bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of a predefined AS threshold in a large cohort of men with localized prostate cancer.
Authors: Canter Daniel , Reid Julia E. , Latsis Maria , Variano Margaret , Halat Shams , Gurtner Kristen E. , Brawer Michael K. , Stone Steven , Bardot Stephen 
Published: February 2018

36 Background: Men with newly diagnosed, localized prostate cancer (PC) have historically been selected for active surveillance (AS) using clinicopathologic features. However, a clinical cell−cycle risk (CCR) score has been developed to include both molecular [cell cycle progression (CCP) RNA signature] and clinical [Cancer of the Prostate Risk Assessment (CAPRA)] features. Previous validations have demonstrated that this combined CCR score provides improved prognostic information relative to molecular or clinical features alone. As such, a CCR threshold score has been recently developed and validated to identify men with low−risk disease who may be candidates for AS. Here, we have evaluated the performance of the AS threshold in a contemporary cohort of men with newly diagnosed localized PC. Methods: Men with localized adenocarcinoma of the prostate who were treated at the Ochsner Clinic between 2006 and 2011 (4 patients were diagnosed in 2012−2014) were evaluated. Formalin−fixed paraffin embedded biopsy tissue and was analyzed for the RNA expression of 46 genes to obtain a CCP score. The CCR score was calculated as (0.57xCCP) + (0.39xCAPRA). A CCR score threshold of 0.8 has been previously validated in a cohort of conservatively managed men. Men with a CCR score equal to the threshold had an estimated 10−year disease−specific mortality risk of 3.3%, while men with scores below the threshold had a 2.7% risk. Results: Complete molecular and clinical information were available for 767 men with a median clinical follow−up time of 5.6 years measured from date of diagnosis. Overall, 217 men had CCR scores ≤ 0.8. Of these, 125 were treated by radical prostatectomy, 61 with radiation, 2 with radiation with hormones, 2 with hormones only, and 19 with watchful waiting. Treatment for eight men was unknown. One patient (0.5%) with a CCR score below the AS threshold progressed to metastatic disease, and was initially treated with radiation. Conclusions: We evaluated the performance of a previously validated AS threshold on a contemporary US cohort. Although the majority of the patients in this study were treated, the observed metastatic event rate of 0.5% supports that the CCR threshold can be safely used to identify candidates for AS.
Is it the time to shift paradigms in castration naïve prostate cancer (CNPC): A meta-analysis of upfront docetaxel and abiraterone in men with CNPC.
Authors: Sun Guangxi , Zhang Xingming , Chen Junru , Liao Banghua , Zhao Jinge , Shen Pengfei , Zeng Hao 
Published: February 2018

360 Background: To systematically review the relevant literature evaluating the therapeutic efficacy of upfront docetaxel (Doc) or abiraterone (Abi) plus androgen deprivation therapy (ADT) on oncological outcome in patients with CNPC. An attempt to identify subgroups of patients who will benefit most either from Doc or Abi plus ADT and further compare the efficacy and safety between these two combination therapies. Methods: A comprehensive search of the PubMed/Medline, Embase databases, ICTRP, Clinical Trial and Cochrane Central Register of Controlled Trials to July 2017 was performed. Results: Six studies involving 6480 patients were included in this meta-analysis, consisting of over sixty percent (4462/6480) of patients with metastatic CNPC (mCNPC, M1), and 31.1% (2018/6480) of patients with non-metastatic CNPC (M0). Totally, combination therapies (ADT plus Doc or Abi) significantly improved overall survival (OS) and failure-free survival (FFS) for all CNPC patients. For M1 patients, combination therapies were dramatically associated with improved OS and FFS, but for M0 patients, only with moderate improvement in FFS. M1 patients with age < 70 years, ECOG performance status (ECOG PS) 0-1, Gleason score ( < 8) or visceral metastases could get better survival benefit from either combination therapies. In indirect comparisons, among M1 patients with younger age ( < 70 years), ECOG PS 0-1 or aggressive Gleason score (GS ≥ 8), upfront Abi showed superiority to Doc in prolonging FFS. The incidence of severe adverse events (AEs ≥ 3) was comparable between these two therapeutic regimens. Conclusions: Upfront Doc or Abi plus ADT should be considered as a standard of care for mCNPC patients who are suitable for either or both of these combination therapies.
Preclinical efficacy of dendritic cells derived from bone marrow hematopoietic stem cells for the treatment of syngeneic prostate cancer immune cell therapy.
Authors: Kim Yunlim , Kim Choung-Soo , Kim Bongmin 
Published: February 2018

