bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of endothelial proliferation and angiogenesis through activating the ERK1/2/EGF pathway mediate by CXC chemokine receptor 2 by chemokine (C-X-C motif) ligand 1.
Authors: Miyake Makito , Goodison Steve , Gomes Evan , Rizwani Wasia , Ross Shanti , Zhang Ge , Rosser Charles Joel 
Published: February 2017

138 Background: Endothelial cell growth and proliferation are critical for tumoral angiogenesis. We report here that blockade of Chemokine (C-X-C motif) ligand 1 (CXCL1) results in reduction of human endothelial cell proliferation and its ability to induce angiogenesis. Methods: Two human endothelial cell lines, HUVEC and HDMEC, were used in the in vitro assays. Proliferation assay and matrigel tube formation assay were performed to test the inhibitory effect of anti-CXCL antibody on the activity of endothelial cells in vitro. Matrigel plug assay in nude mice was performed to test the in vivo angiogenic activity of CXCL1. Results: CXCL1 interacts with its receptor CXC chemokine Receptor 2 and induces endothelial cell proliferation, whereas blockade of CXCL1 is associated with reduction in cellular proliferation through a decrease in levels of cyclin D and cdk4 and inhibition of angiogenesis through EGF and ERK 1/2. Targeting CXCL1 inhibits neoangiogenesis but has no effect on disrupting established vasculature. Furthermore targeting CXCL1 is associated with reduction in migration of human endothelial cells in an in vitro model. Additionally, neutralizing antibody against CXCL1 in a xenograft angiogenesis model resulted in inhibition of angiogenesis. Conclusions: CXCL1-induced regulation of angiogenesis has not been studied extensively in human cancers, thus these findings illustrate a novel contribution of CXCL1 interactions in pathological angiogenesis. Therefore, the ability to selectively modulate CXCL1, specifically in tumoral angiogenesis, may promote the development of novel oncologic therapeutic strategies.
Response to cabazitaxel in CRPC patients previously treated with docetaxel and abiraterone acetate.
Authors: Pezaro Carmel Jo , Le Moulec Sylvestre , Albiges Laurence , Omlin Aurelius Gabriel , Loriot Yohann , Bianchini Diletta , Gross-Goupil Marine , Lorente David , de la Motte Rouge Thibault , Beuzeboc Philippe , Attard Gerhardt , Guillot Aline , Fizazi Karim , De Bono Johann Sebastian , Massard Christophe 
Published: February 2017

155 Background: Cabazitaxel, which is a tubulin-binding chemotherapy, and the CYP-17 androgen biosynthesis inhibitor abiraterone acetate (AA) are both approved for patients with metastatic castration resistant prostate cancer (CRPC) following docetaxel chemotherapy. Recent preclinical data suggest that taxanes impact AR signalling and could imply cross-resistance between new AR targeting treatments and taxane chemotherapy. The aim of this study is to evaluate the antitumor activity of cabazitaxel after AA. Methods: We retrospectively evaluated antitumor activity of cabazitaxel in patients (pts) with metastatic CRPC and progressive disease after docetaxel and AA. Radiological response by RECIST, PSA response by PCWG2 criteria and symptomatic benefit were examined. Results: 89 pts were treated with third-line cabazitaxel, after docetaxel (median 8 cycles; range: 4-12), and AA (median duration of treatment 4.8 months, range: 1-55 months). At cabazitaxel initiation median age was 68 years (range: 53-83), ECOG performance status was 0 or 1 in 70% of pts, and median PSA was 309 ng/ml (range: 3.75-9150). Bone, lymph node and visceral metastases were present in 80 pts (89%), 37 pts (41%), and 12 pts (13%) respectively. An average of 6 cycles of cabazitaxel (range 1-15) were administered. All pts had PSA data available and 44 (49%; 95% CI 39-60%) had a 50% or greater PSA decline. In the 35 pts with RECIST evaluable disease, 7 (20%; 95% CI 8-37%) had a partial response. Conclusions: In men with metastatic CRPC cabazitaxel appears to retain activity in the third-line setting following docetaxel and AA.
Influence of concurrent medications on PSA doubling time (PSADT) in patients (pts) with nonmetastatic biochemically relapsed prostate cancer (BRPC M0) after local therapy (tx).
Authors: Keizman Daniel , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Roubinov Keren , Pili Roberto , Sinibaldi Victoria J. , Hammers Hans J. , Carducci Michael Anthony , Eisenberger Mario A. , Mermershtain Wilmosh 
Published: February 2017

