bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of prior radiation treatment (tx) on sipuleucel-T (sip-T) product parameters in PROCEED patients (pts).
Authors: Finkelstein Steven E. , Nordquist Luke T. , Dakhil Shaker R. , Green Nathan B. , Heath Elisabeth I. , Tutrone Ronald , Vogelzang Nicholas J. , Armstrong Andrew J. , Cooperberg Matthew R. , Tyler Robert Claude , Sims Robert Brownell , Whitmore James Boyd , Higano Celestia S. 
Published: February 2017

183 Background: Sipuleucel-T (sip-T) is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Approval of sip-T was based primarily on the randomized, controlled, phase 3 study (IMPACT) that demonstrated a 22% reduction in the risk of death. Since radiation tx could suppress bone marrow function and therefore immune function, IMPACT excluded patients (pts) who received radiation more than or equal to 28 days prior to registration. PROCEED is an ongoing phase 4 registry enrolling pts tx with commercial sip-T in the real-world setting. Palliative radiation (PR) tx for bone pain prior to sip-T is not restricted in PROCEED, so the effects of prior radiation on sip-T manufacturing parameters can be evaluated. Methods: Pts treated with sip-T at or before six months were eligible. Baseline pt demographics and disease characteristics were collected. Sip-T product parameters that were assessed included: total nucleated cell (TNC) count, antigen presenting cell (APC) count (large CD54+cells), and APC activation (upregulation of CD54; a measure of product potency). Results: Data were available for 1,244 pts enrolled by May 2013, who completed tx; of those, 112 (9.0%) pts received PR to bone metastases prior to sip-T and 517 (41.6%) pts had no prior radiation of any kind (NRT). To ensure that groups (grp) were homogeneous and to limit the comparison of NRT pts with those who had PR only for bone metastases, pts with radical prostatectomy were isolated from each grp for further study, resulting in 44 pts in the PR grp and 159 pts in the NRT grp. Median cumulative APC counts were similar between grp, however TNC counts (PR: 9.89 vs. NRT: 12.09 x 109; P=0.002) and APC activation (PR: 34.2 vs. NRT: 38.5; P=0.048) were lower in the PR grp. However, the percentage of pts receiving all three infusions in each group was comparable (PR: 93.2% vs NRT: 95.0%; P=0.71). Conclusions: In the real-world setting, there is no evidence that prior radiation inhibits successful production of sip-T. Although TNC counts and APC activation were lower, APC counts were comparable in radiation treated pts. Effects on in vivo post treatment immune measures are being collected prospectively in a companion trial called PRIME. Clinical trial information: NCT01306890.
Accuracy of NaF PET/CT scan to detect bone metastases in CRPC.
Authors: Alom Modar , Aleksic Ilija , Ruhle Brian , Iannotta Peter , Okeefe Colin , Mouraviev Vladimir , Albala David , Pieczonka Christopher Michael 
Published: February 2017

186 Background: The current standard for imaging Castration Resistant Prostate Cancer (CRPC) is aimed at detecting metastatic lesions to the bones. However, discovery, validation, and implementation of new imaging modalities have fallen considerably behind that of new therapies for this population. Recent studies have shown the NaF PET/CT Scans are significantly more sensitive and accurate in detecting bone lesions than conventionally used Bone Scintigraphy with Technetium-99 (Tc-99). This study conducted retrospective analysis to compare the competence of these two methods for identifying bone metastases. Methods: We conducted a charts review of 613 patients being currently treated with androgen deprivation therapy (ADT) and identified 55 patients who obtained a Na18F PET/CT Scan. Results: The median age was 75.5 years with a range of 52-89, for our cohort. Of these 55 patients, 5 (11.9%) were determined to have metastasis with Tc-99 Bone Scintigraphy alone while 27 (49.1%) were determined to have metastases with NaF Scan (p<0.005). 8 (19%) patients had equivocal findings on Tc-99 Bone Scintigraphy. Therefore, for all of them we performed NaF scan to define a bone metastatic disease that demonstrated in 5 (62.5%) cases of these as having no bone involvement and 3(37.5%) as positive for bone lesions (Table). However, data of NaF scan also indicated 5(9%) patients as having equivocal findings for metastatic disease. Conclusions: According to our data, NaF is more sensitive for detecting bone lesions (11.9 vs. 49.1%). It was also able to delineating equivocal TC-99 Bone Scintigraphy findings, where it deemed 62.5% as negative and 37.5% as positive for bone lesions. NaF PET scan is a feasible option for CRPC for detecting bone metastases, early in disease progression. With coverage of this procedure by Medicare patients have more sensitive and specific tool for early diagnosis and monitoring of treatment of CRPC. [Table: see text]
Heterogeneity of prostate-specific membrane antigen (PSMA) expression in classic and apoptotic circulating tumor cells (CTC) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Autio Karen A. , Anand Aseem , Krupa Rachel , Louw Jessica , Arslan Zaina , Dittamore Ryan , Scher Howard I. 
Published: February 2017

