bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sunitinib as first-line therapy in elderly patients (age 70 and older) with metastatic renal cell cancer.
Authors: De Giorgi Ugo , Rihawi Karim , Lo Re Giovanni , Sava Teodoro , Masini Cristina , Aieta Michele , Camerini Andrea , Fornarini Giuseppe , Burattini Luciano , De Vincenzo Fabio , Rosti Giovanni , Ferrari Vittorio D. , Moscetti Luca , Chiuri Vincenzo Emanuele , Luzi Fedeli Stefano , Scarpi Emanuela , Basso Umberto 
Published: February 2017

411 Background: Many medical oncologists are still reluctant to use the standard sunitinib regimen in older patients (pts) with metastatic renal cell cancer (mRCC) because of concerns about tolerance. We assessed the routine use of first-line sunitinib in mRCC pts aged ≥70 yrs. Methods: We reviewed the clinical files of 154 pts aged ≥70 yrs with mRCC treated with first-line sunitinib in sixteen Italian Oncology Units from February 2006 to April 2011. Sunitinib 50 mg/d 4 wk on/2 wk off was considered the standard regimen (SR). All alternative schedules of sunitinib administration were considered as adapted regimens (AR). After univariate analysis a multivariate analysis was carried out by Cox regression model and included the following variables: age (<75 vs ≥75 yrs), Eastern Cooperative Oncology Group (ECOG) performance status (PS; 0-1 vs ≥2), presence of comorbidities (0 vs ≥1), lymphocytopenia (<1,000/microL vs >1,000/microL), prognostic score for VEGF-targeted agents according to Heng 2009 (good + intermediate prognosis vs poor prognosis), and treatment schedule (SR vs AR). Results: Median age was 74 yrs (range, 70-88 yrs). One hundred six pts (68.8%) received a SR and 48 (31.2%) received an AR consisting of 37.5 mg/d 4 wk on/2 wk off (32 cases, 67%), 25 mg/d 4 wk on/2 wk off (12 cases, 25%) and 37.5 mg continuous once-daily dosing in (4 cases, 8%). Pts treated with an AR were older than those treated with the SR (≥75 yrs, 56% vs 32%, respectively, p=0.008); with no differences for the other variables. Pts received a median of 4 sunitinib cycles with either SR or AR. Grade 3-4 toxicities occurred in 65% of SR and 42% of AR (p=0.008); dose reductions were required in 64% and 40%, respectively (p=0.005); discontinuations due to therapy-related adverse events occurred in 23% and 21%, respectively (p=0.967). Median progression-free survival (PFS) was 10.6 months (95% CI 8.7-15.3) and median overall survival (OS) was 20.1 months (95% CI 15.5-not reached). In multivariate analysis, only PS and the Heng score were predictors of either PFS or OS. Conclusions: Sunitinib is active and feasible in pts with mRCC aged ≥70 yrs. AR does not appear to influence PFS and OS and has a favorable impact on toxicity.
Overexpression of IL-32 as a novel prognostic factor in patients with clear cell renal cell carcinoma after a nephrectomy.
Authors: Lee Hyo Jin , Lee Hyun-Jung , Liang Zhe Long , Lim Jae-Sung , Kim Jin Man 
Published: February 2017

413 Background: Interleukin-32 (IL-32) is a proinflammatory cytokine, which acts as an important pathogenetic factor in various diseases and malignancies. However, the clinical significance of IL-32 expression in renal cell carcinoma has not been previously investigated. Methods: We examined 112 patients with localized clear cell renal cell carcinoma (CCRCC) who underwent nephrectomy. The clinicopathologic data were obtained by retrospective review and the expression levels of IL-32 were studied by immunohistochemistry. Tumors were classified into four scores based on the staining intensity (0, no staining intensity; 1, weak; 2, intermediate; 3, strong). The cases with staining intensities from 0 to 2 were included in the IL-32 low expression group (LEG); whereas, those with staining intensity of 3 were considered the IL-32 high expression group (HEG). Correlations between IL-32 expression and clinicopathologic features were determined. Results: Staining intensities were determined for all cases as follows: 26 cases (23.2%) (score 0), 43 cases (38.4%) (score 1), 31 cases (27.7%) (score 2), and 12 cases (10.7%) (score 3). IL-32 HEG showed a higher recurrence rate compared to the IL-32 LEG (50% vs. 13%, P=0.001). For survival rates, the 5-year recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) rates were lower in the IL-32 HEG compared with the IL-32 LEG (RFS, 87% vs. 50%, P = 0.001; DSS, 92% vs. 58.3%, P < 0.001; OS, 84% vs. 58.3%, P = 0.026, respectively). Univariate analyses showed that Fuhrman nuclear grade and high IL-32 expression were significant prognostic factors for predicting RFS, DSS, and OS in CCRCC; while, multivariate analyses indicated Fuhrman nuclear grade and high IL-32 expression (RFS, HR, 4.932, P = 0.009; DSS, HR 6.736, P = 0.002; OS, HR, 2.992, P = 0.037, respectively) were still independent risk factors. Conclusions: IL-32 overexpression was associated with high recurrence rates and low RFS, DSS, and OS, suggesting that it could be a novel prognostic factor for predicting outcomes in patients with CCRCC after a nephrectomy.
Treatment patterns: Targeted therapies indicated for first-line management of metastatic renal cell carcinoma in a real-world setting.
Authors: Hess Gregory P. , Borker Rohit , Fonseca Eileen 
Published: February 2017

