Inhibition of atypical protein kinase C­Î¹ effectively reduces the malignancy of prostate cancer cells by downregulating the NF-κB signaling cascade.

Prostate cancer (PC) is the most common type of cancer among men. Aggressive and metastatic PC results in life-threatening tumors, and represents one of the leading causes of mortality in men. Previous studies of atypical protein kinase C isoforms (aPKCs) have highlighted its role in the survival of cultured prostate cells via the nuclear factor (NF)-κB pathway. The present study showed that PKC­Î¹ was overexpressed in PC samples collected from cancer patients but not in non-invasive prostate tissues, indicating PKC­Î¹ as a possible prognostic biomarker for the progression of prostate carcinogenesis. Immunohistochemical staining further confirmed the association between PKC­Î¹ and the prostate malignancy. The DU­145 and PC­3 PC cell lines, and the non-neoplastic RWPE­1 prostatic epithelial cell line were cultured and treated with aPKC inhibitors 2­acetyl­1,3-cyclopentanedione (ACPD) and 5-amino­1-(1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)­1H-imidazole-4-carboxamide (ICA­1). Western blot data demonstrated that ICA­1 was an effective and specific inhibitor of PKC­Î¹ and that ACPD inhibited PKC­Î¹ and PKC­Î¶. Furthermore, the two inhibitors significantly decreased malignant cell proliferation and induced apoptosis. The inhibitors showed no significant cytotoxicity towards the RWPE­1 cells, but exhibited cytostatic effects on the DU­145 and PC­3 cells prior to inducing apoptosis. The inhibition of aPKCs significantly reduced the translocation of NF-κB to the nucleus. Furthermore, this inhibition promoted apoptosis, reduced signaling for cell survival, and reduced the proliferation of PC cells, whereas the normal prostate epithelial cells were relatively unaffected. Overall, the results suggested that PKC­Î¹ and PKC­Î¶ are essential for the progression of PC, and that ACPD and ICA­1 can be effectively used as potential inhibitors in targeted therapy.

Improving risk stratification among veterans diagnosed with prostate cancer: impact of the 17-gene prostate score assay.

BACKGROUND: Active surveillance (AS) has been widely implemented within Veterans Affairs' medical centers (VAMCs) as a standard of care for low-risk prostate cancer (PCa). Patient characteristics such as age, race, and Agent Orange (AO) exposure may influence advisability of AS in veterans. The 17-gene assay may improve risk stratification and management selection. OBJECTIVES: To compare management strategies for PCa at 6 VAMCs before and after introduction of the Oncotype DX Genomic Prostate Score (GPS) assay. STUDY DESIGN: We reviewed records of patients diagnosed with PCa between 2013 and 2014 to identify management patterns in an untested cohort. From 2015 to 2016, these patients received GPS testing in a prospective study. Charts from 6 months post biopsy were reviewed for both cohorts to compare management received in the untested and tested cohorts. SUBJECTS: Men who just received their diagnosis and have National Comprehensive Cancer Network (NCCN) very low-, low-, and select cases of intermediate-risk PCa. RESULTS: Patient characteristics were generally similar in the untested and tested cohorts. AS utilization was 12% higher in the tested cohort compared with the untested cohort. In men younger than 60 years, utilization of AS in tested men was 33% higher than in untested men. AS in tested men was higher across all NCCN risk groups and races, particular in low-risk men (72% vs 90% for untested vs tested, respectively). Tested veterans exposed to AO received less AS than untested veterans. Tested nonexposed veterans received 19% more AS than untested veterans. Median GPS results did not significantly differ as a factor of race or AO exposure. CONCLUSIONS: Men who receive GPS testing are more likely to utilize AS within the year post diagnosis, regardless of age, race, and NCCN risk group. Median GPS was similar across racial groups and AO exposure groups, suggesting similar biology across these groups. The GPS assay may be a useful tool to refine risk assessment of PCa and increase rates of AS among clinically and biologically low-risk patients, which is in line with guideline-based care.

Long-term supplementation of decaffeinated green tea extract does not modify body weight or abdominal obesity in a randomized trial of men at high risk for prostate cancer.

