bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ultrasound targeted gene therapy in a mouse model of prostate cancer: Evaluation of immune response.
Authors: De Carlo Flavia , Thomas Litty , Nande Rounak , Boskovic Olivia , Marshall Gailen , Claudio Pier Paolo , Howard Candace M 
Published: February 2018

120 Background: Gene transfer to malignant sites using human adenoviruses (hAd) has been limited because of their immunogenicity. Murine cells often lack some of the receptors needed for hAd infection; therefore, are generally non-permissive for hAd infection and replication, which limits translational studies of adenoviral gene transfer techniques. We developed a gene transfer method, which uses a combination of lipid-encapsulated perfluorocarbon microbubbles (MBs) and ultrasound (US) to shield and deliver hAds to a specific tissue bypassing the requirement of the coxsackie and adenovirus receptor (CAR). Methods: Transduction efficiency and GFP protein expression of hAd.GFP was assessed by flow cytometry and fluorescence microscopy in murine TRAMP-C2 and human DU145 prostate cancer cells. Innate and acquired immunity response was determined by ELISA and CTL assay in C57BL/6 mice bearing TRAMP-C2 syngeneic tumor grafts following injections of MBs-Ad.GFP complexes in the presence or absence of ultrasound. Results: We observed that the murine prostate cancer cells TRAMP-C2 were transduced less efficiently by hAd.GFP than the human DU145 cells. We showed in vitro that the transduction rate was increased significantly in both TRAMP-C2 and DU145 prostate cancer cells when delivering the Ad particles by a combination of MBs and US. Moreover, we observed expression of the GFP transgene in both cell lines at 48 hours and 72 hours. Lack of activation of the innate and acquired immunity was observed in vivo by quantifying IL-6 and TNF-α cytokines, and by assaying neutralizing IgG antibodies and CTLs activity, following intratumoral or intravenous injections of MBs-Ad.GFP complexes in the presence or absence of ultrasound. Conclusions: This study demonstrates the feasibility of using the TRAMP-C2 murine model of prostate adenocarcinoma to translate our ultrasound-mediated MB-Ad delivery system from the bench to the clinic. Our data provides evidence that the TRAMP-C2 prostate cancer graft model is a suitable system to study in immune competent animals the capacity of lipid-encapsulated perfluorocarbon MBs and US, to shield and deliver hAds to a site-specific tissue bypassing the requirement of specific receptors.
Prognostic factors in men receiving androgen deprivation therapy (ADT) for recurrent prostate cancer: Using absolute PSA and PSA doubling time (DT) to guide timing of ADT initiation.
Authors: Ravi Praful Kumar , Karnes Jeffrey , Rangel Laureano J , Pagliaro Lance C. 
Published: February 2018

129 Background: ADT is the first-line treatment for men experiencing recurrence after undergoing radical therapy for prostate cancer. However, timing of ADT initiation is controversial and there are limited data on prognostic factors in patients starting ADT. Methods: We identified consecutive men who underwent radical prostatectomy (RP) for localized prostate cancer at our institution between 1987 and 2007 and who subsequently received salvage ADT. Early progression on ADT was defined as development of metastatic disease within 2yrs of initiation. The primary outcomes of interest were cancer-specific (CSS) and overall survival (OS). Results: A total of 2418 men were included. Median age at RP was 64yrs and median follow-up was 13.9yrs. 48% and 20% of men had pathologic Gleason scores of 7 and 8-10 respectively. The median PSA was 2.6ng/ml, while 385 men (16%) had metastatic disease at receipt of ADT. Overall, 1060 men (44%) developed clinical metastases, with 625 (59%) of these doing so within 2yrs of starting ADT. On multivariable analysis, longer PSA DT before ADT was associated with lower odds of early progression on ADT (DT 3-9mths, OR = 0.19; DT ≥9mths, OR = 0.10, both p < 0.001). 10- and 20-year CSS were 89% and 70%, and 10- and 20-year OS were 82% and 40% respectively. Independent predictors of lower CSS included metastatic disease at time of ADT (HR = 2.60), PSA at ADT of 5-50ng/ml (HR = 2.68) and > 50ng/ml (HR = 4.33, all p < 0.001), while longer PSA DT was associated with higher CSS (DT 3-9mths, HR = 0.54; DT ≥9mths, HR = 0.45, both p < 0.001). PSA at ADT of 5-50ng/ml (HR = 3.10) and > 50ng/ml (HR = 5.20, both p < 0.001) were independent predictors of OS. Conclusions: PSA DT < 3mths and absolute PSA at ADT initiation of ≥ 5ng/ml are adverse prognostic indicators in men receiving salvage ADT for relapse after RP. For patients with these features, their risk of early progression and death should be part of a discussion about the timing of ADT and consideration given to more aggressive treatment strategies. Conversely, men with biochemical relapse who have longer DT and PSA < 5ng/ml are at lower risk and could make an informed decision to defer ADT initiation.
Do accountable care organizations affect race mediated differences in cancer screening?
Authors: Lee Daniel , Thapa Sunita , Graves Amy J , Buntin Melinda , Penson David F. , Resnick Matthew J. 
Published: February 2018