160 Background: In patients with BRPC(M0) after local tx, the most important prognostic factor is probably the PSADT (high risk < 3, intermediate risk 3–8.9, low risk ≥9.0 months). Pre-clinical and clinical studies in several cancer types have shown that commonly prescribed medications may inhibit tumor growth. The effect of commonly prescribed medications on PSADT in pts with BRPC(M0) is poorly defined. We aimed to study the effect of commonly prescribed medications on PSADT in pts with BRPC (M0) after local tx. Methods: We reviewed the records of 156 BRPC(M0) pts enrolled in 1 prospective (Keizman, CCR 2010) and two retrospective (Keizman, prostate 2012; Mermershtain, EMUC 2011) studies, in 2 centers across 2 countries. The effect of clinicopathologic factors and the use of statins, aspirin, and angiotensin system inhibitors (ASIs; ACE-I and ARBs) on initial PSADT (from the time of first PSA relapse to the initiation of any systemic tx) was analyzed using the Mann-Whitney or Kruskal-Wallis tests and regression analyses. Results: In the whole patient cohort (n=156), median age was 62, prior local tx consisted of radical prostatectomy in128 pts and EBRT in 28, and median PSADT was 6.7 months (mos). Median PSADT in ASIs users (n=48) vs non users (n=108) was 7.85 vs 5.6 mos (p=0.011). In multivariate analysis, the use of ASIs and Gleason score were associated with median PSADT. The use of statins (n=58) or aspirin (n=72), primary tx modality, and time from primary tx to PSA relapse had no significant effect on median PSADT. PSADT risk grouping in ASIs users vs non users was low 48% vs 27%, intermediate 42% vs 49%, and high 10% vs 24% (p=0.02). In multivariate analysis, the use of ASIs, Gleason score, and prior ADT were associated with PSADT risk grouping. The use of statins or aspirin, primary tx modality, and time from primary tx to PSA relapse had no significant effect on PSADT risk grouping. Conclusions: The use of ASIs, Gleason score, and prior ADT may be associated with PSADT (median and risk grouping) of pts with BRPC (M0) after local tx. This should be investigated prospectively, and if validated, applied in clinical practice and clinical trials.
Patient benefit from salvage radiation for prostate cancer.
Authors: Gebhardt Brian Joseph , McDonald Andrew M. , Bae Sejong , Singh Karan P. , Jacob Rojymon , Dobelbower Michael C. , Kim Robert Y. , Yang Eddy Shih-Hsin , Fiveash John B. 
Published: February 2017

175 Background: To identify post-operative prostate cancer patients who are unlikely to achieve long-term biochemical control following salvage radiotherapy (SRT). We hypothesize that patients with node-positive disease, no nadir after radical prostatectomy (RP), or a high pre-radiotherapy (pre-RT) PSA levelwill have a low chance of benefitting from SRT. Methods: Ninety patients who received SRT following RP were retrospectively analyzed to determine factors associated with biochemical failure. Patients on continuous androgen deprivation therapy (ADT) were excluded from statistical analysis. Results: Median follow-up was 30 months (range 6-120). The overall projected 3-year bPFS was 70%. Factors significantly associated with biochemical failure on univariate analysis included Gleason score, positive seminal vesicle invasion, PSA doubling time of 6 months or less, and pre-RT PSA greater than 1.0 ng/mL. All patients with a pre-RT PSA greater than 3.0 ng/mL failed. Patients who did not reach an undetectable nadir following RP had 55% 3-year bPFS compared with 79% in those who did achieve an undetectable PSA (p=0.041). Multivariate analysis demonstrated that GS of 8 and pre-RT PSA were significant predictors. A separate analysis was performed on a subgroup of 8 patients with node-positive disease. Five patients failed at a median of 24 months (range 12-64). Of the remaining 3 patients, 2 had been maintained on long-term ADT, and 1 patient was 11 months out from treatment. Conclusions: Patients with node-positive disease are unlikely to achieve long-term biochemical control from SRT due to extra-prostatic disease spread. Although various factors may influence outcome, no other group demonstrated a very low chance of benefit. Patients with rising PSA benefit from early treatment before PSA rises above 1.0 ng/mL. [Table: see text]
Differential effects of galeterone, abiraterone, orteronel, and ketoconazole on CYP17 and steroidogenesis.
Authors: Jacoby Douglas Burtner , Williams Martin 
Published: February 2017

