Tumor Gleason Score Research Articles

Abstract 226: Verification of prostate cancer genomics biomarker candidates at protein level using PRISM-SRM

Abstract Mass spectrometry (MS) based targeted proteomics such as selected reaction monitoring (SRM) provides an antibody-independent strategy for sensitive, specific and multiplexed verification of genomics biomarker candidates at the protein level. In order to identify a panel of proteins with the potential to discriminate between aggressive and indolent forms of prostate cancer and predict prostate cancer progression, we have selected 52 protein candidates from existing prostate cancer genomics data sets and validated cancer drivers, and performed quantitative proteomics analysis in tumor and control tissue samples using the highly sensitive PRISM (high-pressure, high-resolution separations coupled with intelligent selection and multiplexing)-SRM approach. PRISM-SRM assays have been developed for the 52 prostate cancer biomarker candidates including: prostate cancer prognosis associated genes, prostate cancer associated genes that were up-regulated in transcriptomics studies, and other cancer-related genes (including the ERG or ETV1 isoforms). Two sets of tissue samples were analyzed using PRISM-SRM with heavy isotope-labeled synthetic peptides as internal standards: 1) 10 high Gleason-score (7-9) primary prostate tumors and 10 benign prostatic hyperplasia (BPH) tissues (OCT-embedded specimens); and 2) 10 primary tumors from patients showing metastatic progression, 10 primary tumors from patients who showed biochemical recurrence (BCR), and 10 primary tumors from patients with no BCR or metastatic progression after more than ten years of follow-up after radical prostatectomy (FFPE whole mount prostate specimens). Overall, PRISM-SRM analyses of all the patient tissue samples enabled the detection of 48 out of 52 biomarker candidates, suggesting extremely low level of expression of the remaining 6 genes (HXC6, OSTP, TWST1, and ERG8); in comparison regular LC-SRM can only detect 21 of these candidates at the protein level. In the 10 high Gleason-score tumors and 10 BPH controls, 13 proteins were found differentially abundant with P<0.05. In the 10X10X10 FFPE sample analysis, there were three proteins discriminating between “metastatic progression” and “no progression” tumors, one protein discriminated between BCR and “no progression” tumors, and four proteins discriminated between metastatic progression and BCR tumors (P<0.05). These promising biomarker candidates will be further evaluated, individually and in panels, in independent, larger cohort for their potential prognostic applications. In summary, PRISM-SRM provides a highly sensitive method for quantification and rapid screening of multiple potential biomarker candidates at the protein level. This approach holds great potential for rapidly translating genomics-based discovery candidates into protein-based biomarkers. Citation Format: Hui Wang, Yuqian Gao, Athena Schepmoes, Gyorgy Petrovics, Jennifer Cullen, Thomas Fillmore, Tujin Shi, Wei-Jun Qian, Richard Smith, Brandi Weaver, Robin Leach, Ian Thompson, Sudhir Srivastava, Jacob Kagan, Albert Dobi, Karin Rodland, Shiv Srivastava, Tao Liu. Verification of prostate cancer genomics biomarker candidates at protein level using PRISM-SRM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 226. doi:10.1158/1538-7445.AM2017-226

PSA levels, PSA doubling time, Gleason score and prior therapy cannot predict measured uptake of [68Ga]PSMA-HBED-CC lesion uptake in recurrent/metastatic prostate cancer.

