bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of sunitinib pretreatment on yield from tumor-infiltrating lymphocyte (TIL) cultures in patients with renal cell carcinoma.
Authors: Bex Axel , Guislain Aurelie , van Boven Hester , Blank Christian U. 
Published: February 2017

419 Background: Targeted therapies achieve response rates up to 50% in metastatic RCC, but durable complete remissions are very rare. Therefore additional therapeutic options are warranted. Adoptive transfer (ACT) of tumor infiltrating lymphocytes (TIL) has revealed response rates of up to 72% in melanoma patients and may lead to consolidation of responses upon sunitinib in RCC. Recent data suggest that sunitinib influences lymphocyte infiltration and regulatory T cells (Treg) into tumor, dendritic cells (DC), and myeloid derived suppressor cells (MDSC) in animal models, but impaired proliferation and function of human T cells and was unable to improve human DC activity in vitro. Methods: We compared TIL grown from primary tumors pretreated with 2 courses sunitinib prior to cytoreductive nephrectomy to TIL generated from treatment-naïve RCC. Patients took part in a phase II trial of presurgical sunitinib registered under EudraCT 2006-006491-38 and gave written informed consent. From 6 pretreated primary tumors and 6 untreated controls sterile tumor material was obtained and digested with collagenase, hyaluronidase and DNase to obtain tumor single cell suspension. This TIL/tumor suspension was cultured for up to 25 days in 6000IU/ml interleukin 2 (IL-2) and rapidly expanded by anti-CD3+IL-2 stimulation. Results: TIL harvested after coculture with tumor cells yielded 36+/−SD fold expansion from non-pretreated tumors versus a 128+/−SD fold expansion from tumors from patients that had been pretreated with sunitinib (p=0.015). Phenotypic analysis of culture product indicated a higher content of natural killer (NK) cells from treatment naïve TIL cultures, while sunitinib pretreatment skewed towards NK T cells. Interferon-gamma-production was not different on a per cell level.Rapid expansion after culture using anti-CD3/IL-2 induced 100-200 fold expansion towards a content of more than 75% T cells with no significant differences between both groups. Conclusions: Sunitinib in vivo pretreatment improves TIL grow during initial culture and does not impair function or rapid expansion, allowing higher final yield of TIL for ACT studies in RCC.
Sipuleucel-T product characterization across different disease states of prostate cancer.
Authors: Sheikh Nadeem A. , Small Eric Jay , Quinn David I. , Higano Celestia S. , Lin Daniel W. , Wesley Johnna D. , Haynes Heather , Stewart Frances P. , Poehlein Christian Heinrich , Trager James B. 
Published: February 2017

42 Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). In the Phase 3 mCRPC trials, antigen presenting cell (APC) activation in sipuleucel-T correlated with overall survival. Here product characteristics of sipuleucel-T were compared in patients (pts) from trials in the neoadjuvant (n=42), asymptomatic or minimally symptomatic mCRPC (n=341), and mCRPC (n=104) disease states. Methods: Sipuleucel-T comprises 3 treatments approximately 2 wks apart. Cellular composition and APC activation (CD54 upregulation) were evaluated in all courses of sipuleucel-T, and cumulative CD54 upregulation was calculated for each patient. In some studies, cytokines were assayed from culture supernatants and T cell and B cell activation markers were assessed by flow cytometry during manufacture. Results: Baseline demographics were generally representative of each disease state; neoadjuvant pts were younger with less disease burden; mCRPC pts had the highest disease burden and more frequent prior chemotherapy. While neoadjuvant pts had greater levels of T cells, the patterns of APC activation were similar among all trials, with increased CD54 upregulation at the second and third treatment. The trend for cumulative fold increase in CD54 upregulation was significantly greater in earlier disease pts (neoadjuvant: 35.5, asymptomatic or minimally symptomatic mCRPC: 28.7, mCRPC: 21.8; p<0.0001 (Joncheere-Terpstra test)). During manufacture of the product, lymphocyte activation markers and cytokines consistently showed enhanced expression during the second and third treatments in all disease states. The lymphocyte activation and cytokine profiles were similar between early and later disease state pts. Conclusions: While cellular composition varied with disease state, manufacture of sipuleucel-T activated APCs in both early and late disease states of prostate cancer, and generated similar T and B cell activation and cytokine production profiles consistent with immunological prime-boost. APC activation tended to be more robust in earlier disease states.
Biomolecular characterization of formalin-fixed paraffin-embedded primary renal tumor specimens.
Authors: Medina Vanessa , Aparicio Gallego Guadalupe , Santamarina Isabel , Valladares Ayerbes Manuel , Antón Aparicio Luis M. 
Published: February 2017

