Exosomes and prostate cancer management.

Exosomes (and other extracellular vesicles) are now part of the cancer research landscape, involved both as players in pathophysiological mechanisms, as biomarkers of the cancer process and as therapeutic tools. One step they have yet to take is to move into routine clinical practice and management of prostate cancer is an example of this necessary maturation. More than for many other cancers and because a possible alternative is active surveillance (neither removal nor destruction), the diagnosis of prostate cancer does not only involve the detection of cancerous cells but also the determination of its true aggressiveness. By measuring TRMPRSS2:ERG fusion and PCA3 transcripts in urine exosomes, the EPI assay seems able to help prostate biopsy decision. Results from clinical studies showed that it can reduce the proportion of unnecessary biopsies while missing only a minimal proportion of clinically significant cancers. In metastatic prostate cancer, after failure of a first step androgen deprivation therapy, when a choice has to be made between a second-generation androgen receptor (AR) signaling inhibitor and taxane-based chemotherapy, detection of the AR splicing variant AR-V7 in circulating tumor cells (CTCs) has appeared promising. Whether exosomes could be a better material (simpler to isolate from the bloodstream than CTCs?) to detect AR-V7 has been suggested by some studies and remains to be confirmed. At last, a couple of exploratory studies either targeted or used exosomes to treat prostate cancer, by respectively inhibiting their secretion (to prevent exosome-mediated transfer of biologically active oncogenic actors), or loading them with immunogenic cancer-specific proteins (to generate anticancer vaccine) or with pharmacologic agents. Overall efforts are however still needed to confirm these results and generalize exosome-based diagnostic, prognostic or therapeutic strategies in prostate cancer management.

Urinary PCA3 to predict prostate cancer in a cohort of 1015 patients.

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 in 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 cut-off 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 clinico-biological parameters resulted in a significant increase in predictive accuracy. At the cut-off of 20, about 1/2 of the eventual useless biopsies would have been avoided while ignoring 7 % of cancers with Gleason score ≥ 7. PCA3 score did not correlate to Gleason score but correlated to tumor volume (proportion of invaded cores). CONCLUSION: Urinary PCA3 is a useful test with high diagnostic performance for early prostate cancer diagnosis. Its correlation with cancer aggressiveness seems rather represented by a link to prostate volume than Gleason score.

Additional value of PCA3 density to predict initial prostate biopsy outcome.

PURPOSE: Similar to prostate-specific antigen (PSA) density, PCA3 density (PCA3D: ratio of urinary PCA3 score/prostate volume) can be calculated, but whether it can be an aid to decide biopsy in patients at risk of prostate cancer (PCa) is uncertain. The objective was to demonstrate that PCA3D provides better specificity than PCA3 in predicting initial prostate biopsy outcome. METHODS: Serum and urine samples were obtained from 595 consecutive patients scheduled for initial prostate biopsy. The urinary PCA3 test was performed before biopsy. Additional measures were prostate volume, PSA density (PSAD) and PCA3D. Multivariate logistic regression models including baseline characteristics and the markers were evaluated. The presumed net benefit was assessed through decision curve analyses. RESULTS: PSAD and PCA3D performed better than PSA and PCA3 score, respectively. PCA3D provided the best specificity (76 %). The best calculated cutoff for PCA3D was 1. The risk of positive biopsy significantly increased to 70 % if PCA3D ≥ 1 versus 29 % if PCA3D was <1. Using a cutoff at 0.5 for PCA3D, biopsies could have been avoided in up to 52 % of the patients without PCa while missing 15 % of any PCa and 10 % of PCa with Gleason score ≥7. Decision curve analyses showed that PSAD was the best predictor of Gleason score at biopsy while PCA3D best predicted the proportion of invaded cores. CONCLUSIONS: PCA3D showed a significant increase in specificity when compared with PSA, PSAD and PCA3. PCA3D can be considered an easy-to-use mini-nomogram with a 70 % risk of positive initial biopsy when PCA3D > 1, i.e., PCA3 score > prostate volume.

[Does PCA3 score and prostatic MRI help selection of patients scheduled for initial prostatic biopsy?]. / Le score PCA3 et l'IRM prostatique permettent-ils de sélectionner les patients candidats a une première série de biopsies prostatiques ?