198 Background: Prostate-specific membrane antigen (PSMA) is a folate hydrolase expressed on the surface of PC cells that has been used as a target to detect disease and selectively deliver cytotoxic agents and radionuclides. The ability to detect PSMA levels on circulating tumor cells (CTCs) may identify patients likely to benefit from such targeted therapy. Technology developed by Epic Sciences utilizes high definition imaging of plated nucleated cells. Methods: Blood samples were obtained from patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Cells were stained for CK, CD45, PSMA and categorized as classic CTC (CK+, CD45-, intact/morphologically distinct nuclei) or apoptotic CTC (CK+, CD45-, morphology suggesting apoptosis). Clinical data including treatment, metastatic sites, Veridex CellSearch CTC enumeration, prostate-specific antigen, and alkaline phosphatase was collected. Results: Fourteen pts with mCRPC, including eight with serial samples were analyzed (33 samples in total). At the first draw (t1), classic CTC were detected in 13 pts (93%), (median two cells/ml, range 0 to 40 cells/ml) and apoptotic CTC in 14 pts (100%) (median four cells/ml, range 1 to 18 cells/ml), including six pts (42%) with no CTC by Veridex CellSearch. PSMA expression was detected in five pts (36%) with classic CTC of which a median of 32% of cells (range 5 to 100%) expressed the antigen. Similar intra-patient heterogeneity was seen for the 10 pts (71.4%) with PSMA+ apoptotic CTCs (median 33.5%, range 11 to 75% cells). During treatment, often with more complete androgen suppression, PSMA was detected in 3 of the 8 (38%) pts with no PSMA+ classic CTCs at t1. The presence of PSMA expression in apoptotic CTCs did not appear to change while on therapy. Conclusions: A larger percentage of PSMA expression was seen in mCRPC pts in apoptotic CTC (10 out of 14) than classic CTC (5 out of 14) at t1, with intra-patient cell heterogeneity of PSMA expression in both CTC populations. Serial measures suggest dynamic changes in PSMA expression over time. The threshold of detectable cells and proportion and degree of PSMA expression that associates with drug sensitivity is unknown. Larger samples of pts at discrete time points on therapy are underway to further elucidate the potential clinical relevance.
PSMA, EpCAM, VEGF, and GRPR as imaging targets in locally recurrent prostate cancer after radiotherapy.
Authors: Hoving Hilde , Ananias Hildo J. K. , Rybalov Maxim , Vanderpoel Henk , Rosati Stefano , De Jong Igle 
Published: February 2017

201 Background: Currently, there is no imaging modality that can accurately discriminate between locally and distant recurrent prostate cancer after treatment with curative intent. Major drawback of the available techniques is that they are not prostate cancer specific. Selecting patients for salvage cryotherapy of the prostate or salvage prostatectomy by excluding distant metastases proves a diagnostic challenge. In this retrospective pilot study expression of prostate-specific membrane antigen (PSMA), epithelial cell adhesion molecule (EpCAM), vascular endothelial growth factor (VEGF) and gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy (EBRT) was investigated and their adequacy for targeted imaging was analyzed. Methods: Prostate cancer specimens were collected of 17 patients who underwent salvage prostatectomy because of locally recurrent prostate cancer after brachytherapy or EBRT. Local recurrence was based on rises in PSA and prostate biopsies. Immunohistochemistry was performed on the radical prostatectomy specimens. A pathologist blinded to clinical and pathological data scored the immunoreactivity on a four point scale in prostate cancer and in stroma. Results: Staining for PSMA was seen in 100% (17 out of 17), EpCAM in 82.3% (14 out of 17), VEGF in 82.3% (14 out of 17) and GRPR in 100% (17 out of 17) of prostate cancer specimens. Staining for PSMA, EpCAM, and VEGF was seen in 0% (0 out of 17) and for GRPR in 100% (17 out of 17) of specimens’ stromal compartments. In 11.8% (2 out of 17) of cases GRPR staining intensity of prostate cancer was higher than that of stroma, while in the remaining 88.2% (15 out of 17) of cases GRPR staining in cancer and stroma was equal. Conclusions: Based on the absence of stromal staining PSMA, EpCAM, and VEGF had a high tumor distinctiveness. GRPR had a low tumor distinctiveness as a result of the high stromal expression. Therefore, PSMA, EpCAM, and VEGF can be used for targeted imaging of locally recurrent prostate cancer after radiotherapy.
Validation of differential expression of microRNA profiles in prostate cancer specimens.
Authors: Waingankar Nikhil , Broccoli Nicholas , Rais-Bahrami Soroush , Smith Kevin , Oswald Michaela , Khalili Houman , Lee Annette , Chan Theresa , Yaskiv Oksana , Gregersen Peter , Vira Manish Arvind 
Published: February 2017

