bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of a phase II study of sunitinib (SU) maintenance after response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Eigl Bernhard J. , Eliasziw Misha , North Scott A. , Trudeau Marc G. , Winquist Eric , Chi Kim N. , Ruether Joseph D. 
Published: February 2017

153 Background: Docetaxel (D) remains the standard first cytotoxic therapy in mCRPC. Given its mechanism of action, acceptable toxicity profile and simple administration, SU had potential as maintenance therapy for mCRPC. In this multicenter study, we evaluated the tolerability and efficacy of SU monotherapy in patients (pts) with mCRPC who have responded to D. Methods: Pts withmCRPC and responding/stable disease at the time of D completion were enrolled in this multicentre trial. Pts received 50mg of SU daily on 4/2 week on/off cycles. The primary endpoint was progression-free survival (PFS), defined on the basis of RECIST criteria and worsening disease-related symptoms requiring further therapy. Because the effect of SU on PSA is not well known, PSA progression alone was not considered disease progression. PFS of 180 days was considered to be a clinically meaningful threshold for recommending further study of SU. PSA response was a secondary endpoint. The threshold for PSA-progression (PSA-P) was defined as a 25% increase in PSA over baseline. Results: Twenty-three pts were enrolled and treated. Mean age was 66.5 years (48-78). ECOG scores of 0, 1, and 2 were reported for 9, 13 and 1 pts respectively. Mean number of prior cycles of D was 8.6 (4-12). A total of 92 cycles of SU were administered; a mean of 4 per pt (1-11). Mean follow-up was 5.4 months (0.6-15). A total of 479 adverse events (AE) were recorded, of which 88% were Grade 1-2 and 12% were Grade 3-4. The AE were of a type and severity expected for SU. Three Grade 4s occurred, consisting of hepatitis, myelosuppression, and pneumonia. Median PFS was 133 days (95% CI: 48-154). Most pts had immediate PSA increases without evidence of disease progression, with the mean increases in PSA over baseline being 197%, 342%, and 1437% in Cycles 1, 2, and 3, respectively (p<0.05). Conclusions: Although SU was well tolerated as maintenance therapy with predictable side-effects, median PFS was lower than the predefined threshold of 180 days. PSA values were not informative as significant increases were observed as early as Cycle 2. This agent is not considered worthy of further investigation in this setting of maintenance therapy. Clinical trial information: NCT00550810.
Sensitivity of PTEN-deficient prostate carcinoma cells to ionizing radiation through inhibition of treatment-induced CXCL8 signaling.
Authors: Armstrong Chris , Coulter Jonathan , Maxwell Pamela , Berlingeri Silvia , O'Sullivan Joe M. , Prise Kevin , Waugh David J. 
Published: February 2017

154 Background: We recently demonstrated that loss of PTEN in CaP cell lines increases expression of the pro-inflammatory chemokine CXCL8. Increased expression and signalling of this chemokine is detectable in PIN-foci and increases with disease progression. Our objective was to determine how induction of CXCL8 signalling affects the sensitivity of PTEN-deficient CaP cells to radiotherapy, a major treatment modality used in locally-confined CaP. Methods: Established cell-based models of CaP with differential expression of PTEN were subjected to ionizing radiation (IR) under normal or hypoxic culture conditions. Changes in chemokine expression in CaP cells were analyzed by real-time PCR, immunoblotting, and ELISA. siRNA- or shRNA-directed strategies were used to repress PTEN expression and/or attenuate autocrine CXCL8 signalling by down-regulating CXCR1 and CXCR2 gene expression.The effects of modulating chemokine signaling on cell viability following exposure to clinically-relevant doses of IR were assessed by colony formation assays, cell proliferation analysis, and analysis of apoptosis and/or cellular senescence. Results: Exposure to IR (3 Gy) in normoxic and hypoxic cells increased gene expression of CXCL8 and its receptors CXCR1 and CXCR2, a response potentiated in PTEN depleted cells. Loss of PTEN had different effects on the sensitivity of CaP cell lines; shRNA-mediated loss of PTEN conferred increased radioresistance in DU145 cells but increased the sensitivity of 22Rv1 cells to IR. However, despite these variable responses, siRNA-mediated repression of CXCR1/2 expression increased the sensitivity of all PTEN-depleted cell-based models to IR, under both normal and hypoxic conditions. Interestingly, inhibition of CXCL8 signalling reinforced IR-induced senescence in PTEN-depleted 22Rv1 cells (Tp53 WT) but increased apoptosis in PTEN-depleted DU145 cells (Tp53 mutant). Conclusions: Targeting IR-induced autocrine CXCL8 signalling is a novel therapeutic strategy to enhance the sensitivity of PTEN-deficient CaP cells to IR, taking on added significance in cells harbouring mutations or loss of Tp53 expression.
Is there a predictive value for measurement of tumor percentage and the number of tumor foci after prostatectomy?
Authors: Hinkelammert Reemt , Eminaga Okyaz , Semjonow Axel 
Published: February 2017

