Objectives: To determine whether assessing expression of MUC1 and ZAG proteins in prostate biopsies, by immunohistochemistry, improves prediction of radical prostatectomy histopathology, which in turn predicts longer-term outcomes. Methods: We studied 231 consecutive patients managed by two experienced urologic surgeons (MF, LH). Each patient had prostate biopsies revealing cancer followed by a radical prostatectomy. Expression of MUC1 and ZAG in biopsy tissue was assessed by immunohistochemistry, masked to the radical prostatectomy histopathology. Data were analysed by Chi-square, Fischer exact test & Mann Whitney U test followed by multivariate analysis using binary logistic regression. Results: By univariate analysis, MUC1 expression in prostate biopsies was associated with worse histopathology in the radical prostatectomy specimen (p<0.023), while ZAG expression was associated with better pathology (p=0.03). By multivariate analysis decreased expression of ZAG in biopsies (p=0.02), but not MUC1 expression, improved prediction of high-risk radical prostatectomy pathology beyond conventional biopsy variables; neither MUC1 nor ZAG staining improved prediction of minimal-risk cancers. Conclusions: Assessment of ZAG expression in prostate biopsies, and possibly MUC1 expression, may improve knowledge of prostate cancers in vivo or after radical prostatectomy.
The diagnostic accuracy of standard transrectal ultrasound-guided (TRUL) biopsy is limited due to the finite number of cores that can be obtained.It has been shown that the technique is not sufficiently reliable in defining the location and extent of prostatic cancer.The main aim of this study was to investigate the effectiveness of magnetic resonance imaging (MRI), and positron emission tomography (PET/CT) imaging techniques in pinpointing potential tumour lesions prior to prostate biopsy.Material and methods.The study cohort consisted of 45 men with a raised prostate specific-antigen (PSA) level and/or suspected prostate cancer (PCa) at digital rectal examinations (DRE).Of the 45 patients, 23 had PCa detected with core needle biopsy (CNB).All had 11 C acetate PET/CT imaging.Ten of those 23 patients underwent radical prostatectomy (RP), of those ten patients, eight patients had MR spectroscopic imaging (MRSI) with 3 T and six had diffusion weighted imaging (DWI) with apparent diffusion coefficient calculation (MRI DWI ADC).CNB, PET/CT, 2D MRSI and ADC map results were compared with postoperative specimen histopathology.Results.The sensitivity of CNB, PET/CT, MRSI and DWI ADC were 0.53, 0.55, 0.79 and 0.95, whereas the specificity of was 0.88, 0.87, 0.46 and 0.73, respectively. Conclusion.MRI improves the PCa detection by defining the areas of interest for targeted CNB of the prostate and can reduce the number of biopsies required.
Introduction: To investigate the role of the tumor suppressor gene Pdcd4 (programmed cell death 4) in benign and malignant prostate tissue specimen. Materials and Methodology: Pdcd4 immunohistochemical expression was investigated in 73 prostate cancer and 14 normal tissues. The expression levels were correlated with clinicopathological parameters. Results: Both, cytoplasmic and nuclear Pdcd4 staining was significantly decreased in malignant prostate tissue. Furthermore, Pdcd4 expression decreased with histopathological progression of the tumor. Receiver operating characteristic analyses showed in core staining results high sensitivity (83.3%) and specificity (93.8%) for the discrimination of prostate cancer from non-malignant tissue. Conclusion: Our data support a role for Pdcd4 in prostate carcinogenesis. Pdcd4 immunohistochemical staining turns out to be a possible diagnostic marker for differentiation of prostate carcinoma and benign prostate tissue.
