الفهرس 
PROSTATE CANCEROnly 14 pages are availabe for public view
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Abstract
P
rostate cancer (PC) is one of the most common cancers in men worldwide. The early detection of PC hand in hand with accurate staging is very important issue in the follow up and managing patients with PC and is associated with an improved outcome.
Serum PSA, DRE, bone scan finding and CT scan are current preoperative staging modalities which are available to clinicians, but are poor predictors for extracapsular disease.
Prostate specific antigen (PSA), one of the kallikrein family, in the serum is the most widely accepted marker for monitoring patients with PC. However, serum PSA has many limitations, as it may also be driven by certain non-malignant causes such as nodular hyperplastic changes in the prostate gland and prostatic inflammatory processes and misses a significant number of cancers at cutoff-point 4.0 ng/mL.
Search for valuable markers to discriminate PC patients remains the main issue for clinical research, one of these markers is alpha -methylacyl-coenzyme-A racemase (AMACR).
Immunohistochemical studies showed that AMACR is a highly specific and sensitive marker for prostate cancer cells, even in the earliest stages of malignant progression. These studies also showed an incremental increase in AMACR expression from benign epithelium, to prostatic intraepithelial neoplasia (PIN), to PC. This property of AMACR suggests that AMACR mRNA can be a RT-PCR target for discriminating PC patients and the detection of circulating PC cells, which in turn may correlate with both occult micrometastasis disease and the risk of disease progression.
The aim of the present study was to evaluate the clinical utility of (AMACR) as a promising marker of prostate cancer in diagnosis, prognosis of cancer prostate and its potential role in discriminating PC patients in comparison to the conventionally used PSA using RT-PCR for AMACR mRNA expression.
This study included 3 main subject groups; a control group (n=20), patients’ group (n=30). The control subjects were subdivided into healthy control subgroup (n=10) and diseased control subgroup; patients suffering from benign prostatic hyperplasia (BPH) (n=10). The patients’ group as well was further subdivided into three subgroups: organ confined PC subgroup (n=10), metastatic PC subgroup (n=10) and PC in remission subgroup (n=10). Patients were reclassified according to stage into T2 (n=20) and T4 (n=10). They were also reclassified according to Gleason grading to low grade (n=16) and high grade (n=14).For all subjects, serum tPSA, fPSA and f/t PSA ratio were measured by immunometric chemiluminescent method using the reagent product of DPC, on the“Immulite System”. Detection of AMACR mRNA in the peripheral blood was also performed for all subjects included in the study, using RT-PCR method after RNA extraction with densitometric scanning analysis of DNA fragments. For PC patients, clinical and radiological assessments, as well as histopathological examination of lesions were performed to confirm the diagnosis.
Our results showed that serum tPSA concentration was significantly increased in each of organ confined and metastatic subgroups when compared to healthy control subgroup. In addition serum tPSA levels showed a significant increase in BPH subgroup versus healthy controls. In our study serum tPSA concentration was significantly increased in organ confined PC subgroup and metastatic PC subgroup compared to BPH patients. Our results also showed a statistically significant increase in tPSA levels in metastatic PC patients versus organ confined PC patients. A significant increase in tPSA was also recorded in organ confined PC and metastatic PC subgroups when compared to PC in remission subgroup.
Free/ total PSA ratio showed a highly significant decrease in organ confined and metastatic subgroups when compared to healthy controls. A significant decrease in f/t PSA ratio in organ confined PC and metastatic PC when compared to BPH subgroup was also recorded in our study. While, f/t PSA ratio showed no statistically significant difference between organ confined subgroup and metastatic one. Also, the ratio could not differentiate between low grade tumor and high grade tumor.
Concerning AMACR mRNA, it showed a significant increase in organ confined PC and metastatic PC when compared to healthy controls. Our study recorded no significant difference in AMACR mRNA expression when comparing healthy controls to BPH patients and PC patients in remission. AMACR also showed a significant increase in organ confined PC and metastatic PC when compared to BPH subgroup. A significant increase in AMACR was also recorded in organ confined PC and metastatic PC subgroups versus PC in remission subgroup. On the contrary, AMACR showed no statistically significant difference between organ confined and metastatic PC subgroups but was proved to be significantly increased in patients with high grade tumor when compared to patients with low grade tumor.
