bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of NKTR-214 on the number and activity of CD8+ tumor infiltrating lymphocytes in patients with advanced renal cell carcinoma.
Authors: Hurwitz Michael E. , Diab Adi , Bernatchez Chantale , Haymaker Cara L. , Kluger Harriet M. , Tetzlaff Michael T. , Gergel Ivan , Tagliaferri Mary , Imperiale Michael , Aung Sandra , Hoch Ute , Zalevsky Jonathan , Hwu Patrick , Sznol Mario , Tannir Nizar M. 
Published: March 2017

454 Background: Patients with low baseline CD8+ T-cells within the tumor microenvironment (TILs) have a poor response to immune checkpoint inhibitors. Agents designed to specifically activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs. NKTR-214 is a CD-122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) and preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells. Methods: A dose escalation, open-label, trial was initiated to assess the safety of NKTR-214 and explore immune changes in the blood and tumor microenvironment in patients with advanced solid tumors. NKTR-214 was administered IV in an outpatient setting with initial dosing at 0.003 mg/kg. Pre and post treatment blood and tumor samples were analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by immunohistochemistry. Results: Among 25 patients dosed, 15 had RCC (10@0.006mg/kg, 4@0.009mg/kg, and 1@0.012mg/kg). Treatment with NKTR-214 was well tolerated and the MTD was not reached. One patient experienced DLTs (Gr3 syncope and hypotension) at 0.012 mg/kg. There were no immune-related AEs. Of 12 patients evaluable for response, 75% had SD at their first on treatment scan. Of 5 patients, who were immune checkpoint naïve with ≥ 1 prior TKI treatments, 3 experienced tumor shrinkage, 1 with PR per RECIST 1.1 (unconfirmed). Interrogation of the tumor microenvironment revealed many significant immunological changes post treatment, including increase in total and proliferating NK, CD8+, and CD4+ T cells. There was good correlation between increase in activated CD4+ and CD8+ T cells in peripheral blood with an increase in T cell infiltrates within the tumor tissue. Conclusions: NKTR-214 increased immune infiltration in the tumor and anti-tumor activity in patients who previously progressed on TKIs, with a favorable safety profile. The ability to alter the immune environment and increase PD-1 expression on effectors T cells may improve the effectiveness of anti-PD-1 blockade. A trial combining NKTR-214 and nivolumab is enrolling. Clinical trial information: 02869295.
Meta-analysis of disease free survival (DFS) as a surrogate for overall survival (OS) in localized renal cell carcinoma (RCC).
Authors: Harshman Lauren Christine , Xie Wanling , Moreira Raphael Brandao , Gustavo Ruiz , Sweeney Christopher , Choueiri Toni K. 
Published: March 2017

459 Background: OS is a critical endpoint for adjuvant RCC trials testing the benefit of early systemic therapy to increase cure rates, but requires long duration and significant patient resources. We explored the potential use of DFS as a surrogate for OS when assessing the efficacy of adjuvant therapy in localized RCC. Methods: We performed a systematic literature review following the PRISMA statement. Inclusion criteria required randomized controlled trials (RCT) for adjuvant systemic therapy in localized RCC, which reported on both DFS and OS. DFS was defined from randomization or nephrectomy (R/N) to the first evidence of clinical recurrence (loco-regional or distant) or death from any cause. OS was defined from R/N to death from any cause. We extracted data on hazard ratio (HR) and 5-year event free rate from Kaplan Meier estimates. We performed a meta-analysis and correlated these estimates for OS and DFS, weighted by number of DFS events. R-square >0.7 would indicate a strong correlation and potential surrogacy. Results: Of the more than 315 studies screened, 10 studies investigating various forms of cytokine and vaccine immunotherapy and angiogenesis inhibitors (e.g., sunitinib, sorafenib, thalidomide) between 1987 and 2016 were eligible for the analyses. The total enrolled patients were 5,497, with median follow-up ranging 3 to 10 years. Conclusions: Across trials of adjuvant systemic therapy for localized RCC, we observed a moderate correlation between 5 yr DFS and OS rate and between treatment effects (HRs) on these endpoints. Future meta-analyses of more mature trials in the era of modern adjuvant targeted therapy are needed to evaluate the surrogacy of intermediate endpoints. Further granularity may be achieved using individual patient data to assess different and earlier time points for surrogacy than are commonly reported. [Table: see text]
Stereotactic body radiotherapy for high-risk prostate cancer (5 treatment days): Toxicity results of a phase II trial.
