bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ablative therapy to induce local and systemic immune changes in patients with metastatic renal cell carcinoma.
Authors: Campbell Matthew T. , Matin Surena F. , Slack Rebecca , Sun Jing Jing , Ng Tang Derek , Chen Hong , Blando Jorge M , Zhang Li , Rao Priya , Sharma Padmanee 
Published: March 2017

505 Background: Ablative therapy including cryoablation or radiofrequency ablation is a therapeutic option for small renal cell carcinomas (RCC) and provides effective palliation for symptomatic metastatic lesions, with reports of associated abscopal phenomenon in small numbers of patients. Pre-clinical animal modeling has suggested potential synergy with the use of ablative therapy and immune checkpoint blockade with ipilimumab. Methods: We performed retrospective analysis of 17 patients who underwent an ablative procedure followed later by nephrectomy. These samples were analyzed by IHC and gene expression studies. We also prospectively evaluated pre and post treatment blood samples from a different cohort of 13 patients. These samples were evaluated for immune cell subsets and cytokine profiles. Results: IHC studies revealed an increased frequency of PD-1 + immune cells in post-ablative tumor samples as compared to control samples. Gene expression studies also revealed higher expression of immune gene signatures as compared to control samples. Blood samples detected changes in regulatory T cell subsets and interleukin-6 cytokine levels in the short term, which normalized by 1 month post-ablation, suggested an active downregulation of the initial immune response. Based on these data, we initiated a clinical pilot study to treat patients with anti-CTLA-4 (tremelimumab) with or without cryoablation in patients with metastatic RCC. The primary endpoint of the trial will be safety. Secondary endpoints include objective response rate, progression free survival, and immune monitoring. A total of 30 patients, 15 in each arm, will be accrued. Initial data from the clinical trial will be presented. Conclusions: Ablative therapy causes immune changes that can be detected both at the tissue and systemic level. We hope to capitalize on these changes by combining immune checkpoint blockade and ablation in an ongoing prospective clinical trial.
Impact of pharmacokinetics (PK) of sunitinib (SU) and its metabolite SU12662 on clinical outcome and toxicity in metastatic renal cell cancer (mRCC) patients.
Authors: Martin Nicolas , Borchiellini Delphine , Viotti Julien , Chamorey Emmanuel , Milano Gerard A. , Ferrero Jean-Marc 
Published: March 2017

506 Background: Pharmacological activity of SU is usually attributed to SU and its active metabolite SU12662, known to exhibit similar potency in inhibiting tyrosine kinase activity and cellular proliferation in vitro. However, equivalence is not clearly demonstrated towards clinical endpoints. The objective of this phase 2 study was to determine the impact of SU and SU12662 on clinical outcomes and toxicity in mRCC patients (NCT00943839). Methods: Patients with mRCC, eligible for SU in the first line setting, were prospectively included. SU was given orally at 50 mg qd for 4 weeks on/2 weeks off until progression or unacceptable toxicity. Minimal concentration at steady-state (CSSmin) was evaluated by high-performance liquid chromatography at day 28 of each cycle for both SU and SU12662. Data for tumor response, survival, and toxicity were recorded. Kaplan-Meyer’s curves with log-rank tests and cox regression models were used to identify relationships between PK parameters and survival. Chi2 tests and student t-tests were used to identify relationships with toxicity. Results: 41 patients in 7 French centers were included between 2009 and 2012. 16 patients had favourable prognosis, 13 intermediate prognosis, and 1 poor prognosis according to IMDC risk groups (Heng, J Clin Oncol 2009). Median follow-up was 30.6 months. Median progression-free survival (PFS) was 20.2 months and median overall survival (OS) was 39.5 months. Mean CSSmin for SU and SU12662 were 57.2 and 29.8 ng/ml, respectively. CSSmin of SU12662 was independently correlated to poor PFS and OS (p = 0.01 and 0.003 respectively). Patients with a mean CSSmin of SU12662 higher than 42.5 ng/ml had a worse PFS and OS compared to patients with lower concentrations: 5.7 months and 5.7 months versus 20.6 months and 39.5 months (p = 0.01 and 0.002 respectively). High CSSmin of both SU and SU12662 were associated with increased incidence of asthenia (p<0.001). Conclusions: High exposure to SU12662 was associated with poor outcomes and increased asthenia for patients with mRCC treated with SU in the first line setting. It may be related to a higher metabolism and unequal activity between SU and SU12662 in vivo. Clinical trial information: NCT00943839.
