bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential response of prostate cancer cells to ionizing radiation: The RB status.
Authors: Den Robert Benjamin , Ciment Steve , Sharma Ankur , Mellert Hestia , McMahon Steven , Dicker Adam , Knudsen Karen E. 
Published: February 2017

106 Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation and loss of RB has been observed in 25-30% of prostate cancers. We have previously shown that RB loss results in a castrate resistant phenotype, however the consequences of RB status with regard to radiation response are unknown. We hypothesized that RB loss would downregulate the G1-S cell cycle checkpoint arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to ionizing radiation. Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts. Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in both hormone sensitive and castrate resistant cell lines (p<0.05). Cell death was not mediated through increased apoptosis nor was perturbations in cell cycle noted. However, loss of RB effected DNA repair as measured by gamma H2AX staining as well as cellular senescence. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05). Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. The underlying mechanism appears to be related to DNA damage repair and cellular senescence.
Value of prostate MRI in determining appropriate candidates for active surveillance.
Authors: Margolis Daniel , Tan Nelly , Natarajan Shyam , Chamie Karim , Finley David , Reiter Robert Evan , Huang Jiaoti , Raman Steven 
Published: February 2017

109 Background: The objective was to measure the added benefit of multi-parametric endorectal coil prostate MRI (eMRI) to traditional active (AS) criteria in delineating men with more advanced disease. Methods: We performed a retrospective study of 115 men who underwent robot-assisted laparoscopic prostatectomy (RALP) for their CaP with whole-mount pathological evaluation. All men underwent eMRI for surgical planning—including T2 weighted, diffusion-weighted (DWI), dynamic contrast-enhanced (DCE), and MR Spectroscopy—between July 2008 and March 2011. We examined the diagnostics of Epstein’s criteria (E-AS) for clinically insignificant CaP or in combination with MR parameters (eMRI-AS criteria) in predicting more advanced disease. E-AS criteria included Gleason score (GS) 3+3=6, <3 biopsy cores positive, PSA <10, ≤50% maximum % of cancer in any one core. The addition of apparent diffusion coefficient >0.85x10-3 mm2/sec, Ktrans<0.5 Hz, Kep>1.5 Hz, and normal MRSI defined the eMRI-AS cohort. Outcomes were stratified into low vs. high surgical risk. Low-risk disease was defined as having pT2, GS <3+4 with tumor size <1.5 cm, and negative surgical margins (SM). Conversely, higher-risk disease included men with GS ≥4+3, positive SM, ≥pT3 or those with GS 3+4 with tumor size ≥1.5 cm. Results: We identified 104 who met our inclusion criteria. We excluded 11 (9%) men due to post-biopsy hemorrhage (n=4), failed DCE (n=4), poor DWI (n=2), and two-year delay between MRI and RALP (n=1). Mean age was 60.6 years. Thirty-seven men (35%) satisfied E-AS, while 25 men (24%) satisfied eMRI-AS. On whole-mount sectioning 49 (47%) men were low surgical risk. E-AS to detect low surgical risk revealed a sensitivity, specificity, false positive, false negative and AUC of 67%, 73%, 33%, 27%, and 70%, respectively. eMRI-AS performance parameters were: 62.8%, 94.4%, 37%, 5% and 78%—significantly different than E-AS (p=0.04). Conclusions: eMRI-AS outperformed Epstein-AS in identifying poor candidates from going onto AS. If patients were identified as AS candidates based on traditional criteria, we found that 27% actually had higher risk disease; whereas the addition of eMRI reduced this number to 5%.
TMPRSS2-ERG status and biochemical recurrence following radiotherapy for intermediate-risk prostate cancer.
Authors: Dal Pra Alan , Warde Fiona , Ishkanian Adrian Shea , Meng Alice , Malloff Chad , Lam Wan , Sykes Jenna , Pintile Melania , Squire Jeremy , van der Kwast Theo , Evans Andrew , Milosevic Michael , Bristow Robert Glen 
Published: February 2017

