bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment outcomes of radiotherapy versus prostatectomy for localized prostate cancer with Gleason 8 or more on biopsy.
Authors: Baker Christopher , McDonald Andrew M. , Clark Grant , Dulaney Caleb , Yang Eddy Shih-Hsin , Jacob Rojymon , Fiveash John B. 
Published: February 2017

120 Background: There have been no prospective randomized controlled trials comparing current treatment options for patients with high-risk localized prostate cancer. This study seeks to compare the biochemical and metastatic outcomes of patients that received definitive radiotherapy (dRT) or radical prostatectomy (RP) for localized prostate cancer with Gleason score ≥ 8 on initial biopsy. Methods: A total of 106 patients met the inclusion criteria of Gleason score ≥ 8 on initial biopsy and biochemical follow-up ≥ 1 year. Seventy-one patients were initially treated with dRT (96% also receiving androgen deprivation therapy) and 35 patients were initially treated with RP (with or without postoperative RT). Our primary endpoint was biochemical failure (BF). For dRT patients, BF was recorded according to the Phoenix Consensus or if extranodal metastasis was diagnosed. For surgical patients, BF was recorded according to American Urological Association guidelines or if extranodal metastasis occurred. If adjuvant/salvage RT was given postoperatively, BF was recorded if PSA ≥ 0.5 on two consecutive measures after completion of RT. Pretreatment characteristics were compared using Pearson Chi-square method and independent samples Mann-Whitney U test. Actuarial rates of BF and metastasis were calculated using the Kaplan-Meier method. Results: Median follow-up for all patients was 5.3 years. There was no statistical difference in clinical T-stage, initial PSA, or months of follow up between patients treated initially with radiotherapy vs. prostatectomy. Patients initially treated with dRT were significantly older than those treated with RP. The dRT group had a lower rate of BF compared to the RP group, p < 0.001. The Kaplan-Meier estimate of BF at 5 years was 7.6% in the dRT group compared to 34.5% in the RP group. Additionally, the Kaplan-Meier estimate of distant metastasis at 10 years was 22.7% in the dRT group compared to 55.9% of the RP group, p = 0.01. Conclusions: For our sample of patients with Gleason score ≥ 8 on initial biopsy, initial treatment with dRT was associated with lower rates of biochemical failure and extranodal metastasis when compared to initial treatment with prostatectomy.
Association of NaF PET/CT findings with PSA and alkaline phosphatase in untreated castration-sensitive prostate cancer.
Authors: Couvillon Anna , Turkbey Baris , Lindenberg Maria Liza , Choyke Peter L. , Martinez Mirna , McKinney Yolanda , Kaushal Aradhana , Citrin Deborah E. , Krauze Andra , McNally Deborah , Giordano Luz , Chun Guinevere , Royce Cheryl , Han Hui , Karzai Fatima , Parnes Howard L. , Pinto Peter A. , Gulley James L. , Dahut William L. , Madan Ravi Amrit 
Published: February 2017

122 Background: NaF PET/CT is an emerging imaging technique with potentially high sensitivity in detecting bone metastasis (mets), however, its role in castration-‐sensitive prostate cancer (CSPC) is undefined and it remains unclear which CSPC patients should have NaF PET/CT. Methods: We retrospectively reviewed NaF PET/CT scans done on 45 patients with untreated, high risk CSPC with the goal of determining which disease features were associated with positive findings. Two blinded radiologists reviewed each scan and determined by consensus if findings were negative for metastasis (0% liklihood of mets), possible (50%), probable (75%), or consistent with mets (90%). Prostate specific antigen (PSA) and alkaline phosphatase (AP) values were then evaluated at time of NaF scan when available. Results: Of the 45 patients 2 were Gleason 6, 5 were Gleason 7, 36 were Gleason 8 to 10, 2 unknown. When grouped by findings on NaF PET/CT, there were no substantial differences seen between median PSA or AP values. When patients with both PSA and AP values > median were evaluated, there was no clear association with NaF PET/CT findings. Conclusions: Preliminary findings from this small retrospective analysis suggest that there may be limited associations between PSA and/or AP with findings on NaF PET/CT scan in untreated patients with CSPC. Further analysis in larger cohorts of pts is required. [Table: see text]
Racial variation in positive prostate needle biopsy templates, which include the transition zone.
