bluuebunny/crossref_metadata_2025_split huggingface dataset:
Challenges in enrolling to metastatic castration-resistant prostate cancer (mCRPC) studies that require androgen receptor splice variant (AR-V) positivity.
Authors: Schweizer Michael Thomas , Haugk Kathleen , Cheng Heather H. , Maes Jessica L , Dumpit Ruth F , Nelson Peter , Montgomery Robert B. , Plymate Stephen R , Yu Evan Y. 
Published: March 2017

264 Background: AR-Vs are truncated androgen receptor (AR) isoforms that lack the ligand-binding domain (LBD) and are associated with resistance to drugs targeting the ligand-AR LBD interaction (e.g. abiraterone [Abi], enzalutamide [Enza]). Preclinical studies have shown that niclosamide, an anthelminticsdrug, is able to overcome AR-V mediated drug resistance. Methods: We are conducting a Phase I dose-escalation study testing high-dose niclosamide in combination with the FDA-approved dose of Enza. Niclosamide is given three-times-daily by mouth at one of the following dose-levels: 500, 1000 or 1500 mg. All patients are required to have mCRPC, have received prior Abi, and have detectable AR-V transcripts in circulating tumor cells (CTC) as determined using the AdnaTest ProstateCancerSelect/ProstateCancerDetect assay. Patients are permitted to start Enza prior to the addition of niclosamide. The primary objective is to assess safety. Niclosamide’s pharmacokinetic profile will also be determined. Results: From December 2015 to October 2016 we screened 14 patients. All patients previously progressed on Enza, with 13/14 patients demonstrating a rising PSA on Enza at screening. Two had previously documented AR-Vs as determined from prior transcript profiling studies; however, only one of these patients was AR-V positive (AR-V5-6) at the time of study enrollment. Of the 12 patients without prior evidence of AR-V, none were found to be AR-V+. All patients (14/14) were positive for actin and 10/14 were positive for full-length AR using the AdnaTest. To date, one patient has completed treatment with high-dose niclosamide. No study drug-related adverse events have been observed. Conclusions: Rates of AR-V positivity have been lower than expected in our cohort of patients that have progressed on Abi and Enza – challenging study accrual. Multicenter studies are needed to confirm rates of AR-V positivity in mCRPC populations. Furthermore, in order to ensure enrollment expectations are met, novel biomarkers (e.g. AR-V status as determined using AdnaTest) should undergo pre-study confirmatory testing within institutions prior to use as enrollment criteria. Clinical trial information: NCT02532114.
Sequencing in metastatic castration-resistant prostate cancer (mCRPC): Updated results of the FLAC International Database.
Authors: Delanoy Nicolas , Angelergues Antoine , Efstathiou Eleni , Gyftaki Revekka , Wysocki Piotr Jan , Lainez Nuria , Gonzalez Iria , Castellano Daniel E. , Ozguroglu Mustafa , Garcia Carbonero Iciar , Flechon Aude , Borrega Pablo , Guillot Aline , Campos Balea Begona , Le Moulec Sylvestre , Esteban Emilio , Munarriz Javier , Barker Claire , Birtle Alison J. , Oudard Stephane 
Published: March 2017

267 Background: Optimal sequencing of new androgen-receptor targeted agents (ART) abiraterone and enzalutamide with docetaxel (DOC) and cabazitaxel (CABA) is unknown. In this large retrospective cohort of mCRPC patients (pts) treated with CABA after docetaxel (DOC), we evaluated the impact of 3 different sequences: DOC → CABA (group 1, n = 267) Or DOC → ART → CABA (group 2, n = 183) Or DOC → CABA → ART (group 3, n = 124). Methods: Records of 574 consecutive mCRPC patients were retrospectively collected in 44 centres in 6 European countries (France, Spain, UK, Greece, Poland, Turkey) from August 2012 to July 2016. Disease history and clinical characteristics at initiation of DOC therapy and outcomes were collected. Factors influencing OS were evaluated using multivariate stepwise logistic regression. Results: At DOC initiation, median age was 67 years, 83% of pts were ECOG 0-1, 45.1% had pain and 10.8% had visceral metastases. Median number of DOC cycles was 7 (6 in group 2, 7 in groups 1 and 3). Median number of CABA cycles was 6 (6 in groups 1 and 2, 7 in group 3). Median duration of ART treatment was 5.9 and 4.4 mths in groups 2 and 3, retrospectively. Median OS from first DOC cycle were 30.1, 37.1 and 40.1 mths in groups 1, 2 and 3, respectively. Factors influencing OS are summarized in the table below. Conclusions: Results of this retrospective cohort suggest that patients receiving DOC → CAB → ART show the greatest OS. High baseline PSA, short response to first-ADT and clinical progression of pts are major prognostic factors of OS at DOC initiation. The window of opportunity for chemotherapy should not be missed. [Table: see text]
Long-term androgen deprivation therapy (ADT) with leuprorelin and quality of life in patients with advanced prostate cancer (PCa).
Authors: Hammerer Peter , Manka Lukas , Wirth Manfred 
Published: March 2017