421 Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer. It is required a better understanding of signalling pathways involved in renal cells. Methods: We assessed using immunohistochemistry (IHC) and quantitative real-time PCR (qPCR) with SYBR Green the profile of predictive markers involved in the cascade of events leading to the formation and progression: invasiveness, angiogenesis and antiapoptotic mechanisms. 80 RCC tissues were detected by IHC. RNA of quality only was obtained in 72 (80% clear RCC, 10% papillary RCC and 10% chromophobe RCC) to carry out the study of gene expression through qPCR. A pool of normal kidney-derived RNA samples (N=5) was used as healthy control. GAPDH and YWHAZ were used as reference genes. GenEx software was used for qPCR data processing and analysis. Nonparametric tests (Pearson’s correlation coefficient test and Spearman’s rho test, Kruskal — Wallis and Mann — Whitney) were applied for statistical data analysis (SPSS 19). Results: p53 showed higher expression in those cases with Furhman grade I (p=0.036). Moreover p53 showed a positive association with VEGF, GLUT1, GLUT4, VEGFR-2 and VHL (r=0.241, sig. level 0.05; r=0.291, sig. level 0.01; r=0.456, sig. level 0.01; r=0.187, sig. level 0.097 and Spearman’s rho=0.269, sig. level 0.05 respectively). Hif1- α, Hif1- β, Notch1 and Notch3 were upregulated in chromophobe RCC (p=0.045, p=0.03, p=0.03 and p=0.02 respectively). Hif1- α and Notch3 were upregulated in clear RCC (p=0.034 and p=0.041 respectively). Spearman’s correlation coefficient showed a strong positive correlation between Nocth1-4 members and their receptors and Hif1-α and β genes. Highlight the correlation found between: Notch1 and Hif1-α (Spearman’s rho = 0.740, significance level 0.01) and Hif1-β and Jagged1 (Spearman’s rho = 0.752, significance level 0.01). Conclusions: The pathway involving the tumor suppressor gene p53 could regulate tumor angiogenesis. Co-expression of Notch receptors, their ligands and Hif-1 α and Hif1- β subunits may play a role in human RCC. Notch cascade may represent a novel and therapeutically accessible pathway in chromophobe and clear RCC. More detailed studies of these crossing pathways are in progress.
Interleukin-2 (IL-2) chrono-infusion (CHI) in metastatic renal cell carcinoma (mRCC): A phase I/II study.
Authors: Lo Re Giovanni , Santeufemia Davide ADRIANO , Lenardon Oliviero , Talamini Renato , Del Conte Alessandro , Marus Wally , Nicolosi Gianluigi , Mancinelli Paolo , Tumolo Salvatore , Garbeglio Antonio 
Published: February 2017

