Biochemical Progression Research Articles

Elevated levels of autophagy-related marker ULK1 and mitochondrion-associated autophagy inhibitor LRPPRC are associated with biochemical progression and overall survival after androgen deprivation therapy in patients with metastatic prostate cancer

AimTo evaluate the expression levels and prognostic significance of autophagy-related markers, UNC-51-like kinase1 (ULK1), Beclin1, microtubule-associated protein light chain 3 (LC3), autophagy-related gene 5 (ATG5) and mitochondrion-associated autophagy inhibitor, LRPPRC,...

Proposal for magnetic resonance imaging-guided salvage radiotherapy for prostate cancer

Background: A subset of patients experience a biochemical recurrence following radical prostatectomy. Radiotherapy can salvage those patients, provided that all disease is encompassed within the target volume. We hypothesized that this can be achieved more adequately with magnetic resonance imaging (MRI)-guided treatment planning.Material and methods: From January 2009 to April 2014, 183 patients were referred to our department for salvage radiotherapy (SRT). According to protocol, patients received a planning computed tomography (CT) as well as an MRI in treatment position. All MRI scans were retrospectively reviewed by an experienced uro-radiologist.Results: Median prostate-specific antigen (PSA) value at time of referral was 0.3 ng/ml (range 0.02–4.7 ng/ml). MRI did not show any suspected macroscopic disease in 137 patients (75%). In 46 (25%) patients, MRI did indicate a pelvic recurrence. The mean PSA level was significantly higher in patients with a suspected recurrence on MRI (0.4 vs. 1.4 ng/ml, p < .001) on a Student’s t-test. The mean follow-up was 33 months (range 5–69 months). Biochemical disease-free survival (bDFS) was significantly worse in patients with suspected disease on MRI [hazard ratio (HR) 2.9, p < .0001]. bDFS was significantly worse in the subgroup where the macroscopic recurrences on MRI received a lower radiation dose (HR 3.4, p = .01).Conclusion: MRI detects loco-regional disease in a substantial subset of patients with a biochemical recurrence after prostatectomy, especially in a PSA above 0.5 μg/l. Lack of MRI-based dose escalation on these macroscopic recurrences could explain some of the biochemical progression observed after SRT.

Expression of several cytokines in prostate cancer: Correlation with clinical variables of patients. Relationship with biochemical progression of the malignance

BackgroundThis work is focused on finding new markers that complement or diagnoses currently used towards improving knowledge histological and statistical aspects that allow us to predict the local stage carcinomas and to identify and understand all the factors related to the progression of this disease. Materials and methodsProstates were obtained from: normal prostates from 20 men, diagnosis of BPH (Benign Prostatic Hyperplasia) from 35 men and prostate cancer from 86 men. We studied the behavior of cytokines that have been implicated in inflammatory processes: TNF-alfa, IL-6, IL-1, EGF and TGF-B. Expression of these cytokines and its receptors was analyzed by immunohistochemistry. Spearman’s test, Kaplan-Meier curves, univariate and multivariate Cox proportional hazard regression analyses were performed. ResultsSpearman’s analysis showed that there was at least one correlation between TGFB-B, IL-6, gp-130, IL-1B, IL-1R, IL-1RII and clinic pathological feature (preoperative serum PSA, clinical t stage, pathological t stage, positive surgical margins, biochemical progression, survival). Immunostaining score was correlated with some of the clinicopathological feature. In Cox multivariate analysis between the prognostic variables (pathological T stage, Gleason score and lymph node) and immunohistochemical parameters (TGF-B, IL-1a, intensity TGFBRI and intensity TGFBRII) only the expression of IL-1a was retained as independent predictors of biochemical progression after radical prostatectomy. ConclusionsOur results suggest a role for prostatic expression of TGF-B, IL-1a, TGFBRI and TGFBRII as prognostic markers for prostate cancer. The rational combination of novel agents directed toward the inactivation of TGF-B, IL-1a, TGFBRI and TGFBRII could disrupt complementary tumor cell proliferation pathways.

Sodium-Glucose Cotransporter-2 Inhibition and the Glomerulus: A Review.

