bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in circulating tumor cells (CTC) and markers of inflammation after sipuleucel-T treatment.
Authors: Hepgur Mehmet , Dorff Tanya B. , Cai Jie , Pinski Jacek K. , Reed Mary , Luther Michael , Chan Betty , Quinn David I. 
Published: February 2017

40 Background: Sipuleucel-T (SipT) prolongs survival of men with metastatic castrate-resistant prostate cancer (CRPC). We prospectively collected CTC, LDH, and inflammatory markers as part of an audit to investigate changes after SipT treatment compared to baseline. Methods: Men with CRPC had blood drawn routinely before and after SipT treatment. CTC were run using Veridex assay. LDH, C-reactive protein (CRP) and β2-microglobulin (β2m) were measured in a reference lab. Wilcoxon Signed Rank Test was used to compare pre- and post-treatment (median 3.5 weeks after final infusion) levels. Results: 61 men received SipT at USC from June 2010 to July 2012 and were included in the analysis. Median pre-SipT PSA level was 24.9 and 47% had Gleason 8-9; 20% had received chemotherapy. 18 men had detectable CTCs pre SipT (range 1-170). CTC count declined in 7 men, increased in 6 men, and stayed stable in 2 men (3 inevaluable); in 3 cases the change crossed men over from unfavorable ( >5) to favorable count. PSA declines were noted in 10 men (16.4%) ranging from -0.5% to 99%. Change in CTC and PSA was discordant in 4 cases of 13. When CTC stayed stable PSA increased in 5 and decreased in 5 cases. Median CRP was 0.5 pre and 0.23 post SipT (p=0.025) and β2m was 1.74 pre and 2.01 post (p=0.02). Increased CRP was correlated with decreased CTC (r=0.7, p=0.003 Spearman test) but β2m changes were not (r=0.45, p=0.08 Spearman) and there was no correlation between changes in the inflammation markers and PSA decline. LDH did not change significantly. The relationship between infusion reaction, eosinophilia and inflammatory markers will be presented. Conclusions: We found that CTC counts can decline after SipT treatment, including conversion from unfavorable to favorable range, and can change independently of PSA. Correlation of CTCs with outcomes in a prospective study is warranted to explore this as a potential biomarker. [Table: see text]
Plasma MN (carbonic anhydrase IX) and outcome in sunitinib-treated metastatic renal cell cancer.
Authors: Lamparella Nicholas E. , Ali Suhail M. , Leitzel Kim , Carney Walter P. , Lipton Allan 
Published: February 2017

405 Background: The transmembrane protein MN (carbonic anhydrase IX)(CAIX) catalyzes the hydration of carbon dioxide to carbonic acid and decreases pH. In cancer, up-regulation of CAIX gene expression occurs under hypoxic conditions within tumors. Significant levels of CAIX protein have been detected in a variety of cancers including kidney, cervix, lung, bladder, colon, breast, liver, gall bladder, and pancreas. Methods: Pretreatment plasma CAIX and VEGF-A levels were determined from 52 metastatic renal cell cancer patients enrolled in a phase III first-line trial of sunitinib vs. interferon alpha (IF). The CAIX and VEGF-A ELISAs (WILEX/Oncogene Science, Cambridge MA) were used for determination of plasma biomarker levels. 51 of 52 patients had an MSKCC score of 0 or 1. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with both continuous and dichotomous (median) plasma CAIX and VEGF levels. Results: Pretreatment plasma CAIX levels averaged 371 pg/ml, with a median of 194 pg/ml and 25th and 75th percentile values of 125 and 298 pg/ml, respectively. In the whole population, higher plasma CAIX was significant on a continuous basis for predicting reduced PFS (p < 0.007) and shorter OS (p <0.0001). When analyzed using the median as cutpoint, the elevated plasma CAIX cohort trended for reduced PFS (p = 0. 13) and had a significantly reduced OS (HR 2.77, p = 0.026) (median 94 vs. 115 weeks). In univariate analysis plasma VEGF-A did not predict for PFS or OS when analyzed as a continuous or dichotomous variable. In multivariate analysis for PFS (including treatment arm, CAIX, and MSKCC score), treatment with sunitinib (vs. IF) (p = 0.006) and lower plasma CAIX (p = 0.04) resulted in a significantly longer PFS. In multivariate analysis for OS, again treatment with sunitinib (vs. IF) (p=0.037), and lower plasma CAIX (p < 0.0001) resulted in a significantly longer OS. Conclusions: Elevated pretreatment plasma CAIX predicted for reduced PFS and overall survival in metastatic renal cancer patients. In addition, sunitinib was superior to interferon, regardless of plasma CAIX status.
Discovery and validation of the nuclear export protein CRM1 (XPO1) as a new target for the treatment of renal cell carcinoma (RCC).
Authors: Wettersten Hiromi Inoue , Kauffman Michael , Shacham Sharon , Landesman Yosef , Yang Joy , Evans Christopher , Weiss Robert 
Published: February 2017