PURPOSE:To provide patients and physicians with population-based estimates of mortality from prostate cancer or other causes depending upon the primary treatment modality, stratified by patient age, tumor stage and grade.METHODS:We conducted a 10-year competing-risk analysis of 45,440 men diagnosed with clinically localized (T1 or T2) prostate cancer in California during 1995-1998. Information on patient characteristics, primary treatment and cause of death was obtained from the California Cancer Registry.RESULTS:In this population-based cohort, the most common primary treatment was surgery (40.4%), followed by radiotherapy (29.1%), conservative management (20.8%), and androgen deprivation therapy (ADT) monotherapy (9.8%). Prostate cancer mortality differed significantly (p < 0.0001) across treatment groups among patients <80 years at diagnosis with moderately or poorly differentiated disease; the 10-year disease-specific mortality rates were generally highest for men treated with ADT monotherapy [range: 3.3% (95% CI=0.8-12.5%) to 53.8% (95% CI=34.4-72.2%)], intermediate for men treated with conservative management [range: 1.7% (95% CI=0.7-4.6%) to 30.0% (95% CI=16.2-48.8%] or radiotherapy [range: 3.2% (95% CI=1.8-5.5%) to 18.3% (95% CI=15.1-22.0%)], and lowest for men treated with surgery [range: 1.2% (95% CI=0.8-1.7%) to 11.0% (95% CI=8.4-14.2%)].CONCLUSION:The cause-specific mortality estimates provided by this observational study can help patients and physicians better understand the expected long-term outcomes of localized prostate cancer given the initial treatment choice and practice patterns in the general population.
Prostate cancer (PCa) is the second most prevalent cancer in men after lung cancer.Prostate cancer development and progression is associated with the dysregulation of a number of molecular pathways; hence, therapeutic strategies targeting such pathways bring great promise.Recently we have shown that metformin, the anti-diabetic drug, can inhibit tumor progression when combined with dutasteride, a 5-alpha-reductase inhibitor (5ARI).Interestingly, both metformin and dutasteride have been reported to alter the Sterol Regulatory Element Binding Proteins (SREBP) Fatty Acid Synthase (FASN) pathway.The SREBP pathway is involved with lipid and energy homeostasis.In our present study, we investigated if dutasteride in combination with metformin can reduce the proliferation of LNCaP PCa cells, and whether this is mediated through the SREBP-1/FASN pathway.Human PCa cells were treated with either dutasteride (0-100 µM) or metformin (0-50 mM) alone or in combination.The treated cells were then incubated for up to 24 hours, and proliferation assessed using the MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay.Western blot analysis was performed on cell lysates to assess alterations in key signaling molecules including cleaved SREBP-1, FASN, AR, PSA, pAMPK and apoptotic markers.Results revealed that there was a significant (p<0.05)decrease in cellular proliferation of LNCaP cells treated with a combination of metformin and dutasteride, this effect being greater than either treatment alone.Treating LNCaP cells with both metformin and dutasteride reduced the expression of FASN, cleaved SREBP-1 and pro-caspase-3 with expression of cleaved PARP; suggesting a possible interaction between FASN and apoptosis.All treatments resulted in reductions in AR, PSA and an upregulation of pAMPK, with the highest expression seen in combination treatment.We report for the first time that metformin and dutasteride in combination can reduce the proliferation of androgen-sensitive cell line through the activation of p-AMPK, and SREBP-1/FASN pathway and highlight the importance of targeting the SREBP-1 pathway, for improving future therapeutic strategies for prostate cancer.
It is well established that exposure to ultraviolet (UV) radiation has beneficial effects in reducing prostate cancer risk.To determine if there is a correlation between UV exposure and prostate cancer risk, we assessed sun exposure in a case-control study of 182 African-American men aged 40 years and older residing in the Metropolitan Washington, DC area.Using data on cumulative exposure per year and adult sunbathing scores derived from a validated questionnaire, analysis revealed significant difference in cumulative sun exposure between cases and controls (p=0.003).Additionally, the outdoor and recreation UV exposures were significantly higher in controls when compared to cases (p=0.003;p=0.03 in age-matched cases and controls).Although the results of conditional logistic regression analysis indicate that there was no association between total UV exposure and risk of prostate cancer after adjusting for age (OR=2.04,95% CI 0.54-7.70,p=0.29), outdoor UV exposure was associated with decreased prostate cancer risk (OR= 0.31, 95% CI 0.14-0.65,p=0.002).Furthermore, a trend for reduced prostate cancer risk was found among men with early life high sun exposure during childhood ages 0-5 years (OR=0.17,95% CI 0.03-0.74,p=0.02) and 6-11 years (OR= 0.28, 95% CI 0.07-1.05,p=0.06).Interestingly, this inverse association between prostate cancer risk and early life high sun exposure intensity was also observed among young men at ages 12-17 years although not statistically significant (OR=0.41,95% CI 0.09-1.95,p=0.26).These findings indicate that UV exposure earlier in life may affect susceptibility to prostate cancer.
