bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a small-molecule inhibitor of Stat5a/b through structure-based screen for therapy development for prostate cancer.
Authors: Liao Z. , Gu L. , Shen F. , Dagvadorj A. , Gupta S. , Pattabiraman N. , Nevalainen M. T. , Trabulsi E. J. , Gomella L. G. , McCue P. 
Published: February 2017

17 Background: There are no effective treatments for metastatic or castration resistant prostate cancer. We have shown that transcription factor Stat5a/b is constitutively active in high-grade prostate cancer, but not in normal human prostate epithelium. Stat5a/b is active in 95% of clinical castration resistant prostate cancers, and the expression of active Stat5a/b in primary prostate cancer predicts early disease recurrence. Stat5a/b is critical for the viability of prostate cancer cells in vitro and for growth of prostate xenograft tumors in nude mice. Stat5a/b synergizes with androgen receptor (AR) and Stat5a/b promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Here, we hypothesize that Stat5a/b is a molecular target for rational drug design for prostate cancer. Methods: We identified a small- molecule inhibitor of Stat5a/b dimerization by structure-based virtual screen from a database of 30 million chemical structures. The efficacy of the Stat5a/b inhibitor was determined by reporter gene assays, dimerization by co-immunoprecipitations, nuclear translocation by cytochemistry and binding to DNA by EMSA. Cell viability was analyzed by MTT assay. Results: The novel Stat5a/b inhibitor IST5-002 inhibited transcriptional activity of Stat5a/b at IC50 of 1.5 μ M for Stat5a and 3.5 μ M for Stat5b, but not of Stat3 in prostate cancer cells. IST5-002 inhibited dimerization, nuclear translocation, and binding of Stat5a/b to the Stat5 DNA consensus sequence. Furthermore, IST5-002 inhibited expression of Stat5a/b target gene cyclin D1, and induced massive apoptosis of DU145, CWR22Rv1 and LNCaP human prostate cancer cells. IST5-002 blocked prostate cancer xenograft tumor growth in nude mice and induced death in clinical prostate cancers ex vivo in 3D organ cultures. Conclusions: We have identified a small molecule Stat5a/b inhibitor IST5-002 for therapy development for prostate cancer. Future work will focus on chemical modifications of IST5-002 to achieve IC50 below 1 μ M and oral administration. No significant financial relationships to disclose.
Comorbidity and treatment regret in men with recurrent prostate cancer.
Authors: Nguyen P. L. , Chen M. , Chen R. C. , Hoffman K. E. , Hu J. C. , Bennett C. L. , Kattan M. W. , Sartor A. O. , Stein K. , D'Amico A. V. ,   COMPARE Registry Steering Committee
Published: February 2017

187 Background: To determine whether concurrent comorbidity is associated with treatment regret among men with PSA recurrence following primary therapy for prostate cancer. Methods: Among 795 men in the Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma Registry (COMPARE) study who experienced PSA failure and were assessed a median of 5.5 (interquartile range 2.8-9.1) years after prostatectomy (n=410), external beam radiation (n=237), brachytherapy (n=124), or primary androgen deprivation (n=24), multivariable logistic regression was used to determine whether comorbidity level, sociodemographic factors, and other treatment factors were associated with treatment regret, as defined by a validated two-question screen. Significant comorbidity was defined as myocardial infarction, congestive heart failure, angina, diabetes, stroke, circulation problems, inflammatory bowel disease, or amputation. Results: Of 795 men, 14.8% reportedregret. Men with significant comorbidity were more likely to experience post-therapy bowel toxicity (p=0.029) and urinary problems (p=0.051). On multivariable analysis, significant comorbidity [adjusted odds ratio (AOR)=1.57 (95% CI:1.04-2.37); p = 0.033] and younger age [AOR: 0.965 (0.937-0.994) per year increase in age; p = 0.019] were associated with increased regret even after adjusting for post-therapy bowel and urinary complications. Conclusions: In a population of men with PSA recurrence, those with significant comorbidity were particularly prone to treatment regret, which highlights the growing importance of considering comorbidity when counseling patients about prostate cancer treatment options. To properly set expectations, such men should be informed about their potential for increased post-treatment toxicity, which may reduce their risk of regret if toxicity occurs, and serious consideration should be given to active surveillance. [Table: see text]
Comorbidities predict overall survival (OS) in men with metastatic castrate-resistant prostate cancer (CRPC).
Authors: Halabi S. , Kelly W. K. , George D. J. , Morris M. J. , Kaplan E. B. , Small E. J. 
Published: February 2017

