bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of PET index quantifying skeletal uptake in NaF PET/CT images with overall survival in prostate cancer patients.
Authors: Lindgren Belal Sarah , Sadik May , Kaboteh Reza , Hasani Nezar , Enqvist Olof , Svärm Linus , Kahl Fredrik , Simonsen Jane , Poulsen Mads Hvid , Ohlsson Mattias , Høilund-Carlsen Poul Flemming , Edenbrandt Lars , Tragardh Elin 
Published: March 2017

178 Background: Bone Scan Index (BSI) derived from 2D whole-body bone scans is considered an imaging biomarker of bone metastases burden carrying prognostic information. Sodium fluoride (NaF) PET/CT is more sensitive than bone scan in detecting bone changes due to metastases. We aimed to develop a semi-quantitative PET index similar to the BSI for NaF PET/CT imaging and to study its relationship to BSI and overall survival in patients with prostate cancer. Methods: NaF PET/CT and bone scans were analyzed in 48 patients (aged 53-92 years) with prostate cancer. Thoracic and lumbar spines, sacrum, pelvis, ribs, scapulae, clavicles, and sternum were automatically segmented from the CT images, representing approximately 1/3 of the total skeletal volume. Hotspots in the PET images, within the segmented parts in the CT images, were visually classified and hotspots interpreted as metastases were included in the analysis. The PET index was defined as the quotient obtained as the hotspot volume from the PET images divided by the segmented bone tissue volume from the CT images. BSI was automatically calculated using EXINIboneBSI. Results: The correlation between the PET index and BSI was r2= 0.54. The median BSI was 0.39 (IQR 0.08-2.05). The patients with a BSI ≥ 0.39 had a significantly shorter median survival time than patients with a BSI < 0.39 (2.3 years vs. not reached after 5 years). BSI was significantly associated with overall survival (HR 1.13, 95% CI 1.13 to 1.41; p < 0.001), and the C-index was 0.68. The median PET index was 0.53 (IQR 0.02-2.62). The patients with a PET index ≥ 0.53 had a significantly shorter median survival time than patients with a PET index < 0.53 (2.5 years vs. not reached after 5 years). The PET index was significantly associated with overall survival (HR 1.18, 95% CI 1.01 to 1.30; p < 0.001) and C-index was 0.68. Conclusions: PET index based on NaF PET/CT images was correlated to BSI and significantly associated with overall survival in patients with prostate cancer. Further studies are needed to evaluate the clinical value of this novel 3D PET index as a possible future imaging biomarker.
A phase II study of enzalutamide (Enz) with dutasteride (Dut) or finasteride (Fin) in men ≥ 65 years with hormone-naive systemic prostate cancer (HNSPCa).
Authors: Kilari Deepak , Guancial Elizabeth A. , Sahasrabudhe Deepak M. , Bylow Kathryn A. , Burfeind John D. , Musto Kaylinn , Feng Changyong , Messing Edward M. , Mohile Supriya Gupta , Fung Chunkit 
Published: March 2017

179 Background: Older men are at a high risk for adverse events (AEs) from androgen deprivation therapy (ADT). In prior studies, peripheral androgen blockade with bicalutamide and Fin was better tolerated but less efficacious than ADT in HNSPCa. The potential syngerism of Enz (a potent antiandrogen) and Dut/Fin (5-a reductase inhibitors for conversion of testosterone [T] to dihydrotestosterone [DHT]) provided the rationale for this Phase II study that examined the clinical efficacy and safety of Enz with Dut/Fin in men > 65 years with HNSPCa. Methods: Eligible patients were > 65 years (y) ; at a high risk of AE from ADT by comprehensive geriatric assessment or treating physicians; had metastatic (M1) or biochemical recurrent (M0) HNSPCa with a PSA doubling time < 9 months; and had T > 50ng/dl. They received Enz (160mg daily) and Dut (0.5mg daily) or Fin (5mg daily) until disease progression according to the Prostate Cancer Working Group 2 guidelines. The primary study endpoint is time to PSA progression. The secondary endpoints are time to PSA nadir and treatment-related AEs. Results: As of July 31, 2016, 24 patients were screened (3 ineligible) and 21 were enrolled with a median follow-up of 31 weeks (7-79). Median age at enrollment was 79.5 y (66-94) and 14 %, 72% and 14% had ECOG performance status of 0, 1, and 2, respectively. 57% (n = 12) had M0 and 43% (n = 9) had M1 HNSPCa, with 18%, 62%, 5%, and 10% having Gleason 6, 7, 8, and 9 disease, respectively (5% with unkown Gleason sum). The median PSA at enrollment was 12 ng/ml (2-102). The median time to 90% PSA decline after treatment initiation was 7 weeks (7-20) and 92% achieved 80% DHT decline in 9 months. At the time of analysis, all patients had ongoing PSA decline of > 90% without radiographic evidence of disease progression. Common Grade 1 AEs included gynecomastia (28%), fatigue (28%), hot flashes (19%) and paresthesias (15%). One patient withdrew from the study due to Grade 2 paresthesia. None had Grade 3 or 4 treatment-related AEs. One patient died due to colitis unrelated to study treatments. Conclusions: Enz with Dut/Fin appears to have clinical activity for older patients with M0 and M1 HNSPCa with acceptable side effects. Clinical trial information: NCT02213107.
Clinical utility of CLIA-grade AR-V7 testing in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Markowski Mark Christopher , Silberstein John , Eshleman James R. , Luo Jun , Antonarakis Emmanuel S. 
Published: March 2017

