bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin use and renal cell cancer outcomes among patients with diabetes.
Authors: Khimani Farhad , Shah Nilay , Curley Brendan F. , Newton Michael David , Hogan Thomas F. , Monga Manish 
Published: February 2017

543 Background: Renal Cell Carcinoma (RCC) is the third most prevalent urologic malignancy, and the sixth leading cause of cancer deaths in the United States. RCC is resistant to conventional treatment (chemotherapy, hormonal therapy and radiotherapy) therefore there is tremendous need for the development of new treatment strategies. Evidence indicates that metformin may reduce the risk of cancer and inhibit growth of several cancers, including prostate, breast, liver and colon. Metformin has been shown to inhibit RCC growth in in vitro and in vivo assays. Hence, it is pertinent to explore the role of metformin in RCC. Methods: At West Virginia University we performed an IRB approved retrospective chart review of all patients who were diagnosed with RCC at our institution from 2008-2012. Patients with Diabetes mellitus Type II (DM) were selected and stratified in to two cohorts based on metformin use. Statistical analysis was performed with SPSS Version 20.0. Results: A total of 290 patients with RCC were identified through the institutional tumor registry. Among patients with RCC, 25.1% (73) had DM. Of those DM patients, 60.2% (44) were on metformin therapy at diagnosis of RCC and 50.7% (37) were on metformin at last follow up. 84.9% (39) underwent radical or partial nephrectomy and 17.8% (13) patients received immunotherapy, targeted agents or chemotherapy. 26% (19) either had metastatic disease at diagnosis or developed recurrent disease. The metformin cohort had 27% (12) of patients with metastatic disease or a noted recurrence whereas in the non-metformin cohort 24.1% (7) had metastatic disease or recurrence. This was not statistically significant (p=0.76). No significant association was found between metformin use and mortality (p=0.46) or with stage of disease at diagnosis (p=0.35). Conclusions: Our limited retrospective review did not reveal any association between metformin usage and RCC outcomes, stage at diagnosis, or recurrence rates. However, in vitro and in vivo assays showing metformin inhibits RCC growth encourage further studies on larger patient populations to continue to explore this possible association. [Table: see text]
Dose-modified abiraterone acetate (AA) in men with metastatic castration-resistant prostate cancer (mCRPC): The Princess Margaret Cancer Centre (PM) experience.
Authors: Leibowitz-Amit Raya , Atenafu Eshetu G. , Seah Jo-An , Templeton Arnoud J. , Vera-Badillo Francisco Emilio , Solow Henry L. , Knox Jennifer J. , Sridhar Srikala S. , Tannock Ian , Joshua Anthony Michael 
Published: February 2017

61 Background: AA prolongs survival in mCRPC and is used pre- and post-chemotherapy. In the phase I trial, AA showed anti-tumor activity at 250 or 500 mg daily (‘low doses’). In addition, pharmacokinetic analysis showed that when AA was administered with a high-fat meal vs the fasting state, drug exposure was increased by 4.4-fold [ Attard G et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2008; 26: 4563-4571.]. Based on this, at our cancer centre low-dose AA is sometimes prescribed with high-fat meals to men who otherwise cannot access the drug due to funding constraints, particularly in the pre-chemotherapy setting. Our aim was to study the association between AA dose, PSA response and progression-free survival (PFS). Methods: All men receiving AA at PM (Nov2009-Mar2013) were reviewed retrospectively. PSA response rate (PSA-RR) was defined according to PCWG2 criteria as a confirmed decrease ≥50% in PSA. PFS was defined from start of AA to PSA progression, clinical progression, drug cessation or death. Associations between dose, PSA-RR and PFS were assessed using chi-square and logrank tests, respectively, for all patients and for the sub-group of chemo-naive patients. Results: 109 men were treated with AA, 89 at a full dose of 1000 mg in the fasting state, 20 at low doses with high-fat meals. There was no significant difference in PFS between the two dose levels for all men. PSA-RR was non-significantly lower in chemo-naive men treated with low doses compared to full dose (p=0.09; table). Conclusions: Administration of low dose AA with high-fat meals is not associated with shorter PFS despite a trend to lower PSA-RR. These results are clinically relevant in resource-limited settings and warrant further prospective clinical research. [Table: see text]
Sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) patients ≥80 years-old: Data from PROCEED.
Authors: Nabhan Chadi , Sartor A. Oliver , Cooperberg Matthew R. , Armstrong Andrew J. , Vacirca Jeffrey L. , Concepcion Raoul S. , Berry William R. , Dhawan Manish , Tutrone Ronald , Sandler Andrew , McCoy Candice , Whitmore James Boyd , Tyler Robert Claude , Higano Celestia S. 
Published: February 2017

