Patients with cardioembolic ischemic stroke are commonly prescribed direct oral anticoagulants (DOACs), such as dabigatran (a direct thrombin inhibitor) and factor Xa inhibitors (e.g., apixaban and rivaroxaban), or warfarin to reduce the risk of recurrent stroke. A major concern in anticoagulant therapy is the risk of intracerebral hemorrhage, which is associated with a high mortality rate. Cerebral microbleeds (MBs), small asymptomatic brain hemorrhages detectable by susceptibility-weighted imaging (SWI) on magnetic resonance imaging (MRI), are associated with increased hemorrhagic stroke risk. This study evaluated the incidence of new MBs during 1 year of anticoagulation therapy in patients after cardioembolic stroke. Patients indicated for anticoagulant therapy after cardioembolic stroke and monitored in the cerebrovascular outpatient clinic of our department underwent brain MRI at baseline and after 1 year of therapy. The occurrence of new MBs was assessed using SWI sequences. MBs were categorized based on location into 3 groups: deep (dMBs), lobar (lMBs), and infratentorial (iMBs). A total of 79 patients were included, 53 of whom were male (67.1%), with a median age of 71 years (IQR: 64-76). The majority of patients (n = 50, 63.3%) were treated with apixaban, 16 patients (20.3%) with dabigatran, and 13 patients (16.5%) with warfarin. Baseline MRI revealed MBs in 17 patients (21.5%), including dMBs in 2, lMBs in 16, and iMBs in 2 patients. Follow-up MRI showed new MBs in 8 patients (10.1%), with new dMBs in 1, lMBs in 5, and iMBs in 4 patients. No statistically significant differences were observed in MBs the incidence of new MBs between anticoagulant groups (P = .912). Over 1 year of anticoagulant therapy, new MBs were detected in 10.1% of patients, predominantly in lobar and infratentorial regions. No differences in the incidence of new MBs were identified between the different anticoagulant groups.

• Klíčová slova
• anticoagulation, microbleeds, stroke,
• MeSH
• antikoagulancia * škodlivé účinky   terapeutické užití   MeSH
• cerebrální krvácení * chemicky indukované   diagnostické zobrazování   epidemiologie   MeSH
• cévní mozková příhoda * prevence a kontrola   MeSH
• dabigatran škodlivé účinky   terapeutické užití   MeSH
• incidence MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• pyrazoly škodlivé účinky   terapeutické užití   MeSH
• pyridony škodlivé účinky   terapeutické užití   MeSH
• sekundární prevence * metody   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Názvy látek
• antikoagulancia * MeSH
• apixaban MeSH Prohlížeč
• dabigatran MeSH
• pyrazoly MeSH
• pyridony MeSH

Chronic Kidney Disease (CKD) is associated with heightened risk of thrombosis. Prescription of anticoagulants is key to manage it; however, CKD patients have shown an increased risk of bleeding under anticoagulation therapy compared to non-CKD patients. We hypothesized that the sex could modify the metabolism of indoxyl sulfate (IS), a uremic toxin and Apixaban. Our intoxication model shows that higher doses of IS and apixaban accumulate in the plasma of female mice because of expression differences in efflux transporters and cytochromes in the liver, ileum and kidneys, when compared to males. Furthermore, we found that accumulation of apixaban in females contributes to increased bleeding. Transcriptional analysis of liver samples revealed elevated Sult1a1 but reduced Abcg2 and Cyp3a11 in female mice, while in the kidneys the expression rates of Oat1 and Oat3 were respectively lower and higher than those observed in males, potentially affecting drug clearance. Whole proteomics liver analysis confirmed the previous transcriptional results at the protein level and revealed that sex had a major influence in regulating both coagulation and drug metabolism pathways. Thus, our findings underline the need for inclusive clinical and preclinical trials to accurately reflect sex-specific metabolic variations, and to consider CKD-specific changes to optimize dosing, minimize side effects, and improve patient outcomes.

