bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early docetaxel-resistance in metastatic hormone-sensitive prostate cancer.
Authors: Bukhari Nedal , Potvin Kylea R. , Ernst D. Scott , Sax Lori , Winquist Eric 
Published: March 2017

260 Background: The addition of docetaxel to standard androgen deprivation therapy (ADT) has been shown to improve the survival of men with metastatic hormone-sensitive prostate cancer (MHSPC) (Sweeney 2015, James 2016). We noticed PSA progression in some of our patients (pts) during docetaxel treatment and reviewed their outcomes. Methods: Men with MHSPC treated with docetaxel were identified from an electronic oncology pharmacy database. Eligible pts were prescribed docetaxel for metastatic adenocarcinoma of the prostate within 120 days of initiation of ADT. Pts with castration-resistant disease (CRPC), other histologies, and those without metastatic disease were excluded. Demographic, clinical, treatment and outcome data were extracted retrospectively from electronic medical records. Results: 31 eligible pts with MHSPC treated with docetaxel between August 2014 and July 2016 were identified. Median age was 65 years (53-83) and 28 (90%) had high-volume disease as defined by Sweeney et al (2015). Nadir PSA levels 6-7 months from ADT initiation were < 0.2, 0.2-4, and > 4 ng/mL in 29.0%, 36.7% and 36.7%, respectively. At median follow up of 85 weeks, 45.2% of pts had progressed to CRPC and 22.6% had died. Median time to CRPC was 59 weeks and median overall survival was 85 weeks. Seven pts with high-volume disease (25%) had PSA progression while receiving docetaxel treatment. The median overall survival of this group was 26 weeks (17 to 106+) and six have died. Three had visceral metastases. Nadir PSA was < 0.2 (1 pt), 0.2-4 (2 pts) and > 4 ng/mL (4 pts). After docetaxel 2 pts received BSC alone and 5 pts had 1st-line CRPC therapy. No response to abiraterone/enzalutamide was seen (3 pts). Two pts who discontinued docetaxel immediately at PSA progression and were switched to alternative chemotherapy survived > 1 year. Conclusions: A subset of men with MHSPC has lethal docetaxel-resistant disease characterized by early PSA rise. It is important to recognize these patients, but it is not clear if standard CRPC therapies are effective. An immediate early switch to alternative chemotherapy may be helpful. Further research to predict early docetaxel resistance, characterize response to current therapies and identify more effective treatment is needed.
Stereotactic body radiotherapy for patients with relapsing prostate cancer with bones or nodes oligometastases.
Authors: Laurent Pierre-Antoine , Martin Etienne , Cousin François , Quivrin Magali , Bidault Fabienne , Mazoyer Frederic , Bertaut Aurelie , Crehange Gilles 
Published: March 2017

263 Background: To analyze patients treated by stereotactic body radiotherapy (SBRT) for node or bone oligometastatic recurrence of a prostate cancer previously locally treated, To identify possible pronostic factors of early biochemical failure (BF) after SBRT. Methods: We reviewed patients with a rising PSA treated by SBRT between November 2011 and April 2016 for bone or node oligometastases, diagnosed on a 18F Fluorocholine positron emission tomography-computed tomography (PET-CT) following biochemical failure of a prostate cancer after a local curative treatment. Recurrence-free survival (RFS) was the primary end-point defined as the time interval between SBRT and biochemical failure. Biochemical failure was defined as 2 consecutive elevations of PSA with last dosage superior to PSA dosage before treatment, or clinical failure. PSA value before SBRT, location of metastases, number of lesions treated, concomitant androgen deprivation therapy were analyzed to identify pronostic factors of poor response to SBRT. Results: With a median follow-up from time of SBRT of 12 months, we treated 40 patients and 56 metastatic lesions, with a local-control rate of 85%. 19 patients were treated for 1 to 3 bone lesions and 21 patients for 1 to 3 node lesions. 8 patients with bone oligometastases and 13 patients with node oligometastases had a recurrence (p=0.55). The main sites of failure after SBRT were lymph nodes only (7 ; 33%), bone only (7 ; 33 %), and synchronous node and bone (4 ; 19%). A 2nd and 3rdcourse of radiotherapy was delivered in 8 and 1 patients. Median RFS was 345 days (134-426) in the node SBRT group and 494 days (85-877) in the bone SBRT group (p=0.27). On bivariate analysis, a PSA nadir up to 0.51 ng/mL after SBRT was identified as a pronostic factor of a worse RFS (p=0.0038). This result was not confirmed in multivariate analysis (p=0.87). Conclusions: SBRT for node oligometastases showed a non significant lower rate of RFS when compared to SBRT in bone oligometastases. A larger cohort with a longer follow up is needed to determine whether node and bone oligometastases have similar outcomes after SBRT.
Association of time from definitive therapy (DT) to start of androgen deprivation therapy (ADT) for metastatic disease and survival outcomes in men with new metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Gill David Michael , Stenehjem David D. , Cheng Heather H. , Kessler Elizabeth Riley , Hahn Andrew W. , Gupta Sumati , Alex Anitha , Patel Shiven B. , Chittoria Namita , Twardowski Przemyslaw , Vaishampayan Ulka N. , Agarwal Neeraj 
Published: March 2017

