bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in men with prostate cancer previously treated with taxane.
Authors: Petrylak Daniel Peter , Kantoff Philip W. , Mega Anthony E. , Dreicer Robert , Frank Richard C. , Shore Neal D. , Morris Stephen , Olson William C. , Israel Robert Joseph 
Published: February 2017

107 Background: The abundant expression of prostate specific membrane antigen (PSMA) type II transmembrane glycoprotein on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage and release of free MMAE occur, causing cell cycle arrest and apoptosis. We report results from an ongoing phase 1 dose escalation study of PSMA ADC in patients (pts) with taxane-refractory metastatic castration-resistant prostate cancer (metCRPC). Methods: Eligibility requirements include metCRPC after taxane-containing regimen and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Adverse events, PK, PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS. Dosing cohorts have ranged from 0.4 mg/kg to 2.2 mg/kg. Results: 26 pts have enrolled in six dosing cohorts (0.4, 0.7, 1.1, 1.6, 1.8, 2.0 mg/kg). Treatment has to date been generally well tolerated with the most commonly seen adverse event being fatigue and the most common laboratory abnormalities being reversible changes in liver and hematological parameters. Antitumor activity manifested as reductions in PSA, circulating tumor cells and/or bone pain has been observed in the higher dose cohorts and appears to be dose-related. Exposure to PSMA ADC increased with dose and was ∼1,000-fold greater than MMAE exposure. Similar PK metrics were observed after the first and third doses. Dosing at the 2.2 mg/kg cohort is continuing and an MTD has not yet been reached. Conclusions: In pts with metCRPC previously treated with taxane PSMA ADC has exhibited dose-related antitumor activity. The MTD has not yet been reached and enrollment is ongoing at higher dose levels.
Tumor regression and growth rates determined in two intramural NCI prostate cancer trials: The growth rate constant as an indicator of therapeutic efficacy.
Authors: Adesunloye Bamidele , Stein Wilfred Donald , Wilkerson Julia , Huang Xuan , Karzai Fatima H , Madan Ravi A. , Apolo Andrea Borghese , Figg William Douglas , Dahut William L. , Fojo Tito 
Published: February 2017

133 Background: Like ATTP [bevacizumab + thalidomide + docetaxel + prednisone], ARTP [bevacizumab + lenalidomide + docetaxel + prednisone] is active in CRPC and in both the data suggest acquired resistance does not develop, supporting a strategy that continues therapy if tolerable. Discerning amongst new therapies in CRPC would be helped by novel assessment strategies that yield answers from smaller trials and allow comparisons across trials. We have validated a novel assessment method that quantifies tumor regression (d) and growth (g) rate constants using data obtained while pts are treated in a trial. We utilized this method to evaluate a phase II trial of ARTP in CRPC contrasting this with a previous study using thalidomide instead of lenalidomide (ATTP). Methods: Using PSA values and a two-phase mathematical equation we determined d and g. A three-phase equation was used to determine resistant fractions. Results: The median log g value with ARTP (-2.84) was statistically similar (p=0.204) to that observed with ATTP (-3.16). Both therapies had similar effects on log d (ARTP=-2.18; ATTP=-2.64; p=0.404). In a subset of pts with robust data both regimen are highly effective with only 3.01% and 5.46% of tumor resistant to ATTP and ARTP, respectively. In individual pt, statistically valid g and d values could be estimated after the fourth PSA value had been obtained, long before PSA increased - providing an early indicator of treatment failure. In most pts receiving prolonged treatment – as long as 700 d – the growth rate constant did not change, despite rising PSA values, indicating acquired resistance did not develop, and that if tolerable, therapy can be continued for longer periods of time. Conclusions: The substitution of daily thalidomide with lenalidomide 14/21 days in ARTP resulted in a combination statistically as effective as ATTP. As with ATTP majority of pts experienced marked reductions in the tumor’s g, and surprisingly in most, there was no evidence of acquired resistance, g remaining unchanged over prolonged time periods. Given the tolerability of this combination, pts with marked reductions in g may benefit from prolonged ARTP therapy.
Is systematic 10 core prostate needle biopsy enough for treatment determination of localized prostate cancer?
Authors: Kishimoto Ryo , Tanimoto Ryuta , Bekku Kensuke , Kobayashi Yasuyuki , Ebara Shin , Saika Takashi , Nasu Yasutomo , Kumon Hiromi 
Published: February 2017