268 Background: LHRH analogs are the gold standard for treatment of patients with hormone-sensitive advanced PCa. In this study, we investigated the quality of life (QoL) of PCa patients under long-term treatment with leuprorelin acetate in microcapsules (1, 3, and 6 month depot formulation) for up to 19.8 years. Methods: Observational and retrospective analysis of data from 536 PCa patients treated with leuproreline and 116 patients of a control group (CG, ≥ 77 years of age, > 5 years urological treatment, no cancer, no ADT). Data was collected in 30 German office based urological practices using EORTC questionnaires QLQ-C30 and QLQ-PR25. Results: Mean treatment duration was 8.6 years (range: 4.5 - 19.8 years). Mean age ± SD of PCa patients (79.6 ± 6.3 years) was comparable to CG (80.5 ± 3.1 years), as were body height, weight, BMI, and Karnofsky-Index (88.0 ± 12.7 vs. 88.4 ± 12.0). The general health status (QLQ-C30) was comparable for PCa patients vs. CG: 64.6 ± 20.5 vs. 66.8 ± 20.3; p = 0.3117. Marginal differences were observed regarding physical functioning (73.2 ± 23.1 vs. 78.1 ± 21.0; p = 0.0402) and role functioning (70.6 ± 30.4 vs. 74.4 ± 25.7; p = 0.1648). PCa patients rated fatigue (33.6 ± 25.1 vs. 28.8 ± 23.3; p = 0.0629), dyspnoea (24.0 ± 28.5 vs. 19.6 ± 26.9; p = 0.1307), and insomnia (28.9 ± 32.6 vs. 23.7 ± 27.2; p = 0.0751) slightly worse than CG. As assessed by QLQ-PR25, PCa patients scored lower on sexual activity (12.0 ± 20.6 vs. 23.7 ± 25.7; p < 0.0001) and sexual function (43.3 ± 25.8 vs. 55.9 ± 27.0; p = 0.0067) compared to CG. PCa patients had less urinary tract symptoms (28.2 ± 19.8 vs. 31.2 ± 19.2; p = 0.1472) but stronger symptoms of androgen deprivation (21.4 ± 17.3 vs. 10.8 ± 13.2; p < 0.0001), and they had a higher need of incontinence aids (29.6 ± 34.2 vs. 16.7 ± 20.5; p = 0.0056) – however, 136 of the 536 PCa patients had a prostatectomy. Conclusions: In this study, PCa patients treated with leuprorelin for up to 19.8 years (8.6 years on average) had an overall QoL comparable to an age-matched control group. As expected, sexual activity and sexual function were lower in PCa patients under ADT. Overall, treatment with leuprorelin is a well-tolerated long-term therapy for patients with hormone-sensitive advanced PCa. Clinical trial information: ENA E005(a) / DE-N-LEU-019(a).
Statin inhibits the proliferation of human castration-resistant prostate cancer cells by controlling NFkB-LIN28B-let7 miRNA signaling pathway.
Authors: Jeong Chang Wook , Ku Ja Hyeon , Kim Hyeon Hoe , Kwak Cheol , Kang Minyong 
Published: March 2017

