bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of meta-analysis of clear cell renal cell carcinoma gene expression to define a variant subgroup and identify gender influences on tumor biology.
Authors: Haake Scott Mattox , Brannon A. Rose , Hacker Kate , Pruthi Raj , Wallen Eric , Nielsen Matthew Edward , Rathmell Kimryn
Published: February 2017

412

Background: Clear cell renal cell carcinoma (ccRCC) displays molecular and histological heterogeneity. Previously described subsets of this disease, ccA and ccB, were defined based on multi-gene expression profiles, but it is unclear if these subgroupings reflect the full spectrum of disease or how these molecular subtypes relate to histological descriptions or gender. We sought to determine whether additional subtypes of ccRCC exist, and whether these subtypes are related to VHL inactivation, HIF1/HIF2 expression, tumor histology, or gender.

Methods: Six large publically available ccRCC gene expression databases were identified that cumulatively provided data for 480 tumors for meta-analysis via meta-array compilation. Unsupervised consensus clustering was performed on the meta-arrays. Tumors were examined for the relationship of multigene-defined consensus subtypes and expression signatures of VHL mutation and HIF status, tumor histology, and gender.

Results: Two dominant subsets of ccRCC were observed. However, a minor third cluster was revealed which correlated strongly with a wild type VHL expression profile and indications of variant histologies. When variant histologies were removed, ccA tumors naturally divided by gender. This technique is limited by potential for persistent batch effect, tumor sampling bias, and restrictions of annotated information.

Conclusions: ccA and ccB subsets of ccRCC are robust in meta-analysis among histologically conventional ccRCC tumors. A third group of tumors was identified, which may represent a new variant of ccRCC. Within definitively clear cell tumors, gender may delineate tumors in such a way that could have implications regarding current treatments and future drug development.
Efficacy and safety of pazopanib as a subsequent treatment after failure of other targeted agents in patients with metastatic renal cell carcinoma (mRCC).
Authors: Tan Jiahuai , Heilbrun Lance K. , Fontana Joseph A. , Smith Daryn , Heath Elisabeth I. , Baranowski Karen , Vaishampayan Ulka N.
Published: February 2017

415

Background: Pazopanib is an oral tyrosine kinase inhibitor and is currently approved for treatment of patients with advanced or mRCC in the first-line, or second-line setting, after progression on cytokine therapy. No reports of efficacy and safety are available post targeted therapy. We conducted a retrospective analysis of cases receiving pazopanib after failure of other targeted agents.

Methods: The study was reviewed and approved by our Institutional Review Board. Review of medical records of advanced renal cancer patients, treated with second-line pazopanib from April 2010 to August 2011 at Karmanos Cancer Center was performed. The Common Terminology Criteria for Adverse Events version 4.0 was used to grade the severity of definitely treatment-related adverse events (AEs).

Results: 14 patients are included to date in this ongoing data collection and analysis study. Median age was 58 years, 8 were Caucasian, 4 African American, and 2 other races. By the MSKCC criteria, 1 patient was favorable, 6 were intermediate and 7 poor risk. Pazopanib was utilized as second line in 4 patients, third line in 5, and even later in 5. Prior line targeted therapies included sunitinib (8), temsirolimus (9), everolimus (4), sorafenib (1), bevacizumab (1) and axitinib (1). Nine of 14 patients to date were treated with pazopanib for at least 2 months and were assessed for response by imaging studies. One achieved partial remission; 5 had stable disease, and 3 had progression. The median time to progression after starting pazopanib was 4.0 months. The predominant AEs were grade 1 or 2, which included fatigue (4), liver enzyme elevation (3), diarrhea (2), hypertension (2), skin rash (1), depression (1) and hyponatremia (1). No grade 3 or 4 AEs, or definitely treatment-related deaths were observed.