Authors: Kishan Amar Upadhyaya , Fuller Donald B. , Steinberg Michael L. , Ramirez Victoria , Agazaryan Nzhde , Ruan Dan , Cao Minsong , Kupelian Patrick , King Christopher R. 
Published: March 2017

46 Background: Stereotactic body radiotherapy (SBRT) for high-risk prostate cancer (CaP) remains investigational not only due to undetermined efficacy but also due to concerns for the potential toxicity when the treatment volumes extend beyond the prostate gland itself. Methods: Men with high-risk CaP, as defined by Gleason score > = 8, clinical stage T3-T4, or initial PSA > = 20 ng/mL, were enrolled on a multicenter phase II trial and were treated with 40 Gy to prostate and 25 Gy to pelvic nodes in 5 fractions and 9 months neoadjuvant and concurrent ADT. Treatment with ADT and pelvic nodal radiation was at the discretion of the treating physician. Follow-up assessment was with CTCAE v4 and Expanded Prostate Composite Index (EPIC). Results: A total of 61 patients were treated, with a median follow-up of 12 months. Forty (64.4%) received ADT and 23 (37.1%) received nodal radiation. The median initial PSA was 8.1 ng/mL and 8% of patients had clinical T3-T4 disease; 45.9% and 39.3% had Gleason score 8 and 9-10 disease, respectively. No grade 3 or higher toxicities were seen. Rates of acute and late grade 2 genitourinary toxicities were 13.1% and 6.7%, respectively; rates of acute and late grade 2 gastrointestinal toxicities were 6.6% and 8.2%, respectively. Mean changes in EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were -0.35, +1.44, and -2.38, respectively. For the 32 patients with evaluable EPIC scores at 12 months, mean changes on EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were -1.04, -2.70, and -6.76, respectively. The percentages of patients with minimum clinically important change in EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were 11.9%, 21.4%, and 26.2%, respectively. At 12 months, these figures were 13.9%, 30.6% and 27.8%. The receipt of ADT and/or nodal radiation had no significant effect on either physician- or patient-reported toxicity profiles (p > 0.1, Fisher’s exact test). Conclusions: SBRT regimens can be safely utilized to deliver the entire course in 5 treatment days in patients with high-risk localized CaP. Clinical trial information: NCT02296229.
Prognosis of renal cell carcinoma with bone metastases: Experience in 300 consecutive patients.