159 Background: The prognostic relevance of tumor volume (TV), tumor percentage (TP) and number of tumor foci (NF) as predictors of biochemical recurrence (BCR) in prostate cancer (PCA) following radical prostatectomy (RPE) is controversial. Methods: The cohort consisted of 758 referred subjects who underwent RPE between 2000 and 2005 at the University of Muenster. The mean time of follow up was 62 months. TV, TP and NF were estimated visually with the assistance of a pathologic mapping grid for embedded RPE specimens. In addition, TV and TP were assessed in a categorized fashion by using medians as cut points. Subgroup analyses for high (i.e. any of the following: > pT2, Gleason score ≥ 8, PSA > 20 ng/ml) and low risk (not high risk) patients were performed. Univariate and multivariate Cox propotional hazard analyses for BCR were performed. Results: TV, TP, and NF were strongly related to tumour stage, Gleason score, surgical margin status (SM) and preoperative prostate specific antigen (PSA). In univariate analysis all pathologic parameters including TV, TP, and NF were predictive for BCR. In multivariate analysis only TP, tumour stage, Gleason score, and PSA level were independent predictors. In subgroup analysis, TP was an independent predictor for BCR in the high risk group, but not in the low risk group. Conclusions: TP, but not TV or NF was found to be an independent predictor for BCR in patients after RPE. TP seems to be more relevant in high risk patients.
Effectiveness of abiraterone as salvage therapy in patients with docetaxel- and castration-resistant prostate cancer (mDCPC) that progressed during second-line chemotherapy with carboplatin plus weekly docetaxel (DC).
Authors: Reuter Christoph W. , Morgan Michael A. , Fenner Martin , Grünwald Viktor , Ganser Arnold 
Published: February 2017

162 Background: Our recent data have shown that carboplatin AUC5 on d1 plus docetaxel at a dose of 35 mg/m2 iv on d1, 8, 15 every 4 weeks (q4w) is an effective salvage therapy in mDRPC. Patients (pts) who have progressive disease during DC treatment survive only ~7 months and many are symptomatic. We have demonstrated that high free testosterone (FT) serum levels during DC treatment have a negative prognostic value for PSA response and overall survival in these pts. In this study the impact of abiraterone treatment and other subsequent salvage regimens after DC failure was analyzed. Methods: DC failure was defined as disease progression during DC treatment according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 74 consecutive DRPC pts were treated with at least 2 cycles DC until disease progression. At the time of the current analysis 67 pts have progressed and 41 pts received one or more subsequent therapies (1-3). Results: Overall survival (OS) of all 67 pts who have progressed during DC treatment was 7.1 months (CI 95% 1.8, 12.3). 41 pts received subsequent salvage therapies including mitoxantrone-prednisone-etoposide (MPE) (n=10), cabazitaxel (n=10), docetaxel-oxaliplatin (n=8), abiraterone (n=15) and doxorubicin-ketokonazol (n=5). OS of these 41 pts was 14.6 months (CI 95% 11.0, 18.3).In pts receiving abiraterone as salvage treatment, OS after DC was 21.8 months (CI 95% 7.2, 36.5) versus 11.9 months (CI 95% 9.0, 14.8) in pts receiving other regimens (HR 0.302, CI 95% 0.11, 0.8; p=0.016). Responses of prostate-specific antigen (PSAR; ≥30% and ≥50%) were only observed in pts receiving abiraterone (8/15, 53.3% and 4/15, 26.7%, respectively). Conclusions: Our data demonstrate for the first time that testosterone is an important prognostic factor for PSA response and OS in mDRPC patients receiving DC chemotherapy and that targeting testosterone after DC failure prolongs post-DC survival.
Serum insulin-like growth factor-1 levels in response to dasatinib-based regimens in bone-metastatic prostate cancer.
Authors: Dayyani Farshid , Varkaris Andreas , Araujo John C. , Song Jian H. , Trudel Geralyn C. , Logothetis Christopher , Gallick Gary E. 
Published: February 2017