Conclusions: Pazopanib appears to maintain efficacy and tolerability in mRCC even after failure of other targeted therapies. Further investigations of larger patient cohorts in this setting are recommended.
Incidence and oncologic outcome of renal cell carcinoma in hemodialysis patients detected by annual computed tomography (CT) screening.
Authors: Hatakeyama Shingo , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Kamimura Noritaka , Ohyama Chikara
Published: February 2017

426

Background: Patients with maintenance hemodialysis (HD) have been recognized as a high risk group for cancer. The aim of this study was to verify the incidence and oncological outcomes of patients on maintenance hemodialysis with renal cell carcinoma (RCC) compared with RCC patients without renal dysfunction.

Methods: We have been carried out annual screening for renal mass for the hemodialysis patients.The oncological outcome of pT1N0M0 RCC detected by annual screening of CT imaging were retrospectively reviewed in 1217 patients with HD between January 2002 and December 2010 at Oyokyo kidney Research Institute and Hirosaki University Hospital, Hirosaki, Japan. Overall and cancer specific survival was compared with age matched 106 of pT1N0M0 RCC patients without renal dysfunction who performed radical nephrectomy at the same periods.

Results: Among the hemodialysis patients, 14 RCCs were incidentally detected by screening CT examinations and RCC detection rate in HD patients was 0.27% per year. Total 119 pT1N0M0 RCC patients (13 with HD group, 106 normal kidney function group) were incidentally detected by regular abdominal CT imaging without symptoms. There were no significant differences on age and gender between HD and normal kidney function group. Cancer specific survival after tumor diagnosis was not different, but overall survivals were significantly superior in patients without renal dysfunction compared to those with chronic renal failure (P < 0.0001). Cancer specific and Overall 5-year survival was 95% and 96% in patients without renal dysfunction, 92% and 54% in those with chronic renal failure.

Conclusions: There was no significant difference in cancer specific survival of pT1 RCC between the two groups. However, overall survival was significantly worse in HD patients. Oncological effectiveness of annual CT screening for the HD patients was not evident in the present retrospective study.
Signaling pathway-based stratification of clear cell renal cell carcinoma.
Authors: Bongarzone Italia , Cremona Mattia , Espina Virginia A. , Miccichè Francesca , Veneroni Silvia , Colecchia Maurizio , Pierobon Mariaelena , Deng Jianghong , Mueller Claudius , Procopio Giuseppe , Lanzi Cinzia , Petricoin Emanuel , Liotta Lance A.
Published: February 2017

434

Background: There are marked differences in responses to therapy among patients with clear cell renal cell carcinoma (ccRCC), which makes the outcome difficult to predict. This study is aimed to define a new classification system that would elucidate distinctions between carcinomas in order to facilitate selection of the appropriate treatment. We mapped cell signaling pathways in individual renal cell carcinomas and identified different classes based on commonly shared phosphorylation-driven signaling networks.

Methods: Laser capture microdissection and reverse-phase protein arrays were used to profile 75 key nodes in 16 primary clear cell renal cancers. These nodes represent many signaling pathways known to be important in tumorigenesis and progression.

Results: Statistical analysis revealed significant differences (p <0.05) in signaling levels between two groups of samples, group A (4 samples) and group B (12 samples), for 27 of the 75 endpoints tested. In group A, high activation levels of EGFR, RET, and RASGFR1 converged to activate AKT/mTOR. Group B, showed high phosphorylation levels of ERK1/2 and STAT transcription factors and samples significantly partitioned in two clusters of 7 and 5 cases designated C and D. Group C showed elevated expression of a regulator of autophagy, LC3B; group D showed activation of Src and STAT transcription factors, suggesting the presence of cytokine-mediated cell survival pathways. A DNA copy number analysis was performed on the same samples and the results showed that group B represents some paradigmatic cases of ccRCC, with VHL loss-of-function mutations.

