bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of SETD2, a histone methyltransferase, in advanced clear cell renal cell carcinoma (ccRCC).
Authors: Ho Thai Huu , Monzon Federico A. , Hoang Anh , Tamboli Pheroze , Furge Kyle A. , Dykema Karl , Petillo David , Teh Bin Tean , Tannir Nizar M. , Hung Mien-Chie , Jonasch Eric 
Published: February 2017

368 Background: Although the von Hippel-Lindau (VHL) tumor suppressor gene is mutated in 60% of ccRCC, deletion of VHL in mice is insufficient for tumorigenesis. Sequencing of ccRCC tumors identified loss of function mutations in SETD2, a histone H3 lysine 36 (H3K36) trimethyltransferase. However it is unclear whether histone modifications are misregulated in RCC. We hypothesize that loss of SETD2 methyltransferase activity decreases H3K36 trimethylation (H3K36Me3) in ccRCC, and contributes to the cancer phenotype. Methods: To determine if loss of SETD2 protein expression alters H3K36Me3, SETD2 siRNA oligonucleotides were transfected into HEK293 (human embryonic kidney) cells and H3K36Me3 was analyzed by Western blot. To establish frequency of SETD2 loss of heterozygosity (LOH), genomic DNA was isolated from 51 VHL deficient ccRCC specimens and analyzed with Affymetrix GeneChip Mapping 250K Nsp single-nucleotide polymorphism (SNP) arrays. To evaluate alterations of histone modifications in metastatic advanced ccRCC, H3K36Me3 immunohistochemical (IHC) staining was quantitated on tissue microarrays (TMAs) representing 28 paired ccRCC specimens with unaffected kidney parenchyma controls and 40 metastases. Results: SETD2 siRNA decreases H3K36Me3 (>50%) compared to scrambled controls. Using SNP arrays, LOH at chromosome 3p (location of VHL and SETD2 genes) was detected in >90% of the tested ccRCC tumors. IHC reveals a 27.4% and 52.0% decrease in H3K36Me3 positive nuclei in primary ccRCC and metastases, respectively, when compared to matched adjacent unaffected kidney tissue (P value < 0.0001). Conclusions: SETD2 siRNA decreases H3K36Me3 indicating that SETD2 is a non-redundant H3K36 methyltransferase. LOH of VHL and SETD2 occurs in >90% of tested ccRCC tumors. H3K36Me3 is decreased in primary ccRCC and even more in metastases, suggesting that SETD2 methyltransferase activity is progressively misregulated in RCC. Loss of SETD2 methyltransferase activity may cooperate with VHL silencing to promote tumorigenesis. Future studies will focus on how SETD2 contributes to tumorigenesis and on determining the prognostic and predictive impact of SETD2 phenotypic changes in patients with ccRCC.
Metabolic evaluation of sporadic papillary kidney cancer.
Authors: Shuch Brian , Ricketts Christopher , Sourbier Carole , Tsutsumi Shinji , Zhang Xiu-ying , Belldegrun Arie S. , Wood Christopher G. , Linehan W. Marston , Neckers Len 
Published: February 2017

377 Background: Papillary kidney cancer, which occurs in 15% of patients with kidney cancer, can be aggressive and there is currently no effective form of therapy for this disease. To evaluate the metabolic characteristics of sporadic papillary kidney cancer, we have evaluated metabolic parameters of several papillary kidney cancer cell lines and available gene expression profiles. Methods: Established cell lines derived from patients with sporadic papillary kidney cancer (LABAZ, MDACC-55, HRC-86T2) and from a hereditary form of fumarate hydratase-deficient kidney cancer (UOK262) were evaluated. All sporadic lines were initially sequenced for fumarate hydratase (FH). All cell lines were metabolically profiled using the Seahorse Extracellular Flux Analyzer and further evaluated for reactive oxygen species (ROS), mitochondrial membrane potential, and glucose dependence. Finally gene expression profiles of publically available datasets of papillary and HLRCC tumors were downloaded, normalized, and analyzed. Results: Sporadic lines had no alterations in FH and metabolic analysis demonstrated normal oxygen consumption and minimal lactate production, in contrast to highly glycolytic UOK262. Also unlike UOK262, the sporadic papillary kidney cancer lines were not sensitive to glucose withdrawal, had low levels of ROS, and had normal mitochondria membrane potential. Principal component analysis (PCA) demonstrated that HLRCC tumor specimens are very different from sporadic papillary tumors at the molecular level. Conclusions: Our study of established sporadic papillary RCC and fumarate hydratase-deficient HLRCC cell line together with analysis of available gene expression profiles demonstrates that these sporadic papillary kidney cancer cell lines appear to have a distinct metabolic profile from those in the fumarate hydratase deficient kidney cancer cell line. Understanding the metabolic basis of papillary kidney cancer could provide the foundation for the development of targeted approaches to therapy for patients with this disease.
Effect of bisphosphonates (Bis) combined with sunitinib (Su) on the response rate (RR), progression-free survival (PFS), and overall survival (OS) of patients (pts) with bone metastases (mets) from renal cell carcinoma (RCC).
Authors: Keizman Daniel , Ish-Shalom Maya , Taksey Jason David , Pili Roberto , Hammers Hans J. , Eisenberger Mario A. , Boursi Ben , Berger Raanan , Maimon Natalie , Gottfried Maya , Hayat Henry , Peer Avivit , Kovel Svetlana , Sella Avishay , Carducci Michael Anthony 
Published: February 2017

