bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin (Met): A cost-effective adjunct therapy with enzalutamide (Enza) for metastatic castrate-resistant prostate cancer (mCRPC)?
Authors: Hill Jordan , Paulden Mike , McCabe Christopher , Venner Peter , Danielson Brita Lavender , North Scott A. , Usmani Nawaid 
Published: February 2017

340 Background: Several new therapies have changed the landscape of prostate cancer (PCa) treatment, primarily due to their effectiveness in treating patients with mCRPC. Enza has garnered much attention, but is relatively expensive (~$3175/month). Met is less expensive (~$8.00/month) and has been used for decades to treat patients with non-insulin dependent diabetes. Two recent large population-based studies of PCa have demonstrated that diabetics taking Met had improved PCa specific and overall survival compared to those not taking Met. As a result, we hypothesized that Met has the potential to be a cost-effective adjunct therapy to Enza, although it is not currently used as such. Methods: We constructed a Markov-based decision analytic model to compare the cost-effectiveness of Enza alone versus Enza combined with Met. Through expert elicitation, we assumed that adding Met to Enza increases its efficacy by 15%. All other costs, utilities, and transition probabilities were derived from existing literature or expert elicitation. Effectiveness was measured using quality-adjusted life years (QALYs). Costs and QALYs were considered over a lifetime horizon and discounted at 5% per annum. Cost-effectiveness was considered using a willingness to pay threshold of $50 000/QALY. Results: Adding Met to Enza increases expected lifetime costs per patient by $83 651, and improves the expected effectiveness of treatment by 3.74 QALYs, compared to Enza alone. The incremental cost-effectiveness ratio is $22 374/QALY. Accounting for parameter uncertainty, adding Met to Enza has a 72% probability of being cost-effective. Conclusions: Although Met is not currently used as an adjunct therapy to Enza, doing so would likely be cost-effective provided it is as effective as we have assumed in our model. Additionally, our results indicate that the combination of Enza and Met could be among the most cost effective interventions in oncology. However, given the uncertainty around the effectiveness of such an adjunct therapy, our results support the need for further clinical trials to provide more robust evidence of the effectiveness of such a combination therapy in clinical practice.
Once-nightly (QD) dual CYP17-Lyase (L) inhibitor / androgen receptor (AR) antagonist VT-464 in patients with CRPC.
Authors: Shore Neal D. , Nordquist Luke T. , Gupta Shilpa , Fleming Mark T. , Berry William R. , Zhang Jingsong , Kurman Michael R , Eisner Joel Robert , Moore William R. 
Published: February 2017

343 Background: VT-464 is an oral, CYP17-L inhibitor and non-clinically an antagonist of the AR and its variants associated with clinical resistance to enzalutamide (ENZ) and abiraterone (AA). The safety, tolerability and initial PD effects (tumor responses, PSA and testosterone (T)-decreases) of QD VT-464 were evaluated in this Phase (Ph) 1/2 study (INO-VT-464-CL-004; NCT02361086). Methods: Chemotherapy-naïve (n = 20) M0 (n = 1) and M1 (n = 19) patients with CRPC prior to (TN, treatment-naïve; n = 9), or after AA (n = 6),ENZ (n = 3) or both (n = 2) were enrolled in sequential dose-cohorts of 600 mg QD with dose titration (DT; 300 mg QD q2w), and 600 and 750 mg QD without DT in 28-day continuous dosing cycles. All doses except the first were given at night with dinner. Patient results through the 750 mg QD cohort are reported (data cut off 17 Aug 2015). Results: Patients received VT-464 without steroids at 600 mg QD+DT (n = 3), 600 mg QD (n = 8) or 750 mg QD (n = 9). Eight patients are on study in cycles 3-12. Most adverse events (AEs) were Grade (Gr) 1 or 2. Fourteen Gr 3 AEs were reported with 7 considered unrelated and 7 ≥ possibly related; 5 of the latter were in the 600 mg QD+DT cohort (bradycardia, hypotension, syncope, hypertension and hyponatremia) with 2 in non-DT cohorts (hypotension, bilateral lower leg weakness). No AEs ≥ Gr 4 were reported. One DLT occurred in the 600 mg QD+DT cohort (syncope). No mineralocorticoid excess syndrome, ACTH response changes, or increased LFTs were observed. Plasma T was below the LOQ (0.03nM) in 67% of patients, with progesterone and cortisol unchanged. Cmax was similar in all cohorts to 450 mg bid (de Bono et al, GU ASCO 2015) but AUC was decreased. All 4 TN patients had PSA declines at 600 mg QD including one 30% and one 50% response; there was one 50% response in the 600 mg QD+DT cohort. Both TN patients treated at 750 mg QD had > 50% response. Of 8 patients with ≥ 1 soft tissue target lesion and ≥ 1 post-baseline scan, 5 had stable disease and 1 had a partial response at Cycle 5. Conclusions: The VT-464 750 mg QD regimen demonstrated potent and selective CYP17 L inhibition and has been selected for all Ph 2 clinical studies based upon improved tolerability, PK and efficacy compared to bid+DT dosing (de Bono et al, GU ASCO 2015). Clinical trial information: NCT02361086.
An RT-PCR assay to monitor circulating free DNA (cfDNA) in castrate resistant prostate cancer (CRPC).
Authors: Diaz Patricia M , Patrsch Katherin , Castellanos Olga O. , Ruderman Daniel , Gross Mitchell E. 
Published: February 2017

