Ashkan Mortezavi

KPNA2 Expression Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Purpose: To analyze rates of expression of karyopherin alpha 2 (KPNA2) in different prostate tissues and to evaluate the prognostic properties for patients with primary prostate cancer. Experimental Design: Tissue microarrays (TMA) contained 798 formalin-fixed, paraffin-embedded prostate tissue cores from two different institutes of pathology. TMAs were stained immunohistochemically for KPNA2 and NBS1. SiRNA technologies were used to inhibit KPNA2 expression in vitro, and the effect of this inhibition on cellular viability was determined. Efficiency of knockdown experiments was determined by Western blot analysis. Results: KPNA2 expression was significantly upregulated in carcinomas of the prostate, especially in metastatic and castration-resistant prostate cancer samples. Positive nuclear KPNA2 immunoreactivity was identified as a novel predictor of biochemical recurrence after radical prostatectomy (n = 348), and was independent of the well-established predictive factors preoperative PSA value, Gleason score, tumor stage, and surgical margin status. These results were validated by analyzing a second and independent prostate cancer cohort (n = 330). Further, in vitro experiments showed that the cell proliferation and viability of PC3 cells was significantly reduced when KPNA2 expression was inhibited. KPNA2 knockdown did not induce PARP cleavage as marker for apoptosis. No significantly increased sub-G1 fraction could be found by FACS analysis. Conclusions: KPNA2 is a novel independent prognostic marker for disease progression after radical prostatectomy. This allows to identify patients who need more aggressive treatment. It can moreover be speculated that patients not suited for surveillance regimens might be identified at initial biopsy by a positive KPNA2 immunohistochemistry. Clin Cancer Res; 17(5); 1111–21. ©2011 AACR.

Periostin is up-regulated in high grade and high stage prostate cancer

BackgroundExpression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far.MethodsHere, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93) and a test cohort (n = 325). Metastatic prostate cancers (n = 20), hormone refractory prostate cancers (n = 19) and benign prostatic tissues (n = 38) were also analyzed.ResultsIn total, strong epithelial periostin expression was detectable in 142 of 418 (34.0%) of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%). Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p < 0.01) and advanced tumour stage (p < 0.05) in the test cohort. Whereas periostin expression was weak or absent in the stroma around normal prostate glands, strong periostin expression in tumour stroma was found in most primary and metastatic prostate cancers. High stromal periostin expression was associated with higher Gleason scores (p < 0.001). There was a relationship between stromal periostin expression and shortened PSA relapse free survival times in the training cohort (p < 0.05).ConclusionsOur data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer.

MAGE-C2/CT10 Protein Expression Is an Independent Predictor of Recurrence in Prostate Cancer

The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms. In most cases, no CT antigen is found in normal tissues, except in testis, making them ideal targets for cancer immunotherapy. A comprehensive analysis of CT antigen expression has not yet been reported in prostate cancer. MAGE-C2/CT-10 is a novel CT antigen. The objective of this study was to analyze extent and prognostic significance of MAGE-C2/CT10 protein expression in prostate cancer. 348 prostate carcinomas from consecutive radical prostatectomies, 29 castration-refractory prostate cancer, 46 metastases, and 45 benign hyperplasias were immunohistochemically analyzed for MAGE-C2/CT10 expression using tissue microarrays. Nuclear MAGE-C2/CT10 expression was identified in only 3.3% primary prostate carcinomas. MAGE-C2/CT10 protein expression was significantly more frequent in metastatic (16.3% positivity) and castration-resistant prostate cancer (17% positivity; p<0.001). Nuclear MAGE-C2/CT10 expression was identified as predictor of biochemical recurrence after radical prostatectomy (p = 0.015), which was independent of preoperative PSA, Gleason score, tumor stage, and surgical margin status in multivariate analysis (p<0.05). MAGE-C2/CT10 expression in prostate cancer correlates with the degree of malignancy and indicates a higher risk for biochemical recurrence after radical prostatectomy. Further, the results suggest MAGE-C2/CT10 as a potential target for adjuvant and palliative immunotherapy in patients with prostate cancer.

Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

Purpose: This study investigates SLC18A2 (vesicular monoamine transporter 2) expression in prostate adenocarcinoma and examines its potential as a predictive marker for prostate cancer patient outcome after radical prostatectomy. Experimental Design: Expression and single nucleotide polymorphism microarray analyses identified SLC18A2 as both down-regulated and subject to common loss-of-heterozygosity in prostate cancer. Down-regulated SLC18A2 expression was validated on tissue microarrays containing benign and malignant prostate specimens from an independent patient group (n = 738). Furthermore, SLC18A2 immunoreactivity in radical prostatectomy tumor specimens (n = 506) was correlated to clinicopathologic characteristics and recurrence-free survival. The possibility of SLC18A2 silencing by aberrant DNA methylation in prostate cancer cells was investigated by bisulfite sequencing. Results: Tissue microarray analysis revealed markedly lower cytoplasmic SLC18A2 staining in cancer compared with nonmalignant prostate tissue samples, confirming RNA expression profiling results. Furthermore, multivariate analysis identified cytoplasmic SLC18A2 immunoreactivity as a novel predictor of biochemical recurrence following prostatectomy (hazard ratio, 0.485; 95% confidence interval, 0.333-0.709; P < 0.001) independent of prostate-specific antigen, Gleason score, tumor stage, and surgical margin status. SLC18A2 showed loss-of-heterozygosity in 23% of the tumors and was densely hypermethylated in 15 of 17 (88%) prostate cancer samples plus 6 of 6 prostate cancer cell lines. In contrast, SLC18A2 was unmethylated in 4 of 4 adjacent nonmalignant prostate and 3 of 5 benign prostatic hyperplasia tissue samples, whereas 2 of 5 benign prostatic hyperplasia samples had monoallelic hypermethylation. Methylation and histone deacetylase inhibitory agents rescued SLC18A2 expression in three prostate cancer cell lines. Conclusions:SLC18A2 silencing by DNA hypermethylation and/or allelic loss is a frequent event in prostate cancer and a novel independent predictor of biochemical recurrence after prostatectomy.

Insulin-like growth factor II mRNA binding protein 3 (IMP3) is overexpressed in prostate cancer and correlates with higher Gleason scores

BackgroundThe oncofetal protein insulin-like growth factor II mRNA binding protein 3 (IMP3) is an important factor for cell-migration and adhesion in malignancies. Recent studies have shown a remarkable overexpression of IMP3 in different human malignant neoplasms and also revealed it as an important prognostic marker in some tumor entities. To our knowledge, IMP3 expression has not been investigated in prostate carcinomas so far.MethodsImmunohistochemical stainings for IMP3 were performed on tissue microarray (TMA) organized samples from 507 patients: 31 normal prostate tissues, 425 primary carcinomas and 51 prostate cancer metastases or castration-resistant prostate cancers (CRPC). IMP3 immunoreactivity was semiquantitatively scored and correlated with clinical-pathologic parameters including survival.ResultsIMP3 is significantly stronger expressed in prostate carcinomas compared to normal prostate tissues (p < 0.0001), but did not show significant correlation with the pT-stage, the proliferation index (MIB1), preoperative serum PSA level and the margin status. Only a weak and slightly significant correlation was found with the Gleason score and IMP3 expression failed to show prognostic significance in clinico-pathological correlation-analyses.ConclusionsAlthough IMP3 is overexpressed in a significant proportion of prostate cancer cases, which might be of importance for novel therapeutic approaches, it does not appear to possess any immediate diagnostic or prognostic value, limiting its potential as a tissue biomarker for prostate cancer. These results might be corroborated by the fact, that two independent tumor cohorts were separately reviewed.

Lithium Triborate Laser Vaporization of the Prostate Using the 120 W, High Performance System Laser: High Performance All the Way?

PURPOSE Technical modifications of the 120 W lithium-triborate laser have been implemented to increase power output, and prevent laser fiber degradation and loss of power output during laser vaporization of the prostate. However, visible alterations at the fiber tip and the subjective impression of decreasing ablative effectiveness during lithium-triborate laser vaporization indicate that delivering constantly high laser power remains a relevant problem. Thus, we evaluated the extent of laser fiber degradation and loss of power output during 120 W lithium-triborate laser vaporization of the prostate. MATERIALS AND METHODS We investigated 46 laser fibers during routine 120 W lithium-triborate laser vaporization in 35 patients with prostatic bladder outflow obstruction. Laser beam power was measured at baseline and after the application of each 25 kJ during laser vaporization. Fiber tips were microscopically examined after the procedure. RESULTS Mild to moderate degradation at the emission window occurred in all fibers, associated with a loss of power output. A steep decrease to a median power output of 57.3% of baseline was detected after applying the first 25 kJ. Median power output at the end of the defined 275 kJ lifespan of the fibers was 48.8%. CONCLUSIONS Despite technical refinements of the 120 W lithium-triborate laser fiber degradation and significantly decreased power output are still detectable during the procedure. Laser fibers are not fully appropriate for the high power delivery of the new system. There is still potential for further improvement in the laser performance.