184 Background: Because CYP17 has a central role in converting progestogens to androgens, inhibitors have been developed to treat CRPC. CYP17 has both hydroxylase and lyase catalytic functions. However, selective hydroxylase inhibition causes build-up of progestogens and mineralocorticoids, resulting in secondary mineralocorticoid excess (ME), edema, hypokalemia and hypertension (treated clinically with prednisone). We analyzed four inhibitors for their effects on CYP17 hydroxylase and lyase activities, and more globally on the steroidogenic pathway. Methods: Human CYP17 expressed in yeast microsomes was incubated with pregnenolone or 17α-hydroxypregnenolone and products quantitated using LC/MS/MS. Galeterone, abiraterone, orteronel or ketoconazole were added, and hydroxylase or lyase IC50 values calculated. In a separate experiment, H295R adenocarcinoma cells were incubated with a range of drug concentrations between 0.316 nM and 10 μM for 24 hours and media was analyzed for steroid production by LC/MS/MS. Results: All drugs inhibited CYP17. However, potency and selectivity for hydroxylase and lyase varied significantly. Galeterone was the most potent and selective CYP17 lyase inhibitor. Abiraterone most selectively inhibited hydroxylase, while orteronel and ketoconazole were less potent lyase inhibitors than galeterone. In the cell-based assay, all drugs inhibited testosterone synthesis ≥94% at 1 μM. However, at this concentration, evidence of hydroxylase inhibition was supported by significant elevation of progesterone (abiraterone increased 293-fold), mineralocorticoids (orteronel increased DOC 74-fold), or reductions in cortisol (abiraterone, orteronel, ketoconazole reduced by 91%, 70% and 94%, respectively). In contrast, galeterone produced minimal changes in cortisol (decreased 14%) and other intermediate precursors. Conclusions: Galeterone is a selective and potent CYP17 lyase inhibitor that also antagonizes and degrades the AR, and exhibits minimal evidence of deleterious steroid changes associated with ME. These experimental data recapitulate phase I clinical experience where no ME was observed or prednisone required in CRPC patients.
Prevalence of cardiovascular disease (CVD) risk factors and receipt of preventive care among prostate cancer (CaP) survivors in the United States.
Authors: Pearlstein Kevin Alexander , Hendrix Laura H. , Royce Trevor Joseph , Stokes William A. , Chen Ronald C. 
Published: February 2017

185 Background: CVD is a major cause of mortality in CaP survivors. Prior claims-based studies have reported underutilization of preventive care in cancer survivors, but most CVD preventive care items are not available in claims data. We directly examined the prevalence of CVD risk factors and receipt of care in patients with these risk factors in two population-based data sources: National Health and Nutrition Examination Survey (NHANES) and National Health Interview Survey (NHIS) – both commonly used to examine patterns of care in the US. Methods: 2,938 (NHANES) and 452 (NHIS) men with CaP diagnosed from 1999 to 2011 were included. Statistical analysis accounted for sampling weight, and was stratifiedby Caucasian (CA) vs. non-CA. Results: CVD risk factors are highly prevalent (Table), and appear more so in non-Caucasian survivors. Further, 32% of survivors reported history of actual CVD (prior stroke, myocardial infarction, angina, or coronary heart disease). Overall, the majority of survivors receive preventive care. 89%of CA and non-CA survivors visited a primary care physician in the past 1 year. Among survivors with hypertension or hyperlipidemia, >80% received blood pressure or cholesterol checks within past 1 year. Rates of tobacco cessation and exercise were lower. Conclusions: CVD and associated risk factors are prevalent in CaP survivors. However, the majority of these survivors visit a primary care physician and receive CVD preventive care. [Table: see text]
Beyond IGRT: Daily real time planning (RTP)—Treatment of prostate cancer, clinical implementation, and technique.
Authors: Wong James Robert , Merrick Scott Andrew , Karim Mona , Goldberg Yana P. , Gao Jeff , Li Mei , Wilson Paula , Klingeman Madeline 
Published: February 2017