189 Background: Management of prostate cancer in senior adults represents an important challenge as the median age at diagnosis is 68 and comorbidities in patients increase with advancing age. The objective of this analysis was to determine if baseline comorbidities number (CON) prior to initiating frontline chemotherapy impacts OS in men with CRPC. Methods: Data from a randomized phase III trial of 1,050 men who received docetaxel, prednisone with or without bevacizumab were used in this analysis. Eligible patients had metastatic CRPC with evidence of progressive disease despite castration and anti-androgen withdrawal, ECOG performance status ≤ 2, and adequate bone marrow, hepatic and renal function. Comorbidities on 14 conditions including cardiovascular, hypertension, diabetes, arthritis, thrombosis, AIDS, renal disease, liver disease and peptic ulcer were prospectively collected at baseline from men enrolled on this trial. The proportional hazards model was used to test if CON predicted OS adjusting for treatment arm, age, race, body mass index and predicted survival probability at 24 months using the CALGB nomogram. Results: In 1,048 men with comorbidity data, the mean CON was 1.5 (s.d.= 1.47, range=0-9) and 73% of men had at least one comorbidity. There was a statistically significant association between CON and risk of death. In multivariable analysis, the hazard ratio (HR) for death for one unit increase in CON was 1.09 (95% CI= 1.04- 1.14, p-value=0.0008). Conclusions: To our knowledge, this is the first analysis to show that CON is a statistically significant predictor of OS in men with CRPC. These results require prospective validation in phase III trials of men with CRPC. [Table: see text]
Real-world clinical resource utilization of metastatic prostate cancer patients in the United States: Results from two large claims databases.
Authors: Lafeuille M. , Senbetta M. , McKenzie R. S. , Lefebvre P. 
Published: February 2017

204 Background: In metastatic prostate cancer (MPC) patients, treatment options include hormonal therapies, chemotherapy, and radiotherapy. This study quantifies the real-world healthcare resource utilization of MPC patients. Methods: Health insurance claims from 40 self-insured companies across the US (Employer [E]; 01/1999-02/2009), and from the Medicare 5% ([M]; 1999-2008) databases were analyzed. Patients with a metastasis diagnosis (ICD-9: 196-199) following 2 prostate cancer diagnoses (ICD-9: 185, V10.46) within 365 days were identified. Patients with other malignant diagnoses at baseline, defined as 365 days prior to metastasis diagnosis (index date), were excluded. Patients were evaluated for baseline medical history and for chemotherapy, hormonal agents, radiation, and corticosteroids utilization during both baseline and observation periods. Hospitalization rates and prostate cancer-related procedures post index date were also reported. Results: The study population comprised 11,725 patients (E: 3,227; M: 8,498). Mean age (SD) was 72.8 (10.2) in Employer and 78.1 (7.7) in Medicare. Mean observation period (SD) was 803 (753) days in Employer and 9.2 (8.2) quarters in Medicare. During the baseline period, chemotherapy, hormonal agents, radiation therapy, and corticosteroids were administered to 5%, 52%, 9%, and 21% of Employer, and 2%, 45%, 8%, and 12% of Medicare patients respectively, whereas these interventions increased to 22%, 55%, 39%, and 46% for Employer, and to 21%, 50%, 33%, and 29% for Medicare during the observation period. A total of 66% Employer and 79% Medicare patients were hospitalized post index date. Most patients (E: 92%; M: 98%) had prostate cancer-related procedures, including prostate specific-antigen testing (E: 39%; M: 80%), computerized axial tomography scan (E: 72%; M: 81%), prostate biopsy (E: 47%; M: 54%), X-ray (E: 11%; M: 64%), bone scan (E: 56%; M: 60%), and magnetic resonance imaging scan (E: 35%; M: 37%). Conclusions: This observational study describes real-world utilization patterns in patients with advanced prostate cancer. [Table: see text]
Correlation of elevated alkaline phosphatase (ALP) and survival in metastatic castration-resistant prostate cancer (CRPC) treated with docetaxel chemotherapy: Results of SWSW Uro-oncology Group study from three U.K. centers.
Authors: Bahl A. K. , Bertelli G. , Lewis P. D. , Jenkins P. , Aziz A. , Davies P. J. , Persad R. , Smith C. G. , Hurley K. , Mason M. D. 
Published: February 2017

