bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of a novel whole blood RT-PCR assay measuring AR-V7 expression with outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate (ABI).
Authors: Todenhöfer Tilman , Azad Arun , Stewart Craig , Gao Jian , Eigl Bernhard J. , Black Peter C. , Joshua Anthony M. , Chi Kim N. 
Published: February 2017

223 Background: Expression of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) has been associated with resistance to ABI and enzalutamide (ENZ) (Antonarakis et al. N Engl J Med 2014). We have developed a RT-PCR assay that is neither time sensitive nor requires CTC enrichment for detection of prostate cancer (PCa)-associated transcripts in whole blood. Using this assay, our aim was to correlate AR-V7 expression with outcomes on ABI. Methods: 2.5 ml whole blood was collected into PAXgene RNA tubes from mCRPC patients (pts) commencing ABI. RT-PCR was performed for the following genes: AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG. For each gene, the highest CT value among 20 normal controls was set as the threshold for a positive (+) test. Clinical endpoints were PSA50 response rate (RR) (PSA decline ≥ 50% confirmed ≥ 3 weeks later), PSA30 RR, time to PSA (PCWG2 criteria) or clinical progression (change in anti-cancer therapy or decline in ECOG performance status (PS) ≥ 2 levels due to PCa), and overall survival (OS). Results: Whole blood samples were obtained from 37 pts. Median age was 70. 59% received prior docetaxel. All pts were ABI and ENZ naïve. PSA50 RR was 37% and PSA30 RR was 48%. Median progression-free survival (PFS) was 3.8 months (mos) and median OS was 21.0 mos. 11% (4/37) of pts were AR-V7+. AR-V7+ pts were more likely to have high ALP (P= 0.04; Χ2), high LDH (P= 0.07) and ECOG PS ≥ 2 (P= 0.052). Pts with an AR-V7+ test had lower PSA50 RR (0% vs. 42%, P= 0.10; Χ2) and PSA30 RR (0% vs. 52%, P= 0.051) together with shorter median PFS (0.7 mos vs. 4.0 mos, P< 0.001; log-rank) and median OS (5.5 mos vs. 22.1 mos, P< 0.001). Other factors linked with worse OS were high ALP (P= 0.02), liver metastases (P= 0.03), ≤ 36 mos on primary hormone therapy (P= 0.04), HOXB13+ (P= 0.03) and KLK2+ (P< 0.001). Conclusions: RT-PCR detection of AR-V7 transcripts in whole blood was associated with a 0% PSA RR and significantly inferior PFS and OS in pts treated with ABI. These results reinforce the potential utility of AR-V7 as a prognostic and predictive biomarker for mCRPC. Validation of the assay in larger datasets is ongoing.
Race, inflammation, and prostate cancer: A comparison of African Americans and Caucasians.
