bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of crizotinib on disease control in patient with advanced papillary renal cell carcinoma type 1 with MET mutations or amplification: Final results of EORTC 90101 CREATE.
Authors: Schoffski Patrick , Wozniak Agnieszka , Escudier Bernard , Rutkowski Piotr , Anthoney Alan , Bauer Sebastian , Sufliarsky Jozef , Van Herpen Carla M.L.- , Lindner Lars , Grünwald Viktor , Zakotnik Branko , Lerut Evelyne , Debiec-Rychter Maria , Marreaud Sandrine , Lia Michela , Raveloarivahy Tiana , Collette Sandra , Albiges Laurence 
Published: February 2018

580 Background: Papillary renal cell carcinoma type 1(PRCC1) is associated with MET alterations. Our phase II trial assessed the efficacy and safety of crizotinib in patients (pts) with advanced/metastatic PRCC1 with/without MET mutations( MET+, MET-). Methods: Eligible pts with reference pathology-confirmed PRCC1 received oral crizotinib 250mg twice-daily. Pts were attributed to MET+/ MET- sub-cohorts by sequencing of MET exons 16-19 in tumour tissue. Primary endpoint was objective response rate (ORR). If at least 2 of the first 12 eligible/evaluable MET+ pts achieved a confirmed partial (PR) or complete response (RECIST 1.1), a maximum of 35 pts were enrolled. Other endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and rate (PFSR), overall survival (OS) and safety. Results: 23 of 41 pts consenting were eligible, treated and evaluable. In 4 MET+ pts, 2 achieved a PR and 1 had stable disease (SD) (ORR 50%; 95% CI: 6.8-93.7%), DOR was 666 and 1138 days, 1-year PFSR was 75.0% (12.8-96.1%), 1-year OS: 75.0% (12.8-96.1%). Among 16 MET- pts, 1 achieved a PR lasting 302+ days and 11 had SD (ORR: 6.3%; 0.2-30.2%), 1-year PFSR: 27.3% (8.5-50.4%), 1-year OS: 71.8% (41.1-88.4%). Among 3 pts with unknown MET status ( MET?) due to technical failure, 1 achieved a PR lasting 211+ days and 1 had SD (ORR 33.3%, 0.8%-90.6%), 1-year PFSR: 66.7% (5.4-94.5%), 1-year OS: 100%. MET amplification was found post hoc in 1 MET+ (PR, DOR: 1138 days) and 1 MET- case (SD). Common treatment-related AEs were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%), and blurred vision (34.8%). Conclusions: Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in pts with MET mutations or amplification. Sporadic, durable responses are also seen in MET-/ MET? cases, suggesting the presence of other alterations of MET or alternative pathways. Clinical trial information: NCT01524926.
Homologous repair deficiency in VHL-mutated clear cell renal cell carcinoma.
Authors: Pilie Patrick Glen , Zhou Lijun , Peterson Christine B , Peng Yang , Peng Guang , Jonasch Eric 
Published: February 2018

585 Background: Clear cell renal cell carcinoma (ccRCC) displays genomic instability across all tumor stages, indicative of increased replicative stress and defects in DNA damage response (DDR) pathways including homologous repair (HR); however ccRCC does not display mutations in canonical DDR genes and advanced ccRCC is not traditionally sensitive to DNA damaging agents. We hypothesized that biallelic VHL loss is sufficient to cause HR deficiency (HRD) and that early stage ccRCC is more likely to display HRD than late stage disease. Methods: We performed whole-exome (WES) sequencing of 15 small ccRCC tumors to assess for mutational burden, mutational signature, and cancer-related driver gene mutations. We performed in silico genomic, transcriptomic, and proteomic analysis of tumors in KIRC TCGA to assess for HRD. Finally, we assessed HR efficiency as a product of biallelic VHL loss in engineered cell line models. Results: 15/15 early stage ccRCC had VHL mutations, approximately 100 additional mutations per tumor, but no common mutations found in KIRC TCGA. In silico analysis showed 67% of KIRC TCGA displayed HRD gene signature, and was significantly higher in stage I disease (p = 2.21e-08). Patients with VHL-mutated tumors are more commonly HRD than HR intact (HRI) (p = 0.03), with frameshift/nonsense variants in VHL more likely to result in HRD than missense variants (p = 0.02). Multivariate analysis showed HRD predicted for better overall survival compared to HRI (p < 0.0001). Proteomic analysis of KIRC TCGA revealed HRI samples had significantly higher protein expression of Rad51 and RAPTOR when compared to HRD samples. Lastly, etoposide-treated MEF Vhl-/- cell lines displayed reduced HR efficiency when compared to Vhl intact controls. Conclusions: Biallelic loss of VHL is sufficient to cause HRD. HRD gene signature predicts for significantly better OS in ccRCC patients, and early stage ccRCC is more likely to be HRD. mTOR/PI3K signaling pathway proteins are differentially expressed in HRI patient samples from TCGA compared to HRD, suggesting a possible role for these oncogenes driving a HRI phenotype. Treatment strategies combining PARP inhibitors with PI3K/mTOR inhibitors should be tested in advanced VHL-mutated ccRCC.
Japan multicenter prospective study: FDG PET/CT in the assessment of advanced renal cell carcinoma treated with sorafenib.
Authors: Nakaigawa Noboru , Tateishi Ukihide , Kato Takuma , Kaneta Tomohiro , Kondo Keiichi , Sugimoto Mikio , Yao Masahiro , Inoue Tomio , Kakehi Yoshiyuki , Kubota Yoshinobu 
Published: February 2018