379 Background: Bis are used to prevent skeletal events of bone mets, and may exhibit anti tumor effects. We aimed to evaluate whether Bis can bring a RR, PFS, and OS benefit to pts with bone mets from RCC that are treated with Su. Methods: We performed a multicentre retrospective study of pts with bone mets from RCC who were treated with Su. Pts were divided into Bis users (group 1) and nonusers (group 2). The effect of Bis on RR, PFS and OS, was tested with adjustment for known prognostic factors using a chisquare test from contingency table and partial likelihood test from Cox regression model. Results: Between 2004–2011, 209 pts with metastatic RCC were treated with Su. 76 pts had bone mets, 35 group 1 and 41 group 2. The groups were balanced regarding the following known prognostic factors: past nephrectomy, clear cell/non clear cell histology, time from initial diagnosis to sunitinib treatment (tx), the presence of > 2 mets sites, the presence of lung/liver mets, ECOG performance status, anemia, calcium level >10 mg/dL, elevated alkaline phosphatase, platelets count, pre-tx neutrophil to lymphocyte ratio (NLR) >3, sunitinib induced HTN, and the use of angiotensin system inhibitors. They were also balanced with regard to past cytokines/targeted tx, and mean sunitinib dose/cycle. Objective response was partial response/stable disease 86% (n=30) vs 71% (n=29), and progressive disease 14% (n=5) vs 29% (n=12) (p=0.125, OR 2.48) in group 1 vs 2 respectively. Median PFS was 15 vs 5 months (HR 2.6, p < 0.0001), and median OS 21 vs 13 months (HR 2.1, p=0.029), in favor of group 1. In multivariate analysis of the entire pt cohort (n=76), factors associated with PFS were Bis use (HR 2.2, p=0.035) and pre-tx NLR >3 (HR 0.38, p=0.009). Factors associated with OS were Bis use (HR 2.8, p=0.008), elevated alkaline phosphatase level (HR 0.287, p=0.0003), and Su induced HTN (HR 5.57, p < 0.0001). Conclusions: Bis may improve the outcome of Su tx in RCC with bone mets. Whether this is generalizable to other TKIs is not known. This should be investigated prospectively, and if validated applied in clinical practice and clinical trials.
Population-based analysis of cancer control of partial nephrectomy for high-risk localized renal cell carcinoma.
Authors: O'Malley Rebecca Leigh , Hayn Matthew H. , Wilding Greg , Schwaab Thomas 
Published: February 2017