163 Background: To evaluate whether the systematic 10 cores prostate needle biopsy is enough for determination of NCCN risk classification (NRC), we analyzed migration of Gleason score (GS), cancer location, and NRC between pre and postoperative periods in a cohort of patients who underwent radical prostatectomy. Methods: A total of 197 patients were included in this study. These patients were divided into three groups along the number of biopsy cores: less than 10 (L), 10, and more than 10 (M). We compared between three groups about Gleason score, cancer location and NCCN risk classification change (CC) between prostate biopsy and radical prostatectomy specimen. Statistical analysis were performed with chi-square test, and multiple logistic regression with p<0.05, and Bonferroni correction with p<0.017 considered significant difference. Results: The rate of CC in L, 10, M was 55.1%, 43.0%, 26.5%, respectively. On chi-square test rates of CC were significantly different between three groups (P=0.035), but rates of Gleason score and cancer location were not. On univariate analysis, PSA (Odds rate (OR) 0.872 p<0.001), preoperative NRC (low vs. intermediate, and poor, OR 0.157 and 0.241, p<0.001), prostate volume (normal vs. mild or moderate, OR 1.989 p=0.025), the number of biopsy cores (L vs. M, OR 0.293 p=0.011), GS (6 vs. 8, OR 2.374 p=0.021) were correlated with CC. On multivariate analysis, the most important independent predictive factors for CC were preoperative NRC (low vs. intermediate, p<0.001, OR 0.198, 95% CI 0.09-0.45) and PSA (p=0.007, OR 0.903, 95%CI 0.83-0.98), but the number of biopsy cores was not associated CC significantly. Conclusions: Although multivariate analysis showed no significant difference, the more biopsy cores reduced the risk of CC. Systematic 10 core biopsy might be insufficient for accurate diagnosis and treatment decision of prostate cancer.
Tc-99m labeled small-molecule inhibitors of prostate-specific membrane antigen (PSMA): New molecular imaging probes to detect metastatic prostate adenocarcinoma (PC).
Authors: Osborne Joseph , Akhtar Naveed Hassan , Vallabhajosula Shankar , Nikolopoulou Anastasia , Maresca Kevin P. , Hillier Shawn M. , Joyal John L. , Crummet Robert , Armor Thomas , Tagawa Scott T. , Nanus David M. , Goldsmith Stanley J. , Babich John W. 
Published: February 2017

173 Background: Sensitive and specific imaging remains a clinically-relevant problem for men with PC. PSMA is a well established target for imaging of PC with therapeutic implications. We have recently developed novel 99mTc-labeled small molecule inhibitors of the enzymatic domain of PSMA based on glutamate-urea-glutamate and glutamate-urea-lysine pharmacophores, and contain a bis-imidazole chelator to complex Tc-99m. Preclinical studies with PSMA positive LNCaP cells and xenografts demonstrate that 99mTc-MIP-1404 and 99mTc-MIP-1405 bind to PSMA with high affinity and localize in tumors rapidly. This study reports the first human data in men with metastatic PC and in healthy male subjects. Methods: Under an exploratory IND, using a cross-over design, the pharmacokinetics, biodistribution, and tumor uptake of 99mTc-MIP-1404 and 99mTc-MIP-1405 were compared in 6 healthy men and 6 men with radiographic evidence of metastatic PC. Whole body images were obtained at 10 min, 1, 2, 4 and 24 hr. Single photon emission computed tomography (SPECT) was performed between 3–4 hours post injection. Results: Both agents cleared the blood rapidly with MIP-1404 demonstrating significantly lower urinary activity (7%) compared to MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal and parotid glands. Uptake in liver and kidney was acceptable for imaging at 1-2 hr post injection (PI). In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 hr PI. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone and CT scans, In majority of patients, more lesions including sub-cm lymph nodes were seen with 99mTc-MIP-1404 and 99mTc-MIP-1405. The high contrast images exhibited signal:noise ratios from 3:1 to 28:1 at 4 and 24 hr. Conclusions: 99mTc-MIP-1404 and 99mTc-MIP-1405 identified a greater number of lesions than bone scans and rapidly detected soft tissue PC lesions including sub-cm lymph nodes. Since 99mTc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high risk clinically-localized PC.
Effect of adding short-term androgen deprivation therapy to dose-escalated radiation therapy on failure-free survival for select men with intermediate-risk prostate cancer.
Authors: Bian Shelly , Kuban Deborah A. , Levy Lawrence B. , Oh Jeong Hoon , Castle Katherine , Pugh Thomas , Choi Seungtaek , McGuire Sean E. , Frank Steven J. , Nguyen Paul Linh , Lee Andrew , Hoffman Karen Elizabeth 
Published: February 2017

