bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative comparison of mRNA level of corticotropin- releasing factor peptide family in normal kidney and corresponding clear cell renal cell carcinoma specimens.
Authors: Tezval Hossein , Merseburger Axel S. , Kuczyk Markus A. , von Klot Christoph , Serth Juergen 
Published: February 2017

466 Background: Urocortin (Ucn), a 40 amino acid peptide, belongs to the corticotropin releasing factor (CRF) family and exerts its actions mainly in the periphery through activation of two CRF receptors (CRFRs), CRFR1 and CRFR2 and a binding protein (CRFBP/CRHBP). Both receptors are G-protein coupled and binding of Ucn leads to activation of cAMP-dependent protein kinases via elevation of cAMP levels. Ucn and Urocortin III (UcnIII) are involved in conditions such as regulation of local inflammation, angiogenesis, and inhibition of proliferation. Suppression of neovascularization and inhibition of tumor cell cycling by Urocortins is modulated through CRFRs. Activation of CRFRs by e.g. Ucn inhibits angiogenesis via reduction of vascular endothelial growth factor (VEGF) and suppresses the cell proliferation. Here we characterized the whole CRF family on mRNA levels quantitatively comparing the normal and clear cell carcinoma of the kidney (ccRCC). Methods: In this study we measured the mRNA level of Ucn, UcnIII, CRFR1, CRFR2 and CRHBP in 78 RCC samples and paired histologically normal appearing tissues using quantitative PCR. Statistical analyses were carried out using univariate logistic regression analysis. Results: We found tumour specific down regulation of mRNA expression of UcnIII, CRFR1, CRFR2 and CRHBP in samples of RCCs with clear cell histology compared to paired normal tissues (P<0.01 for all targets). Only Ucn did not show any expression difference between two groups (p=0.17). Conclusions: For the first time we showed the expression profile of the whole CRF peptide family in ccRCC compared to normal kidney on mRNA level. Our data underlines the malfunction of this actually strong protective and anticancer system in renal malignancy and shows the involvement of CRF system in carcinogenesis in kidney. More studies are necessary to find out the detailed roles of the CRF system in renal carcinoma.
Propensity score matched analysis of metastasis-free survival for patients with high-risk prostate cancer treated with definitive radiation therapy or radical prostatectomy.
Authors: Meeks Marshall , Markovina Stephanie Subasic , Vetter Joel , Paradis Alethea , Michalski Jeff M. , Sandhu Gurdarshan Singh 
Published: February 2017

47 Background: National Comprehensive Cancer Network (NCCN) category 1 recommendation for localized high risk prostate cancer (HR-PCa) is definitive radiation therapy (RT) and androgen deprivation therapy (ADT). Radical prostatectomy (RP) is also an accepted treatment for patients with localized HR-PCa. Here we report a propensity score-matched analysis of institutional outcomes for patients with HR-PCa treated with RP or RT. Methods: Medical recor ds of patients with localized NCCN HR-PCa treated at our institution from 2002-2011 were reviewed. RT consisted of 73.8-77.4 Gray to the prostate and seminal vesicles; regional lymph nodes were treated for pre-treatment probability of involvement ≥15%. A combination of nearest neighbor propensity score matching on age, Adult Comorbidity Evaluation-27 score [a validated comorbidity index], prostate specific antigen (PSA), biopsy Gleason, and clinical T-stage (cT) and exact matching on PSA, biopsy Gleason, and cT was performed. Multivariate cox-proportional hazards regression was used to compare metastasis-free survival (MFS) and overall survival (OS) (calculated from date of diagnosis). Results: 246 patients were identified (160 RP and 86 RT). Propensity score matching resulted in 62 matched pairs. For the RP group, minimally invasive surgery (70.9%) and lymph node dissection (100%) were common. ADT was administered to 37.1% and 80.6% of patients receiving RP and RT, respectively. Median follow-up was longer for the RT group (51.4 vs 41 months, p = 0.004). Five-year rates of metastasis for RT and RP were 8.9% and 33% (p = 0.003), and for death were 25.9% and 17.6%, respectively (p = 0.31). MFS was significantly better for patients treated with definitive RT compared to RP, while OS was not different (Table). Conclusions: In our cohort with HR-PCa, treatment with RT resulted in a MFS advantage over RP. This was not accompanied by an improvement in OS.The difference in MFS may possibly be related to the importance of early adjuvant ADT. [Table: see text]
Association of baseline IL-8 and ferritin with clinical outcome with everolimus and BNC105P in the DisrupTOR-1 trial.