Authors: Feibus Allison H. , Levy Justin , Moparty Krishnarao , McCaslin Ian R. , Maddox Michael M. , Sartor Oliver , Silberstein Jonathan L. 
Published: February 2017

125 Background: Reports have suggested that African Americans (AA) with prostate cancer (PCa) have both increased incidence and increased aggressiveness of tumors located in the transition zone (TZ). Our goal was to evaluate the utility of TZ−directed prostate biopsies in a predominantly AA population at a Veterans Affairs Hospital. Methods: After obtaining IRB approval, we retrospectively reviewed all patients with PCa found on a 14 core biopsy in which 12 needle biopsies were directed at the peripheral zone (PZ) and 2 at the TZ, between January 2010 and June 2014. Location of disease was determined by the results of the biopsy, either PZ alone, TZ alone or both. Aggressiveness of disease was defined by Gleason grade, percent involvement of PCa in any core and NCCN risk-stratification. Self−identified race was recorded for all patients. A series of Mann Whitney U and Chi−square tests were used to compare variables. Results: The total patient cohort consisted of 398 men, in which 277 (70%) were AA. When compared with Caucasian Americans (CA), AA patients had more NCCN intermediate or high risk (50% vs 39%, p = 0.25) PCa. Most patients had PCa limited to the PZ only (n=190) or in both the PZ and TZ (n=191). For 17 patients (4%) PCa was limited to TZ core(s) only, 14 (5%) AA vs 3 (2%) CA (p = 0.24). Of these 17 patients, 14 (82%) had Gleason 6 only disease. Patients with PCa in both the PZ and TZ had higher PSA and PSA density, greater volume of disease, higher-grade lesions and worse NCCN category (all values p <0.01) compared with patients in which the positive biopsy was limited to the PZ. Of these 191 TZ and PZ positive patients, a greater proportion were AA (n=135, 49%) compared to CA (n=56, 46%) (p = 0.48). For patients with PZ and TZ disease, the TZ had the highest-grade in 21 (11%) men, 10% AA and 13% CA (p = 0.67). For most patients (89%), PZ tumor grade was equal to or greater than TZ. Conclusions: TZ−directed prostate needle biopsy cores were rarely the sole location of PCa and when found were usually low grade without clear racial variation. Patients with PCa in both the PZ and TZ had aggressive disease regardless of race although the TZ core resulted in upgrading in a minority of patients. TZ-directed biopsies do not appear to be of greater benefit to AA than CA.
Association of "DNA damage signature" with poor outcome in early prostate cancer.
Authors: Iddawela Mahesh , Pazaro Carmel , Lawrence Mitchell , Furic Luc , Taylor Renea , Risbridger Gail 
Published: February 2017

13 Background: Whole genome and matching normal tissue analyses in prostate cancer patients have shown that widespread genomic changes occur in multiple distant regions of the genome simultaneously (Baca et al., Cell. 2013). The inherent genomic instability in prostate cancers causes activation of pathways involved in DNA damage, which could be a prognostic and potentially predictive marker for treatment with agents impacting DNA repair (e.g. PARP inhibitors). Using a published dataset, a “DNA damage signature” was generated to test its role as a potential prognostic marker. Methods: A 10-gene signature was generated, using the top 9 genes (MXD3, ZMYND19, BANF1, TOMM40, UBE2S, SNRPF, RPP21, CDK2AP2 and H2AFX) correlated with H2AFX expression, which is known to be unregulated upon DNA damage. TP53 was added due to its significant role in this pathway. This signature was then assessed in The Cancer Genome Atlas dataset (TCGA, unpublished data at NCI) as a discovery set and then validated in the MSK dataset (Taylor et al., 2010) using mutation, copy number, mRNA and proteomic data. Results: Genes in the signature were altered in 31% (77/246) of patients, by amplification and over expression compared to normal. The most frequent alterations were found in TP53 (15%), MXD3 (7%), BANF1 (7%), UBE28 (7%) and CDK2AF2 (7%). Analysis of protein changes associated with alteration in genomic signature showed upregulation of FOXO3, BCL2L1, BAK1 and PCNA (P<0.05). There were significant correlations between the signature and Gleason score (p=0.0015), PTEN (p=0.003) & RAD51 gene expression (p<0.001), but not with ERG,PSA, PIK3CA or BRCA2. Patients with alterations were associated with poor disease free survival (DFS) (p=0.002). When expression was assessed in the validation set, 73%(62/85) samples showed altered gene signatures and those with alterations also had poor DFS (p=0.003). Conclusions: The DNA damage signature can be used to define a group of patients with poor outcome and has the potential to be used as prognostic marker in treatment decisions in early prostate cancer patients.
