BACKGROUND: Immune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are likely affected by immortal time bias and do not represent causal effects. The aim of this study was to assess the effect of irAEs on outcomes while correcting for immortal time bias, using target trial emulation (TTE). METHODS: TTE was contrasted to adjusted naïve and time-updated Cox models. We performed a multi-institutional retrospective study involving mUC patients under ICI. The primary objective was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the influence of irAEs on objective response rates (ORRs) to ICI and the influence of systemic corticosteroids on outcomes. RESULTS: Among 335 patients (median age: 69 yrs), 69.6% received ICI in the second line or further lines. During a median follow-up of 21.1 months, 122 (36.4%) patients developed irAEs of any grade (grade ≥ 3: 14.9%). Hazard ratios (HRs) for PFS ranged from 0.37 for naïve adjusted Cox model to 0.88 (95% confidence interval (CI), 0.59-1.30) with time-updated covariates, and from 0.41 to 1.10 (95% CI, 0.69-1.75) for OS. TTE accounting for immortal time bias yielded a HR of 1.02 (95% CI, 0.72-1.44) for PFS, and 0.90 (95% CI, 0.62-1.30) for OS. In contrast to the naïve Cox model (HR = 2.26, 95% CI 1.26-4.05), the presence of irAEs was no longer a predictive factor for improved ORR in time-updated Cox models (HR = 1.27, 95% CI 0.68-2.36) and TTE (HR = 1.43, 95% CI 0.89-2.29). In patients with irAEs, systemic corticosteroids did not negatively impact survival. CONCLUSION: Using TTE, we were able to show that the occurrence of irAEs is no longer associated with better survival or improved response rates to ICI in mUC patients, in contrast to the naïve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures.
- MeSH
- inhibitory kontrolních bodů * škodlivé účinky terapeutické užití MeSH
- karcinom z přechodných buněk farmakoterapie mortalita imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádory močového měchýře farmakoterapie mortalita imunologie patologie MeSH
- nežádoucí účinky léčiv etiologie MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- urologické nádory farmakoterapie mortalita imunologie patologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
OBJECTIVE: Patients with deep-seated arteriovenous malformations (AVMs) have a higher rate of unfavorable outcome and lower rate of nidus obliteration after primary stereotactic radiosurgery (SRS). The aim of this study was to evaluate and quantify the effect of AVM location on repeat SRS outcomes. METHODS: This retrospective, multicenter study involved 505 AVM patients managed with repeat, single-session SRS. The endpoints were nidus obliteration, hemorrhage in the latency period, radiation-induced changes (RICs), and favorable outcome. Patients were split on the basis of AVM location into the deep (brainstem, basal ganglia, thalamus, deep cerebellum, and corpus callosum) and superficial cohorts. The cohorts were matched 1:1 on the basis of the covariate balancing score for volume, eloquence of location, and prescription dose. RESULTS: After matching, 149 patients remained in each cohort. The 5-year cumulative probability rates for favorable outcome (probability difference -18%, 95% CI -30.9 to -5.8%, p = 0.004) and AVM obliteration (probability difference -18%, 95% CI -30.1% to -6.4%, p = 0.007) were significantly lower in the deep AVM cohort. No significant differences were observed in the 5-year cumulative probability rates for hemorrhage (probability difference 3%, 95% CI -2.4% to 8.5%, p = 0.28) or RICs (probability difference 1%, 95% CI -10.6% to 11.7%, p = 0.92). The median time to delayed cyst formation was longer with deep-seated AVMs (deep 62 months vs superficial 12 months, p = 0.047). CONCLUSIONS: AVMs located in deep regions had significantly lower favorable outcomes and obliteration rates compared with superficial lesions after repeat SRS. Although the rates of hemorrhage in the latency period and RICs in the two cohorts were comparable, delayed cyst formation occurred later in patients with deep-seated AVMs.