To assess whether clinical prostate cancer (PCA) related factors and therapy status can predict the degree of tracer uptake on [68Ga]PSMA-HBED-CC PET/CT. We retrospectively studied 124 patients with recurrent an/or metastatic PCA who underwent [68Ga]PSMAHBED-CC PET/CT. The maximum standardized uptake value (SUVmax) was determined in the prostate bed as well as in three size categories (≤ 5 mm, > 5-15 mm, > 15 mm) in pelvic lymph node, extrapelvic lymph node, bone and visceral metastases. Significant positive correlations between lesion size and SUVmax were found in pelvic lymph node metastases > 5 -≤15 mm (Spearmans rho = 0.502, p = 0.002) as well as in extrapelvic lymph node metastases5 mm (rho = 0.314, p = 0.033) and > 5 ≤-15 mm (rho = 0.614, p < 0.001). SUVmax tended to be higher in the largest diameter category in each anatomic station than in the middle and lower categories. We were unable to find evidence for a relationship between SUVmax and PSA, PSAdt, Gleason score, androgen deprivation therapy, radiation therapy or chemotherapy status. Measured tracer uptake in [68Ga]PSMA-HBED-CC PET/CT in patients with recurrent/metastasized prostate cancer is significantly influenced by lesion size as a result of partial volume effects in the very small lesions. Clinical indicators of aggressive prostate cancer behaviour such as PSA levels, PSA doubling time or the Gleason score of the primary tumour, as well as the androgen deprivation therapy, radiation therapy or chemotherapy status are not related to measured tracer uptake. ZIEL:: Beantwortung der Frage ob klinisch bestimmbare Faktoren und Therapiestatus bei Prostatakarzinom (PCA) eine Vorhersage zur Traceranreicherung in [68Ga]PSMA-HBED-CC PET/CT liefern können.Material & Methoden: 124 Patienten mit rezidiviertem und/oder metastasiertem PCA die [68Ga]PSMA-HBED-CC PET/CT untergingen, wurden retrospektiv untersucht. Der maximum Standardized Uptake Value (SUVmax) wurde in der Prostataloge gemessen sowie in drei Größen-Kategorien ( 5 mm, > 5-15 mm, > 15 mm) in Metastasen in den pelvinen Lymphknoten-, extrapelvinen Lymphknoten-, Knochen- und viszeralen Metastasen. Signifikant positive Korrelationen zwischen Läsionsgröße und SUVmax wurden in pelvinen Lymphknotenmetastasen > 5 -≤15 mm (Spearmans rho = 0.502, p = 0.002), extrapelvinen Lymphknotenmetastasen5 mm (rho = 0.314, p = 0.033) und > 5 -≤15 mm (rho = 0.614, p < 0.001) gefunden. Für jede anatomische Lokalisation wurde ein höherer Wert SUVmax innerhalb der größten Kategorie verglichen zu mittleren und kleinsten Kategorie gefunden.

Clinical and molecular rationale to retain the cancer descriptor for Gleason score 6 disease.

Treatment choices for men with indolent prostate cancer include active surveillance or definitive local therapy. Overtreatment of these patients is an important current problem. Treatment decisions are often made jointly by the clinician and the patient, partly based on the tumour's Gleason score. To reduce the burden of overtreatment, the clinical significance of Gleason score 3 + 3 = 6 prostate cancer has been questioned and some have advocated that Gleason pattern 3 should be stripped of its cancer status. However, removing the cancer descriptor would have far-reaching clinical consequences that might result in poor patient outcomes, as the evidence of a lack of malignancy is inconclusive in several areas. For example, molecular data suggest that the genomic instability underlying tumour progression precedes histologically visible changes and the absolute risk of metastasis or mortality from Gleason score 6 prostate cancer is not zero. Extreme caution is required when weighing a decision to reclassify Gleason pattern 3 disease as a non-cancer.

Abstract 4963: A distinct AMP-activated protein kinase phosphorylation site is associated with metastasis and castration-resistance in prostate cancer

Abstract AMP-activated protein kinase (AMPK) is a critical regulator of cellular metabolism and plays important role in the development and progression of several human diseases including cancer. We have previously shown that AMPKα activity is significantly inhibited by Ser-485/491 phosphorylation in cell culture and in vivo models of metastatic and castration-resistant prostate cancer. To determine potential translatability, we investigated AMPKα-Ser-485/491 phosphorylation status in clinical prostate cancer specimens and its correlation with metastasis and progression to castration-resistance. Metastasis and matched primary tumor specimens from 45 metastatic prostate cancer patients, 31.1% of which were post-androgen deprivation therapy failure (castration-resistant prostate cancer), and primary tumor specimens from 30 non-metastatic, hormone-dependent prostate cancer patients with undetectable PSA for a mean of 97.1 ± 17.5 months were obtained from the University Hospitals Case Medical Center Pathology Archive. Slides were cut from paraffin blocks, immunostained for p-Ser-485/491 AMPKα and total AMPKα, analyzed by a pathologist, and statistical significance determined by T-test, Kruskal-Wallis test, Fisher's exact test, or Chi-Square test. Mean pre-diagnostic biopsy PSA was 6.5 ng/mL (range 1.20-25.3 ng/mL) in non-metastatic patients and 501.9 ng/mL (range 1.82-3200 ng/mL) in metastatic patients (p &amp;lt; 0.0001). Mean total Gleason score of primary tumors was 6.5 in the non-metastatic group and 8.2 in the metastatic group (p &amp;lt; 0.0001); primary prostate tumor volume (mean ± S.D.) was 22.1 ± 19.5% in the non-metastatic group and 68.1 ± 28.7% in the metastatic group (p &amp;lt; 0.0001). The intensity of overall p-Ser-485/491 AMPKα staining and the number of p-Ser-485/491 AMPKα positively-stained cells was significantly increased in primary prostate tumors (p = 0.0003 and p = 0.0008, respectively) and metastases (p = 0.0011 and p = 0.0062, respectively) of metastatic prostate cancer patients when compared to staining of primary tumor specimens from non-metastatic prostate cancer patients. Further, the intensity of overall p-Ser-485/491 AMPKα staining increased 2.21-fold (p = 0.0050) and the number of p-Ser-485/491 AMPKα positively-stained cells increased 1.77-fold (p = 0.0041) in castration-resistant metastatic prostate cancer specimens compared to androgen-dependent prostate cancer specimens. Therefore, AMPKα Ser-485/491 phosphorylation is associated with metastasis and castration-resistance in clinical prostate cancer and may be a novel target for treatment. Citation Format: Melissa A. Babcook, Mahmut Akgul, Seunghee Margevicius, Gregory T. MacLennan, Pingfu Fu, Robert Abouassaly, Sanjay Gupta. A distinct AMP-activated protein kinase phosphorylation site is associated with metastasis and castration-resistance in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4963.

