bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of a phase II trial of docetaxel (DOC), bevacizumab (BEV), and androgen deprivation therapy (ADT) for biochemical relapse (BCR) after definitive local therapy for prostate cancer (PC).
Authors: McKay Rana R. , Gray Kathryn P. , Hayes Julia H. , Bubley Glenn J. , Rosenberg Jonathan E. , Kantoff Philip W. , Taplin Mary-Ellen 
Published: February 2017

54 Background: Despite primary treatment for localized PC, 20-30% of men experience a BCR, detected by a rise in prostate-specific antigen (PSA). Though 30% of these patients develop metastatic disease, the optimal treatment of men with BCR has yet to be determined. In this trial, we evaluate the efficacy of DOC, BEV, and ADT for men with BCR after local therapy for PC. Methods: 41 men with a BCR and PSA doubling time of ≤10 months (mos) were enrolled. Patients received 4 cycles of DOC (75 mg/m2) every 3 weeks, 8 cycles of BEV (15 mg/kg) every 3 weeks, 18 mos of a luteinizing-hormone releasing hormone (LHRH) agonist, and 15 mos of bicalutamide (50 mg daily) beginning after completion of DOC. The primary endpoint was the proportion of patients free from PSA-progression 1 year after completion of ADT. Secondary endpoints included PSA response, testosterone recovery, and toxicity. Results: Median follow-up was 27.6 mos. Median age at diagnosis was 58 years. Median PSA at diagnosis was 6.7 ng/mL, with the majority of patients (59%) having Gleason 7 disease. Most patients underwent radical prostatectomy +/- radiation therapy (n=36). At baseline, 33 men (81%) had a normal testosterone (> 240 ng/dL). The table describes the PSA responses for the entire cohort. 10 men (28%) had a normal testosterone 6 mos after completing ADT. 17 men (47%) had a normal testosterone 12 mos after completing ADT, of whom 5 (29%) had a PSA <0.2 ng/mL at that time. There were 15% grade 1, 34% grade 2, 39% grade 3, and 12% grade 4 adverse events (AEs). The most frequent grade 3-4 AEs included neutropenia (24%), febrile neutropenia (11%), and hypertension (9%). Conclusions: DOC, BEV, and ADT for BCR resulted in complete responses in 16 men (44%) 1 year after completion of therapy. Longer follow-up is needed to determine the efficacy of this regimen. Clinical trial information: NCT00658697. [Table: see text]
Assessment of time from cytoreductive nephrectomy (CN) to initiation of targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Vuong Winston , Chang Mark , Ruel Nora , Hsu Joann , Carmichael Courtney , Figlin Robert A. , Pal Sumanta Kumar 
Published: February 2017

540 Background: For patients (pts) with de novo mRCC, the initiation of TT typically occurs at a window of 4-6 weeks following CN. Although this practice is thought to mitigate impaired wound healing, bleeding and other complications (cx) in the perioperative period potentially related to antiangiogenic TT, there is limited data to support this practice. Methods: An institutional database including over 670 pts with RCC was interrogated. Pts with de novo mRCC who had received CN and subsequent TT were identified. When available, demographic data, Charlson comorbidity index (CCI), body mass-index (BMI) and surgical data (estimated blood loss [EBL], intraoperative cx, etc.) were recorded. ICD-9 codes recorded up to 90 days following CN were evaluated; newly applied diagnoses with possible relationship to surgery were considered to be potential postoperative cx. For continuous variables, the Spearman correlation test was used to determine associations with time to TT. For categorical variables, Kaplan-Meier analyses were conducted to determine if time to TT varied across subgroups. Results: Of 270 pts with mRCC, 79 pts received cytoreductive nephrectomy. Of these, 36 pts received TT as an initial treatment strategy (others received IL-2, IFN or chemotherapy), and 30 pts had a documented date of TT initiation. Two pts were removed given receipt of preoperative TT, resulting in a total of 28 pts in the current analysis. Median time to TT was 46 days (range, 28-93). Median overall survival for the overall cohort was 17.2 months. No association was found between age, BMI, CCI, number of sites of metastasis and time to TT. Time to TT did not vary by race (Caucasian v other) or class of TT (VEGF-directed therapy v mTOR inhibitor). Furthermore, EBL and the frequency of intraoperative cx did not vary by time to TT. The most frequently encountered postoperative cx included pleural effusion, pain, fatigue and nausea. Conclusions: With the caveat of our small sample size, the lack of an association between operative cx and time to TT suggests that an abbreviated timeframe between CN and TT may be entertained. These findings warrant exploration in larger series and/or prospective validation.
Effect of irradiation of renal cell carcinoma (RCC) cell lines on RCC tumor-associated antigen (TAA) specific CD8+ T-cell stimulation.
Authors: Janda Gregory , Habiby Kermany Mohammad , Romano Michelle , Heit Lilia , Singh Anurag , Warren Graham Walter , Schwaab Thomas 
Published: February 2017

