bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase III results of adjuvant radiotherapy (RT) versus wait-and-see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96-02/AUO AP 09/95): Ten years follow-up.
Authors: Wiegel Thomas , Bottke Dirk , Bartkowiak Detlef , Bronner Claudia , Steiner Ursula , Siegmann Alessandra , Golz Reinhard , Störkel Stephan , Willich Normann , Semjonow Axel , Stöckle Michael , Rübe Christian , Althaus Peter , Rebmann Udo , Kälble Tilman , Feldmann Horst J , Wirth Manfred , Hinke Axel , Hinkelbein Wolfgang , Miller Kurt
Published: February 2017

4

Background: Adjuvant RT for pT3 R1 or R0 patients (pts.) after RP remains controversial. The EORTC-phase-III- study suggested a 20% better biochemical control (bNED) after 10 years for RT but no survival advantage. In contrast, the SWOG trial stated not only a gain in bNED but also an improved metastasis free and overall survival after 12 years follow-up. Now, 10-years results from the ARO 96-02 study are available, which are based on the most precisely defined cohort among the three trials. Methods: 385 men with prostate cancer were randomized to either 60 Gy RT (arm A; n=193) or WS (arm B; n=192) before achieving an undetectable PSA. Pts. were stratified for Gleason-score, margin status, neoadjuvant hormonal treatment and stage (pT3a+b vs. c). When the undetectable PSA-level after RP was not achieved, progressive disease was stated and the pts. left arm A/B. Data analysis was by intent-to-treat (ITT). PSA-progression for pts. with undetectable post-RP PSA was defined as two consecutive increasing PSA. The primary endpoint was bNED. The study was powered to demonstrate a 15% increase in bNED for RT. Results: 78 pts. (20%) did not achieve an undetectable PSA and were stated as progressive disease (arm A: 45 pts., arm B: 33 pts.). Additionally, 34 pts. (23%) from the RT-arm did not receive RT. Therefore, 114 pts. had RT (arm A) and 159 pts. WS (arm B). Median follow up was 111.3 months for arm A and 113.3 months for arm B . bNED at 10 years increased to 56% for arm A (RT) compared with 35% for arm B (WS) (hazard ratio= 0.51; p = 0.00002. Out of 307 ITT pts., 15 died from prostate cancer, 23 for other and 5 for unknown reasons. There was no significant profit from ART regarding the endpoints metastasis-free survival (p=0.56) or overall survival (p=0.59). Worst late side effects to the rectum were two grade 2 cases after ART. Grade ≥2 bladder toxicity occurred in 4 out of 148 ITT pts. No grade 4 events were reported. Conclusions: With only one grade 3 case of late toxicity, ART was safe in pT3 prostate cancer. At 10 years median follow up, it reduced the risk of bNED by 49%. The study was not powered to detect differences in OS. Clinical trial information: ARO 96-02/AUO AP 09/95.
RAD001 and zoledronic acid in patients with renal cell carcinoma with bone metastases (RAZOR): A randomized phase II trial.
Authors: Broom Reuben James , Hinder Vicky , Sharples Katrina , Proctor Janie , Duffey Steven , Pollard Stephanie , Fong Peter C.C. , Forgeson Garry , O'Donnell Anne , Harris Dean Laurence , Deva Sanjeev , Jameson Michael B. , North Richard T. , Grey Andrew , Findlay Michael P. N.
Published: February 2017

402

Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause morbidity, and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (Z) reduces skeletal-related-events (SREs) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving Z. We sought to evaluate the effect on BM of RAD001 (R) (everolimus) alone compared to R+Z in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to R 10mg daily vs. R+Z 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl]). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates, or radiotherapy within 4 wks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, wks-1, 4, 8, and 12. Treatment was continued on allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12 wks. The primary endpoint was urine N-telopeptide (uNTX) level with secondary endpoints being plasma C-telopeptide (CTX), quality of life (FACT-BP, BPI), progression free survival (PFS), SREs, and safety. Results: Heng prognostic group poor, intermediate, and good risk was 20.0%, 46.7%, 33.3% in R+Z and 40.0%, 46.7%, 13.3% in R. Over first 12 wks, the reduction in mean: uNTX on R+Z relative to R was 68.4% (95% CI (60.1%, 74.9%); p<0.0001); CTX on R+Z relative to R was 77% (95% CI (68%, 83%); p<0.0001). For FACT-BP there was no evidence of a difference (p = 0.5) but addition of Z was favourable for BPI Severity -1.1 (-2.2, 0.23; p = 0.05) and BPI Interference -1.3 (-2.5, 0.03; p = 0.06). Median PFS was 7.5 mo (95% CI 3.4, 14.7) on R+Z and 4.6 mo (95% CI 3.2, 6.3) on R (p = 0.03). Median time to 1st SRE was 9.6 mo (95% CI 4.3, 15.5) on R+Z and 5.2 mo (95% CI 1.6-8.2) on R (p = 0.03). Conclusions: Addition of Z to R significantly reduced bone resorption markers in this RCC population of pts with the adverse prognostic feature of BM. Pts receiving R+Z had prolonged time to 1st SRE and PFS; larger studies are required to further evaluate the addition of bone-specific to targeted therapies in this disease. Clinical trial information: ACTRN12609000980235.
Genetic polymorphisms and sunitinib outcome in metastatic renal-cell carcinoma: A prospective observational study and validation.
Authors: Farfán Carlos A. , Castellano Daniel E. , Rodriguez-Antona Cristina , Benitez Julio , De Velasco Guillermo , Villacampa Felipe , de la Rosa Federico , Andres Eva , Sepúlveda Juan Manuel
Published: February 2017

