bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic biomarkers to predict outcome in Gleason Score 9-10 disease.
Authors: Kishan Amar Upadhyaya , Romero Tahmineh , Elashoff David , Grogan Tristan , Rettig Matthew , Reiter Robert Evan , Tran Phuoc T. , Nguyen Paul L. , Nickols Nicholas George , Davicioni Elai , Spratt Daniel Eidelberg , Feng Felix Y , Weidhaas Joanne B. 
Published: March 2019

44 Background: Gleason score (GS) 9-10 prostate cancer (PCa) has classically been considered the most aggressive form of clinically localized disease. However, outcomes remain heterogeneous. Whether specific biomarkers may help guide prognostication within GS 9-10 disease remains unknown. Methods: Microarray-derived gene expression data were obtained from six retrospective radical prostatectomy cohorts (n=1076) and two prospective cohorts with data from the Decipher GRID (n=7000). A total of 957 patients had GS 9-10 disease. Clinical outcomes data (i.e., distant metastasis [DM] and prostate cancer-specific mortality [PCSM]) were available for 1077 patients (201 with GS 9-10 disease). We filtered for genes with high expression levels and differential expression between GS 9-10 and GS ≤8 (via Wilcoxon test with adjustment for false discovery rate [FDR]), and then used using weighted gene co-expression network analysis [WGCNA] to identify distinct modules. Genes with both a low p-value and a high connectivity within each module were included as potential predictors in logistic regression models constructed using elastic net regularization. We also chose genes within the GS 9-10 cohort with q-value <0.01 and <0.3 after FDR correction for outcomes of DM and PCSM, respectively. We used the cross-validated AUC for quantifying the discrimination of each gene set. Results: We identified a set of 12 genes with an AUC of 0.81 for discriminating GS 9-10 vs. GS ≤8. A separate set of 7 genes had an AUC of 0.83 for predicting DM within GS 9-10 patients, compared with an AUC of 0.68 within GS ≤8 patients. A third set of 13 genes had an AUC of 0.93 for predicting PCSM within GS 9-10 patients, but an AUC of only 0.57 for predicting PCSM within GS ≤8. Conclusions: These data suggest that a genomic biomarker signature can strongly discriminate GS 9-10 from GS ≤8. Separate gene sets can also predict DM and PCSM within GS 9-10 patients with high fidelity, but are not as predictive of these outcomes within GS ≤8 patients. These data support the hypothesis that GS 9-10 disease is a biologically distinct yet heterogeneous entity, and biomarker discovery efforts to better guide upfront treatment intensification in this subset are feasible and warranted. (NCT02609269).
Muscle invasive bladder cancer (MIBC) demonstrates neoadjuvant cisplatin-based chemotherapy (NAC) related changes in molecular subtype and immune infiltration.
Authors: Funt Samuel Aaron , Solovyov Alexander , Faltas Bishoy Morris , Iyer Gopa , Boyd Mariel Elena , Cipolla Catharine Kline , Regazzi Ashley Marie , Teo Min Yuen , Lee Chung-Han , Al-Ahmadie Hikmat , Rosenberg Jonathan E. , Greenbaum Benjamin , Bajorin Dean F. 
Published: March 2019

443 Background: Defining the role of MIBC molecular subtypes and immune expression in determining clinical outcomes is an area of active investigation. However, changes in these transcriptomic profiles pre- and post-NAC have not been well characterized. Methods: This retrospective study reviewed 53 pts with MIBC treated with NAC, of whom 12 pts without complete pathological response had both pre- and post-NAC samples of sufficient quality. Post-NAC staging was > = pT2 in 11 pts and pT1 in 1 pt. We performed RNA expression analysis of matched pre-NAC transurethral resection of bladder tumor specimens and post-treatment radical cystectomy primary bladder tumor specimens. We used a customized NanoString panel incorporating previously reported immune signatures (Ayers, JCI 2017; O’Donnell, ASCO 2017) and additional genes to assign basal ( CD14, CD44, PDGFC, KRT14, KRT5) and luminal ( GATA3, PPARG, SHH, CD24, FOXA1, WNT7B, ERBB2) molecular subtypes. Results: We first classified the bladder cancer cohort of The Cancer Genome Atlas into basal and luminal subtypes using the BASE47 signature (Damrauer, PNAS 2014) and the NanoString panel and there was good agreement (Rand Index = 0.72). We then assigned subtypes using the NanoString panel on matched pre- and post-NAC samples and found marked subtype shift (Table). We identified two robust clusters of samples according to immune expression with a 3-fold change of immune expression between them (FDR = 0.0008). We found that 4 pts switched from the low to the high cluster, while 2 switched from the high to the low cluster after NAC (Table). Conclusions: MIBC molecular subtype membership is dynamic and is influenced by NAC. NAC can induce both enhanced and suppressed immune activity. These findings have implications on future studies exploring the predictive value of RNA expression patterns for bladder cancer therapies as well as post-NAC immunotherapy. [Table: see text]
Intra-vesical therapy using 4N1K-peptide in bladder cancer and its effects on tumor growth and angiogenesis.
Authors: Miyata Yasuyoshi , Araki Kyohei , Yuno Tsutomu , Nakamura Yuichiro , Sagara Yuji , Matsuo Tomohiro , Ohba Kojiro , Sakai Hideki 
Published: March 2019

