bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experience of 1,000 patients.
Authors: Iorio Julieta , Eleta Martin , Bambacci Florencia , Cuneo Lucrecia , Polillo David 
Published: February 2018

294 Background: The aim of this study is to present our experience between the correlation of 18 fluorocholine (FCH) positron emission tomography (PET)/computed tomography (CT) findings and PSA levels in detecting local recurrence, lymphatic/haematogenous involvement in patients with prostate carcinoma. Methods: 1075 patients with prostate cancer were enrolled between July 2012 and August 2017. Patients were separated in two main groups: biochemical progression 913 (85%) and 162 (15%) staging. Each group was divided in three subgroups according to PSA levels: ≤1 ng/ml; ≥ 1-5ng/ml and > 5 ng/ml. All of them underwent “Dual phase” PET-CT consisting of intial pelvis starting 20 minutes after the injection of 18 F-Choline followed by 1 hour delayed PET-CT of the whole body. Results: 1641 lesions showed increased uptake on FCH-PET and were interpretated as local recurrence or metastases .According to biochemical progression we identified for each subgroup: 118 patients (13%) (≤1 ng/ml); 265 patients (29%) (≥ 1-5ng/ml); 530 patients (58%) ( > 5 ng/ml) and for staging we identified for each subgroup: 81 patients (50%) (≤1 ng/ml); 47 patients (29%) (≥ 1-5ng/ml); 20 patients (34%) ( > 5 ng/ml). The results are shown on table 1: Patients presenting biochemical progression the majority of them have PSA levels of 5 ng/ml or more and the most frequent site of metastases were pelvic lymph nodes, on the other hand, for staging patients we have found that most of them have PSA levels of ≤1 ng/ml and we detected that they most commonly have local compromise. Conclusions: In our experience 18 FCH PET/CT is a useful tool to detect lesions in patients with biochemical progression but it seems to have limited value for staging. [Table: see text]
Influence of CHAARTED, STAMPEDE, and LATITUDE eligibility criteria on utilization of abiraterone (A) and docetaxel (D).
Authors: Parshad Shruti , Emmenegger Urban 
Published: February 2018

301 Background: A and D improve the survival of men with high-risk localized or metastatic hormone-naïve prostate cancer (HNPC) when combined with androgen deprivation therapy (ADT). However, the two drugs differ regarding side effects, treatment duration, and associated costs. Furthermore, different eligibility criteria were used in the seminal phase III studies. Since the latter may impact on drug access in many constituencies, we decided to study how applying the eligibility criteria of CHAARTED, STAMPEDE and LATITUDE for drug funding purposes might influence the utilization of A versus D. Methods: 102 men with HNPC were referred from 06/2014 to 09/2017 to the medical oncology service at Odette Cancer Centre (Toronto/ON, Canada) for consideration of additional systemic therapy secondary to ADT. After extraction of baseline patient characteristics, we applied the eligibility criteria of CHAARTED (both high-volume [HV] and low-volume [LV] definition), STAMPEDE, and LATITUDE to determine the rate of men qualifying for treatment with A, D, or either of the two agents. Results: 98.0, 69.6, 28.4, and 47.1 percent of all 102 men fulfilled the STAMPEDE, CHAARTED-HV, CHAARTED-LV, and LATITUDE criteria, respectively. Considering that A funding for HNPC therapy is pending in Ontario, and that D funding is limited to men with CHAARTED-HV disease, the rate of D therapy was 62.0, 69.0, and 77.1 percent of patients conforming to STAMPEDE, CHAARTED-HV, and LATITUDE, respectively. 42 of 48 men (87.5%) conforming to LATITUDE would also be candidates for D, whereas 42 of 71 CHAARTED-HV patients (59.2%) would be eligible for A as alternative treatment. Hence, while all men fulfilling the STAMPEDE criteria (100 of 102, 98%) could be considered for either A or D, only 42 of 102 patients (41.2%) would be candidates for both of the drugs if the CHAARTED-HV and LATITUDE criteria were applied. Conclusions: In our patient population, applying the more restrictive CHAARTED-HV and LATITUDE criteria - as opposed to STAMPEDE - would result in around 30% or 50% fewer men offered D or A secondary to ADT, respectively. In addition, only around 40% of men would conform to both CHAARTED-HV and LATITUDE, and thus be candidates for both drugs.
Activity of VERU-111, an novel oral α and β tubulin inhibitor, against paclitaxel sensitive and resistant prostate cancer.
Authors: Getzenberg Robert H. , Dalton James T. , Miller Duane D. , Steiner Mitchell S. 
Published: February 2018