203 Background: MicroRNAs (miRNA) are small, noncoding nucleic acids that regulate expression of genes. Altered expression of miRNA has been implicated as a factor in carcinogenesis. We previously demonstrated 27 miRNA with differential expression that varied greater than two-fold between areas of benign and cancerous prostate glands in 64 patients. The goal of this study was to validate these findings in a selected group. Methods: RNA was extracted from prostate cancer foci and areas of benign glands from paraffin embedded prostatectomy specimens from 29 selected patients. Five patients each were selected with Gleason 3+3, 3+4, 4+3, and 4+4 or higher. The remaining nine selected patients went on to develop metastatic disease. Expression profiles for 577 miRNA were analyzed using Taqman OpenArray. Data analysis was performed using the mean-centering method for normalizing miRNA across the original and validation cohorts. Results: Significant overlap was found between the original and validation cohorts for miRNA that were upregulated at least two-fold between benign and cancerous glands (p<0.05). There were no differences in miRNA expression between T2 and T3 cases. Comparison of Gleason 6 vs Gleason 8+ showed significant difference in expression of mir-185, mir106b, and mir-181a. Interestingly, among the subset of patients that developed metastatic disease, the benign prostate glands demonstrated significant overexpression of mir-21 as compared to the benign glands of the localized cohort. Mir-21 is a known oncomir shown to be overexpressed in other metastatic tumors. Conclusions: This study validates our findings on differential expression of miRNA between cancerous and benign glands. There was a significant difference in expression of three miRNAs between Gleason 6 and 8 cancers, and no differences were found between T2 and T3. miRNA may represent a unique signature in the benign glands of patients with metastatic disease.
Testosterone replacement therapy in men with prostate cancer after proton therapy.
Authors: Bryant Curtis , Hoppe Bradford S. , Mendenhall Nancy P. , Henderson Randal H. , Nichols Romaine Charles , Morris Christopher G. , Williams Christopher R. , Su Zhong , Li Zuofeng , Mendenhall William M. 
Published: February 2017

208 Background: Testosterone replacement therapy (TRT) in patients previously treated for prostate cancer is controversial. We analyzed biochemical relapse and sexual function in patients treated for prostate cancer with proton therapy (PT) at our institution who were later treated with TRT for hypogonadism. Methods: We reviewed the medical records of 27 patients with biopsy-proven, localized prostate cancer treated with definitive proton therapy (PT) at our institution between 2006 and 2012. Each patient had hypogondal symptoms and low-serum testosterone and received testosterone replacement after PT. Biochemical failure was defined by the Phoenix definition. Sexual function was reported using patient-reported data from the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Rates of sexual potency were also reported. Results: Twenty-three patients were included in the present analysis. The median follow-up duration was 38 months after PT and 14 months after initiation of TRT. After one to six months on TRT, the median serum testosterone level in this patient cohort increased from 238 to 497. No patient experienced a biochemical failure. The median prostate-specific antigen (PSA) did not significantly rise during the follow-up period. EPIC sexual summary, sexual function, and sexual bother scores all increased after initiation of TRT. The median sexual bother scores increased from 43.8 before TRT to 59.4 after 7 or more months of TRT. The median sexual summary scores improved from 50 to 61.8 and the median sexual function scores improved from 41.7 to 53 over the same time. Sexual potency also increased after TRT initiation from 50% to 68%, 7 or more months after TRT. Conclusions: For patients diagnosed with hypogonadism who were previously treated for prostate cancer, cautious use of testosterone replacement therapy does not appear to increase the risk of biochemical failure or increase PSA. Sexual function may improve to approximate pre-radiation levels in some cases. A prospective trial with long-term follow up is required to better support our findings.
IDH1 mutation in prostate cancer: R132H and beyond.
Authors: Flaherty Amber Lea , Teer Jamie , Zhang Jingsong 
Published: February 2017

