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Purpose: There is little data on the safety and efficacy of endovascular treatment (EVT) in comparison with intravenous thrombolysis (IVT) in acute ischemic stroke due to isolated posterior cerebral artery occlusion (IPCAO). We aimed to investigate the functional and safety outcomes of stroke patients with acute IPCAO treated with EVT (with or without prior bridging IVT) compared to IVT alone. Methods: We did a multicenter retrospective analysis of data from the Swiss Stroke Registry. The primary endpoint was overall functional outcome at 3 months in patients undergoing EVT alone or as part of bridging, compared with IVT alone (shift analysis). Safety endpoints were mortality and symptomatic intracranial hemorrhage. EVT and IVT patients were matched 1:1 using propensity scores. Differences in outcomes were examined using ordinal and logistic regression models. Findings: Out of 17,968 patients, 268 met the inclusion criteria and 136 were matched by propensity scores. The overall functional outcome at 3 months was comparable between the two groups (EVT vs IVT as reference category: OR = 1.42 for higher mRS, 95% CI = 0.78–2.57, p = 0.254). The proportion of patients independent at 3 months was 63.2% in EVT and 72.1% in IVT (OR = 0.67, 95% CI = 0.32–1.37, p = 0.272). Symptomatic intracranial hemorrhages were overall rare and present only in the IVT group (IVT = 5.9% vs EVT = 0%). Mortality at 3 months was also similar between the two groups (IVT = 0% vs EVT = 1.5%). Conclusion: In this multicenter nested analysis, EVT and IVT in patients with acute ischemic stroke due to IPCAO were associated with similar overall good functional outcome and safety. Randomized studies are warranted.

Summary Eukaryotic genomes harbor invading transposable elements that are silenced by PIWI-interacting RNAs (piRNAs) to maintain genome integrity in animal germ cells. However, whether piRNAs also regulate endogenous gene expression programs remains unclear. Here, we show that C. elegans piRNAs trigger the transcriptional silencing of hundreds of spermatogenic genes during spermatogenesis, promoting sperm differentiation and function. This silencing signal requires piRNA-dependent small RNA biogenesis and loading into downstream nuclear effectors, which correlates with the dynamic reorganization of two distinct perinuclear biomolecular condensates present in germ cells. In addition, the silencing capacity of piRNAs is temporally counteracted by the Argonaute CSR-1, which targets and licenses spermatogenic gene transcription. The spatial and temporal overlap between these opposing small RNA pathways contributes to setting up the timing of the spermatogenic differentiation program. Thus, our work identifies a prominent role for piRNAs as direct regulators of endogenous transcriptional programs during germline development and gamete differentiation., Graphical abstract, Highlights • piRNAs trigger transcriptional silencing of spermatogenic genes through HRDE-1 • Nuclear silencing correlates with a reorganization of distinct nuage condensates • Nuclear silencing is required for sperm differentiation and function • The Argonaute CSR-1 antagonize piRNA targeting to enable spermatogenic expression, PIWI-interacting RNAs (piRNAs) are known to repress foreign transposable elements in animal germlines. Cornes et al. report that piRNAs trigger the transcriptional silencing of endogenous spermatogenic gene expression program during animal development to promote sperm differentiation and functions.

Cophylogeny is the congruence of phylogenetic relationships between two different groups of organisms due to their long‐term interaction. We investigated the use of tree shape distance measures to quantify the degree of cophylogeny. We implemented a reverse‐time simulation model of pathogen phylogenies within a fixed host tree, given cospeciation probability, host switching, and pathogen speciation rates. We used this model to evaluate 18 distance measures between host and pathogen trees including two kernel distances that we developed for labeled and unlabeled trees, which use branch lengths and accommodate different size trees. Finally, we used these measures to revisit published cophylogenetic studies, where authors described the observed associations as representing a high or low degree of cophylogeny. Our simulations demonstrated that some measures are more informative than others with respect to specific coevolution parameters especially when these did not assume extreme values. For real datasets, trees’ associations projection revealed clustering of high concordance studies suggesting that investigators are describing it in a consistent way. Our results support the hypothesis that measures can be useful for quantifying cophylogeny. This motivates their usage in the field of coevolution and supports the development of simulation‐based methods, i.e., approximate Bayesian computation, to estimate the underlying coevolutionary parameters.