605 Background: We previously reported that the early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma (aRCC) treated with tyrosine kinase inhibitors (TKIs) predicted the disease course. In this study, we investigated prospectively the relationship of the clinical outcome of patients with aRCC treated with sorafenib and radiological parameters obtained with FDG-PET/CT at baseline and 4 weeks (4W). Methods: The patients with TKI-naïve aRCC planning to be treated by sorafenib were enrolled and assessed by FDG-PET/CT at baseline and at 4W. The relationship between radiological parameters, (1) max SUVmax at baseline, (2) change in max SUVmax at 4week, and (3) response criteria defined by Ueno D et al. ( The prognosis of aRCC which max SUVmax decreased more or 20% at 4W demonstrated good prognosis. BMC Cancer 2012) and progression-free survival (PFS) and overall survival (OS) was exploratory evaluated. This study is multicenter-study using PET/CT systems which quality is ensured by previous phantom study. Results: Total 34 patients were enrolled. The median PFS were 9.7 months and mean OS were 35.8 months (survival curve did not reach 0.5). The median of max SUVmax (the highest standardized uptake value in each patients) at baseline was 5.1. The median PFS of patients with baseline max SUVmax ≤ 5.1 showed longer PFS and OS compared that with max SUVmax > 5.1 (median PFS 11.9months vs. 9.2 month P= 0.0354, median OS --- vs. 15.3 months P= 0.027 ). The median change ratio in max SUVmax at 4W was -9.5%. The change ratio did not affect the PFS and OS, analyzing the total patients. When the patients with max SUVmax > 4.0 at baseline were focused, the PFS of patients which max SUVmax decreased more or 20% at 4W demonstrated tendency to be longer than that of other patients (median PFS 15.6 months vs 9.2 months, P= 0.0727) Conclusions: In this study, we demonstrated that the pretreatment max SUVmax predicted the PFS and OS of aRCC treated by sorafenib, but change of max SUV max at 4W did not. The change ratio could have potency as a predict marker for the PFS in the cases with high max SUVmax at baseline. It was speculated that the accurate assessment of change ratio in the cases with low max SUVmax at baseline was difficult. Clinical trial information: 000009812.
Using aorta lesion attenuation difference (ALAD) on preoperative contrast-enhanced CT scan to differentiate between malignant and benign renal tumors.
Authors: Grajo Joseph , Terry Russell , Ruoss Justin , Pavlinec Jonathan , Noennig Blake , Bozorgmehri Shahab , Blute Mike , Crispen Paul , Su Li-Ming 
Published: February 2018

