bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of serum androgen and drug levels with response to abiraterone.
Authors: Mostaghel Elahe A. , McKay Rana R. , Cho Eunpi , Zhang Zhenwei , Marck Brett , Matsumoto Alvin M. , Sharifi Nima , Taplin Mary-Ellen , Nelson Peter , Montgomery Robert B. 
Published: March 2019

208 Background: The association of serum ABI and androgen levels with clinical efficacy in men with CRPC is not well understood. Methods: We measured androgens, ABI and its key metabolites (D4A and 5α) in serum at 4, 8, and 12 weeks (wks) in 29 men with CRPC treated with ABI (for associations with PSA response and time to radiographic progression (TTP)); in 58 men from a study of ABI without prednisone; and in 22 men with localized PCa treated with neoadjuvant ABI for 3 months prior to definitive therapy (including prostate levels). Results: Median (Med) TTP was 36 mo (4-104). 52% had a PSA response (decline >30% at wk12), and 34% early progression (TTP < 6 mo). There was no difference in ABI (at wk4 or average of wks 4/8/12) in men with v without PSA response, or in men with early v late TTP. D4A and 5α at wk4 were higher in early v late progressors (2.9 v 1.5 ng/ml, p=0.05; 10.35 v 6.7 ng/ml, p=0.08). TTP was longer in the lowest v highest quartile of drug levels (ABI: 4wk 48 v 30 wks; 8wk 60 v 16 wks; D4A: 4wk 40 v 16 wks; 8wk 60 v 28 wks; 5a: 8wk 41 v 16 wks, p<0.05 all). The lowest quartile of pre-ABI androgens had shorter TTP (DHEAS 24 v 52 wks; T 30 v 52 wks, p<0.05 both). In both CRPC studies, men with pre-ABI DHEAS > Med had 2-5x higher levels of all steroids (DHEAS 110 v 22 ug/dl, DHEA 184 v 49 ng/dl, AED 46 v 26 ng/dl, and T 9 v 4.9 ng/dl, p<0.05 all). While markedly suppressed by ABI in both groups, levels remained detectable and higher in the ‘high’ group (DHEAS 5.4 v 1.6 ug/dl; DHEA 1.3 v 0.6 ng/dl; p<0.05 both) regardless of ABI levels (37.4 ng/ml, 2.75-89; 36.8 ng/ml, 8.7-121, p=ns). Androgens in serum and prostate after neoadjuvant ABI were higher in men with pre-ABI eugonadal serum DHEAS levels > v < Med, regardless of serum or tissue ABI levels on treatment. Conclusions: In men with pre-ABI serum DHEAS < Med, androgens were suppressed even at low serum ABI levels, whereas in men with pre-ABI DHEAS > Med, levels were not completely suppressed even at high ABI levels, explaining the minimal impact of dose escalated ABI and observed noninferiority of low dose ABI previously reported in men with CRPC. The shorter TTP in the highest quartiles of ABI, D4A and 5α may reflect increased conversion to the AR agonist metabolite 5α. Men with pre-ABI DHEAS > Med may warrant stratification to more potent/combination therapy. Clinical trial information: NCT01503229.
Positron emission tomography with 18F-fluciclovine to predict recurrence in post-treatment recurrent prostate cancer and its role in altering treatment plans.
Authors: Chong Julio , Muhleman Mitchel , Say Rollin , Kostakoglu Lale , Ahmed Jalal , Tewari Ashutosh , Stock Richard , Oh William K. 
Published: March 2019

214 Background: 18F-fluciclovine PET/CT can improve the detection of post-treatment recurrent prostate cancer (PCa). We quantified factors which increase the likelihood of a positive scan, assessed the ability of 18F-fluciclovine to alter treatment plans and identified an optimal PSA cut-off to identify radiographic recurrence. Methods: Patients who received 18F-fluciclovine PET/CT for recurrent PCa (n=78) were analyzed. Treatment changes based on positive scans were tracked. A receiver-operator characteristic (ROC) curve was used to estimate the optimal PSA cut-off for a positive scan. Results: 18F-fluciclovine predicted radiographic recurrence in 67.9% of patients. PSA at scan (p = 0.010), salvage therapy (p = 0.03), any use of ADT (p = 0.016) and number of studies (p = 0.042) were all associated with a positive scan. Alteration of treatment plans occurred in 34/58 (58.6%) patients. Recurrence sites are: 79/120 (65.8%) lymph nodes, 27/120 (22.5%) bone, 11/120 (9.2%) prostatic bed, and 3/120 (2.5%) elsewhere. The most common treatment alteration was directed stereotactic body radiation therapy (SBRT) (16/34, 47%), followed by salvage surgical therapy (4/34, 11.7%) and ADT (3/34, 8.7%).The optimal PSA cut-off was 0.5 with sensitivity of 81.13% and specificity of 78.38% (ROC=0.7880). Conclusions: 18F-fluciclovine PET/CT detected radiographic disease in 67.9% of patients, resulting in alterations in treatment plans in 58.6% of cases. SBRT was the most common alteration in treatment plan. Previous use of salvage therapy or ADT are risk factors and when combined with a PSA >0.5, may be associated with radiographic recurrence. [Table: see text]
Morphology-predicted, large-scale transition (LST) number in circulating tumor cells (CTC) as a biomarker of chromosomal instability (CIN) to assess early resistance to standard of care (SOC) drugs in mCRPC.
Authors: Scher Howard I. , Schonhoft Joseph , Hullings Melanie , Carbone Emily , Barnett Ethan , Sutton Ramsay , Jendrisak Adam , Landers Mark Andrew , Wang Yipeng , Dittamore Ryan 
Published: March 2019

