bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interim analysis of a pilot study: Impact of high-dose, single fraction radiation on immunogenicity of sipuleucel-T in metastatic castration resistant prostate cancer patients.
Authors: Yang Yuanquan , George Saby , Levine Ellis Glenn , Schwaab Thomas , Muhitch Jason , Li Qiang , Attwood Kristopher , Groman Adrienne , Abrams Scott I , Kalinski Pawel , Singh Anurag K , Guru Khurshid , Chatta Gurkamal S. 
Published: May 2019

e16538 Background: Sipuleucel-T is known to have modest anti-tumor activity in pts with metastatic castration resistant prostate cancer (mCRPC). Synergy of radiotherapy and immunotherapy has been reported. We conducted a pilot study to assess the impact of radiation on immunogenicity of Sipuleucel-T. Methods: Pts with minimally symptomatic mCRPC and bone metastases were eligible. Pts received Sipuleucel-T every 2 wks x 3 infusions. 8 Gy RT to 1 bone lesion was given 2 days after the first infusion. Peripheral blood was collected at D0, 7d after each infusion, 3 and 6 m. Primary endpoint is the effect of RT on immunogenicity of Sipuleucel-T. Secondary endpoints were safety, PSA changes and survival. We will evaluate T cell proliferation and cytolytic response at baseline and post-treatment using thymidine incorporation assay, IFN-y ELISPOT and flow cytometry. Results: From 10/2013 to 7/2018, a total of 15 pts were enrolled. Median age was 69 years (59-77). 10 pts (67%) had GS > = 8 disease. 7 pts (47%) failed prior abiraterone or enzalutamide. 13 pts completed treatment per protocol (2 withdrew). During a median follow-up of 48 mos, the 3-year overall survival was 48% (95% CI, 21-71); median survival was 30.7 mos (95% CI, 14.6-NR). No PSA responses were observed. 11 pts had post-treatment imaging (non-mandatory). 10 had PD and 1 had SD. 10 pts (67%) had Grade 1-2 drug-related AEs (most common: dizziness and hematoma 20%). No DLT or grade 3-5 drug-related AEs were observed. Conclusions: Sipuleucel-T plus RT is well tolerated. Median overall survival in this limited subset of pts was encouraging, when compared with historical data (25.8 mos in IMPACT trial). The evaluation of immune response is ongoing. (Funded by DENDREON; ClinicalTrials.gov ID: NCT01833208) Clinical trial information: NCT01833208.
Abiraterone acetate in comparison to enzalutamide in African American patients with metastatic castrate-resistant prostate cancer: A single-center retrospective study.
Authors: Telfah Mohammad , Holzbeierlein Jeffrey M. , Shen Xinglei , Wulff-Burchfield Elizabeth Marie , Parikh Rahul Atul 
Published: May 2019

e16547 Background: African American (AA) patients with metastatic castrate-resistant prostate cancer (mCRPC) represent a high-risk population with higher mortality. Recent data suggested that abiraterone acetate (AbA) is more effective in AA in comparison to white patients. There are limited data regarding enzalutamide (Enz) use in AAs. Here, we report the outcomes of (AbA) and (Enz) in AA patients with mCRPC at our center. Methods: A retrospective chart review included AA patients who had a diagnosis of mCRPC and were prescribed AbA and/or Enz at KUMC from 09-01-2008 through 09-01-2018. Patients were divided into two groups: those who started with AbA (abiraterone group) and those who started with Enz (enzalutamide group). Baseline characteristics were compared between the two groups using Fisher’s exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. The primary outcome was progression-free survival (PFS) on AbA and Enz. PFS was measured from the time of starting either of the two medications to the time of formal relapse, defined by relapse that required therapy change or prostate-cancer-related death. A stepwise Cox proportional-hazard model was used to adjust for potential confounders. Results: During the study period, 28 AA patients with mCRPC received AbA and/or Enz. Twenty-two patients received AbA first, while six patients received Enz first. There were no significant differences in the baseline characteristics between the two groups. Median PFS for the abiraterone group was 24.3 months, while it was 11.7 months for the enzalutamide group, Log-rank test p-value 0.04). After adjusting for potential confounders, the hazard ratio of progression remained significant, favoring the abiraterone group, HR: 0.11, p-value 0.009. Median PFS on AbA after progression on previous Enz was 5.7 months, while it was 4.5 months for Enz after progression on previous AbA, p-value 0.2. Conclusions: In this single-center retrospective study, AA patients with mCRPC who were started on AbA rather than Enz had longer PFS. More studies are needed to understand the best sequence of the two medications in this population.