606 Background: To evaluate the ability of Aorta−Lesion−Attenuation−Difference (ALAD) to differentiate malignant renal tumors from renal oncocytomas. Methods: A retrospective review of preoperative CT scans and surgical pathology from robotic assisted partial nephrectomy specimens obtained by a single surgeon was performed. ALAD was calculated by measuring the difference in Hounsfield units (HU) between the aorta and the lesion of interest on the same image slice in the nephrographic phase on preoperative CT scan. The discriminative ability of ALAD to differentiate malignant pathology from oncocytoma was evaluated by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under curve (AUC) using ROC analysis. Results: A total of 218 preoperative CT scans and corresponding pathology reports were reviewed. Pathology review revealed 22 oncocytomas (10.1%), 11 chromophobe RCC (5%), 37 papillary RCC (17%), and 148 clear cell RCC (67.9%). ALAD was able to differentiate malignant pathology from oncocytoma using a HU threshold of 24 with a sensitivity of 84%, specificity of 86%, PPV of 98%, and NPV of 33%. The AUC for malignant pathology versus oncocytoma was 0.86 (95% CI 0.77−0.96). Subgroup analysis showed that ALAD was able to differentiate chromophobe RCC from oncocytoma using a HU threshold of 24 with a sensitivity of 100%, specificity of 86%, PPV of 75%, and a NPV of 100%. The AUC for chromophobe RCC versus oncocytoma was 0.98 (95% CI 0.91−1.00). Conclusions: ALAD measurements based upon preoperative CT scans provide good discrimination between malignant renal tumors and oncocytomas, potentially decreasing the need for biopsy in certain patients. ALAD also discriminates well between chromophobe RCC and oncocytoma, which may aid in the management of patients with indeterminate diagnoses of oncocytic neoplasm on biopsy. Further validation of ALAD will be necessary prior to routine use in clinical practice.
Development of a conversation aid tool for patients with localized renal cell carcinoma at high risk of recurrence.
Authors: Stewart Grant , Bargo Danielle , Kilgariff Sarah , Trennery Claire , Bennett Bryan , Battle Dena , Casper Jochen , Staehler Michael D. 
Published: February 2018

608 Background: Approximately 15% of nephrectomised patients who are diagnosed with loco-regional renal cell carcinoma (RCC) are considered to be at high risk of recurrence according to the postoperative UCLA Integrated Staging System (UISS) and 60% of these patients are expected to recur within five years of diagnosis. This study aimed to develop a conversation aid tool to improve knowledge about RCC for post-nephrectomy RCC patients who are at high-risk of recurrence. Specifically, to enable patients to make an informed decision about whether to proceed/not proceed with adjuvant therapy, should adjuvant therapy become standard-of-care in the future. Methods: A review of existing evidence relating to the development of conversation aid tools and previously developed tools was undertaken. Following the review, a focus group with a steering committee (RCC patients, caregivers and a clinician), and semi-structured interviews were conducted with clinicians to identify information currently provided as standard of care. Additional interviews were conducted with post-nephrectomy patients, to identify information patients would prefer to have been given post-nephrectomy. Results: The evidence review of 10 articles provided a framework for the development of a tool to enable better patient/clinician communication. Clinicians described a typical post-nephrectomy consultation and highlighted key topics of discussion, which included recovery, risk of relapse and ongoing care. The research highlighted that patients are expected to absorb a significant amount of information during consultations in order to take an active role in their care. Findings from the focus group and clinician/patient interviews led to the development of a conversation aid tool providing patients with key questions to ask their clinicians to increase knowledge of RCC post-nephrectomy and also the information they may require when considering adjuvant therapy, including: prognosis, risk of relapse, and the risk/benefit profile of available treatment options. Conclusions: The conversation aid tool may be useful for patients to improve knowledge of RCC and help make informed decisions about their future treatment and care.
Impact of comorbidities on functional recovery from partial nephrectomy.
Authors: Isharwal Sudhir , Ye Wenda , Wang Alice Y. , Abraham Joseph , Zabell Joseph , Dong Wen , Wu Jitao , Suk-Ouichai Chalairat , Caraballo Elvis , Gao Tianming , Campbell Steven C. 
Published: February 2018

612 Background: Preservation of parenchymal mass and ischemia type/duration can influence functional recovery after partial nephrectomy (PN). Some have hypothesized that relevant comorbidities may also impact functional recovery, but this has not been adequately investigated. Methods: 405 patients with PN at our center (2007-2015) had necessary data to determine function/parenchymal mass preserved within the ipsilateral kidney. All comorbidities potentially associated with renal functional status were reviewed. Multivariable linear regression assessed factors associated with functional recovery, defined as percent ipsilateral GFR preserved. Results: Median tumor size and R.E.N.A.L. score were 3.5cm and 8, respectively. Overall, 264 (65%) patients had warm ischemia and 141cold ischemia (median durations = 21/27 minutes, respectively). The median ipsilateral GFR preserved was 79%. Age, comorbidity index, hypertension, and proteinuria all associated with preoperative GFR (all p < 0.01). Parenchymal mass preserved and ischemia characteristics significantly associated with functional recovery (all p < 0.001). On univariable analysis of comorbidities, only hypertension associated significantly with functional recovery. However, on multivariate analysis, none of the analyzed comorbidities associated with functional recovery. Conclusions: Recovery of function after PN depends primarily on parenchymal mass preservation and ischemia characteristics, while comorbidities failed to associate with functional outcomes. Comorbidities can impact function leading into surgery and may influence long-term functional stability, yet our data suggest that they do not influence short-term recovery after PN. [Table: see text]
Real world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Stukalin Igor , Wells J Connor , Graham Jeffrey , Yuasa Takeshi , Beuselinck Benoit , Kollmannsberger Christian K. , Ernst D. Scott , Agarwal Neeraj , Le Tri , Donskov Frede , Hansen Aaron Richard , Bjarnason Georg A. , Srinivas Sandy , Wood Lori , Alva Ajjai Shivaram , Kanesvaran Ravindran , Fu Simon Yuen Fai , Davis Ian D. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2018