Abstract 2235: Clinical results of a Phase I/II trial of adjuvant therapeutic vaccination in high risk resected prostate cancer patients using autologous dendritic cells loaded with mRNA from primary prostate cancer tissue, hTERT and survivin

Abstract Prostate cancer patients diagnosed with high Gleason score (≥ 8) and large tumors (≥T2c) are considered high-risk patients and &amp;gt;50% will develop an early biochemical relapse. Presently, there is no curative therapy available for patients with biochemical relapse. Based on these findings we initiated in January 2011 a Phase I/II dendritic cell (DC) vaccine study. Patients included have pathological stage pT2 - pT3b, Gleason score 7b-10, pN0, pN+ or pNx and postoperative PSA &amp;lt; 0.2 μg/L. Following surgery autologous tumor cell lines were established from each patient using an in-house culturing method. mRNA from the tumor cell line was produced and used for DC vaccination in combination with mRNA hTERT and mRNA Survivin. DCs were differentiated from enriched monocytes, cultured for 2 days with IL4 and GM-CSF and matured with Jonuleit-maturation cocktail for 24 hours. The matured DCs were transfected separately with the 3 different mRNAs and then frozen and stored until use. The vaccination regimen includes one vaccine per week for four weeks, followed by monthly “vaccine boost” during the first year, then every 3 months the second and third year. Recently, a novel 3 days DC protocol using a TLR7/8-agonist maturation cocktail has been implemented at our department. Based on encouraging clinical results with this type of DCs in compassionate use patients with different types of tumors, we decided to change our DCs protocol to the new generation DCs. Of the 20 patients included in this trial 15 patients have been given the standard fast DCs and 5 have been vaccinated with the new type of DCs. 8 Patients given standard DC has completed 3 years of vaccination and 4 has completed 2 years of vaccination. 3 of 15 patient given standard DC has experienced PSA relapse during vaccination. None of the patients given the new type of DC has so far experienced raise in PSA levels. To our knowledge this is the first adjuvant DC vaccine study in high risk prostate cancer and we conclude that the study is feasible, safe and utmost promising. Extensive immune monitoring is ongoing taking advantage of the established autologous tumor cell lines from all patients. Citation Format: Anne Merete Aa. Tryggestad, Karol Axcrona, Iris Bigalke, Else M. Inderberg-Suso, Gjertrud Skorstad, Ulrika Axcrona, Steinar Aamdal, Gustav Gaudernack, Dolores Schendel, Wolfgang Lilleby, Svein Dueland, Gunnar Kvalheim. Clinical results of a Phase I/II trial of adjuvant therapeutic vaccination in high risk resected prostate cancer patients using autologous dendritic cells loaded with mRNA from primary prostate cancer tissue, hTERT and survivin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2235.

High-Resolution Diffusion-weighted Imaging Increases Prostate Cancer Visibility?