To investigate the significance of the percentage of positive biopsy cores (PPBCs) in predicting the biochemical outcome in patients with clinically localised prostate cancer undergoing low-dose rate brachytherapy (LDRB).• A total of 326 consecutive patients underwent LDRB between February 1997 and January 2007.The cohort consisted of 68.7%, 30.4% and 0.9% of low-, intermediate-and high-risk groups respectively as defined by the D'Amico classification.Patients were stratified according to PPBCs (<35%, 35-50%, >50%).• Of the 326 men, 316 (97%) met the study criteria and were included in the analysis.The median follow-up was 66.3 (12.9-147.5)months.Thirty-eight men (12%) developed evidence of biochemical relapse as defined by the Phoenix definition at a median of 44.5 (4-133) months.The overall 5-year and 10-year biochemical relapse-free rate (BRFR) was 91.9% (95% CI 87.9% to 94.6%) and 76.9% (95% CI 66% to 84%) respectively.• On univariate analysis, Gleason score (p=0.03),D'Amico risk groups (p=0.004) and PPBCs (p=0.001) were significant predictors of biochemical failure.In the multivariate model, the PPBCs (p=0.0006) and pretreatment PSA (p=0.004) were the only variables that predicted for biochemical failure.The 5-year biochemical relapse-free rate was 93.5%, 93.0% and 76.5% for the PPBCs <35%, 35%-50% and >50% respectively (p=0.001).Conclusions: • The PPBC is an important independent predictor of the 5-year biochemical relapse-free survival after LDRB.This finding suggests that patients with high volume tumour are at increased risk of biochemical failure with LDRB.
Background: Prostate cancer is the most common form of non-dermatologic cancer and the second leading cause of cancer deaths in the United States.Survival rate for the advanced disease still remains low, so current research is aimed at alternative or adjuvant treatments that will target components of the signal pathways in the progression of carcinogenesis with little or no cytotoxicity.In this study we investigated the effect of genistein on expression levels of genes involved in the immune response pathways.The mechanism of genistein-induced cell death was also investigated.The chemosensitivity of the LNCaP prostate cancer cells to genistein was investigated using ATP and MTS assays, and a caspase binding assay was used to determine apoptosis induction.Several molecular targets/genes were determined using cDNA microarray and RT-PCR analysis. Results:The overall data revealed that genistein induces cell death in a time-and dose-dependent manner, and regulates expression levels of several genes involved in carcinogenesis and immunity including MHC genes that are involved in immune recognition of cells and the DefB1 and the HLA membrane receptor genes involved in immunogenicity. Conclusion:The results of the study indicate that genistein inhibits carcinogenesis of LNCaP prostate cancer growth via regulation of the identified specific targets/pathways in immunogenicity/immune response.The results thus provide significant insight into the roles that genistein could play in immune response to prostate cancer proliferation and potential role in immunotherapy and/or adjuvant therapeutic regimen.