446 Background: The 4N1K-peptide (KRFYVVMWKK), which is derived from thrombospondins has anti-cancer activities in several cancers. We previously found that 4N1K-peptide expression was negatively associated with tumor invasion and prognosis in patients with bladder cancer (BC). The main aim of this study is to clarify whether intravesical therapy using 4N1K-peptide has anti-cancer effects in BC by in vivo and in vitro studies. Methods: Change in tumor growth and apoptosis due to transfection of 4N1K-peptide were evaluated in the BC cell line, T24 cells. Next, to clarify the anti-cancer effects of 4N1K-peptide as intra-vesical therapy, cell survival, apoptosis, and microvessel density (MVD) were investigated in chemical (BBN)-induced BC mouse model. In this study, natural saline (Ns) and 4NGG-peptide which has a similar structure to 4N1K-peptide but does not have any biological activity were used. In addition, survival analyses are performed in these mouse model. Results: In T24 cells, mean/SD of AI in 4N1K-peptide-transfected cells was 7.9/1.1%, which was remarkably higher (P < 0.001) than that in 4NGG-peptide-transfected cells (1.6 / 0.2%). In mouse model, 7 of the 20 mice treated with Ns died because of cancer-related symptoms, and invasive cancer was detected in 9/13 (69.2%). In contrast, in mice treated with 4N1K-peptide, 1 of 15 mice was died and invasive disease was observed in 1/14 (7.1%) at 24 weeks of age. Kaplan-Meier survival cures showed mice treated with 4N1K-intarvesical therapy had better prognosis compared to others (P = 0.036). In mouse tissues, apoptotic index in mice treated with 4N1K-peptide was significantly higher (P < 0.01) than that in others. In contrast, MVD in mice with 4N1K-peptide was significantly lower (P < 0.05) compared to others. In normal urothelium of mouse treated with 4N1K-peptide, change of morphological characteristics was not detected. Conclusions: 4N1K-peptide played as tumor-suppressor by regulating apoptosis and angiogenesis in BC animal model. Therefore, there is the possibility that 4N1K-peptide is a potential useful and safety therapeutic agent for intra-vesical therapy in BC patients.
Potential markers of response and resistance to programmed cell death-1 blockade in first-line therapy of cisplatin-inilegible advanced urothelial cancer.
Authors: Carretero-Gonzalez Alberto , Homet Moreno Blanca , Dueñas Marta , Martínez-Fernández Mónica , Manneh Ray , Bernardini Alejandra , Rubio Carolina , Villacampa Felipe , García Martín Rosa M. , García Escudero Ramón , Rodríguez Peralto José L. , Rueda Daniel , De Velasco Guillermo , Castellano Daniel E. , Paramio Jesús M 
Published: March 2019