213 Background: Previous reports on mutations in the isocitrate dehydrogenase 1 (IDH1) gene in prostate cancer focused on the evolutionarily conserved residue R132 located in the substrate binding site of IDH1. One study reported R132 mutations in 2/75 (2.7%) prostate cancers, whereas the other study did not find R132 mutation in 4 prostate cancers. We therefore studied the IDH1 mutations in our prostate cancer targeted exon sequencing database. Methods: Targeted exon sequencing was performed on 52 treatment naïve prostate cancers as part of Moffitt Cancer Center’s Total Cancer Care initiative. The coverage was set to be at least 50 fold. 51/52 samples are primary prostate cancer obtained during radical prostatectomy and 1 sample is a brain metastasis. The 1000 Genomes and the NHLBI Exome Sequencing Project (ESP) were used to exclude likely polymorphisms. The catalogue of somatic mutations in cancer (COSMIC) was used to identify mutations seen in other sequencing projects, and Polyphen2 was used to predict the potential detrimental effect of the amino acid changes predicted from the genetic mutations. Results: 1/51 (2%) primary prostate cancers harbor the R132H mutation, which is known to generate the oncometabolite, (R)-2-hydroxylutarate. Y183C was identified in 1/51 samples. This amino acid change in exon 6 of IDH1 is seen at 1% allele frequency in 1000 Genomes and ESP-euro. It is classified as "probably_damaging" with a PolyPhen2 score of .999. Another "probably_damaging" amino acid change is T325M mutation, which is identified in a different primary prostate cancer. V178I in IDH1 was also identified and is thought to be an inherited variant, given it has an allele frequency of 4% in 1000 Genomes, 5% in ESP-european, and 8% in ESP-African-American. Among the frequent gene mutations in metastatic prostate cancer, only a missense mutation in the androgen receptor (H875Y) was identified in the treatment naïve brain metastasis. This H875Y has been linked to promiscuous androgen receptor. Conclusions: Mutations in IDH1 R132H and other “probably_damaging” amino acid changes are identified in primary prostate cancers. This holds further implications for future studies on prostate cancer, and may point to an interesting target in the disease.
A closer look at extraprostatic extension (EPE): Evaluation of PSA relapse rates following prostatectomy (RP) for pT3aN0 prostate cancer with or without margin involvement.
Authors: Watkins John Morgan , Watkins Patricia L. , Laszewski Michael , Rodacker Mark , Dufan Tarek A. , Koleilat Nadim 
Published: February 2017

215 Background: EPE is an established risk factor for PSA failure following RP; however, often this is identified in the context of other high-risk feature(s). The objective of the current investigation study is to describe the PSA relapse rate for patients with confirmed EPE and identify associated factors for risk stratification. Methods: Retrospective analysis of patient- and tumor-specific factors. Eligible patients underwent RP for biopsy-proven prostate adenocarcinoma and pathologic finding of EPE. Patients with PSA >30 at diagnosis, involved seminal vesicles or lymph nodes at RP, or who received adjuvant therapy (hormone or radiation) were excluded. Results: Between 2002 and 2010, 644 patients underwent RP, of whom 95 had EPE and were eligible per above. The median age at diagnosis was 64 years (range 44-74), and pre-RP PSA 6.1 (1.8-25.4). At a median PSA follow-up of 64 months (range 13.3-136.5), 38 patients had experienced PSA relapse at a median of 18 months post-RP (1.2-129.8), of whom 28 had involved surgical margins. For the entire population, PSA relapse at 5 years was 39.2% (95% CI, 38.1-40.3%). Factors associated with PSA relapse included pre- and post-RP PSA and Gleason score (GS), and margin status. Subset evaluation by RP Gleason score and margin status is demonstrated in the table. Conclusions: Within the present study, all patients with EPE appear to have elevated rates of PSA relapse within 5 years of RP. Longer follow-up is necessary to determine whether the low-risk group may be safely observed following margin-negative RP. Low-grade EPE cases with involved margin and/or higher-risk Gleason score patients with any EPE/margin involvement have high rates of early PSA relapse, and should be recommended early post-operative (adjuvant) therapy in order to optimize PSA control. [Table: see text]
Preclinical efficacy of growth hormone-releasing hormone antagonist MIA-602 for androgen-dependent and castration-resistant human prostate cancer.
Authors: Rick Ferenc G. , Fahrenholtz Cale D. , Garcia Maria I. , Block Norman L. , Schally Andrew V. , Burnstein Kerry L. 
Published: February 2017