Does focal high-intensity focused ultrasound have a role in treating localized prostate cancer in the elderly?
Authors: Guillaumier Stephanie , McCartan Neil , Dickinson Louise , Fatola Yomi , Freeman Alex , Hindley Richard , Emberton Mark , Ahmed Hashim Uddin 
Published: February 2017

133 Background: There is an increase in the ageing population leading a significant proportion of men diagnosed with prostate cancer being over 75 years of age. Misconceptions regarding treating the elderly are still rife. The body of evidence that has recently emerged shows that this cohort of patients should be offered the same curative therapies as their counterparts. This study looks at the feasibility of focal HIFU in treating localised prostate cancer in those aged over 75 years of age. Methods: Our independent academic HIFU registry incorporates a total of 60 patients who were diagnosed with low, intermediate and high risk localized adenocarcinoma of the prostate, stage T2a-T3aN0M0 and treated with focal HIFU using Sonablate500, between 2004 and 2014. We divided the patient cohort into those that were treated within the remit of a trial protocol, and those that were not. Results: As biochemical failure is difficult to define, we looked at the medium-term transition rates to redo HIFU, local salvage and systemic therapy. 12% required re-treatment with HIFU. 8% transitioned into local salvage or systemic therapy of which 1 patient had radiotherapy and 4 were subsequently treated with androgen deprivation therapy). The table below outlines the complication rates associated with focal HIFU. Conclusions: Focal HIFU has been shown to be both feasible and effective in the elderly population. It is a safe modality of treatment to use in this patient cohort with a low complication profile. Long-term studies are however necessary. [Table: see text]
Final analysis of COMET-1: Cabozantinib (Cabo) versus prednisone (Pred) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E).
Authors: Smith Matthew Raymond , De Bono Johann Sebastian , Sternberg Cora N. , Le Moulec Sylvestre , Oudard Stephane , De Giorgi Ugo , Krainer Michael , Bergman Andre M. , Hoelzer Wolfgang , De Wit Ronald , Boegemann Martin , Saad Fred , Cruciani Giorgio , Thiery- Vuillemin Antoine , Feyerabend Susan , Miller Kurt , Ramies David Albert , Hessel Colin , Weitzman Aaron , Fizazi Karim 
Published: February 2017

139 Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in bone scans, pain, measurable disease, and circulating tumor cells. COMET-1 compared the effects of Cabo versus Pred on overall survival (OS) in men with progressive mCRPC and prior D and A and/or E. Methods: In this randomized, double-blind, controlled phase 3 study (NCT01605227), pts with mCRPC and prior D and A and/or E were randomized 2:1 to receive Cabo (60 mg qd) or Pred (5 mg bid). Pts were stratified by prior treatment with cabazitaxel, ECOG status, and presence of moderate to severe pain. The primary endpoint was OS. The study was designed to observe 578 deaths to provide 90% power to detect a hazard ratio (HR) of 0.75. A secondary endpoint was bone scan response at Week 12 (BSR) determined by central independent radiology committee, defined as a ≥30% decrease in the bone scan lesion area compared to baseline. Exploratory endpoints include PFS and OS subgroup analyses. Results: 1,028 pts were randomized between Jul 2012 and Nov 2013. In the final analysis after 614 deaths, the estimated median OS was 11.0 months for Cabo vs 9.8 months for Pred (HR 0.90; 95% CI: 0.0.76-1.06; P = 0.212). The secondary endpoint of BSR was 41% for Cabo vs 3% for Pred (P <0.001). Median PFS per investigator was 5.5 months for Cabo vs 2.8 months for Pred (HR 0.50; P <0.001). For 191 pts with visceral disease median OS was 7.1 months for Cabo vs 4.8 months for Pred (HR 0.65; P = 0.0215). 