183 Background: The AR-V7 splice variant may confer resistance to AR-targeted therapies but not taxane chemotherapies. Since August 2015, a clinical-grade assay to detect AR-V7 mRNA expression in circulating tumors cells (CTC) has been available through a CLIA-certified lab at Johns Hopkins. In the first 12 months after launch, 195 AR-V7 tests were ordered for clinical purposes. We contacted the ordering providers of the first 100 tests using a questionnaire-based survey to determine how (and if) the results of AR-V7 testing were used in clinical practice. Methods: We identified 100 consecutive mCRPC pts who underwent AR-V7 testing in our CLIA lab. Ordering providers received a questionnaire for each test ordered, asking how (and if) the results of the assay affected their clinical decision-making, and whether a PSA50 response was obtained on next-line therapy after AR-V7 testing was performed. Results: 80 of 100 questionnaires were completed by 26 providers from 17 sites across 14 states. AR-V7 assay results were reported either as CTC negative (21/80: 26%), CTC+ AR-V7 negative (26/80: 33%), or CTC+ AR-V7 positive (33/80: 41%). Prevalence of AR-V7 detection increased with prior exposure to AR targeted drugs (Abi/Enza-naive 29%, post-Abi or Enza 39%, post-Abi and Enza 62%). Overall, management was impacted by AR-V7 testing in 54% of cases (43/80), and even more so with AR-V7+ results (see Table). AR-V7+ pts were commonly switched from AR targeted therapies to a taxane (10/19: 53%) or were offered a clinical trial (8/19: 42%). Pts who had a change in management based on AR-V7 testing were more likely to achieve a PSA50 response on next-line therapy than those not changing treatment (18/36: 50% vs 10/30: 33%). Conclusions: Providers used AR-V7 testing to influence clinical practice more often than not. AR-V7+ pts were most often treated with taxane-based therapy or offered a clinical trial, which may have improved outcomes. Clinical qualification of AR-V7 is ongoing. [Table: see text]
Genomic diversity between primary tumor tissue and tumor circulating cell-free DNA (cfDNA) in patients (pts) with metastatic prostate cancer.
Authors: Carroll Emma , Gill David Michael , Poole Austin , Hahn Andrew W. , Bailey Erin B. , Streeter Jessica , Batten Julia A. , Gupta Sumati , Agarwal Neeraj , Maughan Benjamin Louis 
Published: March 2017

189 Background: Tumor tissue and tumor cfDNA next-generation sequencing (NGS) tests are obtained in pts with metastatic prostate cancer and have demonstrated a diverse genomic landscape. High-level evidence does not exist for utilizing these tests to guide treatment selection in these pts. Targeted therapies are available for metastatic prostate cancer treatment and clinical trials are investigating drugs targeting specific molecular pathways. The objective of this study was to assess type and number of genomic aberrations between tumor tissue and cfDNA. Methods: Pts with metastatic prostate cancer who had both tissue and cfDNA results were selected and genomic profiles were compared between these two technologies. The mean number of tissue mutations was compared to cfDNA mutations for all pts using the t-test. The mutations for both tests were then categorized into five pathways: DNA repair, cell cycle regulation, PI3K, epigenetics, and androgen receptor (AR). For each pathway, the total number of patients with a mutation was compared between tissue and cfDNA using the Mann-Whitney test. Results: Nineteen pts were identified with both tissue and cfDNA results. The mean number of mutations identified was significantly less with cfDNA (95% CI, 2.7-5.3) compared to tissue (95% CI, 7.0-9.7; P < 0.0001). There were significantly more patients with PI3K pathway mutations identified in the tissue compared to cfDNA (73.7% vs 21.1% P = 0.0018), as well as epigenetic mutations (47.4% vs 0.0% P = 0.0012). There was no difference in the number of patients identified to have DNA repair, cell cycle regulation, and AR variances between the two tests. Conclusions: The lower number of aberrations detected by the cfDNA test may have occurred due to lower sensitivity of cfDNA compared to tissue based NGS. Discordance in the type of genomic variances between the two tests suggests intra-individual genetic diversity, and these results may have implications in treatment selection of pts with metastatic prostate cancer. Data are hypothesis generating and need further investigation in a larger cohort.
AR-V7 detection by a novel junction-specific RNA in situ hybridization (RISH) test.
Authors: Zhu Yezi , Sharp Adam , Anderson Courtney M , Silberstein John , Taylor Maritza N. , Demarzo Angelo , Antonarakis Emmanuel S. , Wang Mindy , Luo Yuling , Su Nan , Figueiredo Ines , Nava Rodrigues Daniel , Park Emily , Ma Xiao-Jun , Coleman Ilsa , Morrissey Colm , Plymate Stephen R , Nelson Peter , De Bono Johann S. , Luo Jun 
Published: March 2017