• MeSH
• antikoagulancia MeSH
• chronická renální insuficience metabolismus   MeSH
• indican * metabolismus   MeSH
• játra metabolismus   MeSH
• ledviny metabolismus   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pyrazoly * metabolismus   farmakokinetika   MeSH
• pyridony * metabolismus   farmakokinetika   MeSH
• sexuální faktory MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikoagulancia MeSH
• apixaban MeSH Prohlížeč
• indican * MeSH
• pyrazoly * MeSH
• pyridony * MeSH

OBJECTIVES: To determine whether selected single nucleotide polymorphisms (SNPs) of genes encoding proteins responsible for the activation, transport, or metabolism of dabigatran and apixaban might be associated with a risk of gastrointestinal bleeding in a cohort of adult patients treated with these drugs. No previous study has focused specifically on the association with gastrointestinal bleeding. MATERIALS AND METHODS: Ninety-one patients treated with dabigatran or apixaban were genotyped for selected polymorphisms. The following polymorphisms were studied: ABCB1 gene rs1045642, rs4148738, rs1128503 and rs2032582; CES1 gene rs2244613, rs8192935 and rs2244614; and SULT1A1 gene rs9282861 and SULT1A2 gene rs1136703. Two groups divided by particular drugs and genotypes were compared in terms of the presence (bleeding group) or absence (nonbleeding group) of gastrointestinal bleeding. The genotype distribution was expressed via dominant and recessive models. RESULTS: In patients treated either with dabigatran or with apixaban, no evidence was found to support the association of gastrointestinal bleeding with any genotype for any of the studied SNPs. CONCLUSION: In both dabigatran- and apixaban-treated patients, no associations between the selected polymorphisms and gastrointestinal bleeding risk were found, however the results should be interpreted with caution because of the small cohort size.

• MeSH
• antitrombiny škodlivé účinky   terapeutické užití   MeSH
• dabigatran * škodlivé účinky   MeSH
• dospělí MeSH
• farmakogenetika MeSH
• gastrointestinální krvácení * genetika   chemicky indukované   MeSH
• genotyp MeSH
• inhibitory faktoru Xa škodlivé účinky   terapeutické užití   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• P-glykoproteiny MeSH
• pyrazoly * škodlivé účinky   terapeutické užití   MeSH
• pyridony * škodlivé účinky   terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• antitrombiny MeSH
• apixaban MeSH Prohlížeč
• dabigatran * MeSH
• inhibitory faktoru Xa MeSH
• P-glykoproteiny MeSH
• pyrazoly * MeSH
• pyridony * MeSH

Therapeutic plasma exchange (TPE) is used as an effective treatment modality for a variety of autoimmune disorders. Apart from its desired effect of removing pathological blood components, it also can remove coagulation factors and drugs. Currently, there is an insufficient amount of information regarding the use of direct oral anticoagulants in this setting. In this article, we present a case report of a patient with myasthenia gravis and chronic anticoagulation with apixaban who underwent a series of TPE while continuing apixaban treatment. We observed that only 10% of daily dose was removed by the procedure and plasma levels of apixaban corresponded with expected range. TPE was not associated with shortened drug plasma half-life. We did not observe any significant alteration of apixaban pharmacokinetics during the period of TPE therapy, as well as no thrombotic or bleeding events. This case report supports the use of apixaban in patients treated by TPE, nevertheless, to firmly establish apixaban efficacy and safety profile in this clinical setting further research is needed.

• MeSH
• antikoagulancia aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory faktoru Xa * aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myasthenia gravis farmakoterapie   terapie   MeSH
• poločas MeSH
• pyrazoly * aplikace a dávkování   farmakokinetika   MeSH
• pyridony * aplikace a dávkování   MeSH
• senioři MeSH
• výměna plazmy * metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH
• Názvy látek
• antikoagulancia MeSH
• apixaban MeSH Prohlížeč
• inhibitory faktoru Xa * MeSH
• pyrazoly * MeSH
• pyridony * MeSH