11 Background: Approximately 50% of prostate cancers (PC) contain TMPRSS2-ERG gene fusions leading to ERG overexpression. Pre-clinical data suggest that these fusions are due to altered DNA double-strand break repair status which could have therapeutic ramification for the use of radiotherapy (RT) and PARP inhibitors. The aim of this study was to correlate TMPRSS2-ERG status to biochemical failure following clinical induction of DNA breaks in the form of image-guided radiotherapy (IGRT) in intermediate-risk PC. Methods: Pre-treatment biopsies from two separate cohorts of intermediate-risk PC patients (T1/T2, GS < 8, PSA < 20ng/ml) were analyzed: 1) 126 patients assessed by array Comparative Genomic Hybridization (aCGH) for TMPRSS2:ERG fusion; and 2) 121 patients assessed by tissue microarray (TMA) for ERG expression by immunohistochemistry (IHC). All patients received IGRT with a median dose of 79.8 Gy (60-79.8 Gy). TMPRSS2:ERG status was correlated to Gleason score, T stage, initial PSA and biochemical-free relapse rate (bFRR; Phoenix definition: nadir + 2ng/ml). Results: At a median follow-up time of 6.36 years, the biochemical relapse event rate was 37% and 18% in the aCGH and IHC cohorts, respectively. ERG expression by IHC was found in 49.6% of the 121 PC. TMPRSS2-ERG status was not correlated to increased Gleason score, pre-treatment PSA or T stage. On multivariate analyses in models containing clinical factors, TMPRSS2:ERG status (either using aCGH or IHC) was not prognostic for biochemical outcome (ERG expression: HR=0.78, 95% CI: 0.33-1.85; p= 0.568; TMPRSS2-ERG fusion: HR=0.71, 95% CI: 0.35-1.41; p=0.326). Conclusions: In two separate cohorts, TMPRSS2-ERG status was not prognostic for bRFR after IGRT. Although a trend was observed, these clinical data do not support the hypothesis that these cancers have DNA repair defects that render them significantly more radiosensitive when compared to other PC. Further clinical trials are required to understand the utility of TMPRSS2:ERG status and response to DNA damaging agents, including that of PARP inhibitors. The trans-Canadian PROFIT trial is completing accrual of close to 1200 patients allowing for TMPRSS2:ERG studies in a larger RT cohort.
Association of concurrent AURKA and MYCN amplification in primary prostate adenocarcinoma with the development of lethal neuroendocrine prostate cancer (NEPC).
Authors: Beltran Himisha , Park Kyung , Tagawa Scott T. , Macdonald Theresa , Nanus David M. , Mosquera Juan Miguel , Rubin Mark A. 
Published: February 2017

120 Background: NEPC is an aggressive variant of prostate cancer that most commonly arises from prostate adenocarcinoma (PCA), with likely clonal origin. There is currently no effective therapy with most patients surviving < 1 yr. Recent work identified overexpression and amplification of Aurora kinase A (AURKA) and N-myc (MYCN) in metastatic NEPC, evidence that they cooperate to directly induce a NE phenotype in PCA, and are targetable with Aurora kinase inhibitor therapy (AKI) (Beltran et al). NEPC xenografts demonstrate dramatic and preferential sensitivity to AKI therapy with complete reversal of NE marker expression. We evaluated primary prostate tumors of patients that later developed lethal NEPC for presence of AURKA and MYCN alterations. Methods: 226 primary PCA tumors were evaluated, of which 57 tumors were from patients with NEPC. 22 benign prostate and 57 metastatic NE carcinomas from prostate (38) or other primary site were also evaluated. Histology, immunohistochemistry (IHC), Fluorescence In Situ Hybridization (FISH) were performed and correlated with clinical variables (ie, Gleason, PSA, OS). Results: AURKA and concurrent MYCN amplification were identified by FISH in 75% of primary PCA of patients with NEPC (> 95% cells). In contrast, in an unselected PCA cohort, AURKA and MYCN amplifications were identified in 5% of 169 cases. These results are independent of NE marker expression by IHC. In only one case did MYCN gain occur in absence of AURKA amplification. When metastatic NEPC was compared to primary PCA in same patient, there was 100% concordance of AURKA and MYCN amplification. In prostate tumors with mixed features, there was 94% concordance between NEPC and PCA. 0% benign prostate and 40% metastatic NEPC harbored AURKA and MYCN amplifications. Conclusions: AURKA and MYCN amplification occurs early and are nearly always concurrent despite separate chromosomes. Their presence in primary PCA identifies patients predisposed to the development of an aggressive lethal NEPC variant. These patients may benefit from early intervention with AKI therapy. Therefore, AURKA and MYCN amplification may be new prognostic and predictive biomarkers.
Treating people right: Who goes untreated with systemic therapy for metastatic prostate cancer (mPC)?
Authors: Perlroth Daniella J. , Thompson Stephen F. , Mozaffari Essy , Luna Yesenia , Goldman Dana P. , Lakdawalla Darius N. 
Published: February 2017