191 Background: Previous studies have reported an association between blood-based detection of androgen receptor splice variant-7 (AR-V7) and resistance to abiraterone/enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC). Further characterization of AR-V7 and its clinical correlates are necessary but depend on the development of methods that allow for reliable and specific measurement of AR-V7. In this study, we developed and evaluated a novel junction-specific AR-V7 RNA in situ hybridization (RISH) test. Methods: We developed a novel RISH assay targeting single exon-exon junction, allowing for highly-specific detection of mature cytoplasmic AR-FL and AR-V7 mRNA in native cell and tissue environment. We compared quantitative RISH AR-V7 results generated from an automated scoring system with AR-V7 levels quantified by RT-PCR in a panel of cell lines. Using the validated assay, we quantified AR-V7 signals in 58 prostate tumor biopsies. We conducted preliminary evaluation of the clinical correlates of AR-V7 detected. Results: The novel AR-V7 RISH test specifically detected mature cytoplasmic AR-V7 mRNA and did not detect nuclear pre-mRNA. AR-V7 RISH results were highly concordant with RT-PCR results. We generated quantitative AR-FL and AR-V7 data from 93.1% of the clinical specimens examined (54 of 58). Positive AR-V7 signals were detected in 23 specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 4.6%. Positive detection of AR-V7 was significantly correlated with prior treatment with second-line AR targeting agents and serum PSA ( p <0.05), but not with any other baseline clinical variables. Notably, all castration-sensitive prostate cancer specimens (CSPC) (n = 9) were AR-V7 negative by this method. Association between AR-V7 and treatment outcome has yet to be fully evaluated. Conclusions: We demonstrate for the first time a highly specific and quantifiable AR-V7 RISH test for detection of clinically significant levels of AR-V7 mRNA in prostate tissue specimens. This test may be applied to liquid biopsy specimens to expand the utility. Prospective studies can be designed to evaluate the potential utility of this novel test in drug development and patient management.
Glucocorticoid receptor (GR) expression in circulating tumor cells (CTCs) to prognosticate overall survival (OS) for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with androgen receptor signaling inhibitors (ARSi).
Authors: Wise David , Kelvin James , Graf Ryon , Schreiber Nicole A. , McLaughlin Brigit , Fernandez Luisa , Rivera Normy , Petines Bianca , Harvey Melissa , Nguyen Linda , Oh Aaron , Horiuchi Lee , Dittamore Ryan Vance , Scher Howard I. 
Published: March 2017