416 Background: Limited information about real-world treatment patterns of targeted agents for metastatic renal cell carcinoma (mRCC) is available to inform their use in clinical practice. Methods: This retrospective, observational study employed US claims data (January 2007-November 2010) to identify treatment patterns, including treatment duration and dosing, for targeted agents (sunitinib, sorafenib, pazopanib, bevacizumab, and temsirolimus) indicated in 1st line management of advanced/mRCC. The study included adult mRCC patients who were observed for ≥3 months after initiation of their 1st line therapy with a targeted agent. Descriptive analyses were conducted for the observed treatment patterns. Results: A total of 273 patients on 1st line therapy were identified and included in the study sample out of which 235 patients were treated with sunitinib, 16 patients with sorafenib, and 15 patients with temsirolimus. Pazopanib and bevacizumab were excluded from further analysis due to their small samples; n<10. The median observed treatment durations were: sunitinib 3.3 months, sorafenib 4.0 months, and temsirolimus 2.6 months. Patients initiating therapy on sorafenib (n=16) and temsirolimus (n=15) in the study sample were insufficient for meaningful dosing analyses. In sum, of the n=235 sunitinib patients, 178 (approximately 76%) initiated therapy at the indicated dose of 50 mg. Sixty-five percent of these patients were not observed filling a 4th script (the average number observed), while 26% maintained their starting dose and 9% experienced a dose reduction at their fourth fill. (See table). Conclusions: This study suggests that opportunities exist to improve treatment duration in real-world clinical practice and to better understand possible influences, other than disease progression, on treatment and dose changes. [Table: see text]
Does primary lesion have to be regarded as a target lesion when evaluating response in metastatic renal cell carcinoma (mRCC) treated with sunitinib?
Authors: Park Inkeun , Ahn Yongchel , Park Kwonoh , Park Seongjoon , Ahn Jin-Hee , Song Cheryn , Hong Jun Hyuk , Kim Choung-Soo , Ahn Hanjong , Lee Jae-Lyun 
Published: February 2017

425 Background: Primary lesion in mRCC often shows necrotic change or only density changes to targeted therapy. As most clinical trials for mRCC have enrolled nephrectomized patients (pts), there is no consensus on including primary lesion in target lesion when evaluating response. We investigated whether best overall response (OR) changes when designate target lesions with or without primary lesion, and such discordance lead to difference in predictive value in terms of time to progression (TTP) and overall survival (OS). Methods: We enrolled mRCC pts with intact primary lesion, at least one measurable metastatic lesion, and proper image data who had received sunitinib in our institution between 2003 and 2011. We documented the variation of the sum of the largest diameters (ΔSLD) with all target lesions and with metastasis-only target lesions separately. Response evaluation was calculated with RECIST v1.1. Results: Of 41 pts, 38 received sunitinib as 1st line treatment and 3 did as 2nd line. The most frequent metastatic site was lung (63.4%) followed by lymph node (46.3%) and bone (42.5%). Median ΔSLD of primary lesion and metastatic target lesion were -6.02% (range: -34.00 to 17.60%), and -18.03% (-100.00 to 120.00%). On response evaluation with metastasis-only target lesions, best OR of 2 pts (4.87%) changed from stable disease to partial response. When categorize pts into responders and non-responders, metastasis-only target lesions resulted in significantly better discrimination of TTP (14.949 vs 4.271 mo, p=0.01) and OS (18.497 vs 9.561 mo, p=0.036) between two groups. Using all target lesions, both TTP (14.949 vs 5.355 mo, p=0.056) and OS (17.971 vs 10.579 mo, p=0.155) were statistically insignificant. Conclusions: Our study showed discordance in OR between using all target lesions and using metastasis-only target lesions, and metastasis-only target lesion could have more accurate predictive value. As response rate is often used as an end point in clinical research of mRCC, further discussion is needed whether primary lesion should be included or not in target lesion. [Table: see text]
Retrospective claims analysis of palliative care costs and survival in a U.S. metastatic renal cell (mRCC) population.
Authors: Henk Henry J. , Chen Connie , Benedict Agnes , Sullivan Jane , Teitelbaum April 
Published: February 2017