225 Background: CIN is a mechanism by which tumor cells evolve, adapt, and evade therapeutic insults. We explored the relationship between the presence of LST as a biomarker of CIN through distinct CTC phenotypes, and sensitivity of tumors with the biomarker to standard of care (SOC) drugs. Methods: CTCs from 634 mCRPC blood samples were morphologically characterized by the Epic Sciences platform [Cytokeratin, CD45, DAPI, Androgen Receptor (AR) staining]. Training: 20 digital single cell image features were extracted from 608 CTC images from 26 patients (Pts) and single cell sequenced to determine the number of genomic LSTs. An image feature based algorithm to predict whether the number of LSTs was above the normal range defined by analysis of leukocytes was trained using this cohort (pLST) and parameters were locked. Analytical Validation (AV): the pLST algorithm was applied to a separate cohort of 570 CTCs from 54 Pts that were also sequenced to test single cell analytical performance. Clinical Validation: The pLST algorithm was then applied to CTC detected in 554 Pt samples obtained at prior to (BL, n= 324) and matched on-therapy (OnTx, n= 230) ~1 mo after starting SOC [including AR directed Tx and taxane]. A pre-defined patient scoring of > 3 pLST+ CTC/mL was related to PSA kinetics, time on drug, and overall survival (OS). Results: pLST identifies CTCs with a high number of genomic LSTs. Pts with pLST+ at BL or OnTx had poor survival (see table): 12/13 pts receiving ARSi’s and 17/18 pts receiving taxanes who were pLST+ On-Tx required a change of Tx in a median of 1.3 mo (0.9 to 2.1) or died within 6 mo. Conclusions: CTC morphology can be used to predict CIN as defined by high LSTs. CTC pLST is a strong marker of resistance to SOC Tx in mCRPC pts and treatment failure requiring a change in Tx earlier than standard criteria.[Table: see text]
Tumor testing in men with prostate cancer to predict for germline DNA-damage repair mutations.
Authors: Carlo Maria Isabel , Kemel Yelena , Breen Kelsey , Cadoo Karen Anne , Walsh Michael Francis , Abida Wassim , Autio Karen A. , Danila Daniel Costin , Kampel Lewis J. , Morris Michael J. , Rathkopf Dana E. , Slovin Susan F. , Solit David B. , Offit Kenneth , Stadler Zsofia Kinga , Scher Howard I. , Robson Mark E. 
Published: March 2019

229 Background: Current guidelines recommend genetic testing for patients (pts) who have BRCA1/2 mutations on tumor-only testing, where germline is not subtracted. The clinical utility of this approach, and possible inclusion of other DDR genes associated with cancer susceptibility, has not been examined in men with prostate cancer. Methods: Pts with mostly advanced prostate cancer were prospectively enrolled to a matched tumor-germline DNA sequencing protocol and consented for disclosure of germline results. Germline analysis was done with an institutional, CLIA-certified next generation sequencing (NGS) platform (MSK-IMPACT) and analyzed for likely pathogenic or pathogenic germline mutations in at least 76 cancer susceptibility genes. Clinical data was retrieved from the medical record. We report on the frequencies in the germline and in the tumor of a subset of DDR genes. Results: 1243 men had analysis of both germline and tumor. Median age 64 (range 35-90). 12% had a second malignancy and 40% reported a relative with prostate cancer. 19% were of Ashkenazi Jewish (AJ) descent. 330 (27%) had any mutation in BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, MSH2, MSH6, MLH1, PMS2. 127 (10%) had a germline mutation, of which 36% were AJ founder mutations. For each gene, the percentage of mutations found in germline and tumor is shown in the table. Conclusions: Of prostate cancer pts found to have any DDR mutation on tumor-germline testing, 29% had a germline mutation. Proportion of germline mutations was highest for PALB2, CHEK2 and BRCA2. These findings not only support germline testing when BRCA1/2 mutations are found tumor-only sequencing, but also support germline testing when other DDR mutations are seen. Clinical trial information: NCT01775072. [Table: see text]
SPINK1 expression and outcomes postprostatectomy in race-specific cohorts.
Authors: Faisal Farzana A , Kaur Harsimar B , Tosoian Jeffrey J. , Tomlins Scott A. , Schaeffer Edward M. , Lotan Tamara L. 
Published: March 2019

