bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival of patients with papillary type II renal cell carcinoma treated with tyrosine-kinase inhibitors: A comparison with clear cell histologies.
Authors: Casuscelli Jozefina , Buchner Alexander , Szabados Bernadett , Stief Christian G. , Staehler Michael D. 
Published: February 2017

511 Background: The sequential use of Tyrosine-kinase inhibitors leads to a longer survival in patients with clear-cell renal cell carcinoma (ccRCC). However to-date there is little data available on the survival of patients with non-clear-cell RCC treated with TKI. We focused on papillary type II renal cell carcinoma (papIIRCC) and assessed the outcome of our patients with metastatic disease on systemic treatment. The outcome was compared with our patients with clear cell histology. Methods: Patients with histologic evidence of papillary type II renal cell carcinoma or clear cell renal cell carcinoma were treated with single agent sunitinib or sorafenib. Progression free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier curves. Patients were identified from an institutional database and had to have a follow up of ≥2 years. Subgroup analyses were performed to determine the influence of primary tumor stage and cell differentiation on PFS and OS. Results: 18 patients with papIIRCC received sunitinib (16) or sorafenib (2) while 166 patients with ccRCC were treated with sunitinib (78%) or sorafenib (22%). Median PFS for papIIRCC is 8.9 mos, for ccRCC it is 11 mos. OS for papIIRCC is 15 mos, while ccRCC show an OS of 32 mos. The same tendency for longer PFS and OS is seen in ccRCC patients with low primary tumor grade and highly differentiated carcinomas, whereas large tumors and low differentiation determine a poor prognosis in both groups. Conclusions: Most papIIRCC patients have a poor outcome and shorter PFS than ccRCC on the same therapy. They benefit from the TKI therapy, but the survival is clearly reduced compared with ccRCC patients. This may be due to the poor prognosis of the papillary type II histology, but the assumption is that the administered therapy is not conceived for this type of RCC. Future studies are required to determine the optimal therapy for papillary type II renal cell cancer.
The evolution of debulking nephrectomy and patient characteristics in metastatic renal cell cancer patients enrolled into first-line tyrosine kinase inhibitors clinical trials.
Authors: Sella Avishay , Wang Kongming , Sella Tal 
Published: February 2017

513 Background: The introduction of tyrosine kinase inhibitors (TKIs) revolutionized treatment of metastatic renal cell cancer (mRCC). The role of debulking nephrectomy (DN) still remains unresolved. We reviewed the rate of DN and characteristics of patients enrolled in prospective clinical trials with TKIs through and after 2007 (Motzer, N Engl J Med, 2007). Methods: PubMed, Cochrane library, ASCO and ESMO web sites were searched for phase I-III clinical trials with at least 15 patients of first line TKIs administered alone/combination for mRCC. Expanded access/randomized discontinuation trials were excluded. We used PRISMA guidelines for data collection. All trials included histology, DN, prior cytokine therapy and efficacy data. Trials missing either performance status (PS) or MSKCC criteria data were included. We reviewed 72 trials; 42 trials are included: Group 1: 22 (phase I/II-19, phase III-3) trials completed through 2007 with 2,355 patients, Group 2: 20 trials (phase I/II-17, phase III-3) completed after 2007 with 3,719 patients. Thirty trials with 1,055 patients, all phase I/II, were excluded. Group characteristics were compared using a Pearson Chi-square test at a 2-sided significance level of 0.05, median progression free survival (PFS) with available 95% CI were compared using weighted T-Test. Results: Group 2 had statistically significantly (p<0.001) less DN (85.7% vs 93.7%), less prior cytokine therapy (11.7% vs 46.8%), more poor prognosis (9.8% vs 4.0%), and intermediate prognosis characteristics (56.0% vs 51.9%), more PS 2 (2.8% vs 0.8%), and a similar rate of clear cell histology (97.9% vs 97.2%, p=0.097). Clinical objective response per intent to treat analysis was higher in Group 2 (28.6% vs 23.1%, p<0.001) with similar clinical benefit (73.2% vs 75.3%, p=0.074) and comparable PFS (median 9 vs 8.2 months, p = 0.2528). Conclusions: The use of debulking nephrectomy in patients participating in clinical trials has declined in the TKIs era. More patients with worse prognostic parameters participated in TKI trials after 2007. The reduction in prior cytokine therapy prevents estimation of these changes on TKI efficacy.
Time from nephrectomy (Nx) as an independent prognostic factor in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies (TTs).
Authors: Procopio Giuseppe , Iacovelli Roberto , Verzoni Elena , Grassi Paolo , Testa Isabella , Garanzini Enrico , Nicolai Nicola , De Braud Filippo G. 
Published: February 2017

