Microvascular proliferation is associated with high tumour blood flow by mpMRI and disease progression in primary prostate cancer.

Active angiogenesis may be assessed by immunohistochemistry using Nestin, a marker of newly formed vessels, combined with Ki67 for proliferating cells. Here, we studied microvascular proliferation by Nestin-Ki67 co-expression in prostate cancer, focusing on relations to quantitative imaging parameters from anatomically matched areas obtained by preoperative mpMRI, clinico-pathological features and prognosis. Tumour slides from 67 patients (radical prostatectomies) were stained for Nestin-Ki67. Proliferative microvessel density (pMVD) and presence of glomeruloid microvascular proliferation (GMP) were recorded. From mpMRI, forward volume transfer constant (Ktrans), reverse volume transfer constant (kep), volume of EES (ve), blood flow, and apparent diffusion coefficient (ADC) were obtained. High pMVD was associated with high blood flow (p = 0.008) and low ADC (p = 0.032). High Ktrans, kep, and blood flow were associated with high Gleason score. High pMVD, GMP, and low ADC were associated with most adverse clinico-pathological factors. Regarding prognosis, high pMVD, Ktrans, kep, and low ADC were associated with reduced biochemical recurrence-free- and metastasis-free survival (p ≤ 0.044) and high blood flow with reduced time to biochemical- and clinical recurrence (p < 0.026). In multivariate analyses however, microvascular proliferation was a stronger predictor compared with blood flow. Indirect, dynamic markers of angiogenesis from mpMRI and direct, static markers of angiogenesis from immunohistochemistry may aid in the stratification and therapy planning of prostate cancer patients.

The epithelial-mesenchymal transition regulators Twist, Slug, and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients.

The prognostic importance of transcription factors promoting epithelial-mesenchymal transition (EMT) and angiogenesis has not been well explored in prostate cancer patients with long follow-up, nor the interplay between these factors. The objective of this study was to assess the individual protein expression and co-expression of Twist, Slug (Snai2), Snail (Snai1), and hypoxia-inducible factor-1 alpha (Hif-1α) in prostate cancer in relation to EMT, angiogenesis, hypoxia, tumour features, disease recurrence, and patient survival. Immunohistochemical staining was performed on tissue microarray sections from 338 radical prostatectomies with long follow-up. In addition, 41 cases of prostatic hyperplasia, 33 non-skeletal metastases, 13 skeletal metastases, and 33 castration-resistant prostate carcinomas were included. Our findings were validated in external gene expression data sets. Twist was overexpressed in primary prostate cancer and markedly reduced in distant metastases (p < 0.0005). Strong expression of Twist and Slug was associated with Hif-1α in localised prostate cancer (p ≤ 0.001), and strong Twist was associated with Hif-1α in castration-resistant carcinomas (p = 0.044). Twist, Slug, and increased Snail at the tumour stromal border were associated with vascular factors (p ≤ 0.045). Each of the three EMT-regulating transcription factors were associated with aggressive tumour features and shorter time to recurrence and cancer-specific death. Notably, the co-expression of factors demonstrated an enhanced influence on outcome. In the subgroup of E-cadherinlow carcinomas, strong Slug was associated with shorter time to all end points and was an independent predictor of time to multiple end points, including cancer-specific death (hazard ratio 3.0, p = 0.041). To conclude, we demonstrate an important relation between EMT, hypoxia, and angiogenesis and a strong link between the investigated EMT regulators and aggressive tumour features and poor patient outcome in prostate cancer. Despite the retrospective nature of this long-term study, our findings could have a significant impact on the future treatment of prostate cancer, where tailored therapies might be directed simultaneously against epithelial-mesenchymal phenotypes, angiogenesis, and tumour hypoxia.

Preoperative predictors of pathological tumour stage and prognosis may be used when selecting candidates for intensified treatment in upper tract urothelial carcinoma.