23 Background: The SPINK1 molecular subtype has been shown to be more common in African American (AA) men with prostatic adenocarcinoma (PCa) than European Americans (EA). Other studies have suggested that SPINK1 expression is associated with more aggressive disease. However, there have been limited studies examining clinical outcomes by SPINK1 status in racially diverse cohorts. Methods: The objective was to determine the associations between SPINK1 subtype, race, and clinical and pathologic outcomes after radical prostatectomy (RP). A total of 186 AA and 206 EA men who underwent RP at Johns Hopkins were matched according to pathologic Gleason grade. We examined SPINK1 status by immunohistochemistry on tissue microarrays using a genetically validated assay. ERG and PTEN were assessed previously using validated immunohistochemistry assays. SPINK1 prevalence was compared between races. Logistic regression and Cox proportional hazard analyses assessed the association of SPINK1 status with pathologic and oncologic outcomes in race-specific multivariate models. Results: SPINK1-positive subtype was present in 25% (45/186) of AA and 15% (30/206) of EA men (p = 0.013). SPINK1 expression was generally mutually exclusive with ERG expression and PTEN loss in both racial cohorts. There were no differences in pathologic grade group (GG), pathologic stage, biochemical recurrence (BCR)-free survival, or metastasis-free survival between SPINK1-positive and SPINK1-negative tumors in the overall cohort or by race. In multivariable analyses, SPINK1 expression was not associated with BCR (AA: HR 0.99, 95% CI 0.56-1.75, p = 0.976; EA: HR 0.88, 95% CI 0.43-1.77, p = 0.720) or metastasis (AA: HR 0.79, 95% CI 0.25-2.49, p = 0.691; EA: HR 1.55, 95% CI 0.58-4.11, p = 0.381) in either the AA or the EA cohort. Conclusions: SPINK1-positive subtype is more prevalent in AA than EA men with PCa. While previous studies showed that SPINK1 may be associated with more aggressive PCa, we found that SPINK1 protein expression was not associated with worse pathologic or oncologic outcomes including BCR and metastasis after RP in either AA men or EA men.
Clinical validation of circulating cytokines as markers of prognosis and response to docetaxel in men with metastatic castration-resistant prostate cancer.
Authors: Mahon Kate Lynette , Lin Hui-Ming , Lee-Ng Michelle , Stockler Martin R. , Gurney Howard , Mallesara Girish , Briscoe Karen P. , Marx Gavin M. , Higano Celestia S. , De Bono Johann S. , Chi Kim N. , Brown David , Breit Samuel N. , Horvath Lisa 
Published: March 2019

230 Background: Elevated circulating macrophage inhibitory cytokine -1 /growth differentiation factor 15 (MIC-1/GDF15), interleukins 4 (IL4) and 6 (IL6) levels were associated with poor prognosis and resistance to docetaxel chemotherapy in an exploratory cohort of men with metastatic castration resistant prostate cancer (mCRPC). To establish level 2 evidence of biomarker utility, these cytokines were tested in internal and external validation cohorts. Methods: Internal validation cohort: Plasma samples taken at baseline (BL) and preC2 docetaxel (n = 120). MIC-1/GDF15, IL-4 and IL-6 measured by ELISA assay. External validation cohort: Serum samples taken at BL and/or preC3 docetaxel in 430 men with mCRPC on phase III SYNERGY study (docetaxel +/- custirsen as 1st line chemotherapy in mCRPC with no OS benefit in the experimental arm). MIC-1/GDF15 measured by ELISA assay. Associations between cytokine levels, PSA response, time to PSA progression and OS were assessed by non-parametric tests and Cox Regression survival analyses. Results: Internal validation: At a median follow-up of 14 months, higher MIC-1/GDF15 levels at BL and preC2 were associated with shorter OS (BL; HR 1.2 95%CI 1.0-1.4; p = 0.03 and preC2; HR 1.3 95%CI 1.1-1.5; p = 0.004). Increase in MIC-1/GDF15 after chemotherapy correlated with lack of PSA response (p < 0.001). IL4 and IL6 did not correlate with survival or demonstrate additional value. External validation: At a median follow-up of 23 months, higher MIC-1/GDF15 levels at BL and preC3 predicted shorter OS (BL; HR 1.4 95%CI 1.2-1.6; p < 0.0001 and preC3; HR 1.6 95%CI 1.3-1.8; p < 0.0001). Higher pre C3 MIC-1/GDF15 levels were also associated with shorter time to PSA progression (HR 1.2 95% CI 1.0-1.4; p = 0.02). Rise in MIC-1/GDF15 from BL to preC3 correlated with lack of 50% PSA fall at 12 weeks (p < 0.001). Conclusions: Adherence to a biomarker development pipeline provides level 2 evidence of the prognostic value of circulating MIC-1/GDF15 in men with mCRPC receiving docetaxel. A prospective biomarker led study is now necessary to establish clinical utility.
Predictors of positive lesions in 18F-fluciclovine PET/CT.
Authors: Hougen Helen Y , Mallak Nadine , Chen Yiyi , Degnin Catherine , Kopp Ryan P , Liu Jen-Jane , Isharwal Sudhir , Hung Arthur 
Published: March 2019

