bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic differences and survival in African Americans with metastatic clear cell renal cell carcinoma in the targeted therapy era.
Authors: Rose Tracy Lynn , Krishnan Bhavani , Kuykendal Adam Rea , Smith Angela , Milowsky Matthew I. , Kim William Y. 
Published: February 2017

504 Background: African American (AA) patients with RCC have historically had inferior survival relative to Caucasians. There is little data on racial differences in tumor biology between AA and Caucasians to explain this disparity. In addition, it is not known if racial differences may result in differential response to targeted therapy and if the disparity has changed over time. Our study aims to define racial differences in tumor biology between AA and Caucasians with clear cell RCC (ccRCC) and to evaluate if observed differences in tumor biology are reflected in survival rates in the era of targeted therapy. Methods: We identified AA and Caucasian patients with stage IV clear cell RCC (ccRCC) in the National Cancer Data Base (NCDB) and analyzed survival of AA and Caucasians in the pre- and post-targeted therapy eras (1998-2004 and 2006-2011). We then analyzed The Cancer Genome Atlas (TCGA): Renal Clear Cell Carcinoma dataset to determine differences in somatic mutation rate, molecular subtype, and RNA expression between AA and Caucasians. Results: Overall survival (OS) is significantly longer in Caucasians than AA (9.2 vs 6.5 months, p < 0.01). The adjusted HR for death for AA compared with Caucasian patients was 1.08 (95% CI 1.01-1.14) in the post-targeted therapy era, which was unchanged from the pre-targeted therapy era (HR 1.07, 95% CI 1.01-1.14). AA patients were less likely than Caucasians to have VHL mutations (17% vs 50%, p = 0.04) and were enriched in the ccB molecular subtype (79% in AA vs 45% in Caucasians, p < 0.01). RNA expression revealed upregulation of several HIF-associated pathways in Caucasian compared with AA patients. Conclusions: ccRCC in AA have less frequent VHL mutations, are enriched in the ccB molecular subtype, and have less upregulation of HIF-associated pathways than Caucasians. These molecular features predict for decreased responsiveness to VEGF-targeted therapy and inferior survival in AA compared to Caucasians. Data from a large national database confirm that AA patients maintain inferior survival compared to Caucasians in the era of targeted therapy, potentially related to underlying tumor biology.
Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.
Authors: Bi Xiao , Zhao Siming , Adeniran Adebowale , Kluger Harriet M. , Xie Zuoquan , Nawaf Cayce , Merino Maria J , Valera Vladimir , Pantuck Allan J. , Said Jonathan W. , Belldegrun Arie S. , Lifton Richard P , Shuch Brian M. 
Published: February 2017

509 Background: Sarcomatoid transformation in renal cell carcinoma (ccRCC) is one of the worst prognostic factors and outcome is extremely poor. We evaluate genetic alterations implicated in this process. Methods: Nephrectomy specimens from ccRCC with sarcomatoid transformation had DNA extracted from carcinoma, sarcomatoid, and normal kidney regions. Exome capture/Illumina sequencing was performed in 21 samples. Somatic mutation calling was accomplished by comparing sarcomatoid-normal and carcinoma-normal pairs. Results: Two tumors had evidence of hypermutation and a mutational signature consistent with mismatch repair deficiency. In the remaining tumors, 42.6% of somatic mutations were shared. Sarcomatoid regions had a greater mutation burden (p = 4.0x10-4). A low percentage (57.9%) of tumors had mutations in VHL. Mutations in ccRCC driver genes, including PBRM1, PTEN, SETD2, ARID1A, and BAP1, were common. All mutations in ARID1A and BAP1 were specific to sarcomatoid regions. A high percentage (31.5%) of TP53 mutations were observed, all specific to sarcomatoid regions and occurring with loss of heterozygosity. Lastly, mutations in genes not previously described in ccRCC were observed, most sarcomatoid-specific. These include genes implicated in cell adhesion, polarity, motility, and WNT signaling (FAT1, FAT2, FAT3, PTK7), retinoic acid-regulated cell differentiation (RQCD1, LRIF1), and ubiquitinated protein trafficking and cytokinesis (TSG101). Conclusions: Sarcomatoid transformation in ccRCC results from clonal divergence from a common somatic cell of origin. The sarcomatoid region has significantly greater mutational burden of known cancer driver genes. TP53 mutations occurred at a high frequency and were exclusive to the sarcomatoid region. Hypermutation is a unique characteristic observed in a subset of tumors. Additional cohorts and mechanistic studies are critical to elucidate the role of candidate driver alterations.
The impact of contrast enhancement reduction on tumor response in patients with advanced renal cell carcinoma that treated with presurgical targeting therapy.
Authors: Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2017