166 Background: Dasatinib, an inhibitor of Src-family kinases, combined with docetaxel in men with castrate-resistant prostate cancer (CRPC), affects bone turnover markers. Only a subset of men benefit from this therapy, and predictive markers are lacking. We hypothesized a role for insulin-like growth factor-1 (IGF-1) as a predictive marker, since IGF-1 is important in both prostate cancer (PCa) progression and bone development. Hence, we determined the association of IGF-1 expression to treatment response, and whether this expression resulted from tumor cells, the microenvironment, or their interactions. Methods: We first measured serum IGF-1 levels in men with CRPC treated with dasatinib plus docetaxel. To investigate the source of IGF-1, we utilized different mouse models harboring human PCa cells, and used species-specific IGF-1 ELISA kits (mouse vs. human). Results: In men with CRPC, an increase in IGF-1 levels after one cycle of treatment is associated with a higher response rate and longer duration of treatment with docetaxel and dasatinib. Xenograft experiments with subcutaneous, and intratibial injection of PCa cells and treatment of mice with dasatinib-based combinations suggest that direct interaction of PCa cells with bone microenvironment is necessary for IGF-1 induction, is entirely host-derived, and occurs only in mice that respond to dasatinib-based therapy. Conclusions: Our results support a role for serum IGF-1 as a potential biomarker for dasatinib-based combination treatments in CRPC. Inoculation of human PCa cells into murine hosts was essential in determining that IGF-1 results from the bone microenvironment. Further studies are warranted to validate these findings in a larger cohort of patients in a prospective manner.
Serum IGF-1 levels in men with advanced prostate cancer treated with the ERα agonist, GTx-758.
Authors: Yu Evan Y. , Gittelman Marc , Keane Thomas E. , Tutrone Ronald , Belkoff Laurence , Given Robert , Bass Joel , Chu Franklin , Gambla Mike , Gaylis Franklin , Bailen James , Getzenberg Robert H. , Coss Christopher , Hancock Michael L. , Dalton James T. , Steiner Mitchell S. 
Published: February 2017

171 Background: The insulin pathway and, in particular, insulin-like growth factor-1 (IGF-1), has been implicated in the development of prostate cancer, and serum IGF-1 levels have been associated with advanced disease. GTx-758, an ERα agonist that is being evaluated for the treatment of advanced prostate cancer, reduces serum total testosterone (T) and free T and increases SHBG. Herein, we compare the effects of GTx-758 and leuprolide on serum IGF-1 levels in men with advanced prostate cancer treated with ADT. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Serum samples were collected from all of the men in the study and serum IGF-1 levels (ng/ml) were analyzed by a reference laboratory. All p values describe the comparison of GTx-758 treatment groups to the leuprolide treated men. Results: Through day 90, in men receiving the 1000 mg and 2000 mg doses of GTx-758 , serum IGF-1 levels were decreased by more than 70 ng/ml (greater than 50%), while levels stayed constant or increased slightly in men on leuprolide (p<0.001). As a result of an increased risk of venous thromboembolic events (VTEs) at these higher doses of GTx-758, the trial was stopped prior to its completion, and not all of the men in the study reached the 90 day treatment date (92 men reached that date). Conclusions: In men with advanced prostate cancer, the ERα agonist, GTx-758, can decrease the active form of testosterone, serum free T, to significantly lower levels than leuprolide. Patients receiving GTx-758 experienced a significant decrease in serum IGF-1. Since changes in insulin metabolism are involved in regulating prostate cancer as well as bone and systemic metabolism, the observed decreases in IGF-1 could be significant. A Phase II clinical trial utilizing lower doses of GTx-758 (G200712) is currently ongoing to determine if similar effects can be observed with a lower rate of VTEs. Clinical trial information: NCT01326312.
Impact of body mass index on clinicopathologic outcome and biochemical recurrence after radical prostatectomy in 1,257 Japanese patients with prostate cancer.
Authors: Narita Shintaro , Mitsuzuka Koji , Yoneyama Takahiro , Kawamura Sadafumi , Arai Yoichi , Ohyama Chikara , Tochigi Tatsuo , Yamaguchi Takuhiro , Habuchi Tomonori 
Published: February 2017

