bluuebunny/crossref_metadata_2025 huggingface dataset:
CpG-island methylation of GATA-family members GATA3 and GATA5 in renal cell carcinoma and association with clinicopathological parameters and progression-free survival.
Authors: Peters Inga , Gebauer Kai , Atschekzei Faranaz , Hennenlotter Joerg , Kramer Mario W. , Traenkenschuh Wolfgang , Merseburger Axel S. , Kuczyk Markus , Serth Juergen
Published: February 2017

370

Background: Transcriptional inactivation and CGI methylation of GATA3 and −5 has been reported to be involved in mammary carcinoma, pancreatic cancer, colorectal and gastric carcinogenesis. A recent study demonstrated that a loss of GATA-3 expression due to partially methylation silencing in several renal cell carcinoma (RCC) patients. We quantitatively investigated GATA3 and −5 CGI methylation in RCC and analyzed its association with clinical characteristics as well as progression free survival of patients.

Methods: Methylation data were obtained from a quantitative methylation-specific polymerase chain reaction assay (QMSP) for both genes. We investigated 108 RCC and 77 paired tissue samples as well as six RCC cell lines. Statistical analyses were carried out using the paired t-test for matched tumor (TU) and adjacent normal (adN) samples, logistic regression for comparisons of independent samples and cox regression for survival analysis.

Results: In paired samples we found a significant higher methylation in TU compared to adN for GATA3 (P=0.007) and for GATA5 (P=3.6*10−9) for all RCCs. GATA5 showed also strong correlations between methylation and status of metastasis (P=0.05) and advanced (pT≥3 and/or N+, M+) tumor samples compared to localized (pT≤2, N0, M0) tumors (P=4.7*10−9). A decreased progression free survival in cox proportional hazard model analysis could be demonstrated for patients with a high GATA5 methylation (P=0.0006, HR=6.5) and a trend could also be seen for GATA3 methylated patients (P=0.06).

Conclusions: GATA3 and −5 were identified to demonstrate tumor-specific CGI hypermethylation in renal cell cancer patients. The association of GATA5 CGI methylation with metastasis, advanced disease and progression free survival of patients indicates that epigenetic alterations of both genes are involved in renal cell carcinogenesis. GATA5 methylation could serve as a biomarker for tumor progression. Further prospective and functional investigations are necessary to clarify whether CGI methylation of GATA family members can provide independent information for future clinical management of patients with RCC.
Long-term survival in patients with metastatic renal cell carcinoma (mRCC) in the era of new targeted therapies: Five-year follow-up in a single Spanish medical institution (Genito-Urinary Tumor Unit, University Hospital 12 de Octubre).
Authors: de Velasco Oria G , Sepulveda J , Villacampa F , Ghanem I , Castellano Daniel E.
Published: February 2017

376

Background: Recently, new targeted therapies have proved the efficacy in patients with mRCC in terms of progression-free survival (PFS) and overall survival (OS). There is also growing evidence that successive targeted treatments has achieved objective responses and sustained time to progression. Here, we report data from our insitution analysing the OS benefit of continuing targeted therapy after disease progression.

Methods: We identified 58 metastatic clear cell RCC patients who started targeted therapy between September 2005 and December 2008. The data were collected from our clinical trials registry. The patients were evaluated for differences in baseline characteristics and known prognostic factors (PFs) in metastatic RCC. We assessed overall survival for all patients.

Results: We identified 58 pts, 24 are still alive (43%). Median age was 56 (range 31–78). ECOG PS 0/1/2: 33/24/1. 46% (27) had diagnosis to treatment intervals < 1 year. Sites of metastatic disease included: lung 46%(26), bone 32%(19), hepatic 29%(17) and retroperitoneal 24%(14). Nephrectomy was pesented in 90% of all pts. The number of metastases location was: 1/2/3: 32%/11%/7%. The drugs administered are listed in table. Median number of treatments: 3 (range 1–7). The median overall survival (OS) was 44 months and the 3- year OS was 60.4%. Pts by MSKCC risk-group were: favourable prognostic (FP) 19%, intermediate prognostic (IP) 63%, poor prognostic (PP) 18%. The overall survival for FP group was not reached, and 3-year OS was 81%; for IP group the median survival time was 44 months and 3-year OS was 59%; and for PP group the median survival time was 25 months.

Conclusions: The survival for patients with mRCC who receive multiple lines of targeted therapy has increased to close to 4 years. These results indicate a clear shift in the evolution of mRCC but lack a great deal about what the best sequence. Final analysis of the best sequence of treatment will be presented at the meeting.

[Table: see text]
External validation of the Glasgow prognostic score (mGPS) for renal cancer.
Authors: Master Viraj A. , Johnson Timothy V. , Kucuk Omer , Canter Daniel , Pattaras John , Ogan Ken , Cross Brian , Nieh Peter T , Harris Wayne
Published: February 2017

378

Background: Inflammation has been termed the 7th hallmark of cancer (Hanahan and Weinberg Cell 2011). Measurement of systemic inflammatory responses in malignancy is possible using a selective combination of two commonly available, cost-effective serum assays. The combination of these two serum markers, C-reactive protein (CRP) and albumin, is termed the modified Glasgow prognostic score (mGPS), and is strongly correlated with outcome in a variety of cancers, including mRCC. Recently, mGPS has been shown to be predictive of outcome in localized RCC (ASCO GU 2010 #390). We sought to externally validate these results.