64 Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC based on data from the pivotal phase 3 IMPACT trial that demonstrated a 22% reduction in the risk of death. Given the high prevalence of older men in the mCRPC patient (pt) population, we sought to understand disease characteristics and sipuleucel-T product parameters in pts ≥80 years (yrs). Methods: PROCEED is an ongoing phase 4 registry enrolling pts treated with sipuleucel-T within ≤6 months. Baseline pt demographics and disease characteristics were collected. Sipuleucel-T product parameters that were assessed included: total nucleated cell (TNC) count, antigen presenting cell (APC) count (large CD54+ cells), and APC activation (upregulation of CD54; a measure of product potency). Results: As of May 2013, 1254 subjects were enrolled and have completed treatment. Of these, 278 (20%) pts were ≥80 yrs-old. Disease and infused product characteristics in pts ≥80 yrs vs. <80 yrs are detailed in the table below. Product parameters appear similar between groups. Conclusions: In this large cohort of elderly pts ≥80 yrs treated prospectively with sipuleucel-T immunotherapy, we demonstrate that product parameters were similar to their younger counterparts (<80 years). This implies adequate immune up-regulation in elderly pts. Additional follow-up is needed to explore correlations between OS and various immune parameters in both groups. Clinical trial information: NCT01306890. [Table: see text]
Genomic analysis of circulating tumor cells (CTCs) from men with metastatic castration resistant prostate cancer (mCRPC) in the context of enzalutamide therapy.
Authors: Armstrong Andrew J. , Li Jing , Beaver Joshua , Bitting Rhonda Lynn , Gregory Simon 
Published: February 2017

65 Background: Given the evolving treatments available in metastatic castration resistant prostate cancer (mCRPC), predictive biomarkers are desirable that maximize benefit and minimize harms and costs.The goal of this study was to determine the feasibility of DNA copy number and whole exome sequencing (WES) analysis of circulating tumor cells (CTCs) from men with mCRPC receiving enzalutamide. Methods: We collected CTCs from men with mCRPC in the context of enzalutamide therapy. CTCs were isolated from EDTA blood through red cell lysis, CD45 depletion, and flow sorting on EpCAM/CD45 expression. Whole genomic amplification and array based comparative genomic hybridization (CGH) was performed using Qiagen Repli-Gene Single Cell kit, multiple displacement amplification, and Agilent microarray analysis. CTC copy number changes were compared with patient leukocyte DNA and reference metastatic PC datasets. CTC AR amplification and PTEN loss was confirmed with FISH. WES on REPLI-g amplified CTC and leukocyte DNA was performed using GeneWiz and TruSeq Exome Capture Kit, and sequenced with Illumina HiSeq 2000 (20x). Results: A novel method for CTC array CGH was developed that reproducibly identified genomic lesions previously reported in metastatic CRPC including: AR amplification or focal deletions, deletions of CHD1, Rb, PHLLP, FGFR2, FOXA1, and NCOA2, and amplifications of EZH2 and MYC. AR amplification was noted in a man with mCRPC who subsequently responded to enzalutamide, with loss of AR amplification and gain of MYCN and c-MET amplification noted at progression. CGH analysis was feasible down to 10 to 20 cells using spiked cell lines. Interpatient tumor specific genomic heterogeneity was observed. FISH confirmed AR changes and PTEN loss heterogeneity. WES demonstrated acquired PTEN, MAGI1, SMAD4, and RB1 mutations in a patient who progressed through enzalutamide therapy, in addition to AR region deletion detected by CGH. Conclusions: Whole genome DNA copy number and exome sequencing analysis from CTCs in men with mCRPC is feasible in men with high CTCs and identified previously validated and novel genomic lesions and suggest the potential to identify predictive biomarkers of enzalutamide efficacy and resistance in the clinic.
A population-based study of expectant management utilization and its predictors for low-risk prostate cancer.
Authors: Maurice Matthew J. , Abouassaly Robert , Zhu Hui 
Published: February 2017

