Multicenter Optimization and Validation of a 2-Gene mRNA Urine Test for Detection of Clinically Significant Prostate Cancer before Initial Prostate Biopsy.

PURPOSE: A 2-gene, urine based molecular test that combines mRNA biomarkers with clinical factors can risk stratify patients for clinically significant prostate cancer. To ensure the generalizability of assay results we optimized and validated the clinical model for men with serum prostate specific antigen less than 10 ng/ml who were undergoing initial prostate biopsy. MATERIALS AND METHODS: Urine samples were collected from 1,955 men from The Netherlands, France and Germany prior to an initial prostate biopsy and study subjects were divided into training and validation cohorts. Urinary HOXC6 and DLX1 mRNA levels were quantified and RNA results were then combined with other risk factors in a clinical model optimized to detect ISUP (International Society of Urological Pathology) Grade Group 2 or greater prostate cancer in men with prostate specific antigen less than 10 ng/ml. Results in the validation cohort were compared with the PCPTRC (Prostate Cancer Prevention Trial Risk Calculator), version 2.0. RESULTS: The optimal clinical model included urinary HOXC6 and DLX1 mRNA levels, patient age, digital rectal examination and prostate specific antigen density (serum prostate specific antigen/prostate volume). In the 715 validation cohort subjects with prostate specific antigen less than 10 ng/ml the AUC was 0.82 with 89% sensitivity, 53% specificity and 95% negative predictive value. The PCPTRC AUC was 0.70. The full validation cohort of 916 men including all prostate specific antigen levels yielded an AUC of 0.85 with 93% sensitivity, 47% specificity and 95% negative predictive value. The PCPTRC AUC was 0.76. CONCLUSIONS: The 2-gene based urine assay, which is optimized for biopsy naïve patients with serum prostate specific antigen less than 10 ng/ml, demonstrated high sensitivity and negative predictive value to detect clinically significant prostate cancer. These data support using the test to help guide initial prostate biopsy decisions.

Comparative evaluation of urinary PCA3 and TMPRSS2: ERG scores and serum PHI in predicting prostate cancer aggressiveness.

It has been suggested that urinary PCA3 and TMPRSS2:ERG fusion tests and serum PHI correlate to cancer aggressiveness-related pathological criteria at prostatectomy. To evaluate and compare their ability in predicting prostate cancer aggressiveness, PHI and urinary PCA3 and TMPRSS2:ERG (T2) scores were assessed in 154 patients who underwent radical prostatectomy for biopsy-proven prostate cancer. Univariate and multivariate analyses using logistic regression and decision curve analyses were performed. All three markers were predictors of a tumor volume≥0.5 mL. Only PHI predicted Gleason score≥7. T2 score and PHI were both independent predictors of extracapsular extension(≥pT3), while multifocality was only predicted by PCA3 score. Moreover, when compared to a base model (age, digital rectal examination, serum PSA, and Gleason sum at biopsy), the addition of both PCA3 score and PHI to the base model induced a significant increase (+12%) when predicting tumor volume>0.5 mL. PHI and urinary PCA3 and T2 scores can be considered as complementary predictors of cancer aggressiveness at prostatectomy.

Intraperitoneal cytokine level in patients with peritoneal surface malignancies. A study of the RENAPE (French Network for Rare Peritoneal Malignancies).

