bluuebunny/crossref_metadata_2025_split huggingface dataset:
Newly onset hyperlipidemia in metastatic renal cell carcinoma patients treated with sunitinib.
Authors: Baldazzi Valentina , Tassi Renato , Lapini Alberto , Carini Marco , Mazzanti Roberto 
Published: February 2017

459 Background: To our knowledge effects of sunitinib on serum lipids metabolism are not described. Here we report about the occurrence of hypercholesterolemia and hypertriglyceridemia in patients receiving sunitinib for metastatic renal cell carcinoma (mRCC). Methods: Between July 2008 and September 2011, we prospectively evaluated serum triglycerides and cholesterol in 37 patients receiving sunitinib for mRCC according to classic 6-week schedule. On average they received sunitinib for 10.3 cycles. Serum lipids were measured before the beginning of treatment and at the end of each sunitinib ON period as routine laboratory evaluations. Results: At baseline median triglycerides was 163,83 mg/dl (± 76,6 mg/dl 95% CI) and median cholesterol was 201.6 mg/dl (± 35.5 mg/dl 95% CI). During sunitinib administration 25 patients (67.5 %) presented an elevation of serum lipids as compared to baseline. These abnormalities usually developed within 1.8 cycles (range 1-5 cycles). While on sunitinb median triglycerides was 333,6 mg/dl and median cholesterol was 243.5 mg/dl (+ 103% and + 21% respectively, compared to baseline). Patients who developed hypercholesterolemia presented an increase of both HDL and LDL cholesterol. Conclusions: Hyperlipidemia develops in an elevate percentage of patients on sunitinib. The mechanism of this event remains unclear. Recently, an interaction between platelet derived growth factor receptor (PDGFR) and lipoprotein receptor (LR) family was described and this is supposed to be an important step towards the internalization of LR itself. Because sunitinib inhibits PDGFR, a lower plasma lipoproteins clearance could be expected, resulting in an increase of serum lipids. It is noteworthy that PDGFR inhibition was associated with delayed atherosclerotic plaque formation, having an anti-atherogenetic effect. Therefore treatment with sunitinib, even if associated to hypertension and hyperlipidemia, may not result in an increase of cardiovascular events.
Testosterone suppression: Impact of testosterone level on disease progression in advanced prostate cancer.
Authors: Dason Shawn , Tong Justin , Allard Christopher Brian , Shayegan Bobby 
Published: February 2017

46 Background: In patients with advanced prostate cancer, medical castration remains a mainstay of treatment. A testosterone level below 50 ng/dL has been previously accepted as an adequate level of androgen suppression and remains the benchmark level for clinical trials. However, there is mounting evidence that lower testosterone levels may be associated with improved clinical outcomes. We evaluated our cohort of patients with advanced prostate cancer to assess the impact of testosterone suppression on progression to castrate resistant prostate cancer (CRPC). Methods: Patient data was obtained from a prospective database of patients undergoing androgen deprivation therapy (ADT) at a tertiary centre from 2006-2011. A total of 39 patients were eligible for inclusion with at least 12 months follow-up. Patients were administered LHRH agonists or antagonist with testosterone and PSA assessments every 3 months. Patients were considered to have progressed to CRPC when there were at least 2 consecutive rises in PSA above nadir, clinical progression, or death from disease. Patients were stratified into two risk groups based on 6-month absolute and 1-year mean testosterone levels following initiation of ADT. Baseline characteristics between risk groups were compared using the Student’s t-test and chi-squared test. Probability of disease progression was assessed using the Kaplan-Meier method and compared using the log-rank test. Results: Median patient follow up was 2.3 years with 38% free of disease at last follow up. Patients with 6-month absolute testosterone less than 32 ng/dL had an increased time to CRPC (log rank p=0.06). Patients with 1-year mean testosterone less than 32 ng/dl had a significantly increased time to CRPC (log rank p=0.005). Patients did not differ significantly in their baseline characteristics. Conclusions: Adequate testosterone suppression during ADT may play a clinically significant role in delaying CRPC. While PSA levels are often used to assess for response to ADT, the current study suggests testosterone level in the first year following initiation of ADT may serve as an early predictor of disease progression.
The effects of HDIL-2 in combination with pazopanib or sunitinib on PBMCs’ function and RCC cells’ apoptosis: Preliminary in vitro data.
Authors: Shablak Alaaeldin 
Published: February 2017