Authors: Pal Sumanta Kumar , Azad Arun , Bhatia Sumeet , Drabkin Harry A. , Costello Brian Addis , Sarantopoulos John , Kanesvaran Ravindran , Lauer Richard C. , Sweeney Christopher , Hahn Noah M. , Sonpavde Guru , Richey Stephen Lane , Breen Timothy , Kremmidiotis Gabriel , Leske Annabell F. , Doolin Elizabeth E. , Bibby David C. , Simpson Jeremy Andrew , Iglesias Jose Luis , Hutson Thomas E. 
Published: February 2017

475 Background: The vascular disrupting agent (VDA) BNC105P shows synergy with everolimus in preclinical models. The DisrupTOR-1 trial included a phase I component exploring this combination and a randomized phase II component comparing everolimus with BNC105P (Arm A) to everolimus monotherapy (Arm B) (Pal et al. ESMO 2014). Methods: Pts with clear cell mRCC and 1-2 prior therapies (including ≥1 VEGF-TKI) were randomized in the phase II study component. In Arm A, patients received a 7 day lead-in dose of everolimus followed by dosing with BNC105P. Patients in Arm A had optional blood collections prior to administration of BNC105P and 3 hours after receiving BNC105P. A fluorescence-based assay was used to characterize a broad panel of analytes at each time point. Biomarkers were assessed in both a static and dynamic fashion. For the former, biomarkers were stratified by median value, and progression-free survival (PFS) was compared in resulting subgroups using the Kaplan-Meier method. For the latter, change in biomarker level before and after BNC105P infusion was stratified by median difference, and PFS was compared in resulting subgroups using the Kaplan-Meier method. Results: 139 pts were randomized with 69 and 67 evaluable pts in Arms A and B, respectively. Dynamic biomarkers were assessed in a total of 44 patients who received everolimus with BNC105P. Increases in matrix metalloproteinase-9 (MMP-9) and stem cell factor (SCF) were associated with improved PFS (p=0.0421 and p=0.0291, respectively). Decreases in sex hormone binding globulin (SHBG) and serum amyloid protein (SAP) were associated with improved PFS (p=0.0184 and p=0.0063). With respect to static biomarkers, elevated baseline ferritin and lower baseline IL-8 were associated with improved PFS (p=0.0291 and p=0.0149, respectively). Conclusions: Several static and dynamic biomarkers in the DisrupTOR-1 trial were associated with PFS. A prospective biomarker-driven study examining everolimus with BNC105P selected by baseline IL-8 and ferritin is in development. Clinical trial information: NCT01034631.
Systemic PD-1/PD-L1 inhibition combined with local vascular-targeted photodynamic therapy (VTP): Effects on primary tumor and prevention of lung metastasis in a preclinical RCC model.
Authors: O'Shaughnessy Matthew , Murray Katie S , LaRosa Stephen , Monette Sebastien , Kim Kwanghee , Scherz Avigdor , Coleman Jonathan A. 
