bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response of the human kidney to clamp ischemia.
Authors: Ercole Barbara , Torkko Kathleen , Hilton William , Venkatachalam Manjery A. , Weinberg Joel M. , Parekh Dipen J. 
Published: February 2017

365 Background: Structural changes in tubule cells during clamp ischemia are well characterized for animal models, but their timing and extent in the human kidney has not been established and may differ significantly. To better define the human response, we biopsied uninvolved areas of kidney in patients undergoing open partial nephrectomy for renal masses. Methods: Biopsies of 40 patients undergoing PN were obtained at specified time intervals: before renal artery clamping, then during periods ranging from 15 to 60 min. of warm and cold ischemia (80% > 30 min.), and then after 5 minutes of reflow. These biopsies were assessed for ultrastructure (N=39) and for immunofluorescence and rhodamine phalloidin staining (N=22). Results: During the clamp period, apical membrane structure was remarkably well preserved with only patchy brush border clubbing, fragmentation, desquamation and blebbing and not in all patients. Mitochondria developed progressive swelling, which paradoxically was more prominent in distal than proximal tubule cells. This resolved during the 5 minutes of reflow in most cells in most patients, but persistence of swelling and development of matrix condensation occurred occasionally. Using a composite 0-5 scale covering the full spectrum of ultrastructural changes, average scores were: Preclamp 1.02±0.07, End clamp 2.18±0.07, Post clamp 1.86±0.09. Consistent with the ultrastructure, staining for F-actin with rhodamine phalloidin was well preserved. Immunsotaining for phosphotyrosine, which reflects cellular ATP content was decreased in 68.4% of the clamp biopsises and 52.6% of the postclamp biopsies with larger changes in proximal tubules, however B1 integrin was decreased in only one post clamp biopsy. ICAM-1 expression in peritubular capillaries was increased in 46.7% of the clamp biopsies and 66.7% of post clamp biopsies. None of the patients developed acute kidney injury. Conclusions: These data provide the first detailed analysis of the structural response of the human kidney to clamp ischemia and document many of the expected structural alterations based on prior animal work, but indicate a greater than expected resistance to injury in this commonly used clinical application of clamp ischemia.
Pretreatment (pre-tx) neutrophil to lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with ketoconazole (keto): Association with outcome and predictive model.
Authors: Keizman Daniel , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Carducci Michael Anthony , Eisenberger Mario A. , Sella Avishay 
Published: February 2017

37 Background: The CYP17 inhibitor Keto is active in mCRPC. The NLR, an index of systemic inflammation, is associated with prognosis in several types of cancer. We assessed the association between pre-tx NLR and outcome of mCRPC pts treated with keto. Methods: We performed a multicenter retrospective study of pts with mCRPC, who were treated with keto. We analyzed the pre-tx NLR and previously described factors associated with keto tx outcome as prior response to hormonal tx, pre-tx PSADT, and extent of metastatic disease (limited-axial skeleton/nodal vs extensive- appendicular skeleton/visceral). Progression free survival (PFS) was determined by the Kaplan-Meier method. Multivariate analyses using Cox regression model were performed to determine their independent effect, and to form a predictive model. A survival tree analysis was used to find the best NLR cut-off value. Results: From 1999-2011, 135 mCRPR pts were treated with keto. 67/135 (50%) had ≥ 50% PSA decline. Overall median PFS was 8 months (mos) (range 1-134 ). Excluded from the analysis were pts without available data on pre-tx NLR (n=8), and those with recent (≤1 mos) health event (surgery, n=1) or tx (steroids, n=3 or radiation, n=3) known to be associated with a change of blood counts. 120 pts were included in the analysis. 57 (48%) had an elevated pre-tx NLR >3. Risk factors associated with PFS (table) were pre-tx NLR >3, prior response to GnRH-a <24 mos and to AA <6 mos, and pre-tx PSADT <3 mos. The number of risk factors was used to categorize patients into three risk groups (table): favorable (0-1 factors), intermediate (2 factors), and poor (3-4 factors). Conclusions: In mCRPC pts treated with keto, pre-tx NLR, prior response to hormonal tx, and pre-tx PSADT are associated with PFS, and may be used to categorize pts into risk groups. [Table: see text]
Phase I/II study of a BNC105P/everolimus regimen for progressive metastatic renal cell carcinoma (mRCC) following prior tyrosine kinase inhibitors (Hoosier Oncology Group).
Authors: Hutson Thomas E. , Dang Long H. , Lauer Richard C. , Starodub Alexander , Hauke Ralph J. , Logan Theodore , Bylow Kathryn A. , Galsky Matt D. , Bibby David C. , Kremmidiotis Gabriel , Doolin Elizabeth E. , Lavranos Tina C. , Leske Annabell F. , Hahn Noah M. , Sonpavde Guru , Sweeney Christopher , Sarantopoulos John ,   Hoosier Oncology Group
Published: February 2017