346 Background: Circulating-free DNA (cfDNA) is elevated in many forms of advanced cancer. We used an RT PCR assay for a highly repetitive DNA element (long-interspersed nuclear element-1; LINE1) to assess cfDNA in patients with CRPC. Methods: Plasma was collected from subjects with metastatic CRPC prior to a change in therapy. DNA was extracted and analyzed with an RT-PCR assay targeting a 297-bp LINE1 amplicon using absolute quantification. Leukocyte DNA and plasma from normal males were used as controls. Serial plasma samples were collected to monitor changes in cfDNA relative to treatment interventions. Results: cfDNA was analyzed at baseline in 54 samples categorized according to treatment context as: chemotherapy-naïve, docetaxel, or post-docetaxel (Table, summarized as means ± SD). While LINE1 was elevated in most patients relative to normal controls, no significant differences were noted across patient groups. No correlation was found between LINE1 and other clinical variables. Longitudinal sampling demonstrated concordant changes in LINE1 and PSA in most subjects, while a discordant pattern was noted in others. Conclusions: The LINE1 RT-PCR assay can be used to monitor cfDNA levels in patients with CRPC and may provide independent information to standard clinical assessments in order to monitor tumor composition and therapeutic response. [Table: see text]
Intermittent abiraterone-acetate administration protocol and prognosis prediction for castrate-resistant prostate cancer.
Authors: Morken Jason David , Cherington Chad , Bryce Alan H. , Kuang Yang 
Published: February 2017

353 Background: One mechanism leading to castrate-resistant prostate cancer (CRPC) is upregulation of CYP17. Abiraterone acetate (AA) inhibits CYP17 and continuous AA administration (CAAA) is one the most common and effective CRPC treatments. Mathematical models can be potentially powerful clinical tools for optimizing treatment strategies and eliminating guess work. Here, we introduce a new model which builds on our previous work (Morken JD, Packer A, Everett RA, Nagy JD, Kuang Y. Mechanisms of resistance to intermittent androgen deprivation therapy identified in prostate cancer patients by novel computational method. Cancer Res 2014;74:2673-83.) and may be capable of predicting how patients will respond to CAAA and intermittent AA administration (IAAA). We are currently proposing a personalized IAAA protocol on the basis of these results. Methods: In this ongoing retrospective study, we use PSA data from patients whom underwent CAAA to validate the accuracy of our model of tumor growth and evolution. The PSA output is driven by dynamics of three cell populations—castration-sensitive (CS), castration-resistant abiraterone-sensitive (CSAS), and castration-sensitive abiraterone-resistant (CSAR) cells. We fit the model output to PSA data to find parameter values which minimize normalized mean squared error (NMSE). Once parameters are obtained, we ran simulations employing various IAAA protocols. Results: The model’s PSA dynamics are highly accurate. NMSE is very low across patients ranging from 0.0001-0.0085. Conclusions: Our results suggest that there exists an IAAA protocol for each patient that, at worst, yields the same time to tumor progression as CAAA, yet improves quality of life and reduces cost. In nearly 20% of patients, IAAA appears to delay tumor progression over CAAA. The model is accurate at predicting how patients will respond to CAAA and IAAA for patients whose PSA is regularly monitored. Near-future work aims to personalize IAAA protocol based on patient pre CRPC PSA dynamics and to identify a protocol which delays progression for most patients.
Generating a neoantigen map of advanced urothelial carcinoma by whole exome sequencing.
Authors: Faltas Bishoy , Bhinder Bhavneet , Beltran Himisha , Tagawa Scott T. , Molina Ana M. , Nanus David M. , Elemento Olivier , Rubin Mark A. 
Published: February 2017