510 Background: RECIST is a standard tool for tumor response assessment. However, evaluation for targeted therapy by RECIST is insensitive because tumors often showed a modest change in size despite of significant necrosis. Therefore, we investigated an impact of contrast enhancement reduction for tumor shrinkage in RCC patients with presurgical targeting therapy. Methods: From March 2011 to July 2015, 17 patients (18 tumors) with RCC who underwent presurgical targeting therapy were included. Indications for presurgical targeting therapy were cT3-4, bilateral tumors, poor performance status, or small distant metastasis. Contrast enhancement reduction was evaluated by contrast medium enhanced area (CMEA) before and after targeting therapy. CMEA measurements were performed by OsiriX and Adobe Photoshop. Eighteen tumors were evaluated by RECIST and CMEA. Differences between two methods were compared. Results: Median age and followup after initiation of targeted therapy were 68 years old and 15.3 months. IVC thrombus and small distant metastasis existed in seven (41%) and five (29%) patents, respectively. Fifteen patients (88%) received TKI based (sunitinib and/or axitinib), and three patients (12%) received mTOR inhibitor based (everolimus or temsirolimus) presurgical therapy. The median treatment period of presurgical targeted therapy was 3.3 months. Median tumor responses in RECIST and CMEA were 10.5% and 49.0%, that was significantly correlated by liner regression analysis (P = 0.002). TKI based presurgical therapy showed significant tumor reduction in CMEA than RECIST (P = 0.0062). In addition, tumor reduction rate was significantly higher in TKI based presurgical therapy than mTOR inhibitor (P = 0.014). No patient experienced tumor recurrence. Conclusions: Contrast enhancement reduction might be useful tool for tumor shrinkage in patients with RCC who underwent presurgical targeting therapy.
Durability of responses in patients with metastatic renal cell carcinoma treated with high-dose interleukin-2 (HD IL-2).
Authors: Clark Joseph , Morse Michael A. , Wong Michael K.K. , McDermott David F. , Kaufman Howard , Daniels Gregory A. , Perritt Jessica C , Hua Hong , Aung Sandra 
Published: February 2017

511 Background: HD IL-2 is FDA approved for advanced renal cell carcinoma (mRCC), however, the data supporting its use is 23 years old. In 2011, a HD IL-2 patient database was established called PROCLAIMSM, and comprises the largest active prospective collection of data from mRCC and metastatic melanoma (MM) patients receiving HD IL-2 treatment and provides longitudinal real-time insights into the clinical impact of sequencing drug treatments. These data report on the outcomes and interactions with prior targeted therapies in mRCC patients in the current era. Methods: Inclusion criteria require patients to receive at least one dose of HD IL-2. Patients who received HD IL-2 and had already undergone a post-treatment scan were not eligible. Survival analysis was performed by the method of Kaplan and Meier using datasets as of July 27, 2015. Results: The overall response rate (ORR) and median overall survival (mOS) are described in Table 1. The mOS was not reached (NR) for 364 patients. The 1, 2 and 3 year survival rates were 79%, 63%, and 51%, respectively. For patients with stable disease (SD), the mOS was not reached and the 1, 2 and 3 year survival rates were 96%, 80%, and 60% respectively. There was a significant difference in mOS between SD and progressive disease (PD) patients, NR vs 15.5 months, P<.0001. The mOS was not reached for patients regardless of whether or not they received targeted therapy (TT) prior to HD IL-2. There were 4 reported treatment-related deaths in 364 patients (1.1%), none of these patients had prior TT. Conclusions: PROCLAIM data demonstrate that SD, previously grouped with the non-responders, is associated with extended survival rates. HD IL-2 is an active 2ndline treatment option for patients who have failed TT. These data support that HD IL-2 has a favorable safety profile and remains an effective therapy for eligible patients with mRCC. Clinical trial information: NCT01415167. [Table: see text]
Real world chart review of adverse event management in patients taking tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC) by line of therapy (LoT).
Authors: Srinivas Sandhya , Stein Dara , Teltsch Dana Y , Tao Sunning , Ramaswamy Krishnan 
Published: February 2017