206 Background: Treatment with docetaxel in CRPC based on the results of the TAX 327 study has been recommended by NICE guidance in UK. Paucity of UK data on any significant difference in median survival of CRPC patients receiving chemotherapy with normal or elevated ALP is a possible contributory factor to the delayed consideration of chemotherapy in CRPC. We therefore analysed differences in survival in metastatic CRPC patients with normal or elevated ALP treated with docetaxel chemotherapy in 3 cancer centres in UK with a contemporary referral population. Methods: Survival data were collected on consecutive cases of metastatic CRPC treated with at least 1 cycle of docetaxel chemotherapy in these 3 centres. Variables analysed included: presence or absence of pain, PSADT, Gleason score, Haemoglobin, Alkaline phosphatase and number of previous lines of hormone therapy. Results: Median overall survival in 170 eligible patients was 18.1 months (15.3-20.7) with median follow-up of 30.1 months. 84 cases had normal ALP and 86 cases had elevated ALP at time of commencing docetaxel chemotherapy. Median survival was 14.1 months (95% CI= 11.1-17.1) in the elevated ALP group and 22.2 months (95% CI= 17.5- 26.9) in the normal ALP group. The difference between group medians was significant (p<0.001). In multivariate analysis, elevated ALP was a significant prognostic factor for outcome after docetaxel chemotherapy in metastatic CRPC. Conclusions: Regular monitoring of ALP along with PSA monitoring can be a relatively simple way of ensuring that patients with metastatic CRPC are referred for chemotherapy appropriately. To our knowledge this is the first UK data on the impact of ALP level on survival in this group of patients after docetaxel chemotherapy. It is important that decision regarding chemotherapy is based on the parameters of disease progression and regular ALP monitoring may be a relatively simple and practical way of ensuring the right timescales for referral for chemotherapy in metastatic CRPC. [Table: see text]
Effect of dual inhibition of the Src and insulin-like growth factor-1 receptor (IGF-1R) pathways on antitumor effects in prostate cancer (PCa).
Authors: Dayyani F. , Parikh N. , Song J. H. , Araujo J. C. , Carboni J. M. , Gottardis M. M. , Trudel G. C. , Logothetis C. , Gallick G. E. 
Published: February 2017

21 Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases and IGF-1R, respectively. The aim of this study was to establish antitumor co-operativity by combining IGF-1R and Src blockade in a preclinical PCa model. Methods: LNCaP and PC3 cells were used as models for androgen-dependent and independent PCa, respectively. Inhibition of Src and IGF-1R pathways was accomplished by pharmacologic agents (dasatinib against Src and BMS-754807 against IGF-1R) as well as by shRNA. Serum IGF-1 levels were measured in patients (pts) with castration-resistant PCa (CRPC) treated with dasatinib and docetaxel in a phase II trial. Results: Src inhibition decreased proliferation of PCa cells, and migration in modified Boyden Chamber and wound assays. In contrast, IGF-1R blockade induced apoptosis (increased Sub-G1 fraction cells, Annexin-V(+) cells and PARP cleavage). Phosphorylation of Akt was partially inhibited by either drug alone and almost completely abrogated by the combination. Intraprostatic injection of shIGF-1R or shSrc PC3 cells in nude mice led to an 83% and 60% decrease in tumor size compared to control shRNA, respectively. In both cell lines, all observed antitumor effects were enhanced when dual blockade was used, relative to blocking the Src or IGF-1R pathway alone. In 9/19 (47%) pts with CRPC, treatment with dasatinib resulted in a compensatory increase of serum IGF-1 levels. Conclusions: Dual inhibition of Src and IGF-1R is effective and complementary in PCa, mediated, in part, through inhibition of the downstream target Akt. In about half of pts treated with dasatinib, an increase in soluble IGF-1 levels was observed, indicating there is a compensatory upregulation of survival pathways that might be abrogated by dual inhibition of Src and IGF-1R. The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking complementary processes of tumor growth and progression. [Table: see text]
Racial differences in bone mineral density and fractures in men receiving androgen deprivation therapy for prostate cancer.
Authors: Morgans A. K. , Hancock M. L. , Barnette G. , Steiner M. S. , Morton R. A. , Smith M. R. 
Published: February 2017