191 Background: Image guided radiation therapy (IGRT) corrects for the interfractional movements of the target/CTV. However, the anatomic changes of CTV, and movements of the adjacent organs, are not accounted for. By modifying an online adaptive radiation technique proposed by Li, we have clinically deployed a daily “real-time treatment planning” (RTP) technique for treatment of primary prostate cancers. The technique, rationale and experience of our first 60 RTP treatments are presented. To our knowledge, this is the first clinical implementation of daily treatment planning. Methods: The RTP process is as follows: a) daily CT images are acquired via an in-room diagnostic CT-on-Rails; b) while IGRT evaluation is performed, new target and tissue contours (prostate, rectum and bladder) are drawn, c) new IMRT plan is computed (RTP plan); d) IGRT plan is compared to the RTP plan; e) if RTP plan is dosimetric superior, it will be delivered after f) necessary QA process. This entire process takes less than 20 minutes (excluding IMRT delivery). 60 RTP’s were delivered (10 daily RTP/patient) in 6 consecutive patients. Results: Auto-contouring via auto-segmentation was inadequate when compared to manual anatomic re-contouring. The RTP plan is always superior to or equal to the original IGRT plan. In 20% of the cases, the CTV-DVH by RTP improved by >10%. Slight changes in manual contouring variation can lead to significant change in volume variation. For example, with initial prostate volumes of 15, 20, 30, 40 and 50 cc, a 1 mm increase in contour variation results in an increase volume of 26%, 24%, 21%,19% and 17% respectively, and absolute volume increase of 3.9cc, 4.8cc, 6.2cc, 7.4cc and 8.6cc respectively. Rectal dose improved significantly with RTP when compared to IGRT. In one extreme case, the rectal dose improvement is shown (Table). Conclusions: Daily RTP is feasible for prostate cancer treatments and is superior to IGRT. RTP is especially necessary with extreme anatomic changes. [Table: see text]
Trends in use of intravenous bisphosphonates in patients with prostate cancer and newly diagnosed metastases to bone in two large U.S. integrated health systems.
Authors: Lamerato Lois , Glass Andrew , Richert-Boe Kathryn E. , Edelsberg John , Wolff Greg G. , Czapski Natalie , Dodge Tracy , Lopez Andrea , Chung Karen , Richhariya Akshara , Oster Gerry 
Published: February 2017

192 Background: Bone is a common site of metastatic involvement in patients (pts) with prostate cancer (PC). Bony metastases (mets) are associated with skeletal complications, which can cause significant morbidity and mortality. Intravenous bisphosphonates (IV BPs) have been proven to reduce the incidence and onset of skeletal complications. Patterns of use of IV BPs in clinical practice in pts with bone mets due to PC are largely unknown. Methods: Using the tumor registries and electronic data stores at two large US integrated health systems that serve a total of approximately 1.3 million persons, we retrospectively identified all pts aged ≥18 yrs with primary PC and newly diagnosed bone mets between 1/1/95 and 12/31/09. Information on all administrations of IV BPs between date of diagnosis of bone mets and death, loss to follow-up, or end of study was extracted from administrative data stores and electronic medical records, which also were reviewed by trained medical abstractors for evidence of skeletal-related events (SREs) (spinal cord compression, pathologic fracture, surgery to bone, radiation to bone). Results: We identified a total of 461 pts with primary PC and newly diagnosed bone mets. Mean (SD) age was 72.8 yrs (10.7 yrs); 75% were Caucasian, and 21% were African-American. Median duration of follow-up after diagnosis of bone mets was 1.3 yrs. One-fifth (20.2%) of study subjects received IV BPs (92% zoledronic acid, 8% pamidronate) during follow-up--10.8% prior to, and 9.3% after, first on-study SRE. Median time from diagnosis of bone mets to first administration of IV BPs was 1.7 yrs, and the median number of administrations was 3. The percentage of study subjects receiving IV BPs increased steadily over the 15-yr study period--from 7.5% among those newly diagnosed with bone mets in 1995-1999, to 19.8% among those newly diagnosed with bone mets in 2000-2004, to 27.5% among those newly diagnosed with bone mets in 2005-2009. Conclusions: Despite a high risk of SREs in pts with PC and bone mets, most such pts still do not receive IV BPs.
Phase I dose escalation trial of MVA-BN-PRO in men with nonmetastatic castration-resistant prostate cancer.
Authors: McLeod David G. , Adams George W. , Gittleman Marc C. , Bihartz David L. , Reiling Richard B. , Ruiz Henry E. , Cochran James S. , Prettyman Julie , Delcayre Alain , Godfrey Wayne R. , Legrand Fatema A. , Mann Grace , Bandman Olga 
Published: February 2017