265 Background: Few objective criteria are considered for risk stratification for treatment decision making in men with new mHSPC. Time between DT for localized disease, and start of ADT for new mHSPC may predict response to ADT, and prognosticate outcomes in this setting. Methods: In this multicenter study, men with newly diagnosed mHSPC with prior history of definite therapy for localized prostate cancer were included. Kaplan-Meier and Cox proportional hazard methods assessed time to castration resistance (CRPC) and overall survival (OS) from initiation of ADT, and correlated with the time elapsed from DT to initiation of ADT for new mHSPC. Results: A total of 112 men with new mHSPC initiating ADT, with prior definitive therapy were eligible (all median: age 68 yrs, Gleason score 7, PSA 14 ng/ml, ECOG 0, median time from DT to start of ADT for new mHSPC 54 months). In the univariate analysis, time from DT to start of ADT of < 60 months vs ≥ 60 months significantly correlated with duration of response to ADT and outcomes (Table). After adjustment for Gleason score and log PSA, time from DT to start of ADT for new mHSPC (<60 vs ≥60 months) remained an independent and a significant predictor of time to CRPC (HR 1.92 95% CI 1.02-3.90, p=0.044), and showed trends towards predicting OS (HR 1.77 95% CI 0.60-6.19, p=0.33). Conclusions: Time from DT for localized prostate cancer to initiation of ADT for new mHSPC independently predicts response to ADT, and may aid in risk stratification for treatment decision making in men with new mHSPC. These hypothesis-generating data require validation in a larger cohort. [Table: see text]
A video-based, personalized web page (VBPWP) as a complement to clinical trial (CT) patient management.
Authors: Mills Hannah , McKay Rana R. , Werner Lillian , Jacobus Susanna J. , Pace Amanda Fredericks , Prisby Judith , Walsh Meghara K. , Choudhury Atish Dipankar , Choueiri Toni K. , Pomerantz Mark , Sweeney Christopher , Polacek Laura , Taplin Mary-Ellen 
Published: March 2017

266 Background: Most advances in the diagnosis and treatment (Tx) of patients (pts) with genitourinary (GU) cancers are the result of pt involvement in CTs. There is a clear need to identify ways to improve CT processes for pts and research teams (RTs). The goal of this project is to assess the use of a VBPWP to improve pt compliance, safety, CT quality, and RT efficiency in GU CTs of oral agents. Methods: This is an unblinded, randomized trial using a VBPWP as an intervention (INT) for pts with advanced non-metastatic (M0) or metastatic (M1) GU cancers. Pts consented but not yet started on CTs of oral agents are randomized 2:1 to the INT or control arm. The INT includes videos of provider-pt encounters and educational videos related to dosing and adverse events (AEs). Target accrual is 99 pts. The primary end point is number of cumulative pt violations (PVs) over 4 cycles (4Cs) of INT. PVs are defined as improper dosing, non-compliance, and failure to report AEs or hospitalizations. Herein we report an early pooled analysis of pts who completed 4Cs. Results: 90 pts enrolled (61 M1, 67 prostate, 22 kidney). 58 pts completed ≥ 4Cs. 58% (n = 33) of pts had ≥ 1 PV on study (Table). Despite RT instructions, overall, 7%, 9%, and 3% of pts failed to return pill bottles or report AEs, missed a dose of Tx on 3 occasions, or took a wrong dose, respectively. Median total score of the Functional Assessment of Chronic Illness Therapy Tx Satisfaction-Pt Satisfaction (FACIT-TS-PS) measure was 72 (n = 45) at baseline (BL) and did not significantly change after 4Cs (73, n = 48). Scores of 73 indicate high levels of pt satisfaction. The Perceived Stress Scale (PSS) 10-Item indicated pt stress levels were highest at BL (score = 28) and improved after 1C of Tx (score = 24). Scores ≥ 20 indicate high stress. Stress levels did not significantly change after 4Cs. Conclusions: Longer follow up is needed to compare outcomes between pts randomized to the video INT compared to the control arm. Data show that the majority had ≥ 1 PV. This suggests the need to improve education for CT pts. The use of a VBPWP as a complement to standard CT pt education is feasible and may have the potential to increase pt safety and CT quality. [Table: see text]
Concordance in the relative mortality rates for prostate cancer and gastric cancer in African Americans.
Authors: Henegan John Clark 
Published: March 2017