212 Background: In the general population, black men have higher bone mineral density (BMD) and lower fracture rates than white men. Whether race influences bone loss and fracture risk during androgen deprivation therapy (ADT) for prostate cancer is unknown. Using data from a recently completed prospective, randomized, clinical trial we compared BMD and fracture rates of black and white men receiving ADT for prostate cancer. Methods: Subjects in these analyses (n=516) were members of the placebo group of a two-year randomized controlled trial of toremifene to prevent fractures in men receiving ADT for prostate cancer. All subjects resided in United States and reported their race as either black (n=68) or white (n=448). We compared baseline characteristics, including BMD and prevalent vertebral fractures, between black (n=68) and white men (n=448). We also compared changes in BMD and rates of new vertebral fractures over the two year study period. Results: Black men had higher baseline hip BMD than white men (0.98 ± 0.15 g/m2 and 0.91 ± 0.15 g/m2, respectively; p=0.001). Black men had similar BMD of the spine (1.09 ± 0.22 g/m2 and 1.11 ± 0.22 g/m2 in black and white men, respectively; p=0.51), but fewer prevalent vertebral fractures (7.4% versus 15.0%; p=0.13). Changes in BMD from baseline to 24 months were similar between black and white men (total hip percentage change −2.54 ± 0.26 in white men and −2.09 ± 0.60 in black men; p=0.55; lumbar spine percentage change −1.30 ± 0.33 in white men and −1.67 ± 0.71 in black men; p<0.71). Rates of new vertebral fractures trended towards being lower in black men (1.15% of black men versus 4.83% of white men; relative risk 0.24; p<0.12). Conclusions: Among men receiving ADT for prostate cancer, black men had higher baseline BMD at the hip and fewer prevalent vertebral fractures. Changes in BMD during ongoing ADT were similar for black and white men. Consistent with lower baseline risk for fracture, however, black men had fewer new vertebral fractures than white men. [Table: see text]
Comparison of health care resource use before and after docetaxel treatment among prostate cancer patients.
Authors: Mehra M. , Wu Y. , Dhawan R. 
Published: February 2017

215 Background: Docetaxel is standard of care among late-stage prostate cancer patients. We analyzed patterns of health care resource utilization (RU) among patients before and after exposure to docetaxel using a large commercial claims database. Methods: A random sample of patients (N = 336) with a diagnosis of prostate cancer (ICD 9 code: 185.X) and a claim for docetaxel (2003–2009) was identified from the PharMetrics database, a nationally representative, non-payer-owned integrated commercial U.S. claims database. All patients had ≥ 12 months of enrollment prior to initiation of docetaxel. Patients were followed from their first docetaxel claim until lost to follow-up or June 30, 2009 (censored). RU was defined as all-cause hospitalization, ER, physician, and ambulatory visits. Incidence rates were derived. Results: Mean age of patients was 67.9 years (SD 10.6); mean number of docetaxel prescriptions was 9.9 (SD 10.3). Mean time to study end/lost to follow-up was 15.41 (SD 12.49) months from the index date. The table shows health care RU for the 12 months before, and over the follow-up period after docetaxel initiation. Hospitalizations, ER, physician, and ambulatory visits were significantly higher in the follow-up period. The average length of hospital stay was significantly longer after docetaxel treatment (8.2 vs 5.5 days). Prior to docetaxel, two-thirds of the patients were on hormonal therapy; 51% on analgesics, and 31% on bisphosphonates. After docetaxel, the proportions were 62%, 58%, and 54%, respectively. Conclusions: The significantly higher RU with disease progression in prostate cancer patients suggests a need for new treatment options that can effectively manage and improve patient outcomes. [Table: see text] [Table: see text]
BRAF and KRAS mutations in penile cancer and their correlation with clinical features.
Authors: Valverde C. M. , Hernandez-Losa J. , Ferrandiz-Pulido C. , Morales R. , Suarez C. , de Torres I. , Serrano C. , Carles J. 
Published: February 2017

