bluuebunny/crossref_metadata_2025_split huggingface dataset:
AMG 386 in combination with sorafenib in patients (pts) with metastatic renal cell cancer (mRCC): A randomized, double-blind, placebo-controlled, phase II study.
Authors: Rini B. I. , Szczylik C. , Tannir N. M. , Koralewski P. , Tomczak P. , Deptala A. , Kracht K. , Sun Y. , Puhlmann M. , Escudier B. 
Published: February 2017

309 Background: AMG 386 inhibits angiogenesis by sequestering angiopoietin-1 and -2, thus preventing their interaction with the Tie2 receptor on endothelial cells. Combination with VEGF receptor inhibition has demonstrated additive effects in vivo. The efficacy and tolerability of sorafenib plus AMG 386, an investigational peptide-Fc fusion protein, were evaluated in mRCC pts. Methods: Treatment-naive pts with clear cell mRCC were randomized 1:1:1 to sorafenib 400 mgPO BID plus AMG 386 10 mg/kg (Arm A) or 3 mg/kg (Arm B) QW; or placebo (Arm C) IV QW. Endpoints were progression-free survival (PFS; primary); and (secondary) objective response rate (ORR), change in tumor burden, adverse events (AEs) and pharmacokinetics. Tumor assessment was performed at baseline and every 8 weeks thereafter. Results: 152 pts were randomized: Arms A/B/C, n=50/51/51. 60/61/61% of pts had intermediate and 40/39/37% had low MSKCC risk at baseline. PFS was similar in all 3 arms, whereas ORR was higher in the AMG 386 arms ( Table ). In Arms A/B/C the incidence of grade ≥ 3 AEs was 66/73/86% and serious AEs 36/49/28%. The most common AEs included diarrhea (70/67/56%; grade ≥3 8/10/8%), hand- foot syndrome (52/47/54%; grade ≥3 12/16/28%), alopecia (50/45/50%; grade ≥3 0/0/2%), and hypertension (42/49/46%; grade ≥3 18/20/14%). Median steady-state Cmax and Cmin for AMG 386 were similar to those reported previously. Sorafenib coadministration did not markedly affect AMG 386 exposure. Conclusions: Sorafenib plus AMG 386 was tolerable but did not improve PFS compared with sorafenib plus placebo. Increased ORR and the observed reduction in tumor burden are suggestive of an antitumor effect of AMG 386 in mRCC. [Table: see text] [Table: see text]
A phase III, randomized, controlled study to compare tivozanib with sorafenib in patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Motzer R. J. , Bhargava P. , Esteves B. , Al-Adhami M. , Slichenmyer W. , Nosov D. , Eisen T. , Sternberg C. N. , Hutson T. E. 
Published: February 2017

310 Background: Drugs that block vascular endothelial growth factor (VEGF) pathway signaling, such as the tyrosine kinase inhibitor sorafenib, have become standard treatment for pts with RCC. Tivozanib (AV-951) is a potent, selective small-molecule pan-VEGF receptor (VEGFR) inhibitor, with activity against the VEGFR-1, -2, and -3 kinases at subnanomolar concentrations. Preliminary results from a phase II randomized discontinuation trial of tivozanib (1.5 mg/d; 3 wks on, 1 wk off) in pts with RCC demonstrated an objective response rate (ORR) of 27% and a median progression-free survival (PFS) of 11.8 mo by independent radiology review, with a favorable safety profile. Patients with clear cell RCC who had undergone nephrectomy had an ORR of 32% and median PFS of 14.8 mo (Bhargava, et al. ASCO 2010. Abstract 4599). Based on this antitumor activity a phase III, randomized, controlled, global, multicenter trial is currently in progress to compare tivozanib with sorafenib in pts with advanced RCC. Methods: Approximately 500 adults with clear cell RCC who have undergone nephrectomy and received ≤ 1 prior systemic treatment (no prior VEGF-targeted therapy) were randomized 1:1 to treatment with tivozanib or sorafenib. Pts are receiving 1.5 mg/d tivozanib orally in 4-week cycles (3 wks on, 1 wk off) or continuous 400 mg sorafenib orally twice daily. The primary endpoint will be PFS by independent radiology review; secondary endpoints will include overall survival, ORR, and duration of response. Safety is being monitored through adverse event reporting and laboratory analyses; toxicities are graded using the NCI Common Terminology Criteria for Adverse Events, version 3.0. The effect of therapy on health-related quality of life will be compared between arms using kidney cancer-specific (FKSI-DRS), oncology (FACT-G), and general (EQ-5D) assessments. Pharmacokinetics and biomarker analyses will be performed. Results: Pending. Conclusions: Enrollment completed in August 2010. An ongoing extension study will allow access to tivozanib for pts who demonstrate progressive disease on sorafenib, as well as long-term treatment with tivozanib or sorafenib for pts who demonstrate clinical benefit. [Table: see text]
A phase I study to evaluate safety and antitumor activity of biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in patients with RCC and other advanced refractory malignancies.
Authors: McDermott D. F. , Drake C. G. , Sznol M. , Sosman J. A. , Smith D. C. , Powderly J. D. , Feltquate D. M. , Kollia G. , Gupta A. K. , Wigginton J. 
Published: February 2017

