bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of lipid nanoparticle siRNA delivery systems on silencing clusterin and progression in enzalutamide resistant prostate cancer in vivo.
Authors: Yamamoto Yoshiaki , Lin Paulo JC , Zhang Fan , Kawai Yoshihisa , Beraldi Eliana , Leong Jeffrey , Matsuyama Hideyasu , Cullis Pieter R , Gleave Martin Edwin 
Published: February 2017

256 Background: Clusterin (CLU) is induced by androgen receptor (AR) pathway inhibition and its overexpression confers treatment resistance. Lipid nanoparticle (LNP) facilitates tumor uptake and intracellular processing through an enhanced permeation and retention effect (EPR), currently with multiple products undergoing clinical evaluation. Gene silencing using small interfering RNA (siRNA) is a promising approach but in vivo delivery remains a major barrier. In our study, we investigated the efficacy siRNA tumor delivery using LNP systems in enzalutamide-resistant (ENZ-R) castration-resistant prostate cancer (CRPC) model. Methods: To validate the effect of LNP siRNA tumor delivery in vivo, gene silencing of a reporter gene, luciferase (LUC), in PC3-M-luc stable cell line was treated with LNP LUC-siRNA and examined for Luc activity by the IVIS imaging system. Next, we investigated the efficacy of LNP CLU-siRNA tumor delivery and LNP CLU-siRNA sensitized AR knockdown activity in ENZ-R CRPC LNCaP in vitro and in vivo models. Results: LNP LUC-siRNA exhibited LUC silencing effects in PC-3M-luc xenograft and metastatic models. LNP CLU-siRNA suppressed PSA and decreased AKT and ERK phosphorylation in ENZ-R LNCaP cells in vitro. LNP CLU-siRNA sensitized AR antisense oligonucleotides (ASO) activity, more potently inhibiting ENZ-R cell growth rates and increased apoptosis when compared to AR-ASO monotherapy. In vivo,combinatory treatment of LNP CLU-siRNA and AR-ASO significantly suppressed tumor growth and serum PSA levels compared to LNP LUC -siRNA (control) and AR-ASO in ENZ-R LNCaP xenografts. Conclusions: The LNP CLU-siRNA systems sensitized AR knockdown resulting in inhibition of ENZ-R LNCaP cell growth, providing pre-clinical proof-of-principle as a promising AR co-targeting approach in ENZ-R CRPC.
Bone metabolism biomarkers in men with advanced prostate cancer (PC) and bone metastases treated with denosumab versus zoledronic acid (ZA).
Authors: Smith Matthew Raymond , Brown Janet Elizabeth , Fizazi Karim , Klotz Laurence , Marx Gavin M. , Wang Huei , Warner Douglas , Lipton Allan 
Published: February 2017

267 Background: Denosumab, compared with ZA, has recently demonstrated significant benefits in preventing skeletal-related events (SREs) in a double-blind phase 3 study of men with castration-resistant PC and bone metastases (N=1901). This post hoc analysis was performed to determine if key bone metabolism biomarker levels correlated with time-to-first SRE. Methods: Time-to-Grade ≥2 increase in total serum alkaline phosphatase (ALP) was assessed for correlation with time-to-first SRE. Levels of urinary N-telopeptide (uNTX) and serum bone-specific alkaline phosphatase (BSAP) markers were measured at baseline and study week 13, and correlations with time-to-first SRE were assessed. Covariate analyses were performed using a Cox proportional hazards model, stratified by treatment group or (for baseline analyses) with treatment group as the independent variable. Results: Analysis of the relationship between time-to-Grade ≥2 increase in total ALP and time-to-first SRE demonstrated that Grade ≥2 increases in ALP of PC patients were associated with a higher risk of first SRE (hazard ratio [HR] 1.838, 95% confidence interval [CI] 1.559, 2.167; P<0.0001). In dichotomized analyses (< vs ≥ median), a higher level of uNTX and BSAP (at baseline or week 13) was correlated with an increased risk of first SRE (Table). In baseline covariate analyses, treatment benefit for denosumab was maintained after adjusting for either baseline uNTX (HR 0.818, 95% CI 0.703, 0.951; P=0.0091) or BSAP (HR 0.813, 95% CI 0.700, 0.943; P=0.0061). Conclusions: Higher levels of uNTX or BSAP at baseline or week 13 were associated with worse SRE outcomes in men with advanced PC and bone metastases. Denosumab was more efficacious for preventing or delaying SREs compared with ZA, regardless of bone-related biomarker levels. Relationship of covariate to time-to-first SRE Clinical trial information: NCT00321620. [Table: see text]
Drug-drug interactions in patients with castration-resistant prostate cancer undergoing abiraterone therapy: Characterizing the scale of the problem.