423 Background: The soprachiasmatic nucleus represents the pacemaker coordinating circadian rhythm. Its dysregulation in neoplastic patients (pts) can be an important inducer/promoter of cancer progression. It is a potential mediator of cancer immunosuppressive effect and quality of life (QoL) impairment. CHI allows concentration of time active treatment with possible impact on QoL and immune and hormone set-up. Aim of this study was to evaluate feasibility, dose limiting toxicity and activity of CHI IL-2 in mRCC. Methods: 22 pts were enrolled, 14 were naive and 8 pretreated (chemo/immunotherapy in 6 and targeted in 6). M/F ratio was 16/6, median age 68 y. IL-2 CHI was administered iv in 8 h (peak 1 am, 9 am, 5 pm) from 2 MUI/m2 with escalated dose ( Fibonacci scale) x 3 days/q 2 wks for 4 cycles. Four maintenance cycles were performed in responsive/stable pts. Results: from January 2005 to July 2009, out of 22 pts, 3 were treated onto each Le (I-V ) and 7 in the VI. G3-4 toxicity was reported in four pts (hypotension in 2, renal in 2 and diarrhoea in 1) on the VI Le ( DLT 18,6 MUI/m2). Response: 1 CR, 2 PR, 9 SD, 10 PD. ORR was 25%%. DCR on overall/ good-intermediate group (MSKCC) was 54%/69%. Median PFS and OS were 4,5 and 14,5 mos respectively. In a univariate analysis dose Le (4-6 vs. 1-3), PS (0 vs 1-2), gender (M vs F) and cD3, cD4, cD8 count (gain vs drop) were statistically significant for OS. In a univariate analysis age (< 65 y vs. >65y), Motzer score (0-1-2 vs 3) increase/reduction of cD19, cD16, HLA-DR, cD4/cD8, increase/reduction of prolactine, reduction/increase of ACTH-Cortisol showed a trend of survival improvement. Conclusions: IL-2 CHI aappeared safe in a standard care unit, moderately toxic and active in mRCC. Phase 2 study with dose Le V is now ongoing.
The safety and efficacy of pazopanib prior to planned nephrectomy in metastatic clear cell renal cancer.
Authors: Boleti Ekaterini , Sarwar Naveed , Jones Robert R , Chowdhury Simon , Crabb Simon J. , Shamash Jonathan , Peters John , Oades Grenville , O'Brien Tim S. , Berney Dan , Rockall Andrea , Powles Thomas 
Published: February 2017

427 Background: The safety and efficacy of upfront pazopanib, prior to nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated. The toxicity profile of pazopanib potentially makes it an attractive agent in this setting. Methods: A single arm phase II study (PANTHER 2009-016675-29) evaluated 12–14 weeks of pazopanib prior to planned nephrectomy in untreated patients with metastatic clear cell renal cancer. Patients had MSKCC intermediate and poor risk disease. Pazopanibwas stopped for a minimum of 16 days during nephrectomy. FDG-PET and DCEMRI were performed on a subgroup of patients. The study follows a Simon 2 stage design and we present the results of the initial stage(n=34). Results: Overall 30 (88%) of patients obtained clinical benefit (by RECIST) prior to surgery. The partial response rate of the primary tumor was 21% by RECIST. No patients became inoperable due to local progression of disease. A nephrectomy was performed in 25 (74%) of patients. The reasons for not having surgery were patient choice (n=5) and progression of disease (n=4). Delayed wound healing, a post operative bleed and a post operative death occurred in 1patient each (4%). The median blood loss, hospital stay and surgical time were 350mls, 7 days and 180mins respectively. FDG-PET and DCE MRI responses were reported. Conclusions: This interim analysis suggest nephrectomy after upfront pazopanib can be performed safely in mRCC and obtains control of disease in the majority of patients.
Cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC): Interim safety and quality-of-life (QOL) data from the U.K. early access program (NCT01254279).
Authors: Bahl Amit , Masson Susan , Malik Zafar , Birtle Alison J , Sundar Santhanam , Jones Robert J , James Nicholas David , Mason Malcolm David , Kumar Satish , Bottomley David , Lydon Anna , Chowdhury Simon , Wylie James , De Bono Johann Sebastian 
Published: February 2017

44 Background: Cabazitaxel, a tubulin-binding taxane, improved survival in mCRPC in the TROPIC trial. Notable toxicities were neutropenia and diarrhoea. We report interim safety and QOL data from a single arm multicentre open label study providing early access to cabazitaxel in the UK. Methods: Patients recruited from 12 centres received cabazitaxel 25mg/m2 intravenously every 3 weeks and prednisolone 10mg daily. Safety assessments were performed before each cycle. Patients completed the EQ-5D questionnaire and health state visual analogue scale (VAS) at baseline and at alternate cycles. Patients recruited before March 31st 2011 are included in the safety analysis. QOL data collected before July 31st 2011 at baseline (n=62), cycle 2 (n=50) and cycle 4 (n=26) are included. Results: Median age was 68 years; 24% were aged over 75 years. 93% had bone metastases. 50% had experienced disease progression during or within 3 months of docetaxel and the remaining 50% within 3-6 months. A median of 3 cycles of cabazitaxel were completed with 99% relative dose intensity. 83% continued cabazitaxel at the time of safety analysis. 7 patients stopped before completing the full course, 5 of these were due to disease progression. One treatment related death occurred within 30 days of the last cabazitaxel infusion (2.4%). 85% of patients received granulocyte-colony stimulating factor prophylaxis from cycle 1. The proportion of patients reporting no pain or discomfort increased between baseline, cycle 2 and cycle 4 (22.6% to 38% to 50%). Anxiety and depression, mobility and self-care scores from EQ-5D were stable. Median VAS health state increased from baseline (75%) to cycle 4 (79%). Conclusions: Improvements in pain control and health states were reported during early stages of cabazitaxel treatment. Other EQ-5D QOL measures were stable. Severe toxicity was rare. Results will be updated from final analysis in late 2011. [Table: see text]
A phase I QTc study of tivozanib in patients with advanced solid tumors.
Authors: Chadha Manpreet Kaur , Infante Jeffrey R. , Cotreau Monette M. , Jacobson Lindsey , Strahs Andrew Louis , Slichenmyer William , Vargo Dennis , Moore Kathleen N. 
Published: February 2017