176 Background: Independently, dose-escalated external beam radiation therapy (DE-EBRT) and short-term androgen deprivation therapy (ADT) improve outcomes for men with intermediate-risk prostate cancer; however, the incremental benefit of adding short-term ADT to DE-EBRT is uncertain. The aim of this study was to determine the effect of adding ADT to DE-EBRT and to identify men most likely to benefit from ADT. Methods: We reviewed the medical records of 636 men treated for intermediate-risk prostate cancer with DE-EBRT (>75 Gy) from 1995 to 2009. The adult comorbidity evaluation-27 index categorized severity of comorbidity. Recursive partitioning analysis defined unfavorable disease. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. Results: Median age was 70 years (interquartile range [IQR] 65–74). Overall, 45% received DE-EBRT alone and 55% DE-EBRT with ADT (median 6 months, IQR 6-8). Median follow up was 4.3 years. On Cox-proportional hazard regression analysis that adjusted for differences in comorbidities and tumor characteristics, administration of ADT improved FFS (adjusted hazard ratio 0.36, 95% confidence interval 0.18–0.72; p=0.004). Recursive partitioning analysis of men without ADT classified Gleason 4+3=7 or ≥ 50% positive cores as unfavorable disease (5-year FFS 96.3% favorable vs. 81.6% unfavorable; p<0.001). The addition of ADT to DE-EBRT improved 5-year FFS for men with unfavorable disease (n=334; 81.6% vs. 92.9%; p=0.009) but did not improve FFS for men with favorable disease (n=302; 96.3% vs. 97.4%; p=0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (p=0.006) but did not improve FFS for men with unfavorable disease and moderate to severe comorbidity (p=0.380). Conclusions: The addition of ADT to DE-EBRT improves FFS for men with unfavorable intermediate-risk prostate cancer (Gleason 4+3=7 or ≥ 50% positive cores) especially those with no or minimal comorbidity. Men with favorable intermediate-risk disease or with moderate to severe comorbidity may not benefit from the addition of ADT to DE-EBRT.
Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer.
Authors: Sheikh Nadeem A. , Wesley Johnna D. , Perdue Nikole , Stewart Frances P. , Fong Lawrence 
Published: February 2017

178 Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in subjects with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Methods: Subjects with localized prostate cancer were enrolled in an open-label, Phase 2 study (P07-1; NCT00715104 ) in which they received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to radical prostatectomy. All samples were evaluated for cellular composition and antigen presenting cell (APC) activation pre- and post-culture with PA2024, a fusion protein comprising prostatic acid phosphatase and granulocyte macrophage-colony stimulating factor. Additionally, cytokines within the culture supernatant were assessed, and T and B cell activation were evaluated pre- and post-culture using flow cytometry. Results: Of the 42 enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T. Consistent with previous trials in mCRPC, CD54 upregulation (APC activation) was greater at the second and third infusions relative to the first. While the percent of CD4+ and CD8+ T cells was unchanged with treatment, the expression of early T cell activation markers (CD134, CD137, CD278 and CD279) was increased in pre-culture cells obtained after the first infusion, and further increased post-culture. Similarly, while the percent of B cells was unchanged, there was a progressive increase in memory B cells (CD20+CD27+IgD−CD86+; pre- and post-culture) and activated mature B cells (CD20+CD27+IgD+CD86+; post-culture) following the first infusion. Activated T cell-associated cytokines were significantly elevated (TNF-α, P < 0.001; IFN-γ, P < 0.001; and IL-2, P < 0.001) in the second and third products. Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune system activation that included APCs, memory and activated mature B cells, and both CD4+ and CD8+ T cells. The patterns observed at the second and third infusions, relative to the first, are consistent with an immunological prime-boost profile.
Effect of serum testosterone on treatment outcomes in patients with intermediate- to high-grade prostate cancer.
Authors: Jackson Matthew W. , Ramahi Emma , Swanson Gregory P. , Basler Joseph W. 
Published: February 2017

