary. Results: We demonstrate that the Lalonde biomarker is biased by the cohorts’ proportion of TMPRSS2-ERG (T2E) aberrations illustrating the need to develop different biomarkers for patients with T2E and patients without T2E. Further, we suggest integrative subtypes can be used to select patients with similar genomic profiles for biomarker analysis to improve biomarker validation rates. Conclusions: This analysis provides direct guidance for future biomarker development and addresses an important barrier to clinical use of genomic biomarkers for prostate cancer.
Expression of somatostatin receptor subtypes, aurora kinase A, and interleukin-6 in prostate cancer before androgen ablation.
Authors: Gernone Angela , Trabucco Senia , Resta Leonardo , Napoli Anna 
Published: March 2017

e564 Background: Neuroendocrine differentiation (NED) in prostate cancer (PC) can be detected by immunohistochemistry as single cells in conventional adenocarcinoma. The extent of NED is associated with poor prognosis and early onset of castrate resistant prostate cancer. Aurora kinase A (AURKA) and Interleukin-6 (IL-6) cooperate to induce NED. The aim of this study was to correlate the expression of somatostatin receptor (SSTR) 1- 2- 3- 4- 5 subtypes, AURKA and IL-6 in primary PC with NED pattern and OS. Methods: PC tissues were reviewed from 60 pts who had undergone biopsy or radical prostatectomy for previously untreated advanced or metastatic PC from 2010 to 2016. 10 samples expressed histologically chromogranin A (CgA), a marker of NED expression. Median age was 67 years (47-80), Gleason score ≥ 7, median PSA was 60 ng/ml (1.3-1000), ECOG 0/1 and bone-visceral sites measurable in 90% of cases. For comparison purposes, 8 pathology specimens from pts with primary PC were used. Results: SSTR1-2-4-5 were detected in the nucleus of PC cells in 10/10 samples. SSTR3 and AURKA were not expressed in all 10 samples. IL-6 was detected in 9/10 samples. All 10 pts were associated with a more aggressive clinical course and OS was < 12 mos. Conclusions: In metastatic prostate cancer, pretreatment NED pattern can be a predictor for progression and survival after hormonal and chemotherapy. SSTRs and somatostatin analogs are not potential targets for prostate cancer.
Real life treatment sequences and survival of men with metastatic castrate-resistant prostate cancer (mCRPC) receiving cabazitaxel in clinical practice across England.
Authors: Birtle Alison J. , Bahl Amit , Butt Mohammad , Pan Shermaine , Carter Angela M , Thomson Alastair H 
Published: March 2017

e573 Background: New life-prolonging anticancer treatments (LPT), including docetaxel (D), cabazitaxel (C), abiraterone (A) and enzalutamide (E) have transformed outcomes for patients with mCRPC; however, optimal treatment sequencing is unclear. The aim of this study was to describe the anticancer treatment sequencing and outcomes of patients receiving cabazitaxel in England. Methods: A multi-centre, observational, retrospective study of mCRPC patients treated with cabazitaxel after docetaxel treatment failure was conducted. Data on patient characteristics, anticancer treatments, toxicity and outcomes were collected from medical records between March 2015 and March 2016. Results: 115 patients with mCRPC from 5 English hospitals were evaluated. Mean age at cabazitaxel initiation was 69.4 (SD: 6.7) years. Median time from mCRPC diagnosis to cabazitaxel initiation was 18.0 (interquartile range: 11.4–28.7) months. Cabazitaxel was 2nd line therapy after docetaxel in 58/115 (50%) patients. Patients received a median of 3 (range: 2–4) different LPTs: 5 patients received 2 therapies (DC = 5); 89 patients received 3 therapies (DAC = 44, DCA = 32, DCE = 7, ADC = 4, DEC = 1, EDC = 1); 21 patients received 4 therapies (DACE = 9; DCAE = 5; DCEA = 5; DAEC = 2). Median overall survival (OS) from mCRPC diagnosis and from docetaxel initiation according to number of LPTs is presented in the table. Conclusions: A variety of mCRPC treatment sequences are used in real-world practice. OS was greater in those patients receiving ≥3 LPTs, with a non-significant yet intriguing trend to longer OS with DCA. Further follow up may indicate whether this will become statistically significant. [Table: see text]