373 Background: BNC105P is a Vascular Disruption Agent (VDA) that destabilizes tubulin polymers leading to selective damage of tumor vasculature, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. Preclinical investigations demonstrated that BNC105P is effective at selectively damaging the vasculature in primary and metastatic lesions. Furthermore, BNC105P monotherapy compared well with sunitinib in mice bearing kidney tumors. It follows that the combined use of this VDA with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6 and 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: In the clinic the BNC105P / everolimus combination was well tolerated and no DLTs were observed in any of the phase I patients. Toxicities deemed to be drug-related included single events of Grade 2 anemia, thrombocytopenia and mucositis. Of the 12 patients enrolled to the phase I, 7 remain on treatment. The medium number of cycles is 3 (range: 1–14) and 3 patients have been administered >6 cycles of treatment. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.
Incidence of reduced penis size among men with recurrent prostate cancer previously treated with surgery, radiation plus androgen deprivation, or radiation alone.
Authors: Parekh Arti , Chen Ming-Hui , Hoffman Karen Elizabeth , Choueiri Toni K. , Hu Jim C. , Bennett Charles L. , Kattan Michael W. , Sartor A. Oliver , Stein Karen , D'Amico Anthony Victor , Nguyen Paul Linh 
Published: February 2017

38 Background: The relative incidence of reduced penis size across prostate cancer treatment modalities is not well-known. Methods: The incidence of physician-reported patient complaints about reduced penis size was calculated for 948 men in the COMPARE registry who experienced PSA failure and were assessed a median of 5.45 (2.6-8.9 IQ range) years after prostatectomy or radiation (RT) consisting of either external beam or brachytherapy. Multivariable logistic regression was used to determine factors associated with poorer sexual function and incontinence. Results: Of 948 men, 25 (2.63%) complained of a reduced penis size. The incidence of reduced penis size by treatment was: surgery (19/510=3.73%), RT plus androgen deprivation therapy (ADT) (6/225=2.67%), RT without ADT (0/213=0%). Surgery (p=0.004) and RT+ADT (p=0.016) had significantly more short penis complaints than RT alone. Rates of shortened penis for surgery and for RT+ADT were similar (p=0.47). On multivariable analysis adjusting for age and treatment type, short penis was associated with poorer sexual function (Odds ratio: 2.430, 95% CI: 1.046-5.643) (p=0.0389) and more incontinence (Odds ratio: 4.671, 95% CI: 1.985-10.994) (p=0.0004). Conclusions: Complaints about reduced penis size were more common with RT+ADT or surgery than with RT alone, and were associated with poorer sexual function and incontinence issues.
Proteomic analysis of pre- and post-sunitinib treated renal cancer tissue to assess tumor heterogeneity and differential protein expression.
Authors: Stewart Grant Duncan , O'Mahony Fiach , Eory Lel , Nanda Jyoti , Laird Alexander , O'Donnell Marie , Mullen Peter , Riddick Antony , McNeill Alan , Aitchison Michael , Berney Dan , Peters John , Rockall Andrea , Sahdev Anju , Bex Axel , Faratian Dana , Chowdhury Simon , Harrison David , Overton Ian , Powles Thomas ,   Scottish Collaboration on Translational Research into Renal Cell Cancer \(SCOTRRCC\)
Published: February 2017