517 Background: Nx has been established as a prognostic factor in mRCC and included in current prognostic classifications. Despite this, the prognostic value of time from Nx has not well established in patients (pts) treated with TTs. We aim to investigate if the time from Nx to diagnosis of metastatic disease is a prognostic factor in mRCC pts treated with TTs. Methods: Database of pts treated at Istituto Nazionale Tumori of Milan, was reviewed. Only pts who received an Nx were included in the final analysis. For each pt time from Nx to diagnosis of metastatic disease was collected and pts were divided in three groups based on time ≥ 1 year (A), < 1 year (B) or Nx performed at diagnosis of metastatic disease (C, cytoreductive). Age, sex, ECOG performance status and MSKCC prognostic group were also collected. Overall survival was calculated from the start of therapy to death or last follow-up. Median OSs were estimated with Kaplan-Meier method and compared with log-rank test; association of factors with survival was evaluated with Cox-analysis. Results: A total of 285 pts meet the inclusion criteria: median age was 60.8 y (IQR: 52.5 – 68), 73% were males; ECOG-PS was 0 in 61%, 1 in 34% and 2 in 5%. Prognosis based on MSKCC classification was good in 36%, intermediate in 49% and poor in 15%, and its prognostic value was confirmed (HR: 2.7; 95%CI, 2.1 – 3.4, p<0.001). Time from Nx was ≥ 1 year in 25%, < 1 year in 26% and concomitant to diagnosis of metastatic disease in 49% of cases. The median survival was 44.5 (95%CI, 35.6 – 53.5), 22.3 (95%CI, 16.1 – 28.5), 18.1 months (95%CI, 11.5 – 24.6) for the group A, B and C, respectively with a significant differenced for every comparison (A vs. B: p=0.041; A vs. C p<0.001 and B vs. C p=0.016). When time from Nx was compared to MSKCC in the multivariable analysis, this remain an independent prognostic factor (HR: 0.7; 95%CI, 0.6 – 0.9, p<0.001). Conclusions: In mRCC pts treated with Nx and targeted therapy, time from Nx is an independent prognostic factor. Pts with good prognosis based on MSKCC criteria who had Nx more than 1 year before the diagnosis of metastatic disease have better prognosis compared to a pts with the same MSKCC risk that receive Nx with cytoreductive intent.
Changing treatment paradigms in the era of targeted therapies.
Authors: Papavassilis Philipp Marius , Herrmann Edwin , Krabbe Laura-Maria , Hertle Lothar , Boegemann Martin , Moritz Rudolf , Thielen Barbara 
Published: February 2017

518 Background: Our goal was to describe the change of treatment paradigms for metastatic renal cell carcinoma (mRCC) since targeted therapy became available in 2006. Methods: In this cohort population study we retrospectively investigated all mRCC patients who were treated with targeted therapy between 06/2006 and 06/2012 in the Department of Urology of the University of Münster. To distinguish nominal variables Fisher's exact test was used, in other respects Pearson's χ² test. For metrical variables the Mann-Whitney-U-Test was used. The log-rank test was chosen to derive differences between two or more groups with regard to survival. A p value <0,05 was considered statistically significant. Results: 50/158 (31.6%) patients with a median follow-up of 362 days were initially treated with immunotherapy. The most often used second line treatment after immunotherapy was sorafenib (29 patients, 58.0%). As first line treatment sunitinib was chosen most frequently (68 patients, 63.0%). There was no statistically significant difference in survival between the patients who were treated with immunotherapy and those who were not (572 vs. 554 days, p=0,745). 134 (84.4%) patients received cytoreductive nephrectomy before systemic treatment start. Comparing the survival curves there was a significant survival benefit in favor of nephrectomized patients (632 vs. 169 days, p<0,0001). Conclusions: After introduction of the new agents treatment paradigms have changed substantially. Immunotherapy is used only rarely. Cytoreductve nephrectomy should continue to be regarded as standard treatment.
Duration of targeted therapy in metastatic renal cell carcinoma patients with ECOG PS>2.
Authors: Tsimafeyeu Ilya , Petenko Natalia N. , Snegovoy Anton , Varlamov Sergey , Demidov Lev V. 
Published: February 2017

