bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplexed protein and gene profiling of circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) using automated immunofluorescence and fluorescence in situ hybridization.
Authors: Nagy Dea , Tucker Eric , Rajkovich Samatha , French Steven , Garsha Karl , Yun Steve , Smith Katherine , Sallam Karim , Liabotis Elias , Otter Michael , Marrinucci Dena , Dittamore Ryan 
Published: February 2017

158 Background: Clinically, CTCs are used primarily in longitudinal monitoring of metastatic disease progression. However, the analysis of specific CTC biomarkers has the potential to optimize patient management by identifying those likely to respond to specific targeted agents. Often, mCRPC is driven by dysregulation of the androgen receptor (AR) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) oncogenic pathways such that blockade of one pathway stimulates the other. These functional deficits in the AR and PI3K/AKT pathways are associated with fusion of the TMPRSS2 and ERG genes and with loss of PTEN protein, respectively. Therefore, we sought to characterize CTCs for the simultaneous presence of both these biomarkers using immunofluorescence (IF) and fluorescence in situ hybridization (FISH). Methods: Nucleated peripheral blood cells from mCRPC patients were attached to slides and examined using CTC technology (Epic Sciences). Cytokeratin-positive/CD45-negative cells with an intact nucleus and a malignancy-consistent morphology were identified as CTCs, and their exact positions on the slides were recorded. The slides were then subjected to multiplex Quantum Dot IF and FISH procedures with anti-AR, -ERG, and -PTEN antibodies and 5’ERG, 3’ERG, PTEN, and Cen10 probes, respectively, on an automated slide-staining platform (Ventana Medical Systems, Inc.). The IF and FISH signals were visualized by spectral imaging (Ventana). Results: The automated IF/FISH staining procedure facilitated multiplex characterization of individual CTCs from patient samples for the protein biomarker targets AR, ERG, and PTEN and the genomic biomarker targets 5’ERG, 3’ERG, PTEN, and Cen10. Conclusions: This method for high-sensitivity, multiplex molecular characterization of critical CTC biomarkers in mCRPC patients might aid oncologists in identifying and stratifying those patients likely to respond to combination therapy with targeted PI3K/AKT inhibitors and anti-androgens/Cyp17 inhibitors. Patient trials examining the clinical utility of this assay in mCRPC are currently underway.
Castration resistance and risk of bone metastases among men with nonmetastatic prostate cancer on androgen-deprivation therapy: A population-based cohort study from the Henry Ford Health System (HFHS) in Detroit, Michigan.
Authors: Beebe-Dimmer Jennifer , Cetin Karynsa , Yee Cecilia , Stryker Scott , Lamerato Lois , Schwartz Kendra L. , Shahinian Vahakn B. 
Published: February 2017

163 Background: Androgen deprivation therapy (ADT) is the cornerstone treatment of metastatic prostate cancer (PC), but is frequently used in the non-metastatic (M0) setting. After a variable period of hormone sensitivity, most patients develop castration-resistant prostate cancer (CRPC). These men are at increased risk of developing bone metastases (BM), particularly in those with higher serum PSA and shorter PSA doubling time (DT). The epidemiology and natural history of M0 CRPC has not been well studied in a population-based setting. Methods: Using HFHS patient records, a retrospective cohort study was conducted among 723 men diagnosed with M0 PC between 1996 and 2005 (with follow-up [f/u] for outcomes through 12/31/2008), who received ADT, including 613 men with serial PSA measurements for CRPC determination. CRPC was defined as 2 consecutive PSA rises, with “high-risk” defined as PSA ≥ 8 ng/mL or PSA DT ≤ 10 months (mos) after the development of CRPC. The risk of subsequent BM was estimated for the overall cohort and for the CRPC and non-CRPC subsets. Results: The median age among patients in the study was 73 years, 48% were African American, and median f/u time after ADT initiation was 58 mos. 15% (n=93) met criteria for CRPC during f/u (with a median of 23 mos between ADT initiation and establishment of CRPC), with the majority considered being at high risk (n=81). Among the entire cohort, 74 men (10%) developed BM during f/u. The rate of BM was 4 times higher among CRPC patients compared to non-CRPC patients (p<0.001), with a median of 6 mos between CRPC and subsequent BM. No racial difference was observed with either the incidence of CRPC or BM. Conclusions: The HFHS resource allowed for investigation of disease progression in a racially diverse population. A substantial proportion of M0 PC patients on ADT will eventually develop CRPC and once castration-resistant, risk of BM is high.
Stereotactic body radiation therapy (SBRT) following procedures for benign prostatic hyperplasia (BPH): A report on early toxicity.
Authors: Gurka Marie Kate , Horne Zachary D. , Chen Leonard , Lei Sue , Krishnan Pranay , Kowalczyk Keith , Suy Simeng , Dritschilo Anatoly , Lynch John H. , Collins Sean P. 
Published: February 2017