463 Background: Combination of certain immunotherapies with TKI’s has been used with success in the treatment of metastatic renal cell carcinoma (MRCC) patients. Here we evaluate the in vitro effects of HDIL-2 and pazopanib or sunitinib on the PBMCs’s function and RCC cell lines apoptosis. Methods: PBMCs isolated from healthy donors or RCC patients were treated with different HDIL-2/TKI combination and their proliferation was assessed with CFSE labelling assay. Furthermore, using CD107a degranulation or chromium release assays, the function of these treated cells was evaluated. The BRdU assay was used to examine the effects of these drugs combinations on the proliferation of different RCC cell lines. Results: While HDIL2/sunitinib combination did not inhibit the proliferation of various immune cells induced by HDIL-2 alone, combination of HDIL-2/pazopanib did, on the other hand, inhibit these cells proliferation. Interestingly, none of these combinations had a negative impact on the functional properties of these cells. Significant proportion of RCC cell lines treated with pazopanib underwent apoptosis, while the proportions of apoptotic cells post HDIL-2 or sunitinib treatment were not different from the background. Furthermore, the combination of HDIL-2/pazopanib did not inhibit the pazopanib induced RCC apoptosis. Conclusions: These preliminary data showed that combination of HDIL-2 and either pazopanib or sunitinib could recruit different anticancer mechanism that could enhance the treatment efficacy. Further assessment in this direction is warranted.
Long-term benefit (LTB) of sunitinib (SU) treatment for metastatic renal cell carcinoma (mRCC): Retrospective analysis for clinical biomarkers identification.
Authors: Smaletz Oren , Chacon Matias , de Oliveira Koch Ludmila , de Carvalho Rocha Daniela Regina , Cardoso Fernanda Camila 
Published: February 2017

465 Background: Prospective studies with sunitinib in mRCC have shown median progression-free survival (mPFS) of 11 months (first line) and 8.3 months (second line). In order to identify patients with LTB with SU, we describe the clinical characteristics of patients with mRCC treated with SU with an mPFS of 15 months or more. Methods: This is a retrospective chart review of patients with mRCC treated with SU in two hospitals, Alexander Fleming Institute Buenos Aires in Argentina and Hospital Israelita Albert Einstein in Sao Paulo, Brazil. Inclusion criteria included patients treated with SU who had a PFS of at least 15 months. Results: Between September 1995 and August 2009, 29 cases were identified. Patient demographics were: median age of 56 years, 65% male, 96% with previous nephrectomy, Eastern Cooperative Oncology Group performance status (PS) of either 0 (52%) or 1 (48%), 93% had clear cell histology, 69% received prior systemic therapy, and 78% had ≤ 2 metastatic sites (mostly in the lungs, liver and bone). Patients were started on SU 50 mg 4 weeks on treatment/2 weeks off treatment (4/2) (n=26) or 37.5 mg 6 weeks continuous dosing (n=3). For those patients starting on 4/2, dose reduction was necessary in 59% of the patients to maintain SU therapy. Median duration of therapy was 23.7 months. During treatment, 24 patients (83%) developed hypertension. Response rates were as follows: complete response 7% (n=2), partial response 38% (n=11), stable disease 52% (n=15); data missing for one patient. Conclusions: LTB is seen in patients who are young, have good performance status, and either 1 or 2 metastatic sites. Dose reductions are common in order to maintain treatment while benefiting from SU. Treatment with SU as either first- or second-line therapy did not appear to influence outcome. Hypertension is a common finding and serves as a predictive marker during treatment, but study limitations preclude the identification of pre-treatment predictive factors.
Erectile function following proton therapy for prostate cancer in men 60 years and younger.
Authors: Hoppe Bradford S. , Nichols Romaine Charles , Henderson Randal H. , Mendenhall William M. , Marcus Robert B. , Morris Christopher G. , Williams Christopher R , Costa Joseph A , Li Zuofeng , Mendenhall Nancy Price 
Published: February 2017