BACKGROUND Natural killer (NK) cell impairment is a feature of pulmonary arterial hypertension (PAH) and contributes to disease development in mouse models of NK cell deficiency (Ormiston et al, Circulation, 2012; Ratsep et al, AJP Lung, 2018). PAH is also strongly associated with mutations in BMPR2, the gene encoding the type-II bone morphogenetic protein receptor. Genetic and experimental evidence point to a loss of BMPR2 in the pulmonary endothelium as a critical contributor to disease development. However, the impact of endothelial BMPR2 loss on NK cell impairment in PAH remains unknown. METHODS AND RESULTS SiRNA-mediated silencing of BMPR2 in human pulmonary artery endothelial cells (HPAEC) significantly reduced the surface presentation and secretion of the α-type receptor for interleukin-15 (IL-15Rα), a major regulator of NK cell survival, proliferation and activity. Assessment of IL-15Rα transcriptional variants by RNA-Seq and glycosylation by immunoblotting demonstrated that this reduction was not due to changes in receptor transcription or processing. Treatment of HPAECs with the matrix metalloproteinase inhibitor Batimastat also ruled out a role for altered IL-15Rα cleavage with BMPR2 silencing. Instead, confocal microscopy identified impaired trafficking of IL-15Rα through the trans-Golgi-network (TGN) in BMPR2-silenced cells. To evaluate the effects of impaired IL-15 mediated signaling and NK cell loss on PAH development, NK cell-deficient Il15-/- rats and immune-competent Il15+/+ littermates were exposed to either the monocrotaline (MCT) or SUGEN/hypoxia models of experimental pulmonary hypertension. While both male and female Il15-/- rats developed more severe disease than their wildtype counterparts in the SUGEN/Hypoxia model, only male Il15-/- rats demonstrated this enhanced severity in the MCT model, which is the only one of the two models to reproduce the sex-based difference in disease severity that is observed in human PAH patients. Assessment of genes associated with sex hormone signaling and metabolism identified a potential increase in pulmonary Cyp1b1 expression (n=5-7, p=0.08) in male MCT-challenged Il15-/- rats relative to Il15+/+ controls. CONCLUSION We have identified the loss of IL-15 signaling as a novel BMPR2-dependent contributor to NK cell impairment and pulmonary arterial hypertension pathogenesis. Ongoing work includes assessing the contribution of sex hormones to immune-mediated disease processes in PAH.

The C. elegans genome encodes nineteen functional Argonaute proteins that utilize 22G-RNAs, 26G-RNAs, miRNAs, or piRNAs to regulate their target transcripts. Only one Argonaute is essential under normal laboratory conditions: CSR-1. While CSR-1 has been studied widely, nearly all studies have overlooked the fact that the csr-1 locus encodes two isoforms. These isoforms differ by an additional 163 amino acids present in the N-terminus of CSR-1a. Using CRISPR-Cas9 genome editing to introduce GFP::3xFLAG into the long (CSR-1a) and short (CSR-1b) isoforms, we found that CSR-1a is expressed during spermatogenesis and in several somatic tissues, including the intestine. CSR-1b is expressed constitutively in the germline. small RNA sequencing of CSR-1 complexes shows that they interact with partly overlapping sets of 22G-RNAs. Phenotypic analyses reveal that the essential functions of csr-1 described in the literature coincide with CSR-1b, while CSR-1a plays tissue specific functions. During spermatogenesis, CSR-1a integrates into an sRNA regulatory network including ALG-3, ALG-4, and WAGO-10 that is necessary for fertility at 25°C. In the intestine, CSR-1a silences immunity and pathogen-responsive genes, and its loss results in improved survival from the pathogen Pseudomonas aeruginosa. Our findings functionally distinguish the CSR-1 isoforms and highlight the importance of studying each AGO isoform independently.

Introduction L’allongement du délai de prise en charge initial des cancers broncho-pulmonaires (CBP) aboutit à une progression de la maladie. Une consultation d’urgence oncologique dédiée à la prise en charge de patients ayant une suspicion de CBP a été mise en place au CHRU de Nancy le 1er novembre 2019. La pandémie de COVID-19 a entrainé une sanctuarisation du système de soins, complexifiant la prise en charge des CBP. Peu de données sont disponibles concernant le rôle de programme d’accès rapide au cours de cette pandémie. L’objectif principal est d’évaluer les délais de prise en charge (diagnostique et thérapeutique) après la mise en place d’une consultation d’urgence oncologique thoracique (UOT) et de l’impact de la pandémie de COVID-19 sur ces délais. Méthodes Étude rétrospective au CHRU de Nancy. La population est constituée des patients adressés en UOT entre novembre 2019 et février 2021. Les délais analysés sont le délai diagnostique et le délai thérapeutique. Les patients d’UOT sont classés en 2 groupes. Population « UOT pré-COVID-19 » dont le diagnostic est obtenu avant le 1er mars 2020, population UOT « COVID-19 » dont le diagnostic est obtenu après le 1er mars. Les délais des populations UOT sont comparés aux délais de la population témoin avant UOT, pris en charge au CHRU de Nancy de novembre 2014 à octobre 2015. Résultats Cent six patients ayant bénéficié d’une UOT ont été inclus: 15 patients dans UOT pré-COVID-19 et 91 patients dans UOT COVID-19. Deux cent dix sept patients constituaient la population témoin. Le délai diagnostique moyen était significativement plus court dans le groupe UOT pré-COVID-19, 48,8 jours contre 89,2 jours dans la population témoin, p

Il trauma toracico rimane la seconda causa di mortalita traumatica dopo il trauma cranico. Tre tipi di meccanismi possono essere descritti per i traumi chiusi del torace: le lesioni da compressione/schiacciamento, le lesioni da decelerazione e le lesioni da scoppio. I fattori di gravita da ricercare sono un’eta superiore ai 65 anni, una patologia cronica polmonare o cardiovascolare, un disturbo della coagulazione congenito o acquisito e un meccanismo a cinetica elevata. Questi fattori aumentano il rischio di decesso legato al trauma di un fattore 2-3. Una volta completato il bilancio lesionale e stabilizzato il paziente, le tecniche di osteosintesi toracica si applicano tanto ai traumi acuti che a quelli antichi (pseudoartrosi). I molteplici scopi dell’osteosintesi toracica comprendono il controllo del dolore, il ripristino dell’espansione toracica e della meccanica respiratoria normale e l’emostasi del sanguinamento dalla frattura.

