Background Consolidation durvalumab is standard of care treatment for patients with unresectable, stage III non-small-cell lung cancer without progression after chemoradiotherapy. Additional study is warranted to investigate the long-term efficacy of this regimen in real-world settings. Methods PACIFIC-R (NCT03798535) was an international, observational, cohort study of patients who started durvalumab 10 mg/kg intravenously every 2 weeks within an AstraZeneca-initiated early access program between September 2017 and December 2018. Data were extracted retrospectively from medical records to describe the real-world effectiveness of consolidation durvalumab in patients with unresectable non-small-cell lung cancer without progression after chemoradiotherapy. The primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS). Results Median age was 65.0 years (range 26-88 years); most patients [747/1153 (64.8%)] were male and current [300/1153 (26.0%)] or former [750/1153 (65.0%)] smokers. Among patients with reported data, most had Eastern Cooperative Oncology Group performance status <2 [743/755 (98.4%)], stage IIIB/C disease [584/1090 (53.6%)], non-squamous histology [746/1137 (65.6%)], and programmed death-ligand 1 expression on ≥1% of tumor cells [572/791 (72.3%)]. Median follow-up (censored patients) was 63.5 months for rwPFS and 67.5 months for OS. Median rwPFS was 24.3 months [95% confidence interval (CI) 20.3-28.4 months]; 5-year rwPFS was 35.2% (95% CI 32.4% to 38.1%). Median OS was 59.0 months (95% CI 52.7-64.3 months); 5-year OS was 49.2% (95% CI 46.2% to 52.2%). Encouraging results were observed across subgroups, including among patients who received durvalumab after either concurrent or sequential chemoradiotherapy [median rwPFS (95% CI): 25.8 months (20.9-31.8 months) versus 23.2 months (16.9-29.5 months); median OS: 63.1 months (57.3-73.5 months) versus 47.1 months (35.3-58.1 months)], and irrespective of programmed death-ligand 1 expression [on ≥1% versus <1% of tumor cells; median rwPFS (95% CI): 25.5 months (19.1-32.8 months) versus 16.3 months (10.9-27.5 months); median OS: 62.4 months (55.0 months-not estimable) versus 43.3 months (31.6-60.7) months]. Conclusions PACIFIC-R provides mature data on OS and rwPFS from a large, real-world cohort, supporting consolidation durvalumab as a standard of care in this setting.
BACKGROUND:The bacterial determinants of Group A Streptococcus (GAS) associated with either invasive (IGASI) or non-invasive (NIGASI) infections remain controversial. METHODS:From 2014 to 2018, French children hospitalized for an IGASI were enrolled in a prospective multicenter study aimed at identifying bacterial virulence factors and predisposing immunologic and genetic factors. During the same period, age- and date-matched control children with NIGASI were enrolled. Whole genome sequencing was performed for all GAS isolates. The 27 specific single nucleotide polymorphisms characterizing the M1UK lineage were searched among the emm-1 isolates. RESULTS:A total of 192 GAS isolates were sequenced: 94 from the IGASI group and 98 from the NIGASI group. The emm-1 genotype predominated in the IGASI group (36% vs. 11% in NIGASI group, P < .05) and was followed by emm-4, emm-12, and emm-3 (12%, 11%, and 10% respectively). In the NIGASI group, emm-89 predominated (21% vs 7% in the IGASI group, P<.05). Among the 45 emm-1 isolates, 12 (27%) carried the mutations characterizing clone M1UK in both groups (7 in IGASI group and 5 in NIGASI group). The superantigenic toxins SpeA and SpeJ, SIC protein, and FCT type 1 pilus predominated in the IGASI group but were linked to emm-1 strains. Insertions/deletions in the covS regulator gene were observed in 5 invasive isolates versus 1 non-invasive isolate. CONCLUSIONS:Genotype emm-1 GAS strains remained the main cause of invasive infections in French children, associated to specific GAS virulence factors, and should be monitored together with the rapid spread of the M1UK lineage.
Pleural mesothelioma (PM) urgently requires effective treatments. This study aimed to identify potential therapies using a drug repurposing strategy in the context of the molecular heterogeneity of PM. We performed a multiomics study of a large cohort of patient-derived primary PM cell lines (n = 58) and conducted a multistep pharmacologic study starting with a large-scale drug screen with 1,327 compounds using 11 cell lines to select drugs of interest. Integrated multiomics analysis demonstrated that the molecular landscape of the cell line cohort recapitulates the main findings in tumors and revealed important features of PM. Large-scale drug screening identified 233 active compounds belonging to recurrent therapeutic classes. Subsequent validation of 35 compounds highlighted a subset of 12 compounds performing better than standard chemotherapy, including entinostat and fluvastatin, with therapeutic activity related to molecular sarcomatoid phenotype, BAP1 mutation, and YAP/TAZ activity. Importantly, both compounds displayed the same efficacy in 2D and 3D culture models, and a single treatment with entinostat improved survival in an immunocompetent mouse model compared with fluvastatin and standard cisplatin-pemetrexed chemotherapy, which showed similar antitumor effects. Strikingly, entinostat improved the efficacy of immunotherapy based on anti-PD-1 antibody. Combination of entinostat with anti-PD-1 even eradicated tumors in several mice and immunized them against retransplantation of tumor cells. Overall, the drug sensitivity data provided by this study represent a resource to facilitate future clinical investigations to improve the treatment of PM.Significance: Pharmacogenomic characterization of a cell line biobank provides a valuable resource on drug sensitivity in mesothelioma and identifies entinostat as a promising therapeutic option, particularly in combination with immune checkpoint inhibitors.