269 Background: Although statin use has been associated with improved outcomes in prostate cancer, the molecular mechanism of this action is still unclear. Based on previous findings, we aimed to investigate the potential role of NFkB-Lin28B-let7 miRNA signaling pathway in human prostate cancer, particularly, castration-resistant prostate cancer (CRPC) cells, as a molecular mechanism of statin effect. Methods: Various human CRPC cell lines (PC3, DU145, 22Rv1, C42B) were used in this study. Proliferation of prostate cancer cells were measured by MTT assay and colony formation assay. Lin28B and NF-κB expression were controlled by siRNA transfection and the expression on Lin28 and let-7 miRNA were quantitated using RT-PCR and western blotting. Results: Notably, simvastatin treatment on various CRPC cell lines decreased cell viabilities in a dose dependent manner. It also significantly inhibited cell growth in clonogenic assay. In these CRPC cells, LIN28 gene was highly expressed in mRNa and protein levels. Conversely, micro RNA (miRNA) expressions of let7 family were remarkably downregulated in CRPC cells. By simvastatin treatment, mRNA and protein level of Lin28B were decreased, while let7 miRNA expressions were restored, which was the key finding of the current study. Considering NFkB is the upstream molecule of Lin28B, we found that the double treatment of statin and NF-κB inhibitor (CAPE) resulted in decreased cell viability, Lin28B and cyclin D1 expression, synergistically. Of note, let-7 miRNA levels were restored after simvastatin treatment, and further increased their expression levels by CAPE double treatment. In order to confirm this mechanistic clue, we specifically inhibited Lin28B and NF-κB genes, respectively, resulting in increased cell apoptosis signaling in the Lin28b or NF-κB knock down cells by combined treatment with simvastatin. Conclusions: In conclusion, simvastatin inhibited the cell growth of various human CRPC cell lines by controlling NFkB-LIN28B-let7 miRNA signaling pathway, and therefore; concurrent NF-κB inhibition with simvastatin treatment induce the synergistic anti-cancer effects in human CRPC cells.
Characterization of cancer family history among patients with PCa cancer.
Authors: Ernst Emma M. , Ledet Elisa M. , Schiff Joshua , Lin Shuwen , Garvey Cathryn E. , Sartor Oliver 
Published: March 2017

272 Background: Family history (FH) is a well-documented risk factor for prostate cancer (PCa). Certain cancers (Ca) are also shown to co-segregate in families. This study evaluated Ca FH in PCa patients (pts) and the impact of FH on clinical covariates. Methods: FHs were collected from 535 PCa pts at Tulane Hospital between 2015 and 2016. Incidence rates of familial Cas were analyzed. Age at diagnosis (dx), Gleason score, and the presence of metastases at any time were documented. Chi-square and the Mann-Whitney U tests were performed to identify correlations between clinical parameters and FH. Results: 435 pts (81.3%) had a Ca FH. 281 pts (52.5%) had ≥2 relatives with Ca. Rates of breast, lung, colorectal, pancreatic Ca, and leukemia FH did not vary between pts diagnosed at ≤55 and those diagnosed over 55. Pts with PCa FH were more likely than pts with no PCa FH to have an age of dx ≤55 (p= 0.0169). Median age at dx was 59 for pts with PCa FH and 64 for pts with no PCa FH. PCa FH did not affect Gleason score or the presence of metastases. Conclusions: PCa, breast, lung, and colorectal were the most common familial Cas reported. Pts with PCa FH were younger at dx than those without PCa FH. Further studies are needed to understand the co-segregation of PCa with other Cas and genetic studies are needed to clarify the mechanisms of these trends. [Table: see text]
A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN).
Authors: Bellmunt Joaquim , Kerst Jan M. , Morales Rafael , Vazquez Mazon Federico , Grande Enrique , Medina Ana , Gonzalez Gragera Belen , Rubio Gustavo , Anido Urbano , Fernandez Calvo Ovidio , Gonzalez-Billalabeitia Enrique , van den Eertwegh Alfonsus Johannes Maria , Pujol Eduardo , Perez-Gracia Jose Luis , Gonzalez-Larriba Jose-Luis , Collado Ricardo , Los Maartje , Macia Sonia , De Wit Ronald 
Published: March 2017