Multiparametric MRI of the prostate has become a valuable imaging tool to detect clinically significant prostate cancer (Panebianco et al., 2015, Schoots et al., 2015). This tool consists of anatomical and functional imaging techniques. Currently, diffusion-weighted imaging is the most promising functional technique to detect and characterize prostate cancer. Despite its huge potential, it has some limitations that may hamper further implementation in the clinical practice. The signal-to-noise ratio is currently the major limitation. As a result, the highest in plane resolution, achievable with commercially available sequences, is in the range of 1.5 mm (Barentsz et al., 2012). In EBioMedicine, Sharif-Afshar et al. present an important step forward to overcome the current limitations of diffusion-weighted imaging (Sharif-Afshar et al., 2016). This prospective pilot study included 17 men scheduled for prostate biopsy for active surveillance. They underwent multiparametric MRI of the prostate prior to the prostate biopsy. Additionally, the men underwent a high resolution three-dimensional multi-shot diffusion-weighted imaging sequence, which has advantages over two-dimensional single-shot echo-planer imaging. These include markedly reduced geometric distortion, minimization of susceptibility-related artifacts, and higher achievable spatial resolution. This multishot technique allows differentiation of signal and noise, further improving resolution. The reported in plane resolution is 0.9 × 0.9 × 3.5 mm3, which is improved by a factor 4.4 to 5.4. This resulted in a significantly higher area under the ROC for the high resolution diffusion-weighted MRI compared to the standard clinical diffusion-weighted imaging. Subsequently, the new technique identified significantly more biopsy-proven lesions than standard diffusion MRI. The investigated functional imaging technique has great potentials. Diffusion-weighted MRI may provide an aid to establish the aggressiveness of prostate cancer and help predict those tumors most likely to progress rapidly. Prostate biopsies frequently underestimate the ‘true’ Gleason score of tumors found with transrectal ultrasound compared to radical prostatectomy (ranging from 30 to 50%, depending on initial Gleason score) (Pinthus et al., 2006, Corcoran et al., 2011). This high-resolution technique may further improve lesion characterization and ultimately be used to perform MRI diffusion-weighted imaging-targeted biopsy. A question that arises is whether this higher spatial resolution will improve patient selection for active surveillance. Particular in this patient group, it is difficult to find low-grade lesions with diffusion-weighted imaging. Contrast-enhanced MRI is more helpful in finding those lesions. On the other hand, the proposed technique may be used to exclude males from the active surveillance program. To conclude, high-resolution diffusion-weighted imaging of the prostate has the potential to further improve lesion characterization and visibility. It has paved the way for more accurate MRI-targeted biopsy.

Prostate cancer with a pseudocapsule at MR imaging: a marker of high grade and stage disease?

Clinicopathological correlates of prostate cancer associated with a pseudocapsule at T2-weighted magnetic resonance (MR) imaging are presented in a retrospective series of 15 patients. Of 15 tumors, 14 involved the peripheral zone. Extracapsular extension was seen in 14 cases. Tumor Gleason score was 8 or above in 12 of 15 cases, and ductal type adenocarcinoma was identified in 4 cases. Step section histopathological correlation (n=5) demonstrated that the pseudocapsule corresponded with dense compressive or reactive peritumoral fibrosis. A pseudocapsule around prostate cancer at T2-weighted MR imaging is a rare finding that appears to be associated with high grade and stage disease.

Treatment mapping of prostate cancer in DVPZ prostate centers in Germany

In prostate centers of the Governing Body of German Prostate Centers (DVPZ, Dachverband der Prostatazentren Deutschlands e.V.) treatment data from 3 university clinics, 21 treatment clinics, 3 private clinics and 330 general practitioners incorporated under 22 certificates are collated, in order to document the quality and type of cross-sectoral and interdisciplinary treatment, in particular of prostate cancer (PCA) patients. This analysis is based on the DVPZ UroCloud data sets from 20 July 2015. The UroCloud reflects the web-based chronological disease development and quality parameters. For the descriptive analysis of particular key figures, available complete data sets were selected. Of the centers 22 held a valid certificate and fulfilled all required case numbers and structural prerequisites at the primary certification or recertification. In three cases a reauditing led to requirements before certification. Since 2005 a total of 9650 PCA patients have been pseudonymized and followed up (41,247 follow-up forms, 4.3 forms per patient). In 2014 the median number of newly documented PCA patients was 61 per center (minimum 7 and maximum 295). Radical prostatectomy (RP) dominated with 4491 (56 %) cases followed by primary hormonal therapy (1210 cases, 15 %), irradiation (809, 10 %) and non-interventional therapy, such as active surveillance (AS) or watchful waiting (WW) in 760 cases (10 %). A prostate-specific antigen (PSA) reduction was documented in 50 % of the patients with a preoperative PSA value > 20, in 60 % of pT4 tumors and in 50 % of patients with a tumor Gleason score of 9-10. A positive incision margin (R+) was found in in 15 % of pT2 stages, 41 % of pT3 stages and 85 % of pT4 stages. A secondary intervention was documented in 6.5 % of RP. The DVPZ certificate reflects the complete spectrum of treatment of PCA patients. The strength of the certificate lies in the documentation of patient development and a simultaneous collation of quality parameters.

Multiparametric magnetic resonance tomography and MRI/TRUS-fusion-biopsy for index lesion detection: correlation with radical prostatectomy specimen

Methods We selected 120 consecutive patients who underwent transperineal fusion-biopsy before RP. All men received a saturation biopsy (SB) in addition to targeted biopsies of lesions with PIRADS≥2. On RP specimen, the index lesion was defined as highest Gleason score (GS) or highest tumour volume (TV). GS=3+3 and TV≥1.2ml or GS=3+4 and TV≥0.7ml or GS>3+4 were considered significant PC. We performed Spearmans correlation analysis between mpMRI and RP and Fisher`s test between mpMRI, TB and SB.

