bluuebunny/crossref_metadata_2025_split huggingface dataset:
Your opinion counts: How do you treat atypical/suspicious cytology?
Authors: Longo Thomas Andrew , Gopalakrishna Ajay , Fantony Joseph J , Inman Brant Allen 
Published: February 2017

463 Background: Urine cytology has often been reported as a highly specific but poorly sensitive test. Cytology is reported as positive, negative, atypical, or suspicious. Atypical/suspicious cytologies account for roughly a quarter of the results and present a clinical dilemma. Physicians’ risk aversion means they are typically treated as positive and result in clinical action. We test the effects of this assumption on sensitivity and specificity. Methods: After IRB approval, we queried clinical and pathology databases to identify all subjects at Duke University Medical Center who had undergone both a urine cytology and a cystoscopy from 1/2003 to 1/2012. Diagnostic test performance metrics were calculated using logistic models: (a) a generalized estimating equation (GEE) and (b) a generalized linear mixed model (GLMM). These take into account clustered/correlated test results that occur due to repeated testing within subjects. Results: A total of 990 unique subjects were identified that provided 4,733 pairs of cytology and cystoscopy for analysis. Our cohort was 61% male, 75% Caucasian, and had 54% current or former smokers. Of cytologies, 1898 (40%) were negative, 423 (9%) positive, and 2408 (51%) suspicious or atypical. When suspicious/atypical cytology results using the GLMM model were classified as positive, the specificity was 62% [95%CI: 58-66%] and the sensitivity was 41% [95% CI: 38-44%]. When these results were re-classified as negative, this had the effect of a large increase in specificity 100% [95%CI: 100-100%] with a consequent decrease in sensitivity 0% [95%CI: 0-2%]. Conclusions: In our study, the performance of urine cytology depended heavily on how the equivocal (atypical/suspicious) results were classified and dealt with. Our sensitivity was maximized when equivocal cytologies were considered positive, but at significant detriment of the specificity. Contrarily, our specificity improved greatly when the equivocal results were considered negative, but at the expense of a poor sensitivity. Furthermore, the diagnosis of an atypical/suspicious cytology was higher at our medical center than reported in the literature, and therefore significantly overestimated the performance of the urine cytology test.
Advanced tissue-based image analysis techniques integrated with biomarker-morphometric multiplex immunofluorescence to provide prostate cancer risk stratification models post-surgery.
Authors: Donovan Michael , Khan Faisal M , Scott Richard , Zeineh Jack , Koll Giovanni , Gladoun Nataliya , Charytonowicz Elizabeth , Fernandez Gerardo 
Published: February 2017

47 Background: We have previously validated the importance of utilizing the intact tissue section and quantitative biomarker strategies for developing prognostic prostate cancer outcome models. We sought to further expand upon these constructs by applying next-gen advanced image analysis tools using multiplex immunofluorescence (IF) integrated with clinical variables on an independent cohort. Methods: Utilizing a 686 patient radical prostatectomy tissue microarray population with median 8 years follow-up from Roswell Park Cancer Institute, NY, we selected an initial subset of 98 patients to construct a training model; applying multiplex immunofluorescence with CK-18 (epithelial cells), CK 5/6 (basal cells), androgen receptor (AR), Ki67, AMACR and DAPI (nuclear marker). Images were captured with an Nikon i90 microscope equipped with a CRI multiplex camera, a Bayesian probabilistic approach was used to derive features that reflect tumor grade and co-locate - quantify IF biomarker expression within various glandular sub-types. Multivariate models were constructed to predict disease progression (i.e., clinical failure (CF) = PSA rise post-adjuvant therapy, or metastasis, or death) with c-index (CI) to estimate performance. Results: A 98 patient with the following clinical features: mean PSA 6.6 ng/mL, prostatectomy Gleason score, PGS 6, 34%; >/=PGS 7, 55%; LN+ 2%, +SM 19%; + ECE 49% ; + SVI 3%. CFevent rate 13%. Two models (i.e., +/- LN status) employing 47 features with 7 clinical variables (e.g., PSA and Gleason) had comparable outcomes, CI 0.84. The number one feature selected in both models was an imaging feature reflecting prostate cancer gland architecture and differentiation. Combined AR levels with gland phenotype and CK-18 composition characterized a relevant phenotype dependent upon feature inclusion in the model generated. Conclusions: We have established the importance of utilizing the intact tissue section when developing accurate prognostic prostate cancer models. Additional studies with expanded training and test patient cohorts are underway to confirm and validate these initial findings.
Subgroup analyses of METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Escudier Bernard J. , Motzer Robert J. , Powles Thomas , Tannir Nizar M. , Davis Ian D. , Donskov Frede , Grünwald Viktor , Heng Daniel Yick Chin , Hutson Thomas , Melichar Bohuslav , Nosov Dimitry , Rini Brian I. , Salman Pamela , Sternberg Cora N. , Szczylik Cezary , Wolter Pascal , Arroyo Alan M , Mangeshkar Milan , Agarwal Neeraj , Choueiri Toni K. 
Published: February 2017