542 Background: Radiation increases the immunogenicity of many cancers. We have previously shown increased immunogenicity of RCC with cell line irradiation. Herein, we describe the effect of irradiation of RCC cell lines on the expression of TAAs as well as several molecules involved in CD8+ T Cell (CTL) mediated tumor cytotoxicty and the in vitro effect of tumor irradiation on NY-ESO-1 specific CTL clones. Methods: Six RCC cell lines (ACHN, 786-0, 769-P, Caki-1, A-498, A-704) were cultured and exposed to 0, 12 or 16 Gy of ionizing radiation. Cells were isolated at 2, 24 and 48 hours after irradiation. Expression of cell surface molecules (CD95, CD54, Calreticulin, NYESO-1, CA-9, 5T4, MUC-1 and HSP-70) was assessed using multi-color flow cytometry. Results are reported as mean relative increase from control (dose 0 Gy, time 2 hours post irradiation). In a second experiment, NY-ESO-1 specific CTL clones were cultured in the presence of A-498 cells that were subjected to radiation under the above noted conditions and assessed using an ELISPOT assay. Negative control consisted of only CD8+ T Cells. Results: The ELISPOT experiment demonstrated stimulation of NY-ESO-1-specific CTL by irradiated A-498 cells. Negative control showed no stimulation, with only 4 spots. An increase in spots was observed from 79 and 82 spots at 2 hours post-irradiation to 166 and 205 spots at 48 hours post-irradiation for 0 Gy and 16 Gy, respectively. Conclusions: Sublethal irradiation of human RCC cell lines increases their immunogenicity, provoking TAA-specific T cell stimulation. [Table: see text]
Distribution and geographic accessibility of prostate cancer clinical trials in the United States.
Authors: Galsky Matt D. , Latif Asma , Stensland Kristian D. , Moshier Erin L. , McBride Russell , Hendricks Ryan , Sonpavde Guru , Godbold James H. , Hall Simon J , Oh William K. , Wisnivesky Juan P. 
Published: February 2017

59 Background: An extremely small proportion of patients with cancer in the United States (US) enroll in clinical trials. While several barriers to trial accrual have been described, the geographic distribution and accessibility of clinical trial sites has not been comprehensively explored. Methods: ClinicalTrials.gov was queried to identify all active US clinical trials exploring first-line therapies for metastatic prostate cancer (PCa) on 9/16/2012. We evaluated the geographic distribution of trial sites and determined the relationship between the number of sites and the number of patients with advanced PCa per county and evaluated heterogeneity using Lorenz curves. We also estimated the minimum driving distance required to access a clinical trial site from each ZIP code in the continguous US; a distance >30 miles was defined as high travel burden consistent with prior studies. Results: We identified 958 sites associated with 42 PCa clinical trials (Table). The geographic distribution of clinical trial sites was very inhomogeneous with several states having only 1-2 trial sites. Among 3185 US counties, 2,669 (83.8%) had no clinical trials available for first-line treatment of metastatic PCa. Counties with larger populations of patients with advanced PCa had significantly higher numbers of clinical trial sites. For every 100 additional patients with advanced PCa per county, the number of available trial sites increased by 21.0% (95% CI: 16.5-25.7%). However, Lorenz curves indicated a high degree of inequality in trial accessibility (Gini index 0.71). Approximately 31% of the US population resided >30 miles from a PCa trial site. Conclusions: Clinical trials sites are poorly accessible, geographically, to a large subset of US PCa patients, a finding that likely contributes to dismal accrual. Innovative solutions are required to address geographic barriers to access. [Table: see text]
The effect of low-dose GTx-758 on free testerone levels in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Yu Evan Y. , Getzenberg Robert H. , Smith Jordan , Hancock Michael L. , Tutrone Ronald , Flaig Thomas W. , Dalton James T. , Steiner Mitchell S. , Westenfelder Karl R , Szucs Miklos 
Published: February 2017