68 Background: Expectant management (EM), including active surveillance and watchful waiting, is a strategy to minimize prostate cancer overtreatment. We sought to evaluate contemporary trends in EM utilization and to identify factors associated with its uptake. Methods: Using the National Cancer Database, a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society, we identified men with biopsy-proven low-risk (Gleason score 6 or lower, no Gleason pattern 4 or 5, cT1-cT2a) prostate cancer diagnosed between 2004 and 2011. We then classified men within this cohort as having undergone EM (no first-course surgery, radiation, hormone therapy, or chemotherapy) or active treatment. Patient and provider variables were analyzed using univariate and multivariate logistic regression models to determine predictors of EM selection. Results: Of 287,562 men with low-risk prostate cancer, we identified 34,132 patients (11.9%) who received EM. Beginning in 2008, we observed a significant and steady rise in EM usage with time (range, 9.8% to 18.6%). Compared to 2004, patients diagnosed in 2011 had 2.5 times the odds of receiving EM (odds ratio [OR] 2.52, confidence interval [CI] 2.39-2.64, p<0.0001). Aside from year of diagnosis, age, and Charlson score were strong predictors of EM usage (p<0.0001). Other strong predictors of EM included hospital type and insurance provider. Specifically, patients who were treated at comprehensive cancer centers or who had personal health insurance were significantly less likely to receive EM (OR 0.63, 0.60-0.66, p<0.0001 or OR 0.90, CI 0.88-0.93, p<0.0001, respectively). Patient race, income, and area of residence as well as hospital location were significantly but weakly associated with EM. Conclusions: In recent years, low-risk prostate cancer has been increasingly managed with EM, especially in older patients or patients with multiple comorbidities, who are least likely to benefit from active treatment. Unexpectedly, hospital type and insurance provider also predict EM usage, calling into question whether non-clinical factors are influencing EM selection.
A prognostic score for patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate post chemotherapy.
Authors: Templeton Arnoud J. , Omlin Aurelius Gabriel , Pezaro Carmel Jo , Kheoh Thian San , Leibowitz-Amit Raya , Vera-Badillo Francisco Emilio , Tannock Ian , Attard Gerhardt , Amir Eitan , De Bono Johann Sebastian 
Published: February 2017

70 Background: We aimed to establish a simple prognostic score for men with mCRPC treated with abiraterone following docetaxel and explored incorporation of the neutrophil/lymphocyte ratio (NLR), a marker of host inflammation with prognostic value in many solid tumors. Methods: To develop the model, clinical and laboratory factors for 185 men treated at Royal Marsden were included in a univariable Cox regression analysis. Statistically significant variables were dichotomized using an optimal cut-off chosen by selecting the highest c-index among three potential cut-offs with high Hazard Ratios (HR). All significant variables in univariable analysis were analyzed using multivariable Cox analysis. One risk point was assigned for each variable with a P value of <0.05 in multivariable analysis and the risk points were used to establish three prognostic groups of similar prevalence. The validity of the model is being examined using the large data-set from the abiraterone registration trial (COU-AA-301). Results: Median age was 69 years, 41% had both bone and lymph node metastases (BLN), 15% had visceral disease. Involvement of BLN or visceral disease (HR 1.6, P=0.013), ALP >2.0 x ULN (HR 1.7, P=0.005), LDH >1.5 x ULN (HR 3.4, P<0.001), Hgb <12 g/dL (HR 2.1, P<0.001), and NLR >5 (HR 1.5, P=0.033) were associated with worse OS in the multivariable analysis. Outcomes for three risk groups using these 5 factors are presented in the table. The c-index was 0.73 (95% CI 0.65 - 0.80) for the prognostic score. Patients with NLR >5 at baseline and whose NLR was ≤5 within four weeks of treatment also had longer median survival (15.1 months) than those with NLR >5 at baseline that remained high (median OS 7.6 months, HR 0.48, 95% CI 0.25-0.93, P=0.029). Conclusions: This initial simple risk score provides good prognostic and discriminatory accuracy for men with mCRPC. Data from the validation cohort will be presented. [Table: see text]
ARMOR2: Galeterone in progressive CRPC patients who have failed oral therapy.
Authors: Taplin Mary-Ellen , Montgomery Robert B. ,   ARMOR2 Group
Published: February 2017