Authors: Ernst Emma M. , Ledet Elisa M. , Feibus Allison H. , Silberstein Jonathan L. , Sartor Oliver 
Published: February 2017

246 Background: African-Americans (AA) have the highest rate of prostate cancer (PCa) incidence and mortality. Studies have shown higher rates of chronic prostate inflammation in AAs compared to Caucasians (CA). In order to better understand racial disparity in PCa and chronic inflammation (CI), this study examined the effects of race and CI on clinical parameters among PCa patients. Methods: This retrospective study sample consisted of 61 AA and 52 CA PCa patients who underwent radical prostatectomies (RP) at Tulane Hospital between 2013 and 2015. Clinical data was extracted from biopsy and RP pathology reports. The study examined the relationship between CI, race, percent of positive cores, extra-prostatic extension, PSA, PSA density, urinary PCA3 and TMPRSS2, and prostate size (g). Pearson’s chi-square, Fisher’s exact, and Kruskal-Wallis tests were used to analyze categorical, non-continuous data; ANOVA tests were used to analyze continuous data. Differences between biopsy and surgical/pathologic Gleason scores and clinical/pathological stages were also assessed. Results: 94 patients (52 AAs and 42 CAs) had CI to some degree and 19 did not (9 AAs and 10 CAs). There was no difference in rate of CI between AA and CA patients (P = 0.526). Among all patients sampled, AAs had higher percentages of positive cores (P = 0.005), PCA3 copy levels (P =0.004), and PCA3 scores (P <0.001), lower TMPRSS2 scores (P =0.039), and were more likely to have “high” or “intermediate” NCCN risk strata (P =0.010). Among patients with CI, AAs were more likely than CAs to have extra-prostatic extension (P =0.026) and less likely to have undergone a prior prostate biopsy (P =0.043). Patients without CI were more likely than patients with CI to have positive tumor margins (P =0.035) and SV invasion (P =0.013). There were no significant relationships between race and CI, and changes in either total Gleason score or stage from biopsy to RP. Conclusions: This study showed that AAs and patients without CI had more advanced forms of PCa (possibly due to PSA detection biases). Findings did not reveal any significant link between race and CI. Larger studies are needed to confirm these results and better understand the relationship between race, CI, and PCa.
Patient stem cell (SC)-derived prostate cancer (PC) organoids (Org) to recreate clonal heterogeneity of PC foci and measure therapeutic response potential.
Authors: Ferrari Anna C. , DiPaola Robert S. , Bertino Joseph R. , Kim Isaac Yi , Stein Mark N. , Sabaawy Hatem E. , Bartucci Monica 
Published: February 2017

252 Background: In spite of significant outcome gains in recurrent and de novo metastatic PC, resistance inevitably develops to androgen deprivation (ADT) and chemotherapy. Resistance is supported by clonal heterogeneity due to complex genomic and epigenetic alterations within PC foci in the primary and metastases (mets) and by the enrichment of residual tumor foci with PC SCs that survive therapy. PCSCs maintain self-renewal capacity, adapt over time to different microenvironments and retain tumor propagating activity leading to castration resistant (CR) PC progression. To study these processes, we generated patient SC-derived PC Org from primary and mets specimens. Methods: We isolated cells from normal epithelium and PC foci of 4 histopathologically mapped radical prostatectomy specimens and 2 CRPC mets. We developed a 3D culture system utilizing single tumor initiating cells expressing CD29hi/CD49bhi/CD44hiand co-cultured with epithelial/mesenchymal growth factors. Org growth peaked at 2 weeks, and Org could be passaged up to 6 months without significant deviation from early passages. We evaluated Org morphology, molecular markers and biologic response (proliferation, viability and secondary Org-forming potential) in response to ADT, docetaxel (Doc), abiraterone (Abi), enzalutamide (E), BEZ325,and a BMI-1 inhibitor. Results: The Org, ~6 per region, mirror original foci in morphology (well-organized glandular structure with central E-Cad+ cells of variable nuclear-cytoplasmic ratios, AR and PSA expression, peripheral Vimentin+cells, surrounding basement membrane) and in molecular alterations (TMRSS2-Ets fusions/Erg-overexpression, PTEN loss, RB, CHD1, BMI-1, AR-Vs). ADT decreased growth and Org forming potential. ADT plus Doc, Abi or E further reduced viability and Org-forming potential; ADT plus BEZ325 only reduced viability. The BMI-1 inhibitor selectively blocked self-renewal and restored Doc growth inhibition of a Doc-resistant CRPC-derived Org. Conclusions: We established a personalized SC-derived PC Org system to study in real time the potential efficacy of therapeutic alternatives, as well as mechanisms of resistance.
Objective response of the dual CYP17-Lyase (L) inhibitor / androgen receptor (AR) antagonist, VT-464, in patients with CRPC.