Low dose enzalutamide in metastatic castration-resistant prostate cancer: A retrospective Caribbean study.
Authors: Vinh-Hung Vincent , Diakite Kadiatou , Joachim Clarisse , Bougas Stefanos , Furtos Cristina Ioana , Rakotonarivo Jean-Marc , Lababidi Wadah , Papadopoulou Eva , Escarmant Patrick , Veronique-Baudin Jacqueline , Verschraegen Claire F. 
Published: May 2019

e16548 Background: There is scarce information on the efficacy of low-dose enzalutamide in metastatic castration-resistant prostate cancer. We report on a series treated with half dose enzalutamide. Methods: We observed a trend in our practice to initiate low-dose enzalutamide at the time of disease progression in older patients considered frail, presenting with cardio-vascular comorbidity or with history of neurological symptoms. Records were retrospectively reviewed. The selection criteria were: 1) Metastatic disease demonstrated by at least one imaging modality, CT, bone scan, or positron emission tomography. 2) Progression of prostate specific antigen (PSA). 3) Castrate testosterone level ( < 0.2 ng/mL). 4) Enzalutamide treatment at 80 mg or less, once daily. To estimate the rate of PSA response, we used linear interpolation to compute the time from the initiation of low-dose enzalutamide to 50% PSA reduction. Results: Between November 2015 and December 2018 at the Martinique University Hospital, 10 patients matching the selection criteria were treated with ≤ 80 mg enzalutamide od: 8 started de novo with the low dose, 2 started with 160 mg but required dose reduction for intolerance. The mean age was 78 years (range 67-84). Three had painful bone metastases. The mean PSA at start of low dose enzalutamide was 88 ng/mL (range 1.06 - 251.8). All patients were maintained with reduced dose. At the current follow-up of 9 months (range 0 - 36 months), PSA response was observed in 7 patients ( = 70%), 1 was not evaluable (PSA not assessed), 2 did not respond. Of the 2 non-responders, one had no sign or symptom of disease progression; the other presented with extensive disease progression previously treated with abiraterone, he refused to receive increased dose enzalutamide. Among the 7 responders, the time to 50% PSA reduction was 57 days (range 26 - 119). Currently, the decline of PSA remains sustained in 6 of the 7 responders, it increased in 1 who discontinued enzalutamide. Pain decreased in the 3 symptomatic patients, including the PSA non-responder. Conclusions: Low dose enzalutamide appears efficient in a large proportion of selected frail patients. Further follow-up is required to evaluate the long-term response.
Expression of human leukocyte antigen-a and b2-microglobulin in prostate cancer.