BACKGROUND: Prognosis of peritoneal surface malignancies is influenced by the adequacy of surgical and chemotherapeutic treatment and by tumor spread at the time of diagnosis. By promoting morphological changes in the mesothelium, inflammatory cytokines reflect tumor biology and could be evaluated as biomarkers. Our objective was to evaluate intraperitoneal levels of IL-6, IL-8, IL-10, TNF-alpha, and sICAM in patients with pseudomyxoma peritonei and peritoneal mesothelioma. METHODS: Serum and peritoneal fluid samples were prospectively collected in patients managed for peritoneal surface malignancies including pseudomyxoma peritonei (PMP), mesotheliomas, and other rare primitive peritoneal cancers (cancer group) and patients who underwent intraperitoneal laparoscopic surgical procedures for benign diseases (noncancer group). Samples were analyzed for IL-6, IL-8, IL-10, TNF-alpha, and sICAM concentrations. Correlations were assessed with tumor spread related clinical scores. RESULTS: In both patient groups, intraperitoneal cytokine levels were higher than serum levels. Cancer patients had significantly higher intraperitoneal cytokine levels than noncancer patients. Peritoneal levels tended to increase in cancer patients with free tumor cells in peritoneal fluid. They were significantly higher in patients with tumor implants ≥2 cm and/or patients with peritoneal carcinomatosis index (PCI) >19. Furthermore, patients with malignant pseudomyxoma peritonei (grades II and III) had higher levels than patients with nonmalignant disease (grade I). CONCLUSIONS: Assessment of intraperitoneal IL-6, IL-8, IL-10, TNF-alpha, and sICAM levels can be performed in patients with peritoneal surface malignancies. They can be considered as both diagnostic and prognostic biomarkers that could be used as useful adjuncts for therapeutic decision making.

PCA3 and PCA3-based nomograms improve diagnostic accuracy in patients undergoing first prostate biopsy.

While now recognized as an aid to predict repeat prostate biopsy outcome, the urinary PCA3 (prostate cancer gene 3) test has also been recently advocated to predict initial biopsy results. The objective is to evaluate the performance of the PCA3 test in predicting results of initial prostate biopsies and to determine whether its incorporation into specific nomograms reinforces its diagnostic value. A prospective study included 601 consecutive patients addressed for initial prostate biopsy. The PCA3 test was performed before ≥12-core initial prostate biopsy, along with standard risk factor assessment. Diagnostic performance of the PCA3 test was evaluated. The three available nomograms (Hansen's and Chun's nomograms, as well as the updated Prostate Cancer Prevention Trial risk calculator; PCPT) were applied to the cohort, and their predictive accuracies were assessed in terms of biopsy outcome: the presence of any prostate cancer (PCa) and high-grade prostate cancer (HGPCa). The PCA3 score provided significant predictive accuracy. While the PCPT risk calculator appeared less accurate; both Chun's and Hansen's nomograms provided good calibration and high net benefit on decision curve analyses. When applying nomogram-derived PCa probability thresholds ≤30%, ≤6% of HGPCa would have been missed, while avoiding up to 48% of unnecessary biopsies. The urinary PCA3 test and PCA3-incorporating nomograms can be considered as reliable tools to aid in the initial biopsy decision.

Chronic prostatitis does not influence urinary PCA3 score.

BACKGROUND: The influence of chronic prostatitis on serum PSA level is well known. Whether it also influences potential new biomarkers of prostate cancer (PCa) has to be determined. We conducted a prospective study to evaluate the effect of chronic prostatitis on the PCa urinary marker PCA3. METHODS: Included were 38 patients, mean-aged of 37.5 years, with clinical suspicion of chronic prostatitis. A simplified version of the Meares-Stamey four-glass localization test was performed and urine specimens were collected for cytological analysis and culture. A postprostatic massage urine sample was used for the urinary PCA3 test. RESULTS: Four patients had an eventual diagnosis of urethritis and all had a PCA3 score less than 5. Among the remaining 34 patients, 7 had bacterial chronic prostatitis (NIH II prostatitis), 11 had abacterial chronic prostatitis (NIH IIIa), and 16 had non inflammatory prostatodynia (NIH IIIb). All these patients had a PCA3 score less than 28, that is, under the cutoff of 35, which is commonly used for prostate cancer diagnosis. Patients with NIH category IIIa prostatitis had significantly higher number of leukocytes and red cells as well as prostate cells in urine samples but their PCA3 scores did not differ from those of other prostatitis patients. CONCLUSION: In this study, NIH II and III chronic prostatitis did not influence the PCA3 score. Our results suggest that increased PCA3 score is unlikely to be explained by the sole chronic prostatitis and warrants prostate biopsies to eliminate prostate cancer.