Blood glucose-lowering treatment options generally target insulin action or beta-cell function. In diabetes, expression of the sodium-glucose cotransporter-2 (SGLT2) genes is up-regulated and renal threshold increased, resulting in increased glucose reabsorption from glomerular filtrate, reducing urinary glucose excretion and worsening the hyperglycemic condition. The SGLT2 inhibitors (SGLT2i) are a novel class of anti-diabetic drugs that lower blood glucose levels through the suppression of renal glucose reabsorption thereby promoting renal glucose excretion. The efficacy of SGLT2i is reduced in renal impairment because the ability of glucose-lowering is directly proportional to glomerular filtration rate. On the other hand, ongoing research suggests that SGLT2i may offer potential nephroprotection in diabetes. The SGLT2i have been shown to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and the biochemical progression of chronic kidney disease. Additional mechanisms through which SGLT2i exert nephroprotection may include normalizing blood pressure and uricemia. This review explores this bidirectional relationship of the SGLT2i and the glomerulus. While SGLT2i exhibit reduced efficacy in later stages, they exhibit nephroprotective effects in early stages of renal impairment. Funding: Janssen India (Pharmaceutical division of Johnson & Johnson).

A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study.

The identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa).We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data.Most cancers (n = 3056) including PCa (n = 300) exhibited hypermethylation of THOR. THOR was the only region within the TERT gene that is differentially methylated between normal and malignant prostate tissue (p < 0.0001). Also, THOR was significantly hypermethylated in PCa when compared to paired benign tissues (n = 164, p < 0.0001). THOR hypermethylation correlated with Gleason scores and was associated with tumor invasiveness (p = 0.0147). Five years biochemical progression free survival (BPFS) for PCa patients in the discovery cohort was 87% (95% CI 73–100) and 65% (95% CI 52–78) for THOR non-hypermethylated and hypermethylated cancers respectively (p = 0.01). Similar differences in BPFS were noted in the validation cohort (p = 0.03). Importantly, THOR was able to predict outcome in the challenging (Gleason 6 and 7 (3 + 4)) PCa (p = 0.007). For this group, THOR was an independent risk factor for BPFS with a hazard-ratio of 3.685 (p = 0.0247). Finally, THOR hypermethylation more than doubled the risk of recurrence across all PSA levels (OR 2.5, p = 0.02).

Abstract 1406: Analysis of immune responses as a consequence of androgen deprivation therapy in patients with biochemical progression of prostate cancer

Abstract We evaluated the immune responses in 28 patients enrolled in a phase II trial at the National Cancer Institute (NCI). The aim was to investigate the effects of 3 months of androgen deprivation therapy (ADT) with goserelin on the immune responses in patients with biochemical progression of prostate cancer following local definitive therapy. PBMC and sera were collected before treatment and after 3 months. We performed flow cytometry to evaluate the frequencies of subsets of CD4+ and CD8+ T-cells, regulatory T-cells (CD4+ CD25hi CD127− FoxP3+), MDSCs and CD4 and CD8 recent thymic emigrants. CD4 T-cell proliferation and NK-cell lytic activity were evaluated. Serum samples were analyzed for cytokines, sCD27 and sCD40L. The baseline characteristics were: median age 64 years, testosterone 361 ng/dl, PSA 2.2 ng/ml, PSA-doubling time 7.0 months, and Gleason score 7. After 3 months of ADT we found no significant changes in NK-cell function or frequencies of NK subsets. CD4+ T-cell proliferation decreased slightly. The number of CD4+ effector memory T-cells decreased, but other CD4 subsets were unchanged. The frequencies of CD4 and CD8 recent thymic emigrants did not change. Regulatory T-cells (including the CTLA4+ subset), and the effector:Treg ratio did not change. In contrast, the frequency of granulocytic MDSC decreased (P&amp;lt;0.01). There was an increase in the sCD27:sCD40L ratio (P = 0.012), due to decreased sCD40L. There was a decrease in the serum levels of IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, GM-CSF and IFNγ. There were no changes in the serum levels of TNFα or CXCL2 after therapy. In conclusion, three months of ADT with goserelin did not alter the immune response in a way that would decrease the likelihood of successful immunotherapy after this treatment. The decreased MDSC and the increased sCD27:sCD40L ratio could indicate a more favorable immune environment. Citation Format: Caroline Jochems, Ravi A. Madan, Romaine I. Fernando, James L. Gulley, Kwong Y. Tsang, Jeffrey Schlom. Analysis of immune responses as a consequence of androgen deprivation therapy in patients with biochemical progression of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1406.

