bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular characterization of neuroendocrine prostate cancer (NEPC) and identification of new drug targets.
Authors: Beltran H. , Rickman D. , Park K. , Sboner A. , Macdonald T. , Tagawa S. T. , Gerstein M. B. , Demichelis F. , Nanus D. M. , Rubin M. A. 
Published: February 2017

19 Background: NEPC is an aggressive variant of prostate cancer that can arise de novo or from existing prostate adenocarcinoma (PCA). We sought to better understand the molecular transformation of NEPC and identify new drug targets. Methods: We used Next Generation RNA sequencing and oligonucleotide arrays to profile 7 NEPC, 30 PCA, 5 benign prostate (BEN), and validated findings on tumors from a large cohort of patients (30 NEPC, 118 PCA, 30 BEN) using IHC and FISH. Functional studies were performed using NCI-H660 (NEPC), VCaP and LnCaP (PCA), RWPE (BEN). Results: ERG rearrangement was present in 47% of NEPC, but ERG protein expression was absent and corresponded directly with lack of AR expression. 936/25932 genes were differentially expressed in NEPC versus PCA (P<0.001). Aurora kinases (AURKA, AURKB) and N-myc (MYCN) were overexpressed in NEPC (P<0.001) and AURKA and MYCN amplified. Using IHC and FISH, we validated these findings on a large cohort and found majority (>80%) of NEPC showed Aurora overexpression, 35% had AURKA and MYCN amplification. A small subset of PCA (5%) and no BEN were positive. Transfection of MYCN induced AURKA expression and kinase activity in vitro, and MYCN or AURKA could induce expression of neuroendocrine (NE) markers (SYP, NSE). After validating NCI-H660 as model of NEPC, we observed dramatic and enhanced in vitro and in vivo sensitivity to the Aurora kinase inhibitor PHA-739358 in NCI-H660 compared to minimal to no effect in LnCaP and VCaP. Phospho-H3 expression, a downstream marker of Aurora kinase activity, was inhibited in the treated NCI-H660 and not in PCA. Notably, NE marker expression was also suppressed in the treated NCI-H660 xenografts, again supporting a role of Aurora kinase in modulating the NE phenotype. Conclusions: There is likely clonal origin of NEPC from PCA (with ERG fusion positivity seen in both), but ERG expression is limited to PCA and driven by AR signaling. We discovered significant overexpression and gene amplification of Aurora kinases and N-myc in NEPC and a small subset of PCA, and evidence that that they cooperate and induce a NE phenotype in prostate cells. In vitro and in vivo data confirms that these are novel drug targets for NEPC. No significant financial relationships to disclose.
Effect of dutasteride on prostate cancer progression and cancer diagnosis on rebiopsy in the REDEEM active surveillance study.
Authors: Fleshner N. , Lucia M. S. , Melich K. , Nandy I. M. , Black L. , Rittmaster R. S. 
Published: February 2017

2 Background: The REDEEM (Reduction by Dutasteride of Clinical Progression Events in Expectant Management of Prostate Cancer) study tested whether dutasteride controlled growth of existing low risk, localized prostate cancer (PCa) and hence reduced the need for aggressive therapy in men followed with active surveillance. Methods: 302 men, aged 48–82, with PSA <11 ng/ml, and Gleason score ≤6 PCa (≤3 cores positive, <50% of any core positive) were randomized to dutasteride or placebo for 3 years. Repeat 12-core biopsies were performed at 18 and 36 months, or for-cause at other times during the study. The primary endpoint was time to progression, defined as the earliest of either pathological progression (Gleason score >6, ≥4 cores positive, or >50% of any core positive) or therapeutic progression (radical prostatectomy, radiation therapy, or hormonal ablation). Results: 96% of subjects reached the primary endpoint or had a post-baseline biopsy. Dutasteride reduced time to PCa progression (relative risk reduction 38.9%, 95% CI: 12.4–57.4%, P=0.007). The table presents incidence of progression and Gleason score on final biopsy. 23% of men (N=31) in the placebo group and 36% of men (N=50) in the dutasteride group had no cancer detected on their final biopsy. PCa-related anxiety was reduced in the dutasteride arm compared to the placebo arm (P=0.036), based on the Memorial Anxiety Scale for PCa (MAX-PC). Drug-related adverse events were similar to those previously reported for dutasteride. Conclusions: In men followed with active surveillance, dutasteride delayed the time to PCa progression, increased the percent of men with no detectable PCa, and improved PCa-related anxiety. There was no evidence of increased Gleason score upgrading with dutasteride. Dutasteride may provide a useful adjunct to active surveillance for management of PCa. [Table: see text] [Table: see text]
Gemcitabine, paclitaxel, and doxorubicin for patients (pts) with urothelial carcinoma (UC) and renal insufficiency: Preliminary results of a multicenter phase II study.