302 Background: Following proven efficiacy of docetaxel against hormone sensitive advanced prostate cancer (CHAARTED and STAMPEDE studies), the use of docetaxel for the treatment of hormone sensitive and castrate resistant metastatic prostate cancer has increased. Unfortunately, the utility of taxanes in prostate cancer has been limited because of the development of resistance, the need for IV infusion, and the associated treatment toxicity. VERU-111 is a highly orally available, novel α and β tubulin inhibitor, developed using a rationale design strategy to bind through hydrogen bonds to the α and β subunits of tubulin. VERU-111 inhibits tubulin polymerization and is not a substrate for multi-drug resistance proteins, a common mechanism for taxane resistance. Methods: In this study, dosing regimens of VERU-111 (oral) were tested in comparison with docetaxel (IV) and a vehicle (oral) in PC3 as well as in paclitaxel resistant PC3 (PC3-TXR). xenograft models. VERU-111 was evaluated at 3.3 mg/kg (5 days/week), 10 mg/kg (3 days/week), 15 mg/kg (2 days per week), 15 mg/kg (3 days per week) and 20 mg/kg (1 day/week). The animals were treated for 28 days and tumor volume and percentage size were calculated. Results: In the parental PC-3 model, animals treated with oral VERU-111, in all of the dose schemes tested, performed statistically indistinguishably from the IV docetaxel administration. In the PC3-TXR model, IV docetaxel had no impact on tumor growth whereas oral VERU-111 resulted in almost complete inhibition of tumor growth at 3.3 mg/kg (5 days/week) and 10 mg/kg (3 days/ week) as well as 20 mg/kg (1 day/week). In early toxicity studies, the animals treated with VERU-111 did not suffer any significant safety signals and gained weight during treatment. Conclusions: VERU-111 is a novel, oral α and β tubulin inhibitor that has drug characteristics making it an ideal candidate to be a therapeutic option for hormone sensitive and castrate resistant advanced prostate cancer. VERU-111 can be administered, with efficacy, as infrequent as once per week and will not require daily dosing. Additional toxicity studies are currently being performed with a Phase 1/2 study being planned to begin later this year.
Safety of continued administration of enzalutamide in patients with prostate cancer who showed benefit from prior exposure: A phase 2 open-label extension study.
Authors: Lam Elaine Tat , Szmulewitz Russell Zelig , Appleman Leonard Joseph , Tolcher Anthony W. , Krivoshik Andrew , Baron Benoit , Malan Niel , Ghicavii Vitalii 
Published: February 2018

303 Background: Enzalutamide (ENZA), an androgen receptor (AR) inhibitor that blocks multiple steps in the AR signaling pathway, is approved for patients (pts) with metastatic castration-resistant prostate cancer. This Phase 2, open-label, extension study (NCT01534052) evaluated long-term safety of continued ENZA administration. Methods: Prostate cancer pts previously treated with ENZA in Phase I studies (NCT01902251; NCT01911728; NCT02225093) continued to receive ENZA 160 mg/day until the investigator considered it no longer beneficial or consent was withdrawn. The primary end point was safety. Baseline data from the parent studies were used. Results: 52 pts were enrolled and received ENZA treatment (median age, 67 years [range, 54–88]). Median treatment duration was 443 days (range, 63–2010) since first administration and 392 days (range, 3–1926) in the extension study. In the extension, 43 pts (82.7%) experienced ≥1 any grade treatment-emergent adverse event (TEAE) with the most common (≥10% of pts) being fatigue (26.9% all grades, 13.5% grade 1, 7.7% grade 2, and 5.8% grade 3); arthralgia and back pain (13.5% each); and diarrhea, hot flush, and decreased appetite (11.5% each). Drug-related TEAEs (investigator assessed) were reported in 27 pts (51.9%) with the most common (≥5% of pts) being fatigue (17.3%); hot flush (11.5%); and diarrhea, hypophosphatemia, and muscle weakness (5.8% each). 17 pts (32.7%) had ≥1 serious TEAE. Eight drug-related serious TEAEs were reported in five pts (malignant neoplasm progression [3.8%]; acute pancreatitis, rectal haemorrhage, cerebrovascular accident, dysarthria, hemiparesis, and hypertensive crisis [1.9% each]). One (1.9%) death due to acute myocardial infarction (not drug-related) and four (7.7%) due to malignant neoplasm progression (two drug-related) were reported. No notable changes from baseline in clinical laboratory parameters or clinically meaningful abnormalities in vital signs, physical examinations, or electrocardiogram were found. Conclusions: Long-term continued ENZA treatment is generally well tolerated, with a safety profile consistent with that previously reported. Clinical trial information: NCT01534052.
DNA damage and repair (DDR) gene variants and outcomes in localized and metastatic prostate cancer (mPC).
Authors: Bernard Brandon David , Gray Kathryn P. , Shaw Grace , MacConaill Laura E , Evan Carolyn , Hamid Anis , Choudhury Atish Dipankar , Sweeney Christopher 
Published: February 2018