Resume Introduction En chirurgie thoracique, l’ extracorporeal life support (ECLS) represente un arsenal therapeutique indique en cas de defaillance de l’appareil respiratoire ou comme support mecanique pour un acte therapeutique. Les objectifs de cette revue generale sur l’ECLS en chirurgie thoracique sont de decrire le rationnel des techniques d’ECLS disponibles, de presenter les indications d’ECLS lors de defaillances de l’appareil respiratoire et aussi de demontrer l’interet de l’ECLS pour pratiquer l’ECLS en chirurgie thoracique selon une medecine fondee sur les preuves. Etat des connaissances L’ECLS doit se pratiquer dans des centres experts. Dans le syndrome de defaillance respiratoire aigue severe et refractaire, l’ECLS permet de mettre au repos les poumons en pratiquant une ventilation protectrice. En transplantation pulmonaire, l’ECLS peut etre pratiquee avec de bons resultats en pont a la transplantation pulmonaire, en temps que support cardiorespiratoire peroperatoire et en pont a la recuperation en cas de dysfonction primaire du greffon pulmonaire. L’ECLS en tant que support a un acte therapeutique tracheobronchique et/ou chez un insuffisant respiratoire severe est faisable sans majorer significativement le risque perioperatoire. Perspectives Les indications d’ECLS vont accroitre dans le temps sous l’impulsion des centres experts. Dans les annees a venir, les progres des techniques et de l’ingenierie ainsi que des connaissances approfondies permettront l’amelioration du pronostic des patients atteints de defaillance respiratoire sous assistance mecanique. Des etudes prospectives multicentriques et randomisees affineront les indications et les strategies de prise en charge globale de ces patients. Conclusion L’ECLS est un moyen therapeutique ameliorant le pronostic de patients atteints ou soumis aux risques de defaillance respiratoire.

In origine, l’extracorporeal membrane oxygenation (ECMO) era una tecnica di assistenza respiratoria che utilizzava uno scambiatore gassoso a membrana. Per estensione, l’ECMO è diventata una tecnica respiratoria e cardiopolmonare utilizzata in caso di deficit respiratorio e/o cardiaco nell’attesa della restaurazione della funzione deficitaria o di un eventuale trapianto. Il supporto emodinamico può essere parziale o totale. Gli accessi vascolari possono essere periferici o centrali. Questo tipo di assistenza utilizza il concetto di circolazione extracorporea (CEC) sanguigna che in epoca moderna si è estesa con l’utilizzo di polmoni artificiali a membrana. Il circuito di base è semplice e comprende una pompa, un ossigenatore (che permette al sangue di caricarsi di O2 e di eliminare CO2) e delle vie d’accesso (una di drenaggio e una di reinfusione). La sua attuazione è facile, veloce e può essere avviata al letto del malato. Il miglioramento delle attrezzature, una migliore conoscenza delle tecniche e delle indicazioni, e le politiche di salute pubblica hanno reso popolare questa tecnica. Alcuni centri di chirurgia toracica la utilizzano di routine come assistenza alla realizzazione di un intervento terapeutico (soprattutto trapianto) assieme a team di rianimazione per il trattamento della sindrome da distress respiratorio acuto. Nel quadro della malattia polmonare dell’adulto, l’idea principale è quella di sviluppare il concetto di strategia minimalista con l’uso di una CEC adiuvante parziale – più che sostitutiva totale – che permetterebbe il recupero metabolico ad integrum del paziente. Nei prossimi anni, i progressi della tecnologia e dell’ingegneria così come le conoscenze approfondite permetteranno il miglioramento della prognosi dei pazienti colpiti da deficit respiratorio sotto assistenza meccanica.

Introduction L’objectif de cette etude retrospective etait de comparer la survie et la tolerance des inhibiteurs de tyrosine kinase (ITK) de premiere et de seconde generation chez des patients atteints d’adenocarcinomes bronchiques metastatiques mutes EGFR non selectionnes rencontres en pratique courante. Methodes Dans cette etude multicentrique, les donnees de tous les patients atteints d’adenocarcinome de stade IV mute EGFR et traites par ITK (1re ou 2e generation) entre 2010 et 2018 ont ete revues. Les patients ont ete assignes en 2 groupes : ITK de 1re generation (erlotinib et gefitinib) vs ITK de 2e generation (afatinib). La survie a ete evaluee a l’aide d’un test du Log-rank et du modele a risque proportionnel de Cox. Resultats Deux cent soixante-huit patients ont ete inclus dont 221 (82,5 %) traites par ITK de 1re generation et 47 (17,5 %) par afatinib. Dans les 2 groupes, l’âge median des patients etait similaire (68,40 ans [IQR : 8,28] vs 68,43 ans [IQR : 6,54], p = 0,89), de meme que la proportion de femmes (82,4 % vs 87,2 %, p = 0,42). Les patients du groupe afatinib etaient plus alteres sur le plan general (PS ≥ 2 : 21,3 % vs 13,6 %, p = 0,004), avaient une maladie plus avancee (stade M1b ou M1c : 80,9 % vs 63,3 %, p = 0,004) avec plus de metastases cerebrales, et etaient porteurs de mutations plus rares (25,5 % vs 5,5 %, p Conclusion Dans cette etude, il n’a pas ete mis en evidence de benefice de l’afatinib, comparativement aux ITK de 1re generation en termes de survie chez les patients fragiles.

