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MEN1 mutation predisposes patients to multiple endocrine neoplasia type 1 (MEN1), a genetic syndrome associated with the predominant co-occurrence of endocrine tumors. Intriguingly, recent evidence has suggested that MEN1 could also be involved in the development of breast and prostate cancers, two major hormone-related cancers. The first clues as to its possible role arose from the identification of the physical and functional interactions between the menin protein, encoded by MEN1, and estrogen receptor α and androgen receptor. In parallel, our team observed that aged heterozygous Men1 mutant mice developed cancerous lesions in mammary glands of female and in the prostate of male mutant mice at low frequencies, in addition to endocrine tumors. Finally, observations made both in MEN1 patients and in sporadic breast and prostate cancers further confirmed the role played by menin in these two cancers. In this review, we present the currently available data concerning the complex and multifaceted involvement of MEN1 in these two types of hormone-dependent cancers.

Resume Il est commun d’etablir le diagnostic des dysfonctions thyroidiennes sur des modifications de la thyrostimuline hypophysaire (TSH), et de les quantifier par le degre d’abaissement ou d’augmentation des concentrations de T4 et de T3 circulantes. Cette conception est mise en defaut lorsque des facteurs genetiques, voire pharmacologiques, determinent des alterations de la sensibilite tissulaire a l’action des iodothyronines. La situation la moins rare est celle d’etats de secretion inappropriee de TSH, responsables d’hyperhormonemie thyroidienne familiale sans que ne s’expriment clairement de manifestations thyrotoxiques, en raison de la resistance des recepteurs beta des iodothyronines. Les mutations du recepteur alpha sont responsables de severes modifications du morphotype osseux et du comportement, alors que les concentrations de T4 et T3 et de TSH sont pratiquement normales, mais comportent une subtile majoration du rapport T3/T4. Le transporteur MCT8 est implique dans la penetration de la T3 dans les structures fines neuronales ; des mutations de MCT8 ont permis de comprendre les etats de deficience intellectuelle severe lies a l’X correspondant a l’entite traditionnelle du syndrome d’Allan-Herndon-Dudley. D’autres situations resultant d’un defaut d’activation de T4 en T3, se revelent par des retards de croissance et du developpement intellectuel, des atteintes myopathiques, un deficit immunitaire, une azoospermie. Il existe aussi des etats d’hypersensibilite aux hormones thyroidiennes. Il faut apprendre a reconnaitre ces situations dont la presentation clinique et/ou hormonale n’evoque a priori nullement un desordre thyroidien. Il apparait qu’elles ont des correspondances pharmacologiques et environnementales, notamment avec l’amiodarone, la dronedarone et certains perturbateurs endocriniens. Les pathologies liees aux modifications de la sensibilite hormonale elargissent considerablement le champ traditionnel de l’endocrinologie.

IMPORTANCE: Surgery is a mainstay in the management of hidradenitis suppurativa (HS). Adalimumab is the first drug approved for HS. OBJECTIVE: To investigate the efficacy and safety of adalimumab in combination with wide-excision surgery followed by secondary intention healing. DESIGN, SETTING, AND PARTICIPANTS: The Safety and Efficacy of Adalimumab for Hidradenitis Suppurativa Peri-Surgically (SHARPS) trial was a phase 4, randomized, double-blind, placebo-controlled study of adalimumab in conjunction with surgery. Patients were enrolled in 45 sites across 20 countries from July 18, 2016, to February 2, 2019, with the last patient visit on October 16, 2019. Eligible patients (aged 18-65 years) had moderate to severe HS that required radical surgery in an axillary or inguinal region and had 2 other anatomical regions affected, with 1 or more regions at Hurley stage II or III. Analysis was conducted in November 2019. INTERVENTIONS: Patients were randomized 1:1 to receive continuous adalimumab, 40 mg, or placebo during presurgery (12 weeks), perioperative (2 weeks), and postoperative (10 weeks) periods. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of patients achieving HS clinical response across all body regions at week 12. RESULTS: Overall, 103 patients were randomized to adalimumab and 103 to matching placebo. Among all patients, 51% (n = 106) were women, 94% (n = 193) were White, and the mean (SD) age was 37.6 (11.3) years. At week 12, significantly more patients receiving adalimumab (49 of 103 [48%]) vs placebo (35 of 103 [34%]; P = .049) achieved HS clinical response across all body regions (treatment difference, 14% [95% CI, 0%-27%]). Treatment-emergent adverse events were reported in 74 of 103 patients (72%) and 69 of 103 patients (67%) in the adalimumab and placebo groups, respectively. No increased risk of postoperative wound infection, complication, or hemorrhage was observed with adalimumab vs placebo. Two deaths occurred in the adalimumab group; neither was considered as having a reasonable possibility of relationship to study drug. CONCLUSIONS AND RELEVANCE: Adalimumab was efficacious in conjunction with wide-excision surgery followed by secondary intention healing, with no need to interrupt treatment prior to surgery. These data support further investigation of adalimumab as an adjuvant therapy to surgery in patients with moderate to severe HS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02808975