Common Genetic Variation in CYP17A1 and Response to Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer.

Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54–90); the median prostate-specific antigen was 66 ng/dL (0.1–99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07–0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39–3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy.

The role of mindfulness in distress and quality of life for men with advanced prostate cancer.

ObjectiveTo examine the extent to which mindfulness skills influence psychological distress and health-related quality of life (HRQOL) in men with metastatic or castration-resistant biochemical progression of prostate cancer.Patients and methodsA cross-sectional survey of 190 men (46 % response; mean age 71 years, SD = 8.7, range 40–91 years) with advanced prostate cancer, assessed psychological and cancer-specific distress, HRQOL. Mindfulness skills were assessed as potential predictors of adjustment outcomes.ResultsOverall, 39 % of men reported high psychological distress. One third had accessed psychological support previously although only 10 % were under current psychological care. One quarter had accessed a prostate cancer support group in the past six months.Higher HRQOL and lower cancer-specific and global psychological distress were related to non-judging of inner experience (p < 0.001).Higher HRQOL and lower psychological distress were related to acting with awareness (p < 0.001). Lower distress was also related to higher non-reactivity to inner experience and a lower level of observing (p < 0.05).ConclusionsMen with advanced prostate cancer are at risk of poor psychological outcomes. Psychological flexibility may be a promising target for interventions to improve adjustment outcomes in this patient group.Clinical Trial RegistryTrial Registration: ACTRN12612000306819

EXPERIENCE OF HORMONE DEPENDENT PROSTATE CANCER TREATMENT BY LUTEINISING HORMONE-RELEASING HORMONE ANTAGONIST DEGARELIX

Moscow developmental program results on assessment of luteinizing hormone-releasing hormone (gonadotrophinreleasing hormone) antagonist degarelix efficacy and tolerance in patients with prostate cancer received drug treatment in specialized outpatient polyclinic institutions of Moscow are provided in the original publication. In total 307 patients were included in the study and assigned in 3 groups: 1st (n=174) – patients with progressing prostate cancer after radical treatment (prostatectomy, radiation therapy); 2d (n=92) – patients with prostate cancer had cardiovascular diseases in history; 3d (n=41) – patients with prostate cancer with early castration refractivity occurred on the background of continuous hormone therapy by luteinizing hormone-releasing hormone antagonists. In all groups degarelix was prescribed in standard therapeutic regimen (240 mg/80 mg). Degarelix was effective in all test groups that was manifested by PSA level decrease on the background of one-year drug treatment, high control of testosterone castration level. Treatment by degarelix allowed increasing time before chemotherapy prescription (up to 12 months) in certain group of patients with biochemical progression on the background of luteinizing hormone-releasing hormone analogues administration. Degarelix tolerance was good even in patients with clinically significant cardiovascular pathology in history. In 4% of cases significant reactions were observed in the injection site after start dose administration.

Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial

How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy. This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475. Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% [95% CI 75-84] vs 62% [57-67]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 [8%] of 366 patients had a grade 2 or worse event; 30 patients [8%] had hot flushes and five patients [1%] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the radiotherapy alone group vs 26 [7%] in the radiotherapy plus goserelin group) and sexual disorders (20 [5%] vs 30 [8%]). No treatment-related deaths occurred. Adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population. French Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.

Multigene Testing in Localized Prostate Cancer.

Currently, there are several commercially available multigene tests for risk stratification in prostate cancer. These tests have been validated retrospectively; however, prospective studies are needed to fully establish their clinical roles. In some cases, molecular studies may add value, and updated NCCN Guidelines recommend "consideration" of molecular tests under certain circumstances, such as to help ascertain the likelihood of death from conservative management, of biochemical progression after radical prostatectomy or external-beam therapy, and of developing metastasis after radical prostatectomy or salvage radiotherapy.

