bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomic analysis of pre- and post-sunitinib treated renal cancer tissue to assess tumor heterogeneity and differential protein expression.
Authors: Stewart Grant Duncan , O'Mahony Fiach , Eory Lel , Nanda Jyoti , Laird Alexander , O'Donnell Marie , Mullen Peter , Riddick Antony , McNeill Alan , Aitchison Michael , Berney Dan , Peters John , Rockall Andrea , Sahdev Anju , Bex Axel , Faratian Dana , Chowdhury Simon , Harrison David , Overton Ian , Powles Thomas ,   Scottish Collaboration on Translational Research into Renal Cell Cancer \(SCOTRRCC\)
Published: February 2017

388

Background: To investigate acquired resistance of clear cell renal cell cancer (ccRCC) patients to sunitinib and develop personalised treatment strategies, sequential tissue after a specific period of targeted therapy is required. This approach has proven successful with targeted therapy in chronic myeloid leukaemia; however, we are concerned that extensive tumour heterogeneity occurs in ccRCC. In this study we evaluated heterogeneity and differential protein expression in sunitinib treated and untreated ccRCC samples using high-throughput proteomics.

Methods: Fresh frozen tissue was obtained from 27 sunitinib naïve ccRCC specimens and 27 nephrectomy samples from patients treated with neoadjuvant sunitinib (18 weeks) as part of the SuMR trial. From each tumour frozen sections were performed and up to 5 protein lysates obtained from each morphologically differing region of each tumour as well as matched normal kidney. Reverse phase protein arrays (RPPA) were performed to assess the levels of multiple proteins relevant to ccRCC pathogenesis and sunitinib activity. Appropriate statistical tests were used to examine protein heterogeneity and differential expression, including false discovery rate (FDR) correction. Kaplan-Meier method was used to correlate changes in protein expression with outcome.

Results: Expression of 20 proteins has been examined to date. The range of expression in tumours normalised by matched normal renal tissue had >2-fold differences in untreated (n=8 proteins) and treated samples (n=4 proteins). Four markers displayed significantly increased inter-tumoural variance in sunitinib treated tumours compared with untreated tissue (e.g. VEGFR1, FDR P<0.05). Despite this heterogeneity, sunitinib was associated with significant expression changes for several key proteins (e.g. VEGFR2, CyclinD2; FDR P<0.05).

Conclusions: Protein expression in ccRCC is heterogenous and key proteins showed significantly increased variance of expression with sunitinib therapy. Despite heterogeneity, significant changes in protein expression can be identified with sunitinib treatment and have been correlated with outcome.
Cost comparison of robotic, laparoscopic, and open partial nephrectomy.
Authors: Alemozaffar Mehrdad , Chang Steven Lee , Kacker Ravi , Sun Maryellen , DeWolf William C , Wagner Andrew
Published: February 2017

394

Background: Laparoscopic and robotic partial nephrectomy (LPN and RPN) are increasingly common minimally invasive alternatives to open partial nephrectomy (OPN) for management of renal tumors. The cost discrepancies of these approaches warrants evaluation. We compared hospital costs associated with RPN, LPN, and OPN.

Methods: Variable hospital costs including operating room (OR) time, supplies, anesthesia, inpatient care, radiology, pharmacy, and laboratory charges were captured for 25 patients who underwent OPN, LPN, and RPN at our institution between 11/2008 -9/2010. Fixed costs of acquisition of a laparoscopic suite and a robotic system (including maintenance) were amortized over 7 years. We considered alternative scenarios through one-way and multi-way sensitivity analysis.

Results: We found similar overall variable costs for OPN, LPN, and RPN. Sensitivity analysis demonstrated that RPN and LPN are more cost effective than OPN (excluding fixed costs) if the average hospital stay is < 2 days, or OR time less is than 204 and 196 mins, respectively. By including fixed costs of equipment, RPN and LPN are always more costly than OPN.

Conclusions: There was no difference among variable hospital costs of OPN, LPN, and RPN. Minimizing OR time and hospital stay reduces RPN and LPN costs to levels comparable to OPN. Inclusion of fixed costs makes LPN and RPN more expensive than OPN, but increased utilization and efficiency can decrease cost per case.