449 Background: Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit in advanced urothelial cancer (UC) patients. An alert was issued about a decrease in survival for bladder cancer patients with PD-L1-low status receiving immunotherapy versus chemotherapy as first-line therapy. We studied a small series of UC patients treated with first-line PD-1 checkpoint inhibition in order to analyze their characteristics and patterns of response to therapy. Methods: Eleven UC samples were obtained from patients before undergoing therapy with ICIs. Patients were classified according to their benefit from therapy in responders (n=5) and non-responders (n=6). Genomic and immunohistochemistry analyses were performed. Results: Both luminal and basal UC subtypes showed benefit from ICIs. Tumors from non-responders showed increased mutations in chromatin remodelling genes and the amplification of 3q26-28 region. Transcriptome analyses showed that tumors from responders displayed a significant enrichment of genes associated with interferon γ and α response, TNFα via NFκB, genes upregulated by MYC or E2F1, genes involved in G2/M checkpoint and epithelial-mesenchymal transition compared to non-responders. Specific immune cell subsets were present in the tumor microenvironment of tumors from responders and non-responders. Immunohistochemistry showed that none of the immune cell markers analyzed individually was sufficient to discriminate between responders and non-responders. However, the increase in FOXP-3, PD-L1, PD-1, CD8, β2 microglobulin and CD68 and the decrease in CD4 and CD163 cells identified UC patients that responded to ICIs. Conclusions: Our findings confirm that the evaluation of pre-treatment UC tumor samples provides valuable information that could influence treatment decisions. Despite the clinical benefit of PD-1/PD-L1 inhibition in UC, only a fraction of patients benefit from therapy. Our data suggest that responders and non-responders display diverse genomic and transcriptome changes as well as specific immune cell subsets in the tumor microenvironment that can be identified by conventional IHC staining.
Lentiviral interferon: A novel method for gene therapy in bladder cancer.
Authors: Mokkapati Sharada , Duplisea Jonathan J , Plote Devin , Narayan Vikram M , Lim Amy , Metcalfe Michael J. , Dunner Kenneth , Czerniak Bogdan , Nieminen Tiina , Heikura Tommi , Yla-Herttuala Seppo , Parker Nigel , Schluns Kimberly , McConkey David James , Dinney Colin P.N. 
Published: March 2019

456 Background: Gene therapy for bladder cancer (BLCA) is rapidly evolving. We reported that intravesical adenoviral interferon-alpha (Ad-IFNα) produced a complete response in 35% of patients with BCG-unresponsive BLCA enrolled in a Phase II trial. Lentivirus (LV) is another potential vector for intravesical delivery of IFNα. Unlike the adenovirus, LV can infect non-dividing cells and integrate into the host’s genome, making it one of the most efficient gene delivery vectors. The objective of this study was to investigate lentiviral interferon-alpha (LV-IFNα) BLCA gene therapy in preclinical models. Methods: Murine BLCA cell lines were transduced in-vitro with LV-IFNα using a multiplicity of infection (MOI) of 2:1. IFNα levels were measured by ELISA. Cell viability was assessed using Trypan blue dye exclusion. qPCR was used to identify expression of IFNα target genes. A LV-βGalactosidase reporter construct was delivered intravesically, and urinary IFNα levels were measured in mice treated with LV-IFNα or control virus to assess gene transfer. To assess survival benefit, p53+/- C57/B6 mice were exposed to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) to induce CIS and then treated with LV-IFNα or control virus, and sacrificed when moribund. Results: Efficient LV-IFNα transduction of BLCA cells was observed at an MOI of 2:1, resulting in increased expression of IFNα and its target genes PDL-1, TRAIL, and IRF7 (p<0.001), and reduced cell viability vs. controls (p<0.001). Mechanistically, TRAIL dependent cytotoxicity in the LV-IFNα cells was rescued by Caspase 8 inhibition. βGal expression confirmed efficient transduction of murine urothelium. Urinary IFNα levels were elevated in mice receiving LV-IFNα compared with control virus. BBN mice treated with LV-IFNα had longer overall survival than mice treated with control virus (p=0.04). LV-IFNα induced intratumoral CD8+ T cell infiltration, high expression of PD-L1, and inhibited angiogenesis. Conclusions: LV-IFNα effectively upregulated IFNα target genes, was cytotoxic to murine BLCA cells, and improved the survival of BBN tumor-bearing mice. LV appears to be a promising vector for intravesical gene delivery.
The impact of intratumoral heterogeneity on prognostic biomarkers in localized prostate cancer.
Authors: Brastianos Harry , Murgic Jure , Salcedo Adriana , Chua Melvin Lee Kiang , Meng Alice , Fraser Michael , Brundage Michael Donald , Fleshner Neil Eric , van der Kwast Theodorus , Bristow Robert G. , Boutros Paul Christopher , Berlin Alejandro 
Published: March 2019