371 (54.4%) and 233 (67.3%) pts received salvage therapy in the Cabo and Pred arms, respectively. Subsequent cabazitaxel and/or D was reported in 107 (15.7%) and 104 (30.1%) Cabo and Pred pts, respectively. Serious adverse events of pulmonary embolism, nausea, dehydration and fatigue were more frequent with Cabo. Conclusions: Compared to prednisone, Cabo improved BSR and PFS but did not significantly increase OS. The improvement in OS was greatest in the subset of patients with visceral metastases. The activity and safety profile of Cabo was similar to that observed in phase 2 studies in mCRPC. Clinical trial information: NCT01605227.
A phase 2 study of prostate specific membrane antigen antibody drug conjugate (PSMA ADC) in patients (pts) with progressive metastatic castration-resistant prostate cancer (mCRPC) following abiraterone and/or enzalutamide (abi/enz).
Authors: Petrylak Daniel Peter , Vogelzang Nicholas J. , Chatta Gurkamal S. , Fleming Mark T. , Smith David C. , Appleman Leonard Joseph , Hussain Arif , Modiano Manuel , Singh Parminder , Tagawa Scott T. , Gore Ira , McClay Edward Francis , Mega Anthony E. , Sartor A. Oliver , Somer Bradley G. , Wadlow Raymond Couric , Shore Neal D. , Stambler Nancy , DiPippo Vincent A. , Israel Robert Joseph 
Published: February 2017

144 Background: PSMA is a validated target that is overexpressed selectively on prostate cancer cells. PSMA ADC is a fully human IgG1 antibody conjugated to the microtubule disrupting agent MMAE which binds to PSMA-positive cells, inducing cytotoxicity. A phase 1 study showed activity and tolerability at doses from 1.8-2.5 mg/kg. We have enrolled 119 mCRPC pts who progressed following abi/enz in a phase 2 trial of PSMA ADC. Methods: mCRPC pts (83 taxane experienced (TE) and 36 chemo-naïve (CN)) were administered PSMA ADC 2.5 or 2.3 mg/kg IV Q3 wk for up to 8 cycles. 95% of pts received prior abi and/or enz treatment. Safety, antitumor activity (including PSA, CTCs, and tumor imaging) and exploratory biomarkers were assessed. Results: In all treated pts, PSA declines of ≥30% and ≥50% were 30% and 14%, respectively (n=113); CTC counts showed a decline of ≥50% in 78% of pts and conversion from ≥5 to <5 cells/7.5 ml blood in 47% (n=77) at any time during the study. For 2.3 mg/kg pts (n=82), corresponding PSA declines were 35% and 17%; CTC declines of ≥50% were seen in 81% and conversions in 46% (n=54). For CN pts, PSA declines of ≥30% and ≥50% were 31% and 20% (n=35); CTC declines of ≥50% were seen in 89% and conversion in 53% (n=19). Radiologic response by RECIST in 31 pts with measurable target lesions: PR in 4 pts, SD in 19 pts, and PD in 8 pts. Efficacy responses were associated with: low neuroendocrine serum markers (low CgA, low NSE, and high PSA), high PSMA expression (CTCs or tumor tissue). The most common treatment-related AEs ≥CTCAE grade 3 were neutropenia (TE: 25%; CN: 22%), fatigue (20%; 8%), electrolyte imbalance (16%; 11%), anemia (10%; 8%), and neuropathy (8%; 8%). Grade 1-2 neuropathy occurred in 40% (TE) and 50% (CN) of pts. Two 2.5 mg/kg pts (n=34) and one 2.3 mg/kg pt (n=85) died of sepsis. 2.3 mg/kg was better tolerated than 2.5 mg/kg. Conclusions: PSMA ADC was active in abi/enz refractory mCRPC pts. Clinically significant AEs included neutropenia and neuropathy. CTC conversions/reductions, PSA declines, and radiologic evidence of antitumor activity were seen in CN as well as heavily pretreated pts. Clinical trial information: NCT01695044.