Authors: Nordquist Luke T. , Shore Neal D. , De Bono Johann S. , Gupta Shilpa , Berry William R. , Gillessen Silke , Liu Glenn , Vogelzang Nicholas J. , Efstathiou Eleni , Fleming Mark T. , George Daniel J. , Araujo John C. , Zhang Jingsong , Kurman Michael R , Eisner Joel Robert , Moore William R. 
Published: February 2017

273 Background: VT-464 is an oral, CYP17-L inhibitor and non-clinically an antagonist of the AR and its variants associated with clinical resistance to enzalutamide (ENZ) and abiraterone (AA). The safety, tolerability and initial pharmacodynamic effects (tumor responses, PSA and testosterone (T) decreases) of VT-464 given without steroid supplementation either bid with food or QD at night with dinner were evaluated in the Phase (Ph) 1/2 studies INO-VT-464-CL-001 (NCT02012920) and INO-VT-464-CL-004 (NCT02361086), respectively. Patients were either treatment-naïve (TN), or had failed AA or ENZ or AA/ENZ/chemotherapy (at least 2 out of the three). Preliminary objective response results from both studies are presented herein. Methods: Target lesions were assessed at baseline and during therapy using CT or MRI. Target lesion responses were categorized as a complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) using RECIST 1.1. Patients with ≥ 1 target lesion and ≥ 1 post-baseline scan following VT-464 BID (INO-VT-464-CL-001) or QD (INO-VT-464-CL-004) were included in the analysis. Results are reported through a data cutoff of 01 Sep 2015. Results: Combined, 23 patients (8 TN, 4 AA, 7 ENZ, 4 AA/ENZ/chemotherapy) from both Ph 1/2 studies had ≥ 1 target lesion and ≥ 1 post-baseline scan. Of 15 patients included who were treated BID (Study 001), 1 had PD, 12 had SD and 2 had a PR. Of 8 patients who were treated QD (Study 004), 2 had PD, 5 had SD and 1 had a PR. No patient had a CR in either study. For the 3 patients with PRs one patient had a prior response to ENZ but failed taxane-based chemotherapy, another was de novo resistant to ENZ, while the third was TN. For the 3 PRs, one was confirmed with a repeat scan 8-weeks later and the others have repeat scans pending. Conclusions: Potent and selective CYP17-L inhibition, PSA reductions, and objective tumor responses in TN and ENZ-failure patients have been observed with oral VT-464 administered bid (de Bono et al, GU ASCO 2015) or QD (Shore et al, GU ASCO 2016). Preliminary results demonstrate that the QD regimes are as efficacious as BID regimens. All Ph 2 CRPC studies now utilize a 750 mg QD regimen. Clinical trial information: NCT02012920 and NCT02361086.
PSA levels after dexamethasone withdrawal (DW) in castration resistant prostate cancer (CRPC).
Authors: Zafeiriou Zafeiris , Bianchini Diletta , Rescigno Pasquale , Kolinsky Michael , Mateo Joaquin , Lorente David , Perez Lopez Raquel , Jayaram Anurhada , Mehra Niven , Sumanasuriya Semini , Recine Federica , Sideris Spyridon , Sharp Adam , Wong Sophia , Tunariu Nina , Attard Gerhardt , De Bono Johann S. 