131 Background: Accountable care organizations (ACO) reflect a payment innovation aimed to orient incentives to improve quality and reduce waste. The objective of this study was to determine whether ACO enrollment affects racial disparities in cancer screening, and to characterize the impact on the appropriateness of prostate cancer screening in minority populations. Methods: We built a cohort of Medicare beneficiaries from 2007 to 2013 were comprising a cohort of 11,087,056 person-years among ACO beneficiaries and 37,187,979 person-years among non-ACO beneficiaries. A difference-in-difference-in-differences (DDD) approach was utilized to identify the effect of ACO enrollment on cancer screening in racial/ethnic minorities relative to non-Hispanic whites. We then characterized differences in screening appropriateness after ACO enrollment using age (65-74 vs. 75+) and predicted survival (top vs. bottom quartile). Results: ACO enrollment was associated with approximately a 5% reduction in prostate cancer overscreening for white beneficiaries, namely among the elderly and those with unfavorable predicted survival. Compared to white men in the lowest quartile of predicted survival, Asian and Hispanic men with similarly low survival had a 4.8% and 13.0% relative increase in prostate cancer screening associated with ACO enrollment (DDD p = 0.015, p = 0.011, respectively). Prostate cancer overscreening was common among Asian men, with 46% of elderly Asian men attributed to an ACO undergoing cancer screening compared to 28% of elderly white men. Furthermore, ACO enrollment was associated with a 2.7% increase in screening relative to whites (DDD p = 0.0005). Compared to white beneficiaries, black men had consistently lower rates of prostate cancer screening. ACO enrollment did not narrow the disparity of prostate cancer screening between healthier (DDD p = 0.75) or younger (DDD p = 0.27) black and white beneficiaries. Conclusions: This study provides evidence of ACO-mediated increases in low-value screening for prostate cancer among sick and elderly Hispanics and Asians. Furthermore, ACO enrollment did not narrow known disparities in high-value prostate cancer screening among healthier and younger black men.
Development and pilot testing of a decision support intervention for men with prostate cancer.
Authors: Chan June M. , Cooperberg Matthew R. , Neuhaus John , Bridge Mark , Stupar Lauren , Weinberg Tia , Broering Jeanette M , Tenggara Imelda , Lavaki Emil , Cowan Janet E. , Rosenfeld Stan , Kenfield Stacey A. , Van Blarigan Erin , Simko Jeff , Witte John , Carroll Peter , Belkora Jeffrey 
Published: February 2018

132 Background: We evaluated the feasibility and efficacy of a decision support intervention designed to help men with low-risk prostate cancer consider active surveillance and standard treatments. The intervention incorporated a decision aid with coaching and question-listing. Our decision aid is the first to include data on long-term survival and side effects from men with prostate cancer undergoing active surveillance, surgery, and radiation. Methods: To develop the intervention, we conducted focus groups using the Nominal Group Technique. We used a survey instrument from the International Patient Decision Aids Standards to measure the stakeholder endorsement of our intervention. To test the intervention, we administered it to newly diagnosed men with low-risk prostate cancer (Gleason sum < = 3+4, stage < = T2N0M0, PSA < = 10 ng/ml) seen at UCSF. Before and after the intervention, we administered a survey with questions from the Decision Quality Instrument for Prostate Cancer. Our primary outcome was change in knowledge as assessed by two multiple-choice items: How many men diagnosed with early stage prostate cancer will eventually die of prostate cancer? How much would waiting 3 months to make a treatment decision affect chances of survival? Correct answers were: “Most will die of something else” and “A little or not at all.” Results: The development phase involved 6 patients, 1 family member, 2 physicians, and 5 other health care providers and four iterations of the intervention until consensus endorsement was reached. In the pilot test, 57 men consented, and 44 received the decision support intervention and completed surveys at both timepoints. Before the intervention, 30/44 (68%) got both questions right, compared to 36/44 (82%) after the intervention. 82% maintained or achieved perfect scores; 16% answered 1 or more incorrectly both before and after the intervention; and 2% answered both items correctly before, but 1 wrong after. Conclusions: This novel decision support intervention was feasible, and appeared to improve knowledge and informed decision-making. Data will guide the development of a larger scale randomized clinical trial to improve decision quality in men with prostate cancer, in the community. Clinical trial information: NCT02451345.
A national survey of radiation oncologists and urologists on active surveillance for low-risk prostate cancer.
Authors: Kim Albert , Abouassaly Robert , Kim Simon P. 
Published: February 2018