285 Background: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first line. Vinflunine is EMA approved and used in several European countries. Docetaxel is widely used in second line. Cabazitaxel is a taxane with clinical activity in docetaxel-refractory cancers. A randomised study was conducted to compare its efficacy vs vinflunine. Methods: This was a multicenter, randomised, open-label, phase II/III study, following a Simon’s optimal method with early stopping rules based on an interim futility analysis. The study (NCT01830231) was supported by a research grant from Sanofi. The trial was aiming at superiority of cabazitaxel compared to vinflunine in patients progressing to platinum. ECOG, anemia and liver metastases were stratification factors. The primary objective for the phase II study was overall response rate (ORR), and overall survival (OS) for the phase III. Secondary objectives included safety and progression free survival (PFS). Results: 70 patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Mean age 63 years; 56 (80%) were men. No statistically significant differences were detected between arms for ORR (p=0.26). Three patients (13%) obtained a partial response on cabazitazel (95% CI, 2.7–32.4) and six patients (30%) in the vinflunine arm (95% CI, 11.9–54.3). Median PFS for cabazitaxel was 1.9 months versus 2.9 months for vinflunine (p=0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for OS benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3-4 related adverse events were seen in 41% patients with no difference between arms. The most frequent toxicities associated with cabazitaxel were asthenia, diarrhea, anemia and febrile neutropenia. Conclusions: This phase II/III second line bladder trial comparing cabazitaxel with vinflunine was closed early when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those observed in the phase III. Clinical trial information: NCT01830231.
Subtyping muscle-invasive bladder cancer to assess clinical response to trimodality therapy.
Authors: Efstathiou Jason A. , Gibb Ewan , Miyamoto David Tomoaki , Wu Chin-Lee , Drumm Michael , Lehrer Jonathan , Ashab Hussam Al-Deen , Erho Nicholas , du Plessis Marguerite , Ong Kaye , Bhat Akshay , Mouw Kent William , Davicioni Elai , Shipley William U. 
Published: March 2017

287 Background: Trimodality therapy with TURBT followed by chemoradiation is an acceptable alternative to cystectomy for muscle invasive bladder cancer (MIBC). Recently, genomic profiling has demonstrated MIBC can be divided into three or more subtypes with differing responses to chemotherapy, suggesting genomic subtype may impact therapeutic response. Here, we explore the utility of genomic information to better select patients for bladder-sparing trimodality therapy. Methods: Transcriptome-wide gene expression profiles were generated for 189 MIBC TURBT samples from patients undergoing trimodality therapy at the Massachusetts General Hospital. Of these, 108 passed microarray QC and 100 had complete clinical information. The patient tumors were classified as basal, basal claudin-low, infilrated luminal or luminal subtype. The subtype and the expression of a number of bladder cancer genes were assessed for their association with need for salvage cystectomy and for overall survival. Finally, transcriptome-wide differential expression analysis was used to explore gene set enrichment in trimodality therapy response groups. Results: Our chemoradiation cohort (n = 108) was classified into the four subtypes: basal (n = 45), basal claudin low (n = 13), infiltrated luminal (n = 17) and luminal tumors (n = 33). Survival analysis (n = 100) showed that patients of the luminal subtype trended to better overall survival, but did not reach significance (HR = 0.63, p = 0.1). Fewer patients with infiltrated luminal tumors (12%) required a salvage cystectomy compared to all other subtypes (34+/-1.5%, p = 0.08). We found high expression of BLACAT1 and NORAD (a lncRNA with a role in genome stability) correlated with worse (p = 0.01) and better prognosis (p = 0.008), respectively. Likewise, patients with high levels of the luminal-associated PPARG showed a significant increase in overall survival (p = 0.0002). Gene set enrichment revealed differential regulation of immune pathways in the trimodality therapy responders relative to the non-responders (p < 0.05). Conclusions: Preliminary data exploring MIBC subtyping suggests the possibility of using genomics to predict response to trimodality bladder-sparing therapy.
Small cell carcinoma of the bladder (SCCB): Clinical, histopathologic, and genomic predictors of clinical outcomes.
Authors: Teo MinYuen , Hao XueLi , Desai Neil , Ostrovnaya Irina , Arora Arshi , Funt Samuel , Gopalan Anuradha , Chen Yingbei , Fine Samson , Bochner Bernard H. , Dalbagni Guido , Taylor Barry S. , Berger Michael F. , Solit David B. , Tickoo Satish , Reuter Victor E. , Bajorin Dean F. , Rosenberg Jonathan E. , Al-Ahmadie Hikmat , Iyer Gopa 
Published: March 2017