176 Background: To determine the impact of body mass index (BMI) on the clinicopathological characteristics and biochemical recurrence of prostate cancer (PCa) after radical prostatectomy (RP) in Japanese men. Methods: The medical records of 1,257 men with PCa treated by radical prostatectomy without neoadjuvant therapy at four medical centers between 2001 and 2009 were retrospectively reviewed. Patients were categorized into four groups using the WHO BMI classification and recommended BMI quartiles. Associations of the various BMI categories with clinicopathological characteristics and biochemical recurrences were statistically evaluated. Biochemical recurrence was defined as a prostate specific antigen (PSA) level of >0.2 ng/ml. Results: Of the 1,257 patients, 230 (18.1%) experienced biochemical recurrence during the median follow-up period of 49 months. The median BMI was 23.8 kg/m2, and 1.4% patients were underweight, 65.4% were of normal weight, 30.9% were overweight, and 2.4% were obese (WHO classification). Preoperative PSA levels and PSA density (PSAD) were significantly higher in the underweight group than in the other groups. Pathological characteristics did not differ significantly among BMI categories. As per the WHO classification and quartile categories, biochemical recurrence rate was comparable among the BMI groups. After adjusting for other pre- and perioperative covariables, multivariate Cox proportional hazards analysis revealed that a high BMI did not have an independent impact on biochemical recurrence-free survival. Conclusions: Underweight Japanese PCa patients who underwent radical prostatectomy had higher preoperative PSA levels and PSAD. However, high BMI was not associated with increased biochemical recurrence rate.
Prostate cancer (PC) follow-up and treatment by race in an equal access health system: A pilot study.
Authors: Mitikiri Nirupama Devi , Nallu Anitha , Mullins C. Daniel , Onukwugha Ebere , Hussain Arif 
Published: February 2017

177 Background: There are known racial disparities in the incidence and outcomes of PC as well as in receipt of treatment. Although some studies in the Veterans Affairs Health System (VA) suggest that utilization and outcomes are as good, if not better, for African Americans (AA) as for Whites (WH), race appears to have mixed impact on stage-specific PC survival in the VA population. This pilot study aims to identify racial disparities in PC care in an equal access health system such as the VA. Methods: A retrospective cohort study was conducted of 109 consecutive patients with newly diagnosed PC in the year 2010 at the Baltimore VA Medical Center (BVAMC). Baseline characteristics (age, prostate specific antigen (PSA) at diagnosis, Gleason score (GS), stage, race) were extracted from the electronic medical records. Patterns of treatment and follow-up care, including specialist (urologist, medical oncologist, radiation oncologist) visits, time to first treatment, and primary treatment in the first year of diagnosis were examined. Results: Of 109 patients, 32 (30%) were WH, 69 (63%) AA and 8 (7%) other racial groups. AA and WH had similar median age (62, 64), GS (7, 7) and PSA (8.06, 7.46) at diagnosis. More AA were diagnosed with stage IV PC compared to WH (13% vs. 3%). Median time to first follow-up specialist visit since diagnosis was 15 (0-140) and 19.5 (2-169) days for AA and WH, respectively. Median time to initial treatment was 99.5 (1-306) and 146 (6-345) days for AA and WH, respectively. For localized PC, 30% AA received prostatectomy (RP) and 70% external beam radiation therapy (EBRT); in WH it was 19% and 76%, respectively. Conclusions: In an equal access health system such as the BVAMC, there did not appear to be racial differences in PC follow-up with specialists and time to initial treatment. AA had more advanced disease at diagnosis. Interestingly, although both AA and WH received EBRT more often than RP for localized PC, AA underwent RP more frequently than WH. It will be of interest to determine whether these patterns hold for other years and in other equal access health systems.
11C-choline PET/CT in selection of patients for salvage cryoablation in recurrent prostate cancer.
Authors: Breeuwsma Anthonius J. , Rybalov Maxim , Leliveld Anna Maria , Dierckx Rudi A. , Pruim Jan , de Jong Igle J. 
Published: February 2017