Authors: Jamani Rehana , Lee Esther K. , Berry Scott R. , DeAngelis Carlo , Giotis Angie , Emmenegger Urban 
Published: February 2017

269 Background: Abiraterone acetate (AA), used to treat CRPC, inhibits androgen biosynthesis by blocking cytochrome P450 (CYP) 17. It also inhibits other cytochromes involved in the metabolism of various widely-used medications (strong inhibition of CYP1A2, CYP2D6, and CYP2C8; moderate inhibition of CYP2C9, CYP2C19 and CYP3A4/5). Hence, there is presumably a high potential for drug-drug interactions (DDI) that can either diminish the efficacy of AA or concurrent medications, or increase the risk of DDI-related adverse events (AE); however, the scale of AA-associated DDI is currently unknown. Methods: We conducted a retrospective review of pharmacy records and electronic pt charts to retrieve individual drug histories, comorbidities, and AE of CRPC pts beginning AA treatment between Jan 2010 and Apr 2014. Individual drug histories were analyzed for DDI using two commercial databases, Lexicomp and Micromedex. Results: 91 informative pts were identified. Using Lexicomp, the most common drugs flagged for potential DDI of high clinical significance (i.e., “avoid combination”, or “consider therapy modification”) with AA were dexamethasone, metoprolol, clopidogrel, oxycodone, and citalopram. They were administered to 12 (13%), 10 (11%), 6 (7%), 4 (4%), and 4 (4%) pts respectively. Micromedex assigned a major risk of DDI to oxycodone and a moderate risk to metoprolol. At least 1 potentially significant DDI was found in 38/91 pts (42%) with Lexicomp, and in 42/91 pts (46%) with Micromedex. Most common AE were fluid retention seen in 19 pts (21%), fatigue in 15 (16%), liver-function test abnormalities in 13 (14%), hypertension in 13 (14%), and pain in 11 (12%), all corresponding to AE typically associated with the use of AA. We did not find unequivocal evidence for DDI-related AE. Conclusions: The use of commercial DDI databases reveals a substantial risk of potentially consequential DDI in CRPC pts undergoing AA therapy, although some of the flagged DDI (e.g., between AA and dexamethasone) may be of theoretical rather than practical concern. Further investigation with larger patient populations is required to better establish the clinical relevance of these DDI.
IND 205B: A phase II study of the PI3K inhibitor PX-866 and continued abiraterone/prednisone in patients with recurrent or metastatic castration resistant prostate cancer (CRPC) with PSA progression on abiraterone/prednisone.
Authors: Hotte Sebastien J. , Joshua Anthony M. , Torri Vamsee , Macfarlane Robyn Jane , Basappa Naveen S. , Powers Jean , Winquist Eric , Mukherjee Som , Gregg Richard William , Kollmannsberger Christian K. , Finch Daygen L. , Xu Hao , Hausman Diana Felice , Seymour Lesley , Eisenhauer Elizabeth A. , Chi Kim N. 