Correlation between inflammatory markers in blood and expression of costimulatory molecules on tumor-infiltrating CD8+ lymphocytes in renal cell carcinoma.
Authors: Kissick Haydn T. , Kim Kyu Seo , Chang Yun Min , Master Viraj A. 
Published: March 2017

508 Background: Loss of co-stimulatory molecules by CD8 T-cells is associated with reduced proliferative and cytotoxic function in chronic viral infections, aging, and cancer. Several lines of evidence suggest that a more functional immune system is associated with better patient outcomes, and improved response to immunotherapy in a range of different cancers. For this reason, understanding the features of a patient that predict the loss of T-cell function is important. In this study we characterized how co-stimulatory molecules are expressed by T-cells in the tumors of RCC patients. Additionally, we characterized how distant sites of metastasis differ from the primary tumor, and finally, we evaluated levels of blood inflammatory markers (BIMs) to predict how co-stimulatory on CD8+ TILs change. Methods: Patients that underwent resection of primary and/or metastatic RCC at Emory University Hospital were prospectively enrolled in the study. Levels of pre-op BIMs were retrieved from medical records. A portion of resected tumor tissue was analyzed by flow cytometry to measure percentage of CD8+ cells expression of the co-stimulatory molecules, ICOS, CD27, CD40L, CD226, CD28, and CD2. A composite co-stimulatory score (co-stim score) was calculated by taking a weighted average of the number of co-stimulatory receptors expressed per cell. BIMs were correlated with CD28 expression and co-stim score. Expression of co-stimulatory receptors was compared between patient-matched primary tumor and metastatic tumor pairs. Results: We found that by CD8 T-cells in tumors often lost co-stimulatory molecules. Furthermore, albumin and Hgb both had a strong positive correlation with CD28 expression and overall co-stim score, while WBC, Plt, neutrophil-lymphocyte ratio (NLR), ESR, and CRP was negatively correlated. Expression of co-stimulatory receptors did not differ significantly between primary tumor and metastatic tumor pairs suggesting that a systemic effect controlled TIL phenotype rather than site specific factors. Conclusions: Our data show that BIMs have the potential to predict the immunologic phenotypes of cytotoxic TILs in RCC noninvasively.
Predicting disease progression in men with localized high risk prostate cancer undergoing radical prostatectomy.
Authors: Nyame Yaw A. , Tosoian Jeffrey J. , Alam Ridwan , Wilkins Lamont , Yousefi Kasra , Chappidi Meera , Reddy Chandana A. , Humphreys Elizabeth B. , Sundi Debasish , Chapin Brian F. , Stephenson Andrew J. , Klein Eric A. , Ross Ashley 
Published: March 2017

51 Background: Currently utilized pre-treatment nomograms for prostate cancer were developed and validated using populations primarily composed of men with low and intermediate risk disease. This study aims to construct a nomogram that predicts for biochemical recurrence (BCR) and metastasis (mets) from a contemporary cohort of men with with NCCN high (HR) and very high risk (VHR) prostate cancer. Methods: From 2005 to 2015, 1,241 men with NCCN HR or VHR prostate cancer were identified from two large academic medical centers. The cohort was divided into training (n = 620) and validation (n = 621) cohorts. Primary endpoints were BCR and mets. Cox multivariable regression was performed to model characteristics and outcomes in the training cohort. Model accuracy was assessed using the time-dependent area under the receiver operator characteristic curve (AUC) in the validation cohort. Results: 494 men (245 training and 249 validation) developed BCR, and 123 men (64 training and 59 validation) developed mets, with BCR-free and mets-free probability of 49.0% and 86.5% at 5- years, respectively. Predictive nomograms including age, ethnicity, PSA, Gleason grade, clinical stage, and the number of cores with Gleason 8-10 disease were developed. Models for BCR and mets had AUCs of 0.72 and 0.75. By comparison, the MSKCC preoperative nomogram and CAPRA nomogram provided AUCs of 0.69 and 0.68 for predicting BCR and 0.66 and 0.67 for mets. Conclusions: Individualized risk assessment is imperative for optimal decision making and to design and power clinical trials. The nomograms described here, created from a population exclusively comprised of HR/VHR men, have better discrimination than those previously established on cohorts of primarily low and intermediate risk men, and may represent an ideal way by which oncologic outcomes can be predicted in men with HR or VHR disease.