403

Background: Sunitinib (SU) is an oral small-molecule, multi-targeted receptor tyrosine kinase inhibitor, which is approved as first-line treatment for metastatic renal cell carcinoma (RCC). In a previous study, using a commercially available DNA microarray genotyping system, we identified a group of single nucleotide polymorphisms (SNPs) associated with survival and toxicity in RCC patients, treated with SU. In this study, we validated our previous data using an independent series (García-Donas J, et al. Lancet Oncol 2011). Methods: 27 metastatic RCC treatment-naive patients, recruited prospectively from January 2010 to May 2011. All the patients received SU standard treatment. A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes involved in the pharmacokinetic and pharmacodynamic pathways of drugs, were analyzed using Drug inCode pharmacogenetic service. For validation we performed genotyping in 83 samples using the KASPar SNP genotyping system. Results: In patients with CYP1A2*1F and CYP2C19 *2 and *4 polymorphisms, no statistically significant associations were observed, among drug metabolizing genes and toxicity or survival. Catechol-O-methyltransferase(COMT) is involved in the inactivation of several substances suchs as cathecolamines and estrogens and Val(158)Met polymorphism which were associated with PFS and OS, it was observed in our initial study. Met/Met and Val/Met carriers had statistical significant difference in PFS and OS (p = 0.0001 and p = 0.0001, respectively) compared to Val/Val carriers. In the validation series, we were able to confirm the effect on PFS (p = 0.0102). Conclusions: Our preliminary analysis suggested that CYP1A2*1F and CYP2C19*2 and *4polymorphism may be associated with SU toxicity in RCC patients, but findings were not validated in an independent series. However, we could confirm an association between COMT VAl(158)Met polymorphisms and PFS. To our knowledge this is the first study to report COMT polymorphism to be associated with RCC survival.
Prognostic role of cell cycle–related biomarkers in clear cell renal cell carcinoma.
Authors: Gayed Bishoy A. , Youssef Ramy F. , Bagrodia Aditya , Kapur Payal , Sagalowsky Arthur I. , Lotan Yair , Margulis Vitaly
Published: February 2017

404

Background: Cell cycle regulatory molecules are implicated in various stages of carcinogenesis. In this study we systematically evaluate the impact of aberrant expression of cell cycle regulators on oncological outcomes in clear cell renal carcinoma (ccRCC). Methods: After obtaining IRB approval, immunohistochemistry for Cyclin D, Cyclin E, p16, p21, p27, p53, p57, and Ki-67 was performed on tissue microarray constructs of patients treated with radical or partial nephrectomy for ccRCC between 1997-2010. Comprehensive clinical and pathologic data elements were collected. A prognostic marker score (MS) was defined as favorable if ≤4 biomarkers were altered; unfavorable if >4 biomarkers were altered. The relationship between MS and aggressive pathological features and oncological outcomes was evaluated. Results: The study included 452 patients, 277 males (61%). Median age was of 57 years (range, 17-85) and median follow up of 20 months (range, 0-150). The tumors demonstrated extrarenal extension (pT3-T4) in 120 (27%) patients and advanced grade (G 3/4) in 169 (37%). Regional nodal involvement and systemic metastases at the time of nephrectomy was present in 22 (5%) and 51(11%) patients, respectively. Unfavorable MS was found in 80 (18%) patients and was associated with distant and nodal metastasis, advanced T stage, advanced grade, tumor necrosis, sarcomatoid differentiation, lymphovascular invasion, fat invasion, adrenal involvement, and presence of venous thrombus (p < .05). A statistically significant correlation between unfavorable MS and disease recurrence (HR 6.5 and p = 0.01) and a correlation approaching significance with cancer specific mortality (HR 3.4 and p = 0.06) was demonstrated in Kaplan Meier survival analysis. In a multivariate Cox regression analysis, unfavorable MS was an independent predictor of disease recurrence (HR 2.268, CI 1.00-5.12 p = 0.049). Conclusions: The cumulative number of aberrantly expressed cell cycle biomarkers correlates with aggressive pathological features and inferior oncologic outcomes. Our findings support prospective pathway-based exploration of biomarkers to augment current clinico-pathologic predictors of oncologic outcomes in ccRCC.
Validation of the pretreatment neutrophil-lymphocyte ratio as prognostic factor regarding cancer-specific, metastasis-free, and overall survival in a European cohort of patients with renal cell carcinoma.
Authors: Hutterer Georg C. , Pichler Martin , Stoeckigt Caroline , Chromecki Thomas F. , Stojakovic Tatjana , Golbeck Silvia , Gerger Armin , Pummer Karl , Zigeuner Richard
Published: February 2017