521 Background: This is the first real world study to describe adverse events of special interest (AESI) management for all available TKIs by LoT. A better understanding of optimal AE management can positively impact patient care. Methods: A chart review was conducted largely in community oncology practices in Canada and the US. Patients with mRCC were eligible if they started TKI monotherapy between Nov 15, 2010-Nov 15, 2013 and had ≥ 1 of 5 AESI onset ≤ 3 months post TKI start. AESI included fatigue, hypertension, diarrhea, hand-foot syndrome and stomatitis/mucositis. Data on patient demographics, medical history, drug regimen, and AESI management were collected. Results: 220 patients from 27 centers were included. 63% of patients received TKI in 1st, 22% in 2nd and 15% in 3rd LoT. TKIs included axitinib (9%), pazopanib (27%), sorafenib (8%) and sunitinib (55%). 376 AESI occurred in 220 patients; 87% were non-serious. Fatigue (62%), hypertension (37%), diarrhea (31%), stomatitis/mucositis (29%), and hand-foot syndrome (12%) were reported. 55% of AESI resolved/were resolving within 3.5 months of onset. 8% of patients received AESI prophylaxis (Px) and 59% received treatment (Tx). Incidence of stomatitis/mucositis declined as LoT progressed (37%, 16%, 12%). More patients in 1st vs. ≥ 2nd LoT had AESI related TKI discontinuation (17% vs. 12%), interruptions (17% vs. 12%) and reductions (43% vs. 32%). Fewer patients missed doses as LoT progressed (38%, 25%, 18%). Fatigue was the commonest AESI across LoT, and fatigue as a reason for therapy delay/interruption increased across LoT (7%, 14%, 50%). The rates of Tx or Px for fatigue remained low across LoT. Rates of AESI Px were low across the LoT (10%, 0.4%, 0.3%). More patients in 1st (61%) received AESI Tx vs. 2nd (47%) LoT. Conclusions: Most AESI were non-serious, and over half of patients received some form of AESI Tx. Fatigue was the most common yet least frequently Tx AESI. Very few patients received Px across LoT. More patients in 1st versus 2nd LoT experienced dose modifications/discontinuation and received AESI Tx. More emphasis on Px/Tx options for non-serious bothersome AEs is warranted.
Angiogenic markers during bevacizumab-based treatment in metastatic renal cell carcinoma (RCC).
Authors: Dorff Tanya B. , Longmate Jeff , Groshen Susan G. , Stadler Walter Michael , Fishman Mayer N. , Vaishampayan Ulka N. , Pinski Jacek K. , Pal Sumanta K. , Hu James , Quinn David I. , Lara Primo 
Published: February 2017

522 Background: Targeting the vascular endothelial growth factor (VEGF) pathway delays progression in mRCC, however innate and acquired resistance limit success. CD105 (endoglin) is a TGFb family receptor which is upregulated after VEGF inhibition, possibly mediating resistance. We studied serum CD105 and TGFb at baseline and after treatment, and tissue levels of TGFbR1 & 2 plus AVCRL, to discover biomarkers for treatment response as part of a randomized trial of bevacizumab (Bev) +/- the anti-endoglin antibody TRC105. Clinical data from the trial were presented at ASCO 2015 (Dorff et al, abstr 4542). Methods: Serum was collected at baseline and before cycles 2&4. ELISA was performed using kits from Abcam. Changes from baseline were evaluated and compared overall and between arms using a general linear mixed effects model. Immunohistochemistry was performed on paraffin embedded tissue samples using antibodies from R&D systems; tissue and baseline ELISA data were evaluated for association with PFS using Kaplan-Meier analysis and the logrank test. Results: 54 subjects (24 on Bev and 28 on Bev+TRC105) had at least one analyzed serum sample; 14 and 19 respectively had both baseline and cycle 2 samples. Mean CD105 was 82.8 (95%CI 64.6, 106.2) at baseline and 59.0 (95%CI 43.2, 80.7) at cycle 2; for 16 patients with cycle 4 data the mean was 39.8, significantly lower than baseline (p = 0.024), but not different between treatment arms. Cycle 2 TGFb levels were not different from baseline (p = 0.66) or between arms (p = 0.17). Baseline serum TGFb below the median ( < 10.6) was associated with higher likelihood of PFS at 12 and 24 weeks; (0.78 vs 0.3 and 0.49 vs 0.19, respectively, p = 0.022); baseline CD105 was not (p = 0.83). Tissue was available for 29 subjects. No tissue markers (TGFbR1 &2 or AVCRL) were associated with longer PFS except, in exploratory analysis, higher TGFbR2 staining in patients treated with TRC105 (p = 0.017). Conclusions: No pharmacodynamics markers for TRC105 therapy were identified. Lower baseline serum TGFb levels may be prognostic of PFS during Bev therapy, supporting the notion that this pathway contributes to resistance. Better PFS in TRC105-treated patients with higher tissue TGFbR2 expression warrants further study. Clinical trial information: NCT01727089.
Identification and validation of an 8-gene expression signature for predicting high-Fuhrman grade renal cell carcinoma.
Authors: Wan Fangning , Zhu Yao , Han Chengtao , Xu Qinghua , Dai Bo , Zhang Hailiang , Shi Guohai , Gu Weijie , Ye Dingwei 
Published: February 2017