- MeSH
- dospělí MeSH
- intrakraniální arteriovenózní malformace * chirurgie radioterapie MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- radiochirurgie * metody MeSH
- reoperace MeSH
- retrospektivní studie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
This report summarizes the ASEV-CzeSEV Joint Meeting on Extracellular Vesicles (EVs), held at the Medical University of Vienna in September 2024. The conference focused on introducing and expanding EV research and infrastructure within the Czech Republic and Austria, highlighting areas for collaboration. Key sessions featured research on EV-based diagnostics, tissue regeneration, interspecies communication and therapeutic applications, with an emphasis on shared resources and cross-border partnerships. The program included oral and poster presentations on EV engineering, new isolation techniques, and potential clinical applications, as well as industry updates on the latest EV technologies. The meeting concluded with awards for outstanding presentations reflecting the quality of work presented. Following the conference, a dedicated workshop was held on flow cytometry analysis of EVs, allowing participants to deepen their technical expertise in EV characterization. This report captures the main discussions, findings, and collaborative opportunities explored at the ASEV-CzeSEV meeting, signaling strong regional support for advancing EV research.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The rate of immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) plays the principal role in the development of serious post-transplant complications. However, the post-transplantation course has a significant impact on shaping the immune system of the recipient, per se, thus representing risk factors for subsequent unfavorable outcomes. The predictive power of an interferon gamma (IFNγ) release assay (IGRA) on graft-versus-host disease (GVHD) or hematological relapse in recipients of allo-HSCT treated with post-transplantation cyclophosphamide and the impact of these complications on the restoration of cellular immune responsiveness was evaluated. STUDY DESIGN: A prospective observational study in which 62 adult patients with myeloid hematological malignancies who underwent allo-HSCT with a myeloablative conditioning regimen combined with post-transplantation cyclophosphamide were enrolled. Clinical data were collected and the IGRA was performed before commencement of the conditioning regimen and for 12 months post-allo-HSCT. Multivariate Cox regression and logistic regression models with backward stepwise analyses were used to calculate the predictive values for acute or chronic GVHD, or hematological relapse. RESULTS: Pre-transplantation and early post-transplantation IGRA values and other selected covariables (age, diagnosis, relapse risk, conditioning type, pre-T lymphocyte count, and donor sex), enabled prediction of the 12-month incidence of chronic GVHD with positive and negative predictive values of 75 % and 88 %, respectively. However, the IGRA did not improve the predictive value for acute GVHD or hematological relapse. Patients with myelodysplastic syndrome (MDS) had a significantly lower pre-transplant IGRA value (p = 0.021) and a delayed IFNγ response in IGRA, post-HSCT, than patients with acute myeloid leukemia (AML) (p = 0.015 and p = 0.0063 for 3 and 4 months post-HSCT, respectively). CONCLUSIONS: The IGRA can be used to monitor the recovery of total cellular immunity, post-HSCT and it has shown potential for use in personalized post-transplantation care. In the multivariate backward stepwise logistic regression model, pre-and early post-transplantation IGRA values showed potential for predicting chronic GVHD. Patients with MDS had a significantly lower pre-transplantation IGRA value and delayed IFNγ response in IGRA, post-HSCT, than patients with AML.