Published: February 2017

477 Background: Immune checkpoint inhibitors targeting the PD-1 pathway have shown activity against advanced renal cell carcinoma in phase 2 clinical trials. The response to PD-1 inhibition is not consistent however and may depend on host factors (ie. PD-L1 expression). Strategies that modulate immune regulation in the tumor microenvironment can impact responses to PD-1 pathway inhibitors. We have previously shown that VTP treatment of primary tumors using the novel photosensitizer WST-11 induces a defined local inflammatory response. We sought to evaluate whether response to PD-1/PD-L1 inhibition could be enhanced with VTP treatment of primary tumors. Methods: Balb/c mice bearing orthotopically implanted Renca kidney tumors were treated with IgG alone, anti-PD-1/anti-PD-L1 monoclonal antibodies (mAbs), VTP alone, or VTP + mAbs. VTP treatment of the primary tumor was performed 10 days (d10) after tumor implantation. Primary tumor response, enumeration of lung metastases and histologic analysis was performed on d21. Results: Treatment of the primary tumor with VTP and systemic PD-1/PD-L1 inhibition (n=15) resulted in regression of primary tumors whereas PD-1/PD-L1 inhibition alone (n=21) or VTP treatment alone (n=16) did not (no gross tumor vs. median tumor size 96mm2 vs 36 mm2 vs 81 mm2for combination vs mAbs alone vs VTP alone vs control, p<0.0001). Significant treatment effect was also observed in the combined treatment group by histologic analysis. Furthermore, growth of lung metastases was prevented with the combined treatment regimen compared to either treatment alone (median number lung mets=3 vs 56 vs 53 vs 23 for combination, mAb alone, VTP alone and control, respectively, p=0.0252). Conclusions: Only the combination of systemic PD-1/PD-L1 inhibition and local VTP provided primary tumor control and prevention of distant metastasis. Modulation of the inflammatory response in the tumor microenvironment with local therapy such as VTP may enhance the effects of systemic PD-1/PD-L1 blockade to provide better local and metastatic tumor control that can be investigated in prospective clinical trials.
Correlation of apparent diffusion coefficients (ADCs) on diffusion-weighted (DW) magnetic resonance (MR) imaging with lesion size and prostate cancer risk.
Authors: Salami Simpa Samuel , Yaskiv Oksana , Turkbey Baris , Villani Robert , Ben-Levi Eran , Rastinehad Ardeshir 
Published: February 2017

48 Background: A negative correlation between ADC values and Gleason risk of prostate cancer (CaP) has been reported by the NIH. We correlate ADC values on DW MR imaging with lesion size and risk stratification of CaP. Methods: Men with abnormal DRE or PSA underwent a 3T MP-MRI (T2, DWI, and DCE) with an endorectal coil. ADC maps were calculated using b values of 0, 500, 1,000 and 1,500; additional b 2000 images were obtained separately. Three radiologists (EB, RV, AR) reviewed and graded all lesions using the 5-point Likert scale and PI-RADS score. A total of 268 men with suspicious lesion (s) on MRI were prospectively enrolled. The UroNav system (Invivo, Florida) was used to perform MR/TRUS fusion-guided prostate biopsies, obtaining one biopsy core in axial and sagittal planes from each lesion. Our institution’s pathologist reviewed all biopsies. Lowest ADC values of suspicious lesions were correlated against lesion size and Gleason risk stratification. Results: The median age and PSA were 65.0 years and 7.4 ng/mL respectively. An average of 1.5 (378/256) suspicious lesions per patient was identified on the MP-MRI. Median volume of MRI target lesions was 0.36 cm3. The cancer detection rate of fusion biopsy on lesion level analysis was 45.2 % (171/378). The mean ± SD ADC values (x 10-6 mm2/sec) for lesions negative and positive for CaP were 1022 ± 260 and 724 ± 223 respectively (p <0.0001). The mean ± SD ADC values (x 10-6 mm2/sec) for lesion size < 0.2 cm3, 0.2 – 0.5 cm3, 0.5 – 1.0 cm3, and > 1 cm3 were 771 ± 246, 677 ± 206, 629 ± 119, and 500 ± 86respectively. Higher risk CaP was associated with lower ADC values with AUC of 0.77 (p=0.0001). The mean ± SD ADC values (x 10-6 mm2/sec) for low (≤6), intermediate (7), and high (8-10) Gleason grade CaP were 845 ± 285, 687± 195, and 628 ± 145 respectively. Conclusions: The ADC value of suspicious lesions on MRI has an inverse correlation with lesion size and prostate cancer risk. It may be a useful in predicting CaP and its clinical significance. Further studies are needed to determine its value in stratifying patients for prostate biopsy, active surveillance and/or treatment.