60 Background: Luteinizing hormone-releasing hormone (LHRH) agents used for androgen deprivation therapy (ADT) were designed to lower total testosterone (T) levels to those achieved by orchiectomy for palliative care of advanced prostate cancer. This castration equivalent level was based upon the lower limits of quantitation (50ng/dL) of outdated assays. Contemporary assays reveal that actual total T levels in men after orchiectomy are significantly lower (<20ng/dL), with 30 to 40% of men on LHRH agonists not achieving that level. There is growing literature showing that lower T levels correlate with improved outcomes. Additionally, the biologically active form of T is unbound, free T. GTx-758 (Capesaris) is an oral estrogen receptor α agonist that increases sex hormone binding globulin (SHBG), lowers free T levels, and ameliorates estrogen deficiency side effects associated with ADT. Methods: In a phase II open label study (G200712), 38 men with metastatic castration resistant prostate cancer (mCRPC) were continued on their current form of ADT along with a low dose of GTx-758, 125 mg, for at least 90 days. Exclusion criteria included men at increased risk for venous thrombolic events (VTE). Results: The initial 14 patients in this trial completed 90 days on study and are evaluable for select trial endpoints. All treated men had a greater than or equal to a 150% increase in SHBG levels. Eleven of the 14 men began the study with suboptimal castration (free T >0.7 pg/ml) and 91% (10 out of 11) of these men became optimally castrated by day 90. Four out of 14 patients had a more than 45% decrease in prostate-specific antigen. Stable or improved hot flashes and bone turnover markers were observed in 71% and 73% of treated men, respectively. While some patients experienced adverse events, none were vascular related and there were no serious adverse events or VTEs. Conclusions: The majority of patients on an LHRH agonist enrolled in this phase II study had suboptimal levels of free T that were further lowered by GTx-758 administration. GTx-758 treatment resulted in stabilization and/or improvement in reported hot flashes and bone turnover, two major side effects of ADT. While the phase II clinical trial is ongoing, and full results are forthcoming, these preliminary findings show that 125 mg of GTx-758 has clinical effectiveness and is well tolerated. Exploration of 250 mg a day is planned. Clinical trial information: NCT01615120.
Surgeon volume and disparities in post-operative complications among black men.
Authors: Konijeti Ramdev , Ruhotina Nedim , Reese Stephen , Chung Benjamin I. , Kibel Adam S. , Chang Steven L. 
Published: February 2017

66 Background: Racial and ethnic disparities related to prostate cancer treatment are well-described. Lower rates of postoperative complications are noted in men who undergo radical prostatectomy (RP) at high-volume centers or by high-volume surgeons. We assessed whether access to high-volume providers might account for ethnic disparities in postoperative complications from RP. Methods: Using a nationally representative dataset of hospital discharge information, the Perspective Database (Premier Inc, Charlotte, NC), we examined all men who underwent RP (ICD9 60.5) between 2003 and 2010. Data were stratified based on patient characteristics (age, race, marital status, insurance status, Charlson Comorbidity Index), hospital characteristics (number of beds, teaching vs. nonteaching, urban vs. rural, and geographic region), surgical approach (robotic vs. nonrobotic), surgeon volume (low [less than 5], intermediate [5 to 24], and high [more than 24]), and complications (based on Clavien classifications I-V), if any. A logistic regression model accounting for clustering & survey weights was constructed to assess the association of surgeon volume & ethnicity on postoperative major complications (i.e., Clavien III-V). Results: In a multivariate model incorporating clinicodemographic and hospital information, black men continued to demonstrate a higher odds for major complication (OR 1.3 [1.02-1.7]). However, when further incorporating surgeon volume to the multivariate model, there was no longer any difference in the odds for a major complication for black men (OR 1.2 [0.97-1.6]). Patients who underwent RP by intermediate-volume surgeons and high-volume surgeons had a lower incidence of postoperative major complications compared to those treated by a low-volume surgeon (OR 0.6 [0.5-0.7] & 0.4 [0.3-0.5], respectively). Compared to white men, the odds of undergoing RP by a high-volume surgeon are lower for black men (OR 0.6 [0.5-0.8]). Conclusions: Our data demonstrate that access to high-volume surgeons may explain the increased odds for postoperative major complications among black men undergoing RP. Further research related to barriers to health care access & further efforts at removing said barriers for black men is warranted.
Gleason score upgrade among 10,282 men who underwent surgery as initial treatment in 2010: A population-based study.
Authors: Zhang Hong , Messing Edward M. , Ahmed Hamza , Chen Yuhchyau 
Published: February 2017