Methods: Nephrectomized patients with clinically localized (T1-T4N0M0) clear cell RCC with negative surgical margins were followed for a mean of 25 months (range: 1-81 months). Relapse and survival was identified through routine follow-up. Patients were categorized by mGPS score as Low Risk (mGPS = 0 points), Intermediate Risk (mGPS = 1 point), and High Risk (mGPS = 2 points). One point was assigned to patients for an elevated CRP (>10 mg/L) and hypoalbuminemia (<3.5 mg/dL). Patients with normal CRP and hypoalbuminemia were assigned 0 points. Kaplan-Meier and multivariate Cox regression analyses examined relapse-free survival (RFS) and overall survival (OS) across patient and disease characteristics.

Results: Of 248 patients, 17.9% relapsed and 18.6% died. Of Low, Intermediate, and High Risk patients, 7.2%, 7.7%, and 45.5%, respectively relapsed and 5.2%, 15.4%, and 39.4%, respectively died during the study. In multivariate analysis including stage and grade, mGPS was significantly associated with RFS and OS. Compared to Low-Risk patients, High-Risk patients experienced a 3-fold (OR: 2.906, 95% CI: 1.055-8.001) increased risk of relapse and 4-fold (HR: 3.722, 95% CI: 1.046-13.245) increased risk of mortality. AUC is 0.813, which compares very favorably to existing prognostic algorithms.

Conclusions: In this external validation cohort of US patients, mGPS continues to be a predictor of relapse and overall mortality following nephrectomy for localized RCC. Clinicians may consider using mGPS as an adjunct to identify high-risk patients for possible enrollment into clinical trials, or for patient counseling.
The role of tumor vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) polymorphisms in the prediction of clinical outcome for patients with advanced renal cell carcinoma receiving first-line sunitinib.
Authors: Bianconi Maristella , Scartozzi Mario , Faloppi Luca , Giampieri Riccardo , Maccaroni Elena , Bittoni Alessandro , Del Prete Michela , Loretelli Cristian , Belvederesi Laura , Conti Alessandro , Minardi Daniele , Burattini Luciano , Montironi Rodolfo , Cascinu Stefano
Published: February 2017

380

Background: Metastatic renal cell carcinoma (mRCC) still represents a medical challenge in cancer therapy. In recent years the introduction of new targeted therapies has radically changed the approach to the disease and patients outcome. Currently the therapeutic strongholds are TKIs directed against the VEGF family. The aim of our study is to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms, in determining the clinical outcome of mRCC patients receiving first-line sunitinib.

Methods: 41 histologic samples (biopsies and surgical specimens) of mRCC patients were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients progression free survival (PFS) and overall survival (OS) were analyzed for first line treatment.

Results: VEGF AIV rs833061 C>T polymorphism was statistically significant in PFS (17 months for C vs 4 months for T; P = 0.0029) and OS (35.93 months for C vs 11 months for T; P = 0.0267). VEGF AV rs699947 A>C was statistically significant for PFS (17 months for A vs 3.97 months for C; P = 0.0023) and OS (35.93 months for A vs 10.98 for C; P = 0.0272). VEGF AVI rs2010963 G>C was significant in PFS (16.98 months for G vs 4.65 for G/C vs 2.73 for C; P = 0.0188). VEGR3 III rs6877011 C>G was significant in PFS (8.22 months for C vs 2.22 for C/G; P = 0.0361) and OS (35.93 months for C vs 12.08 for C/G; P = 0.0183).

Conclusions: In our analysis patients with C polymorphism of rc833061 , A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line. These polymorphisms of the VEGF-A gene are probably connected with a better control of the neoangiogenesis process during TKIs therapy, maybe leading to vasculature normalization. Patients with C polymorphism of rs6877011 seem equally to have a favourable impact in first line therapy. VEGFR-3 role is still matter of debate but seems to be involved in vessels sprouting and architecture.
Can we predict malignancy in Bosniak III renal lesions identified on multiphasic CT scan?
Authors: Klink Joseph C. , Goenka Ajit H. , Remer Erick M. , Smith Andrew D. , Obuchowski Nancy A. , Campbell Steven C.
Published: February 2017

381

Background: To identify independent predictors of malignancy in Bosniak III (BIII) renal lesions and to build a prediction model based only on readily identifiable clinical and imaging variables.

Methods: In this IRB-approved retrospective study, radiology and hospital information systems were interrogated for BIII lesions in CT reports from January 1, 1994 to August 31, 2009. Patients with histopathology available were included. The following variables were recorded: age, gender, body mass index (BMI), race, symptoms at presentation, smoking history and history of renal cell carcinoma (RCC), presence of a co-existent BIII or BIV lesion. Univariate analyses were first performed using logistic regression analysis with generalized estimating equations and an exchangeable working correlation matrix to test each variable. Factors with univariate p-values <0.20 were considered in the multiple-variable analysis. The main effects of the factors were first evaluated. For the main effects with p-values <0.10, two-way interactions were assessed. Interactions with p-values <0.05 were included in the final model along with their main effects. The c-index was used to test accuracy of the models. Final model was chosen based on its parsimony and accuracy.

Results: Mean patient age was 58 years (range 27–80). There were 51 females and 50 males. Of the 107 BIII lesions in 101 patients (6 patients had two lesions each), 59 (55%) were malignant and 48 (45%) were benign. The strongest predictors of malignancy were race (p=0.04), history of RCC (p=0.03), co-existing III (p=0.03) or IV lesion (p=0.10) and BMI (p=0.10). In multiple-variable analysis, a history of RCC was the strongest independent predictor of malignancy (OR 12.7, 95% CI 1.8– 91, p=0.01) followed by BMI (OR 1.1, 95% CI 0.99–1.20, p=0.08). No other main effects or interactions had p-values <0.10. The model with these two predictors had an accuracy of 0.68. At >90% probability of malignancy, the model has a 77% sensitivity and 61% positive predictive value.