Authors: Ruatta Fiorella , Derosa Lisa , Albiges Laurence , Massard Christophe , Loriot Yohann , Fizazi Karim , Escudier Bernard 
Published: March 2017

463 Background: Bone metastases (BMs) are associated with significant morbidity and shorter survival in metastatic renal cell carcinoma (mRCC). Our purpose was to identify prognostic factors for mRCC patients (pts) with BMs. Methods: Data from mRCC pts with BMs, treated at Gustave Roussy between April 1992 and March 2016, were retrospectively collected. Age, sex, ECOG-Performance Status (PS), Memorial Sloan-Kettering Cancer Center (MSKCC) score, histology, number and site of BMs, concomitant metastases (presence and sites), therapy for BMs (radical resection or palliative surgery, radiotherapy, other local and systemic treatments), time to BMs, and outcome were analyzed. Synchronous solitary bone metastasis (SSBM) was defined as a single bone metastasis without concomitant visceral lesions at the initial diagnosis of RCC. Overall survival (OS) was calculated from the date of BMs diagnosis to death or last follow-up using Kaplan-Maier method and modelled with Cox-regression analysis. Results: Three hundred pts were identified. Median time to BMs was 32.4 months (range 0–324 months). In 64 pts (21%), bone was the only metastatic site and 22 of them (7%) had a SSBM; 236 pts (79%) had concomitant metastases in other sites. Median OS was 23.22 months. SSBM pts had better OS then those with concomitant metastases (40 vs. 20 months; p<0.001). At univariate analysis, number of BMs (p<0.0001), spinal column as site of BMs (p<0.005), concomitant metastases (p<0.0001), Fuhrman grade (p<0.001), non-clear cell histology (p<0.003), and MSKCC score (p<0.001) were significantly associated with poor prognosis. At multivariate analysis, concomitant metastases remained predictor of poor prognosis while good MSKCC, radical resection, and SSBM were predictors of better OS. Conclusions: To our knowledge,this is the largest single-institution experience evaluating prognosis in pts with BMs from RCC. This study suggests that MSKCC score, number of BMs (1 vs. >1) and radical resection are prognostic factors. Additionally, in presence of solitary bone metastasis without other concomitant metastases at the initial diagnosis of RCC, bone surgery should be considered to achieve local tumor control and increase survival.
Outcomes of PD-1/PD-L1 responders who discontinue therapy for immune-related adverse events (irAEs): Results of a cohort of patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: McKay Rana R. , Martini Dylan , Moreira Raphael Brandao , Hamieh Lana , Norton Craig , Mullane Stephanie Anne , Walsh Meghara K. , Michaelson Dror , McDermott David F. , VanAllen Eliezer , Harshman Lauren Christine , Choueiri Toni K. 
Published: March 2017

467 Background: Nivolumab, a monoclonal antibody against PD-1, has been shown to improve survival for pts with mRCC. The current standard of care is to administer treatment on a continuous basis until progression or toxicity. Outcomes of pts who experience a response to treatment and then discontinue therapy for irAEs have not been fully characterized. The purpose of this analysis was to evaluate outcomes of responders to PD-1/PD-L1 targeted therapy (TT) who discontinue treatment for irAEs. Methods: We identified pts with mRCC having experienced a response to PD-1/PD-L1 TT, which was subsequently discontinued for an irAE. Clinical characteristics, response, and survival data were collected. Results: We identified 9 mRCC pts who were treated with a PD-1/PD-L1 inhibitor, experienced a response to therapy, and subsequently discontinued treatment for an irAE. 8 had clear cell histology and 1 had translocation RCC. 7 pts were treatment naive. 2 pts had International mRCC Database Consortium favorable risk, 4 intermediate risk, and 3 poor risk disease. 44% (n = 4) of pts received PD-1/PD-L1 monotherapy and the overall median duration of therapy was 5 months (mos) (range 4-15). There was 1 complete response, 7 partial responses, and 1 stable disease (17% shrinkage). Treatment was discontinued for the following irAEs: arthritis, uveitis, arthropathy, hypophysitis, myositis, blepharitis, hepatitis, rash, pericarditis, and amylase and lipase elevations. After PD-1/PD-L1 treatment discontinuation, 4 (44%) pts remained progression free with a median time off therapy of 20 mos (range 10-44) and median time on therapy of 9 mos (range 4-15). 5 (56%) pts progressed within 6 mos (range 2-6) of treatment discontinuation and median time on therapy was 4 mos (range 3-10). Conclusions: We demonstrate that some pts can have persistent clinical benefit after discontinuation of PD-1/PD-L1 TT for irAEs. Larger studies are warranted to evaluate the need for continuous drug dosing in all pts, identify pts in which continuous dosing is not required, and evaluate long-term outcomes in this population.
Effects of change in surgical approach in T3 renal cell carcinoma (RCC) with intracaval thrombus on complications and survival.