Authors: Pagliaro L. C. , Munsell M. , Harris D. , Carolla R. L. , Siefker-Radtke A. O. 
Published: February 2017

246 Background: The role of cisplatin-based chemotherapy for the treatment of locally advanced or metastatic UC is well established. Pts with impaired renal function cannot receive cisplatin, however, and substitution with carboplatin yielded inferior results. We initiated a phase II study to assess the efficacy of gemcitabine, paclitaxel, and doxorubicin (GTA) treatment for UC in pts with renal insufficiency. Methods: Eligible pts had metastatic or unresectable UC of bladder, urethra, or upper tract, no prior chemotherapy, glomerular filtration rate < 60 ml/min, ECOG performance status ≤ 2, left ventricular ejection fraction > 40%, and adequate hematopoietic and hepatic function. Pts were excluded if they had brain metastasis, peripheral neuropathy ≥ grade 2, significant heart disease within 6 months of enrollment, or required hemodialysis. Outpatient treatment consisted of 900 mg/m2 gemcitabine, 135 mg/m2 paclitaxel, and 40 mg/m2 doxorubicin on day 1 every 2 weeks. Pegfilgrastim 6 mg sc was given immediately after GTA on day 1, or on day 2 if requested by the pt. Tumor evaluation was repeated every 3 cycles (6 weeks); treatment duration was limited to 9 cycles. A Simon 2-stage design was chosen to detect a target overall response rate of 40% and to reject a response rate of 25% or less. Results: Twenty-five pts enrolled and 21 could be assessed for response. Median (range) age was 72.8 years (53.4, 89.3) and 8 pts (32.0%) were female. RECIST responses occurred in 12 pts (4 complete; 8 partial), for an overall response rate of 57.1% (95% CI 34.0-78.2). Notable grade 3 and 4 toxicities were anemia (9 pts), thrombocytopenia (3 pts), neutropenia (2 pts), dyspnea (1 pt), mucositis (1 pt), and sepsis (1 pt). No adverse events were attributed to same-day pegfilgrastim and there were no treatment-related deaths. Eleven pts (44.0%) died of progressive disease; the median (range) follow-up time for 14 surviving pts was 5.5 months (2.3, 17.5). Conclusions: GTA has been well-tolerated in the setting of renal insufficiency, with an observed response rate in advanced UC exceeding the targeted response. The study will continue to a maximum of 72 pts. [Table: see text]
Phase I trial sunitinib plus everolimus in patients with metastatic renal cell carcinoma (mRCC).
Authors: Molina A. M. , Feldman D. R. , Ginsberg M. S. , Fischer P. , Trinos M. J. , Patil S. , Motzer R. J. 