Detection of Core2 β-1,6-N-Acetylglucosaminyltransferase in Post-Digital Rectal Examination Urine Is a Reliable Indicator for Extracapsular Extension of Prostate Cancer.

To identify appropriate candidates for aggressive treatment such as radical prostatectomy or radiation therapy of localized prostate cancer (PCa), novel predictive biomarkers of PCa aggressiveness are essential. Core2 β-1,6-N-acetylglucosaminyltransferase-1 (GCNT1) is a key enzyme that forms core 2-branched O-glycans. Its expression is associated with the progression of several cancers. We established a mouse IgG monoclonal antibody (mAb) against GCNT1 and examined the relationship of GCNT1 expression to the clinicopathological status of PCa. Paraffin-embedded PCa specimens were analyzed by immunohistochemistry for GCNT1 expression using a newly established mouse anti-GCNT1 mAb by ourselves. GCNT1-positive tumor showed significantly higher Gleason score and larger tumor volume. The number of GCNT1-positive cases was significantly lower in cases of organ-confined disease than in cases of extracapsular extension. GCNT1-negative tumors were associated with significantly better prostate-specific antigen (PSA)-free survival compared with GCNT1-positive tumors. Multivariate analysis revealed that detection of GCNT1 expression was an independent risk factor for PSA recurrence. We established new methods for GCNT1 detection from PCa specimens. Immunoblotting was used to examine post-digital rectal examination (DRE) urine from PCa patients. Over 90% of GCNT1-positive PCa patients with high concentrations of PSA showed extracapsular extension. In conclusion, GCNT1 expression closely associates with the aggressive potential of PCa. Further research aims to develop GCNT1 detection in post-DRE urine as a marker for PCa aggressiveness.

Testosterone Therapy after Radiation Therapy for Low, Intermediate and High Risk Prostate Cancer

Limited literature exists regarding the safety of testosterone therapy in men treated for prostate cancer. We present multi-institutional data on testosterone therapy in hypogonadal men with prostate cancer treated with radiation therapy. We retrospectively reviewed the records of hypogonadal men treated with testosterone therapy after radiation therapy for prostate cancer at 4 institutions. Serum testosterone, free testosterone, estradiol, sex hormone-binding globulin, prostate specific antigen, prostate specific antigen velocity and prostate biopsy findings were analyzed. A total of 98 men were treated with radiation therapy. Median age was 70.0 years (range 63.0 to 74.3) at initiation of testosterone therapy. Median baseline testosterone was 209 ng/dl (range 152 to 263) and median baseline prostate specific antigen was 0.08 ng/ml (range 0.00 to 0.33). In the cohort the tumor Gleason score was 5 in 3 men (3.1%), 6 in 44 (44.9%), 7 in 28 (28.6%), 8 in 7 (7.1%) and 9 in 4 (4.1%). Median followup was 40.8 months (range 1.5 to 147). Serum testosterone increased to a median of 420 ng/dl (range 231 to 711) during followup (p <0.001). Overall a nonsignificant increase in mean prostate specific antigen was observed from 0.08 ng/ml at baseline to 0.09 ng/ml (p = 0.05). Among patients at high risk prostate specific antigen increased from 0.10 to 0.36 ng/ml (p = 0.018). Six men (6.1%) met criteria for biochemical recurrence. Testosterone therapy in men following radiation therapy for prostate cancer was associated with a minor increase in serum prostate specific antigen and a low rate of biochemical recurrence.

Determinants and effects of positive surgical margins after prostatectomy on prostate cancer mortality: a population-based study.

BackgroundThe objective of this population-based study was to assess patient, physician and tumour determinants associated with positive surgical margins after prostatectomy, and to assess the effects of positive surgical margins on prostate cancer-specific survival.MethodsWe included 1’254 prostate cancer patients recorded at the Geneva Cancer Registry who had radical prostatectomy during 1990–2008. To assess factors associated with positive margins, we used logistic regression. We assessed the effects of positive margins on prostate cancer-specific survival by Cox proportional hazard models accounting for numerous other prognostics factors including prostate and tumour volume, the total percentage of tumour, radiotherapy, surgical approach and surgeon’s caseload.ResultsAmong men undergoing prostatectomy, 479 (38%) had positive margins. In the multivariate logistic regression analysis, period, clinical- and pathological T stage, Prostate Specific Antigen (PSA) level, Gleason score and percentage of tumour in the prostate were significantly associated to positive margins. Ten-year prostate cancer-specific survival was 96.6% for the negative margins group and 92.0% for the positive margins group (log rank p = 0.008). In the Cox survival analysis adjusted for tumour characteristics, surgical margin status per se was not an independent prognostic factor while age, pathological T, PSA level and Gleason score remained associated with prostate cancer-specific survival.ConclusionsMore aggressive tumour characteristics were strong determinants for positive margins. Furthermore, surgical margin status per se was not an independent prognostic factor for prostate cancer-specific survival after adjusting by the gravity of the disease in the multivariate analysis.