165 Background: When treating patients with prostate cancer, hypofractionation with SBRT takes advantage of radiobiologically favorable factors as compared to conventional fractionation. However, this may increase the risk of urinary toxicity, especially in patients with prior procedures for BPH. Herein, we report early urinary toxicity following SBRT in patients with a history of procedures for BPH. Methods: Thirty three patients treated with SBRT for localized prostate cancer from February 2009 to October 2011 at Georgetown University Hospital with history of a prior procedure for BPH were included in this retrospective analysis. Treatment was delivered using the CyberKnife with doses of 35 Gy-36.25 Gy in 5 fractions. Toxicities were scored using the CTCAE v.3. Cystoscopy findings were retrospectively reviewed. Patient-reported urinary symptoms were assessed using the American Urological Association Symptom Score (AUA). Results: The median age was 70 years (range, 64 - 84). The median follow-up time was 18.7 months (range 9.2 – 38.9). Grade 2 or 3 urinary toxicity occurred in 9 patients and there were no grade 4 or 5 toxicities. Hematuria occurred in 12 patients. The median time to onset of hematuria from SBRT was 6 months (range 1 – 30). Grade 1 hematuria occurred in 7 patients, grade 2 in 4 patients and 1 patient experienced grade 3. Cystoscopy was performed in 9 of these patients at a median time of 9 months (range 3-27). Eight had hyperemia or evidence of bleeding from the prostatic urethra and 5 of these patients also had evidence of bleeding from the bladder neck/wall. All patients except one, who died from other causes, are still being followed and hematuria has resolved in 9 of the 12 patients. The median baseline AUA symptom score of 7 increased to 11 at 1 month, however decreased to a median score of 6 at 3 months. The median AUA symptom score increased to 9 at 1 year. Conclusions: A history of prior transurethral resection of prostate may predispose patients to increased urinary toxicity and hematuria following prostate SBRT. Stricter urethra/bladder neck dosimetric criteria or alternative fractionation regimens may be required to decrease urinary toxicity in these patients.
PSA doubling time of ≤6 months as the optimal cutoff for predicting clinically relevant outcomes for men receiving salvage radiation therapy post radical prostatectomy.
Authors: Jackson William C. , Johnson Skyler B. , Foster Benjamin , Foster Corey , Song Yeohan , Li Darren , Sandler Howard Mark , Palapattu Ganesh S. , Hamstra Daniel A. , Feng Felix Yi-Chung 
Published: February 2017

167 Background: Short PSA doubling time (PSADT) after biochemical recurrence (BR) post radical prostatectomy (RP) is known to predict worse outcomes following salvage external beam radiation therapy (SRT). The ideal PSADT cut-off, however, in this context remains uncertain. In this study, we sought to identify the best PSADT cut-off for predicting clinical outcomes following SRT for BR after RP. Methods: 575 patients who received SRT at a single institution for BR after RP were retrospectively reviewed in an IRB approved analysis. The impact of PSADT on biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) was assessed using Kaplan-Meier and Cox Proportional Hazards models. Results: Median follow up was 56.7 months post SRT. PSADTs could be calculated for 277 patients. PSADT strongly predicted BF, DM, PCSM, and OS on univariate analysis regardless of cut-off point. There was no statistical difference in BF, DM, PCSM, or OS between patients with PSADT <3 (n=40) and 3-6 months (n=61) or between 6-10 (n=62) and >10 months (n=114). A difference existed in BF (p<0.01 HR: 2.2 [95%CI: 1.4-3.5]) and DM (p=0.02 HR: 2.2 [95%CI: 1.2-4.3]) between PSADT of 3-6 and 6-10 months. PSADT ≤6 had the largest positive predictive value (PPV) for BF (70%), DM (36%), and PCSM (13%) at 5 years. There was no difference in negative predictive value between a PSADT >10 vs. >6 months for BF, DM, PCSM, and OS with 5 year rates of (60% vs. 60%, 86% vs. 86%, 99% vs. 98%, and 95 vs. 94% respectively). On multivariate analysis PSADT ≤6 was a strong predictor of BF (p<0.01 HR: 2.1 [95%CI: 1.5-3.0]), DM (p=0.01 HR: 2.0 [95%CI: 1.2-3.4]), and PCSM (p=0.04 HR: 2.3 [95%CI: 1.1-5.2]), with a trend towards predicting OS (p=0.12 HR: 1.5 [95%CI: 0.9-2.6]). Conclusions: A PSADT ≤6 months was the best predictor of outcomes in our data set, particularly for DM and PCSM. Currently, the most common predictive nomogram for SRT uses PSADT <10 months as the cut-off point for BF. These results suggest that using a PSADT of ≤6 months may improve the ability to predict clinically significant outcomes and hence identify men who may benefit from additional therapy.
Long-term tolerance of neoadjuvant docetaxel/estramustine chemotherapy in patients with high-risk localized prostate cancer treated at IGR in the GETUG 12 phase III trial.
Authors: Bosset Pierre-Olivier , Albiges Laurence , Laplanche Agnes , Massard Christophe , Loriot Yohann , Di Palma Mario , Fizazi Karim 
Published: February 2017