PURPOSE: Intensified treatment such as extended lymph node dissection (LND) and/or perioperative chemotherapy in addition to radical nephroureterectomy (RNU) has been suggested for high-risk cases of upper tract urothelial carcinoma (UTUC). We aimed to identify preoperative predictors of tumour stage and prognosis in the diagnostic work-up before RNU. Further to evaluate if our findings could be used in selecting patients for intensified treatment. PATIENTS AND METHODS: A total of 179 patients treated with RNU for UTUC at Haukeland University Hospital (HUS) and Vestfold Hospital Trust (VHT) during 2005-2017 were included in this retrospective study. All relevant preoperative variables regarding the patient, the CT and the ureteroscopy (URS) were registered and analysed regarding their ability to predict non-organ confined disease (NOCD, pT3+ and/or N+) at final pathology after RNU. The prognosis was assessed calculating survival for the cohort and stratified by preoperative variables. RESULTS: Local invasion and pathological lymph nodes at CT predicted NOCD in uni and multivariate regression analyses (OR 3.36, p=.004 and OR 6.21, p=.03, respectively). Reactive oedema surrounding the tumour (OR 2.55, p=.02), tumour size (4.8 vs. 3.9 cm, p=.006) and high-grade tumour at URS biopsy (OR 3.59, p=.04) predicted NOCD at univariate regression analyses. The 5-year CSS and OS for the entire cohort was 79% and 60%. ECOG, local invasion, pathological lymph nodes and reactive oedema surrounding the tumour at CT predicted CSS. CONCLUSIONS: Several variables at the CT predicted both stage and survival. Local invasion at CT seems the most promising feature for selecting patients for intensified treatment.

Higher than expected and significantly increasing incidence of upper tract urothelial carcinoma. A population based study.

PURPOSE: To register all cases of urothelial cancer and renal cell carcinoma (RCC) in Norway during 1999-2018 to obtain the contemporary incidence of UTUC and UTUC incidence relative to other urothelial cancers and RCC. Further to analyse possible changes over time regarding UTUC incidence, UTUC patient characteristics, tumour characteristics and survival. METHODS: 3502 cases registered with ICD code C65 and C66 during 1999-2018 at the Norwegian cancer registry were entered into a database. After a selection process 3096 cases were included in the study. The crude incidences of UTUC were calculated for each year adjusting for the corresponding population data. Age-standardized rates adjusting to the European standard population (2013) were calculated. Comparisons were made with other cases of urothelial cancer and RCC. For changes over time, the material was split into 5-year periods. Regression analysis was used to calculate yearly changes and for assessing statistical significance. Survival outcomes were calculated using the Kaplan-Meier method. RESULTS: The overall age-standardized incidence rate was 3.88, increasing from 3.21 to 4.70 from first to last 5-year periods. The increase affected all ages except those < 60 years of age, and were observed regardless of gender or anatomical location. UTUC constituted 11.8% of all urothelial cancers, increasing from 9.9 to 12.8%. Mean patient age at diagnosis increased from 71.5 to 73.4 years. The 5-years Cancer-specific survival improved from 57.4 to 65.4%. CONCLUSION: The incidence of UTUC was higher than expected and increasing. Patient age at diagnosis was increasing.

Magnetic resonance radiomics for prediction of extraprostatic extension in non-favorable intermediate- and high-risk prostate cancer patients.

BACKGROUND: To investigate whether magnetic resonance (MR) radiomic features combined with machine learning may aid in predicting extraprostatic extension (EPE) in high- and non-favorable intermediate-risk patients with prostate cancer. PURPOSE: To investigate the diagnostic performance of radiomics to detect EPE. MATERIAL AND METHODS: MR radiomic features were extracted from 228 patients, of whom 86 were diagnosed with EPE, using prostate and lesion segmentations. Prediction models were built using Random Forest. Further, EPE was also predicted using a clinical nomogram and routine radiological interpretation and diagnostic performance was assessed for individual and combined models. RESULTS: The MR radiomic model with features extracted from the manually delineated lesions performed best among the radiomic models with an area under the curve (AUC) of 0.74. Radiology interpretation yielded an AUC of 0.75 and the clinical nomogram (MSKCC) an AUC of 0.67. A combination of the three prediction models gave the highest AUC of 0.79. CONCLUSION: Radiomic analysis combined with radiology interpretation aid the MSKCC nomogram in predicting EPE in high- and non-favorable intermediate-risk patients.

Assessing Extraprostatic Extension with Multiparametric MRI of the Prostate: Mehralivand Extraprostatic Extension Grade or Extraprostatic Extension Likert Scale?