Case Report: Comorbid Hyper-IgD Syndrome and Hidradenitis Suppurativa - A New Syndromic Form of HS? A Report of Two Cases.

Hidradenitis Suppurativa (HS) is a chronic suppurative disease of the pilosebaceous unit. The current model of HS pathophysiology describes the condition as the product of hyperkeratinisation and inflammation at the hair follicular unit. Environmental factors (such as smoking and obesity), gender, genetic predisposition, and skin dysbiosis are considered the main pathogenic drivers of the disease. Autoinflammatory syndromes associated with HS are rare but may help to highlight the potential roles of autoinflammation and dysregulated innate immune system in HS. Therefore, it is of major relevance to increase the awareness about these diseases in order to improve the understanding of the disease and to optimize the management of the patients. Herein, we report for the first time, to our knowledge, two clinical cases of Hyper-IgD syndrome-associated HS. Hyper-IgD is an autoinflammatory syndrome caused by a mevalonate kinase deficiency (MKD), a key kinase in the sterol and isoprenoid production pathway. We describe the potentially shared pathophysiological mechanisms underpinning comorbid MKD-HS and propose therapeutic options for the management of these patients.

Detection of ISUP ≥2 prostate cancers using multiparametric MRI: prospective multicentre assessment of the non-inferiority of an artificial intelligence system as compared to the PI-RADS V.2.1 score (CHANGE study).

INTRODUCTION: Prostate multiparametric MRI (mpMRI) has shown good sensitivity in detecting cancers with an International Society of Urological Pathology (ISUP) grade of ≥2. However, it lacks specificity, and its inter-reader reproducibility remains moderate. Biomarkers, such as the Prostate Health Index (PHI), may help select patients for prostate biopsy. Computer-aided diagnosis/detection (CAD) systems may also improve mpMRI interpretation. Different prototypes of CAD systems are currently developed under the Recherche Hospitalo-Universitaire en Santé / Personalized Focused Ultrasound Surgery of Localized Prostate Cancer (RHU PERFUSE) research programme, tackling challenging issues such as robustness across imaging protocols and magnetic resonance (MR) vendors, and ability to characterise cancer aggressiveness. The study primary objective is to evaluate the non-inferiority of the area under the receiver operating characteristic curve of the final CAD system as compared with the Prostate Imaging-Reporting and Data System V.2.1 (PI-RADS V.2.1) in predicting the presence of ISUP ≥2 prostate cancer in patients undergoing prostate biopsy. METHODS: This prospective, multicentre, non-inferiority trial will include 420 men with suspected prostate cancer, a prostate-specific antigen level of ≤30 ng/mL and a clinical stage ≤T2 c. Included men will undergo prostate mpMRI that will be interpreted using the PI-RADS V.2.1 score. Then, they will undergo systematic and targeted biopsy. PHI will be assessed before biopsy. At the end of patient inclusion, MR images will be assessed by the final version of the CAD system developed under the RHU PERFUSE programme. Key secondary outcomes include the prediction of ISUP grade ≥2 prostate cancer during a 3-year follow-up, and the number of biopsy procedures saved and ISUP grade ≥2 cancers missed by several diagnostic pathways combining PHI and MRI findings. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Comité de Protection des Personnes Nord Ouest III (ID-RCB: 2020-A02785-34). After publication of the results, access to MR images will be possible for testing other CAD systems. TRIAL REGISTRATION NUMBER: NCT04732156.

TM4SF1, a novel primary androgen receptor target gene over-expressed in human prostate cancer and involved in cell migration.