Conclusions: The proteins identified appeared to be linked to pathways that are targeted by drugs typically used to treat clear cell renal cell carcinoma. Thus, this type of analysis could be useful for stratifying patients and selecting the best therapeutic approaches.
Vascular endothelial growth factor (VEGF) therapy in metastatic renal cell carcinoma (mRCC): Differences between Asian and non-Asian patients.
Authors: Wang Ying , Choueiri Toni K. , Lee Jae-Lyun , Tan Min-Han , Rha Sun Young , North Scott A. , Kollmannsberger Christian K. , Heng Daniel Yick Chin
Published: February 2017

451

Background: Several reports have indicated that VEGF targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in the Asian versus Caucasian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterized.

Methods: Eight centers participating in the International mRCC Database Consortium with available dose reduction data on patients with mRCC treated with VEGF targeted therapy were included in this analysis. Asian patients were derived from centers in Korea and Singapore.

Results: 1024 patients with a median follow-up of 29.4 months were included in this analysis. Baseline characteristics are below. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% p=0.1197) but more patients completely discontinued treatment due to toxicity in the non-Asian vs the Asian group (28% vs 21% p=0.0197). When adjusted for the Heng et al poor prognostic criteria, there was no difference in overall survival (HR 0.887, 95%CI 0.729-1.08, p=0.2322) or progression-free survival (HR 1.069, 95%CI 0.910-1.256, p=0.4184) between non-Asians and Asians. Interestingly, when patients were dose reduced due to toxicity, they had a longer treatment duration and overall survival than those that did not require a dose reduction in both the non-Asian (10.6 vs 5.0 months p<0.0001 and 22.6 vs 16.1 months p=0.0016, respectively) and in the Asian populations (8.9 vs 5.4 months p=0.0028 and 28.0 vs 18.7 months p=0.0069).

Conclusions: After adjusting for risk groups, there appears to be no difference in outcome between Asians vs. non-Asian patients with mRCC treated withVEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations possibly due to longer treatment durations, but direct comparisons are needed.

[Table: see text]
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]
Protein BIII-tubulin expression as a prognostic and/or predictive factor of response to docetaxel in patients with hormone-refractory prostate cancer.
Authors: Perez Quionia , Alvarez Carlos , Ruiz Lucrecia , Gutierrez Eduardo , Rodriguez David , Villanueva Noemi , Berros Jose Pablo , Fonseca Paula J. , Vieitez Jose Maria , Esteban Emilio
Published: February 2017

84

Background: Docetaxel is a standard treatment for hormone-refractory prostate cancer. Preclinical-clinical studies suggest that the determination of the BIII-tubulin is associated with response to taxanes. This study analyzes the role of that subunit of microtubules in prostate biopsies of patients with HRPC treated with docetaxel.

Methods: Thirty two patients with prostate biopsy who received docetaxel in first-line chemotherapy between 2006 and 2011 were included in this retrospective cohort analysis. The clinic-pathological characteristics, PSA response, progression-free survival (PFS) and overall survival (OS) were collected. The findings were correlated with the overexpression of BIII-tubulin protein measured by immunohistochemistry techniques (IHC) with a purified and monoclonal Ac mouse.

Results: The median age and Karnofstky index (KI) were 68 years (range 49-77) and 80% (60-90) respectively. Five patients (15.6%) had received only one anti-hormone treatment, fifteen (46.8), two and twelve (37.5) more than two lines. Twenty patients (62.5) had only one metastatic localization. The median of PSA value before the docetaxel treatment was 302 (4-3745). With a median of eight cycles (3-10) of docetaxel (75mg/m2/ /3s) 41% of patients achieved biochemical response with a median PFS and OS of 4.9 and 19.6 months respectively. Moderate-intense overexpression of BIII-tubulin was identified in five patients (15.6) and minimal or absent in 27 (84.4). In univariate analysis, over-expression was correlated with KI, but not with Gleason score. PSA responses to docetaxel was observed in four patients (80%) with over-expression compared with 20% of those with minimal or absent BIII-tubulin staining. The median PFS and OS for patients with over-expression was 8.6 and 20 months respectively compared to 4.3 and 17 months for those with minimal or absent BIII-tubulin.

