bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment (trx) patterns of angiogenesis inhibitors in patients (pts) with metastatic renal cell carcinoma (mRCC) in Ireland.
Authors: McDermott R. S. , Donnellan P. P. , McCaffery J. , Sarda S. P. , Korves C. , Luka A. , Wei R. , Neary M. , Hanley R. , Duh M. S. 
Published: February 2017

383 Background: This study evaluated rates of trx modifications and reasons for these changes among pts treated with angiogenesis inhibitors in Irish clinical practice. Methods: Data from medical records were retrospectively reviewed at 3 large oncology centers in Ireland for mRCC pts who were ≥ 18 years and received sunitinib (SU) (n=54), sorafenib (n=9), bevacizumab (n=6), or temsirolimus (n=7) as first-line trx from 1/1/2005 to 8/31/2010. Proportions of pts with trx discontinuation (d/c), interruption, or dose change, and reasons for modifications and time to modifications were determined. Results: Due to small sample sizes in other groups, only results for SU are summarized. 1.9% of pts had prior cytokine therapy. Median first-line trx duration for SU was 8.7 months (mo), while median progression-free survival was 13.8 mo. 87% of patients treated with first-line SU experienced adverse events (AEs); 18.5% experienced grade 3/4 AEs. AEs led to trx modifications in 42.6% of pts. 94.4% of pts started trx on 50 mg QD 4/2 dosing; 33.3% of them were dose reduced to 37.5 mg QD 4/2 with median time to reduction 2.7 mo. Among pts who discontinued trx, 31.6% discontinued within 18 weeks (w) (15.8% within 0-6 w, 7.9% in 7-12 w, and 7.9% in 13-18 w). Among pts who discontinued trx within 18 w, 66.7% discontinued due to AEs. Conclusions: Over three-quarters of SU pts experienced trx modifications, more than half due to AEs. About 24% of txt discontinuations occurred within the first two cycles. This real-world practice study suggests that treatment tolerability is a challenge for physicians in the clinical care of mRCC pts. [Table: see text] [Table: see text]
GAPDH, YWHAZ, and RRN18S as control reference genes for gene expression studies on renal cell carcinoma (RCC) formaldehyde-fixed paraffin-embedded (FFPE) tissue samples.
Authors: Medina Villaamil V. , Vazquez-Estevez S. , Campos B. , Leon Mateos L. , Fírvida J. L. , Ramos M. , Afonso F. J. , Fernández Calvo O. , Valladares Ayerbes M. , Antón Aparicio L. M. 
Published: February 2017

389 Background: It is mandatory to have a control reference gen (RG) to correctly measure gene expression by real-time quantitative PCR (qPCR). The purpose of this study was to test a panel of 12 RGs (Human Endogenous Control Gene Panel, tataabiocenter) in order to select and validate the most appropriate control genes for expression studies on FFPE RCC tissues. Methods: qPCR followed by Normfinder and geNorm-based analysis was employed (GenEx Standard). The study was performed on 9 selected RCC tumor samples with different local stage (T1, T2 and T3). The most representative RCC histologies were also collected; clear-cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC) and cromophobe renal cell carcinoma (cRCC). A commercial pool (Biochain) of 5 cases of normal kidney was analyzed too. All samples were measured in triplicate. Expression levels of RGs: GAPDH, TUBB, PPIA, ACTB, YWHAZ, RRN18S, B2M, UBC, TBP, RPLP, GUSB and HPRT1 were measured by qPCR on a Light Cycler 480 (Roche) utilizing Light Cycler 480 SYBR Green I Master (Roche). Results: The analysis of experimental data showed that RRN18S is the most stable gene found in our FFEP RCC samples followed by GUSB and TBP. In contrast, ACTB was found to be the least stable gene between our samples. GAPDH together with YWHAZ was showed as the pair of genes introducing the least systematic error into data normalization (M-value < 1) needed to conduct expression gene studies further. Conclusions: These data suggest that GAPDH, YWHAZ and RRN18S are the most suitable RGs for gene expression profile studies in FFEP RCC. Standardization of RGs will help us to compare results from translational studies on RCC FFPE samples genes profiling. No significant financial relationships to disclose.
Correlation of percent of core biopsies positive for prostate cancer and biochemical outcome following I-125 prostate brachytherapy or external beam radiation.
Authors: Tendulkar R. D. , Stephans K. L. , Reddy C. A. , Martires K. , Patel A. R. , Raj D. , Lowes D. , Geng T. , Klein E. A. , Ciezki J. P. 
Published: February 2017