526 Background: Clear cell renal cell carcinoma (ccRCC) is a malignancy with heterogeneous outcomes. Currently, renal mass biopsies are commonly employed to extract disease characteristics and aid prognosis. Although the pathological diagnosis of malignant disease is accurate in contemporary reports, the classification of Fuhrman grade using biopsy specimens is still far from promising. Our aim is to generate a signature biomarker to distinguish high grade ccRCC that could be readily applied to clinical biopsy samples. Methods: Using the Cancer Genome Atlas (TCGA) database, a gene expression signature was developed to distinguish high-grade (G3/4) from low-grade (G1/2) disease. The expression profile was further validated for performance and clinical usage in 283 frozen renal cancer samples and 127 ex-vivo renal mass biopsy samples, respectively. The area under curve (AUC) was used to quantify discriminative ability and was compared using the De-long test. Results: Using the development dataset, we identified a 24-gene signature for high-grade disease with an AUC of 0.884. After applied to the replication dataset, an eight-gene profile was defined and achieved an AUC of 0.823. The accuracy of 8-gene panel was maintained in the RMB samples (AUC = 0.821). Conclusions: Using a two-stage replication design, we validated an eight-gene expression signature for predicting high Fuhrman grade of ccRCC. This tool may help to reveal the characteristics of ccRCC biopsy specimens.
A novel preoperative inflammatory marker prognostic score in patients with clear cell and non-clear cell renal cell carcinoma.
Authors: Sekar Rishi Robert , Patil Dattatraya , Pearl Jeff , Baum Yoram , Kucuk Omer , Harris Wayne B. , Carthon Bradley , Alemozaffar Mehrdad , Filson Christopher Paul , Ogan Kenneth , Master Viraj A. 
Published: February 2017

530 Background: Several inflammatory markers have been studied as potential biomarkers in clear cell renal cell carcinoma (RCC), however few reports have analyzed their prognostic value in aggregate and in non-clear cell histologies. We hypothesize that a combination of preoperative C-Reactive Protein (CRP), albumin, Erythrocyte Sedimentation Rate (ESR), corrected calcium, and AST/ALT ratio into a RCC Inflammatory Score (RISC) could serve as a rigorous prognostic indicator in patients with clear cell and non-clear cell RCC. Methods: Patients that underwent nephrectomy for localized RCC were queried from our nephrectomy database. The optimal threshold for individual biomarkers was determined using grid search methodology, receiver operating characteristic (ROC) analysis, and sensitivity-specificity trade-off analysis. The final score, RISC, was the sum of points accrued from each biomarker (Table). ROC and chi-square analysis was performed to compare the prognostic ability of RISC to SSIGN and UISS. Impact on overall survival was analyzed with multivariate logistic regression analysis. Results: 391 patients were included in the study. Area under the curve (AUC) for RISC, SSIGN, and UISS was 0.78, 0.78, and 0.81, respectively. Chi-square analysis of AUCs revealed no statistically significant difference between RISC, SSIGN, and UISS (p= 0.820, and p =0.317, respectively). On multivariate analysis, after adjusting for confounding variables, each unit increase in RISC was associated with a 32% increase in mortality (HR=1.32, 95%CI 1.17-1.49, p<0.001). Conclusions: RISC is an independent and significant predictor of overall survival in clear cell and non-clear cell RCC with accuracy at least as good as other established prognostic tools. Notably, RISC is composed of standardized preoperative laboratory markers, allowing crucial prognostic information to be integrated into medical decision making prior to surgery. [Table: see text]
The effect of stereotactic ablative radiotherapy on time to change of systemic therapy in extra-cranial renal cell carcinoma metastases.
Authors: Wang Chiachien Jake , Cai Xin , Kim Dong W. , Huelsmann Lorel , Meyer Jeffrey John , Pedrosa Ivan , Brugarolas James , Margulis Vitaly , Timmerman Robert D. , Hannan Raquibul 
Published: February 2017