MP18-16 PROPENSITY SCORE MATCHED COMPARISON OF PARTIAL TO WHOLE GLAND CRYOTHERAPY FOR INTERMEDIATE-RISK PROSTATE CANCER: AN ANALYSIS OF THE COLD REGISTRY DATA

You have accessJournal of UrologyProstate Cancer: Localized: Ablative Therapy1 Apr 2016MP18-16 PROPENSITY SCORE MATCHED COMPARISON OF PARTIAL TO WHOLE GLAND CRYOTHERAPY FOR INTERMEDIATE-RISK PROSTATE CANCER: AN ANALYSIS OF THE COLD REGISTRY DATA Kae Jack Tay, Thomas Polascik, Ahmed Elshafei, Efrat Tsivian, and J. Stephen Jones Kae Jack TayKae Jack Tay More articles by this author , Thomas PolascikThomas Polascik More articles by this author , Ahmed ElshafeiAhmed Elshafei More articles by this author , Efrat TsivianEfrat Tsivian More articles by this author , and J. Stephen JonesJ. Stephen Jones More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2717AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Patients with intermediate-risk prostate cancer constitute a unique group of patients in whom cure may be both necessary and possible. While there has been increasing interest in partial gland therapies to reduce the morbidity of treatment, randomized comparisons to whole gland therapies have been lacking. We aim to compare the oncological and functional outcomes of partial versus whole gland cryotherapy for intermediate-risk prostate cancer. METHODS Men with D'Amico intermediate-risk prostate cancer treated with primary prostate cryotherapy were selected from the Cryo On-Line Data Registry. Men treated with partial prostate ablation (targeted ablation, unilateral/ bilateral nerve-sparing ablations) were matched 1:1 to controls who had undergone whole gland cryotherapy using a propensity score approach. The propensity score was based on age, pre-biopsy serum prostate specific antigen level, biopsy Gleason score, clinical stage, prostate volume, use of neoadjuvant androgen deprivation and year of surgery. The outcomes analysed were biochemical progression free survival (BPFS) using the ASTRO and Phoenix criteria, the 12 month continence rate (defined as being pad-free) and sexual function at 12 months (defined as the ability to have sexual intercourse. RESULTS A total of 1,749 men were identified, of whom 1,488 had undergone whole gland and 288 partial prostate cryotherapy. 200 pairs of men with complete outcome data at a mean follow-up of 30 months were analysed. The 2 and 5 year BPFS rate was 71.6% and 63.5% for whole gland vs. 81.0% and 74.6% for partial prostate ablation using the ASTRO criteria (p=0.0275) and 89.6% and 79.1% for whole gland vs. 79.8% and 68.5% for partial prostate ablation using the Phoenix criteria (p=0.0588). Of 198 pairs of men, the 12- month continence rate was identical at 95%. Of 154 pairs of men, the 12-month rate of successful intercourse was 26.6% for whole gland and 45.5% for partial prostate ablation (p=0.001). The rate of rectal fistula was 0.37% in the partial ablation group. CONCLUSIONS Biochemical progression free survival after partial prostate ablation is not significantly inferior to whole gland cryotherapy in the short to medium term and may result in better sexual function at 12 months. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e199 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Kae Jack Tay More articles by this author Thomas Polascik More articles by this author Ahmed Elshafei More articles by this author Efrat Tsivian More articles by this author J. Stephen Jones More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A single-center experience with abiraterone as treatment for metastatic castration-resistant prostate cancer