Conclusions: Over-expression of BIII-tubulin in tumor prostate tissue, applying the present technique is unusual. Its presence appears to be related with higher biochemical response to docetaxel and improvement in PFS and OS. These findings are discordant with those previously published.
Skeletal events unrelated to bone metastasis in men with castration-refractory prostate cancer.
Authors: Kamoi Kazumi , Okihara Koji , Takaha Natsuki , Iwata Tsuyoshi , Kawauchi Akihiro , Miki Tsuneharu
Published: February 2017

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Background: The purpose of this study was to analyze skeletal events unrelated to bone metastasis in men with castration-refractory prostate cancer (CRPC).

Methods: A total of 68 patients with CRPC treated by secondary hormonal therapy (dexamethasone) and/or chemotherapy including docetaxel were analyzed. Primary endpoint was skeletal related events (SREs) after PSA relapse. PSA relapse was defined as 3 consecutive PSA increase and serum PSA more than 4 ng/ml. Zoledronic acid was given for 31 patients with radiographic bone progression from the initiation of docetaxel-based treatment. For 37 patients without radiographic bone progression, no bone targeted agents or radioisotopes were administered during the observation period.

Results: During median observation period of 17.5 months (range 1 to 76 months), SREs were observed in 17 of 68 patients (25%). In patients with bone progression, SREs was observed in 8 of 37 (22%) patients, whereas 9 of 31 (29%) patients without radiographic bone progression experienced SREs unrelated to bone metastasis. All patients without radiographic progression had been treated by oral steroids (dexamethasone), which might be related to osteoporotic change in these cases.

Conclusions: For CRPC patients without radiographic bone progression, caution needs to be paid for SRE unrelated to bone metastasis. The administration of steroids may cause osteoporotic change, thus preventive administration of anti-osteoporotic agents would be mandatory.
Dose to the muscles of fecal continence during radiation therapy for prostate cancer.
Authors: Waggoner Adam , Brown Michael , Tinnel Brent , Halligan John B , Brand Timothy , Brooks Joseph P , Ninneman Stephanie , Hughs Grant , Macdonald Dusten
Published: February 2017

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Background: Radiation therapy for prostate cancer can lead to loss of fecal continence; our understanding of the dose-volume relationships of this late toxicity continues to develop. The external anal sphincter (EAS), internal anal sphincter (IAS), and the three parts of the levator ani muscle, the puborectalis (PRM), the pubococcygeus (PCM), and the illiococcygeus (ICM), all contribute to fecal continence. We developed a reproducible method for contouring these muscles and in this preliminary study evaluate whether decreased planning target volume (PTV) margins lead to potentially clinically significant decreases in dose to these muscles during definitive radiation therapy for prostate cancer.

Methods: Muscles involved in fecal continence were contoured for 10 consecutive patients on a prospective study of reduced PTV margins for treating low-to-intermediate risk prostate cancer with intensity-modulated radiation therapy (IMRT) using an electromagnetic localization system. IMRT plans to a prescribed dose of 7740 cGy were developed using 10mm PTV margins (5mm posteriorly), and compared with actual treatment IMRT plans using 3mm circumferential PTV margins. Decreases in dose were evaluated for statistical significance using an unpaired t-test.

Results: Reducing PTV margins decreased the mean PTV volume from 176.2 ml to 91.9 ml. Mean doses to the EAS, IAS, and rectum (REC) decreased significantly; from 11.0 Gy to 4.1 Gy (p=0.005), from 30.5 Gy to 15.0 Gy (p = 0.004), and from 43.7 Gy to 35.6 Gy (p=0.006) respectively. Decrease in the mean dose to the PRM was nearly statistically significant, 48.7 Gy to 34.6 Gy (p = 0.055). Decreases in mean doses to the PCM and ICM were not statistically significant; from 61.9 Gy to 55.2 Gy (p = 0.107), and from 40.7 Gy to 34.8 Gy (p = 0.176), respectively.