194 Background: Upregulation of GR protein expression in metastatic biopsies from pts with CRPC has previously been shown to correlate with resistance to enzalutamide and has been validated as a therapeutic target in pre-clinical studies. We sought to determine whether upregulated GR protein expression in CTCs from pts with progressing mCRPC predicted clinical outcomes following treatment with enzalutamide (E) or abiraterone (A). Methods: Pre-therapy blood samples from 54 pts with progressing mCRPC were subjected to CTC analysis using the Epic Sciences platform. Samples were examined to identify CK+ (CK+, CD45- cells, with intact nuclei, morph distinct) CTCs for GR protein expression. GR+ CTCs were defined as having expression greater than the 95th percentile of GR expression in the GR negative LNCAP cell line. Kaplan-Meier analysis was used to test the impact of GR+ CTCs on OS following treatment with A or E. A Cox proportional hazards model with CTC number and GR positivity was used in a multivariate analysis. Results: 37 out of 54 pts (69%) had detectable and viable CK+ CTCs. 28 out of 37 pts (76%) had CTCs with upregulated GR staining with a median of 6 GR+/CK+ cells/ml per patient (range 0.7 – 244 cells/ml). The OS of patients with GR+ CTCs treated with ARSi was significantly worse than that of patients without detectable GR+ CTCs (11.4 mo. vs NA, p < 0.01), an effect independent and additive to the presence of viable CTCs, a previously described prognostic biomarker (see Table). Conclusions: GR protein upregulation in CTCs can be detected in a significant percentage of pts with progressing mCRPC and the presence of GR+ CTCs predicts worse OS in response to ARSi. The data supports previously reported pre-clinical data proposing a pathogenic role for GR in mediating resistance to ARSi therapy. Detection of GR in patient CTCs may be a useful predictive biomarker to guide GR-directed therapies. [Table: see text]
Boosting long-term immune responses to sipuleucel-T (sip-T) by retreatment of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Beer Tomasz M. , Corman John , Lance Raymond S. , Campogan Dwayne , Vu Tuyen , Haynes Heather , Chang Nancy N. , Sheikh Nadeem Anwar , Curti Brendan D. 
Published: March 2017

196 Background: Sip-T, an autologous cellular immunotherapy for asymptomatic/minimally symptomatic mCRPC, induces immune responses to target antigens prostatic acid phosphatase (PAP) and PA2024, a recombinant protein of PAP and granulocyte macrophage colony-stimulating factor. Immune responses with sip-T correlate with overall survival. PROTECT (phase 3 NCT00779402) assessed sip-T in biochemically recurrent androgen-dependent PC. PROTECT pts developing mCRPC were eligible for P10-1 (phase 2 NCT01338012). Methods: PROTECT pts (sip-T arm) were retreated with sip-T in mCRPC. Antigen presenting cell (APC) activation (CD54 molecule ratio after and before culture with PA2024), cellular (PA2024/PAP ELISPOT; T cell proliferation) and humoral responses were assessed and compared with treatment-naïve mCRPC pts (IMPACT NCT00065442; STAMP NCT01487863; STRIDE NCT01981122). Results: Caucasian men (n=8), median follow-up 9.2 y and age 74 y, had an ECOG PS of 0 (75%) or 1. Median APC activation with sip-T infusion 1 was ~3-fold higher in P10-1 (20; n=7) vs treatment-naïve mCRPC pts (7; n=447). In P10-1, high magnitude cellular and humoral responses were seen at baseline (BL) (Table). Immune memory was heterogeneous, strong BL humoral and/or robust cellular memory was observed. Sip-T boosted PA2024/PAP cellular and humoral responses (Table). Immune responses were maintained up to wk 52, and were higher over time vs 1st time treated mCRPC pts. Conclusions: Sip-T in an earlier disease setting generated sustained antigen-specific immune memory lasting up to 10 y. Consistent with vaccine-induced immune responses, sip-T retreatment rapidly boosted both cellular and humoral antigen-specific responses in mCRPC pts. Clinical trial information: NCT01338012. [Table: see text]
The Prostate Cancer Project (PC Project): Translational genomics through direct patient engagement.
Authors: Mullane Stephanie Anne , Painter Corrie , Dunphy Michael , Anastasio Elana , Simoncelli Tania , Zarrelli Kristen , Philippakis Anthony , McKay Rana R. , Choueiri Toni K. , Golub Todd , Lander Eric , Wagle Nikhil , Van Allen Eliezer Mendel 
Published: March 2017