445 Background: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Preclinical and retrospective electrocardiogram (ECG) analyses suggest no effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the effect of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20-30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessing clinical laboratory tests, physical examinations, vital signs, and recording of adverse events. Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received ≥ 1 dose of tivozanib were evaluable. Preliminary data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented. Conclusions: Preliminary data suggest that tivozanib 1.5 mg/d over a 21-day period does not cause clinically significant QT/QTc prolongation over baseline, suggesting that its safety and PK profile is similar to that observed in previous studies, including ECG evaluation in a monkey telemetry study.
Efficacy and safety of sequential usage of everolimus in Asian patients with metastatic renal cell carcinoma (mRCC): Cooperative results from Osaka Urologic Oncology Group (OUOG).
Authors: Inamoto Teruo , Uemura Hirotsugu , Nonomura Norio , Nakatani Tatsuya , Matsuda Tadashi , Azuma Haruhito 
Published: February 2017

456 Background: Data on the efficacy and safety of everolimus (EVE) in Japanese patients (pts) are lacking because only 15 Japanese pts enrolled in the EVE group from the RECORD-1 global study. Efficacy and safety of sequential usage of EVE after other targeted therapies or immunotherapy in Japanese pts were examined. Methods: We retrospectively reviewed the records of consecutive pts with mRCC (median age 65, M:F 78/22, 78% clear cell) who received salvage EVE at 39 tertiary institutions in Osaka Urologic Oncology Group (OUOG) between 10/09-8/11. Data on safety (NCI-CTC) and efficacy (response assessment, progression-free survival [PFS]) were analyzed. 31% of pts had progressed on sunitinib, 22% on sorafenib, 1% on axitinib, 41% on sequential (sunitinib:sorafenib), and 5% no prior therapy. 50% received previous cytokines in addition to targeted therapies. Results: 172 pts with mRCC were enrolled. Median PFS was 2.8 months. Median time to last follow-up was 3.5 months (range 0.4-15.2 months). 44% continued EVE at last follow-up. 4.7% had partial response (PR) and 51.7% had stable disease (SD) by treating physician assessment. Of 112 pts who discontinued EVE, 46% discontinued EVE due to progressive disease (PD) (median time to PD 3.0 months, range 0.1-15.8 months), 43% discontinued due to adverse events (AEs) (median time to PD 1.5 months, range 0.1-12.6 months), and 0.6% died of PD on treatment. There were no treatment related deaths. The incidence of AEs of all grades was 88.4%. Major AEs were stomatitis (44.2%), thrombocytopenia (30.8%), and interstitial lung diseases (ILD) (22.1%). The incidence of AEs (Grades 3-4) was 52.9%. Serious AEs were anemia (7.6%), ILD (5.8%), and hyperglycemia (4.7%). Time to onset for these AEs was less than one month, showing marked contrast to that of ILD which ranged over several months. Conclusions: EVE demonstrated clinically relevant activity in Japanese patients with mRCC following PD with other targeted therapies or immunotherapy. Patients prone to serious AEs should be carefully observed for the occurrence of ILD throughout the treatment period.
Translocation renal cell carcinomas: An evolving entity.
Authors: Bambury Richard Martin , Brady Claire , McCarthy Aoife , Fleming Stewart , Mayer Nicholas J. , Power Derek Gerard 
Published: February 2017

