bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of SMARCB1 deficiency in renal medullary carcinoma (RMC) on genes associated with nucleosome assembly and telomere organization.
Authors: Msaouel Pavlos , Malouf Gabriel G. , Su Xiaoping , Yao Hui , Tripathi Durga N , Gao Jianjun , Rao Priya , He Rong , Karam Jose A. , Wood Christopher G. , Walker Cheryl Lyn , Tannir Nizar M. 
Published: February 2018

614 Background: RMC is a highly aggressive tumor with close to universal fatality despite therapy. It is almost exclusively found in young African-Americans with sickle cell trait, and is characterized by complete loss of expression of SMARCB1, a major chromatin remodeler involved in regulation of gene expression. We investigated the effects of SMARCB1 loss on mutation frequency, gene expression, and cell growth in RMC. Methods: Whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed in RMC tissues from 15 and 11 patients respectively, each with matched adjacent normal kidney tissue controls. In vitro experiments were performed in a cell line (RMC2C) we established from a patient with RMC. SMARCB1 was conditionally re-expressed using a tetracycline-inducible lentivector. Gene ontology (GO) analysis was performed using DAVID. Results: WES showed that RMC harbors a low number (median of < 25/tumor sample) of non-synonymous exomic single nucleotide variants (SNVs) or small indels. GO analysis revealed that the most significant pathways upregulated in RMC compared with normal tissue were those associated with nucleosome assembly and telomere organization (p values < 0.0001). Re-expression of SMARCB1 at near-endogenous levels suppressed the growth rate of RMC2C cells. Subsequent silencing of SMARCB1 expression restored the growth rate of these cells. RNA-seq of RMC2C cells expressing SMARCB1 demonstrated that the most significant downregulated pathways compared with SMARCB1-negative RMC2C cells were those associated with nucleosome assembly and telomere organization (p values < 0.0001). Conclusions: RMC harbors a remarkably simple genome, as evidenced by our WES analysis. Therefore, consistently detected alterations, such as SMARCB1 loss, are likely to serve as drivers for this disease. Indeed, in vitro restoration of SMARCB1 expression suppressed the growth of RMC cells and repressed genes associated with nucleosome assembly and telomere organization, identifying for the first time a causal link between loss of SMARCB1 and dysregulation of these genes. These results provide the basis for future therapeutic strategies targeting SMARCB1 loss in RMC.
Differential expressions of PD-1, PD-L1, and PD-L2 between the primary and metastatic sites in renal cell carcinoma.
Authors: Zhang Xingming , Shen Pengfei , Zeng Hao 
Published: February 2018

616 Background: To evaluate the differential expressions of PD-1, PD-L1 and PD-L2 between the primary and metastatic sites of renal cell carcinoma (RCC), and to find potential factors influencing expression difference. Methods: We included cases of RCC histologically diagnosed at West China Hospital between January 2009 and November 2016. Clinicopathological data were retrospectively extracted. SPPS 22.0 and GraphPad Prism 6 statistical software were used for data analysis. Kaplan-Meier was used to analyze PFS and OS. R software was used to calculate predictive accuracy (PA). Results: A total of 163 patients were included in this study. Immunohistochemistry results suggested significant differential expressions of PD-1, PD-L1 and PD-L2 between the primary and metastasis, with a higher detection rate of the primary than metastasis. Meanwhile, the concordance rate of PD-L1 between the primary and metastasis was only 32.5% (27/83), with a significant statistically difference (χ2 = 4.664, p = 0.031) and poor consistency (Kappa = 0.229, p = 0.031). PD-1 and PD-L1 were highly expressed in the lung/lymph node and PD-L2 was highly expressed in visceral metastases. Survival analysis suggested that PD-1 positive either in the primary or metastasis was a poor prognostic factor for OS (HR: 1.59, 95% CI 1.08-2.36, P = 0.0195). The expression of PD-L1 in the primary was a poor prognostic factor for OS (HR 2.55, 95% CI 1.06-6.15, P = 0.0373). Although the predictive effect of PD-L1 expression on OS was not statistically significant in TKI treated patients, the OS time was shorter in PD-L1-positive patients than those negative (median OS 19.0 vs 41.0 months). In the whole cohort, the PA value of COX regression analysis was 0.683 for PFS, and the addition of PD-1 expression in the primary increased the PA value to 0.699. Conclusions: The assessment of immunological checkpoint-related protein in primary tumor may not be able to provide adequate information for clinicians to evaluate or predict the patient's treatment-related efficacy and prognosis. Biopsy or resection of the metastases may provide a more accurate biological information for clinician's decision-making and the patient's prognosis.
SPAZO2 (SOGUG): Outcomes of patients treated with pazopanib as first line in mRC according to gender in real world.
Authors: Maximiano Constanza , Puertas Alvarez Javier Luis , Maroto Rey Jose Pablo , Pinto Alvaro , Miranda Pallares Maria Jose , Suarez Cristina , Climent Miguel A. , Garcia Carbonero Iciar , Guzman Jose Carlos Villa , Borrega Pablo , De Velasco Guillermo , Fernandez Parra Eva , Crespo Guillermo , García Domínguez Rocío , Gallardo Diaz Enrique , Meana Garcia Andres , Garcia Marrero Rosa , Gonzalez Larriba Jose Luis , Perez Ramirez Sara , Arranz Arija Jose Angel 
Published: February 2018