188 Background: 11C-choline PET/CT has proven to be a sensitive technique for re-staging after radiation therapy (RT). The aim of this study was to analyze the clinical impact of 11C-choline-PET/CT in the selection of patients with biochemical recurrence (BCR) after RT for salvage cryoablation of the prostate. Methods: This prospective study was conducted between November 2006 and February 2012 on patients considered as candidates for salvage cryoablation. 74 patients, mean age 69.2 years, median – 70.3 years (range 49-79), who were being followed up after RT for histological proven prostate cancer (according to ASTRO-Phoenix) were included. Until 2009 we used PET/CT fusion, but from 2009 all patients were examined with an integrated PET/CT system. After receiving 400 MBq 11C-choline intravenously, a whole body scan was made. As reference we used biopsy-proven histology from site of suspicion, confirmative imaging modalities (bonescan, CT) or clinical follow-up. PSA doubling time and velocity was calculated. Results: According to the PET/CT results, 40 (54%) patients had a local recurrence, 20 (27%) had regional/distant metastases and 14 (19%) had a negative scan. The positive PET findings were proved by histology from prostate biopsies and/or pelvic lymph node dissections in 63% of cases. Considering PET/CT results: 50/74 (68%) patients received cryoablation, for 24/74 (32%) treatment was changed (active surveillance or androgen deprivation therapy). Conclusions: 11C-choline-PET/CT could be useful for the selection of patients with BCR after RT for salvage cryoablation of the prostate. 11C-choline-PET/CT was decisive and led to therapy change in 32% of cases. [Table: see text]
Which data for cabazitaxel (Cbz) from the real world? The safety experience from the Italian centres participating in the Expanded Access Programme (EAP).
Authors: Bracarda Sergio , Marchetti Paolo , Gasparro Donatello , Gernone Angela , Boccardo Francesco , Messina Caterina , Gianni Luca , Bortolus Roberto , Fratino Lucia , Fornarini Giuseppe , Carteni Giacomo , Tucci Marcello , Mazzanti Roberto , Scotto Tiziana , Martoni Andrea , Basso Umberto , Procopio Giuseppe , Morelli Franco , Mattioli Rodolfo , Di Lorenzo Giuseppe 
Published: February 2017

189 Background: A significant percentage of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) progressing during or after a docetaxel (D) based therapy are candidates for additional effective treatments. Taxanes remain the mainstay of treatment for a wide range of tumours including mCRPC. Cabazitaxel, a next generation of taxane, was approved based on results from the TROPIC study (NCT00417079). Cbz plus prednisone (P) was associated with a higher overall survival than mitoxantrone (MTX) (15.1 vs 12.7 mo, HR=0.70; P<0.0001). Moreover CbzP was associated with clinical benefits, better PFS, maintenance of ECOG PS, improved tumour and PSA response, longer time to tumour and PSA progression while pain control was similar to MTX. These clear benefits supported a global EAP. Methods: Here we report, the preliminary safety analysis of 165 pts entered in the study from 25 Italian centres between Jan and Nov 2011. Pts received Cbz 25 mg/m2(intravenous every 3 weeks) plus P 10 mg (oral daily). Results: Median age was 70 years (21.8% of the cases were ≥75 years); pts with PS 0-1=98.2%; median number of previous D cycles was 8; 30.8% received 450 ÷ 675 mg, 14.7% received 675 ÷ 900 mg and 28.2% received ≥ 900 mg of D. Median time from last D dose to first CbzP dose was 5 months including any other eventual chemotherapy treatment. 49.1% of the pts entered in this EAP because refractory to D (PD during or within 3 months since the last D administration), overall 72 % of pts had 2 or more met sites. At the time of this analysis approximately 50% of pts received 4 cycles. A total of 68 pts discontinued CbzP due to PD (38.2%), AEs related and not related (38.2)%, Investigator’s decision (2.9%) or other reasons (20.6%). The most common G 3/4 AEs were neutropenia (35.2%), leukopenia (17.6%), anaemia (5.5%) febrile neutropenia (4.2%); main non-haematological AEs were asthenia (4.8%) and fatigue (4.2%). Conclusions: This large analysis confirms a manageable safety profile of cabazitaxel in routine clinical practice. The safety profile showed in EAP study suggests cabazitaxel a safe and effective treatment option in mCRPC pts progressing during or after a docetaxel based therapy. Clinical trial information: NCT01254279.