331 Background: Programmed death-1 (PD-1), a T-cell inhibitory receptor, may suppress antitumor immunity. BMS-936558, a fully human PD-1 blocking antibody, has shown antitumor activity and manageable toxicity after biweekly dosing (Sznol, ASCO 2010, #2506). This report provides an update on safety and antitumor activity with special emphasis on RCC. Methods: An open-label phase I dose escalation study of BMS-936558 was conducted in patients (pts) with treatment refractory metastatic clear-cell renal cell carcinoma (RCC), castrate-resistant prostate cancer (CRPC), melanoma (MEL), non-small cell lung cancer, or colorectal cancer (CRC). Dose escalation continued to 10 mg/kg when an expansion cohort for pts (16) with each tumor type was opened for additional safety and efficacy information. Tumor response (RECIST) was evaluated every 8 weeks. Clinically stable pts with early PD could continue until further PD or clinical deterioration. Results: 126 pts (18 RCC) were treated with 1, 3, or 10 mg/kg. MTD was not reached. Across all doses, the most common AEs (Any/grade 3-4) were fatigue (45.2%/6.3%) and diarrhea (30.2%/0.8%) while the most common drug-related AEs (Any/grade 3-4) were fatigue (20.6%/0.8%), rash (11.9%/0%), pruritus (11.3%/0%), and diarrhea (10.3%/0.8%). There was no apparent relationship between dose and frequency of AEs. One pt died with sepsis while being treated for drug-related grade 4 pneumonitis. The median number of prior treatment regimens in the RCC cohort was 2 (range 1-6). Of the 18 RCC pts, 16 were treated with 10 mg/kg. The median duration of treatment was 7.6+mo. ORR was 5/16 (31.2%) and SD>4mo was 6/16 (37.5%). The median duration of response was 4.0+ mo (3.7-7.4+ mo). Of the 2 RCC pts treated with 1 mg/kg, 1 obtained a CR (12+ mo) and 1 had SD (21+ mo). For evaluable CRPC pts, 1/15 pts (6.7%) obtained a PR (2+ mo) and 3/15 (20%) had SD>4mo. Conclusions: BMS-936558 administered biweekly is tolerable and has encouraging antitumor activity in a previously treated patients with RCC. Data on baseline characteristics, long-term toxicity and response duration will be updated at the meeting. [Table: see text]
Plasma cytokine and angiogenic factors (CAFs) predictive of clinical benefit and prognosis in patients (Pts) with advanced or metastatic renal cell cancer (mRCC) treated in phase III trials of pazopanib (PAZO).
Authors: Liu Y. , Tran H. T. , Lin Y. , Martin A. , Zurita A. J. , Sternberg C. N. , Amado R. G. , Pandite L. N. , Heymach J. ,   VEG105192 Team
Published: February 2017