Published: February 2017

311 Background: Sunitinib a targeted tyrosine kinase inhibitor and everolimus an mTOR inhibitor both inhibit hypoxia-induced factor-dependent signaling and have activity in advanced renal cell carcinoma (RCC). The safety and maximum tolerated dose (MTD) of sunitinib in combination with everolimus was assessed in this phase I trial. Methods: Cohorts of 3–6 patients with mRCC received sunitinib at 37.5 or 50 mg daily for 4 weeks followed by 2 weeks off with everolimus administered either daily (2.5 or 5 mg) or weekly (20 or 30 mg). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine MTD. Results: 20 patients (13 clear cell and 7 non-clear cell RCC) were enrolled in five cohorts. Both patients in the 2nd dose level (everolimus 5 mg daily, sunitinib 37.5mg) experienced grade 3 DLT (thrombocytopenia and mucositis; vomiting). With weekly everolimus dosing, the MTD was everolimus 30 mg /sunitinib 37.5 mg (4th dose level). However, only one of six patients at this dose level tolerated treatment beyond 4 cycles. Grades 3 and 4 toxicities observed with chronic treatment included infection, gastrointestinal hemorrhage, and pulmonary embolism. A total of six patients were treated with everolimus 20b mg weekly/37.5 mg sunitinib (3rd dose level) with better tolerance as chronic therapy. Overall, 5 out of 20 patients achieved a partial response including 3 patients with non-clear cell histology. Conclusions: Partial responses were observed in both clear cell and non-clear cell histologies. However, due to toxicity the combination of sunitinib and everolimus could not be administered at full doses. [Table: see text]
A meta-analysis of bevacizumab plus interferon alfa for previously untreated patients with metastatic clear-cell renal carcinoma (mRCC).
Authors: Likun Z. , Ba Y. 
Published: February 2017

366 Background: mRCC was highly resistant to conventional chemotherapy. Both CALGB study and AVOREN study failed to detect statistic differences in overall survival (OS). To evaluate the effectiveness and adverse-effect of bevacizumab plus IFN-α for untreated mRCC, we performed a meta-analysis. Methods: We searched RCTs that compared bevacizumab plus IFN- alpha with other treatments. For trials without heterogeneity, meta-analysis was carried out by using review manager (Revman 4.2) with fixed or random-effects models. Hazard ratio (HR), relative risk (RR), and 95 percent confidence intervals (CI) were calculated. The primary outcome was overall survival. The secondary outcomes were PFS and the adverse effects. Subgroup analyses were performed by MSKCC risk factors. Results: Two RCTs (CALGB study and AVOREN study) were identified as eligible for inclusion in our meta-analysis. Overall survival: Meta- analysis including 1,381 patients showed a trend in favor of bevacizumab plus IFN-alpha with an HR of 0.89 (95% CI, 0.80-1.00, p=0.05). Meta-analysis of OS which adjusted on stratification factors showed extent improvement in favor of bevacizumab plus IFN-alpha (HR=0.86, 95% CI, 0.76-0.97, p=0.02). Progress-free survival: Meta-analyses showed statistic differences in favor of bevacizumab plus IFN-alpha in both unstratified PFS (HR=0.68, 95% CI, 0.61-0.77, p<0.00001) and stratified PFS (HR=0.67, 95% CI, 0.59-0.75, p<0.00001). Subgroup analysis: There were no statistic differences between bevacizumab plus IFN-alpha and IFN-alpha in MSKCC favorable risk group (HR=0.91, 95% CI, 0.70-1.17, p=0.45) and MSKCC poor risk group (HR=0.79, 95% CI, 0.55-1.14, p=0.21). For MSKCC intermediate risk group, there was statistic difference in favor of bevacizumab plus IFN-alpha (HR=0.85, 95% CI, 0.73-0.99, p=0.04). Adverse effects: There were statistic differences in favor ofIFN-alpha in anorexia, fatigue proteinuria, and bleeding, while no statistic difference in gastrointestinal perforation. Conclusions: Bevacizumab plus IFN-alpha prolonged both OS and PFS as first line therapy for mRCC, especially for MSKCC intermediate risk group. The toxicity was acceptable and well tolerated. No significant financial relationships to disclose.