270 Background: The racial disparity in outcomes for prostate cancer, gastric cancer, and multiple myeloma is demonstrated by these malignancies having the highest age-adjusted mortality rate ratio for black Americans versus white Americans. A variety of factors have been identified as contributing to this disparity, leading to our hypothesis that there would not be concordance, in respect to the mean, when the county-level age-adjusted black: white mortality rate ratio for a malignancy was compared to the other two malignancies. Methods: Publically available information from cancerrates.gov was used to obtain county-level data in regards to race-specific age-adjusted mortality rates for prostate cancer, gastric cancer, and multiple myeloma. Counties with potentially unstable age-adjusted mortality rates were excluded. A malignancy’s age-adjusted mortality rate for blacks was divided by the complementary rate for whites to determine the black: white mortality rate ratio. Across a county, malignancies were compared for concordance in mortality rate ratios relative to the mean ratio for that malignancy. After a preliminary inspection noted that all New Jersey counties had a markedly lower black: white mortality ratio for gastric cancer than other counties in the data set, the New Jersey counties were excluded from analysis and odds ratios for concordance were calculated. Results: All counties (n = 68) had a black: white age-adjusted mortality ratio of > 1 for each malignancy. In the analyzed counties (n = 52), there was a statistically significant concordance in black: white mortality rate ratios for prostate cancer and gastric cancer (OR = 3.26, p = 0.046). The black: white mortality rate ratios for neither prostate cancer (OR = 1.17, p = 0.78) nor gastric cancer (OR = 1.17, p = 0.78) demonstrated a statistically significant concordance with multiple myeloma. Conclusions: The concordance in the black: white mortality rate ratios for prostate cancer and gastric cancer in this dataset indicate that these two malignancies may share common clinical, environmental, or genetic factors in African-Americans. Future research is needed into what common factors may contribute to disparities in these two malignancies.
De novo metastatic prostate cancer: Patterns of PSA testing prediagnosis and disease characteristics.
Authors: Ged Yasser , Greene John Patrick , Murray Hazel , Malone Eoghan Ruadh , Calvert Paula , O'Connor Miriam , Horgan Anne M. , McDermott Raymond S. 
Published: March 2017

271 Background: A small proportion of men with prostate cancer (PCa) will present with metastatic disease at first presentation, termed de novo metastatic PCa. PSA screening is not a national policy, yet PSA testing is commonly performed and national guidelines are available to guide subsequent management. We sought to investigate this group of men to determine if prior PSA testing had been previously performed, and if elevated, to determine if appropriate referrals were being made. We also sought to further characterise and analyse associated risk factors. Methods: A retrospective review of pts who presented with de novometastatic PCa over a three year period was performed in three cancer centres in Ireland. Characteristics such as demographics, Gleason score, symptoms at presentation and disease volume (high v low) were obtained. PSA results done in the primary care for a period of 12-24 months and > 24 months prior to diagnosis were recorded. Results: 100 pts with de novo metastatic PCa were identified between 2013 and 2015. Median age at diagnosis was 72 years (49-90), 77 pts (77%) presented with high volume disease, 11 pts (11%) had evidence of visceral metastasis with a median age of 62 years (51-72). Median PSA level at diagnosis was 106, and 91% of pts (n = 74) had a Gleason score of ≥ 8. Symptoms at presentation were evaluable in 88 pts with the majority of pts presenting with pain (n = 49, 55.6%) and lower urinary tract symptoms (n = 33, 37.5%). 22 pts (22%) had a PSA level done within 12-24 months prior to diagnosis which was higher than 4.0 ng/ml in 18 pts (82%). 57 pts (57%) had a PSA level done over 24 months prior to diagnosis which was higher than 4.0 ng/ml in 35 pts (61.4%), PSA measurement was only repeated in 18 pts (51%) out of 35 pts with high PSA levels prior to diagnosis. Having elevated PSA levels over 4.0 ng/ml within 12-24 months and over 24 months prior to diagnosis was not associated high volume metastatic disease (P = 0.88). Conclusions: A sizeable proportion of pts diagnosed with de novo metastatic PCa had PSA measurements performed more than one year prior to diagnosis which was elevated. Optimization and adherence to national guidelines regarding PSA testing is needed to decrease the number of pts diagnosed with de novo disease.
An oral androgen receptor PROTAC degrader for prostate cancer.
Authors: Neklesa Taavi K , Snyder Lawrence B , Bookbinder Mark , Chen Xin , Crew Andrew P , Crews Craig M , Dong Hanqing , Gordon Deborah A , Raina Kanak , Rossi AnnMarie K , Taylor Ian , Vitale Nicholas , Wang Jing , Willard Ryan R , Zimmermann Kurt 
Published: March 2017