623 Background: Treatment of mRC is not affected by gender, studying possible differences in a real-world study, could increase the knowledge of toxicity and possible prognostic factors. Methods: SPAZO2 (NCT03091465) was a retrospective real-world study to analyze the effectiveness of 1st-line pazopanib and subsequent therapies in mRC. Data from 530 pt treated outside CT were collected in 50 spanish centers, and externally monitored. Ineligibility criteria: ECOG > 1, pure nonclear-cell, Hgb < 9 g/dl, renal failure, severe cardiovascular disease, chronic liver disease, or recent neoplasia Results: 530 pt were included, 67.2% men (M), mean age was 66.2 years (26-92). There were no significant differences (M vs W) in the age > 75 (24.7 vs 24.1%), clear cell carcinoma (77.2 vs 79.9%), nephrectomy (72.5 vs 68.4%), IMDC (favourable: 15.2 vs 12.1%, intermediate: 59.3 vs 64.4%, poor: 25.6 vs 23.6%), metastases (lymph nodes: 46.1 vs 43.1%, lung: 69,7 vs 67,2 %, liver: 16 vs 20.1%, bone: 27 vs 24.1%, skin/soft tissues: 1.1 vs 3,4% and CNS: 4,8% vs 6.3%). Discontinuation due to toxicity or comorbidities was 12.4 vs 9.8%. There were no differences in the second lines received (57.9 vs 56.9%), neither response, PFS and OS (table). Median follow up was 39 mo. The gender has no prognostic value when adjusted for the prognostic groups of IMDC (HR of PFS 0.96, CI 95% 0.78-1.2, HR of OS: 0.92, CI 95% 0.72-1.14). Only diarrhea and elevation of uric acid were higher in the men group. Conclusions: Pazopanib was safe and effective in both groups with similar outcome. Women had less diarrhea and less increased uric acid. There were not differences in OS or PFS. In IMDC subgroup analysis, there is a trend towards a better evolution or PFS in the poor prognosis women subgroup. Clinical trial information: NCT03091465. [Table: see text]
High dose interleukin-2 and response in 944 patients with metastatic renal cell cancer (RCC): Data from the PROCLAIM registry.
Authors: Dorff Tanya B. , Wong Michael K.K. , Clark Joseph , Daniels Gregory A. , Curti Brendan D. , Morse Michael , Kaufman Howard , McDermott David F. , Quinn David I. , Zang Peter , Gregory Nancy C. , Eifler Lisa Maria , Thomas Stephen , White Marci , Singh Jatinder , Dutcher Janice P. 
Published: February 2018