49 Background: A recent investigation into male sexual health and function provided comparative data on sexual function in men treated with EBRT, prostatectomy, and brachytherapy using the PROSTQA database. However, there was a disproportionate percentage of men below 60 years old in the EBRT (N=34, 14%) and brachytherapy (N=54, 21%) subsets compared with surgery (N=249, 49%). Thus, we investigated erectile dysfunction (ED) in young men treated with proton therapy (PT). Methods: 190 men, 60 years old or younger were treated for prostate cancer with definitive PT without androgen deprivation therapy (ADT) on a University of Florida Proton Therapy Institute IRB-approved protocol. Before treatment and q 6 months, men answered the Expanded Prostate Index Composite (EPIC) questionnaire. Men were excluded from analysis because of lack of baseline EPIC (n=10) or follow up EPIC at 2 years (n=23), leaving 157 men for analysis. Potency was defined as a positive response to having “erections firm enough for intercourse,” and sexual function (SF) scores were calculated for EPIC-26. Results: Potency rates prior to treatment and 2 years following treatment were 89% and 72%, respectively. A multivariate analysis showed that dose >78 CGE (p=0.0141) and baseline SF score (p=0.0002) were significantly associated with potency outcome. Potency rates by risk factor stratification are reported in the table. Conclusions: The present study results suggest comparable potency rates following PT in younger men with data recently reported for prostatectomy. We are currently working to provide additional information on potency rates following PT for patients facing these difficult treatment decisions. [Table: see text]
Positive surgical margins and biochemical recurrence in obese patients with intermediate- and high-grade prostate cancer with radical prostatectomy.
Authors: Ramahi Emma Holliday , Ansley Katherine Cox , Jackson Matthew W. , Basler Joseph W. , Du Fei , Swanson Gregory P. 
Published: February 2017

50 Background: The relationship between obesity and prostate cancer outcomes is unclear. We performed a retrospective cohort study to determine the effect of body mass index (BMI) on a cohort of patients with intermediate to high grade prostate cancer treated with radical prostatectomy (RP). Methods: Our retrospective study cohort included 582 men diagnosed with Gleason 7-10 prostate cancer between 1998 and 2008 and treated with RP at a single institution. Patients were stratified into four groups on the basis of their BMI at the time of prostate cancer diagnosis (<25, 25-30, 30-35 or >35). The primary endpoints for comparison were biochemical failure free survival (BFFS) and the incidence of positive margins. PSA >0.2 ng/dl was used to define biochemical failure. Results: After adjusting for age, Gleason score, pre-treatment PSA and the presence of diabetes, we found patients with increasing BMI had an increased frequency of biochemical failure after RP. Compared to patients with a normal BMI (<25), patients with BMI 25-30, 30-35, and >35 had 1.82 (1.12, 2.97; p = 0.02), 2.14 (1.33, 3.45; p = 0.002) and 2.29 (1.1, 4.78; p = 0.03) times higher rates of biochemical failure, respectively. We additionally found increased positive margins after RP in patients with a BMI 30-35 and >35 (41.4% and 45.5%, respectively) when compared to patients with a BMI of <25 and 25-30 (33.3% and 28.9%, respectively); p = 0.02. Conclusions: Patients with increasing BMI seem to be at significantly increased risk for biochemical failure following RP potentially due to the increased technical difficulty of the surgery and increased incidence of positive margins. [Table: see text]
Effect of denosumab on prolonging bone-metastasis-free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.
Authors: Smith Matthew R. , Saad Fred , Shore Neal D. , Oudard Stephane , Miller Kurt , Tombal Bertrand , Sieber Paul , Fizazi Karim , Van Veldhuizen Peter J. , Damião Ronaldo , Marx Gavin M. , Morote Juan , Feng Amy , Dansey Roger , Goessl Carsten Dietrich 
Published: February 2017

6 Background: Denosumab, an anti-RANK-ligand monoclonal antibody, has been shown to prolong BMFS by a median 4.2 months and with a 15% risk reduction vs. placebo in men with non-metastatic CRPC and baseline PSA value ≥ 8.0 ng/mL and/or PSA doubling time (DT) ≤ 10.0 months. To determine the efficacy of denosumab in men at greatest risk for bone metastases, we evaluated BMFS in a subset of men with PSADT < 6 months, a cutoff based on a previous report (Smith MR, et al: J Clin Oncol. 23:2918-2925, 2005). Methods: 1432 men with non-metastatic CRPC (baseline [median] PSA: 12.3 ng/mL, PSADT: 5.1 months, ADT duration: 47.1 months) were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or placebo. The first patient enrolled February 2006; primary analysis cut-off was July 2010, when > 660 men had developed bone metastasis or died. The primary endpoint was BMFS (time to first bone metastasis or death from any cause). BMFS results are presented for men with baseline PSADT < 6 months. Results: Median BMFS in the placebo group of men with PSADT < 6 months was 6.5 months shorter than for the placebo group in the full population (18.7 months vs. 25.2 months), indicating that these men are at particularly high risk. In this group of men with PSADT < 6 months, denosumab prolonged BMFS by a median of 7.2 months and with a 23% reduction in risk compared with placebo (Table). Conclusions: Patients with shortened PSADT are at higher risk of developing bone metastasis and denosumab is markedly effective at prolonging BMFS in this subset of patients. [Table: see text]
Activity of VT-464, a selective CYP17 lyase inhibitor, in the LNCaP prostate cancer xenograft model.
Authors: Pisle Stephen Todd , Pressler Heather M , Troutman Sarah M , Eisner Joel Robert , Rafferty Stephen W , Schotzinger Robert J , Moore William R , Figg William Douglas 
Published: February 2017