615 Background: The immuno-oncology (IO) checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor (TKI) cabozantinib have both been shown in phase III clinical trials to be effective in metastatic renal cell carcinoma (mRCC) after progression on first-line therapy. We sought to explore the real-world efficacy of these therapies in second-line mRCC. Methods: Using the IMDC database, a retrospective analysis was performed on mRCC patients treated with second-line nivolumab or cabozantinib. Baseline characteristics and IMDC risk factors were collected. Overall survival (OS), time to treatment failure (TTF), and response rates were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences. Results: 225 patients were treated with nivolumab and 53 with cabozantinib. There was no significant difference in OS identified, with a mOS for nivolumab of 22.1 months (95% CI 17.18 – NR) and 23.7 months (95% CI 15.52 vs. NR) for cabozantinib, p = 0.6053. The TTF was also similar, with 6.90 months (95% CI 4.60 – 9.20) for nivolumab versus 7.39 months (95% CI 5.52 – 12.85) for cabozantinib, p = 0.1983. The adjusted hazard ratio (HR) for nivolumab vs. cabozantinib was 1.297 (95% CI – 0.728 – 2.312), p = 0.3775. Conclusions: Nivolumab and cabozantinib appear to have similar efficacy in terms of OS and TTF in this real-world patient population, thus both novel agents are reasonable therapeutic options for patients progressing after initial first-line therapy. [Table: see text]
Evaluation of predictive biomarkers for nivolumab in metastatic clear cell renal cell carcinoma (mccRCC) using RECIST and immune-related (IR) RECIST.
Authors: Pignon Jean-Christophe , Jegede Opeyemi , Horak Christine , Wind-Rotolo Megan , Catalano Paul J. , Grosha Jonian , Flaifel Abdallah , Novak Jesse , Mahoney Kathleen Margaret , Freeman Gordon J. , Sharpe Arlene , Wu Catherine J. , Hodi F. Stephen , Motzer Robert J. , Choueiri Toni K. , Atkins Michael B. , McDermott David F. , Signoretti Sabina 
Published: February 2018

619 Background: Development of predictive biomarkers would help select patients more likely to respond to nivolumab (nivo) in mccRCC. Here we evaluated biomarkers for nivo using endpoints based on either RECIST 1.1 (ORR and PFS) or irRECIST (irORR and irPFS), which were proposed to more accurately predict benefit of immunotherapy. Methods: We retrospectively analyzed tumor tissues from the Checkmate 010 trial (PMID: 25452452). PD-L1 expression on tumor cells (TC) was studied by IHC. Percentages of CD8+ tumor infiltrating cells (TIC) expressing the immune checkpoints PD1, TIM3 and LAG3 (either alone or in various combination) were determined by immunofluorescence (IF) and their predictive value assessed by the presence of a dose response relationship (DRR) with PFS or irPFS. The candidate biomarkers were then correlated with clinical outcomes using optimized cutoffs. Results: As previously shown, TC PD-L1 expression was not associated with PFS or ORR. In contrast, pts with TC PD-L1 ≥1% had longer median irPFS and higher irORR (Table). None of the TIC phenotypes determined by IF displayed a DRR with PFS. Conversely, we found that % of CD8+ TIC that are PD1+TIM3-LAG3- (% CD8+ PD1+TIM3-LAG3- TIC) was correlated with irPFS (HR = 0.58, p = 0.007). At the optimized cutoff (36%), pts with high % CD8+ PD1+TIM3-LAG3- TIC had longer median irPFS and higher irORR (Table). Notably, combination of TC PD-L1 expression with % CD8+ PD1+TIM3-LAG3- TIC identified 3 groups of pts for which irPFS and irORR were significantly different (Table). Conclusions: Our results suggest that, in mccRCC, tumor-immune biomarkers for nivo response show improved association with clinical endpoints defined by irRECIST relative to RECIST. The increased predictive value of TC PD-L1 combined with immune checkpoints expression on CD8+ TIC seen in this cohort requires independent validation. [Table: see text]
Hypofractionated external beam radiation therapy in combination with HDR boost for localized prostate cancer: Quality of life outcomes.
Authors: Morgan Tiffany , Press Robert H. , Cutrell Patrick , Zhang Chao , Chen Zhengjia , Rahnema Sara , Sanda Martin George , Pattaras John , Patel Pretesh R , Jani Ashesh B. , Rossi Peter John 
Published: February 2018