Genomic profiling of nephrectomy and metastatic sites in patients with advanced clear cell renal cell carcinoma (RCC).
Authors: de Velasco Guillermo , Madison Russell , Ali Siraj Mahamed , Signoretti Sabina , Mullane Stephanie Anne , Ross Jeffrey S. , Miller Vincent A. , Stephens Philip J. , Schrock Alexa Betzig , Young Lauren , Pal Sumanta K. , Choueiri Toni K. 
Published: March 2017

513 Background: Novel biomarkers are required to accurately assess response in renal cancer. Genomic alterations (GAs) in samples from primary (nephrectomy) (N) as compared distant metastases (M) in clear cell RCC (ccRCC) may have clinical implications as well as mutations in circulating tumour DNA (ctDNA). Methods: 237 primary ccRCC nephrectomy specimens and 156 samples from distant metastases were assayed by hybrid capture based comprehensive genomic profiling (CGP) in the course of clinical care to identify GAs suggesting benefit from targeted therapy. Tumor mutation burden (TMB) was assessed as the number of somatic coding point mutations per megabase of targeted territory. Aditionally, 17 patient-specific assays were developed to quantify ctDNA allele fraction (AF) in plasma of mRCC patients. Results: 1263 GAs and 34 clinically relevant GA (CRGAs) were identified. Most common GA identified were VHL (74%/72%), PBRM1 (40%/51%), SETD2 (28%/26%) in N and m respectively (Table). Additionally, most common CRGA identified were TP53 (8%/15%), PTEN (10%/10%), TSC1 (6%/6%), and TERT(5%/9%) in N and m respectively. No difference in TMB was seen between primary and metastatic samples. By site of metastases, soft tissue, and adrenal gland had the highest TMB and lymph node the lowest. In the 17 patients with available ctDNA, 15/17 (88.2%) have a maximum somatic AF < 1% (median 0.33% [0% - 22%]) suggesting generally low tumor content. Interestingly, ctDNA in 3 patients were successfully sequenced including a patient with an EML4-ALKfusion treated with alectinib. Conclusions: This data supports that both primary and metastatic RCC share the majority of common GA. Quantitation of ctDNA is a promising biomarker for response. [Table: see text]
DNA methylation signature for the assessment of metastatic risk in primary renal cell cancer.