180 Background: Low serum testosterone (TS) has been suggested to be a potential marker for more aggressive prostate cancer. However, there are conflicting data regarding whether or not patients with low TS have a higher rate of biochemical recurrence following radical prostatectomy (RP). We evaluated the relationship between postoperative TS and treatment outcomes in patients with Gleason 7–10 adenocarcinoma of the prostate. Methods: Our retrospective study cohort included 462 men diagnosed with Gleason 7–10 prostate cancer who underwent RP between 1998 and 2008 at a single institution. Patients were stratified into five groups on the basis of their postoperative TS percentile within the study cohort (<10th percentile, 10–25, 25–75, 75–90, or >90th percentile). Primary endpoints for comparison were biochemical failure free survival (BFFS) and overall survival (OS). PSA >0.2 ng/dl was used to define biochemical failure. Results: In the study cohort, mean TS was 345.2 ng/dl ± 125.2 and range 107–872 ng/dl. 44 of the 462 men had TS ≤203 ng/dl. This group had a 5-year BFFS of 43% which was significantly worse than all other TS strata (p=0.0017). Range of 5-year BFFS in all other percentile groups was 61.4 – 68.6%. There was no significant difference noted between patients with TS ≥508 ng/dl (>90th percentile) and all other TS strata (p=0.694). Furthermore, no difference in OS was noted among any of the groups (p=0.842). Groups did not differ significantly with respect to age, BMI, presence of diabetes, or known cardiovascular disease. Conclusions: Patients with exceedingly low TS are at significantly increased risk for biochemical failure following RP. Further prospective study is warranted to elucidate interventions that might improve biochemical outcomes in these patients. [Table: see text]
Non-enrichment-based method for analysis of androgen receptor expression in circulating tumor cells (CTCs) in patients with metastatic castrate-resistant prostate cancer.
Authors: Gross Mitchell E. , Lazar Daniel , Cho Edward H , Luttgen Madelyn , Metzner Thomas , Uson Maria Loressa , Torrey Melissa Louise , Kuhn Peter 
Published: February 2017

194 Background: We have established a fluid phase biopsy approach that identifies CTCs which preserves cytologic features in high-definition (HD) for diagnostic pathology without using immune or surface receptor-based enrichment. HD-CTCs identified with this approach can be used for enumeration and molecular characterization. Methods: Blood was collected from metastatic prostate cancer patients and normal donors in Cyto-Chex tubes (Streck, Omaha, NE) as part of IRB approved protocols at each site. Following erythrocyte lysis, 3 million nucleated cells were deposited on a glass slide. Samples were incubated with a pan-cytokeratin (CK), CD45, and androgen receptor (AR) antibodies and counter-stained with DAPI. LNCaP cells were spiked into normal blood. Images were obtained with a fluorescent scanning microscope and analyzed with a computer algorithm. Candidate HD-CTCs were subsequently verified by expert readers. Slides were re-imaged for quantitative analysis using at a fixed exposure and gain. Results: A total of 227 CTCs from ten patients were compared to 20 LNCaP cells. The median (range) HD-CTCs in this cohort was: 9 (1-62) cells/ml. The mean ± standard deviation measurements in HD-CTCs were observed: CK intensity 60.4±154; total cell area 89.0 ± 53.8 µm2; nuclear area 61.1 ± 36.0 µm2. LNCaP cells spiked into normal blood gave the following values: CK intensity 1166+/−306; total cell area 143 ± 48.1 µm2; nuclear area 63.1 ± 18.6 µm2. CTCs were additionally classified as either AR positive (AR+) or AR negative (AR−). 37 of the 227 (16.3%) HD-CTCs were AR+. The average CK intensity was significantly higher in AR+ versus AR− cells at 174.23 and 39.86, respectively (p<0.001). The AR expression intensity in AR+ HD-CTCs and LNCaP cells was comparable at 979.4 and 902.2, respectively (p=0.824). Conclusions: We find a positive association between AR and CK expression on a per cell basis. Further, we find AR is expressed at comparable levels in CTCs from patients and human prostate cancer cells in culture. The HD-CTC based approach may be used for enumeration and molecular interrogation of CTCs in patients with prostate cancer.
Identifying patients with node-positive prostate cancer who may benefit from adjuvant pelvic radiation following prostatectomy.
Authors: Shukla Monica Erin , Reddy Chandana A. , Stephans Kevin L. , Stephenson Andrew J. , Klein Eric A. , Garcia Jorge A. , Dreicer Robert , Tendulkar Rahul D. 
Published: February 2017