Introduction L’immunotherapie est le standard de traitement en 2e intention des carcinomes bronchiques non a petites cellules. L’objectif de ce travail est d’evaluer si les differentes substitutions d’acide amine de Kirsten rat sarcoma viral oncogene homolog (KRAS) sont des facteurs pronostiques de reponse a l’immunotherapie chez les patients porteurs d’un adenocarcinome pulmonaire en recidive. Methodes Etude retrospective, multicentrique, de patients porteurs d’adenocarcinomes pulmonaires de stade III ou IV, en recidive, dont le statut mutationnel etait connu, et traites par immunotherapie entre 2015 et 2018. Les criteres de jugement etaient la survie globale (SG), la survie sans progression (SSP), la reponse tumorale selon les criteres RECIST, et la tolerance du traitement. Resultats Parmi les 674 patients, 248 (36,8 %) avaient une mutation KRAS, essentiellement du codon 12 (n = 240, 96,8 %), et 426 (63,2 %) etaient KRAS wild type (WT). Les 2 groupes etaient comparables en termes d’âge (âge median de 64,04 ans) et de sexe (65,9 % d’hommes). Le groupe KRAS presentait moins de cancers de stade IV (n = 212, 85,5 %) et de metastases cerebrales (n = 52, 21 %) que le groupe WT (stade IV : n = 402, 94,4 %, p Conclusion Les transversions G12 V et G12D de KRAS seraient un facteur predictif de bonne reponse a l’immunotherapie chez les patients suivis pour un adenocarcinome pulmonaire en recidive.

Genotypic resistance interpretation systems for the prediction and interpretation of HIV-1 antiretroviral resistance are an important part of the clinical management of HIV-1 infection. Current interpretation systems are generally hosted on remote webservers that enable clinical laboratories to generate resistance predictions easily and quickly from patient HIV-1 sequences encoding the primary targets of modern antiretroviral therapy. However they also potentially compromise a health provider’s ethical, professional, and legal obligations to data security, patient information confidentiality, and data provenance. Furthermore, reliance on web-based algorithms makes the clinical management of HIV-1 dependent on a network connection. Here, we describe the development and validation ofsierra-local, an open-source implementation of the Stanford HIVdb genotypic resistance interpretation system for local execution, which aims to resolve the ethical, legal, and infrastructure issues associated with remote computing. This package reproduces the HIV-1 resistance scoring by the web-based Stanford HIVdb algorithm with a high degree of concordance (99.997%) and a higher level of performance than current methods of accessing HIVdb programmatically.

Cophylogeny is the congruence of phylogenetic relationships between two different groups of organisms due to their long-term interaction, such as between host and pathogen species. Discordance between host and pathogen phylogenies may occur due to pathogen host-switch events, pathogen speciation within a host species, and extinction. Here, we investigated the use of tree shape distance measures to quantify the degree of cophylogeny for the comparative analysis of host-pathogen interactions across taxonomic groups.We firstly implemented a coalescent model to simulate pathogen phylogenies within a fixed host tree, given the cospeciation probability, migration rate between hosts, and pathogen speciation rate within hosts.Next, we used simulations from this model to evaluate 13 distance metrics between these trees and the host tree, including Robinson-Foulds distance and two kernel distances that we developed for labeled and unlabeled trees, which use branch lengths and can accommodate trees of different sizes. Finally, we used these distance metrics to revisit actual datasets from published cophylogenetic studies across all taxonomic groups, where authors described the observed associations as representing a high or low degree of cophylogeny.Our simulation analyses demonstrated that some metrics are more informative than others with respect to specific coevolution parameters. For example, the Sim metric was the most responsive to variation in coalescence rates, whereas the unlabeled kernel metric was the most responsive to cospeciation probabilities. We also determined that distance metrics were more informative about the model parameters when the underlying parameter values did not assume extreme values,e.g.,rapid host switching. When applied to real datasets, projection of these trees’ associations into a parameter space defined by the 13 distance metrics revealed some clustering of studies reporting low concordance. This suggested that different investigators are describing concordance in a consistent way across biological systems, and that these expert subjective assessments can be at least partly quantified using distance metrics.Our results support the hypothesis that tree distance measures can be useful for quantifying host and pathogen cophylogeny. This motivates the usage of distance metrics in the field of coevolution and supports the development of simulation-based methods,i.e.,approximate Bayesian computation, to estimate coevolutionary parameters from the discordant shapes of host and pathogen trees. [tree shape; cophylogeny; codivergence; coevolution; host switching; tree metrics; kernel]