Outcome of patients (pts) with renal medullary carcinoma (RMC) treated in the era of targeted therapies (TT): A multicenter experience.
Authors: Tannir N. M. , Dubauskas Lim Z. , Bekele B. N. , Johnson E. D. , Tamboli P. , Vaishampayan U. N. , Plimack E. R. , Rathmell K. , Jonasch E. 
Published: February 2017

386 Background: RMC is a rare, highly aggressive primary neoplasm of the kidney that almost exclusively afflicts young black pts with sickle cell hemoglobinopathies, primarily sickle cell trait. The primary objectives of this study were to evaluate the clinical characteristics and treatment outcome of RMC pts. Methods: We retrospectively reviewed the medical records of pts diagnosed with RMC at four US institutions between 2000 and 2010. Overall survival (OS) was determined from initial diagnosis to date of death or last follow up (F/U). The time interval from date of metastasis to death or last F/U (OSm) was also determined. Kaplan-Meier methods were used to estimate OS and OSm. Results: 20 RMC pts were identified. All pts were black; 14 (70%) were males; 18 had sickle cell trait, 1 had sickle thalassemia and 1 not tested. 19 presented with stages III or IV; 7 (35%) had nephrectomy. Nineteen pts had ≥ 2 metastatic sites. Twelve pts had performance status [PS] 0/1; eight pts had PS 2/3. For the OS analysis, data on 16 pts were available and for the OSm analysis, data on 20 pts were available. The median follow up time for the OS analysis was 722 days. Thirteen of 16 pts died with median OS of 421 days [95%CI: 225–546]. Sixteen of 20 pts died in the OSm analysis with median OSm of 378 days [95%CI: 225–487]. Frontline therapy consisted of TT [sunitinib (5), bevacizumab + erlotinib (1), imatinib (2)], chemotherapy (C) [platinum/gemcitabine or taxane (7), gemcitabine/doxorubicin (2)], C + TT [gemcitabine/cisplatinum/bevacizumab (2), imatinib/doxorubicin (1)]. Three pts achieved a partial response (PR) in first-line (2 with C, 1 with C + TT). Twelve pts received second-line systemic therapies; 4 achieved PR (1 with bevacizumab/erlotinib, 2 with C, 1 with C + TT). Among 15 pts who had TT at any time during their treatment course, only 1 pt had PR. Conclusions: The prognosis of RMC pts remains poor despite initial palliation with systemic therapy. Collaborative multi-institutional efforts are needed to better understand the biology of this disease and improve treatment strategies. No significant financial relationships to disclose.
Hierarchical clustering analysis of tissue microarray immunostaining data on renal cell carcinomas.
Authors: Antón Aparicio L. M. , Medina Villaamil V. , García Campelo R. , Aparicio Gallego G. , Santamarina Caínzos I. , Haz Conde M. , Valbuena Rubira L. , Grande E. , Valladares Ayerbes M. 
Published: February 2017

393 Background: The clinical use of molecular expression profiles could result in more accurate and objective diagnoses of cancers as well as prognoses of disease or response to the treatment. Unsupervised hierarchical clustering (UHC) analysis is a common method to profile the molecular expression of tissue microarray data. Methods: TM4: a free, open-source system for microarray data management and analysis was used in order to identify expression patterns of interest in our cohort of renal cell carcinomas (RCC) (n=80). We investigated 5 pathological predictors: (a) the histological type, (b) Fuhrman grade, (c) depth of infiltration, (d) metastasis in lymph node, (e) TNM stages, and 27 immunohistochemical molecular predictors involved in different pathways of tumor development and progression including: p53 and VHL tumor suppressor proteins; Bcl-2 and Survivin antiapoptotic proteins; Hif1-alpha and Notch proteins as a transcription factors; EGFR, PDGFR-α and VEGF proteins involved in tumor growth and proliferation; Glut proteins involved in tumor cell metabolism. Results: Unfavorable prognosis was significantly correlated with pathological predictors. Clear RCC histological subtype had a worse prognosis than the other ones studied to be accompanied by increased expression of Hif1-alpha and CAIX (p<0.001 in both cases) in patients with a number of metastatic nodes weighed (p<0.001). We found in Fuhrman Grade III samples a higher expression of VEGF (p=0.029). UHC analysis was done using average method with Spearman rank test to group the data with different predictor profiles. A preliminary analysis by hierarchical clustering of RCC produced three separate clusters groups. Conclusions: UHC based on a extended immunoprofile might be a useful, promising and powerful tool for further translational studies and should lead us to define a diagnostic and prognostic signature for RCC. Our laboratory is currently involved in this issue. No significant financial relationships to disclose.