433 Background: Survival and costs outcomes for patients with mRCC receiving palliative or best supportive care (BSC) after stopping active therapy have been poorly characterized. This information is important to understand how resources are utilized at the end of life and to put current treatment costs into perspective. The objective of this retrospective database analysis was to examine survival and costs associated with BSC after receiving 1 or 2 lines of mRCC treatment. Methods: A retrospective cohort analysis using claims data from commercially insured or Medicare Advantage (MCR) enrollees of a large US health plan, with medical and pharmacy benefits. The study cohort consisted of patients with an index diagnosis for RCC [ICD-9-CM 189.0] from 1/1/07 to 6/30/10 initiating any of the following treatments from 30 days prior to index date through disenrollment: sunitinib, temsirolimus, sorafenib, bevacizumab, everolimus, pazopanib, cytokines. Patients were required to have a 6 mos. continuous enrollment ± index date (patients disenrolling due to death within the 6 mos. were retained). Lines of therapy (LOT) were identified based on prescription fill and administration dates, began following the last LOT and continued until disenrollment. Health care costs reported represent the health plan + patient paid amount. Results: The overall study cohort (n=274) was 73% male; mean (±SD) age 63.3 ± 11.1 yr. with the majority of patients commercially insured (80% vs 20% MCR). The majority started BSC following 1st LOT (68% vs 32%). Median survival from start of BSC was similar following 1st and 2nd LOT (126 and 118 days). The mean (median) duration of BSC after 1 LOT was 223 (114) days and 176 (109) days for 2 LOT. Total health care costs incurred during BSC averaged $50,187 ± 96,984 and $37,294 ± 51,101 and monthly costs were similar ($10,284 ± 17979) after 1 and 2 LOT, respectively. In both cases, inpatient hospital costs represented the largest proportion of these costs (47%) while outpatient costs represented 36%. Conclusions: Our study estimating BSC survival and costs in patients with mRCC based on US claims data found monthly cost of $10, 284. These estimates suggest that BSC costs are not insignificant.
Utility of the modified Glasgow prognostic score in patients with metastatic renal cell carcinoma treated with targeted agents.
Authors: Akbashev Mikhail Y. , Lingerfelt Brian Michael , Liu Yuan , Kucuk Omer , Master Viraj A. , Harris Wayne 
Published: February 2017

441 Background: The modified Glasgow prognostic score (mGPS) is a pre-treatment prognostic system based on inflammatory biomarkers that is comparable in accuracy to the Memorial Sloan-Kettering Cancer Center (MSKCC) score for patients with metastatic renal cell carcinoma (mRCC) treated with cytokines. However, data are limited regarding the current utility of prognostic models developed in the cytokine era. In this study we examined the correlation between pre-treatment and post-treatment mGPS values and clinical benefit response (CBR) in patients treated with targeted agents for mRCC. Methods: After obtaining approval from the Emory Institutional Review Board, mGPS values were determined retrospectively using published methods and measurements of serum C-reactive protein (CRP) and serum albumin from patients who received targeted therapy for mRCC of any histology at the Emory Winship Cancer Institute between January 1, 2005 and June 30, 2011. CBR was defined as complete response (CR), partial response (PR) and stable disease (SD). Inclusion criteria included availability of at least 3 CRP values per patient. Results: Of the 635 patients who were screened, 56 were found to meet inclusion criteria. Of these, 43 received one evaluable line(s) of therapy (ELOT), 9 received two, 3 received three and 1 received four. The 74 ELOT included temsirolimus (16), sunitinib (20), sorafenib (14), pazopanib (20), everolimus (3) and bevacizumab/interferon (1). The correlation of post-treatment mGPS values to CBR was greater than pre-treatment mGPS values with sensitivity (81%), specificity (87%), positive predictive value (85%) and negative predictive value (83%). The p values were <0.001 for each parameter. Conclusions: Although these data require prospective validation, they provide evidence for the prognostic utility of mGPS assessments before and after therapy with targeted agents. Of note, the likelihood of having a CBR was much greater in patients who achieved or maintained an mGPS value of 0 after therapy. If confirmed, serial assessments of the mGPS to determine inflammatory response rates may prove to be a valuable and cost effective tool for patient care and drug development in mRCC.
Everolimus post-progression on tyrosine kinase inhibitors in metastatic renal cell carcinoma: A clinical review of patients demonstrating a durable response and the effective management of treatment toxicity.
Authors: Wilson James M. , Ramamurthy Sindhu , Pedley Ian D. , McMenemin Rhona 
Published: February 2017