Authors: Vallinga Marleen Suzanne , Leliveld Anna Maria , Peeters Paul M.J.G. , De Jong Igle J. 
Published: March 2017

471 Background: In patients with T3 RCC with venous tumor thrombus reaching the inferior vena cava, without metastatic disease, a nephrectomy with cavotomy is performed. Before 2000, surgical approach of level 3-4 caval tumorthrombus included sternotomy and cardiopulmonary bypass with circulatory arrest, with high morbidity and mortality rates. After the routine use of liver mobilization around 2000, sternotomy became less necessary. We compared perioperative characteristics, complications and survival pre- and post-2000. Methods: We retrospectively studied 91 patients, operated between 1984 and 2016 in a referral hospital. Patients with a T3 RCC and caval thrombus underwent a radical nephrectomy with thrombectomy. Data on patient and tumor characteristics, operation approach, complications (Clavien-Dindo classification), hospital stay, progression and survival were collected and analyzed using Mann-Whitney U, Chi-Square, and Log-Rank tests. Results: 91 patients (56 male) with a mean age of 65 years were included. 33% had a level 3 or 4 cava thrombus. Surgical management before 2000 included sternotomy with circulation arrest in 32% and liver mobilization in 10%. After 2000, the number of sternotomies lowered to 8% while liver mobilization increased to 74%. See table 1 for perioperative outcomes and complications. Disease specific survival was significant longer in patients operated after 2000 (estimated mean 70 vs. 94 months, p = 0.03). Only N stage influenced progression free survival, patients N+ showed worse survival (p < 0.01). Conclusions: The change in surgical approach including liver mobilization significantly decreased complication rates, blood loss, transfusion rate, hospital stay and increased disease specific survival. [Table: see text]
T cell infiltration in matched renal biopsy (bx) and nephrectomy (nx) samples in renal cell carcinoma (RCC).
Authors: Zahoor Haris , Pavicic Paul G , Przybycin Christopher , Elson Paul , Diaz-Montero C. Marcela , Finke James , Rayman Patricia A. , Gilligan Timothy D. , Grivas Petros , Ornstein Moshe Chaim , Garcia Jorge A. , Rini Brian I. 
Published: March 2017

472 Background: T cell infiltration in tumors has been investigated as a biomarker of response to checkpoint inhibitors. A neo-adjuvant trial of checkpoint inhibition in locally-advanced RCC is ongoing at Cleveland Clinic, where T cell infiltration in pre-treatment renal mass bx will be compared to post-treatment nx specimens. However, there are no data regarding the association of T cell infiltration in matched bx and nx samples without intervening treatment. Understanding this association will enable further study of this potential biomarker in future neo-adjuvant studies. Methods: Matched bx and nx samples (without intervening systemic therapy) were identified from patients with non-metastatic RCC. Demographic and pathological data were collected from chart review. Selected tissue sections from bx and nx samples of each patient were reviewed, and marked for tumor and intra-tumoral lymphocytes by the pathologist. Immunohistochemistry (IHC) was utilized to stain these selected tissue sections for T cell markers (CD3, CD4 and CD8). Intra-tumoral T cells were then quantified in the pre-marked tissue sections as counts per total tumor area surveyed, using Image-Pro Plus (Media Cybernetics, Inc.). Spearman correlation (ρ) was used to measure the strength of association of T cell infiltration between matched samples. Results: 30 matched pairs were investigated. The median interval between bx and nx was 2.8 (0.2-87.7) months. Clear cell was the most common histology (29/30; 97%). 15/30 (50%) had grade 3-4 tumors, 2/19 (11%) patients had sarcomatoid features, 7/25 (29%) had necrosis, and 8/28 (29%) had lymphovascular invasion. We found a positive correlation between the frequencies of CD8+ T cells between matched bx and nx samples (ρ= 0.39; p=0.03). CD3+ and CD4+T cells did not show significant correlation. (Table) Conclusions: Bx material can be used to accurately assess the degree of CD8+T cell infiltration in RCC. [Table: see text]
Real-world economic outcomes among patients (pts) who initiated sunitinib or pazopanib as first targeted therapy (TT) for advanced renal cell carcinoma (aRCC): A retrospective analysis of Medicare data.