71 Background: Galeterone is a first-in-class multitargeted oral steroid analog; it suppresses prostate cancer by a combination of AR modulation (antagonism and degradation) and CYP17 inhibition. Safety and proof of concept of galeterone in CRPC was assessed in ARMOR1. Galeterone was reformulated by spray dry dispersion technology (SDD) to optimize PK and remove food effect. ARMOR2 (NCT 01709734) is an open label, 2-part phase 2 trial that evaluates safety and efficacy of SDD galeterone in 4 populations of CRPC patients. These results report Part 1. Methods: Objectives of Part 1: confirm dose equivalence of SDD formulation with evaluation of PK, safety and PSA response. Metastatic (M1) and non-metastatic (M0) treatment naïve CRPC pts enrolled to groups of 1,700, 2,550 or 3,400 mg PO daily. An abiraterone refractory (Abi-R) group of 3 patients opened at 2,550mg. Results: 28 were enrolled in part 1. Safety: All groups were safe by IMC assessment. There were 4 grade 3 adverse events. 2 were unrelated to study drug. 2 had transient G3 ALT elevations (did not recur with rechallenge). There was no AME: supplemental steroids were not required. G4 angioedema occurred in a pt receiving lisinopril (known association with angioedema). Efficacy: PSA response was improved compared to ARMOR1 (AACR 2012. Taplin et al abstract: CT-07). At early follow up Abi-R pts showed improvements in PSA with 1 PSA30% response, 2 with stablized PSA (decline in PSA-V from +0.44 to -0.39 ng/day). Conclusions: Galeterone in SDD formulation is tolerated at doses up to 3,400mg daily. SDD galeterone provides improved PSA response and durability vs. prior formulation. There is evidence of activity in abiraterone refractory patients. Clinical trial information: 01709734. [Table: see text]
Salvage chemotherapy with carboplatin plus weekly docetaxel in patients (pts) with castration- and docetaxel-resistant prostate cancer (DRPC): Associations of patient and disease characteristics with overall survival (OS).
Authors: Reuter Christoph W. , Morgan Michael A. , Grünwald Viktor , von Klot Christoph A. J. , Merseburger Axel S. , Ivanyi Philipp , Fenner Martin , Ganser Arnold 
Published: February 2017

75 Background: Our recent data suggest that carboplatin is effective in combination with docetaxel (DC) in docetaxel-resistant prostate cancer (DRPC). Platinum(II)-complexes interfere with steroid biosynthesis lowering testosterone levels by inhibiting the cholesterol side chain cleavage enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase (HSD3B1,2) and 17α hydroxylase/C17,20-lyase (CYP17A1). Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of at least two cycles of carboplatin AUC5 iv for 30 min on day one every 4 weeks (q4w), docetaxel 35 mg/m2 iv for one hour on days 1, 8, and 15 plus prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Free testosterone levels were measured before (n=59) and during DC chemotherapy (n=52). Results: Of the 82 pts treated since February 2005, 95.1% had bone, 42.7% had lymph node, 26.8% liver, and 18.3% lung involvement. At the current analysis, the median follow-up time was 15.6 months. The objective response rate was 40.8% and the disease control rate 63.3% in the 49 pts with measureable disease. Response of prostate-specific antigen (greater than or equal to 50%) was observed in 3 out of /82 (47.6%) pts. Median progression-free survival (PFS) was 6.9 months (CI 95% 6.0, 7.8) and median OS was 18.0 months (CI 95% 12.7, 23.3). The most common reversible grade 3/4 toxicity was leukopenia/neutropenia (42.7/37.8%). Median free testosterone (fT) was 0.745 pg/ml before and less than 0.18 pg/ml during DC treatment (nadir levels, p=0.009; detection limit less than 0.18 pg/ml) and median serum androgene (T+DHT=TA) was 0.19 ng/ml and below the detection limit of less than 0.05 ng/ml (p<0.001). In multivariate analyses, lactate dehydrogenase, PSA response, and fT and TA nadir levels were associated with longer OS (p<0.05). Conclusions: These data suggest that carboplatin plus weekly docetaxel may be an important second-line treatment option for DRPC patients by inhibiting the testosterone biosynthesis.
Antigen spread and survival with sipuleucel-T in patients with advanced prostate cancer.
Authors: Drake Charles G. , Fan Li-Qun , GuhaThakurta Debraj , Stewart Frances , Kantoff Philip W. , Small Eric Jay , Gardner Thomas A. , Sheikh Nadeem A. , Trager James B. , Higano Celestia S. 
Published: February 2017

