Raoul Salup

Hyperactivation of STAT3 Is Involved in Abnormal Differentiation of Dendritic Cells in Cancer

Abnormal differentiation of myeloid cells is one of the hallmarks of cancer. However, the molecular mechanisms of this process remain elusive. In this study, we investigated the effect of tumor-derived factors on Janus kinase (Jak)/STAT signaling in myeloid cells during their differentiation into dendritic cells. Tumor cell conditioned medium induced activation of Jak2 and STAT3, which was associated with an accumulation of immature myeloid cells. Jak2/STAT3 activity was localized primarily in these myeloid cells, which prevented the differentiation of immature myeloid cells into mature dendritic cells. This differentiation was restored after removal of tumor-derived factors. Inhibition of STAT3 abrogated the negative effects of these factors on myeloid cell differentiation, and overexpression of STAT3 reproduced the effects of tumor-derived factors. Thus, this is a first demonstration that tumor-derived factors may affect myeloid cell differentiation in cancer via constitutive activation of Jak2/STAT3.

A Phase II Randomized, Placebo-Controlled Clinical Trial of Purified Isoflavones in Modulating Steroid Hormones in Men Diagnosed With Localized Prostate Cancer

Abstract Our purpose was to evaluate the safety and effectiveness of purified isoflavones in producing an increase in plasma isoflavones and a corresponding change in serum sex hormone binding globulin (SHBG) and steroid hormone levels in men diagnosed with early stage prostate cancer. In this Phase II randomized, double-blinded, placebo-controlled trial, 53 prostate cancer patients with a Gleason score of 6 or below were supplemented with 80 mg purified isoflavones or placebo for 12 weeks. Changes in plasma isoflavones, serum steroid hormones, and safety markers were analyzed from baseline to 12 wk. A total of 50 subjects completed the study. Although significant increases in plasma isoflavones (P < 0.001) was observed with no clinical toxicity, the corresponding modulation of serum SHBG, total estradiol, and testosterone in the isoflavone-treated group compared to men receiving placebo was nonsignificant. Increasing plasma isoflavones failed to produce a corresponding modulation of serum steroid hormone levels in men with localized prostate cancer. The study establishes the need to explore other potential mechanisms by which prolonged and consistent purified isoflavone consumption may modulate prostate cancer risk.

Randomized, Placebo-Controlled Trial of Green Tea Catechins for Prostate Cancer Prevention

Preclinical, epidemiologic, and prior clinical trial data suggest that green tea catechins (GTC) may reduce prostate cancer risk. We conducted a placebo-controlled, randomized clinical trial of Polyphenon E (PolyE), a proprietary mixture of GTCs, containing 400 mg (−)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). The primary study endpoint was a comparison of the cumulative one-year prostate cancer rates on the two study arms. No differences in the number of prostate cancer cases were observed: 5 of 49 (PolyE) versus 9 of 48 (placebo), P = 0.25. A secondary endpoint comparing the cumulative rate of prostate cancer plus ASAP among men with HGPIN without ASAP at baseline, revealed a decrease in this composite endpoint: 3 of 26 (PolyE) versus 10 of 25 (placebo), P < 0.024. This finding was driven by a decrease in ASAP diagnoses on the Poly E (0/26) compared with the placebo arm (5/25). A decrease in serum prostate-specific antigen (PSA) was observed on the PolyE arm [−0.87 ng/mL; 95% confidence intervals (CI), −1.66 to −0.09]. Adverse events related to the study agent did not significantly differ between the two study groups. Daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year accumulated in plasma and was well tolerated but did not reduce the likelihood of prostate cancer in men with baseline HGPIN or ASAP. Cancer Prev Res; 8(10); 879–87. ©2015 AACR.

Caveolin expression in adult renal tumors

Histopathological criteria are usually sufficient for the accurate distinction of benign form malignant renal tumors. A minority of cases however, poses a vexing diagnostic dilemma. Recent studies suggest that caveolin, a scaffolding cell membrane protein may prove helpful in predicting the behavior of these neoplasms. We analyzed a series of 40 renal tumors of which 7 were clear cell and 6 granular Renal Cell Carcinomas (RCC), 10 cases of Papillary Carcinoma (PCC), 4 cases of Chromophobe Renal cell carcinomas (CRCR), 11 cases of Oncocytomas (OC) and 2 cases of Collecting Duct Carcinomas (CDC). The distribution of immunoreactivity was analyzed by quantifying caveolin cell membrane staining in each case. There was a statistically significant difference in the expression of caveolin-1 between oncocytoma with a mean labeling index of 91.7 and the cases of malignant renal tumors with a mean labeling index of 26.9 for RCC, 24 for CDC, 21 for CRCR, and 19.2 for PCC. The results suggest an association between loss of caveolin expression among malignant renal tumors that might be useful in distinguishing oncocytoma from malignant renal tumors and possibly implicates this peptide in their pathogenesis.