168 Background: The GETUG 12 phase III trial tested the adjunction of docetaxel-estramustine to standard treatment in 413 patients with high-risk prostate cancer (Eur J Cancer 2012, 48: 209-17). Patients in both arms received androgen deprivation therapy (ADT) for 3 years plus local treatment (radiotherapy: 87%, median dose: 74 Gy). Pts in the chemotherapy arm also received 4 cycles of docetaxel 70mg/m2 /3weeks + estramustine 10 mg/kg/d d1-5, repeated every 3 weeks. Immediate tolerance was acceptable with only 2% of febrile neutropenia and no toxic deaths. As the long-term impact of chemotherapy in this setting is unknown, long-term side effect assessment was undertaken in pts from GETUG 12 who were treated at the Institut Gustave Roussy (n=81). Methods: After pts had completed the planned 3 years of ADT, they were followed-up every 6 months. Data on weight, sexual function, serum testosterone, and cardiac complications were obtained prospectively, in parallel with efficacy data. Pts requiring salvage therapy for cancer progression were censored in this analysis. Results: The median follow-up is 71.6 months (range: 36- 108 months). The main long-term side effects are listed in the table below. 4 (4.9%) and 1(1.2%) cardiovascular events occurred in the ADT and the ADT + chemotherapy arm, respectively. Conclusions: Docetaxel-estramustine chemotherapy had no adverse long-term impact on serum testosterone, weight, and sexual function in patients with high-risk localized prostate cancer treated with ADT and radiotherapy. [Table: see text]
Variations in treatment modality use for the definitive management of prostate cancer in the United States.
Authors: Ciezki Jay P. , Reddy Chandana A. , Ulchaker James , Angermeier Kenneth , Stephans Kevin L. , Tendulkar Rahul D. , Stephenson Andrew J. , Chehade Nabil , Altman Andrew , Klein Eric A. 
Published: February 2017

174 Background: No prospective, randomized comparative efficacy trial exists to guide treatment of definitively managed prostate cancer patients. Despite this, treatment selection varies nationally and we attempt to assess these patterns of use. Methods: The SEER database was queried to identify cases of prostate cancer diagnosed between 1998-2008. The modalities identified were brachytherapy (brachy), combination of brachytherapy and external beam radiation (CombRT), external beam radiotherapy (EBRT), radical prostatectomy and external beam radiotherapy (RP+RT), and radical prostatectomy (RP). The number of cases by year, patient age and SEER region was computed. Results: There were 361,135 men in this analysis: 12.4% brachy, 6.8% CombRT, 27.5% EBRT, 3.1% RP+RT, and 50.3% RP. As expected, treatment modality varied by age with younger men more likely to receive RP and older man more likely to receive EBRT or brachy. There was some variation in choice of treatment modality over time: 6.6% for brachy; 4.2% for CombRT; 1.9% for EBRT; 2.0% for RP+RT; and 7.8% for RP. The variation in treatment modality by region was surprisingly wide (table): 14.4% for brachy; 25.5% for CombRT; 28.5% for EBRT; 3.8% for RP+RT; and 26.8% for RP. Conclusions: Choice of prostate cancer treatment modality varies by age, year of treatment, and most notably geographical region. Surprisingly the changes in reimbursement rates over the study period seem to have had minimal impact on choice of treatment modality. The regional variation implies that affiliations among healthcare providers significantly impact treatment. [Table: see text]
Heterogeneity of treatment effects (HTE) in stage IV prostate cancer (S4PC).
Authors: Mitikiri Nirupama Devi , Reese Emily S , Hussain Arif , Onukwugha Ebere , Pritchard Daryl , Dubois Robert W. , Mullins C. Daniel 
Published: February 2017