Published: February 2017

278 Background: PSA decline (PSAD) in CRPC after withdrawal of antiandrogens and steroid related drugs is well established. DW responses have been anecdotal and not well characterized. In this study we investigated the frequency and magnitude of PSA changes after DW. Methods: We retrospectively identified patients treated in the Royal Marsden for CRPC with D monotherapy. Patients were considered evaluable if they had between DW and their next treatment or radiotherapy an interval of at least 7 days, no other intervention and at least one PSA reading. Patients who received radiotherapy during treatment with D or received D for palliation of symptoms were excluded. The number of patients showing PSAD was recorded together with its percentage change from baseline. Chi-square test was used to compare response rates between different groups and 95% confidence intervals (CI) for the description of frequencies. PSA progression (PSAP) was defined according to Prostate Cancer Working Group 2 criteria. Results: 200 patients were identified who had received D of which 50 were evaluable. During D treatment PSA responses were not available for 5 patients, while 16 (35%, 95%CI [20%-50%]) had a ≥ 50% PSAD which was confirmed a month later with a second reading. For the responders, the median duration of PSA response from initiation of treatment to PSAP was 293 days (range: 219 to 1063). After DW, PSAD was observed in 12 patients (24%, 95% CI [12%,36%]). PSAD ≥ 25%, ≥ 30% and ≥ 50% was observed in 6, 3 and 2 patients respectively (12%, 6% and 4%) and in only one could the ≥ 30% PSAD be confirmed with a second reading a month later. In 5 cases of ≥ 25% PSAD, next treatment was initiated despite a dropping PSA, after 8 to 43 days. In one case only was PSAP reached during DW with a response duration of 53 days from DW to PSAP. The frequency of ≥ 25% PSAW responses was not significantly different between patients with and without prior response to dexamethasone: 6% and 17% respectively, Chi-square test p = 0.29. One patient reported improvement of his urinary symptoms after DW. Conclusions: DW responses are observed in a minority of patients. This phenomenon merits further prospective characterization and needs to be considered in the design of clinical trials.
A phase I/IIa trial of prostate specific membrane antigen (PSMA) positron emission tomography (PET) imaging with 89Zr-Df-IAB2M in metastatic prostate cancer (PCa).
Authors: Morris Michael J. , Martinez Danny Francisco , Durack Jeremy C. , Slovin Susan F. , Danila Daniel Costin , O' Donoghue Joseph A. , Parada Nicole Andrea , Lyashchenko Serge K. , Carrasquillo Jorge A. , Ruan Shutian , Lewis Jason Stuart , Keppler Jennifer , Wu Anna M. , Reuter Victor E. , Weber Wolfgang , Scher Howard I. , Larson Steven M. , Pandit-Taskar Neeta 
Published: February 2017

287 Background: There is a pressing need for improved imaging biomarkers to identify disease distribution and response in both localized and advanced prostate cancer patients. PSMA-directed imaging is undergoing analytic and clinical validation for these contexts of use. IAB2M is an anti-PSMA recombinant minibody (Mb) derived from huJ591. We have previously reported on 28 pts imaged with IAB2M(Pandit-Taskar et al, SNM 2015). Here we report the lesion targeting and uptake (SUV) of the Mb and correlation with pathology of biopsied lesions on the full complement of the 38 pts examined in this trial. Methods: 38 pts with progressive metastatic PCa received escalating amounts of the Mb (16 pts at 10mg, 16 pts at 20mg, 6 pts at 50mg) in a phase I/IIa trial. All pts underwent standard imaging (SI) using CT, bone scintigraphy (BS), FDG PET, followed by imaging with 5 mCi of IAB2M. Whole body PET/CT scans were performed and evaluated for lesion targeting and SUVmax. Biopsy (bx) locations were selected by a consensus panel prioritized on the basis of: IAB2M & FDG positivity, IAB2M & FDG mismatch, and CT or BS positivity & any PET mismatch. Results: A total of 556 lesions (410 bone, 146 soft tissue) in 38 pts were detected by SI or IAB2M. In bone, IAB2M detected 344 lesions (83.9%), CT 209 (51%), BS 211 (51.5%), and FDG 109 (26.6%). For soft tissue, IAB2M detected 119 (81.5%), CT 83 (56.8%), and FDG 79 (54.1%). The SUV for bone lesions ranged from 2.1-60.4 for 10mg Mb, 1.7- 33 in 20mg Mb, and 2.3-17.5 in 50mg Mb. For soft tissue lesions, SUV range was 3.1-45.4, 2.1-20, and 1.9-13.8 respectively. 28 bxs (13 bone, 15 soft tissue) were obtained from 27 pts; 27 bxs were evaluable (1 was non-diagnostic). 20/27 (74.1%) bxs were pos for PCa; 20/24 (83.3%) IAB2M pos lesions were path pos and 3/3 (100%) IAB2M neg lesions were neg on path. All imaging and path correlated (true pos + true neg) in 23/27 (85.2%) bxs. Conclusions: PET imaging with IAB2M has demonstrated higher lesion detection when compared with SI. IAB2M’s high concordance with path suggests pos findings represent bx confirmed PCa. Further studies to examine biochemically recurrent prostate cancer are planned. Clinical trial information: NCT01923727.