361 Background: PCas are characterized by a primary androgen dependent stage, during which growth is promoted by androgen and suppressed by androgen deprivation or blockade, with even metastatic disease being promptly susceptible to hormonal manipulation; however, despite initial success, androgen deprivation therapy eventually fails because of the development of CRPC. Despite the approval of new clinical trials such as docetaxel, enzalutamide and sipuleucel-T, which is a cell therapy drug, the clinical efficacy is limited. Therefore, there is a desperate need for the limited effectiveness of treatment in an aging society and the development of successful treatments for patients who fail treatment. In this study, we investigated the anticancer effect of prostate cancer using anti-cancer immunity cell vaccine based on the next generation dendritic cell immunotherapy. Methods: FACS and ELISA were performed with stem-DC to analyze phenotype and cytokine expression. To quantify the effect on the tumor growth, we constructed a TRAMP-C1 model and observed for safety, efficacy and induction of antigen-specific immune responses. And we also analyzed proliferation and activation of allogeneic-T cells by therapeutic dendritic cells. Results: From the stem-DC, immune-stimulatory cytokine IL-12 and interferone-gamma was measured higher level than monocyte derived DC (Mo-DC). A DC marker CD11c+CD8a+ cell was higher expression in stem-DC than Mo-DC. After DC injection, tumor size was reduced in stem-DC compared to Mono-DC and vehicle group in TRAMP model. To confirm stem-DC/lysate induce more systemic anti-tumor immunity than Mo-DC/lysate, we checked effector T cells in splenic lymphocytes from prostate cancer bearing mice. The frequency of IFN-γ secreting CD8+ T cells in stem-DC treated group was significantly higher than that in Mo-DC treated group. It shows that the therapeutic responses were associated with induction of IFN-γ secreting CD8+ T cells. Conclusions: Stem-DC, which was developed from hematopoietic stem cells in an optimized manner, proved to be effective and stable as an excellent anti-cancer immunotherapeutic agent for prostate cancer.
A phase II study of itraconazole in biochemically recurrent prostate cancer.
Authors: Lee Mina , Hong Haemin , Kim Won , Friedlander Terence W. , Fong Lawrence , Lin Amy M. , Small Eric Jay , Dhawan Mallika Sachdev , Wei Xiao X. , Rodvelt Tammy J. , Miralda Brigid , Ryan Charles J. , Aggarwal Rahul Raj 
Published: February 2018

362 Background: A subset of patients (pts) with biochemically recurrent prostate cancer (BRPC) are at risk for metastasis and lethal outcomes, yet many pts wish to defer or avoid androgen deprivation therapy in this setting. Itraconazole has previously demonstrated anti-tumor activity in castration-resistant prostate cancer independent of modulation of circulating androgen levels. We therefore evaluated itraconazole in a phase 2 study in BRPC as a potentially non-castrating treatment approach. Methods: Pts with BRPC and PSA doubling time (PSADT) ≤ 15 months, without metastases on conventional imaging (whole body bone scan + CT/MRI of the abdomen/pelvis), were enrolled in a single arm phase 2 study. Itraconazole was dosed at 300 mg PO BID until PSA progression by PCWG2 criteria, unacceptable toxicity, or pt withdrawal. The primary endpoint was the proportion of pts who achieved ≥ 50% decline from baseline in serum PSA after 12 weeks of protocol therapy. Secondary endpoints included change in PSADT, adverse events (AEs) by CTCAE version 4.0, and change in serum androgens (including testosterone (T) and androstenedione (ASD) from baseline to week 12. Results: 21 pts were enrolled. The median age was 72 (range 54-76), median baseline PSA was 7.6 ng/mL (range 1.5 – 45.5), and median PSADT was 5.7 months (1.2 – 13.0). Median baseline serum T was 336 ng/dL (165-626). Among the 19 evaluable pts, 9 pts (47%) experienced a PSA decline (mean decline 25.0 %, range 2 – 60 %) by week 12, including one patient (5%) with > 50% PSA decline. Among the 10 pts without a PSA decline, the mean on-treatment vs. pre-treatment PSADT was numerically longer (13.2 vs. 4.8 months, p = 0.17). There was no significant change from baseline to week 12 serum T (mean change = 1.9%, p = 0.77) or ASD levels (mean change = 6.1%, p = 0.83). The most common grade ≥ 3 AE was hypertension (29%); hypokalemia of any grade was also common (24%). Conclusions: Itraconazole can modulate serum PSA levels without lowering serum T in pts with BRPC. However, the magnitude of effect is modest and treatment carries an appreciable risk of toxicities related to mineralocorticoid excess. Exploration of the relationship between mineralocorticoid-related AEs, itraconazole drug levels, and clinical outcomes is ongoing. Clinical trial information: NCT01787331.
Circulating estrogen receptor (ER) mutations and splice variants in men with advanced prostate cancer (APC).
Authors: Qu Liang , Sluka Pavel , Wardan Hady , Davis Ian D. , Pezaro Carmel Jo 
Published: February 2018

