IntroductionIn this study we assessed the contribution of psychopathology, including the two domains of negative symptoms (motivational deficit and expressive deficit), processing speed as an index of neurocognition, and emotion recognition, as an index of social cognition, to poor functional outcomes in people with schizophrenia.MethodsThe Positive and Negative Syndrome Scale was used to evaluate positive symptoms and disorganization and the Brief Negative Symptom Scale to assess negative symptoms. The Symbol Coding and the Trail Making Test A and B were used to rate processing speed and the Facial Emotion Identification Test to assess emotion recognition. Functional outcome was assessed with the Personal and Social Performance Scale (PSP). Regression analyses were performed to identify predictors of functional outcome. Mediation analyses was used to investigate whether social cognition and negative symptom domains fully or partially mediated the impact of processing speed on functional outcome.ResultsOne hundred and fifty subjects from 8 different European centers were recruited. Our data showed that the expressive deficit predicted global functioning and together with motivational deficit fully mediated the effects of neurocognition on it. Motivational deficit was a predictor of personal and social functioning and fully mediated neurocognitive impairment effects on the same outcome. Both motivational deficit and neurocognitive impairment predicted socially useful activities, and the emotion recognition domain of social cognition partially mediated the impact of neurocognitive deficits on this outcome.ConclusionsOur results indicate that pathways to functional outcomes are specific for different domains of real-life functioning and that negative symptoms and social cognition mediate the impact of neurocognitive deficits on different domains of functioning. Our results suggest that both negative symptoms and social cognition should be targeted by psychosocial interventions to enhance the functional impact of neurocognitive remediation.
Aim: Report the final analysis from ASTRIS, the largest real-world study of second-/later-line osimertinib in advanced/metastatic EGFR T790M non-small-cell lung cancer (NSCLC). Methods: Patients with advanced/metastatic EGFR T790M NSCLC and prior EGFR-TKI treatment, received once-daily osimertinib 80 mg. Primary end point: overall survival (OS); secondary end points: progression-free survival (PFS), time-to-treatment discontinuation (TTD) and response rate. Safety was also recorded. Results: In 3014 patients, median OS: 22.8 months (21.6-23.8), median PFS: 11.1 months (11.0-12.0), median TTD: 13.5 months (12.6-13.9), and response rate: 57.3% (55.5-59.2). All end points reported with 95% CIs. Numerically longer median OS was observed in patients with baseline WHO performance status <2 versus 2 (24.0 vs 11.1 months) and those without versus with brain/leptomeningeal metastases (25.4 vs 18.0 months). No new safety signals were identified. Conclusion: Second-/later-line osimertinib demonstrated real-world clinical benefit and safety in advanced/metastatic EGFR T790M NSCLC. Clinical Trial Registration: NCT02474355 (ClinicalTrials.gov).
Zusammenfassung Metabolische Erkrankungen beeinflussen das Leben von Männern und Frauen in den verschiedenen Lebensabschnitten in unterschiedlicher und vielfältiger Weise und stellen eine große Herausforderung für das Gesundheitssystem dar. Die behandelnden Ärztinnen und Ärzte sind mit den unterschiedlichen Bedürfnissen von Männern und Frauen im klinischen Alltag konfrontiert. Geschlechtsspezifische Unterschiede beeinflussen die Pathophysiologie, das Screening und die Diagnose von Krankheiten, sowie Behandlungsstrategien und die Entwicklung von Komplikationen und die Mortalitätsraten. Veränderungen im Glukose- und Lipidstoffwechsel, die Regulation von Energiehaushalt und Körperfettverteilung sowie damit assoziierte kardiovaskuläre Erkrankungen werden stark von Steroid- und Sexualhormonen beeinflusst. Zusätzlich spielen Erziehung, Einkommen und psychosoziale Faktoren eine wichtige Rolle bei der Entstehung von Adipositas und Diabetes und müssen bei geschlechtsspezifischer Betrachtung mitberücksichtigt werden. Männer weisen im jüngeren Alter und bei niedrigerem BMI ein höheres Risiko für Typ 2 Diabetes auf als Frauen, die wiederum von einem starken Anstieg im Risiko für Diabetes-assoziierte kardiovaskuläre Erkrankungen nach der Menopause betroffen sind. Frauen dürften durch Diabetes auch etwas mehr Lebensjahre verlieren als Männer, wobei die höhere Mortalität hauptsächlich auf vaskuläre Komplikationen zurückgeführt werden kann. Bei Männern mit Diabetes scheint dafür der Mortalitätsanstieg durch Krebs gewichtiger als bei Frauen zu sein. Bei Frauen sind Prädiabetes und Diabetes meist mit mehr vaskulären Risikofaktoren assoziiert wie erhöhte Inflammationsparameter, prothrombotische Veränderungen und höherem Blutdruck. Sie weisen deshalb ein relativ höheres vaskuläres Risiko auf. Frauen sind öfter stark übergewichtig und weniger körperlich aktiv, obwohl sie sogar noch mehr als Männer von einem höheren Bewegungsausmaß in ihrer Gesundheit und Lebenserwartung profitieren dürften. In Gewichtsreduktionsprogrammen verlieren Männer häufig mehr Gewicht als Frauen. Frauen und Männern profitieren gleich gut von Präventionsprogrammen mit etwa 40 % Risikoreduktion für Typ 2 Diabetes nach 3 Jahren. Langzeitdaten konnten bisher eine Reduktion der allgemeinen und kardiovaskulären Mortalität nur bei Frauen zeigen. Frauen weisen öfter eine gestörte Glukosetoleranz, Männer hingegen erhöhte Nüchternblutzuckerspiegel auf. Eine Anamnese eines Gestationsdiabetes oder polyzystischen Ovarsyndroms (PCOS) sowie höhere Androgenspiegel, und erniedrigte Östrogenspiegel stellen bei Frauen, das Vorhandensein einer erektilen Dysfunktion oder erniedrigter Testosteronspiegel bei Männern, wichtige geschlechtsspezifische Diabetesrisikofaktoren dar. Viele Studien zeigen des Weiteren, dass Frauen in der Therapie weniger oft die Zielwerte für HbA 1c , LDL-Cholesterin oder Blutdruck erreichen, wobei die Ursachen unklar sind. Generell sollen in der medikamentösen Behandlung geschlechtsspezifische Unterschiede in der Wirkung, Pharmakokinetik und in den Nebenwirkungen mehr Beachtung finden.