410

Background: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammation response and data from previous studies report controversial results about its independent prognostic role in non-metastatic renal cell carcinoma (RCC). Thus, we decided to evaluate the prognostic significance of NLR in a large cohort of RCC patients. Methods: Data from 843 consecutive non-metastatic RCC patients, operated with radical nephrectomy or nephron sparing surgery between 2000 and 2010 at a single tertiary academic center, were evaluated retrospectively. Pre-treatment NLR was calculated one day before surgical intervention. Patients were categorized according to a NLR cut-off value of 3.2. Cancer-specific–, metastasis-free–, as well as overall survival were assessed using the Kaplan-Meier method. To evaluate NLR’s independent prognostic significance, a multivariate Cox regression model was performed for all three endpoints. Results: An increased NLR was associated with several well established prognostic factors including tumor size, tumor grade, and histologic tumor necrosis (all p<0.05). Although an increased NLR was statistically significantly associated with poor outcome for all clinical endpoints (p<0.001), multivariate analysis identified an increased NLR as an independent prognostic factor for overall (HR=1.58, 95% CI=1.12-2.20, p=0.008), but not for cancer-specific (HR=1.55, 95% CI=0.89-2.70, p=0.116), nor for metastasis-free survival (HR=1.37, 95% CI=0.88-2.14, p=0.160). Conclusions: Risk prediction for cancer-related endpoints using NLR does not seem to add independent prognostic information to other well established prognostic factors in patients with non-metastatic RCC. Regarding patients’ overall survival, an increased NLR represented an independent risk factor, which might reflect a higher risk for cardiovascular, infectious, as well as for gastrointestinal morbidities and mortalities.
Retrospective analysis of sorafenib as first- or second-line targeted therapy in patients with mRCC: Three-year Italian experience.
Authors: Procopio Giuseppe , Derosa Lisa , Gernone Angela , Morelli Franco , Sava Teodoro , Zagonel Vittorina , De Giorgi Ugo , Ferrari Vittorio D. , Masini Cristina , Gasparro Donatello , Felici Alessandra , Berardi Rossana , Calvani Nicola , Lo Re Giovanni , Lipari Helga , Brizzi Maria Pia , Sisani Michele , Porta Camillo , Galligioni Enzo , Contu Antonio Silverio ,   RESET Study Group
Published: February 2017

415

Background: The Retrospective analysis of Sorafenib (So) as the first- or second- target therapy (RESET) study in metastatic renal cell carcinoma (mRCC) patients assessed the use and safety of sorafenib under daily-life treatment conditions in a community-based patient population in Italian centers. Methods: RESET was a retrospective, observational, non-interventional field study in mRCC patients. Treatment decisions were determined by each physician according to local prescribing guidelines and clinical practice. Patients for whom a decision to treat with sorafenib single agent as first- or second- target therapy (TT) for mRCC has been made, were eligible for inclusion. Patients that started So treatment between January 1, 2008 and December 31, 2010 were included. Data collection started retrospectively in 2012, in order to have a period of observation of at least 1 year up to 31st Dec 2011. Endpoints included safety, overall survival (OS), progression-free survival (PFS), response rate (RR), and treatment duration. Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, prior therapy, number of metastases, and line of TT with So. Results: From February to Jululy 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.3%), rash (2.3%), hypertension, fatigue, and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.5 – 19.6 mos) and median PFS was 5.9 mos (95% CI 5.0-6.8 mos). Median duration of treatment with So was 5.09 mos. Complete response was observed in 3 (0.8%) pts, partial response in 53(15.0%) pts and stable disease in 139(39.4%) pts. In pts receiving So as first- or second- TT, median OS was 19.9 mos (95% CI 15.4-25.3 mos) and 16.6 mos (95% CI 13.1-18.4 mos) respectively, and median PFS was 6.6 mos (95% CI 4.9-9.3 mos) and 5.3 mos (95% CI 4.4-6.2 mos) respectively. Conclusions: The efficacy and safety of So under routine clinical practice conditions in the setting of community-based practice in Italy were similar to that reported in prospective clinical trials. The efficacy of So was observed in the subgroup of pts receiving So as either the first or second TT for mRCC.
Induction of immunogenicity after irradiation of renal carcinoma cell lines.
Authors: Janda Gregory , Habiby Mohammad , Hoffmeyer Jan , Romano Michelle , Warren Graham Walter , Schwaab Thomas
Published: February 2017

417

Background: Cellular vaccine therapy in RCC has shown disappointing clinical and immunologic results. Poor immunogenicity of tumor associated antigens (TAAs) and their restricted expression may account for a lack of antigen-specific T cell responses. Irradiation induces TAA expression and enhances the immunogenicity of tumor cells. We investigated the influence of irradiation on the immunogenicity of RCC tumor cells. Methods: Six (ACHN, 786-0, 769-P, Caki-1, A-498, A-704) commercially available RCC cell lines were cultured and subsequently exposed to 0, 12, or 16 Gy of ionizing radiation. Alive cells and supernatant were isolated at 2, 24, and 48 hours after irradiation. The TAA expression (CA9, 5T4, MUC-1, NY-ESO-1, HSP-70) was assessed using flow cytometry. Expression relative to control (ERC) was calculated. Cytokine analysis was performed using a 9-plex Luminex human cytokine assay and reported as the mean concentration of all cell lines. Results: CA9, 5T4, and NY-ESO-1 demonstrated a marked increase in expression in 4 of 6 cell lines while MUC-1 and HSP-70 had increased expression in all cell lines after irradiation. The range and mean ERC across all six cell lines at 48 hours after irradiation with 16 Gy are shown in the table. Il-2, Il-6, IFN-gamma and Il-4 increased in irradiated cells with peak concentrations vs. control of: 0.55 vs. 0.47, 1631 vs. 1358, 10.06 vs. 7.61, 1.07 vs. 0.77 pg/ml, respectively. Conclusions: Irradiation of RCC cell lines increased TAA expression in the majority of cell lines. Immunomodulatory cytokines were induced with radiation. These data suggest that RCC tumor irradiation may provide a novel means to increase the immunogenicity and subsequent efficacy of RCC-targeted immunotherapy. [Table: see text]
Relationship of aberrant glycosylation of n-glycan on immunoglobulins with survival of patients with renal cell carcinoma.
Authors: Hatakeyama Shingo , Amano Maho , Koie Takuya , Tobisawa Yuki , Yoneyama Tohru , Mori Kazuyuki , Tsuchiya Norihiko , Habuchi Tomonori , Nishimura Shin-Ichiro , Ohyama Chikara
Published: February 2017