Published: February 2017

279 Background: PX-866 is an irreversible, pan-isoform inhibitor of Class I PI-3K. In part A of this study, PX-866 as a single agent was well tolerated and showed modest activity in CRPC but did not meet a priori benchmarks as a single agent in unselected patients (pts). As androgen receptor inhibition promotes PI3K activity in PTEN-loss PC models, the addition of PX-866 in patients whose PSA is rising on abiraterone acetate plus prednisone (AA+P) may reverse resistance and phase B of the study tested this hypothesis clinically. Methods: In this multicentre, phase II study, CRPC pts with PSA progression on AA+P received PX-866, 8mg daily on a 6-week cycle while continuing AA+P. Primary endpoint was lack of progression at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA and objective response rates. PX-866 would be deemed worthy of further study if at least four of 25 pts were progression free at 12 weeks. Results: 25 pts were accrued and all are evaluable for toxicity and PSA response. Eleven pts had measurable disease of which 11 are evaluable for objective response. Median age was 72, ECOG PS was 0/1 in 10/15 pts. Eighteen pts received prior chemotherapy. Median number of cycles was 2 (range 1–3). 52% of pts received at least 90% of planned dose of PX-866. Most common adverse events (AEs) were fatigue (21 patients), diarrhea, (18), nausea (13), vomiting (11) and anorexia (12); one patient discontinued because of protocol therapy toxicity (grade 3 anemia). Other grade 3 AEs (one patient for each) were diarrhea, vomiting, fatigue, AST and ALT elevation and lymphocyte and platelet changes. Six pts were progression free at 12 weeks. No objective or PSA responses were seen. Of the pts with measurable disease, best objective response was stable disease in six (2.3-3.6m) and best PSA response was non-response in eight pts. Conclusions: The addition of PX-866 to AA+P in unselected pts progressing on AA+P shows no evidence of antitumour effects. Strategies to combine PI3K inhibition with AR targeted therapies should consider initiation earlier in the disease course and/or recruiting a selected population. Clinical trial information: NCT01331083.
Impact of dose-escalated radiation on overall survival in men with nonmetastatic prostate cancer.
Authors: Kalbasi Anusha , Li Jiaqi , Berman Abigail T. , Swisher-McClure Samuel , Smaldone Marc C. , Small Dylan , Mitra Nandita , Bekelman Justin E. 
Published: February 2017

28 Background: Infive publishedRCTs, dose-escalated external beam radiation therapy (EBRT) for prostate cancer resulted in improved biochemical and local control. However, the question of whether dose escalation improves overall survival (OS) remains unanswered. We examined OS among men with non-metastatic prostate cancer undergoing EBRT in the modern era. Methods: Using the National Cancer Database (NCDB), we conducted non-randomized comparative effectiveness studies of dose-escalated versus standard-dose EBRT in men diagnosed from 2004-2006 in three analytic cohorts defined by NCCN risk category: low- (N=12,848), intermediate- (N=14,966) or high-risk (N=14,587) prostate cancer. We categorized patients in each risk cohort into 2 treatment groups: standard-dose (68.4 Gy to <75.6 Gy) or dose-escalated (≥75.6 Gy to 90 Gy) EBRT. The primary outcome was time to death from any cause, measured from diagnosis to NCDB date of death or end of follow-up (December 31, 2011). We compared OS between treatment groups in the three analytic cohorts using Cox proportional hazard models. Inverse probability weighted propensity score methods were used to balance differences between treatment groups in age, race, year of diagnosis, AJCC T- and N-stage, PSA, Gleason score, androgen deprivation therapy, IMRT use, comorbid disease, income, insurance, urban/rural location, facility type and facility volume. In secondary analyses, we evaluated dose response for survival by categorizing dose in approximately 2 Gy increments. Results: Median follow up for survivors was between 73 and 74 months in all three risk cohorts. Dose-escalated EBRT was associated with improved survival in the intermediate-risk (adjusted HR 0.81, 95% CI 0.77 and 0.85, p<0.0001) and high-risk groups (aHR 0.85, 95% CI 0.81 and 0.89, p<0.0001), but not the low-risk group (aHR 0.99, 95% CI 0.92-1.06, p=0.803). For every incremental ~2Gy increase in dose, there was a 9% (95% CI 6% – 11%, p<0.0001) and 7% (95% CI 3% - 10%, p=0.004) reduction in the hazard of death for intermediate- and high-risk patients, respectively. Conclusions: Dose-escalated EBRT is associated with improved survival in men with intermediate- and high-risk, but not low-risk, prostate cancer.