Authors: Peters Inga , Reese Christel , Dubrowinskaja Natalia , Antonopoulos Wiebke Inga , Krause Martin , Dang Tu Nghi , Grote Alexander , Becker Albert , Hennenlotter Jörg , Stenzl Arnulf , Tezval Hossein , Kuczyk Markus A , Serth Juergen 
Published: March 2017

516 Background: Transition from localized renal cell cancer (RCC) to metastatic disease is associated with an immense mortality. Beside clinicopathological risk estimation, a molecular prediction of metastatic risk from primary cancers with a sufficient diagnostic accuracy is not available. We biometrically identified a candidate metastasis associated methylation signature (MAMS) in a genome-wide in silico DNA methylation analysis of TCGA data and carried out a double evaluation study using tissues from localized RCC, primary metastatic RCC, and distant metastases. Methods: Candidate MAMS was identified by genome-wide random forest analyses of TCGA methylation level 3 data aiming for classification of 230 primary RCC without distant metastases and 52 metastasized tumors. Forty-nine pyrosequencing and/or quantitative methylation specific PCR analyses were established for a total of 20 candidate methylated loci. For evaluation of MAMS, DNA was isolated and bisulfite converted from the primary RCC tissue cohort (n=187) as well as 99 distant metastases. Localized RCCs consisted of 92 pT1a/b tumors (clear cell, 73; papillary, 16; chromophobe, 2; not classified, 1) without lymph node or distant metastases. RCC samples of primary metastatic disease were obtained from 31 patients. Results: Single candidate loci showed specific hypermethylation when metastatic tissues were compared to primary RCC samples. Random forest analysis showed that MAMS including nine methylation loci achieved a sensitivity of 93% and a specificity of 89% (AUC 0.95) for differentiation of localized RCC and metastases (chi square, p = 3.4*10-29). Positive, negative likelihood, and diagnostic odds ratios were 8.6, 0.08, and 108. Using this random forest model for prediction of primary RCCs associated with distant or lymph node metastases revealed a sensitivity of 58% and specificity of 94% (AUC 0.84, p = 1.0*10-9). Positive, negative likelihood, and diagnostic odds ratios were 9.2, 0.45, and 20.5. Conclusions: A negative MAMS test result retrospectively reduced the probability of metastasis 15-fold in the localized disease cohort, suggesting a prospective evaluation for a possible clinical translation of MAMS in handling RCC patients.
An exploratory study to investigate the immunomodulatory activity of radiation therapy in combination with pembrolizumab in patients with renal cell cancer.
Authors: Lin Jianqing , Hoffman-Censits Jean H. , Kelly William Kevin , Tuluc Madalina , Shaw Colette , Louie Jennifer , Harshyne Larry , Kean Rhonda , Bar-Ad Voichita , Den Robert B. , Hurwitz Mark , Johnson Jennifer Maria , Hubert Christine , Philipose Sherin , Leiby Benjamin E. , Deshmukh Sandeep P. , Dicker Adam , Hooper D. Craig , Lu Bo 
Published: March 2017

518 Background: Preclinical data suggest there are synergistic effects of radiation therapy (RT) and check point inhibitors in anticancer immunity. The primary objective of this study was to explore the immunomodulatory activity of RT alone or in combination with Pembrolizumab (pembro) in solid tumors including renal cell cancer (RCC) patients (pts). Methods: RCC pts who progressed after at least one front-line therapy were eligible. Pts were treated with either RT (8Gy x 1 or 4Gy x 5) followed by (f/b) pembro or 1 dose pembro f/b RT f/b pembro. Pre- and post RT tumor biopsy was obtained to evaluate PD-L1 expression (assay by QualTeck). Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Treatment response was measured based on modified RECIST criteria. Results: 12 RCC patients were enrolled including 2 with non-clear cell subtype. One pt was not evaluable since pt quickly deteriorated and was taken off study. As of September 30, 2016, 5 pts were still on study with 3 pts having partial response (27.2%, responders) and were on study for at least 9.8 months. 2 responders were treated with 8 Gy f/b pembro while 1 was treated with pembro f/b RT f/b pembro. Six pts (54.5%, non-responders) had PFS between 2 – 4 m and were off study. For adverse events, 1 pt developed grade 4 pneumonitis after 10 cycles of pembro (RT to adrenal mets). Grade 3 AEs include fatigue, nausea, hyperglycemia, lymphopenia, thrombocytopenia, and AST elevation (post RT for liver mets). PDL1 expression and tumor infiltrating lymphocytes presence after RT showed various patterns. Preliminary flow cytometry showed persistent higher numbers of monocytes in non-responders compared with responders. CD4+, CD8+, and NK cells and other markers are under-analyzed and the results will be presented. Conclusions: The combination of RT (8Gy or 20Gy) with pembro is feasible and tolerated, and demonstrates clinical activity. The AE profile is similar to single agent pembro. Monocytes, T, and NK cell kinetics are being examined. Clinical trial information: NCT02318771.