438

Background: Biomarkers for early detection and prediction of patient survival for renal cell carcinoma (RCC) have not yet been established. We have developed a novel glycoblotting method that allows high-throughput, comprehensive, and quantitative glycan analysis of whole human serum. We examined the relationship between serum N-glycan profiling and survival of the patient with RCC. Furthermore, we attempted to identify carrier protein to which the responsible N-glycan attached. Methods: We performed a comprehensive N-glycan structural analysis of sera from 64 patients with RCC using the glycoblotting methods and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). The intensity of the N-glycans was then analyzed with the help of the logistic regression analysis and a receiver operating characteristic curve to select N-glycans which associated with patient survival in RCC. The candidate N-glycans which had statistically significant relationship in overall survival were evaluated their independency using Cox-regression model to elucidate its superiority comparing to other conventional biomarkers of RCC. Then, we recovered the responsible N-glycan together with its carrier protein by sialobloting method to identify the carrier protein. Results: We identified 56 kinds of N-glycans in sera from RCC patients. The intensity of peak 19 was significantly higher, and the intensity of peak 49 was significantly lower in the patients who survived longer. Multivariate analysis revealed that peaks 19 and 49 were independent predictors of overall survival as well as conventional risk factors. Protein analysis for the carrier protein revealed that the aberrant N-glycan was harbored by IgA1 or IgG4. Conclusions: Aberrant glycosylation of N-glycan on IgA1 or IgG4 may serve as novel biomarkers for RCC. Further validation study is warranted.
A comparison of outcomes regarding robotic versus open partial nephrectomy.
Authors: Hamilton Zachary Adam , Le Margaret , Saad Kahlil , Duchene David , Holzbeierlein Jeffrey M. , Mirza Moben
Published: February 2017

441

Background: The latest SEER Cancer Statistics estimated that 60,920 new cases of kidney cancer were diagnosed in 2011 in the United States. The standard of care for small renal masses has transitioned from radical to partial nephrectomy with strong data to support excellent oncologic outcomes, long-term preservation of renal function, and better overall survival. The literature shows that laparoscopic approaches are favorable when compared to open techniques, but outcomes in robotic surgery are still gaining data. The objective of this study is to perform a review of outcomes comparing open versus robotic partial nephrectomy. Our hypothesis is that surgical outcomes and length of stay will favor robotic surgery. Methods: We performed a retrospective review of partial nephrectomies from 2009 to 2012 for solitary masses suspected as carcinoma at the Kansas University Medical Center. Estimated blood loss, age, length of stay, intraoperative transfusion, and margin status were recorded. When available, nephrometry scores were calculated based on preoperative imaging. Results: A total of 78 open partial nephrectomies and 63 robotic partial nephrectomies were analyzed. In the open cohort, the surgical blood loss was higher compared to the robotic cohort (328ml vs. 222ml, p=0.03). Nephrometry scores and mean mass size were higher in the open cohort (7.3 vs. 5.9, p<0.01 and 3.2cm vs. 2.7cm, p=0.01, respectively). The mean length of stay was 2.8 days for the robotic cohort and 4.3 days for the open cohort. No significant difference was noted in age or BMI. Of note, there were five intraoperative blood transfusions in the open group and none in the robotic group. Four margins were positive in the robotic cohort and one in the open cohort. Nephrometry score and mass size did not correlate with blood loss. Conclusions: For partial nephrectomy blood loss is significantly lower with robotic techniques as compared to open surgery. This relationship is not affected by mass size or nephrometry score. Positive margins rate is higher in robotic surgery, while blood transfusion rate is lower in robotic surgery. Length of stay is decreased with robotic surgery. Robotic partial nephrectomy seems to afford the advantage of decreased blood loss and decreased length of stay.
Sunitinib-associated hypothyroidism in patients with metastatic renal cell carcinoma.
Authors: Jagdev Satinder , Hayward Kate , Sim Sheryl
Published: February 2017

443

Background: Sunitinib (sun) treatment for patients (pts) with metastatic renal cancer (mRCC) can often lead to fatigue. The incidence of sun-induced hypothyroidism (HT) in the phase III pivotal study of pts with mRCC was 14% for all grades and 2% for grades 3-4. Subsequent retrospective and prospective studies described incidences of between 30–85%. Elevated TSH alone may be seen in up to 85% of mRCC pts treated with sun. Symptoms of HT, eg: fatigue, constipation, cold intolerance, hair thinning, and dry skin have been reported in the majority of sun-treated pts. Methods: We reviewed of all cases of mRCC pts initiating sun treatment between January 2008 and December 2009 using the electronic record system Patient Pathway Manager. Pts with underlying HT, abnormal TFTs at baseline or those on sun for less than two cycles were excluded. TFTs were performed at baseline and then day 1 of every two cycles. Response was assessed every 2-3 cycles. The aims of the study were to Identify rate of sun-induced HT in St James’s Institute of Oncology and determine whether there is a correlation between HT and disease response. Results: 84 pts were included (median age 62 years). 90% had good or intermediate prognosis disease by Memorial Sloane-Kettering Cancer Centre (MSKCC) criteria. 52 pts had TSH <6mU/L and 32 had TSH of >6mU/L. Progression-free survival was significantly longer in those pts with TSH of >6mU/L (29.6 months) compared to those with TSH <6mU/L (11.3 months). Conclusions: Sun-induced HT occurred in approximately 30% of pts and predicted for improved progression-free survival. Further studies are needed to characterise this and updated data will be presented.
Association of CTCAE v4 grading of hypertension with toxicity in patients with renal cancer receiving vascular endothelial growth factor (VEGF)-targeting agents.
Authors: Akhtar Naveed Hassan , Karpenko Irene , Singh Beerinder , Beltran Himisha , Nanus David M. , Tagawa Scott T.
Published: February 2017