Conclusions: Clinical and imaging variables provide significant ability to predict malignancy for BIII renal lesions. A model encompassing history of RCC and BMI appears promising but merits refinement on an independent dataset.
Long-term durable oncologic outcomes after radiofrequency ablation for T1 renal cell carcinoma.
Authors: Psutka Sarah P. , McGovern Francis J. , Mueller Peter , McDougal W. Scott , Gervais Debra , Feldman Adam S.
Published: February 2017

384

Background: Long-term oncologic outcomes for radiofrequency ablation (RFA) of renal cell carcinoma (RCC) are limited. The objective of this study was to assess the long-term oncological efficacy of RFA for treatment of renal cell carcinoma.

Methods: Between 1998 and 2008, 311 biopsy-proven RCC were treated with RFA in 274 patients. Exclusion criteria included history of prior RCC or known metastatic RCC at time of RFA (n=92). 26 patients were lost to follow-up prior to their 6-month imaging study. We retrospectively reviewed the long-term oncologic outcomes for 193 patients. Mean follow-up was 4.6 yrs (range 1–12, SD 2.3).

Results: Median age was 71 years (IQR: 63 –79 years). Median Charlson Score was 5.46 (IQR: 5–6). Median size of tumor treated was 3 cm (IQR: 2–3.9 cm, range 1–7.1cm) and 64 of these tumors (33%) were endophytic. Tumor breakdown by stage was T1a: n=153 (79%), T1b: n=37 (19%), and T2: n=3 (2%). Initial treatment success rate was 89%. There were 6 local recurrences (3%) in 4 patients with T1b disease and 2 patients with T2 disease with an average time-to-recurrence of 2.9 years (SD 0.7). 95% of patients with T1a RCC were disease free at last follow-up, in comparison to 81% of those with T1b and 33% of those with T2 disease (p=0.008). At last follow-up 178 (92%) patients were disease-free. 16 (8.2%) developed metastatic disease and 4 patients (2%) died of RCC. Mean disease-free survival was 4.3 years (SD 2.4).

Conclusions: In patients who are poor surgical candidates, RFA results in durable local control and a low risk of disease recurrence in T1 RCC. Higher stage, however, correlates with a decreased disease free survival and alternate treatments should be considered when counseling these patients.
Treatment and overall survival (OS) in metastatic renal cell carcinoma (mRCC): A Swedish population-based study (2000–2008).
Authors: Harmenberg Ulrika , Lundstam Sven , Wahlgren Thomas , Kowalski Jan , Jakobsson Maria , Sandin Rickard , Ljungberg Börje , Sandström Per
Published: February 2017

389

Background: This retrospective register study assessed OS in all mRCC patients in Sweden diagnosed before (2000–2005) and after (2006–2008) the introduction of targeted therapies, plus factors and treatment options influencing OS.

Methods: Three Swedish national health registers were used: the Swedish Cancer register (diagnosis and death), the National Patient Register (in-/out-patient data), and the Swedish Prescribed Drug Register. From 2000-2008, 3,243 patients were identified with mRCC; 602 were recorded as receiving 1st-line treatment. Cox proportional hazards regression analysis, including estimation of adjusted OS, was used in three models with the covariates: diagnosis period, age, gender, institution size, nephrectomy status, geographic region (all models); mRCC treatments, defined as any tyrosine kinase inhibitor (TKI; Model 1; n=417); sunitinib (SU), sorafenib (SO), and interferon-alfa (IFN-α) in the 1st-line setting (Model 2; n=602 [SU=244, SO=110, IFN-α=248]); and variations of these drugs as 1st- and 2nd-line treatment sequences (Model 3; n=602).

Results: Amongst mRCC patients diagnosed from 2006–2008 compared with 2000–2005, median adjusted OS was 16.1 vs. 10.9 months, respectively (HR=0.76, 95% CI: 0.69, 0.83; P<0.001). In all three models, factors independently associated with significantly improved OS included female gender, large institution, and prior nephrectomy. Prescription of any TKI (Model 1: HR=0.82, 95% CI: 0.73, 0.93; P=0.002) and 1st-line SU treatment (Model 2: HR=0.79, 95% CI: 0.67, 0.94; P=0.007) were associated with significantly improved OS compared with other or no treatments. A similar significant improvement in OS was also confirmed for patients treated with SU only in Model 3; however, due to a low number of observations, the model had insufficient statistical power to be appropriate for all sequences.

Conclusions: An improved OS for mRCC patients was demonstrated for the period 2006-2008 compared with 2000-2005. Although the observed survival advantage is multifactorial in origin, contribution of targeted therapies is highly probable. Of the drugs studied, given design limitations, only SU was associated with improved OS.
New safety and efficacy data of the ongoing phase I/II study (ASET Study) with an allogeneic tumor vaccine and adjuvant in patients with metastatic renal cell carcinoma.
Authors: Grünwald Viktor , Weikert Steffen , Schmidt-Wolf Ingo GH , Hauser Stefan , Tschaika Marina , Weith Ekaterina , Schroff Matthias , Schmidt Manuel , Wittig Burghardt
Published: February 2017

398

Background: The purpose of this first-in-man phase 1-2 study is to assess safety and efficacy of treatment with investigational drug MGN1601 in patients with advanced renal cell carcinoma. MGN1601 consists of two active ingredients: genetically modified allogeneic (human) cells transfected with four different MIDGE vectors encoding IL-7, GM-CSF, CD80 and CD154 and a synthetic DNA-based immunomodulator dSLIM-30L1, a TLR-9 agonist, acting as adjuvant.