125 Background: We investigated the use of systemic therapies (androgen deprivation therapy and chemotherapy) for men with mPC in the community, comparing those treated and untreated. Methods: 8,295 men diagnosed with mPC at presentation from the 2000-05 Surveillance, Epidemiology, and End Results (SEER) database were linked to Medicare claims. We excluded those diagnosed with other primary malignancies, disenrolling from Medicare Parts A or B (n=3,293), or who died within 1 month of diagnosis (n=468), leaving 4,534 patients. Treatment, service use and comorbidities were measured in Medicare claims, demographic and clinical data in SEER. We compared characteristics of patients by treatment group using univariate and logistic regression to estimate the predicted probability of receiving systemic therapies for black and nonblack patients. Differences across hospital service areas (HSAs) were computed, using logistic regression to adjust for demographic and clinical characteristics. Results: 3,657 patients (80.7%) received systemic therapy and 877 (19.3%) did not. Mean time to systemic treatment was 2.5 months. Follow up was 28.8 months for the treated, 19.2 months for the untreated. Among the treated, 20.4% received ADT and chemotherapy, 78.3% ADT only and 1.3% chemo only. Untreated patients were statistically older (78.6 versus 77.3 years), less likely to be married (48% versus 61%), and more likely residents of lower income areas and black race (26% versus 13%). The two groups scored similarly on a comorbidity index (0.51 versus 0.43). The model predicted a 66% probability of receiving systemic treatment for blacks versus 82% for whites, controlling for other factors. Systemic treatment use varied across regions from 62% to 94%. There was an 8-14% greater likelihood of receiving systemic treatment for men living in above versus below median regions. Conclusions: One in 5 men with mPC in this sample survived long enough to be treated systemically, yet was not. Untreated men with mPC are more likely to be black, unmarried and reside in low income areas, raising concerns for equal access to treatment. Some regions are better at initiating systemic treatment for men with mPC than others.
Evaluating the effect of tobacco on prostate cancer outcomes with VEGF-targeted therapy.
Authors: Harzstark Andrea Lynne , Halabi Susan , Kelly William Kevin , Morris Michael J. , Febbo Phillip G. , Small Eric Jay 
Published: February 2017

129 Background: Docetaxel/prednisone (DP) plus bevacizumab (B) demonstrated a superior progression-free survival (PFS) but did not prolong overall survival (OS) in comparison to DP monotherapy in CALGB 90401, a study of 1,050 patients with metastatic castration-resistant prostate cancer (CRPC) who had not received prior chemotherapy for metastatic disease. Tobacco use increases VEGF levels, suggesting the benefit of bevacizumab may be greater in patients who use tobacco. Methods: The association of tobacco usage and OS was evaluated. Patient-reported history of tobacco usage was prospectively collected for patients on CALGB 90401. Within each smoking status group, the log-rank test was used to compare the survival time between the two treatment arms. The proportional hazards model was used to test for smoking by treatment interaction predicting OS. Results: Of 865 patients with available smoking history, 21%, 30% and 49% were current, former, and never smokers. As summarized in the table below, there was a non-statistically significant improvement in OS for current smokers treated on the DP+B arm compared to the DP arm. However, treatment-by-smoking interaction was not statistically significant in predicting OS (p=0.299). Conclusions: There was a trend toward an improvement in OS for current smokers treated with DP+B. The accuracy of patient-reported smoking status will be confirmed with serum cotinine levels in a pilot study. The effect of tobacco use on cancer outcomes with VEGF targeted therapy will be evaluated in other malignancies.
Use of elevated baseline IL-8, CCL-2, and TNFα to predict for shorter overall survival (OS) in men with metastatic prostate cancer initiating androgen-deprivation therapy (ADT).
Authors: Sharma Jaya , Gray Kathryn P. , Nakabayashi Mari , Petrozziello Gillian , Evan Carolyn , Fichorova Raina , Kantoff Philip W. , Sweeney Christopher 
Published: February 2017