447

Background: The NCI Common Terminology Criteria for Adverse Events (CTCAE) system underwent a change to version 4 in May 2009. In addition to system re-organization, several AE categories underwent changes in grading, including hypertension (HTN). As many anti-neoplastic agents, particularly those targeting VEGF are associated with HTN, changing in the grading system may result in changes to maximum tolerated or recommended phase II doses (MTD or RP2D) in dose-escalation studies using classic trial schemas (such as 3+3 design). Methods: We reviewed individual patient data of a phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC). The phase I portion of the study was conducted to define the dose-limiting toxicity and RP2D of the combination (Am J Clin Oncol, 2011). The phase II portion further assessed efficacy as defined by objective response rate. Initial grading of AE’s during this study used CTCAE v3. Individual patient data was reviewed and HTN AE’s were re-graded using CTCAE v4 criteria for up to 12 cycles of therapy on study. Results: Of 28 pts enrolled, 23 (82.1%) had complete source documents available for the complete evaluation of HTN. The table compares each individual’s highest CTCAE v3 versus v4 grading of HTN on study. All pts had HTN AE’s using CTCAE v4. Only 1 pt maintained grading using both versions (Gr 3), with 22 (95.7%) changing grades. Two (8.7%) moved from Gr 0 to Gr 1, fourteen 60.9(%) from Gr 0 to Gr 2, four (17.4%) from Gr 1 to Gr 2, one from Gr 1 to Gr 3, and two (8.7%) from Gr 2 to Gr 3. Conclusions: Re-classification of grading in this study demonstrates that only 4.3% maintained stable grading of HTN across systems, with 65.2% increasing by 2 grades. The change in AE reporting criteria has the potential significantly impact results of clinical trials. This may be particularly important with VEGF-targeted agents, with emerging data pointing towards HTN as a pharmacodynamic marker in pts with RCC, and may affect dosing of other drugs with blood pressure effects, including CYP17 inhibitors for prostate cancer. Clinical trial information: NCT00121251. [Table: see text]
Molecular expression profiling and pathway analysis of formalin-fixed paraffin-embedded primary renal tumor specimens.
Authors: Antón Aparicio Luis M. , Medina Villaamil Vanessa , Aparicio Gallego Guadalupe , Santamarina Cainzos Isabel , Quindós Varela Maria , Valladares Ayerbes Manuel
Published: February 2017

448

Background: Many studies have demonstrated genetic and environmental factors lead to renal cell carcinoma (RCC) occurring during a protracted period of tumorigenesis. It seemed suitable identify and characterize potential molecular markers which might provide rapid and effective possibilities for early detection of RCC. The purpose from this analysis was to derive predictive models which could predict more accurately than any one factor alone. Methods: We assessed using quantitative real-time PCR (qPCR) with SYBR Green the profile of 32 predictive markers involved in the cascade of events leading to the formation and progression of this disease to evaluate their involvement in oncogenesis. RNA of quality was obtained in 90% of samples (N=80, 52/80 clear RCC, 6/80 papillary RCC and 14/80 chromophobe RCC) to carry out the study of gene expression. GenEx software was used for qPCR data processing and analysis. The potential correlation between mRNA expression and the pathological features of the study subjects was assessed by Pearson Chi-squared. Linear rather than logistic regression models were used (SPSS statistics 21.0 software). Additionally, a knowledgebases of biological pathways, Reactome and Snow (Babelomics), were used to superimpose our quantitative expression data. Results: The best gene predictors related to different pathological variables (histological type, tumor size, Fuhrman grade, number of involved nodes, renal pelvis invasion, lymphatic vessels invasion, and rupture of the renal capsule): Hif1-α (p < 0.001), Hif1-β (p = 0.035), DLL1 (p = 0 .012), DLL3 (p< 0.001), c-Kit (p = 0.002), PDGFR-β (p =0.002), PDGFR-α (p = 0.026), Bax-β (p = 0.005), Survivin (p = 0.028), Notch1 (p = 0.006), Notch2 (p = 0.007), Notch3 (p = 0.016), Notch4 (p = 0.005), EGFR (p = 0.029), Glut3 (p = 0.026), Glut5 (p = 0.036), FH (p = 0.018), CA9 (p = 0.030), and VHL-1(p = 0.015). Conclusions: Our data suggested that altered expression of certain members involved in the main pathways which feed RCC and their downstream targets analyzed together could improve the diagnostic accuracy for renal cancer by combining determinations of mRNA markers.
Is there a "trial effect" on outcome of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib?
Authors: Keizman Daniel , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Pili Roberto , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Boursi Ben , Weitzen Rony , Hayat Henry , Peer Avivit , Neumann Avivit , Kovel Svetlana , Sella Avishay , Mermershtain Wilmosh , Roubinov Keren , Carducci Michael Anthony , Berger Raanan
Published: February 2017