294 Background: SCCB is a rare, aggressive subtype of bladder cancer. We reviewed our center’s experience in SCCB management and investigated potential markers of clinical outcomes. Methods: SCCB cases were identified and re-reviewed for confirmation by detailed histologic evaluation. A subset of SCCB was sequenced with MSK-IMPACT ( > 279 genes) (Cheng et al J Mol Diagn 2015). Clinical stage, treatment response and proportion of neuroendocrine component (%NE) were correlated with progression-free (PFS) and overall survival (OS), calculated from the time of cystectomy. Distribution of somatic alterations (alts) was compared between responders ( ≤ ypT1pN0) and nonresponders. Results: Between 1985 and 2015, 214 SCCB patients (pts) were identified. Median age was 68 years (range: 38 – 94) and 78% were male. Of 199 pts with sufficient data, 147 (74%) were nonmetastatic (M0) and 52 pts (26%) had metastatic disease (M1). 14 pts did not receive SCCB-directed therapies. Of M0 pts, 108 underwent cystectomy: 71 received neoadjuvant (NAC), 14 received adjuvant, 14 had definitive chemoradiotherapy and 23 did not receive chemotherapy. Of M1 pts, 47 received chemotherapy. Cystectomy only pts were older than NAC pts (76 vs 67 years, p < .01). NAC improved PFS and OS compared to cystectomy only (HR 0.55, p = .04 and HR 0.41, p < .01) although only OS remains significant after adjusting for age (p = .01). For NAC pts, pT0pN0 and ≤ pT1pN0 rates were 38% and 48%, respectively. Responders had superior PFS (HR 0.26 p < .01) and OS (HR 0.32 p = .02). Median %NE was 100 (range: 10 – 100) and did not correlate with NAC response. %NE ≥ 95 is more prevalent among M1 pts (85% vs 68%, p = .04). Genomic data were available for 31 NAC pts (44%). Responders were enriched with alts in ERBB2 (33% vs. 0%, p = .02), PI3K pathway ( PIK3CA, PTEN, AKT1, TSC1, TSC2) (33% vs. 6%, p = .02) and histone acetyltransferases (60% vs. 25%, p = .07). Of 22/31 tumors sequenced with a larger gene set (n = 341), ERCC2 and RBM10 alts were enriched in responders (54% vs. 11%, p = .07) and nonresponders (44% vs. 0%, p = .02), respectively. Conclusions: In SCCB, NAC improves survival and response might be characterized by specific somatic alts. M1 pts had higher %NE but it is not predictive of outcome.
Punctuated evolution of copy-number alterations to define two molecular subtypes of muscle-invasive urothelial carcinoma.
Authors: Faltas Bishoy , Prandi Davide , Tagawa Scott T. , Nanus David M. , Molina Ana M. , Beltran Himisha , Demichelis Francesca , Rubin Mark A. 
Published: March 2017

299 Background: Somatic copy-number alterations (SCNAs) are distinct molecular events occurring in muscle-invasive urothelial carcinoma (UC). Defining the biologic role and the timing of SCNAs in UC’s evolution is critical for precision therapy. Methods: To examine whether distinct SCNAs define specific subtypes of UC and characterize the evolutionary dynamics of SCNA acquisition, we conducted whole-exome sequencing (WES) of a discovery cohort of 44 advanced UC tumors and matching germline samples, including 13 pairs of matched primary and metastatic tumors prospectively collected before and after chemotherapy. We queried WES data from 285 UCs from The Cancer Genome Atlas (TCGA) as a validation cohort. We performed a novel in-depth allele-specific copy-number analysis in 2503 cancer genes using the CLONET computational framework, which accounts for tumor ploidy and cellularity to infer the clonal hierarchy of SCNAs. Results: Analysis of SCNAs from tumor pairs within each patient revealed punctuated evolution of SCNAs occurring early in UC’s development followed by minor changes (clonal stasis) throughout the tumor’s lifetime. Two distinct clusters of UCs with strikingly different SCNA profiles in the discovery cohort emerged. Cluster A was defined by diploid copy number background and focal deletions in the 9p21 region (CDKN2A, CDKN2B and MTAP). Cluster B was defined by genome-wide duplications and several enriched amplifications including 1q21.1 (SETDB1 and MLLT11), (P = 0.0002) and 6p22.3 (E2F3), (P = 0.001). TP53 mutations (P = 0.0001) were enriched in the cluster B, consistent with the role of functional p53 as a “guardian of the genome” preventing chromosomal instability. SCNAs clusters A and B were confirmed in the TCGA validation cohort. Cluster A was enriched with tumors belonging to TCGA bladder cancer cluster III (“basal/squamous-like”) (P = 0.02). Conclusions: Using novel allele-specific SCNAs analysis, we define two distinct clusters of UC presenting a framework for understanding this aspect of UC’s biology. In contrast to somatic mutations, SCNAs are clonally static during each tumor’s evolution. This data has important implications for precision medicine for UC.