Authors: Shen Ying-Chun , Jeng Yung-Ming , Kuo Jhe-Cyuang , Tsai Yu-Chieh , Chen Chung-Hsin , Huang Kuo-How , Huang Chao-Yuan , Pu Yeong-Shiau , Cheng Ann-Lii 
Published: May 2019

e16550 Background: Prostate cancer (PC) is generally resistant to current immune checkpoint blockade. Reduced expression of human leukocyte antigen-A (HLA-A) and b2-microglobulin (B2M) of cancer cells can cause deficit immune recognition and attack by cytotoxic T cells, and may be the major mechanism of intrinsic resistance to immune checkpoint blockade in PC patients. Methods: Formalin-fixed paraffin-embedded tissue of human localized or metastatic PC was used for evaluation of expression of HLA-A and B2M by Immunohistochemical staining. The expression was scored as: 0, no tumor cells stained; 1+, < 10% of tumor cells stained; 2+, 10-50% of tumor cells stained; and 3+, > 50% of tumor cells stained. Differences in HLA-A or B2M expression among groups were assessed by Chi-Square or Fisher’s exact test. Results: A total of 134 PC specimens [69 localized PC (LPC), 32 metastatic castration-naïve PC (mCNPC), and 33 metastatic castration-resistant PC (mCRPC)] from 115 patients were assessed. Significant loss (0 or 1+) of HLA-A was found in 56 (81.2%) LPCs, 30 (93.8 %) mCNPCs and 29 (87.9%) mCRPCs; while significant loss of B2M was found in 22 (32.6%) LPC, 11 (34.4%) mCNPCs, and 17 (51.2%) mCRPCs. In localized PCs, the expression of HLA-A or B2M was similar between high-grade prostate intraepithelial neoplasia foci and corresponding malignant counterpart, and did not significantly correlate to biochemical failure. In 14 patients with paired CN and CR PC specimens, significant loss of HLA-A was found in all tumors. B2M expression varied between CN and CR PCs, and progressive loss of B2M was found in 7 (50%) patients. Among 3 patients receiving immune checkpoint blockade, 1 patient with intact expression of HLA-A and B2M in pre-treatment tumor specimen achieved partial response; whereas the others with reduced expression of HLA-A (0) and B2M (1+) did not. Conclusions: Reduced expression of HLA-A or B2M is an early event in prostate carcinogenesis.
Effectiveness and tolerability of depot formulations of leuprorelin acetate in real life: Analysis of 932 patients with prostate cancer from Brazil.
Authors: Freitas Carla Simone Moreira , Soares Aleida Nazareth 
Published: May 2019

e16552 Background: Clinical trials have shown that androgen deprivation therapy (ADT) is a mainstay of treatment for locally advanced and metastatic prostate cancer. Real-life studies with broader selection criteria may help inform clinical practice. Methods: We reviewed the medical records of 1890 patients with prostate cancer seen at our institution between 01/07 and 07/18. We analyzed patients treated with long-acting leuprorelin acetate, grouping these patients into three strata according to the administration of ADT every 1, 3 or 6 months. The primary outcome was the prostate specific antigen (PSA) levels at 6 and 12 months after treatment initiation. We used Friedman test to compare the distribution of PSA levels over time within each treatment stratum, considering two-sided P values < 0.05 as statistically significant. Results: We analyzed a total of 932 eligible patients, with a median age of 72 years and a median time since diagnosis of prostate cancer of 8.5 months. ADT was administered every 1, 3 and 6 months in 115, 637, and 180 patients, respectively. Nearly half of the patients had locally advanced disease. The table presents PSA levels in each stratum at the three time points. Sexual impotence and hot flashes were the most frequently reported toxicities. Conclusions: Our study confirms that serum PSA levels can be effectively reduced, with a favorable toxicity profile, in most patients treated with long-acting leuprorelin acetate. Administration every 6 months may bring the added benefit of convenience and cost savings in clinical practice.[Table: see text]
Prostate carcinoma in African-Americans has miRNA expression and biological markers for aggressive disease.