Dear Sirs, giant cell arteritis (GCA) of the vertebral arteries (VA) is a rare, potentially treatable disease with serious prognosis. In a recent literature review [7], eight cases of bilateral VA-occlusion resulting from GCA were identified [1, 2, 7–9]. Six of these patients died. Both surviving patients were left dependent on assisted living [7]. We report on two patients with GCA of both VA with a favourable outcome. Patient 1: A 75-year-old woman suffered from gait disturbance, vertigo, headache and jaw claudication. She lost 10 kilograms in two months. Neurological examination revealed gaze-evoked nystagmus, gait ataxia and pyramidal signs. Erythrocyte sedimentation rate (ESR) was 110 mm/h. The brain MRI showed bilateral cerebellar and left pontine infarction and an enhancement of the intracranial VA after gadolinium (Fig. 1a, b). Sonology detected a halo around both VA (Fig. 1c). Biopsy of the temporal artery confirmed GCA (Fig. 1d). Her symptoms markedly improved after four days of high-dose IVmethylprednisolone treatment (1000 mg/d). The ESR decreased to 38 mm/h. On sonology, the stenoses regressed but the halos persisted. Patient 2: A 81-year-old man had a syncope, headache, vertigo, blurred vision and jaw claudication. He lost 13 kilograms in two months. Bitemporal indurated and painful arteries were clinically prominent. The ESR was 90 mm/h. Sonology showed a halo around the temporal arteries and stenoses of the V4-segment (Fig. 1e). Contrast-enhancement of the VA walls was present on MRI (Fig. 1f). GCA was confirmed upon biopsy of the temporal artery (Fig. 1g, h). The symptoms resolved after five days of high-dose IV-methylprednisolone treatment (500 mg/d). The ESR decreased to 40 mm/h. Sonology showed regression of the vertebral stenoses. Giant cell arteritis of the vertebral arteries is a rare cause of vertebrobasilar stenoses or occlusions. Eight cases of GCA-related bilateral VA-occlusions have been identified between 1966 and 2001, while another 110 cases of VA-occlusions were attributable to atherosclerosis [7]. The majority of GCA-patients with VA-occlusions died [3, 4, 6, 7]. The two patients reported here had a favourable outcome. In contrast to other cases reported with unfavourable courses [1, 2, 7–9], our patients had stenoses rather than occlusions. Although the degree of hemodynamic compromise may be crucial, one recently reported fatal case with VA-stenoses [3] illustrates that patients with stenoses only do not necessarily have a favourable outcome. It remains to be determined why in some patients VA-involvement caused occlusions while in others the involvement was restricted to the level of stenoses. Other variables theoretically predicting an unfavourable outcome are (i) the involvement of the basilar artery, not directly affected by GCA [9], but resulting from bilateral VA occlusion, and (ii) the lack of sufficient collateralisation from the carotideal circulation. It may be postulated that early high-dose immunosuppression is efficacious, as by observation several of the cases with fatal outcome had no immunosuppressive treatment [6, 7]. However in one case reported, even the addition of IV cyclophosphamide to high-dose IV steroids could not prevent the fatal outcome [3]. In another case, conversely, the delay of immunosuppressive treatment resulting from misinterpretation of imaging findings as VAdissection [5] did not prompt an unfavourable course. Systematic observation of GCApatients with symptomatic stenoocclusive disease of both VA is warranted to identify reliable outcome predictors. Taking into account the low frequency of the disease, a multicenter registry compiling clinical, laboratory and imaging data would be of great value. In conclusion, our two cases illustrate favourable courses among patients with GCA-involvement of both vertebral arteries which have not been reported so far. The identification of prognostic features and the role of early immunosuppressive treatment should be addressed in future clinical research.

Resume Les progres dans le demantelement moleculaire des CBNPC ont conduit a des avancees significatives dans le traitement des tumeurs solides. Les alterations moleculaires qui peuvent etre ciblables par des therapeutiques ciblees correspondent soit a des mutations de genes (Epidermal Growth Factor Receptor [EGFR], KRAS, HER2, BRAF), soit a des rearrangements de genes (Anaplastic Lymphoma Kinase [ALK], ROS1, RET), impliquant qu'outils et methodes soient appropries pour les detecter. Cet article decrit les problematiques liees aux differents types de prelevements realises en vue d'une analyse moleculaire, les criteres de qualite/selection des echantillons tumoraux, les differentes techniques de biologie moleculaires utilisees pour la recherche des mutations, avec en perspective l'utilisation du sequencage de nouvelle generation (NGS), ainsi que l'interpretation des resultats.

Resume Introduction La thoracotomie etait consideree comme la voie d'abord de reference pour la lobectomie. Cependant, les techniques video assistees, dites « VATS » ( Video-Assisted Thoracoscopic Surgery ), offrent une alternative utilisee de facon rapidement croissante. Etat des connaissances : Les techniques VATS sont actuellement indiquees dans les cancers bronchiques de stade I. Leur utilisation est associee a une diminution de la morbidite postoperatoire, permettant leur integration dans des programmes de recuperation rapide, dits « FastTrack ». La duree d'hospitalisation est reduite de facon significative. Ces techniques respectent les regles de resection oncologique, et notamment le curage ganglionnaire complet est realisable. La VATS semble egalement etre associee a une meilleure survie sans recidive, comme globale. Perspectives Du fait des avantages de cette voie d'abord, les resections pulmonaires par VATS pourraient a l'avenir s’etendre aux stades II et IIIA, aux pathologies pulmonaires benignes, mais egalement a la chirurgie des metastases. Conclusion La VATS, de par ses nombreux benefices, est en voie de se positionner comme technique de reference pour les cancers bronchiques de stade I.