354 Background: immune-checkpoint blockade is a promising treatment of advanced urothelial carcinoma (UC) that unleashes pre-existing immune responses against recognized tumor antigens. Somatic mutations lead to the formation of neoantigens, which are highly antigenic mutant proteins. Methods: Our objective was to generate a neoantigen map through analysis of whole exome sequencing data of our cohort of patients (pts) with platinum-resistant UC. Whole exome sequencing (WES) data from 73 prospectively collected UC samples from 34 patients were analyzed using our neoantigen prediction pipeline. We defined neoantigens as mutant nonamers with high affinity binding to predicted class I MHC molecules for each patient. HLA haplotypes were inferred from WES of matched germline DNA. Results: A significant correlation between global somatic mutation rates, and neo-epitope burden was observed (R2 = 0.93), a similar correlation was observed between single nucleotide variants (SNV) and neo-epitope burdens (R2 = 0.94). We identified a strong positive correlation between the numbers of pack-years of smoking and neoepitope burden in patients with advanced UC (p = 0.0004). No correlation between global somatic mutational and predicted neoepitope burdens with overall survival was identified. Metastatic samples had a trend of harboring more SNVs (median 49 vs. 22, P = 0.13), and neoepitopes (median 17 vs 12, P = 0.22) compared to primary samples. Interestingly, only 32% of total SNVs and 8 % of neoepitopes (with binding affinities of ≤ 50nM) that were initially identified, reappeared in metastatic samples from the same patients obtained at a later time point. A significant selection against strong binding neo-epitopes was observed in subsequent samples from metastatic tumors (p-value < 0.005). Conclusions: A strong correlation between mutational burden and predicted neoantigenic load was observed in UC. Neoantigenic signatures were shaped by environmental exposures such as smoking. The significant heterogeneity in primary and metastatic neoantigens was possibly due to immunoediting as the tumor evolved. These findings may have important implications for selecting patients for immunotherapeutic approaches.
IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC).
Authors: Hoffman-Censits Jean H. , Grivas Petros , Van Der Heijden Michiel Simon , Dreicer Robert , Loriot Yohann , Retz Margitta , Vogelzang Nicholas J. , Perez-Gracia Jose Luis , Rezazadeh Arash , Bracarda Sergio , Yu Evan Y. , Hoimes Christopher J. , Bellmunt Joaquim , Quinn David I. , Petrylak Daniel Peter , Hussain Syed A. , Cui Na , Mariathasan Sanjeev , Abidoye Oyewale O. , Rosenberg Jonathan E. 
Published: February 2017

355 Background: The ORR and survival of mUC patients (pts) who progress after platinum-based chemotherapy (pctx) are poor. Atezolizumab (atezo) reinvigorates antitumor immunity by targeting PD-L1 and has shown promising Ph 1 activity in mUC. Methods: IMvigor 210 cohort 2 (NCT02108652) enrolled 316 mUC pts who progressed during or following pctx. Pts received atezo at 1200 mg IV q3w until loss of clinical benefit. The SP142 IHC assay centrally assessed PD-L1 expression. Pts/investigators were blinded to PD-L1 status. Co-primary endpoints were confirmed ORR by RECIST v1.1 per central review (IRF) and modified (m) RECIST per investigator, which were met if null hypothesis (ORR = 10%) was rejected (α = 5%). ORR endpoints were stratified by PD-L1 tumor-infiltrating immune cell (IC) status: IC2/3, IC1/2/3, all comers. Results: Efficacy/safety-evaluable pts (N = 311) had a median age of 66 y, CrCl < 60 mL/min (35%) and ≥ 2 prior regimens for mUC (40%). Many had poor prognostic factors (Table). At 5/5/15 data cutoff (follow up ≥ 24 w), 43/47 responding pts had ongoing responses. Both IRF (Table) and mRECIST ORR correlated with IC status. Durable responses were seen including poor prognostic subgroups (Table). mDOR was not reached in any PD-L1 or prognostic subgroup. mPFS was 2.1 mo in all PD-L1 subgroups. Median treatment duration was 12 w (range 0-46). Treatment-related AEs (most commonly fatigue) occurred in 66% of pts (all Grade); 15% had G3-4 related AE and 4% had G3-4 immune-mediated AE. 27% of AEs led to dose interruption and 3% led to withdrawal. No renal toxicity was seen. Conclusions: IMvigor 210, the first Ph 2 study targeting PD-L1/PD-1 in mUC, demonstrated significantly improved ORR vs historic controls. Responses were durable and associated with higher PD-L1 IC expression; poor prognostic factors did not preclude response. Atezo was well tolerated, and a randomized Ph 3 study vs ctx is ongoing (IMvigor 211; NCT02302807). Clinical trial information: NCT02108652. [Table: see text]
Neutrophiles-to-lymphocytes ratio (NLR): Prognostic value in non-muscle invasive bladder cancer (NMIBC).
Authors: Irani Jacques , Thillou Damien , Bernardeau Simon , Biscans Clément , Sarradin Maxence , Delpech Pierre-Olivier 
Published: February 2017