133 Background: Due to the growing concerns about over-diagnosis and overtreatment of localized prostate cancer (PCa), active surveillance (AS) has become an integral part of clinical practice guidelines. However, many men with low-risk PCa still receive primary therapy with surgery or radiation. Little is known about the barriers regarding the use of AS in clinical practice. To address this, we performed a national survey of radiation oncologists and urologists assessing the current attitudes and treatment for patients diagnosed with low-risk PCa. Methods: From January to July of 2017, 915 radiation oncologists and 940 urologists were surveyed about perceptions of AS for low-risk PCa. The survey queried respondents about their opinions and attitudes towards AS and treatment recommendations for a patient having low-risk PCa with clinical factors varying from patient age (55, 65 and 75 years old), PSA (4 and 8 ng per dl), and tumor volume for Gleason 3+3 disease (2, 4 and 6 cores). Pearson chi-square and multivariable logistic regression were used to identify respondent differences in treatment recommendations for low-risk PCa. Results: Overall, the response rate was 37.3% (n = 691) and similar for radiation oncologists and urologists (35.7% vs. 38.7%; p = 0.18). While both radiation oncologists and urologists viewed AS as effective for low-risk PCa (86.5% vs. 92.0%; p = 0.04), radiation oncologists were more likely to respond that AS increases patient anxiety (49.5% vs. 29.5%; p < 0.001). Overall, recommendations varied markedly based on patient age, PSA, number of cores positive for Gleason 3+3 prostate cancer and respondent specialty. For a 55-year-old male patient with a PSA 8 and 6 cores of Gleason 6 PCa, recommendations of AS were low for both radiation oncologists and urologists (4.4 % vs. 5.2%; adjusted OR: 0.6; p = 0.28). For a 75-year-old patient with a PSA 4 and 2 cores of Gleason 6 PCa, radiation oncologists and urologists most often recommended AS (89.6% vs. 83.4%; adjusted OR: 0.5; p = 0.07). Conclusions: While both radiation oncologists and urologists consider AS effective in the clinical management of low-risk PCa, its use varies markedly by patient age, PCa volume, PSA and physician specialty.
Long-term outcomes of magnetic resonance image-guided partial prostate brachytherapy for favorable-risk prostate cancer.
Authors: King Martin T. , Nguyen Paul L. , Boldbaatar Ninjiin , Tempany Clare Mary , Cormack Robert A. , Beard Clair , Hurwitz Mark , Suh Warren , D'Amico Anthony Victor , Orio Peter F 
Published: February 2018