411 Background: The currently available targeted therapies for RCC have had limited success, so it is imperative to discover new therapeutic approaches for metastatic RCC. In a search for new such targets, we have identified inhibitors of CRM1 (XPO1, exportin1), the major karyopherin that mediates the export of most tumor suppressor proteins from the nucleus. To expand our initial work on the first generation of CRM1 inhibitors, we now evaluate KPT-330, an orally available Selective Inhibitor of Nuclear Export (SINE), the best tolerated among a series of CRM1 inhibitors that is currently in phase I clinical trials. Methods: The RCC cell lines (Caki-1 and 786-O) and a primary normal human kidney (NHK) cell line were treated with KPT-330, and MTT assays were performed. The cells were subjected to immunofluorescence and immunoblotting for appropriate proteins. Caki-1 xenograft mice were treated with KPT-330 for 15 days, and tumor volume was assessed. Results: KPT-330 selectively attenuated CRM1 levels and caused dose-dependent toxicity (EC50 < 1 µM) through apoptosis in all RCC cells. In untreated RCC cells, p21 was localized in the nucleus, where it likely functions as a cell cycle arrest protein, and in the cytosol, where it functions as an anti-apoptotic protein. However, in NHK cells, p21 was confined to the nucleus. KPT-330 increased p53 and p21 and confined them to the nucleus in both NHK and RCC cells. KPT-330 given orally inhibited RCC growth in xenograft mice (85.3 % inhibition, p < 0.001). Moreover, KPT-330 showed synergism with a Bcl-2 inhibitor ABT-737 in vitro, indicating the potential for combination therapy with a CRM1 inhibitor and Bcl-2 inhibitor. In vivo studies to test the combination of KPT-330 with Bcl-2 inhibitors are ongoing. Conclusions: We introduce a new therapeutic approach for RCC treatment based on the inhibition of the nuclear export of key tumor suppressors. Inhibition of CRM1 causes forced nuclear retention, and thereby activation, of several key p53-pathway proteins, leading to apoptosis in RCC cell lines in vitro and tumor growth inhibition in vivo.
Effect of PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, on proliferation in renal cell carcinoma at nanomolar concentrations and prediction of sensitivity by molecular markers.
Authors: Logan Joshua E. , Mostofizadeh Nikayeh , Desai Amrita J. , Von Euw Erika Maria , Conklin Dylan , Konkatkit Veerauo , Hamidi Habib , Eckardt Mark A. , Anderson Lee , Cheng Hsiao-Wang , Ginther Charles , Taschereau Eileen , Christensen James G. , Belldegrun Arie S. , Slamon Dennis J. , Kabbinavar Fairooz F. 
Published: February 2017

413 Background: Cell cycle dysregulation is prevalent in renal cell carcinoma (RCC). PD-0332991 is an orally active, potent, and selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6, blocking retinoblastoma (Rb) phosphorylation at nanomolar concentrations. Methods: 28 RCC and immortalized kidney cell lines were used to examine the effects of PD-0332991 on proliferation to determine the half maximal inhibitory concentration (IC50). Effects of PD-0332991 on cell-cycle, apoptosis, and Rb phosphorylation were assessed with flow cytometry and western blot analysis for five of the cell lines: RCC-HB and SW 156 (sensitive/malignant), R444 and Hs 891.T (resistant/malignant), and CCD 1103 (resistant/immortalized non-malignant). Molecular markers for response prediction were studied using array CGH and gene expression profiling. Results: Concentration-dependent inhibition of proliferation was identified in response to PD-0332991, with IC50values ranging from 25.0nM up to 700nM; five cell lines were identified as completely resistant at 1000nM. PD-0332991 induced G0/G1 cell cycle arrest, as well as induction of late apoptosis in SW 156, and Rb phosphorylation was blocked in a time-dependent fashion in both sensitive cell lines, while resistant lines were unaffected. Genotype and expression data of CDKN2A and CDKN2B were combined and a consensus was made regarding p16 and p15 status; significant association between loss and sensitivity to PD-0332991 was identified for p16 (p = 0.027). For CCND1, CCNE1, E2F1, Rb, CDK4, and CDK6 no amplifications or homozygous deletions were identified by array CGH; cell lines were then classified as having high or low expression for each of these markers. E2F1 had low expression levels significantly associated with response to PD-0332991 (p = 0.041). Conclusions: PD-0332991 shows anti-proliferative activity in RCC through blockade of the cell cycle. The decreased expression of molecular markers p16 and E2F1 predict for sensitivity to PD-0332991 in RCC.
CpG island hypermethylation of corticotropin-releasing hormone-binding protein in kidney cancer and association with clinicopathological parameters.
Authors: Tezval Hossein , Atschekzei Faranaz , Dubrowinskaja Natalia , Merseburger Axel S. , Peters Inga , Becker Jan , Bedke Jens , Kruck Stephan , Stenzl Arnulf , Kuczyk Markus A. , Serth Juergen 
Published: February 2017