BACKGROUND: Evidence continues to demonstrate the role of obesity in prostate carcinogenesis and prognosis, underscoring the need to identify and continue to evaluate the effective interventions to reduce obesity in populations at high risk. The aim of the study was to determine the effect of daily consumption of decaffeinated green tea catechins (GTC) formulation (Polyphenon E® (PolyE)) for 1 year on biomarkers of obesity in men who are at high risk for prostate cancer. MATERIALS AND METHODS: A randomized, double-blinded trial was conducted targeting 97 men diagnosed with HGPIN or ASAP. Subjects were randomized to receive GTC (PolyE) (n = 49) or placebo (n = 48) for 1 year. Anthropometric data were collected at baseline, 6 and 12 months and data analyzed to observe change in weight, body mass index (indicator of obesity) and waist: hip ratio (indicator of abdominal obesity). RESULTS: Decaffeinated GTC containing 400 mgs of the bioactive catechin, EGCG administered for 1 year to men diagnosed with ASAP and HGPIN appears to be bioavailable, well tolerated but not effective in reducing biomarkers of obesity including body weight, body mass index and waist: hip ratio. CONCLUSIONS: The results of our trial demonstrates that men who are obese and at high risk for prostate cancer should resort to effective weight management strategies to reduce obesity and not resort to ineffective measures such as taking supplements of green tea to reduce biomarkers of obesity. Changes in body mass index and abdominal obesity seen in other studies were potentially due to caffeine and not GTC.

Randomized, placebo-controlled trial evaluating the safety of one-year administration of green tea catechins.

PURPOSE: Although preclinical, epidemiological and prior clinical trial data suggest that green tea catechins (GTCs) may reduce prostate cancer (PCa) risk, several preclinical studies and case reports have reported liver toxicities and acute gastrointestinal bleeding. Based on these observations, regulatory bodies have required stringent inclusion criteria with frequent, excessive toxicity monitoring and early stopping rules in clinical trials. These requirements have impeded recruitment and retention of subjects in chemoprevention trials and subsequent progress in agent development efforts. EXPERIMENTAL DESIGN: We conducted a placebo-controlled, randomized clinical trial of Polyphenon E® (PolyE®), a proprietary mixture of decaffeinated 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). PolyE® containing 200 mg EGCG was administered with food, BID. A secondary study endpoint in this trial was a comparison of the overall one-year treatment related adverse events and grade 3 or higher adverse event on the two study arms. Monthly assessments of toxicity (CTCAE 4.0), concomitant medications and organ function, including hepatic panel, PT/PTT and LDH, were performed. RESULTS: Daily intake of a standardized, decaffeinated, catechin mixture containing 200 mg EGCG BID taken with food for 1 year accumulated in plasma and was well tolerated and did not produce treatment related adverse effects in men with baseline HGPIN or ASAP. CONCLUSION: The current data provides evidence of safety of decaffeinated, catechin mixture containing 200 mg EGCG BID to be further tested for prostate cancer prevention or other indications.

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.

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.

Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures.

In spite of the large number of 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 suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention.

Challenges and potential solutions to meeting accrual goals in a Phase II chemoprevention trial for prostate cancer.

OBJECTIVE: The goal of this report is to describe the on going strategies, successes, challenges and solutions for recruitment in this multi-center, phase II chemoprevention trial targeting men at high risk for prostate cancer. METHODS: We developed and implemented a multi-center clinical trial in institutions with supportive infrastructure, lead by a recruitment team of experienced and committed physicians and clinical trial staff, implementing multi-media and community outreach strategies to meet recruitment goals. Screening logs were reviewed to identify trends as well as patient, protocol and infrastructure -related barriers impacting accrual and revisions to protocol implemented. RESULTS: Between January 2008 and February 2011 a total of 3547 individuals were prescreened with 94% (n=3092) determined to be ineligible based on diagnosis of cancer or benign biopsy results. Of these, 216 were considered eligible for further screening with 52% (n=113) declining to participate due to patient related factors and 14% (n=29) eliminated due to protocol-related criteria for exclusion. Ninety-four (94) subjects consented to participate with 34% of these subjects (n=74) meeting all eligibility criteria to be randomized to receive study agent or placebo. Across all sites, 99% of the recruitment of subjects in this clinical trial is via physician recruitment and referral with less than 1% responding to other recruitment strategies. CONCLUSION: A contemporary approach to subject recruitment and frequent evaluation is needed to assure responsiveness to emerging challenges to accrual and the evolving scientific literature. A focus on investing on improving systems for physician recruitment may be key to meeting recruitment target in chemoprevention trials.

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

GOALS OF WORK: Data 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 METHODS: Participants 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 RESULTS: Patients did not differ from comparison subjects in age, ethnicity, race, education, or annual household income (p's > 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 (p's < 0.05). CONCLUSIONS: Current 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.

Relationship between hot flashes and distress in men receiving androgen deprivation therapy for prostate cancer.