IntroductionProstate 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.MethodsThis 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 disseminationEthical 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 numberNCT04732156.

Simple Summary Although the role of HER2 in prostate cancer remains controversial, HER2 can be overexpressed during prostate cancer progression. In this study, we prospectively isolated circulating tumor cells (CTCs) from 41 men with metastatic castration-resistant prostate cancer (mCRPC). Then, we analyzed HER2 expression in CTCs with a highly sensitive assay. HER2 was frequently detected in CTCs of patients (n = 26, 63%) and we showed, for the first time, to our knowledge, that HER2 expression in CTCs was associated with poor long-term clinical outcomes in mCRPC. Moreover, the impact of HER2 expression in CTCs was an independent prognostic factor of progression-free survival. Abstract 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.

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 β-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 β-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 β-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 β-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 β-catenin pathways.

Introduction Le deficit en mevalonate kinase (dMVK ou hyperimmunoglobulinemie D ; transmission autosomique recessive) appartient au groupe des fievres periodiques hereditaires et plus generalement aux maladies auto-inflammatoires hereditaires. Caracterise par des episodes febriles recurrents essentiellement associes a des manifestations digestives (douleurs abdominales, diarrhees, vomissements) et des douleurs articulaires, il n’a pas, jusqu’a present ete decrit en association avec l’hidradenite suppuree (HS). Nous en rapportons deux observations. Materiel et methodes Chez le patient 1, un homme de 34 ans, l’HS evoluait depuis l’âge de 19 ans au niveau perianal et secondairement axillaire (inflammations abcedees et fistulisees). Les traitements ont inclus des antibiotherapies abortives, des cyclines et l’association rifampicine-clindamycine. Le dMVK evoluait depuis la petite enfance avec des acces febriles associes a des douleurs abdominales et myo-articulaires. Les traitements associaient corticoides et colchicine. L’introduction, au diagnostic de l’association syndromique, de l’adalimumab (ada ; dose de charge a 160 mg ; 80 mg a deux semaines puis 40 mg/sem) a entraine une disparition complete des signes de dMVK et de la composante inflammatoire de l’HS. L’excision des lesions fistuleuses et fibreuses axillaires bilaterales a complete le traitement medical. L’ada a ete interrompu spontanement par le patient deux ans apres son introduction. Le patient 2, une adolescente de 15 ans avait des signes de dMVK des la periode neonatale et a ete traitee par corticotherapie, anakinra de 6 a 7 ans puis canakinumab depuis l’âge de 7 ans (injections toutes les 6–8 semaines). Des lesions inflammatoires abcedees et productives sont apparues a l’âge de 14 ans sur le pli inguinal, la grande levre et la face interne de la cuisse, traitees par antibiotherapies courtes et incisions. L’ada a ete introduit (40 mg/2 semaines) avec constatation, sur les 5 premiers mois de traitement, d’une diminution des poussees inflammatoires d’HS et un espacement des injections de canakinumab (toutes les 8–10 semaines). Discussion Les mutations du gene de la MVK induisent une production excessive d’isoprenoides pro-inflammatoires et d’Il-1beta qui pourraient faciliter le developpement des lesions d’HS. Les quelques etudes ayant evalue pour l’HS l’effet des anti-Il-1beta (indiques pour le dMVK) ont montre une efficacite variable (ils n’ont pas empeche l’apparition de l’HS chez la patiente 2). L’ada, seule biotherapie agreee pour l’HS, a montre, chez les deux patients, son interet pour contrer a la fois les manifestations du dMVK et de l’HS. D’autres observations sont necessaires pour evaluer le caractere coincident ou non de l’association decrite ici mais nos cas cliniques renforcent l’hypothese, pour l’HS, d’une maladie auto-inflammatoire a composante genetique.