360 Background: The aim of this retrospective study was to evaluate the prognostic value of NLR in NMIBC as it was recently suggested in the literature. Methods: Patients included in the study were diagnosed between 1992 and 2013 with a T1 stage bladder cancer either primarily or following progression. NLR was calculated using the pre-operative (TURB or cystectomy) work-up. Results were expressed as median and interquartile range (IQ) unless indicated otherwise. Results: Seventy-eight patients were analyzed (12 females and 67 males). Mean age: 68.3 years. At diagnosis (1st TURB): median grade according to the WHO 1973 classification: 3 (IQ = 1), median NLR: 3.1 (IQ = 2.4 and range 1.0- 25.7). There was no significant difference between NLR when comparing stage, grade and gender subgroups. During FU (median 6.2 years): median number of TURB: 3.3. Observed NLR was higher in the highest risk groups, however the difference was significant only for grade progression and when comparing pT0 stage vs pTa or higher at the last biopsy/TURB (see table). NLR variation for each patient (NLR at diagnosis – NLR at the last TURB) was not associated with bladder tumor evolution. Conclusions: We found that NLR was higher in NMIBC with a high risk of progression. These data warrant a further evaluation of this potential, readily available prognostic marker in NMIBC. [Table: see text]
Epigenetic silencing and variable expression of SRD5A2 in specific compartments of human prostate.
Authors: Olumi Aria F. , Wang Zongwei , Ge Rongbin , Wu Shulin , Tabetabaei Shahin , Wu Chin-Lee 
Published: February 2017

38 Background: The steroid-5α reductase type 2 gene (SRD5A2) and protein play a significant role in the development and growth of prostate tissue. SRD5A2 can be expressed in both the epithelial and stromal compartments of the prostate gland. Previously, we have shown that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene. Here we determined whether variability of SRD5A2 expression occurs in specific compartments of prostate tissues. Methods: Frozen and formalin-fixed sections of human adult prostate tissue was used. Laser capture microdissection (LCM) was performed to obtain a pure population of epithelial and stromal cells. Approximately 500–600 excised cells were captured, and the methylation pattern of SRD5A2 was determined by DNA methylation pull-down assay kit. The expression of SRD5A2 protein was identified with immunohistochemistry and quantitated by ELISA. Results: In the whole prostate tissue, samples with high SRD5A2 immunoreactivity had much lower levels of SRD5A2 promoter methylation compared to those with low SRD5A2 immunoreactivity. DNA methylation assay for the epithelial compartment closely resembled the findings of the whole prostate tissue. In contrast, the samples from the stromal compartment showed uniform methylation irrespective of the methylation pattern in the epithelial compartment or the whole tissue. The expression of SRD5A2 protein quantitated by ELISA further showed that the variable expression of SRD5A2 is better determined by epithelial compartment expression. Conclusions: Our data suggests that variability of SRD5A2 expression is dependent on the methylation pattern and expression of SRD5A2 in the epithelial compartment and not the stroma. Therefore, if epithelial expression of SRD5A2 is more representative of the whole prostatic tissue expression, then it is logical that SRD5A2 inhibitor’s efficacy is dependent on involution of the epithelial cells. Our findings will have broad implications for the use of 5ARIs in the treatment of BPH and for the chemoprevention of prostate cancer. Grant support: NIH/R01 DK091353
Frequency and clinical implications of pathologic complete response (pCR) at cystectomy for muscle-invasive bladder cancer (MIBC) with or without neoadjuvant chemotherapy (NAC).
Authors: Galsky Matt D. , Stensland Kristian , Sfakianos John , McBride Russell Bailey , Mehrazin Reza , Tsao Che-Kai , Boffetta Paolo , Oh William K. 
Published: February 2017