External physical and biochemical stimulation to enhance skeletal muscle bioengineering

PURPOSE OF REVIEW Cell based muscle tissue engineering carries the potential to revert the functional loss of muscle tissue caused by disease and trauma. Although muscle tissue can be bioengineered using various precursor cells, major limitations still remain. RECENT FINDINGS In the last decades several cellular pathways playing a crucial role in muscle tissue regeneration have been described. These pathways can be influenced by external stimuli and they not only orchestrate the regenerative process after physiologic wear and muscle trauma, but also play an important part in aging and maintaining the stem cell niche, which is required to maintain long-term muscle function. SUMMARY In this review article we will highlight possible new avenues using external physical and biochemical stimulation in order to optimize muscle bioengineering.

A positive family history as a risk factor for prostate cancer in a population-based study with organised prostate-specific antigen screening: results of the Swiss European Randomised Study of Screening for Prostate Cancer (ERSPC, Aarau).

To assess the value of a positive family history (FH) as a risk factor for prostate cancer incidence and grade among men undergoing organised prostate‐specific antigen (PSA) screening in a population‐based study.

Continuous Low-Dose Aspirin Therapy in Robotic-Assisted Laparoscopic Radical Prostatectomy Does Not Increase Risk of Surgical Hemorrhage

BACKGROUND Withdrawal of oral antiplatelet therapy (OAT) is a major risk factor for stent thrombosis, myocardial infarction, and cerebral strokes. In order to minimize the risk for thrombotic complications, since 2007 robotic-assisted laparoscopic radical prostatectomy (RARP) has taken place under continuous OAT with aspirin at our institution. In this retrospective study we analyzed the risk for perioperative bleeding and surgical outcome after RARP with OAT. PATIENTS AND METHODS All patients who underwent RARP with aspirin OAT at our institution since 2007 were included in this analysis. The OAT group was compared with a group that underwent RARP without OAT, which contained twice the number of patients. Matching of the two groups was performed with regard to the tumor stage and whether a lymph node dissection or nerve-sparing was performed. RESULTS Thirty-eight patients were assigned to the OAT group and 76 to the control group. A difference in the decrease of postoperative hemoglobin concentration was not detectable between the two groups (mean drop of 2.9±1.4 g/dL and 2.9±1.1 g/dL, respectively; P=.93). RARP was completed in all OAT patients without conversion to open surgery. Two of the 38 patients (5.3%) in the OAT group and none in the control group required blood transfusions (P=.11). Equivalent rates of positive surgical margins for pT2 tumors were detected (16% OAT versus 14% control group; P=1.0). No adverse cardiovascular events occurred in either group during the hospitalization. CONCLUSIONS Continued perioperative OAT with aspirin in RARP is safe, feasible, and not associated with increased blood loss.

Intrafascial Dissection Significantly Increases Positive Surgical Margin and Biochemical Recurrence Rates after Robotic-Assisted Radical Prostatectomy

Introduction: Improved visualization and magnification in robot-assisted laparoscopic radical prostatectomy (RALRP) has tempted many urologists to dissect the neurovascular bundle closer to the prostate following the layers of the pseudo-capsule of the prostate. This might bear a higher risk of decreased tumor control. Materials and Methods: An analysis of a consecutive series of 186 patients who underwent RALRP at our institution was performed. The outcome of patients with intrafascial nerve-sparing (INS) was compared with the outcome of patients who underwent interfascial, extrafascial or no nerve-sparing (non-INS). Results: A total of 80 patients (43.0%) received INS. The overall R1 rate was 27.9%. For pT2 tumors the rate of R1 was 33.8% in INS versus 14.8% in non-INS (odds ratio 2.936, 95% confidence interval 1.338–6.443, p = 0.007). Recurrence-free survival was significantly shorter in INS (p = 0.05; hazard ratio 3.791). Conclusion: The intrafascial dissection technique for RALRP bears a high risk of incomplete resection in localized prostate cancer resulting in unfavorable outcome.