624 Background: High dose interleukin-2 (HD IL2) has traditionally been dosed every 8 hours for a maximum of 14 doses each cycle. We evaluated whether alternate dosing schedules and dose intensity affected achievement of complete response (CR) or partial response (PR) in the PROCLAIM registry. Methods: Patients with metastatic RCC were enrolled retrospectively and prospectively into the PROCLAIM registry to collect outcome data. Statistical methods for comparisons were done using Fisher’s and Chi Square tests. Results: From 2006-2017 the registry included 944 RCC patients; 257 (27%) women, 676 (72%) men. 844 (89%) were white. Histologic distribution: 624 (66%) clear cell, 93 (10%) medullary, 79 (8%) collecting duct, 78 (8%) chromophobe and 70 (7%) papillary. 207 (22%) had prior therapy with VEGF/mTOR. Best response was 51 (5.4%) CR and 169 (17.9%) PR; 263 (28%) progressive disease. 13 (1.4%) patients received q12 hour dosing while 830 (88%) received q8 hour dosing. 608 (64%) received 600 KIU/kg and 67 (7%) received 720 KIU/kg. Median # of doses in cycle 1 was 10 for CR and PR patients at 600 KIU/kg and 9 for those with stable or progressive disease. In the 720 KIU/kg group median #doses was 11 for CR, 8 for PR, and 7 for stable or progressive disease. In cycle 2 median doses received was 7.16 for patients with CR, 7.02 for PR and 6.76 for stable disease. Median dose intensity is similar at these two dose levels. Associations with achievement of CR/PR are summarized in the Table. Conclusions: There is no difference in response rate based on dosing schedule but the small number of subjects dosed q12 hours limits interpretation. Good performance patients possess the best opportunity for benefit from HD IL2. There is a trend for response with higher median # doses. Further studies of alternate dosing schedules are warranted. Clinical trial information: NCT01415167. [Table: see text]
Pharmacogenetic-based area-under-curve model to predict efficacy and adverse events from axitinib in individual patients with advanced renal cell carcinoma.
Authors: Yamamoto Yoshiaki , Tsunedomi Ryouichi , Kawai Yoshihisa , Matsumoto Hiroaki , Hazama Shoichi , Nagano Hiroaki , Matsuyama Hideyasu 
Published: February 2018

625 Background: Although titrated-dose axitinib offers a good objective response rate (ORR) for metastatic renal cell carcinoma (RCC), its optimal initial dose is unclear because its dosing regimen is based on a hypertensive reaction. We investigated whether axitinib pharmacogenetics were related to clinical efficacy/adverse events, and calculated a model to predict clinical efficacy and adverse events, using pharmacokinetic data based on gene polymorphisms in a phase 2 trial. Methods: We prospectively evaluated objective response and adverse events to establish a prediction model in 44 consecutive patients with advanced RCC, treated with axitinib between October 2013 and March 2017. Gene polymorphisms, including ABC transporters ( BCRP and MDR1) and UGT1A were analyzed by whole-exome sequencing, Sanger sequencing, and DNA chips. To construct the prediction model for area under curve (AUC), we used an exponential regression model with gene polymorphisms and dosage as covariates. To further validate this prediction model, we prospectively compared the calculated AUC in this model with actual AUCs in 13 additional consecutive patients. Results: Actual AUC was significantly correlated with the best ORR ( P = 0.0002), and adverse events (grade 2–3 hand–foot syndrome [ P = 0.0055]; grade 2 hypothyroidism [ P = 0.0381]); it was also significantly correlated with calculated AUC ( P < 0.0001). Calculated AUC was also significantly associated with best ORR ( P = 0.0044), grade 2–3 hand–foot syndrome ( P = 0.0191) and grade 2 hypothyroidism ( P = 0.0082). Surprisingly, hypertension was associated with neither ORR nor AUC. In the validation study, calculated AUC before axitinib treatment precisely predicted actual AUC ( P = 0.0079) in 13 additional consecutive patients. Conclusions: Our pharmacogenetics-based AUC model may offer a more benign method to determine optimal initial axitinib doses than hypertension, and could contribute to more precise treatment of individuals with advanced RCC. Clinical trial information: UMIN000011147.
Genomic alterations to refine prognostication of patients with metastatic renal cell carcinoma.
Authors: Bosse Dominick , Xie Wanling , Lalani Aly-Khan A. , de Velasco Guillermo , Voss Martin Henner , Tannir Nizar M. , Tamboli Pheroze , Appleman Leonard Joseph , Rathmell Kimryn , Heng Daniel Yick Chin , Sonpavde Guru , Signoretti Sabina , Hakimi A. Ari , Choueiri Toni K. 
Published: February 2018