533 Background: Renal cell carcinoma (RCC) has traditionally been refractory to radiotherapy with conventional fractionation, although recent evidence suggests a response to higher doses per fraction. We evaluated local control of extra-cranial metastases from RCC treated with stereotactic ablative radiotherapy (SABR). Methods: RCC patients with extra-cranial metastases treated with SABR were retrospectively enrolled from a single institution between 2005 and 2015. A total of 188 lesions were identified from 91 patients. Radiation (8-60Gy) was delivered in 1-5 fractions (fx) using stereotactic guidance. Local control (LC) was determined by imaging according to RECIST 1.1. Results: Median age at the time of treatment was 62.4 years. Metastases were detected in bone (39.9%), lung (14.9%), liver (9.6%), lymph nodes (11.7%) and other sites (23.9%). Ninety-seven (51.6%) lesions reached curative intent while 91 (48.4%) only reached palliative intent. The most common radiation regimens were 20Gy/1fx, 30Gy/3fx, and 40Gy/5fx. One-year overall survival was 76.5% with a median follow up of 10.7 months. Patients treated with curative SABR showed a 2-fold median survival as compared to those treated with palliative therapy (3.97 year vs 1.43 year, p<0.05). LC rates at 1 and 2 years were 91.4% and 89.7%, respectively. For the patients that failed, median time to local failure was 6.6 months. LC at 1 year significantly improved when treatment was curative (96.1% vs 84.9%, p<0.05), while it decreased in a re-irradiation setting (94.8% vs 46.7%, p<0.05). The median biological equivalent dose (BED) for the lesions that failed was 103Gy, corresponding to 6Gy x 5fx, and was significantly lowered compared to controlled lesions (BED 134Gy). Although 79% of patients developed new lesions within 1 year following SABR, 34.8% did not switch systemic therapy. Switching systemic therapy was delayed in patients treated with curative as compared to palliative SABR (13.4 vs 2.5 months, p<0.05). Conclusions: SABR improved LC of extra-cranial RCC metastases and delayed change to systemic therapy. SABR may complement systemic therapy to improve outcome in the present patient population.
Variation in national use of long-term ADT by disease aggressiveness among men with unfavorable-risk prostate cancer.
Authors: Muralidhar Vinayak , Mahal Brandon Arvin Virgil , Reznor Gally , Choueiri Toni K. , Sweeney Christopher , Martin Neil E. , Orio Peter F. , Chen Yu-Wei , Nezolosky Michelle Daniel , Hoffman Karen E. , Feng Felix Yi-Chung , Trinh Quoc-Dien , Nguyen Paul L. 
Published: February 2017

54 Background: Current National Comprehensive Cancer Network (NCCN) guidelines uniformly recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer. We sought to determine whether the use of long-term ADT varied by the subcategory of disease, including the recently-defined subcategories of high-risk disease (favorable, other, and very-high) versus intermediate-risk disease. Methods: We identified 5,836 patients with NCCN intermediate-, high-, or very high-risk prostate cancer diagnosed between 2004 and 2007 and managed with external beam radiation therapy (EBRT) using the Surveillance, Epidemiology, and End Results database linked to Medicare claims data. Patients were stratified by risk group: intermediate-risk, favorable high-risk (previously defined and validated as T1c, Gleason 4+4=8, PSA < 10 ng/mL or T1c, Gleason 6, PSA > 20 ng/mL), other high-risk, or very high-risk. We used competing risks regression to estimate the rates of long-term (≥ 2 years) ADT in each of these groups. Differences were compared using multivariable regression modeling, adjusting for year of diagnosis, race, marital status, income level, age, and comorbidity. Results: Men with favorable high-risk prostate cancer were significantly less likely to receive 2 years of ADT than others with high-risk disease (21.9% vs. 29.3%, adjusted hazard ratio [AHR] 0.78, 95% confidence interval [CI] 0.67-0.90, p = 0.001), and similarly likely as those with intermediate-risk disease (AHR 1.08, 95% CI 0.94-1.25, p = 0.288). Others with high-risk disease were less likely to receive 2 years of ADT than those with very high-risk cancer (29.3% vs 36.4%, AHR 0.84, 95% CI 0.74-0.96, p = 0.010). Conclusions: Patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Despite NCCN guidelines recommending long-term ADT for all high-risk or very high-risk prostate cancer, our results might reflect the view that these patients represent a heterogeneous group, with favorable high-risk cancer possibly warranting less aggressive therapy than other high-risk or very high-risk disease.