64 Background: With the recent FDA approval of abiraterone acetate, CYP17 (17α hydroxylase/C17, 20-lyase) has become a proven target for the treatment of castration- resistant prostate cancer. Inhibition of CYP17-lyase causes a decrease in circulating androgens, severely hampering activation of the androgen receptor signaling pathway that prostate cancer relies on for proliferation. However, inhibition of CYP17-hydroxylase, a second enzymatic activity of CYP17, leads to an increase in upstream steroids that can cause mineralocorticoid excess syndrome as well as a decrease in cortisol production. VT-464 is a novel, selective CYP17 lyase inhibitor with decreased activity against CYP17 hydroxylase. The study objectives were to observe the effects of VT-464 in a prostate cancer xenograft model and to compare its activity to abiraterone acetate and surgical castration. Methods: SCID mice were implanted subcutaneously with LNCaP cells. When tumors reached 100mm3, mice were randomized to receive vehicle (0.5% CMC in saline, 5ml/kg), or VT-464 at 15, 50, or 100mg/kg p.o. bid. A second cohort of LNCaP tumor-bearing mice received vehicle, surgical castration, or VT-464 or abiraterone acetate at 100mg/kg p.o. bid for 28 days. Results: In the LNCaP xenograft model, percent growth inhibition (± S.E.) of 9.6 (±15.6), 38.5(±12.4), and 73.9 (±13.2) was observed on day 21 of treatment for the VT-464 doses of 15, 50, and 100 mg/kg, respectively. VT-464 -treated (100mg/kg) mice had a signiﬁcantly reduced tumor volume ratio (V/V0) on day 28 compared to control and abiraterone acetate (p<0.05, p<0.01, respectively). Reduction in tumor volume ratios were similar between VT-464-treated (100 mg/kg) and castrate animals. Conclusions: VT-464 exhibited dose-dependent growth inhibition with significantly reduced tumor growth at the highest dose compared to abiraterone acetate. The reduction in tumor growth in VT-464-treated animals was similar to that of castrate animals. These preclinical results show promising activity of VT-464 in the treatment of prostate cancer.
Can PSA doubling time exactly predict the candidates for active surveillance in patients with low-risk prostate cancer?
Authors: Maruyama Satoru , Shinohara Nobuo , Abe Takashige , Sazawa Ataru , Nonomura Katsuya 
Published: February 2017

65 Background: Currently, there are few well-validated data of PSA kinetics (PSA doubling time [PSADT] and PSA velocity) in active surveillance protocols. The objective of the study was to elucidate whether PSADT could predict patients with low-risk prostate cancer suitable for active surveillance (AS). Methods: The study included 149 consecutive patients treated with radical prostatectomy (RP). We selected patients who could be candidates for AS (PSA≤10ng/ml and Gleason score (GS)≤3+3 and cT1-2N0M0). PSA had been measured two times at least in a year before surgery. After all, from April 2000 to March 2008, we retrospectively reviewed a total of 47 patients (median age were 64 years, range: 53-75). Patients were divided into the following two groups: patients whose PSADT<36 months (Rapid group) and the others (Non-rapid group). We determined the respective rates of upgrading, upstaging and biochemical relapse-free survival (bRFS) in each group. Risk factors were evaluated using a Cox proportional hazards model. Results: In the whole specimen of 47 pts, upgraded to Gleason score 7-8, extracapsular extension (ECE: pT3a disease), seminal vesicle involvement and upstaged were 23 (49%), 7 (15%), none (0%) and 7 (15%), respectively. No statistical significance was observed in occurrence rates of upgrading and upstaging between Rapid group (56%, 19%) and Non-rapid group (45%, 13%). There was no significant difference in biochemical-free survival rates in two groups (5-year bRFS were 71% and 77%, respectively). The Cox proportional hazards analysis demonstrated that any pre-operative factors including PSADT were not significant risk factors for biochemical relapse. Conclusions: Our findings revealed that pre-opeative PSADT did not reliably predict pathology and prognosis after RP in those who were candidates for AS. PSADT is not suitable for selection criteria and for monitoring on active surveillance.
Combination of a polyamine-free oral nutritional supplement (ONS) with docetaxel in castrate-resistant prostate cancer (CRPC) patients (pts): A phase II trial.
Authors: Artignan Xavier , Miglianico Laurent , Bligny Dominique , Abraham Christine , Moulinoux Jacques Philippe , Cipolla Bernard 
Published: February 2017

