Search

Introduction Differents variants de fusion ont ete decrits dans les rearrangements du gene ALK au sein des cancers pulmonaires non a petites cellules (CPNPC) et influeraient sur la sensibilite cellulaire au traitement par crizotinib. Le but de cette etude etait de tester et d’ameliorer l’efficacite du sequencage massif parallele (NGS) a partir d’ARN base sur des PCR multiplexes (RNA-seq) dans la detection du rearrangement et des variants de fusion ALK par rapport a l’immunohistochimie (IHC) et l’hybridation in situ en fluorescence (FISH) dans des echantillons de CPNPC. Le second objectif etait de mettre en evidence un lien entre la nature du variant de fusion ALK et la reponse au crizotinib. Methodes Cinquante-trois echantillons fixes au formol et inclus en paraffine ALK-positifs en FISH et/ou en IHC et 23 echantillons ALK-negatifs ont ete testes par RNA-seq. Dans un 2e temps, un protocole associant le RNA-seq a une PCR ancree multiplexe a ete evalue sur 10 echantillons en echec apres RNA-seq. Resultats Un resultat concluant par RNA-seq a ete obtenu dans 75 % des echantillons. Parmi les 33 cas ALK-positifs en RNA-seq, un transcrit de fusion a ete identifie parmi 27 echantillons. Comparees a l’association IHC/FISH, la sensibilite et la specificite du RNA-seq etaient respectivement de 80 et 100 %. Dans les cas ALK-positifs en IHC et en FISH, le RNA-seq a detecte un rearrangement ALK dans 100 % des cas analysables. Le RNA-seq a rendu un resultat concluant dans tous les cas equivoques et/ou borderlines en FISH et IHC. Concernant les cas discordants en IHC et FISH, le RNA-seq a ete mis en echec pour 5 des 7 echantillons. Sur les 10 echantillons consideres en echec apres RNA-seq testes, l’ajout d’une PCR ancree multiplexe dans le protocole de RNA-seq a permis de detecter 3 transcrits de fusion dont un variant CLIP1(12)-ALK(20) jamais decrit auparavant. Au sein des patients traites par crizotinib, la survie sans progression mediane etait plus allongee pour ceux presentant un variant 1 ou 2 d’EML4-ALK par rapport a ceux arborant un variant 3a/b (314 contre 192 jours, respectivement ; p = 0,1743). Conclusion Le RNA-seq est efficace pour le diagnostic des rearrangements ALK dans les CPNPC et pourrait etre integre a l’algorithme diagnostique de cette anomalie. De plus, il autorise l’identification des transcrits de fusion ALK qui pourraient constituer un marqueur pronostique chez ces patients.

Background Occurrence of pulmonary arterial hypertension (PAH) in idiopathic inflammatory myopathies (IIM) without extensive interstitial lung disease (ILD) has been rarely described. Objectives This study aimed to report all cases with association of PAH and IIM in the French Pulmonary Hypertension (PH) Registry, to identify IIM features associated with PAH, and to describe treatment modalities of these patients. Methods All cases of IIM-PAH were retrieved from the French PH Registry, which gathers PAH patients prospectively enrolled by 21 referral centers across France. Patients were excluded if they had an extensive ILD or overlap syndrome. Characteristics of IIM-PAH patients were compared to a control group of IIM patients without PH. Results Among the 5223 PAH patients in the Registry, 34 had a diagnosis of IIM. Among them, 3 IIM-PAH patients had no sign of extensive ILD or overlap syndrome, and were included in this study. In these patients, dermatomyositis (DM) was the only identified IIM. Two of them had a myopathic DM, confirmed by electromyography and biopsy. The last patient had an amyopathic DM, associated with anti-Ku antibodies. Pre-capillary PH was hemodynamically proven in all patients. PAH always developed after IIM onset, was severe in all cases, and led to a marked functional impairment. By pooling our cases with 6 previously reported patients, and comparing them to a control cohort of 35 IIM patients without PH, we identify several IIM characteristics possibly associated with PAH occurrence, including DM subtype (78% vs. 46%, p =0.02), skin involvement ( p =0.04), anti-SSA antibodies ( p =0.05) and peripheral microangiopathy ( p =0.06). Overall, IIM-PAH patients were managed by corticosteroids and/or immunosuppressants, either alone or combined with PAH therapy. Patients that did not receive PAH therapy did not seem to respond to IIM treatment alone. Conclusions Our study reports for the first time the rare but possible association of PAH and IIM in a large prospective PH Registry. In that setting, PAH seems associated with DM, skin involvement, peripheral microangiopathy and anti-SSA positivity. The best therapeutic strategy for IIM-PAH remains to be defined. Disclosure of Interest None declared