195 Background: Three PRTs address the role adjuvant radiotherapy (RT) following radical prostatectomy (RP) in men with locally advanced and/or margin positive prostate cancer (PCa), one of which demonstrated an improvement in overall survival by the addition of early RT. Not addressed in these studies is the role of adjuvant RT in lymph node positive (LN+) PCa. Methods: We reviewed an IRB-approved prospective database at the Cleveland Clinic and identified 84 men with non-metastatic, LN+ PCa treated with RP from 1987-2010. Men receiving neoadjuvant therapy or adjuvant RT were excluded from this analysis. Pelvic failure (PF) was defined as recurrence in the prostate bed or pelvic LN up to the common iliacs. Distant failures (DF) were defined as any LN recurrence beyond the common iliacs, bone, or other solid organ metastases. Kaplan-Meier estimates of pelvic failure (PF), distant failure (DF) and overall survival (OS) were conducted. Results: Median follow-up was 6 years. The median initial PSA was 10.1 ng/mL, 50% had Gleason 7, 12% had Gleason 8, 31% had Gleason 9 disease. The median number of LNs dissected was 11 (range 1-49) and 36% had >1 LN+. Extracapsular extension was present in 90%, seminal vesicle invasion in 66%, and surgical margins positive in 55%. The 6 week post-operative PSA was undetectable (<0.2 ng/ml) in 58%. Overall, 41% received immediate androgen deprivation therapy (ADT), and 45% received delayed ADT after biochemical or clinical failure, while 23% received salvage RT and 22% received chemotherapy. The 10-year OS was 61%. Clinically documented PF and DF occurred in 14% and 24%, respectively. Gleason score was the factor most predictive of PF, DF, and OS. Comparing Gleason score of ≤7 vs. ≥8, the 5-year PF rate was 3% vs. 24% (p=0.006), the 5-year DF rate was 2% vs. 37% (p<0.0001), and 5-year OS was 97% vs. 74% (p<0.0001), respectively. The number of LN+ was not prognostic. Conclusions: Men with Gleason score ≥8 LN+ PCa have a high rate of pelvic recurrence, and pelvic radiation may be worthy of prospective investigation.
Androgen receptor and HIF-1α interaction in prostate cancer.
Authors: Reece Kelie M , Troutman Sarah M , Pressler Heather M , Pisle Stephen T , Figg William Douglas 
Published: February 2017

197 Background: Prostate cancer is the most common noncutaneous cancer among men in the United States, and its progression is largely controlled by the androgen receptor (AR). Androgen deprivation therapy (ADT) is an initially effective treatment for prostate cancer, but most tumors eventually become castrate resistant. Tumor hypoxia also appears to be associated with a poor prognosis in prostate cancer. HIF-1a regulates the transcription of genes that allow tumor survival and growth in low oxygen conditions. Our laboratory has data showing that in response to castration and anti-androgen therapy in mice, there was a strong transcriptional relationship between HIF-1a and AR, as measured by quantitative RT-PCR, suggesting an interaction between the two proteins. Thus, the purpose of this study was to determine if there is a molecular interaction between HIF-1a and AR in prostate cancer cells. Methods: We used Western blot analysis to examine the expression levels of HIF-1a and AR in LNCaP prostate cancer cells to determine if they are upregulated together at the protein level. Four experimental conditions were tested: control (no treatment), DHT for induction of AR expression, CoCl2 for induction of HIF-1a, and a combination treatment of DHT and CoCl2. Immunoprecipitation experiments were carried out to determine if there is an association between HIF-1a and AR. In addition, cells were fractionated into nuclear and cellular cells extracts, followed by Western blot analysis to determine where in the cells this interaction occurs. Results: Western blot analysis of cell lysates showed synergistic upregulation of both HIF-1a and AR expression only under combined CoCl2 and DHT treatment conditions. In addition, immunoprecipitation experiments showed that HIF-1a and AR exist in a complex with one another, and fractionation experiments indicated this complex occurs in the nucleus. Conclusions: Our results demonstrate that HIF-1a and AR associate with one another in cells. Binding assays are in progress to determine the nature of this interaction. In addition, we are examining the cellular consequences of this protein interaction, as it is possible that upregulation of HIF-1a in response to low androgen contributes to the development of tumor resistance to ADT.