Methods: The ASET study is conducted as multicenter, open, single-arm phase 1-2 study. The study therapy consists of 8 MGN1601 treatments administered as follows: the first 3 treatments are administered weekly, and the consecutive 5 treatments bi-weekly. Patients who achieve disease control are proposed to continue the therapy in an extension phase. Such patients receive 5 further applications up to week 120. In this study, safety and efficacy of the study treatment will be evaluated based on extensive clinical and laboratory assessments, monitoring of patients’ quality of life, immunological tests, and radiological investigations.

Results: Eighteen patients have been included into the study so far and received up to 9 treatments with MGN1601. Eight patients completed the 12 week treatment per protocol (TPP). Two of these patients (25% of TPP) achieved disease control (one PR and one SD) after 12 weeks and currently continue the treatment in the extension phase. 48 adverse events were reported during the treatment phase. Of them, 10% were judged as possibly related, 23% unlikely and 67% as not drug-related by the investigators. Possible adverse events include mild fever, edema of the ankle, exanthema crook of the arm, pruritus crook of the arm and arthralgia intermittent. The therapy is well tolerated – no treatment-limiting toxicities or grade 2–4 toxicities occurred in these patients.

Conclusions: The results of the clinical study in late stage RCC patients show promising efficacy and a favourable safety profile of the cell-based tumor vaccine consisting of genetically modified allogeneic transfected RCC cells and the immunomodulator.
Use of R.E.N.A.L. nephrometry scoring system to predict the functional efficacy of nephron-sparing surgery in the solitary kidney.
Authors: Buethe David D. , Moussly Sammy , Lin Hui-Yi , Zhao Xiuhua , Spiess Philippe E. , Sexton Wade Jeffers
Published: February 2017

399

Background: Recently, the R.E.N.A.L. nephrometry scoring system was introduced to objectively describe renal masses with respect to size, the degree to which they are exo/endophytic, the nearness to the collecting system, whether they are anterior or posterior and the location relative to polar lines. It is our aim to evaluate the R.E.N.A.L. nephrometry scoring system’s ability to predict functional renal loss attributed to nephron-sparing surgery (NSS).

Methods: We evaluated 42 patients presenting with either an anatomic (32) or functionally solitary (10) kidneys undergoing partial nephrectomy (PN). Each renal unit was assigned a R.E.N.A.L. nephrometry score utilizing pre-operative cross-sectional imaging. The CKD−EPI equation was applied to serum creatinine levels to generate corresponding estimated glomerular filtration rates (eGFR). The difference between the eGFR at baseline and at post-operative time points served as a measurement of renal function loss attributed to PN.

Results: Forty-two patients underwent PN with mean pre-operative eGFR of 61.5 mL/min/1.73m2. The median total nephrometry score was 8, ranging from 4–10. Twenty-eight (66.7%) of the renal lesions were ≤ 4 cm, 13 (31%) were between 4 and 7 cm, and 1 (2.4%) was >7 cm in diameter. The majority (54.8%) of the patients had tumors with more than 50% of tumor burden lying outside the expected renal border whereas 3 patients (7.1%) had tumors considered to be completely endophytic. Twenty-seven (64.3%) were within 4 mm of the collecting system. Tumor locations defined as: completely polar, interpolar, and completely central were assigned to 11, 15, and 16 lesions respectively. By post-operative month 6, the overall average eGFR of 53.9 mL/min/1.73m2 was significantly less (p = 0.0293) than the pre-operative value. However, we were unable to correlate change in post-operative eGFR with pre-operative total or individual R.E.N.A.L. scoring parameters.

Conclusions: Neither the individual components of the R.E.N.A.L. nephrometry scoring system nor the total nephrometry score correlated with realized functional loss as assessed by eGFR in patients with a solitary kidney undergoing NSS.
Prognosis of patients with renal cell carcinoma with disease recurrence following nephrectomy for localized disease.
Authors: Shinohara Nobuo , Abe Takashige , Maruyama Satoru , Sazawa Ataru , Nonomura Katsuya
Published: February 2017

400

Background: We investigated the prognosis of Japanese patients with recurrent renal cell carcinoma (RCC) following nephrectomy, and analyzed the prognostic impact of metastasectomy and Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification in these patients.

Methods: Between 1995 and 2005, 214 patients with recurrent RCC were the subjects of this retrospective analysis. At recurrence, MSKCC risk classification was used to classify patients as being at favorable, intermediate, and poor risk. The endpoint of the present study was overall survival (OS) from time of recurrence. Relationships between overall survival and potential prognostic factors were assessed using the Cox proportional hazard model.

Results: Median time to recurrence following nephrectomy was 25 months. At recurrence, 148 (69%) patients had metastasis in one organ and lung was the most common site of recurrence (123 pts, 57%). The median survival from the time of recurrence was 40 months; the estimated 2-year survival rate was 66% (95% CI 60-73). When the MSKCC risk classification was applied to the patients, the median overall survival was not reached, 29 months, and 11 months in the patients classified as favorable (59 pts), intermediate (101 pts), and poor risk (24 pts), respectively. Metastasectomy was performed in 76 (36%) patients. The median survival from the time of recurrence in these patients was 122 months, which was significantly longer than the median survival (27 months) of patients who did not undergo metastasectomy (p<0.001). Multivariate analysis demonstrated that a better risk category of MSKCC risk classification and metastasectomy were associated with more favorable survival (p<0.001).

Conclusions: In patients with recurrent RCC following nephrectomy for localized disease, patients classified as favorable risk according to MSKCC risk classification have a good opportunity for long-term survival, especially those who undergo metastasectomy.
Cytogenetic changes in renal cell carcinoma: Basis for sensitivity and resistance to everolimus.
Authors: Caldwell Imogen Rose , Oei Paul , Ng Daniel , Fong Peter C.C. , Broom Reuben James
Published: February 2017

403

Background: The mTOR inhibitors have improved outcomes for pts with metastatic renal cell carcinoma (mRCC) but the duration of benefit is variable. Currently there are no predictive biomarkers for pre-selecting pts who are likely to respond to these agents. We undertook an exploratory translational study evaluating cytogenetic changes in the context of response to everolimus therapy.