Purpose: To validate the MRI grading system proposed by Mehralivand et al in 2019 (the "extraprostatic extension [EPE] grade") in an independent cohort and to compare the Mehralivand EPE grading system with EPE interpretation on the basis of a five-point Likert score ("EPE Likert"). Materials and Methods: A total of 310 consecutive patients underwent multiparametric MRI according to a standardized institutional protocol before radical prostatectomy was performed by using the same 1.5-T MRI unit at a single institution between 2010 and 2012. Two radiologists blinded to clinical information assessed EPE according to standardized criteria. On the basis of the readings performed until 2017, the diagnostic performance of EPE Likert and Mehralivand EPE score were compared using receiver operating characteristics (ROC) and decision curve methodology against histologic EPE as standard of reference. Prediction of biochemical recurrence-free survival (BRFS) was assessed by Kaplan-Meier analysis and log rank test. Results: Of the 310 patients, 80 patients (26%) had EPE, including 33 with radial distance 1.1 mm or greater. Interrater reliability was fair (weighted κ 0.47 and 0.45) for both EPE grade and EPE Likert. Sensitivity for identifying EPE using EPE grade versus EPE Likert was 0.83 versus 0.86 and 0.86 versus 0.91 for radiologist 1 and 2, respectively. Specificity was 0.48 versus 0.58 and 0.39 versus 0.70 (P < .05 for radiologist 2). There were no significant differences in the ROC area under the curve or on decision curve analysis. Both EPE grade and EPE Likert were significant predictors of BRFS. Conclusion: Mehralivand EPE grade and EPE Likert have equivalent diagnostic performance for predicting EPE and BRFS with a similar degree of observer dependence.© RSNA, 2020Keywords: MR-Imaging, Neoplasms-Primary, Observer Performance, Outcomes Analysis, Prostate, StagingSupplemental material is available for this article.See also the commentary by Choyke in this issue.

Tumour architecture, grade and location remain predictors of non-organ-confined upper tract urothelial carcinoma at time of radical nephroureterectomy: results from a multicenter Norwegian external validation study.

PURPOSE: Selecting patients for intensified treatment for upper tract urothelial carcinoma can be challenging, partly due to the lack of accurate preoperative staging tools. Several preoperative staging models for upper tract urothelial carcinoma have been presented, but none have been externally validated. The aim of the current study was to perform an external validation of the Margulis nomogram for predicting non-organ-confined upper tract urothelial carcinoma at time of nephroureterectomy. METHODS: 209 patients from two high-volume centres in Norway were treated with radical nephroureterectomy during the period 2005-2017. 163 patients with complete data necessary for external validation of the Margulis nomogram were included in the study. All relevant covariates were analysed with uni- and multivariate regression analysis to assess their ability to predict non-organ-confined disease. The Margulis nomogram was applied on the present cohort to calculate predicted risk of non-organ-confined disease. This was compared to the observed risk to assess model calibration. The Margulis nomogram accuracy was measured as the area under the curve in a receiver operator characteristics curve to evaluate model discrimination. RESULTS: Tumour grade (OR 28.1, p = 0.001) and architecture (OR 4.72, p < 0.001) were independent predictors of non-organ-confined disease. There was a high concordance between predicted and observed risk quantified with a Cronbach alpha of 0.96. The Margulis nomogram had an area under the curve of 0.83 in predicting non-organ-confined disease when applied on the current cohort. CONCLUSIONS: We consider the Margulis nomogram validated for clinical use.

FOXC2 expression and epithelial-mesenchymal phenotypes are associated with castration resistance, metastasis and survival in prostate cancer.