A comprehensive molecular characterization of aggressive variant prostate cancer (PC).
Authors: Aparicio Ana , Shen Li , Tapia Elsa Li Ning , Lu Jing-Fang , Chen Hsiang-Chun , Zhang Jiexin , Wu Guanglin , Wang Xuemei , Troncoso Patricia , Broom Bradley McIntosh , Baggerly Keith A. , Logothetis Christopher , Maity Sankar N. 
Published: February 2017

149 Background: Unusually aggressive PC behavior is linked to small cell carcinoma (SCC) morphology. We observed SCC clinical features in association with morphologically heterogeneous PC and, in a prospective clinical trial (NCT00514540), also with chemotherapy responsiveness. Our previous studies in patient derived xenografts (PDX) revealed a distinct molecular profile for SCC. Here we sought to support the hypothesis that clinically defined aggressive variant PCs also share relevant biology with SCC. Methods: 59 PC samples, and 8 PDX, from 42 men registered to NCT00514540 were stained for RB, p53, AR, NKX3-1, ASCL1, AURKA, UBE2C and Ki67. Labeling indices (LI) were calculated as the ratio of positive epithelial cells to total of epithelial cells, at 200x. We determined copy number alterations (CNA) by Onco Scan® in 36 of 59 samples and 8 PDX lines. We used Western Blot and qRT-PCR to expand pathway analyses and their associations in PDX models. Results: Donor patients were similar to non-donor patients except for higher ECOG PS and LDH values. Strong positive correlations between nuclear AR (AR-N) and NKX3.1, AR-N and RB, AR-N and nuclear AURKA (AURKA-N), NKX3.1 and RB, p53 and nuclear UBE2C (UBE2C-N), Ki67 and UBE2C-N, Ki67 and cytoplasmic UBE2C (UBE2C-C) as well as a strong negative correlation between NKX3.1 and Ki 67 were observed. Frequent copy number losses were found for PTEN (largely gene-specific) and RB1 (often associated with regional-CNA). Gene-specific AURKA amplifications were not observed. Only RB1 CNA showed a positive correlation with its LI. Samples were segregated by quantity of CNA. PDX models shared these features and showed that only AR-negative tumors expressed pro-neural transcription factors, albeit heterogeneously. Conclusions: Our results support the hypothesis that clinically defined aggressive variant PC (including SCC and non-SCC morphologies) are characterized by frequent Rb, p53 and PTEN alterations, aberrant expression of mitotic, neural development and AR-signaling pathways, and high rates of CNA. Ongoing studies will confirm whether these molecular features distinguish this variant from the more common bone-homing, bone-forming, AR-driven adenocarcinomas of the prostate.
Cautionary tale of active surveillance in intermediate-risk patients: Overall and cause-specific survival in the Sunnybrook experience.