304 Background: Moderate frequencies of DDR gene variants exist in mPC. Their prognostic role in localized and mPC is unclear. This study aims to characterize DDR variants in a cohort of hormone sensitive localized and mPC and assess for association with outcome. Methods: A retrospective cohort of men with PC and ≥ 2 follow up visits at DFCI and targeted next generation sequencing of prostate or metastatic tissue was identified. Biomarker (BM) positive was defined as pathogenic changes in the following DDR genes: ATM BAP1 BRCA1 BRCA2 BRIP1 CHEK2 MSH2 MSH6 PALB2 PMS2. For localized PC, outcome endpoints included event-free survival (EFS) (time from prostate biopsy to PSA relapse/metastasis/death), metastasis-free survival (MFS) (time to metastasis/death), time to castration resistance (CRPC), and death (OS); for mPC, outcome events included time from androgen deprivation start to CRPC and OS. BM status was descriptively summarized. Kaplan-Meier method and Cox regression model assessed associations of BM status with clinical outcomes. Results: Of the 237 men included, 16 (7%) were BM positive; 12 (6%) in 205 localized PC, 6 (14%) in 43 mPC. BM positive genes included 9 (4%) ATM, 6 (3%) BRCA2, and 2 (0.8%) CHEK2. In men with localized PC, EFS events occurred in 58% (7/12) BM positive vs 34% (66/193) BM negative at median follow up of 3.1 years; BM positive trended toward a shorter EFS (median 1.9 vs 5 years) than BM negative (HR 2.17, 95%CI 0.99-4.76). MFS events were observed in 17% (2/12) BM positive vs 7% (15/193) BM negative. CRPC events occurred in 17% (2/12) BM positive vs 6% (11/193) BM negative. In men with mPC, there were CRPC events in 100% (6/6) BM positive vs 67% (25/37) BM negative at median follow up of 3.3 years; BM positive trended toward a shorter time to CRPC (median 4 vs 8.8 months) compared to BM negative (HR 1.87, 95%CI 0.76-4.64). There was no association between BM status and OS. Conclusions: DDR variants appear infrequently in localized PC but may portend a shorter time to PSA relapse and metastasis. Similarly, DDR variants in mPC may be associated with a shorter time to CRPC. Low frequency of variants and short follow up limit these analyses. The prognostic value of DDR variants remains unclear and requires further research.
Detection of actionable BRAF missense mutations by ctDNA-based genomic analysis in prostate cancer.
Authors: Prophet Malshundria , Xiao Kun , Gourdin Theodore Stewart , Nagy Rebecca J , Kiedrowski Lesli Ann , Ledet Elisa , Sonpavde Guru , Sartor A. Oliver , Lilly Michael B. 
Published: February 2018

306 Background: Activating BRAF fusion proteins are rare in prostate cancer (PCa) patients. Driver missense BRAF mutations have not been reported in detail in this population. Methods: We examined ctDNA-derived genomic profiles (Guardant 360) from 2,721 unique PCa patients, to identify BRAF genomic anomalies (SNVs, amplification). The ctDNA results were compared with PCa tissue-based genomics from the TCGA database (1,851 unique patients). Results: BRAF missense mutations were found in 76 ctDNA patients (2.8%) and were from all known mutation classes (I, II, III) as well as variants of unknown significance (VUSs). Only 4 patients had the V600E mutation. Multiple examples of known, autonomously active, non-canonical mutations were found (27), including K601E (12), G469A (5), D594G (2), and G466E (2). There were 45 VUSs. Mutations were primarily clonal but subclonal mutations were also found. In addition BRAF was commonly amplified, usually in the presence of multiple other amplified genes. BRAF missense mutations were more common with ctDNA than TCGA (2.8% vs 1.4%). Neither dataset identified frequent V600E mutations (ctDNA: 4/2,721; TCGA 1/1,851). However patients with the same non-canonical BRAF mutations were found in each dataset (K601E, G469A, G466E, D594G). Each dataset contained unique mutations found in only one patient. BRAF mutations potentially treatable with BRAF or MEK inhibitors (class I, II) were about half of all mutations (ctDNA 40.8%; TCGA 50%). We treated a PCa patient with a clonal BRAF(G469A) mutation with targeted therapy. The patient was resistant to multiple lines of hormonal and cytotoxic therapy. Trametinib produced a clinical and RECIST response. Conclusions: ctDNA-based genomic analysis identified multiple BRAF amplifications and missense SNVs in PCa patients. SNVs are largely non-canonical, but include known activating mutations that could act as drivers. The analysis also identified more BRAF missense mutations than did tissue genomic profiling, but the mutational landscape, overall frequency of mutations was similar with either method. ctDNA-based genomic profiling can identify actionable BRAF driver mutations that may respond to MEK and BRAF inhibitors.
Assessment of immunohistochemical testing for androgen receptor splice variant 7 as a biomarker to predict resistance to androgen receptor signaling inhibitors in metastatic prostate cancer.
Authors: Vyas Ojas Harihar , Butler Matthew James , Bowhay-Carnes Elizabeth Ann , Pathan Muhammad , Datta Paromita 
Published: February 2018