Prostate MRI: evaluating tumor volume and apparent diffusion coefficient as surrogate biomarkers for predicting tumor Gleason score.

To investigate whether tumor volume derived from apparent diffusion coefficient (ADC) maps (VolumeADC) and tumor mean ADC value (ADCmean) are independent predictors of prostate tumor Gleason score (GS). Tumor volume and GS were recorded from whole-mount histopathology for 131 men (median age, 60 years) who underwent endorectal diffusion-weighted MRI for local staging of prostate cancer before prostatectomy. VolumeADC and ADCmean were derived from ADC maps and correlated with histopathologic tumor volume and GS. Univariate and multivariate analyses were performed to evaluate prediction of tumor aggressiveness. Areas under receiver-operating characteristics curves (AUC) were calculated to evaluate the performance of VolumeADC and ADCmean in discriminating tumors of GS 6 and GS ≥7. Histopathology identified 116 tumor foci >0.5 mL. VolumeADC correlated significantly with histopathologic tumor volume (ρ = 0.683). The correlation increased with increasing GS (ρ = 0.453 for GS 6 tumors; ρ = 0.643 for GS 7 tumors; ρ = 0.980 for GS ≥8 tumors). Both VolumeADC (ρ = 0.286) and ADCmean (ρ = -0.309) correlated with GS. At univariate analysis, both VolumeADC (P = 0.0325) and ADCmean (P = 0.0033) could differentiate GS = 6 from GS ≥7 tumor foci. However, at multivariate analysis, only ADCmean (P = 0.0156) was a significant predictor of tumor aggressiveness (i.e., GS 6 vs. GS ≥7). For differentiating GS 6 from GS ≥7 tumors, AUCs were 0.644 and 0.704 for VolumeADC and ADCmean, respectively, and 0.749 for both parameters combined. In patients with prostate cancer, ADCmean is an independent predictor of tumor aggressiveness, but VolumeADC is not. The latter parameter adds little to the ADCmean in predicting tumor GS.

Feasibility and Preliminary Experience of Quantitative T2* Mapping at 3.0 T for Detection and Assessment of Aggressiveness of Prostate Cancer

To assess the feasibility of quantitative T2* mapping at 3.0T for prostate cancer detection and to investigate the use of T2* values to characterize tumor aggressiveness, with whole-mount step-section pathologic analysis as the reference standard. Prostate multiecho T2* was performed in 55 consecutive patients with prostate cancer using a multishot fast-field echo sequence at 3.0T magnetic resonance imaging. T2* mapping was obtained by exponentially fitting the multiecho T2* images pixel by pixel with different echo times for each slice. Generalized estimating equations were used to test the T2* value difference between normal and malignant prostate regions and the association between T2* value and tumor Gleason scores. The T2* values of the cancerous prostatic regions (mean: 42.51±0.65milliseconds) were significantly lower (P<.001) than those of the normal prostatic regions (mean: 74.87±0.99milliseconds). Adopting a threshold value of 59.27milliseconds, T2* mapping resulted in 94.8% sensitivity and 77.3% specificity in the identification of prostate cancer. A lower mean T2* value was significantly associated with a higher tumor Gleason score (mean T2* values of 53.53, 43.75, 33.66, and 22.95 milliseconds were associated with Gleason score of 3+3, 3+4, 4+3, and ≥8, respectively P<.05). From these preliminary data, quantitative T2* mapping seems to be a potential method in the characterization of prostate cancer. T2* mapping may provide additional quantitative information that significantly correlated with prostate cancer aggressiveness.

Salvage radiotherapy in patients with prostate cancer and biochemical relapse after radical prostatectomy

In patients with prostate cancer (PC) and biochemical relapse after radical prostatectomy, salvage radiotherapy (SRT) could improve PC-specific survival (PCSS) but the timing for initiation is still under discussion. We have demonstrated a low rate of biochemical relapses in a patient series with very low pre-SRT PSA levels after a median follow-up of 42 months. Here, we present an update of that study. Overall, 151 patients were analyzed. A biochemical relapse after SRT was diagnosed when the PSA exceeded the post-SRT nadir by 0.2 ng/ml with subsequent increase. Parameters with significant impact on biochemical progression-free survival (BPFS), PCSS, and overall survival (OS) in univariate analysis were included in a multiple Cox regression analysis. After a median follow-up of 82 months, 18 patients (12%) had died with 10 (6.6%) deaths being PC-related. A biochemical progression was diagnosed in 83 patients (55%). Univariate analysis revealed a significant impact of pre-SRT PSA level, Gleason score, and PSA doubling time (PSADT) on BPFS and for initial tumor stage and Gleason score on OS. Multivariate analysis confirmed the impact of pre-SRT PSA level, Gleason score, and PSADT on BPFS and tumor stage on OS. In this update, the rate of biochemical relapses increased compared with our previous data. Compared to similar studies, we found a remarkably low rate of PC-related deaths. Our data support early initiation of SRT. However, this treatment strategy, triggered by very low PSA levels, could carry the risk of overtreatment in at least a subset of patients.