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.

Proof of the clinical utility of a biomarker is when its use informs a management decision and improves patient outcomes relative to when it is not used.To model the clinical benefit of the nuclear-localized androgen receptor splice variant 7 (AR-V7) test for men with progressing metastatic castration-resistant prostate cancer (mCRPC) at the second line of therapy or greater to inform the choice of an androgen receptor signaling inhibitor (ARSI) or a taxane.The study population was a cross-sectional cohort of 193 unique patients with progressing mCRPC from whom 255 samples were drawn at the time of the second line or later treatment decision who then received an ARSI or taxane, with up to 3 yr of additional follow-up Circulating tumor cells (CTCs) were identified from blood samples and tested for AR-V7. Physicians were blinded to AR-V7 status and the testing laboratory was blinded to outcomes.We measured physician propensity for choosing an ARSI or taxane based on patient prognosis. We also measured overall survival (OS) adjusted for physician propensity by drug class; OS data were analyzed both without and with knowledge of nuclear-localized AR-V7 status.Treating physicians had a propensity for choosing a taxane over an ARSI for patients with more advanced disease or who received an ARSI as the immediate prior therapy. After adjusting for physician propensity, discernible OS differences were not observed between taxane- and ARSI-treated patients (median 15.6 vs 14.4 mo; p =0.11). Patients with detectable nuclear-localized AR-V7 in CTCs had superior survival with taxanes over ARSIs (median 9.8 vs 5.7 mo; p = 0.041). AR-V7-negative patients had superior survival on ARSIs over taxanes (p = 0.033) but overlapping curves limit the interpretation. Mutivariable models showed a robust interaction between AR-V7 status and drug, and a lower risk of death on taxanes for AR-V7-positive men.Use of the nuclear-localized AR-V7 CTC test to inform treatment choice can improve patient outcomes relative to decisions based solely on standard-of-care measures.Men with metastatic prostate cancer who test positive for AR-V7 protein in circulating tumor cells are likely to live longer if taxane chemotherapy is used.

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.

International audience; 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.

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.

INTRODUCTION AND OBJECTIVES:A 2-gene, urine-based molecular test that combines mRNA biomarkers with clinical factors can risk stratify patients for high-grade prostate cancer (PCa). To ensure the g...

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.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.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.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.

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. 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. 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. 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.

Resume But Evaluer la capacite du test urinaire PCA3 a predire le resultat des biopsies prostatiques dans une large cohorte issue du centre hospitalier Lyon-Sud. Patients et methodes Le score PCA3 a ete determine prospectivement chez 1015 patients adresses pour biopsies prostatiques. La capacite predictive du score PCA3 a ete evaluee par la comparaison des aires sous les courbes ROC, de modeles de regression logistique et une analyse par decision curve analysis (DCA). Resultats Le score PCA3 median etait significativement plus eleve chez les patients avec biopsies positives. L’AUC etait de 0,76, significativement plus elevee que celle du PSA a 0,55. Au seuil de 35, la sensibilite etait de 68 %, la specificite de 71 %, les valeurs predictives positive et negative de 67 % et 71 %, et l’efficience de 69 %. En analyse multivariee, le score PCA3 etait predicteur independant du resultat des biopsies et son addition a un modele de base comportant les donnees clinico-biologiques classiques apportait un gain diagnostique significatif. Au seuil de 20, pres de la moitie des biopsies a posteriori inutiles auraient ete evitees, tout en ayant ignore 7 % des cancers avec score de Gleason ≥ 7. Le score PCA3 n’apparaissait pas correle au score de Gleason, mais etait bien correle au volume tumoral (evalue par la proportion de carottes envahies). Conclusion Le test urinaire PCA3 presente des performances diagnostiques elevees pour le diagnostic precoce du CaP. Sa correlation avec l’agressivite du cancer s’exprime a travers le volume tumoral plus que par le score de Gleason. Niveau de preuve 5.