308 Background: Androgen receptor splice variant 7 (AR-V7) has been shown to confer resistance to androgen receptor signaling inhibitors (ARS-I) such as enzalutamide (enza) and abiraterone (abi). Resistance can be observed at the time of initial treatment, or may be acquired later in the disease course. Prior research has primarily focused on AR-V7 expression in circulating tumor cells (CTCs) but the utility of more affordable immunohistochemical (IHC) testing to predict for primary resistance to ARS-I remains unknown, which is of particular relevance as ARS-I gain use as initial therapy. Methods: We identified patients in the South Texas Veterans Health Administration Tumor Registry with metastatic, castrate-resistant prostate cancer who received ARS-I since 2011. IHC for AR-V7 staining was validated on controls and performed on tissue from the most recent tissue specimen (diagnostic biopsy, prostatectomy, or biopsy of a metastatic site) on all identified patients with adequate tissue available. Results: 25 of 42 (60%) patients receiving abi had PSA response with median duration of response (DOR) of 231 days. 14 of 26 (54%) of patients receiving enza experienced PSA response with a median DOR of 165 days. IHC is currently being interpreted on stored tissue specimens to assess predictive efficacy of AR-V7 staining. The de-novo rate of AR-V7 expression and correlation with response to ARS-I in the veteran population will be reported with final results. Conclusions: IHC testing for AR-V7 may provide a cost-effective biomarker to identify patients resistant to ARS-I, thus avoiding thus avoiding time-consuming and costly treatment with ineffective therapy. Further study is warranted to assess cost-effectiveness and reduction in unnecessary toxicity by the use of IHC testing for AR-V7 in the front-line setting to predict primary resistance for patients that would otherwise qualify for ARS-I.
Cell surface GRP78 activation by anti-GRP78 autoantibodies in relation to prostate tumour growth via tissue factor activation.
Authors: Al-Hashimi Ali , Austin Richard , Shayegan Bobby 
Published: February 2018

31 Background: Prostate cancer (PC) is characterized by increased prothrombotic state due to enhanced tissue factor (TF) expression/procoagulant activity (PCA). We and others observed that GRP78, a molecular chaperone, is expressed on the surface of PC cells where it functions as a signaling receptor to promote cell proliferation and survival. Further, exposure of GRP78 on the surface of PC cells stimulates the production of anti-GRP78 autoantibodies in PC patients. We have reported that binding of these autoantibodies to cell surface GRP78 enhances TF PCA. We hypothesize that this autoantibody/cell surface GRP78 complex interaction increases PC progression and that disruption of this complex would represent a viable target for the treatment of advanced PC. Methods: Wild type, TF knockdown DU145 cells, and NOD/SCID mouse model system was used to investigate the effect of anti-GRP78 autoantibodies on tumor growth. Protein expression was determined using western blotting and qRT-PCR. TF activity was determined using the TF PCA continuous assay. Blood samples from patients diagnosed with PC were obtained from the Ontario Tumour Bank and St. Joseph’s Hamilton. Results: Pre-prostatectomy patients demonstrated high levels of anti-GRP78 autoantibodies (60-100µg/ml) vs. healthy individuals (5-10µg/ml). These titers were significantly reduced 24-weeks post prostatectomy. We show here that anti-GRP78 autoantibodies upregulate TF and its PCA through a mechanism involving depletion of ER Ca2+ stores. This very effect on ER Ca2+ stores also caused activation of the unfolded protein response, a pro-survival cellular pathway. Furthermore, these autoantibodies were shown to accelerate tumor growth in a NOD/SCID mouse model. Finally, heparin and low molecular weight heparin were shown to interfere with the binding of these antibodies to cancer cells and prevent PC cell activation. Conclusions: We have identified the function of an agent in patients' blood, anti-GRP78 autoantibodies, that correlate with PC stage in patients and increase TF PCA and promote PC progression in mice. The effect of this autoantibody can be reversed using heparin, thus, this acts as a new potential therapeutic target for PC.
NGS, RNA-Seq, TIL, and PTEN analyses in prostate cancer specimens from patients enrolled in the study of the Akt inhibitor ipatasertib (Ipat) combined with abiraterone acetate (AA).
Authors: Zhang Liangxuan , Koeppen Hartmut , Maslyar Daniel J. , Fillos Dimitri , Xu Na , Chan Wai Y. , Font Pous Albert , Jinga Viorel , Massard Christophe , Bracarda Sergio , Radavoi George Daniel , De Giorgi Ugo , Arranz Arija Jose Angel , Riisnaes Ruth , Nava Rodrigues Daniel , De Bono Johann S. , Gendreau Steven 
Published: February 2018