180 Background: HTE occurs when individual patient factors modify a treatment’s effect on health outcomes in a non-random and predictable manner. HTE results in specific subgroups of patients in the same study having different responses to the same treatment due to interactions between their individual factors and the treatment. Methods: A systematic literature review was conducted of articles published between 1946 and 2011. Inclusion criteria required that articles examine the impact of HTE factors on survival outcomes (OS, TTP, PFS) or QOL among S4PC patients, in the context of a specific treatment. The quality of evidence was graded as good, fair or poor, per AHRQ guidelines. Results: The search identified 2,659 articles of which 92 met study inclusion criteria. Most articles (46%) were post-hoc analyses of randomized clinical trials. PC treatments included chemotherapy, radiation, hormonal therapy (74%) and bone-modifying agents. HTE in S4PC was identified for both biologic and non-biologic factors. Factors related to clinical signs/symptoms, laboratory tests and disease severity have been extensively studied in the literature (Table). Age and race seldom showed any correlation with PC outcomes. Conclusions: Current evidence reveals diverse factors contributing to HTE in S4PC. Ultimately, such knowledge can help oncologists prescribe more personalized medicine, help patients make more informed treatment choices, and inform policy making and treatment coverage decisions. [Table: see text]
Genetic instability after radiotherapy in prostate cancer: TMRSS2-ERG fusion in salvage radical prostatectomies.
Authors: Pfister David J. K. P. , Lindemann Katarina , Porres Daniel , Piper Charlotte , Knuchel Ruth , Heidenreich Axel 
Published: February 2017

182 Background: TMRSS2-ERG fusion is the most frequent genetic abberation in prostate cancer. Till now its expression is not associated with a poorer prognosis. In cell line models the fusion can be induced by exogenic factors as hormonal treatment or radiotherapy. Additionally its expression leads to different sensitivities to radiotherapy in different cell line models. We analyzed TMPRSS2-ERG fusion for the first time in patients with salvage radical prostatectomy and correlated it to radical prostatectomy specimen without prior treatment. Methods: 38 radical prostatectomy specimen of patients formaly treated with radiotherapy and recurrent disease and 38 primary RPEs were analyzed for ERG expression (15 external RT, ERT, 18 LDR, 5 HDR). ERG expression was detected by a highly sensitive monoclonal antibody as described recently. Results: Median PSA preoperatively was 3.6 (0.1-27) ng/ml. More patients had locally advanced dieseasae in the final pathologic specimen (17:21). In 18 (47,4%) patients (8 (44,4%) in LDR, 3 (60%) in HDR, 7(46,7%) in ERT) an ERG expression was detected. There is no difference in the ERG expression compared to an independend cohort of radical prostatectomy specimen (47,4% versus 47,4%). Conclusions: We are the first to analyze ERG expression in salvage radical prostatectomies. In this cohort there is no difference in the ERG expression rate after applied radiotherapy. The risk of inducing a gene fusion by external influence as seen in cell cultures cannot be transferred to daily practice.
Wait time intervals for patients with prostate cancer in a multidisciplinary rapid diagnostic unit compared to a community-based referral pattern.
Authors: Sethukavalan Perakaa , Zhang Liying , Jethava Vibhuti , Stevens Christiaan , Flax Stan , Buckley Roger , Bondy Sue , Loblaw D. Andrew 
Published: February 2017