Improved survival outcomes in clinically relevant patient subgroups from COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel-based chemotherapy.
Authors: Scher H. I. , Logothetis C. , Molina A. , Goodman O. B. , Sternberg C. N. , Chi K. N. , Kheoh T. S. , Haqq C. M. , Fizazi K. , De Bono J. S. 
Published: February 2017

4 Background: AA is a selective androgen biosynthesis inhibitor that blocks the action of CYP17. Preclinical and early clinical studies suggest that AA potently inhibits persistent androgen synthesis from adrenal and intratumoral sources, thus suppressing an important growth stimulus for mCRPC. Methods: COU-AA-301 ( NCT00638690 ) is an international, randomized, double blind study of AA (1,000 mg + P 5 mg po BID) vs placebo + P administered to men with mCRPC progressing after docetaxel-based chemo. OS is the primary endpoint. Patients treated with previous ketoconazole or > 2 prior chemo regimens were excluded. Results: Data are drawn from a planned, stratified interim analysis, unblinded in August 2010, based on significant OS improvement in the AA + P treatment group compared to the placebo + P group [median OS 14.8 vs.10.9 months; HR = 0.646 (0.54-0.77), P < 0.0001]. A subgroup analysis for OS is presented in the table. Mineralocorticoid- related AEs were more common in the AA arm vs placebo: fluid retention 30.5% vs 22.3%, hypokalemia 17.1% vs 8.4%; but grade 3/4 hypokalemia (3.8% vs 0.8%), and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent. LFT abnormalities were observed in 10.4% AA vs 8.1% placebo; and cardiac disorders were observed in 13.3% AA vs 10.4% placebo. Conclusions: AA significantly prolongs OS in patients with mCRPC who have progressed after docetaxel-based chemo. AA's favorable treatment effect on OS, observed across multiple patient subgroups (HR range 0.59 – 0.74 vs placebo + P), was consistent with the survival benefit for the overall study population. [Table: see text] [Table: see text]
Fluorescence-activated cell sorting (FACS) and immunofluorescence (IF) detection and characterization of circulating tumor cells (CTC) from men with castrate-resistant prostate cancer (CRPC).
Authors: Szmulewitz R. Z. , Wyche A. J. , Posadas E. M. , Stadler W. M. 