BackgroundContinuous stimulation of the androgen receptor (AR) axis is a prerequisite for growth in castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) is a potent inhibitor of extracellular and intracellular androgen synthesis by inhibition of the CYP-17 enzyme system, which has been shown to be up-regulated in CRPC. AA was recently introduced in the management of patients with metastatic CRPC (mCRPC) both before and after taxane-based chemotherapy. The purpose of this study is to report the initial clinical experience obtained from mCRPC patients managed on AA at Rigshospitalet, Denmark, and compare the results with phase III trial outcomes. Material and methodsSingle-centre, retrospective study including consecutive patients managed on AA for more than 2-year period. Treatment consisted of 1,000mg AA and 5mg prednisone twice daily. Outcomes of interest were prostate-specific antigen (PSA) response, clinical and radiological progression, and overall survival. ResultsA total of 73 consecutive patients with mCRPC undergoing treatment with AA between November 2012 and October 2014 were included. Median follow-up was 9.9 (0.9–23.4) months. PSA decline>50% was found in 39% of the patients. Time to biochemical and radiological progression was 3.5 and 4.9 months, respectively. Overall survival was 13.2 months (95% CI: 9.0–17.4). ConclusionOur initial experience with AA in the routine management of patients with mCRPC demonstrates an efficacy-effectiveness gap compared with clinical trial. Except for PSA response (>50% decline) in patients managed with AA, postchemotherapy results were inferior to phase III studies. This is most likely because of patient selection, which is a typical weakness when transferring results from phase III trials into clinical practice.

554 Does salvage lymphadenectomy for biochemical progression following radical prostatectomy and additional radiotherapy has an impact on overall survival? Initial results from a case-control study

554 Does salvage lymphadenectomy for biochemical progression following radical prostatectomy and additional radiotherapy has an impact on overall survival? Initial results from a case-control study

Five-Year Biochemical Results, Toxicity, and Patient-Reported Quality of Life After Delivery of Dose-Escalated Image Guided Proton Therapy for Prostate Cancer

To report clinical outcomes in patients treated with image guided proton therapy (PT) for localized prostate cancer. The medical records of 1327 men were reviewed. Each man was enrolled on an outcomes tracking study. Dual enrollment on a prospective clinical trial was allowed. Each patient was treated for localized prostate cancer with PT at our institution between 2006 and 2010. Ninety-eight percent of patients received 78 Gy (radiobiological equivalent [RBE]) or higher; 18% received androgen deprivation therapy (ADT). The 5-year freedom from biochemical progression (FFBP), distant metastasis-free survival, and cause-specific survival rates are reported for each risk group. Data on patient-reported quality of life and high-grade toxicities were prospectively collected and reported. A multivariate analysis was performed to identify clinical predictors of biochemical failure and urologic toxicity. The median follow-up time was 5.5 years. The 5-year FFBP rates were 99%, 94%, and 74% in low-risk, intermediate-risk, and high-risk patients, respectively. The actuarial 5-year rates of late grade 3+ Common Terminology Criteria for Adverse Events, version 4.0, gastrointestinal (GI) and genitourinary (GU) toxicity were 0.6% and 2.9%, respectively. Multivariate analysis showed a significant correlation between grade 3+ GU toxicity and pretreatment prostate reductive procedures (P<.0001), prostate volume (P=.0085), pretreatment α-blockers (P=.0067), diabetes (P=.0195), and dose-volume histogram parameters (P=.0208). The median International Prostate Symptom Scores pretreatment scores and scores at 5 years after treatment were 7 and 7, respectively. The mean Expanded Prostate Cancer Index Composite (EPIC) scores significantly declined for sexual summary for patients not receiving ADT (from 67 to 53) between baseline and 5 years. Image guided PT provided excellent biochemical control rates for patients with localized prostate cancer. The actuarial rates of high-grade toxicity were low after PT. From pretreatment to 5 years of follow-up, a significant decline was found only in mean EPIC sexual summary scores. Prospective clinical studies are needed to determine the comparative effectiveness of PT and other radiation treatment strategies.

BCL9, a coactivator for Wnt/β-catenin transcription, is targeted by miR-30c and is associated with prostate cancer progression.