Authors: Vogelzang Nicholas J. , Pal Sumanta K. , Ghate Sameer , Li Nanxin , Swallow Elyse , Peeples Miranda , Zichlin Miriam , Meiselbach Mark , Perez Jose Ricardo , Agarwal Neeraj 
Published: March 2017

475 Background: Evidence on economic outcomes could provide insight on comparative economic benefit of TTs. This study assessed all-cause healthcare resource utilization (HRU) and costs among aRCC patients who initiated pazopanib and sunitinib, two commonly-used first TTs. Methods: Pts with aRCC who initiated sunitinib or pazopanib as first TT (index therapy/index date) were identified in this 100% Medicare data + Part D linkage (1/1/2006-12/31/2014). Characteristics were assessed during the 1 year prior to index date (baseline period) and pts were followed until death, end of eligibility, or end of data (study period), whichever was earliest. Pts were stratified by first TT initiated and 1:1 matched using propensity scores based on age, sex, race, year of RCC diagnosis, metastatic sites, comorbidities, and baseline inpatient, outpatient, emergency room, and pharmacy costs. Study period all-cause HRU and costs (2015 USD) were assessed on a per pt per month (PPPM) basis and compared between the matched cohorts. Results: Before matching, the cohorts were similar in baseline characteristics; however, the pazopanib cohort (n=526) was associated with higher outpatient visits and costs and lower pharmacy costs during the baseline period than the sunitinib cohort (n=1,185; all p<0.05). After matching, all baseline characteristics were balanced (n=522 for both). First TT with pazopanib was associated with significantly lower total healthcare costs ($10,416 vs. $8,845, mean difference [MD]):$1,571, p<0.01), total medical costs ($6,904 vs. $5,460, MD:$1,444, p<0.01), inpatient costs ($4,035 vs. $2,914, MD:$1,120, p<0.01), inpatient admissions (0.26 vs. 0.18, MD:0.08, p<0.01), and inpatient days (1.9 vs. 1.4, MD:0.5, p<0.01) compared with the sunitinib cohort. Conclusions: In this retrospective analysis of Medicare aRCC pts, treatment first line with pazopanib compared to sunitinib had lower follow-up all-cause healthcare costs and resource use, particularly with lower inpatient admissions and shorter length of stay.
Impact of immune checkpoint protein expression in tumor cells and tumor infiltrating CD8+ T cells on clinical benefit from PD-1 blockade in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Pignon Jean-Christophe , Jegede Opeyemi , Mahoney Kathleen M. , Moreira Raphael Brandao , Novak Jesse , Conen Hilla , Norton Craig , Harshman Lauren Christine , Van Allen Eliezer Mendel , Wu Catherine J. , Atkins Michael B. , Freeman Gordon J. , Catalano Paul J. , Choueiri Toni K. , McDermott David F. , Signoretti Sabina 
Published: March 2017

477 Background: PD-1 blockade with nivolumab has demonstrated efficacy in mccRCC patients who have failed prior therapy; however, durable benefit is observed only in a subset of patients. Correlative studies have demonstrated that tumor PD-L1 expression alone fails to reliably identify patients likely to benefit. Therefore, the development of more robust predictive markers is warranted. Methods: We studied 20 mccRCC patients treated with nivolumab (n=17) or atezolizumab (n=3) with distinct clinical outcomes: 8 pts who experienced durable clinical benefit (DCB) for ≥ 12 months and 12 pts with limited clinical benefit (LCB) for ≤ 6 months from start of therapy. Expression of PD-L1 and PD-L2 on tumor cells and density of tumor infiltrating CD8+ T cells and Foxp3+ cells were evaluated by immunohistochemistry. Percentages of tumor infiltrating CD8+T cells expressing the immune-inhibitory molecules