A retrospective analysis of clinical factors influencing response to treatment with cabazitaxel in patients with metastatic castration resistant prostate cancer.
Authors: Yokom Daniel , Alimohamed Nimira S. , Winquist Eric , Berry Scott R. , Hubay Stacey , Lattouf Jean-Baptiste , Leonard Helene , Girolametto Carla , Saad Fred , Sridhar Srikala S. 
Published: February 2017

281 Background: The TROPIC trial demonstrated that cabazitaxel improves overall survival (OS) in mCRPC patients progressing on or after docetaxel; a setting where both abiraterone and enzalutamide are also approved. We evaluated baseline factors that may help predict prostate specific antigen (PSA) response or PSA progression defined as per the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria and OS in mCRPC patients treated with cabazitaxel. Methods: Forty patients from five centres participated in an early access program and were retrospectively reviewed to capture baseline characteristics, disease history, prior and subsequent treatments, PSA response, and OS. The influence of selected variables on PSA response and OS were evaluated by univariate and multivariate stepwise regression analysis. Results: At cabazitaxel initiation, median age was 65, ECOG 0-1 (90%), median PSA was 216 ng/mL, 25% had visceral disease and 70% had pain. Median number of prior docetaxel cycles was 9 and median time from treatment was 9.6 months (5-14.2). Median number of cabazitaxel cycles was 7 (1-27). Fourteen patients received abiraterone before cabazitaxel. In patients with prior abiraterone treatment there was no impact on PSA response compared to patients with no prior abiraterone. In the multivariate regression analysis, presence of visceral disease, low albumin (≤40g/L), low hemoglobin (<100 g/L) and longer time between last docetaxel dose and start of cabazitaxel were correlated with PSA response to cabazitaxel (p<0.10). Age < 65, BMI ≥ 30kg/m2 and presence of pain were linked to an increased likelihood of PSA progression. None of the factors selected were significantly associated with OS. Conclusions: In routine clinical practice, this study suggests that mCRPC patients with visceral disease and a longer time elapsed between last docetaxel dose and start of cabazitaxel may experience a greater PSA response with cabazitaxel.
Clonal heterogeneity in platinum-resistant metastatic urothelial cancer.
Authors: Faltas Bishoy , Beltran Himisha , Eng Kenneth , Pauli Chantal , Robinson Brian D. , Mosquera Juan Miguel , Nanus David M. , Tagawa Scott T. , Elemento Olivier , Rubin Mark A. 
Published: February 2017

290 Background: Beyond platinum-based chemotherapy, there are currently no approved therapies for advanced PRUC. Our objective was to generate the first detailed genomic profile of metastatic PRUC to identify molecular changes critical to platinum-resistance and metastasis development. Methods: Following informed consent, we collected 50 urothelial cancer (UC) tissue samples, from 23 patients. Metastatic tumor samples were obtained from biopsies or metastatectomy. Germline samples were prospectively collected and matched archival formalin-fixed paraffin-embedded primary tumors from the same patients were retrieved. Our cohort comprises 23 metastatic samples, 37 PRUC samples and 18 trios of matched primary, metastatic and germline samples including 2 rapid autopsies yielding tumor samples from multiple sites. We performed whole exome sequencing of all tumor and germline samples followed by integrated analysis of somatic single nucleotide variants and copy-number alterations and to analyze clonality. We utilized DAVID bioinformatic tool for pathway analysis. Results: Advanced PRUC samples were enriched for several molecular alterations, we identified 414 recurrently mutated genes including common genes such as TP53 (45%) as well as actionable alterations in PIK3CA (11%) and TSC1 (19%). We also identified frequent alterations in novel genes such as DPCR1 (38%) and NIN (28%). Frequent copy number alterations included CDKN2A deletion (33%), E2F3 amplification (10%) and ERBB2 amplification (7%). Pathway analysis showed enrichment of mutations in the apoptosis (p=1.0E-7) and cell cycle regulation (p=1.6E-2) pathways compared to TCGA primary UC dataset. We reconstructed phylogenetic trees from matched primary, metastatic and germline trios. Variant allele frequencies of certain shared mutations increased from primary tumors to lymph node and visceral metastases revealing clonal selection of mutations present in primary tumors. Conclusions: This study generates a detailed profile of the genomic landscape of advanced PRUC revealing extensive heterogeneity and clonal selection underlying platinum-resistance and metastatic spread.