388 Background: To investigate acquired resistance of clear cell renal cell cancer (ccRCC) patients to sunitinib and develop personalised treatment strategies, sequential tissue after a specific period of targeted therapy is required. This approach has proven successful with targeted therapy in chronic myeloid leukaemia; however, we are concerned that extensive tumour heterogeneity occurs in ccRCC. In this study we evaluated heterogeneity and differential protein expression in sunitinib treated and untreated ccRCC samples using high-throughput proteomics. Methods: Fresh frozen tissue was obtained from 27 sunitinib naïve ccRCC specimens and 27 nephrectomy samples from patients treated with neoadjuvant sunitinib (18 weeks) as part of the SuMR trial. From each tumour frozen sections were performed and up to 5 protein lysates obtained from each morphologically differing region of each tumour as well as matched normal kidney. Reverse phase protein arrays (RPPA) were performed to assess the levels of multiple proteins relevant to ccRCC pathogenesis and sunitinib activity. Appropriate statistical tests were used to examine protein heterogeneity and differential expression, including false discovery rate (FDR) correction. Kaplan-Meier method was used to correlate changes in protein expression with outcome. Results: Expression of 20 proteins has been examined to date. The range of expression in tumours normalised by matched normal renal tissue had >2-fold differences in untreated (n=8 proteins) and treated samples (n=4 proteins). Four markers displayed significantly increased inter-tumoural variance in sunitinib treated tumours compared with untreated tissue (e.g. VEGFR1, FDR P<0.05). Despite this heterogeneity, sunitinib was associated with significant expression changes for several key proteins (e.g. VEGFR2, CyclinD2; FDR P<0.05). Conclusions: Protein expression in ccRCC is heterogenous and key proteins showed significantly increased variance of expression with sunitinib therapy. Despite heterogeneity, significant changes in protein expression can be identified with sunitinib treatment and have been correlated with outcome.
Cost comparison of robotic, laparoscopic, and open partial nephrectomy.
Authors: Alemozaffar Mehrdad , Chang Steven Lee , Kacker Ravi , Sun Maryellen , DeWolf William C , Wagner Andrew 
Published: February 2017

394 Background: Laparoscopic and robotic partial nephrectomy (LPN and RPN) are increasingly common minimally invasive alternatives to open partial nephrectomy (OPN) for management of renal tumors. The cost discrepancies of these approaches warrants evaluation. We compared hospital costs associated with RPN, LPN, and OPN. Methods: Variable hospital costs including operating room (OR) time, supplies, anesthesia, inpatient care, radiology, pharmacy, and laboratory charges were captured for 25 patients who underwent OPN, LPN, and RPN at our institution between 11/2008 -9/2010. Fixed costs of acquisition of a laparoscopic suite and a robotic system (including maintenance) were amortized over 7 years. We considered alternative scenarios through one-way and multi-way sensitivity analysis. Results: We found similar overall variable costs for OPN, LPN, and RPN. Sensitivity analysis demonstrated that RPN and LPN are more cost effective than OPN (excluding fixed costs) if the average hospital stay is < 2 days, or OR time less is than 204 and 196 mins, respectively. By including fixed costs of equipment, RPN and LPN are always more costly than OPN. Conclusions: There was no difference among variable hospital costs of OPN, LPN, and RPN. Minimizing OR time and hospital stay reduces RPN and LPN costs to levels comparable to OPN. Inclusion of fixed costs makes LPN and RPN more expensive than OPN, but increased utilization and efficiency can decrease cost per case. [Table: see text]
Circulating microRNAs as potential biomarkers in patients with renal tumors.
Authors: Antón Aparicio Luis M. , Medina Vanessa , Valladares Ayerbes Manuel , Santamarina Isabel , Aparicio Gallego Guadalupe , Diaz Prado Silvia , Quindós Varela Maria , Alonso-Jaudenes Curbera Guillermo 
Published: February 2017