[Table: see text]
Circulating microRNAs as potential biomarkers in patients with renal tumors.
Authors: Antón Aparicio Luis M. , Medina Vanessa , Valladares Ayerbes Manuel , Santamarina Isabel , Aparicio Gallego Guadalupe , Diaz Prado Silvia , Quindós Varela Maria , Alonso-Jaudenes Curbera Guillermo
Published: February 2017

405

Background: MicroRNAs (miRNAs), a class of small RNAs, have been intensely investigated recently because of their important regulatory role in gene expression. Circulating miARNs are potential biomarkers for cancer not only abundant in blood, but also very stable, which are important prerequisites as clinical biomarkers. Detection of circulating tumor cells (CTC) may provide diagnostic and prognostic information in genitourinary renal tumors. The aim of this work is identify miRNAs potentially useful for CTC detection in blood samples from patients with renal tumors to assess their potential clinical significance.

Methods: We examined blood levels of three miRNAs, let-7c, miR-200c and miR-31 in 48 patients with renal tumors with locally advanced or metastatic disease and 18 healthy persons using quantitative real-time PCR. The clinicopathologic characteristics of the population under consideration include among other: sex, age, tumor location, histological type, Fuhrman grade, tumor size, number of involved nodes, tumor stage, time to progression and overall survival.

Results: We found that the median levels of miRNAs, let-7c, miR-200c and miR-31 were significantly higher in patients with renal tumors than those in healthy controls (p=.002, p=.000 and p=.004, respectively). Receiver-operator characteristic (ROC) curve analyses indicate that these blood miRNAs may be useful markers for discriminating patients with renal tumors from healthy controls (AUC=.750, AUC=.853 and AUC=.738, respectively).

Conclusions: miRNAs in the circulation are relatively stable, very accessible, low invasive and easily testable biomarkers. Our results suggest let-7c, miR-200c and miR-31 as novel stable blood-based markers for renal cancer detection. This work was supported by Grants PI07/0477 from Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III.S. Díaz Prado is supported by an Isidro Parga Pondal research contract by Xunta de Galicia (A Coruña, Galicia, Spain). Cancer research in our laboratory is supported by the “Fundación do CHU A Coruña”.
Outcomes of “real world” treatment for metastatic renal cell carcinoma (mRCC).
Authors: Harrison Michael Roger , George Daniel J. , Walker Mark S. , Hudson Lori L. , Chen Connie , Korytowsky Beata , Stepanski Edward J. , Abernethy Amy P.
Published: February 2017

406

Background: Targeted therapies have expanded treatment options for mRCC. Using a joint community/academic center database, we determined outcomes for “real world” mRCC patients (pts) in order to understand current treatment patterns and their effectiveness.

Methods: A retrospective cohort dataset included all identified adult mRCC pts receiving care in Duke University Health System and 11 community oncology practices, diagnosed and alive since Jan. 2007, and not enrolled in a trial. Standardized chart abstraction supplemented the electronic medical record. Demographics, comorbidities, tumor characteristics, treatment patterns and outcomes were recorded. Pts were grouped by exposure sequence (TKI [sorafenib, sunitinib or pazopanib], mTOR [temsirolimus or everolimus], TKI/mTOR, etc.) for 9 sequences. Outcomes analysis for overall survival (OS) included Cox regression.

Results: The cohort included 385 pts, 64 yrs old (±10.1), 66% male, 72% Caucasian; 64% had clear cell histology (25% unknown). Median OS was: mTOR (N=33; 5.4 mo), mTOR/TKI (N=11; 9.3 mo), TKI/mTOR (N=33; 13.7 mo), TKI (N=108; 21.1 mo), TKI/mTOR/TKI (N=18; 29.8 mo), TKI/TKI/mTOR (N=11; 33.1 mo), Other (N=40; 38.2 mo), TKI/TKI (N=32; 42.9 mo), No Therapy (N=99; not reached). “Other” pts received a combination or a non-TKI, non-mTOR monotherapy in the 1st three exposures. “No Therapy” pts had received no systemic therapy as of data analysis; most were alive and censored. Pts in the mTOR only sequence had trends toward worse disease at baseline with more metastatic sites (median 2.0; p=.067) and impaired performance status (18%; p=NS). When significant covariates were controlled, OS (vs. No Therapy) was poorest for pts receiving mTOR only (Hazard Ratio[HR]=2.3) and best for pts receiving TKI/TKI (HR=0.50). Significant risks were evident with liver metastasis (HR=1.7) and impaired performance status (HR=3.1).