BACKGROUND: The Androgen Receptor (AR) plays a key role in controlling prostate gland homeostasis and contributes to prostate carcinogenesis. The identification of its target genes should provide new candidates that may be implicated in cancer initiation and progression. METHODS: Transcriptomic experiments and chromatin immunoprecipitation were combined to identify direct androgen regulated genes. Real-time quantitative PCR (RT-qPCR) analyses were performed to measure TM4SF1 mRNA levels in prostate cancer and benign prostatic hyperplasia (BPH) specimens. Immunohistochemical methods were used to compare TM4SF1 protein expression profiles in the same cohort. A targeted siRNAs knockdown strategy was used, prior to wound healing assays, to analyze the role of TM4SF1 in cell migration in vitro. RESULTS: We demonstrate for the first time that TM4SF1 is a direct target gene of the AR, a transcription factor of the steroid nuclear receptor family. A functional androgen response element was identified in the promoter region of the gene. In addition, TM4SF1 mRNA expression was higher in cancer samples compared to BPH tissues. The TM4SF1 protein mediates cell motility of prostate cancer cells where it is predominantly localized in the cytoplasm, in contrast to its apical membrane localization in normal prostate epithelial cells. CONCLUSIONS: Our results reveal a novel function for TM4SF1 in AR signaling. The TM4SF1 mRNA expression is higher in prostate cancer tissues as compared to BPH samples. Inhibition of cell migration after targeted knockdown of TM4SF1 protein expression suggests its contribution to prostate cancer cell metastasis.

Urinary PCA3 score predicts prostate cancer multifocality.

PURPOSE: The urinary PCA3 gene test has proved helpful for deciding whether to (re)biopsy to diagnose prostate cancer. We searched for pathological features that influence the shedding of PCA3 producing prostate cancer cells in urine after digital rectal examination. MATERIALS AND METHODS: Included in our study were 102 patients with an informative PCA3 score on the Progensa® PCA3 assay who underwent radical prostatectomy. Correlations were evaluated between PCA3 score and histopathological factors on prostatectomy, including tumor site in the prostate and the number of cancer foci. RESULTS: PCA3 score significantly correlated with total tumor volume in prostatectomy specimens (p <0.001) but not with prostatectomy Gleason score or pathological stage. PCA3 score positively correlated with apical and basal invasion, and with bilaterality and multifocality. On multivariate analysis multifocality was an independent factor influencing PCA3 score (p = 0.012). CONCLUSIONS: Site in the prostate gland and the number of cancer foci may explain the observed PCA3 score variation in patients operated on for prostate cancer. The PCA3 test could be helpful in preoperatively selecting patients with unifocal and unilateral cancer who could benefit from active surveillance or focal therapy.

[Value of PCA3 urinary test for prostate biopsy decision: the Lyon-Sud University Hospital experience]. / Intérêt du test urinaire PCA3 dans la décision de biopsie prostatique : l'expérience du Centre hospitalier Lyon-Sud.

The poor specificity of diagnostic strategy for prostate cancer (digital rectal examination and seric PSA) induces both a great number of useless prostate biopsies and diagnosis of non evolutive cancers. A urinary test (Progensa PCA3(®), Gen-Probe) measuring the expression of PCA3, a prostate cancer-specific gene, has recently be proposed to indicate re-biopsy. The aim of this prospective study was to evaluate diagnostic value of urinary PCA3 test for prostate cancer. In the urines of 245 patients submitted to prostate biopsy, expression of the PCA3 gene was measured and reported to that of PSA to calculate PCA3 score using a method amplifying and detecting RNA. Patients with informative samples (98%) were classified depending of the presence (n = 126) or absence (n = 114) of cancer tissue on biopsies. The median PCA3 score was significantly higher in the group with positive biopsies (p < 0.0001). Area under ROC curve was 0.70 for PCA3 as compared to that of PSA (0.53) and free/total PSA ratio (0.65). At the best threshold of 38, PCA3 test had a 59%-sensitivity and a 72%-specificity, as compared to 66% and 32% for total PSA (threshold 4 ng/mL) and 81% and 28% for free/total PSA ratio (threshold 25%). These performances were maintained in patients with seric PSA within the grey zone (4-10 ng/mL) and those with previous prostate biopsies. This study confirms the clinical value of PCA3 urinary test in helping decision for biopsies in patients with suspected prostate cancer.