520 Background: Targeted therapy has improved clinical outcomes in metastatic renal cell carcinoma (mRCC). However, patients with unfavorable performance status are often under-represented in clinical trials of mRCC. Methods: Patients with mRCC (clear or non-clear cell) and ECOG PS >2 were included in retrospective study.Primary objective of this study was to evaluate the overall duration of targeted therapy (ODT). ODT was defined as time from initiation of first-line therapy until the end of last-line therapy. Results: 79 patients with ECOG PS >2 (median age, 60 [48-70]; male, 73%; clear-cell RCC, 95%; MSKCC intermediate/poor risk, 97%/3%) were treated with sunitinib (77%), sorafenib (23%), everolimus (20%), bevacizumab + IFN (15%), pazopanib (4%), temsirolimus (2.5%) of which 55 (70%) received only first-line therapy, 24 (30%) received 2 lines, and 9 (11%) received 3 lines of therapy. The median ODT was 9.8 months (95% CI 6–13.6). The median time to progression of patients that received 1, 2 or 3 lines was 7.1, 5.9, and 6.3 months, respectively. One patient showed complete response and 2 patients had partial responses during first-line therapy, 2 patients had partial responses during second-line therapy, and 1 patient had partial response after 2 months of third-line therapy. Among the patients who discontinued treatment, disease progression was the most common reason for discontinuation. There was no unexpected serious toxicity. Conclusions: mRCC patients with unfavorable performance status could be treated with targeted therapy during 9.8 months.
Association of reduced GATA1 mRNA expression with clinicopathology and shortened recurrence-free survival in clear cell renal cell carcinoma.
Authors: Peters Inga , Dubrowinskaja Natalia , Kogosov Michael , Abbas Mahmoud , Hennenlotter Joerg , Kramer Mario W. , Scherer Ralph , Merseburger Axel S. , Kuczyk Markus A. , Serth Juergen 
Published: February 2017

521 Background: GATA1, a zinc-finger transcription factor and member of the GATA family proteins 1-6, is known to be involved in cell growth and apoptosis, especially in the erythroid lineage. Recent studies demonstrated that GATA1 interacts with p53 and its overexpression leads to an inhibition of the p53 gene function. Increased p53 expression levels have been shown to be associated with prognosis and tumor progression in renal cell carcinoma. Methods: Quantitative real-time reverse-transcribed polymerase chain reaction was applied to measure relative GATA1 mRNA expression levels in 135 kidney tissue samples, including 77 clear cell RCC (ccRCC) tissues and 58 paired adjacent normal renal tissue samples. Relative GATA1 expression levels were determined using the ΔΔCt method. Results: The mean GATA1 expression levels were significantly decreased in tumor tissues compared to adjacent normal tissues (p < 0.001, paired t-test). In univariate logistic regression analysis decreased GATA1 mRNA expression was associated with advanced tumor disease (p = 0.005), positive status of distant metastasis (p = 0.03) and lymph node metastasis (p = 0.011). Reduced GATA1 expression was associated with an increase risk of disease recurrence (p = 0.005, hazard ratio HR = 0.05). Status of distant metastasis remained also a significant independent parameter in the bivariate Cox regression model (p = 0.05, HR = 3.01). Conclusions: GATA1 mRNA expression is reduced in ccRCC and associates with a poor clinical outcome and worse clinicopathology, indicating a possible role of GATA1 in tumor development and aggressiveness of ccRCC. GATA1 could therefore serve as a new biomarker for tumor progression in ccRCC.
Neutrophil-lymphocyte ratio in small renal masses.
Authors: Bazzi Wassim , Dejbakhsh Sheila , Bernstein Melanie , Russo Paul 
Published: February 2017

522 Background: Neutrophil-lymphocyte ratio has been shown to be a prognostic serum marker in some malignancies. We evaluated the association between preoperative neutrophil-lymphocyte ratio and baseline characteristics in patients with small renal masses. Methods: The charts of patients with renal masses ≤ 4 cm who underwent nephrectomy at Memorial Sloan-Kettering Cancer Center from January 2007 to July 2012 were reviewed retrospectively. Bivariable and multivariable analyses were used to examine the association between preoperative neutrophil-lymphocyte ratio (absolute neutrophil count/absolute lymphocyte count) and demographic and clinicopathologic variables. Results: Our cohort consisted of 1001 patients. Bivariable analysis showed significantly higher mean preoperative neutrophil-lymphocyte ratios in men (3.0 vs. 2.6 in women, p < 0.001) and Caucasians (2.9 vs. 1.9 in African-Americans, p < 0 .001), but no significant differences between patients with high (III−IV) or low (I−II) co-morbidity scores (2.9 vs. 2.8, p = 0.085) or between benign or malignant pathology (2.9 vs. 2.8, p = 0.972). Linear regression analysis showed a positive correlation between age and preoperative neutrophil-lymphocyte ratio (Pearson correlation coefficient (r) = 0.1268; p < 0.001), and a negative correlation between preoperative estimated glomerular filtration rate and preoperative neutrophil-lymphocyte ratio (r = -0.1246; p < 0.001). Multivariable analysis showed older age, male gender, and lower preoperative estimated glomerular filtration rate were associated with higher preoperative neutrophil-lymphocyte ratio. Conclusions: In patients with small renal masses, there is no evidence of an association between preoperative neutrophil-lymphocyte ratio and tumor pathology, but there is evidence it is affected by age, gender, and renal function.
A phase II study of S-1 in combination with sorafenib in metastatic renal cell carcinoma.
Authors: Sakai Hideki , Ohba Kojiro , Hashine Katsuyoshi , Tomita Yoshihiko , Shinohara Nobuo , Fujisawa Masato , Eto Masatoshi , Ozono Seiichiro , Tsukamoto Taiji , Akaza Hideyuki , Naito Seiji 
Published: February 2017