414 Background: Significance of Urocortin (Ucn or UcnI), Ucn2, Ucn3, and their receptors, Corticotropin Releasing Factor Receptor 1 and 2 (CRFR1 and CRFR2), and the binding protein, Corticotropin-Releasing Hormone-Binding Protein (CRHBP) in oncology is growing rapidly. Recently we found that the UCN system may also be a relevant structure in renal cell cancer. Here we investigate whether CRHBP CGI methylation occurs in cc-RCC and whether its methylation is associated with clinicopathological parameters of patients. Methods: Tumoral tissues of 109 patients with renal cell cancer and their corresponding normal tissues have been used. Combined bisulfite restriction analysis (COBRA) for detection of relative degree of CpG island (CGI) methylation and pyrosequencing have been performed. Results: We found an approximately five-fold increase in mean methylation of the CRHBP CGI for tumor tissues (p < 0.00005). Higher DNA methylation of the CRHBP CGI showed a positive correlation with advanced disease as well (p = 0.024). Conclusions: To our knowledge we report for the first time the CGI methylation of CRHBP in clear cell renal cell carcinoma indicating a contribution of epigenetic alteration of CRHBP to RCC tumorigenesis. Moreover, our results suggest CRHBP as a potential molecular marker for assessment of progression and aggressiveness of tumors.
Interstitial lung diseases during treatment with sunitinib or mTOR inhibitors in metastatic renal cell carcinoma.
Authors: Ivanyi Philipp , Fuehner Thomas , Adam Meike , Eichelberg Christian , Herrmann Edwin , Merseburger Axel S. , Grünwald Viktor 
Published: February 2017

420 Background: Targeted therapies are the mainstay for metastatic renal cell carcinoma (mRCC) treatment. Interstitial lung disease (ILD) represents an adverse event (AE) of such therapies while its incidence and management is poorly defined. Here, the experience on ILD with targeted agents in mRCC is reported. Methods: Retrospective analysis of mRCC patients receiving sunitinib, everolimus, or temsirolimus at three German tertiary centers between January 2006 and August 2009 was performed, accessing ILD incidence, management, and outcomes. Results: In total 26 ILD patients were identified out of 306 mRCC patients (8.5%) treated with targeted therapies. Median treatment duration to ILD diagnosis was 3.8 (range 0.98-21.5) months. ILD occurred in 6 of 204 sunitinib treated patients (2.9%), and in 20 of 102 mTOR inhibitor (mTORi) treated patients (19.6%). Cough represents the predominant symptom (69.2%, n=18). Chest CTs revealed 4 patterns: interstitial (n=13), nodular (n=3), ground glass opacities (n=8), or complex patterns (n=2). Pulmonary function tests (PFT) illustrates frequently a restrictive disorder (n=9), often accompanied by a diminished diffusion capacity (n=8). In 53.8% (n=14) a bronchoscopy with broncho-alveolar-lavage (BAL) was performed (lymphocytic cellularity n=6, eosinophilic cellularity n=4). Dose reduction (42.3%, n=11), temporary interruption (46.2%, n=12), or treatment withdrawal (53.8%, n=14) occurred frequently. Nine patients (34.6%) received steroids. Continuation of targeted therapies was maintained in 65.4% (n=17). No patient died from ILD. Conclusions: ILD represents a frequent AE with targeted therapies and also occurs in sunitinib treated patients. For diagnosis of ILD chest CTs are mandatory, whereas PFT and BALs are important subsidiary tools. Clinical relevance of ILD may vary and management of ILD ranges from watch and wait to termination of treatment and steroid pulse therapy. Severe complaints were more frequently associated with eosinophilic BAL, often required an aggressive treatment. However, in most patients, temporary interruption and/or dose reduction with subsequent continuation of targeted therapy remain sufficient to manage ILD.
Incidence and outcome of interstitial lung disease (ILD) with everolimus treatment for metastatic renal cell carcinoma.
Authors: Hongo Fumiya , Oishi Masakatsu , Ueda Takashi , Kimura Yasunori , Nakamura Terukazu , Naya Yoshio , Mikami Kazuya , Miki Tsuneharu 
Published: February 2017