Objectives: To perform a pilot hypothesis generating study of neoadjuvant docetaxel, estramustine, and androgen deprivation therapy for high-risk patients prior to radical prostatectomy. Patients and Methods: Twenty-eight patients received 4 cycles of docetaxel and estramustine administered on an every three week schedule in combination with androgen deprivation therapy (LHRH analog and bicalutamide) prior to radical prostatectomy. Following the prostatectomy, androgen deprivation therapy was continued for 8 months. End-points were pathological complete response (pCR), time-to-relapse (TTR), feasibility and tolerability, and biochemical or clinical correlates of relapse. Results: With a median of 80 months (6.6 years) of follow-up, 18/28 patients have relapsed and one patient died from unrelated causes while in remission, with median TTR of 44 months (3.6 years). Tumor downstaging, perhaps as a result of neoadjuvant therapy, was associated with a decreased risk of relapse (P=0.0002). Consistent with this result, positive margin status was associated with an increased risk of relapse, which was not affected by adjuvant radiation therapy. Increased expression of a possible tumor stem cell marker, (Sry-related high mobility group box-9) Sox-9, both at the time of prostatectomy (P=0.005) and in the pre-treatment tumor biopsy cores was associated with an increased risk of relapse (P=0.03). Conclusions: The neoadjuvant chemohormonal regimen may have benefited some patients, especially those who exhibited pathologic downstaging. Sox-9 expression in prostate cancer specimens warrants prospective validation in both pre-prostatectomy tissue as well as patients undergoing an ongoing randomized trial using a similar neoadjuvant regimen.
A common treatment for Prostate Cancer includes androgen-deprivation for a period of months prior to radiation or surgery.Some data suggest that this may exacerbate the already elevated depression levels of these patients, arguing for concomitant application of antidepressant therapy.However, the various waves of antidepressants developed in the last 40 years have shown only arguable specific efficacy over placebo, plus significant side-effects which may hinder treatment decision-making and compliance.This paper outlines two emerging and potential pathways for development of new pharmacological agents for depression that hold promise of helping patients to reduce their depressive symptomatology.
Cancer immunotherapy is based on a concept that persistent presence of tumors in cancer patients is a result of immunological breakdown and/or downregulation of the tumor immunogenecity. In view of their limited efficacies, it can be argued that the problem lies not in a particular vaccine, but in tumors themselves. It is known that the rapidly dividing cells express free sulfhydryl groups on the membrane surfaces that can undergo disulfide exchange reactions with thiols of other biomolecules. Under physiological conditions sulfhydryl groups of circulating plasma proteins are engaged in the intramolecular disulfide bridges and are not available for the exchange. However, in neoplastic diseases, particularly in the prostate cancer, such an exchange reaction takes place between fibrinogen and human serum albumin resulting in the formation of a fibrin-like aggregate. A characteristic feature of such an insoluble aggregate is its remarkable resistance to proteolytic degradation not only by plasmin but by active lysosomal proteases as well. As a consequence prostate cancer cells accrue a protective coat of 'self ' proteins that is not recognizable by the body's immune system. Moreover, even if some of the unmasked tumor antigens do elicit immune response, the fibrin coat is refractive to degradation by the prote- ases released by natural killer cells. Consequently, in order to achieve successful immunotherapy the protective barrier of disulfide crosslinked fibrinogen-albumin complex has to be first eliminated. This can be done by the pretreatment with four-valent sodium selenite but not with other chemical forms of selenium. Selenite oxidizes thiols of the tumor cell membranes to disulfides thus making them unavailable for the exchange reaction with partially reduced plasma proteins. Although selenite is known to be toxic to humans when given orally, its body's concentration can be safely increased by the parenteral administration. In conclusion, specific chemical properties of sodium selenite warrant its careful evaluation as a potential improvement of the efficacy of prostate cancer vaccines thus contributing to the reduction of mortality of this deadly form of cancer
The presence of small amounts of circulating DNA in plasma was demonstrated 60 years ago.Since then, cell-free DNA has been tested for quantity, fragmentation pattern and tumor-specific sequences in patients with various malignancies.The introduction of improved detection methods showed that all these alterations are regularly detectable in many cancer patients and the investigation of cell-free DNA may provide useful diagnostic and prognostic information.Herein, we review the recent findings on cell-free DNA alterations in patients with prostate cancer and discuss its diagnostic and prognostic potential.
Androgen deprivation may be used in conjunction with definitive treatment of prostate cancer. The indications and benefits vary widely with the type of treatment and the patient’s risk group determination. The role of neoadjuvant and adjuvant androgen deprivation therapy is greater and more widely studied in large controlled randomized studies in conjunction with external beam radiation [4-7]. However data is available for patients treated with brachytherapy [8] as well as those undergoing a prostatectomy [9-11] - although not as robust, and generally of a lower category than that with external beam radiation.