363 Background: Circulating DNA and RNA have been studied in APC as biomarkers of potential clinical significance. Candidates include androgen receptor amplification or emergence of splice variants. ER signalling has been associated with prostate cancer progression in vitro but blood-based detection of ER variants has not been studied. Methods: Men with APC were recruited for serial blood collection during routine management, from which cell-free DNA (cfDNA) and cell-free RNA (cfRNA) were extracted. Six well-described ERα mutations (E380Q, L536Q, Y537C, Y537S, Y537N & D538G) and six ER splice variants (ERα-66, ERα-36, ERβ1, ERβ2, ERβ4 & ERβ5) were quantitated using droplet digital polymerase chain reaction. These markers were explored in association with clinical and treatment variables using descriptive statistics. Results: 44 men were included for a total of 92 cfDNA and 94 cfRNA samples, with a median of 2 (range: 1-6) sequential samples per patient. Two mutations (E380Q & D538G) were detected in both cfDNA and cfRNA samples, and two (L536Q & Y537S) were detected in cfRNA samples only. The ER splice variants were widely detected in cfRNA samples, including in non-cancer controls. ERα-36 was detected at lower levels than the other splice variants investigated (p < 0.0001). Despite ubiquitous detection, the levels of splice variants altered consistently with analysis of the following clinical variables: during castration therapy; following castration resistance; and with number of previous treatments. No clear patterns of expression were observed for ER mutants. Serial sample analysis associated increased ERα-36 levels with response to docetaxel or abiraterone therapy. ERβ splice variant levels decreased with progression on all studied therapies. Development of E380Q and L536Q mutations was observed in patients with disease progression. Conclusions: We identified circulating ER mutants and splice variants in men with APC. These variants may be associated with previous treatment use, as well as disease progression on castration therapy or other APC treatments. Further work will explore their utility for predicting treatment response.
Contemporary trends in abiraterone and enzalutamide prescription by provider specialty.
Authors: Pucheril Daniel , Wang Ye , Zlatev Dimitar V. , Nguyen Paul L. , Kibel Adam S. , Chang Steven Lee 
Published: February 2018

366 Background: Androgen deprivation therapy (ADT) with LHRH-agonists and anti-androgens, is established in the management of prostate cancer and is administered by urologists, medical oncologists, and radiation oncologists. Newer agents for ADT, abiraterone acetate (ABI) and enzalutamide (ENZA) were approved by the FDA in 2011 and 2012, respectively, for the management of metastatic castrate resistant prostate cancer (mCRPC) after failing chemotherapy. We evaluated the contemporary economic burden of ABI and ENZA and their adoption by specialty. Methods: Because a majority of men with mCRPC are > 65 years of age, we utilized Medicare Part D data from 2013-15. The specific outcome variables of interest included the aggregate reimbursement and total number of prescriptions for ABI and ENZA, by specialty. Descriptive statistics and trend analysis were performed. Results: From 2013-15, the total number of prescription rose from 52457 to 81058 for ABI and from 17141 to 69181 for ENZA. Though medical oncologists prescribed more than 75% of ABI/ENZA prescriptions each year, the proportion of prescriptions written by urologists increased annually. The greatest increase in the percentage of prescriptions originating from urology occurred from 2013-2014 for ABI (3.96% to 8.62%) and from 2014-15 for ENZA (5.42% to 15.64%); meanwhile, prescriptions by radiation oncology were negligible throughout the study. Southern states accounted for greater than one third of ABI and ENZA prescriptions. By 2015, the aggregate reimbursement of Part D claims for ENZA and ABI was $790 million each. Among all medication claims, ENZA and ABI represent the 29th and 30th most expensive by aggregate cost. Conclusions: While medical oncologists account for the vast majority of ENZA and ABI prescriptions, the prescriptions by urologists is increasing while prescriptions by radiation oncologists remain negligible. Though approved for mCRPC patients, ENZA and ABI are already among the costliest medications covered by Medicare. As Level 1 indications for the use of these medications increase and now include castrate-sensitive patients, further study should be directed at determining optimal timing and indication for prescription.
Combination of selective polo-like kinase 1 (PLK1) inhibitor PCM-075 with abiraterone in prostate cancer and non-androgen-driven cancer models.
Authors: Patterson Jesse Christopher , Varmeh Shohreh , Erlander Mark G. , Yaffe Michael B. 
Published: February 2018