Epithelial-mesenchymal transition (EMT) is important for tumour cell invasion and metastasis and is a feature of aggressive carcinomas. EMT is characterised by reduced E-cadherin and increased N-cadherin expression (EN-switch), and increased expression of the EMT-regulating transcription factor Forkhead box protein C2 (FOXC2) has been associated with progression and poor prognosis in various malignancies. FOXC2 was recently highlighted as a novel therapy target in prostate cancer, but survival data on FOXC2 are lacking. This study evaluates the expression of FOXC2, E-cadherin and N-cadherin in different prostatic tissues focusing on EMT, clinico-pathological phenotype, recurrence and patient survival. Tissue microarray sections from 338 radical prostatectomies (1986-2007) with long and complete follow-up, 33 castration resistant prostate cancers, 33 non-skeletal metastases, 13 skeletal metastases and 41 prostatic hyperplasias were stained immunohistochemically for FOXC2, E-cadherin and N-cadherin. FOXC2 was strongly expressed in primary carcinomas, including castration resistant tumours and metastatic lesions as compared to benign prostatic hyperplasia. A hybrid epithelial-mesenchymal phenotype, with co-expression of E-cadherin and N-cadherin, was found in the majority of skeletal metastases and in a substantial proportion of castration resistant tumours. In localised carcinomas, the EN-switch was associated with adverse clinico-pathological variables, such as extra-prostatic extension, high pathological stage and lymph node infiltration. In univariate survival analyses of the clinically important, large subgroup of 199 patients with Gleason score 7, high FOXC2 expression and EN-switching were significantly associated with shorter time to clinical recurrence, skeletal metastases and cancer specific death. In multivariate Cox' survival analysis, high FOXC2 and the EN-switch, together with Gleason grade group (GG3 versus GG2), were independent predictors of time to these end-points. High FOXC2 gene expression (mRNA) was also related to patient outcome, validating our immunohistochemical findings. FOXC2 and factors signifying EMT or its intermediate states may prove important as biomarkers for aggressive disease and are potential novel therapy targets in prostate cancer.

Intensity-based volumetric registration of magnetic resonance images and whole-mount sections of the prostate.

OBJECTIVE: Magnetic Resonance Imaging (MRI) of the prostate provides useful in vivo diagnostic tissue information such as tumor location and aggressiveness, but ex vivo histopathology remains the ground truth. There are several challenges related to the registration of MRI to histopathology. We present a method for registration of standard clinical T2-weighted MRI (T2W-MRI) and transverse histopathology whole-mount (WM) sections of the prostate. METHODS: An isotropic volume stack was created from the WM sections using 2D rigid and deformable registration combined with linear interpolation. The prostate was segmented manually from the T2W-MRI volume and registered to the WM section volume using a combination of affine and deformable registration. The method was evaluated on a set of 12 patients who had undergone radical prostatectomy. Registration accuracy was assessed using volume overlap (Dice Coefficient, DC) and landmark distances. RESULTS: The DC was 0.94 for the whole prostate, 0.63 for the peripheral zone and 0.77 for the remaining gland. The landmark distances were on average 5.4 mm. CONCLUSION: The volume overlap for the whole prostate and remaining gland, as well as the landmark distances indicate good registration accuracy for the proposed method, and shows that it can be highly useful for registering clinical available MRI and WM sections of the prostate.

Optimising preoperative risk stratification tools for prostate cancer using mpMRI.

PURPOSE: To improve preoperative risk stratification for prostate cancer (PCa) by incorporating multiparametric MRI (mpMRI) features into risk stratification tools for PCa, CAPRA and D'Amico. METHODS: 807 consecutive patients operated on by robot-assisted radical prostatectomy at our institution during the period 2010-2015 were followed to identify biochemical recurrence (BCR). 591 patients were eligible for final analysis. We employed stepwise backward likelihood methodology and penalised Cox cross-validation to identify the most significant predictors of BCR including mpMRI features. mpMRI features were then integrated into image-adjusted (IA) risk prediction models and the two risk prediction tools were then evaluated both with and without image adjustment using receiver operating characteristics, survival and decision curve analyses. RESULTS: 37 patients suffered BCR. Apparent diffusion coefficient (ADC) and radiological extraprostatic extension (rEPE) from mpMRI were both significant predictors of BCR. Both IA prediction models reallocated more than 20% of intermediate-risk patients to the low-risk group, reducing their estimated cumulative BCR risk from approximately 5% to 1.1%. Both IA models showed improved prognostic performance with a better separation of the survival curves. CONCLUSION: Integrating ADC and rEPE from mpMRI of the prostate into risk stratification tools improves preoperative risk estimation for BCR. KEY POINTS: • MRI-derived features, ADC and EPE, improve risk stratification of biochemical recurrence. • Using mpMRI to stratify prostate cancer patients improves the differentiation between risk groups. • Using preoperative mpMRI will help urologists in selecting the most appropriate treatment.

A positive Real-Time Elastography (RTE) combined with a Prostate Cancer Gene 3 (PCA3) score above 35 convey a high probability of intermediate- or high-risk prostate cancer in patient admitted for primary prostate biopsy.