The necessity of dynamic contrast enhanced imaging for prostate MRI: A study of pathologic outcomes on prostate biopsy.
Authors: Druskin Sasha C. , Tosoian Jeffrey J. , Young Allen , Ghabili Kamyar , Andreas Darian , Macura Katarzyna , Ross Ashley 
Published: March 2017

52 Background: PIRADS version 2 guidelines for the interpretation of multi-parametric prostate MRI (mpMRI) stipulates that dynamic contrast-enhanced (DCE) imaging be used to classify diffusion weighted imaging (DWI) score 3 peripheral zone lesions into PIRADS-3 (DCE-) or PIRADS-4 (DCE+) lesions. Despite this, it is unknown if DCE based classification separates lesions into clinically meaningful pathologic groups. Because use of contrast adds time, risk (though modest), and cost to mpMRI, we sought to examine whether use of DCE indeed improves detection of clinically-significant cancer. Methods: Using the Johns Hopkins MRI-ultrasound fusion prostate biopsy database and including only patients without a prior diagnosis of prostate cancer (n = 232), we identified patients with peripheral zone DWI-3 or DWI-4 lesions who underwent targeted biopsy of those lesions. Each lesion meeting the MRI criteria was considered separately, and grouped into one of three lesion MRI classifications – DWI-3/DCE-/PIRADS-3, DWI-3/DCE+/PIRADS-4, or DWI-4/PIRADS-4. The rates of benign, grade group (GG) 1, and GG ≥ 2 pathology were compared between the MRI classification groups. Results: One hundred forty-eight peripheral zone DWI-3 or DWI-4 lesions from a total of 106 patients were identified. The rate of benign(%)/GG1(%)/GG ≥ 2(%) biopsy pathology in the groups DWI-3/DCE-/PIRADS-3 (61 lesions), DWI-3/DCE+/PIRADS-4 (37 lesion), and DWI-4/PIRADS-4 (47 lesions) was 68.9/18.0/8.2, 59.5/13.5/18.9, and 44.7/23.4/27.7, respectively (P > 0.05 for the difference in rates of GG ≥ 2 pathology between the two PIRADS-4 groups and the two DWI-3 groups). Conclusions: Given the cost and morbidity of using intravenous contrast agents in prostate MRI, their clinical utility must be determined. In this study, DWI-3 peripheral zone lesions with DCE positivity appear to have a higher rate of clinically-significant (GG ≥ 2) cancer on biopsy. This study supports the use of DCE to better classify DWI-3 peripheral zone lesions however further study with expanded cohorts is indicated.
Analysis of overall survival (OS) based on tumor target lesion change in the phase 3 METEOR trial of cabozantinib (cabo) versus everolimus (eve) in advanced renal cell carcinoma (RCC).
Authors: Pal Sumanta K. , Motzer Robert J. , Fishman Mayer N. , McDermott Raymond S. , Passos-Coelho Jose , Kopyltsov Evgeniy , Garcia del Muro Xavier , Donas Jesus Garcia , Yildiz Ramazan , Wood Lori , Zalewski Pawel , Costello Brian Addis , Stadler Walter Michael , Kuzel Timothy M , Williamson Stephen K. , Kondo Takeyoshi Alfonso , Markby David W , Escudier Bernard , Powles Thomas , Choueiri Toni K. 