369 Background: The majority of metastatic castration-resistant prostate cancer (mCRPC) patients will become resistant to abiraterone. Drug combinations with abiraterone offer the possibility to extend patient benefit to anti-androgen therapy. PLK1, an essential mitotic kinase for onset of G2/M transition and cytokinesis, is over-expressed in prostate cancer, correlated positively with Gleason grade and PLK1 RNAi induces G2/M arrest and apoptosis in prostate cancer cells. PCM-075 (formerly NMS-1286937) is a potent, highly selective PLK1 inhibitor currently in clinical trials for the treatment of acute myeloid leukemia. Combination of PCM-075 with abiraterone was examined in mCRPC models and other cancer types for synergistic interaction. Methods: We used a variety of tumor cell lines (C4-2, LNCaP, BT-20, AU565, SK-OV-3), animal and computational modeling techniques to elucidate the mechanism and assess the potential clinical utility of synergistic tumor cell killing by PLK1 inhibitors (PLK1i), including PCM-075, with abiraterone. Results: Synergy was observed between abiraterone and PLK1i, including PCM-075, in models of CRPC (C4-2). In addition, PLK1i and abiraterone were synergistic in murine C4-2 xenografts. Unexpectedly, PLK1i sensitized a subset of non-prostate cancer cells to abiraterone, including AR-negative breast and ovarian cancer cells. In contrast to PLK1i, other mitotic arrest agents do not synergize with abiraterone. To elucidate the molecular basis this synergy, we screened a panel of cell lines and implemented a new computational method that links RNA expression patterns to drug combination synergy. This analysis implicated signaling through the retinoic acid (RA) nuclear receptors as a component of this synergy, which was validated experimentally. Increased basal expression of genes involved in RA metabolism in cancer cells is associated with increased synergy. Conclusions: Abiraterone has AR-independent effects that provide a mechanism and biomarkers predictive for synergistic killing when combined with the PLK1i PCM-075. This combination has potential to extend mCRPC patient benefit to abiraterone regardless of AR status.
Initial whole blood-based gene expression profile assays in mCRPC pts.
Authors: Tsumagari Koji , Miller Patrick , Moses Marcus Marie , Ledet Elisa , Sartor A. Oliver 
Published: February 2018

370 Background: Although second generation androgen receptor (AR) targeting therapy, abiraterone (Abi) and enzalutamide (enza), improve therapeutic effect for patients of mCRPC, acquired resistance occurs. Biomarkers are clearly needed to predict the efficacy of AR targeting drugs for mCRPC patients and much work is occurring on this important issue. Circulating tumor cells are attractive biomaterials because of non-invasive collecting methods. In this study, we assessed whole blood RNA as a non-invasive methodology to access biomarkers of potential interest. Methods: We used whole blood (~5mL) preserved in PAXgene tubes from 10 patients (pts) with mCRPC with acquired resistance following Abi and 11 controls without prostate cancer. Total RNA was extracted followed by qRT-PCR for assessment of 10 transcripts including ARV7, HOXB13, GHLR2, KLK3, KLK2, FOXA1, SchLAP1, KIF2C, MIA, and NCAM1. All amplicons were normalized to β-actin. Results: ARV7 (2/10), GRHL2 (2/10), HOXB13 (4/10), KLK3 (7/10), and KLK2 (4/10) amplicons were detected only in the mCRPC prostate pts. FOXA1 (7/10) and SchLAP1 (3/10) amplicons were detected in mCRPC pts at higher concentrations in mCRPC pts as compared to controls ( p< 0.001 and p = 0.02, respectively). In contrast, KIF2C (5/11), MIA (11/11), and NCAM1 (11/11) amplicons were present in pts but in lower concentrations in mCRPC as compared to controls (p = 0.03, p< 0.001, and p< 0.001, respectively). Conclusions: We identified 5 transcripts that can be detected from whole blood RNA assays only from PCa pts, additional transcripts were expressed at higher or lower concentrations as compared to controls. Although this is a small cohort, these findings highlight the potential role for whole blood RNA to assess mCRPC pts.
Combination of carboplatin (AUC4) and cabazitaxel (25 mg/m2) in mCRPC patients not or no longer responding to cabazitaxel monotherapy.
Authors: Louhanepessy Rebecca , van Rijssen Margriet , van der Noort Vincent , Bergman Andre M. 
Published: February 2018

