O. Chinot

Divergent effect of TGFβ1 on growth and proteolytic modulation of human prostatic-cancer cell lines

Plasminogen activators (PAs) play a key role in malignant transformation. PA secretion by tumoral cells is strongly correlated with their aggressive phenotype. Regulation of invasive potential by growth factors has been also demonstrated. This study was designed to investigate the effects of 5α‐dihydrotestosterone (DHT), epidermal growth factor (EGF), transforming growth factor beta1 (TGFβ1), retinoic acid and basic fibroblastic growth factor (bFGF) on cell growth and PA expression and secretion in DU145 and PC3 cells, 2 human prostatic‐cancer cell lines. The proliferation of 2 cell lines was significantly increased only by EGF (about 30%), but decreased by TGFβ1 (40% inhibition). However, EGF‐treated cells showed significant enhancement (about 400%) of u‐PA secretion. A similar effect was observed when cells were cultured with DHT (200%) and with TGFβ1 (300%). Nevertheless, u‐PA mRNA level in EGF‐, TGFβ1‐ or DHT‐treated cells was amplified only between 110 and 180% of control, suggesting that growth factors differently controlled the steps of PA expression. Furthermore, our results clearly showed the divergent effect of TGFβ1, i.e., an inhibition of prostatic‐cell‐line growth accompanied by an increase in proteolytic activity.

Traitement des méningiomes par hydroxyurée

Resume Objectif La prise en charge des meningiomes inoperables n’est pas completement codifiee. Nous avons instaure a partir de mai 1997 un protocole d’etude clinique de phase II (HU-MEN 97) afin de tester l’efficacite d’une chimiotherapie par l’hydroxyuree Hydrea ® dans la prise en charge therapeutique de ces meningiomes. Materiels et methodes A partir de mai 1997 ont ete inclus 43 patients (28 femmes pour 15 hommes) avec un recul minimum de 18 mois. La duree moyenne du traitement etait de 23,7 mois. La dose orale quotidienne d’hydroxyuree etait de 20 mg/kg, adaptee en fonction de la tolerance clinique et hematologique. La surveillance des tumeurs a ete realisee par une imagerie par resonance magnetique dans 95 % des cas ou par tomodensitometrie. La mesure des deux plus grands diametres de la tumeur etait le critere de surveillance. Resultats Le caractere evolutif des meningiomes avant l’instauration du traitement a pu etre retrouve chez 67,5 % des patients sur le plan clinique et chez 46 % des patients sur le plan radiologique. Sous hydroxyuree, 3 patients ont eu une amelioration radiologique ou clinique, 6 patients ont ete stabilises. Par contre, 26/43 (60,5 %) patients ont vu leur meningiome progresser sous hydroxyuree, et 65 % des meningiomes evolutifs avant traitement ont poursuivi leur evolution malgre le traitement par l’hydroxyuree. La toxicite du produit etait peu importante avec 12 cas (28 %) de toxicite hematologique et 23,5 % d’intolerance clinique (asthenie). Trois patients ont du cesser leur traitement mais aucun cas de mortalite lie au traitement n’a ete retrouve. Conclusion L’analyse de notre serie n’a pas permis de mettre en evidence un effet anti-tumoral majeur de l’hydroxyuree sur les meningiomes. Cette therapeutique ne doit pas faire differer un traitement chirurgical ou une radiotherapie.

Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network

BACKGROUND Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort. METHODS We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014. RESULTS Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs <1 y), and management at relapse/progression (palliative care vs salvage therapy). Patients who relapsed early after first-line therapy (ie, PFS < 1 y) had a poor outcome, comparable to that of refractory patients. Conversely, patients experiencing late relapses (PFS ≥ 1 y) and/or undergoing consolidation with ICT + AHSCT experienced prolonged survival. CONCLUSIONS About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.

Identification of secondary structure in the 5′-untranslated region of the human adrenomedullin mRNA with implications for the regulation of mRNA translation

Adrenomedullin (AM) is a multifunctional regulatory peptide with important angiogenic and mitogenic properties. Here we identify a region of stable secondary structure in the 5′-untranslated region (5′ UTR) of human AM mRNA. Reverse transcriptase–polymerase chain reaction of the 5′ UTR consistently resulted, in addition to the product with the expected size of 155 base pair (bp), in a second product with an ∼65-bp deletion from the central region of the 5′ UTR, suggesting the presence of a secondary structure. The presence of a stem–loop structure was confirmed by probing the 5′ UTR with RNases with selectivity for single- or double-stranded RNA. We investigated the role of this stem–loop structure in expression of luciferase reporter gene in cultured cell lines. Reporter assays using a chimeric mRNA that combined luciferase and the 5′ UTR of AM mRNA demonstrated a dramatic decrease of the reporter activity owing to a decreased translation, whereas the deletion of the stem–loop structure localized between nt +31 and +95 from the cap site led to the recovery of activity. Gel migration shift assays using cytosolic extracts from mammalian cell lines demonstrate a specific binding of a cytosolic protein to riboprobes containing the 5′ UTR of AM but not to riboprobes either corresponding to other areas of the message or containing the 5′ UTR but lacking the region of secondary structure. Although we conclude that the 5′ UTR of the human AM mRNA can modulate the translation of AM mRNA in vivo, and that the predicted stem–loop structure is necessary for this inhibition, the functional consequences of the cis element-binding activity remain to be determined.