Feasibility of salvage focal nodal SBRT or protracted elective nodal irradiation in 18F fluoro-choline PET based nodal failures from prostate cancer.
Authors: Lepinoy Alexis , Martin Etienne , Quivrin Magali , Gauthier Mélanie , Maingon Philippe , Brunotte Francois , Cochet Alexandre , Crehange Gilles 
Published: February 2017

290 Background: 1) To establish the feasibility of salvage nodal radiotherapy in patients with 18F Fluoro-choline (FCH) PET+ nodal recurrence only from a prostate cancer. 2) To compare salvage focal FCH PET+ stereotactic radiation therapy (sf-SRT) with salvage elective nodal irradiation with a protracted FCH PET+ nodal boost (seni-PRT) . Methods: Between 2009 and 2014, 42 patients out of 102 patients with FCH PET for a rising PSA after RP or radiotherapy had positive lymph nodes only. Twenty nine patients had sf-SRT and 13 patients had seni-PRT in a curative intent. Acute and late genito urinary (GU) and gastro intestinal (GI) toxicities were assessed with CTCAE v4. Failure was defined as a rising PSA higher than the maximal pre-therapeutic PSA value followed by 2 consecutive rises or a nodal or distant metastatic failure or the initiation of any salvage therapy. Results: Seventy-six nodes were diagnosed with FCH PET/CT with a median PSA value of 2.8 [0.3 -29.2] at time of failure. Mean number of nodes was higher in the seni-PRT group than in the sf-SRT group (2.8 vs 1.6). The median prophylactic dose of WPRT and/or LA was 48.0 Gy [36.0-54.0] and the median dose delivered to involved FCH PET+ nodes was 66.0 Gy [46.0-70.0] with a median dose per fraction of 2.0 [1.8-2.2]. In the sf-SRT group, the median dose to the involved nodes was 36 Gy [18-45] with a median dose per fraction of 7.5 Gy [6-15]. After a median follow-up of 19.1 months [2.9-74.1], no difference was observed for GI or GU toxicities between the 2 groups (p = 0.26 and p = 0.19). One grade 4 GI and GU toxicity occurred in 1 patient in the seni-PRT group. The median freedom from failure (FFF) time was 14.8 months for sf-SRT and 37.6 months for seni-PRT with 2-year FFF rates of 47.8 % and 72.7 %, respectively. Conclusions: FCH PET+ node-targeted salvage radiotherapy is feasible with very low rates of toxicity. Freedom from failure was significantly improved with protracted elective nodal irradiation, suggesting that nodal disease diagnosed on FCH PET may not be an oligometastatic disease. Dose escalated seni-PRT is currently being investigated in a French phase II trial (Oligopelvis- GETUG P07).
Optimal sequencing of enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Maughan Benjamin Louis , Suzman Daniel L. , Nadal Rosa Maria , Bassi Sunakshi , Antonarakis Emmanuel S. 