405 Background: MicroRNAs (miRNAs), a class of small RNAs, have been intensely investigated recently because of their important regulatory role in gene expression. Circulating miARNs are potential biomarkers for cancer not only abundant in blood, but also very stable, which are important prerequisites as clinical biomarkers. Detection of circulating tumor cells (CTC) may provide diagnostic and prognostic information in genitourinary renal tumors. The aim of this work is identify miRNAs potentially useful for CTC detection in blood samples from patients with renal tumors to assess their potential clinical significance. Methods: We examined blood levels of three miRNAs, let-7c, miR-200c and miR-31 in 48 patients with renal tumors with locally advanced or metastatic disease and 18 healthy persons using quantitative real-time PCR. The clinicopathologic characteristics of the population under consideration include among other: sex, age, tumor location, histological type, Fuhrman grade, tumor size, number of involved nodes, tumor stage, time to progression and overall survival. Results: We found that the median levels of miRNAs, let-7c, miR-200c and miR-31 were significantly higher in patients with renal tumors than those in healthy controls (p=.002, p=.000 and p=.004, respectively). Receiver-operator characteristic (ROC) curve analyses indicate that these blood miRNAs may be useful markers for discriminating patients with renal tumors from healthy controls (AUC=.750, AUC=.853 and AUC=.738, respectively). Conclusions: miRNAs in the circulation are relatively stable, very accessible, low invasive and easily testable biomarkers. Our results suggest let-7c, miR-200c and miR-31 as novel stable blood-based markers for renal cancer detection. This work was supported by Grants PI07/0477 from Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III.S. Díaz Prado is supported by an Isidro Parga Pondal research contract by Xunta de Galicia (A Coruña, Galicia, Spain). Cancer research in our laboratory is supported by the “Fundación do CHU A Coruña”.
Outcomes of “real world” treatment for metastatic renal cell carcinoma (mRCC).
Authors: Harrison Michael Roger , George Daniel J. , Walker Mark S. , Hudson Lori L. , Chen Connie , Korytowsky Beata , Stepanski Edward J. , Abernethy Amy P. 
Published: February 2017

406 Background: Targeted therapies have expanded treatment options for mRCC. Using a joint community/academic center database, we determined outcomes for “real world” mRCC patients (pts) in order to understand current treatment patterns and their effectiveness. Methods: A retrospective cohort dataset included all identified adult mRCC pts receiving care in Duke University Health System and 11 community oncology practices, diagnosed and alive since Jan. 2007, and not enrolled in a trial. Standardized chart abstraction supplemented the electronic medical record. Demographics, comorbidities, tumor characteristics, treatment patterns and outcomes were recorded. Pts were grouped by exposure sequence (TKI [sorafenib, sunitinib or pazopanib], mTOR [temsirolimus or everolimus], TKI/mTOR, etc.) for 9 sequences. Outcomes analysis for overall survival (OS) included Cox regression. Results: The cohort included 385 pts, 64 yrs old (±10.1), 66% male, 72% Caucasian; 64% had clear cell histology (25% unknown). Median OS was: mTOR (N=33; 5.4 mo), mTOR/TKI (N=11; 9.3 mo), TKI/mTOR (N=33; 13.7 mo), TKI (N=108; 21.1 mo), TKI/mTOR/TKI (N=18; 29.8 mo), TKI/TKI/mTOR (N=11; 33.1 mo), Other (N=40; 38.2 mo), TKI/TKI (N=32; 42.9 mo), No Therapy (N=99; not reached). “Other” pts received a combination or a non-TKI, non-mTOR monotherapy in the 1st three exposures. “No Therapy” pts had received no systemic therapy as of data analysis; most were alive and censored. Pts in the mTOR only sequence had trends toward worse disease at baseline with more metastatic sites (median 2.0; p=.067) and impaired performance status (18%; p=NS). When significant covariates were controlled, OS (vs. No Therapy) was poorest for pts receiving mTOR only (Hazard Ratio[HR]=2.3) and best for pts receiving TKI/TKI (HR=0.50). Significant risks were evident with liver metastasis (HR=1.7) and impaired performance status (HR=3.1). Conclusions: In the real world setting pts receiving mTOR as the 1st treatment exposure had worse OS, likely because pts with more aggressive disease were preferentially treated with mTOR. Outcomes were consistent with contemporary trials; however, several sequences (e.g. TKI/TKI, No Therapy) had surprisingly long OS, which requires further evaluation.
The effect of activation of angiogenesis pathways independent of VEGF in renal cell carcinoma on resistance to VEGF-targeted antiangiogenic therapy.
Authors: Han Kyung Seok , Gust Kilian , Awrey Shannon , Raven Peter A. , Li Estelle , Fazli Ladan , Gleave Martin E. , So Alan I. 
Published: February 2017