449 Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus has been licensed as a second line treatment in metastatic renal cell carcinoma (mRCC) following treatment failure with a tyrosine kinase inhibitor (TKI). A randomised placebo control trial of everolimus used in this setting demonstrated only a modest median progression free survival of 4.9 months (Motzer RJ, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010;116:4256-65). Methods: We present 2 patients with a prolonged treatment response - both encountered mTOR inhibitor specific adverse events, the management of which will be discussed. Results: Patient 1: A 47 year old man with mRCC, previously treated with the Atzpodien regimen followed by sunitinib. A radiological response was seen after 2 treatment cycles of Everolimus and has remained stable for 25 months to date. A triglyceride level of 32.2 mmol/l has responded to a 50% dose reduction, dietary advice and the addition of a fibrate without loss of disease control. Patient 2: A 62 year old man with mRCC initially treated with Interferon followed by sunitinib. He developed radiological evidence of pneumonitis after 2 months of everolimus but did not experience (G3) symptoms until 2 months later. Pneumonitis responded to treatment deferral and corticosteroids and did not recur when everolimus was reintroduced. He achieved 18 months of PFS. Conclusions: Everolimus can initiate prolonged periods of progression free survival when used after progression on a TKI. The treatment is well tolerated and adverse events can be easily managed to allow ongoing therapy. Our further investigation, including tumor gene profiling, of such patients will allow a more personalised approach in the management of mRCC and improved prognostication in the clinic.
Treatment of patients with metastatic renal cell carcinoma (RCC) and end-stage renal disease (ESRD) with targeted therapy (TT): A case series.
Authors: Flaherty Amber , Matrana Marc Ryan , Atkinson Bradley J. , Tannir Nizar M. 
Published: February 2017

453 Background: Studies have shown that RCC is more prevalent in patients with ESRD, and RCC outcomes in patients with ESRD differ from those of the general RCC population. There is limited data regarding the use of TT in patients with metastatic RCC (mRCC) who are maintained on dialysis for ESRD. Methods: We retrospectively reviewed records of patients with mRCC who were seen at UT MD Anderson Cancer Center and received TT (sunitinib, sorafenib, pazopanib, temsirolimus, everolimus, erlotinib, or bevacizumab) over the last eight years (2003-2011) and who also had ESRD and underwent hemodialysis (HD) or peritoneal dialysis (PD). Overall survival (OS) was determined from initiation of TT to death. Results: Eleven patients (6 males; 8 with clear cell, 3 with papillary) were identified who met the above inclusion criteria. Median age was 57.4 years. Comorbidities included hypertension in 10, diabetes in 4, and hyperlipidemia in 6. Median number of TT was 4 (range, 1-6). Median time on treatment (TOT) was 769 days (range, 73-1792), Seven patients have died. Seven patients were on both HD and TT for over 1 year. Median OS was 1075 days (95% CI, 722-1428). TT related adverse events (AEs) included hypertension (HTN), hand-foot skin reaction (HFS), fatigue, diarrhea, rash and pneumonitis [Table]. There were no treatment related deaths. Conclusions: In this small retrospective series of patients with mRCC and ESRD who were treated with TT, adverse events were acceptable, and relatively prolonged disease courses were noted. [Table: see text]
Evaluation of the expression levels of S100A2 mRNA in renal cell carcinoma.
Authors: Sugiyama Takayuki , Takayama Tatsuya , Miyazaki Miki , Kai Fumitake , Takaoka Naohiro , Furuse Hiroshi , Mugiya Soichi , Ozono Seiichiro 
Published: February 2017