Summary Aim To evaluate the performance of urinary PCA3 test to predict prostate biopsy outcome in a large French cohort. Patients and methods A urine sample was prospectively obtained from 1015 patients undergoing prostate biopsies to determine the PCA3 score. The predictive value of PCA3 was explored using receiver operating characteristic curve analysis (ROC), multivariable logistic regression analysis and decision curve analysis. Results The median PCA3 score was significantly higher in patients with positive biopsies. The PCA3 score AUC was 0.76 (0.73–0.79), significantly higher than that of PSA (0.55; 0.51–0.58). At the cutoff of 35, sensitivity was 68%, specificity 71%, positive and negative predictive values 67% and 71%, and accuracy 69%. Using multivariate analysis, PCA3 score appeared as an independent predictor of biopsy outcome and its addition to a base model including usual clinicobiological parameters resulted in a significant increase in predictive accuracy. At the cutoff of 20, about 1/2 of the ultimately unnecessary biopsies would have been avoided while ignoring 7% of cancers with Gleason score ≥ 7. PCA3 score did not correlate with Gleason score but did correlate with tumor volume (proportion of positive cores). Conclusion Urinary PCA3 is a useful test with high diagnostic performances for early prostate cancer diagnosis. Its correlation with cancer aggressiveness seems rather represented by a link to prostate volume than Gleason score. Level of evidence 5.

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.

Bexarotene (Targretin), approved since 1999 as a second-line treatment for late stage cutaneous T-cell lymphomas, has been shown to induce significant hypothyroidism through TSH suppression. This review revisits, through a case report, mechanisms by which rexinoids repress the expression ofTSHBgene as well asαTSHandTRHgenes. It appears that rexinoids suppress TSH independently from tri-iodothyronine. Bexarotene also differently affects the gene expression of deiodinases 1 and 2 as well as the peripheral clearance of thyroxine. These data might open new ways of research on the potential interaction between thyroid axis and endogenous rexinoids.

Resume Objectifs Determiner si l’ajout du score PCA3, et/ou de l’IRM prostatique permet d’ameliorer la selection des patients candidats a une premiere serie de biopsies de prostate. Methodes Une IRM prostatique multiparametrique (IRM MP) et un dosage de PCA3 ont ete realises avant biopsie chez les patients ayant une indication de premiere biopsie pour un toucher rectal anormal et/ou un PSA superieur a 4 ng/mL. Les sequences T2, dynamiques et de diffusion recherchaient une cible suspecte cotee sur un score de 4. Les patients ont ete inclus de facon prospective dans un seul centre. Les performances du PCA3 urinaire et de l’IRM ont ete evaluees par comparaison aux resultats des biopsies. Resultats Soixante-huit patients ont ete inclus, le PSA median etait de 5,2 ng/mL (3,2–28). La valeur predictive negative (VPN) des sores IRM 0, 1 et 2 etait respectivement de 80 %, 43 % et 69 %. La valeur predictive positive (VPP) des scores IRM de 3 et 4 etait de 50 % et 81 %. La valeur seuil discriminante pour le PCA3 etait de 21 (Se : 0,91 ; Sp : 0,50). Un seul patient avec des biopsies positives (0,5 mm de score de Gleason 3 + 3) avait a la fois une IRM negative et un PCA3 inferieur a 21. Conclusion L’association de l’IRM MP et du PCA3 permettait, dans cette etude, d’envisager une reduction du nombre de primo-biopsies inutiles sans ignorer la presence d’une eventuelle tumeur agressive.

To systematically review the evidence for the use of PSA and other biomarkers in the early detection of prostate cancer, we searched PubMed for clinical trials and studies assessing PSA and other biomarkers in the early detection of prostate cancer, published between 2000 and May 2013 that included >200 subjects. The level of evidence (LOE) for clinical utility was evaluated using the tumor marker utility grading system. A total of 84 publications, corresponding to 70 trials and studies were selected for inclusion in this review. We attributed a level of evidence (LoE) of IA to PSA for early PCa detection, but we do not recommend its use in mass screening. Emerging biomarkers were assessed in prospective case-control and cohort studies: PCA3 (n=3); kallikreins (n=3); [-2]proPSA (n=5); fusion oncogenes (n=2). These studies used biopsy results for prostate cancer to determine specificity and sensitivity, but they did not assess the effect on PCa mortality. The LoE attributed was III-C. PSA can be used for early prostate cancer detection but mass screening is not recommended. Studies on other biomarkers suggest that they could be used, individually or in combination, to improve the selection of patients with elevated PSA levels for biopsy, but RCTs assessing their impact on prostate cancer management and mortality are needed. A better use of available tests is possible for men at risk in order to maximize the risk-benefit ratio.