409 Background: VEGF-targeted anti-angiogenic therapy provides significant growth inhibition in clear cell type renal cell carcinoma (CCRCC). However, evasive resistance develops in most responding cases due to unclear mechanisms. We investigated the mechanism of resistance to VEGF-targeted therapy in CCRCC both in vitro and in vivo. Methods: Two different conditioned cell lines were developed from wild type Caki-1. Sunitinib-conditioned Caki-1 was developed by chronic exposures to sunitinib (up to 15uM) and hypoxia-conditioned Caki-1 was developed by chronic exposures to hypoxia (1% oxygen). We characterized these conditioned cells in vitro and response patterns to sunitinib were evaluated using subcutaneous xenograft models with parental and conditioned cells. In vivo angiogenesis assays were performed to characterize angiogenesis potentials in these cells. Finally, mRNA microarray was performed to find pathways that induce resistance to anti-angiogenic therapy. Results: Sunitinib inhibited proliferation of HUVEC cells, but did not inhibit tumor proliferation in CCRCC cells at pharmacologically relevant doses. In vitro sunitinib-conditioned Caki-1 cells did not show obvious resistance to sunitinib compared to parental cells, but when tested in vivo these cells appeared to be highly resistant to sunitinib therapy. In contrast, hypoxia-conditioned Caki-1, although more resistant to hypoxia and showing increased vascularity by upregulating VEGF production, did not develop sunitinib resistance either in vitro or in vivo compared to parental cells. In vivo matrigel plug assay with sunitinib treatment confirmed that tumor angiogenesis was relatively intact and less affected by sunitinib treatment in xenografts of sunitinib-conditioned cells compared to parental cells. Conclusions: Resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced by interactions with VEGF-targeted drug but not by hypoxia. Our results suggest that more broad inhibitions of tumor angiogenesis are required to prevent development of resistance to anti-angiogenic therapy in CCRCC.
The role of stereotactic radiosurgery in the treatment of renal cell carcinoma patients with five or more brain metastases.
Authors: Mohammad Mohammadi Alireza , Chao Samuel T. , Rini Brian I. , Garcia Jorge A. , Suh John H. , Angelov Lilyana 
Published: February 2017

410 Background: Whole brain radiation therapy (WBRT) is considered standard treatment in patients with multiple brain metastases (BM). However, WBRT has limited efficacy in patients with BM from radio resistant tumors like renal cell carcinoma (RCC) where median survival is 2–4 months. The aim of this study is to evaluate outcomes in RCC patients with ≥5 BM treated with Stereotactic Radio-surgery (SRS) monotherapy or as part of a multimodality regimen. Methods: Data from 16 consecutive RCC patients with ≥5 simultaneous BM (99 lesions) treated with SRS at our institution (1999–2010) were analyzed. Patient demographics, tumor characteristics, treatment related factors and outcomes were statistically evaluated. Results: 12 male and 4 female patients (median age of 59) were treated. 62% of patients had concurrent systemic metastases to multiple organs at the time of treatment. 31% of patients were on active systemic treatment before SRS. Patients had prior cranial surgery 2(12%), WBRT 6(37%) and SRS 2(12%) previous to their presentation with ≥5 BM. Median interval between primary diagnoses and SRS was 2years (range 0–16). At the time of current SRS treatment 75% of patients had only mild neurological symptoms and median KPS was 80; 87% of patients were Recursive Partitioning Analysis Class II. Median number of lesion was 5 (max 10), and median total intracranial disease burden was 2cc (range 0.2–36.4). Post SRS for ≥5 BM, 9 of 16 patients required further intracranial therapy for new lesions, WBRT 3(19%) and SRS 6(37%). Mean follow up was 6.5 months from SRS for ≥5 BM (range 1-19). 12 patients (75%) died during follow up with neurological cause of death in 3(25%). Median overall survival (OS) was 7.1 months (range1–21). OS was 50% after 6 month and 31% after 1 year. Local control rate was achieved in 91% of targets in all evaluated patients. Conclusions: SRS is traditionally used to treat patients with a limited number of BM. This is the first series to evaluate the role of SRS in the management ≥5 BM in RCC. We demonstrate that using SRS in these patients results in excellent local disease control (91%) and acceptable OS. Hence, SRS should be considered in the ongoing management of patients even with extensive intracranial disease.