Resume Introduction La chirurgie constitue le traitement de choix des CBNPC de stades precoces. Malgre une chirurgie a visee curative, il existe un risque non nul de recidive et de deces par cancer. Etat des connaissances La chimiotherapie adjuvante est indiquee pour les stades II et III, debattue dans les stades IB. Les meta-analyses publiees ont conclu a un benefice de survie absolu de 5 % a 5 ans. La place de la chimiotherapie neoadjuvante est moins codifiee. La seule meta-analyse publiee comparant les deux schemas n'a pas note de difference significative en termes de survie. Perspectives : Le benefice de l'utilisation des inhibiteurs de tyrosine kinase (ITK), chez les malades mutes Epidermal Growth Factor Receptor (EGFR) de stades avances, a fait se poser la question de l'interât de leur utilisation perioperatoire chez les stades precoces. A ce jour, peu de donnees sont disponibles dans la litterature, mais sont encourageantes quant a leur interât en situation neoadjuvante afin d'augmenter la resecabilite et, en adjuvant afin d'allonger la survie sans progression, chez des malades selectionnes. Conclusion Le moment de la chimiotherapie semble avoir peu d'importance sur la survie. La place des ITK, bien que prometteuse, reste a definir.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second most common cause of cancer-related deaths in the world (Weitz et al, 2005). In 2012, CRC was the second most diagnosed cancer in Europe with 450 000 new cases and the second leading cause of death with 215 000 cases (Ferlay et al, 2013). Up to nearly 50% of patients will experience metastases during their lives, mainly located in both the liver and the lung (August et al, 1984; McCormack et al, 1992). Thoracic metastasectomy of CRC remains controversial despite several published series that have reported a 5-year overall survival (OS) ranging from 20 to 60% after surgery (Sauter et al, 1990; McAfee et al, 1992; Baron et al, 1996; Girard et al, 1996; Okumura et al, 1996; Zanella et al, 1997), compared with the 5-year OS of the conventional treatment with 5-fluorouracil (5-FU)-based chemotherapy that does not exceed 5% (Poon et al, 1989). Because the resection of lung parenchyma can cause morbidity and always alters respiratory function, several risk factors for a poor outcome after thoracic surgery have been identified to help select appropriate candidates for surgery. These risk factors include a high preoperative level of carcinoembryonic antigen (CEA), a short disease-free survival (DFS), an association with hepatic metastases, the number of thoracic metastases, an incomplete resection or lymph node involvement (LNI; Adam et al, 2011; Zabaleta et al, 2011; Hamaji et al, 2012; Sclafani et al, 2013). However, the past few years have seen an increased understanding of the molecular alterations in tumours that has led to many changes in the management of patients. In particular, clinicians can offer a more accurate prognosis, predict tumour response to therapy and personalise treatment approaches more accurately (Karagkounis et al, 2013). Two of the proto-oncogenes present in CRC have been extensively studied: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and V-raf Murine sarcoma viral oncogene homolog B1 (BRAF). The involvement of KRAS in the carcinogenesis of CRC, specifically its role in the development of adenocarcinoma of the large intestine, has been known for many years (Vogelstein et al, 1988; Karagkounis et al, 2013). Some studies have suggested that the KRAS mutation is an independent prognostic factor in paired primary and metastatic CRC (Conlin et al, 2005). Furthermore, it is well known that the presence of KRAS mutations is strongly associated with resistance to anti-epidermal growth factor receptor (EGFR) therapies (Lievre et al, 2006; Karapetis et al, 2008; Diaz et al, 2012). In addition, the presence of the V600E mutation in the BRAF gene is associated with an increased risk of death in CRC patients (Samowitz et al, 2005; Richman et al, 2009; Roth et al, 2010; Price et al, 2011). Only one single study has previously evaluated the potential role of molecular markers (that is, EGFR KRAS and BRAF) as risk factors for early recurrence after lung metastasectomy of CRC (Schweiger et al, 2014). However, to the best of our knowledge, no studies have focused on the possibility of using both KRAS and BRAF as biomarkers in selecting appropriate candidates for thoracic metastasectomy of CRC. Thus, we evaluated whether patients with the mutant KRAS (mKRAS) and mutant BRAF (mBRAF) had worse OS after thoracic surgery than patients with wild-type (WT) BRAF and KRAS.

Lymph node status is currently one of the most important prognostic factors for the management of non-small cell lung cancer (NSCLC). According to the current guidelines (1), in case of clinical N2 or N3, patients are not candidate to surgery and they are referred to neoadjuvant or definitive chemotherapy and/or radiotherapy, meanwhile in case of clinical N0/N1 surgery is the treatment of choice. Nonetheless, the definition of both N1 and N2 is still based only on merely anatomical criteria and they therefore enclose a wide range of different pathological situations with different prognosis (2). Moreover, the extent of lymph-node dissection has been debated, but to date no strong evidences are available to support one technique or another.