453

Background: Several studies have suggested the existence of a trial effect, in which for a given treatment, participation in a clinical trial is associated with a better outcome of cancer patients. The VEGFR inhibitor sunitinib is a standard treatment for mRCC. The effect of clinical trial participation on the outcome of sunitinib treatment in mRCC is poorly defined. We aimed to study the effect of clinical trial participation on outcome of mRCC patients treated with sunitinib. Methods: Records from 275 mRCC patients treated with sunitinib from 2004 to 2012 in 7 centers across 2 countries were reviewed. We compared the response rate, progression free survival, and overall survival, between clinical trial participants (n=49) and a matched cohort of non participants (n=49) who received standard therapy. Each patient participating in a clinical trial was individually matched with a non-participant by clinicopathologic factors. Progression free survival and overall survival were determined by Cox regression. Results: The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 24%, intermediate 60%, poor 16%), ECOG performance status (0-1 92%), prior nephrectomy (92%), renal cell carcinoma histology (clear cell 80%), sunitinib induced hypertension (56%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants vs. non participants, objective response was partial response/stable disease 80% (n=39) vs. 73% (n=36), and progressive disease at first imaging evaluation within the first 3 months (mos) 20% (n=10) vs. 27% (n=13) (p = 0.63, OR 1.2). Median progression free survival was 10 vs. 11 mos (HR=0.96, p = 0.84), and median overall survival 23 vs. 24 mos (HR=0.97, p=0.89). Conclusions: In mRCC patient treated with sunitinib, the outcome of clinical trial participants was similar to matched non participants who received standard therapy.
VHL protein (pVHL) and Src expression in metastatic RCC.
Authors: Robinson Kyle William , Chen Yiyi , Podolak Jennifer , Forquer Kerri , Cook Megan , Thomas George , Ryan Christopher W.
Published: February 2017

457

Background: Rational therapeutic strategies are lacking for RCC with intact pVHL expression. We recently demonstrated that Src signaling output was elevated in RCC cells expressing pVHL (Suwaki Sci Transl Med 2011). We sought to prospectively identify and clinically characterize RCC patients according to tumor expression of pVHL and Src using an immunohistochemical (IHC) assay, including the association of pVHL and Src expression with response to targeted therapies. Methods: Metastatic RCC patients with available archival tumor tissue provided written informed consent. Primary and metastatic tumors were evaluated by IHC staining using the following scale: 0: absent; 1: weak; 2: moderate-strong. We scored the percent of tumor cells staining at these intensities, giving a total possible score of 200. Association of pVHL and Src score was determined using Spearman correlation coefficient. Time to treatment failure (TTF) > 300 days was used to stratify patients as treatment success versus failure. Logistic regression was used to analyze whether there was an association between pVHL and Src staining and clinical outcome, and ROC curve analysis was used to find the predictive ability of pVHL and Src positivity. Results: 27 patients were consented, from which the nephrectomy specimens of 23 patients and 17 metastatic tumor samples were available. 22 patients had received systemic therapy (21 with VEGF TKI, 1 with mTOR-I). Expression of pVHL and Src were positively correlated (p<0.001). Expression of pVHL in primary tumor, but not Src, was associated with fewer treatment failure events (p=0.0384). Those who had TTF > 300 days had a mean pVHL score of 127.3, and Src of 134, while those with TTF < 300 days had mean pVHL of 57.5, and Src 89.5. Performing ROC analysis, the combination of pVHL and Src score displayed a higher area under the curve (c=0.8) in predicting treatment failure or success than pVHL or Src score alone. Conclusions: We have shown a correlation between pVHL and Src expression in tumors from a prospective population of RCC patients. Accrual continues to this study of a novel quantitative IHC profile that could identify patients for whom currently available therapies may not be effective or for whom a clinical trial of a Src inhibitor may be appropriate.
Correlation of pathologic findings after brief neoadjuvant sorafenib with results of dynamic-contrast enhanced (DCE) and diffusion-weighted magnetic resonance imaging (DW-MRI) in patients with locally advanced or metastatic clear cell renal cell carcinoma (RCC).
Authors: MacVicar Gary R. , Miller Frank , Rustogi Rahul , Chen Zong-Ming , Martone Brenda K. , Kuzel Timothy
Published: February 2017

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Background: Many pts receiving tyrosine kinase inhibitors for RCC manifest stable disease as their best response by RECIST criteria. We hypothesized that tumor necrosis by DCE and DW-MRI after brief treatment with neoS may correlate with pathologic findings. We investigated in a pilot study whether these MRI changes may serve as an imaging biomarker predictive of clinical outcome. Methods: Pts with locally advanced or metastatic clear cell RCC undergoing nephrectomy or metastastectomy were treated with neoS 400mg PO bid for 28 days prior to surgery. The feasibility and safety of neoS was determined. Tumor necrosis detected by DCE and DW MRI’s pre- and post-neoS were compared and correlated with survival and pathologic findings at surgery. RECIST/WHO criteria were also compared. Results: 9 pts were enrolled, and all underwent surgery after neoS, 4 weeks (n=7) or less for toxicity (n=2). Clear cell/sarcomatoid histology was noted in 8 pts, and papillary in 1. All pts had T3 or T4 disease. 7 had M1 disease. No surgical complications occurred. 7 pts (78%) experienced grade 3 toxicities, including hypertension (n=1), pancreatitis (n=1), hand-foot syndrome (n=1), hyponatremia (n=2), and rash (n=2). No grade 4 or 5 toxicities were observed. 4 of 8 clear cell/sarcomatoid pts (50%) have died, 3 because of progressive disease and 1 of unrelated causes. DCE and DW MRI’s with direct surgical pathological correlation were available in 7 of these pts. The mean ADC DW MRI changes in the renal lesion of 4 longer term survivors (median survival = 43 months) was +.22 vs. –0.07 in the 3 short term survivors (median survival = 13 months). RECIST/WHO criteria did not correlate with response. Evaluation of lack of enhancement on DCE MRI and increase in ADC on DW MRI were seen and correlated with necrosis on pathologic specimens. Conclusions: Four weeks of neoS is associated with significant necrosis that correlates with DCE-MRI and DW-MRI. There may be a trend in survival with greater necrosis, suggesting a role for these imaging biomarkers to assess early benefits of therapy. Clinical trial information: NCT00727532.
Prognostic factors and validation of prognostic nomograms in patients (pts) treated with three targeted therapies (TTs) for metastatic renal cell carcinoma (mRCC): Results from an Italian survey.
Authors: Iacovelli Roberto , Milella Michele , Santoni Matteo , Di Lorenzo Giuseppe , Ortega Cinzia , Sabbatini Roberto , Ricotta Riccardo , Lorusso Vito , Messina Caterina , Atzori Francesco , Zucali Paolo A. , Cinieri Saverio , Mosca Alessandra , Verzoni Elena , Primi Francesca , Baratelli Chiara , Cortesi Enrico , Carteni Giacomo , Sternberg Cora N. , Procopio Giuseppe
Published: February 2017