183 Background: Wait times in cancer diagnosis and treatment are important measures of how quickly patients are getting access to care. Prolonged wait times may affect a cancer patient’s treatment outcome, prognosis and quality of life. A previous study conducted in 2003 found the median wait time from suspicion of prostate cancer to radiotherapy (RT) was 247 days. The purpose of this study was to capture wait time intervals for patients referred to and treated with radical RT at the Odette Cancer Centre, comparing patients diagnosed in a rapid diagnostic unit (RDU) versus the usual community referral process. Methods: Patients were screened during RT planning for their newly diagnosed, biopsy-confirmed prostate adenocarcinoma. A semi-structured interview and chart abstraction was conducted in order to obtain the best estimation of key wait time milestones in the care pathway. Results: A total of 87 patients participated in the study: 44 RDU patients and 43 community patients. The median overall wait time interval from suspicion of prostate cancer to RT was 138 days for the RDU cohort and 183 days for the community cohort (p=0.046). There were statistically significant differences between the two cohorts, favouring the RDU cohort, for other key intervals, namely, suspicion to decision-to-treat (DTT; p=0.012), urologist to diagnosis (p=0.0094), diagnosis to DTT (p=0.018), and diagnosis to treatment (p=0.016). Among all patients, 25% perceived a delay in treatment and among those patients, 64% identified a systematic reason for the delay. There was no significant difference on the cause of delay between the RDU and community cohorts (p=0.86). Conclusions: Wait time intervals from suspicion to treatment are significantly shorter for prostate cancer patients in 2011-2 than in 2003 when diagnosed and referred in the community setting. A prostate-specific RDU further reduced wait time intervals supporting more multidisciplinary RDUs for common diseases. However, even in the RDU system, a minority of patients met provincial consensus-based wait time standards. Further work needs to be done to identify why delays are occurring and develop new processes to minimize delays.
Photoselective vaporization of the prostate compared to transurethral resection of the prostate in patients who develop prostatic obstruction following brachytherapy.
Authors: Abelson Benjamin , Reddy Chandana A. , Ciezki Jay P. , Angermeier Kenneth , Ulchaker James , Klein Eric A. , Wood Hadley 
Published: February 2017

187 Background: Patients who undergo brachytherapy are at risk of developing prostatic obstruction, and a subset of these patients requires prostate reduction surgery. These patients pose a challenge to urologists who seek to determine the appropriate form of intervention given the reduced healing capacity of irradiated tissue. Given our observation that certain patients suffer recalcitrant prostatic obstruction following photoselective vaporization of the prostate (PVP), we evaluated outcomes after TURP compared to PVP for patients who experienced bladder outlet obstruction after brachytherapy. Methods: Cleveland Clinic’s prostate cancer database includes 3,600 patients who have undergone prostate brachytherapy since 1996. We cross-referenced these patients with the EMR to identify patients who required prostate reduction surgery following brachytherapy. We reviewed operative notes for these patients to identify the type of intervention completed, and we used the EMR to identify post-PVP/TURP complications requiring intervention. Clinical and demographic characteristics were obtained from the prospective database. Results: Sixty of the 3,600 patients developed urinary retention requiring prostate reduction surgery. The average age of these patients was 69 and the average prostate size was 52 grams. Forty patients underwent TURP and 20 patients were treated with PVP. Of the TURP patients, 19/40 (47.5%) required subsequent TURP, dilation, incision or permanent diversion, including 9 patients (22.5%) who required at least 2 further procedures. Of the PVP-treated patients, 10/20 (50%) required subsequent instrumentation including 4 (20%) who underwent at least 2 procedures. Conclusions: Half of the patients who require prostate reduction surgery for urinary retention following brachytherapy may require further procedures regardless of whether TURP or PVP is performed. Neither procedure confers less morbidity. [Table: see text]
Novel methodology for cost evaluation of anticancer drugs in castrate-resistant prostate cancer.
Authors: Guirgis Helmy M. 
Published: February 2017

200 Background: There is a need for a screening methodology to evaluate cost effectiveness of anticancer drugs. High costs raise concerns on approval, affordability and utilization. Objectives: Develop simplified methodology to screen and score cost versus value survival of docetaxel, cabazitaxel, abiraterone and sipuleucel-T in castrate- resistant prostate cancer (CRPC) Methods: Estimated costs in US $ of the entire course of an evaluated drug were added to downstream ancillary costs. The total was divided by the reported median survival gain over control in days. A reference value scale between 0- 100% was constructed with 0% assigned to cost/overall survival (OS) > $750, life threatening/ fatal adverse events (AEs) and worsened quality of life (QoL). A plan was designed to correct for AEs and QoL. Results were expressed as cost/OS and value and corrected scores. Results: Abiraterone at $5,000 per month x 6 months demonstrated cost/OS of $256 with 66% value and 61% corrected scores. Abiraterone x 9-12 months raised cost/OS and decreased scores. Generic docetaxel x 8 cycles demonstrated $63 cost/OS and 92% value score. Ancillary treatment increased cost/OS to $136 and decreased score to 82%. Cost/OS of cabazitaxel x 6 cycles ranged from $477- $596 with 21-36% scores. Corrections for AEs and QoL reduced scores to 6-21%. Sipuleucel-T demonstrated relatively higher cost/OS and lower scores. Conclusions: Preliminary findings would support utilization of docetaxel and abiraterone more than cabazitaxel and sipuleucel-T. The proposed methodology of cost versus value-survival could facilitate cost evaluation and budgetary planning of anticancer drugs.