We describe a technique of S isotope analysis in sulfate form with the first separation stage involving anion-exchange and the second stage of mass-spectrometric analysis by MC-ICP-MS using standard-sample-standard bracketing. Ammonium in 1 : 1 stoichiometric proportion with sulfate was used to improve transmission and stability and to avoid cone and membrane clogging by condensable species. The working resolution of similar to 9000 allowed the main interferences, notably (SH)-S-32 on S-33, to be resolved. The matrix effect caused by phosphorus present in biological samples is negligible for S/P ratios \textgreater= 10: our chemical protocol allows S/P \textgreater= 150 to be routinely achieved. Replicate measurements of S standard solutions give values of isotopic abundances within errors of accepted values and demonstrate a reproducibility of +/- 0.10 parts per thousand for delta S-34 and +/- 0.15 parts per thousand for delta S-33 (2s). The technique is adequate for quantities as small as 10 nanomoles. We investigated the delta S-34 of 110 samples of cancer patients and 10 samples of rheumatoid arthritis patients. We avoided the use of blood collection tubes with sulfate-containing heparin. Sulfur in serum is transported by albumin and fibrinogen. Most serum and plasma delta S-34 values fall within a narrow interval of similar to 1 parts per thousand around a mean delta S-34(VCDT) of similar to 6.0 parts per thousand. The delta S-34 values of total blood, serum, and plasma are very similar. Despite the short turnover time of albumin and fibrinogen, S is surprisingly well regulated. Subtle variations of 0.2-0.3 parts per thousand around the mean value can be assigned to sex and age, with sulfur in male and adult samples tending to be heavier than in their female and juvenile counterparts. This narrow range of variations across the spectrum of a large number of individuals not selected for controlled dietary habits seems paradoxical. In general, breast and prostate cancer and rheumatoid arthritis have very little effect on the average serum delta S-34, but increase the scatter of values. We confirm that the serum of patients affected by liver cancer and other pathologies is depleted of albumin-born sulfur. While sulfur in the serum of patients with non-malignant liver pathologies tends to be isotopically light, the serum delta S-34 of medicated hepatocellular carcinoma patients tends to be at the high end of control values.

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. Prostate 72:549–554, 2012. © 2011 Wiley Periodicals, Inc.

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. Prostate 71:1239–1250, 2011. © 2011 Wiley-Liss, Inc.

The prostate cancer 3 (PCA3) gene was discovered in 1999, on the basis of differential expression between cancer and noncancerous prostate tissue. Including the first study published in 2003, 11 clinical studies have evaluated its utility for the diagnosis of prostate cancer by measuring the number of PCA3 RNA copies in urine enriched with prostate cells. Although the sensitivity of the PCA3 test was less than that of serum prostate-specific antigen (PSA), its specificity appeared to be much better, particularly in patients with a previous negative biopsy. Recent studies also have suggested that this test could be used to predict cancer prognosis.

Resume Le gene PCA3 a ete decouvert en 1999 sur la base de son expression differentielle entre le cancer et le tissu prostatique non cancereux. Plusieurs etudes ont evalue l’interet diagnostique dans le cancer de la prostate de la mesure, dans les urines enrichies en cellules prostatiques, du nombre de copies des ARN produits par PCA3. Pour une sensibilite legerement inferieure a celle du dosage serique du PSA, la specificite et les valeurs predictives positive et negative de ce dosage (test PCA3) apparaissent meilleures. Le test PCA3 apparait ainsi comme un bon indicateur du resultat des biopsies prostatiques. La mise a disposition d’une trousse commerciale offre l’opportunite d’engager des etudes a grande echelle pour confirmer les resultats, preciser les indications du test et evaluer son interet en economie de la sante. L’un des objectifs est une meilleure selection des patients qui doivent etre orientes vers des biopsies prostatiques.