427 Background: Interstitial lung disease (ILD) is known as one of the adverse events during treatment with everolimus for metastatic renal cell carcinoma (mRCC). Methods: We retrospectively assessed the incidence and outcome of ILD in mRCC patients treated with everolimus. From April 2010 to August 2012, 25 cases were treated with everolimus after failure of one or two TKIs in our institute. All adverse events were graded in accordance with NCI CTCAE, version 3.0. Results: A total of 25 patients received treatment with everolimus. They included 18 male and 7 female patients ranging in age from 21 to 84 years (median 62). According to MSKCC risk criteria, 6 cases were at favorable risk, 16 cases were at intermediate risk, and 3 cases were at poor risk. Median treatment term was 4 months (range 2-17 months). SD was in 19 cases and PD was in 6 cases. Progression free survival was 3.5 months and overall survival was 12 months. ILD was found in 7 cases (28%). 1 was G1, 5 were G2 and 1 was G3. Corticosteroid therapy was initiated in 3 cases. In 5 of 7 ILD cases, everolimus was re-challenged. In our series, patients with ILD showed significantly better progression free survival than those without ILD (PFS was 8 months vs. 3 months. Log-rank, p < 0.001). There were no significant different between the 2 groups in over all survival (12 months in patients with ILD vs. 10 months in patients without ILD. Log-rank, NS). Conclusions: Everolimus appears to be effective and well-tolerated in our institute. Re-challenge of everolimus was feasible after improving of everolimus-induced ILD in cases of grade 1-2.
Immune cell repertoire in patients with indolent metastatic renal cell carcinoma.
Authors: Zhu Hui , Rayman Pat A. , Elson Paul , Rapp Sarah , Garcia Jorge A. , Dreicer Robert , Gilligan Timothy D. , Shepard Dale Randall , Finke James , Rini Brian I. 
Published: February 2017

429 Background: Immune dysfunction is well documented in renal cell carcinoma (RCC) patients and likely influences tumor progression. An ongoing prospective trial of observation in metastatic RCC patients prior to systemic therapy is investigating circulating immune cell populations. Methods: Asymptomatic patients with low volume metastatic disease are enrolled and followed until starting initial systemic treatment. Peripheral blood specimens are collected at the time of enrollment and again at the time of initiating therapy. The immune parameters measured include CD3+ and CD4+ INF-γ producing T cells (INF-γ+ T), CD4+CD25+FoxP3+ regulatory T-cells (Treg), and CD33+HLADr-CD15+CD14- neutrophilicmyeloid-derived suppressor cells (N-MDSC). Similar immune parameters were recorded for treatment-naïve patients prior to immediate systemic therapy and healthy volunteers on separate IRB-approved protocols. Results: 25 patients are enrolled in the study, of whom 14 started systemic therapy and had immune function analyzed for this report. Patient characteristics included 100% male, median age 74. 13 patients were favorable or intermediate risk by both MSKCC and Heng prognostic criteria; one patient was poor-risk. The median observation period was 13.9 months. The median tumor burden at the time of enrollment was 3.6 cm, which increased 38% during the observation period. As shown in the table below, the observation group had lower levels of Tregand N-MDSC, and higher levels of INF-γ+ T compared to the treatment group. In contrast, the observation group’s INF-γ+ T was similar to that of controls although N-MDSC was elevated. Conclusions: Metastatic RCC patients with indolent disease have low levels of Tregand N-MDSC, and a relatively preserved immune cell repertoire compared to patients requiring immediate therapy. [Table: see text]
The molecular relationship among concurrent prostate cancer foci.
Authors: VanderWeele David James , Taxy Jerome B. , Stadler Walter Michael , White Kevin P. 
Published: February 2017