Conclusions: Using electromagnetic tracking to reduce PTV margins leads to a significant decrease in dose to the muscles of fecal continence, with mean dose decreases in a range that may be clinically significant.
Neoadjuvant hormone therapy for radical prostate radiotherapy: A case-matched study comparing bicalutamide to LHRH agonist therapy.
Authors: O'Hare Jolyne , McGivern Ursula , McDowell Cliona , Mitchell Darren M. , Corey Gemma , O'Sullivan Joe M.
Published: February 2017

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Background: To assess and compare the biochemical failure free survival (BFFS), PSA kinetics and absolute PSA responses in men receiving radical radiotherapy for localized prostate cancer (RT) receiving either neoadjuvant bicalutamide or neoadjuvant LHRH agonist therapy.

Methods: A retrospective review of consecutive cases with prostate cancer treated with BC monotherapy prior to radical radiotherapy was individually case matched to men treated with neoadjuvant LHRHa monotherapy from April 2004 to December 2008. PSA kinetics and absolute pre-RT, post neo-adjuvant hormone PSA (PRPH-PSA) level and subsequent BFFS were analyzed.

Results: 65 men treated with BC monotherapy were individually matched with 65 men treated with LHRHa. The median follow-up was 44 months and 54 months respectively. There were no significant differences in pre-treatment patient or tumour characteristics. Statistically significant differences were noted between groups in the PRPH-PSA with a geometric mean of 2.0ng/ml (range 0.1 – 11.2ng/ml) for BC patients and 1.0ng/ml (range 0.1 – 11.1ng/ml) for LHRHa patients (p<0.001). The geometric mean PSA halving time during the neo-adjuvant period of 14.6weeks (range 2 – 160weeks) in the BC treated group was statistically significantly different when compared to the mean of 16.1 weeks (range 2.1-96.8 weeks) for LHRHa patients (p=0.056). There were however no differences in PSA velocity. A PRPH-PSA of <1.0ng/ml and <0.1ng/ml was seen in 16(24.6%) and 2 (3%) of the BC patients and 34(52.3%) and 3(4.6%) of LHRHa patients respectively. Phoenix biochemical failure was seen in 10(15.4%, 95%CI [8.6%, 26.1%]) and 8(12.3%, [6.4%, 22.5%) of BC and LHRHa patients respectively. Neither PRPH-PSA level nor PSA kinetics during the neo-adjuvant period predict for subsequent BFFS at this duration of follow-up.

Conclusions: In this case-matched study, we found that although neo-adjuvant BC therapy did not result in equivalent PRPH-PSA suppression when compared to neo-adjuvant LHRHa alone, there was no difference in biochemical failure rates between the cohorts at an overall median follow-up of 44 months. Longer follow-up is required.
Predictive factors for acute and late urinary toxicities after permanent prostate brachytherapy.
Authors: Tanimoto Ryuta , Bekku Kensuke , Kobayashi Yasuyuki , Ebara Shin , Araki Motoo , Katayama Norihisa , Nasu Yasutomo , Kumon Hiromi
Published: February 2017

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Background: To describe the frequency of acute and late Radiation Therapy Oncology Group (RTOG) urinary toxicity associated with predictive factors and International Prostate Symptom Score (IPSS) in consecutive prostate brachytherapy patients.

Methods: From January 2004 to April 2011, 466 patients underwent permanent 125I-seed brachytherapy (median follow-up, 48 months). The IPSS and RTOG toxicity data were prospectively collected. The prostate volume, IPSS before and after brachytherapy and postimplant analysis were examined for an association with urinary toxicity which was defined as urinary RTOG toxicity 1 or more. Logistic regression analysis was used to examine the factors associated with urinary toxicities.