ANALYSIS OF THE PSA RESPONSE AFTER TESTOSTERONE SUPPLEMENATATION IN PATIENTS WHO HAVE PREVIOUSLY RECEIVED MANAGEMENT FOR THEIR LOCALIZED PROSTATE CANCER

1247 ANALYSIS OF THE PSA RESPONSE AFTER TESTOSTERONE SUPPLEMENATATION IN PATIENTS WHO HAVE PREVIOUSLY RECEIVED MANAGEMENT FOR THEIR LOCALIZED PROSTATE CANCER Hugo H Davila*, Charles N Arison, Mary K Hall, Raoul Salup, Jorge L Lockhart, Rafael E Carrion. Tampa, FL. INTRODUCTION AND OBJECTIVE: 60 years ago, Huggins et al. demonstrated that suppression of testosterone (T) levels caused regression of prostate cancer (Pca). However, despite decades of research there is no compelling evidence that that T has a causative role in Pca. Our aim was to investigate the impact of testosterone supplementation (TS) in patients having undergone radical prostatectomy (RP) antigen (PSA) was closely monitored after commencing TS. METHODS: We retrospectively studied 20 men with hypogonadal symptoms or low T levels who underwent TS with either injections 200mg/q2w (n=8) or transdermal-gel 5g qd (n=12). These patients had previously undergone an open (n=8) or laparoscopic (n=6) RP (group A), or external bean radiation therapy (EBRT) (n=6) (group B) undetectable PSA and normal digital rectal exam (DRE) post therapy and before starting TS. T and PSA levels were evaluated before and after TS. RESULTS: When we compared group A/B, the Mean Age was 69/66, mean time after Pca therapy was 74/57 months, and mean follow up time after TS was 12/9 months. Moreover, the Gleason score was 6.2/5, body mass index (BMI) was 28/35 (p 0.05) and 630 vs 834 (p>0.05). Using the same time points, the PSA level was 0.1 vs 0.2 (OR 0.14, 95% CI -3.33-3.47, p>0.05) and 0.1 vs 0.1 (OR 0.22, 95% CI -2.94-3.17, p>0.05) CONCLUSIONS: TS by T injection or transdermal-gel is effective in improving T level and hypogonadal symptoms in men follow

Cognitive impairment in men treated with luteinizing hormone–releasing hormone agonists for prostate cancer: a controlled comparison

Goals of workData suggest that treatment with luteinizing hormone–releasing hormone (LHRH) agonists may be associated with reduced cognitive functioning. The purpose of the current study was to compare rates of clinically significant cognitive impairment in men treated with LHRH agonists to a matched sample of healthy men without cancer.Materials and methodsParticipants were 48 men receiving LHRH agonist therapy for prostate cancer and 48 men with no history of cancer matched to patients on age and education. Participants were administered a battery of neuropsychological tests assessing the domains of verbal memory, verbal fluency, visuospatial memory, visuospatial abilities, and executive function. Clinically significant impairment on individual tests was defined as −1.5 SD below the normative mean; overall impairment was defined as impaired performance on two or more tests.Main resultsPatients did not differ from comparison subjects in age, ethnicity, race, education, or annual household income (ps > 0.05). No statistically significant differences in test means were found. Nevertheless, patients displayed greater overall impairment in cognitive functioning than comparison subjects (42% of patients versus 19% of comparison subjects, p < 0.05). Among patients, prior prostatectomy was associated with impaired immediate and delayed verbal memory (ps < 0.05).ConclusionsCurrent findings suggest that LHRH agonists and surgery for prostate cancer are associated with clinically significant impairment in cognitive functioning. Longitudinal studies are needed to examine changes in cognitive impairment before and after surgical and hormonal treatment for prostate cancer. Patients undergoing LHRH agonist therapy should be monitored for cognitive changes while on treatment.

Safety of Purified Isoflavones in Men With Clinically Localized Prostate Cancer

Abstract Our purpose was to evaluate the safety of 80 mg of purified isoflavones administered to men with early stage prostate cancer. A total of 53 men with clinically localized prostate cancer, Gleason score of 6 or below, were supplemented with 80 mg purified isoflavones or placebo for 12 wk administered in 2 divided doses of 40 mg to provide a continuous dose of isoflavones. Compliance, changes in plasma isoflavones, and clinical toxicity were analyzed at baseline, 4, and 12 wk. A total of 50 subjects completed the 12-wk intervention. A continuous, divided-dose administration of 80 mg/day of purified isoflavones at amounts that exceeded normal American dietary intakes significantly increased (P < 0.001) plasma isoflavones in the isoflavone-treated group compared to placebo and produced no clinical toxicity. With the current evidence on the cancer preventive properties of isoflavones, these results are significant and offer promise for these phytochemicals to be developed as potent agents to prevent cancer progression.