Published: March 2017

522 Background: In the METEOR study (NCT01865747), cabo demonstrated improved progression-free survival (median 7.4 vs. 3.8 mo; HR 0.58, 95% CI 0.45–0.74; p<0.0001), OS (median 21.4 vs. 16.5 mo; HR 0.66, 95% CI 0.53-0.83, p=0.0003), and objective response rate (17% vs. 3%; p<0.0001) compared with eve in patients (pts) with advanced RCC who had received prior VEGFR TKI therapy (Choueiri NEJM 2015, Lancet Oncol 2016). Here we evaluate the impact of changes in target lesion size from baseline on OS. Methods: 658 pts were randomized 1:1 to receive cabo (60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC risk group and number of prior VEGFR TKIs. Target lesion size was assessed per independent radiology review by CT/MRI scans at baseline, every 8 weeks for the first 12 months, and every 12 weeks thereafter. Three subgroups were defined by best change in target lesion size from baseline: decrease ≥30%, decrease <30%, and any increase. Results: The rate of target lesion regression was higher in the cabo arm (75%) compared with the eve arm (48%). A higher fraction of pts had a decrease ≥30% in target lesion size in the cabo arm, while a higher fraction of pts had an increase in target lesion size in the eve arm (Table). Medians for OS with cabo were not estimable (NE) (95% CI, NE‒NE), 20.8 mo (95% CI, 18.1‒NE), and 11.1 mo (95% CI, 7.6‒15.2) for the ≥30% decrease, <30% decrease, and any increase subgroups, respectively. Medians for OS with eve were NE (95% CI, 19.3‒NE), 18.0 mo (95% CI, 15.9‒20.4), and 14.0 mo (95% CI, 10.5‒16.3) for the ≥30% decrease, <30% decrease, and any increase subgroups, respectively. Median duration of follow-up for OS was 18.7 mo (IQR 16.1–21.1) for cabo and 18.8 mo (16.0–21.2) for eve. A higher proportion of pts received subsequent anticancer therapy in the any increase subgroup compared with the other subgroups. Conclusions: Cabo demonstrated a higher rate of tumor target lesion regression than eve, and greater target lesion regression was associated with improved OS in pts with advanced RCC. Clinical trial information: NCT01865747. [Table: see text]
Retrospective review of cytotoxic chemotherapy and anti-angiogenic combinations in renal cell carcinoma: A single institution experience.
Authors: Carthon Bradley Curtis , Tabba Manal , Ellis Carla , Harris Wayne , Bilen Mehmet Asim , Canter Daniel , Master Viraj A. , Kucuk Omer 
Published: March 2017

523 Background: Despite many therapeutic advances, Renal Cell Carcinoma (RCC) still is a leading cause of cancer morbidity and mortality. A recent phase 2 study has examined the combination of Sunitinib and Gemcitabine in a poor risk RCC trial population (Michaelson et al., Cancer 2015). There is limited data on such combinations in a non-clinical trial population. This retrospective study examines our institutional experience in treating predominantly high risk RCC patients with a combination of gemcitabine and an anti-angiogenic agent. Methods: IRB approval was obtained in order to review pathological and clinical data of RCC patients. A retrospective cohort was identified of RCC patients treated with Gemcitabine as well as an anti-angiogenic agent (Sunitinib or Pazopanib) between January 2011 and December 2015 at the Winship Cancer Institute at Emory University. Patient data was reviewed for clinical and pathological characteristics, treatments, prognostic factors, and tolerance. Kaplan Meier analysis was used to assess treatment associated time-to-disease progression (TTP) and overall survival (OS). Results: 12 patients received Gemcitabine and either Sunitinib (n=11) or Pazopanib (n=1). Clear cell (n=5) and non-clear cell varieties including papillary (n=5), chromophobe (n=1), and collecting duct (n=1) RCC were represented. The median line of therapy was 2 (range 0-5 prior therapies). 50% of patients were poor risk, 33% were intermediate risk, and 17% of patients had good risk disease by Heng Criteria. The overall median TTP was 2.9 months (range 0.82-16.5 months) and overall median OS was 8.3 months (range 2.3-16.5 months). This regimen was well tolerated with the most common adverse effects being fatigue in 50% (6/12) of patients, fever in 33% (4/12) of patients, and nausea in 33% (4/12) of patients. Conclusions: Our experience suggests that this combination is effective in advanced and heavily pretreated RCC patients, including poor risk RCC patients outside of a clinical trial format. Additional prospective data using similar combinations, may provide improved outcomes of RCC patients, especially with non-clear cell RCC patients.