Authors: Agrawal Malhaar , Bukhari Zaheer , Stevasarova Aksiniya , Tenniswood Martin , Gupta Raavi 
Published: May 2019

e16558 Background: African American (AA) men have twice the incidence and mortality in Prostate Cancer (PCa) as compared to non-Hispanic Whites. The identification of a biological basis for this disparity is crucial in providing focused treatment. In this study, we have characterized the pathological features and molecular markers of PCa in AA men. Methods: 91 proctectomies for primary PCa and 23 biopsies for metastatic PCa with their pathological data were retrieved. Tissue microarrays were constructed and the expression of Programmed Cell Death 1 (PD-1), Programmed Death Ligand 1 (PD-L1) and Mismatch Repair (MMR) (MLH1, MSH2, MSH6 and PMS2) proteins was assessed by immunohistochemistry. miRNA expression of 24 cases of primary PCa and adjacent normal prostate tissue from proctectomies was identified by microarray in situ hybridization. Spearman’s rank-correlation was used to correlate variables and p < .05 was considered significant. TargetScan and DIANA analysis software were used to identify modulation in miRNA expression. Results: In a supervised heat map, overall the downregulation of microRNA was more than upregulation in tumor tissue; 11 miRNA were upregulated and 12 were downregulated, with a log fold change of 1.5. miR-345, a component of the mismatch repair and DNA Replication pathway, showed significant up-regulation (p = 9.4E-02); has been linked to more aggressive PCa. PD-L1 expression was lower in primary PCa (16%) than in metastatic PCa (35%). PD-1 expression was high in almost half of primary and metastatic PCa patients. MMR protein expression was largely intact in both primary and metastatic PCa cases. Both of these protein markers have been associated with biochemical recurrence and low survival. Conclusions: The biological characteristics (low expression of PD-L1, high expression of PD-1, intact MMR and distinct miRNA signature) identified in our cohort of exclusively AA men are indicators of aggressive PCa. These results explain the biological basis of widely documented poor prognosis of PCa in AA men.
Evolution of androgen receptor variant (ARV) profiles in serial metastatic solid and liquid biopsies in metastatic castrate resistant prostate cancer (mCRPC) treated with abiraterone acetate/ prednisone (AA/P).
Authors: Giridhar Karthik , Sosa Carlos , Sicotte Hugues , Wang Liewei , Wang Liguo , Sinnwell Jason P. , Tan Winston , Costello Brian Addis , Quevedo Fernando , Pitot Henry C. , Bryce Alan Haruo , Jimenez Rafael E. , Weinshilboum Richard M. , Dehm Scott , Kalari Krishna R. , Kohli Manish 
Published: May 2019

e16559 Background: ARVs that develop early during treatment with abiraterone acetate/ prednisone (AA/P) may play a role in treatment resistance. We evaluated metastatic site and whole blood mRNA expression of full-length AR (AR-FL) and ARVs to characterize treatment-emergent ARVs (TE-ARVs) from men with mCRPC pre- and post- 12 weeks of AA/P collected in a prospective clinical trial (NCT#01953640). Methods: RNAseq performed on paired metastatic site biopsy (n = 40) and whole blood (n = 25) passed quality control. Reads were aligned to the GRCh38 reference genome with the spliced-alignment TopHat2 package. AR-FL or ARVs were detected if ≥ 2 splice reads aligned to unique splice junctions for AR-FL, AR-8, AR-45, AR-23, AR-V3, AR-V5V6, AR-V7, AR-V8, AR-V9, AR-V10, AR-V12, AR-V13, and AR-V14, and normalized to splice reads per million (SRPM). Cox proportional hazard regression analysis was performed on AR-FL and AR-Vs with ≥1 SRPM for association with time to treatment change (TTTC). Results: In metastatic site biopsies post-AA/P, the average number of splice reads was 27,376,541 (range 7,753,998 to 62,456,773). The median number of ARVs detected was 2 (range 0-8), with a total of total of 110 ARVs identified (Table). Dynamic shifts in ARV profiles were observed post-AAP, with 41 TE-ARVs identified in 17 unique patients. The most common TE-ARV was AR-8 (n = 8), followed by AR-45 (n = 5), AR-23 (n = 5), and AR-V7 (n = 4). The presence of AR-V7 post-AAP was adversely associated with TTTC (hazard ratio 2.46, p = 0.013). The identification of early TE- ARV was not associated with TTTC. In whole blood samples, post-AA/P detection of AR-FL was low (n = 3) and no ARVs were detected. Conclusions: No specific patterns were observed in ARV profiles obtained in the metastatic biopsies after 12 weeks of treatment with AA/P. Clinical trial information: 01953640. [Table: see text]
Association of radiomic features from prostate bi-parametric MRI with Decipher risk categories to predict risk for biochemical recurrence post-prostatectomy.