Published: February 2017

308 Background: Both enzalutamide and abiraterone are approved for the treatment of mCRPC, each demonstrating improved overall survival (OS) versus placebo. However, it is unclear what the optimal sequencing of these two therapies should be to maximize clinical outcomes and survival. Here, we compare clinical outcomes among patients with mCRPC who received enzalutamide first followed immediately by abiraterone (enza-to-abi) or the opposite sequence (abi-to-enza). Methods: A retrospective review of consecutive mCRPC patients treated at Johns Hopkins with enza-to-abi or abi-to-enza was conducted. The combined PFS (PFS = PFS1 + PFS2) was the primary endpoint, measured from the start of the first therapy (i.e. enza or abi) until disease progression on the subsequent therapy (i.e.abi or enza). The OS from the start of the first therapy until death was the secondary endpoint. Cox proportional hazards multivariable regression analysis was performed to determine whether one sequence was better than the other after adjusting for baseline characteristics. Results: 71 patients were identified: 58 received abi-to-enza and 13 received enza-to-abi. Comparisons of baseline characteristics between groups identified differences in PSA levels (P = 0.007), hemoglobin (P < 0.001), and presence of visceral disease (P = 0.035). The abi-to-enza group had a longer combined PFS than the enza-to-abi group: median 16.3 vs 12.5 mo (HR 0.53, P = 0.04). There was also a numeric improvement in OS in the abi-to-enza group compared to the enza-to-abi group: median 29.0 vs 21.0 mo (HR 0.51, P < 0.10). In multivariable analyses incorporating PSA level, hemoglobin, visceral disease and prior docetaxel use, both combined PFS (HR 2.59, P = 0.03) and OS (HR 4.59, P < 0.01) demonstrated improved outcomes with the abi-to-enza sequence. Conclusions: This hypothesis-generating study potentially suggests superior PFS and OS in men with mCRPC receiving abiraterone then enzalutamide (compared to enzalutamide then abiraterone), although this could be due to baseline imbalances or the small sample size of this study. Prospective validation of this concept is ongoing (NCT02125357).
Pre-treatment nomogram to predict potency after treatment for localized prostate cancer.
Authors: Zabell Joseph , Sanda Martin G. , Litwin Mark S. , Suarez Jose Francisco , Regan Meredith M. , Saigal Christopher , Kwan Lorna , Gao Tianming , Rabah Danny , Klein Eric A. , Kattan Michael W. , Stephenson Andrew J. 
Published: February 2017

32 Background: Radical prostatectomy (RP), external beam radiotherapy (EBRT), and brachytherapy are commonly utilized treatments for localized prostate cancer and may negatively impact sexual function to varying degrees. Patient-, disease-, and treatment-specific factors may all impact post-treatment sexual function. We aimed to evaluate predictors of post-treatment impotency, and develop a prognostic nomogram using prospective, patient-reported data from multiple validated health-related quality-of-life (HRQOL) instruments. Methods: Between 1999 and 2011, patient-reported data regarding treatment-related effects on erectile function were obtained from 2668 patients enrolled in one of four prospective longitudinal HRQOL protocols from the United States and Spain. Patients were treated with RP (n=1,294), EBRT (n=630), or brachytherapy (n=744). Although different HRQOL instruments were used in each protocol, questions pertaining to quality and frequency of erections were identical across the different instruments. Patient responses were obtained at baseline and 2 years after treatment. The endpoint of the model was impotency at 2 years post-treatment. Logistic regression analysis was used to model clinical information and outcome data. Internal validation was performed using bootstrapping. Results: 1,306 patients were potent at baseline and had 24-month follow-up. Differences in baseline patient characteristics such as patient age, ethnicity, and disease severity existed between the treatment groups. The impotency rate at 2 years was 62%, 53%, and 41% for patients treated by RP, EBRT, and brachytherapy, respectively. In multivariable analysis, age, PSA, modality of treatment, frequency of preoperative erections, diabetes, and hypertension were associated with post-treatment impotency (all p<0.05). A nomogram based on the predictive parameters had a concordance index of 0.726 and predictions were well-calibrated with observed outcome. Conclusions: A validated nomogram that predicts 2-year risk of impotency after treatment of localized prostate cancer has been developed and is anticipated to be useful for patient counseling regarding treatment options.