13 Background: Inflammation associated chemokines and cytokines have been shown in preclinical models to lead to the induction of castration resistance. We assessed whether higher blood cytokines and chemokines were associated with shorter time to CRPC and OS in patients initiating ADT for metastatic prostate cancer. Methods: A retrospective analysis of inflammatory markers including IL1β, IL-6, IL-8, TNFα and CCL-2 was undertaken in men initiating ADT for metastatic prostate cancer. Proteins were measured using multiplex electrochemiluminescence assays. The analytical cohort of 122 patients included a prospective trial (50 patients) and chart review (72 patients). A multivariate COX model was used to investigate the relationship between serum markers of inflammation and time to CRPC and OS. The covariates were age at time of ADT, ECOG score, race, baseline PSA, and extent of disease. Results: At time of initiating ADT, the median age of the cohort was 67 years, median PSA was 27.4, 82% had an ECOG PS of 0, 62% had extensive metastatic disease and 91% were Caucasian. Median OS was 42.2 months. The median (med) baseline levels for IL8 was 9.3pg/ml, TNFα was 2.4 pg/ml and CCL-2 was 507.5 pg/ml. As detailed below, patients with elevated IL-8, TNFα and CCL-2 had a significantly shorter OS and showed a non-significant shorter time to CRPC. Conclusions: In men with metastatic prostate cancer starting ADT, higher serum inflammatory markers are associated with poorer OS. This correlative data suggests that anti-inflammatory strategies which improved ADT efficacy in preclinical models may be relevant to the clinical setting. [Table: see text]
Multidisciplinary care and pursuit of active surveillance in low-risk prostate cancer.
Authors: Aizer Ayal , Paly Jonathan J. , Zietman Anthony L. , D'Amico Anthony Victor , Nguyen Paul Linh , Beard Clair , Rao Sandhya K , Kaplan Irving D. , Hirsch Michelle S. , Wu Chin-Lee , Efstathiou Jason Alexander 
Published: February 2017

131 Background: Factors associated with pursuit of active surveillance in men with low-risk prostate cancer are not well-delineated. Methods: 701 patients with low-risk prostate cancer (clinical stage < T2b, Gleason score < 7, and PSA < 10 ng/mL), treated in 2009 at three tertiary care centers affiliated with the same medical school and within the same health care system were identified. All patients were evaluated by one or more urological, radiation, and/or medical oncologists specializing in genitourinary malignancies, either sequentially at independent appointments with differing dates/locations, or concurrently at a multidisciplinary genitourinary oncology clinic in which all three specialists evaluated the patient jointly during a single visit. Pre-treatment and treatment-related variables were recorded. Logistic regression was performed to identify demographic and clinical factors associated with the employment of active surveillance. Results: Forty three percent of patients referred to a multidisciplinary clinic underwent active surveillance, as opposed to 22% of patients seen by individual practitioners (p<.001). On multivariate logistic regression, older age (OR 1.09 (per year), p <.001), increased comorbidities (OR 1.41 (per unit increase in Charlson score), p=.01), unmarried social status (OR 1.76, p=.04), a smaller percentage of positive cores (OR 0.92 (per percent core increase), p<.001), and referral to a multidisciplinary clinic (OR 2.22, p<.01) were all significantly associated with pursuit of active surveillance. The number of physicians or specialities seen in consultation was not significantly associated with pursuit of active surveillance. Conclusions: Older age, increased comorbidities, unmarried social status, and a smaller percentage of positive cores are associated with pursuit of active surveillance. Notably, referral to a multidisciplinary genitourinary oncology clinic significantly increases rates of active surveillance in men with low-risk prostate cancer, implying that the multidisciplinary clinic itself, and not merely the number or type of physicians seen, is important to the shared decision making process for a patient to elect active surveillance.
Image-guided proton therapy for low- and intermediate-risk prostate cancer: Three-year results of two prospective trials.
Authors: Henderson Randal H. , Hoppe Bradford S. , Nichols Romaine Charles , Mendenhall William M , Marcus Robert B , Su Zhong , Williams Christopher R , Li Zuofeng , Morris Christopher G. , Mendenhall Nancy Price 
Published: February 2017