334 Background: PAZO is a multikinase inhibitor approved for the treatment of mRCC. From phase II study of PAZO in mRCC (VEG102616), plasma CAF analysis from 3 different platforms (cross platform correlation r >0.70) revealed several candidate CAFs including HGF, IL-6, IL-8, TIMP-1, VEGF, E-Selectin and OPN were found to be significantly correlated with clinical benefit (Tran ASCO 2010, #4522). To validate these findings, plasma were analyzed for CAFs from mRCC pts enrolled in phase III randomized, placebo controlled trial with PAZO where progression-free survival (PFS) of 9.2 months of PAZO and 4.2 months of placebo (hazard ratio:0.46 p<.0001) and overall response rate 30% was observed (Sternberg, JCO, 2010). Methods: Plasma samples (n=344) from phase III randomized, placebo-controlled trial (VEG105192) were analyzed for candidate CAFs by a CLIA-certified laboratory (Aushon Biosystems, MA). These markers of PAZO and placebo arms were correlated with PFS by Cox regression and plotted in Kaplan Meier by using median concentration of each marker as a cutoff. Results: Higher levels of IL-8 (p<0.006), HGF (p<0.01), OPN (p<0.001) and TIMP-1 (p<0.006) were associated with shorter PFS in PAZO treated pts. Higher levels of all these markers except HGF were also associated with shorter PFS in the placebo arm (IL-8 (p<0.002), OPN (p<0.001), IL-6 (<0.001), TIMP-1 borderline at p= 0.052) and were therefore prognostic. Only IL-6 was predictive of PFS benefit; pts with high IL-6 had a greater relative benefit from PAZO compared to placebo with a HR of 0.32 in the high IL-6 group and 0.57 in the low IL-6 group (p value for interaction 0.009). Conclusions: This study validated HGF, IL-8, OPN, and TIMP-1 as markers associated with clinical benefit with PAZO treatment. IL-8 and OPN were confirmed as prognostic markers in the placebo arm and IL-6 was both a prognostic marker and predictive marker for pazopanib therapy. [Table: see text]
Adjusted indirect comparison of everolimus and sorafenib in sunitinib-refractory mRCC patients using a robust matching technique.
Authors: Di Lorenzo G. , Casciano R. , Malangone E. , Buonerba C. , Sherman S. , Wang J. , Liu Z. , De Placido S. 
Published: February 2017

378 Background: Vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFr-TKIs) sunitinib (SU) and sorafenib (SO) are approved for first- and second-line (after cytokines) use in metastatic renal cell carcinoma (mRCC). Because most patients progress after first-line VEGFr-TKI, the need for an effective second-line treatment is compelling. Although SO is frequently considered after SU failure, no randomized controlled trials have established clinical benefit in this scenario. Results from the RECORD-1 phase III trial suggest that second-line everolimus (EVE) therapy leads to improved overall survival (OS) vs. placebo. No trial data exist comparing treatment outcomes for EVE vs SO in the second-line setting. Thus, the current analysis provides a robust estimate from an indirect comparison examining the OS benefit of EVE and SO as second-line treatment options after SU failure. Methods: The single-arm SO study was selected as a basis by which to match an EVE SU-refractory subpopulation of the RECORD-1 trial. Patients were limited to those with clear cell histology. An adjusted matching approach was taken in which 1,000 repeated random samples matched to the SO population on risk score distribution were produced. These data were used to generate a distribution of survival outcomes and infer a 95% CI around the mean of all sampled median OS estimates. Results: After adjusted matching, the estimated median OS benefit, based on SO patients with clear cell histology (n = 45) and 1000 random samples of n = 41 from the 127 SU-refractory EVE patients, was 82 weeks (95% CI: 78, 86) and 32 weeks (95% CI: 22, 64) for EVE and SO, respectively. Conclusions: These indirect comparison results suggest that SU-refractory mRCC patients treated with EVE may experience significantly improved OS outcomes compared with patients treated with SO. [Table: see text]
Unexpected hyperparathyroidism in metastatic renal cell carcinoma patients treated with sunitinib.
Authors: Mazzanti R. 
Published: February 2017

380 Background: Sunitinib malate is a tyrosine kinase inhibitor, active against tyrosine kinase receptors involved in tumour growth and angiogenesis, and is a potent substrate of p-glycoprotein. This study was conducted to assess whether sunitinib could affect phospho-calcium metabolism. This because both sunitinib and parathyroid hormone have been suggested to be substrates of p-glycoprotein. Here we report the incidence of newly onset hyperparathyroidism in a cohort of patients affected by metastatic renal cell carcinoma (mRCC), treated with sunitinib. Methods: Parathyroid and calcium metabolism function tests were prospectively evaluated in patients receiving a daily 50 mg sunitinib for mRCC according to classic 6-week schedule. Between July 2008 and July 2010, 25 patients received a sunitinib treatment at our institution and resulted eligible for evaluation. Median patients age was 64.3 years old (range 48-79). Parathyroid hormone (PTH), serum and urinary phosphate and calcium, were measured at the beginning of treatment and at the end of each sunitinib ON period. Results: During sunitinib therapy, 17 patients (68%) developed elevated serum parathyroid hormone, with low-to-normal serum calcium and phosphate. On average patients presented an elevation of PTH after 3 sunitinib cycles (range 1-5). Those presenting elevated PTH showed low or undetectable urinary calcium levels. Conclusions: Hyperparathyroidism develops in a high percentage of patients undergoing sunitinib. A similar observation was reported among patients on imatinib, due to an inhibition of PDGF receptor both on osteoclasts and osteoblasts. In these patients, a temporary decrease of serum ionized calcium was supposed as the pathogenetic mechanism of hyperparathyroidism. As sunitinib inhibits PDGF receptors', similar events could be hypothesized. This observation suggests that abnormalities in bone metabolism are a common feature of tyrosine kinases inhibitors targeting PDGF receptors. Routine monitoring of bone metabolism during sunitinib therapy is therefore recommended. No significant financial relationships to disclose.
Use of quantitative gene expression in primary and highest Gleason pattern cancers to identify genes associated with clinical recurrence after radical prostatectomy.
Authors: Klein E. A. , Falzarano S. M. , Maddala T. , Millward C. , Novotny W. F. , Pelham R. J. , Magi-Galluzzi C. 
Published: February 2017