138 Background: To report long-term outcomes of magnetic resonance image-guided partial prostate brachytherapy of the peripheral zone. Methods: We conducted an institutional-board approved retrospective review of all men who underwent 0.5 Tesla GE Signa SP MRI-guided partial prostate brachytherapy to the peripheral zone. We estimated actuarial rates of biochemical progression (nadir +2 definition), as well as cumulative incidences of biopsy proven local recurrence, distant metastasis, and prostate cancer specific mortality. Fine and Gray’s competing risk regression was utilized in order to evaluate clinical factors associated with times to metastasis and prostate cancer specific mortality. Results: Between 1997 and 2008, 354 men underwent MRI-guided partial prostate brachytherapy. The numbers of patients with low and intermediate risk disease were 295 (83%) and 59 (17%), respectively. Sixty-seven (19%) patients received supplemental external beam radiotherapy. The median follow-up was 8.6 years. For National Cancer Center Network (NCCN) low risk-disease, 8-year estimates of biochemical progression, local recurrence, metastasis, and prostate cancer specific mortality were 23.5% (17.4-29.1), 6.4% (3.6-10.2), 2.0% (0.6-4.8), and 0%. Corresponding estimates for intermediate risk disease were 51.2% (31.3-65.4), 21.2% (10.2-34.9), 6.6% (1.7-16.3), and 5.4% (0.9-16.2). Twenty of 45 biopsy proven local recurrences occurred outside of the implanted peripheral zone. Of the 22 patients who developed distant metastases, 14 events occurred more than 10 years from therapy. On multivariate analyses, biopsy proven local recurrence was the only factor to demonstrate a significant association with metastasis (hazard ratio 2.50; p = 0.05) and a trend with prostate cancer specific mortality (5.02; p = 0.09). Conclusions: MRI-guided partial prostate brachytherapy to the peripheral zone in men with favorable risk prostate cancer is suboptimal with respect to long term cancer control outcomes. Additional studies using contemporary MRI techniques including 3 Tesla based multi-parametric imaging and fusion biopsy may lead to improved outcomes.
Prospective clinical study of a prostate cancer (PCa) rule-out blood test for PSA gray zone patients using a sensitive circulating tumor cell assay.
Authors: Pang SEE-TONG , Chang Ying-Hsu , Lin Po-Hung , Chang Ying , Watson Drew , Segurado Oscar , Lu Si-Hong , Wu Jen-chia , Lai Jr-Ming , Shao Hung-Jen , Chang Shih-En , Hsieh Ben , Javey Mana , Mei Rui 
Published: February 2018

143 Background: The diagnostic confirmation of prostate cancer in patients with a PSA in the gray zone (4–10 ng/ml) is controversial, often leading to unnecessary biopsies. The sensitivity of the PSA test at a 4 ng/mL cut-off can be as low as 21%. We introduce a new test for prostate cancer detection in PSA gray zone patients, with the potential to decrease the number of unnecessary prostate biopsies. Methods: A single-center, multi-year, IRB-approved, prospective, blinded clinical study was conducted in 200 high-risk subjects. 4 mL of blood was drawn and processed for CTC analysis using the CellMax biomimetic platform (CMx). The CMx CTC test uses a proprietary microfluidic biochip that accurately captures and enumerates CTCs with antibodies to EpCAM, CK18 and PSMA. All patients underwent routine screening including PSA and digital rectal exam (DRE). Gray zone and those diagnosed as ‘diseased’ based on PSA & DRE also underwent a biopsy. Multivariate generalized linear models incorporating CMx test results were utilized to derive age adjusted CTC scores predictive of clinical outcomes. Results: A subset of 84 subjects with PSA levels in the gray zone (4–10 ng/ml) were included in this study. Prostate biopsy results were available for 42 patients; 10 had confirmed cancer. A CTC Score was calculated as a nonlinear weighted combination of the CTCs captured with CK18 and PSMA antibodies. After adjustment for age and PSA, the CTC score remained a significant predictor of clinical outcome in the PSA “gray zone” (likelihood ratio p-value = .015) whereas PSA was not. The sensitivity and specificity of the CTC Score were 80.0% (95% CI: 44.4%, 97.5%) and 93.8% (95% CI: 79.2%, 99.2%). Negative % agreement and Positive % agreement was 93.8% (95% CI: 79.2%, 99.2%) and 80.0% (95% CI: 44.4%, 97.5%). Given the observed odds ratio for CTC score in the study- approximately 0.90 (95% CI 0.79, 0.98), the study is appropriately powered. Conclusions: The CMx CTC assay is an accurate, affordable blood based assay, with the potential to reduce unnecessary biopsies in PSA gray-zone patients by up to 90%.
Genomic and phenotypic evidence for prostate cancer osteomimicry in circulating tumor cells from men with metastatic castration resistant prostate cancer (mCRPC) treated with radium-223.
Authors: Armstrong Andrew J. , Gupta Santosh , Healy Patrick , Kemeny Gabor , Leith Lauren Beth , Zalutsky Michael , Spritzer Charles , Davies Catrin , Ware Katie , Somarelli Jason , Wood Kris , Glover Wayne , Hsu Shiaowen David , Gerber Drew , Rothwell Colin , Mundy Kelly , Anand Monika , Gregory Simon , Halabi Susan , George Daniel J. 
Published: February 2018