Methods: 10 pts with mRCC treated with everolimus therapy were enrolled. Pre-treatment paraffin-embedded tissue specimens were analysed for cytogenetic changes using fluorescence in situ hybridisation (FISH) and clinical data including PFS (RECIST 1.1) were obtained. The gene probes chosen for this analysis were; VHL, FHIT, FGFR1/3, PDGFb, PDGFRb, EGFR, MYC and IGH@.

Results: Results are displayed in the table below. The median PFS was 8.25mo (months). Eight pts were treated 1st-line (on clinical trial), one 2nd-line and one 3rd-line. The longest responder (PFS 25.5mo, 3rd-line) had a normal VHL status but loss of FHIT. Two pts with the longest PFS and one with a PFS of 5.5mo had gain of both PDGFb and PDGFRb. Gain of FGFR1 and FGFR3 was seen in two and three pts respectively. Two specimens were unsuitable for full analysis.

Conclusions: Loss of FHIT but a normal VHL status was seen in one pt with mRCC who had an enduring response to everolimus. Concomitant gain of PDGFband PDGFRb was observed in three pts with a good response. FGFR1/3 may be of relevance in the setting of alternative targeted therapies. Further research evaluating the utility of these potential biomarkers is required.

[Table: see text]
Association of high cytoplasmic expression of p27 Kip1 on cancer-specific survival in clear cell renal cell carcinoma.
Authors: Bedke Jens , Amend Bastian , Scharpf Marcus , Sievert Karl-Dietrich , Stenzl Arnulf , Kruck Stephan
Published: February 2017

418

Background: p27Kip1 is considered to contribute to the progression of ccRCC and is targeted by next generation dual-therapies. Cytoplasmic and nuclear differences of p27 Kip1 expression and localization in benign and clear cell renal cell carcinoma (ccRCC) were analyzed with regard to overall survival (OS) and cancer-specific survival (CSS).

Methods: In 140 patients, ccRCC and corresponding benign kidney tissue were analyzed for nuclear and cytoplasmic staining of p27Kip1 by immunohistochemistry using a tissue microarray technique. Staining intensity and percentage of positive stained cells are given as expression scores. p27Kip1 expression was categorized as high if ccRCC tissue stained stronger than the respective level of the corresponding benign tissue and categorized as low if ccRCC tissue stained less than or equal to the corresponding benign tissue. Differences in OS and CSS were analyzed by log-rank analysis and expression levels were correlated with tumour and patient characteristics using Fisher’s exact test.

Results: Cytoplasmatic (mean [SD]: 13.8% [1.2%] vs 10.7% [1.7%]; P = 0.04) and nuclear (mean [SD]: 75.6% [2.7%] vs 13.6% [2.1%]; P < 0.001) staining of p27Kip1 were significantly stronger in ccRCC tissues compared to benign tissue. High cytoplasmic p27Kip1 expression was significantly associated with a higher T and N stage, Fuhrman grade and the presence of metastatic disease (P < 0.001). The median follow-up time was 38.2 months. There was no difference in OS between the low and high expression groups, although CSS was significantly lower in patients with high cytoplasmic p27Kip1 (P < 0.001) and CSS heavily tended to be lower in the nuclear low expression group (P = 0.069).

Conclusions: High cytoplasmic p27Kip1 levels in renal cancer tissues are associated with advanced disease and reduced cancer specific survival, whereas low nuclear expression levels appear to be beneficial. The present study corroborates the consideration of cytoplasmic p27Kip1 for future diagnostic and targeted therapeutic approaches in RCC establishing a potential protective shift of p27Kip1 from the cytoplasm to the nucleus.
Discrepancy between reported progressive disease per radiology report and treating oncologist tumor measurements in patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib.
Authors: Ali Khaled B. , Shah Shetal N. , Wood Laura S. , Garcia Jorge A. , Dreicer Robert , Gilligan Timothy D. , Rini Brian I.
Published: February 2017

420

Background: The determination of progressive disease (PD) on sunitinib in mRCC by conventional tumor size criteria is often complex. Frequently, radiology reports cite disease progression that does not meet RECIST criteria or does not adequately describe index lesions. Characterization of the frequency and magnitude of this phenomenon has not been previously reported.

Methods: The medical records of a subset of mRCC patients treated at The Cleveland Clinic who had received sunitinib for > 12 months were retrospectively reviewed. All Radiology reports from post-baseline scans were reviewed for the presence of text in the body or conclusion of the report consistent with disease progression (specifically the terms ‘progressive’, ‘new’ and/or ‘interval enlargement/worsening’). The date of the report first containing one or more of these terms was recorded, as was the date of RECIST-defined PD determined by the treating Oncologist.

Results: Twenty patients were identified in an initial review. Patient characteristics included: 85% male, 100% clear cell histology, 90% prior nephrectomy and 80% with prior systemic therapy. Thirteen patients (65%) had a radiology report citing a progressive disease term prior to treating physician-determined RECIST-defined PD. The median time from first radiology report citing a progressive disease term until RECIST PD per Oncologist measurements was 2.9 months (range, 0 to 12.8 months).