472 Background: Translocation renal cell carcinomas (RCCs) are a novel, rare and distinct clinicopathological entity. The term refers to RCCs with overexpression of transcription factor E3 (TFE3) due to translocation involving the Xp11 locus or less commonly with overexpression of transcription factor EB (TFEB) due to a t(6:11) translocation. In children it is estimated that these tumours account for 40% of RCCs but in adults this proportion is estimated to be 1-4%. As these neoplasms are only recently recognised, outcome data are premature. We report 2 cases of translocation RCC in an Irish regional cancer centre and describe clinicopathological characteristics and early outcome. Methods: In our recent practice, 2 renal cell carcinomas were suspected to be translocation tumours based on morphology and immunohistochemical features (RCC+/CK7-/EMA-). Using immunohistochemistry we tested for expression of TFE3 and TFEB. Results: Both tumours were translocation RCCs. The first case was a 74 year old lady who presented with right upper quadrant pain and had a 9cm right renal mass with no metastatic disease on CT imaging. Radical nephrectomy was performed and histology revealed a pT3aN2, Fuhrman grade 4 renal cell carcinoma with papillary architecture and eosinophillic hyaline nodules within many of the papillae. Staining for TFE3 showed focal nuclear positivity consistent with an Xp11 translocation RCC. She remains disease free 6 months post surgery. The second case was a 46 year old man with an incidental finding of a right renal mass on ultrasound abdomen performed after a new diagnosis of haemochromatosis. Staging CT imaging revealed no metastatic disease and he underwent laparoscopic nephrectomy. Histology revealed a pT1aNx, Fuhrman grade 3 renal cell carcinoma with predominantly alveolar architecture and focal papillary and microcystic areas. Staining for TFEB was positive consistent with a t6:11 translocation RCC. He remains disease free 5 months post surgery. Conclusions: We report 2 new cases of this rare subset of RCC. The therapeutic implications for patients with these mutations are as yet unclear. We plan to update with ongoing follow-up and identification of new cases to determine the clinical behaviour of these rare cancers in the Irish setting.
Comparison of ERG oncoprotein expression among matched cohorts of African American and Caucasian American patients with prostate cancer.
Authors: Pfister David J. K. P. , Rosen Philip , Young Denis , Petrovics Gyorgy , Chen Youngmei , Dobi Albert , McLeod David , Heidenreich Axel , Srivastava Shiv , Sesterhenn Isabell 
Published: February 2017

52 Background: The ERG proto-oncogene is frequently overexpressed in Prostate Cancer (CaP) following genomic fusion, which places ERG under the control of the TMPRSS2 promoter. Recent studies show higher frequency of ERG rearrangement or ERG oncoprotein expression in CaP of Caucasian-American (CA) patients compared to African-American (AA) patients. The frequency of the ERG oncoprotein expression in prostate tumors of matched CA and AA CaP patients is evaluated to better understand the biological basis for differences in prostate cancer between the two populations. Methods: Ninety-one AA CaP patients were matched for age, Gleason sum and pathologic stage to 91 CA CaP patients. All underwent radical prostatectomy between 1993 and 2010. Whole mount prostate specimens were used for immunohistochemical detection of the ERG oncoprotein by an ERG monoclonal antibody (clone 9FY). Individual foci of tumors were noted as either positive or negative. ERG staining data was linked to dinico-pathologic data. Results: Fifty-nine of 91 CA patients (64.8%) and 41191 (45.0%) AA patients had at least one focus of tumor positive for ERG in a whole-mount prostate section (p = 0.0073). The index tumor was positive for ERG expression in 55/89 (61.8%) CA and 24/85 (28.2%) of AA patients (p <0.001). Seventy-seven of 183 (42.1%) individual foci were positive in CA versus 511196 in AA (26.0%; P <0.001). There was a trend towards increased biochemical recurrence in CA patients with ERG positive index tumors. Conclusions: The prevalence of ERG oncoprotein expression is significantly higher among Caucasian- American patients. Differences in pattern of ERG positivity of index and non-index tumors between Caucasian-American and African-American prostate cancer patients and trends towards decreased biochemical recurrence-free survival suggest a more accelerated growth of ERG-positive tumors in Caucasian-American patients. Differences in ERG expression have the potential to delineate biological distinctions of CaP in these patient populations.