39 Background: Prostate biopsy may not adequately sample small, secondary or tertiary Gleason pattern tumors which can drive clinical outcome. We conducted a study to determine whether tumor-derived gene expression profiling could identify a distinct underlying biology associated with clinical recurrence (cR) after radical prostatectomy (RP) across both the primary and highest Gleason pattern (GP) samples. Methods: All patients (pts) with clinical stage T1/T2 prostate cancer treated with RP at Cleveland Clinic from 1987 to 2004 were identified (n∼f2,600). A cohort sampling design was used to select 127 patients with cR and 374 patients without cR after RP. Each patient had two spatially distinct tumor specimens sampled that included the primary GP and the highest GP. Surgical GS and clinical data were centrally reviewed. RNA was extracted from 6 manually dissected 10 μ m fixed paraffin embedded tissue sections obtained from the RP tumor specimens and expression of 732 cancer-related and reference genes was quantified using RT-PCR. Clinical recurrence-free interval (cRFI) was analyzed using Cox PH regression. Results: Blocks from 441 patients were evaluable. Median F/U was 5.8 years. Pts were mostly Caucasian (83%), clinical stage T1 (66%), had baseline PSA <10 ng/mL (82%), and had surgical GS ≤7 (87%). As expected, surgical GP, biopsy GP, path T- stage, clin T-stage, baseline PSA, and year of surgery (p<0.05, unadj) were associated with cRFI. In the primary and highest GP specimens respectively, 295 and 297 genes were significantly associated (unadj. p<0.05) with cRFI. 235 genes were associated with cRFI in both specimens, well in excess of the number expected by chance. In a multivariate model adjusted for AUA risk group and allowing a 10% false discovery rate, 289 genes remained significantly and strongly associated with cRFI. Conclusions: Gene expression analysis using quantitative RT-PCR identified a large number of genes, and underlying biology, that are strongly associated with clinical recurrence in both the primary and highest GP. This information can be used to develop a biopsy-based assay that distinguishes indolent versus aggressive disease. [Table: see text]
Is there a role for targeted therapies in the collecting ducts of Bellini carcinoma?
Authors: Procopio G. , Verzoni E. , Iacovelli R. , Guadalupi V. , Nicolai N. , Torelli T. , Biasoni D. , Colecchia M. , Salvioni R. 
Published: February 2017

396 Background: Carcinoma of Bellini collecting ducts (CDC) is very uncommon but it is one of the most aggressive urological entities. For this tumor, originating from the epithelium of Bellini ducts in the distal tubule and preferentially occurring in young populations, no standard effective therapy has been so far established. Results of previous clinical experiences with chemo- or immunotherapy have been disappointing. We report our experience in 7 cases of CDC treated with targeted therapies. Methods: From December 2004 to May 2010, 333 patients with advanced renal cell carcinoma have been treated with targeted therapies at Istituto Nazionale Tumori of Milan. From the global database analysis, seven cases with histological subtype of CDC have been identified. All patients had advanced disease and received a targeted therapy as first-line treatment. Six of them underwent previous nephrectomy, all had nodal involvement, and three had two or more sites of disease including lung, liver, and adrenal glands. Four patients received sorafenib as first-line treatment, two sunitinib, and one temsirolimus. After sorafenib failure, two patients received a second-line treatment consisting of both sunitinib and temsirolimus. Results: Five patients developed early progression of disease with a very short 4-month survival. One patient had a long term partial response of 33 months with sorafenib, he underwent second-line sunitinib and had no progression for further 10 months. The last patient reached a progression-free survival of 6 months with temsirolimus; when progressed, he achieved a disease control for further 9 months during sunitinib therapy. Both patients are alive after 50 and 15 months of treatment, respectively. The most common adverse events, low or moderate in severity, consisted of fatigue, hand-foot skin reaction, diarrhea, hypertension, and anemia. Conclusions: Prognosis of advanced CDC remains unfavorable. New target agents may be active in this disease and need further prospective phase II studies. [Table: see text]
Three-dimensional ultrasound-based spectroscopic imaging for detection of prostate cancer in men.
Authors: Chung H. T. , Sofroni E. , Papanicolau N. , Sugar L. , Morton G. , Yaffe M. , Nam R. , Czarnota G. J. 
Published: February 2017