La chirurgia polmonare e una chirurgia non priva di rischi. In effetti, la mortalita ospedaliera varia dall’1% al 10% in funzione dei vari tipi di exeresi, che vanno dalla semplice resezione atipica alla pneumonectomia. La mortalita puo, tuttavia, avvicinarsi al 12% nelle pneumonectomie destre piu o meno allargate e al 18% nelle lobectomie di totalizzazione a destra. Per tale motivo, l’attuale tendenza e di ridurre l’estensione delle exeresi parenchimali. Cio si spiega con diversi elementi: un’alterazione meno importante della funzionalita respiratoria postoperatoria, l’apporto della radiochemioterapia neoadiuvante che permette, a volte, una resezione meno importante grazie alla diminuzione della massa tumorale e una mortalita ospedaliera tre volte meno importante dopo una lobectomia. In questo articolo, affronteremo in successione il bilancio preoperatorio, i principi generali di anestesia e di chirurgia e, infine, le complicanze postoperatorie.

Background Pulmonary metastasectomy of renal cell carcinomas (RCC) remains controversial. Thoracic lymph node involvement (LNI) is a known prognostic factor. The aim of our analysis is to evaluate whether patients with LNI, and particularly N2 patients, should be excluded from surgical treatment. Methods We retrospectively reviewed data from 122 patients who underwent operations at two French thoracic surgery departments between 1993 and 2011 for RCC lung metastases. Results The population consisted of 38 women and 84 men; the average age at time of metastasectomy was 63.3 years (min: 43, max: 82). LNI was identified as a prognostic factor using univariate and multivariate analysis (median survival: 107 months vs. 37 months, P = 0.003; HR = 0.384 (0.179; 0.825), P = 0.01, respectively). Although differences in survival between metastases at the hilar and mediastinal locations were not significant (median survival: 74 months vs. 32 months, respectively, P = 0.75), length of survival time was associated with disease-free interval less than 12 months (median survival: 23 months vs. 94 months, P

Introduction Les resultats des series de cas suggerent un taux de succes eleve de la transplantation renale pour des insuffisances renales chroniques terminales liees a une vascularite associee aux ANCA (VAA). Le risque de recidive de VAA sur greffon est faible, mais les facteurs de risque de recidive ne sont pas bien connus. L’objectif de cette etude etait de decrire le devenir de patients atteints de VAA apres transplantation renale et de rechercher les facteurs predictifs d’une recidive de VAA sur greffon. Patients/Materiels et methodes L’etude a porte sur 39 adultes (25 hommes) ayant recu 41 transplantations pour une nephropathie de VAA dans 7 centres de la region parisienne entre 1988 et 2013. Les dossiers medicaux ont ete analyses pour colliger les donnees demographiques, les traitements immunosuppresseurs recus, les recidives de VAA, les rejets, infections, la survie des greffons et des patients. La recidive de VAA sur greffon et le rejet de greffon ont ete evalues sur les criteres histologiques apres relecture des biopsies renales par un seul anatomopathologiste. Observation/Resultats Les nephropathies initiales etaient 8 granulomatoses-avec-polyangeite, 14 polyangeites-microscopiques, et 17 glomerulonephrites-extracapillaires-pauci-immunes-associees-aux-ANCA sans atteinte extra-renale. L’intervalle moyen entre le diagnostic de VAA et l’initiation de la dialyse etait de 4 ans, et 28/32 (87 %) avaient recu au prealable un traitement par cyclophosphamide. Quatre patients n’avaient pas recu de traitement (ou une corticotherapie seule) en raison de la presentation d’emblee terminale de l’atteinte renale. L’incidence du rejet aigu etait de 36 % (incluant les rejets infra-cliniques) ; 8/26 (31 %) patients sont retournes en dialyse et 2 ont recu une seconde transplantation, au cours d’un suivi moyen de 4,8 ans (ET : 3,5). Un patient est decede suite d’un syndrome lymphoproliferatif post-transplantation. Deux patients (5 %) ont presente une recidive renale de VAA : une en contexte d’IRA a 3 mois de la greffe, et une infraclinique a 1 an sur biopsie systematique. Le risque relatif de recidive de VAA chez les patients naifs de cyclophosphamide etait de 29 (p = 0,02). Discussion/Conclusion Dans l’ere des traitements anti-rejet modernes, le taux de recidive de VAA faible. Neanmoins, on observe des recidives precoces, et qui semblent survenir electivement chez des patients non traites prealablement pour leur vascularite. Nous avons constate une association histologique de lesions de rejet et de vascularite dans ces cas-la. Cela evoque une intrication des phenomenes d’allo- et d’auto-immunite entrant dans le cadre d’une activation immunitaire persistante. L’ensemble de ces donnees nous questionne sur la prise en charge de ces malades en periode pregreffe.

La miastenia gravis e una malattia autoimmune, legata alla presenza di anticorpi diretti contro i recettori dell’acetilcolina. Malattia prevalentemente della donna giovane, essa e spesso associata ad anomalie del timo (iperplasia o timoma). La timectomia ha un suo posto nel trattamento multidisciplinare di questi pazienti, come complemento dei vari trattamenti farmacologici, offrendo dei tassi di remissione che variano dal 13% al 51% a cinque anni. Il bilancio preoperatorio deve permettere di adattare la strategia chirurgica, che differisce in funzione dei dati morfologici, e, se e sospettato un timoma, facendo preferire, allora, una sternotomia alle vie mini-invasive. Negli altri casi, devono essere proposte ai pazienti le vie d’accesso mini-invasive. Infatti, esse hanno mostrato un’efficacia uguale alle altre tecniche in letteratura e offrono dei vantaggi innegabili, in particolare in termini di sequele estetiche, in questi pazienti giovani.