BACKGROUND: The standard of care in patients with suspected prostate cancer (PCa) is systematic prostate biopsies. This approach leads to unnecessary biopsies in patients without PCa and also to the detection of clinical insignificant PCa. Better tools are wanted. We have evaluated the performance of real-time elastography (RTE) combined with prostate cancer gene 3 (PCA3) in an initial biopsy setting with the goal of better identifying patients in need of prostate biopsies. METHODS: 127 patients were included in this study; three were excluded because of not measureable PCA3 score leading to 124 evaluable patients. A cut-off value of 35 was used for PCA3. All patients were examined with a Hitachi Preirus with an endfire probe for RTE, a maximum of five targeted biopsies were obtained from suspicious lesions detected by RTE. All patients then had a 10-core systematic biopsy performed by another urologist unaware of the RTE results. The study includes follow-up data for a minimum of three years; all available histopathological data are included in the analysis. RESULTS: There was a significant difference in PCA3 score: 26.6 for benign disease, 73.6 for cancer patients (p < 0.001). 70 patients (56 %) were diagnosed with prostate cancer in the study period, 21 (30 %) low-risk, 32 (46 %) intermediate-risk and 17 (24 %) high-risk. RTE and PCA3 were significant markers for predicting intermediate- and high-risk PCa (p = 0.001). The combination of RTE and PCA3 had a sensitivity of 96 % and a negative predictive value (NPV) of 90 % for the group of intermediate- and high-risk PCa together and a NPV for high-risk PCa of 100 %. If both parameters are positive there is a high probability of detecting intermediate- or high-risk PCa, if both parameters are negative there is only a small chance of missing prostate cancer with documented treatment benefit. CONCLUSIONS: RTE and PCA3 may be used as pre-biopsy examinations to reduce the number of prostate biopsies.

Grading of urothelial carcinoma of the upper urinary tract according to the World Health Organization/International Society of Urological Pathology classification from 2004 is a valuable tool when considering whether a patient is suitable for endoscopic treatment.

Objective The aim of this study was to analyse the results regarding survival, recurrence and kidney preservation after endoscopic treatment for upper urinary tract urothelial carcinoma (UTUC) in a Norwegian hospital during the period from 2001 to 2012, and compare them with results reported in the literature. A further aim was to re-examine all initial histopathological specimens, and stratify primary results according to the World Health Organization/International Society of Urological Pathology grading system of urothelial carcinoma from 2004. Materials and methods Forty-three patients were treated endoscopically with curative intent for UTUC during 2001-2012. Of these, 28 patients were candidates for nephroureterectomy (CNU) with an elective indication, while 15 were non-candidates for nephroureterectomy (NCNU). Analyses were performed separately for the CNU and NCNU groups. Results In the CNU group, the 5 year overall and disease-specific survival (OS and DSS) were 71% and 94%, respectively. In the NCNU group, the OS and DSS were 25% and 41%, respectively. Histopathological verification was available in 40 patients (93%), and re-examination showed 27 low-grade and 13 high-grade tumours. In patients with a low-grade tumour, the OS and DSS were 75% and 96%, respectively. In patients with a high-grade tumour, the OS and DSS were 23% and 39%, respectively. The 5 year kidney protection rate was 51% in the CNU group. The 5 year recurrence-free survival was 72%. Conclusions The endoscopic treatment of UTUC is feasible and safe in histopathologically verified low-grade tumours. The endoscopic treatment of high-grade tumours has poor results, and must be reserved for patients where nephroureterectomy is truly contraindicated.

Prostate cancer antigen-3 (PCA3) and PCA3-based nomograms in the diagnosis of prostate cancer: an external validation of Hansen's nomogram on a Norwegian cohort.

OBJECTIVE: The aim of this study was to test the ability of prostate cancer antigen-3 (PCA3) and Hansen's PCA3-based nomogram to predict prostate cancer (PCa) probability in a Norwegian cohort, with the goal of reducing unnecessary biopsies. MATERIAL AND METHODS: Altogether, 127 consecutive patients were recruited to this study at Haukeland University Hospital, Norway. Prostate-specific antigen (PSA), PCA3 score, digital rectal examination (DRE), prostate volume (Pvol) and age were determined. All patients had an extended 10-core biopsy. The performance of PCA3 score and Hansen's nomogram was tested. RESULTS: There were 124 evaluable patients. Among these, 59 patients had PCa on the initial biopsies. Mean PSA, PCA3 score and age were significantly higher and Pvol was significantly lower in patients with PCa. PCA3 scores of 35 and 21 led to a sensitivity of 71% and 81% and specificity of 72% and 55%, respectively. Hansen's nomogram gave an area under the curve (AUC) of 0.806. The intraclass correlation was 0.959 (Cronbach's alpha). Applied to this material, PCa would be missed in 15.2% of patients when applying the suggested threshold probability of 30%, among whom 66.7% had high-grade PCa. With a threshold probability of 20% only one patient had PCa and this was low grade. CONCLUSIONS: Hansen's PCA3-based nomogram is valid for this cohort. A threshold probability of 20% seems more adequate than 30% for this less screened cohort. PCA3 score only affects the biopsy indication in some patients and is recommended only for this subset. The results need to be confirmed in a larger study.