529 Background: The potential of S-1, an oral fluoropyrimidine derivative anticancer agent, for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We therefore studied the efficacy and safety profile of S-1 in combination with sorafenib in Japanese patients with mRCC. The recommended dosage of this combination therapy was based on the results of an associated phase I study, presented at the 2012 Genitourinary Cancers Symposium (Abstract #447). Methods: In this phase II study, we enrolled patients with clear-cell or papillary carcinoma who had received no previous treatment or not more than 1 regimen of cytokine therapy. S-1 was administered orally at 80-120 mg/day according to body surface area for 28 consecutive days of a 42-day cycle in combination with sorafenib (800 mg/day) until disease progression. The primary endpoint was the objective response rate (ORR), reviewed by an independent review committee. Results: A total of 21 patients aged 41-78 years were enrolled and were fully assessable for efficacy and safety. Most patients (90.5%) had clear-cell carcinoma, and 8 (38.1%) had received prior cytokine treatment. The ORR was 52.4% (90% CI, 32.8-71.4). One (4.8%) of the 21 patients had a complete response to this combination therapy, 10 (47.6%) had partial responses, and 10 (47.6%) had stable disease. The median progression-free survival was 9.8 months (95% CI, 6.5-14.3). There were no deaths. This combination therapy was well tolerated, and most adverse events were grade 2 or lower. The most common grade ≥3 drug-related adverse events were hypophosphatemia (71.4%) and elevated lipase levels (33.3%). Conclusions: Combination therapy with S-1 plus sorafenib showed promising results regarding the primary endpoint of ORR and had an acceptable toxicity profile in patients with mRCC. Clinical trial information: JapicCTI-090973.
Activity of abiraterone acetate in metastatic patients with castration-resistant prostate cancer (mCRPC) previously treated with ketoconazole: A prospective phase II study from the prostate cancer clinical trials consortium.
Authors: Kim Won , Wilton John , Zhang Li , Lin Amy M. , Fong Lawrence , Friedlander Terence W. , Hsieh Andrew Caleb , Aggarwal Rahul Raj , Rodvelt Tammy J. , Morse Allison , Bozeman Jeffrey , Weinberg Vivian K. , Molina Arturo , Mohler James , Fetterly Gerald J. , Szmulewitz Russell Zelig , Small Eric Jay , Ryan Charles J. 
Published: February 2017