160 Background: Radium-223 is a targeted alpha therapy that improves survival in men with mCRPC. The biologic basis for radium-223 efficacy is not completely understood. We hypothesized that PC osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to the intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. Methods: We conducted a pharmacodynamic study of radium-223 in men with bone predominant mCRPC to investigate genomic and phenotypic alterations in circulating tumor cells (CTCs), ctDNA, and metastases. Prior to radium and 3 and 6 months after radium, liquid and metastatic biopsies were collected, including CTCs for phenotypic characterization and CTC/ctDNA genomic analysis. The primary objective was to describe the prevalence of CTC bone alkaline phosphatase (BAP) over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. Results: We enrolled 20 men with heavily pre-treated symptomatic bone predominant mCRPC and treated with radium-223 over a median of 6 doses. 55% had elevated serum BAP. PFS was 5.5 mo; OS was 13.3 mo; 10% had unfavorable (≥5) to favorable ( < 5) Cellsearch CTC conversion; 5% had ≥30% PSA decline. We found evidence of persistent CTC BAP expression in both EpCAM+ and EpCAM- CTCs in the majority of men over time during radium treatment. We identified genomic gain of key osteomimicry regions in CTC DNA, including loci for BAP, osteopontin, and OB-cadherin. Radium-223 uptake was observed in tumor to a greater degree than surrounding normal bone. CTC DNA and matched ctDNA and CTC cultures suggested persistence of CTCs with aggressive genomic alterations such as AR, FOXA1, and MYC gain and PTEN and RB1 loss. We established multiple CTC cultures and one CTC PDX; cells exhibited evidence of epithelial plasticity with BAP expression. Conclusions: Osteomimicry may contribute to the uptake of Radium-223 within bone metastases and may thereby enhance the therapeutic benefit of radium-223. We found genomic and phenotypic evidence of osteomimicry in CTCs and CTC cultures from men with mCRPC. Clinical trial information: NCT02204943.
SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Small Eric Jay , Saad Fred , Chowdhury Simon , Hadaschik Boris A. , Graff Julie Nicole , Olmos David , Mainwaring Paul N. , Uemura Hiroji , Lopez-Gitlitz Angela , Trudel Geralyn Carol , Espina Byron M. , Shu Youyi , Park Youn C. , Rackoff Wayne R. , Yu Margaret K. , Smith Matthew Raymond ,   On Behalf of the SPARTAN investigators
Published: February 2018

161 Background: Pts with nmCRPC are at risk for developing metastatic disease and cancer-specific mortality. There are no approved treatments for nmCRPC. APA is an orally administered next-generation androgen receptor inhibitor with antitumor activity in CRPC. SPARTAN evaluated the effects of APA on metastasis-free survival (MFS) in men with nmCRPC. Methods: Pts with nmCRPC and prostate-specific antigen doubling time (PSADT) of ≤ 10 mos were randomized 2:1 to APA (240 mg QD) or PBO. The primary end point was MFS, defined as the time from randomization to first radiographic distant metastasis (per blinded central review) or death. Secondary end points included time to metastasis (TTM), progression-free survival (PFS), time to symptomatic progression (SymProg), and overall survival (OS). Pts were eligible to receive study-provided abiraterone acetate plus prednisone after developing distant metastases. Second progression-free survival (PFS2, the time from randomization to disease progression or death after first treatment for metastatic CRPC) was also evaluated. Results: 1207 pts were randomized. Baseline PSADT was < 5 mos in both groups. APA decreased the risk of distant metastasis or death by 72% (HR = 0.28; 95% CI, 0.23-0.35; p < 0.0001), with a median MFS of 40.5 vs 16.2 mos in the PBO group. Secondary end points (TTM, PFS, and SymProg) were all significantly improved. At an interim analysis for OS, there was a trend favoring APA. At a median follow-up of 20.3 mos, 61% of APA and 30% of PBO pts were still on treatment. Rates of discontinuation due to adverse events were low in both groups (10.7% APA, 6.3% PBO). Mean baseline health-related quality of life scores were maintained with treatment, with no difference between groups over time. Of those whose disease progressed, 80% of PBO and 56% of APA pts received therapy for metastatic CRPC. PFS2 was significantly longer for APA vs PBO. Conclusions: APA significantly improved median MFS by 2 years in men with nmCRPC. APA also significantly increased TTM, PFS, SymProg, and PFS2. APA was associated with improved OS. These results support the addition of APA to androgen deprivation therapy in men with nmCRPC. Clinical trial information: NCT01946204.