Genetic polymorphisms of PDGFR/VEGFR2/VEGFR3/RET and their relevance to thrombocytopenia in mRCC patients treated with sunitinib.
Authors: Sheng Xi Nan , Kong Yan , Chi Zhihong , Cui Chuan Liang , Si Lu , Mao Li Li , Lian Bin , Li Si Ming , Tang Bixia , Wang Xuan , Yan Xieqiao , Dai Jie , Guo Jun 
Published: February 2017

481 Background: Since Asian are more susceptible to hematologic toxicity caused by sunitinib. The adverse effect difference differs from that of Caucasian may be related to genetic polymorphism. This study is to explore the characteristics of gene phenotypes and potential relationship between genetic polymorphisms and thrombocytopenia in Chinese patients with metastatic clear-cell renal cell carcinoma (mcc-RCC) treated with Sunitinib. Methods: Ninety-three mcc-RCC patients treated with sunitinib were enrolled in this study. Genotype analyses were done before treatment and thrombocytopenia was recorded on the first three cycles of treatment. Genetic polymorphisms of PDGFR (rs35597368, rs1800810, rs1800813, rs1800812) AVEGFR2 (rs2071559, rs1531289, rs7692791, rs1870377) AVEGFR 3 (rs307826) ARET (rs1799939) were analyzed for a possible association with thrombocytopenia (grade 3/4) incidences. Results: Gene types of total of 10 single nucleotide polymorphisms in 4 candidate genes were according with Hardy-Weinberg law. Grade 3/4 thrombocytopenia incidence is 29%. Test results demonstrated that the incidence of grade 3/4 thrombocytopenia was increased when CG genotype in PDGFR 1171C/G (rs1800810) (p=0.048) or when GA genotype in PDGFR 735G/A (rs1800813) (p=0.050) or when AA genotype in VEGFR2 1718T/A (rs1870377) (p=0.001) were present. Conclusions: The mutation in locus of rs1800810, rs1800813 and rs1870377 may intensify the inhibition of PDGFR or VEGFR2 by sunitinib, causing the increase thrombocytopenia incidence. It is help to look for the biomarker about side effect for the patients with metastatic clear-cell renal cell carcinoma treated with sunitinib.
Sunitinib and pazopanib treatment patterns and cost outcomes in Medicare supplemental-covered patients with renal cell carcinoma.
Authors: Harnett James , MacLean Elizabeth A. , Bhattacharyya Helen , Cisar Laura A. , Hoang Caroline , Mardekian Jack 
Published: February 2017

485 Background: Few studies compare targeted treatments for renal cell carcinoma (RCC) so understanding real world treatment patterns and healthcare utilization may inform decision making. This study evaluated treatment naïve RCC patients initiating sunitinib (SUN) or pazopanib (PAZ) and the potential impact of administration schedules on duration of therapy (persistence) assessments using claims data. Methods: This retrospective cohort analysis used de-identified Truven Marketscan Medicare Supplemental claims data. Included patients were ≥20 years, diagnosed with RCC with ≥1 prescription (Rx) for SUN or PAZ between Oct. 2009–Sept. 2013 and continuously enrolled ≥6 months prior to and 12 months after index. Patient characteristics, treatment patterns, persistence, RCC-related and all-cause costs were evaluated. Chi-square, Student t-test, or Wilcoxon signed-rank test were used to compare groups (α=0.05). A generalized linear model was used to evaluate costs controlling for patient demographics and characteristics, index medication dose, persistence and index medication. As the recommendation for most patients receiving SUN is 4 weeks on, 2 weeks off, a sensitivity analysis was conducted imputing 42 days supply (DS) for SUN Rx with 28 or 30 DS. Results: 291 patients initiated SUN (76.6%) and PAZ (23.4%). There were no significant (NS) differences between groups in demographics, Charlson Comorbidity Index scores, or proportion with pre-index inpatient admission. Mean time from earliest RCC diagnosis to index was longer for PAZ compared to SUN (518 vs. 398 days, p<0.05). There was NS difference in mean persistence in the non-imputed (154 vs. 175 days, p=0.20) and imputed DS (182 vs. 175, p=0.69) analyses for SUN and PAZ, respectively. Adjusted mean RCC-related ($65,993 vs. $65,254, p=0.68) and all-cause ($92,121 vs. 87,962, p=0.18) costs were NS different between SUN and PAZ cohorts, respectively. Conclusions: This analysis indicates NS differences in treatment persistence or costs for Medicare Supplemental patients with RCC initiating SUN or PAZ. Understanding the implications of SUN’s dosing schedule on DS values for persistence and other calculations is critical.