40 Background: The percentage of positive cores (PPC) on biopsy for prostate cancer has been identified as a predictor of outcome following definitive local treatment. We aim to identify whether this observation holds true for a modern cohort of patients (pts) treated at Cleveland Clinic with permanent prostate brachytherapy (PB) or external beam radiation therapy (EBRT). Methods: We retrospectively reviewed pathology reports of pts treated with either PB or EBRT from our IRB-approved prospective prostate cancer registry. No pts underwent both PB and EBRT. The number of biopsy cores sampled, number of cores positive for prostate cancer, and maximum length of any core positive for prostate cancer were collected. Cox proportional hazards regression was used to analyze biochemical relapse free survival (bRFS) using the nadir + 2 ng/ml definition. Results: We identified 1253 PB and 879 EBRT pts with complete pathology and clinical information. Among PB pts, 46% were low risk, 40% intermediate risk, and 14% high risk, while 78% had <50% PPC, and 22% had >=50% PPC. The 5-year bRFS for PB was 92.0% for <50% PPC, vs. 83.1% for >=50% PPC (HR 2.1, p=0.0005). For PB pts, significant predictors of bRFS on univariate analysis included: PPC, clinical T stage, PSA, biopsy Gleason score, androgen deprivation, and frequency of PSA testing. On multivariate analysis, only PPC, biopsy Gleason score, and PSA frequency remained significant predictors following PB. Among EBRT pts, 11% were low risk, 36% intermediate risk, and 53% high risk, while 55% had <50% PPC, and 45% had >=50% PPC. The 5-year bRFS for EBRT was 85.6% for <50% PPC, vs. 77.1% for >=50% PPC (HR 1.8, p<0.0001). For EBRT pts, significant predictors of bRFS on univariate analysis included: PPC, clinical T stage, PSA, biopsy Gleason score, androgen deprivation, EBRT dose, and frequency of PSA testing. On multivariate analysis, only PPC, biopsy Gleason score, and PSA frequency remained significant predictors following EBRT. Conclusions: Following PB or EBRT, the percent of positive cores for prostate cancer was a significant predictor of bRFS on multivariate analysis, more so than conventional predictors such as T stage and PSA. No significant financial relationships to disclose.
Long-term therapy with sunitinib and sorafenib in patients with metastasizing renal cell carcinoma.
Authors: Richter S. , Piper C. , Pfister D. A. , Brehmer B. , Heidenreich A. 
Published: February 2017

407 Background: Multitargeted tyrosine kinase inhibitors (MTKIs) constitute the established therapy in patients with metastasizing renal cell carcinoma. There are only few data concerning efficiency and safety, the reasons for a longterm response with good tolerability under MTKIs is still unknown. Methods: We retrospectively analyzed the data of patients (pts.) under long-term therapy (>1 year) with sorafenib or sunitinib. Localization of metastases, number of cycles, sequence of therapy, treatment-associated toxicities, and frequency of dose reductions were our main focus of interest. Results: 15 pts. (14 male, one female) with an mean age of 66,33 (44-81) years, were treated with 19,86 (12-35) cycles of sorafenib or sunitinib. 14/15 pts. underwent radical nephrectomy before the treatment. Localization of metastasis were as follows: pulmonary (9/15), hepatic (4/15), nodal (8/15), osseous (3/15), and pancreatic (2/15). In four pts. two or more organs were affected, in six pts. only one organ. As a first-line therapy nine pts. received sunitinib for 20.67 (12-35) cycles and one patient sorafenib for 44 cycles. For second line therapy two pts. were treated with sunitinib for 13 (12-14) cycles and three pts. with sorafenib for 23.33 (18-28) cycles. In five pts. a dose reduction of 25-50% was necessary due to significant treatment associated side effects, afterwards toxicities were tolerable under long term therapy (grade 1 in 10 pts.). Conclusions: The results show, that longterm therapy with sunitinib or sorafenib is tolerable and efficacious independent on previous treatment. Prognostic factors concerning longterm response and low toxicity profile at a molecular biological level are still unknown, further investigations are of importance and are currently performed at our institution. No significant financial relationships to disclose.
MicroRNAs as emerging biomarkers for micrometastasis detection in genitourinary tumors.
Authors: Medina Villaamil V. , Santamarina Caínzos I. , Aparicio Gallego G. , Quindós Varela M. , Dopico Vázquez D. , Antolín Novoa S. , García Campelo R. , Reboredo M. , Valladares Ayerbes M. , Antón Aparicio L. M. 
Published: February 2017