371 Background: Cabazitaxel monotherapy is a second line treatment option for mCRPC patients. However, not all patients have a PSA response on this treatment, while a proportion of patients develop resistance during cabazitaxel treatment. Platinum drugs might be effective in poorly differentiated disease. Ongoing trials suggest effectivity of the combination in mCRPC, however, thus far clinical parameters cannot predict a response. Therefore, we investigated the addition of carboplatin to cabazitaxel in mCRPC patients who do not have a psa response on cabazitaxel monotherapy or have a PSA rise during treatment. Methods: 19 patients (WHO PS ≤2) who were not responding to ≥2 cycles cabazitaxel monotherapy (25 mg/m2) or two rises of PSA during cabazitaxel were included in this prospective cohort study. All patients received the combination of carboplatin (AUC 4) and cabazitaxel (25 mg/m2). Previous therapies, PSA response, WHO performance score, Progression Free Survival (PFS), Overall Survival (OS) and adverse events were monitored. Results: Median age was 66.7 years, 21% of patients had a WHO PS of 2, 68% had a Gleason score ≥8, 74% had bone metastases, 63% lymph node metastases and 26% visceral metastases. All patients received docetaxel prior to cabazitaxel, 6 patients (31,6%) received abiraterone and 15 patients (78,9%) enzalutamide. Combination therapy was initiated after a median of 4.1 cycles monotherapy [IQR 3.0-6.0]. Patients were treated with a median of 3.8 [IQR 2.8-6.3] cycles of combination therapy. Eight patients (42,2%) had a PSA decrease of > 25% and 4 patients (21,1%) had a PSA decrease of ≥50%. One patient had a WHO PS improvement of 2. Median PFS was 8.1 [IQR 6.0-15.1] months and median OS 13.0 months. Anemia was the most common adverse event (≥ grade 2) during combination therapy (62%), while thrombopenia was only found in one patient (5%). Other common adverse events were fatigue (43%), nausea (24%), pain (33%) and constipation (10%). Conclusions: Our data suggests that combination treatment of cabazitaxel and carboplatin might be effective in heavily pretreated patients not, or no longer responding to cabazitaxel monotherapy.
Serum-based biomarkers and liver metastases in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Cotogno Patrick , Ranasinghe Lahiru , Ledet Elisa , Lewis Brian E. , Sartor A. Oliver 
Published: February 2018

372 Background: Metastatic castrate-resistant prostate cancer patients with liver metastases have a poor prognosis. No large studies to date have investigated the clinical and biochemical parameters associated with liver metastases in this population. Methods: Patient data was obtained from 1,281 men with mCRPC that were enrolled on to three phase III clinical trials for the treatment of their disease. This clinical trial data was obtained from Project Data Sphere (www.projectdatasphere.org), an initiative of the CEO Roundtable on Cancer's Life Sciences Consortium. Multiple logistic regression was performed on clinical and biochemical baseline variables to test their association with the presence of liver metastases on baseline CT/MRI imaging. Variables assessed included prior docetaxel exposure, ECOG performance status, albumin, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), hemoglobin, lactate dehydrogenase (LDH), prostate specific antigen (PSA), and total bilirubin. The investigation included lab variables when treated as both dichotomous (based on normal-abnormal ranges) and continuous. Results: Multiple variable analysis demonstrated that an abnormally elevated serum AST and/or LDH was associated with an increased likelihood of having documented radiographic liver metastases (p < 0.0001). The predicted probability of having liver metastases for an abnormally elevated AST or LDH was 13.90% (95% CI 9.12 – 20.59) and 16.80% (95% CI 13.19 – 21.16), respectively. Patients with both an elevated AST and LDH had a 31.31% (95% CI 24.0 – 39.73) probability of having liver metastases as compared to only 6.67% (95% CI 5.17 – 8.57) for those with normal values. The ROC curve for the final model (AST + LDH) containing dichotomous predictors was 0.6683 (p < 0.0001), which was not significantly different when treating the predictors as continuous (p = 0.4858). Conclusions: Our analysis demonstrated a significant association between the presence of liver metastases and elevated serum levels of AST and LDH. More research is needed to validate these biomarkers and determine their application in the clinical setting.