Conclusions: There is significant discrepancy between the first mention of disease progression by a Radiology report and when a treating Oncologist measures disease progression per RECIST criteria. This discrepancy could impact patient care by influencing drug discontinuation. These data emphasize the importance of multidisciplinary scan review and tumor measurements by both radiologists and treating physicians. Analysis is ongoing in additional patients.
Upper pole kidney tumors: Open or laparoscopic partial nephrectomy?
Authors: Narayanan Ramkishen , O'Malley Rebecca Leigh , Mehedint Diana , Schwaab Thomas
Published: February 2017

429

Background: Partial nephrectomy in upper pole kidney tumors represents a distinct surgical challenge. Data on minimally invasive nephron sparing surgery in this context are scarce. We set out to investigate the role of laparoscopic and open approaches to partial nephrectomy in these tumors.

Methods: The Roswell Park Cancer Institute prospective, IRB-approved kidney surgery database was reviewed containing 690 patients. Only patients completing a radical or partial nephrectomy for unilateral, localized, non-metastatic tumors < 7cm were included. The resulting cohort contained 400 patients. Average patient age at surgery was 59.9 ± 13.2 years (range: 22-88). Tumor stages included benign (13.5%), T1a (53.0%), T1b (25.0%), T2 (1.5%), T3a (7.0%). Upper pole tumors (n=128; 27%) and lower pole/ mid-pole tumors (n=270; 67.5%) were recorded. Intraoperative complications were recorded; postoperative complications were tabulated as low or high grade per Clavien-Dindo classification. SPSS (version 19.0) software was used to analyze the dataset.

Results: Total intraoperative complication rate was 11.3% (45/400 cases). After stratification by tumor location and partial vs. radical nephrectomy, intraoperative complication rates were higher for laparoscopic/robotic partial nephrectomies involving upper pole tumors (72.7% of all intraoperative complications) compared to lower pole tumors (27.3%, p=0.04), in Chi-Square test. In the delayed postoperative period, total low-grade Clavien complication rate was 97.8% (391/400 cases); high-grade complication rate was 2.3% (9/400). After controlling for tumor location and nephrectomy extent, the high-grade delayed complications were present only in the open nephrectomies involving upper-pole tumors. However, laparoscopic/robotic partial nephrectomies involving upper-pole tumors had significantly more delayed low-grade complications (92.4% of all delayed complications) compared to lower-pole tumors (7.6%, p<0.01), in Chi-Square.

Conclusions: Upper pole kidney tumors represent a challenging surgical situation. We here demonstrate that minimally invasive partial nephrectomy in this context requires significant surgical expertise and an open approach could be considered.
Novel prognostic model of overall survival in patients undergoing cytoreductive nephrectomy: Importance of pretreatment clinical and serological parameters.
Authors: Buethe David D. , Verma Nilesh , Lin Hui-Yi , Pow-Sang Julio , Sexton Wade Jeffers , Zhao Xiuhua , Fishman Mayer N. , Spiess Philippe E.
Published: February 2017

430

Background: Over the past decade, there has been an increasing interest in combining surgical and systemic therapy to combat metastatic renal cell carcinoma (mRCC) with upfront cytoreductive nephrectomy (CN) favored in well selected patients. This study presents a novel risk stratification model to identify those who may benefit from upfront CN within the current targeted therapy era.

Methods: Eighty-two patients with mRCC who underwent CN within our tertiary care referral center were identified. Potential pre-operative clinical and serologic predictors of overall survival (OS) were evaluated using both univariate and multivariable Cox-Regression analyses. A Recursive Partitioning and Regression Tree (RPART) model was subsequently developed allowing for stratification of patients into risk groups on the basis of OS.

Results: The derived RPART tree, was able to stratify patients into 4 risk groups ranging from “low risk” to “very high risk” with respect to their expected OS utilizing the number of metastatic sites at diagnosis, serum hemoglobin (Hgb), and serum white blood cell count (WBC) count as partitioning parameters. Within the 4 groups, the median OS ranged from 4.3 months to 72 months.

Conclusions: Our proposed simple quantitative risk-stratification model based on the pre-operative metastatic burden, Hgb, and WBC count is useful to predict OS when contemplating upfront CN prior to systemic therapy. Furthermore, a pre-operative serum WBC count ≥ 7.15 K/uL appears to be indicative of a poor prognosis.
Nephrotoxicity induced by VEGF-target agents in patients with metastatic renal cell cancer.
Authors: Kato Tomoyuki , Nakayama Shoko , Narisawa Takafumi , Yamagishi Atsushi , Sakurai Toshihiko , Naito Sei , Kawazoe Hisashi , Ichiyanagi Osamu , Bilim Vradimir , Nagaoka Akira , Tomita Yoshihiko
Published: February 2017

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Background: A study was undertaken to investigate the association between treatment with vascular endothelial growth factor (VEGF)-targeted therapy for metastatic renal cell cancer (mRCC) and nephrotoxicity.

Methods: Retrospective data were collected for mRCC patients received VEGF-targeted therapy between January 2005 and December 2010. We investigated renal adverse events and clinically significant increased serum creatinine level in patients who received VEGF target therapy. GFR was estimated with the Modification of Diet in Renal Disease (MDRD) formula.

Results: Ninety one patients with mRCC who received sunitinib (n=46), sorafenib (n=38), axitnib (n=9) were included in this analysis. As for renal adverse events, acute renal failure occurred in 1 (2.2%) of 46 sunitinib recipients. Facial edema occurred 17 (37.0%) in sunitinib recipients, 2 (5.3%) of sorafenib recipients, 2 (22.2%) of axitinib recipients. In sunitinib recipients, all of these adverse events observed in ‘off’ period. During administration, gradual and significant increase of serum creatinine was observed in sunitinib recipients compared for sorafenib or axitinib recipients (p= 0.04). Significant decrease of GFR compared for baseline correlated with increase of serum creatinine level developed in ‘on’ period of 6 sunitinib administration cycle (p=0.013), but returned to baseline level after 2weeks cessation. No significant change was observed in serum creatinine level and GFR in patients received other VEGF-target agents.