52 Background: MicroRNAs regulate numerous aspects of normal and pathological cellular processes, including cancer. Detection of circulating tumor cells (CTC) may provide diagnostic and prognostic information in genitourinary (GU) tumors. miRNAs may also be considered as potential therapeutic targets when overexpression is associated to pathogenic effect. miRNAs may constitute a promising new class of cancer biomarkers for CTC detection. The aim of this work is identify miRNAs potentially useful for CTC detection in blood samples from patients with GU tumors: bladder, prostate and renal tumors. Methods: miRGator, miRBase, smiRNAdb, GeneHUB-GEPIS, microRNA.org and miRNAMap free databases were used in order to identify miRNAs as biomarkers for CTC detection. In silico data were used to identify miRNAs highly expressed in GU tumors, but absent in hematopoietic-derived sources. RNA enriched in miRNAs was isolated from: GU tumors (bladder: HT1376, HT1197; prostate: VCaP, LNCaP and renal: ACHN, A704) and hematopoietic cell lines, GU tumor tissues (N= 6) and healthy blood samples (N= 19). mirVana miRNA and RiboPure Blood isolation kits were used. Using qRT-PCR miRNAs tumor-related were amplified. Results: Bioinformatic analysis included tissue-specific and oncogenic miRNAs and showed that mir-31, mir-136, mir-133a, mir-145, mir-187, mir-200a, mir-200b, mir-200c, mir-368 and hsa-let-7c levels were up-regulated in tumor tissues from patients with advanced GU tumors. For instance, relative expression of mir-31 was 6-timeshigher in bladder cell lines than in normal peripheral blood, mir-200c was 104-times higher in renal tumor tissue than in normal peripheral blood and finally hsa-let-7c was 3-times higher in prostate tumor tissue than in healthy blood samples. Conclusions: These results suggest that this bioinformatic approach is an useful high-throughout method to identified GU tumors-associated miRNAs. The selected miRNAs should be further evaluated for their potential as markers for CTC detection, prognosis and therapeutic outcome. This work was supported by Grants PI07/0477 from Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III. No significant financial relationships to disclose.
Androgen pathway constitutional polymorphism predictors of progression-free and overall survivals in advanced castrate-resistant prostate cancer (CRPC) patients treated with ketoconazole (KC).
Authors: Davis T. L. , Jung J. , Carr K. A. , Philips S. , Mohammadi Y. , Campbell M. T. , Li L. , Sweeney C. , Skaar T. C. , Hahn N. M. 
Published: February 2017

54 Background: Recent trials have highlighted the clinical utility of second-line hormonal therapies for CRPC. KC, an oral inhibitor of CYP3A4 and CYP17, is commonly used in this setting. Germline SNPs in genes critical to hormone synthesis, transport, metabolism, binding sites, and degradation may contribute to variability in outcomes observed in KC treated CRPC pts. Methods: Between 1/07 and 10/08, all PCa pts seen in the Indiana University Simon Cancer Center oncology clinics were approached for recruitment to the Prostate Cancer Genetic Risk Evaluation of SNPs Study (PROGRESS). Participants completed a demographic and clinical questionnaire and provided a peripheral blood sample. Only pts with initiated on KC were included in this analysis. Germline DNA was analyzed for SNP genotyping on a 128-SNP chip using a TaqMan OpenArray GT Kit. The chip included genes critical to hormone signaling, transport, and elimination pathways with minor allele frequencies > 5%. Pts were followed for progression-free survival (PFS) and overall survival (OS) endpoints. Univariable analyses were performed to identify significant associations between SNP genotype, clinical parameters, and PFS and OS outcomes. Results: Between January 2007 and October 2008, 39 pts with CRPC initiated on KC therapy enrolled. Demographics included: age (median) – 70 yrs, prostate specific antigen (PSA) (median) – 13.0 ng/ml, PSA doubling time (median) – 2.9 months, metastatic –85%, ECOG PS 0– 74%. Age < 70 was associated with shorter PFS (p=0.010) and age > 70 was associated with shorter OS (p=0.030). SNPs significantly associated with PFS and OS are summarized in the table. Conclusions: Interpatient differences in hormonal pathway germline SNPs may contribute to variability in clinical outcomes in pts treated with KC. [Table: see text] No significant financial relationships to disclose.
Use of serum and tissue biomarker analysis embedded in a phase II clinical trial of cytarabine in castration-refractory prostate cancer to investigate prostate cancer biology.
Authors: Niraula S. , Emmeneger U. , Adams L. , Tannock I. , Sridhar S. S. , Knox J. J. , Day J. R. , Manthe J. , Groskopf J. , Joshua A. M. 
Published: February 2017