385 Background: Partial nephrectomy (PN) has reported equivalent oncologic outcomes with superior renal function outcomes when compared to radical nephrectomy (RN) for treatment of localized renal cell carcinoma (RCC). Whether PN provides adequate cancer control in high risk disease is unclear. To clarify, survival outcomes were compared between those who underwent RN and PN for high risk RCC. Methods: Using the Surveillance, Epidemiology, and End Results database patients with RCC who underwent PN or RN for a localized tumor ≤ 7cm were identified. Cancer-specific (CSS) and overall survival (OS) were compared between those with high risk disease (defined as poorly or undifferentiated grade and/or pathologic stage T3) who underwent PN or RN. Results: Of 51,183 patients with localized RCC ≤ 7cm, 24.9% had high risk disease, 85.2% and 14.8% of which underwent RN and PN, respectively. Five-year CSS was superior in the PN group vs. the RN group (93.3% vs. 86.0%, p<0.001). On multivariable analysis undergoing RN was no longer predictive of CSS (HR 1.23, p=0.08). Similarly, 5-year OS was superior in the PN versus RN group (79.5% vs. 70.1%, p<0.001). RN remained independently associated with poor OS on multivariable analysis (HR 1.16, p=0.031). Propensity analysis accounting for factors affecting selection for type of nephrectomy produced similar results. RN did not influence CSS but portended a 20% increased risk of death from all causes (p=0.008). Conclusions: In patients with high risk RCC, partial nephrectomy is associated with improved OS and does not compromise cancer control as compared to radical nephrectomy.
Development of a molecular profiling assay for circulating tumor cells (CTCs) utilizing automated multiplexed in situ hybridization for metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Nagy Dea , Crespo Mateus , Attard Gerhardt , Miranda Susana , Garsha Karl , Sathyanarayana Ubaradka G. , Yun Steve , Otter Michael , Miller Phillip , Pestano Gary , De Bono Johann Sebastian , Dittamore Ryan 
Published: February 2017

39 Background: ERG gene rearrangements lead to overexpression of the ERG oncogene in 50% of localized and metastatic prostate cancers. Recent studies have indicated that this gene fusion correlates with androgen sensitivity in prostate cancer patients and an association with increased DNA Repair activity (PARP1). The PTEN tumor suppressor has also been shown to regulate the AKT pathway, and related to increased PARP1 activity. We hypothesized that future PARP1 inhibitors and other targeted therapies for mCRPC will likely require the development of a companion diagnostic assay for measuring ERG rearrangement and PTEN deletion status in CTCs. Methods: We isolated CTCs utilizing the CellSearch system from mCRPC patients for enumeration. Following enumeration, the cells were transferred to glass slides and interrogated utilizing the automated Benchmark staining platform with multiplexed Quantum Dot FISH inclusive of probes for 5’ERG, 3’ERG, PTEN, and Cen 10. FISH signals were visualized utilizing spectral imaging. Results: Successful transfer of the CTCs from the CellSearch to a glass slide were achieved In model cell line systems, in cultured cells (LnCaP and VCaP) either directly or after spiking to PBL and five out of 6 times we were able to successfully demonstrate simultaneous single copy 5’ and 3’ ERG and PTEN/Cen 10 labeled probes. Studies are in progress to extend the clinical utility of this assay to isolated CTC from cases with metastatic prostate cancer. Conclusions: CTCs are likely to be utilized clinically for monitoring disease progression mCRPC patients as measures for therapeutic efficacy. As more therapeutics are approved for use in mCRPC patients, the ability for oncologists to molecularly characterize the type of CTCs driving tumor burden is likely to play a significant role in optimizing patient management by determining the type and the sequence of future targeted therapies. We have for the first time demonstrated a platform to molecularly characterize patient CTCs on an automated platform that is amenable to standard clinical use.
Prostate-specific antigen testing among primary care physicians and urologists: Patterns of care and impact of professional society guidelines.
Authors: Prasad Sandip M. , Alexander G. Caleb , Eggener Scott E. 
Published: February 2017

40 Background: During the past decade, the incidence of prostate cancer in the United States has declined. We hypothesized this was related to lower rates of prostate-specific antigen (PSA) testing and sought to evaluate PSA testing rates nationally. Methods: Using the National Ambulatory Medical Care Survey, a nationally representative sample of outpatient visits in the United States, we analyzed rates of PSA testing in men age 40 years or older who visited PCPs or urologists from 1997 to 2008. Results: An estimated 26.6 million (95% CI: 24.8-28.4 million) PSA tests were ordered during 94.5 million (95% CI: 90.9-98.1 million) office visits to urologists and 95 million (95% CI: 87.5-102.8 million) tests were ordered during 1.17 billion (95% CI: 1.15-1.18 billion) visits to PCPs, with an annual increase of 3.4% and 6.0%, respectively (P=0.055 and P<0.001 for trend). After adjusting for year, race, ethnicity, region, insurance and provider type, testing by PCPs was more likely among older men and highest among men aged 60 to 69 years (reference: 40-49 years; OR 2.32, 95% CI: 1.88-2.85). Compared to men without a chronic medical condition, those with one chronic condition had greater odds of receiving a PSA test (OR 1.28, 95% CI: 1.08-1.52). Conclusions: Prostate cancer incidence has declined over the past decade despite increasing rates of office-based PSA testing by PCPs and urologists during the period. Increasing rates of PSA testing merit scrutiny, especially in men with limited life expectancies who are unlikely to benefit from screening.
Everolimus (E) and temsirolimus (T) associated pneumonitis (P) in patients with metastatic renal cell cancer (mRCC): A single-center experience.
Authors: Cauley Diana H. , Atkinson Bradley J. , Ng Chaan S. , Wang Xuemei , Xiao Lianchun , Corn Paul G. , Jonasch Eric , Tannir Nizar M. 
Published: February 2017