499 Background: Cabozantinib (C) inhibits tyrosine kinases including VEGFRs, MET, and AXL. The METEOR phase 3 trial (NCT01865747) met its primary endpoint of significant improvement in PFS with C versus everolimus (E) in pts with advanced clear cell RCC and prior exposure to VEGFR TKIs (7.4 mo median PFS [C] vs 3.8 mo [E], HR = 0.58, 95% CI, 0.45 to 0.75; p < 0.001). The improvement in PFS was accompanied by a significant improvement in ORR and a trend for improved OS at an interim analysis. Safety profiles of C and E in this trial were similar to prior experience with each drug in this pt population. This analysis further evaluates PFS and ORR across pt subgroups. Methods: Pts had advanced RCC with clear cell component, measurable disease per RECIST 1.1, KPS ≥ 70%, and were stratified by MSKCC prognostic criteria and number of prior VEGFR TKIs. Pts must have progressed during treatment or within 6 months of the last dose of their most recent VEGFR TKI. 658 pts were randomized 1:1 to receive C (60 mg QD) or E (10 mg QD). The primary endpoint was PFS among the first 375 pts randomized. ORR was a secondary endpoint. Results: In the PFS group, 187 pts were randomized to C and 188 to E. 73% pts had 1 and 27% pts ≥ 2 prior VEGFR TKIs; 43% pts had favorable, 41% intermediate, and 15% poor risk by MSKCC criteria. Across multiple subgroups defined by baseline characteristics, PFS HRs favored C over E. PFS HRs were similar for subgroups defined by prior number of TKIs (HR = 0.56 [1 prior] and 0.67 [ ≥ 2 prior]), and showed higher activity of C over E in pts with fewer MSKCC risk factors (HR = 0.54 [0 factors], 0.56 [1 factor], 0.84 [ ≥ 2 factors]) or with metastases in various organs (HR = 0.47 [lung mets], 0.53 [liver mets], 0.50 [bone mets]). Detailed analysis of the clinical activity of C and E (PFS and ORR) across pt subgroups will be presented, including treatment duration with first VEGFR TKI ( < or ≥ 6mo), receipt of prior anti-PD1/PDL1 agents, time to progression after most recent TKI ( < or ≥ 3mo), and frequency/location of metastases. Conclusions: The METEOR trial met its primary endpoint of improved PFS, and subgroup analyses of the endpoints PFS and ORR generally favored C over E in patients with advanced RCC. Clinical trial information: NCT01865747.
Immunomodulation by HDAC inhibition: Results from a phase II study with entinostat and high-dose Interleukin 2 in renal cell carcinoma patients (CTEP#7870).
Authors: Pili Roberto , Quinn David I. , Hammers Hans J. , Monk Paul , George Saby , Dorff Tanya B. , Olencki Thomas , Shen Li , Hutson Alan , Piekarz Richard , Carducci Michael Anthony 
Published: February 2017