Authors: Li Lin , Shiradkar Rakesh , Leo Patrick , Purysko Andrei , Algohary Ahmad , Klein Eric A. , Magi-Galluzzi Cristina , Madabhushi Anant 
Published: May 2019

e16561 Background: Decipher test examines expression levels of 22 metastasis-related RNA sequences and provides a risk score (DS) for assessing metastasis risk within 5 years after radical prostatectomy (RP). Our previous work has shown that radiomics or computer extracted texture features are associated with DS on multiparametric MRI (mpMRI). DS associated radiomics (RDS) may capture signatures related to poor prognosis of prostate cancer (PCa) following RP. Thus, we sought to evaluate whether RDS were also able to predict the risk of biochemical recurrence (BCR), a surrogate clinical endpoint of metastasis, after RP. Methods: Two patient cohorts from two institutions who underwent 3T mpMRI prior to RP were used in this study - I1: 70 PCa patients who had a Decipher test following RP; I2: 120 PCa patients with at least 5-year follow-up after RP. I1 was investigated as a training set to identify RDS and develop a multivariate logistic regression model (CL). I2 was used as a testing set to validate CL for predicting BCR. A total of 150 radiomics were extracted within each lesion from T2-weighted MRI (T2WI) and apparent diffusion coefficient (ADC) maps. Area under the receiver operating characteristic curve (AUC) and Kaplan-Meier (KM) analysis were used to evaluate performance of CL. Results: Radiomics quantifying lesion spot and ripple texture patterns on ADC maps and T2WI intensity gradient changes were able to differentiate Decipher high and low/intermediate groups in I1 (AUC = 0.92). The same model CL was then applied to I2 resulting in a significant difference in BCR-free survival time between the predicted risk groups (p < 0.05, hazard ratio (HR) = 2.54) independent of Gleason Grade Group (GGG, p < 0.05, HR = 7.61) and PIRADS-v2 (p < 0.05, HR = 5.64) in multivariate testing. Especially, for patients with GGG > 2 (n = 57), CL predicted BCR risk groups shown HR = 3.1 (p < 0.05) while GGG alone was not prognostic (p > 0.05, HR = 1.93). Conclusions: Our radiomic model was able to predict DS and was found to also be prognostic of BCR-free survival. Further work will involve evaluating whether these radiomic features are predictive of PCa metastasis. [Table: see text]
MiR-1271-5p: An AR-modulatory microRNA with a distinct role in prostate cancer progression, through SND1 and MORF4L1 interaction.
Authors: Kalofonou Foteini , Leach Damien , Hamilton Mark , Mcguire Sean Eric , Fletcher Claire , Waxman Jonathan , Bevan Charlotte L 
Published: May 2019

e16562 Background: Current screening methodologies for prostate cancer (PCa) are relatively insensitive and there is a need for new treatments for castrate resistant disease. MicroRNAs (miRs) are considered to be master regulators of the genome. We have investigated the role of miRs in modulating androgen receptor function and their potential as treatments of PCa. We report that the AR-modulatory miR-1271-5p also targets SND1 and MORF4L1 and may have a role in PCa progression and screening. Methods: AGO2-PAR-CLIP analysis was performed to ascertain miR-1271-5p target genes in human PCa cell lines. MiR-1271-5p levels were manipulated in cell lines by transfection with miR mimic and or antisense inhibitor. SND1 and MORF4L1 were confirmed as targets by real-time qPCR and western blotting. The functional role of miR-1271-5p and its target genes was assessed by SRB growth assays . Immunohistochemical detection of SND1 and MORF4L1 expression was studied in a cohort of 63 PCa patients and compared with normal controls. Results: MORF4L1 mRNA levels were significantly reduced with the use of miR-1271-5p mimic in 22RV1 cells (p = 0.001), while SND1 mRNA levels were significantly decreased with the use of miR-1271-5p inhibitor in C42 cells (p = 0.0014). Targeting SND1 or MORF4L1, in combination with miR inhibition, significantly reduced C42 (p = 0.0003) and 22RV1 (p = 0.0014) cell growth. MORF4L1 expression was higher in patients with Gleason score (GS) 4+3 relative to those with GS 3+4 and in PCa tissue, as compared with normal prostatic tissue, but did not reach significance. SND1 immunostaining was significantly higher in patients with GS 4+3 or GS 3+4 PCa, compared with normal prostatic tissue (p = 0.0211, p = 0.0007 respectively). SND1 staining was significantly higher in patients with GS 4+3, compared to GS 3+4 (p = 0.0431) or GS 3+3 (p = 0.0251). Conclusions: MiR-1271-5p is an AR-modulatory microRNA, which shows great potential as a biomarker and therapeutic target in PCa. The interaction of miR-1271-5p with its target genes SND1 and MORF4L1 could provide the basis for therapeutic advance in screening and in the treatment of castrate resistant PCa.