199 Background: While there has been substantial advancement in the genomic understanding of prostate cancer (PCa), there is still much to be discovered. Additional progress is dependent upon obtaining a large amount of clinically annotated genomic data. As PCa is often treated in a community setting, where research samples are not collected, we are starting a direct-to-patient nationwide research initiative where patients can donate their medical records and biospecimens to accelerate research. Previously, we launched the metastatic breast cancer project (MBCproject; mbcproject.org) that leverages social media to engage the MBC community. Based on the initial success with this approach, we now aim to build out the PCproject. Methods: In collaboration with patients, we are developing a website to enable participation in the PCproject. Enrolled patients will be sent a saliva kit, used for germline DNA. We will also obtain medical records. Metastatic patients will also be sent a blood draw kit for circulating tumor DNA (ctDNA). Whole exome sequencing of the ctDNA will be performed. We will use the recruitment infrastructure, clinical record abstraction, and biospecimen processing developed for the MBC project. The data will be shared widely with the research community. Aggregate study results will be reported to patients. Results: In the first year of the MBCproject, 2912 MBC patients from all 50 states enrolled. 2766 (95.0%) completed the 16-question survey about their cancer, treatments, and demographic information. 1716 (58.9%) completed the online consent form permitting acquisition and analysis of medical records, tumor tissue, and saliva samples. 936 (68.8% success rate) saliva samples have been received. To date, we have obtained medical records from 155 patients (72.1% success rate) and tumor samples from 60 patients (72.3% success rate). Based on initial recruitment and surveys among PCa patients, we estimate that 500 patients will enroll in 2017. Conclusions: Based on experience from the MBC project, we will partner directly with patients to recruit and drive the PCproject forward. Remote acquisition of medical records, saliva samples, and tumor tissue for patients located throughout the US is feasible.
Genomic analysis of untreated prostate adenocarcinoma, treatment-emergent neuroendocrine carcinoma, and circulating tumor cells.
Authors: VanderWeele David James , Lack Justin , Gillard Marc , Cam Maggie , Paner Gladell 
Published: March 2017

200 Background: The prostate cancer genome evolves in response to therapeutic pressure, requiring repeated evaluation as the disease progresses. Biopsies of metastatic sites are invasive and often low yield. Circulating tumor cells (CTCs) offer an alternative source, but few studies have evaluated their genomic relationship with untreated and contemporaneous disease. Methods: We performed exome sequencing of untreated tumor tissue, a late stage liver biopsy, and the amplified genome of EpCAM+ CTCs in a patient with therapy-emergent neuroendocrine carcinoma. Results: Exome sequencing of CTCs captured 71% of the founder mutations shared between the two tissue samples. The allele fraction of founder mutations in the CTCs was 47.8%, indicating a nearly pure population of CTCs from a single clonal disease. Other mutations were at lower allele frequency, suggesting genomic heterogeneity among pooled CTCs. CTCs demonstrated late divergence from the contemporaneous neuroendocrine carcinoma liver biopsy, with 62% of mutations also found in this tissue. An acquired premature stop codon mutation in the Retinoblastoma (RB1) gene, which is associated with progression to small cell cancer, was identified in neuroendocrine and CTC samples, but not untreated tissue. Conclusions: These data support the clonal relationship of untreated adenocarcinoma and treatment-emergent neuroendocrine carcinoma. They also support the use of pooled EpCAM+ CTCs to facilitate the genetic analysis of late stage prostate cancer, including neuroendocrine carcinoma.
Studies of a novel modified E2F-targeted peptide with activity against castration-resistant prostate cancer.
Authors: Bertino Joseph R. , Szekely Zoltan , Scotto Kathleen W 
Published: March 2017

205 Background: The E2F family of genes encodes transcription factors that are key to the regulation of a number of target genes, including those encoding cyclins , CDKs , checkpoints regulators, and DNA repair and replication proteins. One of the primary functions of the E2Fs is to control the cell cycle, playing a major role in regulating the G1/S transition. One of the primary regulators of E2F expression is the retinoblastoma gene, RB, a chromatin associated protein that, in its unphosphorylated state, binds to and negatively regulates E2F; hyperphosphorylation of RB releases E2F, allowing cell cycle progression. Many tumor cells have mutant or dysfunctional RB, allowing the aberrant overexpression of the E2Fs and tumor cell proliferation; this aberrant overexpression is better tolerated when p53 is mutated, suppressing subsequent apoptosis. Overexpression of E2F, particularly E2F1, has thus been an attractive target for therapeutic intervention. However, this approach has not yet been successful, most likely due to the redundancy of the E2Fs and the lack of biomarkers for sensitivity. Methods: Using phage display, we have previously identified a novel peptide that, when coupled with penetratin (PEP) to enhance uptake), targets the E2F consensus site in E2F1,2 and 3a, leading to the downregulation of the activating E2Fs and their downstream targets. We have recently enhanced the stability and potency of this peptide by substituting L-Arg within the peptide with D-Arg. Results: Castrate resistant prostate cancer (CRPC) cells, DU-145, lack functional RB, have mutant p53, and are more sensitive to the D-Arg PEP than LnCap or PC-3 cells, with functional RB. Xenograft studies in mice show that the PEP, when encapsulated in PEGylated liposomes (PL-D-Arg PEP) , regresses DU-145 tumors without toxicity. Current studies are examining the combination of the (PL-D-Arg PEP) with taxotere, cisplatin and irradiation in prostate cancer xenografts and organoids from patients. Conclusions: A peptide that inhibits transcription of the activating E2Fs has promise to treat CRPC.