For the past 40 years, primary hyperparathyroidism has been recognized as a common endocrine disease which is, most often, “non-symptomatic”, without the occurrence of nephrolithiasis or osteitis fibrosa cystica. Our knowledge in the pathophysiology has increased largely and diagnosis of primary hyperparathyroidism is usually easy. The only radical treatment is surgery and the surgical indications have been codified by several consensus conferences. For patients who do not undergo surgery, prolonged medical monitoring is needed.

Background Minimally invasive surgery, stereotactic radiotherapy, and radiofrequency ablation are commonly proposed in the case of pulmonary colorectal-metastasis as alternatives to conventional open surgery. Preoperative imaging assessment by computed tomography (CT) scan and fluorodeoxyglucose positron emission tomography (FDG-PET) are critical to guide oncologic radical treatment. Our aim was to investigate the accuracy of CT and FDG-PET for the evaluation of the number of pulmonary colorectal metastases and thoracic lymph nodal involvement (LNI). Methods Patients who underwent lung surgical resection for pulmonary colorectal metastases from 2004 to 2014 were analyzed. Concordance between histology, CT scan, and FDG-PET findings were assessed. Results Data of 521 patients were analyzed. Of those, FDG-PET was performed in 435 (83.5%). A moderate agreement between both CT scan (kappa index: 0.42) and FDG-PET (kappa index: 0.42) findings and the histologically proven number of metastases was observed. The number of histologically proven metastases was correctly discriminated in 61.7% of cases with CT scan and in 61.8% of cases with FDG-PET. Multiple metastases were discovered in 20.9% of clinical single metastasis cases with CT scan, and in 24.4% of those cases with FDG-PET. One hundred fifty patients (29.1%) presented with pathologic LNI. A poor agreement was observed between LNI and CT scan findings (kappa index: 0.02), and a weak agreement was observed concerning LNI and FDG-PET findings (kappa index: 0.39). Conclusions Computed tomography and FDG-PET have limitations if the objective is to detect all malignant nodules and to discriminate the LNI in cases of pulmonary metastases of colorectal cancer.

Massive hemoptyses are serious clinical conditions that can quickly jeopardize the vital prognosis. The major risk is asphyxiation, due to the bleeding into the tracheobronchial tree. The clinician should provide in parallel support for diagnosis and treatment, locating the bleeding but also finding its cause. Such patients should be cared for by a multidisciplinary team, having quick access to an important technical support. The association fiberoptic bronchoscopy-chest CT scan seems to be the most effective to locate and identify the cause of the bleeding. The development of bronchial artery embolization has revolutionized the management of these patients, replacing surgery in many of its indications. The latter still keeps a place in the management of these patients. Indeed, it is the main etiological treatment, preventing the vast majority of recidivism. It is absolutely indicated in the treatment of bleeding from the pulmonary vessels, and in case of failure of other techniques. It should be performed whenever possible away from the episode of hemoptysis, in order to minimize the operative risk.

Objectifs L’ALAM est une complication rare, soudaine, et potentiellement mortelle. Les formes graves necessitent un diagnostic precoce et une epuration extra-renale (EER) urgente [1] . La metformine (Met) est une petite molecule (500 Da), hydrophile, non liee aux proteines plasmatiques, a grand Vd (3,1 L/kg) d’elimination exclusivement renale ; sa demi-vie est de 6,5 h chez le sujet normal. Methodes Serie monocentrique prospective (43 cas) declares en pharmacovigilance de 2006 et 2016 ( Tableau 1 ). Les circonstances de l’ALAM etaient : 1 intoxication volontaire, 27 gastro-enterites aigues, 6 infections, 6 iatrogenes (iode, lithium, chimio-), 1 hypothermie, 1 IRA obstructive, 1 sans facteur declenchant. Meme pour un DFG > 60 mL/min, le rein diabetique presente une perfusion arteriolaire et glomerulo-tubulaire grele avec une sensibilite a l’hypovolemie, a l’hypotension et aux medicaments nephrotoxiques, avec un risque accru d’IRA, point de depart de l’accumulation de la Met dans l’organisme, qui peut parfois declencher l’ALAM. Conclusion Sur 11 ans de suivi en pharmacovigilance, l’ALAM survient majoritairement pour des patients avec DFG basal > 60 mL/min. L’insuffisance renale aigue est le facteur declenchant qu’il faut savoir prevenir et/ou corriger rapidement avant l’ALAM.

We propose a new estimation method for the characterization of the Hodgkin-Huxley formalism. This method is an alternative technique to the classical estimation methods associated with voltage clamp measurements. It uses voltage clamp type recordings, but is based on the differential evolution algorithm. The parameters of an ionic channel are estimated simultaneously, such that the usual approximations of classical methods are avoided and all the parameters of the model, including the time constant, can be correctly optimized. In a second step, this new estimation technique is applied to the automated tuning of neuromimetic analog integrated circuits designed by our research group. We present a tuning example of a fast spiking neuron, which reproduces the frequency-current characteristics of the reference data, as well as the membrane voltage behavior. The final goal of this tuning is to interconnect neuromimetic chips as neural networks, with specific cellular properties, for future theoretical studies in neuroscience.