BACKGROUND: ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation) demonstrated that apixaban, compared with aspirin, significantly reduced stroke and systemic embolism (SE) but increased major bleeding in patients with subclinical atrial fibrillation. OBJECTIVES: To help inform decision making, the authors evaluated the efficacy and safety of apixaban according to baseline CHA2DS2-VASc score. METHODS: We performed a subgroup analysis according to baseline CHA2DS2-VASc score and assessed both the relative and absolute differences in stroke/SE and major bleeding. RESULTS: Baseline CHA2DS2-VASc scores were <4 in 1,578 (39.4%) patients, 4 in 1,349 (33.6%), and >4 in 1,085 (27.0%). For patients with CHA2DS2-VASc >4, the rate of stroke was 0.98%/year with apixaban and 2.25%/year with aspirin; compared with aspirin, apixaban prevented 1.28 (95% CI: 0.43-2.12) strokes/SE per 100 patient-years and caused 0.68 (95% CI: -0.23 to 1.57) major bleeds. For CHA2DS2-VASc <4, the stroke/SE rate was 0.85%/year with apixaban and 0.97%/year with aspirin. Apixaban prevented 0.12 (95% CI: -0.38 to 0.62) strokes/SE per 100 patient-years and caused 0.33 (95% CI: -0.27 to 0.92) major bleeds. For patients with CHA2DS2-VASc =4, apixaban prevented 0.32 (95% CI: -0.16 to 0.79) strokes/SE per 100 patient-years and caused 0.28 (95% CI: -0.30 to 0.86) major bleeds. CONCLUSIONS: One in 4 patients in ARTESiA with subclinical atrial fibrillation had a CHA2DS2-VASc score >4 and a stroke/SE risk of 2.2% per year. For these patients, the benefits of treatment with apixaban in preventing stroke/SE are greater than the risks. The opposite is true for patients with CHA2DS2-VASc score <4. A substantial intermediate group (CHA2DS2-VASc =4) exists in which patient preferences will inform treatment decisions. (Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation; NCT01938248).

• Klíčová slova
• CHA(2)DS(2)-VASc score, apixaban, aspirin, major bleeding, stroke/systemic embolism, subclinical atrial fibrillation,
• MeSH
• Aspirin * terapeutické užití   MeSH
• cévní mozková příhoda * prevence a kontrola   etiologie   epidemiologie   MeSH
• fibrilace síní * farmakoterapie   komplikace   MeSH
• hodnocení rizik metody   MeSH
• inhibitory faktoru Xa * terapeutické užití   MeSH
• krvácení chemicky indukované   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• pyrazoly * terapeutické užití   MeSH
• pyridony * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• apixaban MeSH Prohlížeč
• Aspirin * MeSH
• inhibitory faktoru Xa * MeSH
• pyrazoly * MeSH
• pyridony * MeSH

BACKGROUND: Health-related quality of life (HRQL) is an important goal for patients with major depressive disorder (MDD), but whether antidepressants improve HRQL in these patients is unclear. Here, we describe the real-world effects of trazodone once-a-day (TzOAD) and selective serotonin reuptake inhibitor (SSRI) treatments on HRQL and functioning in adults with MDD. METHODS: This 8-week prospective, observational, open-label, multicenter study was conducted in adults with moderate or severe MDD for whom TzOAD or SSRI were prescribed as monotherapy. The primary outcome was life enjoyment and satisfaction assessed via the patient-reported Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) from baseline to week 8. Secondary outcomes included change in Q-LES-Q-SF from baseline to weeks 1 and 2; severity of depressive symptoms using the Montgomery Åsberg Depression Rating Scale (MADRS) and sleep disturbance via the PROMIS SF-SD 8b questionnaire at weeks 1, 2, and 8; and overall functioning via the Sheehan Disability Scale (SDS), hedonic capacity using the Snaith-Hamilton Pleasure Scale (SHAPS), and cognitive dysfunction using the Perceived Deficits Questionnaire (PDQ-5) at baseline and week 8. RESULTS: The study included 208 adults with MDD (mean [SD] age = 50.2 [14.3] years; 68.6% female; 98.4% White). Life enjoyment and satisfaction improved from baseline to week 8 for both treatment groups: Q-LES-Q-SF mean (SD) scores were 27.5 (20.4) for the SSRI group and 39.0 (22.1) for the TzOAD group. Depressive symptoms and sleep disturbances also reduced from baseline to week 8: MADRS (SSRI, -15.7 [8.3]; TzOAD, -21.0 [9.8]); PROMIS SF-SD 8b (SSRI, -9.9 [12.6]; TzOAD, -22.0 [12.6]). Mean change scores in Q-LES-Q-SF, MADRS, and PROMIS SF-SD 8b improved as early as week 1 in both groups. Mean scores also improved from baseline to week 8 on SDS (SSRI, -9.2 [7.4]; TzOAD, -14.3 [7.5]), SHAPS (SSRI, -6.6 [4.3]; TzOAD, -8.3 [4.4]), and PDQ-5 (SSRI, -5.8 [4.5]; TzOAD, -7.7 [5.0]). CONCLUSIONS: In adults with MDD who received TzOAD or SSRIs, overall and individual HQRL domains improved rapidly and in parallel with improvements in depressive symptoms, with a slightly greater improvement observed in the TzOAD group.