B-cell lymphoma 9 (BCL9), a component of aberrantly activated Wnt signaling, is an important contributing factor to tumor progression. Our previous data indicated that downregulation of the tumor suppressor microRNA-30c (miR-30c) was a frequent pathogenetic event in prostate cancer (PCa). However, a functional link between miR-30c and BCL9/Wnt signaling, and their clinical and pathological significance in PCa, have not been well established. The present study demonstrated that miR-30c serves as a key negative regulator targeting BCL9 transcription in PCa cells. Ectopic expression of miR-30c was associated with reduced expression of Wnt pathway downstream targets, including c-Myc, cluster of differentiation 44 and sex determining region Y-box 9 in DU145 human PCa cells. Examination of clinical prostate specimens revealed higher levels of BCL9 expression in PCa compared with that in benign prostate tissues. After substantiating this finding by patient sample analysis, BCL9 expression or activity was observed to be closely correlated with PCa biochemical recurrence (BCR) and disease progression, whereas it was inversely associated with miR-30c. Furthermore, overexpression of BCL9 in PCa acted cooperatively with miR-30c low expression to predict earlier BCR in PCa. These findings indicate that inhibition of BCL9/Wnt signaling by miR-30c is important in the progression of PCa. Furthermore, the combined analysis of miR-30c and BCL9 may be valuable tool for prediction of BCR in PCa patients following radical prostatectomy.

Diabetes and type of diet as determinant factor in the progression of atherosclerosis

The purpose of this review is to analyze the biochemical progression of atherosclerotic plaque and its association with diet and diabetes. This study shows the scientific evidence of demonstrating that diabetic patients present high levels of fatty acids like palmitic acid and linoleic acid in their atheroma plaques in comparison with non-diabetic patients. This study also establishes how patients with diabetes mellitus have a higher prevalence of atherosclerotic heart diseases in the form of Coronary Thrombosis and have different anatomopathological appearance like higher necrotic core and thin fibrotic layer than the general population. Furthermore this review describes the different anatomopathological appearance and cellular changes involved in the formation of these plaques and how diet can affect the development of these plaques.

Prospective evaluation of the response to prednisone-dexamethasone switch in castration-resistant prostate cancer patients treated with abiraterone pre- and post-docetaxel.

327 Background: Abiraterone acetate (AA) administered with prednisone (P) to reduce mineralocorticoid-related adverse events improves survival in CRPC with a favourable tolerance profile. However, in the phase I/II of AA without steroids, dexamethasone 0,5mg/day was added after biochemical progression reaching a 25% of PSA decline. Lorente et al (BJC, 2014) showed durable biochemical responses in 40% of cases treated with AA and steroid switch in the post-docetaxel setting. We hypothesize that P to D switch in patients with biochemical progression to AA+P would lead to secondary responses also in the pre-docetaxel setting. Methods: Change of P 5mg/12h to D 0.5mg/24h was prospectively tested in clinically stable CRPC with biochemical progression ( &gt; 25% PSA rise over nadir, confirmed in a second determination) and/or limited radiological progression ( &lt; 3 new bone/lymphatic metastasis, non-bulky), after ³12 weeks of AA+P. PSA was monitored q4wks. CT- &amp; bone-scans were performed every 12-16 weeks. Biochemical and radiological responses were evaluated by PSAWG2 and RECIST criteria. Survival outcomes were calculated using Kaplan-Meier method. Results: 18 patients were included (11 pre- &amp; 7 post-docetaxel). Median age 72 (60-85); visceral, bone and/or lymph metastasis were present in 17%, 83% and 50% of patients. Median PSA at AA+P and AA+D commencement was 81 ng/ml and 100ng/ml, respectively. Biochemical response was observed in 83% of patients: 56% with a PSA decrease ≥ 30%, and 28% with PSA decrease ≥ 50%. Median biochemical progression-free survival (bPFS) with AA+P was 5.7 months (CI95% 2.9-9.1) and 3.8m (CI95% 1.4-6.5) in the pre- and post-docetaxel setting, respectively. Median bPFS with AA+D was 5.4m (1.2-8.8) and 2.5 (CI95% 1.1-2.9) in the pre- and post-docetaxel settings. Two radiological partial responses were observed with AA+D. Conclusions: Clinically stable patients with limited disease progression after AA+P may benefit from steroid switch in both the pre- and post-docetaxel settings.