383 Background: Subsets of patients (pts) with MIBC, with or without NAC, have no pathologic evidence of disease at cystectomy. The frequency and implications of pCR in “real world” pts has not been well characterized. Methods: Using the National Cancer Database, pts with cT2-4aN0M0 bladder cancer who underwent cystectomy alone (CYS) or with NAC from 2003-2011 were identified. pCR was defined as pT0N0M0. In the CYS and NAC cohorts, the association between pCR and overall survival was analyzed using Cox proportional hazard methods. Results: 12,245 pts met eligibility (CYS: 10,940; NAC: 1,305). The pCR rate with CYS was 4.8% (95% CI 4.4-5.3%) and with NAC was 21.6% (95% CI 19.4-24.0%). In both cohorts, logistic regression revealed lower cT stage and higher cystectomy volume were associated with increased pCR. pCR was associated with a significant improvement in survival in both cohorts (Table). Conclusions: The frequency of pCR in real world pts was substantially lower than reported in clinical trials; however, pCR was associated with markedly improved survival in both CYS and NAC groups. Molecular predictors of pCR in both groups warrant evaluation. Whether the survival benefit associated with pCR in the CYS cohort simply reflects the “smallest/best” tumors or whether there is a role, and mechanistic rationale, for surgical approaches to increase pCR (i.e., re-TURBT in MIBC) warrants study. Finally, our findings lend further support for use of pCR as an endpoint in NAC clinical trials. [Table: see text]
Safety and efficacy of extended-duration thromboembolic prophylaxis following radical cystectomy.
Authors: Zaid Harras B. , Yang David , Tollefson Matthew K. , Frank Igor , Parker William P. , Thompson Robert Houston , Karnes R. Jeffrey , Boorjian Stephen A. 
Published: February 2017

389 Background: Venous thromboembolism (VTE) has been reported in approximately 5-7% of patients undergoing radical cystectomy (RC). While extended-duration pharmacologic prophylaxis (EDPP) has been investigated following surgery for a variety of malignancies, limited data exist in bladder cancer. Herein, we evaluated the efficacy and safety of EDPP after RC. Methods: We instituted a change in our clinical practice beginning in May 2014 such that patients undergoing RC were prescribed 30 days of enoxaparin at discharge. We recorded symptomatic VTE and lymphocele rates within 30 days of RC among patients treated from 5/14-6/15, and compared these outcomes to the cohort of all patients who underwent RC at our institution in the year prior to EDPP implementation. Patients in both groups received subcutaneous unfractionated heparin and mechanical prophylaxis during hospitalization. Patients with a history of VTE prior to surgery (n = 24) were excluded from study. Unadjusted descriptive statistics and univariate analyses were performed using the Pearson or Fisher chi-square test for categorical variables and Wilcoxon rank-sum test for continuous variables. Results: In total, 58 patients who received EDPP and 82 patients who had not received EDPP after RC were included for analysis. Baseline clinicopathologic demographics were similar between the cohorts. We found that only 1 patient (1.9%) discharged with EDPP was diagnosed with a VTE within 30 days of RC, compared to 5 (6.1%) who had not received EDPP. Mean time to VTE was 18.0 days after RC (range 9-28 days). Events consisted of DVT alone (n = 2), DVT and PE (n = 2), and PE alone (n = 2). The odds ratio for VTE in the absence of EDPP was 3.31 (95% CI 0.38, 29.2). Overall, 3 patients developed a symptomatic lymphocele within 30 days of RC: 1 (1.9%) who received EDPP and 2 (2.4%) who had not (p = 0.84). No patient in either cohort was rehospitalized for bleeding complications. Conclusions: Our initial experience suggests that EDPP was associated with a lower rate of VTE following RC, and does not increase the risks of bleeding or symptomatic lymphocele. Future evaluation in a larger-scale prospective clinical trial setting is needed to confirm the benefit of EDPP in RC patients.