Context: RTH alpha is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TR alpha 1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T-4/free T-3 (FT4/FT3) ratio. Objective: A 27-year-old patient presenting with dwarfism and a low FT4/FT3 ratio was investigated. Design: Clinical, biochemical, and radiological data were collected. Whole exome sequencing was performed in the patient and her relatives. Results: The patient exhibited congenital macrocytic anemia and severe bone malformation with growth retardation, dwarfism, clavicular agenesis, and abnormalities of the fingers, toes, and elbow joints. In adulthood, she presented with active behavior, chronic motor diarrhea, and hypercalcemia. Treatment with T3 led to heart rate acceleration, worsening of diarrhea, and TSH suppression. Low resting energy expenditure normalized on T-3. rT(3), SHBG, and IGF-1 remained normal. A de novo monoallelic missense mutation in THRA was discovered, the N359Y amino acid substitution (c. 1075A>T), which affected both the TR alpha 1 and the non-receptor isoform TR alpha 2. The mutant TR alpha 1 had a decrease in transcriptional activity related to decreased T-3 binding and a dominant-negative effect on the wild-type receptor. Conclusions: This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TR alpha 1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTH alpha

International audience; Since 2012, eight different abnormalities have been described in the THRA gene (encoding the TRα1 thyroid hormone receptor) of 14 patients from 9 families. These mutations induce a clinical phenotype (resistance to thyroid hormone type α) associating symptoms of untreated mild congenital hypothyroidism and a near-normal range of free and total thyroid hormones and TSH (the T4/T3 ratio is nevertheless usually low). The phenotype can diversely include short stature (due to growth retardation), dysmorphic syndrome (face and limb extremities), psychoneuromotor disorders, constipation and bradycardia. The identified genetic abnormalities are located within the ligand-binding domain and result in defective T3 binding, an abnormally strong interaction with corepressors and a dominant negative activity against still functional receptors. The identification of patients with consistent phenotypes and the underlying mutations are warranted to better delineate the spectrum of the syndromes of reduced sensitivity to thyroid hormone.

La pseudohypoparathyroidie est une affection hereditaire rare, caracterisee par des resistances hormonales multiples. L’examen clinique et radiologique d’une patiente de 26 ans, atteinte d’une pseudohypoparathyroidie, montre un sujet brachycephale, euryprosope (du grec : eurus, large et prosopsis, visage) et transfrontal, avec un etage moyen de la face diminue, des arcades dentaires larges, des diastemes, des dents hypoplasiques avec des racines courtes et des pulpes larges ainsi qu’un prognathisme (classe III squelettique) majore par une propulsion spontanee due a l’absence de calage posterieur bilateral. La mandibule est courte, arquee, ancree posterieurement, avec un champ mandibulaire developpe, associee a une brachymaxillie ; les corticales des os du crâne sont denses, la pneumatisation des sinus importante. Une image radioclaire, peu dense et large, situee entre les deux incisives centrales maxillaires fait evoquer un kyste de la papille palatine. (Med Buccale Chir Buccale 2006; 12: 83-88).

Objectifs Le but de notre etude etait d’evaluer la capacite du test serique PHI a predire le resultat des biopsies prostatiques dans une large cohorte monocentrique. Methodes Entre 04/2010 et 05/2014, 594 patients adresses pour biopsies prostatiques du fait d’une suspicion de cancer prostatique (PSA eleve, TR anormal et/ou antecedent familial) ont ete inclus. Le PHI a ete determine a partir du dosage du PSA total, du PSA libre et du P2PSA (PHI = ([–2]proPSA/free PSA) × √(total PSA, Access Immunoassay Systems, Beckman Coulter ® ). Resultats Le PHI median etait significativement plus eleve chez les patients avec biopsies positives et Gleason ≥ 7. L’AUC etait respectivement de 0,79 et de 0,83. En analyse multivariee, le PHI etait predicteur independant du resultat des biopsies et son addition a un modele de base apportait un gain significatif. Au seuil de 25, 45 % des biopsies a posteriori inutiles auraient ete evitees tout en ayant ignore 4 % des cancers avec score de Gleason ≥ 7. Dans la meme population, le score PCA3 est apparu lui aussi comme un predicteur independant de la positivite des biopsies et l’association des deux marqueurs etait plus performante que chaque marqueur evalue individuellement ( Fig. 1 ). L’addition du PCA3 au PHI n’apportait par contre pas de gain supplementaire pour la prediction d’un cancer de Gleason ≥ 7 ( Fig. 2 ). Conclusion Le test serique PHI presente des performances diagnostiques elevees pour le diagnostic precoce du CaP. Son association au score urinaire PCA3 est utile pour predire la positivite des biopsies mais seul le PHI est utile pour predire un cancer de Gleason ≥ 7.