401 Background: P is a known adverse effect (AE) of mammalian target-of-rapamycin inhibitors, with a literature reported incidence of 25-45%. The goal of this review was to characterize the incidence, timing, management, and overall survival (OS) of pts treated at our center. Methods: Retrospective review of 332 patients (pts) with complete, evaluable records, who received E and/or T between 6/1/2007 and 10/1/2010. Clinical correlation was made in conjunction with serial radiologic imaging studies. Results: P occurred in 25.2 of E and 8.1 % of T pts. 10.7 of E and 11.1 % of T pts reported no symptoms (sx). 60.7 and 72.2 % reported cough, 67.9 and 61.1 % dyspnea, 17.9 and 5.6 % fever, and 67.9 and 88.9 % fatigue, with E and T, respectively. The median # of sx/pt was 2 and 3; 42.9 and 50 % received steroids, 35.7 and 22.2 % received antibiotics, 21.4 and 27.8 % had a pulmonary consult, and 10.7 and 16.7 % received oxygen, with E and T, respectively. Providers discontinued tx in 75 and 38.9%, continued tx in 17.9 and 27.8%, continued at reduced dose in 0 and 5.6%, held and later dose reduced in 7.1 and 16.7%, and held then resumed at same dose in 0 and 11.1% of pts, with E and T, respectively. The median NCI-CTC P grade was 2 (range 1–3) in both groups. No patients died from P. Conclusions: A higher incidence of P was observed in pts treated with E than T. The finding of improved OS in pts who develop P with E is intriguing and should be further investigated. [Table: see text]
Incidence of syn- and metachronous adrenal metastasis following tumor nephrectomy: A retrospective bicenter analysis.
Authors: Peters Inga , Herrmann Thomas R. W. , von Klot Christoph , Wegener Gerd , Stransky Petr , Hes Ondrej , Hora Milan , Kuczyk Markus , Merseburger Axel S. 
Published: February 2017

417 Background: Metastases of adrenal gland occur in approximately 1.2 - 10% in kidney cancer patients. Synchronous adrenalectomy has become dispensable since studies have demonstrated no clinical benefit. The aim of this large bi-institutional study was to determine the appearance of syn- and metachronous metastasis to the adrenal gland as detected by CT, PET-CT or MRI imaging with consecutively surgically removal of suspicious lesions. Methods: We retrospectively reviewed the clinical and pathological records of 2308 patients (1200 pts. from Medical School Hanover until 2009 and 1108 pts. from University Hospital Plzeň until 2010) who underwent radical/partial nephrectomy. Synchronous adrenalectomy was carried out in 222 of all cases (10.4%). Metachronous adrenalectomy was performed in 11 cases including 8 ipsilateral and 3 contralateral adrenalectomies due to suspicious imaging among follow-up. In cases of metachronous metastasis pre-operative imaging, surgical and histopathological results were correlated. Results: Metastatic spread in patients with synchronous adrenalectomy was found in 17/222 cases (7.6%), as suspected. In metachronous procedures positive pathological results was found in 10 of 11 (91%) cases. In one case it was a benign pathological result. In all positive cases a metastasis from the former clear cell carcinoma was pathologically confirmed. 27% of all cases were detected in the contralateral adrenal gland. Conclusions: Synchronous adrenalectomy is not routinely recommended with nephrectomy. In case of preoperative suspicious imaging an intraoperative frozen section should be performed. Radiological investigations are of high diagnostic value for detecting metachronous tumor growth within the adrenal gland. Surgery in this scenario should be recommended due to the here reported malignancy rate of 91%.
Pleotrophic action of renal cell carcinoma: Dysregulated microRNAs on hypoxia-related signaling pathways.
Authors: Bjarnason Georg A. , Lichner Zsuzsanna , Mejia-Guerrero Salvador , Ignacak Monika , Krizova Adriana , Bao Tian Tian , Girgis Andrew , Youssef Youssef M. , Yousef George M. 
Published: February 2017