• Klíčová slova
• health‐related quality of life (HRQL), major depressive disorder, selective serotonin reuptake inhibitors, trazodone,
• MeSH
• antidepresiva druhé generace aplikace a dávkování   terapeutické užití   farmakologie   MeSH
• depresivní porucha unipolární * farmakoterapie   patofyziologie   MeSH
• dospělí MeSH
• kvalita života * MeSH
• lidé středního věku MeSH
• lidé MeSH
• obnova funkce účinky léků   MeSH
• prospektivní studie MeSH
• selektivní inhibitory zpětného vychytávání serotoninu * aplikace a dávkování   farmakologie   MeSH
• trazodon * farmakologie   aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Názvy látek
• antidepresiva druhé generace MeSH
• selektivní inhibitory zpětného vychytávání serotoninu * MeSH
• trazodon * MeSH

BACKGROUND: The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry. METHODS: Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA. RESULTS: Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs. CONCLUSION: Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.

• Klíčová slova
• Atrial Fibrillation, Biostatistics, Pharmacology, Clinical, STROKE,
• MeSH
• antikoagulancia terapeutické užití   MeSH
• aplikace orální MeSH
• cévní mozková příhoda * prevence a kontrola   etiologie   MeSH
• fibrilace síní * farmakoterapie   komplikace   MeSH
• hodnocení rizik metody   MeSH
• inhibitory faktoru Xa * terapeutické užití   aplikace a dávkování   MeSH
• lidé MeSH
• pyrazoly * terapeutické užití   MeSH
• pyridony * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• randomizované kontrolované studie jako téma metody   MeSH
• registrace MeSH
• rivaroxaban * aplikace a dávkování   terapeutické užití   MeSH
• rizikové faktory MeSH
• senioři MeSH
• vitamin K antagonisté a inhibitory   MeSH
• výběr pacientů * MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• antikoagulancia MeSH
• apixaban MeSH Prohlížeč
• inhibitory faktoru Xa * MeSH
• pyrazoly * MeSH
• pyridony * MeSH
• rivaroxaban * MeSH
• vitamin K MeSH

An imbalance in coagulation is associated with cardiovascular events. For prevention and treatment, anticoagulants, currently mainly xabans and gatrans, are used. The purpose of the present study was to provide a head-to-head comparison since there are no studies directly evaluating these novel anticoagulants. An additional aim was to find whether selected anthropological and biochemical factors can affect their anticoagulant properties as they are used in fixed doses. In this cross-sectional study, blood from 50 generally healthy donors was collected, and coagulation responses to dabigatran, argatroban, rivaroxaban, and apixaban, at a concentration of 1 μM, were analyzed. Heparin was used as a positive control. Prothrombin time (PT) expressed as international normalized ratio (INR) and activated partial thromboplastin time (aPTT) were measured and compared. Rivaroxaban was the most active according to PT/INR while argatroban according to aPTT. The ex vivo anticoagulant effect measured by INR correlated inversely with body mass index (BMI) in all four anticoagulants tested. Shortening of aPTT was associated with higher cholesterol and triglyceride levels. No sex-related differences were observed in response to the anticoagulant treatments. As this was an ex vivo study and pharmacokinetic factors were not included, the influence of BMI is of high therapeutic importance.