193 Background: MVA-BN-PRO is an investigational prostate cancer immunotherapy comprising of a highly attenuated non-replicating vaccinia virus engineered to encode prostate specific antigen (PSA) and prostate acid phosphatase (PAP) proteins. Preclinical studies in mouse tumor models demonstrated vaccine-mediated induction of anti-PSA and PAP specific immune responses and anti-tumor activity. Results of the open-label multi-center evaluation in subjects with non-metastatic castration resistant prostate cancer are presented. Methods: Eligible subjects had documented prostate cancer with a rising PSA while on androgen suppression therapy and were chemotherapy naïve. Three cohorts of subjects were immunized subcutaneously receiving either 1, 2 or 4 injections of study drug (1 injection = 1×108 tissue culture infectious dose, TCID50) at monthly intervals for three months (treatment). If the vaccinations were tolerated, re-treatment with an additional 3 monthly vaccinations was administered at the same dose. Responders, defined as subjects with stable or declining PSA at week 29 compared with baseline, were offered a 1-year extended treatment of up to 12 monthly vaccinations. Subjects were followed for one year after their last vaccination. The primary endpoint was safety. Immune responses (humoral and cellular) to MVA-BN-PRO including the transgenes PSA and PAP were assessed by the ELISA and ELISPOT assays, respectively. Exploratory analyses included anti-tumor activity as evaluated by serum PSA levels and progression by bone scan, per investigator determined, or death. Results: Twenty-four subjects were dosed. All subjects completed the initial 3 vaccinations (treatment) and 21 subjects received 6 vaccinations (re-treatment). Seven responders received additional vaccinations during the extended treatment. No dose-limiting toxicities were reported. There were no reported ≥ Grade 3 treatment-related adverse events (AE). The most common related AEs were Grade 1 or 2 general disorders and administration site reactions. Conclusions: MVA-BN-PRO was well tolerated. Results from immune analysis and clinical activity measured by PSA levels or radiological progression will be presented. Clinical trial information: NCT00629057.
Associations between single nucleotide polymorphisms (SNPs) in inflammation-related genes and quality of life after radiation therapy (RT) for prostate cancer.
Authors: Schoenfeld Jonathan D. , Margalit Danielle Nina , Shui Irene M. , Kasperzyk Julie L. , Sesso Howard D. , Martin Neil E. , Nguyen Paul Linh , Kantoff Philip W. , Rider Jennifer R. , Mucci Lorelei A. 
Published: February 2017

2 Background: Prostate-directed RT results in local inflammation that may contribute to short-term toxicity and subsequently effects on long-term quality of life (QOL). We sought to explore the hypothesis that SNPs in inflammation-related genes may influence QOL sequelae following definitive prostate cancer RT. Methods: We studied Caucasian participants in the prospective US Physicians’ Health Study diagnosed and treated with RT for non-metastatic prostate cancer between 1982 and 2006. Forty-three SNPs in 10 inflammation-related genes were genotyped and analyzed using the additive model. Men were followed for cancer-specific QOL outcomes with regularly administered questionnaires. We dichotomized the maximum score for four parameters (decreased urinary stream, increased urinary frequency, rectal urgency and impotence) relevant to RT reported at least one year following RT and analyzed associations between scores and SNPs using Fisher’s exact tests and logistic regression. Results: We identified 264 men with QOL data who previously provided blood for genotype analysis and received RT at a median age of 72 years (IQR 68 – 76 years). Features at diagnosis included: 67% PSA<10, 61% Gleason<7, 95% T1/T2 disease and 71% Charlson co-morbidity index 0-1. QOL questions were completed a median of 6 years following RT. Without adjusting for multiple testing, 13 SNPs had nominally significant associations (p < 0.05) with QOL parameters; 7 remained significant after adjusting for age, features at diagnosis, and use of brachytherapy (Table). Conclusions: We identify candidate SNPs in inflammation-related genes that can be further explored in regards to their associations with long-term effects of prostate-directed RT. [Table: see text]