Phase II study of pazopanib with weekly paclitaxel in refractory urothelial cancer.
Authors: Srinivas Sandy , Narayanan Sujata , Harshman Lauren Christine , Pachynski Russell Kent , Lam Anthony P. , Fan Alice C. , Poushnejad Shermeen , Haas Denise , Vaishampayan Ulka N. 
Published: February 2017

294 Background: Currently, there are no standard treatments for relapsed or refractory urothelial carcinoma (UC). Discouraging results have been observed in trials evaluating established chemotherapeutics as single agents or in combination regimens. Paclitaxel has moderate activity when used alone and in combination in UC. Pazopanib is active in other solid tumors secondary to its potent anti-angiogenic effects. We report the results of a multi-center phase II study evaluating the combination of paclitaxel with pazopanib in refractory UC. Methods: Eligible patients (pts) had histologically confirmed UC, with disease that progressed on upto 2 chemotherapeutic regimens. Pazopanib (800 mg) was administered daily, with weekly paclitaxel (80mg/m2) for 3 weeks in a 28 day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of the study was response-rate (RR) based on RECISTv 1.1 criteria. Secondary endpoints included safety, and progression free-survival (PFS). Results: From April 2010 to September 2014, 32 patients were enrolled. Median age was 67 years (29-89) and median ECOG performance status was 1 (0-2). 17 pts (54%) had UC of the upper urinary tract disease and 15(47%) had primary bladder tumors. All pts had multiple metastatic sites, including 9 (28%) with liver metastases. Median number of prior cytotoxic regimens was 2, and 50% were considered cisplatin responsive. Objective responses were observed in 58% with 3 (12%) complete responses (CR), and 12 pts (46%) with partial responses (PR). Another 9 (35%) acheived stable disease (SD). High grade toxicities included grade 3 hypertension (n=2), grade 3 fatigue (n=4), grade 3 thrombosis (n=2) and grade 4 neutropenia (n=2). Nearly half of the patients( n= 14 ) required growth factor support. Conclusions: Our phase II study combining paclitaxel and pazopanib demonstratedsignificant anti-tumor activity in relapsed/refractory UC. This combination is safe, effective and is worthy of evaluation in randomized phase 3 study. Clinical trial information: NCT01108055.
PDL1 status in muscle-invasive urothelial carcinoma in the context of neoadjuvant cisplatin-based chemotherapy.