Conclusions: In the real world setting pts receiving mTOR as the 1st treatment exposure had worse OS, likely because pts with more aggressive disease were preferentially treated with mTOR. Outcomes were consistent with contemporary trials; however, several sequences (e.g. TKI/TKI, No Therapy) had surprisingly long OS, which requires further evaluation.
The effect of activation of angiogenesis pathways independent of VEGF in renal cell carcinoma on resistance to VEGF-targeted antiangiogenic therapy.
Authors: Han Kyung Seok , Gust Kilian , Awrey Shannon , Raven Peter A. , Li Estelle , Fazli Ladan , Gleave Martin E. , So Alan I.
Published: February 2017

409

Background: VEGF-targeted anti-angiogenic therapy provides significant growth inhibition in clear cell type renal cell carcinoma (CCRCC). However, evasive resistance develops in most responding cases due to unclear mechanisms. We investigated the mechanism of resistance to VEGF-targeted therapy in CCRCC both in vitro and in vivo.

Methods: Two different conditioned cell lines were developed from wild type Caki-1. Sunitinib-conditioned Caki-1 was developed by chronic exposures to sunitinib (up to 15uM) and hypoxia-conditioned Caki-1 was developed by chronic exposures to hypoxia (1% oxygen). We characterized these conditioned cells in vitro and response patterns to sunitinib were evaluated using subcutaneous xenograft models with parental and conditioned cells. In vivo angiogenesis assays were performed to characterize angiogenesis potentials in these cells. Finally, mRNA microarray was performed to find pathways that induce resistance to anti-angiogenic therapy.

Results: Sunitinib inhibited proliferation of HUVEC cells, but did not inhibit tumor proliferation in CCRCC cells at pharmacologically relevant doses. In vitro sunitinib-conditioned Caki-1 cells did not show obvious resistance to sunitinib compared to parental cells, but when tested in vivo these cells appeared to be highly resistant to sunitinib therapy. In contrast, hypoxia-conditioned Caki-1, although more resistant to hypoxia and showing increased vascularity by upregulating VEGF production, did not develop sunitinib resistance either in vitro or in vivo compared to parental cells. In vivo matrigel plug assay with sunitinib treatment confirmed that tumor angiogenesis was relatively intact and less affected by sunitinib treatment in xenografts of sunitinib-conditioned cells compared to parental cells.

Conclusions: Resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced by interactions with VEGF-targeted drug but not by hypoxia. Our results suggest that more broad inhibitions of tumor angiogenesis are required to prevent development of resistance to anti-angiogenic therapy in CCRCC.
The role of stereotactic radiosurgery in the treatment of renal cell carcinoma patients with five or more brain metastases.
Authors: Mohammad Mohammadi Alireza , Chao Samuel T. , Rini Brian I. , Garcia Jorge A. , Suh John H. , Angelov Lilyana
Published: February 2017

410

Background: Whole brain radiation therapy (WBRT) is considered standard treatment in patients with multiple brain metastases (BM). However, WBRT has limited efficacy in patients with BM from radio resistant tumors like renal cell carcinoma (RCC) where median survival is 2–4 months. The aim of this study is to evaluate outcomes in RCC patients with ≥5 BM treated with Stereotactic Radio-surgery (SRS) monotherapy or as part of a multimodality regimen.

Methods: Data from 16 consecutive RCC patients with ≥5 simultaneous BM (99 lesions) treated with SRS at our institution (1999–2010) were analyzed. Patient demographics, tumor characteristics, treatment related factors and outcomes were statistically evaluated.