Total or partial prostate sparing cystectomy for invasive bladder cancer : long-term implications on erectile function

To review the long‐term results in patients treated with either total or partial prostate‐sparing cystectomy, focusing on erectile function (EF), as en‐bloc radical cystectomy (RC) with or without urethrectomy has been the method of choice for managing invasive bladder carcinoma, but has inherent risks of subsequent urinary incontinence and erectile dysfunction, with a marked effect on quality of life, especially in younger patients.

Efficacy of vaccination with plasmid DNA encoding for HER2/neu or HER2/neu-EGFP fusion protein against prostate cancer in rats

Despite early diagnosis and improved therapy, 31,500 men will die from prostate cancer (PC) this year. The HER2/neu oncoprotein is an important effector of cell growth found in the majority of high-grade prostatic tumors and is capable of rendering immunogenicity. The antigenicity of this oncoprotein might prove useful in the development of PC vaccines. Our goal is to prove the principle that a single DNA vaccine can provide reliable immunity against PC in the MatLyLu (MLL) translational tumor model. The parental rat MatLyLu PC cell line expresses low to moderate levels of the rat neu protein. To simulate in vivo human PC, MatLyLu cells were transfected with a truncated sequence of human HER2/neu cDNA cloned into the pCI-neo vector. This HER2/neu cDNA sequence encodes the first 433 amino acids of the extracellular domain (ECD). MatLyLu cells were also transfected with the same HER2/neu cDNA sequence cloned into the N1-terminal sequence of EGFP reporter gene to produce a fusion protein. The partial ECD sequence of HER2/neu includes five rat major histocompatibility (MHC)-II-restricted peptides with complete human-to-rat cross-species homology. The HER2/neu protein overexpression was documented by Western Blot analysis, and the expression of fusion protein was monitored by confocal microscopy and fluorimetry. Vaccination with a single injection of HER2/neu cDNA protected 50% of animals against HER2/neu-MatLyLu tumors (P < 0.01). When the tumor cells were engineered to express HER2/neu-EGFP fusion protein, the antitumor immunity was enhanced, as following vaccination with HER2/neu-EGFP cDNA, 80% of these rats rejected HER2/neu-EGFP-MatLyLu (P<0.001). Both vaccines induced HER2/neu-specific antibody titers. Rats vaccinated with EGFP-cDNA rejected 80% of EGFP-MatLyLu tumors and, interestingly, 40% of HER2/neu-MatLyLu tumors. None of the cDNA vaccines induced immunity against parental MatLyLu cells. Our data clearly demonstrate that a single injection of HER2/neu-EGFP cDNA is a very effective vaccine against PC tumors expressing the cognate tumor-associated antigen (TA). The antitumor immunity is significantly more pronounced if the tumors express xenogeneic HER2/neu-EGFP fusion protein as opposed to only the syngeneic HER2/neu oncoprotein. Our data suggests that the HER2/neu-EGFP-MatLyLu tumor is a potential animal tumor model for investigating therapeutic vaccine strategies against PC in vivo and demonstrates the limitations of a cDNA vaccine only encoding for MHC-II-restricted HER2/neu-ECD sequence peptides.

Prostate Cancer Chemoprevention Targeting High Risk Populations: Model for Trial Design and Outcome Measures

Inspite of the large number of promising nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in high-risk cohorts are required to inform design of phase II clinical trials. Additionally, a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must be utilized to evaluate effectiveness in these trials. The goal of this paper is to provide a model, using a systematic approach for evaluating the safety, effectiveness and mechanism of action of a well characterized nutrient-derived agent-isoflavones - in a phase II clinical trial for prostate cancer (CaP) chemoprevention, targeting a population of African American (AA) and Caucasian men. Based on our previous observations, we hypothesize that the effects of isoflavones on prostate carcinogenesis are mainly mediated through the down regulation of androgen receptor (AR) and AR activity in AA men is higher due to its shorter length of Glutamine repeats in its N-terminus. We thus believe that isoflavones will exert a stronger protective effect for CaP in AA men and cause a higher activation of FOXO factors and their target genes. The aim of the study is to evaluate the comparative effectiveness of the study agent and placebo, in addition to a comparison of the effectiveness and safety in African American men compared to Caucasian men treated with this agent.