OBJECTIVE: Side effects of cancer treatment have been found to have a significant impact on patients' psychological well-being. Each of the primary treatment options for prostate cancer is associated with significant side effects that can have a dramatic impact on quality of life. Hot flashes are a notable side effect of androgen deprivation therapy (ADT) and a potential source of distress due to their episodic nature and low frequency in a normal aging male population. The current study sought to examine the relationship between hot flashes and cancer-related distress during the first three months of ADT. METHODS: Participants were 68 men with various stages of prostate cancer scheduled to begin ADT for the first time. Study measures were completed at the beginning of treatment and 3 months later. RESULTS: Repeated measures ANOVA indicated that men who did not experience hot flashes had a significant decrease in total cancer-related distress and avoidance over the 3-month period, while men with hot flashes exhibited no change in distress. Among men with hot flashes, results of hierarchical regression analyses indicated that a worse experience with hot flashes was a significant predictor of greater increases in intrusion and total cancer-related distress over the 3-month period. CONCLUSIONS: These results suggest that hot flashes serve to maintain levels of distress during the treatment period. Further research should extend these findings by lengthening the follow-up period and using ecological momentary assessment to refine measurement of these constructs and provide evidence for the direction of causality between hot flashes and distress.

Visualization of the neurovascular bundles and major pelvic ganglion with fluorescent tracers after penile injection in the rat.

OBJECTIVE: To evaluate whether fluorescent tracers can consistently label the neurovascular bundles (NVBs) and major pelvic ganglion (MPG) after an intracavernosal penile injection, as the reported incidence of erectile dysfunction (ED) in men after radical prostatectomy (RP) is 55-65% and thus preservation of erectile function, sparing one or both of the NVBs remains one of the most vital factors. MATERIALS AND METHODS: Male Sprague-Dawley rats (3 months old) received penile injections (20 microL; seven rats/group) of either deionized water (DW), Fluoro-Gold (FG), Fast-Blue (FB), Fluoro-Ruby (FR) or green fluorescent pseudorabies virus (GF-PRv). The rats were killed at 2, 3 and 14 days after injection and the NVBs and MPG were harvested and placed directly under fluorescence light. Image analysis was done by computer, coupled to a microscope equipped with a digital camera. Each NVB and MPG were analysed for its staining pattern and consistency. RESULTS: When compared with the FB, FR and GF-PRv rats, the FG-injected rats had better staining of the NVB at 2, 3 and 14 days after injection. Under x200, FG highlighted the axons of the cavernous nerve (CN) and cell bodies (MPG). This indicates that FG injection into the penis induced the strongest CN labelling (positive staining) at 2 and 3 days after injection as compared with FB-, FR- and GF-PRv-injected rats. CONCLUSION: FG injection into the penis has consistent retrograde staining of the NVBs and MPG after 3 days. Therefore, we predict that FG could potentially be used to improve the identification of the NVB in other models. However, further studies need to be carried out before these tracers can be used in humans.

A Phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer.

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.

Safety of purified isoflavones in men with clinically localized prostate cancer.

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.

OBJECTIVE: 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. PATIENTS AND METHODS: Between 2003 and 2005 we assessed 21 men (mean age 56 years) who had either a prostate apex-sparing cystectomy (PASC, 15) or total prostate-sparing cystectomy (TPSC, six). The mean follow-up was 30 months for PASC and 24 months for TPSC. The evaluation before surgery included standard bladder cancer staging, prostate specific antigen level, a digital rectal examination and a complete medical history, with attention to self-reported EF before surgery and the EF domain of the International Index of EF (IIEF) after surgery. RESULTS: The EF domain score was 20 after PASC and 30 after TPSC; this correlates with mild to moderate ED in the PASC group vs normal erectile function in the TPSC group. After transurethral resection of the bladder tumours (TURBT) 10 of 14 in the PASC group were T1 or T2a, and in the TPSC group, five of six were T2a and one patient was T2b. From the cystectomy specimen, in the PASC group eight were understaged compared with the TURBT specimen (T2b/T4a vs T1/T2a), while in the TPSC group there was understaging two (T3a vs T2a/T2b); this was significantly different (P < 0.05). There was recurrence of urothelial carcinoma in one of 15 and one of six after PASC and TPSC, respectively. CONCLUSION: The EF domain score after PASC was 10 points lower than after TPSC, representing a 30% increase in EF by preserving the entire prostate. We conclude that in patients with invasive bladder cancer, EF can be significantly preserved by prostate-sparing cystectomy. If adequate selection criteria are applied, EF can be preserved without compromising cancer control.

The specific role of isoflavones in reducing prostate cancer risk.