Baseline genomic and circulating tumor cell (CTC) correlative data from very high-risk (VHR), localized, node-negative prostate cancer patients.
Authors: McBride Sean Matthew , Zelefsky Michael J. , Spratt Daniel Eidelberg , Paller Channing Judith , Kollmeier Marisa , Slovin Susan F. , Aghalar Jahan , Hearn Jason W.D. , Den Robert Benjamin , Deville Curtiland , Xiao Han , Abida Wassim , Scher Howard I. , Rathkopf Dana E. 
Published: May 2019

e16563 Background: Few data exist on CTC frequency and number, genetic landscape, and tumor mutational burden (TMB) in VHR, node negative, localized prostate cancer (PCa). Methods: We are conducting a single-arm phase 2 trial of ultra-hypofractionated radiation (RT) with 6 months of abiraterone, apalutamide and leuprolide in VHR PCa, defined as: Gleason (Gl) 9-10 or 2 high risk features (including radiographic (r) T3/T4 disease) or > 4 cores of Gl8. We report baseline correlatives in the first 38 screened patients (pts). CTCs were isolated using a non-selection based platform (EPIC Sciences). Additional analyses were conducted using MSK IMPACT, a next generation sequencing assay. Results: Median PSA was 14.8 ng/mL (IQR, 7.7-28.1); Gl7 was present in 5% (n = 2), Gl8 in 32% (n = 12), Gl9 in 61% (n = 23) and Gl10 in 2% (n = 1) of pts; on MR, 42% of pts were rT2 (n = 16), 39% had rT3a disease (n = 15) and 18% had rT3b disease (n = 7). CTC data were available on 31 pts; 74% (n = 23) had ≥1 detectable CTC (range, 0.8-14.6 cells per mL); 29% (n = 9) had CK+ clusters (range, 0.8-7.1 clusters per mL). IMPACT was available for 20 pts: KMT2D/C mutations were present in 25% (n = 4), TP53 missense mutations in 20% (n = 4), FOXA1 mutations in 20% (n = 4), PTEN truncating or missense mutations in 15% (n = 3), SPOP missense mutations in 15% (n = 3), PIK3CA activating mutations in 15% (n = 3), APC deletions in 15% (n = 3); 85% (17/20) had alterations in one of these genes. No clinically significant germline mutations were present. Median TMB was 2.63 mutations/mB (range, 0.87-60.56); the TMB-highest pt had an in-frame deletion in MSH2. Among IMPACTed pts with normalized testosterone post-protocol treatment (n = 16), there was a trend towards an association with SPOP/FOXA1 mutations and undetectable ( < 0.05 ng/mL) PSA; 5/6 pts with mutations had undetectable PSA (83.3%) vs 3/10 without (30%) (p = 0.12). The trial is managed by the PCCTC and funded by Janssen. Conclusions: The genetic profile and TMB of VHR, localized PCa resembles non-castrate, metastatic disease. The frequency of detectable CTCs is high with implications for post-treatment surveillance. SPOP/FOXA1 mutations may predict initial response to RT with total androgen blockade. Clinical trial information: NCT02772588.