46 Background: Genomic biomarkers can identify patients that harbour aggressive disease. The utility of these biomarkers is uncertain due to genomic variation between prostate biopsy specimens. To quantify the robustness of genomic biomarkers, we performed spatio-genomic characterization of distinct tumor foci. We scored three validated DNA-based biomarkers of early biochemical recurrence: percentage of genome with a copy number aberration (PGA), a 100-loci biomarker, and an optimized 31- loci biomarker derived from the previous. For each biomarker, we determined their robustness to intratumoral heterogeneity in association with predicting early biochemical recurrence (eBCR; ≤18 months) and long term control (LTC; ≥48 months). Methods: We queried a registry of 1054 patients with high-risk prostate cancer who underwent a radical prostatectomy (RP). We developed a cohort (n = 42) risk matched by clinicopathologic prognostic indices. Half of the patients had eBCR, while the other half had LTC. We profiled multiple tumor foci per patient, analyzing 119 tumor foci. For each focus, CNA profiles were generated, and three biomarker scores were calculated. For each patient and biomarker, we calculated the score of the lowest-score region, the highest-score region, or sampling of all foci and use the mean score. Results: All three biomarkers distinguished LTC from eBCR. PGA scores separated the two groups with an area under the receiver operator curves (AUC) ranging from 0.75-0.80. The 100- and 31-loci signatures, had AUCs ranging from 0.76-0.85 and 0.76-0.80 respectively. Using Cox proportional hazards modeling, we found that PGA was associated with LTC (Hazard ratio (HR) range: 2.56-6.22; p < 0.05. This was replicated for the 100-loci signature (HR range: 3.55-5.23; p < 0.05). The 31-loci detected associations with eBCR independent of how different foci were summarized (log-rank p-value range: 5.1 x 10-4- 5.9 x 10-3). Conclusions: Despite divergence in biomarker scores, all three predicted eBCR. Our study suggests that genomic biomarkers can overcome intratumoral heterogeneity, making discrete samples potentially adequate in patients with high-risk disease to determine the risk of eBCR after radical treatment.
MRI-guided prostate brachytherapy dose escalation to the dominant intraprostatic lesions: A retrospective analysis of urinary toxicity and biochemical response.
Authors: Wakil George , Côté Nicolas , Lymberiou Timothy , Aaron Lorne , Antebi Elie , Arjane Philippe , Derashodian Talar , Do Vien , Jolicoeur Marjory , Nachabe Mahmoud , Van Nguyen Huynh Thu , Duguay-Drouin Patricia 
Published: March 2019

47 Background: Magnetic resonance imaging (MRI) allows for delineation of the dominant intraprostatic lesions (DIL) thus minimizing the risk of a geographic miss. At our center, using MRI planning following the brachytherapy implant, the DIL is defined as the gross tumor volume (GTV) and receives at least the prescribed dose. This retrospective analysis studies the biochemical response and urinary symptoms of a MRI-guided escalated dose to the DIL during prostate brachytherapy. Methods: Intermediate- or high-risk patients with a visible DIL on the diagnostic MRI, treated between 2013 and 2016, with combined external-beam radiation therapy (46 Gray) and a high-dose rate whole prostate brachytherapy (15 Gray), were analyzed. Baseline characteristics and dosimetric values were obtained as well as PSA and International prostate symptom score (IPSS) at baseline, 3, 6, 12, 18, 24, 36 and 48 months (mos). Results: A total of 117 patients were studied, of which 58% were intermediate-risk and 42% high-risk. Median follow-up was 31 months (10-69 months). The biochemical progession-free survival (bPFS) was 97.4%. The median GTV D100 (dose to 100% of the GTV) and CTV V100 (percentage of the clinical target volume, defined as the whole prostate, receiving 100% of the prescribed dose) were 119% and 97.97%. The median PSA at 12, 24, 36 and 48 months for all patients and for patients treated without androgen deprivation therapy (ADT), was 0.18, 0.11, 0.06, 0.07 μg/L, and 0.73, 0.35, 0.1, 0.08 μg/L, respectively. The median IPSS score at baseline was 6 and remained stable over time. Conclusions: MRI-guided dose escalation to the GTV during brachytherapy boost yields an excellent bPFS and a rapid PSA drop without an increase in urinary symptoms. [Table: see text]
Results from a phase I/Ib trial of enzalutamide and gemcitabine and cisplatin in metastatic bladder cancer (mBC).
Authors: Gupta Shilpa , Dhillon Jasreman , Magliocco Anthony Martin , Puskas John , Caceres Gisela , Masawi Fadzai , Doronin Yulia , Zhang Jingsong 
Published: March 2019