Results: The rate of RTOG urinary toxicity Grade 1 or more at 1, 6, 12, 24, 36, 48 months was 67%, 40%, 21%, 31%, 27%, 28%, respectively. Grade 2 or more urinary toxicities were less than 1% at an each point. IPSS was highest at 3 months and returned to normal level at 12 months after brachytherpapy. On univariate analysis, patients with larger prostate size, greater baseline IPSS, the higher post V100 (volume of the prostate covered by 100% of the dose), higher post V150 and higher post D90 (dose that 90% of the target volume received) had more acute urinary toxicities 1 month as well as 12 months after brachytherapy. On multivariate analysis, the significant predictors for urinary toxicities were a greater baseline IPSS and post V100 one month as well as 12 months after brachytherapy (shown below).

Conclusions: Most urinary symptoms were tolerated and resolved within 12 months after prostate brachytherapy. Acute and late urinary toxicities after brachytherapy were strongly related with baseline IPSS and the post V100.
Safety, efficacy, and pharmacodynamics of the investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer (mCRPC): Updated data from a phase I/II study.
Authors: Agus David B. , Stadler Walter Michael , Shevrin Daniel H. , Hart Lowell , MacVicar Gary R. , Hamid Omid , Hainsworth John D. , Gross Mitchell E. , Wang Jingyuan , Webb Iain James , MacLean David , Dreicer Robert
Published: February 2017

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Background: The investigational agent orteronel (TAK-700) is a selective 17,20 lyase inhibitor that down regulates androgenic steroid production in vitro and in vivo. Since phase 1 data in patients (pts) with mCRPC were promising, this open-label, multicenter study was expanded to gather additional data on safety and antitumor activity.

Methods: The phase 2 portion of this study included four additional dose cohorts. Pts had no prior chemotherapy, and had baseline testosterone <50 ng/dL and prostate-specific antigen (PSA) ≥5 ng/mL.

Results: 97 pts received orteronel 300 mg BID (n=23), 400 mg BID + prednisone 5 mg BID (n=24), 600 mg BID + prednisone (n=26), or 600 mg QD (n=24). At data cut-off (23 May 2011), 62% of pts had withdrawn (including 19% due to AEs and 19% for disease progression [PD]). Most common AEs were fatigue (76%), nausea (47%), and constipation (38%); most common grade ≥3 AEs were fatigue (12%) and hypokalaemia (8%). PSA response rates (≥50% decrease) at 12 wks were 63%, 50%, 41%, and 60% in the 300 mg BID, 400 and 600 mg BID + prednisone, and 600 mg QD groups. Of 51 RECIST-evaluable pts, 10 had partial responses (of which 5 confirmed), 22 stable disease, and 15 PD. At 12 wks, median testosterone decreased from baseline in all groups: (ng/dL, 12 wks/baseline) 0.98/8.50 (300 mg BID), 0.30/9.90 (400 mg BID +prednisone), 0.07/7.33 (600 mg BID + prednisone), 0.49/6.31 (600 mg QD). Similarly, at 12 wks, median dehydroepiandrosterone sulfate (DHEA-S) decreased from baseline in all groups: (µg/dL, 12 wks/baseline) 8.65/53.0 (300 mg BID), 0.10/36.3 (400 mg BID + prednisone), 0.10/51.7 (600 mg BID + prednisone), 5.30/31.5 (600 mg QD). Overall, mean circulating tumor cell numbers decreased from 16.6 (per 7.5mL blood) at baseline to 3.9 at 12 wks.

Conclusions: Orteronel ≥300 mg BID appears active and well tolerated in pts with mCRPC, with similar efficacy ± prednisone. PSA response rates suggest that testosterone, rather than DHEA, may be a more reliable marker of lyase inhibition efficacy. Preclinical data and changes in pharmacodynamic parameters in this study suggest partially selective 17,20 lyase inhibition. Final data will be reported.