72 Background: Active surveillance is now accepted initial management for men who have localized prostate cancer with low risk of disease progression. Many criteria have been used for patient identification, including Gleason score (GS) obtained from prostate biopsy. Because of concerns of sampling error, some have recommended repeated biopsy before committing to active surveillance. However, there is limited information about the risk of missing high grade disease using the current standard biopsy approach. This study seeks to compare GS difference from biopsy and surgery to provide an estimated rate of GS upgrade. Methods: The Surveillance, Epidemiology, and End Results (SEER) program was used to identify men with American Joint Committee on Cancer stage T1-2cN0M0 prostate cancer diagnosed between January 2010 and December 2010. Patients who underwent prostatectomy were selected for further analysis. Based on prostate-specific antigen (PSA) levels and GS, cases were divided into low (PSA <=10 and GS <=6) and intermediate (10<PSA<=20 or GS=7) risk groups. The rates of GS upgrade were reported for each group. Chi-square tests were used to assess differences in categorical variables (e.g. age and race) between groups of GS upgrade and no change/downgrade. Results: A total of 10,282 men were evaluated, with 9.2% (n=942) having low-risk disease, and 90.8% (n=9340) having intermediate-risk disease. Among men with low-risk prostate cancer, 22.3% (n=210) had GS upgrade and 0.8% (n=8) had GS 8 disease. Among men with intermediate risk disease, 26.2% (n=2446) had GS upgrade and 2.3% (n=214) had GS 8 disease. There was no statistically significant difference in either age or race distribution among men who had GS upgrade versus no change or downgrade at the time of surgery. Conclusions: A substantial number of low- and intermediate-risk prostate cancer patients had GS upgrade at the time of surgery, but few had upgraded to GS 8 high risk disease. These observations suggest that repeat biopsy prior to active surveillance may not be necessary.
Biologic consequences of androgen receptor (AR) activity in MDV3100-resistant LNCaP cells and dependence on AR full length.
Authors: Yamamoto Yoshiaki , Loriot Yohann , Beraldi Eliana , Zhou Tianyuan , Kim Youngsoo , Monia Brett P. , MacLeod A. Robert , Fazli Ladan , Zoubeidi Amina , Gleave Martin Edwin 
Published: February 2017

74 Background: While recent reports link androgen receptor (AR) variants (AR-Vs) to castration resistant prostate cancer (CRPC), the biological significance of AR-Vs in AR-regulated cell survival and proliferation, independent of AR full length (AR-FL), remains controversial. To define the functional role of AR-FL and AR-Vs in MDV3100-resistant (MDV-R), we designed antisense oligonucleotide (ASO) targeting exon 1 and exon 8 in AR to knockdown AR-FL alone or in combination with AR-Vs and examined these effects in MDV-R LNCaP-derived cells in vitro and in vivo. Methods: We generated by selection MDV-R LNCaP-derived sub-lines that uniformly expressed high levels of both AR-FL and AR-V7 compared to CRPC LNCaP xenografts. Cell growth rates, protein and gene expression were analyzed using crystal violet assay, western blotting and real-time PCR, respectively. Exon 1 and 8 AR-ASO were evaluated in MDV-R49F CRPC LNCaP xenografts. Results: AR-V7 was transiently transfected in MDV-R49F cells and differential knockdown of AR-V7 and/or AR-FL by exon 1 versus exon 8 AR-ASO was used to evaluate relative biologic contributions of AR-FL versus AR-V7 in MDV-R LNCaP AR-V7 overexpressing cells. Exon 1 and 8 AR-ASO treatment in these cells similarly decreased prostate-specific antigen (PSA) expression and induced apoptosis as measured by caspase-3 and PARP cleavage and cell growth inhibition. To further define the functional role of AR-Vs in MDV-R LNCaP cells, we used a CE3 siRNA that specifically silenced AR-V7, but not AR-FL in MDV-R LNCaP cells. AR-V7 knockdown did not decrease PSA levels, did not induce apoptosis, and did not inhibit cell growth. In MDV-R LNCaP cells, exon 1 and 8 ASO similarly suppressed cell growth and AR-regulated gene expression in vitro and in vivo. Conclusions: These results indicate that the AR remains an important driver of MDV3100 resistance and, the biologic consequences mainly driven by AR-FL in MDV-R LNCaP models.
Sequential monitoring and characterization of circulating tumor cells (CTCs) using the epic sciences platform in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with recently approved therapeutics.
Authors: Ferraldeschi Roberta , Krupa Rachel , Louw Jessica , Tucker Eric , Bales Natalee , Marrinucci Dena , Flohr Penelope , Figueiredo Ines , Lorente David , Dittamore Ryan , De Bono Johann Sebastian , Attard Gerhardt 
Published: February 2017