MEN1 silencing aggravates tumorigenic potential of AR-independent prostate cancer cells through nuclear translocation and activation of JunD and ß-catenin.

BACKGROUND: Recent studies highlighted the increased frequency of AR-low or -negative prostate cancers (PCas) and the importance of AR-independent mechanisms in driving metastatic castration-resistant PCa (mCRPC) development and progression. Several previous studies have highlighted the involvement of the MEN1 gene in PCa. In the current study, we focused on its role specifically in AR-independent PCa cells. METHODS: Cell tumorigenic features were evaluated by proliferation assay, foci formation, colony formation in soft agar, wound healing assay and xenograft experiments in mice. Quantitative RT-PCR, Western blot and immunostaining were performed to determine the expression of different factors in human PCa lines. Different ChIP-qPCR-based assays were carried out to dissect the action of JunD and ß-catenin. RESULTS: We found that MEN1 silencing in AR-independent cell lines, DU145 and PC3, resulted in an increase in anchorage independence and cell migration, accompanied by sustained MYC expression. By searching for factors known to positively regulate MYC expression and play a relevant role in PCa development and progression, we uncovered that MEN1-KD triggered the nuclear translocation of JunD and ß-catenin. ChIP and 3C analyses further demonstrated that MEN1-KD led to, on the one hand, augmented binding of JunD to the MYC 5' enhancer and increased formation of loop structure, and on the other hand, increased binding of ß-catenin to the MYC promoter. Moreover, the expression of several molecular markers of EMT, including E-cadherin, BMI1, Twist1 and HIF-1α, was altered in MEN1-KD DU145 and PC3 cells. In addition, analyses using cultured cells and PC3-GFP xenografts in mice demonstrated that JunD and ß-catenin are necessary for the altered tumorigenic potential triggered by MEN1 inactivation in AR-independent PCa cells. Finally, we observed a significant negative clinical correlation between MEN1 and CTNNB1 mRNA expression in primary PCa and mCRPC datasets. CONCLUSIONS: Our current work highlights an unrecognized oncosuppressive role for menin specifically in AR-independent PCa cells, through the activation of JunD and ß-catenin pathways.

Non-genomic signaling of steroid receptors in cancer.

Steroid receptors (SRs) are members of the nuclear receptor family, which are ligand-activated transcription factors. SRs regulate many physiological functions including development and reproduction, though they can also be involved in several pathologies, especially cancer. Highly controlled cellular responses to steroids involve transcriptional regulation (genomic activity) combined with direct activation of signaling cascades (non-genomic activity). Non-genomic signaling has been extensively studied in cancer, mainly in breast cancer for ER and PR, and prostate cancer for AR. Even though most of the studies have been conducted in cells, some of them have been confirmed in vivo, highlighting the relevance of this pathway in cancer. This review provides an overview of the current and emerging knowledge on non-genomic signaling with a focus on breast and prostate cancers and its clinical relevance. A thorough understanding of ER, PR, AR and GR non-genomic pathways may open new perspectives for the development of therapeutic strategies.

Men1 disruption in Nkx3.1-deficient mice results in ARlow/CD44+ microinvasive carcinoma development with the dysregulated AR pathway.