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Background: Outcomes of pts treated with three TTs for mRCC have not been well characterized. Survival data as well as existing prognostic criteria in this population were evaluated. Methods: Pts with clear-cell mRCC who received 3 TTs were included. A questionnaire was send to main Italian centers involved in the treatment of mRCC. Demographic data, history of RCC, type, and length of first-, second-, and third-lines were collected. Values of serum Hb, PLT, neutrophils, LDH and Ca, ECOG-PS, previous RT and number of metastatic sites >2 before the start of third-line were evaluated. Cleveland Clinic, French, Heng, and MSKCC scores and relative survival were calculated. Results: Following the screening of 1,905 pts, 252 (13%) with 3 TTs were identified. The median age was 60 yrs (range 52-68), 73% were male, 96% had nephrectomy and 38% were metastatic at diagnosis. At first-line, the Motzer class was good, intermediate, and poor in 48%, 47%, and 5% of pts, respectively. The median OS from the start of third-line was 14.3 mos (95%CI, 10.1–18.6). Rate and survival by prognostic group according to each classification are reported in table below. When prognostic factors were considered separately, at the univariate analysis ECOG-PS≥2, Hb1.5ULN, Ca>ULN; PLT>ULN; Neu>ULN, and sites of disease >2 had negative prognostic role. Multivariate analysis shows an independent prognostic role only for ECOG-PS≥2 (HR: 1.8; 95%CI: 1.1–2.8), HbULN (HR: 2.1; 95%CI: 1.2–3.8). Pts were stratified in 3 groups according to the presence of none, 1 or ≥2 prognostic factors. The median OS was 20.3, 13.6 and 7.8 months, respectively (p<0.001). Conclusions: Current nomograms are able to predict survival in patients with mRCC before the third-line with TT. Neutrophils, hemoglobin and ECOG-PS were the most important prognostic factors. [Table: see text]
Severe lack of comprehension of common prostate health terminology in underserved populations: External validation.
Authors: Master Viraj A. , Wang Daniel Shin-Ping , Tai Caroline Gar-Ling , Sesay Musu , Kilbridge Kerry L. , Goodman Michael , Jani Ashesh B.
Published: February 2017

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Background: Patients diagnosed with prostate cancer are often counseled about treatment options by healthcare providers who commonly use terms that are part of the ‘core’ vocabulary of prostate cancer. We hypothesized that a predominantly lower-literacy patient population would demonstrate a severe lack of comprehension of prostate cancer terms, which would validate the findings of Kilbridge et al. (JCO, 2009) who found a profound lack of comprehension in a single institution series. Methods: A previously developed survey was used to evaluate understanding of terms related to urinary, bowel, and sexual function. The survey was conducted by trained evaluators, recruiting patients, age ≥ 40, from two low-income safety-net clinics with primarily African-American populations. Comprehension was assessed using semi-qualitative methods coded by two independent investigators. Literacy and numeracy were also evaluated. Results: 109 patients completed the study. Overall prostate cancer knowledge was poor, with only 5% of patients understanding the function of the prostate, 15% understanding the term ‘incontinence’, 29% understanding ‘urinary function’ and 32% understanding ‘bowel habits’ (see Table). Comprehension decreased with the use of compound words, such as ‘intercourse’ (95%) vs. ‘vaginal intercourse’ (58%), validating previous work. Median school level completed was the 12th grade; yet median literacy level was only 9th grade, and reading level was significantly correlated with comprehension. Only 30% of patients correctly calculated both a fraction and a percent. Conclusions: Lack of comprehension of terms related to prostate health is pronounced in this patient population and may be widespread. This lack of comprehension potentially limits the ability of patients to participate in shared and informed decision-making. These results validate the findings of previous studies and support a continued need for refined methods of prostate cancer education. [Table: see text]
Feasibility of RNA sequencing to detect TMPRSS2:ERG fusions following laser capture microdissection of prostate cancer.
Authors: Kim Won , Foye Adam , Bengtsson Henrik , Kim Hyunsung John , Taylor Barry S. , Pourmand Nader , Febbo Phillip G.
Published: February 2017