When studying the correlation between AMACR mRNA and tPSA value, this study revealed absence of significant correlation between circulating AMACR mRNA and tPSA levels or f/tPSA ratio in BPH patients. However, a highly significant positive correlation was found between tPSA and AMACR. A highly significant negative correlation between tPSA and f/t PSA ratio as well as a highly significant negative correlation between f/t PSA ratio and AMACR was revealed in PC patients as a whole (organ confined+ metastatic+ PC in remission).
Receiver-operating characteristic (ROC) curve analysis was applied to assess the diagnostic performance of the different studied parameters in discriminating organ confined PC+ metastatic PC from healthy control subgroup. For tPSA, the AUC was 1.00, and the optimum cut-off level was 4.0 ng/mL. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 100%, respectively. For fPSA, the AUC was 0.910, and the optimum cut-off level was 1.3 ng/mL. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 90, 90, 81.8, 94.7 and 90%, respectively. The two missed cases were patients with organ confined PC. For f/t PSA ratio, the AUC was 0.990, and the optimum cut-off level was 0.4. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 95, 100, 90.9, 100 and 96.7%, respectively. The only missed case was a patient with organ confined PC. Finally, regarding AMACR, the AUC was 0.945, and the ROC cut-off level having the best diagnostic accuracy was 46.1. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 85, 100, 76.9, 100 and 90%, respectively. The three missed cases were patients with organ confined PC.
A second ROC curve analysis was done to assess
the diagnostic performance of the different studied parameters in discriminating organ confined PC and metastatic PC from PC in remission subgroup. tPSA showed AUC of 0.990 and an optimum cut-off level of 5.2 ng/mL. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 100, 90, 100, 95.2 and 96.7%, respectively. AS for fPSA, the AUC was 0.726, and the optimum cut-off level was 1.4 ng/mL. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 90, 70, 77.8, 85.7 and 83.3%, respectively. f/t PSA ratio showed AUC of 0.852 and an optimum cut-off level of 0.2. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 85, 100, 76.9, 100 and 90%, respectively. The optimum cut-off level of AMACR was 50.6 with AUC of 0.910. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 95, 100, 90.9, 100 and 96.7%, respectively. The three false negative cases were for patients with organ confined PC.
Multi ROC was done to assess the diagnostic performance of the combined use of tPSA and AMACR in discriminating organ confined PC and metastatic PC from PC in remission. It revealed better efficacy (100%) than single use of each marker alone.
Another ROC curve analysis was done to assess the diagnostic performance of the different studied parameters in discriminating organ confined PC subgroup from metastatic PC subgroup. tPSA showed AUC of 0.920 and an optimum cut-off level of 50.4 ng/mL. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 100, 90, 100, 90.9 and 95%, respectively. fPSA showed AUC of 0.980 and an optimum cut-off level of 2.3 ng/mL. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 100, 80, 100, 83.3 and 90%, respectively. f/t PSA ratio showed AUC of 0.695 and an optimum cut-off level of 0.1. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 100, 50, 100, 66.7 and 75%, respectively. As for AMACR, AUC was 0.580 and the optimum cut-off level was 59.9. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 100, 50, 100, 66.7 and 75%, respectively.
Finally, ROC curve analysis was done to assess the diagnostic performance of the different studied parameters in discriminating organ confined PC and metastatic PC from BPH subgroup. tPSA showed AUC of 0.840 and an optimum cut-off level of 5.0 ng/mL. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 100, 80, 100, 90.9 and 93.3%, respectively. fPSA showed AUC of 0.735 and an optimum cut-off level of 1.3 ng/mL. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 90, 40, 66.7, 75 and 73.3%, respectively. f/t PSA ratio showed AUC of 0.872 and an optimum cut-off level of 0.2. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 85, 100, 76.9, 100 and 90%, respectively. Regarding AMACR, AUC was 0.853 and the optimum cut-off level was 48.0. This had a diagnostic sensitivity, specificity, negative predictive value, positive predictive value and diagnostic efficacy of 95, 80, 88.9, 90.5and 90%, respectively. The only missed case was in a patient with organ confined PC.