428 Background: The von Hippel-Lindau (VHL) gene is lost in 70% of clear cell Renal Cell Carcinomas (ccRCC); however, additional mechanisms are proposed to regulate VHL expression, including suppression by microRNAs (miRNAs). miRNAs are a class of naturally occurring, small non-coding RNA molecules that downregulate gene expression of target mRNAs. We demonstrate that ccRCC-dysregulated miRNAs can target multiple members of the ccRCC-related signaling pathways. Methods: miR-17 and miR-224 mimics and inhibitors were transfected into ccRCC cell lines using siPORT (Ambion). PicTar and TargetScan were used for target prediction. Target expression and miRNA expression was analyzed by qRT-PCR (Ambion). Western blot antibodies were purchased from Millipore or Cell Signaling. Cell lines were purchased from ATCC. All methods followed the manufacturer’s protocol. Results: According to our preliminary results, the miRNAs that are dysregulated in ccRCC specimens are predicted to target multiple members of the hypoxia-related pathways. To confirm the in silico analysis, miR-17 and miR-224 were selected for experimental target validation, as they were among the most up-regulated miRNAs in ccRCC. We experimentally validated VHL and HIF1α as likely direct targets of miR-17 and miR-224. Luciferase reporter assay confirmed that miR-17 directly downregulates VHL. Moreover, VHL protein level decreased upon miR-17 and miR-224 transfection. We also established a negative correlation between the expression of miR-17 and two predicted targets VEGF-A, EGLN3 in RCC specimens, and miR-224 and its predicted targets SMAD4 and SMAD5. This suggests that downstream signaling pathways are also modulated by miR-17 and miR-224. These results confirm the most important findings of the bioinformatics analysis: miR-17 targets different molecules along the same signaling pathway and that multiple ccRCC-dysregulated miRNAs can synergistically suppress a single target, which functions in the pathogenesis. Conclusions: Our results indicate that miRNAs possibly regulate hypoxia-related pathways at multiple points. This is of special interest as miRNAs may serve as potential therapeutic targets.
Risk of treatment failure after first-line sunitinib therapy in patients with metastatic renal cell carcinoma.
Authors: Chen Chi-Chang , Hess Gregory P. , Liu Zhimei , Gesme Dean H. , Agarwala Sanjiv S. , Hill Jerrold W. , Guo Min Amy 
Published: February 2017

438 Background: Treatment options for metastatic renal cell carcinoma (mRCC) are rapidly evolving. Current treatment options include surgery, immunotherapy, and several targeted therapies including kinase inhibitors, mTOR inhibitors and anti-VEGF agents. The aim of this study was to inform choices and outcomes on the sequential use of targeted therapies for mRCC through the evaluation of the comparative effectiveness of common second-line targeted therapies following 1st line sunitinib treatment. Methods: A retrospective observational study using claims data was conducted. Final study subjects were mRCC patients who received everolimus, sorafenib or temsirolimus from 4/1/2008 to 2/29/2011 following 1st line sunitinib treatment. Patients were followed from the start of second-line treatment until treatment failure or last observation in the database. Treatment failure was defined as advancement to a third-line of mRCC therapy, or mortality. Results were analyzed using Cox proportional hazards model controlling for baseline clinical and demographic factors. Results: The study sample consisted of 257 mRCC patients who received everolimus (n=117), temsirolimus (n=75) and sorafenib (n=65) following 1st line sunitinib treatment. Patients had a mean age of 63 years, and 72% were male. The mean observation period from the start of second-line treatment was ∼6.4 months. Treatment failure was observed in 38.5% (20.2% advanced from 2nd to 3rd line and 18.3% died) of the study sample and 61.5% of patients were censored at last observation without any treatment failure event. Results from the Cox proportional hazards model indicated that, compared to everolimus, both sorafenib and temsirolimus patients experienced a statistically significant higher adjusted risk of treatment failure (sorafenib: HR=1.77, p=0.043; temsirolimus: HR=2.05, p=0.004). Conclusions: Following systemic treatment for mRCC with first-line sunitinib, patients on second-line targeted therapies were observed with differential risks of treatment failure, as defined by line advancement or death. The risk of treatment failure was significantly higher with sorafenib and temsirolimus as compared to everolimus.