Results: 12 male and 4 female patients (median age of 59) were treated. 62% of patients had concurrent systemic metastases to multiple organs at the time of treatment. 31% of patients were on active systemic treatment before SRS. Patients had prior cranial surgery 2(12%), WBRT 6(37%) and SRS 2(12%) previous to their presentation with ≥5 BM. Median interval between primary diagnoses and SRS was 2years (range 0–16). At the time of current SRS treatment 75% of patients had only mild neurological symptoms and median KPS was 80; 87% of patients were Recursive Partitioning Analysis Class II. Median number of lesion was 5 (max 10), and median total intracranial disease burden was 2cc (range 0.2–36.4). Post SRS for ≥5 BM, 9 of 16 patients required further intracranial therapy for new lesions, WBRT 3(19%) and SRS 6(37%). Mean follow up was 6.5 months from SRS for ≥5 BM (range 1-19). 12 patients (75%) died during follow up with neurological cause of death in 3(25%). Median overall survival (OS) was 7.1 months (range1–21). OS was 50% after 6 month and 31% after 1 year. Local control rate was achieved in 91% of targets in all evaluated patients.

Conclusions: SRS is traditionally used to treat patients with a limited number of BM. This is the first series to evaluate the role of SRS in the management ≥5 BM in RCC. We demonstrate that using SRS in these patients results in excellent local disease control (91%) and acceptable OS. Hence, SRS should be considered in the ongoing management of patients even with extensive intracranial disease.
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

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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.
Racial and gender disparities in renal cell carcinoma.
Authors: Mozayen Mohammad , Tesfaye Anteneh , Katato Khalil
Published: February 2017

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Background: In spite of advancements in early diagnoses and better cancer treatments in the United States, ethnic and gender disparities still exist. In some types of cancer, African Americans and males generally tend to have higher disease frequency and worse outcomes. Studies about survival outcome among various racial groups in RCC are very scarce. Our study compared stage distribution and overall survival in relation to ethnicity and gender in patients with renal cell carcinoma (RCC).

Methods: We retrospectively reviewed 205 patients diagnosed with RCC between 1995 and 2008 in a community hospital setting. Patients with additional malignancies, lymphoma of the kidneys, or no follow up data were excluded from the study. Demographics, pathology, disease stage, operative note, and subsequent follow up data were reviewed. Patients were divided into groups according to race and gender.

Results: A total of 205 patients were included, Caucasians were 176 (85.9%), African Americans were 13.7% and Asians were 1 (0.5%). Males (M) were 127 (62.3%) and females (F) were 77 (37.7%). The median age of the study population was 65 (22-91). Clear cell histology was seen in 79%. Stage I was seen in 53.9%, II in 23.5%, III in 13.7% and IV in 8.8% of the study population. Advanced stages (III, IV) were seen in 18% of African American and in 23% of Caucasians (p=0.45). Advanced disease (III, IV) was seen in 22% of Females compared to 24% in Males (p=0.6). The 3 year overall survival for the study population was 67.3% (95% CI: 60.4-73.7). The 3 year overall survival for African Americans was 50% compared 71.5% in Caucasians (p=0.02). The 3 year overall survival for Females was 68.4% compared to (68.8%) (p=0.54).

Conclusions: Our study showed that in patients with RCC, African Americans had worse survival outcome compared to Caucasians in spite of similar stage distribution. Our study didn’t show any gender based disparity in overall survival. Large studies are necessary to determine the causes of poor survival outcome in African American population in RCC.
Korean population-based external validation of western prognostic models for survival in metastatic renal cell cancer.
Authors: Ahn Yongchel , Park Kwonoh , Park Seongjoon , Park Inkeun , Lee Jae-Lyun , Song Cheryn , Ahn Jin-Hee , Hong Jun Hyuk , Kim Choung-Soo , Ahn Hanjong
Published: February 2017

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Background: Prognostic models have been proposed to predict factors affecting survival in metastatic renal cell cancer (RCC). We retrospectively reviewed clinical features and survival data to validate MSKCC and Heng’s models in Korean metastatic RCC patients.

Methods: 270 patients with first-line Vascular Endothelial Growth Factor (VEGF) targeted therapy, regardless of prior immunotherapy, were enrolled. We reviewed medical records to find clinical factors affecting overall survival (OS). Predictive accuracy for survival of two models was evaluated by Harrell’s concordance-index (c-index).