Conclusions: Our data suggest that nephrotoxicity developed in a high percentage of patients on sunitinib compared for sorafenib and axitinib in mRCC patients. Clinicians should observe renal function of sunitinib recipients more carefully in ‘off’ period as well as ‘on’ period.
Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.
Authors: Armstrong Andrew J. , Turnbull James D. , Cobert Julien , Jaffe Tracy , Harrison Michael Roger , George Daniel J.
Published: February 2017

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Background: Given a lack of clinical information on therapeutic efficacy of agents following progression after vascular endothelial growth factor (VEGF) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in metastatic renal cell carcinoma (mRCC), we investigated the activity of single agent bevacizumab (B) in this setting.

Methods: We conducted a retrospective analysis of single agent B-treated patients with mRCC in the second/third line setting, and identified 21 subjects who met inclusion criteria. The primary endpoint was progression-free survival (PFS). Baseline characteristics, survival, response efficacy outcomes, and toxicities were assessed and summarized.

Results: 21 patients (15 women/6 men) were treated with B at a dose of 5 mg/kg/week, dosed q2-3 weeks. Median age was 63, 80% were white, 14% black; 80% had clear cell histology. Median time from diagnosis to B therapy was 3 years (range 1-18); 100% had prior VEGF TKI therapy; 43% had prior mTOR inhibitor; 43% had prior IFN and 19% prior IL-2; median number of prior therapies was 3 (range 1-7); 100% were considered Motzer intermediate risk. Median PFS on B for all subjects was 4.4 mo (95% CI 2.8-9.6) and median OS was 19.4 mo (95% CI 9.9-NR) from start of B therapy. ORR was 2 CR/PR (9.5%), 11 SD (52%), 5 PD, 3 NE. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4/13.2 mo. Toxicities were as expected and severe adverse events included grade 3-4 fatigue (6), grade 3-4 dehydration (5), and grade 4 failure to thrive (2), grade 4 constipation (2), and grade 3 muscle weakness (2).

Conclusions: Single agent B therapy has acceptable toxicity and moderate disease stabilizing activity in selected patients with mRCC who have failed prior VEGF TKI and mTOR inhibitor therapy, and suggests a benefit to continued ongoing VEGF inhibition. Further prospective study of B alone, in combination with mTOR inhibition, or with alternative targeted agents is warranted.
Influence of risk factors for renal cell carcinoma (RCC) on outcome of patients (pts) with metastatic disease treated with sunitinib.
Authors: Keizman Daniel , Ish-Shalom Maya , Taksey Jason David , Pili Roberto , Hammers Hans J. , Eisenberger Mario A. , Boursi Ben , Berger Raanan , Maimon Natalie , Gottfried Maya , Hayat Henry , Peer Avivit , Kovel Svetlana , Sella Avishay , Carducci Michael Anthony
Published: February 2017

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Background: Obesity, smoking, hypertension (HTN) and diabetes (DM) are risk factors for RCC development. Their presence has been associated with a worse outcome of therapy (tx) in various metastatic cancers. We sought to determine their influence on the progression free survival (PFS) and overall survival (OS) of Su tx in mRCC.

Methods: We performed a multicentre retrospective study of pts with mRCC, who were treated with Su. We analyzed the pre-tx status of smoking (active vs past vs never), BMI (obese=BMI≥30 vs overweight=BMI 25-29.9 vs normal weight=BMI <25), HTN, DM, and known prognostic factors including past nephrectomy, clear cell/non clear cell histology, time from initial diagnosis to Su tx, > 2 metastasis (mets) sites, lung/liver/bone mets, ECOG performance status, anemia, calcium level > 10 mg/dL, elevated alkaline phosphatase (AP), platelets count, pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su induced HTN, use of angiotensin system inhibitors (ASIs), past cytokines/targeted tx, and mean Su dose/cycle. PFS and OS were determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed to determine their independent effect.

Results: Between 2004-2011, 209 pts with mRCC were treated with Su. 40 pts were active smoker, 51 obese, 55 diabetic, and 122 had pre-tx HTN. In the entire pt cohort, median PFS was 8 months (mos) and OS 15 mos. Factors associated with PFS were active smoking (HR 2.5, p= 0.005, median PFS 4 vs 10 mos in past smokers vs 10 mos in never smokers), non clear cell histology (HR 1.8, p=0.023), pre-tx NLR >3 (HR 0.2, p<0.0001) and the use of ASIs (HR 1.66, p=0.028). Factors associated with OS were were active smoking (HR 2.1, p= 0.03, median OS 8.5 vs 18 mos in past smokers vs 18 mos in never smokers), AP (HR 1.76, p=0.049), pre-tx NLR >3 (HR 0.294, p<0.0001), and liver mets (HR 0.553, p=0.04). BMI, DM, and pre-tx HTN were not associated with PFS or OS.

Conclusions: Active smoking may decrease the PFS and OS of pts with mRCC that are treated with Su. BMI, DM, and pre-tx HTN were not found to be associated with outcome. These results should be investigated prospectively, and if validated applied in clinical practice and clinical trials.
Clinical prognostic factors associated with outcome in patients with metastatic clear-cell renal cell cancer treated with everolimus.
Authors: Amato Robert J. , Flaherty Amber , Saxena Somyata , Stepankiw Mika
Published: February 2017

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Background: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy affects tumor growth by blocking growth factor stimulation, arresting cell cycle progression, and inhibiting angiogenesis. mTOR inhibitors and agents with primarily antiangiogenic activity have been shown to have efficacy in renal cell cancer (RCC). This study expanded the original everolimus study of 41 patients with metastatic clear cell renal cell cancer to 66 patients to examine outcome and clinical prognostic factors associated with outcome

Methods: Patients had confirmed predominantly clear cell RCC. Everolimus was given at a dose of 10 mg daily orally without interruption (28-day cycle), with dose modifications for toxicity (graded according to National Cancer Institute Common Toxicity Criteria, version 3.0). Patients were evaluated every 2 cycles (8 weeks) using Response Evaluation Criteria in Solid Tumors (RECIST).