Fluid mobilization on epithelia is ensured by the motile cilia of differentiated multiciliated cells (MCCs). Key transcriptional regulators of motile ciliogenesis include CCNO, MCIDAS, RFXs, and the transcription factor FOXJ1, whose precise role in humans remains unclear. We show that, unlike CCNO and MCIDAS, FOXJ1 expression persists in well-differentiated human airway epithelial cells (hAECs), suggesting functions beyond cilia initiation. ChIP-seq in hAECs allowed us to refine the consensus target motifs of FOXJ1 and RFXs, as well as their close proximity, which strongly suggests functional cooperation within a transcriptional complex. By combining ChIP-seq in normal cells with RNAseq from patients with FOXJ1-related primary ciliary dyskinesia (PCD), we identified 683 direct FOXJ1 target genes. Among these, 89 MCC-enriched genes-particularly those encoding axonemal proteins such as microtubule-inner proteins (MIPs) and dynein arm docking components-were downregulated in FOXJ1-deficient cells. Collectively, these findings provide new insights into how FOXJ1 contributes to human motile ciliogenesis, and reveal a potential role for FOXJ1 in maintaining MCCs differentiation and ciliary function by sustaining the expression of ciliary proteins, particularly those in direct contact with axonemal tubulin.
Objectifs Le hikikomori correspond à une conduite de retrait social extrême et d’auto-claustration prolongée au domicile, typiquement celui des parents car cela concerne majoritairement des adolescents et des jeunes adultes. Dans ces cas, la famille devient la dernière interface entre le jeune reclus et le monde extérieur. Porteuse d’une demande de changement, c’est entre autres par la famille que les soins doivent s’envisager. Une bonne connaissance des caractéristiques de ces familles s’avère donc essentielle et, à cette fin, nous proposons la présente revue narrative. Méthode Via PubMed et ScienceDirect, nous analysons les publications répondant à la commande « hikikomori AND (family OR families OR parent OR mother OR father OR sibling OR sister OR brother) », parues entre 2008 et mars 2025, en anglais et en français dans des revues psychologiques, psychiatriques et médicales. Résultats Sur les 507 publications concernant le hikikomori, 163 respectent les critères d’inclusion et 43 d’entre elles ont été conservées dans le cadre de notre revue. Au terme de notre analyse, nous dégageons huit thèmes : profil familial type, communication au sein de la famille, conflictualité intrafamiliale, profils parentaux, styles parentaux, antécédents traumatiques, altération de la temporalité et compétences familiales. Discussion Typiquement, le hikikomori survient dans des familles de classe sociale moyenne-supérieure au sein desquelles les parents sont souvent séparés, le père étant distant voire absent et la mère omniprésente auprès de l’enfant. Le style parental est souvent indulgent-surprotecteur. Des antécédents traumatiques chez le jeune, vécus à domicile ou bien auprès des pairs sont récurrents. Les deux parents présentent des antécédents psychiatriques significatifs, sont émotionnellement très affectés par l’enfermement prolongé de leur enfant et finissent par se retrouver eux-aussi isolés. La communication familiale est globalement dysfonctionnelle, la conflictualité intrafamiliale élevée et ces familles présentent des compétences familiales globalement déficitaires. Au cours d’une réflexion systémique-relationnelle, nous suggérons que les familles de hikikomori présentent des caractéristiques communes avec les familles psychosomatiques et plus spécifiquement avec les familles dont un enfant souffre de trouble du comportement alimentaire (TCA). Enchevêtrement, rigidité, surprotection, évitement de la conflictualité et implication du jeune dans un conflit parental caché, ces familles verraient leur cycle de vie s’enrayer et leur temps suspendu. Conclusion Parmi les multiples facteurs impliqués dans le hikikomori, des dynamiques familiales dysfonctionnelles semblent être particulièrement à l’œuvre. Ainsi, davantage d’études d’orientation systémique-relationnelle et incluant les fratries ainsi que les grands-parents seraient souhaitables à l’avenir. Cela contribuerait à une meilleure compréhension du hikikomori ainsi qu’à l’élaboration d’interventions familiales voire multifamiliales.