221 Background: Advanced hormone-sensitive prostate cancer (PCa) responds to androgen deprivation therapy (ADT). However, therapeutic options for castration-resistant disease are limited. As growth hormone-releasing hormone receptor (GHRH-R) and ligand GHRH are regulated in an autocrine fashion in PCa, GHRH-R inhibition represents a novel approach to PCa treatment. We investigated the effects of a new, highly potent GHRH antagonist, MIA-602, on growth of androgen-dependent and castration-resistant PCa cells in vitro/in vivo. Methods: All three cell lines used in this study expressed androgen receptors (ARs). 22Rv1 cells are castration-resistant and also express clinically relevant AR splice variants. LNCaP and VCaP lines are androgen dependent models that progress to castration resistance following ADT. Protein and mRNA levels of GHRH-R and its biologically active splice variant, SV1, were evaluated in cell lines and tumors by immunoblot and real-time RT-PCR. The influence of MIA-602 on cell proliferation and tumor formation was examined. Results: GHRH-R and SV1 were present in 22Rv1, LNCaP, and VCaP. LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared to 22Rv1. However, 22Rv1 expressed higher levels of SV1. Inhibition of GHRH-R using MIA-602 decreased cell proliferation in vitro of 22Rv1, LNCaP, and VCaP PCa cell lines respectively by 70.4%, 60.7% and 20.3% (P<0.05 for all). MIA-602 decreased 22Rv1 xenograft volumes in mice by 63% after 3 weeks of treatment. VCaP showed a substantial inhibition of xenograft growth following therapy with MIA-602 in vivo. MIA-602 effectively inhibited VCaP xenografts as a single agent or in combination with ADT by surgical castration. Conclusions: The effectiveness of the novel Miami class GHRH antagonist, MIA-602, in inhibiting growth of androgen-dependent and castration-resistant PCa models in vitro and in vivo was demonstrated. The inhibitory effect of GHRH antagonists appear to be due to effects exerted through GHRH receptors on cancer cells and/or possibly by indirect mechanisms. Further investigations of GHRH antagonists for PCa treatment are warranted.
Patient risk factors and pegfilgrastim use in cabazitaxel-treated prostate cancer pateints in an academic setting.
Authors: Kaymakcalan Marina Dusevic , Stuver Sherri , Sweeney Christopher , Choueiri Toni K. , Elfiky Aymen 
Published: February 2017

224 Background: Cabazitaxel can offer a survival advantage in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). Febrile neutropenia (FN) has emerged as a serious complication, with a rate of 8% in the TROPIC trial (de Bono, Lancet 2010). Prophylaxis with pegfilgrastim (P) can decrease the risk of FN, although predictors of FN continue to evolve. We performed an analysis on the effect of prophylactic P use on FN and the impact of certain risk factors on FN rates. Methods: We conducted a retrospective analysis of mCRPC patients treated with cabazitaxel from June 2010 to August 2013 at Dana-Farber Cancer Institute. Patient clinical and treatment variables were extracted. Fisher’s exact test was used to evaluate the association between potential risk factors and FN. Results: A total of 89 patients were treated at our institution and included in this analysis. All patients received at least one dose of cabazitaxel and received a mean of four cycles. Five pts (5.6%) developed FN; 3 out of 70 (4.3%) receiving P and 2 out of 19 (10.5%) not receiving P (p=0.3). Of the 24 patients that started cabazitaxel at a reduced dose, none developed FN. No toxic death was reported. Among several risk factors including P use, age older than 65, pre-existing neutropenia, prior chemotherapy, pre-existing infection, poor performance status, liver and renal dysfunction, and recent surgery, only a prior history of palliative radiation had a significant association with FN (p=.002). Conclusions: The rate of FN in a large academic practice is similar to what was reported in the TROPIC trial. Prior radiation may be a risk factor for FN in cabazitaxel-treated mCRPC patients. Other factors that may help better predict the risk of FN in different groups of patients receiving cabazitaxel must be identified.