67 Background: Polyamines (PA) are essential for cancer cell growth. Reducing exogenous PA (foods + gut flora) and blocking PA synthesis, reduces tumour growth and potentializes chemotherapy in rodent tumour models. We have developed a PA “free” ONS, which inhibits tumour growth by 40% in pre-clinical models and assessed its tolerance with docetaxel in CRPC pts. Methods: 30 pts, 71 ± 7 years, with metastatic CRPC, median PSA: 95 ng/ml, were assessed for tolerance, quality of life (QLQ C-30 questionnaire), W.H.O. performance status (P.S.), pain scores and prostate specific antigen (PSA) response. 90% pts were painful. 75% pts had opiate or morphinic analgesics at day 0 (D0). Median pain score is 5 (0 to 10 scale). The PA free ONS was given as sole diet (6 cans a day) for 14 days then progressively reduced and given with low PA containing foods. Docetaxel administration started on day 21 for 6, 75 mg/m2 injections, every three weeks with prednisone. Nutrialys Medical Nutrition, France, provided the PA free ONS. Results: 27 pts were evaluated for the PA ONS free phase. 18 pts completed the trial at scheduled dates and docetaxel doses. 9 pts did not complete the trial: disease progression (n=4), initial thrombocytemia (n=2), 2 deaths and 1 GI intolerance PA free ONS stage: No specific toxicity was recorded. Quality of life (p=0,03), pain (p=0,03) and anorexia (p=0,01) are improved at day 14. 1 pt had a > 50 % PSA decrease. PA free ONS + docetaxel stage: grade 1 or 2 nausea, vomiting or diarrhoea are observed in less than 35 % pts with no onycholysis or neuropathy. Body weight and biological parameters are preserved except for two grade 4 neutropenias. P.S., pain scores and anorexia are improved. 50% pts reduced their analgesic consumption by 50%. 13 pts (46 % of the whole population, 70% pts who completed the trial) had an > 50% PSA decrease. Conclusions: The PA free ONS is well tolerated during the neo-adjuvant phase with quality of life and pain improvements. The docetaxel PA free ONS combination tolerance is excellent with improved P.S., pain score and analgesic consumption. AE during chemotherapy are minimal. PSA responses are observed in a significant proportion of treated patients.
Parametric effect size estimates from sipuleucel-T randomized trials.
Authors: Blumenstein Brent A. 
Published: February 2017

75 Background: Median survival differences are frequently used as measures of effect size because they are easily understood. Other effect size estimates can more fully represent the whole of survival distributions, however, and are less subject to local variations. The sipuleucel-T D9901 (Small, JCO 2006) and IMPACT (Kantoff, NEJM 2010) trials provide 4.5 and 4.1 month estimated median survival differences, respectively, and hazard ratio estimates of 0.586 and 0.752 (not stratified or adjusted). These estimates are based on non-parametric (median) or semi-parametric (hazard ratio) methods. Parametric statistical models are used to illustrate alternative effect size estimates. Methods: Parametric models used are based on the Weibull distribution and a modification of the Weibull distribution allowing for delay of effect. Delay of effect is often conjectured as being responsible for delayed separation of Kaplan-Meier estimates in immunotherapy evaluations (Hoos, JNCI 2010), and both trials exhibit some degree of delayed separation. Parametric models specify the general shape of the hazard functions. Results: The following table repeats estimates given above and shows parametric modeling results. For D9901 the median difference estimate from the Weibull model suggest a much larger effect, and the median difference and the hazard ratio estimates using the delayed effect Weibull model are both indicative of more effect. For IMPACT the median difference and hazard ratio estimates from the Weibull model indicate more effect, but not as dramatic as for D9901. The delayed effect modified Weibull model for IMPACT does not support the conjecture of delayed effect. Conclusions: Statistical modeling illustrates alternative methods of obtaining effect size estimates. For the sipuleucel-T trials there is a suggestion of more effect than obtained from non-parametric or semi-parametric methods. [Table: see text]