43 Background: Prostate cancer management is influenced by how one views prostate cancer progression and how one calculates the risk of prostate cancer metastases and death. Currently this is based largely on histologic appearance, or Gleason score. Cancers with a Gleason score of 6 exhibit indolent behavior and are often considered low risk. NCCN guidelines endorse surveillance for many of these tumors. Malignancies with a Gleason score of 8-10 exhibit aggressive behavior and are considered high risk. Methods: Prostate cancer is usually multifocal, and these concurrent foci are often histologically distinct. In this study the molecular relationship between a Gleason 6 focus and a concurrent Gleason 8 or higher focus was determined for four subjects. In two subjects a lymph node metastasis was also examined. Laser capture microdissection was used to isolate these multiple matched foci, and somatic mutations were identified using exome sequencing. Results: We obtained an average of 40-fold median coverage of the exome, with an average high confidence mutation rate of 0.64/Mb, excluding nonsynonymous mutations. Seventy of 80 (0.875) high confidence somatic mutations in low grade disease were private to the low grade foci. For the cases for which a metastatic focus was available, 17 of 79 (0.215) high confidence somatic mutations in the high grade focus were private. Eight of the 79 (0.101) were shared with low grade foci, and 62 (0.785) were shared with metastatic foci. Conclusions: The pattern of shared versus private mutations was consistent with early divergence between Gleason 6 and Gleason 8 or 9 disease, and late divergence between Gleason 8 disease and lymph node metastases. These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores.
Progression-free survival (PFS) and overall survival (OS) in patients receiving three targeted therapies (TTs) for metastatic renal cell carcinoma (mRCC).
Authors: Verzoni Elena , Iacovelli Roberto , Rizzo Mimma , Felici Alessandra , Cascinu Stefano , Di Lorenzo Giuseppe , Cerbone Linda , Ortega Cinzia , Masini Cristina , Giganti Maria Olga , Lorusso Vito , Messina Caterina , Atzori Francesco , De Vincenzo Fabio , Sacco Cosimo , Boccardo Francesco , Valduga Francesco , Massari Francesco , Tassi Renato , Procopio Giuseppe 
Published: February 2017

431 Background: In recent years, TTs have improved the prognosis of mRCC patients (pts). Despite a non-negligible number of pts received 3 TTs in clinical practice, no TTs have been evaluated as third-line. Aim of this study is to investigate the clinical outcome in pts who received 3 TTs. Methods: Pts with clear-cell mRCC who received 3 TTs were included. A questionnaire was sent to main Italian centers involved in the treatment of mRCC. Demographic data, history of RCC, type and length of first-, second- and third-line were collected; MSKCC risk class was calculated before starting the first-line. Sequences were evaluated by class (TKI-TKI-mTOR vs. TKI-mTOR-TKI) or by drug (Su-So-Ev vs. Su-Ev-So). Median PFS, OS and Time to Strategy Failure (TTSF: from start of first- to end of thrid-line) were estimated with the Kaplan-Meyer method with 95% CI and curves were compared with log-rank test. Cox model was used to explore predictors of TTSF and OS. The study had the ethical approval. Results: 2,065 pts were screened and 281 pts (13%) were treated with 3 TTs. No differences were found between TKI-TKI-mTOR and TKI-mTOR-TKI groups. The TTSF was 36.5 (30.5–42.6) mos vs. 29.3 (23.6–34.9) mos (p=0.059), and the OS was 50.7 (40.6–60.8) vs. 37.8 (34.2–41.5) mos (p=0.004), for TKI-TKI-mTOR and and TKI-mTOR-TKI, respectively. TTSF for Su-So-Ev was 32.1 vs. 30.4 mos for Su-Ev-So (p=0.006). The median OS was not reached in the group treated with Su-So-Ev compared to 35.6 (95%CI, 31.6–39.6) mos in the group treated with Su-Ev-So (p<0.001). The univariate and multivariable Cox analyses for TTSF and OS showed that the only predictive factor is the primary resistance to 1st line (HR: 3.15, 95%CI, 1.98-4.99; p<0.001). The Prognostic factors are the initial MSKCC group (HR: 2.07, 95% CI, 1.41 -3.05; p<0.001), the sequence of therapy (HR: 2.59, 95% CI, 1.59-4.22; p<0.001) and the primary resistance to first line (HR: 2.20, 95% CI, 1.16-4.11; p<0.001). Conclusions: We report as the sequential treatment with two antiangiogenic inhibitors followed by an mTOR inhibitor could increase survival and the control disease in metastatic renal cell carcinoma.