Results: From 2005 to 2010, 197 males (72.6%) and 73 females received therapy at a median age of 58 years (range, 17 - 86). After median follow-up of 16.0 months (range 0.0 - 78.0), median OS (mOS) was 22.7 months (95% CI, 18.3 - 27.1). 55 patients (20.4%) had prior immune therapies and 162 (60.4%) were initially metastatic. None was treated with bevacizumab, thus 221 (81.9%) were treated with sunitinib and 49 with sorafenib. Multivariate analysis showed 5 of Heng’s factors were independent: Karnofsky scale < 80% (HR = 1.53, 95% CI 1.01 - 2.31, p=0.047), from diagnosis to treatment < 1 year (HR=1.94, 95% CI 1.35 - 2.79, p < 0.001), anemia (HR 1.66, 95% CI 1.13 - 2.43, p = 0.010), hypercalcemia (HR = 1.92, 95% CI 1.21 - 3.05, p=0.006) and neutrophilia (HR = 1.96, 95% CI 1.21 - 3.16, p = 0.006). Validation of MSKCC and Heng’s model showed c-index of 0.836 (95% CI, 0.698 - 0.941) and 0.800 (95% CI, 0.655 - 0.915), each. We further applied each model’s stratification by risk grouping. First with MSKCC (log-rank p < 0.001), mOS in no risk (n = 80), 1 risk (n = 128) and 2 or more risks (n=51) were 35.5 months (95% CI, 24.0 - 47.0), 23.7 months (95% CI, 18.2 - 29.2) and 7.4 months (95% CI, 4.5 - 10.3), respectively. Second with Heng’s (log-rank p < 0.001), mOS in favorable (no adverse factors, n = 37), intermediate (one or two adverse factors, n = 161) and poor (three to six adverse factors, n=61) were respectively 43.8 months (95% CI, 31.8 - 55.8), 25.4 months (95% CI, 21.5 - 29.3) and 7.5 months (95% CI, 4.9 - 10.1).

Conclusions: Western prognostic models were accurate and feasible in Korean metastatic RCC patients treated with anti-VEGF therapy.
Metastatic renal cell carcinoma (mRCC) in elderly patients: Can a personalized approach be an effective therapeutic option?
Authors: cossu Rocca Maria , Verri Elena , Blotta Simona , Adamoli Laura , Radice Davide , Riva Davide Francesco , Nole Franco
Published: February 2017

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Background: Renal cell carcinoma (RCC) is the third most common genitourinary cancer. Up to 30% of patients (pts) with RCC presents with advanced disease. Sunitinib(S), an orally available tyrosine kinase inhibitor, is the well established first-line therapy for these population. Actually few data are available in the literature about its use in patients > 75 yrs investigating the feasibility, the efficacy and the toxicity in this population.

Methods: From 2007 to 2011, 16 pts >75 yrs with mRCC received S. 75% of pts had a clear cell carcinoma, 87.5% had a surgery on primary tumor, 18.7% had a metastic disease at diagnosis and the median time to metastatic progression was 13.5 months. Median age was 78 years (range 71-88y).All patients had 0-1 performance status and 69% of them received S as first-line treatment. Four pts started S on the approved 50 mg /d 4-week-on-2-off schedule, but three of them reduced to 37.5 mg continuous once daily dosing(ODD)starting from the third cycle. Five out of 8 pts receiving 37.5 mg continuous ODD reduced the dose at 25 mg continuous ODD or modified the schedule. Four pts started with 25 mg continuous ODD and 2 of them continued the treatment at modified schedule. Median number of cycles administered was 7 (range 2-16).

Results: Response rate was 87% (13pts) in 15 evaluable pts. Overall response included 40% (6 pts) of PR, 20% (3pts) of CR, 33% (5pts) of SD > 6 mos. Progressive disease was observed only in 1patient. TTP was 12.4 months (95% CI, 4.8-32.6). Overall survival was 34.2 months (95% CI, 27.3- ). The main toxicity requiring dose reduction or schedule modification was haematological (46%), G3Anemia in 1 pt G3-4 thrombocytopenia in 3pts and G3 leukoneutrophenia in 3pts. No any toxicity required treatment interruption.