626 Background: The IMDC risk score is a valid and simple tool to prognosticate patients (pts) with metastatic renal cell carcinoma (mRCC). Some non-VHL common genomic alterations may be associated with outcomes. We therefore assessed the prognostic value of most commonly mutated genes in mRCC beside VHL overall, and within IMDC risk groups. Methods: We identified patients treated at Dana-Farber Cancer Institute (n = 65) or part of TCGA (n = 33) who had genomic data available and were treated with first line vascular endothelial growth factor tyrosine kinase inhibitors. Information on genomic alterations (GA) focused on PBRM1, BAP1, SETD2, KDM5C and TP53 was extracted. Cox regression was performed to assess the association of each GA with overall survival (OS), adjusting for IMDC risk groups and age. Results: Overall, 98 pts were identified. 96/98 pts had clear-cell histology. Pts distribution by IMDC risk groups was: 7% good, 58% intermediate, 27% poor and 8% unknown. Mutation rates were 27% PBRM1, 17% BAP1, 29% SETD2, 9% KDM5C and 8% TP53. In multivariable models, there was an association between GA and worse OS for BAP1 and BAP1 or TP53 combined (Table). When stratified by IMDC risk groups, GA in BAP1 or TP53 was associated with shorter median OS in poor risk pts [12.1 mo (95%CI 8.3- 24.0) v. 27.6 mo (95%CI 18.9- 53.4), aHR 4.64 (95%CI 1.32-16.4), p = 0.017] and a trend toward worse median OS in intermediate risk pts [20.5 mo (95%CI 7.4-54.6) v. 36.3 mo (95%CI 21.1, NR), aHR 2.11 (95%CI 0.94-4.74)] compared to pts without GA in BAP1 or TP53. Too few death events were observed in good risk pts to assess the prognostic value of GA in BAP1 or TP53. Conclusions: GA in BAP1 or TP53 are prognostic in mRCC and further discriminate pts with distinct outcomes within IMDC risk groups. Validation in larger dataset is ongoing. [Table: see text]
Everolimus (E) plus bevacizumab (B) is effective first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) with papillary features (PF): Results from a phase II trial.
Authors: Feldman Darren R. , Lee Chung-Han , Molina Ana M. , Knezevic Andrea , Chen Yingbei , Chaim Joshua , Coskey Devyn Taylor , Ged Yasser , Tickoo Satish , Reuter Victor E. , Patil Sujata , Xiao Han , Aghalar Jahan , Apollo Arlyn J. , Carlo Maria Isabel , Motzer Robert J. , Voss Martin Henner 
Published: February 2018

627 Background: We previously reported on a phase II trial of E+B across various non-clear cell RCC histologies and observed significant activity among pts with papillary or unclassified RCC ( uRCC ) with PF (objective response rate [ORR] 39%, median progression-free survival [PFS] 12.9 months [m]; Voss, JCO, 2016). An expansion cohort limited to these two histologies was conducted to confirm the efficacy of E+B. Methods: E + B was administered at standard doses until progressive disease (PD) or intolerance to therapy. The current analysis included 19 pts with pRCC or uRCC with PF in the initial cohort and 20 pts in the expansion cohort (total n=39). The primary endpoint was 6 month PFS with secondary endpoints of ORR, median PFS, and overall survival (OS). Correlative analyses included next generation sequencing (NGS) from tumor and germline across >341 genes of interest. Results: Of 39 pts, 24 had uRCC with PF, 14 had papillary RCC, and 1 had translocation RCC with PF. Among 37 evaluable pts, the ORR was 35%; 43% for uRCC with PF and 23% for papillary RCC. Six-month PFS for all 39 pts was 78%; 82% for uRCC with PF and 68% for papillary RCC. Median PFS was 13.7m; 13.7m for uRCC with PF and 8.4m for papillary RCC (Table). With median followup of 17.6m, median OS is 33.9m. Toxicity with E+B was similar to previous reports. 33 of 39 pts had NGS performed and partial responses were observed across a wide spectrum of genomic alterations, including several recurrently seen in papillary RCC variants such as mutations in FH, MET, NF2, and ARID1a. Conclusions: The expansion cohort confirms the activity of E+B for pts with advanced papillary RCC or uRCC with PF with superior ORR, PFS, and OS compared to historical results with sunitinib for these histologies. E+B represents a new standard first-line treatment option for these pts. Clinical trial information: NCT01399918. [Table: see text]
Validation of a testosterone-deficiency symptoms rating-scale in prostate cancer patients treated with androgen deprivation therapy and radiotherapy.
Authors: O'Cathail Micheal , Little Jessica , Hosni Shaymaa , Sundar Santhanam 
Published: February 2018