Dysregulated androgen receptor (AR) plays a crucial role in prostate cancer (PCa) development, though further factors involved in its regulation remain to be identified. Recently, paradoxical results were reported on the implication of the MEN1 gene in PCa. To dissect its role in prostate luminal cells, we generated a mouse model with inducible Men1 disruption in Nkx3.1-deficient mice in which mouse prostatic intraepithelial neoplasia (mPIN) occur. Prostate glands from mutant and control mice were analyzed pathologically and molecularly; cellular and molecular analyses were carried out in PCa cell lines after MEN1 knockdown (KD) by siRNA. Double-mutant mice developed accelerated mPIN and later displayed microinvasive adenocarcinoma. Markedly, early-stage lesions exhibited a decreased expression of AR and its target genes, accompanied by reduced CK18 and E-cadherin expression, suggesting a shift from a luminal to a dedifferentiated epithelial phenotype. Intriguingly, over 60% of menin-deficient cells expressed CD44 at a later stage. Furthermore, MEN1 KD led to the increase in CD44 expression in PC3 cells re-expressing AR. Menin bound to the proximal AR promoter and regulated AR transcription via the H3K4me3 histone mark. Interestingly, the cell proliferation of AR-dependent cells (LNCaP, 22Rv1, and VCaP), but not of AR-independent cells (DU145, PC3), responded strongly to MEN1 silencing. Finally, menin expression was found reduced in some human PCa. These findings highlight the regulation of the AR promoter by menin and the crosstalk between menin and the AR pathway. Our data could be useful for better understanding the increasingly reported AR-negative/NE-negative subtype of PCa and the mechanisms underlying its development.

Improved Androgen Receptor Splice Variant 7 Detection Using a Highly Sensitive Assay to Predict Resistance to Abiraterone or Enzalutamide in Metastatic Prostate Cancer Patients.

BACKGROUND: In metastatic castration-resistant prostate cancer (mCRPC), androgen receptor splice variant 7 (AR-V7) expression is associated with a low response to androgen receptor signaling (ARS) inhibitors such as abiraterone or enzalutamide. OBJECTIVE: To perform a highly sensitive assay for detecting AR-V7 (hsAR-V7) in circulating tumor cells (CTCs) and evaluate its ability to predict response to ARS inhibitors. DESIGN, SETTING, AND PARTICIPANTS: From 41 mCRPC patients, CTCs were prospectively enriched using AdnaTest platform and analyzed for AR-V7 with and without the highly sensitive assay. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The first objective of the study was to compare AR-V7 detection rates with and without the highly sensitive assay. Next, we investigated how AR-V7 (detected without the highly sensitive assay) and hsAR-V7 status influenced prostate-specific antigen (PSA) response and long-term clinical outcomes (PSA progression-free survival [PFS] and radiological PFS) after ARS-inhibitor treatment. Finally, discriminatory abilities of the assays were assessed by C-index to compare their impact on long-term clinical outcomes. RESULTS AND LIMITATIONS: AR-V7 detection rates increased from 22% to 56% when the highly sensitive assay was used. The discriminatory abilities of hsAR-V7 for PSA PFS (C-index, 0.74; 95% confidence interval [CI], 0.60-0.88) and radiological PFS (0.70; 95% CI, 0.55-0.85) were higher than those of AR-V7 detected without the highly sensitive assay (0.60, 0.51-0.72, and 0.56, 0.44-0.67, respectively). After ARS-inhibitor treatment, PSA response was lower in hsAR-V7+ (53%) than in hsAR-V7- (93%) patients (p = 0.016). AR-V7+ patients had shorter median PSA PFS (3.0 vs 10.6 mo, p = 0.032) and nonsignificantly shorter median radiological PFS (6.0 vs 14.8 mo, p = 0.24) compared with AR-V7- patients. The hsAR-V7+ status was associated with shorter median PSA PFS (3.0 mo vs not reached, p = 0.0001) and radiological PFS (median, 6.0 mo vs not reached, p = 0.0026). CONCLUSIONS: The hsAR-V7 assay achieved the highest AR-V7 detection rates among those reported in mCRPC. Discriminatory abilities for long-term clinical outcomes were better with hsAR-V7 assay. PATIENT SUMMARY: We prospectively analyzed circulating tumor cells from men with metastatic castration-resistant prostate cancer for androgen receptor splice variant 7 (AR-V7) status using a highly sensitive assay. It yielded higher AR-V7 detection rates and predicted resistance to androgen receptor signaling inhibitors with better discriminatory abilities for long-term clinical outcomes.

Her2 Expression in Circulating Tumor Cells Is Associated with Poor Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer.