INTRODUCTION: Determinate if the adjunction of PCA3 score and/or prostatic MRI can improve the selection of the patients who have an indication of first prostate biopsy. PATIENTS AND METHODS: Multiparametric prostatic MRI and PCA3 score were made before biopsy to men scheduled for initial prostate biopsy for abnormal digital rectal examination and/or PSA superior to 4 ng/mL. T2-weighted imaging, diffusion-weighted imaging and dynamic contrast-enhanced imaging looked for suspect target classified on a scale of four. It was a prospective, single centre study. The diagnostic accuracy of PCA3 score and MRI was to evaluate in comparison with biopsy results. RESULTS: Sixty-eight patients were included, median PSA was 5.2 ng/mL (3.2-28). Negative predictive value (NPV) of MRI score 0, 1 and 2 were respectively 80%, 43% and 69%. Positive predictive value (PPV) of MRI score 3 and 4 were 50% and 81%. The PCA3 cutoff with best accuracy was 21 (Se: 0.91; Sp: 0.50). Only one patient with positive biopsy (0.5mm of Gleason score 3+3) had negative MRI and PCA3 inferior to 21. CONCLUSION: MRI and PCA3 score in association allowed, in this study, to consider reduction of unnecessary initial biopsy without ignoring potential aggressive tumor.

[Value of urinary PCA3 test for prostate cancer diagnosis]. / Place du test urinaire PCA3 pour le diagnostic du cancer de la prostate.

PCA3 gene has been discovered in 1999 because of its differential expression between prostate cancer and nonneoplastic tissue. Several studies evaluated its value for prostate cancer diagnosis. These papers are consistent with significant statistical accuracy of measure of the urinary number of PCA3 copies (PCA3 test). While sensitivity is slightly weaker than that of seric PSA, specificity as well as positive and negative predictive values are quite better. PCA3 test seems therefore to be a good indicator of prostate biopsy results. As a commercial kit is available, large studies will be conducted to confirm these results, precise when to perform the test and evaluate the benefit/cost ratio. One of the aims is better selection of those patients who will really benefit from prostate biopsies.

[Are preoperative examinations useful in the management of patients with renal hyperparathyroidism?]. / L'imagerie préopératoire des hyperparathyroïdies des insuffisants rénaux a-t-elle un intérêt en pratique clinique?

AIM OF THE STUDY: To evaluate the efficiency of preoperative parathyroid ultrasonography and scintigraphy in the management of renal hyperparathyroidism. PATIENTS AND METHODS: The charts of the last consecutive 200 patients who underwent surgery for renal hyperparathyroidism from 1998 to 2003 were retrospectively reviewed to collect data concerning parathyroid gland function, results of preoperative ultrasonography and scintigraphy, as well as modalities and results of surgical exploration. RESULTS: Ultrasonography and scintigraphy sensibilities were 36.4% and 49.3%, respectively. Efficiency of both examinations was improved when they were combined (sensibility of 64.7%) and in those patients managed for recurrent hyperparathyroidism. Were more often detected by preoperative examinations glands with high weight and/or greatest diameter, orthotopic and inferior glands as well as glands exhibiting nodular hyperplasia content upon pathological examination. CONCLUSION: Parathyroid ultrasonography and scintigraphy are of poor interest in the management of renal hyperparathyroidism. In a preoperative setting, they should be performed only in patients with recurrent disease.

Pseudohypoparathyroidism Ia and hypercalcitoninemia.

Pseudohypoparathyroidism Ia (PHP Ia) is characterized by resistance to PTH and many other stimuli because of deficiency of stimulatory G protein alpha-subunit. To determine the incidence, natural history, and mechanism of C cell dysfunction in PHP, calcitonin assays were performed in six patients with PHP Ia and four with pseudopseudohypoparathyroidism from three unrelated families. Controls included healthy subjects and patients with PHP Ib or hypoparathyroidism. The mean basal level of calcitonin was higher in PHP Ia patients than in controls (95.3 +/- 112.7 vs. 3.7 +/- 2.4 pg/mL; P = 0.005; n < 10). In PHP Ia patients, calcitonin levels rose over the normal range (30 pg/mL) after pentagastrin infusion in five patients and remained normal in one. Familial medullary thyroid carcinoma was clinically, biologically, and ultrasonographically ruled out over a mean follow-up exceeding 3 yr. Genomic screening for RET protooncogene mutations failed to reveal any anomaly. The calcitonin infusion test, which induced a significant increase in plasma cAMP in controls 30 and 60 min after infusion, failed to produce this response in PHP Ia patients, suggesting that the action of calcitonin was specifically impaired. PHP Ia may therefore be an independent etiology of hypercalcitoninemia and hyperresponsiveness to pentagastrin infusion.