PD-1, TIM-3, or LAG-3 either alone or in combination were determined by multiplex immunofluorescence, using the Inform algorithm (Perkin Elmer). The association between clinical benefit (CB) and biomarker expression was assessed using Fisher exact test. Results: Baseline patient characteristics were similar in the DCB and LCB groups. When analyzed separately, tumor cell expression of PD-L1 or PD-L2 showed no association with CB. However, when positivity was defined as expression of either or both PD-L1(≥ 1% cutoff) and PD-L2 (≥ 5% cutoff), a significant association with CB was found (7/8 DCB vs 4/11 LCB, p = 0.04). A low percentage of tumor infiltrating CD8+PD-1+ T cells co-expressing either or both TIM-3 and LAG-3 (75thpercentile cutoff) was also significantly associated with CB (8/8 DCB vs 7/12 LCB, p = 0.05). Conclusions: Our results suggest that expression of a PD-1 ligand on tumor cells (PD-L1 and/or PD-L2), and a low percentage of severely exhausted T cells, i.e. CD8+PD-1+ T-cells co-expressing the immune-inhibitory receptors TIM-3 and/or LAG-3, might represent valuable predictive biomarkers for response to PD-1 blockade in mccRCC. Independent validation in a larger patient cohort is ongoing.
Epigenetic targeting of clear cell renal cell carcinoma (ccRCC) with ascorbic acid (AA) via upregulation of Ten-Eleven Translocation (TET) methylcytosine dioxygenase activity.
Authors: Shenoy Niraj Konchady , Bhagat Tushar , Pagliaro Lance C. , Witzig Thomas E. , Verma Amit 
Published: March 2017

479 Background: We and others have previously shown that the ccRCC epigenome is characterized by widespread DNA hypermethylation (CCR 2014, Nature 2014). Various important tumor suppressor genes (TSGs), such as SMAD7 (inhibitor of oncogenic TGF-β signaling), are under-expressed due to aberrantly methylated promoters or enhancers. We hypothesized that the hypermethylation in ccRCC could be due to low activity of the TET enzymes, which convert methylcytosine (5-mc) to hydroxymethylcytosine (5-hmc). Loss of function of TET enzymes can occur with an inactivating mutation (TET-2 is mutated in about 6% of ccRCC (Science Signaling 2013) or hypoactivity of normal TET enzymes, through inhibition by metabolic intermediates. AA is an essential co-factor for TET enzymes (JACS 2015). We hypothesized that high dose AA treatment of ccRCC could potentially increase the functional activity of TET enzymes leading to demethylation of the RCC genome, and enhance expression of TSGs. Methods: In vitro TET activity was performed on ccRCC cell line 769P with increasing doses of AA (L-AA). Genome wide quantitative 5-mc and 5-hmc was evaluated using mass spectrometry. SMAD7 expression was determined using qRT-PCR. Proliferation assay (MTT) was performed with AA in combination with pazopanib. Cell cycle and apoptosis assays were performed. Results: AA, at doses achieved only by the intravenous route (1-10mM), increased TET activity in ccRCC cell line 769P. Genome wide 5-mc was significantly reduced and 5-hmc was increased, correlating with increase in TET activity. SMAD7 expression was increased with AA treatment. High dose AA led to proliferation inhibition with a cell cycle arrest in the G1 phase, and had a synergistic effect with pazopanib. Since AA leads to the generation of H2O2 in-vitro, catalase was used as control. This did not reverse the effect of AA on epigenetic changes; and proliferation inhibition was seen despite catalase control. Conclusions: High dose AA causes TET mediated DNA demethylation of the hypermethylated RCC genome, resulting in the re-expression of TSGs, and proliferation inhibition. Sequencing and xenograft studies are underway.