471 Background: Novel targeted therapies are an unmet need in mBC. Androgen receptor (AR) is a rational target in BC and we conducted a phase 1/1b trial assessing safety and tolerability of AR antonist, enzalutamide (ENZ) in combination with gemcitabine and cisplatin (GC) in mBC. Methods: The dose escalation phase allowed patients with mBC regardless of the AR status (assessed on routine IHC) and dose expansion cohort allowed only AR+ pts. The dose escalation phase had 2 cohorts testing ENZ at doses of 80 and 160 mg respectively with GC (G 1000 mg/m2 on days 1, 8 and C 70 mg/m2 on day 1 every 21 days). After 6 cycles of ENZ+GC, pts. continued maintenance ENZ until disease progression. Primary objective was safety and tolerability of ENZ and GC. Secondary objectives were PFS, OS and objective tumor response. Exploratory objectives included evaluation of AR expression in tumor tissues and correlation with outcomes and CTC evaluation at baseline and prior to cycle 3, including AR expression in CTCs and correlation with clinical outcomes. Key eligibility criteria included ECOG PS of 0-1, and no contraindications to ENZ and GC. Results: A total of 10 pts were enrolled between Nov. 2014 and Jan. 2017; 6 pts were enrolled on the dose escalation phase, there were no DLTs observed and ENZ dose of 160 mg was used for the dose expansion cohort, which enrolled 4 pts. The combination of ENZ and GC was well tolerated with expected toxicities, mainly from GC. Median age was 65.6 yrs, 9/10 pts were male; of the 8 evaluable pts, 1 had CR, 4 had PR, 2 had SD and 1 had PD; median OS was 10.59 mos and median PFS was 7.68 mos. CTCs were detectable in 9/10 pts and correlated with disease response. The pt with CR was a female pt with strongly AR + tumor (>90%) and continues to remain in CR 24 months from starting treatment. Exploratory analysis from CTCs and is ongoing. Conclusions: This is the 1st clinical trial to target AR signaling in mBC with ENZ and to evaluate safety of ENZ with GC. While there were limited number of pts enrolled, the results from this study provide early evidence that AR is a rational target in BC and anti-AR therapies can be safely combined with chemotherapy. Clinical trial information: NCT02300610.
Germline alterations in urothelial carcinoma (UC) patients with family history of UC.
Authors: Nassar Amin , Mouw Kent William , Esplin Edward D. , Yang Shan , Callis Tom , Nuzzo Pier Vitale , Chanza Nieves M. , Choueiri Toni K. , Kwiatkowski David J. , Sonpavde Guru 
Published: March 2019

474 Background: UC is associated with germline alterations in a small minority of patients (pts). The prevalence of germline alterations in those with familial UC is unknown. We identified genomic alterations among familial UC pts to provide insights into pathogenesis and improve management. Methods: We analyzed deidentified data for UC pts with germline multigene panel testing (Invitae) who had a family history of UC, defined as a 1st-3rd degree relative with UC. Massively parallel sequencing used customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number variations (CNVs) for 1-126 genes. Pathogenic and likely pathogenic (P/LP) variants underwent orthogonal confirmation, per standard policy, including single nucleotide variants (SNVs)/small indels/CNVs. Patient characteristics were compared using the Fisher’s Exact and Wilcoxon-Rank Sum test. Results: 79 UC pts with a family history of UC were identified (67 bladder, 6 upper tract, 6 unknown). Six patients (8%) were excluded as the relation of the family member was unknown. 48/73 (66%) pts had first-degree relatives (fdr) with UC (4 upper tract, 39 bladder, 5 unknown) and 25 (34%) had second-degree (or higher) relatives (sdr) (2 upper tract, 22 bladder, 1 unknown). 56 germline alterations were found in 38 (52%) pts. 14 known pathogenic alterations occurred in 13 (18%) pts: SDHC (1), MITF (2), BRIP1 (1), BRCA2 (1), MSH2 (3), BRCA1 (1), CHEK2 (1), PTCH (1), MUTYH (2), BAP1 (1). 8/48 (17%) pts with fdr had pathogenic variants vs. 5/25 (20%) pts with sdr or more. There was no difference in the prevalence of pathogenic variants based on gender (p=0.37) or age (p=0.77). The limitations are modest sample size and differences in panels of genes. Conclusions: This is the first study to our knowledge to report germline alterations in UC pts with a family history of UC. Pathogenic germline alterations were seen in 18% of pts, which were enriched for DNA damage repair gene alterations, and could have important therapeutic implications. Further study of germline alterations using larger panels in pts with family history of UC may provide novel insights, since most pts did not have pathogenic alterations.