Conclusions: In summary these results show the feasibility and the efficacy of S in elderly population with high response rate regardless the doses and schedule used.
A new modified sunitinib schedule for metastatic renal cell cancer (mRCC): A pilot study.
Authors: Buti Sebastiano , Donini Maddalena , Lazzarelli Silvia , Brighenti Matteo , Passalacqua Rodolfo
Published: February 2017

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Background: Oral sunitinib administration at 50 mg daily given for 4 weeks followed by 2 weeks off treatment (4+2 schedule) is a standard first line for mRCC treatment. About 20% of patients had to discontinue treatment permanently and 50% of patients are forced to reduce the doses due to adverse events [Motzer RJ, J Clin Oncol. 2009]. A meta-analysis showed that increase exposure to sunitinib is associated with improved clinical outcome [Houk BE, Cancer Chemother Pharmacol. 2010].

Methods: This is a pilot study in which consecutive mRCC patients admitted to our hospital who had at least a grade 2 toxicity with sunitinib, were switched to a modified schedule maintaining the same dose-intensity of 4+2 schedule: starting on Monday, 1 tablet (50 mg) a day for 5 consecutive days a week for 5 weeks and 1 tablet per day on days 1, 3 and 5 in the sixth week (28 tablets in 6 weeks), until disease progression. Primary end points were toxicity changes assessment and schedule feasibility, secondary end point was overall progression free survival (PFS).

Results: Eight nephrectomized patient were enrolled: 6 males; median age 61; 37% good, 50% intermediate and 13% poor MSKCC risk; 3 patient pretreated; 6 clear cell histologies, 1 papillary and 1 undifferentiated histotypes. Median time from start therapy to switch was 7.4 months (range 1.4-16.1). Treatment delays and dose reductions were reduced from 50% to 25% and from 37% to 12% of patients respectively. The table shows the toxicity changes: there were no new toxicities. PFS was 16.3 months (CI 95% 5.6-23.4).

Conclusions: This new modified schedule requires and deserves further studies.

[Table: see text]
Randomized study on the effect of zoledronic acid treatment for prostate cancer with bone metastasis during initial combined androgen blockade.
Authors: Ueno Satoru , Mizokami Atsushi , Namiki Mikio , Fukagai Takashi , Fujimoto Naohiro , Ooka Hitoshi , Kondo Yukihiro , Arai Gaku , Ide Hisamitsu , Kataoka Kazuyoshi , Kawaguchi Kohei , Shimamura Masayoshi , Orito Matsuo , Ishida Takeyuki , Ikeda Daisuke
Published: February 2017

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Background: Zoledronic acid (ZA) eventually reduces risk of skeletal morbidity carries beneficial effect on bone pain. Moreover, ZA eventually extends a period to bone pain and the SRE onset after CRPC (castration-resistant prostate cancer) and improves the QOL of the patients. ZA, therefore, has become a standard supportive therapy for CRPC with bone metastasis. However, it remains unclear when the physicians should start ZA treatment for prostate cancer (PCa) patients with bone metastasis. In the present study, we investigated whether we could extend a period before androgen sensitive PCa with bone metastasis becoming CRPC by ZA treatment.

Methods: The patients were randomly classified in two groups (combined androgen blockade (CAB) alone group and CAB + ZA treatment group) based on Gleason score (less than 7 or more) EOD score (less than 2 or more). Four mg ZA treatment was conducted every 4 weeks. We evaluated serum PSA value, bone-related markers, and SRE. The first end point was a period before androgen sensitive PCa with bone metastasis becoming CRPC.

Results: Untreated 59 PCa patients with bone metastasis were enrolled by 2011 from 2006. Thirty patients were classified in the CAB alone group and 29 patients in the CAB + ZA group. There were no significant difference in age (72,5 and 71.7 yo, respectively), PSA (381.3 ng/ml and 399.0 ng/ml, respectively), Gleason score, and EOD score between CAB alone group and CAB + ZA group. Although there was no significant difference in PSA-progression free survival (PFS) (p=0.14), tendency that CAB + ZA shows better PFS than CAB alone group was observed (time to 50% PFS was extended 9.4 months than CAB alone group). Moreover, the sub analysis using the patients with more than Gleason score 7 or with more than EOD score 1, CAB +ZA group showed better PFS (p=0.074 in Gleason score and p=0.028 in EOD score.

Conclusions: This result indicates that CAB with ZA from initial treatment can extend a period before PCa, especially high advanced PCa recurring.