Background The HUDSON platform study (NCT03334617) explores investigational therapies in patients (pts) with NSCLC who progressed on immune checkpoint inhibitors (ICIs) to overcome immune resistance in the post-ICI setting. HUDSON allocated treatment based on biomarker selection or on time (<24 vs. ≥ 24 weeks) before progression on prior ICI. Here, we report on the results of Durvalumab (anti-PD-L1) + T-DXd (anti-HER2 antibody drug conjugate) treatment (module 6) in pts with HER2 overexpressing or HER2 mutant tumours. Methods Pts had documented advanced/metastatic NSCLC with centrally confirmed HER2 overexpression (HER2e) or activating mutations (HER2m), received platinum-based therapy and progressed on prior ICI. Pts received durvalumab 1120 mg iv and T-DXd 5.4 mg/kg iv every 3 weeks until disease progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria; secondary endpoints included progression-free survival (PFS), overall survival (OS) and frequency of adverse events (AEs). Results A total of 43 pts (HER2e n=23, HER2m n=20) started therapy between 23/6/2020 and 16/9/2021. Differences in main demographic and disease characteristics at study entry were observed between HER2e and HER2m pts (sex, smoking status, extent of disease, primary resistance to prior ICI; extended report of the characteristics at the conference). Confirmed ORR was 26.1% (80% CI, 14.3–41.3) in HER2e pts and 35% (80% CI, 20.7–51.8) in HER2m pts. Median PFS was 2.8 mo (80% CI, 2.2–5.5) in HER2e pts and 5.7 mo (80% CI, 5.5–6.5) in HER2m pts. Median OS was 9.5 mo (80% CI, 6.6–12.4) in the HER2e group and 10.6 mo (80% CI, 8.9-NC) in the HER2m group. Median duration of follow-up in censored subjects was 16.5 mo (range, 7.3–24.2) in the HER2e pts and 17.1 mo (range, 4.4–27.6) in HER2m pts. Grade (G) ≥3 treatment emergent AEs (TEAEs) occurred in 55% of all pts (61% of HER2e pts, 50% of HER2m pts); the most common G ≥3 AEs were pneumonitis (none were fatal), pulmonary embolism and anemia. All grade and G≥3 treatment-related pneumonitis occurred in 9.3% (8.7% of HER2e pts, 10% of HER2m pts) and in 7% (8.7% of HER2e pts, 5% of HER2m pts) of all pts, respectively. Conclusions Durvalumab+T-DXd combination was tolerated and showed antitumor activity in HER2 altered NSCLC in the post-ICI setting, with a trend toward higher response in HER2m pts. The small sample size limits the overall conclusions of the study.
Chronic obstructive pulmonary disease (COPD) has been traditionally understood as a self-inflicted disease caused by tobacco smoking which, in so-called "susceptible smokers," accelerates the decline of lung function that occurs physiologically with age. However, research over the past few years has shown that there are several life-long lung function trajectories and that, through several genetic and/or environmental mechanisms, about 4–12% of the general population never reach normal peak lung function in early adulthood and can develop COPD with a normal rate of lung function decline. In particular, it is now known that early life events, both in utero and after birth during infancy and adolescence, have a very important role in the pathogenesis of COPD. This new knowledge, which is discussed in detail in this article, opens novel temporal windows of opportunity for prevention as well as for early diagnosis and treatment. In essence, COPD (and other chronic human diseases) can be understood now as the end result of a number of dynamic gene-environment interactions that occur from conception to death which eventually determine the balance between two main biologic mechanisms, organ development, maintenance and repair, on the one hand, and cumulative tissue injury and aging, on the other.