• Klíčová slova
• Activated partial thromboplastin time, Anticoagulants, Body mass index, Lipid, Prothrombin time,
• MeSH
• antikoagulancia * farmakologie   MeSH
• arginin * analogy a deriváty   MeSH
• dabigatran farmakologie   MeSH
• dospělí MeSH
• hemokoagulace * účinky léků   MeSH
• index tělesné hmotnosti MeSH
• INR MeSH
• kyseliny pipekolové * farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• parciální tromboplastinový čas MeSH
• protrombinový čas MeSH
• průřezové studie MeSH
• pyrazoly farmakologie   MeSH
• pyridony farmakologie   farmakokinetika   MeSH
• rivaroxaban * farmakologie   MeSH
• sulfonamidy farmakologie   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
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• apixaban MeSH Prohlížeč
• argatroban MeSH Prohlížeč

INTRODUCTION: Most patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotics (AF) have progressive disease despite treatment. A switch of AF may improve survival, but evidence from randomised controlled trials is missing. We aimed to evaluate the efficacy of an AF switch on survival and FVC decline in patients from the European MultiPartner IPF registry (EMPIRE). METHODS: The study included 612 patients who discontinued the first antifibrotic therapy. Patients were grouped and analysed from two perspectives: (1) whether they had received a second antifibrotic treatment after the discontinuation of the first therapy, and (2) a reason for discontinuation of the first AF - "lack of efficacy" (LE) and "intolerance" (INT). RESULTS: While 263 (43%) of 612 patients received no second AF ("non-switched"), 349 (57%) patients switched. Overall survival was higher in patients who received a second AF (median 50 vs. 29 months; adjusted HR 0.64, P=0.023). Similarly, the annual FVC decline was significantly reduced in switched patients: -98ml/y in switched and -172ml/y in non-switched patients (P=0.023), respectively. The switched patients had similar risk for mortality in both LE and INT groups (adjusted HR 0.95, P=0.85). The high impact of switching on survival was demonstrated in LE patients (adjusted HR 0.27, P<0.001). CONCLUSION: The patients without a second AF had significantly shorter overall survival. Our analysis suggests the importance of switching patients with an ineffective first AF therapy to a second AF therapy.

• Klíčová slova
• Antifibrotic agents, Registries, Survival, Treatment switch,
• MeSH
• antifibrotické látky * terapeutické užití   MeSH
• idiopatická plicní fibróza * farmakoterapie   mortalita   MeSH
• indoly MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada léků * MeSH
• progrese nemoci MeSH
• pyridony terapeutické užití   MeSH
• registrace * MeSH
• retrospektivní studie MeSH
• senioři MeSH
• vitální kapacita MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• antifibrotické látky * MeSH
• indoly MeSH
• nintedanib MeSH Prohlížeč
• pirfenidone MeSH Prohlížeč
• pyridony MeSH

BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.

• Klíčová slova
• BRAF, Chemotherapy, Child, First-line, MAPK, Pediatric low-grade glioma, Tovorafenib, pLGG,
• MeSH
• dítě MeSH
• gliom * farmakoterapie   genetika   metabolismus   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy MeSH
• mladý dospělý MeSH
• mutace MeSH
• oximy MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf MeSH
• pyridony MeSH
• pyrimidinony terapeutické užití   MeSH
• světluškovití * metabolismus   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladý dospělý MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• mitogenem aktivované proteinkinasy MeSH
• oximy MeSH
• protoonkogenní proteiny B-Raf MeSH
• pyridony MeSH
• pyrimidinony MeSH