HER2-dependent signaling may support the development of metastatic castration-resistant prostate cancer (mCRPC) by activating androgen receptor signaling through ligand-independent mechanisms. From 41 mCRPC patients (including 31 treated with Androgen Receptor Signaling Inhibitors [ARSI]), Circulating Tumor Cells (CTCs) were prospectively enriched with AdnaTest platform and analyzed with a multiplexed assay for HER2 and AR-V7 mRNA expression. Then, we evaluated the impact of HER2 expression on PSA-response, Progression Free Survival (PFS) and Overall Survival (OS). HER2 expression was detected in CTCs of 26 patients (63%). Although PSA response was similar regardless of HER2 status, patients with HER2 positive CTCs had shorter PSA-PFS (median: 6.2 months versus 13.0 months, p = 0.034) and radiological-PFS (6.8 months versus 25.6 months, p = 0.022) than patients without HER2 expression. HER2 expression was also associated with a shorter OS (22.7 months versus not reached, p = 0.05). In patients treated with ARSI, multivariate analyses revealed that the prognostic impact of HER2 status on PSA-PFS was independent of AR-V7 expression and of the detection of CTCs by an AdnaTest. We showed for the first time the poor prognostic value of HER2 expression in CTCs from patients with mCRPC. The therapeutic interest of targeting this actionable pathway remains to be explored.

Cost-effectiveness of SelectMDx for prostate cancer in four European countries: a comparative modeling study.

BACKGROUND: Low specificity of prostate-specific antigen results in a considerable number of unnecessary prostate biopsies in current practice. SelectMDx® predicts significant prostate cancer upon biopsy and is used to reduce the number of unnecessary initial prostate biopsies. Furthermore, potential overtreatment of insignificant prostate cancer can be reduced. Besides the diagnostic accuracy of the test, also the context in a specific country determines the potential health benefit and cost-effectiveness. Therefore, the health benefit and cost-effectiveness of SelectMDx were assessed in France, Germany, Italy, and Spain. SUBJECT AND METHODS: A decision model was used to compare the current standard of care in which men undergo initial prostate biopsy in case of an elevated prostate-specific antigen, to a strategy in which SelectMDx was used to select men for biopsy. Model inputs most relevant to each of the four countries were obtained. With use of the model long-term quality-adjusted life years (QALYs) and healthcare costs were calculated for both strategies. RESULTS: In all four countries, the SelectMDx resulted in QALY gain and cost savings compared with the current standard of care. In France, SelectMDx resulted in 0.022 QALYs gained and cost savings of €1217 per patient. For Germany, the model showed a QALY gain of 0.016 and a cost saving of €442. In Italy, the QALY gain and cost savings were 0.031 and €762. In Spain 0.020 QALYs were gained and €250 costs were saved. CONCLUSIONS: The results of the model showed that with SelectMDx, QALYs could be gained while saving healthcare costs in the initial diagnosis of prostate cancer. The significant presence of overtreatment in the current standard of care in all four countries was the main factor that resulted in the beneficial outcomes with SelectMDx.

The fate of the duplicated androgen receptor in fishes: a late neofunctionalization event?

BACKGROUND: Based on the observation of an increased number of paralogous genes in teleost fishes compared with other vertebrates and on the conserved synteny between duplicated copies, it has been shown that a whole genome duplication (WGD) occurred during the evolution of Actinopterygian fish. Comparative phylogenetic dating of this duplication event suggests that it occurred early on, specifically in teleosts. It has been proposed that this event might have facilitated the evolutionary radiation and the phenotypic diversification of the teleost fish, notably by allowing the sub- or neo-functionalization of many duplicated genes. RESULTS: In this paper, we studied in a wide range of Actinopterygians the duplication and fate of the androgen receptor (AR, NR3C4), a nuclear receptor known to play a key role in sex-determination in vertebrates. The pattern of AR gene duplication is consistent with an early WGD event: it has been duplicated into two genes AR-A and AR-B after the split of the Acipenseriformes from the lineage leading to teleost fish but before the divergence of Osteoglossiformes. Genomic and syntenic analyses in addition to lack of PCR amplification show that one of the duplicated copies, AR-B, was lost in several basal Clupeocephala such as Cypriniformes (including the model species zebrafish), Siluriformes, Characiformes and Salmoniformes. Interestingly, we also found that, in basal teleost fish (Osteoglossiformes and Anguilliformes), the two copies remain very similar, whereas, specifically in Percomorphs, one of the copies, AR-B, has accumulated substitutions in both the ligand binding domain (LBD) and the DNA binding domain (DBD). CONCLUSION: The comparison of the mutations present in these divergent AR-B with those known in human to be implicated in complete, partial or mild androgen insensitivity syndrome suggests that the existence of two distinct AR duplicates may be correlated to specific functional differences that may be connected to the well-known plasticity of sex determination in fish. This suggests that three specific events have shaped the present diversity of ARs in Actinopterygians: (i) early WGD, (ii) parallel loss of one duplicate in several lineages and (iii) putative neofunctionalization of the same duplicate in percomorphs, which occurred a long time after the WGD.