1.5-T multiparametric MRI using PI-RADS: a region by region analysis to localize the index-tumor of prostate cancer in patients undergoing prostatectomy.

BACKGROUND: The use of multiparametric magnetic resonance imaging (mpMRI) to detect and localize prostate cancer has increased in recent years. In 2010, the European Society of Urogenital Radiology (ESUR) published guidelines for mpMRI and introduced the Prostate Imaging Reporting and Data System (PI-RADS) for scoring the different parameters. PURPOSE: To evaluate the reliability and diagnostic performance of endorectal 1.5-T mpMRI using the PI-RADS to localize the index tumor of prostate cancer in patients undergoing prostatectomy. MATERIAL AND METHODS: This institutional review board IRB-approved, retrospective study included 63 patients (mean age, 60.7 years, median PSA, 8.0). Three observers read mpMRI parameters (T2W, DWI, and DCE) using the PI-RADS, which were compared with the results from whole-mount histopathology that analyzed 27 regions of interest. Inter-observer agreement was calculated as well as sensitivity, specificity, positive predictive value (PPV), and negative predicted value (NPV) by dichotomizing the PI-RADS criteria scores ≥3. A receiver-operating curve (ROC) analysis was performed for the different MR parameters and overall score. RESULTS: Inter-observer agreement on the overall score was 0.41. The overall score in the peripheral zone achieved sensitivities of 0.41, 0.60, and 0.55 with an NPV of 0.80, 0.84, and 0.83, and in the transitional zone, sensitivities of 0.26, 0.15, and 0.19 with an NPV of 0.92, 0.91, and 0.92 for Observers 1, 2, and 3, respectively. The ROC analysis showed a significantly increased area under the curve (AUC) for the overall score when compared to T2W alone for two of the three observers. CONCLUSION: 1.5 T mpMRI using the PI-RADS to localize the index tumor achieved moderate reliability and diagnostic performance.

GRK3 is essential for metastatic cells and promotes prostate tumor progression.

The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen against human kinases to identify those with previously undocumented roles in metastasis. We discovered that G-protein-coupled receptor kinase 3 (GRK3; or ß-adrenergic receptor kinase 2) was not only necessary for survival and proliferation of metastatic cells, but also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 stimulated angiogenesis, at least in part through down-regulation of thrombospondin-1 and plasminogen activator inhibitor type 2. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastatic tumors. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis.

A positive real-time elastography is an independent marker for detection of high-risk prostate cancers in the primary biopsy setting.

OBJECTIVE: To evaluate the performance of real-time elastography (RTE) in an initial biopsy setting. PATIENTS AND METHODS: In the period from February 2011 to June 2012, 127 consecutive patients were included in the study. We used a Hitachi Preirus with Hi-RTE module, a prostate end-fire transrectal probe was used for RTE and for targeted biopsies, and a simultaneous biplane probe was used for the standard systematic biopsies. The peripheral zone of the prostate was divided into six regions, and each biopsy obtained was referred to a specific region. All patients were first examined with RTE and, if cancer was suspected, targeted biopsies were taken. A standard systematic 10-core biopsy was then taken in all patients. RESULTS: In all, 64 (50%) patients were diagnosed with prostate cancer in the initial biopsy setting. Three patients were diagnosed solely on RTE-targeted biopsies, 31 were found only in systematic biopsies, and 30 were correctly diagnosed with both methods. In the RTE-positive group there was a significantly higher frequency of positive cores, a lower prostate volume, a higher Gleason score, and a higher fraction of cancer tissue in each core. In a multiple regression model RTE was an independent marker for high-risk cancer. The sensitivity of 42% for all prostate cancers increased to 60% for high-grade prostate cancers. Similarly, the negative predictive value increased from 79% to 97%. An additional eight patients were diagnosed with prostate cancer during the study period. CONCLUSIONS: A positive RTE is an independent marker for detection of high-risk prostate cancer, and a negative RTE argues against such. RTE with targeted biopsies cannot replace systematic biopsies, but provides valuable additional information about the tumours.

Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1.

UNLABELLED: Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1(+) myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1(+) donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1(+) bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1(+) myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1(+) cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. SIGNIFICANCE: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow­derived Gr1+myeloid cells. A 5-amino acid peptide with Tsp-1­inducing activity was identified as a therapeutic agent against metastatic cancer.

Combination of real-time elastography and urine prostate cancer gene 3 (PCA3) detects more than 97% of significant prostate cancers.

OBJECTIVE: The prostate cancer gene 3 (PCA3) score in urine is a promising biomarker for prostate cancer. Real-time elastography (RTE) is a well-documented ultrasound modality. The objective of this study was to evaluate the ability to detect significant cancer foci in the prostate with these methods alone and in combination. MATERIAL AND METHODS: From September 2009 to September 2010, 40 patients planned for radical prostatectomy underwent a PCA3 urine test and RTE before operation. A Hitachi EUB-8500 with prostate end-fire transrectal probe was used. The PCA3 score was evaluated with a standard cut-off value of 35. RTE was evaluated in correlation with whole-mount section pathology. Three patients fulfilled the criteria for insignificant prostate cancer and were excluded from the study. RESULTS: The PCA3 score was increased in 26 patients (70%). RTE identified at least one tumour in 33 out of 37 patients (89%). RTE detected the largest tumour in 27 out of 37 patients (73%). More than one cancer was present in 29 patients and RTE identified more than one tumour in 13 of these. The RTE was false positive in four patients. The PCA3 score was increased in three out of four false-negative RTE patients. By combining both methods, 36 out of 37 patients (97%) with significant prostate cancer were detected. CONCLUSIONS: The combination of PCA3 score and RTE detected 97% of significant prostate cancers. The combinative use of RTE and PCA3 will be further investigated in an unselected series of men with suspected prostate cancer.

TMPRSS2:ERG fusion transcripts in urine from prostate cancer patients correlate with a less favorable prognosis.

The transcription factor ERG is highly upregulated in the majority of prostate cancers due to chromosomal fusion of the androgen responsive promoter of TMPRSS2 to the ERG reading frame. Our aim was to identify this gene fusion in urine samples from prostate cancer patients prior to radical treatment and to compare fusion status with clinicopathological variables. Urine fractions from 55 patients (with and without prior prostatic massage) were analyzed for the presence of TMPRSS2:ERG isoforms using real-time qPCR. Sixty-nine percent of urine samples following prostatic massage were positive for TMPRSS2:ERG isoforms a or b, five out of which were positive for both, vs 24% of samples obtained without prior massage. Isoform a seems to be most prevalent and some patients may be positive for more than one fusion variant, reflecting the multifocality of prostate cancer. Prostatic massage prior to sampling, analysis of pelleted urine material and detection of cDNA provided the highest sensitivity. Positive statistical correlations were identified between TMPRSS2:ERG fusion and high s-PSA, pathological stage and Gleason score. Our findings contribute to the increasing elucidation of the role of TMPRSS2:ERG in the development of prostate cancer.

Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1.

Metastatic tumors can prepare a distant site for colonization via the secretion of factors that act in a systemic manner. We hypothesized that non- or weakly metastatic human tumor cells may act in an opposite fashion by creating a microenvironment in distant tissues that is refractory to colonization. By comparing cell lines with different metastatic potential, we have identified a tumor-secreted inhibitor of metastasis, prosaposin (Psap), which functions in a paracrine and endocrine fashion by stimulating the expression of thrombospondin-1 (Tsp-1) in fibroblasts present in both primary tumors and distant organs, doing so in a p53-dependent manner. Introduction of Psap in highly metastatic cells significantly reduced the occurrence of metastases, whereas inhibition of Psap production by tumor cells was associated with increased metastatic frequency. In human prostate cancer, decreased Psap expression was significantly associated with metastatic tumors. Our findings suggest that prosaposin, or other agents that stimulate p53 activity in the tumor stroma, may be an effective therapy by inhibition of the metastatic process.