[Identification of eight new mutations in the c-erbAB gene of patients with resistance to thyroid hormone]. / Identification de huit nouvelles mutations dans le gène c-erbAB chez des patients atteints de résistance aux hormones thyroïdiennes.

Resistance to thyroid hormone (RTH) is a rare genetic disorder, usually associated with different mutations in the c-erbAB gene that encodes the beta type receptor of thyroid hormone (TRB). It is characterized by elevated serum thyroid hormone and inappropriate TSH secretion. The numerous mutations so far detected are clustered in three hot spot areas in the ligand binding domain of TRB. In the context of a national survey we have detected 16 different mutations in the c-erbAB gene, in 22 families presenting with RTH. Eight of these mutations had not been described previously. Two are located in an area not known to harbor naturally occurring mutations. This observation could lead to define a fourth cluster of mutations in the c-erbAB gene.

[Apoptosis and the thyroid: the Fas pathway]. / Apoptose et thyroïde: le face à Fas.

THE APOPTOTIC FAS/FAS-L PATHWAY: Represents a major apoptotic pathway and involves the specific interaction between a membrane receptor, Fas, harbored by the target cell and a membrane ligand, Fas-L, harbored by the cytotoxic cell. FAS AND NORMAL THYROID GLAND: Normal thyrocytes express Fas receptor but not its ligand. The control of thyroid gland volume results from an equilibrium between the trophic action of TSH and thyrocyte apoptosis, which is limited to some extent by resistance to Fas activation by producing an inhibitor of the apoptotic signal transduction. FAS AND HASHIMOTO'S THYROIDITIS: Aberrant expression of Fas-L by thyrocytes induces their fratricide apoptosis. Thyroid-infiltrating lymphocytes are resistant to apoptosis by overexpressing the antiapoptotic protein Bcl2. FAS AND GRAVES' DISEASE: Autoantibody-dependant stimulation of the thyrotropin receptor favors goiter formation by reducing thyrocyte apoptosis. It induces repression of Fas expression and production of a soluble Fas, whose serum levels are correlated with clinical course. FAS AND THYROID CANCER: Tumoral cells are resistant to apoptosis by inhibiting the apoptotic signal transduction and exert Fas counter-attack by inducing apoptosis of antitumoral lymphocytes.

[Pendred's syndrome. Current features]. / Le syndrome de Pendred. Aspects actuels.

Introduction Pendred's syndrome is a recessive autosomal disease, traditionally defined as the association of deaf-mutism, goiter and dysfunctional iodide organization revealed by the perchlorate discharge test. It represents 4 to 10% of the causes of congenital hypoacusis. Although described more than a 100 years ago, the association of thyroid and cochleo-vestibular damage remained unclear for many years. Genetic abnormalities Progress in molecular biology has revealed that the disease is related to alterations in the PDS gene situated on chromosome 7. The PDS gene is responsible for the production of pendrine, protein involved in anion (l-, Cl-) transportation, notably in the apical pole of the thyreocyte and the cochlear duct, where the endolympha is produced. Practical implications The truncation of pendrine related to the genetic alterations be responsible for the morpho-functional alterations in the cochlear apparatus and the thyroid. In this perspective, Pendred's syndrome would appear as a genetic disorder in anion transportation.

[Physiology and pathophysiology of thyroid hormone receptors: the contributions of murine models]. / Physiologie et physiopathologie des récepteurs thyroïdiens: l'apport des modèles murins.