Background: In prostate carcinoma, there is controversy about optimal use of hormonal therapy with external beam radiotherapy: who will benefit, for how long, neo-adjuvant versus concurrent versus adjuvant.Patients and Methods: Evidence from randomized studies in the light of recent published articles and updates were reviewed in order to address these issues.Results and Conclusions: From this review it was concluded that the benefit of long-term hormonal therapy in combination with conventional-dose radiotherapy (<74 Gy) in high-risk prostate cancer is evident.For the intermediate risk, the evidence is still weak and studies are awaited to clarify this matter.
Androgen deprivation has long been a therapeutic option in the treatment or prostate cancer since Huggins & Hodges described the effect of castration on the prostate gland [1].Since then, the results of a large number of retrospective and prospective studies helped support the important role of androgen deprivation in prostate cancer [2].However, increasing attention has been focused on the possible side effects of androgen deprivation [3].Thus, the importance of understanding the mode of action, types of available preparations, as well as the appropriate indications and supporting literature on the subject has never been greater.The gains achieved through the integration of androgen deprivation may be lost if androgen deprivation is used inappropriately with a resultant decrease in the risk-benefit ratio.A comprehensive review of androgen deprivation in localized prostate cancer will include its use in the external beam, brachytherapy and prostatectomy settings per available literature.A review of the mechanism of action, side effects and new developments will be embarked upon.
Radical prostatectomy (RP) as a monotherapy is most likely to be curative only in patients with truly organ-confined PC. Several clinical and pathologic factors affect recurrence following RP. In an effort to improve the outcome Androgen deprivation therapy (ADT) has been evaluated in conjunction with RP. In this review we summarize the available evidence from prospective randomized studies concerning the use of ADT in both the preoperative and postoperative scenarios.
PSA is still recognized as the best marker available for detection and treatment monitoring of prostate cancer. However limitations of PSA testing raise a need for other valuable cancer markers. Expression of AMACR protein is recognized as a potential predictive marker, highly competitive to the PSA. Based on preliminary study on AMACR urine detection, the urine without prior prostate manipulations was tested for AMACR detection and radiotherapy treatment monitoring of prostate cancer. Urine samples derived from 57 patients were analyzed. Mainly, there were prostate cancer patients - 43 cases, benign prostate disease - 4 cases and lung (7 cases) as well as urinary bladder (3 cases) cancer patients. Samples were examined for AMACR and PAP staining using Western blot. In none of the prostate cancer patients AMACR protein was identified. However in 1/3 of urine samples of bladder cancer patients AMACR protein was detected. PAP staining performed on the same samples was positive in all prostate but not in other cancer (lung, bladder) cases. Testing of the urine without prior prostate manipulations (massage, USG, biopsy) is the most probable reason for the Western blot AMACR negative results. On the other hand positive AMACR staining in bladder cancer raise the possibility of false positive results. Therefore urine AMACR testing in prostate cancer cannot be recommended.
Prostate cancer is a major cause of cancer-related deaths in American men.The development and growth of prostate cancer depends on the androgen receptor (AR) and its high-affinity binding of dehydrotestosterone (DHT), which derives from testosterone (T).Most prostate tumors regress after therapy to prevent testosterone production by the testes, but the tumors eventually recur and cause death.The AR, a member of the steroid receptor family that is activated by testicular androgens, is the major regulatory transcription factor in normal prostate growth and development and in the growth of androgen-dependent prostate cancer.Recent evidence suggests that the AR may also contribute to prostate cancer growth during its recurrence in the androgen-deprived patient.A role for AR-mediated gene activation in recurrent prostate cancer is supported by its expression together with the expression of androgen-regulated genes.This review highlights the different mechanisms of the available androgen deprivation therapies and also focuses on the novel targeted therapies in advanced or metastatic prostate cancer.Furthermore, we provide a molecular basis for the AR and its role in activation and progression in recurrent or castration resistant prostate cancer.