The efficacy of suppressing TSH secretion with levothyroxine (L-T(4)) in reducing solitary thyroid nodule growth is still controversial. In this prospective multicenter, randomized, double-blind, placebo-controlled trial, 123 patients with a single palpable benign nodule were included and randomly allocated to an 18-month treatment with L-T(4) or placebo. Individual dose was adjusted to allow a serum TSH level below 0.3 mIU/liter. Clinical and ultrasonographic nodule characteristics were assessed before treatment and 3, 6, 12, and 18 months thereafter. The largest mean nodule size assessed on palpation and largest volume, assessed by ultrasonography, decreased in the L-T(4) group and increased slightly in the placebo group [size, -3.5 +/- 7 mm vs. +0.5 +/- 6 mm (P = 0.006); volume, -0.36 +/- 1.71 ml vs. +0.62 +/- 3.67 ml (P = 0.01), respectively]. The proportion of clinically relevant volume reduction (or =50%) rose significantly in the L-T(4) group [26.6% vs. 16.9% (P = 0.04)]. The proportion of patients with a reduced number of infraclinical additional nodules was significantly higher in the L-T(4) group [9.4% vs. 0 (P = 0.04)]. It is concluded from this study that suppressive L-T(4) therapy is effective in reducing solitary thyroid nodule volume and improving infraclinical extranodular changes.

International audience; Objectives: Annexin A3 (ANXA3) is a potential marker for prostate cancer (PCa). We aimed to develop robust immunoassays suitable for quantifying ANXA3 in urine samples obtained following digital rectal examination (DRE) in order to facilitate the diagnostic performance evaluation of this marker. Design and methods: Anti-ANXA3 monoclonal antibodies were generated and their epitopes mapped. Two different ANXA3 assay prototypes were established on the VIDAS (R) automated immunoanalyser and analytical validation was carried out using post-DRE urine samples obtained from patients with PCa (n = 23) or benign prostate hyperplasia (n = 31). Results: The assays had the same capture antibody (TGC44) but different detection antibodies (13A12 or 5C5), recognizing novel distinct epitopes. Both had a lower limit of quantification

Objectifs Le but de notre etude etait d’evaluer la capacite du test urinaire PCA3 a predire le resultat des biopsies prostatiques dans une large cohorte monocentrique francaise. Methodes Entre 12/2007 et 05/2014, 1029 patients adresses pour biopsies prostatiques du fait d’une suspicion de cancer prostatique (PSA eleve, TR anormal et/ou antecedent familial) ont ete inclus. Le score urinaire PCA3 a ete determine a partir des mesures des nombres de copies des ARN de PCA3 et de PSA (Progensa PCA3®, DTS400 system, Hologic Gen-Probe). Resultats Le score PCA3 median etait significativement plus eleve chez les patients avec biopsies positives (47 %). L’AUC etait de 0,76, plus elevee que celle du PSA ( Fig. 1 ). Au seuil de 35, la sensibilite etait de 68 %, la specificite de 71 %, les VPP et VPN de 67 et 71 %. En analyse multivariee, le score PCA3 etait predicteur independant du resultat des biopsies et son addition a un modele de base comportant les donnees clinico-biologiques classiques apportait un gain diagnostique significatif (DCA : Fig. 2 ). Au seuil de 20, environ la moitie des biopsies, a posteriori inutiles, auraient ete evitees tout en ayant ignore 7 % des cancers avec score de Gleason ≥ 7. Le score PCA3 n’apparaissait pas correle au score de Gleason, mais etait bien correle au volume tumoral (proportion de carottes envahies). Conclusion Le test urinaire PCA3 est un test robuste avec des performances diagnostiques elevees pour le diagnostic precoce du CaP. Sa correlation avec l’agressivite du cancer s’exprime a travers le volume tumoral plus que par le score de Gleason.