Extracellular Vesicles in Prostate Cancer Carcinogenesis, Diagnosis, and Management.

Extracellular vesicles (EVs), especially exosomes, are now well recognized as major ways by which cancer cells interact with each other and stromal cells. The meaningful messages transmitted by the EVs are carried by all components of the EVs, i.e., the membrane lipids and the cargo (DNAs, RNAs, microRNAs, long non-coding RNAs, proteins). They are clearly part of the armed arsenal by which cancer cells obtain and share more and more advantages to grow and conquer new spaces. Identification of these messages offers a significant opportunity to better understand how a cancer occurs and then develops both locally and distantly. But it also provides a powerful means by which cancer progression can be detected and monitored. In the last few years, significant research efforts have been made to precisely identify how the EV trafficking is modified in cancer cells as compared to normal cells and how this trafficking is altered during cancer progression. Prostate cancer has not escaped this trend. The aim of this review is to describe the results obtained when assessing the meaningful content of prostate cancer- and stromal-derived EVs in terms of a better comprehension of the cellular and molecular mechanisms underlying prostate cancer occurrence and development. This review also deals with the use of EVs as powerful tools to diagnose non-indolent prostate cancer as early as possible and to accurately define, in a personalized approach, its present and potential aggressiveness, its response to treatment (androgen deprivation, chemotherapy, radiation, surgery), and the overall patients' prognosis.

Thyroid hormone receptor expression in the obligatory paedomorphic salamander Necturus maculosus.

Amphibian metamorphosis is under the strict control of thyroid hormones (TH). These hormones induce metamorphosis by controlling gene expression through binding to thyroid hormone receptors (TRs). Necturus maculosus is considered to be an obligatory paedomorphic Amphibian since metamorphosis never occurs spontaneously and cannot be induced by pharmacological means. Since metamorphosis depends on the acquisition of response of tadpole tissues to thyroid hormone, we aimed to determine TR gene expression patterns in Necturus maculosus as well as the expression of two TH-related genes: Cytosolic Thyroid Hormone-Binding Protein (CTHBP)-M2-pyruvate kinase, a gene encoding a cytosolic TH binding protein and stromelysin 3, a direct TH target gene in Xenopus laevis. Tissue samples were obtained from specimens of Necturus maculosus. We performed in situ hybridization using non-cross-hybridizing RNA probes obtained from the cloned Necturus TRalpha and TRbeta genes. We found clear expression of Necturus TRalpha gene in several tissues including the central nervous system, epithelial cells of digestive and urinary organs, as well as myocardium and skeletal muscle. TRbeta was also expressed in the brain. In other tissues, hybridization signals were too low to draw reliable conclusions about their precise distribution. In addition, we observed that the expression of CTHBP and ST3 is largely distinct from that of TRs. The fact that we observed a clear expression of TRalpha and TRbeta which are evolutionary conserved, suggests that Necturus tissues express TRs. Our results thus indicate that, in contrast to previously held hypotheses, Necturus tissues are TH responsive.