231 Background: The 18F-Fluciclovine (FACBC) PET/CT scan has higher sensitivity than traditional imaging modalities for detection of prostate cancer (PCa) recurrence. We aim to identify the PSA characteristics as predictors of positive FACBC scan. Methods: Seventy-eight patients who underwent FACBC scan in 2018 at our institution were identified. Patient demographics, prior PSA, clinical information including prior treatment was recorded. Scans were deemed positive if definitive lesions were noted at the prostate bed, pelvic lymph nodes, or skeletal level. Detection rate was the ratio of positive over total scans and was calculated for PSA ranges. PSA velocity (PSAV) was calculated for patients who did not initiate androgen-deprivation therapy 12 months prior to the scan. The baseline PSA and PSAV were modeled as predictors of having a positive scan using logistic regression. Results: The median baseline PSA is 2.7 (range 0.2 - 226.5). The rates of positivity increased with increasing baseline PSA (Table 1). Positive scans had higher median baseline PSA (3.0, range 0.2-226.5 vs. 1.2, range 0.2-26.0; p = 0.0015) and higher PSAV (median 2.3, range -0.6-1478.7 vs. 1.0, range -0.5-31.9; p = 0.025). Baseline PSA (AUC = 0.712) was better predictor than PSAV (AUC = 0.656) of a positive scan. Combining the two variables does not improve their predictive ability (AUC = 0.719). There is a 50% detection rate in post-radical prostatectomy (RP) patients (Table 2). Conclusions: FACBC PET’s detection rate increases with increasing baseline PSA. While higher PSAV is associated with higher rate of positive scan, it did not increase the predictive ability of baseline PSA for a positive scan in prostate cancer recurrence patients. [Table: see text][Table: see text]
Clinical events associated with cumulative corticosteroid use in patients with castration-resistant prostate cancer: An administrative claims analysis.
Authors: Lowentritt Benjamin H , Penson David F. , Wilson Samuel C. , Song Yan , Yang Hongbo , Ramaswamy Krishnan , Schultz Neil M. 
Published: March 2019

236 Background: Corticosteroids (CSs) are used in the treatment of castration-resistant prostate cancer (CRPC) to manage adverse events and tumor-related symptoms. This study evaluated the impact of cumulative CS use on the risk of developing specific clinical events in men with CRPC. Methods: Adult chemotherapy-naïve patients who initiated a CRPC treatment following surgical or medical castration were identified from the MarketScan database (2007–2016). Patients were grouped into 4 cohorts based on their cumulative CS dose since 1 year before initiating their CRPC treatment: no use (0 g); low use ( < 0.5 g); medium use (0.5–2.0 g); and high use ( > 2.0 g). Time-dependent Cox proportional hazards models adjusting for baseline characteristics were used to evaluate the association between CS use and the risk of events (fracture, infection, endocrine disorders, acute cardiovascular [CV] events, peptic ulcer, and mental health conditions), with no CS use as the reference group. Results: This study included 9425 patients: 6765 no CS use; 1660 low use; 655 medium use; and 345 high use. On average, the no-CS-use cohort was older and had a lower comorbidity burden than the other 3 cohorts. During the study period, cumulative CS exposure (across all categories) was associated with a significantly higher risk of developing an infection (comparing high-use vs. no-use cohort, adjusted hazard ratio [HR] = 2.55; p for trend < 0.001), fracture (HR = 1.59; p for trend < 0.001), and acute CV events (HR = 1.62; p for trend < 0.001). Also, patients in the high-CS-use cohort were more likely to develop endocrine disorder (HR = 1.61; p for trend < 0.001), peptic ulcer (HR = 1.91; p for trend < 0.001), or mental health condition (HR = 1.28; p for trend = 0.014) in comparison with patients in the no-use cohort. Conclusions: Cumulative CS exposure was associated with a greater risk of clinical events such as infection, fracture, and acute CV events among men with CRPC. The risk was more pronounced with higher cumulative CS doses of > 2.0 g. The study provides important data on the impacts of cumulative CS use on the risk of clinical events among CRPC patients who tend to be older and more prone to these events.
Cell plasticity associated to taxane-resistance in preclinical cell models and in circulating tumor cells from metastatic castration-resistant prostate cancer patients.
Authors: Montalbo Ruth , Jiménez Natalia , Mila Maria , Reig Òscar , Victoria Iván , Prat Aleix , Marin Mercedes , Mellado Begona 
Published: March 2019