Lag time to adverse events after radical prostatectomy and curative radiotherapy.
Authors: Thellenberg-Karlsson Camilla , Fridriksson Jon , Folkvaljon Yasin , Nilsson Per , Robinson David , Franck Lissbrant Ingela , Ehdaie Behdar , Eastham James Andrew , Widmark Anders , Stattin Pär 
Published: February 2017

49 Background: Men who are curatively treated with radiotherapy (RT) or radical prostatectomy (RP) for localized prostate cancer have long life expectancy but data on long term complications to treatment are scarce. Methods: In the nationwide, population-based Prostate Cancer data Base Sweden (PCBaSe), we identified men who underwent RT or RP between 1997 and 2012. Date of radiotherapy and dose of radiation were reassessed in an audit. For each case five controls from the background population, matched for age and county of residence, had been identified. The National Patient Register was used to identify diagnoses and surgical procedures indicating a complication to treatment, such as urinary incontinence, lower urinary tract symptoms and gastrointestinal symptoms, up to twelve years after treatment. The incidence rate ratio of complications for men who received RT and RP relative to their matched controls was calculated and relative risks (RR) were calculated for RT vs RP adjusted for treatment year, age, Charlson comorbidity index, educational level, PSA-level, clinical T stage and biopsy Gleason score. Results: In total, 37,420 men met the study criteria, of whom 12,534 had undergone RT and 24,886 had undergone RP. There were 186,624 matched controls. The risk of receiving any of the analyzed diagnoses or surgeries at 12 years after treatment was higher after RT; RT vs RP RR 1.20 (95%CI 1.08-1.34) and RT vs RP RR 1.49, (95% CI 1.36-1.64) for the diagnoses and surgical procedures respectively. At 3 years the risk of receiving any of the analyzed diagnoses was comparable between the treatments; RT vs RP RR 1.02 (95% CI 0.91-1.16) but the risk of undergoing any of the analyzed surgical procedures remained higher after RT during the entire study period. Men who underwent RP had a higher risk of being diagnosed or treated for urinary incontinence; RT vs RP RR 0.09 (95% CI 0.04-0.19) and RR 0.04 (95% CI 0.01-0.11) for the selected diagnoses and surgical procedures respectively. Conclusions: Complications after RP mostly occurred within the first 3 years after surgery whereas complications after RT were more frequent at a later date after treatment.
Can neutrophil-to-lymphocyte ratio be used to identify patients with metastatic renal cell carcinoma who may gain greater benefit from cytoreductive nephrectomy?