Results: Of 66 evaluable and treated patients, 73% were male, and 45% were >60. Forty-five percent had right kidney involvement, 49% left kidney involvement, and 6% had dual kidney involvement. Eighty-six percent had prior systemic therapy, and 76% of patients had at least two metastatic sites including lung (72%), liver (26%), bone (48%), lymph nodes (50%), adrenal (21%), and other (39%). Twenty-four (36%) of patients had a progression-free survival (PFS) of ≥12 months, and 40 patients (61%) had an overall survival (OS) ≥12 months. Factors most likely to have an influence on OS benefit was high LDH, alkaline phosphatase, and calcium; low hemoglobin; and prior treatment with tyrokinase inhibitors.

Conclusions: Everolimus was found to have clinical benefit in patients with clear cell RCC. Clinical prognostic factors may help determine patients most likely to receive benefit from everolimus. Information regarding curves and correlation between prognostic factors and OS and PFS will be presented.
Does obesity affect the outcome of renal cell carcinoma?
Authors: Mozayen Mohammad , Tesfaye Anteneh , Katato Khalil
Published: February 2017

444

Background: Obesity has been associated with increased risk of renal cell carcinoma (RCC). However the prognostic significance of obesity in the survival of patients with RCC is still undefined. Our study examined prognostic significance of obesity on the overall survival of patients (pts) with RCC in community hospital settings.

Methods: A retrospective review of pts diagnosed with RCC between 1995 and 2008 in a community hospital setting was done. Pts with additional malignancies, lymphoma of the kidneys and no follow up data were excluded from the study. Demographics, body mass index(BMI) at diagnoses, pathology, disease stage, operative note, and subsequent follow up data were reviewed. The WHO BMI classification was used to group pts into Underweight (UW) < 18.5; Normal (NL): 18.5-24.99; Pre-obese (PO): 25-29.99; Obese I (Ob I): 30-34.99; Obese II (Ob II): 35-39.99; Obese III (Ob III): ≥40. The primary outcome was 3 years overall survival.

Results: A total Of 205 pts reviewed, 127 (62.3%) were males, 176 (85.9%) were Caucasians. The median age of the study population was 65 (22-91). The prevalence of obesity was 42.3% in the study population; 46.2% in females and 39% in males (p=0.19). The median BMI was 28.8 (16-54.6). Pts were categorized based on their BMI as: UW (1.5%), NL (21.4%), PO (34.7%), Ob I (26%), Ob II (8.2%), and Ob III (8.2%). Clear Cell was the commonest histology (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. The 3 year overall survival for the study population was 67.3% (95% CI: 60.4-73.7). The 3-year overall survival of obese and non obese pts with RCC were 66.4% and 69.5% respectively (p=0.34). There was no difference in the 3-year overall survival of patient in the BMI groupings: (UW: 66.7%, NW: 59%, Pre-Ob: 70.6%, Obese I: 70%, II: 75%, III: 62.5%; p=0.8).

Conclusions: Our study didn’t find any association between BMI and 3 year overall survival in pts with RCC. Larger randomized trials are warranted before excluding the negative impact of obesity in the overall survival of pts with renal cell carcinoma.
Venous thromboembolism in patients with renal cell carcinoma: Incidence, risk factors, and prognostic implication.
Authors: Lee Ha-young , Park Eunhee , Lee Soohyeon , Hong Soojung , Park Hyun Jung , Shin Sang Joon , Kim Hyo Song , Rha Sun Young
Published: February 2017

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Background: Renal cell ca (RCC) is one of solid tumor with relatively highest incidence of venous thromboembolism (VTE). But, there have been to no large-scale studies that focused on VTE in RCC. The aim of this study was to investigate the incidence, time course of VTE, risk factors, and prognosis associated with VTE in RCC patients in Korea.

Methods: The medical records of RCC patients (n=1248) histologically diagnosed at Severance Hospital, Yonsei University College of Medicine, Seoul, Korea from Jan 2005 to Mar 2011 were retrospectively reviewed.

Results: Among 1248 RCC patients, 69.6% were men, median age was 56years (range: 4∼89), and stage distribution was stage I 65.1%, stage II 9.2%, stage III 10.4%, stage IV 12.5%. The 2-year cumulative incidences of tumor induced VTE (tVTE) was detected in 78 patients (6.3%), while 1-month, 6-months and 1-year cumulative incidence of tVTE were 5.3%, 5.7% and 6.0%, retrospectively. Two-year cumulative incidence of tVTE seemed to increase with stage (0.6%, 3.5%, 22.3% and 24.3% in stages I, II, III and IV, retrospectively). Almost tVTE events developed in the first few months after diagnosis. Stage and metastatic disease were independent risk factors for developing tVTE. In multivariate analysis, the development of tVTE was a significant predictor of survival (P=0.004) and stage, age, ECOG PS was also independent predictor of survival.

Conclusions: This is the first study that specially focused on tVTE in RCC. The 2-year cumulative incidence of tVTE in Korean patients with RCC was 6.3%, which is similar to other ethnic group. As tVTE related to poorer survival, RCC patients with advanced stage and metastasis with higher risk of tVTE, close follow-up is recommended and proactive prophylaxis of VTE might be needed.