273 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Further, we sought to make an orally bioavailable AR PROTAC. Methods: Medicinal chemistry efforts yielded a small molecule AR PROTAC that simultaneously binds E3-ubiquitin ligase and AR, thus leading to ubiquitination and degradation of AR. This molecule has been characterized in in vitro and in vivo preclinical studies. Results: Our lead oral AR PROTAC degrades 92-98% of total AR in all cell lines tested, with 50% degradation concentration (DC50) < 1 nM. AR degradation suppresses the expression of AR-target gene PSA, inhibits cell proliferation, and induces potent apoptosis in VCaP cells. No activity is observed in AR-null cell lines, such as PC-3. While enzalutamide loses its activity in the presence of elevated androgens, AR PROTAC maintains its antiproliferative activity. Further, AR PROTAC is able to degrade all clinically relevant mutant AR proteins. A robust oral bioavailability is observed across multiple species and overall ADME properties are encouraging. Approximately 95% AR degradation is observed in AR-amplified VCaP xenografts at doses as low as 10 mg/kg. Congruent with AR degradation, a dose responsive tumor growth inhibition is observed in AR-dependent xenograft studies. Conclusions: In summary, we report the first orally bioavailable AR PROTAC that robustly degrades AR in vitro and in vivo.
Efficacy of additional chemotherapy following failure of currently approved therapies in patients with castration-resistant prostate cancer.
Authors: Campedel Luca , Blanc-Durand Paul , Assoun Sandra , Mateescu Cristian , Roupret Morgan , Bitker marc-Olivier , Vaessen Christophe , Parra Jerome , Comperat Eva , Boostandoost Haide Angele , Malouf Gabriel G. , Spano Jean-PHilippe 
Published: March 2017

274 Background: Approved therapies for patients with castration resistant prostate cancer (CRPC) include next generation androgen receptor inhibitors as well as taxanes which are given sequentially. After failure of these drugs, physicians may use additional chemotherapy such as carboplatin, paclitaxel, mitoxantrone and vinorelbine. The clinical benefit of these drugs in this setting remains fully unknown. Methods: A retrospective monocentric study of patients treated for CRPC was performed. Presence of metastasis and visceral involvement at diagnosis and at castration resistance, time between start of hormonotherapy and castration resistance were recorded as well as several clinical and biological parameters at start of CRPC first line. The cohort was divided into two groups according to the use of additional chemotherapies following failure of currently approved therapies. Results: Fourty subjects out of 138 cases (28.9%) fulfilled the inclusion criteria. At diagnosis, median patients age was 68 years (range, 53-86), median Gleason grade was 8 (6-10) and 53% of them harbored distant metastasis. At castration-resistance stage, 93% were metastatic including 27% out of them wihich harbored visceral involvement. Median overall survival (OS) of patients since castration-resistance was 34.9 months (range, 7.4-88.0). The two groups were comparable in terms of age, PSA level, and Gleason grade. Median OS for patients in the additional chemotherapy group (n = 16) was 42.4 months as compared to 37.3 months in the non additional treatment group (n = 24), with no statistical difference (p = 0.961). Main treatments administered consisted of carboplatin (n = 6), paclitaxel (n = 4) and mitoxantrone (n = 4). PSA response rate (decrease > 50%) obtained with use of additional treatment was 12%. Median progression-free survival was 1.9 months (range, 0.7-13.1) and median overall survival was 4.2 months (range, 2.2-17.8). Conclusions: Our retrospective study suggests that additional treatment after standard treatment failure for CRPC is associated with limited benefit. Further studies are needed to clarify the role of new agents therapies in this setting.
Modes of action of low-dose cabazitaxel in combination with the antiangiogenic and antitumoral pigment epithelium-derived factor in prostate cancer.
Authors: Nelius Thomas , Jarvis Courtney , Filleur Stephanie 
Published: March 2017