500 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that the class I HDAC inhibitor entinostat has synergistic antitumor effects in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model by down-regulating Foxp3 expression and function of Tregs. Thus, we have conducted a Phase I/II clinical study with entinostat and high dose IL-2 in patients (pts) with metastatic clear cell renal cell carcinoma. Methods: The primary objectives were to evaluate the safety, tolerability and efficacy of this combination strategy. The main eligibility criteria were clear cell histology and being fit to receive high dose IL-2. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, PO every14 days) and a fixed dose of IL-2 (600,000 units/kg every 8 hrs). To test our hypothesis, the fixed sample size at the Phase II dose level was 36 with a type I/II error of 10%. If 11 or more of the pts have a response, the hypothesis that the response rate is ≤ 20% is rejected. Results: Dose levels 1 and 2 were completed without DLTs and 5 mg entinostat was the Phase II recommended dose. No severe adverse events were observed during the first 45 days of treatment. The most common transient grade 3/4 toxicities were lymphopenia (50%), neutropenia (9%), and hypophosphatemia (6%). To date, we have enrolled 39 pts at dose level 2, and 35 have completed one cycle (84 days). Four pts were not evaluable. Twelve pts have achieved objective response (39%; 9 PR, 3 CR) with a median time to response of 81 days (55-96). The median PFS has not been reached with a median follow-up of 437 days (30-1428). Preliminary results show decreased Tregs and monocytic MDSCs following treatment and suggest an association of increased CD14+/CD86+ and CD14+HLADR+cells with objective response. Conclusions: The results from this phase I/II suggest that entinostat may increase the therapeutic effect of high dose IL-2 by modulating immunosuppressive cells (R21CA137649; U01CA70095). Clinical trial information: NCT01038778.
FGFR2 expression to predict survival outcome in patients with metastatic papillary renal cell carcinoma.
Authors: Tsimafeyeu Ilya , Naumova Alexandra , Stepanova Evgenia , Khasanova Alfia , Varlamov Ilya , Wynn Nigel , Snegovoy Anton , Demidov Lev V. 
Published: February 2017

506 Background: In our previous study we showed that fibroblast growth factor receptor 2 (FGFR2) mutations are rare across papillary types of renal cell carcinoma (pRCC). The aim of the present study is to test FGFR2 expression for association with survival outcome in the largest patient cohort to date. Methods: Formalin-fixed, paraffin-embedded specimens of removed primary tumors from 214 untreated metastatic pRCC patients were evaluated by immunohistochemistry with FGFR2 antibody (Santa Cruz Biotechnology). Expression was quantified by consensus of two independent observers using a four-value intensity score (0, 1+, 2+, and 3+) and the percentage (0-100%) of the extent of reactivity. Expression was scored according to the percentage of positive cells present among all tumor cells in the section. The cytoplasmic and nuclear expression score was obtained by multiplying the intensity and reactivity extension values (range, 0-300). FGFR2 expression was tested for associations with progression-free survival (PFS), overall survival (OS) and best objective response. Results: Expression of FGFR2 was observed in 23% (49/214) of primary pRCC, mostly in cytoplasm of tumor cells. 2 of 214 (1%) patients had nuclear FGFR2 expression. Intensity was 3+ in all cases. Expression of FGFR2 was significant lower in the normal tissue of kidney (1%, P=0.001). FGFR2 expression was strongly associated with a number of metastatic sites (2 and more metastatic sites vs. 0-1), type 2 of pRCC, lower nucleolar grade (P<0.001). FGFR2-positive patients had significantly shorter OS and PFS in first-line therapy (P<0.05; Table). On multivariate analysis, FGFR2 expression, MSKCC risk group, and type of pRCC were found to be independent predictors of survival. Conclusions: In this study, we described immunohistochemical expression of FGFR2 in a large series of pRCC specimens. FGFR2 expression was found to be prognostic factor for survival in patients with metastatic pRCC. Clinical trial information: rosoncoweb2011. [Table: see text]
Analysis of mutational status in recurrently mutated genes in clear cell renal cell carcinoma and overall survival in patients with metastatic disease at time of nephrectomy.
Authors: Manley Brandon , Casuscelli Jozefina , Tennenbaum Daniel , Hakimi A. Ari , Hsieh James 
Published: February 2017