Objectifs Il a ete suggere que l’index PHI pouvait etre utile pour le suivi de patients sous surveillance active pour cancer de la prostate [1] , [2] . Le but de cette etude etait de tester la relation entre l’index PHI a l’inclusion dans le protocole de surveillance active et le risque de reclassification biopsique. Methodes Notre etude, prospective, a inclus 64 patients en surveillance active sur les criteres suivants retrouves sur deux series successives de biopsies prostatiques realisees a 3 mois d’intervalle : T1c, densite de PSA Resultats Le p2PSA et le PHI medians etaient significativement plus eleves chez les 9 patients (14 %) avec cancer reclasse comme agressif a 12 mois. Seul PHI etait predictif independant de la reclassification. L’addition du PHI a un modele de base incluant l’âge et % PSA libre entrainait une augmentation de l’AUC de 0,76 a 0,84. Le suivi moyen des patients apres inclusion dans le protocole etait de 22 mois. A la date des dernieres nouvelles, 15 patients (23 %) avaient un cancer reclasse en agressif. L’âge a l’inclusion, le % PSA libre et PHI etaient predicteurs de la reclassification mais seul PHI etait independant. Un seuil de 33 pour PHI permettait le meilleur compromis entre sensibilite (67 %) et specificite (69 %). Les courbes de survie sans reclassification (modeles de Cox) etaient significativement differentes ( Fig. 1 ). Conclusion Le PHI realise au moment de l’inclusion dans un protocole de surveillance active permet de predire la reclassification des cancers indolents en cancers agressifs a 12 mois et au-dela.

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.

Correction for ‘Sulfur isotope analysis by MC-ICP-MS and application to small medical samples’ by Emmanuelle Albalat et al., J. Anal. At. Spectrom., 2016, DOI: 10.1039/c5ja00489f.

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. 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. 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). 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.

1184 > La superfamille des recepteurs couples aux proteines G (GPCR) comprend plus de 500 proteines a sept domaines transmembranaires qui, activees par la fixation d’un ligand, recrutent et controlent l’activite de proteines G heterotrimeriques intracellulaires [1]. Ces recepteurs transmettent des signaux endogenes (amines biogeniques, peptides, glycoproteines, lipides, nucleotides, ions, proteases) et exogenes (photons, particules odorantes) [1]. La rhodopsine, activee par les photons et exprimee par les cellules photosensibles de la retine, constitue, avec le recepteur β2 adrenergique, le GPCR le plus etudie [1]. Un autre signal activateur de ce type de recepteur est la thyrotropine (TSH), une hormone glycoproteique de 30 kDa, qui controle la production des hormones thyroidiennes par la glande thyroide. La maniere dont des agonistes de taille et de nature aussi diverses sont capables d’activer les GPCR par un mecanisme que l’on peut supposer commun, etant donne leur tres grande identite de structure, reste une question centrale non resolue. NOUVELLE

La faible specificite de la strategie diagnostique du cancer de la prostate (toucher rectal et dosage serique de l’antigene prostatique PSA) conduit a la realisation de nombreuses biopsies inutiles et au diagnostic de cancers indolents, sans potentialite evolutive. Un test urinaire (Progensa PCA3 ®, Gen-Probe) mesurant l’expression du gene PCA3, specifique des cellules cancereuses prostatiques, a recemment ete propose pour orienter les indications de re-biopsies. Le but de notre etude, prospective, etait d’evaluer l’interet diagnostique du score PCA3 dans le cancer de la prostate. Dans les urines de 245 patients adresses pour biopsie prostatique, l’expression du gene PCA3 a ete determinee par une technique d’amplification et de detection de l’ARN et rapportee a celle du PSA. Les patients avec echantillon informatif (98 %) ont ete classes selon la presence (n = 126) ou l’absence (n = 114) de cancer sur les biopsies. Le score PCA3 median etait plus eleve dans le groupe avec biopsies positives (p < 0,0001). L’aire sous la courbe ROC pour le PCA3 etait de 0,70 versus 0,53 pour le PSA total et 0,65 pour le rapport PSA libre/total. Au meilleur seuil de 38, le test PCA3 avait une sensibilite de 59 %, une specificite de 72 % (respectivement : 66 %, 32 % pour le PSA total au seuil de 4 ng/mL et 81 %, 28 % pour le rapport PSA libre/total au seuil de 25 %). Ces performances etaient maintenues chez les patients ayant un PSA dans la zone grise (4-10 ng/mL) ou ayant des antecedents de biopsies prostatiques. Notre etude confirme l’interet du test urinaire PCA3 dans l’aide a la decision de biopsies prostatiques.