78 Background: The enumeration and molecular characterization of circulating tumor cells (CTCs) may allow sequential evaluation of drug-induced changes and mechanisms of drug resistance that cannot be practically performed by tissue biopsies. Methods: We utilized the Epic Sciences platform to identify and characterize traditional CTCs (CK-CD45+) and other CTC subpopulations (CK-CD45- CTCs and small CTCs) in sequential samples obtained from metastatic castration-resistant prostate cancer (mCRPC) patients (pts) receiving abiraterone acetate (AA), enzalutamide (E), or cabazitaxel (C). Peripheral blood was collected pre-treatment, during treatment (at 1 to 4 weeks, to evaluate pharmacodynamics effects) and at progression. Nucleated cells were plated onto glass slides and subjected to immunofluorescence staining for CK, CD45, and AR, and CTC identification by fluorescent scanners. CTCs from a subset of patients were tested for PTEN loss and ERG rearrangements by FISH. CTCs from a second blood sample collected at the same time were captured and enumerated using CellSearch (Veridex). Fresh CRPC biopsies were available for 9 pts. Results: Initial results are available from 24 mCRPC pts (16 pts treated with AA; four with E; four with C; 17 out of 24 previously treated with docetaxel). Pre-treatment, the median CK+CD45- CTC count was 3.5 (range 0 to 98) cells/mL blood. Eleven pts had more than or equal to 5 CK+CD45- CTCs/mL pre-treatment and 5 out of 11 pts had an Epic CTC conversion to less than 5 CK+CD45- CTCs/mL with treatment. 8 out of 11 pts had a decline in CK+CD45- CTC count greater than 30%. Changes in AR expression and AR subcellular localization were observed during treatment as well as changes in count of CTC subpopulations. CellSearch count was available for 22 out of 24 pts. Twelve out of 22 had more than or equal to five CTCs/7.5mls captured using CellSearch, including 7 out of 12 with more than or equal to five CTCs/ml using Epic platform. Conclusions: Enumeration and molecular characterization of CTCs on the Epic Sciences platform during treatment is feasible and demonstrates drug-induced changes associated with changes in CTC count, AR expression and AR subcellular localization. These assays warrant further studies to validate their role as clinically useful biomarkers in mCRPC.
Identifying men at greatest risk of weight gain from androgen deprivation therapy.
Authors: Seible Daniel Martin , Gu Xiangmei , Hyatt Andrew , Beard Clair , Efstathiou Jason Alexander , Miyamoto David Tomoaki , Mitin Timur , Martin Neil E. , Beckman Joshua , Basaria Shehzad , Nguyen Paul Linh 
Published: February 2017

80 Background: Androgen deprivation therapy (ADT) is a mainstay of prostate cancer therapy. Weight gain is among the adverse metabolic changes associated with ADT, and may contribute to cardiovascular comorbidity. A better understanding of the risk factors for weight gain on ADT is important for optimal management of ADT-associated morbidity. Methods: A retrospective review assessed weight change among 118 men with nonmetastatic prostate cancer treated with ADT. The primary endpoint was weight change at one year from ADT initiation, with the secondary aim to stratify risk of weight gain by baseline patient characteristics. Statistical analyses were performed using two-tailed t-tests and linear regression. Results: Men in our cohort exhibited a significant increase in weight (p=0.0005) in the one year following ADT initiation. Three risk factors for weight gain on ADT were identified: younger than age 65 (5.98 pounds gained, p=0.001 vs. 1.63 pounds, p= 0.09 for age 65+), body mass index (BMI) less than 30 (4.36 pounds gained, p=0.00002 vs. 0.22 pounds, p=0.87 for BMI 30+), and non-diabetic status (3.43 pounds gained, p=0.0003 vs. 0.57 pounds, p=0.74 for diabetics). An aggregate risk scoring system was contrived to allow for weight change prediction by total number of risk factors present: scores of 0, 1, 2, and 3 risk factors corresponded to weight changes of -2.42 (p=0.43), +0.9 (p=0.56), +2.9 (p=0.01) and +8.3 pounds (p= 0.0001) respectively. Weight gain increased significantly with increasing risk score (p-trend= 0.0005), decreasing baseline age (p-trend= 0.004) and decreasing baseline BMI (p-trend= 0.01). Conclusions: Younger than age 65, BMI less than 30, and non-diabetic status were each significantly associated with weight gain one year after starting ADT. Increasing weight gain was strongly associated with increasing number of baseline risk factors. Although metabolic consequences were previously considered most significant for patients with preexisting comorbidity, these data suggest younger, slimmer, and non-diabetic patients may be at higher risk for gaining weight on ADT. As these three categories of men generally have higher endogenous testosterone (T) levels prior to ADT compared to older, obese, and diabetic men, the magnitude of T decline following ADT might explain these findings.