520 Background: Using the genetic profile of a tumor, clinicians may be able to give insight in to the aggressiveness or indolence of a patient’s disease. The choice to initiate or hold systemic therapy for those with metastatic disease may be aided by knowing which mutations put a patient at an accelerated risk of death from their disease. Identifying genomic markers in clear cell renal cell carcinoma (ccRCC) for patients with metastatic disease at time of nephrectomy may assist in the decision to initiate early systemic therapy even in those with stable clinical disease. Methods: Using available data from The Cancer Genome Atlas (TCGA), The International Cancer Genome Consortium (ICGC), The Cancer Genomics Project Tokyo, Japan and our intuitional database we identified 157 patients who had metastatic disease at time of nephrectomy. We performed statistical analysis to compare the presence of mutations in five recurrently mutated genes (VHL, PBRM1, SETD2, BAP1 and KDM5C) in ccRCC and overall survival. For each gene, Kaplan-Meier estimates for patients with and without mutations were generated and compared using the Log-rank test and Cox proportional hazards regression. Results: Out of the five recurrently mutated genes analyzed, we found that only mutations in BAP1 showed a statistically significant decrease in overall survival for patients who had metastatic disease at time of nephrectomy. Patients without a mutation in BAP1 had an estimated median overall survival of 32.2 months, whereas patients with a mutation in BAP1 had an estimated median overall survival of 15.4 months, HR 1.717 (CI 1.038 –2.839), p-value=0.0326. Conclusions: Patients with mutations in BAP1 show a statistically significant decrease in overall survival compared to those without mutations in these patients with terminal disease. Given these findings early initiation of systemic therapy may be considered even in those with small or stable residual disease.
The anticancer effects of supinoxin (RX-5902) in renal cell cancer.
Authors: Lee Young , Mazhari Reza , Kim Deog Joong 
Published: February 2017

524 Background: DEAD box RNA helicase DDX5/p68 may play several important roles in cancer. In particular, phosphorylated p68 has been shown to be associated with cell transformation, epithelial mesenchymal transition (EMT), and cell migration, deeming it a promising target for novel anti-cancer therapeutics. We have previously shown that Supinoxin (RX-5902) interacts with phosphorylated p68 on Tyr593, interfering with the phosphorylated p68-β-catenin signaling pathway. Methods: In this study, we first demonstrated anti-proliferative effects in ten renal cancer cell lines with a high level of sensitivity to Supinoxin (IC50 of 39 nM); TK-10 was the only resistant cell line in this study. We also sought to examine the tumor growth inhibition (TGI), tumor growth delay (TGD), and survival benefits of Supinoxin in the human renal cell carcinoma tumor (Caki-1) xenograft mouse model, using two different dosing schemas: weekly dosing at 20-160 mg/kg for 4 weeks, or 50-70 mg/kg daily (5 days on/2 days off) for 3 weeks. Results: Weekly dosing of Supinoxin at 160 mg/kg resulted in a 75% TGD (P < 0.001). Daily administration of Supinoxin resulted in dose-dependent TGI (80 and 96%; Day 21) and TGD (68 and 104%, P < 0.001), and extended the overall survival of the animals at both doses (P < 0.0001). At the dose of 70 mg/kg daily, 6/10 animals demonstrated partial tumor regressions and 1/10 a complete tumor regressions. Supinoxin did not result in a reduction in body weight gain, treatment related deaths, or clinical observations in either of the dosing schemas. Sunitinib (60 mg/kg; daily for 21 days) resulted in TGD for both in vivo studies validating the Caki-1 model herein. Conclusions: These data support the potential therapeutic activity of Supinoxin in renal cell cancers. A Phase I study of Supinoxin on relapse/refractory solid tumors is ongoing (NCT02003092).
Phase II trial of high-dose interleukin-2 (IL-2) and stereotactic radiation therapy (SABR) for metastatic clear cell renal cell carcinoma (ccRCC): Interim analysis.
Authors: Hannan Raquibul , Ishihara Dan , Louder Kristi , Ahn Chul , Margulis Vitaly , Arriaga Yull Edwin , Courtney Kevin Dale , Timmerman Robert D. , Brugarolas James 
Published: February 2017