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Background: Recent sequencing efforts continue to fuel our growing insight into the genetic basis of prostate cancer (PCa). One of the key challenges remaining is to identify genetic events that drive PCa biology. RNA sequencing (RNA-seq) is commonly used to determine unbiased gene expression as a proxy for tumor biology. However, tumors often contain a mixture of cancer and normal cells that can confound data analysis. Cancer cells can be isolated by laser capture microdissection (LCM), but the feasibility of RNA-seq on small amounts of RNA following LCM of PCa tissue needs to be assessed. Methods: A set of 5 localized PCa specimens, frozen at the time of prostatectomy, was analyzed. RNA was isolated following LCM from these 5 specimens and assessed for quality with an Agilent Bioanalyzer and for quantity with RiboGreen. Paired-end, 300-bp insert sequencing libraries were prepared from the 5 specimens in duplicate; one specimen was also prepared for sequencing without LCM. The 12 samples were then sequenced on a single lane of an Illumina HiSeq. Sequencing reads were aligned with Tophat to build hg19 of human genome. Initial quality control was performed with Picard using refFlat and ribosomal RNA (rRNA) annotations provided by UCSC. PCR using previously published primer pairs was used to confirm the presence of TMPRSS2:ERG fusions. Results: 4-5mm2 of tumor was targeted by LCM from each PCa specimen. At least 100ng of total dsDNA was generated for library construction. For the first run, an average of 8,743,722 reads per paired-end was obtained (range: 1,335,939 to 16,134,097); the second run was comparable (mean: 8,612,188 reads; range: 1,312,823 to 15,842,480). Mapping of the sequences revealed no 5’ or 3’ read coverage bias, but the percentage of mappable reads per sample was less than 30%; sequencing was inefficient due to a high percentage of rRNA (mean: 38% per sample; range 28 to 44%). However, TMPRSS2:ERG fusions were confirmed in the samples with known fusion-positive status. Conclusions: RNA-seq is feasible and can detect fusions that are known and highly expressed. The inclusion of rRNA reduces the depth of coverage of the transcriptome and additional optimization is required to maximize efficiency.
Maximum tumor diameter as a predictor for outcome following salvage radiation for prostate cancer.
Authors: Johnson Skyler B. , Jackson William C. , Song Yeohan , Foster Benjamin , Li Darren , Foster Corey , Palapattu Ganesh S. , Mehra Rohit , Kunju Priya , Feng Felix Yi-Chung , Hamstra Daniel A.
Published: February 2017

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Background: While maximum tumor diameter (MTD), as identified on radical prostatectomy (RP) specimens, has been associated with prostate cancer recurrence, the prognostic significance of this variable is unknown in the context of salvage external beam radiation therapy (EBRT) following a rising PSA after RP. Here, we investigate associations between MTD and outcomes in this setting. Methods: From an IRB approved retrospective single-institutional cohort, 575 patients treated with salvage radiation therapy (SRT) were identified, with MTD data available on 173. ANOVA and chi-square were utilized to compare prognostic variables with MTD. The impact of MTD on biochemical failure (BF), metastasis (Mets), prostate cancer-specific mortality (PCSM) and overall survival (OS) was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox-proportional hazards regression. Results: Median follow up was 76.5 months (IQR, 46.5-104.0) and median MTD was 18 mm (IQR, 13-22). Median RT dose was 68.4 Gy (IQR, 64.8-68.4). MTD size correlated with pT-stage, Gleason score, and presence of seminal vesicle invasion or lymph node invasion. Receiver operator characteristic (ROC) curve analysis was used to correlate MTD with clinical end-points and identified 14 mm as the most prognostic cut-point. A MTD >14 mm was associated with a 1.8, 4.0 and 8-fold increase in the risk of BF (p<0.02), Mets (p<0.002), and PCSM (p<0.02), respectively. As a continuous variable, on multivariate analysis, MTD was shown to be a marginally significant predictor of OS (p=0.056, HR [95%] 1.6 [1.0-2.5]), and a significant predictor of PCSM (p<0.03, HR [95%] 2.0 [1.1-3.8]) and Mets (p=0.01, HR [95%] 1.7 [1.1-2.6) but not BF. In this model, for every 10 mm increase in MTD, there is a 1.7, 2.0, and 1.6 fold risk of metastasis, prostate cancer death and overall death, respectively. Conclusions: As a categorical and continuous variable, MTD is a significant predictor of prostate cancer outcomes following SRT and should be used in clinical decision making in this population and in future clinical risk assessment tools.
Genomic analysis of prostate cancer.
Authors: Barnett Christine M. , Heinrich Michael C. , Nelson Dylan A. , Lim Jeong Youn , Beadling Carol , Warrick Andrea , Neff Tanaya , Thomas George , Garzotto Mark , Higano Celestia S. , Beer Tomasz M. , Qian David Z.
Published: February 2017

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Background: The characterization of actionable mutations is a prerequisite for the development of individualized, targeted therapy. We sought to characterize the prevalence of potentially therapeutically actionable mutations in patients with high risk prostate cancer. Methods: 48 samples of formalin fixed paraffin embedded prostatectomy tissue from a neoadjuvant chemotherapy trial (Garzotto M, Cancer 2010 Apr 1;116(7):1699-708) were analyzed. DNA was extracted from microdissected tumor. Tumor DNA was analyzed for 643 common solid tumor point mutations in 53 genes using mass spectroscopy based sequencing (Sequenom MassArray). Low level mutations were validated using ion chip pH based sequencing (Ion Torrent). In addition, PTEN loss and ERG translocations were examined using immunohistochemistry in associated tissue microarrays. Correlation with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations examined. Results: Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 45 tumors evaluable for IHC, 36% had PTEN loss (6% with a heterogenous pattern) and 40% had ERG rearrangement (2% with heterogeneous pattern). Individual mutations were not frequent enough to determine associations with progression. Using Kaplan-Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median progression free survival, 19 vs. 106 months (p = .01). Conclusions: This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. While point mutations alone did not have a statistically significant effect on relapse, PTEN loss was associated with an increased relapse in high risk prostate cancer treated with chemotherapy followed by surgery. It is yet unclear if the 16 weeks of chemotherapy played a role in selecting for tumors with these biologic features, and this will therefore be the subject of future investigations. [Table: see text]