Positive surgical margins after radical prostatectomy

Positive surgical margins (PSMs) in radical prostatectomy specimens are usually considered a negative prognostic parameter. However, their definition and the management of patients with PSMs remain unclear. The aim of the present review is to define pathological features of PSMs,to report their incidence and risk factors and to update PSMs prognostic meaning and possible treatment modalities.The average incidence of PSMs in contemporary series ranges from 6.5% to 32%. The likelihood of PSMs is influenced by pre-operative PSA (total-PSA and PSA-density), tumor features (volume,grade and stage), previous prostatic surgery (open or TURP), patients’ characteristics (BMI andpelvis shape) and surgeons' skill. Although PSMs are a predictor of biochemical recurrence, their impact on cause specific survival is highly variable and largely influenced by the tumor Gleason Score. Adjuvant radiotherapy is an effective treatment in PSMs patients but early salvage radiotherapy may be an alternative option that guarantees equivalent survival benefits with less side effects. Further studies are required to define the best candidates to adjuvant or early salvage radiation therapy.

Correlation of Endothelin-1 expression in prostate cancer with tumor prognostic markers: an Iranian experience

<h3>Background</h3> The importance of Endothelin-1 expression in tumor aggressiveness and metastatic potential has been confirmed in a variety of different organ tumors including prostate gland as well as recent trials of targeted therapy. As the prostate adenocarcinoma is one of the most common malignant tumors in males, looking for a marker with predictive value of aggressiveness and metastatic potential in an apparently localized cancer in initial needle biopsy specimens could help clinicians to make the more appropriate decision for treatment planning and perhaps choosing targeted therapy. <h3>Method</h3> In a cross sectional study, 83 patients who underwent radical prostatectomy were studied in 2 groups: 43 with extraprostatic extension (EPE) and 40 without EPE. Immunohistochemical staining with Endothelin-1 was performed on formalin fixed paraffin embedded (FFPE) blocks of their pre-operative needle biopsies. <h3>Results</h3> Endothelin-1 was positive in 11 (26%) of 43 patients with no extraprostatic extension, but showed increased expression in cases with extraprostatic extension up to 29 (72%) of 40 patients (<i>p</i><0.001). The Endothelin-1 positive group showed higher serum PSA levels than the Endothelin-1 negative group (44.6 ± 10.2ng/mL vs 18.6 ± 6.8ng/mL) with <i>p</i>=0.039. This marker was positive in 29 (67%) of 43 patients with perineurial invasion and so in 11 (27%) of 40 patients who didn't show perineurial invasion (<i>p</i><0.001). The marker was positive in 9 (32.1%) of 28 patients with Gleason's score=6, 18 (54.5%) of 33 patients with Gleason's score=7, 10 (58.8%) of 17 patients with Gleason's score=8,2 (50%) of 4 patients with Gleason's score=9 and in 1 (100%) patient with Gleason's score 10 (<i>p</i>=0.261). <h3>Conclusions</h3> These results supported correlation of Endothelin-1 expression in needle biopsy specimens with extraprostatic extension of tumor in radical prostatectomy specimens, perineurial invasion and serum PSA levels at the time of diagnosis, but didn't show correlation between expression of Endothelin-1 and tumor Gleason's score.

Transition Zone Prostate Cancer: Incremental Value of Diffusion-weighted Endorectal MR Imaging in Tumor Detection and Assessment of Aggressiveness