275 Background: Despite the approval of several new agents, taxanes remain the main alternative treatment for castration-refractory metastatic prostate cancer (mCRPC). In a previous work, we have demonstrated that cabazitaxel is more efficient in a low-dose setting than docetaxel in inhibiting the proliferation and inducing apoptosis of CRPC cells in vitro, and delaying tumor growth in vivo. In the present study, we have investigated the efficacy of low-dose cabazitaxel when combined with the anti-angiogenic and anti-tumoral Pigment Epithelium-Derived Factor (PEDF). Methods: CRPC CL1 cells (LNCaP-derivative) that express PEDF or control plasmid were used. Tumor cells were injected s.c. into C.B.17-SCID mice. After two weeks, mice were randomized into groups: 1) Placebo; 2) Docetaxel: 5mg/kg i.p. d4; and 3) Cabazitazel 5-1-0.5-0.1mg/kg i.p. d4, d1-7, d2, and daily. To investigate the molecular mechanisms involved in the anti-tumor effect of the combined treatment, tumor cell migration was measured using the inverted Boyden chamber assay. Tumor cell phagocytosis was also assessed in CL1-RAW264.7 macrophages co-cultures. Results: We showed that while 0.5 and 0.1 mg/kg cabazitaxel did not improve PEDF efficacy on tumor growth, 1mg/kg was extremely toxic, killing 1/2 animals within the first week of treatment. In contrast, we demonstrated that PEDF combined with 5mg/kg cabazitaxel lead to stabilization of the disease. PEDF/cabazitaxel was also found to be drastically more efficient than PEDF/docetaxel in delaying the disease. In vitro, PEDF/cabazitaxel inhibited tumor cell migration at a superior level compared to PEDF/docetaxel. Finally, PEDF/cabazitaxel induced more phagocytosis of the tumor cells by macrophages than PEDF/docetaxel suggesting that the combination may target macrophages within the tumor microenvironment. Conclusions: Our data demonstrated that PEDF with low-dose cabazitaxel could be used as a novel therapeutic combination to treat CRPC. Our results also emphasize on the importance in closely evaluating the cytotoxicity of the combination tested and investigating the role of the tumor microenvironment in the anti-tumor effect.
The natural history, treatment, and survival of 199 patients with sarcomatoid carcinoma of the prostate.
Authors: Biswas Roy Sreeja , Cheney Scott , Brunnhoelzl Daniel , Wang Jue 
Published: March 2017

278 Background: Sarcomatoid carcinoma of the prostate (SCP) is a rare and aggressive subtype of prostate cancer. Current data on clinical features, appropriate management and long-term outcomes of SCP are limited. Methods: A systematic review of literature was performed to identify published reports on SCP using keywords “sarcomatoid”, “prostate”, and “carcinosarcoma”. No randomized trials were identified. Four single-center case series and one registry-based study were included in final analysis. Results: In total, 199 patients were included in the review (54 from the SEER registry, 145 from the four case series). SCP occurs more frequently in the late sixth to seventh decade of life (age range: 28-91 years). Many patients with SCP (range, 48%-78%) have a history of prostate adenocarcinoma, with variable time to SPC onset (range, 0.5-20 years). Most tumors are high grade, with locally advanced or distant stage. Urinary obstruction was the most common symptom (50%-92%). Advanced stage was associated with poor prognosis in all reports. Although prostatectomy as part of multimodality treatment likely affected cancer-specific survival in select patients, large variation was observed in prostatectomy and adjuvant therapy rates. No effective systemic chemotherapy was reported. Conclusions: SCP is an aggressive variant of prostate adenocarcinoma. Molecular studies are needed to illuminate their aggressive underlying biology and develop individualized therapeutic approaches. The results of this analysis may help increase awareness of this rare malignancy and serve as a baseline for future clinical studies. [Table: see text]