Published: February 2017

41 Background: Men with progressive CRPC have identifiable CTC. The currently available technologies for isolation of these CTC are limited by requiring send out to a central lab, high cost, and relative inflexibility with regards to characterization of the CTC. We hypothesized that modern FACS techniques followed by IF could be utilized for point of care isolation and characterization of CTC from men with CRPC. Methods: Patients (pts) with progressive CRPC according to Prostate Cancer Working Group 2 criteria were eligible. 15mL of whole blood was collected in BD CPT Vacutainer tubes. The mononuclear cell layer was labeled with primary antibodies against CD45 and EpCAM conjugated to separate flours. The EpCAM+/CD45− population was sorted directly onto a chamber slide, fixed and stained for multiplex IF imaging of markers including: pan-cytokeratin (CK), PSA, and the androgen receptor (AR). Imaged cells were considered CTC if were nucleated and PSA or CK positive. The methodology would be considered feasible if ≥ 5 of the first 15 pts had detectable CTC. Results: 15 pts with progressive CRPC were accrued to the study. Of these, 14 had documented skeletal metastases and 13 had progressed through docetaxel chemotherapy. 13/15 pts had EpCAM+/CD45− events on flow cytometry; median 94 (range 0–1700). Ten patients had CTC imaged after IF staining. A median of 4 (0–25) CTC were detected, but in 7 pts with >100 events by flow, all had detectable CTC with a median 22 (10–25) (p<0.001 vs. # events <100). A total of 9 contaminating cells (nucleus but no CK or PSA) were observed. All CTC stained positive for AR with variable intensity. Conclusions: FACS followed by IF is feasible for detection of CTC from men with metastatic CRPC. There is considerable loss of CTC during the processing, however, in men with >100 EpCAM+ events, CTC can be imaged and characterized routinely with these methods. This is a promising technique for utilization in translational research given the relative flexibility, ease and cost. Patients are now being enrolled for pre-analytical validation of IF staining for multiple prostate cancer biomarkers including AR. No significant financial relationships to disclose.
A double-blind randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated advanced urothelial cancer.
Authors: Choueiri T. K. , Vaishampayan U. N. , Yu E. Y. , Quinn D. I. , Hahn N. M. , Hutson T. E. , Ross R. W. , Rosenberg J. E. , Jacobus S. J. , Kantoff P. W. 
Published: February 2017

LBA239 Background: Vandetanib (V) is a novel small-molecule inhibitor that targets key signaling pathways in cancer including VEGF and EGF. V in combination with docetaxel (D) was assessed in patients (pts) who received prior platinum-based chemotherapy for advanced urothelial cancer (UC). Methods: Patients eligible for this randomized, multicenter, double-blind, investigator-initiated trial had metastatic UC after failure of prior platinum-based chemotherapy. Up to 3 prior therapies were allowed including paclitaxel. The primary objective was to determine whether once-daily oral V (100 mg) + D (75 mg/m2 IV q21 days) prolonged progression-free survival (PFS) vs. placebo (P) + D (80% power to detect 60% improvement in median PFS with 1-sided α=0.05). Patients on D+P, had the option to cross over to single agent V. Overall survival (OS), overall response rate (ORR), stable disease (SD), and safety were secondary objectives. Results: One-hundred and forty-two pts were enrolled at 16 institutions, 68% men; median age 65y; ECOG PS 0/1: 52%/48%; visceral involvement: 66%. 80% of patients had ECOG PS 1 and/or visceral metastases. 44% of patients had 2 or more prior systemic therapies and 15% had prior paclitaxel. Baseline characteristics were balanced in both arms. Median PFS was 11.1 weeks (wks) for D+V arm vs. 6.9 wks for D+P arm (HR=1.04, p=0.92). Median OS was 25.4 wks for the D+V arm vs. 30.6 wks for the D+P arm (HR 1.21, p=0.35). ORR was 7.1% for the D+V arm vs. 11.1% for the D+P arm (OR=0.6, 90% CI [0.2–1.6]). SD or better rates were 50.0% vs. 37.5% on D+V and D+P, respectively. As of December 2010, 5 pts were on therapy and 70% of pts died. Median follow-up for pts still alive is 7.2 months. Treatment-related grade >3 toxicities for D+V arm was 60% vs. 36% for the D+P arm (p=0.055) and were generally manageable (grade 4, 14% vs. 11%). Grade >3 toxicities that were more commonly seen in the D+V arm were rash/photosensitivity (11% vs. 0%) and diarrhea (7% vs. 0%). Conclusions: In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR or OS. Toxicities were greater but manageable. [Table: see text]