AIMS: To evaluate the effectiveness of supplementing a group of early stage prostate cancer patients, with 60 mg of soy isoflavones in producing a change in hormonal and proliferative risk parameters that are implicated in prostate cancer promotion. METHODS: Seventy six eligible prostate cancer patients with a Gleason score of 6 or below, between ages 50 and 80 were admitted and supplemented with soy isoflavones or placebo for a 12 week period and changes in PSA and steroid hormones were analyzed at baseline and post intervention. RESULTS: Fifty-nine patients completed the 12-week intervention. Serum free testosterone was reduced or showed no change in 61% of subjects in the isoflavone group compared to 33% in the placebo group. Serum total PSA decreased or was unchanged in 69% of the subjects in the isoflavone treated group compared to 55% in the placebo group. However, we did not see an increase in SHBG levels. Nineteen percent of subjects receiving soy isoflavones reduced total PSA by two points or more during the intervention period. CONCLUSIONS: These data suggest that supplementing early stage prostate cancer patients with soy isoflavones, even in a study of short duration, altered surrogate markers of proliferation such as serum PSA and free testosterone in a larger number of subjects in the isoflavone supplemented group than the group receiving placebo. The study establishes the need to explore further the effects of prolonged and consistent soy consumption, which could potentially delay onset of histologic disease in this patient population.

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.

Full-length dominant-negative survivin for cancer immunotherapy.

PURPOSE: The goal of this study is to investigate the possible utility of dendritic cells (DCs) transduced with the human full-length dominant-negative survivin for cancer immunotherapy. EXPERIMENTAL DESIGN: Mononuclear cells were collected from HLA-A2-positive healthy volunteers and patients with prostate cancer. DCs were transduced with an adenoviral vector containing a full-length, dominant-negative survivin gene. After three rounds of stimulation, the T-cell response against three different survivin-derived HLA-A2-matching peptides was tested in IFN-gamma enzyme-linked immunospot and CTL assays. RESULTS: Seven of eight healthy volunteers and cancer patients showed a significant response to at least two different survivin-derived epitopes in the enzyme-linked immunospot assay. One patient responded to only one peptide. All four healthy volunteers and two of three patients tested demonstrated a specific CTL response against T2 target cells loaded with one survivin-derived epitope. Two donors and two patients had a significant CTL response against two different epitopes. Significant cytotoxic activity was seen against HLA-A2-positive MCF-7 tumor cells that express survivin. That response was specific for survivin and was MHC class I restricted. Because survivin is expressed in CD34(+) hematopoietic progenitor cells (HPCs), we tested whether the antisurvivin CTLs can recognize normal HPCs. The incubation of survivin-specific CTLs with CD34(+) cells did not significantly decrease the colony-forming ability of HPCs. CONCLUSIONS: DCs transduced with dominant-negative survivin induce potent survivin-specific CTL responses able to recognize and kill tumor cells. This response does not significantly affect HPCs. Thus, this study may provide rationale for immunotherapeutic clinical trials using a DC vaccine transduced with the dominant-negative survivin.

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.

Immunohistochemical expression of Mdm2 and p53 in penile verrucous carcinoma.

Verrucous carcinoma (VC) of the penis is an uncommon squamous tumor that pursues a biologically indolent course. Unlike conventional squamous cell carcinoma (SCC) of the penis, pathogenic roles for human papillomavirus (HPV) infection and p53 mutation have not been reported in VC. We compared the immunohistochemical expression of Mdm2 and p53 in 7 cases of VC and 7 cases of SCC. The Mdm2 gene product preferentially labeled the perinuclear membrane in the granular layer of VC tumor cells, whereas SCC cases showed weak, focal, cytoplasmic staining for Mdm2. The mean labeling index for Mdm2 was higher in VC compared to SCC [79.3 (SE +/- 7.2) in VC vs 18.3 (SE +/- 2.4) in SCC, p < 0.001]. In SCC cases, the normal surrounding skin showed mild granular-layer staining and dysplastic foci that failed to stain with Mdm2 antibody. Weak p53 immunolabeling was seen within nuclei of scattered tumor cells in the cases of VC, whereas the SCC cases showed strong nuclear staining of p53 throughout the tumors. The mean labeling index for p53 was lower in VC compared to SCC [24.8 (SE +/- 3.9) in VC vs 64.7 (SE +/- 9.0) in SCC, p < 0.01]. In SCC cases, the normal surrounding skin showed moderate staining for p53, preferentially confined to the basal layer. Dysplastic foci in the cases of SCC showed increased p53 labeling. In summary, immunohistochemical analysis showed significantly different levels of expression of Mdm2 and p53 in penile VC vs SCC. Overexpression of the Mdm2 gene product may be important in the pathogenesis of VC. Since Mdm2 is a negative regulator of p53, overexpression of Mdm2 may explain why p53 is down-regulated and, therefore, permissive to oncogenic transformation.