Thyroid hormones are involved in vertebrate development and metabolic homeostasis. Their actions are mediated through several nuclear receptors encoded by TRalpha and TRB genes. The interspecies conservation of 3 functional receptors (TRalpha1, TRB1 and TRB2) and their partially distinct tissue distribution suggest that they serve non-redundant physiological functions. The exclusive TRB gene involvement in the resistance to thyroid hormone (RTH) reinforces the hypothesis of a functional specificity. Recent mouse knock-out and transgenesis methods allow invalidation or overexpression of a gene of interest, respectively. They therefore provide powerful means to determine the specific function of a gene and have been applied to the thyroid hormone receptor genes. Mice TRB(-/-) represent a model of the recessive form of RTH. They have been shown to develop goiter and high thyroid hormone and TSH (Thyroid Stimulating Hormone) levels, suggesting an unique role for TRB in the negative regulation of TSH pituitary secretion. The associated disorder in audition maturation also showed that TRB plays an essential role in the development of audition. By contrast, mice TRalpha(-/-) exhibited thyroid gland atrophy along with decreased thyroid hormones and TSH levels. Clinical phenotype included growth interruption and retardation of both intestine and bone maturation, but no hearing loss. Mice TRalphaB(-/-) combined the disorders, including delayed neonatal development despite hyperactive hypothalamus-pituitary axis. Finally, transgenic overexpression of a mutant TRB gene reproduced the dominant form of RTH and confirmed the major role of dominant negative activity in the occurrence of some phenotypic key-features such as high circulating hormone levels despite high TSH levels, hyperactivity and lack of severe hearing loss. From these studies, it is suggested that TRalpha and TRB receptors are to some extent able to cooperate or substitute for each other. However some organs constitute TR-specific T3 target-tissues such as inner ear, pituitary, heart, liver, bone and small intestine.

Resistance to thyroid hormone in a family with no TRbeta gene anomaly: pathogenic hypotheses.

UNLABELLED: Syndromes of resistance to thyroid hormone (RTH) are almost always linked to a defective triiodothyronine-receptor B gene (TRB). Only six families with RTH exhibiting a normal TRB gene have been reported so far. We report another and discuss possible mechanisms. PATIENTS AND METHODS: We studied a kindred expressing a typical RTH phenotype. DNA was amplified and the TRB gene was sequenced. Linkage analysis assessed linkage between the TRB gene and RTH phenotype. RESULTS: Direct sequencing of the TRB gene failed to identify any anomaly in the coding exons. Linkage analysis demonstrated that the RTH phenotype was not linked to the TRB gene in this family. CONCLUSION: TRB1 and TRB2 genes were not defective in this family. Multiple mechanisms might account for this situation at the pre-receptor, receptor and post-receptor levels. The most likely hypothesis is the involvement of an abnormal nuclear cofactor serving a specific function in the regulation of thyroid hormone action.

The Ets family member Erg gene is expressed in mesodermal tissues and neural crests at fundamental steps during mouse embryogenesis.

The Erg gene belongs to the Ets family encoding a class of transcription factors. To gain new insight on the in vivo functional specificity of the Erg gene within the wide Ets family, we used in situ hybridization to determine its expression pattern during murine embryogenesis. We found that the Erg gene expression predominates in mesodermal tissues, including the endothelial, precartilaginous and urogenital areas. A specific Erg gene expression was also identified in migrating neural crest cells. A comparison with Fli-1, the most closely Erg-related gene, revealed that both gene expressions partially overlap, suggesting that they may contribute to related functions in these tissues. Like other Ets family genes, Erg seems involved in several fundamental developmental steps in murine embryogenesis, including epithelio-mesenchymal transition, cell migration, settlement and differentiation.

Liver transplantation eliminates insulin needs of a diabetic patient.

Organ transplantation and subsequent therapeutic agents may induce or worsen preexisting diabetes mellitus. We report the case of a diabetic patient whose insulin needs disappeared after liver transplantation. Non insulin-dependent diabetes mellitus was diagnosed when she was 47, and was treated by hypoglycemic drugs and then insulin. Chronic post-hepatitis C cirrhosis was diagnosed at the age of 55 and required liver transplantation 2 years later. During the postoperative course, the insulin doses required to maintain normal glucose levels progressively decreased, and insulin became completely unnecessary by the 29(th) postoperative day. After insulin was stopped, glucose levels remained within normal ranges for the 5-year-long follow-up, despite the worsening of a preexisting diabetic nephropathy and the occurrence of a diabetic retinopathy. This case highlights the fact that liver transplantation may eliminate insulin needs in a diabetic patient but also shows that degenerative complications may occur despite apparent remission of diabetes.