88 Background: Tumor cell death in response to an immunotherapy may lead to the release of secondary (i.e. non-targeted) tumor antigens that prime subsequent immune responses (antigen spread). This may contribute to tumor control and reveal post-treatment biomarkers of clinical outcome. Sipuleucel-T, approved in the U.S. for treatment of patients with asymptomatic or minimally symptomatic, metastatic castration-resistant prostate cancer (mCRPC), is designed to elicit an immune response to prostatic acid phosphatase. Here we show that sipuleucel-T also elicits humoral antigen spread that may be associated with clinical benefit. Methods: We used protein microarrays and Luminex xMAP to identify and validate post-treatment serum immunoglobulin G (IgG) responses against secondary antigens. Association between IgG responder status (≥ 2-fold IgG elevation post-treatment) and overall survival (OS) was assessed using a Cox regression model adjusted for baseline prognostic factors (prostate-specific antigen [PSA], lactate dehydrogenase [LDH], bone lesions, Gleason score) and prior bisphosphonate use. Results: In IMPACT (NCT00065442, the pivotal trial of sipuleucel-T), IgG responses against secondary antigens were consistently observed three to four months post-treatment in the sipuleucel-T arm but not in the control arm. In evaluable sera from IMPACT (sipuleucel-T n=93; control n=40), IgG responses against an array of secondary antigens, including an oncogene (K-RAS) and a prostate-specific antigen (KLK2/hK2), were confirmed by Luminex xMAP in sipuleucel-T-treated patients (Wilcoxon test, p≤10-6); responses were not observed in control patients (p>0.1). Antigen spread was also observed post-sipuleucel-T treatment in ProACT (Wilcoxon test, p≤0.01), an independent study in patients with mCRPC (NCT00715078, evaluable n=26). In IMPACT, OS was longer in sipuleucel-T-treatment patients with IgG response to greater than or equal to two secondary antigens than in those without such response (Cox model, p≤0.01, HR≤0.4). Conclusions: Sipuleucel-T treatment resulted in humoral antigen spread that was associated with improved OS in IMPACT. These results contribute to an understanding of sipuleucel-T’s mechanism of action, and may enable identification of post-treatment biomarkers of clinical outcome. Clinical trial information: NCT00065442.
A prospective randomized phase III trial comparing consolidation therapy with or without strontium-89 following induction chemotherapy in androgen-independent prostate cancer.
Authors: Wang Jennifer , Tu Shi-Ming , Pagliaro Lance C. , Weiss Matthias , Hajdenberg Julio , Tseng Jennifer , Wade James Lloyd , Belt Robert J. , Cannon Michael W. , Fisch Michael 
Published: February 2017

90 Background: New therapies have shown benefit for advanced prostate cancer, but are not curative. Bone metastases cause significant prostate cancer morbidity. Preliminary studies showed that bone-targeted therapy with strontium-89 (Sr-89) with doxorubicin was feasible in patients with stable or responding metastatic castration-resistant prostate cancer (mCRPC) after KAVE (ketoconazole and doxorubicin alternating with estramustine and vinblastine) induction with promising time to progression (13.9 vs. 7.0 months) and overall survival (27.7 vs. 16.8 months). We conducted this phase III, randomized, double-blind, multicenter study to determine the effectiveness of consolidation therapy with or without Sr-89. Methods: Patients with progressive mCRPC with bone disease received induction with KAVE or docetaxel/prednisone (D) chosen by the treating physician. Patients with stable or responding disease were randomized at week 16 to receive doxorubicin with either one dose (4 mCi) or no Sr-89. Primary endpoint was overall survival (OS). Results: This study was activated in April 2002 with planned randomization of 480 patients (240 patients per study arm). The trial closed early with a total of 265 patients: median age 67; median prostate-specific antigen (PSA) 71.2; 109 received KAVE; 155 received D, 127 (47.9%) patients went on to randomization, 43 (39.4%) from the KAVE arm, and 84 (54.2%) from the D arm. Multivariate Cox proportional hazards regression was used to control for induction regimen, Eastern Cooperative Oncology Group (ECOG) status, and number of bone metastases. Median survival from times of registration and randomization in the no-Sr-89 arm were 26.5 months (95% CI: 21.1, 29.9) and 22.8 months (95% CI: 17.7, 26.1), respectively, compared to 27.9 months (95% CI: 23.6, 34.2) and 24.3 (95% CI:19.8, 29.9) months in the Sr-89 arm. OS from registration (p=0.61) and randomization (p=0.62) were not statistically significant on univariate or multivariate analyses. Conclusions: The addition of Sr-89 to consolidation chemo did not improve OS in this study. This community-based, multicenter study closed prematurely due to slow accrual, demonstrating challenges in conducting trials in the US that combine radionuclide therapy with chemotherapy. Clinical trial information: MDA 3410.