310 Background: In Phase III studies, ipilimumab did not extend OS in unselected populations with metastatic castration-resistant prostate cancer (mCRPC) (Kwon, 2014; Beer, 2014), suggesting that successful cancer immunotherapy development strategies require the evaluation of treatment effects in biomarker-driven segments. In addition, PTEN loss has been identified as a potential mechanism of resistance to immunotherapy (Peng, 2016). Therefore, we explored possible associations between cancer immunity (CI)-related biomarkers and PTEN loss in mCRPC samples. Methods: Tumor samples obtained in the Phase II study of AA ± Ipat in patients with mCRPC (de Bono, ESMO 2016) were retrospectively profiled. DNA alterations and tumor mutational burden (TMB) were assessed by FoundationOne. RNA-seq analysis of multiple CI-related expression signatures was performed. Tumor-immune lymphocyte (TIL) scores were analyzed in 3 compartments (stromal, sTIL; intratumoral, iTIL; peritumoral, pTIL) based on H&E stained specimens. Up to 10 evenly distributed fields were examined; the average of these fields was used to estimate the %TILs for each compartment. Results: Strong associations were observed between multiple CI-related signatures (e.g., INFγ-induced, immune checkpoints, Treg, checkpoint inhibitors). Fewer than 10% of the samples had a high level (≥ 10% of the tumor area) of TIL infiltration in any compartment (Table). TIL scores, TMB values, PTEN status and Gleason score all appeared to be independently associated, and none were associated with CI-related gene signatures, except for a possible association between pTILs and the B-cell signature (ρ = 0.49, P < 0.0001). Conclusions: Comprehensive high-content profiling of prostate cancer samples suggests that PTEN status and CI-related biomarkers were independently associated, while TMB and TIL values were generally not associated with CI-related signatures. Clinical trial information: NCT01485861. [Table: see text]
Germline variant in SLCO2B1 and response to abiraterone acetate plus prednisone (AA) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hahn Andrew W , Patel Darshan , Gill David Michael , Froerer Camryn , Nussensveig Roberto , Poole Austin , Hale Peter , Farnham James M. , Maughan Benjamin Louis , Cannon-Albright Lisa A , Agarwal Neeraj 
Published: February 2018

311 Background: Currently, there are no predictive biomarkers of response to AA in mCRPC routinely used in the clinic. SLCO2B1 encodes a sodium-independent organic anion transporter that mediates transport of endogenous sex hormones and drugs, including AA, into tissue. Single nucleotide polymorphisms (SNPs) in SLCO2B1 are a validated predictive biomarker of response to androgen deprivation therapy in hormone sensitive prostate cancer. In a recent pre-clinical study, the AA/AG genotype for rs12422149 and the AA genotype for rs1789693 of SLCO2B1 had significantly higher mean tissue abiraterone levels. We hypothesize that the variant allele for rs12422149 and rs1789693 are predictive of improved response to AA in mCRPC. Methods: Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line AA in men with mCRPC. We performed pre-specified multivariate Cox regression analyses to assess the independent predictive value of SLCO2B1 rs12422149 and rs1789693 on PFS on AA (table). Results: 76 men with mCRPC treated with first-line AA were included. In a multivariate analysis for rs12422149, a trend towards improved median PFS was seen with the AG genotype (11.2 months) vs. the GG genotype (6.4 months) (HR 0.50, 95% CI 0.24-1.02, p=0.056). No such correlation was seen with rs1789693 genotypes. Conclusions: Consistent with pre-clinical studies, the AG genotype in rs12422149 of SLCO2B1 may be predictive of response to AA in men with mCRPC. This hypothesis-generating data needs further interrogation in larger and independent cohorts. [Table: see text]