Authors: Musunuru Hima Bindu , Klotz Laurence , Vespirini Danny , Zhang Liying , Mamedov Alexandre , Sethukavalan Perakaa , Jethava Vibhuti , Yamamoto Toshihiro , Jain Suneil , Loblaw D. Andrew 
Published: February 2017

163 Background: To document the long-term outcomes of intermediate risk (IR) prostate cancer patients managed on active surveillance (AS) protocol in a single institute. Methods: Patients(pts) with PSA >10ng/ml or Gleason score 7 or clinical stage T2b/2c were identified from a prospectively collected database of 945 patients managed on AS between 1995 and 2013. Intervention was offered to those pts with a PSA doubling time of < 3 years, Gleason score or clinical progression.Overall survival (OS), cause-specific survival (CSS) for IR and low risk (LR) pts were analyzed as well as metastasis free survival (MFS) and treatment-free survival (TFS) for IR pts. Results: 237 (23.9%) pts had IR disease, with a median follow up of 6.9 years (IQR 3.89, 10.85) .708 pts had LR cancer with a median follow up of 6.4 years (IQR 3.76, 9.03). 61.2% of the IR cohort was older than 70 years. 86 IR pts (36.3%) received treatment (mainly radiation). The median treatment free interval for IR pts was 12.3 years (range 10.1 - 19.8). 33 IR patients developed biochemical failure and 17 developed metastatic disease [11 IR pts(4.6%) and 6 LR pts(0.8%)].The 10 and 15year OS was 68.4% and 50.3% for IR pts;83.6% and 68.8% for LR pts (p value <0.0001).Similarly 10 and 15 year CSS was 95.5% and 88.5% for IR ; 98.2% and 96.3% for LR pts (p value=0.006).The hazard ratio for IR pts versus LR pts was 2.08 for OS and 3.75 for CSS.IR pts had 3.75 times higher chance of dying from prostate cancer when compared to LR pts (Table). 10 year MFS and TFS were 92.1% (87.4-97.1%) and 58.5% (51.6-66.4%) in the IR cohort. Survival outcomes did not vary according to the year of patient enrollment. Conclusions: AS for intermediate risk prostate has significantly lower OS and CSS compared to low risk patients and therefore extreme caution should be exercised if it were to be implemented in intermediate risk patients. [Table: see text]
Molecular characterization of heterogeneity in circulating tumor cells (CTCs) and tumor samples of metastatic castration-resistant prostate cancer (mCRPC) patients: The multicenter PETRUS program.
Authors: Massard Christophe , Oulhen Marianne , Le Moulec Sylvestre , Loriot Yohann , Auger Nathalie , Beuzeboc Philippe , Albiges Laurence , Culine Stephane , Oudard Stephane , Hennequin Christophe , Vielh Philippe , Farace Françoise , Fizazi Karim 
Published: February 2017

165 Background: In order to optimize molecular screening in advanced prostate cancer patients, we implemented a prospective molecular triage trial PETRUS (NCT01786031), based on molecular characterization of fresh tumor biopsies and circulating tumor cells (CTCs) in patients with mCRPC. The primary objective was to investigate the feasibility of prospectively performing molecular profiling of CRPC patients. Methods: A tumor biopsy from a metastatic and tumor primary site, along with blood samples specimen were collected from patients, and both frozen and FFPE samples were obtained. CTCs were detected using two methods, CellSearch and filtration (ISET, isolation by Size of Epithelial Tumor cells) combined to four-color immunofluorescent staining. Results: From December 2012 and March 2014, 51 CRPC patients with metastases accessible for biospy were included in 5 centres in France. Tumor biospy were successful (≥ 50% tumor cells) in 36/51 pts (72%). CTCs with different phenotypes were detected by CellSearch and ISET combined to four-color immunofluorescent staining in 28 (51%) pts. FISH AR and ERG was successful in only 54% and 32% of metastasis biopsies and primitive tumors respectively, most likely due to the absence of tumor cells or overfixation. The ISET platform was able to detect CTCs clusters, CTCs expressing epithelial and vimentin markers. AR amplification and ERG rearrangement analyses showed high level of heterogeneity with evidence of multiple CRPC iCTC subpopulation. A high level of heterogeneity between CTCs, metastasis biopsies and primitive tumors was observed for ERG rearrangement and AR amplification status. Conclusions: Our results demonstrate that CTCs could be an alternative source for surrogate molecular marker assessment in mCRPC, but neither approach could truly reflect the extreme heterogeneity observed in CTCs from mCRPC. Our preliminary results suggest also the operational feasibility of metastatic tumor biopsy: high interest for patients, significant yield of tumor biopsies and ad hoc molecular analysis. Clinical trial information: NCT01786031.