Authors: Liu Jen-Jane , Baras Alexander S , Gandhi Nilay M , Guner Gunes , Munari Enrico , Faraj Sheila , Taube Janis M. , Schoenberg Mark , Hahn Noah M. , Drake Charles G. , Netto George J. , Bivalacqua Trinity 
Published: February 2017

300 Background: Although complete and partial response rates to cisplatin-based neoadjuvant chemotherapy (cNAC) are 40-50% in patients with muscle-invasive urothelial carcinoma (MIUC), post-cystectomy cancer specific survival (CSS) for patients who fail to respond to cNAC is poor (5-y CSS = 27%). Therefore, up to half of MIUC could be amenable to alternative systemic therapies. Anti-programmed death ligand (PDL1) has shown promising results in tumors with proven PDL1 expression, including advanced stage MIUC. We evaluated PDL1 expression in MIUC in a cohort categorized by pathologic response to cNAC to test the hypothesis that anti-PDL1 therapy is a rational therapeutic option for patients non-responsive to cNAC. Methods: We studied 150 patients who received cNAC followed by open radical cystectomy (RC) from 2000-2013. Pathologic response (<pT1 N0 at RC) and CSS were compared to patients who had RC without cNAC. Tissue microarrays of MIUC specimens representing patients with and without response to cNAC were stained with PD-L1 (Cell-Signaling, E1L3N, 1:100) and FOXP3 (eBioscience, 236A/E7, 1:250). The degree of tumoral PDL1 and tumoral lymphocyte FOXP3 staining was manually scored. Tumors with 5% and >15/hpf staining were considered positive for PDL1 and FOXP3, respectively. Percentage of non-responders to cNAC staining positive for PDL1 was the primary outcome of our study. Results: The rate of PDL1 positivity in MIUC cNAC non-responders was 47% which was similar to the 43% rate in responders. There was a strong positive correlation of tumoral PDL1 staining with tumoral lymphocytes FOXP3 staining, Goodman-Kruskal gamma=0.71 (p<0.0001), which was independent of cNAC responder status (Table). Conclusions: Patients with MIUC that are non-responders to cNAC have poor long term CSS. Our results demonstrate that cNAC non-responders exhibit frequent PDL1 tumoral staining, suggesting that neoadjuvant or adjuvant anti-PDL1 therapy represents an attractive therapy worthy of prospective clinical trial testing in MIUC patients whose tumors do not respond to or in patients who cannot tolerate cisplatin based chemotherapy. [Table: see text]
Incidence, predictors, and cost implications of gastrointestinal complications following intensity-modulated radiation therapy for prostate cancer.
Authors: Wood Monica J. , Reznor Gally , Trinh Quoc-Dien , Nguyen Paul Linh 
Published: February 2017

31 Background: The objective of this study was to examine the incidence and predictors of gastrointestinal (GI) complications following intensity-modulated radiation therapy (IMRT) for prostate cancer and their impact on national healthcare expenditure. Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data, we identified 11,781 men diagnosed with non-metastatic prostate cancer from 2002 to 2006 who underwent definitive IMRT, had no pre-existing GI toxicity, and had at least 36 months of follow-up after IMRT initiation. Annual incremental spending was defined as the difference between the total Medicare payments in the year after the development of the first GI complication and the total Medicare payments in the year preceding prostate cancer diagnosis, excluding prostate cancer treatment-related costs. We used multivariate logistic regression to evaluate the odds ratio of developing IMRT-related GI toxicity, and quantile regression to compare the annual incremental costs between groups. All analyses were done using SAS 9.3. Results: Over the 36-month follow-up period, the incidence of post-IMRT GI complications was 26.5% (n=3,118). Patients on anti-coagulation therapy or receiving brachytherapy boost were more likely to develop IMRT-related GI toxicities (OR 1.11, 95% CI 1.01-1.22 (p=0.029) and OR 1.18, 95% CI 1.08-1.30 (p<0.001), respectively). The median Medicare annual incremental cost per patient associated with post-IMRT GI complications was $3,375 in 2014 dollars (95% CI $3,222-3,529, p<0.0001). Among patients with post-IMRT GI complications, the presence of diabetes was associated with an additional $610 (95% CI $206-1,014, p=0.003) per patient in Medicare spending. Conclusions: Medicare spending associated with post-IMRT GI complications is considerable, often in excess of 10% of IMRT cost. Quantifying these expenditures may better frame the potential for cost savings of emerging technologies that aim to reduce the incidence and severity of IMRT-related GI toxicities.