59 Background: Other than the androgen receptor, the TMPRSS2-ERG genomic aberrations in prostate cancer provide the first recent opportunity to target therapy in castration refractory prostate cancer (CRPC). We initiated a phase II clinical trial of cytarabine in docetaxel refractory CRPC on the basis of microarray, in vitro and case report evidence that cytarabine may be particularly effective in men harbouring abnormalities of the ERG oncogenes. Embedded in this clinical trial was the first use of blood mRNA levels of prostate cancer related genes as biomarkers of response and prognosis. Methods: Patients with docetaxel refractory progressive CRPC received intravenous cytarabine at doses between 1g/m2-0.25 g/m2 q3 weekly. Responses were defined according to PCWG2C. 10 patients were enrolled between June 2007 and January 2010. TMPRSS2:ERG, PSA and PCA3 mRNA copies in whole blood collected with PAXgene tubes at the beginning of each cycle and at trial termination were quantified using transcription-mediated amplification assays. The prototype TMPRSS2:ERG assay detects the gene fusion isoform TMPRSS2 exon1 to ERG exon4. Results: No patients demonstrated a serum PSA response (PCWG2C). The average number of cycles administered was 2.6. Significant toxicities including grade 3-4 thrombocytopenia (2) and grade 3-4 neutropenia (3). These toxicities necessitated several dose reductions in the protocol, however most patients were removed from trial for serum PSA progression alone. PCA3 and PSA mRNAs were detectable in 8/10 and 9/10 cases, respectively; there was no correlation between serum PSA and PCA3 or PSA mRNA copy levels in blood. Testing for TMPRSS2:ERG in blood was able to predict the presence or absence of the TMPRSS2-ERG rearrangement in 9/10 cases when compared to 3 colour FISH carried out on baseline biopsies/ prostatectomies (2/10 positive for Exon 4:Exon 1 deletion). Conclusions: Cytarabine administation is ineffective in docetaxel refractory CRPC. Blood mRNA levels of prostate cancer genes reveal novel aspects of prostate cancer biology and have implications for the understanding of circulating tumour cells. [Table: see text]
Identification of gene copy number and whole-genome methylation changes associated with lethal metastatic castration-resistant prostate cancer (CRPC).
Authors: Friedlander T. W. , Roy R. , Tomlins S. A. , Kobayashi Y. , Rubin M. A. , Pienta K. J. , Chinnaiyan A. , Small E. J. , Ryan C. J. , Paris P. 
Published: February 2017

6 Background: Metastatic CRPC undergoes significant genomic evolution compared to primary, localized disease. Multiple genetic mechanisms contribute to this evolution including changes in gene copy number as well as and changes in CpG island methylation. In this study, copy number and methylation status of metastatic CRPC tissue obtained at autopsy were assessed by high-resolution array comparative genomic hybridization (aCGH) and whole genome methylation microarray profiling. Methods: Array CGH was performed on DNA isolated from metastatic CRPC samples obtained from the University of Michigan Rapid Autopsy Program, using the Agilent Human Genome 244K CGH Microarray. A total of 15 samples comprising 7 metastatic liver implants and 8 soft tissue metastases were analyzed with DNA Analytics 4.0 software. Expression of genes identified as commonly amplified or deleted was assessed in a confirmatory fashion using existing Agilent 4×44 Expression Array data. The Illumina Infinium HumanMethylation27 BeadChip was used to determine whole genome methylation status. Results: A total of 79 amplified and 419 deleted genes common to >66% of samples were identified. There was significant correlation (p<0.05) of gene copy number to the mRNA level for 9 of the amplified and 76 of the deleted genes, including amplification/overexpression of AR and deletion/underexpression of the tumor suppressors PTEN and RB. While copy number was normal for the androgen synthesis genes CYP17A1, HSD17B3, HSD17B4, and HSD3B2, methylation analysis indicates their upregulation in the majority of samples, suggesting an alternative mechanism of intratumoral hormone production. There was promoter hypermethylation and gene deletion of RB1 in >85% of samples, suggesting that inactivation of this tumor suppressor through multiple pathways is critical to tumor cell survival. Conclusions: This is the first known study examining both gene copy number and whole genome CpG island methylation status in metastatic CRPC. Integration of this data allows for identification of specific genes or pathways that confer a selective growth advantage to prostate cancer cells harboring those changes. No significant financial relationships to disclose.
High dose rate brachytherapy as a single 15 Gy fraction combined with hypofractionated external beam radiotherapy for intermediate-risk prostate cancer.
Authors: Morton G. , Loblaw D. A. , Chung H. T. 
Published: February 2017