221 Background: Penile cancer is a rare disease in developed countries. While surgery may be curative for patients with localized disease, for metastatic patients systemic chemotherapy may offer palliation with usually short-lived responses. Thus, new options in this setting are needed. Retrospective series have reported EGFR overexpression in more than 90% of the cases and also interesting results of EGFR directed therapies in these patients have been comunicated. The role of KRAS status or other molecular markers as prognostic or predictive factors remains unclear. The aim of this study was to determine the prevalence of BRAF and KRAS somatic mutations in penile cancer and their correlation with clinicopathologic features. Methods: We analyzed 28 samples collected from de archives of the Pathology Department at our institution from 1996 to 2009. The DNAs were extracted from FFPE blocks by Biorobot EZ1 following the manufacturer protocol of the EZ1-DNA Tissue kit (Qiagen). KRAS and BRAF mutations were amplified with specific primers, and sequenced by Sanger with Bigdye terminator v3.1 Cycle Sequencing Kit. Medical records were reviewed for clinical data. Results: No BRAF mutations were found, but we identified somatic missense mutations in the KRAS gene (all activating G12D mutations) in 6/27 samples (22%, one not evaluable). Median age at diagnosis (73 vs. 71), grade and histologic subtype did not differ between wt and mutated (mt) patients. There was a trend toward a more advanced stage at diagnosis in mt versus wt : 33 versus 47% stage I, 16 versus 9% stage II and 50 versus 38% stage III respectively. 2/6 mt patients died (due to other causes) as did 5/21 wt patients (3 of them because of disease progression). Conclusions: BRAF mutations seem not involved in the EGFR pathway in penile carcinomas. The prevalence of KRAS mutations was unexpectedly high in our series and mt patients tended to be diagnosed at a more advanced stage. Unfortunately, no correlation was found with other clinicopathologic features, including overall survival in our small series. These results suggest a role of KRAS mutation in the development of these carcinomas and support the importance to determine KRAS status in patients to be treated with anti-EGFR based therapies. No significant financial relationships to disclose.
Late CT surveillance in nonseminoma germ cell tumors (NSGCT).
Authors: Singhera M. , Johnson B. , Harris V. , Horwich A. , Dearnaley D. P. , Huddart R. A. 
Published: February 2017

223 Background: Testicular cancer is the commonest solid malignancy in 18-35 year old men. With the introduction of cisplatin, most patients with metastatic disease are cured.Over recent years a risk of late relapse (>2 years after first line therapy) has been recognised in 2- 6% of NSGCTs. Appropriate follow-up strategies have not been determined. To investigate, the utility of long term CT surveillance we initiated a study to see if late CT could detect late relapses at an early stage. Methods: Eligible patients had been treated for Stage IM – Stage IV NSGCT diagnosed 5 years prior to entry. CT scans were at study entry and 5 years. Patients are reviewed annually with tumour markers and clinical examination. We plan to recruit 300 patients. This reports details the outcome of a planned interim analysis of the first round of screening after recruiting 100 patients Results: 108 patients have been enrolled into the study since 2006. Full clinical data was available for 88 patients. Median age was 31 years at diagnosis. 52 patients had evidence of teratoma differentiated (TD) in the primary.Stage at treatment was IM (1), II (45), III (6) and IV (36). Treatment was BEP [bleomycin, cisplatin and etopside (3 cycles: 30), (4 cycles: 20)], CBOP/BEP (16) and other platinum schedule (8) at diagnosis. 27 patients relapsed.Overall 38 had retroperitoneal lymph node.TD noted in 28. 10 had a metastatectomy [brain (2), pelvic mass (1:TD), pulmonary (6;TD:2), neck (2), iliac node (1:TD)]. Study scan was reported normal in 71 patients. None of these have relapsed however 1 patient died of interval lung cancer. Radiological abnormalities were identified in14 patients. 4 underwent surgery (3 RPLND and 1 lung nodule excision). 2 were benign and 2 had TD.1 patient had liver lesions proven to be cysts on ultrasound. 8 had small volume nodal abnormalities which are stable on repeat imaging. 1 is on annual CT surveillance for indeterminate lung nodules.4 patients are awaiting the initial study scan Conclusions: Late CT scan detected significant abnormalities in patients treated for NSGCT leading to surgery. Abnormalities not deemed appropriate for surgical intervention are being followed up surveillance scans. No significant financial relationships to disclose.