Authors: Dai Daphne , Kanjanapan Yada , Kwan Edmond Michael , Yip Desmond , Lawrentschuk Nathan , Davis Ian D. , Azad Arun , Rosenthal Mark , Arifeen Shams Ul , Alam Mahmood , Gibbs Peter , Tran Ben 
Published: February 2017

490 Background: Two randomized trials demonstrated survival benefits associated with cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the interferon era. However, the role of CN in the era of targeted therapies is yet to be defined. In recent years, neutrophil-to-lymphocyte ratio (NLR) has emerged as a clinically useful prognostic marker in several cancers including mRCC. In this multi-center retrospective study, we aim to assess the impact of CN in mRCC and the value of NLR in risk stratification and patient selection. Methods: Patients with de novo mRCC diagnosed between 2006 and 2012 from three large Australian hospitals were identified using an electronic database. Data regarding clinicopathological features, MSKCC risk group, NLR at the time of metastatic diagnosis, treatments received and survival were collected. NLR ≥5 was used as the cutoff for statistical analyses. Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses used the Cox proportional hazards method. Results: Our study identified 91 de novo mRCC patients. CN was performed in 46 (51%) patients. Patients who underwent CN were more likely to be younger (median age 59.0 vs. 64.6, p=0.019), and to have received systemic therapy post CN (91% vs. 76%, p=0.043). Median overall survival (mOS) was significantly improved in patients who underwent CN (23.0 mo vs. 10.9 mo, p=0.039). Patients with NLR <5 also had superior mOS (16.7 mo vs. 6.2 mo; HR 0.53; 95% CI; 0.24-0.84; p=0.013). While CN was associated with substantially improved survival in patients with both NLR <5 (mOS 31.1 mo vs. 7.0 mo; HR 0.41; 95% CI, 0.18-0.64; p=0.0009) and NLR ≥5 (mOS 10.9 mo vs. 2.3 mo; HR 0.33; 95% CI, 0.11-0.69; p=0.009), the absolute survival difference was greater in patients with baseline NLR <5. Significant survival benefits associated with CN were maintained in multivariate analyses (HR 0.31; 95% CI, 0.18-0.55; p<0.0001). Conclusions: CN is associated with significantly improved OS in de novo mRCC. The incremental survival benefit associated with CN was seen irrespective of NLR.
Analyses of the transcriptome and metabolome to elucidate the role of HIF1α in clear cell renal cell carcinoma metabolism.
Authors: Minton Denise R. , Fu Leiping , Chen Qiuying , Robinson Brian D. , Gross Steven S. , Shevchuk Maria M. , Nanus David M. , Gudas. Lorraine J. 
Published: February 2017

493 Background: Clear cell renal cell carcinoma (ccRCC) is characterized by altered metabolism, including a shift from oxidative phosphorylation to glycolysis and lactate production (the Warburg effect). Here we evaluate human ccRCC tissue samples and kidney samples from the TRACK transgenic mouse model of ccRCC (that express constitutively active HIF1α in proximal tubule cells) [1] to characterize the effect of HIF1α on the renal cancer metabolome. Methods: We performed untargeted metabolomics analyses of 12 primary human ccRCCs and 10 TRACK kidney samples. In addition, we analyzed human ccRCC mRNA expression (Oncomine database) and performed RNA sequencing (RNAseq) on six TRACK kidney samples for expression of HIF1α target genes that regulate metabolism. Results: Analysis of RNA expression of HIF1α target genes in human ccRCCs and TRACK kidneys identified significantly increased transcript levels of genes responsible for mediating glucose uptake and glycolysis and suppressing the activity of the TCA cycle and mitochondrial respiration, including glucose transporter 1 (SLC2A1), glycolytic enzyme phosphofructokinase (PFKP), TCA cycle inhibitor pyruvate dehydrogenase kinase (PDK1), oxidative phosphorylation inhibitor NADH dehydrogenase 1 alpha subcomplex, 4-like 2 (NDUFA4L2), and lactate transporter (SLC16A3). Metabolomics analysis similarly demonstrated a significant increase in glycolytic intermediates and lactate, in association with a decrease in metabolites of the TCA cycle. Conclusions: These studies show that in both human ccRCC and TRACK mice HIF1α mediates a metabolic switch to aerobic glycolysis, implicating HIF1α in RCC tumorigenesis. Additionally, these data suggest that targeting the metabolic pathway (or inhibition of HIF1α) is a novel approach to treat ccRCCs.