457 Background: The human S100 proteins are a calcium-binding protein comprising around 20 sort, at least 16 of these genes included pseudogenes are clustering to chromosome 1q21 , known as the epidermal differentiation complex. We have reported that S100A1 and A10 are expressed in human renal cell carcinoma (RCC) (Teratani T et al; Cancer Lett 2002, Teratani T, et al; BBRC 2002, Domoto, et al Cancer Sci. 2007). Diminished expression of S100A2 has been reported in some kinds of cancers (ex. lung, breast, prostate), but not reported in renal cell carcinoma (RCC). The aim of the present study is to evaluate the expression level S100A2 mRNA in human renal cell carcinoma. Methods: Sixty-one patients, pathologically diagnosed for clear cell RCC performed nephrectomy, were used in this study. Genomic DNA and RNA were extracted from RCC part and matched normal part in each patient. First-strand cDNA was synthesized from 2 micrograms RNA using Superscript-2 reverse transcriptase (Invitorgen), and reverse transcription polymerase chain reaction (RT-PCR) were performed using specific primers for S100A2. We also check the CpG methylation in the promoter region of the S100A2 gene using COBRA assay (combined bisulfite restriction analysis). Results: 45 cases (73%) showed decreased S100A2 expression in RCC parts. In53 cases of clear cell RCC, S100A2 expression decreased in fourty-two (79%) cases. In contrast clear cell RCC, 5 cases showed expression S100A2 in non-clear RCC (8cases; 62%), and 2 cases of clear cell RCC in VHL disease patients also had expression of S100A2. 30 cases of clear cell RCC were used in COBRA assay, S100A2 methylation were seen in all cases. Conclusions: Diminished expression of S100A2 is frequently shows in RCC, especially clear cell RCC. It suggests that property of clear cell RCC is different from other type of RCC.
Analysis of the p53 pathway in clear cell renal cell carcinoma to identify novel drug combinations.
Authors: Boyd Mark T. , Ahmed-Ebbiary Amro , Polanski Radoslaw , Noon Aidan , Parsons Keith , Rubbi Carlos P. , Vlatkovic Nikolina 
Published: February 2017

460 Background: p53 is rarely mutated in clear cell renal cell carcinoma (ccRCC) with typical mutation frequencies between 0 and 5%. Recent studies have shown that combined p53/MDM2 expression is significantly linked with reduced survival (P<0.0001, HR=3.2) and is an independent prognostic indicator (Cox multiple regression analysis, P=0.027). Studies have also found that p53 is negatively regulated by MDM2 in RCC cells but that rescue of p53 stability is not effective at inducing apoptosis. Studies of normal kidney have shown that signalling to p53 by genotoxic agents is intact, but fail to elicit an apoptotic response. We have therefore investigated a rational combinatorial approach to drug targeting in RCC cells in which both MDM2 is inhibited and apoptosis is stimulated. Methods: Senescence was quantitated by assaying SA-β-galactosidase. Drug sensitivity was determined by measuring MTT conversion at multiple time points. Data from these were used to generate isobolograms and combination indices. Further details of the drugs used will be presented. Results: Using a p53-MDM2 antagonist (currently in clinical trials), our results indicate that in RCC cells rescue of p53 induces some growth arrest and senescence but not apoptosis (IC70 range 7-30 μM). Similarly, using a pro-apoptotic drug (also in clinical trials) which has been demonstrated to promote apoptosis in a wide range of cells, we find little growth inhibitory effect (IC70 range 2.5-30 μM). However, combining a p53-MDM2 antagonist with the pro-apoptotic drug leads to dramatic synergy (combination indices as low as 0.26 [<1 indicates synergy]) and rapid p53-dependent apoptosis in a range of p53 wild-type RCC cell lines. Crucially, the drug combinations have no impact on non-tumour renal cells (neither IC70 nor IC50 could be determined, but both exceed 30 μM) suggesting these may have a high therapeutic index. Conclusions: Rationally designed combinatorial approaches for the treatment of RCC can lead to dramatic enhancement of RCC cell sensitivity and clearly warrant further investigation in both pre-clinical studies (under development) and in clinical trials for RCC due to the retention of wild-type p53 in this disease.