63 Background: Androgen deprivation therapy (ADT) plays an important role in the management of non-metastatic prostate cancer (NMPC). We prospectively assessed the performance of a symptom rating scale, the aging men’s symptoms score (AMS) in relation to other validated QOL tools. Methods: Following ethics approval, 145 patients with a diagnosis of NMPC receiving ADT as part of radical treatment were enrolled after informed consent. Data was collected using the EORTC QLQ-C30, the AMS and the International Index of Erectile Function score (IIEF-5) questionnaires at baseline, 3 months (post ADT) and after ADT was stopped. Results: Eighty six (58.1%) patients had ADT for <9 months, 7 (4.7%) had 9 -18 months and 55 (37.2%) had 27-36 months. A third (32.3%) of patients had moderate/severe symptoms of testosterone deficiency (TD) at baseline vs 62% and 44.4% at time points 2 & 3 (p<0.0001). Severe erectile dysfunction was common and worsened with ADT (45.3% & 74.1% respectively) and did not recover post ADT (p<0.0001). Few (1.6%) patients retained normal erectile function at the end of the study vs 15.6% at baseline. Self-reported QoL using EORTC QLQ C30 (Q.30) remained high at all time points (80.8%, 76.2%,75.8% respectively for a score of 5-7, 7 =very good, 1=very poor). Conclusions: TD due to ADT resulted in significant symptoms only in a subset of patients and not all symptoms resolved post ADT. However, self-reported QoL remained unaffected indicating that andropause symptoms may not affect QoL in radically treated prostate patients. This prospective data validates AMS scale and it could be used in routine clinical practice to assess TD symptoms in this group. [Table: see text]
Phase1 clinical trial of high doses of Seleno-L-methionine (SLM), in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients.
Authors: Zakharia Yousef , Garje Rohan , Brown James A. , Nepple Kenneth Gerard , Dahmoush Laila , Gibson-Corley Katherine , Spitz Douglas , Milhem Mohammed M. , Rustum Youcef M. 
Published: February 2018

630 Background: The overexpression of hypoxia induced factor (HIF) 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with the standard dose of axitinib to patients with metastatic RCC. Primary endpoint is safety, secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 9 patients with metastatic RCC; who failed one or more prior lines of treatment; are enrolled. The first 3 patients were treated at 4000 µg, the second and third 3 patients were treated at 2500 and 3000 µg respectively. No dose limiting toxicity (DLT) is encountered. Six patients are evaluable to date. Of the 4000 µg cohort, 2 patients achieved complete remission (CR) at 18 and 20 months, 1 patient with partial response (PR) at 19 month. Of the 2500 µg cohort, one patient achieved PR at 9 months, 1 patient had stable disease for 9 months before progression, and 1 patient had disease progression at 4 months. The 3000 µg cohort is too early to evaluate for efficacy. Of interest the 4000μg SLM dose yielded a plasma selenium concentration of 40-50μM which is comparable with SLM dose determined synergistic with anti-cancer drugs in preclinical models. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT02535533.
Trends and morbidity for minimally invasive versus open cytoreductive nephrectomy in the management of metastatic renal cell carcinoma.
Authors: Zlatev Dimitar V. , Ozambela Manuel , Salari Keyan , Wang Ye , Mossanen Matthew , Pucheril Daniel , Ingham Matthew D. , Chung Benjamin I. , Chang Steven Lee 
Published: February 2018

632 Background: Cytoreductive nephrectomy (CN) prior to systemic therapy for metastatic renal cell carcinoma (RCC) is recommended in patients with a surgically resectable primary tumor. Traditionally performed as open surgery, the advent of laparoscopic and robotic surgery provides a minimally invasive alternative to CN with a potential for accelerated recovery and earlier initiation of systemic therapy. We sought to compare the trends and morbidity of laparoscopic, robotic, and open CN for patients with metastatic RCC. Methods: Using the Premier Hospital Database (Premier, Inc., Charlotte, NC), we identified 24,145 patients who underwent elective radical nephrectomy for metastatic RCC in the United States between 2003 and 2015. Comparative analysis between laparoscopic, robotic, and open CN was performed with propensity weighting on rates of 90-day complications, blood transfusion, intensive care unit (ICU) admission, prolonged length of stay (LOS), discharge destination, 90-day readmission, operative time, and direct hospital costs. Results: Over the course of the study period, the rates of open CN decreased from 76.7% to 66.4%, laparoscopic CN decreased from 22.3% to 11.4%, and robotic CN increased from 0.6% to 22.1%. Compared to open CN, the laparoscopic approach was associated with a 30% decreased odds of 90-day major complications (OR 0.70, 95% CI 0.50 - 0.97, p < 0.05). Compared to open CN, both laparoscopic and robotic approaches were associated with significantly decreased odds of blood transfusion (OR 0.46 and 0.38, respectively), ICU admission (OR 0.57 and 0.48, respectively), and LOS (OR 0.50 and 0.35, respectively). Direct costs were lowest for laparoscopic CN. Conclusions: Compared to open CN, minimally invasive CN is associated with decreased rates of blood transfusion, ICU admission, and LOS. Laparoscopic CN is additionally associated with decreased major complications and direct costs compared to open CN. When technically feasible, the utilization of minimally invasive CN, especially laparoscopic, may be associated with improved outcomes, decreased costs, and accelerated recovery prior to systemic therapy in patients with metastatic RCC.