62 Background: There is limited data to support the use of hypofractionated external beam radiation (HypoF) in combination with high dose rate brachytherapy (HDR). We report our quality of life (QOL) outcomes when treating intermediate (IR) and high risk (HR) prostate cancer patients with external beam radiation (EBRT) plus HDR. Methods: The charts of 54 patients with localized adenocarcinoma of the prostate treated with standard fractionation (SF) or HypoF EBRT plus HDR boost at a single institution between 2012 and 2015 were reviewed. All patients completed the American Urological Association Symptom Score (AUASS) and Expanded Prostate Index for Prostate Cancer – Clinical Practice (EPIC-CP) quality of life assessments prior to treatment and completed at least one follow-up survey. Linear mixed models were performed to test whether there was any significant change over time for each outcome and to detect whether there was any significant difference in each outcome between the different treatments. Results: Thirty-eight patients were treated with SF and 16 with HypoF. Median age at treatment was 68 years (range 55-82 years). Median follow-up for the cohort was 22.2 months (range 1.57-50.60 months). A majority of patients had clinical T1c disease (n = 35), Gleason score of 7 (n = 35), and a PSA < 10 (n = 39). Thirty-one patients had NCCN IR, and 23 had HR disease. There was no significant difference in AUA score (p = 0.98), incontinence and urinary irritation/obstruction scores (p = 0.81 and p = 0.62, respectively), and rectal toxicity (p = 0.97) between the two dosing groups over time, or at any discrete time point. Likewise, sexual function, vitality score, and QOL scores were not significantly different between the dose groups over time (p = 0.59, p = 0.37, and p = 0.71, respectively). All QOL categories, except sexual function, trended toward baseline with increasing time from intervention. Conclusions: Our study suggests HypoF EBRT can be delivered in combination with HDR for patients with IR and HR adenocarcinoma of the prostate without increasing toxicity compared to SF with an HDR boost. This has important implications in terms of patient convenience and resource utilization.
Application of Canadian hereditary renal cell carcinoma risk criteria to a population database.
Authors: Kushnir Igal , Kirk Leah , Mallick Ranjeeta , Kim Raymond , Graham Gail E , Breau Rodney H. , Lattouf Jean-Baptiste , Violette Philippe , Pautler Stephen E. , Care Melanie , Kapoor Anil , Jewett Michael A.S. , Wood Lori , Tanguay Simon , Heng Daniel Yick Chin , Basappa Naveen S. , So Alan I. , Pouliot Frederic , Reaume M. Neil 
Published: February 2018

621 Background: Canadian criteria for identifying patients (pts) and families at risk for hereditary renal cell carcinoma (RCC) were published in 2013. They included characteristics for pts with RCC (age ≤ 45 years, bilateral or multifocal tumours, associated medical conditions and non-clear cell histologies with unusual features) and for any pts who have a family history of specific clinical or genetic diagnoses associated with renal neoplasms. The clinical impact of these criteria on genetic testing had yet to be evaluated. Methods: The Canadian hereditary RCC risk criteria were applied to pts from 16 centres in the Canadian Kidney Cancer Information System prospective database. The primary endpoint was the proportion of pts who met at least one criterion. Secondary endpoints included the number of pts with more than one criterion and the number of pts receiving genetic testing (with or without at risk criteria). Results: From January 2011 to May 2017, 8097 pts were entered in the database. 2827 (35%) met at least one criterion for genetic testing. The majority (83%) met just 1 criterion, while 16% met 2 criteria. The criterion of non-clear cell histology with unusual features contributed the largest proportion of at risk pts (59%), followed by age ≤ 45 years (29%), then first or second degree relative with renal tumour (16%). 69 pts underwent genetic testing, with 59 being classified at risk ( < 3% of at risk). Details about the genetic testing results will be presented. Conclusions: The application of the Canadian hereditary RCC risk criteria to a population database resulted in 35% of pts being identified at risk for hereditary RCC. However, the true incidence of hereditary RCC in this population is unknown as most pts did not undergo genetic testing, and thus the sensitivity or specificity of the criteria cannot be determined. The low proportion of at risk pts that underwent genetic testing was disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing. The results have helped determine the proportion of at risk pts in Canada, what criteria are most common, and importantly, have established a foundation and benchmark to improve upon.