53 Background: Abiraterone acetate (AA), like ketoconazole (keto), inhibits CYP17, the rate-limiting enzyme in androgen biosynthesis. Since patients (pts) with prior keto treatment were excluded from the pivotal phase III AA trials, the utility of AA after keto is not well understood. This prospective study evaluated the efficacy of AA in pts who had received prior keto. Methods: Pts with progressive castration-resistant prostate cancer (mCRPC), prior keto therapy 28 days or more, and normal baseline organ function (including ACTH stimulation) tests were treated with AA 1,000 mg PO daily and prednisone 5 mg PO BID. Pts with prior chemotherapy were excluded. Serum androgen levels, including dehydroepiandrosterone (DHEA), were measured by liquid chromatography/mass spectroscopy (LC/MS) at baseline and during treatment for exploratory analyses. Radiographic progression-free survival (rPFS) was defined as freedom from: death, radiographic progression, or unequivocal clinical progression. Results: Forty two pts were enrolled. Median age was 71. Median prostate-specific antigen (PSA) was 47.5ng/dL. Median duration of prior keto was 38 weeks (range 5 to 207). Treatment with AA resulted in 30% or greater decline in PSA at 12 weeks in 20 pts (48%, 95% CI, 32-63%), and 50% or greater decline in PSA at 12 weeks in 16 pts (38%, 95% CI 24-54%). Median time to PSA progression (TTPP) was 16 weeks (range 4 to 64). Median rPFS was 24 weeks (range 1 to 88). Baseline serum DHEA levels were measured in 40 pts. Nine pts had DHEA less than the limit of quantitation (LOQ, 0.250ng/mL), and 31 pts had DHEA greater than or equal to LOQ. One pt with DHEA less than LOQ (1 out of 9, 11%, 95% CI 0.6-49%) had PSA decline 30% or more at 12 weeks, compared to 17 pts (17 out of 31, 55%, 95% CI 36-72%) with DHEA greater than or equal to LOQ (p=0.028). Median time to pain progression (TTPP) was 8 weeks (range 4 to 32) for pts with DHEA less than LOQ, compared to 18 weeks (range 4 to 64) for pts with DHEA greater than or equal to LOQ (p=0.012). Median rPFS was 12 weeks (range 4 to 24) for pts with DHEA less than LOQ, compared to 36 weeks (range 1 to 88) for pts with DHEA greater tha or equal to LOQ (p = 0.0006). Six pts remain on AA. Conclusions: A significant proportion of pts with prior keto exposure demonstrate clinical response to AA. DHEA levels via LC/MS merits further study as a predictive biomarker in pts treated with androgen synthesis inhibitors. Clinical trial information: NCT01199146.
A phase Ib study exploring the combination of everolimus and dovitinib in VEGF-refractory clear cell renal cancer.
Authors: Fitzpatrick Amanda Marie , Greenwood Michelle , Foreshew Abigail , Nixon Jude , Sahdev Anju , Sarwar Naveed , Lim Louise , Jones Robert J. , Chowdhury Simon , Crabb Simon J. , Powles Thomas 
Published: February 2017

531 Background: Everolimus (mTOR inhibitor) and dovitinib (VEGF and FGF-2 inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. In this study we establish the tolerability and an early activity signal of this combination. Methods: Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalated doses of daily oral everolimus (5-10 mg PO OD) and dovitinib (200-500mg 5/7 days PO) Dose-limiting toxicities (DLTs) were assessed determine the MTD. An expansion cohort (n=15) was treated to obtain additional efficacy and safety information. Results: Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5 mg PO OD and dovitinib 200mg PO day 1-5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (CTC grade 1-4) of patients respectively. Frequent biochemical abnormalities occurred such as hypertrygliceridaemia in 67%. Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% CI 2.2-11 months). Conclusions: Dovitinib and everolimus had modest activity, but did not meet all of the the planned efficacy endpoints. Fatigue was the dose limiting toxicity. Clinical trial information: NCT01714765.
Markers of sunitinib-resistance in clear cell renal cell carcinoma: A gene expression analysis.
Authors: Reig Òscar , Marín-Aguilera Mercedes , Lozano Juan José , Gonzalez Blanca , Mallofré Carme , Campayo Marc , Gascon Pedro , Mellado Begoña 
Published: February 2017

533 Background: Sunitinib is a standard first line treatment of metastatic renal cell carcinoma (ccRCC). Approximately 20% of patients experience primary resistance to therapy and no predictive biomarkers are available. The aim of our study is to discover novel biomarkers to predict response to sunitinib and to generate hypothesis about mechanisms of intrinsic resistance. Methods: Gene expression analysis was performed in formalin-fixed paraffin embedded (FFPE) samples from 44 patients with metastatic ccRCC treated with sunitinib in our institution. Affymetrix Human Gene 2.0 ST array was performed in primary tumors from 6 extremely sensitive (progression free survival (PFS) > 24 months) and 8 refractory (progression disease as best response) ccRCC. Technical validation with qPCR (Fluidigm Dynamic 96.96 Array) was performed in the whole cohort. The ΔΔCt method was used to quantify the relative amount of mRNA. Clinical and pathological data were correlated with gene expression. Results: 330 genes were differentially expressed between refractory and sensitive patients (p≤0.05). Network analysis showed 16 significant networks represented. Gene expression of 96 selected markers was tested in 47 primary tumors and 24 metastases. We found IL8, VEGF and NOTCH pathways upregulated on refractory patients. Survival analysis showed that the overexpression of IL8 correlated with a worse PFS (HR: 2.42, 95%CI1.27 – 4.63, p=0.0075) and overall survival (OS) (HR: 3.42, 95%CI 1.50 – 7.79, p=0.0034). Overexpression of VEGFBcorrelated with a prolonged PFS (HR 0.52, 95% CI 0.28 – 0.98, p=0.0415). Conclusions: Our results confirm the predictive value of IL8 expression in a cohort of ccRCC patients treated with sunitinib and suggests novel biomarkers of response to sunitinib. These data will be further validated in an independent cohort of patients.