57 Background: The objective of this translational research was to investigate the use of real-time novel three-dimension, quantitative ultrasound-based spectroscopic imaging of the prostate as a means of cancer detection. Methods: Ten patients with T2-3 prostate cancer underwent a 6-9 MHz trans-rectal ultrasound scan of the prostate prior to radical prostatectomy. Equally spaced axial ultrasound images (0.5 cm separation) corresponding elasticity and spectroscopy data were collected in each patient. Colour-coded spectroscopic parametric maps of 0-Mhz intercept (0-Mhz), mid-band fit (MBF) and slope of line of best fit (slope) were generated indicating where the disease in the prostate gland is hypothetically located. Quantitative data (% volume of cancer over the prostate gland) were compared to whole-mount radical prostatectomy histopathology maps to determine the sensitivity and accuracy in parametrically delineating prostate cancer. Results: Representative data indicate spectral changes were associated with the presence of co-incident disease as located on correlative histopathology whole mount sections. Of the 10 patients enrolled, 7 have been analyzed and presented here. The mean % difference between 0-MHz and MBF, with H&E, was 14% (SD 38%) and 21% (SD 24%), respectively. Gross areas of disease were readily visualized in ultrasound parametric maps and corresponded to a maximum 10dB decrease in 0-MHz or MBF. Parametric maps generated from the spectral slope offered no discrimination of disease. Conclusions: Initial results suggest that there is good correlation between spectroscopic maps with disease on whole-mount specimens. This method may ultimately permit ultrasound-guided targeted biopsies to improve detection rates and non-invasive assessment of disease for radiotherapy planning. No significant financial relationships to disclose.
Elective nodal irradiation for prostate cancer patients: Comparison of available dynamic techniques.
Authors: Urbanczyk H. , Hawrylewicz L. , Kulik R. , Szczepanik K. , Ciechowicz J. , Tarnawski R. 
Published: February 2017

96 Background: The few recent studies showed that regional lymph node metastases of prostate cancer (PCa) could be successfully treated. It means that role of pelvic nodes (PN) irradiation could increase in next period. A problem is rectal and bladder toxicities of this treatment. Intensity modulated dynamic irradiation techniques (DT) may potentially help to reduce treatment related side effects. The aim of study is to compare three different radiotherapy techniques: conformal (CRT), static field intensity modulated (SF IMRT) and rapid arc (RA) for elective pelvic lymph nodes irradiation. Methods: We analyzed CRT, IMRT and RA plans of irradiation PN for ten patients. PTVs included PN iliac, iliac external upper then acetabulum, iliac internal and obturatory. Prescribed doses were 44 Gy/22 fractions. We compared the doses delivered to PTV rectum and bladder using dose volume histograms. The U Mann-Whitney, W Shapiro-Wilk and ANOVA rang Kruskal-Wallis tests were used for statistical analysis. Results: The median PTV doses were not statistically different in analyzed plans. The minimum doses for PTV were significantly lower in IMRT and RA plans but the differences were not clinically significant. Maximum doses were significantly higher for CRT plans. The doses calculated for rectum and bladder were statistically significantly lower for dynamic techniques in whole range of volumes and doses. SF IMRT is the most efficient technique in reducing the dose to bladder. The doses observed in half of the rectum and bladder volumes bladder were also statistically significant different (p=0.002 for rectum and 0.001 for bladder). The median doses for rectum were 43.6 Gy for CRT plans, 33.5 Gy for IMRT and 37.9 Gy for RA, median doses calculated for bladder were 44 Gy for CRT, 35.6 Gy for IMRT and 39.6 Gy for RA. Conclusions: CRT does not allow to reduce the dose to organs at risk. Both DT reduce the doses to bladder and rectum while maintaining the high homogenous dose to PTV. SF IMRT is more efficient in reducing the dose to bladder than RA. SF IMRT technique seems to be better than Rapid Arc for PN irradiation. It is probably because the nodal PTVs are large and their structures are complicated. No significant financial relationships to disclose.