66 Background: High dose rate (HDR) brachytherapy for prostate cancer is commonly given in multiple fractions combined with external beam radiotherapy (EBRT) over 5 weeks. We report results of a phase II clinical trial of single fraction HDR combined with hypofractionated EBRT over 3 weeks. Methods: Eligible patients had T1 or T2 carcinoma of the prostate with a PSA < 20 and Gleason score of 7 or less, without use of androgen deprivation. The trial accrued 125 patients with a median PSA of 6.8 ng/ml; 93% had Gleason 7. Single 15 Gy HDR was delivered to the prostate, followed 2-weeks later by EBRT to 37.5 Gy in 15 fractions. Patients were followed for toxicity (CTCAE v 3.0), health related quality of life (EPIC), urinary symptoms (IPSS), and clinical and biochemical control. Results: Median follow-up is 3 years (range: 1-4.5 years), with no biochemical failures. Median PSA at 3 years is 0.24 ng/ml. One of 38 biopsies at 2 years had persistent cancer. Two patients (1.6%) had acute grade 3 urinary toxicity, and median IPSS score returned to within 2 points of baseline by 3 months. The prevalence of grade 2 rectal and urinary toxicity at 2 years was 2% and 25%, respectively. Mean EPIC urinary and bowel domain scores decreased in the first 2 years, but returned to within 5 points of baseline at 3 years. Mean sexual function scores declined over the first 4 years although sexual bother scores returned to baseline at 3 years. On multivariate analysis, baseline IPSS score (p=0.0125), V100 (p=0.0002) and V200 (p=0.0141) were associated with acute grade 2 urinary toxicity. Decline in EPIC urinary quality of life domain was associated with HDR dose to 10% of urethra (p=0.0168), with a threshold of 120%. Decline in sexual scores was associated with smaller prostates and high baseline erectile functioning. Conclusions: Single fraction 15 Gy HDR combined with hypofractionated external beam radiotherapy is a well tolerated and effective treatment for intermediate risk prostate cancer. No significant financial relationships to disclose.
High-dose radiotherapy with or without androgen-deprivation therapy for intermediate-risk prostate cancer: Cancer control and toxicity.
Authors: Edelman S. , Rossi P. J. , Cooper S. , Jani A. B. 
Published: February 2017

67 Background: Randomized studies show an improvement in biochemical failure-free survival (BFFS) and overall survival (OS) with the addition of androgen therapy (ADT) to external-beam radiotherapy (EBRT) for high-risk prostate cancer (PC). However, the role of ADT in intermediate risk PC in the current dose-escalation era remains poorly defined, as studies evaluating ADT in this group have included high-risk patients or did not use dose-escalation. Our goal was to evaluate the impact of ADT on cancer control and toxicity in intermediate-risk PC. Methods: From a multi-institutional IRB-approved database of 850 pts, we identified 251 intermediate risk PC patients (defined as ≥ T2b or PSA > 10 or Gleason score [GS] of 7, with none of the following: ≥ T3, PSA > 20, GS ≥ 8, positive nodes, distant metastases) treated with EBRT to a dose of ≥70 Gy (no brachytherapy or prostatectomy). Eighty-seven men received ADT; 164 did not. BFFS (Phoenix definition) and OS survival curves for ADT vs no-ADT arms were compared with the log rank test. Univariate and multivariate analyses of major demographic, disease and treatment factors were performed, as were chi-square analyses of genitourinary (GU) and gastrointestinal (GI) toxicity. Results: Median follow up was 47 mo. Mean dose [ADT vs no-ADT] was 76.8 Gy vs 76.2 Gy (p=0.41; range: 70.0-81.0 Gy). The ADT group had a higher mean PSA (12.0 vs 8.9, p<0.001), proportion of ≥ T2b (22 vs 11%, p<0.01) and proportion of pelvic XRT use (49 vs 22%, p<0.001) than the no-ADT group, but the groups were well-balanced by age, race, GS, EBRT dose and intensity-modulated radiotherapy (IMRT) use. For ADT vs no-ADT, 5-yr BFFS was 80% vs 76% (p=0.17) and 5-yr OS was 84% vs 76% (p=0.82). On multivariate analysis, only ADT (p=0.006) and GS (p=0.006) were significantly associated with BFFS, and only PSA (p=0.028) and IMRT use (p=0.011) reached significance for OS. There were no significant differences in acute or late GU or GI toxicity. Conclusions: While RTOG 0815 is exploring this study question in a randomized setting, our study suggests that the addition of ADT to dose-escalated EBRT may improve BFFS, but without a demonstrated OS benefit, and is not associated with additional EBRT-related GI or GU toxicity. No significant financial relationships to disclose.