238 Background: Treatment resistance is associated with tumor cells molecular plasticity. In metastatic castration resistant prostate cancer (mCRPC), alterations in androgen receptor (AR) have been described as predictors of shorter response to hormonal treatments. Previously, we associated epithelial to mesenchymal transition (EMT) phenotype with chemotherapy resistance. However, other molecular changes responsible of such resistance should be elucidated. Here, we investigate the effect of taxanes on cell plasticity through in vitro models and in circulating tumor cells (CTCs) from mCRPC patients. Methods: Molecular differences due to taxane-exposure were evaluated in cell models of mCRPC (PC-3 and DU-145 resistant to taxanes). Global gene expression (GE) analysis was performed using Affimetrix GeneChip Human Gene 2.0 arrays. GE related with AR axis, EMT and neuroendocrine (NE) phenotypes was validated by quantitative (qRT-PCR). Clinical validation was performed in CTCs from 24 mCRPC patients collected prior and post taxane-treatment. CTCs enrichment was achieved by Isoflux technology through a personalized combination of EpCAM, CDH2 and PSCA antibodies. Results: GE analysis revealed a different deregulation pattern related to the EMT, NE and AR-related phenotypes in resistant CRPC-cells compared to parental cells. Docetaxel resistance was more associated to an EMT phenotype while cabazitaxel resistance to NE patterns. GE patterns in CTCs at post taxane-treatment showed a common upregulation of AR-related genes compared to pre-treatment collected samples. Moreover, most patients experienced upregulation of EMT and NE markers after treatment, which was more pronounced after docetaxel than cabazitaxel therapy. Conclusions: GE changes related to taxane-resistance observed in pre-clinical models also occur in CTCs. This supports the great value of CTCs to evaluate cell plasticity due to taxanes treatment. Further investigation is ongoing to better characterize cellular plasticity and to improve personalized therapeutic strategies that would enhance better clinical outcomes in mCRPC.
Risk of subsequent dementia from androgen deprivation therapy (ADT) versus orchiectomy among men with prostate cancer.
Authors: Parikh Ravi Bharat , Chhatre Sumedha , Malkowicz S. Bruce , Li Bingnan , Jayadevappa Ravishankar 
Published: March 2019

239 Background: Retrospective studies have suggested an association between ADT and cognitive dysfunction among men with prostate cancer. This association may be mediated directly by ADT or indirectly by long-term decreased androgen levels. We hypothesized that there would be no difference in rates of subsequent dementia among elderly men who received ADT vs orchiectomy for treatment of prostate cancer. Methods: We conducted a retrospective cohort study using the SEER-Medicare database of men ≥66 years old diagnosed with localized or advanced prostate cancer between 1996 and 2003 who were treated with ADT (n = 60146) or orchiectomy (n = 1760), either alone or as part of combined therapy. We used propensity score-adjusted regression to study the association between ADT or orchiectomy and subsequent risk of Alzheimer’s disease or dementia. We excluded patients diagnosed with dementia before or within 2 years of therapy. Results: Men receiving ADT were younger and less likely to be married than men receiving orchiectomy (Table). There was no difference in ethnicity, comorbidity index, or socioeconomic status (SES) between the two groups. ADT did not carry a higher risk of subsequent Alzheimer’s (HR 1.10, 95% CI 0.95-1.28) or dementia (HR 0.93, 95% CI 0.83-1.05) compared to orchiectomy. Conclusions: Among a large cohort of elderly men with prostate cancer, ADT and orchiectomy carried similar long-term risks of subsequent dementia. [Table: see text]