- MeSH
- chronická nemoc MeSH
- cyklofosfamid * terapeutické užití MeSH
- dospělí MeSH
- hematologické nádory terapie MeSH
- homologní transplantace MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- myeloablativní agonisté terapeutické užití MeSH
- nemoc štěpu proti hostiteli * diagnóza prevence a kontrola etiologie MeSH
- příprava pacienta k transplantaci * metody MeSH
- prospektivní studie MeSH
- senioři MeSH
- test pomocí interferonu gama MeSH
- transplantace hematopoetických kmenových buněk * škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
BACKGROUND: Fingolimod is a first-in-class, orally administered drug indicated for the treatment of relapsing-remitting multiple sclerosis. It acts as an immunomodulator, is classified as a "disease-modifying therapy", and its main mechanism of action is the modulation of sphingosine-1-phosphate receptors. In this prospective pilot study, whole blood concentrations of fingolimod and fingolimod phosphate obtained during routine health care were measured. In this study, we aimed to determine whether therapeutic monitoring of fingolimod and fingolimod phosphate concentrations can help personalise pharmacotherapy for patients with multiple sclerosis. METHOD: The study group consisted of 73 patients treated with oral fingolimod (0.5 mg) once daily. Blood samples were collected between July 2021 and January 2022. The whole blood concentrations of fingolimod and fingolimod phosphate were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. The relationship between the measured concentrations and the absolute peripheral blood lymphocyte count was evaluated. RESULTS: Fingolimod concentrations ranged from 0.61 to 6.21 μg/L, and fingolimod phosphate concentrations from 0.48 to 4.28 μg/L. Significantly higher concentrations of the active metabolite, fingolimod phosphate, and a significantly higher fingolimod phosphate/fingolimod concentration ratio were observed in women. The sum of fingolimod and fingolimod phosphate concentrations was significantly higher in the subgroup of patients with a lower absolute peripheral blood lymphocyte count. CONCLUSION: Although all patients were treated with the same dose of fingolimod (0.5 mg orally daily), a 10-fold difference was observed in the achieved whole blood concentrations of fingolimod and fingolimod phosphate. This wide inter-individual variability may lead to potential toxicity or suboptimal concentrations, with the risk of further deterioration in the clinical condition of patients with multiple sclerosis. Therefore, fingolimod is a suitable candidate for therapeutic drug monitoring, including monitoring patient adherence to treatment.
- MeSH
- dospělí MeSH
- fingolimod hydrochlorid * krev aplikace a dávkování farmakologie MeSH
- imunosupresiva * krev aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- monitorování léčiv metody MeSH
- pilotní projekty MeSH
- prospektivní studie MeSH
- relabující-remitující roztroušená skleróza farmakoterapie krev MeSH
- roztroušená skleróza farmakoterapie krev MeSH
- tandemová hmotnostní spektrometrie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Impaired physical performance and muscle strength are recognized risk factors for fragility fractures, frequently associated with osteoporosis and sarcopenia. However, the integration of muscle strength and physical performance in the comprehensive assessment of fracture risk is still debated. Therefore, this cross-sectional study aimed to assess the potential role of hand grip strength (HGS) and short physical performance battery (SPPB) for predicting fragility fractures and their correlation with Fracture Risk Assessment Tool (FRAX) with a machine learning approach. METHODS: In this cross-sectional study, a group of postmenopausal women underwent assessment of their strength, with the outcome measured using the HSG, their physical performance evaluated using the SPPB, and the predictive algorithm for fragility fractures known as FRAX. The statistical analysis included correlation analysis using Pearson's r and a decision tree model to compare different variables and their relationship with the FRAX Index. This machine learning approach allowed to create a visual decision boundaries plot, providing a dynamic representation of variables interactions in predicting fracture risk. RESULTS: Thirty-four patients (mean age 63.8±10.7 years) were included. Both HGS and SPPB negatively correlate with FRAX major (r=-0.381, P=0.034; and r=-0.407, P=0.023 respectively), whereas only SPPB significantly correlated with an inverse proportionality to FRAX hip (r=-0.492, P=0.001). According to a machine learning approach, FRAX major ≥20 and/or hip ≥3 might be reported for an SPPB<6. Concurrently, HGS<17.5 kg correlated with FRAX major ≥20 and/or hip ≥3. CONCLUSIONS: In light of the major findings, this cross-sectional study using a machine learning model related SPPB and HGS to FRAX. Therefore, a precise assessment including muscle strength and physical performance might be considered in the multidisciplinary assessment of fracture risk in post-menopausal women.
- MeSH
- hodnocení rizik MeSH
- kostní denzita * fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- osteoporotické fraktury * epidemiologie etiologie MeSH
- postmenopauza MeSH
- průřezové studie MeSH
- rizikové faktory MeSH
- senioři MeSH
- síla ruky MeSH
- tělesná a funkční výkonnost MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
This is the second in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy.