Comparison of abiraterone acetate (Abi) versus ketoconazole (Keto) in chemotherapy-naive patients (CN-pts) with metastatic castration resistant prostate cancer (mCRPC).

260 Background: Abi is a standard treatment (tx) in CN-pts with mCRPC. It is a potent and selective CYP 17 inhibitor. However, in many countries where abi has not been approved yet, keto is used as an alternative CYP 17 inhibitor. Preclinical data suggests that keto is a less specific and potent inhibitor of CYP 17. Clinical data (Peer et al, Prostate 2014) suggests that in docetaxel (D) refractory mCRPC, the outcome of abi tx may be superior to keto. However, there are limited clinical data comparing both agents in CN-pts with mCRPC. We aimed to compare the clinical effectiveness of abi vs keto in CN-pts with mCRPC, who were treated after the year 2004 (approval of D for the tx of mCRPC). Methods: Records from 72 CN-pts with mCRPC treated with abi in 5 Israeli centers were reviewed retrospectively, and matched by pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012) to pts treated with keto 200 - 400 mg 3x day (international database, n = 156, from 4 centers across the US and Israel). We compared the PSA response (decrease ≥ 50% from baseline), biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. Results: The groups were matched by pre-tx risk category (favorable, intermediate, poor; Keizman, Oncologist 2012), based on pretreatment NLR and PSA doubling time, and the prior response to a gonadotropin-releasing hormone agonist. The groups were balanced regarding age (72 abi vs 70 keto), time from primary tx to disease relapse, gleason score, pre-tx disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral), and ECOG PS. In the groups of abi vs keto, PSA response was 75% vs 47% (OR 3.8, p = 0.04), median biochemical PFS 12 vs 6 months (HR 0.62, p = 0.03), median radiological PFS 16 vs 8 months (HR 0.54, p = 0.01), median OS not reached after a median follow-up time of 18 months vs 26 months, and tx interruption d/t adverse events 10% vs 22% (0R 0.65, p = 0.05). Conclusions: In CN-pts with mCRPC, the outcome of pts treated with abi may be superior to keto.

Long-term outcomes and predictive factors in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) showing abiraterone withdrawal syndrome (AWS) after docetaxel (DOC) treatment.

324 Background: AWS has been rarely described as a possible PSA reduction, with or without radiological responses, observed after abiraterone acetate (AA) suspension due to disease progression. According to this possibility, all pts progressing under AA were usually monitored for at least 4 wks to evaluate if they developed AWS; if PSA decreased, the subsequent treatment was delayed until the occurrence of biochemical and/or radiological progression. The present study is aimed to assess long-term outcomes and predictive factors in DOC pre-treated mCRPC pts experiencing AWS. Methods: We evaluated a consecutive series of 73 pre-treated mCRPC pts, who received AA in our Hospital after DOC failure: all pts were treated with AA 1,000 mg po + prednisone 10 mg po daily; the treatment continued until progression disease (PD) which required to be confirmed by imaging. For each pt we have recorded the pre and post-AA clinical history, the treatment details and outcomes. All pts stopped AA due to progressive disease and AWS was defined by PSA reduction ≥ 25%, compared to the AA-end values, observed in the first month after AA stop. A logistic regression analysis was performed in order to assess the ability of a series of 18 selected clinical factors to predict AWS. Results: AWS was observed in 7 pts (9.5%) with a median duration of 17 wks (range 9-33). Two pts undergoing the 3-monthly radiographic restaging showed an objective response. A significant difference in terms of post-AA median OS was observed between AWS- and AWS+ pts (3.6 vs 27.9 mos; p = 0.02); this differences was confirmed by 1-month landmark analysis (4.6 vs 27.9 mos; p = 0.03). Among the factors, only the absence of pain at AA therapy baseline was able to predict the AWS: 100% of AWS+ pts were asymptomatic, compared to 64.6% of AWS- pts (p = 0.04). Conclusions: Despite AWS remains an unpredictable and rare phenomenon, it could represent a chance to delay the start of subsequent therapeutic line after AA failure. Moreover, our results seem to suggest that the occurrence of AWS may have a positive impact on the OS of mCRPC pts.