To evaluate the incremental value of using diffusion-weighted magnetic resonance (MR) imaging in addition to T2-weighted imaging for the detection of prostate cancer in the transition zone and the assessment of tumor aggressiveness. This retrospective HIPAA-compliant institutional review board-approved study included 156 consecutive patients (median age, 59.2 years) who underwent MR imaging before radical prostatectomy. Two readers who were blinded to patient data independently recorded their levels of suspicion on a five-point scale of the presence of transition zone tumors on the basis of T2-weighted imaging alone and then, 4 weeks later, diffusion-weighted imaging and T2-weighted imaging together. Apparent diffusion coefficients (ADCs) were measured in transition zone cancers and glandular and stromal benign prostatic hyperplasia. Areas under the receiver operating characteristic curves were used to evaluate detection accuracy, and generalized linear models were used to test ADC differences between benign and malignant prostate regions. Whole-mount step-section histopathologic examination was the reference standard. In overall tumor detection, addition of diffusion-weighted imaging to T2-weighted imaging improved the areas under the receiver operating characteristic curves for readers 1 and 2 from 0.60 and 0.60 to 0.75 and 0.71, respectively, at the patient level (P = .004 for reader 1 and P = .027 for reader 2) and from 0.64 and 0.63 to 0.73 and 0.68, respectively, at the sextant level (P = .001 for reader 1 and P = .100 for reader 2). Least squares mean ADCs (× 10(-3) mm(2)/sec) in glandular and stromal benign prostatic hyperplasia were 1.44 and 1.09, respectively. Mean ADCs were inversely associated with tumor Gleason scores (1.10, 0.98, 0.87, and 0.75 for Gleason scores of 3 + 3, 3 + 4, 4 + 3, and ≥ 4 + 4, respectively). Use of diffusion-weighted imaging in addition to T2-weighted imaging improved detection of prostate cancer in the transition zone, and tumor ADCs were inversely associated with tumor Gleason scores in the transition zone.

Transition Zone Prostate Cancer: Incremental Value of Diffusion-weighted Endorectal MR Imaging in Tumor Detection and Assessment of Aggressiveness

To evaluate the incremental value of using diffusion-weighted magnetic resonance (MR) imaging in addition to T2-weighted imaging for the detection of prostate cancer in the transition zone and the assessment of tumor aggressiveness. This retrospective HIPAA-compliant institutional review board-approved study included 156 consecutive patients (median age, 59.2 years) who underwent MR imaging before radical prostatectomy. Two readers who were blinded to patient data independently recorded their levels of suspicion on a five-point scale of the presence of transition zone tumors on the basis of T2-weighted imaging alone and then, 4 weeks later, diffusion-weighted imaging and T2-weighted imaging together. Apparent diffusion coefficients (ADCs) were measured in transition zone cancers and glandular and stromal benign prostatic hyperplasia. Areas under the receiver operating characteristic curves were used to evaluate detection accuracy, and generalized linear models were used to test ADC differences between benign and malignant prostate regions. Whole-mount step-section histopathologic examination was the reference standard. In overall tumor detection, addition of diffusion-weighted imaging to T2-weighted imaging improved the areas under the receiver operating characteristic curves for readers 1 and 2 from 0.60 and 0.60 to 0.75 and 0.71, respectively, at the patient level (P = .004 for reader 1 and P = .027 for reader 2) and from 0.64 and 0.63 to 0.73 and 0.68, respectively, at the sextant level (P = .001 for reader 1 and P = .100 for reader 2). Least squares mean ADCs (× 10(-3) mm(2)/sec) in glandular and stromal benign prostatic hyperplasia were 1.44 and 1.09, respectively. Mean ADCs were inversely associated with tumor Gleason scores (1.10, 0.98, 0.87, and 0.75 for Gleason scores of 3 + 3, 3 + 4, 4 + 3, and ≥ 4 + 4, respectively). Use of diffusion-weighted imaging in addition to T2-weighted imaging improved detection of prostate cancer in the transition zone, and tumor ADCs were inversely associated with tumor Gleason scores in the transition zone.

Effects of angiotensin-converting enzyme (ACE) inhibitors on the outcomes of patients receiving primary radiotherapy for prostate cancer (PC).

e16016 Background: ACE inhibitors have been linked with an increased incidence of prostate, breast and lung cancer as well as increased recurrence rates in breast cancer. However the effects of ACE inhibitors on patients receiving primary radiation therapy for PC are unknown. Methods: We conducted a retrospective medication review of a prospective cohort of 1956 men who received primary radiotherapy (RT) for PC at the Peter McCallum Cancer Institute, Melbourne, Australia from 2003 -07. A competing risks model was developed for statistical analysis of the data. Results: 56% of patients who received RT also had concurrent salvage androgen deprivation therapy (sADT). A total 502 men had subsequent biochemical failure, 314 had initiated sADT and 125 had died of prostate cancer. Median follow up after RT was 71 months and 41 months after initiation of sADT. Of the 603 men who were on ACE-inhibitors, 160 received sADT. After adjusting for patient age, initial tumor stage, Gleason Score and PSA, along with planned ADT usage and ACE27 co-morbidity score, there were significant association between ACE-inhibitors and PC-specific mortality both from the time of RT and sADT (p= 0.035 and 0.01 respectively), with a strong increase in hazard (HR 1.58 [95%CI 1.03-2.42) and 2.02 [95%CI 1.16-2.90]). No significant association was seen with time to metastasis development, suggesting the impact of ACE inhibitors may be in the post-metastasis phase of the disease. Conclusions: ACE inhibitors may increase the rates of PC-specific mortality in men receiving primary RT for PC. However these results need to be further validated by randomized controlled studies and the mechanisms need to be investigated.