532 Background: We report a planned interim analysis of a single-arm, open-label, phase II trial of HD IL-2 and SABR in multiple ccRCC metastatic sites. Methods: Metastatic ccRCC patients eligible for IL-2 were enrolled and received SABR of 1 or 3 fractions (fx) to up to 6 sites. IL-2 (Proleukin) was administered within 84 hours from the last SABR fx at 600,000 IU/kg every 8h for up to 14 doses in a monitored setting followed by another week after a week break. Eligible (responding) patients received a second course in > 12 weeks. The primary endpoint is the response rate (RR) as evaluated by iRECIST. The study is powered to detect a 60% improvement compared to the historically reported 23% RR for IL-2. Results: 16 patients were enrolled between August 2013 and July 2015; two were withdrawn from the study due to cardiac events prior to receiving IL-2 infusions. The median follow up was 9 months. A median of 2 (1-3) sites were treated with SABR with a median dose of 24.5 Gy (21-27 Gy) for single fx and 30Gy for 3 fx (25-33 Gy). All patients received the first week of IL-2 with a median of 10.5/14 doses; 64% received the second week (9/14) with a median of 7/14 doses. Two patients refused a second week of IL-2 and one was unable to receive it due to thyrotoxicosis. PICC line DVT delayed the second week of IL-2 in two patients. 29% of patients (4/14) received a second course of IL-2. The rate of grade 3 toxicity was 64% with no > grade 3 toxicity. The overall toxicities were expected of IL-2 treatment, transient and resolved after treatment discontinuation. In two cases, grade 1 toxicity was attributed to SABR. At this interim, ten patients underwent at least two follow up scans and were evaluable for outcome analysis. The RR was 40%, with one patient presenting complete response and 3 patients showing partial response. The median duration of overall response was 5 months, with a median stable disease duration of 6 months. Local control rate for SABR-treated lesions was 95%. Conclusions: The addition of SABR to IL-2 increased the RR in mRCC patients of about 2-folds compared to IL-2 alone, despite the reduced number of patients receiving the second week of IL-2. No significant increase in toxicity was observed. Clinical trial information: NCT01896271.
The impact of active smoking on survival outcome in metastatic renal cell carcinoma patients treated with targeted therapy.
Authors: Li Haoran , Kroeger Nils , de Velasco Guillermo , Donskov Frede , Sim Hao-Wen , Wells Connor , Stukalin Igor , Agarwal Neeraj , Parekh Hiral D. , Rini Brian I. , Knox Jennifer J. , Pantuck Allan J. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2017

552 Background: Smoking increases the risk of developing renal cell carcinoma (RCC). The prognosis of active smokers compared with non-smokers with metastatic RCC (mRCC) has not been well characterized. Methods: Smoking data from 1,842 patients with mRCC treated with targeted therapy were collected through the International mRCC Database Consortium (IMDC) from 8 Cancer Centers. Patients were categorized as current, former and non-smokers at the time of starting targeted therapy, and analyzed for differences in IMDC risk criteria, response rate (RR), progression- free-, (PFS) and overall survival (OS). Results: Overall, 292 (15.9%), 755 (41.0%), and 795 (43.1%) were current, former, and non-smokers. There were no differences in sarcomatoid features, number of metastatic sites or non-clear cell histology in either former or current smokers when compared with non-smokers. Likewise, former smokers had statistically similar IMDC risk groups compared to non-smokers. However, current smokers were more likely to have hypercalcemia (p=0.004), neutrophilia (p=0.038), thrombophilia (p=0.002), and more patients had higher numbers of IMDC risk features (p=0.014) when compared with non-smokers. The RR at first-line targeted therapy of former (p=0.89) and current smokers (p=0.13) were similar to non-smokers. No differences in PFS were noted: 7.7 vs. 7.6 vs. 6.2 months (mo) in non-, former (p=0.92), and current smokers (p=0.66). Interestingly, while former- and non-smokers had comparable OS times (23.7 vs. 23.1 mo; p=0.71), current smokers had significantly shorter OS (15.8 mo; p=0.001) than non-smokers. Current but not former smoking status was an independent poor prognosis factor (HR=1.28; p=0.006) when adjusted for the IMDC risk criteria. Moreover, each pack year increased the risk of death 1% (HR=1.01; p=0.039). Conclusions: Active smoking is associated with more advanced IMDC risk criteria and diminished OS in mRCC patients treated with targeted therapy agents. On the other hand, patients who quit smoking returned to a similar risk of death compared to patients who never smoked. Smoking cessation should be a counselling priority among mRCC patients receiving targeted agents.