152 Background: To report outcomes in two prospective proton therapy (PT) trials for localized prostate cancer. Methods: From 2006 to 2007, 171 low- and intermediate-risk prostate cancer patients were treated with PT on prospective trials. Low-risk patients (N=89) were treated on PR01 with 78 CGE/39 fractions to the prostate. Intermediate-risk patients (N=82) were treated on PR02, a dose-escalation trial, with 78-82 CGE to the prostate and proximal seminal vesicles. Based on organ-constraint goals, 57 (69%), 13 (16%), and 12 (15%) PR02 patients received 82 CGE, 80 CGE, and 78 CGE, respectively. Toxicity was scored by CTCAE v3 and biochemical failure defined as nadir + 2 ng/mL. Results: The proportions of PR01 and 02 patients alive with no evidence of disease are 83 (93%) and 73 (89%); alive with disease, 1 (1%) and 1 (1%); and dead of intercurrent disease, 5 (6%) and 8 (10%), respectively. Only 2 patients had disease progression, both isolated pelvic-node recurrences. No patient died of prostate cancer or recurred locally. Grade (GR) 3 genitourinary (GU) and gastrointestinal (GI) complications occurred in 2 of 101 (2%), 0 of 13, and 4 of 57 (7%) patients receiving 78, 80, and 82 CGE, respectively. GR 3 GU toxicity occurred in 1 PR01 and 3 PR02 patients, including hematuria in 1 PR01 patient on anticoagulation; posttreatment TURP in 2 who had pretreatment (pre-tx) TURP; and dysuria in 1 with severe chronic pre-tx prostatitis. Multivariate analysis (MVA) of protocol, dose, age, prostate volume, pre-tx IPSS, pre-tx medical or surgical GU symptom management (SM), anticoagulation, and bladder wall V70 or V30 showed only pre-tx SM (P< .0001) and age (P =.007) to be associated with GR2+ toxicity. GR 3 GI toxicity occurred in 2 PR02 patients, including rectal bleeding in a patient on anticoagulation, and rectal bleeding and proctitis in a patient on anticoagulation who had a transrectal prostate biopsy. MVA of protocol, age, dose, anticoagulation, and rectal wall V70 or rectum V30 showed only rectal wall V70 (.045) and rectum V30 (.027) to be associated with GR 2+ rectal bleeding and proctitis. Conclusions: PT may provide sufficiently reduced toxicity to permit further dose intensification and/or concomitant chemotherapy.
Pretreatment serum biomarkers and clinical outcome in the phase II trial of zibotentan (endothelin A receptor antagonist) in metastatic CRPC.
Authors: Shelkey Julia , Bisen Ajit , Leitzel Kim , Ali Suhail M. , Carney Walter P. , Lipton Allan 
Published: February 2017

154 Background: Three angiogenesis-related serum biomarkers [TIMP-1 (tissue inhibitor of metalloproteinase-1), CA IX (carbonic anhydrase 9), and VEGF] and PSA were correlated with outcome in the phase II zibotentan [endothelin A (ETA) receptor inhibitor] trial in metastatic CRPC. Methods: Pretreatment serum samples were available from 206 of 312 patients enrolled in the multicenter phase II trial evaluating zibotentan in patients with metastatic CRPC and bone metastases who were pain free or mildly symptomatic for pain, with a 1:1:1 randomization to zibotentan 10mg, 15mg, or placebo. The CA IX, TIMP-1, and VEGF ELISAs were from WILEX Inc./Oncogene Science, Cambridge, MA. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling. Results: In the final efficacy report, there were no statistical differences in PFS, but a trend for OS improvement was observed in the zibotentan arms compared with placebo: 15 mg (HR 0.76; 80% CI 0.61–0.94; p= 0.103) and 10 mg (HR 0.83; 80% CI 0.67–1.02; p= 0.254) (James et al, BJUI 106L966-973, 2010). In the retrospective serum biomarker analysis (206 patients), there were no apparent differences for PFS with any of the 3 novel biomarkers in the whole population, or within treatment arms. For OS in the whole population, patients with higher serum TIMP (> median) had reduced OS (17.5 mos), compared with patients who had lower serum TIMP-1 (< median) (28.4 mos). Within treatment arms, patients with higher serum CA IX (> median) treated with zibotentan had increased OS in both the 10 mg arm (median 28.4 mos), and the 15 mg arm (median 25.7 mos) compared with those in the placebo arm (median 15.4 mos). In a Cox model, including serum biomarkers and bisphosphonate use, for PFS only PSA was significant (p< 0.0001); for OS only PSA (p< 0.0001) and TIMP-1 (p< 0.002) were significant. Conclusions: Higher pretreatment serum CA IX (a marker of hypoxia) may identify a cohort of metastatic CRPC patients more sensitive to zibotentan treatment, and higher serum TIMP-1 may identify patients at risk for reduced overall survival. These serum biomarkers deserve further study in larger ETA receptor inhibitor trials.